Biologics in Rheumatology New Developments, Clinical Uses and Health Implication 2016

NEW DEVELOPMENTS IN MEDICAL RESEARCH
BIOLOGICS IN RHEUMATOLOGY
NEW DEVELOPMENTS, CLINICAL USES
AND HEALTH IMPLICATIONS
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BIOLOGICS IN RHEUMATOLOGY

COZIANA CIURTIN, PHD FRCP

AND
DAVID A. ISENBERG, MD FRCP FAMS
EDITORS
New York
Copyright 2016 by Nova Science Publishers, Inc.
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CONTENTS
Preface ix
Biologic Treatments in Autoimmune Rheumatic Diseases 1

Chapter 1 Biologic Therapies for Systemic Lupus Erythematosus 3
Maria Mouyis, Coziana Ciurtin and David A. Isenberg
Chapter 2 Biologics in Juvenile Systemic Lupus Erythematosus 33
Claire-Louise Murphy and Nicola Ambrose
Chapter 3 Biologic Treatments for Idiopathic Inflammatory Myopathies 45
Serena Fasano and David A. Isenberg
Chapter 4 Biologic Treatment Advances in Sjgrens Syndrome:
Understanding the Implications of Using Biologic Therapies
in Selected Categories of Patients 57
Coziana Ciurtin, Nicolyn Thompson and David A. Isenberg
Chapter 5 Biologic Therapies in Systemic Sclerosis 83
Svetlana I. Nihtyanova and Christopher P. Denton
Chapter 6 The Role of Biologics in the Treatment of Small and
Medium Vessel Vasculitis 109
Lubna Ghani and Eleana Ntatsaki
Chapter 7 Imaging and Pathogenesis in Large Vessel Vasculitis: Early
Lessons for Biologic Treatments 145
Philip P. Stapleton, Katerina Achilleos, Dimos Merinopoulos
and Bhaskar Dasgupta
Chapter 8 Biologics in Behet Syndrome 177
Emon Khan
vi Contents
Biologic Treatments in Chronic Inflammation Arthritides 197

Chapter 9 Tumour Necrosis Factor Inhibitors Used in the Treatment of
Rheumatoid Arthritis: Evidence of Safety, Efficacy and
Health Implication 199
Katie Bechman, Laura Attipoe and Coziana Ciurtin
Chapter 10 Biologic Treatments (Other than Anti-TNF Therapy) Licensed for
Use in Rheumatoid Arthritis 229
Laura Attipoe, Katie Bechman and Coziana Ciurtin
Chapter 11 New Biologic Agents and Biosimilars Developed for
Rheumatoid Arthritis 259
Laura Attipoe, Katie Bechman and Coziana Ciurtin
Chapter 12 Biologics in Spondyloarthritis 283
Mediola Ismajli and Maria Leandro
Chapter 13 Established and New Biologic Therapies for
Psoriatic Arthritis and Psoriasis 307
Benjamin J Thomas, Sarah Elyoussfi and Coziana Ciurtin
Chapter 14 Biologics in Juvenile Idiopathic Arthritis 347
Charalampia Papadopoulou and Nicola Ambrose
Miscellanea 375
Chapter 15 Biologic Disease Modifying Anti-Rheumatic Drugs in
Pregnancy and Breast-Feeding Period 377
Hanh Nguyen and Ian Giles
Chapter 16 Biologic Therapy in Osteoporosis:
New Developments, Clinical Uses and Health Implications 405
Maria Mouyis and Judith Bubbear
Chapter 17 Biologic Treatments for Pulmonary Involvement in
Rheumatic Disease 425
Helen S. Garthwaite and Joanna C. Porter
Chapter 18 Additional Benefits of Tumour Necrosis Factor Inhibitor Therapies 449
Angela Pakozdi and Vanessa Morris
Chapter 19 Infection and Biologics 465
Maria Krutikov and Jessica Manson
Chapter 20 Participant Information Sheets in Clinical Research:
Compromising the Ethics of Informed Consent? 495
Andra F. Negoescu, Leslie Gelling and Andrew J. K. str
Chapter 21 Biologic Treatment: The Young Patients Perspective 501
Nicola Daly
Contents vii
Chapter 22 Strategies and Safety Nets:

Nurse-Led Care of the Patient on Biologics 507
Pauline Buck and Victoria Howard
About the Editors 521
Index 523
PREFACE
Significant progress has recently been achieved in the treatment of many autoimmune
rheumatic diseases (ARD) with the introduction of biologic treatments, which target specific
molecules implicated in their pathogenesis. In the past two decades, these developments have
substantially improved the long-term outcome of patients with ARD, both in terms of their
survival rates and quality of life. The principal biologic approaches in clinical use include
biologic agents that (a) interfere with cytokine function, (b) inhibit the co-stimulatory
signal required for T cell activation and (c) deplete the circulatory B cells. The first
rheumatic condition that benefitted from the introduction of the biologic agents was
rheumatoid arthritis, and following the great therapeutic success of this approach, the majority
were subsequently tested in other autoimmune diseases.
More recently, new biologic agents have emerged that are tailored to the immune
abnormalities characteristic of a particular ARD. Apart from discussing the established and
newly developed biologic therapies, this book also reviews the small molecule inhibitors
licensed or tested in different rheumatic diseases.
This book is a collaborative effort on the part of many rheumatologists in the UK, which
critically appraises the level of evidence behind the use of biologic agents in diverse
rheumatic conditions. The profound effects on long-term health and less commonly explored
aspects of the use of biologics are also addressed in different chapters of the book.
The established and newly developed biologic drugs are reviewed in separate chapters
focusing on rheumatoid arthritis, systemic lupus erythematosus, myositis, systemic sclerosis,
Sjgrens syndrome, seronegative spondyloarthropathies, psoriatic arthritis and psoriasis,
small, medium and large vessel vasculitis (including a separate chapter on Behets disease),
osteoporosis and interstitial lung disease associated with rheumatic conditions.
In addition, in the second section of the book, miscellaneous aspects of the benefits of
biologic therapies from adult and adolescent rheumatology nurse perspectives can be found,
together with a discussion of ethical issues related to consenting patients for in clinical trials
with biologic drugs. Furthermore, we have also included chapters which explore the infection
risk associated with the use of each class of biologics. Another chapter has been dedicated to
the use of these drugs during pregnancy and breast-feeding.
The book is aimed at a wide audience, including rheumatology specialists, trainees and
nurses. In order to help guide health professionals with their therapeutic choices, aspects of
the cost-effectiveness of different biologic therapies, together with national and international
x Coziana Ciurtin and David A. Isenberg
guidelines supporting their use in the rheumatic diseases are discussed in detail for every
licensed biologic therapy.
We hope that readers who are interested in improving their knowledge about the recent
advances in the use of biologic treatments in rheumatic diseases will find this book helpful.
Dr. Coziana Ciurtin, PhD FRCP

University College London, UK
Prof. David A. Isenberg, MD FRCP FAMS

Academic Director of Rheumatology
University College London, UK
BIOLOGIC TREATMENTS IN AUTOIMMUNE
RHEUMATIC DISEASES
In: Biologics in Rheumatology ISBN: 978-1-63485-274-6
Editors: Coziana Ciurtin and David A. Isenberg 2016 Nova Science Publishers, Inc.
Chapter 1
BIOLOGIC THERAPIES
FOR SYSTEMIC LUPUS ERYTHEMATOSUS
Maria Mouyis1, MRCP,

Coziana Ciurtin2,3, PhD FRCP
and David A. Isenberg2,3, MD FRCP FAMS
1
Department of Rheumatology, Northwick Park Hospital, London, UK
2
Department of Rheumatology,
University College London Hospital NHS Foundation Trust, London, UK
3
Centre for Rheumatology, Department of Medicine, University College London,
London, UK
ABSTRACT
Advances in molecular biology have led to the development of biologic therapies.
This is particularly relevant in systemic lupus erythematosus (SLE), which is a
multisystem autoimmune rheumatic disease (ARD) associated with potentially life-
threatening complications if not adequately treated. The availability of new biologic
drugs has improved the prognosis of SLE in selected cases associated with unsatisfactory
response to conventional therapies. Over the last decade, there have been developments
in the availability of biologic agents for SLE treatment based upon the advances in the
understanding of the disease pathogenesis. Even if the evidence of biologic treatment
efficacy in SLE is weaker than in other autoimmune rheumatic diseases, such as
rheumatoid arthritis (RA), significant progress was made, as the first biologic treatment
for use in SLE patients received approval in 2011. These new biologic therapies for SLE
range from anti-CD20/CD22 (clusters of differentiation characteristic to B cells), to anti-
B cell activating factors and anti-interferon alpha (IFN). This chapter reviews the
various biologic agents used in SLE, their mechanism of action and safety profile. The
most common side effects to biologic treatments include infection, tuberculosis (TB)
reactivation and allergic reactions. Less common side effects include development of
Correspondence to: Prof. David A Isenberg, Academic Director of Rheumatology, Centre for Rheumatology, 424
The Rayne Institute, 5 University Street, University College London, London, WC1E 6JF, UK, email:
d.isenberg@ucl.ac.uk.
4 Maria Mouyis, Coziana Ciurtin and David A. Isenberg
lymphoma and anti-drug or autoimmune antibody formation. Despite their toxicity

profile, biologic agents are gaining ground in clinical practice, due to the limited efficacy
or increased toxicity of conventional disease modifying agents (DMARDs). Biologic
therapies targeting B cells, such as rituximab, and B cell activation factors, such as
belimumab, are currently used in the treatment of refractory SLE. Furthermore,
aggressive treatment, including the use of biologic agents, reduces long-term
complications associated with prolonged use of steroids in SLE, such as cardiovascular
disease and osteoporosis. In the short term, the biologic agents are expensive when
compared to traditional DMARDs; however, there is evidence that their use is associated
with long term benefits for patients with SLE, such as reduced hospital admission and
disease complications, and improved patient outcomes. This chapter provides a summary
of most biologic agents tested in SLE patients, considering their efficacy and safety
profile, as well as the health implications associated with their use. We also take a brief
look at newer agents currently investigated in clinical trials.
Keywords: systemic lupus erythematosus, biologic treatments, safety, efficacy, biosimilars
INTRODUCTION
SLE is a complex ARD characterised by clinical manifestations that range from mild to
severe. For many years the main treatments used were the traditional DMARDs, such as
hydroxycholorquine, azathioprine, cyclophosphamide, methotrexate and mycophenolate
mofetil (MMF). Unfortunately, these therapeutic agents have increased toxicity or, in some
cases, limited efficacy in controlling the complex symptoms of this disease. Despite the
progress made in optimising the treatment of severe disease manifestations (e.g., lupus
nephritis), the long-term prognosis of this disease has not changed dramatically in the last 30
years [1]. Patients with SLE are often treated for many years with prednisolone, which
provides an additional array of complications, such as hypertension, glaucoma, steroid
induced diabetes and osteoporosis. Although the treatment of SLE has, on the whole,
improved lupus outcomes, less success was achieved in preventing or addressing the
increased morbidity of this condition [2-4]. The availability of biologic agents is leading to a
new treatment era for SLE patients, and there is hope for a better therapeutic management in
the future.
PATHOGENESIS
A deeper understanding of the pathogenesis of SLE facilitated the discovery and
development of many biologic agents targeting various molecules or receptors [5]. The
correlation between different cellular and molecular players (identified as key factors in lupus
pathogenesis) and the available biologic therapies targeting the abnormalities associated with
lupus are illustrated in Figure 1. SLE is largely a B cell driven phenomenon with interplay
between genetic, hormonal and environmental factors [6].
External triggers, such as ultraviolet (UV) radiation or Ebstein-Barr virus (EBV)
infection, in conjunction with a maladaptive immune system and altered epigenetics are
known to lead to the accumulation of apoptotic nuclear debris, comprising anti-double
Biologic Therapies for Systemic Lupus Erythematosus 5
stranded DNA (dsDNA) fragments and RNA antigens [7-9]. The debris is then processed by
B cells, which function as antigen presenting cells (APC). This process then precipitates the
formation of antibody production and the release of pro-inflammatory cytokines, such
as interleukin (IL) 6, IL10, interferon (IFN), B lymphocytes stimulator/a proliferation-
inducing ligand (BLyS/APRIL) and tumour necrosis factor alpha (TNF). These cytokines
promote auto B cell and auto T cell activation leading to a sustained inflammatory response
[10].
T cells are important in the homeostatic control of the B cell responses. In SLE patients T
cells are dysregulated. T1 helper cells are overexpressed and release significant amounts of
IL12, IL18 and IFN. T2 helper cells are not overexpressed in comparison to T1 helper cells,
but they secrete increased IL10 levels [11, 12]. There is also a decreased production in IL2
levels [13]. Regulatory T cells (Tregs), which are meant to dampen the pro-inflammatory T
cell profile, are suppressed in SLE [14].
Legend: APRIL - a proliferation-inducing ligand; BAFF B cell activating factor; BlyS - B

lymphocytes stimulator; CD20 cluster of differentiation 20 marker expressed from late pro-B
cells through memory cells, but not on either early pro-B cells or plasma blasts and plasma cells;
CD22 cluster of differentiation 22 found on the surface of mature B cells and to a lesser extent
on some immature B cells; CD80 cluster of differentiation 80 is a protein found on activated B
cells and monocytes that provides a costimulatory signal necessary for T cell activation and
survival; IL interleukin.
Figure 1. Schematic presentation of targeted therapy of SLE.

Furthermore, there are changes in signalling subunits on the T cell receptors which lead
to an increase production of co-stimulatory molecules, such as cluster of differentiation 40
ligand (CD40L) [15]. The role of T cells in SLE is still being researched and new target
biologic therapies are currently explored.
Another pathogenic process associated with lupus is the formation and deposition of
immune complexes [16]. In SLE there is a failure of clearing immune complexes leading to
immune complex deposition in organs such as kidneys or blood vessels, causing
inflammation and tissue injury [17].
Every aspect of the immune abnormalities associated with lupus can be theoretically
explored for therapeutic purposes. Progress has been achieved in testing different
experimental biologic drugs. Recently, belimumab, an anti B cell activating factor (BAFF)
therapy, became the first biologic treatment ever approved by Food and Drug Administration
agency (FDA) for use in SLE patients, and the only treatment for lupus approved in over 50
years. It has also been approved for use in SLE patients in Europe, Middle East and Africa.
Despite the impressive advances in molecular biology and drug technology, this complex
autoimmune disease is still associated with increased morbidity and mortality. New treatment
options are continuously explored to address the unmet need of a better quality of life and
outcomes for patients (Figure 1).
BIOLOGIC THERAPIES
The biologic therapies, currently in use or under development for lupus, target B cells, T
cells, IFN, IL6, and fusion proteins. This chapter explores the main biologic therapies
available for the treatment of SLE patients, including the agents currently under investigation,
detailing their mechanism of action, side effects and dosages. The level of evidence of
efficacy and safety related to the efficacy of these biologic agents is summarised in Table 1.
Table 1. An overview of biologic therapy in SLE
Biologic Trial Mechanism of Side effects Dosage Organ specific

Agent action indication
B-cell depleting agents:
Rituximab EXPLORER Anti-CD20 Infusion reaction 1 g IV twice, 2 weeks SLE nephritis
LUNAR chimeric Increased infection apart Non-renal SLE
monoclonal risk (despite
antibody PML 375 mg/m2 IV every 4 negative RCTs
Lymphoma weeks results)
750 mg
cyclophosphamide may
be given with the first
infusion to increase B
cell depletion effect
Ofatumumab RA trials. Fully human Infusion reactions 300, 700, 1000 mg IV Arthritis (RA)
Case reports in monoclonal Urticaria every 2 weeks for 24 ?SLE
SLE. antibody Rash weeks.
Rhinitis
Nausea

Ofatumumab RA trials. against URTI 300, 700, 1000 mg IV Arthritis (RA)
Case reports in membrane Headaches every 2 weeks for 24 ?SLE
SLE. proximal Fatigue weeks.
epitope on Flushing
CD20
molecule
Ocrelizumab Phase III trials Fully human Severe infections 400 mg or 1,000 mg SLE nephritis
in SLE monoclonal (increased in ocrelizumab, given as
antibody patients treated an IV infusion on days 1
against CD20 with MMF) and 15, followed by a
single infusion at week
16 and every 16 weeks
thereafter
Anti-B-cell activating factors
Epratuzumab EMBODY-1 IgG1 Infusion reaction, 600 mg IV every week Neuro-
EMBODY-2 monoclonal URTIs for four weeks or 1,200 psychiatric,
antibody Fever mg IV every two weeks muco-cutaneous
against the Headache for four weeks and
CD22 Nausea and musculoskeletal
molecule dizziness SLE
manifestations.
Belimumab BLISS 52 Human Nausea 10 mg/kg IV every 2 Non renal SLE
BLISS 76 monoclonal Diarrhoea weeks x 3 and then once Non cerebral
immunoglobuli Headaches every 4 weeks SLE
n (IgG1y) URTI
against Fever
BAFF/BLySS. Cystitis
Infusion reaction
Tabalumab IILUMINATE Human URTI 240 mg SC loading Non-renal SLE
monoclonal UTI dose, followed by 120 Non-cerebral
antibody Injection site mg SC every 2 or 4 SLE
against BAFF reactions weeks
Myocardial infarct
Discitis
Osteomyelitis
Breast cancer
Cerebrovascular
accident
Pulmonary fibrosis
Blisibimod Phase II Fusion protein, Injection site 200 mg weekly Non-renal SLE
PEARL-SC selective reactions Non-cerebral
antagonist of SLE
BAFF
Atacicept Phase II TACI-Ig LRTI/URTI 75 mg or 150 mg SC SLE nephritis-
APRIL-SLE fusion protein Injection site weekly study terminated
(terminated) that inhibits reaction because of side-
BLyS and Fever effects.
Phase II APRIL Arthralgia
ADDRESS-II Sinusitis
(ongoing) Headache
Fatigue
Rhinitis
Dizziness
Depression
Table 1. (Continued)

Anti-IFN alpha
Sifalimumab Phase III trial IFN Infusion reaction 0.3, 1.0, 3.0, or 10.0 SLE nephritis
monoclonal Fatigue mg/kg IV- still
antibody URTI undergoing trials
UTI
Sinusitis
Dizziness
Arthralgia
Headache
Lymphopenia
Anaemia
Rontalizumab Phase II trial A recombinant Viral infections 750 mg IV 4 weekly Moderate-severe
humanised Reactivation of 300 mg SC 2 weekly SLE
monoclonal Herpes infection 0.3-10 mg/kg
antibody to Sinusitis
IFN Bronchitis
Blockade of T cell activation
Abatacept Phase III trials Human IgG1 Nausea 10-30 mg/kg IV Discoid SLE
heavy chain Headache Arthritis
fused with Infusion reaction Serositis
CTLA4 that Fever
blocks T cell Hypertension
activation by B Back pain
cells. Infections
IL6 inhibition
Tocilizumab RA trials Monoclonal URTI 4 or 8 mg/kg IV SLE nephritis
Phase 1 SLE IgG1 antibody GI infections SLE with
trials to IL6 receptor TB moderate
GI perforation activity
Non-melanoma
skin tumours
Malignancies
Abnormal LFT
High cholesterol
levels
Suppression of
CRP
Legend: CRP - C reactive protein; CTLA4 - cytotoxic T-lymphocyte-associated protein 4; GI - gastro-intestinal;
IFR - individual funding request form, IFN - interferon; Ig - immunoglobulin; IL - interleukin, IV -
intravenous; LFT - liver function tests; LRTI - lower respiratory tract infection; MMF - mycophenolate
mofetil; PML - progressive multifocal leukoencephalopathy; RA - rheumatoid arthritis; RCT - randomised
controlled trial; SC - subcutaneous, SLE - systemic lupus erythematosus, TB - tuberculosis; URTI - upper
respiratory tract infection; UTI - urinary tract infection.
Advantages and Disadvantages
The advantages of biologic therapies compared with some of the conventional therapies
used for moderate-severe manifestations of SLE include potential efficacy in terms of disease
control and relative safety in pregnancy, especially when compared to methotrexate, MMF
and cyclophosphamide, which are contraindicated in pregnancy. The biggest disadvantage of

both, biologic and non-biologic DMARDs, is that of immunosuppression, which is associated
with increased risk of infection. Patients treated with biologics have to be screened for TB
and hepatitis, as both infections can reactivate during the biologic therapy administration. A
more significant concern, with most biologic agents, is the risk of progressive multifocal
leukoencephalopathy (PML). This is not a drug specific phenomenon; although extremely
rare, it is associated with significant mortality [18].
Another concern is that of the cost of biologic therapies. Biologic agents are expensive as
they are manufactured through advanced processes of biotechnology and genetic engineering.
However, the cost of treatment needs to be compared to the cost of having to manage all the
challenging aspects of the disease. SLE patients in general utilise more health resources
according to the severity of their disease and age at diagnosis, and patients with active lupus
nephritis or regular flares even more so than a patient with mild or quiescent disease [19-21].
The cost of a patient having SLE includes direct and indirect costs [22]. The indirect
costs are related to an individuals quality of life and ability to work [23]. The cost of an
individuals loss of work on average in the US is was estimated at approximatively $16,345
per year in 2011 [19]. About 10 years ago, direct costs were assessed in a tri-nation study,
which evaluated patients with SLE from several tertiary centres in Canada, US and UK
respectively [24]. The direct cost of lupus treatment, including productivity over a 1 year
period, was approximately $20,000 in the US [24]. There were also significant differences of
the health system indirect costs in different countries [25, 26], and differences in the access of
patients with lupus to the health care system across the world [27, 28]. A study from 2008
estimated that the annual (direct and productivity) cost for patients with lupus of employment
age was $20,924 [23]. The cost of rituximab is approximately 4000 for two infusions in the
UK, and there are data suggesting the cost-saving potential of rituximab in the management
of lupus nephritis [29]. With the advent of biosimilars, the cost of treating SLE may become
cheaper, but the efficacy of biosimilars (arguably having similar properties to the original
biologic treatment) has yet to be proven [30, 31]. In the context of discussing the cost-
effectiveness of biologic treatments it is worth mentioning that another advantage of the use
of biologic agents is the intravenous (IV) administration of some of the available agents,
which improves patient compliance and adherence to medication. New therapies, such as
atacicept are already available as subcutaneous (SC) injections; therefore, the above
advantage might be lost for some of biologic therapeutic options. On the other hand,
preserving the patient independence and enabling them to self-administer injectable
treatments can contribute in itself to the reduction of additional health care costs. A study
from 1991 by Petri et al. reported poorer adherence amongst Afro-Caribbean patients leading
to more significant renal SLE and indirect increase in the healthcare costs [32]. Ultimately,
the cost of treatment needs to be balanced against the economic cost of disease for a realistic
estimate of the cost-efficacy of different biologic therapeutic options.
The use of biologic agents in different countries is highly variable. In countries with
poorer economic status, the access to expensive treatment options is limited and not always
fairly distributed in the population. Mortality in lupus was associated with lower education,
shorter duration of follow up and poor medical coverage in a large study from South
American countries [33].
Belimumab is licensed for use to treat SLE in the US, Europe, but in the UK, the funding
of the treatment is based on an individual funding request (IFR). The disparity between the
outcome of patients with lupus nephritis with private vs. public health insurance in US is well
recognised [27, 34].
Belimumab has just been approved (July 2016) by NICE (National Institute of Clinical
Excellence) in the UK having previously considered too expensive based on the QALY
(quality-adjusted life year) calculations. Real life experience has shown some clinical benefits
in patients with skin and joint manifestations [35]. Arguably QALY, which aims to appreciate
the disease burden by taking into consideration both, the quality and duration of life, is a
flawed measurement tool in the healthcare system [36]. An ideal system treatment for SLE
would ensure an increased good quality life span at the lowest possible health care cost. This
challenge is compounded by the dilemma of using biosimilars, which supposedly have similar
efficacy as the biologic agents and the advantage of lower cost. However, data regarding the
efficacy of biosimilars in head-to-head clinical trials aiming to compare them with the
original biologic agent are missing for the majority of available options.
Table 1 summarises the most studied biologic treatments in patients with lupus, with
particular emphasis on their efficacy for certain SLE manifestations, dosage and toxicity
profile.
Biologic Therapies Affecting B Cells

1. Anti-CD20 - rituximab, ofatumumab, ocrelizumab, veltuzumab
2. Anti-CD22 - epratuzumab
Rituximab
Mechanism of Action and Dosage

Rituximab is a chimeric/humanised monoclonal antibody against CD20. It was the first
biologic to be used in the treatment of SLE. The drug depletes CD20 B lymphocytes. The
CD20 antigen is found on pre - B cells which would then form mature B cells [37]. Depletion
of the B cell therefore reduces cell apoptosis and complement activation [38, 39]. Although
the function of CD20 is unknown, it is considered that it may play a role in Ca2+ influx across
plasma membranes, maintaining intracellular Ca2+ concentration and allowing differentiation
and activation of B cells.
The fragment antigen binding (Fab) domain of rituximab binds to the CD20 antigen on B
lymphocytes, and the fragment crystallisable (Fc) domain recruits immune effector functions
to mediate B cell lysis in vitro; in addition, rituximab increases the expression of major
histocompatibility complex II (MHC II), and lymphocyte function-associated antigens 1 and 3
(LFA-1, LFA-3), triggers shedding of CD23, down-regulates B cell receptor and induces the
apoptosis of CD20 B cells [40].
The standard dose currently recommended for the treatment of SLE is 1 g of IV
rituximab given 2 weeks apart. Each dose is preceded by premedication with
methylprednisolone, antihistamine and paracetamol to reduce the risk of infusion reactions.
Cyclophosphamide may also be given pre-first dose to increase the efficacy of rituximab and
enhance B cell depletion [41].
Efficacy and Side Effect Profile

Rituximab is considered effective in treating refractory SLE, although two large trials,
LUNAR (clinical trial of patients with lupus nephritis) and EXPLORER (clinical trial which
included non-renal patients) did not meet their primary endpoints. The reason for this is likely
related to the concomitant use of high dose of steroids and concomitant conventional
immunosuppressant therapy [42, 43]. However, some significant clinical and serological
results were noted (e.g., significant reduction in proteinuria, lower steroid requirement, etc.).
Despite the failure of these clinical trials, numerous case-reports and studies using rituximab
off-label in lupus patients have shown a 70-90% response rate [43-46]. The role of rituximab
as a steroid sparing agent has also become evident. Condon et al. reported results on 50 lupus
nephritis patients treated with 1 g of rituximab 2 weeks apart and 500 mg of IV
methylprednisolone [47]. No oral steroids were given and MMF was used as maintenance
therapy. 70% (n = 36) of the patients achieved remission in a mean time of 36 weeks. The
conclusion of the researchers was that oral steroids can be avoided (only 2/50 patients
required them in a 2 year follow up period), and B cell depletion might be considered early in
the treatment of lupus nephritis and other systemic manifestations of SLE. Rituximab
minimised the need for additional steroids and was effective in ensuring a better long term
control of the disease. An earlier, albeit smaller study of eight newly diagnosed rituximab
treated patients (each case carefully matched to three conservatively treated patients) reported
similar steroid sparing capacity of rituximab in non-renal lupus patients [48]. An international
trial comparing rituximab and MMF in lupus nephritis patients treated with minimal dose of
steroids vs. standard therapy with high doses of steroids and MMF (the RITUXILUP study) is
currently undergoing and should provide more definitive answers regarding the exciting
possibility to treat patients with lupus with low doses of steroids and rituximab.
Side-effects of rituximab include infusion reactions, as documented in the initial
oncology studies [49]. The most common side-effects are fever, bronchospasm, rash and
hypotension, which usually settle on stopping the infusion. Patients are usually followed up
carefully post-rituximab treatment to monitor for the development of common bacterial and
viral infections, or other infections, such as TB and hepatitis B or C. Based on the experience
acquired from treating RA patients with rituximab, this biologic agent is considered
reasonably safe in the context of history of TB [50, 51]. There are reports of both reactivation
of hepatitis B following treatment with rituximab [52], as well as effective treatment of
vasculitis associated with hepatitis C with rituximab [53, 54]. Human anti chimeric antibodies
have also been reported [55], and side-effects to medication are considered to be linked to the
immunogenicity of these antibodies [56]. The effect of B cell depletion lasts for 6-12 months
in about 75% of cases, and the response to therapy is variable [38, 57, 58], and, as shown
recently, the longer the duration of B cell depletion, the better the outcome [59]. The process
of B cell repopulation following B cell depletion therapy with rituximab in lupus is still not
fully understood [60]. For safety reasons, it is recommended to check immunoglobulin (Ig)
levels and CD19+ B cell count every 2 months until B cells normalise, as accumulated doses
of rituximab may also cause hypogammaglobulinaemia which may be linked to an increased
the risk of infection [61, 62].
The expert consensus is that rituximab is a safe and effective treatment option for patients
with refractory renal and non-renal lupus and can reduce significantly the steroid burden [48,
63-65], despite the negative trial results.
Ofatumumab

Ofatumumab is a fully human monoclonal antibody anti-CD20 [66]. The treatment is
licensed for use in patients with chronic lymphocytic leukaemia based on its proven efficacy
in treating refractory cases [67, 68]. Most studies assessing dosing regimens in patients with
rheumatic conditions have been done in RA patients, in whom the treatment was also
associated with clinical benefit [69, 70]. The current recommended dose is 700 mg IV every 2
weeks. Similarly with other biologic agents, premedication is administered beforehand, to
minimise the risk of infusion reactions [71].

The safety profile and efficacy of ofatumumab has also been established in a few RA
clinical trials [69, 71]. The drug has been proved effective as B cell depletion agents as was
associated with significant clinical improvement of symptoms of arthritis at different doses
[71]. The pharmacokinetic of the medication was found similar in chronic lymphocytic
leukaemia and RA [72]. A recent case report has suggested some benefit in the treatment of
SLE [73].
Although safety profiles were established in phase 1 and II trials, the most comprehensive
information related to the drugs safety profile was provided by a phase III clinical trial in RA
[69]. The most common side-effects were rash (21%) and urticaria (12%), which mostly
occurred on the day of first infusion and they declined significantly with the second course.
Most adverse events were of mild or moderate intensity (see Table 1).
Ocrelizumab

Ocrelizumab is another fully human monoclonal antibody against CD20, developed for
RA, SLE, and B cell derived malignancies [74, 75], which was tested for efficacy in patients
with lupus nephritis [76]. The doses used in the largest phase III clinical trial were 400 mg or
1,000 mg ocrelizumab, given as an IV infusion on days 1 and 15, followed by a single
infusion at week 16 and every 16 weeks thereafter [76].

Despite reaching an overall response rate of 66-67% in the ocrelizumab treatment arm,
the difference in response vs. standard of care treatment did not reach statistical significance
[76]. The study was terminated earlier as there was an infection-related safety signal in
relation with increased risk of opportunistic and fatal infections in the ocrelizumab treatment
groups [77]. The proportion of patients experiencing serious infections was twice as high in
patients who received concomitant treatment with MMF (32% vs. 16% in the placebo arm),
and it was increased in Asian patients [76].
Although ocrelizumab has been unsuccessful in one clinical trial in SLE, this negative
result may be attributed to the use of concomitant MMF. It has also been trialed in relapsing
and remitting multiple sclerosis with only 3 of 55 patients experiencing significant adverse
events. The treatment was associated with a reduction in neurological lesions on magnetic
resonance imaging (MRI) [78]. It remains possible that this drug can still be used in SLE
pending additional trials.
Veltuzumab

Veltuzumab is a second generation humanised anti CD20 monoclonal antibody with a SC
formulation, developed for the treatment of refractory pemphigus vulgaris and hematologic
malignancies [79, 80]. A case report showed improved serological outcome with treatment
with veltuzumab in a lupus patient who developed anti - drug antibodies (HACA) to
rituximab [81]. The role of veltuzumab in SLE has yet to be clearly determined but may be
used where rituximab is ineffective or there is resistance, as seen in patients with non-
Hodgkin lymphoma (NHL) [82].
Bispecific Monoclonal Antibodies
Recent laboratory studies suggested that the use of bispecific antibodies (anti CD22/
CD20) might be effective in the treatment of lupus, as they were associated with increased
trogocytosis. Trogocytosis is a process whereby lymphocytes conjugated with APC extract
surface molecules from APCs and express them on their own surface in vitro, resulting in
decreased levels of B cell surface markers associated with considerably less B cell depletion
and therefore less risk of severe immunosuppression [83].
Epratuzumab

CD22 is a B cell transmembrane glycoprotein that is found on mature B cells.
Epratuzumab is an IgG1 monoclonal antibody against the CD22 molecule, which inhibits B
cell receptor activation and leads to subsequent B cell apoptosis. The ALLEVIATE-1 and
ALLEVIATE-2 randomised clinical trials (RCTs) proved that 360 mg/m2 IV dose was more
effective than the 720 mg/m2 IV dose as a steroid-sparing medication in patients with severe
lupus. The responses correlated with improvements in health-related quality of life [84]. The
EMBLEM study was an early phase II B study performed to determine the effective dose
regimen in patients with moderate-severe lupus, which showed that patients receiving a total
of 2400 mg had significant improvement in the disease activity [85].
The phase III studies, EMBODY 1 and 2, enrolled SLE patients who received placebo or
treatment with 2400 mg of epratuzumab over four 12-week treatment cycles, administered as
600 mg every week for four weeks or 1,200 mg every two weeks for four weeks. The primary
endpoint of both studies (which was defined as the percentage of patients meeting treatment
response criteria at week 48 according to the British Isles Lupus Assessment Group (BILAG)
- based Combined Lupus Assessment - BICLA) was not met and the research program was
discontinued. BICLA, like the SRI (SLE responder index) system, requires patients to meet
response criteria across three assessment tools: the BILAG-2004 index, SLEDAI index (SLE-
disease activity index) and a physicians global assessment (PGA).
Epratuzumab is considered to reduce on average only 35% of circulating B cells in

patients, and has minimal antibody and complement-dependent cellular cytotoxicity (when
evaluated in vitro), and it was hypothesised that its therapeutic activity may not result
completely from B cell depletion [83]. However, this was not translated in clinical benefits.
Side Effect Profile

Epratuzumab has been used in the treatment of both SLE and Sjgrens syndrome [85-
87]. The drug has been proven to reduce BILAG scores, as well as neuropsychiatric (62.5%),
muco-cutaneous (21.9%) and musculoskeletal symptoms (32%) compared to placebo [85].
Provisional encouraging results in SLE were not confirmed in a large phase III trial however.
The common side effects included infusion reaction, upper respiratory tract infections
(URTIs), fever, headache, nausea and dizziness. A small proportion of patients developed
human antidrug antibodies (HAHA). In contrast to rituximab, no severe decrease in the Ig
levels was noted and this may be in relation to a partial depletion of B cells.
Anti B Cell Activating Factors

1. Belimumab
2. Tabalumab
3. Atacicept
Belimumab

This is a monoclonal humanised Ig which binds to the BLyS protein. It is a
transmembrane protein expressed by T cells, dendritic cells and neutrophils. The BlyS protein
binds to 3 receptors on the B cell surface: the B cell maturation antigen (BMCA), BAFF-
receptor (BR3, BAFF-R) and a transmembrane activator and calcium modulating ligand
interactor (TACI); via these receptors it has a role is in B cell differentiation, Ig production
and levels of disease activity [88]. Patients with SLE have high levels of BlyS, therefore
binding of the BlyS protein leads to decrease B cell activation, maturation and antibody
production. The dose used in lupus clinical trials was 10 mg/kg IV every 2 weeks for 6 weeks
and thereafter monthly.

Belimumab is considered effective in patient with non-renal and non-cerebral SLE. FDA
has approved it for mild to moderate SLE for those with skin and joint disease. It is not
approved for active renal lupus or cerebral lupus. BLISS 52 and BLISS 76 studies have
shown efficacy at 52 and 76 weeks [89]. BLISS 52 was carried out in countries from Central
and Eastern Europe, Asia-Pacific, and Latin America. At 52 weeks, there was a 58% patients
who had been treated with 10 m/kg of belimumab met the primary outcome, which was the
SRI response rate (P = 0.017). SRI comprises criteria from three different internationally
validated indices, SELENA-SLEDAI, PGA and BILAG 2004. BLISS 76 was a clinical trial
which included patients from North America, and Western and Central Europe. Similarly, at
week 52, 43% of patients treated with 10 mg/kg of belimumab met a similar primary outcome
(p < 0.02). The 52 week response was not maintained at 76 weeks. The results of these large
clinical trials suggested that improvement of disease control is more likely in patients with
low C3 and high dsDNA levels [90]. A pooled post-hoc analysis of the combined phase III
studies suggested a possible benefit in lupus nephritis as well [91]. Belimumab was
associated with improvement of disease activity, reduced flares, decrease in dsDNA levels
and low rate of side effects and it is currently licensed for use in non-renal lupus patients. The
one drawback of belimumab is the delay onset of action and therefore, it is not ideal for an
acute flare treatment. It can take up to 6 months to achieve 70% B cell depletion. Common
side effects included nausea, diarrhoea, headaches and URTIs, but their frequency was low.
The rates of patients experiencing adverse events, as assessed from pooled data from one
phase II and two phase III RCTs were 16.6%, 19.5%, 13.5%, and 18.0% with placebo, and
belimumab 1, 4, and 10 mg/kg, respectively [92]. There was also evidence of low rate of
serious infusion reactions (including hypersensitivity reactions) occurring at a lower
frequency that 1% in both placebo and active medication patient groups [92]. The side effect
profile is not dose dependent. There is one case report of a severe delayed anaphylactic
reaction which was fatal [92].
Tabalumab

BLyS, also known as BAFF, belongs to the TNF family. It is expressed by multiple cells
including macrophages, monocytes, neutrophils and dendritic cells. BLys/BAFF binds to 3
receptors called BR3, thus affecting B cell lineage. TACI receptor is found on T cells and
marginal zone B cells. BCMA (B cell maturation antigen) receptor is found on plasma cells.
Activation of these receptors leads to auto-antibody production, increase in B cells and
possibly potentiate malignancies [93].
In contrast to belimumab, tabalumab is an anti BAFF monoclonal antibody, which targets
both membrane bound and soluble BAFF, currently used in RA [94]. The ILLUMINATE-1
study, a phase III RCT of tabalumab in patients with SLE, used the following dose regimen:
240 mg SC loading dose, followed by 120 mg every 2 weeks or 4 weeks in combination with
traditional SLE treatments. The primary endpoint was the proportion of patients achieving an
SLE Responder Index 5 (SRI-5) response at week 52. The SRI-5 is a composite endpoint
defined as 5 point improvement (reduction) in SELENA-SLEDAI score, no new BILAG
2004 index score of A or no more than one new BILAG B score, and no worsening (increase
0.3 points from baseline) in PGA [95]. The study did not meet the primary endpoint.
Similarly, no difference in the secondary outcomes (which included time to first severe SLE
flare on the SELENA-SLEDAI Flare Index, proportion of patients with reduction in
corticosteroid dose by 25% to 7.5 mg/day prednisone (or equivalent) for 3 consecutive
months from weeks 24 through 52, and change from baseline on the Brief Fatigue Inventory
at week 52), was found between the active and placebo groups. However, in a sensitivity
analysis which did not exclude the patients who decreased antimalarial, steroid or
immunosuppressant therapy, SRI-5 response was achieved with tabalumab 120 mg every 4
weeks (37.0% vs 29.8% placebo; p = 0.021), suggesting a potential for this biologic agent to
be effective in selected categories of lupus patients [95]. Furthermore, the ILLUMINATE-2
study, which was set up in a broadly similar way to ILLUMINATE-1, but not excluding these
patients whose concomitant medications were reduced, did not meet its primary endpoint.
Unfortunately, despite the encouraging results, Eli-Lilly have terminated the tabalumab
program in lupus.
The side-effects noted from the initial RA trials include infections and injection site
reactions [96]. The most common infections included URTI and urinary tract infections
(UTIs). Severe adverse events were also noted, such as myocardial infarct, discitis,
osteomyelitis, breast cancer, cerebrovascular accident and pulmonary fibrosis [96, 97]. The
treatment with tabalumab was associated with slight increase in the incidence of depression
and suicidality compared to placebo in the ILLUMINATE-1 study, but these side-effects
were uncommon [98]. The incidence of serious infections and severe infections were similar
in the tabalumab and placebo groups in SLE patients [95].
Atacicept

This novel agent inhibits both BLyS and APRIL in B cells, affecting B cells ranging from
immature to mature. It is a TACI-Ig fusion receptor protein [99]. As described above, by
inhibiting BlyS and APRIL it causes a reduction in B cell proliferation, IFN and Ig
production [100]. The doses used in the phase II/III RCT in lupus were either 75 mg or 150
mg atacicept SC biweekly for 4 weeks and then weekly versus placebo [101].

In the APRIL-SLE phase II RCT, the 150 mg atacicept arm was terminated early due to
two fatal infections [101]. Despite this, a post-hoc analysis of atacicept 150 mg has shown
that this dose regimen reduced the incidence of flares and time to first flare compared to
placebo (flare rate 37% vs. 54%, odds ration - OR = 1.15 (0.73-1.8), and time to flare HR =
0.56, P = 0.009) [102]. There was no difference between atacicept 75 mg and placebo. The
clinical response was accompanied by decrease in B cells, Ig levels and increase in
complement levels. The 75 mg arm failed to meet the primary endpoint, defined as a
significant decrease in the proportion of patients experiencing at least one flare of BILAG A
or B [101].
The main safety concern regarding atacicept is that of potential increased incidence of
hypogammaglobulinaemia and therefore risk of infection. A study in patients with lupus
nephritis was terminated after the enrolment of only 6 patients because of the severe
decreased in the level of Ig [103]. A closer look at the concomitant medication, showed that
these patients hypogammaglobulinaemia developed when the patients were given MMF
before they were treated with atacicept [104]. It was hypothesised that targeting APRIL in
autoimmune disease might be associated with significant risk of toxicity [105]. Further phase
II/III clinical trials of atacicept in lupus are currently undergoing (ADDRESS II) and should
be able to provide additional information about the safety profile of this biologic agent. Apart
from the two deaths encountered in the 150 mg atacicept group in the APRIL-SLE trial, the
proportion of the serious infections was not statistically significantly different between the 75
mg atacicept arm when compared to placebo [101]. Furthermore, the death and injection rates
were similar to those reported in the belimumab studies. The most common infections
encountered included haemophilus influenzae pneumonia, legionella pneumonia and bacillus

bacteraemia. Preclinical studies showed an increase in liver transaminases [101].
Blisibimod

Blisibimod is a fusion protein consisting of four BAFF binding domains fused to the Fc
region of a human antibody, which acts as a selective antagonist of BAFF. Blisibimod
selectively inhibits both soluble and membrane-bound BAFF.

The efficacy and safety of blisibimod in subjects with SLE was investigated in a phase II
RCT, PEARL-SC study, which found that the highest tested dose of 200 mg blisibimod
administered SC once weekly was associated with increased SRI-5 response rates, but
without reaching statistical significance when compared with placebo. The treatment was
more effective in patients with SELENA-SLEDAI improvement of 8, and in a subgroup of
patients with severe disease (SELENA-SLEDAI 10) [106].
Blisibimod was associated with a decrease in the number of nave B cells (24-76%) and a
transient relative increase in the memory B cell compartment in the phase 1 studies [107]. It
was also associated with significant decrease of dsDNA, increase in the complement C3 and
C4, and reductions in serum B cell levels in the PEARL-SC study [106]. Blisibimod is
currently being tested in a phase III study for SLE, CHABLIS-SC1, and a phase II study,
BRIGHT-SC, for IgA nephropathy.
The treatment with blisibimod was safe, as the incidence of serious side-effects was
similar to the placebo arm. Injection site reactions were reported more frequently with
blisibimod compared with placebo, but they were mild (erythema) [106]. Taking into
consideration this treatments serological benefits in SLE patients and acceptable safety
profile, the results of the phase III study are awaited with interest as if proven more effective
than belimumab, the treatment has a good chance to be the next licensed biologic treatment
for lupus.
Anti-Interferon Alpha (IFN)

1. Sifalimumab
2. Rontalizumab
3. Anifrolumab
Mechanism of Action
Sifalimumab and rontalizumab are anti-IFN monoclonal antibodies. An increase in
BAFF occurs via signalling of INF. The signalling pathway is activated by the stimulation of
the IFN-1 receptor. In SLE pathogenesis there is activation of type 1 IFN, which is associated
with lupus nephritis [108, 109]. Neutralisation of IFN will lead to a reduction of
inflammation by a reduction in BAFF levels, mature B cells, antibody production and T cell
activation [110, 111].
Sifalimumab
Dosage
An optimal dose is yet to be confirmed as trials are currently underway. The phase I RCT
in lupus used the following doses: 0.3, 1, 3, 10 or 30 mg/kg as a single IV administration
[112]. The results of a promising phase II RCT of sifalimumab in SLE were presented at the
2014 American College of Rheumatology (ACR) annual meeting [113].
The patients were randomised to receive monthly IV doses of sifalimumab at 200, 600, or
1200 mg or placebo for 1 year based on their disease activity, IFN signatures and geographic
region. The primary endpoint, defined as the percentage of patients achieving an SRI at day
365, was achieved in all the treatment active arms (sifalimumab 200, 600, and 1200 mg doses
were associated with 58.3, 56.5, 59.8%, SRI response respectively, compared to 45.4% in the
placebo group). Surprisingly, there were no significant changes of the dsDNA or complement
levels despite the good response to treatment [113].

The results from the early phase clinical trials showed a reduction in SLE disease activity
[108, 113], and phase 3 trials are currently underway. Sifalimumab is considered safe
although there have been reports of increase incidence of herpes zoster infection. Other side
effects typically include infusion reactions, nausea, URTIs, UTIs, headache and arthralgia
[108, 114].
Rontalizumab

Rontalizumab has a similar mechanism of action as sifalimumab [109]. In an early phase,
dose-escalation study, patients were enrolled into dose groups ranging from 0.3 to 10 mg/kg,
administered via IV or SC routes [115].

A recent phase II studies with rontalizumab in lupus did not meet the criteria for efficacy
which were reduction in disease activity as assessed by the BILAG and SRI [116]. A phase I
study showed a dose dependent decrease in the level of IFN, but no decrease in levels of
dsDNA. The side effect profile was deemed similar to placebo, although an increase in viral
infections was noted [115, 116]
Anifrolumab

Anifrolumab is a type I IFN receptor antagonist [117], which was recently tested in a
phase II RCT in patients with SLE using two dose regimens: 300 and 1000 mg IV
anifrolumab, monthly administration (ACR abstract data, Merrill et al., 2015 in press).

The primary endpoint of this phase II RCT of anifrolumab in patients with moderate to
severe SLE was a composite SRI response at day 169 with sustained reduction of the steroid
dose (<10 mg/day dose maintained between days 85 and 169. Both treatment regimens (300
and 1000 mg anifrolumab) improved patients outcomes and reached the primary endpoint
(34.3% and 28.8% respectively, vs. 17.6% placebo). Steroid dose reduction (<7.5 mg daily) at
day 365 was achieved by 26.6% patients in the placebo group vs. 56.4% in the 300 mg
anifrolumab group (p = 0.001) and 31.7% in the 1000 mg anifrolumab arm (p = 0.59).

The treatment with anifrolumab was associated with similar serious adverse events than
placebo. A higher incidence of influenza (most unconfirmed) and a dose-dependent increase
in herpes zoster were reported in the anifrolumab treatment arms compared to placebo.
The results from previous clinical trials with monoclonal antibodies to IFN have shown
encouraging results and further trials are ongoing.
Blockade of T Cell Activation
Abatacept

This is a fusion protein which interferes with the co stimulatory interactions between B
and T lymphocytes. Activated T cells express cytotoxic T-lymphocyte-associated protein 4
(CTLA4) which interacts with co-stimulatory receptor B7-1 (CD80). Abatacept is a
combination of human IgG (Fc portion) and CTLA-4. It therefore blocks stimulation of B
cells leading to a reduction in antibody formation and immune response [118]. The doses
used in lupus trials range from 10-30 mg/kg [119-123]

Initial murine studies showed improvement in lupus nephritis, proteinuria and
autoantibody titres but this has not yet translated into human studies. Phase II/III trials in
lupus nephritis did not meet outcome measures, although, when the same data were analysed
using different criteria (LUNAR trial response criteria) there was a 20% response rate in the
abatacept arm compared to placebo [119, 121].
The side effect profile is comparable to other biologics and is detailed in Table 1.
IL6 Blockage
1. Tocilizumab
2. Sirukumab
Tocilizumab

In mouse models exogenous IL6 has been shown to increase autoantibody production and
progression of lupus nephritis. By blocking IL6, there is a decrease in antibody formation,
proteinuria and mortality. IL6 is released by intrinsic kidney cells and causes mesangial cell
proliferation, activation of T and B cells and autoantibody secretion [124]. High IL6 levels
are associated with SLE disease activity as well as dsDNA levels. The blockage of IL6 also
causes a decrease in inflammation, B cell differentiation and autoantibody production [124].
Binding of IL6 to the receptor is prevented by tocilizumab, a fully humanised monoclonal
antibody. It can bind to membrane bound or soluble IL6R [125]. The starting dose is 4 mg/kg
monthly and this can be increased to 8 mg/kg monthly, pending clinical response [124].

Although a well-established treatment in RA and systemic juvenile idiopathic arthritis
(JIA) [126], its role in SLE is yet to be established. A phase I clinical trial in SLE proved the
safety and efficacy of tocilizumab in lupus patients [124].
The side effect profile is thought to be less severe than with other biologic agents. URTIs
and gastrointestinal infections are most common. The treatment with tocilizumab is
associated with suppression of C - reactive protein (CRP), haematological abnormalities, non-
melanoma skin tumours, and malignancies. Gastro-intestinal perforation has been reported in
phase III trials in RA. Liver dysfunction and increased levels of LDL and total cholesterol has
also been reported in clinical trials in RA [127, 128]. In the only clinical trial in lupus, the
treatment was associated with decreased neutrophil levels, but without major impact in
increasing the risk of infections [124].
Sirukumab
Sirukumab is a humanised monoclonal antibody against IL6, similar to tocilizumab
[129]. The results of a proof of concept study were reported at the ACR meeting in 2014
[130, 131]. Preliminary data suggested some improvement of the patient-outcome measures
and transient improvement in clinical parameters [132]. The treatment with sirukumab was
associated with a dose-dependent decrease in absolute neutrophil count and platelet count
[133].
FUTURE TREATMENT OPTIONS

Anti-Complement Therapies: Eculizumab
Complement activation is strongly involved in the pathogenesis of SLE. The function of

complement is to help clear immune complexes and a deficiency in this leads to the
development of SLE. Eculizumab has been developed to inhibit terminal complement
activation and maintain early complement function [134]. It is a monoclonal antibody against
C5. By blocking C5 it prevents the formation of C5a and C5b and the formation of the
terminal membrane attack complex [135]. This drug is in phase 1 trials, and the limited data
currently available suggested a delay in the onset of proteinuria and improved outcomes in
patients with hemolytic-uremic syndrome after renal transplantation [136]. A recent case
report also suggested clinical benefit in treating severe lupus nephritis in a paediatric patient
[137].
CONCLUSION
The various clinical and laboratory abnormalities associated with SLE need tailored
therapeutic interventions. Despite the large number of biologic treatments with potential
efficacy for controlling different aspects of lupus disease, it is worth mentioning that only one
biologic treatment, belimumab, was proven effective in large phase III clinical trials leading
to the licensing of a new therapy for lupus. The strict inclusion criteria used in clinical trials
suggest that even if shown effective, these treatments might only be useful for selected
categories of SLE patients and the generalisation of the results from clinical trials is not
indicated. However, despite the lack of efficacy in clinical trials, rituximab is widely
acknowledged as effective in treating refractory SLE and it is currently widely used off
license in many countries. Future research should lead to reconciliation between the clinical
trial results and clinician expertise related to the use of biologic treatments for the benefit of
SLE patients.
ACKNOWLEDGMENTS
The authors would like to thank to Dr. Marwan Bukhari, Consultant Rheumatologist,
Royal Lancaster Infirmary, Lancaster, UK (email: Marwan.Bukhari@mbht.nhs.uk) for
reviewing the chapter.
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Chapter 2
BIOLOGICS IN JUVENILE SYSTEMIC

LUPUS ERYTHEMATOSUS
Claire-Louise Murphy, MRCP

and Nicola Ambrose, PhD
Department of Rheumatology, University College London Hospital, London, UK
ABSTRACT
Juvenile Systemic Lupus Erythematosus (JSLE) is a chronic autoimmune
multisystem disease. The prognosis of JSLE has greatly improved over the past number
of decades likely due to a combination of better recognition, early diagnosis as well as
aggressive treatment in specialist units. Adult SLE and juvenile SLE have similarities,
but also important differences. Patients with JSLE have more aggressive disease. They
have frequent haematological and renal involvement. The female to male ratio is less
pronounced in JSLE. Few clinical trials have been undertaken in paediatric
rheumatology, and the use of biologics in JSLE is largely based on their use in the adult
population. There is a resultant paucity of efficacy and safety data in JSLE. Reassuringly,
clinical experience suggests that biologic drugs may be as efficacious in paediatric, as
they are in adult populations. In this chapter we review current biologic agents being used
and those with potential for use in children and adolescents with JSLE.
Keywords: biologic agents, systemic lupus erythematosus, juvenile SLE, B cells,

autoimmunity
Corresponding author: Dr. Nicola Ambrose, Consultant Rheumatologist, Department of Rheumatology, 3rd Floor
Central, 250 Euston Road, University College London Hospital, London, NW1 2PG, UK, email:
nicola.ambrose@uclh.nhs.uk.
34 Claire-Louise Murphy and Nicola Ambrose
INTRODUCTION
Juvenile SLE is an autoimmune disease with multisystem involvement. Twenty percent
of all SLE patients present before the age of 18 [1]. Median age of onset is around the onset
of puberty. The cause of JSLE is unknown. It is likely multifactorial, with the immune
system, genetics, hormones and the environment all playing a role [2, 3]. In fact all
components of the immune system appear to be involved with dysregulation of both the
innate and adaptive systems. Therefore the immune system is a prime target for biologic
treatment.
Patients with JSLE tend to have more severe disease than adult SLE [4]. Children and
adolescents have been shown to accrue more damage than adults and have higher
standardised mortality risks [5]. Both the disease itself and disease modifying drugs may have
detrimental effects on children and adolescents psychological and physical development. The
aim of treatment is to maintain remission and to improve overall quality of life and long-term
survival.
Constitutional symptoms such as fever, lymphadenopathy, rashes and oral ulceration are
more frequently seen. Diffuse proliferative glomerulonephritis is more severe.
Haematological features such as haemolytic anemia, leucopenia and thrombocytopenia are
more prevalent in JSLE [6]. Autoimmune hepatitis [7] and arthritis are also more frequently
seen in JSLE. Interestingly, cardiopulmonary features are rare in children and adolescents
with JSLE, but they have been shown to be at increased risk of cardiovascular disease [8].
There are also laboratory differences between both diseases. Anti-double stranded DNA
(dsDNA), anti-ribosomal P antibodies and anti-histone are all more prevalent in JSLE than in
adult onset-SLE [9]. Macrophage activation syndrome is more commonly seen in children
and can be life-threatening [10].
Pharmacodynamic and pharmacokinetic differences between adolescents and children
need to be taken into consideration [4]. Young children and adults have evolving immune
systems. The use of biologics and their potential long-term adverse effects, including
infertility and infection, are unknown. Beukelman et al. showed that patients with JSLE are
likely to have an increased risk of malignancy regardless of their medication use [11].
Management requires a holistic multidisciplinary approach focusing on controlling
disease rapidly to prevent damage and also providing support for patients and their families.
Transfer from paediatric to adult care can be a difficult milestone, and should be
individualised for each patient. This chapter focuses on biologics currently in use and biologic
agents that show promise in the future for children and adolescents with JSLE.
BACKGROUND
To date there are no large randomised controlled trials (RCTs) performed on the use of
biologic agents in JSLE. These drugs have shown efficacy in adults with SLE; however their
use in children and adolescents is mainly in an ad hoc unlicensed manner.
Biologics are expensive treatment choices. They are generally reserved for patients who
have difficulty in controlling their disease activity despite the use of traditional DMARDs
(disease modifying anti rheumatic drugs) therapy. To date, there is only one licensed biologic
Biologics in Juvenile Systemic Lupus Erythematosus 35
for use in adult onset SLE and none available in JSLE. Therefore, we mainly rely on adult
population studies, clinical experience and small cohort studies to guide treatment. National
and international collaborative studies should help guide better treatment strategies.
Biosimilars appear to have safety and efficacy data comparable to biologics and should
help reduce the cost of these agents [12]. They have been introduced into the United Kingdom
(UK) for use in rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis in February
2015. The estimated cost saving of biosimilars (compared to the original biologic agents) is
approximately 15-30%, but despite this, they still remain an expensive therapeutic option
[12].
BIOLOGICS IN JSLE
Biologic agents target components of the immune system, and therefore, better
knowledge of immune abnormalities associated with JSLE is essential in order to develop
effective treatments. The immune system appears to be over active with upregulation of B
cells, T cells, natural killer cells, monocytes and dendritic cells. Antinuclear antibodies
(ANA) are found in over 90% of patients with JSLE and adult onset SLE [13]. However, anti-
dsDNA and low C3 are more common in JSLE.
Cytokines including interleukin 6 (IL6), interleukin 10 (IL10), interleukin 17 (IL17), type
I interferon (IFN), B Lymphocyte Stimulator (BLyS), tumour necrosis factor alpha (TNF-)
have all been implicated in SLE pathogenesis. Anti-TNF drugs have revolutionised the
treatment of autoimmune diseases such as juvenile inflammatory arthritis (JIA) but can rarely
induce a lupus like syndrome in children and adolescents.
Neutrophil extracellular traps (NETs) are fibrous networks of chromatin and
antimicrobial factors that are released by neutrophils to trap and kill pathogens. Increased
NET formation (NETosis) or insufficient degradation of NETs can promote autoimmunity
due to the contents being exposed to the immune system [15].
The role of inflammasome in autoimmune processes in also important. This cytoplasmic
complex leads to caspase-1 activation and subsequent production of inflammatory cytokines
such as IL18 and IL1. Pattern recognition receptors, such as NLRP1 (NLR family pyrin
domain 1) can assemble an inflammasome in response to danger signals or pathogens [16].
Genetic overproduction of IFN and complement deficiencies has been shown to lead to
monogenic SLE [17].
T cells appear to play a role in SLE disease progression. The main T cell subsets involved
in SLE are CD4+ T helper (Th) cells and regulatory T cells (Tregs). CD4+ T cells are known
to regulate B cell autoantibodies via the production of cytokines. Beresford et al. measured
IL17A and Th1/Th2-related cytokine concentrations from patients with JSLE. IL17A levels
were higher compared to healthy controls, and JSLE T cells once activated had a better ability
to secrete Th17 associated cytokines [18].
Midgley et al. showed that patients with JSLE have increased expression in low density
granulocytes, which are a subset of neutrophils. These appear to correlate with British Isles
Lupus Assessment Group (BILAG) disease activity scores and dsDNA levels, and may have a
role in pathogenesis [19].
B cells play a pivotal role in the pathophysiology of JSLE and therefore have been by
different therapies. B lymphocytes have numerous roles including antibody production, act as
antigen presenting cells, interact with T cells, secrete cytokines and modulate dendritic cells.
CD20 is a B cell specific antigen expressed on both immature and mature B cells [20]. There
is evidence for the use of two B cell targeted biologics, rituximab and belimumab, in JSLE
[21, 22]. However, to date, there are no biologic agents licensed for use in JSLE. Currently,
there is one RCT investigating the efficacy and safety of belimumab in children and
adolescents with JSLE.
TREATMENTS FOR JSLE

Rituximab is a chimeric monoclonal antibody (mAb) against CD20, which is present on
all stages of B cell development, from late pro-B cells to memory cells (but not on plasma
cells). Rituximab causes the apoptosis of CD20 expressing B cells, and was initially used as
treatment for patients with non-Hodgkins lymphoma and subsequently in rheumatoid arthritis.
It was observed that patients with both lymphoma and rheumatoid arthritis, who were treated
for lymphoma experienced improvement in their rheumatoid arthritis. The success of
rituximab in the treatment of rheumatoid arthritis led to a study treating fifty adults with SLE
who had failed conventional treatment. Using the BILAG disease activity index, 42% of
patients with SLE achieved full remission post rituximab. DsDNA antibody levels dropped
and C3 levels improved [23].
Rituximab is beneficial in the treatment of adults with renal disease [24]. Its use in JSLE
has increased over the past number of years, especially in children with refractory lupus
nephritis. The optimal dose and timing remains uncertain [25].
Rituximab has a good safety profile and its effect generally lasts between 6 to 12 months.
Rituximab has been used to treat children with immune thrombocytopenia purpura (ITP) and
autoimmune haemolytic anaemia. It appears effective in the treatment of renal and
neuropsychiatric manifestations of JSLE. The two RCTs, the EXPLORER (Exploratory
Phase II/III SLE evaluation of Rituximab) and the LUNAR trial (Lupus Nephritis Assessment
with Rituximab Study), which both enrolled patients age 16-75, unfortunately failed to meet
their primary end-points [26, 27]. Despite this rituximab continues to be widely used because
patients with SLE improve on this treatment.
The EXPLORER trial assessed rituximab use in 257 patients with moderate to severe
SLE. Using the classic BILAG disease activity index, the primary endpoint was to achieve
remission at week 24 and to avoid flare at week 52. The trial failed to meet its primary end-
point; however beneficial effects were noted in African-American and Hispanic patients. Post
hoc analysis showed that patients had lower dsDNA and higher C3 levels.
The LUNAR trial involved 144 patients with class III/IV lupus nephritis. These patients
were also given mycophenolate mofetil (MMF) and glucocorticoids, which may have had an
impact on why the study did not reach its primary end-point. Other potential reasons for why
these studies failed include trial design or sample size. Despite this frustrating discrepancy,
there is plenty of clinical evidence including numerous case reports, supporting the benefit of
treatment with rituximab in SLE [20, 28].
The largest cohort study to date involving children and adolescents with SLE treated with
rituximab, was conducted in the UK. A retrospective analysis of 63 patients treated in the
period 2003-2013 was used to identify pediatric and adolescent patients treated with
rituximab. The mean age at diagnosis was 12.2 years in this cohort, and 79% of patients were
females. All patients had been treated with previous immunosuppressant treatments. They
received on average 104 courses of intravenous (IV) rituximab at a dose of 750 mg/m2 given
on two different occasions, approximately two weeks apart. Most patients were on
glucocorticoids. Patients on rituximab had a reduced BILAG disease activity index score
from 4.5 to 3, although this did not reach statistical significance. Patients required less
corticosteroids and their laboratory markers improved. Adverse events including neutropenia,
fever, infection and infusion reactions were experienced in 18%, according to this study [29].
Long-term studies are necessary to assess the safety of rituximab in the future.
A further study by Lightstone et al. assessed the treatment of patients with rituximab
without corticosteroids compared with those treated with conventional treatment [30, 31].
This study suggested that early treatment of patients with rituximab appears to be safe and
effective. The RITUXILUP trial is a multicenter RCT that aims to demonstrate whether
addition of rituximab to MMF is helpful in treating a new flare of lupus nephritis, and
whether it has long lasting steroid-sparing effects with equal efficacy and greater safety than
MMF and oral prednisolone. Eligibility criteria include adults and children aged 12-17 years
old with active lupus nephritis. If successful, this trial has the potential to dramatically change
how lupus nephritis in adults and children with JSLE is managed.
Children who have had rituximab may develop long-lasting B cell depletion and
hypogammaglobulinaemia, sometimes requiring immunoglobulin (Ig) replacement. There is
conflicting data regarding Ig levels post rituximab treatment in children and adolescents. Ig
levels may be mildly depleted, remain normal or be severely depleted [32].
One of the largest and most detailed analyses of children treated with rituximab reviewed
91 children with immune thrombocytopenia. In total 108 adverse events were noted, of which
84% were considered to be mild to moderate. However, one patient developed prolonged
hypogammaglobulinaemia [33].
A pilot study of twelve children/adolescents with either lupus nephritis or treatment
resistant lupus were treated with combination of rituximab 750 mg/m2 to 1 gram, and
cyclophosphamide 750 mg/m2 over eighteen months. Combined treatment significantly
reduced the need for steroids and response was maintained over a 5 year period [34].
B lymphocyte stimulator (BLyS) also known as BAFF (B lymphocyte activating factor)
or TNF superfamily member 13B, is a cytokine that promotes B cell proliferation and
survival [35]. It therefore promotes the secretion of immunoglobulins. BLyS is produced as a
285-amino acid transmembrane protein. It is cleaved at a furin protease site and released in its
soluble form. BLyS is produced from myeloid cells and binds to three receptors on the B cell
(BAFF-receptor, BCMA - B cell maturation antigen and TACI - transmembrane activator and
cyclophilin ligand interactor) [36]. BLyS is upregulated in response to IL10 and IFN [37].
Therefore, blocking BLyS makes therapeutic sense as a treatment option in JSLE.
Hong et al. tested 56 blood samples from patients with JSLE and showed that plasma
BLyS protein and blood leucocyte BLyS micro-ribonucleic acid (mRNA) levels were
significantly elevated in these children. There was a positive correlation between plasma
BLyS protein levels and disease activity, which adds strength to the hypothesis that BLyS
may be a therapeutic target in JSLE [38]. A similar BLyS expression profile was observed in
both children and adolescents with JSLE as was found in adults with SLE. Interestingly,
BLyS expression in patients with JSLE was independent of corticosteroid treatment.
Belimumab is a fully humanised mAb that binds to soluble human BLyS. It inhibits the
activity of BLyS and has been shown to reduce dsDNA levels in patients with lupus. The
Food and Drug Administration (FDA) first approved belimumab for use in patients with
active SLE in 2011, which is the first drug in sixty years to be approved for SLE treatment
[39].
Belimumab is given IV at a dose of 10 mg/kg every fortnight for the first month and then
every 28 days. Belimumab has no known drug interactions and dose adjustments are not
required for renal or hepatic dysfunction [40]. The SLE Responder Index (SRI) was the
composite index used as the primary outcome measure in the belimumab clinical trials.
BLISS 52 and BLISS 72 were the two large multicenter RCTs that compared belimumab to
placebo in patients with SLE who on standard treatment. The patients enrolled had to meet
the American College of Rheumatology (ACR) criteria for the diagnosis of SLE, to have
active disease, and to be seropositive (ANA titer 1:80 or anti-dsDNA antibody titer 30 IU
per milliliter) at screening.
Both studies showed significant improvement in the SRI with 10 mg/kg being the most
effective dose. In the BLISS-76 trial, differences in SRI between belimumab at 10 mg/kg and
placebo were no longer significant at 76 weeks [40].
Pediatric Lupus Trial of Belimumab plus Background Standard Therapy (PLUTO) is a
multicenter, randomised study to evaluate the safety, pharmacokinetics, and efficacy of
belimumab in children and adolescents aged 5 to 17 years old with active SLE (Systemic
Lupus Erythematosus Disease Activity Index - SELENA SLEDAI score 6). The study will
consist of three phases: a 52-week randomised, placebo-controlled, double-blind phase; a
long term open label continuation phase; and a long term safety follow up phase. The long
term open label continuation and safety follow up periods will continue for at least 5 years
and possibly up to 10 years from a subjects initial treatment with belimumab.
Atacicept is a human fusion protein that inhibits BLyS and APRIL (a proliferation-
inducing ligand) [41]. APRIL is one of the TNF family cytokine with a stronger affinity to
BCMA receptor than B cell-activating factor receptor (BAFF-R). BCMA is important in B
cell survival. Unfortunately, the clinical trial of atacicept with corticosteroid and MMF had to
be terminated due to significant hypogammaglobulinaemia experienced by some of the
patients [42]. Elolemy et al. showed in a study of 29 patients with JSLE that serum BLyS and
APRIL were elevated in JSLE compared to controls. Although BlyS correlated with disease
activity as measured by SLEDAI (p = 0.042), serum APRIL levels were inversely correlated
to the disease activity (p = 0.02). However, there was a statistically significant association
between elevated serum APRIL levels and negative anti-dsDNA in JSLE patients (p = 0.017),
suggesting the possibility of APRIL being a down-regulator of pro-inflammatory signals in
JSLE.
Epratuzumab is a humanised mAb that targets CD22 antigen on B cells [43].
Epratuzumab and rituximab have different effects on B cells. Epratuzumab has distinct effects
on cell growth, and inhibits B cell receptor activation, leading to subsequent B cell apoptosis.
A total of 786 patients with SLE participated in the EMBODY 1, and 788 patients in
EMBODY 2 trials investigating the efficacy of epratuzumab in lupus. Patients included were
18 years of age or older, and none of the studies included patients with JSLE. In addition to
standard treatment with glucocorticoids and other treatments (including immunosuppressant
therapies and hydroxychloroquine), patients received 600 mg of epratuzumab every week for
a period of 4 weeks, 1200 mg every 2 weeks for a period of 4 weeks, or placebo.
Disappointingly, the phase III clinical trial showed that epratuzumab failed to meet its
primary end-point.
Patients who are intolerant to rituximab may benefit from novel anti-CD20 mAbs.
Ocrelizumab is humanised anti-CD20 IgG1 mAb with modifications in the fragment
crystallisable (Fc) region. A phase III trial of ocrelizumab in adult onset SLE for the treatment
of lupus nephritis was stopped because of high rates of serious infections. Of note, these
patients had also been on concomitant cyclophosphamide, prednisolone, azathioprine or
MMF [44].
Ofatumumab is a human IgG1 heavy chain mAb that binds CD20 on B cells but at a
unique epitope. It has been shown to be effective in the treatment of rheumatoid arthritis.
There is no clinical trial data regarding its efficacy in JSLE. However, it had beneficial effects
in the treatment of a 22 year old lady with severe JSLE from the age of 11, who became
intolerant of rituximab [45].
Eculizumab which inhibits complement 5 (C5) was successful in treatment of a 4 year old
girl with lupus and diffuse proliferative lupus nephritis. She was treated previously with
prednisolone, plasma exchange and cyclosporine, and despite this aggressive therapy, she
developed atypical haemolytic uremic syndrome. Eculizimab led to remission of vasculitis,
proteinuria and haematuria with normalisation of renal function. This biologic treatment be of
benefit for patients with JSLE in the future [46].
Low levels of C1q (first component of the C1 complex of the classical pathway of C
activation) protein and high titres of C1q antibodies have been shown to be involved in the
pathogenesis of JSLE, especially lupus nephritis and therefore may be another therapeutic
target [47].
Studies identifying biomarkers associated with disease activity in JSLE might provide
suitable therapeutic targets. A study analysed serum levels of high mobility group box 1
antibody (HMGB1), IFN and leucocyte associated inhibitory receptor 1 (LAIR-1)
expression on plasmatoid dendritic cells (pDCs) of patients with JSLE. 26 patients with JSLE
aged between 8-16 years were tested. It was found that serum levels of HMGB1 and IFN in
patients with JSLE were significantly increased compared to healthy controls, and also in
those with active JSLE compared to those with inactive JSLE. LAIR-1 was lower than in
healthy controls. Blocking of HMGB1 and its receptors or increasing expression of LAIR-1
on dendritic cells may be a potential therapeutic target [48].
Polymorphisms in the inflammasome receptor NLRP1 and adult-onset SLE have been
reported. Selected polymorphisms in inflammasome genes were analysed in 90 children and
adolescents with JSLE and 144 healthy controls. A single polymorphism in the IL1B gene
was associated with JSLE, suggesting that IL-1B is involved in the pathogenesis of SLE [16].
CHALLENGES OF RECRUITING JSLE PATIENTS IN

CLINICAL TRIALS INVOLVING BIOLOGIC AGENTS
Clinical trials have been curtailed in JSLE due to the small number of eligible patients
and due to the heterogeneity of disease. International collaboration is imperative in order to
discover effective biologic agents to treat JSLE. For this to occur, more children need to be
given the opportunity to be involved in research. In 2007, the European medicines regulations
were updated and children and adolescents are now allowed to enroll in clinical trials, which
should facilitate our understanding and management of JSLE in the future.
PRINTO (Paediatric Rheumatology International Trials Organisation) is a non-
governmental international research network, which includes 59 countries with the goal to
conduct international clinical trials and outcome studies in children with rheumatic diseases
[51].
Measurement of disease activity is crucial for achieving the clinical trials endpoints, and
assess the efficacy of biologic therapies. The BILAG index, SLEDAI and SLAM (Systemic
Lupus Activity Measure) indices are validated for use in SLE. The BILAG-2004 index is
based on the physicians intention to treat and has been shown to measure SLE disease
activity better than the SLEDAI-2000 [52].
The BILAG index was adapted for use in JSLE and subsequently used in the UK Juvenile
SLE cohort study and was named the paediatric BILAG (pBILAG). The pBILAG index
collects more detailed information about organ-related disease activity than that incorporated
within the ACR criteria [53]. However, this index was designed for adults with lupus so may
not capture the full spectrum of disease.
CONCLUSION
Biologic agents show promise in the treatment of patients with JSLE in the future.
Children and adolescents with JSLE have higher mortality rates than adults with SLE and
therefore it is essential that we can use biologics in these difficult to treat patients. Children
and adolescents with JSLE have evolving immune systems so we should not be depending on
adult studies. To date, we have no licensed biologic agents for use in JSLE but there is
evidence that rituximab is of great benefit.
Growth delay, obesity and psychological effects of both the disease and treatments can
pose major problems in management of children and adolescents. Patients need support so
they can live a fulfilling life despite having a chronic debilitating disease. Further national
and international collaboration is required. Now that children and adolescents are allowed to
enroll in clinical trials, we should be able to use this opportunity to discover new biologic
agents aiming at optimizing the management of children and adolescents with JSLE in the
future.
ACKNOWLEDGMENTS
The authors would like to tank to Dr. John Ioannou, Reader and Honorary Consultant in
Adolescent and Adult Rheumatology, Principal Investigator - Arthritis Research UK Centre
for Adolescent Rheumatology, University College London, London, UK for reviewing the
chapter (email: y.ioannou@ucl.ac.uk).
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Chapter 3
BIOLOGIC TREATMENTS FOR

IDIOPATHIC INFLAMMATORY MYOPATHIES
Serena Fasano1, MD and David A. Isenberg2,, MD FRCP FAMS

1
Rheumatology Unit, Second University of Naples, Naples, Italy
2
Centre for Rheumatology, Department of Medicine,
University College London, London, UK
ABSTRACT
The idiopathic inflammatory myopathies are a group of acquired, heterogeneous,
systemic diseases of skeletal muscle. As these conditions are uncommon, current
treatment of myositis is based mainly on case reports and few randomised studies with
small numbers of patients enrolled. Therefore, the current treatment paradigm is still
relies primarily on clinical experience. High dose corticosteroids continue to be the first
line therapy. In order to avoid side effects, the prednisolone dose should be reduced based
on patients clinical response. Other immunosuppressive drugs are used in refractory
cases, as well as steroid-sparing agents. Nevertheless, a Cochrane review concluded that
there was insufficient evidence from the available studies to confirm the value of
immunosuppressive agents in myositis. In patients with myositis resistant to conventional
treatment, rituximab is a potential treatment option. Several agents could be of interest
for future studies of myositis treatment; however more randomised controlled trials are
needed to identify eligibility criteria, outcome predictors and the adequate regimen. The
identification of responsive patients and specific therapies targeting the correct myositis
subset may be cost-effective and potentially prevent incorrect use of biologics.
Keywords: idiopathic inflammatory myopathies, myositis, biologics, dermatomyositis,

polymyositis, rituximab
Corresponding author: Prof. David A. Isenberg, Academic Director of Rheumatology, Centre for Rheumatology,
424 The Rayne Institute, 5 University Street, University College London, London, WC1E 6JF, UK, email:
d.isenberg@ucl.ac.uk.
46 Serena Fasano and David A. Isenberg
INTRODUCTION
The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of acquired
systemic diseases, including adult polymyositis (PM), adult dermatomyositis (DM),
childhood myositis (juvenile DM and juvenile PM), inclusion body myositis (IBM), and
myositis associated with neoplasia or another autoimmune rheumatic disease.
Due to the rarity and the heterogeneity of these disorders, few randomised controlled
trials have been conducted in IIMs, making it difficult to provide clear recommendations.
There has never been any adequate clinical trial of corticosteroids in IIMs, but they clearly
remain the first choice for the treatment of these diseases.
To reduce the side effects of corticosteroids, immunosuppressive drugs are widely used
as steroid-sparing agents. They are also indicated in corticosteroid-resistant cases or when
disease relapses. However, a significant number of patients do not show an adequate response
to those traditional treatments. For patients with refractory DM, intravenous immunoglobulin
(IVIg) may provide short-term clinical efficacy, but offers only a transient benefit and more
studies are needed to assess the long-term safety and efficacy.
Related to recent advances in the understanding of the inflammatory pathways involved,
newer therapies are emerging as potential treatment options for IIMs. Although mainly case-
reports and small non-controlled studies are available, literature review suggests that novel
agents may offer some benefit in refractory cases.
Rituximab seems to be the most promising treatment. Tumour necrosis factor (TNF)
inhibitors have shown mixed results, and data on T lymphocyte co-stimulation blockade, anti-
interleukin (IL) 1 and anti-IL6 therapy are limited. In this chapter, we summarize the recent
developments in the use of biological treatments of the inflammatory myopathies. Further
investigations are needed to define the optimal therapy in the future.
RITUXIMAB
Rituximab is a chimeric monoclonal antibody directed against the CD20 protein on the
surface of B cells at most, but not all, stages of their development. It is not present on plasma
cells. It is approved for treating non-Hodgkins lymphoma, rheumatoid arthritis (RA), and
granulomatosis with polyangiitis and microscopic polyangiitis, but it has also shown efficacy
in treating other autoimmune diseases. Strategies targeting B cells may be of clinical benefit
in IIMs because B lymphocytes have been implicated in the initiation and propagation of the
immune response in the pathogenesis of myositis [1]. They are localised around the
perivascular region of muscles in patients with DM and they are found in the inflammatory
muscle fibres in both PM and DM patients. In addition, B cells produce autoantibodies
triggering the deposition of immune complexes in the dermal-epidermal junction of skin
lesions in patients with DM and present antigen to T cells, causing their activation. In 2005,
the first small open-label study with rituximab was conducted in 6 patients with DM
refractory to conventional treatment. Improvement in creatine kinase (CK) levels, muscle
strength and skin lesions, associated with the depletion of B cells, was observed in each
patient. Four of them experienced a relapse of symptoms beginning by 24-36 weeks, which
coincided with the return of B lymphocytes [2]. Later, several case series have reported
Biologic Treatments for Idiopathic Inflammatory Myopathies 47
beneficial effects of B cell depleting therapy in patients with IIMs. For example, rituximab
has shown efficacy in PM, including a refractory subset of myositis patients with anti-signal
recognition particle (SRP) antibodies [3, 4].
Beneficial effects of rituximab have been reported in open-label studies in patients with
DM with improvement of both muscle and skin disease [2, 5, 6]; although other reports
describe limited response in patients with refractory skin involvement [7, 8]. Case series
suggested that B cell depletion treatment may also be effective in patients with JDM [9, 10]
and with antisynthetase syndrome (ASS) [11, 12].
In the French Auto-Immunity and Rituximab (AIR) Registry [13], 16 out of 30 patients
with refractory IIMs showed a good response with significant improvement in CK levels,
daily steroid dose and physicians global opinion. Although this study has several limitations
related to the small population size, the absence of a control group, the lack of a standardised
assessment of muscle strength (e.g., manual muscle testing [MMT] was only done in 5
patients), there was a favourable trend in over 50% of patients. These promising reports
constituted the premise for the Rituximab In Myositis (RIM) trial [14]. The RIM trial was a
prospective, randomised, double-blind trial conducted in 200 treatment-refractory patients
with adult DM or PM or juvenile DM, in a unique placebo phase design in which 96 patients
received two rituximab infusions at baseline (early rituximab group), whereas 104 patients
received rituximab 8 weeks later (late rituximab group). The primary endpoint compared the
preliminary definition of improvement, defined as a time to achieve the 20% improvement
in at least 3 of 6 core set measures (see Table 1), between the 2 patient groups, as validated by
the International Myositis Assessment and Clinical Studies Group (IMACS) [15].
Table 1. IMACS core set of measures to classify a patient with myositis as clinically
improved * [15]
Core set domain Validated method of assessment
Physicians global activity assessment Horizontal 10 cm VAS

Patients/parents global activity assessment Horizontal 10 cm VAS
Muscle strength MMT, including proximal, distal, and axial muscles
assessed on 010-point
or expanded 05-point scale
Physical function HAQ/C-HAQ; CMAS
Muscle-associated enzymes At least 2 of CK, LDH, AST, ALT, or
aldolase tests
Extramuscular activity assessment Extramuscular portion of the Myositis
Disease Activity Assessment Tool
Legend: ALT - alanine aminotransferase; AST - aspartate aminotransferase; C-HAQ - Childhood HAQ;
CMAS - Childhood Myositis Assessment Scale; CK - creatine kinase; HAQ - Health Assessment
Questionnaire; IMACS - International Myositis Assessment and Clinical Studies Group; LDH - lactate
dehydrogenase; MMT - manual muscle strength testing; VAS - visual analogue scale.
Although overall 83% (161/195) of subjects achieved the definition of improvement

during the course of the 44-week clinical trial, there was no significant difference in response
time between the two treatment arms. However, rituximab demonstrated a significant steroid-
sparing effect and was generally well tolerated.
Potential reasons for the failure of the RIM trial to achieve its efficacy endpoints may be
associated with the study design (too short a placebo phase to allow a significant distinction),
selection of patients (clinical heterogeneity of myositis), core set of measures and definition
of improvement [16].
Another important question is which patients may have more benefit from receiving B
cell depleting treatment. In the final multivariable model of the RIM trial, it was established
that the presence of an antisynthetase antibody, primarily antiJo-1 (hazard ratio [HR] 3.08, P
< 0.01), antiMi-2 (HR 2.5, P < 0.01), or other autoantibody (HR 1.4, P 0.14) predicted a
shorter time to improvement compared to the absence of autoantibodies [17].
Despite the negative results of the RIM study, in a review of the literature on use of
rituximab in the treatment of myositis patients until 2012, 80% of patients showed a
significant improvement [18]. Thus, there remains a belief that rituximab may be of value,
especially in antibody positive patients with IIMs.
TNF INHIBITORS
TNF and its soluble receptors are overexpressed in the muscle biopsies of subjects with
IIMs [19], suggesting that the use of TNF inhibitors might be associated with clinical benefits
in myositis. Despite the initial promising case reports [20, 21], infliximab treatment has
shown limited clinical improvement in a pilot study conducted in 13 patients with refractory
IIMs (five with PM; four with DM; and four with IBM), and in an open-label trial of
infliximab combined with weekly methotrexate in drug-naive patients [22, 23]. However, the
use of infliximab was associated with a slower progression of calcinosis in juvenile DM [24].
Literature review shows only one case report of the use of adalimumab in myositis [25],
probably due to evidence that anti-TNF therapy in patients with autoimmune diseases can be
associated with new onset of myositis [26].
Some conflicting results have been reported for patients treated with etanercept. Sprott et
al. [27] firstly reported a case of PM refractory to conventional drugs, whose treatment with
etanercept led to the discontinuation of corticosteroids due to stability of the clinical and
laboratory findings. This positive result was not confirmed by a small study with etanercept
conducted in five cases of DM refractory to prednisone and to DMARDs [28]. All patients
showed elevation of their CK levels, no improvement in the cutaneous manifestations and
worsened their muscle weakness.
In 2006, Efthimiou et al. [29] reported the results of eight patients (three with DM, five
with PM) treated with TNF blockade agents, who had previously failed conventional
treatment. In all, six were treated with etanercept, one with infliximab and one received
sequential therapy with both drugs. Six of the 8 patients responded to treatment with
improvement of strength and a decrease in serum levels of muscle enzymes. This report is
confounded as TNF agents were an add-on treatment and concomitant therapy with
corticosteroids, immunosuppressive drugs and IVIg was continued.
In a pilot randomised placebo-controlled trial [30] conducted in treatment-nave patients
with DM and those who had taken prednisone for less than 2 months, etanercept
demonstrated a significant steroid-sparing effect. All patients in the placebo group were
treatment failures, while 5 out of 11 subjects treated with etanercept were successfully
weaned off prednisone. Although this trial failed to enroll the initially planned number of
patients, at the end of the study, etanercept-treated patients showed improvement of many
IMACS criteria including the manual muscle-testing, physician global and Health Assessment
Questionnaire (HAQ), in contrast to the placebo-treated subjects. However, there was no
statistically significant difference between the treatment groups with regard to IMACS
definition of improvement [15]. These preliminary data support the need for larger
randomised controlled trials to substantiate the efficacy of this drug.
TOCILIZUMAB
Tocilizumab is a humanised anti-interleukin 6 (IL6) receptor antibody. Several studies
have reported increased levels of IL6 in muscle tissue and in the sera of patients with myositis
[31, 32]. In addition, blockade of IL6 was effective in amelioration the severity of myositis in
murine models [32]. Some case reports showed efficacy and safety of tocilizumab with
improvement of clinical and laboratory findings in two patients with refractory PM [33], and
in a patient with refractory overlap syndrome with DM, scleroderma and RA [34]. Thus,
tocilizumab may be an option to consider in the treatment of refractory myositis, although
proof of its efficacy also requires randomised controlled trials.
ABATACEPT
Abatacept is a human fusion protein of cytotoxic T lymphocyte antigen 4 (CTLA4) and
the fragment crystallisable (Fc) portion of human immunoglobulin (Ig) G1, which blocks the
activation of CD28 receptor expressed on effector T cells. The rationale for using T cell
blockade in patients with myositis is the increasing evidence for the involvement of
infiltrating T lymphocytes and the expression of costimulatory molecules in biopsies of
patients with PM [35].
Abatacept was reported to show efficacy in three case reports. Beneficial effects of this
drug on clinical manifestations and on serum values of muscle enzymes have been described
in a patient with refractory PM [36], in a case of juvenile DM complicated by ulceration and
calcinosis [37], and a third case with refractory necrotizing myopathy [38]. Recently, a pilot
study assessing the effects of abatacept on disease activity and on muscle biopsy features of
patients with DM or PM was published as abstract at the ACR 2015 meeting [39]. The
treatment with abatacept resulted in improved muscle performance and health-related quality
of life in half of the patients.
Though the evidence is limited, abatacept may be a potential novel approach for the
treatment of myositis.
ANAKINRA
Anakinra is a recombinant interleukin 1 (IL1) receptor antagonist, which inhibits
activities of both IL1 and IL1. Although initially introduced for the treatment of RA, it is
little used for this condition. An increased presence of these interleukins has been described
in muscle tissue of patients with myositis [31, 40]. A 12-month open-label study with
anakinra showed a clinical response to treatment in seven out of 15 patients with refractory
myositis, according to IMACS definition of improvement [41]. Predictors of clinical
improvement were the presence of extra-muscular signs and the absence of biomarkers such
as muscle CD163, which is a macrophage marker.
Interestingly, the IL1 expression and inflammatory infiltrates persisted in repeat muscle
biopsies and it was not correlated to clinical response. However, in peripheral blood a shift of
differentiation of T cells from T helper 17 (Th17) to T helper 1 (Th1) cells was recorded,
suggesting a likely systemic effect of anakinra.
Unfortunately, this encouraging result has not been confirmed by a pilot study including
four patients with IBM, in which no improvement in muscle strength was observed after
treatment with anakinra [42].
SIFALIMUMAB
There is a good evidence to support the belief that the type I interferon (IFN) / pathway
is involved in the pathogenesis of myositis. Cluster of genes induced by type I IFN were
highly over-expressed in active myositis patients compared to controls and the type I IFN
inducible proteins and the IFN-regulated chemokines have been identified in muscle biopsies
and sera of patients with DM and PM [43].
In a first phase 1b clinical trial [44], the IFN-blocking antibody sifalimumab showed a
moderate neutralization of the type 1 IFN gene signature in both blood and muscle of DM or
PM patients. A positive correlation between gene suppression and improvement of muscle
strength by MMT8 was also observed. Furthermore, a follow-up study of this trial reported a
suppressive effect on T cell-related proteins including soluble IL2RA, TNF receptor 2 and
IL18, and a reduction of T cells infiltration in the muscle of myositis patients by blocking
type I IFN [45]. Although the clinical effect was not clear, these preliminary data suggest that
sifalimumab may be beneficial in the treatment of myositis.
ALEMTUZUMAB
Alemtuzumab is a humanised monoclonal antibody targeting the glycoprotein CD52,
which is predominantly expressed on the surface of mature T lymphocytes and monocytes.
A proof-of-principle study conducted in a group of 13 patients with IBM showed that
alemtuzumab was effective in reducing the endomysial T cells in repeated muscle biopsies
and was able to arrest disease progression during the 6-month period [46].
In a recently published long-term follow-up case of PM, alemtuzumab demonstrated a
significant steroid sparing effect, and a persistent improvement of muscle enzymes levels and
of muscle strength [47]. The risk of developing secondary autoimmunity following
alemtuzumab treatment should be considered in therapeutic decisions [48].
BIMAGRUMAB
Bimagrumab is an inhibitor of a transforming growth factor- (TGF) superfamily
receptor. A receptor type IIB (ActRIIB). ActRIIB mediates the signalling of myostatin to
inhibit the differentiation and growth of skeletal muscle. Increased signalling in this pathway
causes muscle atrophy. Amato et al. [49] evaluated the blockade of ActRIIB in 14 patients
with IBM. A single dose of bimagrumab increased the thigh muscle volume as assessed by
MRI at 8 weeks (primary outcome) and showed trends in improvement during the subsequent
24 weeks of follow up.
Potential Novel Biologic Therapies
Understanding the key mediators of inflammation in myopathies offers the opportunity

for therapeutic intervention. A broad spectrum of T and B cell cytokines, chemokines and
growth factors has been found to be significantly overexpressed in patients with IIMs as
compared with controls [50]. These molecules vary among the different IIM subsets, which
could reflect their distinct clinical manifestations. For instance, chemokine (C-X-C motif)
ligand 10 (CXCL10) secretion by skeletal muscle cells has been found elevated in the IIMs
and makes it a potential target for therapeutic intervention [51]. In addition, B cell activating
factor (BAFF) transcripts were reported significantly upregulated in muscle tissues of patients
with myositis [52]. These findings suggest the potential use of these cytokines as viable
pharmacological targets in the future. Other potential novel therapies include eculizumab [53]
(which binds complement fraction C5 and inhibits the cleavage of C5 to C5a and C5b-9,
which is involved in the pathogenesis of DM) and IMO-8400 (an ongoing clinical trial is
attempting to investigate the efficacy of this Toll like receptor antagonist) [54].
HEALTH IMPLICATIONS OF USING BIOLOGICS IN MYOSITIS

The treatment goals in IIMs are to increase muscle strength and to ameliorate extra-
muscular manifestations. Although a significant number of patients with myositis respond
adequately to treatment with steroids, an additional immunosuppressive agent is usually
administered in order to minimize the side effects to steroids. In most cases that fail to
respond to treatment with steroids, steroid-sparing immunosuppressive agents alone are
usually ineffective. Older age, association with cancer, pulmonary fibrosis, calcinosis are
factors associated with poor prognosis. Some new therapeutic approaches are currently being
investigated in order to identify more effective drugs with fewer adverse effects. Among
them, rituximab is the best studied and can provide some benefit, especially for patients with
antibody positivity. There are a core set measures used to quantify response to a certain
therapy (Table 1).
The cost of biologic therapy is a major concern. Not every patient responds to every
biologic agent. The identification of biomarkers with a potential to predict the response to a
specific agent may be cost-effective and can prevent incorrect use of biologics and the risk of
side effects. Unfortunately, due to the rarity of IIMs and the lack of large controlled trials,
treatment management is still based on clinical experience. The availability of new

monoclonal antibodies or fusion proteins are promising as treatment options for myositis and
need to be tested in controlled trials.
CONCLUSION
Until now, the current treatment of IIMs is still mainly empirical with glucocorticoids and
steroid-sparing immunosuppressive drugs. However, a proportion of patients do not respond
to these conventional therapies. With improved understanding of the pathogenesis of the
different subsets of myositis, novel therapies targeting B cells, T cells and key cytokines are
now emerging. Currently, rituximab is the most promising biological drug for resistant cases.
However, predictors of response are not yet known and it is still unclear which group of
patients might be the most likely to benefit from this treatment. Further investigations are
needed to provide a better evidence for the role of biological therapies in refractory myositis.
ACKNOWLEDGMENTS
The authors would like to thank Dr. Patrick Gordon, Consultant Rheumatologist from
Kings College Hospital NHS Foundation Trust, London, UK (email:
patrick.gordon2@nhs.net) for reviewing the chapter.
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Chapter 4
BIOLOGIC TREATMENT ADVANCES IN SJGRENS

SYNDROME: UNDERSTANDING THE IMPLICATIONS
OF USING BIOLOGIC THERAPIES IN SELECTED
CATEGORIES OF PATIENTS
Coziana Ciurtin1,2, PhD FRCP, Nicolyn Thompson2,

and David A. Isenberg1,2, MD FRCP FAMS
Department of Rheumatology,
1
University College London Hospital NHS Foundation Trust, London, UK

2
ABSTRACT
The discovery of potential therapeutic targets and their translation into biologic
therapies has revolutionised the treatment of autoimmune conditions. Even if at present
there are no licensed biologic treatments for Sjgrens Syndrome (SS), the advances in
understanding the pathogenesis of this disease should lead in the future to better long
term outcomes for patients. SS is an autoimmune rheumatic disease (ARD) characterised
by decreased exocrine gland function and systemic manifestations. Patients have few
treatment options and mainly limited to symptomatic care. Therapies targeting B cells,
such as rituximab, epratuzumab and belimumab showed promising results in clinical
trials, but further studies are needed to validate these findings. Early phase studies with
abatacept and alefacept suggested that therapies targeting T cell stimulation are
potentially effective for some disease manifestations. Other treatment targets, such as
interferon (IFN), interleukin 6 (IL6) and toll-like receptors (TLR) are currently being
investigated. As SS is a heterogeneous disease, with clinical features ranging from
dryness, pain and fatigue affecting nearly all patients, to severe, extra-glandular and
Correspondence to: Dr. Coziana Ciurtin, Department of Rheumatology, University College London Hospital NHS
Foundation Trust, 250 Euston Road, London, NW1 2PG, email: c.ciurtin@ucl.ac.uk
58 Coziana Ciurtin, Nicolyn Thompson and David A. Isenberg
systemic involvement in a more limited subset of patients, individually tailored treatment

options are required. Disease impact on quality of life measures is substantial and
comparative studies demonstrated that the quality of life scores in SS were quantitatively
worse than in patients with heart failure or many cancers, which has a considerable
impact on the costs associated with the health care of these patients. This chapter includes
a literature overview of the efficacy and safety of biologic treatments in SS. Based on
available evidence we make some clinical recommendations about the use of biologic
treatment in selected categories of SS patients and discuss general aspects of health
implications associated with the use of non-licensed biologic therapies.
Keywords: Sjgrens syndrome, biologic treatments, rituximab, epratuzumab, belimumab,

abatacept, tocilizumab, interferon-targeted therapies, quality of life, efficacy, safety
INTRODUCTION
Sjgrens Syndrome (SS) is an ARD associated with decreased quality of life [1-3],
despite the recent advances in understanding the immune abnormalities associated with the
chronic inflammatory process that affects the exocrine glands [4]. It may be classified as
primary, if occurs in the absence of any other associated autoimmune conditions, and
secondary when it complicates another rheumatic condition [5]. Patients are affected by
various degrees of mouth dryness (xerostomia), decreased tear secretion (xerophthalmia),
joint pains and fatigue. Less commonly, patients present with vasculitis or pulmonary, renal
and peripheral nervous system involvement [6]. The disease has a benign course in the
majority of cases; however, this condition is associated with increased risk for non-Hodgkin
lymphoma (NHL) [7-9]. The presence of autoantibodies was described in the serum over 40
years ago. The most typical antibodies associated with the disease are the anti-nuclear
antibodies, anti-Ro/SSA or La/SSB antibodies and rheumatoid factor, together with the
recently characterised anti-fodrin and anti-calpastatin antibodies [10, 11]. None of these
antibodies are specific for SS, and there are controversies regarding the sex differences
between their positivity in patients with SS [12, 13].
The frequency of positive anti-Ro/SSA and/or anti-La/SSB antibodies in patients with SS
is approximately 70-80% and 30-40% respectively [14]. In 2002, the American-European
Consensus Group (AECG) developed classification criteria for both primary and secondary
SS. Additional criteria for SS classification have been proposed by the American College of
Rheumatology (ACR) and the Sjgrens International Collaborative Clinical Alliance in an
effort to increase their specificity and improve diagnosis accuracy [15, 16]. The diagnosis is
based on the presence of subjective symptoms of dryness, associated with objective evidence
of decreased exocrine gland secretion or changes in the structure of the salivary gland as
assessed by biopsy and presence of autoantibodies (one of the last two criteria being
mandatory).
The decrease in the glandular function leads to the sicca complex, a combination of dry
eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), which are present in a large
proportion of patients [6, 17]. Sicca symptoms are also described in a wide variety of other
disorders including infections, neurological disorders, diabetes, sarcoidosis, radiation, and
some other poorly defined medical conditions such as fibromyalgia/chronic fatigue syndrome,
and they also increase with age [18].
Biologic Treatment Advances in Sjgrens Syndrome 59
According to the AECG criteria, primary SS has an approximate prevalence of 0.1-0.6%

[16]. It is estimated that the condition is severely underdiagnosed in the total population and
in patients with other autoimmune conditions [19]. The disease has a huge impact on patients
quality of life as the treatments available aim only at supplementing and stimulating the
exocrine secretion without addressing the cause of glandular tissue changes and altered
function. Particular interest has been given to the oral complications and their impact in the
quality of life of patients with SS [20-21], and more recently to that of sexual dysfunction
[22].
The rationale for developing new therapies aiming to address the pathological changes
linked to the disease abnormalities and progression is justified by advances in understanding
the aetiopathogenesis of SS. As glandular epithelial cells express high levels of human
leucocyte antigen (HLA)-DR [23], it is hypothesised that these cells present antigens (viral or
autoantigen) to the invading T cells [24]. Furthermore, SS is associated with increased pro-
inflammatory cytokine production (tumour necrosis factor alpha - TNF, interleukins - IL17,
IL21 and interferon gamma - IFN) [25-27], abnormal B cell activation and autoantibody
production leading to increased risk for B cell derived malignancies [28].
However, there is still a controversy around the hypothesis that the biological changes
described in SS are strictly correlated to the clinical manifestations of the disease. The
traditional view that chronic inflammation is the only explanation for the loss of function and
destruction of the exocrine glands in SS is almost certainly simplistic, as in many cases there
is a lack of clinico-pathological correlation. However, the histological assessment has a
recognised prognostic value in identifying the patients at risk for developing lymphoma [29].
There is a variable degree of correlation between the amount of glandular tissue damage as
assessed by labial biopsy, the ultrasound assessment of salivary glands and the saliva
production [30]. These findings lead to the speculation that there is an active inflammatory
process in the salivary glands which is underestimated by the histological assessment of
damage, and also that the value of the biopsy is limited in the context of other clinical
parameters or concomitant treatment with immunosuppressant therapy [31].
In this chapter, we review the available literature data regarding the efficacy of all the
biologic treatments used to treat patients with pSS, with particular emphasis of the results of
the randomised controlled trials (RCTs) of biologic treatments in pSS and appraise the
evidence regarding their efficacy and safety (Table 1). We also discuss aspects of the health
implications related to the implementation of these unlicensed therapies in selected cases and
discuss further areas of research that might address the question of cost-effective treatment
approaches in the management of this undertreated autoimmune condition.
Outcome Measures of Treatment
Several disease outcome measures have been designed to capture the level of activity and
damage in SS [32]. They are used in clinical trials together with patient report outcome
measures [33, 34] to assess the effectiveness of new therapies.
Several disease activity indices have been validated for use in clinical trials [35]; the SS
disease activity Index (SSDAI) and the Sjgrens systemic clinical activity index (SCAI)
were the first to be used [32, 36]. The European League against Rheumatism (EULAR)
promoted a global collaboration aiming to achieve a consensus on the topic of outcome
measures in SS. This resulted in the validation of two more indices: the EULAR Sjgrens
syndrome patient reported index (ESSPRI), which is a patient questionnaire to assess patient
symptoms, and the EULAR Sjgrens syndrome disease activity index (ESSDAI), which is a
systematic activity index to assess systemic complications [37, 38].
The Rationale for the Use of Experimental Biologic Treatments in SS
B cell hyperactivity is a key feature of SS pathogenesis. 35-40% of patients with SS have

hypergammaglobulinaemia. The production of auto-antibodies (anti-Ro and anti-La or the
cytoskeletal antigen -fodrin), together with the replacement of normal immunoglobulin
(Ig)A producing plasma cells by IgG producing plasma cells in salivary glands, and increased
risk for B cell lymphoma are all well-established findings in SS [39]. Given the central role of
B cell in the pathogenesis of SS, several treatments targeting B cells or their proliferating
factors were trialed to establish their efficacy. The assessment of primary SS salivary gland
biopsies showed a decrease in the IgA expressing plasma cells and an increase in the IgG
expressing plasma cells (the last also correlated with the serum IgG levels) when compared
with patients who did not fulfill the criteria for SS diagnosis [40].
T cells predominated in the glandular tissue and ocular surfaces in patients with SS and
they seem to respond to the autoantigens presented on apoptotic cells, and they tend to
perpetuate the disease [41]. The salivary epithelial tissue is also involved in co-stimulation
and presentation of antigens, and can promote T cell activation. In addition, dysfunction of
cytokine production is generated by the imbalance between the T helper (Th) 1 and Th 2
cells. More recently, a predominance of Th17 cells (which are also implicated in B cell
stimulation) was reported, as well as a dysfunction of the regulatory T cells (Tregs) [4, 42].
There is also evidence for a T cell directed toxicity mediated by Fas (cell death surface
receptor) and perforin, which contribute additionally to the glandular tissue destruction [43];
although this mechanism is considered to be a rare event in the pathogenesis of the disease
[44]. Treatments targeting T cell co-stimulatory molecule have also been tested in SS
recently.
B CELL TARGETED THERAPY

Monoclonal Antibodies Anti Cluster of Differentiation (CD) 20
Rituximab, a chimeric monoclonal antibody (mAb) directed against CD20 which is

expressed on most B cell precursors, was initially developed to treat non-Hodgkin lymphoma
and chronic lymphocytic leukemia patients [45]. CD20 mediates B cell activation,
proliferation and differentiation. Rituximab may also have role in T cell independent antibody
responses [46] and in complement induced cytotoxicity [47]. Rituximab was subsequently
used in other autoimmune diseases [rheumatoid arthritis (RA), systemic lupus erythematosus
(SLE) and myositis], and in patients with SS complicated with lymphoma [48].
Because of the fact that rituximab was associated with improvement of symptoms in SS
patients treated for lymphoma [49, 50], this mAb targeting B cells has been proposed as a
potential therapeutic option for patients with SS. Several clinical trials have been designed
following the success of rituximab in treating cases with refractory SS symptoms [51-53].
The first open-label clinical trial of rituximab in SS patients was published in 2005 [54].
The patients were treated with 4 infusions of rituximab (375 mg/m2) weekly, following
premedication with prednisone (25 mg) and anti-histaminic tablets. The treatment improved
significantly the salivary secretion at 12 weeks and the clinical outcome of the mucosa-
associated lymphoid tissue (MALT)-type lymphoma subgroup. Similarly, rituximab used off-
label was shown to be effective in controlling symptoms of systemic SS [55], which were
also mirrored by changes in the B cell biomarkers [56]. Another open-label study showed
reasonable toxicity profile of rituximab in SS, rapid peripheral B cell depletion and efficacy
in controlling symptoms of dryness, arthritis and fatigue [57].
The first RCT of rituximab in SS recruited 30 patients and has proven the efficacy of the
drug in improving the saliva flow rate, the lacrimal gland function as assessed by the
lissamine green test, the fatigue scores and visual analogue scores (VAS) for dryness [58].
The clinical response correlated with the improvement in the histological aspect of salivary
gland biopsies performed in a subgroup of patients [59]. The benefit of rituximab was
maintained up to 120 weeks in a prospective study of 41 patients with SS, and it correlated
with reduction in the lymphocytic infiltrate and germinal-like centre formation as assessed by
salivary gland biopsy [60].
Although treatment with rituximab was clearly associated with B cell depletion and
control of systemic symptoms, no unequivocal data have confirmed that it can increase
lacrimal and/or salivary gland function. It was suggested that patients with long-standing
disease and minimal lacrimal and salivary gland secretory capacity, might be particularly
refractory to disease-modifying treatment [61]. In other words, the salivary glands may be
more in a state of permanent damage than active inflammation by the time the treatment is
attempted.
Ocrelizumab is a humanised anti CD20 mAb, which binds a different (but overlapping
epitope as rituximab) and has similar complement directed cytotoxicity, but up to five fold
increase in the antibody-dependent cellular cytotoxicity compared to rituximab [62]. The
treatment was already proven effective in the intravenous formulation, and the subcutaneous
formulation is currently tested in RA [63]. Ofatumumab, another humanised anti CD20 mAb
was also tested and found efficacious in RA (in both intravenous and subcutaneous
formulations) [64, 65], but there are no studies or case reports to assess its use in the
treatment of SS.
Monoclonal Antibody Anti CD22
Epratuzumab is a humanised IgG1 anti CD22 which modulates the activation of B cells,
being less depleting than rituximab and ocrelizumab. CD22 is expressed from the pre-B cell
stage and has Ig-like extracellular domains and is an inhibitory receptor, which upon binding
enhances the inhibition of B cell receptor (BCR) mediated activation of B cells [66]. Anti
CD22 antibodies were first used as a therapeutic strategy in NHL [67]. Available data about
efficacy of epratuzumab in SS are limited.
The first clinical trial using epratuzumab in SS was an open-label study including 16
patients (who received 4 infusions of 360 mg/m2 epratuzumab once every 2 weeks and were
followed up for six months) which reported encouraging results [68]. The authors developed
their own composite endpoint score (including the Schirmer-I test, unstimulated whole
salivary flow, fatigue, erythrocyte sedimentation rate (ESR), and IgG levels), according to
which they found clinical significant responses in half of the patients for at least 18 weeks
(53% at week 6, 53% at week 10, 47% at week 18 and 67% at week 32). The clinical
response was associated with a modest decrease (39-54%) in the levels of B cells circulating
levels and with minimal evidence for immunogenicity [68]. Additional benefit was noted in
the improvement of fatigue, patient, and physician global assessments. The treatment was
well tolerated, and only one patient discontinued the treatment because of an acute reaction
following the infusion.
Monoclonal Antibodies against BAFF/BLyS (B Cell Activating Factor/

B Lymphocyte Stimulator)
Another potential biologic target for the treatment of B cell driven autoimmune diseases
was focused on interfering with B cell activation. It is well recognised that BAFF/BLyS
induces B cell proliferation, maturation, survival, and Ig secretion [69]. BAFF is a member of
the TNF family known to be up-regulated by IFN, IFN and viruses [70]. Higher levels of
BAFF were found in SS, with elevated levels of circulating BAFF, as well as up-regulation of
BAFF expression in salivary glands [71]. BAFF is a critical survival factor during B cell
maturation within the spleen, where the self-reactive B cell are eliminated as a result of the
immune tolerance check point [70]. Excess BAFF levels mediates self-reactive B cell
accumulation, and the BAFF transgenic mice model is prone to develop an autoimmune
disease associated with inflammation of the salivary glands and kidney, similar to SLE and
SS [72]. Despite the fact that effector T cells are found in a higher proportion in BAFF
transgenic mice BAFF, and T cells from salivary gland biopsies of patients with SS express
BAFF, their role is uncertain as it was shown that autoimmune abnormalities similar to SS
can develop in animal models in the absence of T cell dependent mechanisms [73, 74].
The detection in the salivary gland biopsies and serum samples collected from patients
with SS of the marginal zone-like B cells (memory cells expressing CD27) is paralleled by
their presence in the BAFF transgenic mouse model (peripheral blood, salivary glands and
lymph nodes). They are characterised by self-reactivity, increased risk of auto-immunity and
B cell malignancy. The sequestration of these self-reactive B cells within the marginal zone
of the spleen is one of the mechanisms of maintaining self-tolerance [75].
Several clinical studies found increased BAFF levels in patients with SS, witch correlated
with the circulating levels of autoantibodies (rheumatoid factor - RF, anti-Ro and anti-La), Ig
G levels and histological lymphocytic scores [76]. BAFF levels are decreased following
therapy with hydroxychloroquine, and increased after the treatment with rituximab [77, 78].
These observations lead to the use of biologic therapies targeting BAFF in SS. Two
biologic agents have been trialed in SS: a mAb, belimumab, targeting BLyS/BAFF, and a
recombinant fusion protein, atacicept, which blocks the activity of both BLyS/BAFF and a
proliferation-inducing ligand (APRIL) (another cytokine that is important for B cell activation
and differentiation). The Food and Drug Administration (FDA) approved belimumab for SLE
patients with skin and joint involvement.
The BELISS study is an open-label, phase II study, which included 30 patients and tested
for the first time the efficacy of belimumab in SS. The study achieved its primary end-point,
defined as significant VAS changes in dryness, fatigue, pain, activity and changes in B cell
activation biomarkers. This outcome was met in 60% of the treated patients [79]. In addition,
statistically significant improvement was also reported in the ESSDAI and ESSPRI indices,
along with improvements in mean dryness, fatigue and pain scores as assessed separately by
VAS scores [80]. Despite this, no objective increase in the salivary and lacrimal flows was
noted. The treatment was generally well tolerated. The dose used was 10 mg/kg belimumab
intravenously, at weeks 0, 2 and 4 and then every 4 weeks. If patients achieved response at
week 28, or if the clinician and the patient agreed to continue the study in the absence of side
effects, treatment was continued for 1 year, and the results reported separately [80]. A large
proportion of the initial responders at week 28, also responded at week 52 (87.5%). However,
no improvement in the histological scores was also reported at week 52 [80]. The
improvement of the glandular, lymphadenopathy and articular domains, as assessed by
ESSDAI score, was particularly significant.
Despite the theoretical potential of atacicept to provide therapeutic benefit in patients
with SS, this treatment has not been tested in these patients. The treatment achieved
promising results in early phase clinical trials in SLE [81] and RA [82]. Based on their
mechanism of action correlated with the autoimmune abnormalities characteristic for SS, it
can be hypothesised that therapies targeting BLyS/BAFF alone, or in combination with B cell
depletion approaches, may be a treatment option for SS. There is one case-report in the
literature suggesting that this may be a suitable approach for selected cases [83], although
safety and efficacy of this sequential biologic regime needs to be tested in larger clinical
trials.
T CELL TARGETED THERAPIES

T cells were initially identified as the predominant cells within the salivary gland
infiltrates and have been shown to be involved in the generation and perpetuation of
inflammatory infiltrates in salivary glands in SS [84, 85]. Early studies found that T cell
infiltration of the salivary glands was dominated by CD4 expressing cells in the early phase
of the disease [86], and B cell infiltration in the later stages of the disease [87]. Further
correlation with the cytokine expression in saliva proposed the hypothesis of a dynamic
balance between CD4 and CD8 positive T cells, with a predominance of Th1 phenotype in
patients with increased histological scores and presence of serum autoantibodies [88]. Recent
identification of high levels of IL17 in saliva, along with the increased expression of IL17A,
IL23 and IL22 supported the hypothesis of Th17 polarization within the salivary gland tissue
of patients with SS triggered by local exposure to transforming growth factor (TGF), IL23,
IL21, and IL6 [84].
Adhesion molecules also play an important role in the T cell mediated autoimmune
process characterizing SS. They regulate leucocyte circulation, migration throughout
endothelial cells and T cell stimulation. T cell immune responses involve the formation of a
special junction between T cell and the antigen-presenting cell mediated by the presence of
adhesion molecules. Several adhesion molecules, such intercellular adhesion molecule-1
(ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) have increased expression in the
salivary tissue samples from patients with SS and their presence correlated with the
histological scores, suggesting a possible role in T cell recruitment and localised vasculitic
lesions [89].
After the initiation of the abnormal immune process in SS, it is hypothesised that
autoantigens are expressed on the surface of endothelial cells, triggering T cell migration to
exocrine tissue and activation in situ, along with increased B cells autoantibody production
locally [90]. Recent therapeutic approaches included efforts to develop new drugs targeting
adhesion molecules.
As there are clinical and immunological similarities between RA and SS, the available T
cell targeted biologic therapy for RA, abatacept, was also trialed in SS. Abatacept is a soluble
fusion protein approved for RA, that consists of the extracellular domain of human cytotoxic
T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified fragment crystallisable
(Fc) portion of human IgG1 [91]. It blocks CD80 and CD86 ligands and interferes with
activation of T lymphocytes. Recent evidence suggests that CTL4 contributes to homeostatic
control of T CD4 proliferation and down-regulates T cell activation. CTL-4 haplotypes are
more frequently identified in SS patients than in controls according to some studies [92], but
no according to others [93].
The first pilot study of abatacept in SS patients was published in November 2013.
Despite the small number of patients (n = 11) and the short duration of treatment (24 weeks),
a significant reduction in glandular inflammation and an increase of saliva production
(influenced by disease duration) were found [94]. Another open-label, proof of concept
prospective, single-centre, pilot study with similar design, recruited 15 patients with SS and
showed improvement in the disease activity, laboratory parameters, fatigue and quality of life
after 8 doses of intravenously administered abatacept at 10 mg/kc body weight [95].
Although these two studies have shown encouraging data, it is notable that in the first
study, none of the patients recruited had extra-glandular manifestations [96]. Similar finding
were recently reported by another study, an open-label, one year prospective clinical trial in
patients with RA and secondary SS, which included 32 patients [97]. The treatment improved
tear and saliva volumes and disease activity parameters and was reasonably well tolerated.
ADHESION MOLECULE TARGETED THERAPIES

Therapies targeting T cell activation indirectly (through interaction with adhesion
molecules) also excited interest due to their proven efficacy in other autoimmune diseases but
have not been trialed to date in SS. However, the general expert opinion is that they might be
a suitable therapeutic option for SS as well [96, 98-99].
Alefacept is a biologic drug that targets T cell binding CD2 that blocks the lymphocyte
function associated antigen - 3 (LFA-3)/CD2 interaction (necessary for proliferation and
activation of T lymphocytes). Widely used in psoriasis [100], it has not yet been tested in SS,
SLE or RA. Although having demonstrated long term remission in psoriasis, there is a
concern about alefacept causing significant T cell depletion [101].
Efalizumab was a humanised mAb initially approved for psoriasis, targeting the CD11a
component of leukocyte function-associated antigen-1 (LFA-1), preventing its binding to
intercellular adhesion molecules. It interferes with T cell activation, reactivation and

migration to exocrine glands, and inhibits leukocyte extravasation [102]. A RCT using
efalizumab in SS suggested a potential risk of developing severe infections, such as
progressive multifocal leukoencephalopathy; therefore the treatment was withdrawn due to
safety issues [98].
The interest in blocking T cell activation in SS is justified by the histological findings
that support the role of T cell activation in perpetuating the glandular involvement. However,
treatments targeting CD3 were associated with significant infusion reactions and side-effects,
despite signals of clinical efficacy. For example, otelixizumab (anti CD3 antibody) have
demonstrated preservation of beta cell function in early diabetes [103] and has also been
tested in patients with psoriasis [104]. No studies assessed its efficacy in SS patients.
ANTI-TNF TARGETED THERAPIES

Both the innate and adaptive immune systems have been shown to have a major role in
the pathogenesis of SS. The TNF family of cytokines is considered to act as a bridge between
the innate and autoimmune B cell activation in SS, and the disease is characterised by a
dysregulation of the cytokine network [105], with overexpression of pro-inflammatory
cytokines and down regulation of anti-inflammatory cytokines [27, 106]. Increased
concentration of TNF has been detected in glandular lesions of patients with SS [27, 107].
Glandular T cells secrete TNF, which is thought to have a role in the promotion of the
apoptosis of glandular epithelial cells, which was shown to be Fas mediated [43, 108].
Infliximab, a chimeric mAb directed against TNF was the first anti-TNF therapy that
was assessed for efficacy in SS. Even though the first open-label pilot trial conducted in 16
patients achieved a statistical improvement in clinical and functional parameters 8 weeks after
the third infliximab infusion, this response was not replicated in longer studies. After one year
of follow up [109, 110], a large double-blind placebo-controlled RCT failed to demonstrate
any beneficial effect [111]. Subsequently, the study which had reported benefit from
treatment with infliximab was retracted [112].
Etanercept, a fusion protein combining the TNF receptor with the constant end of the
IgG1 antibody, was also tested in two pilot trials in patients with SS. The treatment failed to
show any improvement in the clinical symptoms or salivary gland histological scores [113-
114]. It was hypothesised that the drug did not achieve the therapeutic concentration in the
salivary glands, or that the results were hampered by the presence of significant glandular
damage due to ongoing inflammation associated with fibrosis. These could have been
responsible for the treatment failure [114]; however, data that are more recent showed that
etanercept exacerbated the IFN pathway activation and BAFF production in patients with SS
treated with this drug [115].
IFN AND ANTI-IFN TARGETED THERAPIES

IFN proteins have potent immunomodulation properties and antiviral activity. The gene
expression profiling of biologic samples of patients with SS has identified signatures of IFN
pathway activation in peripheral blood leucocytes and in minor salivary gland biopsies [116].
Despite the apparent contradiction between IFN signature involvement in the pathogenesis of
SS and its therapeutic role and association with disease activity [117], there is evidence that
low doses of oral IFN increase the unstimulated salivary output [118]. It is also hypothesised
that IFN administered via the oro-mucosal route may increase saliva secretion by up-
regulation of aquaporin 5 transcription in the parotid gland epithelium [119]. The first study
using low doses of oral IFN for SS treatment was published in 1996 and demonstrated
effectiveness in controlling symptoms or dryness and improvement of the salivary output
[118]. Two other early phase RCT succeeded in showing improvement of the sicca symptoms
related to SS [120, 121]. Ulterior, the results of the phase II and III clinical trials were re-
analysed together, and data from 497 SS patients were published, concluding that overall no
significant differences in oral dryness or in stimulated salivary flow in the treated group have
been observed [122]. However, this cumulative analysis found a significant increase in
unstimulated salivary flow between the treated and placebo groups [122]. It remains
uncertain, whether IFN agonists have a role in the therapeutic armamentarium of SS.
Based on the previously described pro-inflammatory role of IFN, we hypothesize that
the two available monoclonal antibodies directed against IFN (rontalizumab and
sifalimumab), which are currently under investigation for the treatment of SLE and psoriasis,
might be worth trying in patients with SS [96].
THERAPIES TARGETING DIFFERENT INTERLEUKINS

Serum IL6 is increased in serum, saliva and tears of patients with SS. IL6 plays a pivotal
role in B cell activation, in T cell differentiation, and is linked to fatigue. Tocilizumab is a
mAb that blocks the IL6 receptor. A case report suggested beneficial effect of this treatment
in a case with neuromyelitis optica spectrum disorder complicated with SS [123]. Currently,
there is an ongoing phase III RCTs led by French investigators, comparing tocilizumab with
placebo, which is planned to be completed by January 2017 (NCT01782235).
NON-SPECIFIC BIOLOGIC THERAPIES

The role of intravenous immunoglobulins (IVIg) in the therapeutic armamentarium of SS
also merits attention. An open label study of 19 patients with pSS reported improvement of
sensory-motor neuropathy in 42% of patients [124]. Similar positive results were report by
other small studies of patients with SS and painful sensory neuropathy [125].
The IVIg treatment was also proven effective for treating foetal congenital heart block
associated with the presence of maternal anti Ro antibodies [126] and severe
thrombocytopenia associated with SS [127].
OTHER POTENTIAL BIOLOGIC THERAPIES

(NOT INVESTIGATED IN SS)
Increased levels of IL1 were identified in animal models of SS, being produced by both
infiltrating immune cells and exocrine gland cells [128, 129]. There is also evidence that IL1
triggers the apoptosis of the epithelial cells and IL1 receptor antagonist in decreased in the
saliva of patients with SS [130]. A recent RCT showed efficacy of IL1 inhibition in
improving fatigue associated with SS [131]. It was hypothesised that local administration of
therapies targeting IL1 could be beneficial [132].
The role of IL10 and IL12 in triggering salivary autoimmune abnormalities of animal
models of SS was established many years ago [133]. T cell clones from salivary biopsies of
patients with SS expressed increased levels of IL10 [134], and it was also found increased in
serum samples from patients with SS in association with IL10 polymorphism, positive
serology and glandular histological changes [135]. Several studies reported a decrease in the
Tregs [136, 137], and increase expression of Th17 cells in the salivary glands in a mouse
model [138] and in the serum samples from patients with SS [139]. Despite evidence of
possible involvement of these cytokines in the pathogenesis of SS, no biologic treatments
targeting these molecules have been investigated to date.
The up-regulation of TLRs, which are recognised as implicated in initiation of both
the innate and adaptive immune response, is believed to contribute to salivary gland
inflammation. The overexpression of TLR7 and TLR9 was also identified in the salivary
glands of patients with SS and might have a role in the aberrant B cell differentiation [140].
There are potential therapeutic agents targeting TLR7 currently under investigation in lupus.
Chemokines are responsible for directing lymphocyte trafficking and formation of
ectopic lymphoid structures [141]. These structures were identified in salivary gland biopsies
from patients with SS and it is hypothesised that their formation is generated by autoreactive
B cells triggered by viral infections [142]. Their accumulation and differentiation is supported
by the local presence of different chemokines, such as CXCL-12 and 13 [141]. Further work
is needed to define the lymphocyte regulation role of these chemokines, and to date, no
treatment targeting these molecules was studied in SS.
There are some other less-investigated molecules, which are associated with SS
manifestations, and have a theoretic therapeutic potential. Serum Fms-like tyrosine kinase 3
ligand is a transmembrane protein with role in stimulating the growth of progenitor cells in
the bone marrow and blood, which was identified as a potential biologic marker of lymphoma
secondary to SS [143]. CD6 expression is increased on the surface of B and T cells in salivary
gland biopsies of patients with SS and might facilitate the cellular infiltration of target tissues
[144] (e.g., itolizumab, a mAb targeting CD6 could have potential therapeutic value as an
inhibitor of the immune activation). Lymphotoxin receptor blockage in the non-obese mice
model of SS was associated with decrease in the size and number of glandular focal infiltrates
[145, 146], suggesting that this could be another possible molecular target for SS treatment.
Table 1. Evidence of efficacy of different biologic agents based on the disease phenotype, using the level of evidence classification
(Oxford Centre of Evidence-based Medicine)
Treatments Ocular dryness Oral dryness Fatigue Arthralgia Patient Physician ESSDAI ESSPRI Biomarkers/
VAS VAS histological scores
Rituximab Yes Yes Yes Yes Yes Yes Yes Yes
(I b) (I b) (I b) (I b) (I b) (I b) (I b) (I b)
Epratuzumab Yes (composite Yes (composite score) Yes Yes Yes Yes
score) (composite score)
(2b)
(2b) (2b) (2b) (2b) (2b)
Belimumab Yes Yes Yes Yes Yes
(VAS assessment) (VAS assessment) (VAS
No assessment)
(objective No
measurement) (objective measurement)
(2b) (2b) (2b) (2b) (2b)
Abatacept Yes Yes Yes Yes Yes Yes Yes Yes Yes
(objective (objective measurement)
measurement)
(2b) (2b) (2b) (2b) (2b) (2b) (2b) (2b) (2b)
Infliximab No No No No (tender and No No
(1b) (1b) (1b) swollen joints) (1b) (1b)
(1b)
Etanercept No No Yes
(objective (objective measurement (ESR only)
measurement and and VAS) No (histological
VAS) scores)
(1b) (1b) (1b)
Oral Interferon Yes
(VAS dryness and stimulated
saliva)
(1b)
No
(VAS dryness and stimulated
saliva)
Yes (unstimulated saliva) (1a)
Legend: ESR erythrocyte sedimentation rate; ESSDAI EULAR Sjgrens syndrome disease activity index; ESSPRI EULAR Sjgrens syndrome patient reported index, VAS visual
analogue scale.
We summarise in Table 1 the evidence of efficacy of different biologic agents based on

the disease phenotype, using the level of evidence classification (Oxford Centre of Evidence-
based Medicine):
1a. Systematic reviews (with homogeneity) of randomised controlled trials

1b. Individual randomised controlled trials (with narrow confidence interval)
1c. All or none randomised controlled trials
2a. Systematic reviews (with homogeneity) of cohort studies
2b. Individual cohort study or low quality randomised controlled trials (e.g., <80% follow-up)
2c. Outcomes Research; ecological studies
3a. Systematic review (with homogeneity) of case-control studies
3b. Individual case-control study
4. Case-series (and poor quality cohort and case-control studies)
5. Expert opinion without explicit critical appraisal, or based on physiology, bench research or
first principles.
CONCLUSION
Despite the large number of biologic therapies potentially useful for treating patients with
SS, there are no many effective treatments available for the large majority of patients. All the
biologic treatments discussed above are experimental or only used off-license for selected
cases. Apart from the increased cost of biologic agents, another challenge to implement these
therapies in the current practice is posed by the difficulty to predict their efficacy solely based
on the immune abnormalities associated with a certain disease phenotype. Research efforts
have been invested in defining methods to stratify patients in term of prediction of response to
certain therapies. B cell and IFN pathway related gene expression profile was studied as a
potential method to predict SS patients response to rituximab therapy [147]. Even if several
genes were different between the responders and non-responders to rituximab treatment,
further validation of the findings in clinical trials is required.
There is also a big difference between the characteristic of the patient population
included in clinical trials and patients seen in the routine clinics. The patients recruited in
clinical trials tend to have a better characterised disease, with shorter duration and no
significant co-morbidities; therefore, they have increased likelihood to report improvement
with different therapies. In addition, even if some biologic treatments failed to achieve the
primary endpoint in clinical trials (e.g., rituximab), they can still be effective for selected
categories of patients.
Pijpe et al. hypothesised that biologic therapeutic interventions are more effective in
patients with early disease compared to those with longer disease duration [148]. They also
found that the improvement of symptoms of dryness is more likely to occur in patients with
residual salivary gland function rather than in those with impaired gland function [59]. It
seems reasonable to hypothesize that patients with extra-glandular involvement and early and
active disease would be the best candidates to receive biologic treatments.
The majority of therapeutic targets are proposed based on the molecular and cellular
biology studies of the disease pathogenesis; however, despite the fact that there was evidence
of increased TNF production in saliva collected from patients with SS, and the TNF gene
polymorphism was associated with SS [149], anti-TNF therapies were not particularly
effective.
Among the new potential biologic targets, IL6, IL17 and BAFF are probably the most
promising, as there is clear evidence of their likely role in the pathogenesis of the disease.
These new and expensive drugs have demonstrated a wide range of different outcomes in
clinical trials and practice (ranging from poor-to-moderate efficacy), and all have potential
associated toxicity.
Unfortunately, the majority of clinical trials of biologic therapies in SS do not usually
include patients with significant systemic/extra-glandular disease. It is difficult to draw
conclusions for their efficacy on this small, but important, subset of patients. The authors feel
that patients with extra-glandular manifestations should have priority for access to biologic
therapies, as their disease seem to respond better and the severity of their manifestation can
also justify the cost of biologic agents.
The use of biologic treatments in SS is potentially associated with significant health
implications. Several aspects should be taken into consideration to ensure adequate access
and use of biologic therapies in the future:
1. The selection of patients with clinical features likely to respond to biologic therapy
should be rigorous;
2. The extra-glandular manifestations of SS should have priority for access to biologic
treatment as they could evolve rapidly and be associated with significant morbidity
and mortality.
3. It is reasonable to expect that patients would be initially treated with conventional
DMARD therapy before being prescribed biologic therapy, unless there are clinical
reasons to necessitate rapid therapeutic intervention using a biologic agent (such as
central nervous system involvement, vasculitis, B cell lymphomatosis secondary to
SS, etc.)
4. The evidence of irreversible damage already caused by longstanding disease and
unlikely to be influenced by any therapy will preclude the use of expensive biologic
agents.
The prescription of biologic treatment in SS is likely to be restricted until we have more

re-assurance from further ongoing clinical trials that they can provide benefits that other,
much cheaper, conventional drugs, cannot achieve. Ideal RCTs will probably combine
different therapeutic targets (such as B cell depletion with anti BAFF therapy), stratify
patients based on their phenotype (early vs. longstanding disease) and gene profiling (IFN
signature associated with prediction of better response to rituximab therapy), and address
clinical outcomes important for the quality of life of SS patients.
ACKNOWLEDGMENTS
The authors are very grateful to Dr. Nurhan Sutcliffe, PhD, Consultant Rheumatologist,
Department of Rheumatology, Barts Health NHS Trust for reviewing this chapter (email:
nurhan.sutcliffe@bartshealth.nhs.uk.
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Chapter 5
BIOLOGIC THERAPIES IN SYSTEMIC SCLEROSIS
Svetlana I. Nihtyanova, MD
and Christopher P. Denton, PhD FRCP
Centre for Rheumatology and Connective Tissue Disease,
UCL Medical School, Royal Free Campus, London, UK
ABSTRACT
Systemic sclerosis (SSc) is a rare connective tissue disease. Patients can present with
a different combination of organ complications and can have varying disease severity and
rates of progression. This poses a challenge to researchers interested in evaluating
efficacy of therapies as studies usually aim at recruiting homogenous cohorts. So far, no
treatment has been convincingly shown to modify disease course and outcome, although
there have been a number of controlled trials, demonstrating some effect of wide-
spectrum immunosuppressant agents on skin and lung disease. As understanding of
disease pathogenesis is broadening, exploration of therapies, targeting specific molecular
pathways or cell types that play a role in the progression of the disease becomes possible.
Although biologic therapies have transformed management of many autoimmune
rheumatic conditions, their efficacy in treatment of SSc has so far been more limited.
This likely reflects the pathophysiological complexity of the disease and the challenges of
trial design, posed by the conditions rarity, slow disease course and wide clinical
variability. The number of randomised controlled trials in SSc is comparatively small and
short trial duration and paucity of validated end-points make results difficult to interpret.
Nevertheless, new treatment options are being explored and improved knowledge about
the disease has led to better disease monitoring, earlier detection of organ complication
and resulting overall better survival among patients with the more severe diffuse subset
of SSc.
Keywords: systemic sclerosis, biologic treatment, modified Rodnan skin score, pulmonary
fibrosis, rituximab, alemtuzumab, tocilizumab, abatacept, interferons, anti-thymocyte
therapy, IVIg, anti TFG-
Correspondence to: Prof. Christopher Denton, Centre for Rheumatology and Connective Tissue Disease, UCL
Medical School, Royal Free Campus, London, UK, email: c.denton@ucl.ac.uk
84 Svetlana I. Nihtyanova and Christopher P. Denton
INTRODUCTION
Systemic sclerosis (SSc) is a rare connective tissue disease with prevalence of about
1/10000 [1-4] and it has the highest disease-related mortality rates of all connective tissue
diseases. According to the currently used classification of SSc there are two major subsets of
the disease, based on the extent of skin involvement [5, 6]. Patients with the diffuse cutaneous
subset (dcSSc) develop skin thickness over both distal and proximal parts of the body, while
those with the limited cutaneous subset (lcSSc) are generally less severely affected in terms of
skin involvement, which does not spread proximally to the elbows and knees. The natural
disease course and the subtle differences between the two subsets need to be taken into
consideration when designing clinical trials of drug therapies for SSc.
Skin sclerosis is a hallmark feature of SSc and according to the new American College of
Rheumatology (ACR) / European League against Rheumatism (EULAR) classification
criteria, presence of thick skin proximal to the metacarpophalangeal joints alone is sufficient
for the diagnosis of SSc [7]. In terms of skin disease, patients with lcSSc often have only
finger involvement (sclerodactyly), which does not change much during the disease course
[8]. On the other hand, skin involvement in dcSSc patients is much more severe and wide-
spread. Thickness worsens rapidly over the first years of disease, on average reaching a peak
at around 3 years from disease onset and gradually softens in about 80% of the patients
thereafter [9]. Although a degree of skin thickness normally persists in the later stages of
disease, in many patients this is confined only to the distal parts of the arms and legs and to
the face. In late stage SSc, skin thickness changes very little and the great majority of cases
present with skin stability. Modified Rodnan skin score (mRss) is a validated tool for
assessing skin thickness. It uses 17 body sites, scoring skin thickness on a scale of 0-3, where
0 is given to normal skin and 3 is thickened skin, impossible to roll into a skin fold. The most
used primary endpoint in the great majority of studies exploring treatments in SSc is the
mRss, and this may be one of the reasons for the small number of positive trials. The natural
history of skin involvement makes it very difficult to assess treatment effect, especially in
uncontrolled studies. Comparison between mRss at baseline and after a period of treatment is
very likely to be influenced by the tendency for skin to improve spontaneously. Even in
controlled trials, it is often difficult to judge to what extent skin improvement is due to the
treatment. In addition, changes in skin score are relatively slow and often improvement takes
several years. For that reason, drug trials with less than a year follow-up are often not
powered to detect treatment benefit to skin, even if there is such.
Organ complications can develop in both subsets of SSc and mild skin disease or
improvement in skin thickness does not preclude development of severe organ complications
[9, 10]. Although some organ complications are less frequent in lcSSc, they still develop and
can be severe. Lung involvement is the most frequent disease-related cause of death in SSc
patients. There are two lung-based pathologies that scleroderma patients develop - pulmonary
fibrosis (PF) and pulmonary hypertension (PH). While PF normally develops early in the
disease and the majority of patients who develop clinically significant PF reach this endpoint
within five years of disease onset, PH usually develops later in the disease course and has a
relatively constant rate of annual incidence of 1-2% [10]. In addition clinically significant PF
affects dcSSc patients about twice as frequently compared to lcSSc patients, with 5 and 10
year cumulative incidence of 34% and 45% among dcSSc and 16% and 21% among lcSSc
Biologic Therapies in Systemic Sclerosis 85
patients, respectively. On the other hand, there is no difference in incidence of PH between

the two subsets - 5 and 10 year cumulative incidence of 4% and 13% among those with
diffuse and 5% and 15% among those with limited disease. PF and PH can coexist
independently or PH can develop secondary to underlying extensive PF.
Other organ problems include scleroderma renal crisis (SRC), which is a rarer
complication, affecting about 12% of dcSSc and 4% of lcSSc patients. In the majority of
patients who develop SRC, it is either a presenting symptom or develops within 3 years from
disease onset. Cardiac involvement in SSc is still not well understood and clinically
significant cardiac disease develops only in a very small proportion of patients (less than 5%)
and has been described both early and late in the disease. Although very rarely life-
threatening, gastro-intestinal involvement is almost universal among SSc patients (affecting
over 90%) and can include oesophageal, small and large bowel dysfunction. Although not
life-threatening, certain SSc-related morbidities, such as digital ulceration, calcinosis or ano-
rectal disease, affect a large proportion of patients and have significant impact on quality of
life.
Patients can present with a different combination of organ complications and can have
varying disease severity and rates of progression. This poses a challenge to researchers
interested in evaluating efficacy of therapies as studies usually aim at recruiting homogenous
cohorts. On one hand, the disease variability makes assessment of effect difficult and
recruitment of homogenous population challenging, while on the other, it is difficult to
generalise findings to the whole SSc population, as the studies only include patients with very
specific characteristics. Skin thickness improvement may develop even without treatment and
is therefore not an ideal primary endpoint in clinical trials. PF in general is irreversible,
therefore studies, assessing treatments for PF should be powered to detect small changes in
pulmonary function, which may not be clinically significant.
So far, no treatment has been convincingly shown to modify disease course and outcome,
although there have been a number of controlled trials, demonstrating some effect of broad-
spectrum immunosuppressant agents on skin and lung disease. Two placebo-controlled trials
investigated treatment effect of cyclophosphamide (CYC) given intravenously or orally for
treatment of patients with PF [11-13]. Both showed borderline significant difference in forced
vital capacity (FVC), favouring CYC, although the absolute changes were small and
arguably, not clinically significant. Preliminary analysis of the Scleroderma Lung Study II
was also recently presented, demonstrating equivalence between mycophenolate mofetil
(MMF) and CYC in their effect on skin and lung function with small degree of improvement
in mRss and FVC in patients from both treatment arms at 24 months [14]. MMF was much
better tolerated, with significantly greater proportion of CYC-treated patients withdrawing
from the study. Methotrexate (MTX) is another disease-modifying drug that is a mainstay in
current SSc therapy, based on two randomised, placebo-controlled trials providing some weak
evidence in favour of MTX for treatment of skin disease [15, 16]. In recent years, evidence
supporting the use of high dose immunosuppression followed by autologous haematopoietic
stem cell transplantation (HSCT) for treatment of severe dcSSc also became available. Two
controlled trials provide data on the efficacy of HSCT use in SSc, but also highlight the
substantial early treatment-related mortality, associated with the procedure [17, 18]. Careful
consideration should be given to eligibility of patients for this treatment, taking into account
the high mortality among those with renal or cardiac involvement [18-21]. Tyrosine kinase
inhibitors focused the interest of researchers, with promising preclinical data. Unfortunately,
the subsequent randomised, placebo-controlled clinical trials of imatinib in SSc showed no

benefit from treatment. In addition, there was poor tolerability of the active drug, with one of
the trials being discontinued before completion due to high rates of treatment-related adverse
events. Those included most prominently peripheral oedema and gastro-intestinal symptoms,
which necessitated treatment at a lower than the target dose [22, 23].
In 2009, the EULAR Scleroderma Trials and Research group (EUSTAR) published
recommendations for treatment of SSc, based on the available evidence at the time [24].
Those included MTX for treatment of skin involvement and CYC for treatment of SSc-PF. As
described above, several other treatments have emerged since, although the strength of
evidence varies and management of SSc remains a challenge. Researchers more often begin
to focus on disease-specific molecular pathways and biological therapies are starting to play a
more prominent role in the disease treatment armamentarium [25].
PATHOGENESIS OF SYSTEMIC SCLEROSIS

SSc is a condition with complex pathogenesis, many aspects of which remain unclear.
There are three pathophysiological processes involved in the development of SSc -
autoimmune inflammation, vasculopathy and tissue fibrosis [26]. There is a great variability
in clinical phenotype and most often patients present with both vascular complications (digital
ulcerations, pulmonary vasculopathy or kidney involvement with hypertensive renal crisis)
and features of tissue fibrosis, such as skin fibrotic changes or interstitial lung disease (ILD).
It is unclear which the leading process is and more recently authors stipulate that all three
facets of the disease develop concurrently. SSc etiology is unknown but published literature
suggests that a combination of genetic predisposition and a trigger event, which may include
environmental exposure, with chemical or infective agents, or another pathological
abnormality, such as an endocrine or malignant process, may initiate the disease.
Combination of autoimmunity and vascular damage are considered central in the
activation of fibroblasts, their differentiation into myofibroblasts and the increased production
of extra-cellular matrix molecules and the resulting tissue fibrosis. Functional and structural
vasculopathy develop very early and often symptoms of Raynauds phenomenon and
abnormalities of the nailfold capillaries precede the onset of skin and organ disease by months
or even years. Among a wide range of vasoactive substances, endothelins (ET) play a
prominent role in pathogenesis through their potent vasoconstrictive and pro-fibrotic
qualities. In addition, excessive production of reactive oxygen species, which is increased in
SSc, leads to endothelial damage and impaired vasculogenesis. A change in the balance
between the ET pathway and vasodilating pathways - nitric oxide (NO) and prostacylin based,
is considered to result in SSc-related microvascular dysfunction. This provides basis for the
current advanced therapies for both digital and pulmonary vasculopathy, including
prostanoids, such as epoprostenol, treprostinil and iloprost, ET-1 receptor antagonists
(bosentan and ambrisentan), and NO pathway stimulating therapies (sildenafil, tadalafil and
riociguat).
Autoimmune inflammatory processes are also major contributors in SSc pathogenesis,
particularly in the early stages of disease. This is evidenced by the presence of auto-
antibodies against nuclear antigens in the serum of the vast majority of scleroderma patients.
The role of auto-antibodies is still unclear although more evidence for their direct role in SSc
pathogenesis emerges [27]. Studies have demonstrated that higher serum levels of anti-
topoisomerase I (Scl70) antibody correlate well with disease severity and extent of skin
involvement [28]. Immune cells also play a major role and T and B lymphocytes are routinely
observed in affected skin biopsies of patients with early disease. The role of B cells has been
demonstrated by many authors, showing B cell activation with overexpression of CD19 with
expansion of the nave B cells and proportionately reduced, but activated memory B cells [29,
30]. Apart from antibody secretion, B cells are also involved in production of pro-fibrotic
cytokines, such as interleukin (IL) 6 and transforming growth factor beta (TGF). They
interact with other inflammatory cells, including macrophages and T cells. T cell activation
also plays a role in the autoimmune processes that drive SSc and studies suggest that there is
an imbalance between the anti-fibrotic T helper (Th)17 and the pro-fibrotic Th2 T cell subsets
[31, 32].
Multiple cytokines and growth factors have also been implicated in SSc pathogenesis, in
particular those mediating development of tissue fibrosis. TGF has a prominent position,
through promoting the differentiation of fibroblasts into activated myofibroblasts, producing
extracellular matrix proteins, thereby leading to development of fibrotic tissue in multiple
organs, such as skin, lung, heart and kidneys. Similarly, IL6 causes immune cell activation
and proliferation and increased levels of IL6 have been demonstrated in patients with active
dcSSc, providing another potential treatment target [33]. Other cytokines, such as tumour
necrosis factors alpha (TNF) promote endothelial cell activation and leukocyte adhesion and
extravasation.
Legend: IL6 interleukin 6; TGF transforming growth factor beta.
Figure 1. Biological therapies targeting potential pathogenic pathways in systemic sclerosis. This figure
summarises the key cellular interactions implicated in the pathogenesis and progression of systemic
sclerosis, and highlights how candidate biological agents targeting cytokines, growth factors or cell
surface antigens may attenuate the disease. Many of the agents shown are under clinical evaluation for
skin or lung fibrosis in systemic sclerosis.
As understanding of disease pathogenesis is broadening, exploration of therapies,

targeting specific molecular pathways or cell types that play a role in the progression of the
disease becomes possible. Nevertheless, it is generally accepted that all three pathogenic
processes are important and a better understanding of their role and interaction is needed in
order to find appropriate treatment targets [34]. So far, biologic therapies that have been tried
in SSc patients have targeted mainly autoimmune inflammation and fibrosis (Figure 1).
B CELL/T CELL DIRECTED THERAPIES

Rituximab
B cell hyperactivity and dysregulation in SSc have been described by many authors.
Published studies demonstrate increase in nave B cells in SSc patients compared to healthy
controls, with reduced, but activated, memory B cells [29]. As a result, B cell depletion has
been proposed as a possible treatment strategy [35-39]. Rituximab is a monoclonal anti-CD20
antibody that over recent years emerged as a new potential therapeutic option for SSc.
Multiple case reports [40-45] and a number of retrospective cohort and prospective open-label
uncontrolled studies [46-58] examine its use in patients with SSc (Table 1). To date, there
have been no randomised controlled trials of rituximab treatment in SSc.
None of the studies have shown convincing evidence for treatment effect on skin
thickness. Although the majority of published studies report improvement in skin thickness
compared to baseline, this could easily be attributed to the natural history of the disease.
There has been only one controlled study, Daoussis et al. [59], and this did not show
significant difference in mRss between the active and control patients at the end of follow-up.
The evidence for efficacy of rituximab in treatment of SSc-ILD is somewhat stronger. In
an open-label, randomised, controlled study, Daoussis et al., compared 8 patients who had
rituximab treatment 6-monthly together with standard therapy to 6 patients who were treated
with standard therapy alone[59]. The authors report a significant improvement in FVC and
diffusing capacity for carbon monoxide (DLCO) in the actively treated group compared to
controls at 12 months of follow-up. In a further publication, they also reported the two-year
follow up of the rituximab-treated patients from this study, showing some further
improvement in pulmonary function compared to baseline [49].
In two retrospective cohort studies, Keir et al., described a total of 58 severe ILD
patients, treated with rituximab, a subgroup of those (41 patients) having connective tissue
disease (CTD)-associated ILD (9 of those with SSc) [52, 53]. All CTD-ILD patients had
severe disease, not responding to standard immunosuppressive treatment and showing a
decline in both FVC and DLCO prior to rituximab treatment. The authors described an
overall improvement in FVC and stabilisation in DLCO post treatment, suggesting that
rituximab could be a good rescue therapy in severe advanced cases, where standard
immunosuppressive treatments are ineffective. Those findings were also supported by another
smaller, uncontrolled study, showing improvement in FVC and DLCO over the first 12
months of treatment, followed by stabilisation over the second year of follow-up in 5 patients
with advanced SSc-PF, not responding to treatment with intravenous (IV) CYC [55, 56].
Based on the above evidence, rituximab is currently used in the context of SSc mainly as
treatment for ILD, unresponsive to conventional therapies (MMF and CYC) and for treatment
of inflammatory arthritis overlap, where TNF inhibitors may be contraindicated due to
potential association with development of new or worsening of existing PF.
Basiliximab
CD25 is the -chain of the IL2 receptor and is expressed on activated T and B
lymphocytes, which play a role in SSc pathogenesis. Studies have shown raised serum soluble
IL2 receptor levels in SSc patients. In addition, treatment with basiliximab, an anti-CD25
monoclonal antibody, has been shown to be effective in graft versus host disease.
After a case report suggested that basiliximab may have utility as a treatment for active
aggressive dcSSc, showing improvement in skin thickness, pulmonary function and digital
ulcers in a single patient treated with a combination of basiliximab, CYC and oral
Prednisolone, a small open-label study on 10 patients was performed. In this study, 20mg IV
basiliximab was given every 4 weeks together with conventional immunosuppressive
treatment (mainly IV CYC) for 6 months [60, 61]. Patients were followed with assessments
of mRss (for 68 weeks) and PFTs (for 44 weeks). In 3/10 patients there was disease
progression and subsequent treatment with HSCT and those were excluded from the final
analysis. Among the remaining 7 patients there was no significant change in FVC and DLCO
over the follow-up period, while there was some improvement in mRss at 68 weeks,
compared to baseline (26/51 vs. 11/51, p = 0.015). Half of the patients experienced drug-
related side effects and in one of those the reaction was severe (Table 2).
Alemtuzumab
Alemtuzumab is an anti-CD52 antibody. CD52 is expressed on the surface of B and T

lymphocytes and monocytes. A case report of a patient with vinyl chloride exposure related
dcSSc, who was treated with alemtuzumab, described rapid, sustained improvement in skin
thickness following administration of the drug [62].
Abatacept
Abatacept inhibits T cell activation through binding CD80 and CD86 on antigen-
presenting cells. It is licensed for use in rheumatoid arthritis (RA). To date, two studies
presenting case series and one double-blind, randomised, placebo-controlled trial exploring
the use of abatacept in SSc patients have been published [63-65] (Table 3). The results from
the cohort study from the EUSTAR network, presenting data from 12 patients with
SSc/arthritis or myositis overlap, demonstrated improvement in joint disease, but no change
in myositis, skin or pulmonary function after treatment for a minimum of 6 months [63]. A
smaller study of 4 patients with active dcSSc, unresponsive to conventional
immunosuppression showed improvement in mRss compared to baseline in all study subjects
[64]. Most recently, in a clinical trial Chakravarty et al., randomised 7 patients to abatacept
and 3 to placebo [65]. At the end of 24 weeks, there was a significant difference in mRss (10
units) between the actively-treated subjects and those on placebo in favour of abatacept. The
treatment was well-tolerated with no difference in the incidence of adverse events when
compared to placebo. As a result of the promising findings, a larger phase 2 randomised,
placebo-controlled trial - A Study of Subcutaneous Abatacept to Treat Diffuse Cutaneous
Systemic Sclerosis (ASSET), is ongoing.
Anti-Thymocyte Globulin
Anti-thymocyte globulin (ATG) is a polyclonal IgG, which is developed by immunising

animals with human T cells. Treatment with ATG causes T cell depletion and subsequent
change in the CD4:CD8 ratio with increase in suppressor T cells. In the 1980s and 1990s
several case reports suggested that ATG may be a potential treatment for patients with
aggressive dcSSc [66, 67]. Two open-label studies [68, 69] investigated the use of ATG for
induction of immunosuppression in patients with early dcSSc. Treatment was given at study
entry and patients were followed up for 12 months. In the study by Stratton et al. [69], ATG
treatment was followed by maintenance immunosuppressive therapy with oral MMF.
Assessment of changes in mRss at the end of follow-up showed improvement in mRss
compared to baseline in the study using maintenance immunosuppression, while there was no
sustained benefit for skin in the study using ATG alone. In both studies pulmonary function
remained unchanged. Both reported substantial proportions of the treated patients developing
adverse events, in particular serum sickness (5/13 and 1/10 respectively). The side effect
profile and the lack of sustained effect on skin limit the use of ATG in SSc treatment.
Nevertheless, it is routinely used as part of the conditioning stage of HSCT in SSc patients.
SPECIFIC CYTOKINE-DIRECTED THERAPIES

Anti-TGF
TGF is an important cytokine in the development of fibrotic tissues and has emerged as
a key factor in SSc pathogenesis, through activation of fibroblasts and stimulation of collagen
synthesis. There are three isoforms identified in humans (TGF1, 2 and 3). So far, two agents
inhibiting TGF have been studied in SSc (Table 4).
In a randomised, double-blind, placebo-controlled phase I/II study, 43 patients received
three different doses (0.5, 5 or 10 mg/kg) of metelimumab (CAT-192) or placebo on day 0
and weeks 6, 12 and 18 [70]. The treatment was safe and well tolerated with no drug-related
adverse events. Nevertheless, there was no evidence of treatment effect on skin thickness or
lung function.
More recently, fresolimumab, a human monoclonal antibody, binding all three TGF
isoforms was tested in an uncontrolled, open-label series of 15 patients with early dcSSc, who
were treated with either one 5 mg/kg or two 1 mg/kg doses of fresolimumab [71]. The
treatment was associated with rapid reduction in the levels of markers of fibrosis in skin.
There was similar initial improvement in mRss in both treatment groups, followed by skin
deterioration at the end of study follow-up.
Tocilizumab
IL6 overexpression has been demonstrated in patients with active dcSSc and inhibition of
IL6 trans-signalling pathway emerged as a viable treatment strategy [33]. IL6 receptor
blockade was shown to be beneficial for skin fibrosis in mouse models of SSc [72]. In
addition, serum IL6 levels have been demonstrated to predict deterioration of PF in SSc
patients [73].
Tocilizumab is a humanised monoclonal antibody, binding both the membrane-bound
and soluble IL6 receptors. Summary of published studies of treatment with tocilizumab in
SSc patients is presented in Table 5. A number of case reports suggested that tocilizumab
might be a potential treatment for SSc skin involvement, showing improvement in skin
thickness after treatment [74-76]. Another small cohort study explored its use for treatment of
SSc/arthritis overlap in 15 patients, demonstrating improvement in disease activity score, 28
joints (DAS28), but no effect on skin or pulmonary function [63]. Preliminary 24-week
results from one randomised, double-blind, placebo-controlled trial have been presented in an
abstract form [77]. The interim analysis did not show any significant difference in mRss
between the actively treated group and the placebo, although mean reduction in mRss and
proportion of patients showing improvement was slightly larger for the tocilizumab-treated
arm. The 48-week data from the trial provided some weak evidence for beneficial effect of
tocilizumab on skin in SSc, with treatment difference at 48 weeks favouring the active
treatment [78]. In addition, a significantly smaller number of patients on tocilizumab
experienced worsening in FVC compared to placebo. As a result of these findings, together
with an acceptable safety profile a confirmatory phase 3 clinical trial assessing benefit on skin
and other disease manifestations is underway.
Tumour Necrosis Factor (TNF) Inhibitors
TNF inhibitors have transformed the treatment of inflammatory arthropathies and have
successfully been used in other inflammatory conditions, such as Crohns disease. Although
very effective in suppressing autoimmune inflammation, the effects of TNF blockade on
fibrosis are unclear and the available evidence in the literature is contradicting [79, 80]. The
effectiveness of anti-TNF agents for treatment of arthritis overlap conditions provided the
initial rational for studying their effect in SSc patients, in particular, those in the early
inflammatory stage. The available evidence is based on retrospective case series and
prospective, open label, uncontrolled studies of infliximab and etanercept (Table 6).
Initially, etanercept was used for treatment of early dcSSc over 6 months in 10 patients,
demonstrating stability in lung function and stability or improvement in skin thickness at the
end of follow-up [81]. Two subsequent publications reported improvement in the symptoms
of inflammatory arthritis in patients with SSc/arthritis overlap [82, 83]. Another case series of
4 CTD-ILD patients (one with SSc), with deteriorating lung function were treated with
infliximab, resulting in stabilisation of the lung disease [84]. Based on those findings, an open
label, uncontrolled pilot study of 16 patients was set to investigate efficacy and safety of
Infliximab in early dcSSc [85]. This did not demonstrate any significant change in mRss over
the study period. As no other immunosuppressive agents were used in the study subjects, 7 of
them developed infusion reactions and 5 developed anti-infliximab antibodies.
EUSTAR performed a literature review and a Delphi exercise, including 79 centres.
Information on 65 SSc patients treated with anti-TNF agents from EUSTAR centres was
analysed, showing that response was mainly observed for symptoms of arthritis. The expert
recommendations based on the available data were that anti-TNF agents should be used either
for treatment of SSc/arthritis overlap syndromes or in the context of randomised controlled
trials [80].
More recently, a number of publications have suggested possible detrimental effect of
anti-TNF treatment on the lung with development of new onset or worsening of existing ILD
[86-92]. Together with the lack of evidence for effectiveness, this has restricted the utility of
anti-TNF agents in SSc to cases with predominant features of inflammatory arthritis overlap
and no evidence of ILD.
Interferons
Interferons have been shown to have anti-fibrotic action and two randomised controlled
trials were reported in the late 1990s. The interferon- trial was open-label, recruited 44
patients with relatively mild SSc (excluding truncal involvement), many of whom had late-
stage disease (disease duration of up to 34 years), who received either interferon or no
treatment [93]. The study analysis did not demonstrate any beneficial treatment effect on skin
thickness or organ-based complications at the end of follow-up.
Another trial investigated the effect of interferon in a randomised, double-blind,
placebo-controlled trial of early dcSSc patients [94]. Thirty-five subjects received either
active treatment or placebo on weekly basis. Although the trial was planned to continue for 12
months, a large number of withdrawals due to death, adverse events or disease progression
(11/19 from the active treatment arm and 3/16 from the placebo arm) led to an interim
analysis showing no benefit to skin disease with greater reduction in mRss among placebo-
treated patients. As a result, the trial was discontinued.
BROAD-SPECTRUM IMMUNE-MODULATORY THERAPIES

Intravenous Immunoglobulin (IVIg)
Human immunoglobulin is developed by pooling plasma obtained from a large number of

healthy individuals. It contains polyclonal IgG against both foreign and auto-antigens and has
immunomodulatory effect. Several open label studies and a retrospective cohort analysis have
suggested benefit for skin and joint disease in SSc patients treated with IVIg [95-98]. Very
recently, the results of a double-blind, placebo-controlled trial of 63 patients were published
[99]. This showed that at 12 weeks there was no significant difference in the changes of mRss
between the actively-treated patients and those on placebo. Follow-up after the completion of
the double-blind part of the study, where patients were re-treated suggested some long-term
benefit to skin with greater improvement in subjects who received additional IVIg doses.
Another recent open-label study of SSc patients receiving IVIg for treatment of overlap
myositis showed additional benefit for gastro-intestinal symptoms, with improvement in
gastro-oesophageal reflux frequency and intensity [100].
Tolerance to Human Type I Collagen
SSc patients have been shown to be reactive to type I collagen more frequently than
healthy subjects. The structures of human and bovine type I collagen are almost identical
(92% homology), which allowed for testing of oral bovine type I collagen for induction of
immune tolerance to human type I collagen. Initially, 17 patients with both disease subsets,
majority of which had disease duration greater than 3 years, received oral solubilised bovine
type I collagen for 12 months in an open-label study [101]. There was an overall
improvement in mRss, particularly among patients with the diffuse subset. In addition, the
study provided evidence for reduction in T cell immunity towards type I collagen. Treatment
was well-tolerated with no side effects. Subsequently, a larger placebo-controlled trial was
conducted in 168 dcSSc patients [102]. Analysis of the data from all patients showed no
significant difference in mRss change at 12 or 15 months from study entry between subjects
receiving type I collagen and those on placebo. Sub-analysis of early and late stage dcSSc
patients revealed that although there was no demonstrable effect on skin among the early
dcSSc subjects, those with late-stage disease, who receive type I collagen had greater
improvement in mRss at 12 months which continued after discontinuation of the treatment
and at 15 months the difference in mean mRss in the two groups was statistically significant,
favouring the active treatment. Possible explanations of the lack of effect in patients with
short disease duration are the general tendency for skin to soften early in the disease course
and the different role of T lymphocytes in the early and late stages of SSc.
Relaxin
Relaxin is a hormone secreted during pregnancy, which is involved in remodeling of the

uterus and leads to loosening of the pelvic ligaments before birth. It also has anti-
inflammatory and anti-fibrotic properties [103, 104]. There have been two randomised,
double-blind, placebo-controlled trials of relaxin for the treatment of early dcSSc [105].
Initially, thirty-six patients were randomised to receive one of either high or low doses of
relaxin (25 or 100 mg/kg/day), or placebo over 24 weeks. Interestingly, there was a
significant reduction in mRss in the low dose treatment arm compared to placebo, but no
significant difference between placebo-treated patients and those receiving the high dose of
relaxin. In a subsequent larger trial, 231 patients with early dcSSc were treated with 25 or 10
mg/kg/day of relaxin or placebo [106]. There was no difference in mRss between the two
treatment groups and the controls. In addition, after discontinuation of relaxin, there was a
significant increase in serum creatinine levels compared to baseline with development of
renal crisis in some of the patients.
Table 1. Studies assessing rituximab in systemic sclerosis
Reference Study design Number Treatment regimen Duration of Inclusion criteria Findings Safety profile
patients follow-up
Lafyatis open label, 15 Rituximab 1g, given 2 6-12 months dcSSc, <18 no significant change mRss 7 (46.7%) of the
et al., 2009 uncontrolled weeks apart months duration and SHAQ at 6 and 12 patients had infusion
[46] (no premedication) months; HRCT and PFTs reactions; 2 patients
at 6 months had infections; 1 SAE
- prostate cancer
(unrelated)
Bosello open label, 9 rituximab 1g and 100mg 6-36 months dcSSc, >10% significant improvement in No infections or
et al., 2010 uncontrolled methylprednisolone, given worsening of mRss, activity and severity infusion reactions;
[47] 2 weeks apart mRss after IV indices, HAQ and GH; no 1 SAE - occult breast
CYC change in PFTs cancer (unrelated)
Daoussis open label, 8 active, 6 rituximab 375 mg/m2, 4 12 months dcSSc, ILD, anti- significant improvement in 1 patient had an
et al., 2010 randomised, controls weekly infusions, at Scl70+ FVC and DLCO in infection
[59] controlled baseline and 6 months in rituximab group vs.
addition to standard controls; significant
therapy vs. standard reduction in mRss vs. BL
therapy alone in rituximab group; no
improvement in mRss vs.
control; significant
improvement in HAQ vs.
BL
Daoussis open label, 8 rituximab 375 mg/m2, 4 24 months dcSSc, ILD, significant improvement in 2 patient had an
et al., uncontrolled weekly infusions, at anti-Scl70+ FVC, DLCO and mRss vs. infections, 1 mild
2012* [49] baseline, 6, 12 BL infusion reaction
and 18 months
in addition to standard
therapy
Smith open label, 8 rituximab 1g and 100mg 24 weeks dcSSc, <4 years significant improvement in 2 SAEs - CABG and
et al., 2010 uncontrolled methyl-prednisolone, duration, mRss mRss vs. BL low grade fever with
[50] given 2 weeks apart 14 or disease hospitalisation
activity score 3
Reference Study Number Treatment regimen Duration Inclusion criteria Findings Safety profile
design patients of follow-
up
Smith et al., open label, 8 rituximab 1g and 100mg 24 months dcSSc, <4 years significant improvement in Several infections,
2013** [51] uncontrolled methylprednisolone, given duration, mRss mRss vs. BL; significant including 1 death from
2 weeks apart at BL and 26 14 or disease reduction in FVC vs. BL sepsis, considered
weeks activity score 3 probably unrelated to
treatment.
Moazedi-Fuerst open label, 5 3-monthly cycles of 12 months, anti-Scl-70 + improvement in FVC, N/K
et al. 2014 uncontrolled rituximab 500mg 24 months dcSSc and ILD, DLCO and mRss over 12
[109], Moazedi- not responding to months, followed by
Fuerst et al. IV CYC stability over 2nd year of
2015 [56] follow-up
Maslyanskiy open label, 5 rituximab 1g, 100mg 6 months progressive dcSSc improvement in arterial N/K
et al. 2014 [54] uncontrolled methylprednisolone and wall stiffness and mRss
500 mg IV CYC, given 2
weeks apart
Bosello open label, 20 rituximab 24 progressive dcSSc improvement in skin and 2 deaths, 1 infection,
et al., 2015 [48] uncontrolled 1g and 100 mg months FVC vs. BL 1 breast carcinoma.
methylprednisolone, given
2 weeks apart
Giuggioli case series 10 rituximab 18 SSc improvement in mRss at N/K
et al., 2015 [57] 1g and 100 mg months 6m in dcSSc; improvement
methylprednisolone, given in arthritis
2 weeks apart on 1 or more
occasions
Jordan et al., retrospective 63 various SSc improvement in mRss vs. 1 - Cardiac and renal
2015 [58] cohort BL and matched controls involvement; infections
in dcSSc; improved DLCO in 11/53, serum
and stable FVC vs. BL; sickness/hypersensitivity
decline in FVC and no reaction in 2/54 patients.
difference in DLCO vs.
matched controls;
Legend: * 2 year follow-up with further 2 treatment cycles of the active arm of Daoussis et al., 2010 study; ** 2 year follow-up of the subjects from Smith et al., 2010 study; BL -
baseline; CABG - coronary artery bypass graft; dcSSc -diffuse cutaneous systemic sclerosis; DLCO - carbon monoxide diffusion capacity; FVC - forced vital capacity;
HRCT - high-resolution computed tomography; ILD - interstitial lung disease; IV CYC - intravenous cyclophosphamide; mRss - modified Rodnan skin score; PFTs -
pulmonary function tests; SAE - serious adverse event; SHAQ - Scleroderma health assessment questionnaire.
Table 2. Studies assessing treatment with basiliximab in systemic sclerosis
Reference Study Number Treatment regimen Duration of Inclusion Findings Safety profile
design patients follow-up criteria
Scherer et al., case 1 IV CYC, prednisolone, 9 months Active improvement in skin, cardiac
2006 [61] report basiliximab aggressive and lung involvement
dcSSc
Becker case 10 6 courses of IV basiliximab 20 44 weeks dcSSc, <5 3 dropouts for progression of 4/10 patients -
et al., 2011 series mg 4 weekly, together with years duration disease; in the rest - transient nausea,
[60] standard treatment (IV CYC) improvement in mRss vs. erythema, fatigue
baseline; no change in PFTs and weakness;
1/10 - severe
reaction
Legend: dcSSc - diffuse cutaneous systemic sclerosis; IV - intravenous; IV CYC - intravenous cyclophosphamide; mRss - modified Rodnan skin score; PFTs -
pulmonary function tests.
.
Table 3. Studies assessing abatacept in systemic sclerosis
Reference Study Number Treatment regimen Duration of Inclusion criteria Findings Safety profile
design patients follow-up
Elhai et al., cohort study 12 abatacept 10 mg/kg/month 616.5 months SSc overlap skin/PFTs - unchanged; 1/12-headache;
2013 [63] & 3/12 Methotrexate (5/12-arthritis; improvement in DAS28; 3/12-infections
7/12-myopathy), no change in muscle
unresponsive to disease
DMARDS
de Paoli et al., case series 4 abatacept 500 mg or 750 mg <18 months dcSSc, unresponsive improvement in mRss vs. N/K
2014 [64] at weeks 0, 2, 4 and to conventional BL
monthly thereafter treatment
Chakravarty double-blind, 10 7/10 - abatacept 24 weeks dcSSc improvement in mRss vs. pruritus; infections
et al., 2015 randomised, 500 mg or 750 mg at day 1, placebo
[65] placebo- 15, 29, and every 28 days
controlled for a total of seven doses;
trial 3/10 - placebo
Legend: BL - baseline; DAS28 - disease activity score, 28 joints; DMARDS - disease-modifying anti-rheumatic drugs; dcSSc - diffuse cutaneous systemic sclerosis;
mRss - modified Rodnan skin score; N/K - not known; PFTs - pulmonary function tests; SSc - systemic sclerosis.
Table 4. Studies assessing anti-TGF therapies in systemic sclerosis
Reference Study design Number Treatment regimen Duration of Inclusion criteria Findings Safety
patients follow-up profile
Denton randomised, 43 either 0.5, 5 or 10 mg/kg 24 weeks dcSSc 18m duration, no effect on skin no drug-
et al., 2007 double-blind, metelimumab or placebo, on active severe skin thickness or lung related AEs
[70] placebo-controlled day 0, weeks 6, 12 disease function
and 18
Rice et al., case series 15 2 courses of 1 mg/kg 24 weeks dcSSc, no significant initial mRss no treatment-
2015 [71] fresolimumab (7/15 patients) lung involvement improvement related AEs
or one course of 5 mg/kg
fresolimumab (8/15 patients)
Legend: AEs - adverse events; dcSSc - diffuse cutaneous systemic sclerosis; mRss - modified Rodnan skin score.
Table 5. Studies assessing tocilizumab in systemic sclerosis
Reference Study design Number Treatment regimen Duration of Inclusion criteria Findings Safety profile
patients follow-up
Shima et al., case series 2 tocilizumab 8 mg/kg 6 months dcSSc improvement in mRss in none
2010 [74] monthly for 6 months both patients
Elhai et al., 2013 cohort study 15 tocilizumab 311.5 SSc arthritis, skin/PFTs - unchanged; 1/15 - nausea;
[63] 8 mg/kg/month and months unresponsive to improvement 1/15 -
8/15 methotrexate DMARDS in DAS28; abnormal liver
function
Saito et al., 2014 case report 1 tocilizumab 600 mg 9 months SSc/arthritis improvement in DAS28; none
[110] monthly and overlap no change in skin
methotrexate
6 mg weekly
Khanna et al., double-blind, 87 43/87 - tocilizumab 162 24 weeks active dcSSc 5 no significant change in infections
2014 [77] randomised, mg weekly; 44/87 - years skin
placebo- placebo
controlled trial
Fernandes das case series 3 tocilizumab 8 mg/kg 6 months refractory SSc improvement in mRss vs. none
Neves et al., monthly BL; at 9 months - 2/3 no
2015 [76] change and 1/3 -
deterioration in ILD
Shima et al., case report 1 tocilizumab 8 mg/kg 16 months dcSSc improvement in mRss and N/K
2015 [75] monthly joint contractures
Legend: BL - baseline; DAS28 - disease activity score, 28 joints; DMARDS - disease-modifying anti-rheumatic drugs; dcSSc - diffuse cutaneous systemic sclerosis; ILD
- interstitial lung disease; mRss - modified Rodnan skin score; N/K - not known; PFTs - pulmonary function tests; SSc - systemic sclerosis.
Table 6. Studies assessing anti-TNF agents in systemic sclerosis
Reference Study Number Treatment Duration of Inclusion criteria Findings Safety profile
design patients regimen follow-up
Ellman open label, 10 Etanercept 25 mg 6 months dcSSc <5 years mRss - 4/9 improved and minor injection
et al., uncontrolled twice a week 5/9 unchanged; site reactions
2000 [81] PFTs - unchanged
Bosello open label, 4 Methotrexate and 6 months SSc according to the improvement in DAS, N/K
et al., uncontrolled Infliximab (3 mg/kg) at ACR classification criteria; mRss and SHAQ
2005 [82] weeks 0, 2, 6 and 14, erosive polyarthritis,
followed by Etanercept unresponsive to
25 mg SC twice a week corticosteroid or
methotrexate treatment
Lam et al., retrospective 18 Etanercept 50 mg once 2 to 66 SSc according to the ACR or 15/18 (83%) 1/18 - lupus-like
2007 [83] analysis or 25 mg twice a week (mean 30) 3 out of 5 CREST features; of patients inflammation reaction;
months signs of synovitis or or synovitis improved; 1/18 - significant
inflammation mild reduction in FVC deterioration in
and DLCO PFTs
Antoniou open label, 4 Infliximab 3 mg/kg at 12 months worsening symptoms with no significant change in no adverse
et al.,2007 [84] uncontrolled (1 SSc) weeks 0, 2, 6, and >10% decline in FVC and/or FVC and DLCO, some events
8-weekly thereafter >15% decline in DLCO improvement in fibrosis
extent on HRCT
Denton open label, 16 Infliximab 5 mg/kg at 26 weeks dcSSc; worsening mRss no significant change in7/16 (44%)
et al., 2009 [85] uncontrolled weeks 0, 2, 6, 14 and 22. >10% or >4 units over <3 mRss, HAQ-DI, FS and of patients
months period physician VAS developed
infusion
reactions
Legend: ACR - American College of Rheumatology; BL - baseline; CREST syndrome - calcinosis, Raynauds phenomenon, oesophageal dysmotility, sclerodactyly, and
telangiectasia; DAS28 - disease activity score, 28 joints; dcSSc - diffuse cutaneous systemic sclerosis; DI - Health Assessment Questionnaire Disability Index;
DLCO - carbon monoxide diffusion capacity; DMARDS - disease-modifying anti-rheumatic drugs; FVC - forced vital capacity; HAQ- FS health assessment
questionnaire - functional score; HRCT - high-resolution computed tomography; ILD - interstitial lung disease; mRss - modified Rodnan skin score; N/K - not
known; PFTs - pulmonary function tests; SSc - systemic sclerosis; SHAQ - Scleroderma health assessment questionnaire; VAS - visual analogue scale.
Hyperimmune Caprine Serum
Hyperimmune caprine serum is obtained by vaccinating goats with human

immunodeficiency virus (HIV) viral lysate and contains caprine immunoglobulins and
various cytokines, including IL4 and IL10. Its disease modifying effect was tested in 20
subjects with late stage dcSSc in a randomised, double-blind, placebo-controlled trial [107].
Analysis of changes in mRss provided some weak evidence for treatment benefit with
trends towards mild skin improvement in the group receiving caprine serum. Nevertheless,
the small size of the trial makes the results difficult to interpret and further studies are needed
to explore this therapy. There were no safety concerns and the treatment was well-tolerated.
CONCLUSION
Although biologic therapies have transformed management of many autoimmune
rheumatic conditions, their efficacy in treatment of SSc so far has been disappointing. This
likely reflects the pathophysiological complexity of the disease and the challenges to trial
design, posed by the conditions rarity, slow disease course and wide variability in
presentation. The number of randomised controlled trials in SSc is comparatively small and
short trial duration and lack of established markers of disease activity make results difficult to
interpret. Nevertheless, even when underpowered, some of the more recent trials provide new
insights into SSc pathogenesis and demonstrate evidence for possible disease modification
even at the later stages of disease. Published evidence also suggests that longer treatment
periods are needed to objectively assess the effect of many therapeutic agents. New treatment
options are being explored and improved knowledge about the disease has led to better
disease monitoring, earlier detection of organ complication and resulting overall better
survival among patients with the more severe diffuse subset of SSc [108].
ACKNOWLEDGMENTS
The authors would like to thank Dr. Voon H. Ong, Senior Clinical Lecturer in
Rheumatology, Centre for Rheumatology and Connective Tissue Diseases, UCL Medical
School, Royal Free Campus for his helpful comments (email: v.ong@ucl.ac.uk).
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Chapter 6
THE ROLE OF BIOLOGICS IN THE TREATMENT

OF SMALL AND MEDIUM VESSEL VASCULITIS
Lubna Ghani1, MRCP and Eleana Ntatsaki2, MRCP

1
UCL Centre for Nephrology, Royal Free Hospital, London, UK
2
Rheumatology Department, University College London, London, UK
ABSTRACT
The systemic vasculitides are a family of complex multisystem conditions that if left
untreated may lead to significant morbidity and mortality. Over the last few decades,
their prognosis has been significantly improved by newer and more effective
immunosuppressive therapies. The current armamentarium of treatment options has been
significantly enhanced by the addition of current and emerging targeted biologic
therapies. In this chapter we will review the spectrum of the primary systemic
vasculitides and focus on the use of biologic therapies for the small and medium vessel
vasculitides, broadly dividing these into ANCA (anti - neutrophil cytoplasmic antibody)-
associated and non-ANCA-associated vasculitides.
Keywords: ANCA-Associated Vasculitis, medium and small vessel vasculitis, Non-ANCA

Associated Vasculitis, biologic therapies
INTRODUCTION
The term vasculitis literally means inflammation of the vessels and is used to describe a
group of relatively rare conditions with a broad spectrum of clinical presentations that can
Correspondence to: Dr. Eleana Ntatsaki, Rheumatology Department, 250 Euston Road, University College
London, NW1 2PG, London, email:e.ntatsaki@ucl.ac.uk
110 Lubna Ghani and Eleana Ntatsaki
cause significant morbidity and mortality. The systemic vasculitides are complex overlapping
multisystem conditions and although their natural history has been significantly altered by
current therapies, they remain a challenge for both patients and clinicians.
Classification and Diagnostic Criteria in Vasculitis
The classification of the vasculitic syndromes is usually made according to the size of the
vessels affected [1], but also according to the presence of specific antibodies, mainly ANCA
antibodies, that characterise the pathology of some of the individual conditions. In addition
vasculitides can be either primary or secondary to an underlying systemic disease,
malignancy, or infection (Figure 1 and Table 1).
The primary systemic vasculitides are characterised by inflammation and necrosis of
small and medium blood vessels. They are heterogeneous, multi-system disorders and despite
recent advances in our understanding of their pathogenesis particularly regarding the ANCA-
associated vasculitides, their true aetiology is still unknown.
Three distinct clinico-pathological syndromes, often associated with ANCA antibodies,
known as ANCA-associated vasculitis (AAV), have been identified and collectively comprise
the most common subgroup: granulomatosis with polyangiitis (GPA), previously known as
Wegeners granulomatosis, eosinophilic granulomatosis with polyangiitis (EGPA), previously
known as Churg-Strauss Syndrome, and microscopic polyangiitis (MPA) (see Tables 1 and
2). A small subset of these patients will present with typical clinical or pathological features
of ANCA-associated disease without a detectable ANCA and are usually described as having
ANCA-negative small vessel vasculitis. These should not be confused with other forms of
vasculitis which are not ANCA-associated and are defined by their clinico-pathological
features (see Tables 1 and 2).
Note: The ANCA associated vasculitides are shown in red.

Legend: GBM - glomerular basal membrane; Ig A - immunoglobulin A.
Figure 1. Classification of vasculitis according to vessel size.

The Role of Biologics in the Treatment of Small and Medium Vessel Vasculitis 111
Table 1. Classification of Vasculitides (based on data from the 2011-2012 International

Chapel Hill Consensus Conference Nomenclature of the Vasculitides [1])
a. PRIMARY VASCULITIDES
According to vessel size

Large Vessel Medium Vessel Small Vessel Variable Vessel
Takayasu Polyarteritis Nodosa ANCA-Associated Vasculitis Behets
Arteritis Disease
Kawasaki Disease Anti-GBM Disease Cogans
Giant Cell Syndrome
Arteritis Immune Complex
Single Organ
Isolated Cutaneous Arteritis Cutaneous Leukocytoclastic
Aortitis Angiitis
b. SECONDARY VASCULITIDES
Vasculitis Associated with Probable Aetiology

Infection Hepatitis C Virus-Associated Cryoglobulinemic vasculitis
Hepatitis B Virus-Associated vasculitis
Syphilis-Associated Aortitis
Drugs Drug-related Immune e.g., sulfonamides, penicillins, thiazide diuretics
Complex
Drug -related ANCA- e.g., carbimazole, propylthiouracil, hydralazine and
Associated Vasculitis allopurinol (mainly with induction of MPO-ANCA)
Systemic Lupus Vasculitis
disease Rheumatoid Vasculitis
Sarcoid Vasculitis
Spondyloarthropathy-related Vasculitis and others
Cancer Malignancy developing Bladder cancer
in patients with a Lymphoma
diagnosis of primary Leukaemia
systemic vasculitis Non-melanoma skin cancer
Renal cell carcinoma
Malignancy associated Myelodysplasia
with subsequent Lymphoma
development of Hairy cell leukaemia
vasculitis Myeloma
Solid tumours
Other Miscellaneous vasculitides
Table 2. Small Vessel Vasculitis Sub-Classification (based on data from the 2011-2012
International Chapel Hill Consensus Conference Nomenclature of the Vasculitides [1])
Small Vessel Vasculitis

ANCA-Associated Vasculitis
Microscopic Polyangiitis
Granulomatosis with Polyangiitis (Wegeners granulomatosis)
Eosinophilic Granulomatosis with Polyangiitis (Churg Strauss Syndrome)
Non-ANCA-associated Vasculitis
Anti-GBM Disease (Goodpastures)
Immune Complex
Cryoglobulinaemic Vasculitis
IgA Vasculitis (Henoch-Schnlein)
Hypocomplementaemic Urticarial Vasculitis (Anti-C1q Vasculitis)
Legend: C1q - complement fraction C1q; GBM - glomerular basal membrane; Ig A - immunoglobulin
A.
Although there have been several classification criteria, there are in fact no validated
diagnostic criteria for primary systemic vasculitis. The American College of Rheumatology
(ACR) initially devised classification criteria for different vasculitides and the Chapel Hill
consensus conference (CHCC) in 1994 recommended definitions for GPA, EGPA and MPA
[2]. The CHCC definitions provide a useful description of disease and include some
features that have been used for classification purposes; however they were not intended for
classification or diagnosis. The updated CHCC definitions in 2012 accommodated
developments in knowledge about ANCA and the aetiopathogenesis of the conditions [1].
The ACR have also created classification criteria for large vessel vasculitis such as giant cell
arteritis, Takayasus arteritis, and also medium and small vessel syndromes such as
polyarteritis nodosa (PAN) and immunoglobulin (Ig)-A vasculitis (Henoch-Schnlein) [3].
Throughout this chapter we will be referring to the CHCC 2012 nomenclature and
definitions using the broad classification described in the tables to categorize the different
syndromes whilst reviewing the role of biologic treatments.
Biologic Treatment in Systemic Vasculitis
Since the introduction of corticosteroids as a therapy in the 1950s and the advent of
modern immunosuppression with combinations using cyclophosphamide (CYC), there have
been significant advances in the treatment of the vasculitides. Newer biologic therapies have
emerged over the last three decades and were first introduced into vasculitis therapy in the
late 1980s [4]. Their clinical development in vasculitis has been slow, but as with systemic
lupus erythematosus (SLE), is now beginning to gain ground. Biologics are now increasingly
used as rescue therapy and will probably have a more substantive role as part of induction and
maintenance therapy in the future. The specificity of some biological agents enables both
pathogenic and therapeutic studies to advance simultaneously.
A summary of the type of biologic drug, explaining the mechanism of action/target

molecule discussed in this chapter and their main clinical use in vasculitis is presented in
Table 3.
Table 3. Summary of Biologic Drug Use in Medium and Small Vessel Vasculitis
Biologic Mechanism of action Main clinical use in vasculitis

B Cell depleting agent
Rituximab IgG1 chimeric, murine/human GPA and MPA
monoclonal antibody against CD20 Case reports in PAN, KD, UV, IgAV
and CV
Anti B cell activating factor
Belimumab human monoclonal IgG1 antibody Under investigation as a potential
against B lymphocyte stimulator therapeutic option in GPA
(BLyS)
Interleukin inhibitors
Tocilizumab humanised monoclonal antibody Randomised controlled trial in GCA is
against interleukin 6 receptor (IL6R) currently underway
Mepolizumab humanised monoclonal antibody Resistant cases of EGPA
against interleukin 5 (IL5)
Anakinra interleukin1 (IL1) receptor antagonist Successful case report in UV
Canakinumab humanised monoclonal against IL1 Open label study of 10 patients with
antibody severe UV some success
IgE antibody
Omalizumab humanised monoclonal antibody Severe refractory EGPA-related asthma
against IgE Case reports of beneficial effects in UV
Tumour necrosis factor (TNF) inhibitions
Etanercept p75 Fc fusion protein which acts as a GPA
receptor blocker for TNF Prospective study open label trial using
etanercept as adjunctive therapy for
IVIG in acute KD was safe and effective
Infliximab chimeric murine/human monoclonal GPA and MPA
antibody against TNF Multicenter RCT showed infliximab
effective and safe in refractory KD
Adalimumab humanised monoclonal antibody AAV with renal involvement
against TNF
Anti-T cell therapy
Alemtuzumab humanised anti-CD52 monoclonal Ongoing trial for AAV
antibody (CAMPATH-1H) selectively No widespread use yet
depletes the peripheral circulation of
T lymphocytes, monocytes and
macrophages
Abatacept fusion protein composed of the Fc Open-label study of AAV patients with
region of IgG1 fused to the mild relapsing GPA reported remission
extracellular domain of CTLA4 which induction in the majority of patients
inhibits T cell co-stimulation (80%) and overall good tolerance
Legend: AAV - ANCA associated vasculitis; BLyS - B lymphocytes stimulator; CTLA4 - cytotoxic T lymphocyte-
associated protein 4; CV - cryoglobulinaemic vasculitis; EGPA - eosinophilic granulomatosis with polyangiitis; Fc -
fragment crystallisable region of the antibody; GCA - giant cell arteritis; GPA - granulomatosis with polyangiitis,
IgAV Ig A vasculitis; IgG1 - immunoglobulin G1; IVIG - intravenous immunoglobulins; KD - Kawasaki disease;
MPA - microscopic polyangiitis, PAN - polyarteritis nodosa, RCT - randomised controlled trial; UV - urticarial
vasculitis.
ANCA-ASSOCIATED VASCULITIS (AAV)

The ANCA-associated vasculitides (AAVs) are a group of rare autoimmune conditions
comprising of three separate syndromes (GPA, MPA and EGPA). They are characterised by
the development of necrotising vasculitis and share a number of clinical features, and are
therefore treated using similar treatment protocols. Their definitions as per the Chapel Hill
Consensus definitions (2012) for primary systemic vasculitis are seen in Table 4.
Table 4. Definitions for ANCA-Associated Vasculitis
Definitions for ANCA-associated vasculitis

ANCA-Associated Necrotising vasculitis, with few or no immune deposits,
Vasculitis (AAV) predominantly affecting small vessels (i.e., capillaries, venules,
arterioles and small arteries), associated with MPO-ANCA or PR3-
ANCA. Not all patients have ANCA.
A prefix is frequently added indicating ANCA reactivity,
e.g., PR3-ANCA, MPO-ANCA, ANCA-negative (not to be
confused with non-ANCA associated vasculitis).
Granulomatosis with Necrotising granulomatous inflammation usually involving the
Polyangiitis upper and lower respiratory tract, and necrotising vasculitis
(Wegeners) (GPA) affecting predominantly small to medium vessels (e.g., capillaries,
venules, arterioles, arteries and veins). Necrotising
glomerulonephritis is common.
Eosinophilic Eosinophil-rich and necrotising granulomatous inflammation often
Granulomatosis with involving the respiratory tract, and necrotising vasculitis
Polyangiitis predominantly affecting small to medium vessels, and associated
(Churg-Strauss) with asthma and eosinophilia. ANCA is more frequent when
(EGPA) glomerulonephritis is present.
Microscopic Necrotising vasculitis, with few or no immune deposits,
polyangiitis (MPA) predominantly affecting small vessels (i.e., capillaries, venules, or
arterioles). Necrotising arteritis involving small and medium arteries
may be present. Necrotising glomerulonephritis is very common.
Pulmonary capillaritis often occurs. Granulomatous inflammation is
absent.
Legend: ANCA - anti - neutrophil cytoplasmic antibodies; MPO-ANCA - ANCA antibodies directed to
myeloperoxidase; PR3-ANCA - ANCA antibodies directed to proteinase 3.
Epidemiology
A considerable body of data on the epidemiology of the AAV has been built in the past
25 years with interesting age, geographic, and ethnic variations. Most of the data come from
white European populations and the overall annual incidence is estimated at approximately
10-20/million with a peak age of onset in those aged 65 to 74 years, with GPA generally
being the most common and CSS the least frequent. In other regions of the world, such as the
far-east, MPA is more common than GPA [5]. The aetiopathogenesis is unknown but like
most autoimmune diseases these conditions are thought to arise from an interaction between
an environmental factor and a genetically predisposed host.
The introduction of CYC combined with prednisolone resulted in a significant
improvement in mortality for AAV over the last 30 years. In 2010, the European Vasculitis
Study (EUVAS) Group trials reported 11.1% mortality at 1 year, with an overall better long-
term prognosis of survivors and late deaths, mainly due to cardiovascular disease or infection
[6]. Although the mortality has indeed improved from a mean survival of 5 months and a 1
year mortality rate of 82% for GPA in the 1960s [7], there is still considerable morbidity
associated with both treatment as well as the disease leading to a reported 5 year survival rate
of only 81% for MPA and 87% for GPA in the new millennium [8].
Clinical Diagnosis
In the early phase of the disease, the symptoms can be non-specific and a high index of
suspicion is required to achieve an early diagnosis. Symptoms that should prompt
consideration of a diagnosis of vasculitis are unexplained systemic disturbance, arthritis or
arthralgia, polymyalgia, episcleritis, neuropathy, microscopic haematuria, proteinuria,
pulmonary infiltrates or nodules and maturity onset asthma and upper airways symptoms [9].
When major organ involvement occurs, then the diagnosis usually becomes more evident.
Unfortunately the presence of more advanced disease at diagnosis limits the potential benefit
of therapy. Detailed clinical and laboratory assessments are key in obtaining a complete
picture of the disease presentation and are very important in identifying the specific type of
vasculitis in most cases [10]. In addition to laboratory tests, imaging studies are essential in
helping to confirm a clinical diagnosis but are of limited value in the absence of clinical signs
when systemic vasculitis is part of the differential diagnosis [11]. Patients with multisystem
illness or pyrexia of unknown origin should be assessed for vasculitic syndromes; however
clinicians should be mindful that there are many conditions that can mimic vasculitis,
including infections, non-infectious inflammatory diseases, malignancy, drugs and factitious
illnesses.
Disease Assessment
In order to be able to measure outcomes and response to treatment it is important to have

an appropriate toolset to measure damage and activity relating to the condition. The most
commonly used measures of disease activity, severity and damage are the Birmingham
Vasculitis Activity Score (BVAS) and the Vasculitis Damage Index (VDI) [12-16].
Interestingly, these do not incorporate ANCA as part of the assessment of disease activity.
Both BVAS and VDI are validated clinical tools that are most widely used in clinical trials as
measures of disease severity, activity and damage. Although they were originally designed
and used for trial purposes, they are becoming more frequently used in everyday clinical
practice.
Treatment Paradigm
Traditionally the treatment of AAV is divided into two distinct phases; rapid and
effective induction of remission achieved with initial immunosuppressive therapy and
maintenance therapy thereafter to control the disease and prevent relapse. The main stages in
treatment follow these key principles of management:
Rapid diagnosis
Rapid initiation of treatment
Early induction of remission to prevent organ damage
Maintenance of remission with the aim of eventual drug withdrawal
Prevention of drug toxicity
The standard of practice and current guidelines recommend the use of CYC or rituximab
with steroids as an induction treatment, to be followed by maintenance with either
azathioprine (AZA) or methotrexate (MTX) or continue with rituximab.
Legend: AZA - azathioprine; CYC - cyclophosphamide; GC - glucocorticoids; MTX - methotrexate,

PLEX - plasma exchange; RTX - rituximab.
Note: Algorithm for the management of ANCA-Associated Vasculitis according to the British Society of
Rheumatology Guidelines, adapted with permission from [9]
Figure 2. Treatment algorithm for the management of AAVs.

There are now evidence-based national and international guidelines for the treatment of
AAV suggesting that the treatment pathway is mostly common, especially between GPA and
MPA [9, 17]. One of the main areas updated in the recent revision of the British Society of
Rheumatology (BSR) guideline in 2014, was the use of biologics in AAVs with specific focus
on the use of rituximab, based on emerging evidence (see Figure 2). The impact of novel
therapies is becoming more apparent and the prognosis for AAV has improved considerably
over the past 30 years. However, the natural history of untreated GPA and MPA remains one
of a rapidly progressive, usually fatal disease.
Although the AAVs comprise three separate syndromes, the main principles of treatment
are shared, hence during the next section of this chapter we will refer to them collectively.
Most of the trials have focused on GPA and MPA, however we will make special reference to
any particular treatment relevant to EGPA only. In this chapter we will focus solely on the
use of biologics and will not elaborate any further on conventional immunosuppressive
therapy.
BIOLOGICS IN ANCA-ASSOCIATED VASCULITIS (AAV)

B Cell Target Therapy
B cells have a key role in the regulation of immune responses and production of
antibodies. They function as antigen presenting cells; produce cytokines and express co-
stimulatory molecules. They are also involved in the differentiation and activation of T
lymphocytes and dendritic cells [18]. B cells are active participants in the pathogenesis of
AAV and the number of activated B cells has been linked to disease activity and to the extent
of organ involvement [19]. In AAV the ANCA producing lymphocytes are present in the
peripheral blood. Interestingly, the absolute antibody level does not necessarily reflect disease
activity [20]. Clinical observations suggest that ANCA are involved in disease pathogenesis
but are not conclusive [19].
Recent advances in understanding the pathophysiology of AAV and the importance of B
cells in the immunological pathways implicated have resulted in a growing interest in using B
cell depletion therapies, and more specifically rituximab, for the treatment of AAV. There are
a number of recent trials which indicate that rituximab may be a safe and effective alternative
or addition to conventional treatment.
Rituximab
Rituximab is a chimeric monoclonal antibody against the cluster of differentiation 20
(CD20) which is found on the surface of all B cells from early pre-B cells to later in
differentiation, but it is absent on terminally differentiated plasma cells. CD20 is a
hydrophobic transmembrane protein expressed on the surface of B lymphocytes which is
believed to function as a calcium channel subunit. The chimeric structure of rituximab
comprises human IgG 1 and kappa-chain constant regions and heavy and light-chain variable
regions from a murine antibody to CD20 [21]. Chimeric anti CD20 antibodies were first
shown to deplete B cells in mouse models in 1992. Rituximab was licensed in Europe and
USA in 1997 for patients with refractory lymphoma. In 2002, rituximab was shown to have
efficacy in AAV, SLE and rheumatoid arthritis (RA) and in 2007 was approved by the
National Institute for Health and Care Excellence (NICE) in the United Kingdom (UK) for
RA patients who have failed tumor necrosis factor (TNF) inhibitor treatment. In 2010 two
major randomised controlled trials (RCT) compared rituximab with standard treatment for
AAV [22, 23], and in 2011 rituximab was approved by the United States Food and Drug
Administration for the management of AAV (GPA and MPA). Since 2014, its use in AAV
has been endorsed in the UK by the funding regulator for the National Health System in
England (NHS England) [24] and by NICE [25], following recommendations from the
national guidelines by the British Society of Rheumatology (BSR) [9]. Rituximab is also
recommended as first line induction therapy for newly diagnosed severe GPA or MPA by the
ACR and the French Vasculitis Study Group, when CYC use is not preferable due to risk of
infertility or infection [26, 27].
Induction of Remission
There have been two large RCTs; four smaller RCTs, and numerous uncontrolled reports
(mostly on the GPA population). The characteristics of the key studies relating to rituximab
are presented in Table 5. Most of these studies relate to GPA and MPA. EGPA (Churg
Strauss Syndrome), is much rarer (10% of all cases), but shares similar clinical features and
treatment strategies to the other two conditions. Although there have been no large trials of
rituximab for EGPA because of its rarity, and use in this condition is off-label, case series
data report similar efficacy to that seen in the other two subtypes.
Rituximab for ANCA associated vasculitis (RAVE) and rituximab vs. CYC in ANCA
associated renal vasculitis (RITUXVAS) are both RCTs which have examined the efficacy of
antiB lymphocyte therapy in the induction phase of treatment for AAV. Both showed that
rituximab was as efficacious in inducing remission as CYC, comparing rituximab with oral
and intravenous (IV) CYC respectively. Both trials used glucocorticoids as an IV pulse
initially and then orally with a decreasing regime. The key difference between these two trials
is that RITUXVAS included 2 or 3 doses of CYC in patients in the rituximab arm, whereas
the RAVE trial used rituximab alone for induction. Both studies permitted emergency
treatment and used significant doses of steroids. The third RCT looking at the use of
rituximab in induction of remission was a much smaller study which compared infliximab
with rituximab with an overall follow up period of 30 months [30].
Dosing Regimes
There have been two different dosing regimens used for rituximab administration in all
trials; the lymphoma regime and the RA regime which are of equal efficacy [31]. These
regimes are derived from extensive experience in using rituximab in lymphoma and RA
patients. The lymphoma regime uses a dose of 375 mg/m2/week for 4 consecutive weeks
with a cumulative dose of 2.5-3g. The RA regime administers two infusions of 1g
rituximab given with a fortnightly interval. Both RAVE and RITUXVAS used the
lymphoma regime.
Table 5. The Main RCT Trials with Rituximab in AAV
RAVE RITUXVAS MAINRITSAN Rituximab vs. infliximab

Study design Double-blind double- Open label randomised Open-label RCT rituximab vs. AZA RCT of refractory GPA
dummy, randomised two group parallel design for maintenance in patients with new rituximab vs. infliximab
non inferiority non superiority or relapsing AAV after induction
multicenter (9 centres) Multicenter (8 centres) with
(USA based) (Europe/Australia) IV-CYC
Reference Stone et al. [23] Jones et al. [28] Guillevin et al. [29] De Menthon et al. [30]
Level of evidence 1B 1B 1B 1B
Number of patients 197 (GPA:MPA 3:1) 44 (GPA:MPA 1:1) 117 (GPA:MPA 4:1) 17 GPA only
Indication Induction Induction Maintenance Induction
Randomisation 99 rituximab + PLC vs. 98 33 rituximab vs. 11 CYC 58 rituximab vs. 59 AZA 8 rituximab vs. 9 infliximab
CYC +PLC
Inclusion criteria i) ANCA+ i) ANCA+ Newly diagnosed or relapsing Refractory systemic GPA
ii) severe disease ii) renal involvement GPA/MPA/ ANCA + renal or intolerant to steroids
iii) BVAS/WG>3 iii) new diagnosis involvement in complete remission
iv) new or old diagnosis after CYC+GC regime
Primary Endpoint Steroid free remission at 6 Remission at 12 months Major relapse rate at 28 months Complete remission at 12
months months
Rituximab dose 375 mg/m2 x 4 weeks 375 mg/m2 x 4 weeks 500 mg rituximab on days 1 and 15, 375 mg/m2 x 4 weeks
and then 6 monthly over 18 months
Control group CYC vs. CYC AZA (2 mg/Kg/day for 22 months) Infliximab (3 mg/Kg in day 1
placebo 15 mg/kg IV and 14, then 3 mg/kg or 5 mg/kg
2 mg/kg/day orally (x2 pulses, 1st&3rd) monthly)
15 mg/kg IV (6-10 cycles)
Outcome Rituximab was non-inferior Rituximab and CYC regime Rituximab was superior to AZA for At 12 months rituximab better at
rituximab vs. control to CYC for remission was non-inferior to CYC maintenance of remission with obtaining remission
induction alone for remission induction significant reduction (six-fold) in
64% vs. 53% 76% vs. 82% major relapses in rituximab-treated
(p value<0.001) (p value 0.68) patients
RAVE RITUXVAS MAINRITSAN Rituximab vs. infliximab

Long term At 18 months, comparable At 24 months, At 34 months, At 31months,
follow up rates of remission in both no difference between groups rituximab was superior to AZA, with rituximab was superior to
groups in combined endpoint of lower rates of both relapse and death infliximab with 10/17 (59%)
Superior rates of remission relapse, ESRD or mortality responding to rituximab,
with rituximab for relapsing 1 to infliximab and 2 to other
patients strategies
Safety No significant differences No significant differences No significant differences No significant differences
rituximab vs. Control
Infection rates 7 infections in both arms 36% vs. 7% 11 cases (rituximab) vs. 12 (AZA) 1 case of aspergillosis causing
death
SAEs 31% vs. 39% 42% vs. 36% 26% vs. 30% No significant differences
Cancer 5% vs. 1% 6% vs. 0 1 cancer 2 cancers (2:0)
Death 6 deaths1% vs. 1% 18% vs. 18% 2 deaths (0:2) 2 deaths (1:1)
Legend: AZA - azathioprine; BVAS - Birmingham vasculitis score; CYC - cyclophosphamide, GPA - granulomatosis and polyangiitis; GC - glucocorticoids;
ESRD - end stage renal disease; Methylpred - methylprednisolone, MPA - microscopic polyangiitis; PLC - placebo; Pred - prednisolone; SAE - severe
adverse event.
In a retrospective review of 65 patients, Jones et al. [31] compared the two regimes for
AAV and found them to be of equal efficacy. There was no difference in the duration of B
cell depletion or the therapeutic effect, despite the fact that the mean serum concentration
after using the lymphoma regime is higher than that achieved with the RA regime. It was
suggested that the 2 x 1g infusions given with a fortnightly interval may be sufficient for the
treatment of AAV. Although the lymphoma regime of rituximab is the only one licensed
for this indication, the majority of existing centres managing patients with AAV use
rituximab in routine clinical practice at the lower dose of two 1g infusions two weeks apart.
This is also the dose schedule used in all other autoimmune rheumatic diseases e.g., RA
(licensed dose) and SLE (off label use). This regime results in a lower total dose of rituximab,
delivered over a shorter period of time, and is therefore more convenient for patients [24].
Other regimes used are 2 infusions of 750 mg/m2 given two weeks apart usually in
paediatric patients [32].
Side Effect Profile

RAVE and RITUXVAS did not demonstrate the expected benefit of rituximab regarding
safety profile with similar rates of infection in both arms of the trials and in addition mild to
moderate infusion reactions were not uncommon. The rate of malignancy shown in RAVE
was higher in the rituximab arm (5% compared to 1% in the control arm), although the
majority of these patients had also had previous exposure to other immunosuppression such
as CYC which could predispose them to malignancy. Interestingly, despite the expressed
concern regarding the development of progressive multifocal leucoencephalopathy (PML),
there were no reports of PML in these two trials. It is worth noting that in the RITUXVAS
study, the patients enrolled had more severe disease, as demonstrated by higher BVAS scores
on enrolment, which might account for the slightly higher death rates. Nevertheless, mortality
rates in RITUXVAS are relatively comparable to previous studies.
Efficacy
Aries et al. [33] reported lack of efficacy of rituximab in GPA with refractory
granulomatous manifestations, especially in patients with ophthalmic manifestations such as
retro-orbital granulomata. In contrast, more recent studies on a series of 10 similar patients
have shown clinical improvement [34]. In order to understand the diversity of response to
treatment it is important to recognise that the orbital granulomas of GPA have a variable
histopathological picture of inflammation including fibrinoid necrosis and excessive fibrosis.
However, the efficacy of rituximab in refractory granulomatous manifestations remains a
contentious issue as there are conflicting data from different case series. Nevertheless,
rituximab appears to be effective in the treatment of refractory pulmonary granulomatous
inflammation. Henderson et al., reported a case series of 5 patients with refractory pulmonary
granulomatosis who were treated with repeated courses of rituximab and found that persistent
B cell depletion was associated with significant radiological improvement [35].
Other possible reasons for the lack of efficacy of rituximab in some subjects include the
development of human anti-chimeric antibodies (HACA). The development of humanised
anti-CD20 monoclonal antibodies (e.g., ofatumumab, ocrelizumab, and veltuzumab) may well
address this problem [36]. Ofatumumab has been licensed for treatment of resistant chronic
lymphocytic leukaemia. However, none of these fully humanised anti-CD20 antibodies have
been approved for the treatment of AAV, but they have been used off label in patients who
have allergic reactions to rituximab [37].
Maintenance Therapy
The main indications for using rituximab for maintenance therapy are the inability to
tolerate or relative contraindications to both AZA and methotrexate, which are considered
standard maintenance therapy, with mycophenolate mofetil (MMF) also being widely used, or
continued relapses despite being on those immunosuppressants. On the other hand there is
evidence to suggest a sustained response to rituximab when used as a rescue and maintenance
therapy in refractory and relapsing cases of AAV [38].
The maintenance of remission using rituximab in systemic AAV (MAINRITSAN) trial
(see Table 5) was an open-label randomised-controlled study comparing 500mg of rituximab
administered every 6 months to daily AZA. The 158 patients that enrolled in MAINRITSAN
were stratified depending on whether they had new or relapsing disease and patients who had
previously received rituximab were not eligible for this study. Once remission was achieved
with IV CYC, patients were randomised in two groups: either to receive rituximab 500 mg at
day 0, 2 weeks and then month 6, 12, and 18 or AZA (initially at 2 mg/kg daily and tapered
off). Those treated with AZA had a 6-fold increase in the rate of major relapse compared with
the rituximab group. At month 28, major relapse had occurred in 17 AZA-treated patients
(29%) compared with only 3 (5%) patients in the rituximab arm. The safety and tolerability of
the two regimes were similar. Follow-up of MAINRITSAN patients to a median of 34 months
demonstrated continued superiority of rituximab with the overall survival being higher in the
rituximab arm (zero deaths) compared with the AZA-arm (four deaths).
This is the first and largest trial published to date directly comparing rituximab to
conventional maintenance therapy for AAV. However, this study has received criticism as it
was felt that the AZA dose used may have been tapered more rapidly than one would expect
in clinical practice. In addition, all patients received induction therapy with CYC, therefore
raising the concern that the result may not be relevant to patients that had rituximab as an
induction agent. The ongoing RITAZAREM trial (ClinicalTrials.gov Identifier:
NCT01697267) is randomising patients with relapsing disease after rituximab induction
therapy and should help with such unanswered questions [39].
Other B Cell Therapies

The RAVE trial and other clinical trials provided clear evidence that rituximab was not
inferior to CYC for remission induction, and rituximab appeared even more beneficial in
patients with relapsing disease. This raised hopes that other B-cell-targeted therapies directed
either against CD19, CD20, CD22, or B-cell survival factors such as B-cell activating factor
of the tumor necrosis factor family (BAFF), also known as B lymphocyte stimulator (BLyS),
or A Proliferation-Inducing Ligand (APRIL) could also be beneficial for the management of
AAV [40].
B-Cell-Activating Factor (BAFF)

Local production of BAFF in granulomatous lesions and elevated levels of serum BAFF
in AAV provide a rationale for BAFF-targeted therapies not only in AAV but also in other
forms of vasculitis such as Behets disease, large-vessel vasculitis, or cryoglobulinaemic

vasculitis secondary to chronic hepatitis C infection. BAFF-targeted therapies have a very
solid safety profile, and may have an additional benefit of preferentially targeting newly
arising autoreactive B cells over non-self-reactive B cells [40].
BAFF neutralisation with the fully humanised monoclonal antibody belimumab has
already shown success in human SLE and, along with another anti-BAFF agent blisibimod,
has been investigated in phase II and III clinical trials in AAV. BIANCA-SC (A Study of the
Efficacy, Safety, and Tolerability of Blisibimod in Addition to Methotrexate during Induction
of Remission in Subjects with ANCA-Associated Small Vessel Vasculitis) was a phase II trial
to determine the efficacy and safety of blisibimod in addition to methotrexate for induction of
remission in patients with AAV. It was designed to exclude patients with severe disease
requiring CYC treatment. However this study was withdrawn prior to recruiting participants
(ClinicalTrials.gov Identifier: NCT0159885).
Interestingly, BAFF as a potential biomarker in AAV appears to be less reliable
compared to more traditional disease activity markers such as non-specific inflammatory
markers like Erythrocyte sedimentation rate (ESR) and C - reactive protein (CRP).
Furthermore, BAFF levels also failed to correlate with ANCA titers. Nevertheless, induction
therapy with a B-cell-depleting agent (e.g., rituximab) followed by maintenance therapy with
anti-BAFF reagents could potentially reduce the numbers of relapses and thus aid in
achieving a sustained remission in AAV [40]. However, further clinical trials are required to
assess clinical efficacy and safety of anti-BAFF agents in AAV [41].
Belimumab
Belimumab in Remission of Vasculitis (BREVAS) is a phase III study focused on the
efficacy and safety of belimumab (10 mg/kg) in combination with AZA for maintenance of
remission in GPA and MPA. The primary outcome is time to first relapse. This study is
currently open for enrolment (ClinicalTrials.gov Identifier: NCT01663623).
TNF Inhibition Therapy
The role of TNF inhibition in the treatment of AAV is currently not clearly defined with
concern about the rates of infection and malignancy arising from the outcomes of prospective
trials. At present, agents which inhibit TNF are not routinely used in either the induction or
maintenance of remission in AAV [42].
Infliximab
Blockade of TNF with infliximab was one of the first established therapeutic targets in
rheumatologic conditions, mainly RA. Infliximab is a chimeric monoclonal antibody which
binds soluble and transmembrane forms of TNF. In AAV, infliximab showed efficacy for
inducing and maintaining remission when used with conventional therapy in a large yet
uncontrolled study, with the benefit of providing a steroid-sparing effect, however the main
disadvantage was an increase in the rate of severe infections [43].
A prospective randomised multicenter study that compared efficacy and tolerability of
infliximab to rituximab in patients with refractory disease (GPA) showed benefit with both
drugs, favouring rituximab in the long-term follow up with 10 out of 17 patients responding
to rituximab, one to infliximab and two to other treatment strategies (see Table 5).
Etanercept
Etanercept is a fusion protein consisting of two extracellular p75 TNF-receptor domains
linked to the fragment crystallisable (Fc) portion of human IgG1. A RCT of etanercept in 180
patients with GPA by the Wegeners Granulomatosis Etanercept Trial group (WGET)
comparing etanercept vs. placebo in addition to standard therapy for maintenance in patients
with GPA, mainly without severe renal disease, showed no benefit in the induction or
maintenance of remission with a high rate of treatment-associated complications, mainly
increased incidence of solid organ tumours [44].
Adalimumab
Adalimumab is a humanised monoclonal antibody against TNF that has been trialed in a
small openlabel prospective study of 14 patients. There was no benefit of the addition of
adalimumab to prednisolone and CYC for the treatment of severe AAV, with similar response
rates and adverse events to standard therapy alone, but with the benefit of reduced steroid
exposure. There have been no larger studies [45].
Interleukin Inhibitors
Tocilizumab
Tocilizumab is a humanised monoclonal antibody against the interleukin 6 receptor
(IL6R) that has been widely used in RA and recently successfully trialled in large vessel
vasculitis. Although there are reports of elevated IL6 serum levels or intra-lesional IL6
expression for histologically-confirmed MPA or GPA, there is only one anecdotal case report
of a beneficial effect in refractory AAV (MPA). Therefore further evidence is needed to
support the role of IL6 in the pathogenesis of AAV for it to be a potential target for treatment
[46].
Mepolizumab
Mepolizumab is a humanised monoclonal antibody against IL5 which has been used in
resistant cases of EGPA. In two open label trials, mepolizumab was well tolerated and
demonstrated a steroid-sparing effect. However, although remission was induced, relapses
occurred in both studies after cessation of treatment, suggesting that prolonged therapy may
be necessary [47, 48]. A RCT (ClinicalTrials.gov Identifier: NCT02020889) using the
subcutaneous regime of 300 mg every 4 weeks is currently underway.
Omalizumab
Omalizumab is a humanised monoclonal antibody against IgE that has been anecdotally
used for severe EGPA with refractory asthma symptoms. There are a few case reports of
successful use but no controlled trial to date [49]. A very small case series of five patients
reported that in patients with EGPA and moderate to severe allergic asthma, omalizumab
appeared both beneficial and safe. It allowed corticosteroid tapering while decreasing
eosinophilia and improving asthma symptoms over 36 months [50].
T cell Inhibition Therapy
Alemtuzumab
Alemtuzumab is a humanised anti-CD52 monoclonal antibody (CAMPATH-1H) that
selectively depletes the peripheral circulation of T lymphocytes, monocytes and macrophages.
Alemtuzumab has been studied in an open long term follow-up study of 71
relapsing/refractory AAV patients (mainly GPA) who were followed up for 5 years. Although
the majority of patients (85%) achieved clinical remission, 72% relapsed after a median of 9
months post-therapy completion. Adverse events included severe infections, malignancy and
8 patients who developed Grave's disease [51]. A randomised controlled open label study,
alemtuzumab for ANCA Associated Refractory Vasculitis (ALEVIATE), looking to
determine the clinical response and severe adverse event rates associated with alemtuzumab
therapy among patients with relapsing or refractory AAV is ongoing.
Abatacept
Abatacept is a fusion protein composed of the Fc region of IgG1 fused to the extracellular
domain of CTLA4 which selectively modulates T cell co-stimulation by blocking the
engagement of CD28. It has been trialled in 20 patients with non-severe relapsing GPA in an
open label study and reported remission induction in the majority of patients (80%) with
overall good tolerance [52].
Other Agents
Eculizumab
Eculizumab is a monoclonal antibody to complement component 5a (C5a) and is a
terminal complement inhibitor used for the treatment of paroxysmal nocturnal
haemoglobulinuria and atypical haemolytic uraemic syndrome. There is good experimental
evidence from animal models that complement plays an important role in the development of
AAV [53] and elevated plasma and urinary C5a levels indicate complement activation in
human AAV [54]. A small phase II study evaluating the effectiveness and safety of blocking
C5a receptors in patients with newly diagnosed renal AAV suggested that CCX168, an orally
administrated C5a receptor blocker could potentially be used as a steroid sparing agent in
combination with CYC [55]. However there are no conclusive data from a published RCT to
date and one significant factor limiting the use of eculizumab is its prohibitive cost.
There are two further registered phase IIb studies, CLEAR (ClinicalTrials.gov Identifier:
NCT01363388) which was recently completed and CLASSIC (ClinicalTrials.gov Identifier:
NCT02222155) investigating the efficacy and safety of CCX168 on both the renal and non-
renal manifestations of AAV. Preliminary results of the CLEAR study which was a
randomised, double-blind, placebo-controlled clinical trial, showed renal disease efficacy of
oral 30 mg CCX168 given twice daily for 12 weeks based on estimated glomerular filtration
rate (eGFR), urinary albumin creatinine ratio (ACR) and other renal parameters. In addition
to this effect on renal disease activity, there was also a beneficial effect on non-renal disease
activity based on the non-renal component of the BVAS. A phase III study is currently being
planned [56].
Intravenous Immunoglobulin (IVIg)

Although IVIg is not strictly considered a biologic, its use and benefit has been shown in
small studies, especially in the context of persistent and refractory disease [57, 58]. It is
speculated that IVIg interferes with the binding of ANCA to their antigens and hence inhibits
ANCA-induced neutrophil activation [59], although it is likely that this is not the sole
mechanism of action. However, a Cochrane review in 2009 concluded that there is not
enough evidence from one RCT to confirm that IVIg adjuvant therapy has a true therapeutic
advantage when compared to standard therapy alone [60]. IVIg use in AAV continues to be
largely ad hoc and anecdotal, offering a particular advantage in patients with concurrent
infection in whom significant immunosuppression is undesirable.
BIOLOGICS IN NON-ANCA ASSOCIATED VASCULITIS

Medium Vessel Vasculitis
Polyarteritis Nodosa
Polyarteritis nodosa (PAN) is a systemic necrotising vasculitis that predominantly affects
medium-sized muscular arteries [61]. Small arteries may be involved, but small vessels,
including arterioles, capillaries, and venules, are usually spared. Therefore,
glomerulonephritis is not part of the spectrum of PAN [62].
PAN may encompass a spectrum of disorders. It may be idiopathic or triggered by
specific agents. The most typical is hepatitis B virus (HBV). Before vaccination against HBV
was available, more than one-third of adults with PAN were infected by HBV. Currently, less
than 5% of patients with PAN are HBV-infected in developed countries [63].
In some cases other viruses such as hepatitis C (HCV), HIV, parvovirus B19 and
cytomegalovirus have been detected. Interestingly, hairy cell leukaemia has also been
implicated in the pathogenesis of PAN in some cases [64-66]. PAN may be a systemic disease
however variants are single-organ disease and cutaneous PAN (cPAN) [62].
cPAN lacks significant internal organ involvement. The aetiology is unknown. Clinical
manifestations include tender subcutaneous nodules, livedo reticularis, cutaneous ulcers and
necrosis. Mild cases may resolve with nonsteroidal anti-inflammatory drugs. If more severe,
treatment with systemic corticosteroids generally achieves adequate response; however,
adjunctive therapy is often necessary to allow reduction in steroid dosage. Patients with
isolated cutaneous disease when first seen and initially treated may relapse with disease in
other organs, and should be monitored periodically [65, 67].
Single-organ PAN is usually a monocyclic disease, which typically does not relapse. It is
often discovered by histological examination of surgical specimens. Treatment beyond
surgical excision (e.g., isolated PAN of the gallbladder) is usually not necessary [62]. Like
cPAN follow up is recommended to determine if additional organs or other clinical features

are present or developing [65].
In this section we will concentrate on PAN. The annual incidence of PAN currently
ranges from 0 to 1.6 cases/million inhabitants in European countries [68, 69] and its
prevalence is about 31 cases/million [63, 70]. PAN affects patients of all ethnic groups. It
typically occurs in patients in their 4th and 6th decade of life and women are less frequently
affected than men [71].
The grounds on which patients with necrotising vasculitis have been classified as PAN
have evolved over the years. Therefore it is difficult to conclude what the optimal therapy for
PAN is as most studies have been performed on mixed cohorts of patients with PAN and
AAV [64].
The prognosis of PAN depends on the organs involved, which guides treatment. The
French Vasculitis Study Group (FVSG) proposed the Five Factor Score (FFS), a prognosis
index with the following factors: presence of renal involvement (serum creatinine >149
mol/L) or proteinuria (>1 g/day), severe gastrointestinal tract disease, cardiac disease and
central nervous system involvement. When present, each of these is given a score of 1 [72].
In patients with FFS >2 a 46% 5-year mortality was observed. This is only 12% in
patients with a score of 0 [72]. In 2011 this score was revised and now includes only four
factors. The FVSG group excluded the central nervous system involvement and proteinuria,
thereby replacing them with age >65 which is considered a poor prognostic indicator [73].
Mild forms of PAN (FFS 0) and cPAN as mentioned earlier are usually treated solely
with corticosteroids. First-line corticosteroid treatment is able to achieve and maintain
remission in only about more than half of patients with mild PAN. The remaining 40% of
patients require additional immunosuppressive therapy [71].
There are few randomised trials of treatment; however observational studies of PAN have
shown the efficacy of glucocorticoids and CYC in patients with more severe disease. Monthly
doses of CYC are preferred over daily oral CYC due to a better safety profile [74].
As previously discussed in this chapter, rituximab has been beneficial in treating AAV.
There have been a few case reports suggesting that rituximab is also effective against
corticosteroid-resistant PAN without HBV. However therapeutic trials are needed to
determine the real efficacy and place of rituximab in the treatment of PAN [75].
In the past HBV-PAN was treated in the same way as non-viral PAN and patients
received corticosteroids and immunosuppressive agents, such as CYC. This is no longer
recommended as this regime promoted viral persistence and replication [65]. Eradication of
hepatitis B is part of the management for HBV-PAN as once seroconversion is achieved,
complete remission usually occurs without relapse. Combining an anti-viral drug with
plasmapheresis may facilitate seroconversion and prevent the development of long-term
hepatic complications of HBV [76].
Unlike HBV PAN there are no large series describing treatment approaches for HCV
PAN and HIV PAN. The approach used in HBV PAN (short glucocorticoid treatment
followed by specific anti-viral therapy) may be suitable for other virus-associated PAN [64,
65].
In a few case reports, infliximab has been used in refractory forms of PAN or when
standard therapies are unsuccessful or contraindicated, and it seems to be effective, which
raises the possibility that this may have a role in challenging cases of PAN [39, 77].
In summary, current treatment policy includes high-dose corticosteroids, which are

combined with immunosuppressive agents when critical organ involvement or life-
threatening complications occur. A frequently used therapy is IV pulse CYC in the remission
induction phase, later switched to a safer immunosuppressant for remission maintenance [64].
The literature has shown that there is a role for biologics in PAN with a few cases reports
highlighting a possible role for rituximab and TNF inhibition therapy. However, as definition
of this vasculitis evolves and the pathogenesis of PAN becomes clearer, the role of targeted
biological treatments should evolve.
Kawasaki Disease
Kawasaki disease (KD), formerly called muco-cutaneous lymph node syndrome, is one
of the most common vasculitides of childhood. It is the leading cause of childhood-acquired
heart disease in the developed world [78]. The stimulus for the cascade of inflammation in
KD is unknown. If untreated, approximately 2025% of children develop coronary artery
aneurysms, which may lead to myocardial infarction and death [79-80].
KD has a universal distribution and can manifest in children of any ethnicity. However it
is more prevalent in Asian countries, especially in Japan where in 2010, the annual incidence
was found to be 240 per 100,000 in children <5 years of age [81]. In France the incidence of
KD is 9 per 100,000 children <5 years of age [82].
Standard initial therapy is IVIg and aspirin. Non-responders to initial therapy remain a
challenge. Interestingly the mechanism of action of IVIg is unknown, a single dose given
together with aspirin within 10 days of fever onset results in rapid resolution of clinical
symptoms in 8090% of patients, and has been shown to reduce the risk of coronary disease
from 2025% to about 24% [83].
Adult-onset KD (AKD) is rare and often misdiagnosed. A recent review including post-
infectious cases described 100 cases of AKD [84]. A French group looked at 43 patients, the
largest series of patients with AKD. The findings showed that these patients had a high
frequency of cardiac involvement and complications and that early IVIg treatment seems to
improve the outcome. These results seem similar to those found for childhood KD [85].
Approximately 1015% of patients with KD fail to respond to standard therapy.
Unfortunately, the optimal treatment of patients with refractory KD has not been
determined, as there are few controlled data available. The general consensus is
administration of a second dose of IVIg if symptoms do not resolve with the first dose [86].
However, if there is failure to respond to two doses of IVIg there is no consensus in the
literature regarding the next step and most experts consider a third dose of IVIg, whereas
others may trial methylprednisolone or use biologics such as TNF inhibitors [87].
TNF and TNF soluble receptors I and II concentrations are increased in the acute phase
of KD, and are highest in children who subsequently develop coronary artery aneurysms.
Therefore, TNF inhibitor agents, such as etanercept and infliximab have been studied as both
adjuvant therapy for primary disease and as monotherapy for refractory KD.
A recent randomised double-blind, placebo-controlled trial assessed the benefit of adding
infliximab to the primary standard therapy of KD. This study showed that adding a dose of
infliximab prior to the IVIg treatment did not reduce IVIg treatment resistance, as measured
by coronary artery z scores at 5 weeks. However, infliximab was safe, reduced fever duration,
some markers of inflammation and IV immunoglobulin reaction rates [88].
Starting in 2004, isolated case reports of infliximab treatment of refractory KD began to

appear in the literature [89]. A multicenter, randomised and prospective trial showed that
infliximab is an effective and safe agent for treatment in refractory KD [90]. Thereafter, a
large retrospective review showed that in patients with IVIg-resistant KD, whose first re-
treatment was infliximab rather than IVIg, had faster resolution of fever and fewer days of
hospitalisation. Coronary artery outcomes and adverse events were similar however the power
of the study was limited [91].
In 2010 the first prospective, open-label clinical trial using TNF inhibition as adjunctive
therapy for IVIG treatment of acute KD was published. Patients, aged 6 months to 5 years,
received etanercept over a 2-week period as adjunctive treatment for the first IVIg dose. None
of the 15 patients completing the trial required retreatment or rescue therapy. Thus etanercept
appears to be safe and well-tolerated in children with KD [92]. Currently, there is a study
undergoing, which is investigating the use of etanercept along with IVIg as a first-line
treatment, aiming to reduce need for re-treatment [93].
A single case has been reported in the literature of the use of rituximab in a child with KD
refractory to IVIg and glucocorticoids. The case was associated with significant lesions of
the coronary arteries which were treated successfully with rituximab. Rapid clinical,
biological, and cardiac improvement was observed with rituximab. The patient tolerated the
treatment well. No recurrence was noted when steroids and aspirin were discontinued [94].
These results need to be confirmed with future studies.
Small Vessel Vasculitis
Urticarial Vasculitis
Urticarial Vasculitis (UV) is a variant of cutaneous vasculitis. UV is a rare small vessel
vasculitis with predominant skin involvement. The lesions in UV typically last > 24 hours in
a fixed location, resolve with residual hyperpigmentation, and may or may not be pruritic. In
contrast, standard urticaria lesions persist < 24 hours, leave no trace, and are always pruritic.
Histopathologically, UV presents as leukocytoclastic vasculitis with a perivascular mixed
infiltrate of lymphocytes, neutrophils, and eosinophils, as well as fibrin deposits [95].
UV can be divided into 2 groups according to complement levels, i.e., normo-
complementaemic UV and hypocomplementaemic UV (HUV); the latter is associated with
anti-C1q antibodies. According to the Revised International Chapel Hill Consensus
Conference Nomenclature of Vasculitides (2012), HUV is also called anti-C1q vasculitis [1,
96]. Laboratory findings for HUV include low complement levels of the classical pathway,
namely C1q, C2, C3, and C4, together with an acute-phase response [96].
Although both subtypes are associated with typical symptoms such as angioedema, chest
or abdominal pain, fever, and joint pain, the symptoms are more prominent in HUV.
Interestingly, HUV may be associated with SLE and other autoimmune connective tissue
diseases, serum sickness, cryoglobulinaemia, infections, medications, and malignancies,
whilst normocomplementaemic UV in most instances is idiopathic [95, 97-98].
Hypocomplementemic Urticarial Vasculitis Syndrome (HUVS) is a rare, distinct, and
potentially severe form of UV with multi-organ involvement. Its aetiology and link with other
diseases are still unknown. HUVS is characterised clinically by persistent urticarial skin
lesions, leukocytoclastic vasculitis, and a variety of systemic manifestations, including severe
angioedema, laryngeal oedema, arthritis, arthralgia, glomerulonephritis, ocular inflammation,

obstructive lung disease and recurrent abdominal pain [99, 100]. In the literature there is
controversy regarding the nomenclature and classification of HUV; furthermore the
relationships between idiopathic normocomplementaemic UV, HUV, and HUVS have not
been well defined [101].
To date the largest reported series of patients presenting with HUV was a recent French
nationwide retrospective study that included 57 patients and showed that the best strategy for
treating HUV has yet to be defined [101]. Treatment options include oral antihistamines, oral
corticosteroids, dapsone, colchicine or hydroxychloroquine. Monoclonal antibodies such as
omalizumab (anti-IgE) have also been suggested for treatment of urticarial vasculitis [98].
Omalizumab has been approved by the United States of Americia Food and Drug
Administration (FDA) in March 2014 for chronic idiopathic urticaria in adults and children
aged 12 years or older who remain symptomatic despite anti-H1 antihistamine treatment
[102]. Studies have shown that omalizumab significantly reduces the activity and symptoms
of chronic urticarial, and improves quality of life [98, 102]. UV with eruptive erythematous
wheals resembles chronic urticaria, but the individual lesions usually last longer than in
chronic urticaria. Symptoms are more frequently burning rather than itching and resolve with
hyperpigmentation. At present, omalizumab is not the treatment of choice for UV. However,
there have been a few case reports which show that it has a beneficial effect on patients with
UV. There is a need for clinical trials with a greater number of patients with UV that compare
standard treatment with omalizumab [98].
Rituximab has been shown to be useful in cases of refractory UV [103]. The interleukin1
(IL1) receptor antagonist anakinra has been used to treat normocomplementaemic UV with
some success [104]. Interestingly, a dramatic response to anakinra has been described in
patients with Schnitzlers syndrome, a rare syndrome characterised by chronic urticarial-like
rashes, a monoclonal immunoglobulin M gammopathy, and systemic inflammation usually
presenting as fever. Anakinra is now the first-line treatment of choice in these patients [105].
TNF inhibition agents have been associated with an increasing number of cases of
autoimmune diseases, principally cutaneous vasculitis [106-108], thus discouraging its use in
UV.
A recent open label study with 10 patients suggests that canakinumab, a long acting fully
humanised monoclonal antiIL1 antibody, could be used in severe UV. However, further
evaluation is required including the analysis of long-term effects and safety of canakinumab
in larger patient samples with UV [109].
IgA Vasculitis (IgAV) (HenochSchnlein Purpura)

IgA vasculitis (IgAV), also termed Henoch-Schnlein purpura is an immune complex
vasculitis predominantly affecting small vessels [1]. IgAV is a common childhood systemic
vasculitis with clinical characteristics of cutaneous palpable purpura, arthralgia/arthritis,
bowel angina, and haematuria/proteinuria. In a population-based study from the United
Kingdom, the annual incidence was 20 per 100000, and was highest between the ages of 4
years and 6 years (70 per 100000) [110].
Histopathological findings of leukocytoclastic vasculitis and IgA-immune deposits in
vessel walls and/or glomeruli increase the diagnostic sensitivity and specificity [97]. When
present in adults, the severity of IgAV tends to be worse and renal involvement is common
[111-112].
Rituximab, depleting B cells, may reduce immune complexes containing IgA during IgA
vasculitis and reduce disease activity [113-114]. In the literature there are a few case series of
patients with frequent relapses or severe renal impairment where rituximab has been
beneficial [114]. A Japanese group reported complete remission using rituximab in an adult
patient with nephritis and skin involvement refractory to corticosteroids plus CYC [115].
Furthermore, a recent case report described an adult with moderate nephritis and severe skin
vasculitis treated first line with rituximab without corticosteroids, the patient achieving
complete and sustained skin and renal remission [113]. There have been two other reports
where rituximab has been successfully used [116-117]. Finally the efficacy of rituximab has
also been reported in three children in standard treatment-refractory chronic IgAV [118].
However, further studies are required to confirm the efficacy of rituximab as treatment in
IgAV.
There have been two studies demonstrating high levels of serum TNF in IgAV patients
with renal involvement. However, the pathogenic role of TNF in IgAV remains unclear.
There have been a few case reports of IgAV following the use of three commonly used TNF
inhibitors; etanercept [119, 120], infliximab [121] and adalimumab [122, 123]. IgAV
occurred after several months of TNF inhibitor therapy in all cases. This suggests that the
increased TNF levels may not be a central mediator in the initial development of IgA-
mediated diseases such as IgAV and that further research is needed into the link between
IgAV and TNF levels.
Cryoglobulinaemic Vasculitis
Mixed cryoglobulinaemia syndrome (MCS) is a systemic vasculitis characterised by
multiple organ involvement due to the vascular deposition of immune complexes, mainly the
cryoglobulins, in small and medium-sized vessels [124]. The term cryoglobulinaemic
vasculitis (CV) is frequently used as a synonym.
B-lymphocyte expansion represents the underlying pathological alteration, which is
frequently triggered by hepatitis C virus (HCV) infection and, occasionally, hepatitis B. It can
also be associated with autoimmune or lymphoproliferative disorders and, rarely, can be
idiopathic [125].
HCV-induced mixed cryoglobulinaemic vasculitis manifestations respond to clearance of
HCV using combination antiviral therapy with pegylated interferon (PegIFN) plus ribavirin
[126, 127]. Patients treated for HCV infection who relapsed after responding to antiviral
therapy, also experienced relapses of their vasculitis with the return of viraemia [128].
In 2002 it was observed that there were increased soluble TNF receptor concentrations
in HCV-associated CV, suggesting a role for this cytokine in the pathogenesis of this disease
[129]. There have been only 3 case reports in the literature with refractory hepatitis C-
associated CV treated with TNF inhibitors with conflicting results, with some patients even
experiencing severe flare of the disease [39, 130, 131]. However, around this period there was
promising evidence emerging related to rituximab.
From 1999-2011 anecdotal observations, two pilot studies and a multicenter cohort study
showed the efficacy and safety of rituximab treatment in patients with CV, often resistant or
intolerant to other therapies [132]. Thereafter, two open-label randomised trials suggested that
rituximab is effective in patients with CV.
The first study, an open-label, randomised, controlled, single-center trial involving 24 (12
in each treatment group) patients with HCV-related CV, received either rituximab or
continued with their current treatments. All patients had either failed to achieve a clinical
response with antiviral therapy alone or failed to tolerate antiviral therapy. Baseline disease
activity and organ involvement were similar in the two groups. Ten patients in the rituximab
group (83%) were in remission at study month 6, as compared with one patient in the control
group (8%). The median duration of remission for rituximab-treated patients who reached the
primary end point was 7 months. This shows that rituximab can induce sustained remission in
patients with HCV-associated CV following failure of antiviral therapy. Rituximab treatment
was well tolerated and did not appear to increase HCV replication or worsen the underlying
hepatitis [133].
The second study, a recent multicenter, phase III, RCT of 59 patients, demonstrated the
superiority of rituximab monotherapy as compared to conventional therapy with
corticosteroids, AZA, CYC, or plasmapheresis for the treatment of severe HCV-associated
CV, when therapy with antiviral agents failed or was contraindicated. Clinical improvement
was noted at 12 and 24 months in greater than 60% of patients receiving rituximab [134].
These trials showed that rituximab therapy was effective in patients with CV with severe
manifestations. Furthermore, rituximab resulted in reductions in glucocorticoid use, and did
not lead to a worsening of hepatitis.
For non-infectious CV there is also some evidence that rituximab is effective. In the
French multicenter CryoVas survey, 242 patients were identified who were HCV, HBV, and
HIV negative and who had mixed cryoglobulinaemia and vasculitis; 30% had an underlying
rheumatologic disorder, 22% had a lymphoproliferative disorder, and the remainder had
idiopathic mixed cryoglobulinaemia. Rituximab plus corticosteroids showed greater
therapeutic efficacy (compared with corticosteroids alone and alkylating agents plus
corticosteroids) to achieve complete clinical, renal, and immunologic responses and a
prednisone dosage <10 mg/d at 6 months. However, severe infections were more common
with rituximab, especially in elderly patients with renal failure in whom high-dose
glucocorticoids were also used, and mortality was similar regardless of the treatment used.
The role of each of these strategies remains to be defined in well-designed RCTs [135].
Anti-Glomerular Basement Membrane (GBM) Disease (Goodpastures Syndrome)

Anti-glomerular basement membrane (GBM) disease (Goodpastures syndrome) is a
vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with basement
membrane deposition of anti-basement membrane autoantibodies. Lung involvement causes
pulmonary haemorrhage, and renal involvement causes glomerulonephritis with necrosis and
crescents. Anti-GBM disease is an autoimmune disorder that mostly presents as rapidly
progressive glomerulonephritis and pulmonary haemorrhage, together with raised titres of
antibodies against the GBM. The target Goodpasture antigen is the non-collagenous (NC1)
region of the 3 chain of type IV collagen.
Treatment is generally immunosuppression combined with plasma exchange. Most
patients with pulmonary haemorrhage respond rapidly to methylprednisolone and plasma
exchange. Early plasmapheresis removes circulating anti-GBM antibodies and other
inflammatory mediators, and therefore it is usually the treatment of choice. Plasmapheresis
with immune-suppression, usually CYC and steroids, is effective in the treatment of
pulmonary haemorrhage and substantially improves renal function [136].
With regards to therapy, few advances have been made, with the exception of isolated
case reports of the use of rituximab and MMF in resistant disease. Rituximab has been used
effectively in case series however there is no RCT to date [137]. A retrospective
observational study of 8 patients with severe and/or refractory GBM disease that received
rituximab therapy 4 weekly, using the lymphoma regime dose of rituximab (375 mg/m2),
showed good response with 7 out of 8 patients achieving complete remission 3 months after
rituximab therapy, with mean patient and renal survival of 100% and 75% respectively after a
follow-up of 25.6 months (range 4-93) [138].
The importance of T cell responses in the pathogenesis of anti-GBM disease was
evaluated using a rat model of anti-GBM, where blockade of CD28-B7, the costimulatory
pathway for T cell activation, was shown to ameliorate disease. The rationale for this attempt
was the observation that T cellmediated mechanisms may play a direct role in the glomerular
and alveolar injury that occurs in anti-GBM disease [139].
Further studies using the nephrotoxic nephritis model in the mouse have established the
importance of CD4-positive T cells, in particular Th1 and Th17 cells as effectors in the
pathogenesis of crescentic glomerulonephritis. Drugs inducing lymphocyte depletion, such as
alemtuzumab, may disrupt these natural lymphocyte regulatory processes and promote
disease [136]. Preliminary data suggest that removal of anti-GBM antibody by means of
immunoadsorption may be beneficial in patients with anti-GBM disease. However, these
results must be verified before immunoadsorption can be recommended as a therapeutic
option.
CONCLUSION
Significant morbidity and mortality associated with the systemic vasculitides has been
transformed in recent years by the introduction of aggressive immunosuppressive therapies.
However, these treatments are associated with significant adverse effects, notably infection,
malignancy and effects on fertility, as well as incomplete remission rates and high relapse
rates, particularly in AAV.
Understanding the role of B cell activity in the pathophysiology of AAV has created a
clinical need for more targeted treatment, which should also aim to minimise toxicity.
Currently, rituximab is the best studied B cell depleting agent. There is good quality evidence
to support using rituximab for remission induction in AAV, as it appears to be at least as
efficacious and as safe as the standard treatment with CYC. Moreover, in refractory and
relapsing patients rituximab was found to be superior to standard treatment, and there is now
evidence that rituximab may work effectively as a maintenance agent. The data is less
compelling for the non-ANCA associated vasculitides; however, there are promising
advances in both medium and small vessel vasculitis with rituximab being used more widely
than any other biologic agent.
For patients in whom the cumulative exposure to immunosuppressive agents is highest,
the implementation of safer and less toxic treatment is required as a priority, making the need
for further data on the long-term safety profile of biologics drugs even more relevant.
As our understanding of disease pathogenesis develops and the potential of novel
biologic therapies unfolds, more agents are developed in order to target the relevant
pathways. With these advances came new methods to monitor and assess response to these
treatments, both clinically (e.g., validated disease activity assessment tools) and using
biomarkers (e.g., minimal residual disease flow cytometric detection to confirm B cell
depletion). However, reliable biomarkers of remission and relapse are yet to be determined to
guide clinicians in their decision to initiate, titrate or altogether discontinue
immunosuppression or consider a biologic agent.
Despite the gradual accumulation of more evidence for the use of biologic agents in
vasculitis, there are still unanswered questions and uncertainties. Further controlled studies
are necessary to support the preliminary observations, and most importantly to clarify how
biologics should be best used for each condition, either in combination with other
immunosuppressive therapies or as monotherapy.
ACKNOWLEDGMENTS
The authors would like to thank Dr. Sally Hamour, UCL Centre for Nephrology, Royal
Free Hospital, London (email:sallyhamour@nhs.net) for reviewing the chapter and providing
helpful comments.
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Chapter 7
IMAGING AND PATHOGENESIS IN

LARGE VESSEL VASCULITIS:
EARLY LESSONS FOR BIOLOGIC TREATMENTS
Philip P. Stapleton1, MD PhD,

Katerina Achilleos1, MRCP,
Dimos Merinopoulos1, MD
and Bhaskar Dasgupta1,2,3, MD FRCP
1
Department of Rheumatology, Southend University Hospital, Essex, UK
2
University of Essex, Colchester, UK
3
Anglia Ruskin University, Essex, UK
ABSTRACT
This chapter focuses on large vessel vasculitis (LVV), encompassing Giant Cell
Arteritis (GCA), Takayasus Arteritis (TA) and aortitis defined by the 2012 Revised
International Chapel Hill Consensus Conference Nomenclature of Vasculitides [1]. We
include Polymyalgia Rheumatica (PMR), which can occur with GCA and aortitis.
Glucocorticoids (GC) are the mainstay treatment of large vessel vasculitides and PMR [2-
4]. However, the majority will have flares (>50%), remaining on GC for a minimum of 1-
3 years with their cumulative dose often resulting in side effects [5]. Furthermore, steroid
resistance has been frequently recorded in a subset of patients. Relapse remains common
despite use of GC and synthetic immunomodulators. We explore the use of biologic
therapies and address the unmet need of patients who are resistant or intolerant to GC
therapy, along with their use as steroid sparing agents. Having reviewed current literature
Correspondence to: Philip P. Stapleton, Department of Rheumatology, Southend University Hospital, Prittlewell
Chase, Westcliff-on-Sea, Essex, SS0 0RY, UK (email: philip.stapleton@southend.nhs.uk).
146 Philip P. Stapleton, Katerina Achilleos, Dimos Merinopoulos et al.
and clinical trials we will focus our attention on when best to commence biologic therapy
and who is most likely to benefit.
Keywords: large vessel vasculitis, imaging, glucocorticoids, anti-TNF therapy, tocilizumab,

cytokines
INTRODUCTION
GCA and PMR have a predilection for those over 50 years of age, unlike TA, which
typically affects women aged 20 to 40 years [6]. Both disease processes demonstrate chronic
granulomatous inflammation. All conditions may exhibit systemic symptoms and an
inflammatory response.
Cranial GCA is the most common of all the large vessel vasculitides, with an incidence of
22 per 100,000 patients in the United Kingdom [7]. Approximatively 20% of patients suffer
the perilous complication of permanent visual loss [8]. Large vessel GCA (LV-GCA) occurs
in younger patients with fewer cranial symptoms. Temporal artery biopsy is frequently
negative in patients with 18F-2-deoxy-2-fluoro-D-glucose positron emission tomography (18F-
FDG-PET) uptake localised around the subclavian, aorta and femoral arteries [9]. Such
patients have 17 times greater risk of developing a thoracic aortic aneurysm [10].
Aortitis has a number of causes and may be thought of as part of a spectrum of GCA and
TA. However when not attributed to a disorder, it is termed isolated idiopathic aortitis. It is
seen more frequently in males in their sixth decade. Patients with isolated aortitis often
exhibit non-specific constitutional symptoms and back pain, underestimating the true disease
prevalence [11].
Large vessel involvement in cranial GCA, TA and aortitis commonly affects the aortic
root and ascending aorta, although the aorta in its entirety and its branches can be affected.
Depending on the location of aortic inflammation, vessel dilation and luminal narrowing
occurs, occasionally resulting in critical ischaemia. Where aortic root involvement develops,
aortic insufficiency and life threatening dissection may ensue. Additional sequelae include:
hypertension, accelerated atherosclerosis and heart failure. Stenotic and occlusive lesions
occur in 90% of TA patients. The aim of treatment in this instance is to prevent vascular
progression [9].
PMR is considered a heterogeneous disease that covers a spectrum of clinical features
ranging from inflammatory arthritis to LVV. It is characterised by marked pain and prolonged
morning stiffness in the shoulders, neck and pelvic girdle that promptly respond to GC [12-
13]. PMR, like GCA is a condition of older persons with frequent overlap. PMR is observed
in 4060% of GCA patients at diagnosis, and 1621% of PMR patients develop GCA,
particularly if left untreated [14]. In up to one third of patients with PMR, subclinical arteritis
may arise at disease outset, making the requirement for further imaging, especially in patients
with constitutional symptoms and grossly elevated inflammatory markers essential [14].
Patients with refractory PMR commonly demonstrate cranial and/or extra-cranial arteritis on
imaging polymyalgia arteritica [15]. We present two case reports from patients diagnosed
with GCA who presented with constitutional symptoms with polymyalgia (Figure 1, appendix
1).
Imaging and Pathogenesis in Large Vessel Vasculitis 147
Figure 1. Imaging in LVV.
Legend: (A) Ultrasound image of axillary artery revealing thickening of arterial wall (+) suggesting
extra-cranial Giant cell arteritis (GCA); (B) 18F-FDG PET/CT and (C) 18F-FDG PET/CT images
indicate tracer uptake in the aorta and large arteries (arrows); (D-F) CT scans indicating thickening of
the aortic wall (arrowhead).
GC remain the mainstay treatment of LVV. Relapse is common with steroidal withdrawal
or tapering, as is increased morbidity with prolonged use [2, 4, 16, 17]. Synthetic
immunomodulators have been used as steroid-sparing agents in resistance cases with varying
results [18-22], which themselves do not come without side effects. A meta-analysis of
adjunctive methotrexate (MTX) with GC in the management of GCA at best demonstrated a
35% reduction in relapse rate and lower cumulative steroid dose, but no reduction in adverse
events [19].
One third to half of PMR patients develop a flare on tapering or discontinuation of GC
[23-25], whilst in just over two thirds of TA patients GC-dependence will occur [26],
requiring a second line agent (MTX, azathioprine (AZA) or mycophenolate mofetil (MMF))
in 46-84% patients, to be able to maintain remission despite an adequate dose of GC [17, 27].
In one study, 65% of patients with PMR incurred at least one serious GC-related side effect
[28].
GLUCOCORTICOID ADVERSE EFFECTS

The immunosuppressive and anti-inflammatory benefit from GC therapy is not without
cost. Their undesirable effects are well documented, especially at higher dosages. Up to 85%
of GCA and PMR patients treated with chronic GC therapy will experience adverse effects.
Commonly recorded complications can be categorised into GC-induced osteoporosis and
fragility fractures, metabolic and cardiovascular. Others include: avascular necrosis,

hypertension, cataracts, gastrointestinal effects, skin and psychological manifestations and
increased risk of infections [29]. Amongst those patients experiencing an adverse event, the
median time from initiation of treatment to first recorded side effect was 1.1 years [30]. High
cumulative GC doses were the significant contributing factor, irrespective of the initial
starting GC dose after adjusting for age and sex [30]. A positive benefit/risk ratio should be
taken into account, with patients with multiple co-morbidities such as osteoporosis, diabetes
or a predisposition to infections (e.g., bronchiectasis) benefiting from a lower starting dose
[29-31]. Alternatives to oral GC would be via the intramuscular route, which in the long term
would lower the overall cumulative GC dose, as well as contributing to a reduction in weight
gain [32].
IMAGING IN LVV
Temporal artery biopsy is the traditional gold standard test for GCA. Colour Doppler
ultrasound (CDS), magnetic resonance imaging (MRI), computed tomographic angiography
(CTA) and 18F-FDG-PET visualize both the lumen and the vessel wall of the aorta and its
branches (Figure 2).
Figure 2. Diagnosis/Imaging in GCA: addressing an unmet need.
COLOUR DOPPLER SONOGRAPHY

Colour Doppler sonography is a novel imaging modality and seems to be a promising
technique in the diagnosis of LVV. Ultrasound is easy to perform, cost effective, non-invasive
and offers real-time images, which aids management decisions. Ultrasound of the axillary
arteries improves sensitivity [33].
The inflamed vessel wall is easily identifiable by ultrasonography as a hypoechoic,
homogeneously, circumferential thickness in active untreated disease. This is also known as
the halo sign. As the disease progresses into an indolent, inactive or treated form, the wall
then becomes hyperechoic, making it difficult to differentiate from hyperechoic
atherosclerotic plaques [34]. Another feature of temporal arteritis is the compression sign
[35], defined as a persistence of hypoechoic linear signals from inflamed vascular wall, while
the lumen is occluded with probe pressure, which is then returned to normal. Furthermore,
stenosis and occlusions can also be visualised, however this in not a specific sign of LVV.
Ultrasound of the shoulders and hips may also demonstrate sub deltoid bursitis, bicipital
tenosynovitis and effusions.
Ultrasound of high quality is necessary for the examination of the temporal arteries and
large vessels. It may improve diagnostic accuracy in PMR where subdeltoid bursitis, biceps
tenosynovitis, glenohumeral or hip synovitis are characteristic findings.
We have found vascular ultrasonography to be a highly valuable analytical tool in the
clinical setting with significant benefits to the patient not least of which is the possible
avoidance of an invasive procedure. In our opinion, all rheumatologists should possess the
knowledge and competence to assess vascular pathology by ultrasonography, with this as a
standard imaging modality for GCA offered in rheumatology practice.
MAGNETIC RESONANCE IMAGING AND COMPUTED

TOMOGRAPHIC ANGIOGRAPHY
MRI provides multiplanar anatomic information about the lumen (stenosis, aneurysms),
mural thickness and perivascular tissue. MRI is particularly useful in evaluating deep, large
vessels such as the aorta, which is frequently involved in LVV. Vessel wall thickening and
oedema precede the development of stenosis or aneurysms, facilitating early diagnosis. 3T
cranial MRI with contrast [36] has been used for the imaging of inflamed cranial arteries in
GCA.
Both MRI and CTA are useful in diagnosing extra-cranial LVV where detection of
stenotic and aneurismal lesions can complicate GCA [37]. CTA provides non-invasive
angiographic sequences to assess the lumen and vascular wall. Mural thickenings, as well as,
wall enhancement in the venous phase, are considered signs of active vasculitis [37, 38].
Aneurysmal lesions at onset may indicate resistant disease and worse vascular prognosis [39].
As with ultrasonography, atherosclerosis can also elude to wall thickening, which may
accentuate the appearance of stenosis.
18F-FDG-PET
18F-FDG-PET
has a good negative predictive value [42] in steroid and DMARD nave
patients. In our experience a daily dose of <7.5mg prednisolone (or equivalent) used one
week prior to imaging helps increase diagnostic yield. Patients already on high dose steroids
for longer than a week may in fact make diagnosing LVV unreliable [42, 43]. High uptake is
also seen with atherosclerotic plaques, however this can be distinguished from vessel wall
inflammation by its non-uniform uptake [44].
In patients with PMR a characteristic pattern of pathologic 18F-FDG uptake is seen in the
soft tissue and ligaments (perisynovitis or enthesitis) around the shoulders, hips, lumbar,
ischial tuberosities, and in many cases cervical spinous processes [45]. Due to high 18F-FDG
uptake by the brain, the cranial arteries are not visualised.
PATHOGENESIS
Granulomatous inflammation is a histological feature of several of the vasculitides
including: GCA, TA, granulomatosis with polyangiitis (GPA) and eosinophilic
granulomatosis with polyangiitis (EGPA). Although the pathogenesis of the vasculitides is
not yet fully understood, this is an area that continues to stimulate research interest. The
improved knowledge about granuloma cellular environment, inflammatory responses,
immunologic derangements, and steroid responsive and resistant pathways helped shedding
more light on pathophysiologic mechanisms driving tissue responses in vasculitis. Vasculitis
can affect any size vessel and although presentation and risk factors associated differ with
varying anatomic sites these conditions should be considered as a spectrum of disease and not
as individual diseases.
Large Vessel Remodelling

Inflammation and damage perturb tissue homeostasis evoking responses that may lead to
tissue remodeling, with shear stress perpetuating this response [9]. Temporal artery biopsy is
frequently used to guide treatment for suspected temporal arteritis [46]. Biopsy specimens
from patients with active GCA showed distinct morphological features compared with
uninvolved tissue. Inflamed vessels develop an altered architectural framework through a
cascade of cellular events encompassing interaction between many cell types, cytokines and
growth factors. Ensuing intimal hyperplasia increases the potential for ischaemic related
events. Platelet-derived growth factor (PDGF) is important in stimulating intimal hyperplasia.
In GCA, PDGF is produced by CD68+ macrophages, smooth muscle cells, and multinucleated
giant cells, with macrophages at the media-intima border being the dominant source [47].
Intimal macrophages also produce vascular endothelial growth factor (VEGF), which
promotes intimal proliferation. Medial macrophages generate metalloproteinases, leading to
vascular compromise, including the internal elastic lamina [48]. Adventitial macrophages
produce interleukin 6 (IL6), augmenting the inflammatory response.
A study to determine cell adhesion molecule expression in GCA showed that constitutive
(PECAM-1, ICAM-1, ICAM-2, and P-selectin) and inducible (E-selectin and VCAM-1)
endothelial adhesion molecules for leukocytes are mainly expressed by adventitial
microvessels and neovessels within inflammatory infiltrates. Expression of the inducible
endothelial adhesion molecule correlated with the intensity of the systemic inflammatory
response [49]. Inflammation disrupts endothelium integrity and promotes neovascularization.
Adhesion molecules are more intensely expressed on these neovessels than in the vessel
lumen. Cid et al. [49] demonstrated that different adhesion molecules might regulate how
leukocytes and endothelial cells interact in different temporal artery tissues.
A cellular immune reaction to elastin has been implicated in the pathogenesis of GCA
[50]. Gillot et al. [51] reported that degradation of native elastin by leukocyte elastase could
provide elastin-derived peptides that act as autoimmune targets for T cells in GCA.
Supporting a hypothesis that elastin is an inciting antigen, disease severity has been shown to
correlate with the amount of elastic tissue within the vessels [52]. It is postulated that the
intra-cerebral arteries are typically spared from vasculitic attack due to paucity of elastic
tissue in their walls [53].
CYTOKINES IN VASCULITIS
The cytokine milieu in vasculitic tissue has been widely studied with a view to
clarification of putative cellular mechanisms/pathways, which may provide opportunity for
intervention in active disease. Study of the expression and tissue distribution of numerous
cytokines, as well as adhesion molecule expression, metalloproteinases and other components
comprising cellular inflammatory mechanisms has provided exciting findings, while also
failed to support a central role in LVV for certain inflammatory mediators prominent in other
inflammatory conditions.
A pivotal role for tumour necrosis factor alpha (TNF) in chronic inflammatory
conditions is well established with anti-TNF therapies widely used for management of
difficult to treat rheumatologic conditions. Elevated circulating TNF levels in active GCA
and increased expression in the temporal artery wall of patients with GCA were previously
reported [54]. However, the significance for this increased expression remains unclear, as
treating GCA with TNF inhibitors, (infliximab, adalimumab and etanercept) did not support
a role for this cytokine in the pathogenesis of this condition [55]. Enhanced circulating TNF
levels are reported in TA [56]. Anti-TNF therapies are the most frequently used biologic
agents in TA, and have documented efficacy in attenuating disease activity [57-61].
A literature review showed that, 135 patients with TA have been treated with anti-TNF
agents to date (109 with infliximab, 17 with etanercept and 9 patients with adalimumab), of
which 70-90% achieved remission, not achieved nor maintained with GC or DMARDS alone
[62].
Hoffman et al. [57] describes one study where 15 patients with active relapsing TA were
recruited into an open label trial of anti-TNF agents. All had received prior GC treatment,
whilst 13 had required additional immunosuppressive therapy (MTX (13), cyclophosphamide
(6), AZA (3), MMF (3), tacrolimus (2) and cyclosporine (2)). Of these, 8 patients had
received at least 2 agents in addition to GC. All 6 agents failed to maintain remission or allow
for steroid tapering. Eight patients received infliximab whilst 7 were treated with etanercept;
however, of those 7 patients, 3 were later switched to infliximab (1 due to relapse; 2 due to
lack of drug availability, although 1 switched back to etanercept due to infliximab infusion
reaction). Dosage of anti-TNF agents where based on rheumatoid arthritis regimens.
Etanercept was administered subcutaneously. Ten of the 15 patients (67%) achieved sustained
remission, which was regarded as the ability to discontinue GC in the absence of new
vascular lesions. This was achievable for only 1-3.3years. Four patients (27%) maintained
partial remission with a GC dose reduction of at least 50%. The remaining one patient failed
to respond, not only to anti-TNF treatment but also to other adjuncts.
Similar findings to those in TA have been documented in case reports/series of PMR
patients treated with infliximab [63, 64] and etanercept [65]. However, randomised controlled
trials (RCTs) of anti-TNF strategies in GCA have been unsuccessful. Hoffman et al. [66]
were unable to show benefit from infliximab in GCA patients. They did however
acknowledge limitations to their study, which had a small sample size and short follow-up.
They also used a low dose of infliximab and rapidly tapered patients off prednisolone.
Despite these limitations, they felt that TNF blockade in a larger it is likely to offer only
minimum benefit at best. A study by Kreiner et al. [65] evaluating the efficacy of etanercept
was also less impressive than it had been anticipated. While there was a documented benefit
in GC nave PMR patients, the response was moderate. The authors concluded that despite
elevated circulating TNF in PMR, this cytokine might only have minor contribution to the
pathogenesis of PMR. Interestingly, despite a positive effect on TA with anti-TNF agents,
two studies reported development of TA in patients treated with anti-TNF medications for
other reasons [67, 68]. The 2015 European and American (EULAR-ACR) PMR
recommendations do not support the use of anti-TNF biologic agents for PMR because of
lack of benefit and associated high costs [69].
IL6 in LVV
IL6 is a pro-inflammatory cytokine secreted by numerous cell types including T cells,
macrophages, and endothelial cells. It orchestrates a plethora of biological functions
depending on its target cell [70]. Physiologic effects mediated by IL6 include triggering the
hepatic synthesis of acute phase proteins. It facilitates the development of specific immunity
[71] and is important for B- and T-lymphocyte differentiation, generation of Th17 cells and
fibroblast proliferation [72].
Increased circulating IL6 in untreated GCA and PMR with significant decline in levels
after steroid therapy was first reported by Dasgupta and Panayi [73]. Further reports have
shown that circulating IL6 levels correlate with disease activity [73, 74]. Increased circulating
levels are also well documented in TA [75] and chronic periaortitis [76], with elevated serum
IL6 levels reflecting disease activity. IL6 mRNA and protein are reported in arterial media
and adventitia explants from patients with histologically proved GCA. IL6 is mainly derived
from macrophages in the media, whereas fibroblasts are the source of IL6 in the intima.
Neither endothelial cells nor giant cells express the IL6 gene. Corticosteroid treatment
attenuated increased IL6 serum concentrations to normal levels in most patients [77]. With
extensive documentation of elevated IL6 levels in conditions encountered in rheumatologic
practice contemplating a role either pivotal or peripheral for this cytokine in the pathogenesis
of these conditions is reasonable.
The advent of tocilizumab, a humanised monoclonal antibody against the IL6 receptor
(IL6R), has offered new depth to our ability to manage difficult to treat conditions such as
PMR, GCA and TA. Unlike strategies targeting TNF in refractory LVV, which proved
disappointing, the data-to-date from targeting IL6 pathways, is encouraging. Literature
searches show an expansion of global studies in diverse patient populations with typically
positive results. Much attention has focused on GCA patients with disease refractory to GC or
intolerance due to adverse effects from prolonged therapy.
Studies and case reports have demonstrated the benefits of tocilizumab monotherapy, not
only in inducing remission in DMARD naive individuals, but also in enabling corticosteroid
tapering safely. Caution should be taken in patients with known diverticular disease, as there
is risk of bowel perforation that is increased with concomitant NSAIDs or long-term steroid
use [78, 79]. In our experience, we have found that refractory GCA patients demonstrated an
adequate response to tocilizumab, although with relapse occurring once the treatment was
discontinued, indicating that long-term therapy is required, which is consistent with other case
studies [26]. It remains unclear whether tocilizumab can prevent GCA-related ischemic
events [17].
Salvarani et al. [80] reported tocilizumab effectiveness and tolerance in a small group of
LVV patients presenting with either GCA or TA. Other groups reported similar findings in
GCA [81-84], TA [85, 86] and PMR [87, 88]. Interestingly, Takenaka K, et al. [89] treated a
single patient with an ANCA associated vasculitis (AAV) complicated by a rare combination
of aortitis and hypertrophic pachymeningitis. This condition was refractory to conventional
management with GC and cyclophosphamide. By replacing cyclophosphamide with
tocilizumab, the aortitis improved with successful steroid tapering. While tocilizumab had
been reported beneficial in aortitis associated with TA and GCA, the findings from this study
suggested that tocilizumab may also offer a novel therapeutic option in AAV.
Refractory or relapsing TA to both non-biologic therapy and anti-TNF inhibitors has
been shown to respond well to tocilizumab (even as monotherapy), in steroid nave, newly
diagnosed TA patients, with most of them achieving remission within 3 months. These
responses were reflected on repeat 18F-FDG-PET CT imaging demonstrating reduced
uptake/re-vascularisation of stenotic vessels at 6 months [80, 90, 91]. However, other studies
have reported negative results with tocilizumab, with progression of vascular lesions on
imaging, irrespective of normalization of inflammatory markers in patients with TA [92, 93].
Data regarding tocilizumab efficacy in PMR is limited and based on case reports.
According to the literature, only 11 PMR patients have been treated with tocilizumab to date,
7 of which had co-existent GCA. Five patients received tocilizumab alone, whist the
remaining required additional GC. A favourable clinical and biochemical response was
documented in all patients without any severe adverse events, although disease remission was
variable [13].
While current reports are generally encouraging, it is widely acknowledged that larger
studies are required in this area. Specific awareness to potential detrimental effects from
chronic blockade of a pivotal player in host defence such as IL6 must be considered.
Does IL1 Have a Role in LVV?

IL1 is an immune mediator with pleiotropic functions, affects virtually all cells and
organs in the body [94, 95]. IL1 may be a central player in the pathogenesis of many auto-
inflammatory, autoimmune, infectious diseases, and in sterile inflammation [96]. The IL1
family comprises a total of 11 members, including the two activating cytokines IL1and
IL1 as well as an inhibitory mediator, the IL1 receptor antagonist. IL1 is processed and
activated by a caspase-1 dependent mechanism in conjunction with inflammasome assembly,
as well as by caspase-1 independent processes that involve neutrophil proteases. These
mediators are mainly pro-inflammatory but can also be anti-inflammatory and are important
in almost all inflammatory conditions, exerting their specific effects via IL1 receptors (IL1R)
[97].
IL1 and IL1 bind to the same receptor (IL1R type I - IL1RI), and have similar
biological functions, mainly pro-inflammatory activities. IL1 is biologically active as a
precursor molecule; however, IL1 is produced following inflammasome activation. Once
activated, IL1 and IL1 act as potent pro-inflammatory cytokines at the local level,
triggering vasodilatation and attracting monocytes and neutrophils to sites of tissue damage
and stress. Unrestricted IL1 activation is a central component of some inflammatory diseases,
including rare hereditary syndromes with mutations in inflammasome-associated genes or
more frequently encountered inflammatory conditions, such as gout. Like TNF- and IL6,
IL1 is highly expressed in inflamed arterial walls of patients with GCA. Deng et al. [98]
showed that two pathogenic pathways mediated by Th17 and Th1 cells contribute to the
systemic and vascular manifestations of GCA. Plasma interferon-gamma (IFN) and IL17 and
frequencies of IFN-producing and IL17-producing T cells were markedly elevated before
therapy in patients with GCA. Glucocorticoid treatment suppressed the Th17, but not the Th1
cells in the blood or vascular lesions. IL17-producing Th17 cells are sensitive to
glucocorticoid-mediated suppression, but IFN-producing Th1 responses persisted in treated
patients. It was suggested that targeting steroid-resistant Th1 responses is necessary to resolve
chronic smoldering vasculitis, while monitoring Th17 and Th1 frequencies may aid in
assessing disease activity in GCA.
Four IL1 inhibitors are currently available for clinical use: anakinra (an IL-1 receptor
antagonist), rilonacept (a dimeric fusion protein consisting of the ligand-binding domains of
the extracellular portions of the human IL1 receptor component (IL1R1) and IL1 receptor
accessory protein (IL1RAcP) [99], canakinumab (a human monoclonal antibody directed
against IL1 [100], and gevokizumab a monoclonal antibody with high affinity for IL1
[101].
Ly et al. [102] reported on three patients with refractory GCA successfully treated with
anakinra, with improvement in inflammation biomarkers and/or in their symptoms for all
patients, and resolution of arterial inflammation in PET/CT in two patients. A randomised
multi-centre double-blind, placebo-controlled proof-of-concept study to evaluate the efficacy
and safety of gevokizumab on polymyalgic non-ischemic flares of GCA symptoms receiving
oral GC was prematurely closed because gevokizumab failed its primary outcome in Behets
disease trials [103].
IL33 and LVV

IL33 is a cytokine belonging to the IL1 superfamily. It induces Th cells, mast cells,
eosinophils and basophils to produce type 2 cytokines. IL33 mediates its biological effects by
interacting with the receptors ST2 (also known as IL1RL1) and IL1 Receptor Accessory
Protein (IL1RAP) and activating intracellular molecules in the NF-B and MAP kinase
signalling pathways that drive production of Th2 cytokines from polarised Th2 cells.
IL33 is a recently described novel activator of endothelial cells, which promotes adhesion
molecules and pro-inflammatory cytokine expression in the endothelium, and angiogenesis
and vascular permeability, both in vitro and in vivo [104].
A role for IL33 in inflammatory diseases, such as rheumatoid arthritis and psoriasis, has
been demonstrated, and IL33 was identified as a potential therapeutic target in chronic
inflammation [105]. Ciccia et al. [106] quantified tissue IL33 levels in temporal artery biopsy
specimens from 20 GCA patients and 15 controls. They reported significantly elevated tissue
IL33 levels in the inflamed arteries of GCA patients. The neovessels scattered through the
inflammatory infiltrates, were the main sites of IL33 expression. Arteries from
glucocorticoid-treated patients had an attenuated expression of IL33.
A meta-analysis of 1,363 biopsy-proven GCA patients and 3,908 healthy controls from
four European cohorts (Spain, Italy, Germany and Norway) concluded that there is indication
for a role of the IL33 rs7025417 polymorphism in the genetic network underlying GCA
[107]. Further study evaluation IL33 in GCA is needed before robust conclusion regarding a
role for this cytokine in this condition can be confidently attributed, but early research is
supportive of this hypothesis.
T Cells in LVV
Cellular responses to an unknown stimulus and cell-cell interactions, which both
characterise the pathogenesis of LVV are complex. The vessel wall, which is generally
considered an immune-privileged site, accommodates granuloma formation with an ensuing
nidus of inflammation, leading to structural changes, intimal hyperplasia, and vassel
occlusion. This process is dependent on T cells that produce IFN in the vicinity of the vasa
vasorum which are localised in the adventitia [108].
Although granulomatous infiltrates are composed of CD4 T cells and activated
macrophages, the genesis of GCA inflammatory process is due to the activated dendritic cells
embedded in the vessel wall [109, 110]. These cells positioned at the media-adventitial
junction act as sentinels. Dendritic cells within a granuloma express the chemokine receptor
CCR7, which, by binding with CCL19 and CCL21, retains the activated dendritic cells within
the arterial wall. Krupa et al. [111] proposed that restricted movement of these cells to
lymphoid organs is critical in maintaining the T cell activation and granuloma formation in
GCA.
When activated, vascular dendritic cells initiate a cascade of events resulting in T cell
activation. T cells have been extensively evaluated in GCA; this led to the identification of
two pathogenic pathways mediated by Th17 and Th1 cells that contribute to the systemic and
vascular manifestations of GCA. The gold standard treatment for GCA remains the
immediate administration of steroids. Deng et al. [98] have shown that the response to
steroids was orchestrated by corticosteroid sensitive IL17 producing Th17 cells, with Th1
derived IFNmediated responses resistant to steroid therapy. They suggested that monitoring
Th17 and Th1 frequencies can aid in assessing disease activity in GCA, and targeting steroid-
resistant Th1 responses may be necessary to resolve chronic smouldering vasculitis.
IMMUNOSENESCENCE
Age as a risk factor for GCA and PMR may be influenced by altered immune function.
Immunosenescence results in decline of the nave T-cell pool, weakened T-cell diversity, and
impaired innate immunity. Deteriorating capacity of immunocompetent cells in the aging host
alters protective immunity, and confers risk for pathogenic immunity leading to chronic
inflammatory tissue damage. Aging also imposes vascular changes with the arterial wall
undergoing structural changes with loss of pliability and elasticity in medium and large
arteries. These changes parallel immunosenescence [112]. Age as a risk factor in GCA and
PMR may well be influenced by dual loss of vessel wall integrity and a weakened immune
repertoire.
B CELLS IN LVV
Current evidence suggests that B cells do not play a significant role in the pathogenesis of
LVV or PMR. Initial reports showed that B cells are not predominant in the inflamed
temporal arteries of GCA patients or detected in the affected joints of PMR patients [113,
114]. This view is changing however, with reports that Serum B cell activating factor (BAFF)
also known as B-lymphocyte stimulator (BlyS) is increased in these conditions, and that
BAFF with IL6 show the most robust correlation with disease activity in both GCA and PMR
[115].
BAFF is a member of the TNF family, and is pivotal in B cell development by promoting
B cell survival and transition from the immature to mature B cell stage as well as Ig-class
switching and antibody production. Besides B cells, BAFF can also augment certain Th1
responses in vivo [116]. Several cell types are capable of making BAFF with cells of the
monocyte/macrophage lineage appear to be a primary source of BAFF production in vitro
[117].
Van der Geest et al. [118] evaluated the relationship between B cell numbers, B cell
phenotype, and serum BAFF levels in patients with newly diagnosed GCA and PMR. Active
disease was characterised by an inverse relationship between decreased B cell numbers,
especially low B effector (but not regulatory B) cells, and increased serum levels of BAFF.
Following corticosteroid treatment, serum BAFF and the number of B effector cells
normalised. B effector cells generated enhanced IL6 levels, and the authors speculated that B
cell-derived IL6 might potentiate T cell-mediated autoimmune responses (Th17 responses),
linking these two arms of the immune system together. This hypothesis was accentuated with
the observation of a positive correlation between serum BAFF and IL6 levels in both GCA
and PMR.
With these findings BAFF continues to attract interest regarding its potential importance
in the pathogenesis of LVV, and as a putative therapeutic target in these conditions. Nishino
et al. [119] reported elevated BAFF levels in patients with active TA, and attenuation of these
levels in disease activity remission.
Belimumab, a monoclonal antibody to BAFF is approved in the United States, Canada
and Europe for of SLE, and is currently under investigation in the BREVAS trial for AAV.
With new insight into a possible role for B cells in LVV, opportunities may present for the
development of strategies to target B cell biology in refractory PMR, GCA and other large
vessel vasculitides.
CLINICAL TRIALS IN LVV

With disease flares common and serious co-morbidities associated with chronic GC
therapy, alternative treatment strategies have been explored in LVV and PMR, primarily as
steroid-sparing agents. Steroid-resistant GCA was also reported [20], underlying a need for
safe and effective steroid-sparing therapies in GCA. Methotrexate has demonstrated modest
benefit, whilst the anti-TNF agents, such as infliximab and etanercept, have not shown
efficacy [120, 121]. With the identification of accentuated circulating IL6 levels in these
conditions by Dasgupta and Panayi [122], cause and effect was explored with IL6 receptor
blockade targeted as a novel therapeutic strategy for GCA and PMR. The role of biologic
therapy in LVV remains to be established (Figure 3).
Figure 3. Biologic therapy in LVV: addressing an unmet need.
There are many case series and reports of efficacious and safe IL6 receptor blockade with
in refractory and relapsing cases of GCA, PMR and LVV, with good clinical and biochemical
response [82, 84, 85, 123-126]. In addition, several studies achieved a significant reduction or
complete withdrawal of GC [80, 82, 123-125]. However, significant adverse effects are
documented in two reports [82, 124]. Tocilizumab showed good clinical response in a series
of 30 patients with GCA from the Mayo clinic, with complete remission at week 12 and
relapse-free at week 52 [127]. Tocilizumab was also found to be effective in a retrospective
French study of 34 patients with refractory GCA; however, four significant adverse events
were recorded including tuberculosis pericarditis, liver cytolysis and neutropenia with one
death from septic shock [127]. Tocilizumab was administered as monotherapy to 20 GC nave
patients with PMR, with improvement in all clinical and biochemical parameters [128]. In a
retrospective multi-centre French study of 8 patients with TA, tocilizumab showed efficacy
and reduction of steroid dose [129]. Long-term use of tocilizumab showed good symptomatic
and biochemical responses in a case series of 8 patients with refractory GCA, in which cases
GC dose reduction was achieved successfully. However, one significant adverse event
(empyema) was reported, indicating the need for careful monitoring of infection in patients
treated with tocilizumab [130].
GiACTA is the first on-going phase III, multicentre, randomised, placebo-controlled,
double blind, and parallel-group trial in patients with GCA on tocilizumab. The primary
objective of this study is to evaluate the efficacy of tocilizumab (subcutaneous injections 162
mg given every week or 2 weeks) compared with placebo, in combination with a 26-week
prednisone taper regime, in GCA, as measured by the proportion of patients in sustained
steroid-free remission at week 52, following induction and adherence to the prednisolone-
tapering regime. The inclusion criteria for this study were: diagnosis of GCA, age >50 years,
ESR >50 mm/hour, and unequivocal cranial symptoms of GCA or symptoms of PMR and
positive temporal artery biopsy, or evidence of large vessel vasculitis by angiography or
cross-sectional imaging such as MRA, CTA or PET-CTA [131]. A planned total of 254
patients have been enrolled and assigned to one of four treatment arms. After a follow up of a
year patients may continue on open label extension for another 2 years. Results are awaited in
the autumn of 2016.
A trial evaluating the efficacy of abatacept (T cell activation inhibitor) in GCA showed
that the addition of abatacept to a standard treatment regimen with prednisone reduced the
risk of relapse of vasculitis, and was not associated with a higher rate of toxicity compared to
prednisone alone. The SIRRESTA study evaluating sirukumab (IL6 inhibitor) in GCA (Table
1) is also undergoing. This study aims to recruit approximately 204 subjects, aiming to
evaluate the efficacy and safety of sirukumab and characterize the benefit-to-risk profile of
this agent in the treatment of active GCA. The study is designed with two phases, part A: a
52-week double-blind treatment phase and part B: a 104-week extension phase, with the
option to receive open-label sirukumab based on disease status and a further 16-week follow-
up assessment, if applicable.
There have been two clinical trials relating to aortitis. One in the context of carotid artery
neovascularisation in TA and GCA, and the other related to immunoglobulin G4 (IgG4)-
related disease. However, due to the rarity of this condition, little evidence has been found
with regards to biologic treatment of idiopathic aortitis. What is known is based on case
reports and scientific abstracts. Tocilizumab seems to be the most trialled agent of choice
[132].
Various factors, either single or cumulative, often impede patient recruitment into clinical
trials. An obstacle to recruitment for GCA trials has been requirement for histological
confirmation by temporal artery biopsy [133]. This may be overcome in future studies, by
using colour Doppler ultrasonography as a primary diagnostic modality, negating the need for
temporal artery biopsy. This question was addressed in the TABUL trial, which was
completed in December 2014 with results awaited.
In a review of clinical trial design in AAV and LVV, Tarzi et al. [134] addressed many
important areas for consideration in trial design. Such issues include imaging, outcome
measures, steroid tapering and patient recruitment. The authors suggest that trials with LVV
are more challenging than AAV trials, due to less robust disease activity indices and lack of
valid biomarkers able distinguish active disease from damage.
Attempts to address such limitations led to an initiative to develop a core set of outcome
measures for use in clinical trials of LVV, launched by the international OMERACT
Vasculitis Working Group in 2009 [135]. A second such undertaking, led to the elaboration of
the Indian Takayasu Clinical Activity Score (ITAS 2010) as a measure of clinical disease
activity in TA [136].
When presented with a case of suspected GCA, the clinicians desire to preserve sight is
paramount.
Table 1. Biologic therapy clinical trials in LVV/PMR
Condition with Target Biologic agent Outcome Trial Status

inclusion criteria
GCA with new TNF Infliximab A multicentre double blind-RCT G. Hoffman, et al., Terminated
(cranial) symptoms 5 mg/kg/8 weeks + oral (n = 44) of infliximab enrolling new GCA patients 2007 [66] early
responsive to prednisone 40-60mg (ACR criteria) was terminated early due to lack of
glucocorticoid benefit of this therapy.
therapy 5 days,
No difference between groups (at 22 weeks) was
on GC for less than 4 noted: patients without a relapse [12 (43%) vs. 8
weeks and stable (50%)], patients in glucocorticoid-free remission [11
oral prednisone 40- (39%) vs. 7 (44%)], cumulative GC dose (3.2 g vs.
60mgfor more than 1 3.1 g)
week
GCA TNF Etanercept A single-centre, 15-months double blind-RCT V. Martinez-Taboada, Completed
(n = 17) of etanercept in GCA (TAB+) in remission, et al., 2008 [121]
GCA in remission, found a lower cumulative GC dose in the etanercept
on stable oral compared to the placebo group (1.5 g vs. 3.0 g at
prednisone dose 10 12 months, p = 0.03), but did not find differences
mg/day regarding other outcomes. Only 6/17 patients
for 4 weeks, completed the first 12 months of this trial.
patients with one or

more side-effects to
glucocorticoids
GCA, new (cranial), TNF Adalimumab n = 70; adalimumab, n = 34; placebo, HECTHOR Completed
on GC for less than n = 36. Adding a 10-week treatment of adalimumab ClinicalTrials.gov
14 days, with no to prednisolone did not increase the number of Identifier:
ocular/vascular patients in remission on less than 0.1 mg/kg of GC at NCT00305539
manifestation 6 months.
GCA, IL6 Tocilizumab IV given n = 30 patients on tocilizumab + GC Tocilizumab for patients Completed
newly diagnosed monthly 8mg/kg vs. n = 20 patients on placebo + GC. with GCA.
placebo for 1 year Maintenance of remission in treated group 85% vs. S. Adler, et al. [126]
20%, p = 0.008.

inclusion criteria
GCA, newly IL6 Tocilizumab 2 doses n = 250; 52-week blinded treatment phase GiACTA Completed
diagnosed or 162mg weekly or followed by 104 weeks of open-label recruitment, in
relapsing, fortnightly vs. placebo extension. Steroid tapering to nil at 26 and 52 S. Unizony, et al., 2013, [131] follow up
meeting modified with steroid withdrawal in weeks.
1990 ACR criteria, 6 months
biopsy positive SOC arm with steroid
withdrawal in 12 months
GCA, newly IL6 Sirukumab n = 204; SIRRESTA: Sirukumab for Recruiting
diagnosed or Part A 52-week double-blind treatment phase, treating GCA.
relapsing, meeting with a pre-specified prednisone taper GlaxoSmithKline
modified 1990 ACR (complete steroid withdrawal in 3 or 6 ClinicalTrials.gov Identifier:
criteria, biopsy or months. NCT02531633
imaging positive Part B, a 104-week extension phase.
GCA, relapsing, IL1 Gevokizumab A randomised, double-blind, placebo- Gevokizumab for treating Closed because
with no ischemic controlled proof-of concept study of the GCA. gevokizumab
features efficacy and safety of gevokizumab in the EU Clinical Trials Register failed primary
treatment of patients with GCA EudraCT Number: 2013- outcome in
002778-38 Behets trial
GCA/TA, T cells Abatacept IV given at n = 49 received study drug, with 41 reaching AGATA: Abatacept for Completed
newly diagnosed days 0,15,29 and at week week 12 (abatacept = 20; placebo n = 21) Treating Adults With Giant
or relapsing 8, and randomised at week Relapse free survival with abatacept 49% vs. Cell Arteritis and Takayasu's
12 to monthly abatacept or placebo 31% (p = 0.049) Arteritis.
placebo C. Langford, et al., 2015 [148]
PMR, newly TNF Etanercept Randomised single centre; Etanercept treatment in the Completed
diagnosed n = 40 - PMR, early course of PMR. F.
n = 20 - controls. Kreiner et al. [65]
No difference between groups (2 weeks):
PMR activity score (32 vs. 31 points).
Etanercept related adverse events (at 2
weeks): local injection reactions occurred in 2
(20%) vs. 1 (8%) patients
inclusion criteria
PMR, newly TNF Infliximab 3 No difference between groups at week 52 C. Salvarani, et al., 2007 Completed
diagnosed, untreated mg/Kg/ -patients without a relapse [6 (30%) vs. 10 (37%)], [149]
8 weeks + GC -discontinuation of GC [10 (50%) vs. 14 (54%)] Australian Clinical Trials
initially 15 mg -duration of glucocorticoid therapy (26 vs. 22 weeks), Registry number:
daily vs. GC -cumulative glucocorticoid dose (1.7g vs. 1.2 g) ACTRN012606000205538
alone -glucocorticoid adverse events (1 vs. 6 events).
Infliximab related adverse events (52 weeks)
-numerically higher rate of infusion reactions (4 vs. 0
events)
-systemic infections (1 vs. 0) in the infliximab group
PMR, new untreated IL6 Tocilizumab n = 20; 3 infusions of tocilizumab at weeks 0, 4, 8, with Tenor; V. Devauchelle, et Completed
monotherapy week 12 - 24 on GC treatment. al., 2015 [128]
Primary end point PMR-AS < 10.
At week 12, all reached the primary end point.
Median PMR-AS at week 12 and 24 were 4.5 (IQR: 3.2-6.8)
p < 0.001 and 0.95 (IQR: 0.4-2) p < 0.001.
Improvement in all parameters, CRP, ESR, patient VAS
pain, fatigue, physician VAS, QOL, MCS, PCS
Aortitis B cells Rituximab n = 30 on rituximab, Rituximab in IgG4-related Complete
n = 26 on GC. disease.
Rituximab appears to be an effective treatment for IgG4- ClinicalTrials.gov
related disease, even without concomitant GC therapy Identifier:
p<0.00001 NCT01584388
Legend: ACR - American College of Rheumatology; CRP - C reactive protein; GC - glucocorticoids; ESR - erythrocyte sedimentation rate; IQR - interquartile range; MCS -
mental component score; PCS - physician component score; PMR-AS - polymyalgia rheumatica activity score; QOL - quality of life; SOC - standard of care; TAB+ -
temporal artery biopsy positive; VAS - visual analogue scale.
While immediate high dose GC therapy is essential for minimizing the risk of irreversible
damage, this treatment can be rapidly discontinued in the ensuing days, if the diagnosis of
GCA is not confirmed. More complex situations arise however in patients with established
GCA, commonly presenting with symptoms such as new or worsening headache. This can
lead to increasing GC doses, even though other clinical and serologic markers may argue
against an acute exacerbation. Inappropriate augmentation of steroid therapy is frequently a
response to concern regarding risk of irreversible sight loss. Often steroid-sparing regimens
are inconsistent and poorly defined when designing clinical trials in LVV, which may lead to
suboptimal outcome, despite sound rationale supporting the evaluation of a novel agent
efficacy for induction of disease remission or maintenance. This common problem was
recognised and addressed in the design of the GiACTA trial.
The cost of clinical trials is a very important consideration. Cost analysis and return on
outlay is important and must be considered. Due diligence for costs should be given to the
design of any clinical trial, and while frustrations often arise from financial constraints, it is
the duty of every clinician and researched to ensure that limited budgets are utilised in the
most cost effective and equitable manner to ensure that continuation of realistic and feasible
research is possible.
ADVERSE EVENTS ASSOCIATED WITH THE USE

OF BIOLOGIC THERAPY
The British Society for Rheumatology Biologics Register (BSRBR) revealed that,
although patients treated with TNF antagonists are not associated with increased risk for
developing serious infections compared to traditional DMARDs, they have a significantly
increased risk for skin and soft tissue infections [137, 138].
As with other biologics, the risk of infections with tocilizumab, in particular respiratory
tract and gastrointestinal infections is increased [139]. Furthermore, when combined with
MTX, this risk is increased to 23%, albeit most of the reported infections are mild [140]. Risk
factors for increased risk of infection include the concomitant treatment with GC, leflunomide
or proton-pump inhibitors (Table 2). The majority of data were derived from patients with
rheumatic disorders [141].
Table 2. Tocilizumab Toxicity profile
Common side effects Less common side effects

Tocilizumab Deranged lipid enzymes Recurrent pneumonia
Deranged liver function tests CMV infection
Neutropenia Skin and soft tissue infections
Mild upper respiratory tract infection Infective endocarditis
Lower gastrointestinal perforation
Demyelination
AN INFECTIOUS AETIOLOGY
Infections, mainly viral, are considered among the cause of some vasculitides.
Associations between hepatitis B virus with polyarteritis nodosa (PAN), and mixed
cryoglobulinemia and hepatitis C virus are well-established. Many groups have investigated
the role of infectious triggers in LVV. Despite a paucity of compelling data, speculation
persists for an infectious aetiology for LVV, with a yet to be defined microbiologic trigger
leading to maturation of dendritic cells localised in the adventitia of arteries.
Infectious stimuli, including Chlamydia pneumonia [142], varicella virus [143], and
parvovirus B19 [144] are reported in GCA. However, conflicting reports argue against
infectious stimuli in these patients. Cause and effect for Borrelia infection was suggested in
one study in PMR/GCA, in which 12 from 19 patients tested positive for IgG titres against
Borrelia antigens [145]. In a case report, an association between Mycobacterium tuberculosis
and TA was also proposed [146].
The co-existence of infectious agents should be considered in patients with active LVV.
Patients frequently develop infections, as a consequence of immunosuppressive treatment
[147]. Whilst identification of an infectious trigger for these conditions remains elusive, this
should not be dismissed out of hand, particularly in light of wider use of biologic therapies for
LVV.
CONCLUSION
Large vessel vasculitides, despite being less common than inflammatory joint diseases for
example, represent a significant cause of morbidity in rheumatic patients. There is a well-
documented predilection for TA in younger women of Asian descent; however, in Europe, we
are likely to see more GCA and PMR in the years ahead because of the ageing population. It
is important to recognise these conditions not only as unique entities, but as a spectrum of
diseases, with bias for specific anatomic sites involvement based on shared physiology. For
example, although PMR and GCA present with different clinical pictures, they are commonly
regarded as variations of the same disease.
While GC therapy is a well-established corner stone for management of LVV and PMR,
there is also universally acknowledged that steroids are associated with significant co-
morbidities. With greater emphasis on the importance of research underlying current clinical
practices and advancing technology, we are witnesses to a thriving generation of biologic
agents, aiming to expand the therapeutic options for our patients. Better understanding of the
complexities and intricate workings of inflammatory responses and immune system, should
be exploited in the future for patients benefit. Specific molecular targeted therapies, such as
blockage of TNF and IL6, were developed through a meticulous understanding of the role of
these proteins in inflammatory/immune responses, and this has translated into better disease
control in refractory cases.
The pathogenesis underlying LVV is complex and undoubtedly multifactorial. Age and
genetic predisposition cannot be addressed by therapies, however, counteracting the
pathological aspects of the disease can minimize the risk for long-term morbidity associated
with LVVs.
In this chapter, we addressed selected areas of research and therapeutic advances in

LVVs, reflecting as accurately as possible on the current treatment strategies.
We acknowledge however, that the literature in this area is vast, and a full review of the
cellular mechanisms or molecular pathways proposed to underlie precipitation and
progression of LVVs is beyond the scope of this chapter.
KEY LEARNING POINTS

Colour Doppler sonography is a novel imaging modality in the diagnosis of LVV.
GC remain the mainstay in the treatment of large vessel vasculitides, however there
is an unmet need for steroid sparing agents.
There is a moderate reduction in the cumulative GC dose with the use of synthetic
immunomodulators
Alternative/adjunctive therapies that can add in tapering the GC doses should be
considered in patients with multiple co-morbidities and exacerbation of concurrent
conditions
Anti-TNF therapy was not found to be efficacious in the management of GCA or
PMR.
The IL6 inhibitor tocilizumab appears a promising treatment in all large vessel
vasculitides.
Tocilizumab has shown efficacy in mediating GC dose reduction.
Recurrence of disease was frequently reported on cessation of biologics, and
increased doses of drug are often required over time to maintain disease remission,
thus lifelong treatment is required, especially in the case of TA.
Trials are currently underway looking into the efficacy of abatacept and sirukumab in
GCA and TA.
Monitoring patients on tocilizumab should not be solely reliant on the inflammatory
markers. Instead, a combination of clinical features and repeated imaging is required
to rule out active disease, and assess for the presence of new pre-stenotic lesions.
The risk of infection (particularly soft tissue and skin infections) is increased, as are
lower gastrointestinal perforation, in patients treated with steroids and biologics.
Further studies are required to establish the adequate strategy of additional biologic
therapies in LVV.
As the biologic agents are expensive, we need further clinical trials to identify their
utility: either reserved for refractory cases or part of an induction treatment regimen.
APPENDIX 1: EXEMPLARY CASES OF GCA WITHOUT

CLASSIC CRANIAL MANIFESTATIONS
Case 1: A 73-year old man with a history of COPD, hypertension, coronary artery disease
and a previous complicated cholecystectomy, noticed weight loss (14kg) and epigastric pain
radiating to his back. He was referred for urgent investigation. Circumferential thickening
throughout the aortic wall and an infra-renal aortic aneurysm was found on a CT scan.
Rheumatologist assessment revealed prolonged early morning stiffness, in addition to
constitutional symptoms, suggesting PMR. Blood tests found a CRP of 100mg/L. Vascular
ultrasound demonstrated a halo sign bilaterally affecting the axillary, temporal and facial
arteries. An 18F-FDG PET/CT scan confirmed aortitis, as well as involvement of the
subclavian and femoral arteries. Changes typical of giant cell arteritis, with prominent intimal
hyperplasia, lumen narrowing and numerous giant cells in the medial and external lamina
were reported in temporal artery biopsy specimens. High dose prednisolone resulted in rapid
resolution of abdominal pain, polymyalgic and constitutional symptoms, as well as decrease
in the inflammatory markers. Subsequently, the patient has been in remission on leflunomide
10 mg and prednisolone 5 mg daily.
Case 2. A 78-year old man developed recent onset anorexia, myalgia, weight loss, and
progressive breathlessness. Chest radiography, high-resolution chest CT and lung function
tests were consistent with pre-existing interstitial lung disease; however, this was not thought
sufficient to explain his recent constitutional symptoms. Further investigations including a CT
of the abdomen and colonoscopy revealed diverticular disease, without other pathology. CRP
was elevated to 154 mg/l; ANA titre was weakly positive, with further autoimmune screen
negative. Subsequent PET/CT scan showed tracer uptake in a number of large vessels,
including the aorta.
The rheumatologist review highlighted polymyalgic symptoms with subacromial
impingement and early morning stiffness. His temporal arteries were thickened but not tender,
and he denied headache. Vascular ultrasound showed a prominent halo in the axillary and
temporal arteries, and a subsequent temporal artery biopsy revealed classical histological
changes of active GCA, with oedematous fibroplasia of the internal layer, as well as
transmural inflammation with giant cells engulfing necrotic elastic fibres. High dose
prednisolone (60 mg daily) was started. On steroids, he made excellent symptomatic
improvement with near normalization of the inflammatory markers.
ACKNOWLEDGMENTS
We wish to express our sincere appreciation to Dr Elisabeth Brouwer, Department of
Rheumatology and Clinical Immunology, AA21, Hanzeplein 1, P.O. Box 30 001, 9700 RB,
Groningen, Netherlands (email: e.brouwer@umcg.nl) for reviewing this chapter.
We would also like to express our appreciation to Dr Faidra Laskou for her tireless
efforts in helping to format and review references for this chapter.
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Chapter 8
BIOLOGICS IN BEHET SYNDROME
Emon Khan, MRCP, FARCP *

Department of Rheumatology, University College London, London, UK
ABSTRACT
The management of Behets syndrome is complicated by its unknown aetiology,
multi-systemic manifestations and the lack of validated outcome criteria, and available
biomarkers to identify those at risk. A number of patients will have severe disease,
particularly those with ocular, neurological and vascular involvement, and these patients
tend to be refractory to more conventional therapy, such as colchicine, azathioprine,
cyclosporine and methotrexate. Since the approval of infliximab for use in the late 1990s,
there have been numerous biologic agents that have come onto the market, with multiple
targets, such as tumour necrosis factor alpha (TNF), interleukin (IL) 1, IL6, IL2 and
IL17. These cytokines have been shown to play a role in the pathogenesis of Behets
syndrome manifestations, and monoclonal antibodies to these targets have been used in
its treatment. Herein, I discuss the use of anti-TNF and anti-IL1 agents in particular, as
well as more novel agents such as tocilizumab, secukinumab and alemtuzumab. One of
the concerns when assessing the role of these therapies is the paucity of large clinical
studies, so, much of the data is from open-label trials, case series reports and expert
opinion. This remains a concern when coming to conclusions regarding therapy, so more
studies of greater weight need to be performed focussing on specific subsets of Behets
syndrome patients.
Keywords: Behets syndrome, biologic treatment, conventional therapy, disease clinical

manifestations
Corresponding author: Dr. Emon Khan, Department of Rheumatology, University College London Hospitals NHS
*
Trust, 250 Euston Road, , NW1 2PG, London, UK (email: emon.khan@uclh.nhs.uk).

178 Emon Khan
INTRODUCTION
Behets syndrome is a chronic inflammatory condition of unknown aetiology with
multi-systemic manifestations [1]. It is a disease of antiquity, which was first described by
Hippocrates in the 5th century BC in his Third Book of Endemic diseases. There were further
case descriptions in the late 19th and early 20th centuries that could be consistent with this
diagnosis [2]. The first formal description of this condition was made in 1930 by the Greek
ophthalmologist Benediktos Adamantiades. He published a case of a 20-year-old male with
oral ulceration and thrombophlebitis, who then developed hypopyon and sterile arthritis [3,
4].
Hulusi Behet, a Turkish Dermatologist, published a series of three cases with similar
symptoms, and first identified the triple symptom complex of recurrent oral ulceration,
genital ulcers and uveitis in the early 1940s [5-8]. Following his description, the term
Behets syndrome was coined. Adamantiades is still acknowledged as contributing to the
description of the disease, but as of January 2016, a PubMed search for Behets revealed
8714 articles, in comparison to the lower number of 153 articles attributed to Adamantiades-
Behet.
The diagnostic criteria for Behets syndrome have evolved from early attempts by Curth
and Mason and Barnes, based upon Hulusi Behets original descriptions, to recent
international collaborations centred upon work from Iran [6, 9, 10]. The 1990 International
Study Group classification criteria developed after assessing 914 participants from 12 centres
in 7 countries remain the most commonly used and recognise the value of recurrent oral
ulceration as the sine qua non for diagnosis [11]. The criteria have a sensitivity of 85%, and
are particularly specific in comparison with previous diagnostic criteria (96% in the 60%
training sample, and 95% in the 40% test sample) [12]. The more recent International Criteria
for Behets Disease are the result of a collaboration of 27 centres focussing on increasing the
sensitivity of criteria for diagnosis [10]. This was achieved by removing the oral ulceration
from the mandatory feature for diagnosis, which increased the sensitivity to 95%. More
weight was placed on genital ulceration and eye lesions, with pathergy test being considered
not essential for diagnosis, because a proportion of about 30% of patients were not tested. By
removing the central place of oral ulceration from the diagnosis, these criteria are
controversial, and are not widely used.
The multi-system manifestations of Behets syndrome make it a complex condition to
manage. Patients can present with severe ocular inflammation, sterile arthritis,
papulopustulosis, meningoencephalitis, dural sinus thrombosis, recurrent venous thrombosis
and aneurysms. All can cause considerable morbidity and increase mortality in this condition.
These multiple manifestations are reflective of its underlying polygenic nature, and frequency
of different manifestations can vary with geographical area, suggesting that epigenetic
phenomena are also involved in the aetiology of this syndrome.
Human leucocyte antigen (HLA)-B51 was first found to be associated with Behets
syndrome in the early 1980s [13]. A number of genome wide association studies have
confirmed that HLA-B51 is the most common genetic link to Behets syndrome [14-16].
These studies also identified the genes encoding interleukin (IL)10, shared IL23/12 receptor
(IL23R-IL12RB2), signal transducer and activator of transcription 4 (STAT4) and
endoplasmic reticulum aminopeptidase 1 (ERAP1) as susceptibility loci. Studies have shown
Biologics in Behet Syndrome 179
increased levels of cytokines IL1, IL4, IL6, IL8, IL10 and tumour necrosis factor (TNF) in
Behets syndrome patients [17, 18]. In a study of 20 Behets syndrome cases with active
disease, biopsy specimens were taken from aphthous ulcers, pseudo folliculitis and pathergy
lesions, specimens were digested by TRIzol and underwent reverse transcriptase polymerase
chain reaction for various cytokines. There was a 700-fold increase in IL8, 65-fold increase in
monocyte chemoattractant protein 1 (MCP1), 71-fold increase in interferon gamma (IFN)
and 69-fold increase in IL12 compared with healthy control baseline, consistent with a T
helper cell 1 (Th1) signature [19].
This suggests that cytokine inhibition has a role in the management of Behets
syndrome, and the utility of thalidomide in ameliorating mucocutaneous manifestations
supports this [20]. This has long been used in management and has been shown, both in vitro
and in vivo, to inhibit the action of TNF. In endotoxin treated rat models, there was a
significant reduction in TNF levels in treated with thalidomide vs. untreated rats, leading to
an increased dose dependent survival of treated rats [21].
CONVENTIONAL THERAPY
In 1998, the Cochrane collaboration published a review of pharmacotherapy in Behets
syndrome, which predated the approval of infliximab by both the Federal Drug and European
Medicines Agencies [22]. Ten trials with 679 participants fulfilled the inclusion criteria, and
there was no evidence found to support or refute the various therapies that were commonly
used at the time. These therapies included azathioprine, cyclophosphamide, colchicine and
cyclosporine, which remain commonly used to this day.
Two further Cochrane collaborative reviews assessed the evidence behind the
management of oral ulcers and neurological disease in Behets syndrome [23, 24]. In neither
review recommendations could be made, because there were no trials of sufficient quality.
The 2008 The European League Against Rheumatism (EULAR) guideline on the
management of Behets syndrome was based upon expert opinion, open-label studies and
case studies [25]. At that stage, glucocorticoids and glucocorticoid-sparing therapy were
recommended, and it was recognised that anti-TNF and interferon alpha (IFN) therapies
could also play a role in the management of this condition.
Since the publication of the EULAR guidelines, other biologics have come onto the
market and been used in Behets syndrome. There have also been studies of apremilast and
IFN in Behets syndrome. Apremilast, a phosphodiesterase - 4 inhibitor, which has been
approved by the Food and Drug Administration (FDA) agency in the management of
psoriasis and psoriatic arthritis, was shown to significantly reduce pain and frequency of oral
ulceration in a phase II placebo controlled trial (both p < 0.001) [26]. Interferon-2a (IFN-
2b) has been shown to reduce the frequency of orogenital ulcers, although a recent
randomised control trial of pegylated IFN-2b, did not show a reduction in corticosteroid use.
There was, however, a significant improvement in quality of life, reduction in
immunomodulatory therapy and increased regulatory T cells (Tregs) and downregulated T
helper 17 (Th17) cell response, the latter suggesting a mode of action [27].
There remains a paucity of randomised control trials on the utility of biologic therapy in
Behets syndrome, so expert opinion; small case series and open-labelled trials still provide
180 Emon Khan
much of the evidence for advice. Herein, I will focus on the current evidence to support the
use of biologic therapy in Behets syndrome.
MUCOCUTANEOUS AND JOINT

Mucocutaneous involvement is a universal feature of Behets syndrome, and joint
symptoms will occur in almost 90% of patients. Both manifestations normally respond to
colchicine or oral immunosuppressant therapy. In those with severe mucocutaneous disease or
joint involvement refractory to such therapy, the biologic therapy can play a role. The sole
prospective study examining this was a four week, double-blind, placebo controlled trial of
etanercept 25 mg twice weekly in 40 patients [28]. Pathergy and cutaneous response to
monosodium urate crystals were not ameliorated by etanercept, and there was no change in
the frequency of genital ulceration or papulopustulosis. There was, however, a significant
reduction in oral ulcers (p = 0.0017) and nodular lesions (p = 0.0002). Moreover, etanercept
led to a decrease in arthritis, once the glucocorticoids were ceased (p = 0.02), and there was a
return of arthritis once etanercept was stopped.
Other evidence supporting the use of biologics in managing skin and joint symptoms
come from single case reports and case series. A 48-year-old Israeli female had a history of
recurrent orogenital ulceration, folliculitis, and erythema nodosum. She also had uveitis in the
past and was HLA-B51 positive [29]. This patient had a refractory disease course despite
being treated with colchicine 500mcg thrice daily, prednisolone 2030mg daily and
azathioprine 50mg daily. Subsequently, the patient was commenced on infliximab 5mg/kg,
with a standard loading regimen, followed by 8-weekly infusions. The patients oral ulcers
resolved, with no recurrence at 6-week follow-up. Similarly, a 29-year-old female patient
who had severe genital ulceration, unresponsive to prednisolone 60mg daily and prednisolone
30mg daily in combination with azathioprine 50mg daily, responded to infliximab, with
disease remission induced from the fourth infusion onwards [30].
In Korea, a series of five cases of recurrent oral ulceration (including 2 patients with
Behets syndrome) treated with infliximab have been reported [31]. The Behets patients
were a 34-year-old male and 48-year-old female, both of whom suffered from recurrent
orogenital ulceration. As with the other cases, there was little response to conventional
therapy, so infliximab was used with some benefit. In the first patient, remission was
maintained by additional therapy with methylprednisolone, and the second case maintained
control of the disease with intermittent infliximab infusions.
Switching between anti-TNF agents is also beneficial. A 47-year-old Italian male
patient had severe genital ulceration unresponsive to sequential use of thalidomide,
cyclosporine and azathioprine, so was predominantly maintained on moderate to high dose
prednisolone [32]. Infliximab was trialled, with rapid resolution of symptoms, but his
symptoms flared after the fifth infusion. Therefore, infliximab was switched to etanercept,
with no benefit at 100mg weekly, so was it was then switched to adalimumab. Remission was
induced after the second dose, and there had been no further flares after two years follow-up.
Two further cases, 38-year-old British female and 33-year-old Italian male, demonstrate
the benefit of switching to other TNF inhibitors after failing to respond to the first ones. Both
had predominantly mucocutaneous disease unresponsive multiple therapies, including
cyclosporine and moderate dose corticosteroids. In the former case, the patient was
unresponsive to etanercept, but responded after the first infusion of infliximab in combination
with methotrexate, which led to improved arthralgia, mucocutaneous ulceration, erythema
nodosum and fatigue [33]. The second patient responded to eight-weekly infliximab for one
year, but the therapy became less effective, presumably as a result of neutralizing antibodies;
so he was switched to combination adalimumab and methotrexate with success [34]. Of note,
this patient had vasculitic leg ulcers, which also resolved with the second anti-TNF agent.
Late responses to therapy can occur, as demonstrated by a report from Brazil [35]. This
paper presented two female patients, aged 30 years and 46 years, with predominant
mucocutaneous disease. The first patient was unresponsive to multiple therapies, and was
controlled by infliximab, which led to a decline in ulcer frequency. The second patient
developed aseptic meningitis despite being on azathioprine, and after initially failing to
respond to adalimumab, she improved on treatment with infliximab.
Anti-TNF agents remain the most commonly used biologics. However, there have been
reports of anti-IL1 therapy success in Behets syndrome. Canakinumab, a human
monoclonal antibody to IL1, has been used in a series of three patients: two female patients,
one with predominantly mucocutaneous disease and the second with concurrent ocular
disease, and one male patient who had recurrent venous thrombi [36]. All cases were
refractory to corticosteroids and oral immunosuppression. The first case was of a 20-year-old
female who, following failure of oral immunosuppression, received etanercept and
infliximab, both of which were ceased due to recurrent infection. Anakinra was commenced
with benefit, but was stopped due to generalised pruritus, following which canakinumab was
trialled with benefit. Unfortunately, the patient had a venous thrombosis after 16 months of
therapy, and it was unclear whether this was a consequence of poor disease control or not.
The second female patient, a 41-year-old, had refractory eye disease, and had been well-
controlled on adalimumab for 4 years following failure of oral immunosuppression and
etanercept. The benefit of adalimumab gradually diminished, presumably as a result of
developing neutralizing antibodies, so she was given anakinra, which was ineffective.
Canakinumab was eventually commenced, and the patient responded and remained in
remission for 12 months. The third patient, a 47-year-old male, had persistent venous
thrombosis and commenced anakinra following poor control on oral immunosuppressive
therapy. His skin manifestations settled, but the thrombus did not improve over 18 months
therapy, which was eventually ceased due to a rash. Canakinumab was commenced
afterwards, and managed to maintained patients disease remission from mucocutaneous
manifestations, whilst his thrombi resolved. There is evidence that IL1 inhibition is effective,
particularly for mucocutaneous disease, although it is unclear whether it is effective in
treating vascular manifestations, and ought to be reserved for those patients failing or
intolerant to anti-TNF.
OCULAR DISEASE
Ocular disease is a common manifestation that causes considerable morbidity, and is
associated with a more aggressive disease course and worse prognosis. A retrospective study
of 880 Turkish patients, showed that the condition was predominant in males (two-thirds of
182 Emon Khan
patients were male). The mean age of presentation was 30, and male patients had more
aggressive disease with a shorter preceding disease duration than females (1.93 2.56 years
vs. 3.45 4.71 years, respectively) [37]. Bilateral ocular involvement was present in 78.1%,
60.2% of patients had panuveitis and 89% retinal vasculitis, whilst macular oedema was the
most common complication (44.5%). This study suggested that more aggressive therapy led
to better outcomes in these patients, with biologics playing a significant role in their
therapeutic management. The presence of ocular manifestations is more commonly the trigger
leading to commencement of biologic therapy [38].
The first published report of infliximab in Behets uveitis was from Greece, and
presented the cases of four males and one female, which were collected over 6 years [39]. All
patients had panuveitis and were given a one-off dose of infliximab 5mg/kg after
cyclosporine or azathioprine, in combination with moderate dose prednisolone. Follow-up
was short, but all had resolution of retinal vasculitis by day 14.
The efficacy of a one-off infliximab infusion compared with corticosteroids was
demonstrated in 22 patients with acute ocular attack. The success of the biologic therapy was
also associated with decreased anterior chamber cells (p = 0.024), retinal vasculitis (p =
0.0082), and macular oedema (p = 0.0065) [40]. Moreover, a pilot study of intravitreal
infliximab 1mg vs. intravitreal corticosteroids, showed similarly beneficial results, but the
follow-up was over four weeks only [41].
In patients on regular infliximab infusions, the response to treatment has been shown to
be sustained in 7 Italian patients, with 21 relapses prior, and 6 relapses in the 2 years
following commencement of biologic treatment, and in 19 Saudi Arabian patients (with a
mean follow-up of 44.1 36.5 months), 9 of whom went into complete remission [42, 43]. In
both studies, patients received infliximab 5mg/kg 8-weekly, following a standard loading
regimen. The benefit of infliximab is not just confined to relapse of ocular disease. A
retrospective non-randomised study of 43 patients has shown an overall better visual outcome
(p = 0.0059) in patients receiving six infliximab infusions, compared with those azathioprine
or methotrexate, including resolution of retinal vasculitis [44].
Adalimumab has also been shown to be effective in treating ocular Behets patients. In
another study of 11 male Saudi patients receiving adalimumab 40mg fortnightly, 10 patients
went into complete remission, whilst 3 out of 5 patients previously on cyclosporine were able
to discontinue this treatment [45]. Case series of 3 and 8 patients switched from infliximab to
adalimumab, reported success of this therapeutic strategy in all but one patients over long-
term follow-up [46, 47]. There has been one case report of a 28-year-old male who
successfully switched to golimumab after relapsing, after one year of successful treatment
with infliximab [48]. This suggests that monoclonal antibodies against TNF are effective in
managing ocular disease.
Analysis of larger cohorts has also shown the benefit of these agents in the management
of Behets eye disease. A Spanish multi-centre study of 124 patients refractory to
conventional therapy, including cyclosporine, azathioprine and methotrexate, showed the
benefit of escalating therapy to infliximab or adalimumab [49]. At the end of the study, in the
99 patients who completed the follow-up, there was a significant increase in the visual acuity
(p < 0.01), decrease in the median prednisolone dose from 37.5 mg daily to 6.25 mg daily (p
< 0.01). In addition, two-thirds of patients were in remission, which was drug-induced in the
majority of them. This was an interventional case series with an open-label design, which
demonstrated the benefit of anti-TNF therapy in patients previously exposed to conventional
immunosuppression. Similar results were also shown in a retrospective, multi-centre French

study of 124 patients, which showed a significant decreases in panuveitis and macular
oedema (50.7% of patients were complete responders, and 39.7% partial responders) [38].
This study also assessed patients who switched between biologic agents, often due to
inefficacy of the original agent, and showed similar results. Mucocutaneous disease was
positively associated with response to biologic therapy on univariate analysis, but significance
was not maintained on multivariate analysis, whilst retinal vasculitis was negatively
associated on multivariate analysis, reaffirming the importance of the presence of eye disease
on the overall prognosis of Behets syndrome (p = 0.03) [38].
Gevokizumab, a recombinant humanised monoclonal anti-IL1 antibody, has been
trialled in 7 patients with posterior uveitis or panuveitis refractory to oral immunosuppression
in combination with prednisolone [50]. Patients immunosuppression and colchicine were
withdrawn at the enrollment in the trial, and prednisolone was reduced to less than 10mg
daily, except for one patient who remained on 20mg daily. Only one gevokizumab infusion
was given, although the option was there for a further infusion after 28 days, if remission had
been previously achieved. The total follow-up was 92 days. Otherwise, increases in the
prednisolone dose up to 80mg daily were allowed in exacerbations. All patients responded
rapidly to gevokizumab with resolution of uveitis after 10 14 days, however, all apart from
one patient either required a second gevokizumab infusion or increase in the prednisolone
dose after 28 days. This showed that gevokizumab was effective at inducing remission as
monotherapy, but further study is required within a larger cohort for gathering safety data, as
well as the optimal schedule of drug administration.
Alternative biologic agents have also been investigated in ocular disease. IL17 has been
shown to be upregulated in Behets patients with active uveitis [51]. As a result, the
SHIELD study, a double-blind prospective randomised control trial of two dosing regimens
of secukinumab compared with placebo, in 118 patients was undertaken, but there was no
difference in relapse rate and in visual acuity between the treatment arms [52]. This failure
led to the premature cessation of the two other randomised controlled trials of secukinumab in
non-Behets non-infectious uveitis.
A study of tocilizumab administration in 8 patients with non-infectious uveitis
unresponsive to multiple therapies, including anti-TNF therapy, showed that 6 patients
responded well to this treatment, although none of them had concomitant Behets syndrome
[53]. A randomised placebo controlled trial of daclizumab, a humanised monoclonal antibody
to cluster of differentiation (CD) 25 in 17 patients with uveitis showed no difference between
the therapeutic and placebo arms [54]. IFN has also been used in those refractory to
corticosteroids in non-controlled studies, with some benefit [55].
Bevacizumab is a monoclonal antibody to vascular endothelial growth factor. It has been
increasingly used in the management of many eye diseases, such as diabetic retinopathy and
macular degeneration, in which inhibiting angiogenesis is effective. A 24-year-old male
patient, with worsening visual acuity and persisting macular oedema despite IFN, received
intravitreal bevacizumab [56]. There was improvement in both visual acuity and resolution of
macular oedema, with no relapse on one years follow-up. A case series of 12 eyes in 7
patients treated with bevacizumab, showed improved visual acuity in 7/12 eyes, but there was
no significant difference in macular oedema [57].
An expert opinion paper from 2014 stated that infliximab and adalimumab ought to be
first or second-line corticosteroid sparing agents in Behets uveitis, and that etanercept can
184 Emon Khan
be considered afterwards, although there was insufficient evidence for this recommendation
[58]. Caution ought to be shown with etanercept, since there are concerns that it can promote
uveitis. A case report demonstrated no ocular response to etanercept in a patient Behets,
who was subsequently successfully treated with infliximab [33, 59]. Currently, anti-TNF
agents remain the therapy of choice in refractory cases to conventional immunosuppression,
with no obvious role for anti-IL1 or IL6 biologic agents. Bevacizumab may have a role in
refractory cases, but better quality data is required to support its use.
GASTROINTESTINAL DISEASE
Gastrointestinal involvement in Behets syndrome is most common in Japan, and an
expert opinion paper suggested that anti-TNF therapy should be standard treatment for
gastrointestinal Behets syndrome [60]. EULAR guidelines state that gastrointestinal disease
should be managed in similar way as in other inflammatory bowel diseases, so mesalazine,
azathioprine and TNF blockage are all recommended [25].
The first publication of anti-TNF therapy success in gastrointestinal Behets syndrome
was from the UK in 2001 [61]. Herein, was a report of two female patients, both of whom had
mucocutaneous Behets and developed gastrointestinal manifestations, with ulcers found at
colonoscopy. Both patients were refractory to combination prednisolone and thalidomide, but
responded rapidly to infliximab. A good response to infliximab was also reported in a female
Korean patient in her fifth decade, who was unresponsive to mesalazine, and developed
deranged liver function on 6-mercaptopurine [62]. As with the previous report, the patient had
predominant mucocutaneous disease, and developed gastrointestinal symptoms (including
bleeding), with ulcers proven on colonoscopy. The therapeutic regimen was the same as that
given to inflammatory bowel disease patients.
Larger case series have been published in China and Japan, reviewing the role of
etanercept and adalimumab, respectively [63, 64]. There were 54 patients in a Chinese study,
35 managed on combination methotrexate and prednisolone, and 19 on etanercept for 12
months. Unlike other studies, the Mason-Barnes criteria for Behets diagnosis were used,
rather than the more commonly used International Study Group 1990 criteria, resulting in a
broader selection of patients diagnosed with Behets syndrome. Relapse within this study
was defined as recurrence of disease symptoms within 3 months of remission. After 12-month
follow-up, there was an increase in the resolution of abdominal symptoms in the etanercept
arm (95% vs. 57%).
In the Japanese study, 20 Behets syndrome patients were given adalimumab for one
year [64]. All patients fulfilled local Japanese criteria for Behets syndrome diagnosis, which
are similar to the International Study Group criteria, and are more specific for the Japanese
population. All patients had gastrointestinal involvement, proven by the presence of typical
ulcers on colonoscopy. Seventeen patients were able to complete the full yearlong course of
adalimumab. At the end of the study, 12 patients had marked improvement, 4 were in
remission, two-thirds of patients had resolution of orogenital ulcerations, and 88% had
resolution of their erythema nodosum.
NEUROLOGICAL DISEASE
Headache is the most common manifestation of neurological involvement in Behets
syndrome. In a study of 327 Behets patients, 270 (82.5%) had headache, with the majority
of those having neurovascular type (98.5%) lasting on average 1.5 days and occurring five
times per month [65]. Consequently, many patients with headache do not have underlying
parenchymal disease or dural sinus thrombosis, so imaging ought to be limited to those who
have a change in quality of headache, additional neurological signs, or other red flag
symptoms.
A recent Cochrane Collaboration review covering biologics, corticosteroids, colchicine
and IFN in neuro-Behets syndrome stated that there was no quality evidence to support
any therapy [24]. An international consensus statement on the management of neuro-
Behets, also commented that there were no randomised control trials in this condition, so
much of the commentary in this consensus was based on case reports, open label studies
and expert opinion. For acute and sub-acute neuro-Behet, intravenous methylprednisolone
followed by six months prednisolone, with disease modifying drugs in those with
parenchymal disease relapse, is recommended. Anti-TNF agents and IFN ought to be used in
those with persistent relapsing disease and associated systemic features [66]. More
specifically, in a study of 37 patients with chronic progressive neuro-Behets syndrome, the
28 patients receiving methotrexate were less likely to die or end in a bedridden state,
suggesting that conventional therapy can still play a role in the management of neurological
manifestations [67].
The first two case reports of infliximab in neuro-Behets syndrome were from Italy and
Switzerland, of a 59-year-old female and 23-year-old male, respectively [68, 69]. Both
patients developed neuro-Behets syndrome, despite conventional immunosuppressive
therapy and additional cyclophosphamide, and responded rapidly to the first infusion of
infliximab. An Italian study assessed the efficacy of infliximab in combination with oral
immunosuppressants in 5 patients with new symptoms and 3 who had relapses, all
demonstrating significant initial response to infliximab [70]. Subsequently, one patients
response to infliximab declined, and was successfully switched to etanercept. Etanercept has
also been shown to be an effective therapy for a case report of neuro-Behet in the UK [71].
Adalimumab has also been proven efficacious, following infliximab failure to control the
disease in two other case reports from Spain and Italy. A 36-year-old Spanish male
commenced cyclosporine for panuveitis and recurrent oral ulceration, but then developed
left hemiparesis after ten years of therapy [72]. Magnetic resonance imaging (MRI)
demonstrated a high intensity signal in the right hemisphere, so he was started on intravenous
methylprednisolone and monthly cyclophosphamide. The MRI lesions persisted and he
developed spastic paraparesis, so he was commenced on infliximab. This was given
concomitantly with azathioprine, but failed to lead to any improvement after two doses. The
patient was then switched onto adalimumab with success, and his symptoms and MRI lesions
resolved. In the second case, a 40-year-old male with panuveitis, developed nephrotoxicity on
cyclosporine, so was switched to infliximab and corticosteroids [73]. Corticosteroids were
withdrawn after five infliximab infusions, and the patient was remained well controlled on
monotherapy with infliximab. The patient then developed dysarthria and confusion, and his
brain MRI showed high signal in the thalamus, right mesencephalon and right frontal
186 Emon Khan
subcortical white matter. Following a course of intravenous methylprednisolone, he was

switched to adalimumab with successful resolution of both symptoms and MRI lesions. As a
result of case reports, TNF blockers are recommended for patients with aggressive disease,
especially infliximab as it is associated with a rapid onset of action [74].
TNF blockers are also useful in transverse myelitis. A 43-year-old male presented with
double incontinence, acute paralysis, orogential ulceration and positive pathergy test [75].
MRI scan confirmed transverse myelitis, whilst cerebrospinal fluid (CSF) examination
showed raised protein and IL6 at 214 pg./ml (normal < 40 pg./ml). There was
some response to intravenous methylprednisolone with reduction in IL6 to 60.2 pg./ml. The
patient commenced methotrexate, but subsequently developed paraplegia. Infliximab was
commenced leading to a partial response within 24 hours, and resolution of symptoms in 4
weeks. There was also a concomitant drop in CSF IL6 to 18.3 pg./ml.
The first two reports of tocilizumab in neuro-Behets syndrome were in a 30-year-old
female and a 46-year-old male, both of whom were unresponsive to infliximab [76, 77]. Both
had resolution of their neurological features, but the former continued to suffer from ulcers,
whilst the second patient developed a scrotal abscess. A recent report of three patients also
showed positive response to tocilizumab, following lack of response to cyclophosphamide
and infliximab [78].
Notably, there have been other case reports of tocilizumab leading to a paradoxical flare
in mucocutaneous disease in Behets syndrome, and in mouth and genital ulcers with
inflamed cartilage (suggesting MAGIC syndrome, which is similar to Behets) [79, 80]. In
the former report, one patient was unresponsive to infliximab and given tocilizumab, which
caused worsening of his ulcers. Afterwards, the patient was successfully commenced on
golimumab. In the second case, the patient was unresponsive to corticosteroids and
colchicine, and the caring physician was advised to commence tocilizumab. This was
ineffective and led to withdrawal of tocilizumab, so the patient was switched to infliximab
with success. Therefore, tocilizumab may be effective for neuro-Behets syndrome, but does
not appear to be as effective in extra-neurological disease.
VASCULAR DISEASE
Management of thrombosis in Behets syndrome remains controversial. EULAR
guidelines state that anticoagulation is not necessary, since thrombi have been demonstrated
to strongly adhere to the inflamed endothelium in post-mortem studies, so rarely cause
embolism [25, 81]. A small prospective Korean study showed no difference in recurrence in
thrombosis rates between patients treated with immunosuppression only or combination
immunosuppression and anticoagulation, with increased thrombotic events in the
anticoagulation only arm [82]. Similar results were found in retrospective analysis of larger
French and Turkish cohorts [83, 84]. Despite that the management of patients with vascular
manifestations often differs between endemic and non-endemic areas, once aneurysms are
ruled out, anticoagulation in combination with immunosuppression is still thought to have a
role [85].
As with other manifestations of Behets syndrome, there are few reports of the use of
biologics in the management of vascular complications, whether thrombotic or aneurysmal.
There have been concerns about the thrombotic potential of anti-TNF agents, but there was no
evidence of this in the BSR registry of rheumatoid arthritis patients on biologics [86].
Seyahi et al. produced the first report of anti-TNF treatment efficacy in patients with
thrombosis [87]. This report documented 3 cases of hepatic vein thrombosis in two paediatric
and one adult male patients with Behets syndrome. All patients had liver failure, with the
first two cases having hepatic encephalopathy and dying within weeks of commencing
infliximab. The third patient developed dural sinus thrombosis within weeks of commencing
infliximab, so was switched to pulsed cyclophosphamide with success. It is unclear whether
these events represent treatment failures or side-effects of TNF blockade, since the first two
cases had fulminant liver disease, whilst the latter developed dural sinus thrombosis soon
after commencing infliximab (which is likely the result of the pre-existing inflammatory
state).
A further case report of a 60-year-old male, presenting with oral ulceration, orchitis,
erythema induratum and uveitis came from Japan [88]. The patient remained stable on low
dose oral corticosteroids and cyclosporine for almost 20 years, and then presented with
bilateral lower limb deep venous thromboses. He was heparinised and corticosteroids were
increased, but there was no resolution of symptoms. Cyclosporine was switched to
methotrexate, whilst he was still anticoagulated, but he developed progressive lower limb
oedema, and was found to have thrombus extending into the inferior vena cava. Infliximab
was commenced, and his symptoms resolved over a month with marked reduction in
thrombus on repeat CT scan examination.
The first case report of infliximab in treating pulmonary artery aneurysms was from Baki
et al. [89]. This was of a 25-year-old male with recurrent orogenital ulceration and
epididymitis that had been difficult to control. He developed a cardiac thrombus, was treated
with azathioprine and corticosteroids, but subsequently presented with life-threatening
haemoptysis and haematemesis. CT angiogram demonstrated pulmonary artery aneurysms,
and the decision was made to commence infliximab. The patient responded very well, and
had no further relapses, being well-controlled on azathioprine after completing 14 months of
infliximab.
Adalimumab has also been shown to be effective in a case of a 43-year-old gentleman
with haemoptysis and dyspnoea, on the background of recurrent orogenital ulceration and
venous thromboembolism, so he was initially anticoagulated and given colchicine [90]. He
then presented with shortness of breath, and chest x-ray and CT confirmed the presence of
bilateral pulmonary artery aneurysms with co-existent thrombi, so the patient received
cyclophosphamide, without significant benefit. Further CT confirmed little regression of his
aneurysms, so he was given adalimumab 40mg weekly for five doses only, and he remained
stable on prednisolone 2.5mg daily since then. The presence of pulmonary artery aneurysm
and deep venous thrombosis (Hughes-Stovin syndrome) is well recognised. Anticoagulation
can be associated with catastrophic bleeding in these patients [91]. Therefore, it is important
that patients with thrombosis have extensive vascular imaging prior to commencing
anticoagulation.
Adler et al. reported on seven cases collected between 2003 and 2010 who received
infliximab [92]. There were five males and two females, three of whom had aortic
involvement, two with retinal vasculitis, one with recurrent venous and arterial thromboses,
and one recurrent femoral vein thromboses. These patients were refractory to standard
immunosuppressive therapy, such as cyclosporine, azathioprine, methotrexate and
188 Emon Khan
intravenous methylprednisolone, whilst only the patients with recurrent venous thromboses
received anticoagulation. All patients responded well to infliximab therapy, with two of the
patients able to stop regular infliximab infusions and remain on oral immunosuppression
only. This study advocated the use of infliximab in the management of Behets syndrome
patient with severe vascular manifestations.
OTHER BIOLOGICS
Davatchi et al., compared the efficacy of rituximab and methotrexate vs. combination
cyclophosphamide, azathioprine and corticosteroids in patients with retinal vasculitis and
macular oedema [93]. At 6-month follow-up, there was an overall reduction in posterior
uveitis (p = 0.001) in the rituximab group, which was not seen in the combination treatment
group. There was a more marked reduction in macular oedema in the rituximab group
compared to combination therapy (p = 0.014). This did not translate into improvement in
visual acuity, with the majority of patients in both arms worsening during the study. Although
this was a secondary endpoint, this result suggested that rituximab is not effective, and is not
as effective as anti-TNF agents in treating Behets eye disease.
A case from the United States did demonstrate positive response to rituximab in an 18-
year-old female with severe mucocutaneous disease refractory to conventional oral
immunosuppression, infliximab and cyclophosphamide [94]. She was given rituximab with
some benefit, including reduction of corticosteroid dose, but the duration of the follow-up
was short. Contrastingly, a paediatric case report describes severe ulcerative colitis following
rituximab infusion to treat renal disease [95]. Without any further evidence to support its use,
rituximab should be avoided in Behets syndrome.
IL12 has long been shown to stimulate Th1 responses, which are known to drive many of
the manifestations of Behets syndrome [96]. As described earlier, there is a susceptibility
locus at IL12/IL23R in the genome wide association studies. Therefore, ustekinumab, a
monoclonal antibody to IL12 and IL23 ought to be effective. There is one case of
ustekinumab use in Behets syndrome in a patient who also had psoriasis and hidradenitis
suppurativa [97]. This 35-year-old patient had both a flare or orogenital ulceration and
psoriasis, so commenced ustekinumab, with resolution of both symptoms. In view of the
genetic findings, ustekinumab warrants further study.
Alemtuzumab, a humanised anti-CD52 antibody, has been trialled in Behets syndrome.
A group of 18 patients received alemtuzumab who were off other immunosuppressant agents
[98]. This group of Behets patients had a mix of organ involvement: eight patients had
neurological, five ocular and three gastrointestinal manifestations. Twelve went into complete
and six into partial remission at 6 months. Six relapsed later, requiring either a further
treatment or corticosteroids, but at the end of the study, one patient was lost to follow-up, 6
had active disease and the rest were stable either with or without therapy.
Th22 cells producing IL22 and TNF are increased in Behets syndrome patients
peripheral blood compared to that from healthy controls [99]. Anti-TNF agents have been
shown to partially reduce the production of IL22 from Th22 cells, but anti-IL22 agents would
be required for complete inhibition, suggesting this as a possible target for the future.
CONCLUSION
Biologics have become increasingly used in rheumatologic conditions since the turn of
the millennium, and that is reflected by their increased use in Behets syndrome. They have
revolutionised the treatment of difficult, complex cases with severe organ involvement that
have proven refractory to standard conventional therapy, and in those patients with multiple
drug intolerances. Safety concerns, particularly of anti-TNF therapy in Behets syndrome,
are similar to those of their use in other conditions. The most common adverse events remain
respiratory tract infections, although there were 4 cases of reactivated and 1 new case of
tuberculosis in study of 369 patients [100]. For every patient commencing anti-TNF therapy,
standard precautions, including screening for tuberculosis, ought to be taken.
Although there are a number of position papers that recommend the use of biologics,
much of the data is derived from small case series rather than from robust prospective
randomised clinical trials. This is also the case for the use of other therapies in Behets
syndrome, such azathioprine, methotrexate and mycophenolate, where there are very few
quality trials to recommend their use. Therefore, further trials are needed, but a number of
factors complicates the possibility to deliver robust clinical research. Firstly, Behets is
common in areas where prospective large randomised controlled trials are difficult to execute.
This could be because the potential lack of financial gain and local experience of running
large trials. Secondly, serological biomarkers and other markers of disease activity are not
robust enough to withstand scrutiny in a large prospective trial. There are several initiatives
aiming to develop validated outcome measures for use in Behets syndrome clinical trials
[101]. Finally, the heterogeneous presentation of Behets syndrome, because of its polygenic
aetiology and complex interaction with epigenetic phenomena, makes it difficult to impose
recommendations on management, without performing expensive international multicentre
trials.
Currently, the use of biologics in Behets is based upon their efficacy in other
conditions, often with similar immunopathologic basis. By developing validated outcome
criteria and new biomarkers, then assessment of these agents would improve. Data from
genome wide association studies showed common findings between populations, although
there were differences found as well. This is reflective of the differing manifestations of
Behets syndrome between groups of patients, such as more ocular inflammation and
vascular inflammation in younger male patients, compared to more mucocutaneous disease in
females. This suggests that the approach to Behets syndrome in the future ought to be to
target management at different subsets of presentation, rather than a general approach, such as
developing anti-IL22 agents to manage refractory eye disease to anti-TNF therapy.
ACKNOWLEDGMENT
EK would like to thank Professor Farida Fortune, Queen Mary University of London,
London (email: f.fortune@qmul.ac.uk) for reviewing the chapter.
190 Emon Khan
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BIOLOGIC TREATMENTS IN CHRONIC
INFLAMMATION ARTHRITIDES
Chapter 9
TUMOUR NECROSIS FACTOR INHIBITORS USED

IN THE TREATMENT OF RHEUMATOID ARTHRITIS:
EVIDENCE OF SAFETY, EFFICACY AND
HEALTH IMPLICATION
Katie Bechman1, Laura Attipoe 2

and Coziana Ciurtin, PhD FRCP2,3*
1
Department of Rheumatology, Hammersmith Hospital, London, UK
2
Department of Rheumatology, University College London Hospital
NHS Foundation Trust, London, UK
3
ABSTRACT
Rheumatoid arthritis (RA) is a systemic autoimmune condition characterised by
inflammation and destruction of synovial joints. The pathogenesis of inflammation is
underpinned by interaction and activation of immune cells, which release inflammatory
cytokines such as tumour necrosis factor (TNF) and interleukins. These mechanisms of
disease pathogenesis were targeted by specific drugs in the form of monoclonal
antibodies (mAb) or soluble receptors. The advent of biological disease modifying
therapies (bDMARDs) has revolutionised the management of RA. These agents
dramatically reduce synovial inflammation, halt the progression of radiographic joint
damage, and improve functional ability and health related quality of life outcomes. This
has a positive impact on the socioeconomic burden of RA. This chapter reviews the
pathogenesis of RA and evidence behind the use of TNF inhibitors licensed for RA
treatment. We focus on clinical efficacy, safety profile and cost-effectiveness of
infliximab, etanercept, adalimumab, certolizumab, golimumab. Additionally, we discuss
*
Corresponding author: Dr. Coziana Ciurtin, Department of Rheumatology, University College London Hospital
NHS Foundation Trust, 250 Euston Road, London, NW1 2PG, email: c.ciurtin@ucl.ac.uk.
200 Katie Bechman, Laura Attipoe and Coziana Ciurtin
national and international recommendations for the clinical use of TNF inhibitors, with
further consideration of the financial implications. Examples of clinical randomised
controlled trials (RCTs), which have proven the efficacy of different TNF inhibitors in
RA are also included in this chapter. The use of TNF inhibitor biosimilars will be
discussed in chapter 11.
Keywords: rheumatoid arthritis, TNF inhibitors, efficacy, cost-effectiveness, safety
INTRODUCTION
RA is a common and debilitating autoimmune inflammatory disease. It affects
approximately 0.5-1% of European and North-American adults with considerable regional
variation. Women are three times more frequently affected than men, with a peak age
incidence of 50-60 years [1].
AETIOLOGY
The initiation of RA results from a combination of predetermined (genetic) and stochastic
(immune, random and environmental) events. The human leukocyte antigen (HLA) major
histocompatibility (MHC) genes are the most important, but many other genes are involved
and contribute to RA susceptibility and severity. Less is understood regarding the
mechanisms for the environmental component. The most likely mechanism is repeated
activation of the innate immune system. This process can take many years, with gradually
increasing autoimmunity, until an unknown process tips the balance toward clinically
apparent disease. One key element is citrullination. This is conversion of the amino acid
arginine to citrulline, which occurs with any environmental stress, including in alveolar
macrophages in cigarette smokers [2], [3]. In RA, clearance of citrullinated cells is
inadequate, which increases the propensity for immune reactivity to neoepitopes [4]. Specific
HLA-DRB1 genotypes, termed shared epitopes, no longer recognise proteins as self,
leading to the production of anti-citrullinated protein antibodies (ACPAs). Later
consequences are immune complex deposition and continued loss of tolerance to self [5],[6].
PATHOGENESIS
All elements of the immune system have fundamental roles in initiating, propagating, and
maintaining the autoimmune process of RA. The exact orchestration of cellular and cytokine
events is complex, involving T and B cells, antigen-presenting cells, and both pro-
inflammatory, anti-inflammatory cytokines, and cytokine pathways.
Immune cells invade the normally relatively pauci-cellular synovium. These cells and
their cytokine messengers propagate the inflammatory response. The stimulation of
angiogenesis and the development of organised lymphoid structures sustain the inflammatory
response within the synovium [7], [8]. In time, mesenchymal transformation and
Tumour Necrosis Factor Inhibitors 201
osteoclastogenesis lead to the destructive lesions characteristic of established RA (local

cartilage destruction and bone erosions) [9] (Figure 1).
Figure 1. Overview of RA pathogenesis.
Antigen presenting cells present antigens to T cells, causing them to differentiate into Th1 or Th17
cells. These cells then stimulate macrophages to secrete pro-inflammatory cytokines, which in turn
promote production of autoantibodies by B cells. These autoantibodies bind to antigens to form
immune complexes. These immune complexes then engage receptors on complement and macrophages;
thereby further increasing secretion of cytokines such as TNF and IL6. These cytokines exert cartilage
and bone damage through chondrocyte and osteoclast activation via the receptor activator of nuclear
factor kappa-B ligand (RANK-L)/RANK system. Biologic drugs target different cytokines known to
contribute to synovial inflammation.
Historically, RA followed a pattern of relentless progression to irreversible joint damage.

In the last two decades, there has been a vast transformation in the landscape of this disease.
It is now recognised that the longer the interval from diagnosis to starting treatment the
poorer the outcome. This is due to the apparent ability of the disease to activate aggressive
phenotypes, and to the accrual of irreversible joint damage. Early intensive treatment
strategies within this window of opportunity have resulted in improved outcomes and long-
term prognosis with subsequent increased probability of drug free remission [10].
In the last two decades, the research in RA has been dominated by clinical trials of
biologic therapies. Development of these agents has provided further insight into the
pathogenesis of RA, revealing disease mechanisms. These biologic therapies are mAbs or
soluble receptors that target specific aspects of disease pathogenesis. They have the potential
to rapidly and completely arrest inflammation and joint damage.
This chapter will discuss the different biologic treatments licensed for the treatment of
RA and their impact on clinical efficacy and safety, whilst highlighting new emerging
biologic agents. Current national and international recommendations for the clinical use of
biologics are also illustrated below. Efficacy data from relevant RCTs is included in reference
tables as appendages, to provide further details to accompany the body of the text.
TUMOUR NECROSIS FACTOR ALPHA (TNF) INHIBITORS

History
Advances in research on the pathogenesis of RA and cytokine biology converged on TNF

and interleukin 1 (IL1) as key factors in joint inflammation and matrix destruction [11], [12].
The theory arose that increased concentrations of TNF at the sites of inflammation were
driving disease, and the removal of excess became a therapeutic goal [13], [14]. Transgenic
mice expressing high concentrations of TNF spontaneously developed arthritis, which was
clinically and histopathologically similar to RA [15]. Following the promising results in
controlling experimental arthritis by blocking TNF in animal models, the first pilot study was
performed in patients with RA using a neutralizing, chimeric, monoclonal anti-TNF antibody,
infliximab [16]. This study opened the era of multiple RCTs using biologic agents targeting
TNF, which unequivocally demonstrated the efficacy of anti-TNF therapies in reducing
disease activity in RA [17].
Mechanism of Action
TNF is produced by numerous cell types, including immune (macrophages, B and T

lymphocytes, natural killer cells, basophils, eosinophils, dendritic cells, neutrophils and mast
cells), and non-immune cells (astrocytes, fibroblasts, glial cells, granuloma cells and
keratinocytes) and many tumour cells. TNF must bind to one of two structurally distinct
receptors present in all cell types (except erythrocytes) to exert its biological function [18]:
TNF has the following physiological actions:
1. Is a potent inducer of the inflammatory response, activating the synthesis of a large

range of proinflammatory cytokines and chemokines.
2. Induces the expression of vascular endothelial growth factor (VEGF), which
promotes angiogenesis, and secretion of matrix metalloproteinases (MMPs) involved
in the degradation of components of the cellular matrix.
3. Stimulates vascular endothelial cells to express adhesion molecules allowing
leukocytes to adhere to the endothelial surface.
4. Inhibits the function of T regulatory cells. These cells play a role in the development
of immunological tolerance and prevention of an excessive immune response.
5. Is involved in reverse signalling; TNF exists both as a soluble and transmembrane
cytokine. This membrane-integrated ligand form can receive signals, act as a receptor
and transmit positive and negative feedback signals into the cell.
Structure, Dosing and Price
All TNF inhibitors except etanercept are mAbs or fragments thereof. Natural mAbs are
derived from single B cells that clonally express copies of a unique heavy and light chain,
which are covalently linked to form an antibody molecule of unique specificity (Figure 2).
Engineered mAbs can be structurally identical to natural mAbs but are created by gene
splicing and mutation procedures, mimicking natural gene rearrangement and somatic
mutation events [19].
Below we detail the characteristics of every TNF inhibitor and their current costs in the
UK, according to the British National Formulary version 70 (BNF70).
Adalimumab (HumiraTM, Abbvie) is a human-sequence immunoglobulin G1 (IgG1)
antibody. It binds to soluble and transmembrane forms of TNF and neutralises its biological
function by blocking its interaction with cell-surface TNF receptors. It is given as a
subcutaneous (SC) injection at a dose of 40 mg every other week. The half-life is 10-20 days.
The price of a 40-mg prefilled syringe in the UK is estimated at 352.14 excluding VAT
(BNF70) [20]. The annual cost for 26 doses at a dose of 40 mg every other week is 9156.
Etanercept (EnbrelTM, Amgen) is a recombinant human TNF-receptor fusion protein. It
consists of two extracellular domains of human soluble TNF receptor 2, which binds to TNF
and an Fc fragment of human IgG that serves as a stabiliser. It interferes with the
inflammatory cascade by binding to TNF, thereby blocking its interaction with cell-surface
receptors. It is given as a SC injection at a dose of 50 mg once weekly or alternatively 25mg
twice weekly. The half-life is 3 days. The price of a 50-mg injection in the UK is 178.75
(excluding VAT; BNF70). The annual cost is 9295.
Infliximab (RemicadeTM, Janssen) is a chimeric mAb, 25% murine and 75% human
derived with a constant human region (IgG1) and a variable mouse region that binds to
soluble and transmembrane TNF. It is given at a dose of 3 mg/kg as an intravenous (IV)
infusion over 2 hours at weeks 0, 2 and 6 and thereafter every 8 weeks. If there is an
inadequate response, the dose can be incremented to a maximum of 7.5 mg/kg every 8 weeks
or administrated 4 weekly. The half-life is 8-10 days. The price for a 100 mg vial in the UK is
419.62 (excluding VAT; BNF70). Assuming an average weight of 70 kg and a dose of 3
mg/kg, the annual cost (including the loading doses) is between 7553 and 8812. This does
not include administration related costs.
Certolizumab pegol (CimziaTM; UCB) is a PEGylated Fab fragment of a humanised mAb.
It contains a TNF-specific Fab fragment of a humanised mAb, which binds to both soluble
and membrane-bound TNF and a fragment conjugated to 40-kDa polyethylene glycol to
enhance its plasma half-life. It does not contain an Fc region and, therefore, does not engage
complement or cause antibody-dependent cell-mediated cytotoxicity. This also means it may
be less likely to cross the placenta, with implications for use in pregnancy [21]. It is given at a
dose of 400 mg subcutaneously at weeks 0, 2 and 4, followed by a maintenance dose of 200
mg subcutaneously every 2 weeks. The half-life is 14 days. The price for 200 mg in the UK is
715 (excluding VAT, BNF70). The cost for the first year including loading doses is
10,367.50 with an annual cost thereafter of 9295. These costs may vary in different settings
with negotiated procurement discounts; currently in the UK, the manufacturer has agreed with
the Department of Health that the first 12 weeks therapy (10 pre-loaded syringes of 200 mg
each) is free of charge.
Golimumab (SimponiTM, Janssen) is a fully human anti-TNF IgG mAb with affinity for
both soluble and transmembrane forms of TNF. It prevents the binding of TNF to its
receptors thereby neutralising its activity. It is given subcutaneously at a dose of 50 mg per
month. If there is an inadequate clinical response after 3-4 injections and the patients weight
is greater than 100 kg, the dose can be increased to 100 mg monthly. The half-life is 7-20
days. The price for a 50 mg injection in the UK is 762.97, with an annual drug cost is 9156.
The UK Department of Health has agreed that a 100 mg dose is available to the National
Health Service (NHS) at the same cost as a 50 mg dose.
National/International Guidelines
British (British Society of Rheumatology (BSR) [22] and National Institute of Clinical
Excellence (NICE) [23] and European (European League Against Rheumatism, EULAR) [24]
guidelines recommend anti-TNF therapy in patients with high disease activity who have
failed a trial of two csDMARDs, including methotrexate (MTX), unless contraindicated, over
a 6 month period. Anti-TNF therapy should be continued only if there is an adequate response
at 6 months.
Figure 2. Anti-TNF Structure.
American guidelines (American College of Rheumatology, ACR) [25] recommend the

use of agents, plus or minus MTX, in patients with early or established RA (disease duration
<6 months) who have failed csDMARD monotherapy. However, double csDMARD therapy
is stipulated as an alternative.
Switching Anti-TNF Therapy
Data from trials, open-label studies and registries confirm that switching TNF inhibitors
is effective. Furthermore, intolerance may be idiosyncratic rather than a TNF inhibitor class
effect. Therefore, despite non-response to one TNF agent, patients may respond to another
drug in this class. There is some evidence that switching may be less beneficial than treatment
with the first TNF inhibitor, especially in seropositive patients [26][30]. In the UK,
seropositive patients who fail first anti-TNF are switched to a different bDMARD; rituximab
is the most preferred option. Patients intolerant to MTX who have failed the first TNF
inhibitor can be switched to a second TNF agent, as recommended by NICE in the UK;
however, data from the Swiss RA registry suggested that it is more beneficial to switch to
rituximab as a second biologic agent after TNF treatment failures, irrespective of additional
csDMARD therapy [31]. Analysis of the Finnish registry of biologics found that a second
TNF blocker can restore the response in cases of secondary loss of efficacy to a first TNF
blocker, and maintain it after switching due to an adverse event (AE), irrespective of the
concomitant MTX therapy [32].
Monotherapy
British and European guidelines [23], [24] clearly prefer maintenance of combination
therapy, and all anti-TNF agents are recommended to be used in combination with
csDMARD therapy (such as MTX). However, UK guidance does recommend adalimumab or
etanercept monotherapy in patients who have had an inadequate response to at least one TNF
inhibitor, as rituximab therapy is preferred in patients able to take MTX.
American guidelines recommend anti-TNF treatment with or without MTX after failure
of csDMARD therapy [25].
EFFICACY
Infliximab [Table 1]
In established RA, the pivotal phase III study, ATTRACT, reviewed patients with an
inadequate response to MTX therapy. The study compared MTX + placebo with MTX +
infliximab, at four dose regimens. Infliximab groups exhibited significantly greater
improvement after 1 year with higher ACR20, ACR50 and ACR70 responses and reduced
progression of total Sharp score (TSS) [33]. Several studies have replicated and extended this
data [34][36]. The Sharp score is a scoring system for assessing erosions and joint space
narrowing in hand radiographs. The modified version (Sharp/van der Heijde score - SHS),
which also includes foot joints, gives each joint a separate score for erosion and joint space
narrowing, whereas the total score combines the results to give one score per joint [37]. The
ACR established a core data set that was more likely to show efficacy in trials and represent
the breadth of RA manifestations. ACR20 response represents a 20% improvement in tender
and swollen joint count, patients assessment of pain, global assessment of disease activity
and physical function, physicians assessment of physical function, and acute phase reactant
value [38]. ACR50 and 70 responses represent a 50% and 70% improvement, respectively.
Table 1. Infliximab
Author/Date Duration, type of study, treatment, number

Main results
published of patients (N)
Maini et al. 1999 30 week phase III RCT Week 30 ACR20:
ATTRACT Group 1: Infliximab 3mg/kg every 4 weeks Group 1: 53%
+ MTX Group 2: 50%
Group 2: Infliximab 3mg/kg every 8 weeks Group 3: 58%
+ MTX Group 4: 52%
Group 3: Infliximab 10mg/kg every 4 Group 5: 20%
weeks + MTX (P<0.001)
Group 4: Infliximab 10mg/kg every 8
weeks + MTX
Group 5: Placebo + MTX (N = 88)
N = 340 for combined infliximab groups

Smolen et al. 54 week RCT in MTX nave patients. Week 54 results:
2006 CRP, ESR and swollen
ASPIRE Group 1: Escalating doses of MTX to 20 joint count were associated
mg/week with greater joint damage
and progression in
Group 2: Infliximab at weeks 0, 2, and 6, MTX/placebo group,
and every 8 weeks thereafter + escalating while none of these
doses of MTX to 20 mg/week parameters were
N= 1004 associated with
progression in the
infliximab group.
Mean changes in SHS

with highest CRP/ESR
tertiles in placebo group
were 5.62 and 5.89
respectively, compared
with 0.73 and 1.12 in
infliximab group
(P<0.001).
Patients with greater joint

damage at baseline
(SHS 10.5) showed less
progression in infliximab
group compared with
MTX/placebo
(-0.39 vs. 4.11; P<0.001).
Author/Date Duration, type of study, treatment, number of

Main results
published patients (N)
Quinn et al. 2005 12 month RCT with attempted remission 54 weeks, ACR20:
induction in DMARD nave patients. Clinical Group 1: 80%
observation to 24 months Group 2: 60%
Group 1: Infliximab + MTX (N = 10) 104 weeks, ACR20:
Group 2: Placebo + MTX (N = 10) Group 1: 70%
Group 2: 50%
Importantly, at 1 year after
stopping induction therapy,
response was sustained in
70% in MTX/infliximab
group, with median DAS28
of 2.05 (remission range).
Goekoop- 52 week RCT in early RA 3 Months, Dutch-HAQ:
Ruiterman et al. Group 1: sequential csDMARDs (N = 126) Group 1: 1.0
2008 Group 2: step up combination csDMARDs (N = Group 2: 1.0
BeST 121) Group 3: 0.6
Group 3: combination csDMARDs with tapered Group 4: 0.6
prednisone (N = 133) (P<0.001)
Group 4: combination csDMARD and 12 Months, Dutch-HAQ:
infliximab (N = 128) Group 1: 0.7
Group 2: 0.7
Group 3: 0.5
Group 4: 0.5
(P=0.009)
Groups 3 and 4 resulted in
earlier functional
improvement than groups 1
and 2, with mean scores on
Dutch-HAQ at 3 months of
1.0 in groups 1/2 and 0.6 in
groups 3/4 (P<0.001) and at
12 months 0.7 in groups 1/2
and 0.5 in groups 3/4
(P=0.009).
The median increases in total
SHS were 2.0, 2.5, 1.0, and
0.5 in groups 1-4,
respectively
(P<0.001).
Legend: ACR 20 - American College of Rheumatology 20% response criteria; CRP - C reactive
protein; DAS 28 - disease activity score 28; csDMARDs - conventional disease modifying anti-
rheumatic drugs; ESR - erythrocyte sedimentation rate; HAQ - health assessment questionnaire;
MTX - methotrexate; N - number of patients; RA - rheumatoid arthritis; RCT - randomised
controlled trial; TSS - total Sharp score; SHS - Sharp/van der Heijde score.
A meta-analysis concluded that the benefit of infliximab is significantly larger in patients

with longer disease duration and MTX failure [39]. Recent studies have demonstrated
improved efficacy when infliximab is used in early disease. The ASPIRE study indicated
higher response rates at each ACR category compared to rates in established disease [40].
Other studies have produced similar findings [41]. The Behandel Strategieen (BeSt) study
concluded that the introduction of infliximab to MTX at an early disease stage led to
significant improvements in clinical disease activity and prevention of erosive progression.
Additionally, this strategy induced a remission state that was maintained upon cessation of
infliximab [42], [43]. The results of BeST study suggest additional benefit of early treatment
with a biologic agent, supporting the hypothesis of a window of opportunity in improving
the long-term outcome of patients with RA. It is also recognised that infliximab can induce
the generation of regulatory T cell subsets that may promote reinstitution of immune
tolerance [44].
Adalimumab [Table 2]
Several RCTs support the use of adalimumab in RA, and indicate its superiority to
placebo in controlling disease activity and retarding progressive radiological damage [45],
[46]. The pivotal phase III study in established RA (ARMADA) found adalimumab, in
conjunction with MTX, to be superior to placebo in reducing erosive progression and
improving ACR responses [47]. These findings were maintained at 4 years of open follow up
[48]. In early RA, of less than 3 years duration, the PREMIER study compared adalimumab +
MTX treatment, and treatment with MTX and adalimumab monotherapy. Combination
therapy was significantly better than either monotherapy agent, as assessed by ACR50
response and radiographic progression outcomes.
The only advantage of adalimumab monotherapy over MTX was a reduction in
radiographic joint damage [49]. Furthermore while adalimumab is effective for RA
irrespective of disease duration, there is a trend towards superior clinical, functional and
radiographic outcomes in patients with early disease [50].
A meta-analysis of five studies in patients with an inadequate response to csDMARDs
suggested adalimumab was statistically significantly more effective than control (either
placebo or existing csDMARDs) across a range of outcomes, including ACR20 and ACR70
response, Health Assessment Questionnaire (HAQ) score and SHS per year [51].
Subsequent meta-analyses have suggested similar results, with more robust evidence
regarding the efficacy of combination therapy [52], and adalimumab appearing to be more
effective in comparison to etanercept and infliximab in long-term treatment [53].
The HAQ score is a patient reported outcome measure looking at five different domains:
disability, pain, medication effects, costs of care and mortality [54].
Table 2. Adalimumab
Author/Date Duration, type of study, treatment, number of patients

Main results
published (N)
Wienblatt et al. 24 week RCT in MTX inadequate responders. Week 24 ACR20:
2003 Group 1: Adalimumab SC 20mg every other week Group 1: 47.8%
(e.o.w..) + MTX (N = 62) Group 2: 67.2%
Group 2: Adalimumab SC 40mg e.o.w. + MTX (N = 69) Group 3: 65.8%
Group 3: Adalimumab SC 60mg e.o.w. + MTX (N = 67) Group 4: 14.5%
Group 4: Placebo + MTX (N = 73) (P<0.001)

Main results
published (N)
Breedveld et al. 52 week multicenter, double-blind, active comparator- Week 52 ACR50:
2006. controlled study in MTX nave. Group 1: 62%
Group 1: Adalimumab SC 40mg e.o.w. + MTX (N = P<0.001
268) Group 2: 41%
Group 2: Adalimumab monotherapy (N = 274) Group 3: 46%
Group 3: MTX monotherapy (N = 257)
Furst et al. 2003. 24 week RCT in MTX poor responders Week 24 ACR20:
STAR study Group 1: Adalimumab 40mg e.o.w. + csDMARDs (N = Group 1: 52.8%
318) P0.001
Group 2: Placebo (N = 318) Group 2: 34.9%
Keystone et al. 52 week RCT study in RA patients with inadequate Week 52 ACR20:
2004 response to MTX Group 1: 59%
Group 1: Adalimumab 20mg SC e.o.w. + MTX (N = Group 2: 55%
207) Group 3: 24%
Group 2: Adalimumab 40mg SC e.o.w. + MTX (N = (P<0.001)
212)
Group 3: Placebo (N = 200)
Jamal et al. 52 week RCT to compare response to adalimumab Group 1: ACR20
2009 Group 1: Early RA 3 years) vs. 61%, HAQ
Group 2: Established RA (>3years) improvement 0.44,
N = 407 mean reduction in
TSS 5.32
Group 2: ACR20
56%, HAQ
improvement 0.25,
mean reduction in
TSS 2.06
Van de Putte 2004 26 week RCT in RA with inadequate response to 26 Week ACR20,
csDMARDs. mean HAQ
Group 1: Monotherapy adalimumab 20mg e.o.w. (N = improvements:
106) Group 1: 35.8%,
Group 2: Monotherapy adalimumab 20mg weekly (N = (0.29
112) Group 2: 39.3%,
Group 3: Monotherapy adalimumab 40mg e.o.w. 0.39
(N=113) Group 3: 46.0%,
Group 4: Monotherapy adalimumab 40mg weekly (N = 0.38
103) Group 4: 53.4%,
Group 5: Placebo (N = 110) 0.49
Group 5: 19.1%,
0.07
(P0.01)
Legend: ACR 20 - American College of Rheumatology 20% response criteria; csDMARDs -
conventional disease modifying anti-rheumatic drugs; e.o.w. - every other week; HAQ - health
assessment questionnaire; MTX - methotrexate; N - number of patients; RA - rheumatoid arthritis;
RCT - randomised controlled trial; SC - subcutaneously; TSS - total Sharp score.
Etanercept [Table 3]
Several RCTs provide evidence for the benefit of etanercept in reducing clinical
inflammation and radiographic progression, and improving functional and quality of life
indices. In early RA, a pivotal phase III study comparing MTX monotherapy with etanercept
monotherapy demonstrated rapid rates of improvement, with etanercept monotherapy superior
in reducing disease activity, arresting structural damage, and decreasing disability [55].
A significant trial demonstrating superior efficacy of the etanercept and MTX
combination regimen was the TEMPO study [56]. The combination therapy demonstrated
superiority as far as the ACR responses and retardation of radiographic progression were
concerned. However, most of the patients were MTX nave and had a shorter disease
duration, which might explain the superiority of the combination treatment.
The ADORE study [57], assessing patients with true MTX resistance showed
combination MTX and etanercept therapy was no better than etanercept alone, suggesting that
etanercept monotherapy may be an option for patients unable to take MTX or unresponsive to
it. Another study which demonstrated the benefit of combination therapy, assessed the
efficacy of etanercept added to MTX in MTX partial or non-responders [58].
Similarly, a further RCT demonstrated the superiority of etanercept alone or in
combination with sulphasalazine compared with sulphasalazine alone [59].
The COMET study assessed the efficacy of etanercept as first line therapy in patients
with early RA and high disease activity (DAS28 > 5.1). The DAS28 score is a disease activity
score (DAS) comprising of the patients global visual analogue score (GVAS), ESR or CRP,
and the number of tender and swollen joints out of 28 joints in the upper limbs and knees
[60]. In the etanercept + MTX combination treatment arm, 50% of patients achieved clinical
remission (DAS28 < 2.6) compared with 28% on MTX monotherapy. Very early RA patients
(defined as having <4 months disease duration) demonstrated higher rates of remission [61],
[62].
Table 3. Etanercept

Main results
Bathon et al. 2000. 52 week RCT Mean increase in erosion score
ERA Study Group 1: Etanercept 10 mg twice weekly (N = 208) during the first 6 months
Group 2: Etanercept 25 mg twice weekly (N = 207) Group 1: Numerical value not
Group 3: Methotrexate (N = 217) available
Group 2: 0.30
Group 3: 0.68 (P=0.001)
Group 2: more rapid rate of
improvement, with significantly
more patients achieving ACR20,
50 and 70 during the first six
months (P<0.05)
Weinblatt et al. 24 week RCT 24 Week, ACR20:
1999. Group 1: Etanercept 25 mg + MTX Group 1: 71%
(N = 59) Group 2: 27%
24 weeks, numeric index of the
ACR response (area under the
24 week RCT
Klareskog et al. curve AUC), mean TSS
Group 1: Etanercept 25 mg
2004. Group 1: 14.7%, 0.52
Group 2: MTX
TEMPO (P<0.0001)
Group 3: Etanercept + MTX
Group 2: 12.2%, 2.8 (P<0.0001)
N = 682
Group 3: 18.3%, -0.54
(P<0.0001)

Main results
16 Week, ACR20:
Group 1: 71.0%
Group 2: 67.1%,
DAS28 improvement of >1.2
16 week randomised open-label study
units
van Riel et al. 2006 Group 1: 75.2%
Group 1: Etanercept + MTX (N = 155)
ADORE Study Group 2: 72.8%
Group 2: Etanercept (N = 160)
(P=0.658).
EULAR good or moderate
response
Group 1: 82.4%
Group 2: 80.0%
52 Week, DAS28 clinical
remission:
52 week RCT in MTX nave RA patients
Group 1: 28%,
Emery et al. 2008 Group 1: MTX (N = 268)
(95% CI 23-33%)
Group 2: Etanercept 50 mg/week + MTX (N =
Group 2: 50%
274)
(95% CI 44-56%)
(P<0.0001).
24 week, % of patients achieving
24 week RCT in inadequate responders to
ACR20:
sulphasalazine
Group 1: 28%
Combe et al. 2006 Group 1: Sulphasalazine (N = 50)
Group 2: 73.8%
Group 2: Etanercept (N = 103)
Group 3: 74%
Group 3: Etanercept + Sulphasalazine (N = 101)
(P<0.01)
Legend: ACR 20 - American College of Rheumatology 20% response criteria; ACR 50, 70 - American College of
Rheumatology 50% and 70% response criteria; AUC - area under the curve; CI - confidence intervals; DAS 28
- disease activity score 28 joints; EULAR - European League Against Rheumatism; MTX - methotrexate; N -
number of patients; RA - rheumatoid arthritis; RCT - randomised controlled trial; TSS total Sharp score.
Newer TNF Inhibitors
The frequency of primary and secondary non-response (defined as lack of initial response
and loss of response, respectively) has contributed to the perceived need for developing new
agents, such as: certolizumab pegol and golimumab. Each drug within the TNF class has its
own specific pharmacokinetic properties and thus potential different mechanisms of action.
This was hypothesised as useful in overcoming the problem of non-responsiveness [63].
Certolizumab [Table 4]
Three pivotal phase III clinical trials provide evidence for the efficacy and safety of
certolizumab in patients for whom MTX or other csDMARDs have been ineffective.
Certolizumab was superior to placebo in MTX non-responder patients, with significantly
more patients achieving ACR20 response in the certolizumab treatment arm (RAPID I, and
RAPID II trials). There was no difference in efficacy between 200mg or 400mg doses.
Further post-hoc analysis of RAPID I data has confirmed that response within the first 12
weeks of treatment determines the likelihood of achieving a good long-term response.
Both trials demonstrated prevention of progression of structural damage. Patients who did
not achieve ACR20 response were withdrawn at week 16. Interestingly, this group still
demonstrated improved radiographic scores, implying that inhibition of joint damage occurs
even in poor clinical responders.
This has also been demonstrated with other TNF inhibitors [64], [65]. The REALISTIC
trial stratified patients according to concomitant use of MTX, prior anti-TNF treatment and
disease duration and showed a significant difference in ACR20 response in the certolizumab
treatment group vs. placebo, regardless of disease duration, concomitant DMARDs or prior
anti-TNF therapy [66].
Induction of remission in patients with low or moderate disease activity was evaluated in
the CERTAIN trial. A significant difference in remission rates (defined by the clinical disease
activity score - CDAI) was achieved (19% of certolizumab group vs. 7% of controls). A
loading regimen was shown to improve the speed of treatments onset of action [67].
Evidence for certolizumab effectiveness as monotherapy, administered as a 4-weekly
400mg dose, was provided by the FAST4WARD trial, which established that this dose
regimen was clinically effective, and led to lower rates of ACR20, 50 and 70 responses
compared with combination therapy [68]. The differences in the study design might be
responsible for the disparity of the reported efficacy of different TNF inhibitors.
In two of the trials of certolizumab, the patients considered as treatment failures were
withdrawn at week 16 (likely to represent a large proportion of the patients on placebo). As
less patients receiving placebo remained in the study at week 24, the placebo response rate
was low. It is possible that some patients would have responded to csDMARDs from 1624
weeks. As a consequence, the benefits of treatment may appear greater with certolizumab
than with other TNF inhibitors mainly because of the use of a loading dose and the study
design incorporating a short duration of csDMARDs in the comparator arm [69].
Table 4. Certolizumab

Main results
Keystone et al. 2008 52 week RCT Week 52, ACR20
RAPID 1 Group 1: Certolizumab 200mg e.o.w. (N = 393) Group 1: 60.8%
Group 2: Certolizumab 400mg e.o.w. + MTX Group 2: 58.8%
(N = 390) Group 3: 13.6%
Week 24 ACR20, mean
HAQ-DI
Group 1: 57.3%, -0.50
Group 2: 57.6%, -0.50
24 week RCT
Group 3: 8.7%, -0.14
Group 1: Certolizumab 200mg e.o.w. + MTX (N =
(P0.001).
246)
Smolen et al. 2009 Week 24, radiographic
Group 2: Certolizumab 400mg e.o.w. + MTX (N =
progression mean
246)
changes from baseline
Group 3: Placebo e.o.w. + MTX (N = 127)
mTSS
Group 1: 0.2
Group 2: -0.4
Group 3: 1.2
(P0.01).

Main results
24 week RCT Week 24, ACR20
Fleishmann et al.
Group 1: Certolizumab 400mg every 4 weeks (N = Group 1: 45.5%
2009.
111) Group 2: 9.3%
Group 2: placebo every 4 weeks (N = 109) (P<0.001)
12 week RCT
Group 1: Certolizumab 400 mg at weeks 0, 2, 4 with Week 12, ACR20
Weinblatt et al. 2010 subsequent 200mg (N = 851) Group 1: 51.1%
REALISTIC Group 2: Certolizumab 400 mg at weeks 0, 2, 4 with Group 2: 25.9%
subsequent placebo added to current treatment. (N = (P<0.001)
212)
52 week DAS28 low
disease activity
Group 1: 63%
(P<0.001)
Group 2: 29.7%
52 week RCT 52 week CDAI
Group 1: Certolizumab (400mg at weeks 0, 2, 4, remission
Smolen et al.
then 200 mg e.o.w.) + current csDMARDs Group 1: 18.8%
2015
Group 2: Placebo + current csDMARDs Group 2: 6.1%
(N= 194) (P0.05)
52 week HAQ-DI
change from baseline
Group 1: -0.25
Group 2: -0.03
(P0.01)
Legend: ACR 20 - American College of Rheumatology 20% response criteria; CDAI - clinical disease
activity index; csDMARDs - conventional disease modifying anti-rheumatic drugs; e.o.w. - every other
week; HAQ - health assessment questionnaire; HAQ-DI - health assessment questionnaire damage
index; MTX - methotrexate; mTSS - modified total Sharp score; N - number of patients; RCT -
randomised controlled trial.
Golimumab [Table 5]
A pivotal RCT demonstrated the efficacy and safety of golimumab in MTX-nave

patients (GO-BEFORE), MTX inadequate responders (GO-FORWARD) and those after anti-
TNF failure (GO-AFTER).
Table 5. Golimumab

Main results
Emery et al. 2009. 52 week RCT in early RA, MTX-nave 52 week, mean change in SHS
GO- BEFORE. patients. from baseline
Group 1: MTX + placebo every 4 weeks (N = Group 1: 1.4 4.6
160) Group 2: 1.3 6.2 (P=0.266)
Group 2: Golimumab 100mg + placebo every Group 3: 0.7 5.2 (P=0.015)
4 weeks (N = 155) Group 4: 0.1 1.8 (P=0.025)
Group 3: Golimumab 50mg + MTX every 4
weeks (N = 158)
Group 4: Golimumab 100mg + MTX every 4
weeks (N = 159)

Main results
Kay et al. 2008 48 week RCT dose-ranging study in Week 16, ACR20
inadequate responders MTX. 61% golimumab groups
Group 1: Placebo + MTX compared with 37% in placebo
Group 2: Golimumab 50 mg every 2 weeks + (P=0.010).
MTX
Group 3: Golimumab 100 mg 4 weeks + MTX
Keystone et al. RCT in active RA despite MTX. Week 14, ACR20
2009. Group 1: Placebo + MTX Group 1: 33.1%
GO- FORWARD Group 2: Placebo + Golimumab 100mg Group 2: 44.4% (P=0.059)
Group 3: Golimumab 50mg + MTX Group 3: 55.1% (P=0.001)
Group 4: Golimumab 100mg + MTX Group 4: 56.2% (P<0.001)
N = 444
Keystone et al. 52 weeks RCT. GO-FORWARD extension Week 52, ACR20
2010. Group 1: Placebo + MTX (From week 24 Group 1: 44%
Golimumab 50mg + MTX i.e., group 3) Group 2: 45%
Group 2: Golimumab 100mg + Placebo Group 3: 64%
Group 3: Golimumab 50mg + MTX Group 4: 58%
Group 4: Golimumab 100mg + MTX
N = 444
Smolen et al. Multicentre RCT Week 14, ACR20
2009. Group 1: Placebo Group 1: 18%
GO-AFTER. Group 2. Golimumab 50mg every 4 weeks + Group 2: 35% (P=0.0006)
csDMARDs. Group 3: 38% (P=0.0001)
Group 3: Golimumab 100mg every 4 weeks +
csDMARDs
At week 16 patients with <ACR20 were given
rescue therapy and changed from placebo to
golimumab 50mg or from golimumab 50mg
to 100mg.
N = 461
Legend: ACR 20 - American College of Rheumatology 20% response criteria; csDMARDs - conventional
disease modifying anti-rheumatic drugs; e.o.w. - every other week; HAQ - health assessment
questionnaire; HAQ-DI - health assessment questionnaire damage index; MTX - methotrexate; N -
number of patients; RA - rheumatoid arthritis; RCT - randomised controlled trial; TSS - total Sharp
score; SC - subcutaneously; SHS - Sharp/van der Heijde score.
The GO-BEFORE study enrolled patients with early RA (less than 3 years). A reduction
in joint progression was demonstrated [70], but there was no significant ACR50 difference
between golimumab + MTX and MTX monotherapy. However, lower response rates, as
assessed by ACR20 criteria, were not considered, and it was hypothesised that this was the
cause of failing to meet the primary endpoint. ACR20 response improved significantly with
the same dose regimen in another similar study [71].
The GO-FORWARD study demonstrated significantly higher ACR20 responses detected
as early as 4 weeks, and sustained unto 52 weeks [72], [73]. The GO-AFTER study
demonstrated that golimumab in combination with csDMARDs led to a significantly greater
proportion of patients achieving ACR20 compared with placebo [74]. In all the
aforementioned trials there was no difference in efficacy of golimumab doses 50mg and
100mg, but the 100mg dose was associated with higher rates of serious adverse events.
A Cochrane systemic review found that when used with MTX, golimumab was
associated with greater efficacy than placebo for achieving ACR20/50/70 responses and
lower DAS28 scores. The ACR50 rates were similar to those reported in systematic reviews
of other TNF-blockers, suggesting that all the TNF inhibitors are equivalent [75].
Meta-Analyses
Unfortunately, there are few head-to-head studies comparing the efficacy of one anti-
TNF agent to another. In the absence of superiority studies, indirect comparisons prove the
best evidence for demonstrating differences between these agents [76].
Review of biologic agents found no significant difference in the proportion of patients
achieving ACR50 response between the first generation TNF inhibitors (adalimumab,
infliximab, etanercept) [77]. Other meta-analyses have demonstrated similar results [76],[78].
One systemic review suggested infliximab may require an increased dose to reach comparable
effectiveness to the standard doses of etanercept and adalimumab [76]. A meta-analysis from
2010 demonstrated that the highest proportion of ACR20 and 50 responses was achieved with
etanercept, and the highest risk ratio for achieving ACR70 was with adalimumab. Over a
longer treatment course (1-3 years) adalimumab demonstrated the highest relative risk (RR)
for achieving all these response parameters [53].
Meta-analyses comparing newer anti-TNF agents (certolizumab and golimumab) have
not revealed improved efficacy over already existing first generation agents [79], [80]. An
indirect treatment comparison found no significant difference in efficacy between different
agents [81]. A mixed treatment comparison demonstrated improved outcomes with etanercept
and certolizumab, which may relate to reduced immunogenicity compared with the antibody
therapies. Due to the lack of anti-TNF head-to-head trials, mixed treatment comparisons
combine evidence from placebo-controlled trials of different treatments and thereby derive an
estimate of effect of one treatment against another. The rank order of efcacy for HAQ
improvement as an outcome measure was etanercept, certolizumab, adalimumab, golimumab
and then iniximab [82].
Cost-effectiveness
Economic evaluations have generally shown anti-TNF to be cost effective across multiple
healthcare settings for patients in whom csDMARD therapy has failed, in comparison to
continuing management with csDMARD therapies [83][85]. There were 5.87-6.16 quality-
adjusted life years (QALYs) gained with anti-TNF compared with 4.76 QALYs gained with
cDMARDs. The incremental cost-effectiveness ratio (ICER) was estimated to be 23,577-
30,112 per QALY gained for anti-TNF compared with cDMARDs [86]. The use of two
sequential anti-TNF therapies only increases the cost per QALY by 2% [83]. Anti-TNF
therapy is not thought to be cost effective in a csDMARD nave population [87].
Safety
Because of the immunological alterations it provokes, anti-TNF therapy is associated
with an increased risk of infection and/or reactivation of viral, bacterial or fungal organism.
Safety data from clinical trials and post marketing registries has provided mixed results [88].
Serious infection events are rare and as such, their absolute risk of occurrence remains small.
Several registries have shown the risk of infection in patients treated with anti-TNF compared
to those with csDMARDs is highest during the first 6 months of treatment [89]. Analysis of
data from the US CORRONA registry revealed an increase in all non-opportunistic infections
with an adjusted rate per 100 person-years of 30.9 for MTX monotherapy and 40.1 for anti-
TNF monotherapy [90].
TNF is essential for the control of tuberculosis (TB) and is implicated in the disease
immunopathogenesis [91]. The alveolar macrophages and dendritic cells ingest TB bacilli.
These cells fuse to form giant cells and isolate TB bacilli within a granuloma. TNF enables
the formation and maintenance of a granuloma via activation of focal adhesion kinases. TNF
signalling via TNF receptor-1 is particularly required for this function. TNF works in synergy
with IFN- stimulating the production of reactive nitrogen intermediates thereby mediating
the tuberculostatic function of macrophages [92].
Several studies have showed that TNF inhibitors increase the risk of both TB and other
granulomatous infections. The first clinical observation came from a FDA report which found
an increase in TB shortly after initiation of infliximab therapy suggesting reactivation of
latent disease [93]. An increased risk of TB was seen in the Spanish BIOBADASER database
of patients receiving infliximab before TB screening was introduced routinely. A review of
the French database concluded the risk of TB was 12 fold for patients taking TNF inhibitors
[94]. The BSR Biologics Register (BSRBR) identified that infliximab and adalimumab were
associated with a three to four fold higher rate of TB compared to etanercept [89]. The
observed difference rates with etanercept may be due to its mechanism of action (via TNF
receptor Fc fusion protein) or pharmacokinetics, although no consensus has been reached
[88].
Prior to commencing anti-TNF, all patients should be screened for mycobacterial
infections, and consideration of prophylactic anti TB therapy should be given to patients with
evidence of latent disease. Screening standards vary from country to country, depending on
endemic rates of TB, and may include TB skin testing, serum interferon release assays
(IGRA) and/or chest radiograph. The role of IGRA screening has not been fully validated in
RA populations and is not widely available; however, the test is sensitive when used in
immunosuppressed hosts or patients who have received BCG immunisation [95].
Screening for latent TB prior to initiation of biologic therapy decreased the risk of
reactivation of this organism in susceptible patients; although no screening test can assess the
risk of infection with atypical mycobacteria. Non tuberculosis mycobacterial infections have
been found to be twice as frequent as TB in US patients treated with anti-TNF agents [96].
Data from two national registries reveal a significantly higher risk of varicella zoster
virus (VZV) reactivation in patients treated with TNF inhibitors than those receiving
csDMARD. Spanish registry (BIODABASER) data estimates an incidence rate (IR) of
hospitalisation due to chickenpox of 26 cases per 100,000 patient-years with an expected IR
in the general population of 1.9. German registry (RABBIT) data shows a significantly
increased risk occurring with the use of mAbs but not with etanercept [97], [98].
TNF inhibitors have also been associated with reactivation of hepatitis B. Hepatic failure
is more likely to occur in patients with active infection rather than chronic carriers [99]. There
are several case reports and an open label case series describing the use of anti-TNF therapy
in human immunodeficiency virus (HIV) positive patients. The consensus is that biologic
treatment is reasonably safe if HIV treatment is started and effective in keeping the HIV
infection under control. There were no significant clinical adverse effects (disease progression
related to CD4 counts and HIV viral loads, and no opportunistic infections) [100].
A meta-analysis of clinical registries and prospective observational studies between 1999

and 2010 identified no increase in malignancies, other than skin cancers (including
lymphoma) associated with the use of TNF inhibitors [101]. A large study, reviewing
databases of health care utilization, found no significant increase in malignancy rates with
TNF inhibitors compared to MTX alone, whilst post approval data suggesting that the rate of
Hodgkins and Non Hodgkin lymphoma were not significantly raised [102]. Data from an
American national data bank of incident cancers found an increased rate of skin cancers (OR
2.3 for melanoma and OR 1.5 for non-melanoma skin cancer) in patients receiving anti-TNF
therapy [103]. Another study comparing RA to osteoarthritis, found a significantly increased
risk of developing non melanoma skin cancer, with history of anti-TNF and prednisolone use
also being implicated [104].
Psoriasis has been reported in patients treated with anti-TNF therapy. Interestingly the
rash might resolve with topical treatment alone, temporary discontinuation and re-challenge
with anti-TNF, a switch to an alternative anti-TNF agent or introduction of MTX [105],
[106].
Current recommendations are to avoid use of anti-TNF agents in patients with clinically
significant heart failure (New York Heart Association, NYHA, class III/IV). Concerns about
possible adverse effects stem from a RCT of TNF inhibitors when trialled as a potential
therapy for patients with stable heart failure (NYHA class III/IV). The combined risk of death
from any cause or hospitalization for heart failure through 28 weeks was increased in patients
randomised to 10 mg/kg infliximab vs. placebo (hazard ratio 2.84, 95% CI 1.01-7.97;
nominal P=0.043 [107], [108]. Registry data has generally been reassuring [109], [110].
Patients with interstitial lung disease (ILD) should be monitored and the anti-TNF agent
stopped if lung function deteriorates or new features of ILD develop. Data suggests that anti-
TNF therapy may worsen ILD specific mortality but further studies are required before firm
conclusions can be drawn [111].
An increased risk of demyelinating conditions was reported in BSRBR and the general
recommendation is that patients with a history of demyelinating diseases should not receive
TNF blocking agents. There are case reports in the literature of demyelinating disease
complicating the use of all three 1st generation anti-TNF agents. In terms of central nervous
system involvement, the highest rate of demyelinating events is reported with etanercept. In
peripheral nerve disease, symptoms develop over a wide range of time intervals (from 8 hours
to 2 years), and withdrawal of biologic medication most often resulted in slow resolution of
symptoms [95], [112].
Injection site reactions are frequently reported with all the TNF inhibitors, but in different
proportions. Localised skin reactions are usually managed with topical treatment. Severe
infusion reactions have been described in the case of infliximab administration, but they are
rare. The general recommendation is that appropriate resuscitation facilities should be
available for patients treated with infliximab [95].
A prolonged activated partial thromboplastic time was reported in 5% of patients in the
RAPID II trial with certolizumab. This is due to an interference of polyethylene glycol with
phospholipids used in the commercial assay and it is considered that it does not translate into
any effect on coagulation in vivo [65].
CONCLUSION
The age of biologic treatment, in the past 20 years, has transformed the treatment of RA
with subsequent reduced morbidity and socio-economic burden [113]. Well established
biologics, such as anti-TNF blockers, have extensive data on safety and efficacy. The long-
term experience of the use of these biologic agents in real-life clinical settings has increased
the confidence of patients and clinicians in their benefits. The lack of direct comparison
between the effectiveness of different TNF inhibitors or their safety profile makes the
decision of choosing a certain anti-TNF agent instead of another quite difficult to justify.
Differences in their mechanism of action and safety profile in the context of increased risk of
TB, along with patients choice based on frequency and route of administration are the main
reasons for the selection of a certain TNF inhibitor in clinical practice. Observational data
provided by national biologic registries will continue to inform practitioners and patients
about the long-term efficacy of TNF therapy.
As highlighted in this chapter, the introduction of first biologic therapeutic agents
changed the landscape of RA treatment, leading to a real progress in achieving better disease
control in RA patients who had exhausted conventional treatment options. This eventually
enabled a significant improvement of the quality of life of RA patients.
ACKNOWLEDGMENTS
The authors will like to thank to Dr. Maria Leandro (maria.leandro@ucl.ac.uk), Senior
Lecturer and Consultant Rheumatologist, University College London, Department of
Inflammation, Infection and Immunity, for reviewing the chapter and providing very useful
comments.
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Chapter 10
BIOLOGIC TREATMENTS (OTHER THAN

ANTI-TNF THERAPY) LICENSED FOR USE
IN RHEUMATOID ARTHRITIS
Laura Attipoe1, Katie Bechman2

and Coziana Ciurtin, PhD FRCP1,3,*
1
2
Rheumatology Department, Hammersmith Hospital, London, UK
3
ABSTRACT
Despite the huge progress made by the use of tumour necrosis factor (TNF)
inhibitors in the treatment of rheumatoid arthritis (RA), there was still an unmet need for
discovering and implementing new biologic therapies for RA patients who lost response
or had side-effects to TNF inhibitors. The advances in molecular biology and
understanding of the complex pathogenesis of RA enabled the identification of other
pivotal molecules, whose blockage was associated with clinical benefits in RA. This
chapter reviews the clinical efficacy, safety profile and cost-effectiveness of several
biologic agents licensed for use in RA patients, which target different interleukins (IL),
such as IL1 (anakinra) and IL6 (tocilizumab), or are associated with B cell depletion
(rituximab), T cell co-stimulatory blockage (abatacept) and small molecule inhibition
(tofacitinib). In addition, we discuss the national and international guidelines for use of
these biologic agents in relation to the use of TNF inhibitors in patients with moderate-
severe RA, providing examples of switching between various biologic therapies.
*
230 Laura Attipoe, Katie Bechman and Coziana Ciurtin
Keywords: rheumatoid arthritis, licensed biologic therapies, anakinra, tocilizumab,

rituximab, abatacept, tofacitinib, efficacy, safety, cost-effectiveness.
INTRODUCTION
After the introduction of TNF inhibitors, new biologic agents have been developed and
used in large randomised controlled trials (RCTs), which led to their licensing for treatment in
RA patients. These new biologic treatments can be used in patients exposed or naive to anti-
TNF therapy, based on the available evidence regarding their efficacy. There are differences
between the licensing of these biologic therapies in European countries and the USA, mainly
due to their cost-effectiveness. In addition to data about their safety and efficacy, here we also
discuss the costs of different biologic agents in the UK, as per the British National Formulary,
version 70 (BNF70).
IL6 INHIBITION
Tocilizumab (RoActemra, Roche) [Table 1]
Mechanism of Action
IL6 is a pleiotropic cytokine with important biologic effects on liver cells, lymphocytes,
monocytes and platelets. IL6 can activate these cells via both membrane-bound (IL6R) and
soluble receptors (sIL6R).
IL6 stimulates B cells to differentiate into plasma cells and produce immunoglobulins. It
also influences T cell development by stimulating the proliferation and differentiation of T
lymphocytes into Th17 cells which produce IL17 [1-3]. IL6 has a direct role in the
development of synovitis and articular symptoms. It is one of most abundantly expressed
cytokines [4]. IL6 increases the levels of the angiogenic mediator, vascular endothelial
growth factor (VEGF), which promotes migration of endothelial cells and induces vascular
permeability [5-6]. IL6 also influences osteoclastogenesis, increasing osteoclast recruitment, a
key cell involved in mediating erosions [7]. It also increases proteinases (e.g., matrix
metalloproteinases) which correlate with articular cartilage destruction.
IL6 is also involved in the development of systemic symptoms. It is a principal stimulator
of acute-phase protein synthesis through hepatocyte stimulation, and serum IL6 levels
correlate with C-reactive protein (CRP) levels. IL6 also induces the expression of hepcidin by
hepatocytes. This peptide regulates iron metabolism and can decrease serum iron levels,
contributing to the anaemia of chronic inflammation. IL6 can affect lipid metabolism by
stimulating hepatic fatty-acid synthesis and adipose-tissue lipolysis, increasing cholesterol
synthesis and decreasing cholesterol secretion. Combined with endothelial dysfunction, this
contributes to atherosclerosis and increased risk of cardiovascular disease [4], [8].
Early studies in knockout mice demonstrated IL6 as essential in the development of RA
[9]. Wild-type animals developed joint inflammation after intra-articular injection of antigen,
whilst IL6 knockout mice were resistant with no inflammatory response or synovial
inflammation induced.
Biologic Treatments (Other than Anti-TNF Therapy) Licensed 231
Structure, Dosing and Pricing

Tocilizumab is a humanised monoclonal antibody (mAb) that binds the IL6 receptor
thereby inhibiting its affinity for IL6. It is given as a dose of 8 mg/kg, once every 4 weeks as
an intravenous (IV) infusion over 1 hour.
Table 1. IL6 Inhibition
Duration, type of study,

Author/Date published treatment, number of patients Main results
(N)
Smolen et al. 2008 RCT Week 24, ACR20
Group 1: Tocilizumab Group 1: 59%
8mg/kg every 4 weeks + Group 2: 48%
MTX Group 3: 26%
Group 2: Tocilizumab
4mg/kg every 4 weeks +
MTX
Group 3: Placebo every 4
weeks + MTX
N = 623
Fleischmann et al. 2013 RCT Week 104, mean change
LITHE Group 1: Placebo+ MTX from baseline in GmTSS,
Group 2: Tocilizumab adjusted mean AUC of
4mg/kg + MTX change from baseline in
Group 3: Tocilizumab HAQ-DI
8mg/kg + MTX Group 1: 1.96, -139.4
Group 2: 0.58 (P=0.0025), -
287.5 (P<0.0001)
Group 3: 0.37, -320.8
(P<0.0001 for both)
Genovese et al. 2008 RCT, multicenter study Week 24, ACR20:
TOWARD Group 1: Tocilizumab Group 1: 61%
8mg/kg + csDMARDs Group 2: 25%
Group 2: Placebo + (P<0.0001)
csDMARDs
N = 1220
Gabay et al. Phase IV double-blind Week 24, mean change from
2013 parallel-group, multicentre baseline in DAS28
ADACTA superiority study in RA > Group 1: -3.3 (P<0.0001)
6months, in those intolerant Group 2: -1.8
to MTX
Group 1: Tocilizumab
8mg/kg every 4 weeks
Group 2: Adalimumab 40mg
every 2 weeks.
N = 452
Legend: ACR 20 American College of Rheumatology 20% response criteria; AUC area under
curve; csDMARDs conventional synthetic disease modifying antirheumatic drugs; GmTSS
Genant-modified total Sharp score; HAQ-DI health assessment questionnaire damage index;
MTX methotrexate; N number of patients; RA rheumatoid arthritis; RCT randomised
control trial.
Doses exceeding 800 mg per infusion are not recommended. A 400mg vial costs 512 in
the UK (excluding VAT, BNF70) [10]. The drug cost per year for a patient weighing
approximately 70kg is 9295 (BNF70) via a pre-agreed patient access scheme in the UK.
Subcutaneous (SC) tocilizumab is given at a dose of 162 mg per week. The annual cost is also
9295 (BNF70). This does not include administration related costs.
Efficacy [Table 1]
There are three randomised double-blind, placebo-controlled trials assessing the clinical
effectiveness of tocilizumab in patients who responded inadequately to methotrexate (MTX)
(OPTION and LITHE) [11],[12], or conventional synthetic disease modifying anti-rheumatic
drugs (csDMARDs) (TOWARD) [13]. All three studies demonstrate significantly greater
American College of Rheumatology (ACR) 20 responses at week 24. The LITHE study also
demonstrated protection from structural damage at 52 weeks. The TOWARD study reviewed
the efficacy of tocilizumab added to MTX or other csDMARDs, which may be a more
clinically representative population. A meta-analysis of these RCTs confirms that tocilizumab
is numerically and statistically more effective at a dose of 8mg/kg than at a dose of 4mg/kg
[14].
The RADIATE trial assessed efficacy of tocilizumab in RA patients who failed treatment
with a TNF inhibitor. This study demonstrated significantly greater ACR20, 50 and 70
responses compared with placebo, with significantly more patients entering remission
(disease activity score 28 (DAS28) <2.6) in the higher dose group [15].
The AMBITION study reviewed tocilizumab monotherapy in patients who were MTX
and biologics nave. Tocilizumab monotherapy demonstrated superior efficacy compared to
MTX monotherapy [16]. Several Japanese studies in patients with an inadequate response to
MTX have demonstrated similar results, with superiority of tocilizumab monotherapy in ACR
response criteria at all-time points [17-18]. A Cochrane systematic review [19] concluded that
patients on tocilizumab monotherapy are 21 times more likely to achieve an ACR50
compared with placebo, and 2.76 times more likely compared with MTX. The CHARISMA
study suggested that tocilizumab monotherapy was inferior to combination therapy with
MTX, although it was not powered to look at this aspect [20]. The ACT-RAY study
suggested similar findings, with a numerical superiority in DAS28 remission rates in
combination therapy compared to tocilizumab monotherapy for most outcomes, although no
statistically significant difference was found [21].
The ADACTA study was one of the first head-to-head superiority RCTs comparing
tocilizumab monotherapy and adalimumab monotherapy in a study population of MTX
inadequate responders. It demonstrated tocilizumab superiority in all main efficacy endpoints;
European League against Rheumatism (EULAR) remission, low disease activity,
ACR20/50/70 and clinical disease activity index (CDAI) remission [22]. It is recognised that
tocilizumab treatment is associated with a profound decrease of the inflammatory markers
(CRP and erythrocyte sedimentation rate - ESR). Many disease activity tools require use of
inflammatory marker levels; therefore, tocilizumab could falsely lower the disease activity
scores on this basis alone. However, tocilizumab was proven effective for treatment of RA
patients, even when disease activity was appreciated using the CDAI, which is calculated
without using inflammatory markers [23].
There are no other head-to-head studies reviewing the clinical effectiveness of
tocilizumab compared to other biologic agents. Systematic reviews have, however, attempted
to compare these agents. A meta-analysis from 2010, assessing MTX inadequate responders,
found that anti TNF therapies had a similar probability of achieving an ACR response as
non-anti TNF agents (after exclusion of certolizumab trials) [odds ratio (OR) 1.30, 95%
confidence interval (CI) 0.91 to 1.86]. However, when comparing agents individually, the
meta-analysis concluded that anti-TNF drugs demonstrated a higher probability of reaching
an ACR50 response than abatacept (OR 1.52; 95% CI 1.0 to 2.28), but not in comparison to
rituximab and tocilizumab. After an inadequate response to anti-TNF, no differences were
found between tocilizumab, abatacept, rituximab or golimumab [24]. A separate meta-
analysis of mixed treatment comparisons suggested that tocilizumab was associated with
significantly greater rates of ACR70 when compared to TNF inhibitors and abatacept;
however, there was no significant difference in ACR20 or 50 responses [25].
SC tocilizumab demonstrated comparable efficacy and safety to IV tocilizumab in head-
to-head studies. Serum trough concentrations were similar between the two forms of
administration [26]. In general, the data for SC tocilizumab is similar to IV tocilizumab, albeit
with a higher frequency of injection site reactions. Given that most patients prefer SC
administration, this is likely to become a mainstay treatment option [27].
Safety
IL6 is essential for CRP production in the liver [28]; therefore, CRP levels are reduced
and signs of clinical infection potentially diminished in patients treated with tocilizumab. A
Cochrane review of safety in RA patients on tocilizumab however did not show any
statistically significant differences in serious adverse effects, or withdrawals due to adverse
events [19]. French registry data have shown serious infection rates with tocilizumab to be in
the higher range compared to other biologics after 1.3 years of follow up [29]; however, 5
year UK safety data showed tocilizumab treatment to have a similar risk to that of anti-TNF
drugs [30]. A German study of RA patients in an outpatient setting showed a higher rate of
infections (23.2%, 58/100 patient-years) [31] compared to other RCTs [11], [13] or Cochrane
safety data [19]. The patients in this study had a longer duration of disease, and higher
number of previous csDMARD use compared to other RCTs, possibly accounting for this
increased risk [32]. The main adverse events (AEs) reported are nasopharyngitis, respiratory
tract disorders and, skin and soft tissue pathologies [33].
Tocilizumab may be associated with a transient alteration in lipid profile. However, this
is not linked to an increase in cardiovascular events or episodes of pancreatitis [13], [33].
Trials have reported significantly reduced neutrophil counts compared with controls, but
importantly, there were no reported associations between neutrophil levels and infection rates
or infection severity. Neutropenia detected was usually transient but may require dose
adjustments [11], [13], [15].
Cases of gastro-intestinal (GI) perforation have been reported with tocilizumab. In a
pooled meta-analysis of 5 RCTs and 2 long-term extension studies, GI perforation occurred at
a rate of 2.0 per 1000 patient-years in the control population, and 2.8 per 1000 patient-years
in the tocilizumab population [34]. Sixteen of the 18 cases of lower GI perforation occurred in
patients with diverticulitis, with the majority having concomitant treatment with
corticosteroids and non-steroidal anti-inflammatories (NSAIDs) [35]. A different systematic
review found the risk of diverticular perforation with tocilizumab slightly higher than with
anti-TNF drugs and lower than with corticosteroids and NSAIDs [36].
Following immune system suppression, concern exists regarding possible reactivation of

latent infections, most notably tuberculosis (TB). A large meta-analysis of 6 trials [33] did not
identify patients with TB reactivation, and they included patients who were not screened for
TB. However, cases of TB have been reported [18], and it is therefore advisable to continue
to screen patients for TB prior to initiating treatment with tocilizumab. The same meta-
analysis found no significant increase in the rate of malignancy in those treated with
tocilizumab.
Cost-effectiveness
Tocilizumab may improve cost-effectiveness in patients with moderate to severe RA,
when used first or second line, by enhancing quality-adjusted life years (QALYs) expectancy
[37]. A Swedish study has shown tocilizumab combined with MTX to be more cost-effective
as a first line biologic than adalimumab and etanercept combination therapy [38]. There were
5.87 QALYs gained with IV tocilizumab compared with 4.76 QALYs gained with
csDMARDs. The incremental cost-effectiveness ratio (ICER) was estimated to be 35,949
per QALY gained for tocilizumab compared with csDMARDs [39].
National/International Guidelines on Use

The 2012 National Institute of Clinical Excellence (NICE) guidance stated that
tocilizumab can be used as a first line biologic agent in csDMARD failure. It is also
recommended for use in patients whom have an inadequate response to anti-TNF agent at 6
months (improvement in DAS28 <1.2) and have a contraindication or inadequate response to
rituximab, or are intolerant to MTX [40]. The 2013 European guidelines recommend
treatment with tocilizumab as an initial biological DMARD. This differs from the 2010
previous recommendations, which stated current practice would be to start a TNF blocker.
This change is related to increasing clinical experience and registry data on tocilizumab [41].
The ACR guidelines on the use of tocilizumab recommend its use for treatment of patients
who failed csDMARD monotherapy. They also recommend alternative treatment strategies
with combination csDMARD therapy or another biologic agent [42].
CO-STIMULATORY SIGNAL INHIBITION

Abatacept (Orencia, Bristol-Myers Squibb)
Mechanism of Action
Abatacept inhibits the co-stimulation of T cells by binding to cluster of differentiation
(CD) 80/86 epitopes on antigen presenting cells and modulating its interaction with CD28 on
the T cell receptor. This leads to reduced T cell proliferation and reduced production of
inflammatory cytokines [43], [44].
Abatacept, if administered at time of immunisation, prevents the development of collagen
induced arthritis in mouse models and improves symptoms if given after disease onset [45].

Abatacept is a fully humanised protein construct, consisting of the extracellular domain
of human cytotoxic T lymphocyte associated antigen 4 (CTL4) and a genetically engineered
fragment of the Fc region of human immunoglobulin G1 (IgG1).
IV abatacept is administered as a 30-minute infusion. After an initial baseline infusion,
subsequent infusions are at week 2, week 4, and then every 4 weeks.
IV abatacept is available in 250 mg vials at a cost of 302.40 per vial in the UK
(excluding VAT; BNF70) [10]. The dose of abatacept is weight dependent. People weighing
less than 60kg, 60-100kg, and over 100kg are administered 500mg, 750mg and 1000mg
respectively. The annual cost for a person weighing 60-100kg is 12,700.80 in the first year
and then 11,793.60 in subsequent years. This does not include administration related costs.
SC abatacept is administered as a 125 mg pre-filled syringe per week with an annual cost of
15,724.8. Procurement agreements within the UK have meant that healthcare services pay
the same price for SC abatacept as they do for the IV formulation.
Efficacy [Table 2]
IV abatacept has been shown to be effective in MTX nave patients and patients who
have not responded to DMARDs, including MTX, and anti-TNF.
Table 2. Abatacept

Author treatment, number of patients Main results
(N)
Kremer et al. 2005 12-month results for a phase 12 month ACR20
IIb RCT of CTLA4-Ig in Group 1: 36.1%
those with an inadequate Group 2: Numerical results
response to MTX. unavailable
Group 1: Placebo (N = 119) Group 3: 62.6%
Group 2: CTLA-4Ig 2mg/kg
(N = 105)
Group 3: CTLA-4Ig 10mg/kg
(N = 115)
Kremer et al. 2006 12 month RCT of abatacept 12 month ACR20
AIM vs. placebo Group 1: 73.1%
Group 1: Abatacept + MTX Group 2: 39.7%
(N = 433)
Group 2: Placebo + MTX
(N = 219)
Schiff et al. 2008 ATTEST 12 month randomised, 12 month ACR20
double-blind, double- Group 1: 72.4%
dummy, placebo- and active- Group 2: 55.8%
controlled trial Group 3: Numerical results
Group 1: Abatacept +MTX unavailable
(N = 156)
Group 2: Infliximab + MTX
(N = 165)
Group 3: Placebo + MTX
(N = 110)

Author treatment, number of patients Main results
(N)
Westhovens et al. 2009 5 year extended phase IIb 5 year results
study of abatacept 10mg/kg ACR20 82.7%
following 1 year of variable
dose abatacept or placebo
(N = 419)
Genovese et al. 2005 6 month randomised double- 6 month ACR20
ATTAIN blind, Phase III trial Group 1: ACR20 50.4%
Group 1: Abatacept + Group 2: ACR20 19.5%
DMARDs
Group 2: Placebo +
DMARDs
Emery et al. 2010 ADJUST Randomised, double-blind, 1 year results
placebo controlled phase II Group 1: 46% developed RA,
trial mean change from baseline
Group 1: Abatacept to year1 in total GmTSS = 0
Group 2: Placebo Group 2: 67% developed RA,
mean change from baseline
to year1 in total GmTSS =
1.1
Westhovens et al. 2009 12 month double-blind study At 1 year:
AGREE followed by 12 month open Group 1: ACR50 64.7%
label treatment with Group 2: ACR50 50.2%
abatacept and MTX At 2 years
Group 1: Abatacept and Group 1: ACR50 74.1%
MTX Group 2: ACR50 67%
Group 2: Placebo and MTX
Legend: ACR20 American College of Rheumatology 20% response criteria; ACR50 American
College of Rheumatology 20% response criteria; CTLA4 cytotoxic T lymphocyte associated
antigen 4; DMARDs disease modifying anti-rheumatic drugs; GmTSS Genant-modified total
Sharp score; MTX methotrexate; N number of patients; RCT randomised controlled trial.
IV abatacept is more efficacious than placebo in patients with early RA who are MTX
nave [46-47], with a significantly different ACR50 response of 64.7% vs. placebo response
of 50.2% at 1 year (P<0.001). DAS28 remission was similarly impressive with a 46.1%
occurrence in the abatacept group vs. 26.1% in the placebo group. Results were maintained
up to a further year at follow up [47].
IV abatacept has also been shown to delay the progression of inflammatory joint
symptoms in patients who have undifferentiated inflammatory arthritis/very early rheumatoid
arthritis not fulfilling the ACR criteria for RA [48].
A phase II trial investigating abatacept in patients with an inadequate response to MTX
showed superiority of 10mg/kg dosing over lower doses. ACR20/50/70 responses were
consistently greater for the higher dose [49]. Various 6 month [50] and 12 month [49], [51]
study results showed similar statistically significant ACR responses, and confirmed 10mg/kg
to be the most effective, yet safe, dose. Abatacept has also been shown to be superior to
infliximab [52]. Long term data shows abatacept efficacy to be maintained at 5 [53] and 7
years [54] of follow up.
IV abatacept is similarly effective in patients who have an inadequate response to anti-
TNF [55],[56], with an ACR20 response rates of 50.4% vs. 19.5% at 6 months, and
achievement of DAS28 remission of 10% vs. 0.8% (P<0.001) [55].
Few studies have investigated abatacept monotherapy. An IV dose ranging study showed
abatacept monotherapy to be effective compared with placebo, albeit with lower ACR
responses compared to other studies of abatacept combination therapy [49]. Abatacept has
been shown to maintain efficacy after dose reduction [47]. Its effect also persists after drug
withdrawal [48], [57-58].
A weekly SC preparation of abatacept (125mg) is now available, and has been shown to
have a similar efficacy and side effect profile to the IV regime. This option has cost saving
implications and provides greater flexibility to patients in that they can administer their own
treatment. A phase III study showed SC abatacept to be non-inferior to IV abatacept [59]. A
head to head study comparing SC abatacept to SC adalimumab, both in combination with
MTX, did not show inferiority [60]. SC abatacept monotherapy has been shown to be as
effective as MTX monotherapy and less effective than abatacept and MTX combination
therapy [57].
A Cochrane systematic review of over 2900 patients treated with abatacept showed that,
in comparison to placebo, patients on abatacept were 2.2 times more likely to achieve an
ACR50 response at one year [risk ratio (RR) 2.21, 95% CI 1.73 to 2.82] with a 21% (95% CI
16% to 27%) absolute risk difference between groups. The number needed to treat to achieve
an ACR50 response was 5 (95% CI 4 to 7) [61].
Other meta-analyses of abatacept in combination with MTX also show this treatment to
be more effective than MTX monotherapy, and of comparable efficacy to other biologic
DMARDs (bDMARDs) at 24 weeks, when ACR20/50/70, DAS28 < 2.6 (remission) and
Health Assessment Questionnaire (HAQ) change from baseline response rates were assessed
[25], [62]. An exception was tocilizumab, which appeared to be more effective at reducing
DAS28 scores. This however, is likely due to the fact that tocilizumab has a specific effect on
reducing CRP levels used in calculating DAS28 scores [62]. Both IV and SC abatacept seem
to have slightly better safety outcomes in comparison to TNF blockers and tocilizumab,
however, these differences were not statistically significant [25]. Serious adverse events were
increased when abatacept was given in combination with other biologics (RR 2.30, 95% CI
1.15 to 4.62) [61].
Abatacept has been shown to significantly improve health-related quality of life.
Clinically meaningful and significant improvements of Short Form 36 questionnaire (SF-36)
scores have been shown [52], [55], [63]. HAQ scores also statistically improve at 6 and 12
months assessments in abatacept vs. placebo groups [49], [51], [55]. These improvements
have been sustained in 5 year follow up data [53]. Patient reported outcomes for SC abatacept
have been similar [57], [59-60].
Abatacept significantly slows radiographic progression with 50% reduction in Genant
modified total Sharp scores (GmTSS) (radiographic score assessing for the disease associated
damage) compared to baseline [49]. This has been corroborated by other studies at short and
long term follow up [48], [64].
Cost-effectiveness
Provided that TNF blockers are used as first biologic agents, abatacept has a similar cost-
effectiveness to rituximab or a second anti-TNF, when used as a second line biologic agent
[65]. There were 6.09 QALYs gained with abatacept compared with 4.76 QALYs gained with
csDMARDs. The incremental ICER was estimated to be 23,357 per QALY gained for
abatacept compared with csDMARDs [39].
Safety
Abatacept is well established as a relatively safe biologic for RA treatment. RCTs
confirm that the incidence of AEs for placebo and IV abatacept treatment groups is similar.
The same is true for serious adverse events (SAEs). Acute infusion reactions occur at less
than 10%. The most common adverse events have been headache, nasopharyngitis, nausea
and cough [49], [51], [55-56], [63], [66]. AEs and SAEs occur at similar frequencies between
IV and SC abatacept [59]. Injection site reactions were distinct to the SC groups but with no
difference in occurrence rates between SC abatacept and SC placebo. Long term safety data
[67] with 4 years of follow up data has shown SC abatacept to have a similar safety profile to
IV abatacept.

According to NICE [40], EULAR [41] and ACR [42] guidelines, abatacept can be used
as first line biologic, preferentially in combination with MTX or other csDMARDs. NICE
however, specifically stipulate that abatacept should not be used as a monotherapy due to its
greater efficacy when given as a combination therapy. Abatacept treatment is licensed as a
monotherapy in the USA.
B CELL DEPLETION THERAPY - ANTI-CD20

Rituximab (Rituxan, Genentech and Biogen USA, Canada and Japan;
Mabthera, Roche - Europe)
Mechanism of Action
B cells have been shown to be involved in chronic rheumatoid synovitis and the
production of rheumatoid factor, a well-recognised prognostic factor for aggressive RA [68].
Rituximab is a genetically engineered mouse-human chimeric anti-cluster of
differentiation (CD)20 monoclonal antibody. CD20 is a phosphoprotein that is highly
expressed by nave, mature, and memory B cells, but not by early B cell precursors and
antibody-producing plasma cells.
CD20 is not present on stem cells and therefore B cells may be depleted by rituximab
without preventing their regeneration, whilst potentially eliminating the autoantibody-
producing clones. CD20+ B cell depletion in RA is complete at 1 month after the start of a
single treatment dose, and is sustained for several months [69][72]. Peripheral B cells
repopulate to almost baseline levels 6-10 months after treatment [73-74].
The three mechanisms by which rituximab achieves B cell depletion [75 -76] are:
a. Antibody dependent cell mediated cytotoxicity and phagocytosis, in which natural

killer cells, macrophages, and monocytes are recruited through their Fc receptors
bound to surface CD20. This induces CD20+ B cell lysis.
b. Complement dependent cytotoxicity induced by rituximab bound to surface CD20
and binding C1q. This results in activation of the complement cascade and
generation of the membrane attack complex, causing CD20+ B cell lysis.
c. Promotion of CD20+ B cell apoptosis.
Structure, Dose and Pricing

Rituximab is a chimeric molecule consisting of human IgG1 kappa constant regions and
small variable light and heavy chain regions from the anti-CD20 murine antibody fragment,
which is reactive to human CD20.
A cycle of rituximab consists of two 1000 mg IV infusions given two weeks apart. The
cost of a single cycle of rituximab is 3492.6 in the UK (excluding VAT, BNF 70) [10], with
an annual cost of 6,985.2. This does not include the administration related costs. The need
for further rituximab courses should be evaluated 24 weeks following the previous course.
Retreatment should be given at that time if residual disease activity remains, otherwise
retreatment should be delayed until disease activity returns. However, clinicians are looking
into establishing the pattern of RA relapse specific to every patient, to be able to administer
the rituximab course before they flare.
Efficacy [Table 3]
A case report in the late 1990s documented that remission of coexisting RA occurred in
patients with non-Hodgkin lymphoma who were treated with rituximab [77]. A small open
label study of rituximab, albeit with concomitant steroid and cyclophosphamide, in patients
with RA was the first to show the efficacy of rituximab [70]. All five patients included in this
study met the ACR50 criteria six months post rituximab, and three patients also met the
ACR70 criteria. An extension to this initial open label study [78], and further small,
independent, open label studies also provided evidence of rituximab being an effective
treatment for RA with ACR20-70 responses in the majority of patients [184, 194].
A RCT (DANCER) to evaluate the efficacy of rituximab in RA patients, who were non-
responders to MTX, showed rituximab to be more effective than placebo in controlling
symptoms of arthritis, with 54% of patients achieving ACR20 responses at week 24 [80].
Similar efficacy of rituximab was reported in patients with a prior inadequate response to
anti-TNF (REFLEX) [81]. Evidence from further independent RCTs supported the evidence
of efficacy of rituximab in RA (72, 80, 81) and also that its efficacy was longstanding, lasting
up to a year after initial treatment course [70] [82].
Rituximab in combination with MTX has been found to be more effective than rituximab
monotherapy [83]. Other csDMARDs given in combination, including leflunomide, were also
effective and safe [84].
A study (TAME) comparing rituximab (2 x 500 mg) with a TNF inhibitor (adalimumab),
to MTX with rituximab, and MTX alone did not show increased infection rates in the TNF
inhibitor group; however there was no difference in efficacy between the two groups,
therefore this combination therapy is not currently recommended [85]. An open label study of
rituximab (2 x 500 mg) with either etanercept, infliximab, adalimumab or abatacept did not
show increased infection rates [86]. There was some evidence of increased efficacy with the
combination of rituximab and another biologic agent; however, as this study did not have a
control arm and patients characteristics varied, no generalizable conclusion can be drawn.
Table 3. Anti-CD20
Duration, type of study, treatment,

Author/Date published Main results
number of patients (N)
Emery et al. 2006 24 week RCT of rituximab 2x500mg Week 24: ACR20 55% vs.
DANCER (N = 124) vs. rituximab 2x1000mg (N 54% vs. 28% (P<0.0001).
= 192) vs. placebo (N = 149) ACR50 33% vs. 34% vs. 13%
(P<0.001)
Cohen et al. 2006 24 week RCT of rituximab + MTX (N At 24 weeks - ACR20: 51%
REFLEX = 311) vs. vs. 18%, ACR50: 27% vs. 5%,
placebo + MTX (N = 209) ACR70: 12% vs. 1%.
Finckh et al. 2007 6 months prospective cohort study of Mean decrease in DAS28 at 6
rituximab (N = 50) vs. alternative months: -1.61 vs. -0.98
TNFi (N = 66)
Emery et al. 2010 48 week RCT of rituximab 2x500mg ACR20 55.7% vs. 57.6%,
SERENE (N = 167) vs. rituximab 2x1000mg (N ACR50 32.9% vs. 34.1%,
= 170) ACR70 12.6% vs. 13.5%
Hubbert-Roth et al. 48 week RCT of different rituximab Group 1+2 at week 48: ACR20
2010 MIRROR recurrent dosing regimens. 64%
Group 1:2x500mg + 2x500mg Group 3 at week 48: ACR20
Group 2:2x500mg + 2x1000mg 72%
Group 3:2x1000mg + 2x1000mg
Legend: ACR 20 American College of Rheumatology 20% response criteria; ACR 50 American
College of Rheumatology 50% response criteria; ACR 70 American College of Rheumatology
70% response criteria; DAS 28 disease activity score 28 joints; MTX methotrexate; RCT
randomised control trial; TNFi tumour necrosis factor inhibitor.
Swiss [87] and Swedish [88] cohort data analysis has shown that switching seropositive
RA patients to rituximab rather than to an alternative anti-TNF therapy, once initial anti-TNF
therapy has failed, leads to better outcomes.
Rituximab retreatment is relatively safe and efficacious [89][92]. Rituximab is licensed
for treatment every 6 months in the UK, and every 4 months in the USA. There is no
consensus on whether treatment should be given at fixed six monthly intervals, or rather
guided by when patients begin to have symptoms. An open label study has shown that there is
no significant difference in the efficacy and safety of rituximab when comparing the fixed 6
month interval administration, with the administration guided by patients flare [93]. Other
studies however showed that better clinical outcomes, with no significant difference in safety,
were reported with the 6 month fixed retreatment courses [82], [91], [94-95].
A Cochrane systematic review of RCTs, including over 2700 patients, on rituximab (two
1000 mg doses) in combination with MTX compared with MTX monotherapy has shown that
the ACR50 response rates were statistically significantly improved in the rituximab and MTX
combination therapy groups, compared with MTX alone from 24 to 104 weeks. The RR for
achieving an ACR50 at 24 weeks was 3.3 (95% CI 2.3 to 4.6). A proportion of 29% of
patients receiving rituximab combination therapy achieved ACR50 compared to 9% of
controls. The number needed to treat (NNT) was six (95% CI 4 to 9). At 24 weeks, the RR for
achieving a clinically meaningful improvement in HAQ scores (> 0.22) for patients receiving
rituximab combined with MTX compared to patients on MTX alone was 1.6 (95% CI 1.2 to
2.1) [96]. Other meta-analyses also provided evidence that rituximab is an effective treatment
for patients with active RA [97], [98].
Studies on patient reported outcomes have consistently shown rituximab to improve
degree of disability (HAQ-DI), levels of fatigue (FACIT-F) and patients perception of
physical and mental health (SF-36) [99][101].
Rituximab is effective at reducing radiographic progression [196, 217219] and joint
damage, as assessed by MRI [105]. Pooled results from meta-analyses show 57% of patients
receiving rituximab in combination with MTX had no radiographic progression compared to
39% of patients taking MTX alone [96].
Though overall similar in cost-effectiveness, rituximab is more cost-effective than
abatacept or a second anti-TNF agent in RA patients who have failed one anti-TNF drug [65],
[106], [107]. This is partly due to the fact that rituximab has lower than average treatment
costs compared to other biologics [108].
Safety
Rituximab is well established as a relatively safe biologic for RA treatment. RCTs
confirm that the incidence of AEs is similar between placebo (70-88%) and rituximab (73-
85%) active treatment groups [70], [80], [81], [87]. The same is true for SAEs, ranging from
3-10% for placebo to 5-15% for rituximab groups. The most common adverse events tend to
be headache, respiratory tract infection, nasopharyngitis, nausea and arthralgia. Rituximab
can cause infusion reactions therefore premedication with steroid and antihistamine is
required. Infusion reactions typically occur during the first infusion and can include urticaria,
hypotension, angioedema and bronchospasm. Symptoms can be minimised by reducing
infusion rates or stopping the infusion until the symptoms resolve. Immunoglobulin levels
need to be checked regularly, as these can fall following rituximab treatment and potentially
increase the risk of infection.
According to a Cochrane systematic review of patients treated with rituximab in different
RCTs, a greater proportion of patients receiving rituximab in combination with MTX
developed AEs after their first infusion, compared to those receiving MTX monotherapy and
placebo infusions (RR 1.6, 95% CI 1.3 to 1.9). No statistically significant differences were
noted in the rates of SAEs [96].
Progressive multifocal leukoencephalopathy (PML) is a life-threatening demyelinating
infection of the brain caused by the JC (John Cunningham) virus in immunosuppressed
individuals [109]. Very rare cases of PML (documented as <1/10,000 patients in the
rituximab summary of product characteristics (SPC), [110]) have been reported following the
use of rituximab. Analysis of an American inpatient database from 1998 to 2005 estimated
the rate of PML in patients with RA being 0.4 per 100, 000 discharges, compared with 0.2 for
the general population [111].

British and European guidelines [40], [41], [112] on the use of rituximab in RA state that
rituximab can be used in adult patients with seropositive RA who are eligible for biologic
treatment and have had an inadequate response to one or more anti-TNF medications, or are
unable to take anti-TNF due to a contraindication. Evidence thus far has shown rituximab to
be more efficacious in seropositive patients; but despite this, British NICE guidelines
recommend its use as a second line biologic treatment in all RA patients.
American (American College of Rheumatology, ACR) 2015 guidelines [42] now state
that rituximab can be used as first line biologic, if appropriate, after csDMARD monotherapy
failure. Rituximab can be used if patients have a history or solid organ malignancy or non-
melanoma skin cancer within the past 5 years [110].
INTERLEUKIN 1
Anakinra (Kineret, SOBI)
Mechanism of Action
IL1 is a pro-inflammatory cytokine produced abundantly by synovial cells. Early studies
of tissue samples have observed a far greater proportion of cells produce IL1 rather than TNF
[113]. Experimental studies suggested this cytokine played an important role in promoting
tissue inflammation and remodelling. In addition, IL1 is the principal mediator of bone and
cartilage destruction. It stimulates the release of matrix metalloproteinases inhibiting cartilage
repair and activates osteoclast augmenting bone resorption [114], [115]. Experimental models
have demonstrated that IL1 blockage produces significant but often modest anti-inflammatory
effects and potent inhibition of cartilage and bone damage [116].

Anakinra is a recombinant, non-glycosylated form of human IL1-receptor antagonist that
inhibits the activity of IL1. It is administered by SC injection at a dose of 100 mg once daily.
It costs 20.47 per day in the UK (excluding VAT, BNF70) [10], equivalent to 7450 per
annum.
Efficacy [Table 4]
Several RCTs reviewed anakinra with MTX compared to MTX monotherapy and
demonstrated significantly greater ACR responses. This was often rapid and associated with
significantly less radiographic progression [117], [118].
Table 4. Anakinra

Author/Date published Main results
Cohen et al. 2004 24-week double-blind, randomised, ACR20 at week 24:
placebo-controlled trial. Group 1: 38%, P<0.001
Group 1: Anakinra 100mg SC daily Group 2: 22%
+ MTX (N = 250)
Group 2: Placebo + MTX (N = 251)
Legend: ACR 20 American College of Rheumatology 20% response criteria; MTX methotrexate; N
number of patients; SC subcutaneously.
However, indirect comparisons based on meta-analyses of placebo-controlled trials found

anakinra to be less effective than anti-TNF therapy. The comparison of the two agents
revealed a non-significant RR of ACR50 response of 0.67 (95% CI 0.38 to 1.17), favouring
anti-TNF, but concluding that anakinra was inferior to first generation TNF inhibitors [119],
[120].
A subsequent meta-analysis found anakinra to be less effective than TNF inhibitors,
although this was only statistically significant for comparisons with adalimumab and
etanercept [121].
A subsequent study, designed to determine if there were any additive or synergistic
effects of combination therapy with anti-TNF (etanercept), did not find any benefit and
reported increased safety concerns [122].
Other agents targeting IL1, including anti-IL1 antibodies, anti-IL1 receptor and IL1
TRAP (consisting of IL1 receptors and an Fc subunit), have all failed to show clear efficacy
in RA [123], [124].
Safety
A Cochrane review showed that, at doses of 50150 mg/day, the rates of injection site
reactions were 71% for the anakinra-treated groups vs. 28% for placebo [125]. One of the
disadvantages of this biologic agent is the frequency of administration (daily). A meta-
analysis of RCTs indicated a significantly increased risk of serious infections with high doses
of anakinra [126]; however, no difference was found in the Cochrane review. Neutropenia
can occur with the potential for resolution on temporary discontinuation and re-challenge of
anakinra [127].
Like TNF blockers, anakinra is an anti-cytokine biologic agent. However, unlike TNF
agents, invasive opportunist infections are exceptionally rare, suggesting a difference in
mechanisms of action between these biotherapies [126]. A 3 year open study reported a
higher than expected incidence of melanoma and lymphoma compared with the general
population. However due to the presence of additional risk factors and confounders in the RA
group included in this study, this risk cannot be attributed to anakinra alone [114].

British NICE guidance [40] does not recommend anakinra for the treatment of RA as
although there is clinical effectiveness in the short term, the extent of benefit was not
sufficient to justify cost. Anakinra is not specifically mentioned in the abbreviated EULAR
recommendations, although the more detailed summary does suggest that some patients may
respond to this biologic agent [41]. Anakinra is not recommended for RA treatment by the
2015 ACR guidelines [42].
SMALL MOLECULE INHIBITORS

Janus Kinase Inhibitors [Table 5]
Janus kinase inhibitors, also known as JAK inhibitors, function by inhibiting the activity
of one or more of four Janus kinase enzymes (JAK1, JAK2, JAK3, TYK2 (TYrosine Kinase
2). Activation of Janus kinases leads to phosphorylation of cytokine receptors and formation
of docking sites for the STAT (Signal Transducer and Activation of Transcription) family of
transcription factors. After phosphorylation, the STATs translocate to the nucleus where they
bind to deoxyribonucleic acid (DNA) and regulate gene expression [128]. Janus kinase
inhibitors interfere with this JAK-STAT signalling inflammatory pathway.
Cytokines that signal through heteromeric receptors containing the gp130 subunit,
including IL6 and IL11, primarily utilize JAK1 and JAK2. Type II cytokine receptors that
bind IL10, IL19, IL20 and IL22 utilize JAK2 and TYK2 for signalling. Receptors for
hormone-like cytokines, such as growth hormone, prolactin and growth factors erythropoietin
(EPO), thrombopoietin (TPO), IL3 or GM-CSF use JAK2.
Table 5. Janus Kinase Inhibitors

(N)
Fleischmann et al. 2012 6-month phase III, RCT Month 3 ACR20, and mean
parallel-group trial. change from baseline in
Group 1: 5mg PO tofacitinib HAQ-DI results:
(N = 243) Group 1: 59.8%, -0.50
Group 2: 10mg PO Group 2: 65.7%, -0.57
tofacitinib (N = 245) Group 3: 26.7%, -0.19
Group 3: Placebo (N = 122) P<0.001 for all groups.
Burmester et al. 2013 6-month phase III RCT, Month 3 ACR20, and mean
placebo-controlled, parallel- change from baseline in
group trial. HAQ-DI results:
Group 1: 5mg BD PO Group 1: 41.7%, -0.43
tofacitinib (N = 134) P<0.001 for all groups.
van Vollenhoven et al. 2013 12-month phase III RCT, Month 6 ACR20 (P<0.001),
placebo-controlled, parallel- and mean change from
group trial. baseline in HAQ-DI
Group 1: 5mg BD PO (P<=0.05) results:
Group 3: 40mg SC e.o.w. Group 4: 28.3%, -0.24
adalimumab (N = 204)
van der Heijde et al. 2013 24 month phase III RCT Month 6 ACR20 (P<0.0001),
Group 1: 5mg BD PO and mean change from
tofacitinib (N = 321) baseline in HAQ-DI, and
Group 2: 10mg BD PO total SHS results:
tofacitinib (N = 316) Group 1: 51.5%, -0.40, 0.12
Group 3: Placebo (N = 160) Group 2: 61.8%, -0.54
(P<0.0001), 0.06 (P<=0.05)
Group 3: 25.3%, -0.15, 0.47

(N)
Kremer et al. 2013 12 month RCT Month 6 ACR20, and mean
Group 1: 5mg BD PO change from baseline in
tofacitinib (N = 318) HAQ-DI results:
Group 3: Placebo (N = 159) Group 3: 30.8%, -0.16
P<0.001
Lee et al. 2014 24 month RCT, parallel Month 6 ACR20, and mean
group trial. change from baseline in
Group 1: 5mg BD PO HAQ-DI, and total SHS
tofacitinib (N = 373) results:
Group 2: 10mg BD PO Group 1: 71.3%, -0.8, 0.2
tofacitinib (N = 397) Group 2: 76.3%, -0.9, <0.1
Group 3: Placebo (N = 186) Group 3: 50.5%, -0.6, 0.8
P<0.001
Legend: ACR 20 American College of Rheumatology 20% response criteria; BD twice daily; e.o.w.
every other week; HAQ-DI health assessment questionnaire damage index; N number of
patients; PO oral administration; RCT randomised control trial; SC subcutaneously; SHS -
Sharp/van der Heijde score.
The receptors for IFN receptor use JAK1 and JAK2, whereas cytokines like IL2, IL4,
IL7, IL9, IL15 and IL21 signal through gamma chain containing receptors JAK1 and JAK3.
Several of these cytokines when dysregulated contribute to the pathogenesis of RA [129]
[131].
Tofacitinib (Xeljanz, Pfizer)
Tofacitinib is an oral Janus kinase (JAK) inhibitor. Tofacitinib preferentially inhibits

signalling through receptors associated with JAK1 and/or JAK3 [129], [130].
There have been six global phase III RCTs investigating tofacitinib in RA patients with a
prior inadequate response to DMARDs and/or biologics. Tofacitinib has been shown to be
statistically more effective than placebo (P<0.001), at both 5mg and 10mg twice daily dosing
regimens, either as monotherapy [130], [132] or with combination csDMARDs [133][136].
A head to head study of adalimumab vs. tofacitinib showed similar efficacy [134]. Similar
beneficial results were reported in the mean change from baseline in HAQ-DI scores [130],
[132][136], mean change in TSS [132], [135], and clinically meaningful change in FACIT-F
fatigue scores [132], [133], [135]. The most effective dose was 10 mg administered twice
daily. AEs were similar across all studies but with noted rises in low-density lipoprotein
(LDL) cholesterol and ALT/aspartate transferase (AST), and falls in neutrophil counts. The
most common AEs were upper respiratory tract infections, nasopharyngitis, headache and
diarrhoea.
A meta-analysis of 8 phase II and III RCTs [137] showed that tofacitinib, 5mg twice
daily, was associated with statistically significant improvement in ACR20/50/70 response
criteria after 12 weeks of treatment when compared to placebo (P<0.00001), and when
compared to adalimumab in ACR50 criteria responses (P=0.003). Further systematic review

confirmed statistically significant improvement in HAQ scores (P<0.0001) [138].
Tofacitinib is the first oral biologic treatment to receive approval by the Food and Drug
Administration of the United States Health and Human services (FDA) for treatment of RA
patients with an inadequate response to MTX. In the European Union, tofacitinib has not been
approved due to safety concerns and insufficient evidence of consistent reduction in disease
activity and radiographic joint damage [139]. This may change however with the release of
new data.
CONCLUSION
The therapeutic armamentarium for RA is continuously expanding. In addition to TNF
inhibitors, other biologic agents have been shown as effective in treatment of patients with
RA, providing opportunities for better disease control in patients who had an unmet need
through lack or loss of response to conventional DMARDs or TNF blockage, or intolerance to
these therapies. As ever, the cost implications of such treatments can limit which patients
have access to these drugs, especially in countries without free at point of access healthcare.
Further research in stratifying RA patients based on biomarkers or clinical phenotype will
enable a better selection of the most suitable treatment options for a certain RA patient, at a
certain stage in their disease course. More head-to-head clinical trials aiming to compare the
available biologic agents for RA treatment are required to inform clinicians about differences
between the licensed biologic therapies and guide their treatment decisions.
ACKNOWLEDGMENTS
The authors will like to thank to Dr. Maria Leandro (maria.leandro@ucl.ac.uk), Senior
Lecturer and Consultant Rheumatologist, University College London, Department of
Inflammation, Infection and Immunity, for reviewing this chapter.
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Chapter 11
NEW BIOLOGIC AGENTS AND BIOSIMILARS

DEVELOPED FOR RHEUMATOID ARTHRITIS
Laura Attipoe1, Katie Bechman2

and Coziana Ciurtin, PhD FRCP 1,3,*
1
2
Department of Rheumatology, Hammersmith Hospital, London, UK
3
ABSTRACT
The pathogenesis of rheumatoid arthritis (RA) is characterised by interactions
between several types of immune cells, which are associated with the release of multiple
inflammatory cytokines. Recently, numerous biologic treatments targeting classes of
immune cells, cytokines or intra-cellular pathways of pro-inflammatory signals have been
developed. Some of them are currently under research as potential therapeutic options for
RA patients. This chapter reviews the available evidence regarding the safety and
efficacy of new biologic agents targeting B cells, proinflammatory interleukins (IL), T
helper 17 (Th17) pathway and intracellular enzymes. This chapter reviews the most
relevant randomised controlled trials (RCTs) which have proven the efficacy of different
biologic agents and small molecule inhibitors in controlling the inflammation associated
with RA. The management of RA remains a dynamic and evolving field. The
development of less expensive biosimilar drugs, analogous to existing licensed biologic
therapies, is an emerging area of research that deserves particular attention.
*
Keywords: rheumatoid arthritis, new biologic therapies, ofatumumab, ocrelizumab,

veltuzumab, tregalizumab, alemtuzumab, mavrilimumab, ustekinumab, secukinumab,
apremilast, biosimilars, efficacy, safety, cost-effectiveness
INTRODUCTION
Following the therapeutic success of biologic agents targeting B cell depletion and IL6
inhibition, the research in the field of rheumatology led to the discovery of other biologic
agents with similar targets, but different mechanisms of action, properties and dose regimens.
In addition, new biologic pathways, such as the Th17/IL17 pro-inflammatory pathways were
explored. Agents blocking intracellular enzyme activation or other pro-inflammatory
interleukins were tested in patients with RA, and showed promising results. As the cost-
effectiveness of biologic agents is a limiting factor for their widespread use, additional
interest was directed into developing biosimilars of the already licensed biologic treatments
for RA.
B CELL DEPLETION THERAPY (ANTI CD-20)

Ofatumumab
Ofatumumab is a fully human anti-CD20 monoclonal antibody (mAb). A joint phase I/II
study investigated the safety and efficacy of ofatumumab in active RA patients who had not
had an adequate response to one or more disease modifying anti-rheumatic drugs (DMARDs).
A proportion of 70% of patients had a moderate or good European League against
Rheumatism (EULAR) response and there were no significant safety concerns [1].
A phase III RCT in biologic-naive patients looked at the effect of ofatumumab, 700mg
intravenously (IV) given two weeks apart, in combination with methotrexate (MTX). At week
24, ofatumumab achieved statistically significant American College of Rheumatology (ACR)
20 responses of 50% compared to a 27% placebo response (P<0.001). The most common
adverse events (AEs) were rash and urticaria, especially on the first infusion day. First dose
infusion related reactions were significantly higher at 68% vs. 6% placebo; however, this rate
of AEs for the active drug was markedly reduced to <1% with the second infusion. There
were no episodes of immunogenicity [2]. Ofatumumab has a unique binding site (epitope) on
the human CD20 molecule, compared to other antiCD20 mAbs including rituximab. The
membrane proximity of this epitope likely accounts for the greater efficacy of complement
activation and B cell depletion observed with ofatumumab [3].
Other phase III trials were prematurely terminated as the sponsor wanted to refocus
clinical development on subcutaneous (SC) preparations rather than IV delivery, with the aim
of achieving a slower rate of absorption and B cell depletion, with subsequent fewer infusion
reactions [4-5]. A phase I/II trial of SC ofatumumab has shown efficacy at low doses, with
mild to moderate infusion reactions with higher doses [6].
New Biologic Agents and Biosimilars Developed for Rheumatoid Arthritis 261
Ocrelizumab [Table 1]
Ocrelizumab is a humanised mAb that selectively targets CD20 positive B cells. Like
rituximab, it is also given as 2 infusions 2 weeks apart.
Clinical trials of ocrelizumab in combination with MTX in patients with an inadequate
response to MTX monotherapy [7]; and of ocrelizumab in combination with either MTX or
leflunomide in patients with an inadequate response to tumour necrosis factor (TNF) blockers
were completed [8]. Both trials showed statistically significant (P<0.0001) improvement in all
ACR responses, disease activity score 28 (DAS28) remission, and clinically meaningful
improvement in health assessment questionnaire disability index (HAQ-DI) scores, compared
to placebo.
In inadequate responders to TNF inhibitors, 200mg dosing vs. 500mg dosing was
associated with ACR20 responses at week 24 of 42.2% and 47.9% respectively, in
comparison to a placebo response of 22%. All ACR responses were sustained at week 48. The
500mg dosing regimen showed superiority with a statistically significant reduction in
radiographic progression of 61% (P=0.0017). AEs were of similar frequency between all
groups, serious infections were more common in the ocrelizumab group. The most common
AEs were infusion related reactions with 19.1% in the 200mg group and 23.8% in the 500mg
group.
A Japanese study of ocrelizumab and MTX combination therapy in patients who had
failed MTX monotherapy was terminated early due to an increased incidence of serious
infection, including Pneumocystis jiroveci, in the ocrelizumab group [9].
As a consequence of the above studies not showing significant benefit over existing
biologics, including rituximab, a decision was made not to further investigate ocrelizumab as
a treatment for RA [7]. Further studies continue to see if ocrelizumab may be of benefit in
multiple sclerosis and other immune mediated conditions.
Table 1. Anti-CD20
Author/Date Duration, type of study, treatment,

Main results
published number of patients (N)
Genovese 48 week RCT of ocrelizumab IV with Week 24 ACR20, change from
et al. 2015 MTX or leflunomide baseline in HAQ-DI scores
(SCRIPT) Group 1: ocrelizumab 200mg x2 Group 1: 42.2%, 52.3%
Group 2: ocrelizumab 500mg x2 Group 2: 47.9%, 58.5%
Group 3: placebo Group 3: 22%, 32.9%
Legend: ACR 20 American College of Rheumatology 20% response criteria; HAQ-DI health
assessment questionnaire damage index; IV intravenously; N number of patients; RCT
Veltuzumab
Veltuzumab is a humanised anti-CD20 mAb. A phase II RCT of veltuzumab, in patients

who had failed either MTX or MTX in combination with TNF inhibitors, was terminated for
study re-design with no safety issues having been identified. No results have been published
[10]. Delays in production leading to termination of licensing agreements have been reported
in the press.
ANTI-CD4
Tregalizumab
CD4+CD25+ regulatory T cells are vital for maintaining autoimmune tolerance. The
humanised CD4-specific mAb, tregalizumab, activates T regulatory cells by binding to CD4
and activating downstream pathways [11].
A 6 week phase I/IIa dose escalation trial of tregalizumab monotherapy in RA patients
with an inadequate response to DMARDs showed a meaningful improvement in
ACR20/50/70 responses [12]. Numerical results are not available. However, a subsequent 24
week phase IIb study failed to reach its primary endpoint and the trial was terminated [13].
ANTI-CD52
Alemtuzumab
Alemtuzumab (CAMPATH-1H) is an anti-lymphocyte humanised immunoglobulin (Ig)

G1 mAb, directed against the surface antigen CD52, which is present on all lymphocytes and
some monocytes.
A phase I trial of alemtuzumab in RA was terminated early due to concerns over toxicity,
primarily severe adverse events (SAEs) [14]. There was one death due to opportunistic
infection and one episode of haemolytic uraemic syndrome. Efficacy was assessed by
modified Paulus criteria. A 50% Paulus response required four out of six of the following:
> 50% improvement in tender joint score, swollen joint score, early morning stiffness,
erythrocyte sedimentation rate (ESR) or C reactive protein (CRP) and/or >2-point
improvement in patient global assessment or physician global assessment. Three out of five
patients with a disease duration of < 3 years achieved a 50% Paulus response for 6 months.
Only 4 out of 30 with a disease duration of > 3 years achieved this same end point (P=0.07)
[15].
RA patients at 12 year follow up continued to have long-term alterations in lymphocyte
subsets compared to age-matched disease controls. The clinical significance of this remains
uncertain, however, vaccine responses were within normal limits [16]. Due to a lack of
efficacy over already available licensed biologics, alemtuzumab was not developed further as
a treatment for RA.
INTERFERON BETA 1
Interferon beta 1 is a cytokine shown to reduce synovial inflammation by inhibition of
TNF and IL1 secretion, whilst also increasing production of the IL1 receptor antagonist [17-
18]. A 6 month phase II trial of three times weekly SC interferon beta-1 injections, in
combination with MTX, did not show any clinical or radiological benefit [19].
ANTI-GRANULOCYTE COLONY MACROPHAGE STIMULATING

FACTOR (GM-CSF) [TABLE 2]
Mavrilimumab is a fully human mAb targeting the alpha subunit of the GM-CSF
receptor. GM-CSF is thought to modulate the pathogenesis of RA through the activation and
differentiation of neutrophils and macrophages.
A 12 week, phase II study RCT investigating mavrilimumab and MTX combination
therapy in patients with an inadequate response to MTX showed efficacy of all mavrilimumab
doses, with success in achieving the primary end point of 1.2 decrease in DAS28-CRP (41-
66.7% versus placebo response of 34.7%. The highest mavrilimumab dose, 100mg SC every
fortnight, also significantly improved DAS28 scores, all ACR categories and HAQ-DI. AEs
were mild to moderate with the most common being a reduction in diffusing capacity of the
lungs for carbon monoxide (DLCO) >20% from baseline, nasopharyngitis and upper
respiratory tract infections [20]. Similar findings were found in a Japanese cohort of patients
[21]. Results are currently pending from a trial of mavrilimumab versus golimumab [22].
Table 2. Anti-GMCSF

Main results
Burmester 12-week, phase II randomised, double blind, 1.2 decrease in DAS28-CRP at
et al. 2013 placebo-controlled trial. week 12:
Group 1: 10mg mavrilimumab SC every fortnight
(N = 39) Group 1: 41%
Group 2: 30mg mavrilimumab SC every fortnight Group 2: 61%
(N = 41) Group 3: 53.8%
Group 3: 50mg mavrilimumab SC every fortnight Group 4: 66.7%
(N = 39) Group 5: 34.7%
Group 4: 100mg mavrilimumab SC every fortnight
(N = 39)
Legend: DAS28-CRP disease activity score assessing 28 joints and the C reactive protein; N number of patients;
SC subcutaneously.
INTERLEUKIN 12/23 [TABLE 3]

Ustekinumab (Stelara, Janssen) and Guselkumab
Ustekinumab acts against the p40 subunit of both IL12 and IL23, whereas guselkumab is
specific to the p19 subunit of IL23 [23].
A phase II RCT evaluating the anti IL12/23 agents ustekinumab and guselkumab in
patients with active RA, despite concomitant MTX therapy, has not shown any statistically
significant efficacy [24]. The AE rate was similar between active and placebo groups.
Table 3. Anti IL12/23

Main results
published (N)
Smolen et al. A 28-week phase II, randomised, double blind, ACR20 at week 28:
2015 placebo-controlled, parallel-group trial. Group 1: 52.7%
Group 1: 90mg ustekinumab 8 weekly (N = 55) Group 2: 54.5%
Group 2: 90mg ustekinumab 12 weekly (N = 55) Group 3: 44.4%
Group 3: 200mg guselkumab 8 weekly (N = 54) Group 4: 38.2%
Group 4: 50mg guselkumab 8 weekly (N = 55) Group 5: 40%
Group 5: Placebo (N = 55) Not statistically significant
Legend: ACR 20 American College of Rheumatology 20% response criteria; N number of patients.
INTERLEUKIN 15
IL15 is produced in RA synovium. Treatments given to block IL15 have suppressed IL15
dependent T cell lines and induced apoptosis. CD3+ T cell subsets expressing CD69 have
also been reduced. CD69 is a marker of T cell activation, thereby implying that IL15 is
partially involved in T cell activation in the synovium [25].
HuMax-IL15 is a high-affinity, fully human IgG1 antiIL15 mAb generated in human
Igtransgenic mice.
A phase I-II, 12 week, proof of concept study of HuMax-IL15 SC monotherapy in 30
patients showed an ACR20 response in 63% [25]. Side effect profile was similar to other
biologics, with reports of mild injection site reactions, transient pyrexia, upper respiratory
tract infections and influenza like symptoms. No further studies have been published.
INTERLEUKIN 17 [TABLE 4]
The interleukin-17 (IL17)/IL17 receptor (IL17R) family have an important role in the
pathogenesis of RA. Mouse models for inflammatory arthritis demonstrated that blocking
endogenous IL17A suppresses arthritis development and joint damage [26][28]. Agents that
directly target IL17A or its receptor are currently available, and have been tested in several
autoimmune rheumatic diseases. Secukinumab is a highly selective, fully human
immunoglobulin G1k (IgG1k) mAb directed against the IL17A cytokine. Ixekizumab, a
humanised IgG4 anti-IL17A mAb, and brodalumab, a fully human IgG2 anti-IL17RA mAb,
are also in clinical development and have shown efficacy in autoimmune disease [29-30].
Table 4. Anti IL17
Author/Date
Duration, type of study, treatment, number of patients (N) Main results
published
Hueber et al. 2010 16 week, randomised, placebo controlled trial. ACR20 Results
Group 1: secukinumab 10mg/kg (N = 26) Group 1: 54% (P=0.8)
Group 2: placebo (N = 26) Group 2: 31%
Genovese 52 week phase II randomised, double blind, and placebo- ACR20 Results:
et al. 2010 controlled, dose-finding trial. Group 1: 53.7%
Group 1: 300mg SC secukinumab (N = 41) Group 2: 46.5%
Group 2: 150mg SC secukinumab (N = 43) Group 3: 46.9%
Group 3: 75mg SC secukinumab (N = 49) Group 4: 34%
Group 4: 25mg SC secukinumab (N = 54) Group 5: 36%
Group 5: Placebo (N = 50) Not statistically significant
Genovese 16 week Phase I randomised, double-blind, placebo-controlled, ACR20 Results at week 10
et al. 2010 proof-of-concept trial. (primary endpoint):
Group 1: 0.2mg/kg ixekizumab (N = 19) Group 1: 73.7%
Group 2: 0.6mg/kg ixekizumab (N = 20) Group 2: 70%
Group 3: 2mg/kg ixekizumab Group 3: 90% (P<0.05)
(N = 20) Group 4: 55.6%
Genovese 12 week phase II randomised, double blind, placebo-controlled, ACR20 Responses:
et al. 2014 dose-ranging trial. BIOLOGIC NAIVE
BIOLOGIC NAIVE Group 1: 45%
Group 1: 3mg SC ixekizumab (N = 40) Group 2: 43%
Group 2: 10mg SC ixekizumab (N = 35) Group 3: 70% (P=0.001)
Group 3: 30mg SC ixekizumab (N= 37) Group 4: 51%
Group 6: Placebo (N = 54) (P=0.001 for 30mg group,
ANTI-TNF INADEQUATE RESPONDERS P=0.031 for all other
Group 1: 80mg SC ixekizumab (N = 65) groups)
Group 2: 180mg SC ixekizumab (N = 59) ANTI-TNF
Group 3: Placebo (N = 64) INADEQUATE
RESPONDERS
Group 1: 40%
Group 2: 39%
Group 3: 23%
(P<0.05 for all groups)
Martin et al. 2013 85 day phase 1b randomised, double blind, placebo-controlled, ACR20 Results at Day 85:
multiple-dose trial. Group 1: 33%
Group 1: 50mg SC brodalumab (N = 6) Group 2: 33%
Group 4: 420mg IV brodalumab (N = 6) Group 5: 67%
Group 5: 700mg IV brodalumab (N = 6) Group 6: 33%
Group 6: Placebo SC (N = 6) Group 7: 0%
Group 7: Placebo IV (N = 4) Not statistically significant
Pavelka 12 week randomised, double blind, placebo-controlled, multiple- ACR50 at week 12:
et al. 2015 dose trial of brodalumab (N = 189) vs. placebo (N = 63). Group 1: 16%
Group 1: 70mg SC brodalumab Group 2: 140mg SC brodalumab Group 2: 16%
Group 3: 210mg SC brodalumab Group 3: 10%
Group 4: placebo SC Group 4: 13%
Not statistically significant
Legend: ACR20 American College of Rheumatology 20% response criteria; ACR50 American College of
Rheumatology 50% response criteria BD twice daily; IV intravenously; N number of patients; SC
subcutaneously; TNF tumour necrosis factor.
Secukinumab
The first human study of secukinumab was a 16-week RCT where patients received 2
doses of secukinumab at week 0 and 3 versus placebo. The study achieved its primary
endpoint, with 54% of patients showing an ACR20 response at week 16, compared with 31%
in the placebo arm [31].
A phase II RCT did not reach its primary endpoint of achieving a statistically significant
ACR20 response at week 16 in the active treatment group compared with placebo [32]. No
statistical significance was reached in the HAQ-DI scores comparison between the
secukinumab and placebo groups, although there was a greater reduction from baseline in the
secukinumab group. The reported rate of AEs was similar between the secukinumab and
placebo groups with infection rates not being dose-dependent. The most common infections
were nasopharyngitis, upper respiratory tract infection, sinusitis and urinary tract infection.
There were no reported cases of immunogenicity.
There are two-phase III secukinumab trials currently in different stages of progress. Both
studies are looking at short and long-term efficacy, safety and tolerability of 75 mg and 100
mg secukinumab versus placebo in patients with active RA with an inadequate response to
anti-TNF. NURTURE 1, is a RCT with up to one year follow up, which was completed in
February 2015 and has pending results [33]. REASSURE 1 study, with up to two years follow
up, is estimated to be completed in October 2016 [34].
Ixekizumab
The tolerability and efficacy of ixekizumab, in RA patients taking background oral

csDMARDs, has been evaluated in a phase I RCT. Variable SC doses (0.2, 0.6, 2mg/kg) were
given every 2 weeks for a total of 5 doses, followed by a 16 week evaluation period. ACR20
responses were reached at week 10 with the 2mg/kg dose in 90% of patients (p 0.05). AEs
in the ixekizumab groups were not dose related. Leucopenia and vertigo were the most
common. AEs in the combined ixekizumab group each occurred in 6.8% of patients. Anti-
ixekizumab antibodies were detected in 2 patients with no change in AE or pharmacokinetics.
One patient was deemed to have a type III immune mediated reaction [35].
A 12-week phase II RCT investigated the efficacy of ixekizumab in RA patients who
were biologic naive or had a prior inadequate response to anti-TNF. ACR20 responses across
all varying dose ixekizumab groups were statistically significant in the active treatment arms,
with no apparent linear dose response. AEs were of similar frequency with the most common
being headache, urinary tract infections (UTIs) and injection site pain/erythema [36].
Brodalumab
A phase 1b [37] and phase II trial [38] have not shown any clinical benefit of brodalumab
in RA, and therefore no further clinical trials to assess its efficacy were planned.
INTERLEUKIN 18 (IL18)
IL18 is a cytokine shown to induce chronic inflammation with downstream production of
other cytokines such as TNF and GM-CSF [39-40]. Caspase 1 is a protein involved in the
cleavage of the IL18 precursor. IL18 has been detected in the synovium of RA patients [40-
41]. Arthritis mouse models had more severe disease when primed with IL18 [39], and had
reduced disease when IL18 effects were blocked [42]. RA patients have been shown to have
high serum levels of IL18, which decreased following treatment with MTX [43]. Phase I trials
of a soluble IL18 binding protein, in healthy volunteers and RA patients, displayed dose-
dependent pharmacokinetics with a favourable safety profile [44]. A phase II trial
investigating an inhibitor of caspase 1, pralnacasan, showed poor results and was terminated
due to an animal study showing liver abnormalities [45]. Clinical trials investigating the
blockade of IL18 and its receptor are currently in progress in inflammatory disease other than
RA.
IL20 and its receptors are upregulated in the synovium of RA patients. Activated
monocytes and dendritic cells are the main sources of IL20 via the p38 MAP kinase and
nuclear factor kB (NF-B) pathway.
NNC0109-0012 is a SC selective antiIL20 recombinant human mAb that targets and
neutralises IL20. A phase IIa proof of concept trial was designed to assess the efficacy, safety,
and tolerability of NNC0109-0012 in patients with an inadequate response to MTX [46].
ACR20 responses were found in 59% of patients with efficacy also shown in DAS28-CRP
and HAQ-DI parameters. Tolerability profile was acceptable and similar to other biologics.
Subsequent phase IIb trials were terminated/withdrawn as primary and secondary
endpoints were not met.
IL21 is produced by activated CD4+ T cells and induces activation of T cells and pro-
inflammatory cytokine secretion in RA. IL21 expression correlates with Th17 cell presence in
synovial fluid and peripheral blood of RA patients [47-48]. The IL21 receptor has been
shown to be produced in RA synovium [49]. Improvement in arthritis has been seen in RA
animal models where the IL21/IL21 receptor pathway has been blocked [50].
Phase I and II trials have been conducted in RA patients with results yet to be posted [51-
53].
PHOSPHODIESTERASE 4 INHIBITORS
Apremilast (Otezla, Celgene) [Table 5]
Apremilast is an oral phosphodiesterase 4 inhibitor involved in the inhibition of anti-TNF

and other cytokines.
Apremilast has not been shown to be an effective treatment for patients with RA. A phase
II study was terminated early due to lack of clinical efficacy [54]. The rate of AEs was similar
between the 20mg twice daily (BD) and 30mg BD treatment groups. Diarrhoea and nausea
were the most commonly reported AEs. Weight loss greater than 5% was seen at a higher rate
in the apremilast treatment groups compared to placebo.
A second phase II trial was completed in 2014 with results yet to be published [55].
Table 5. Apremilast
Author/Date Duration, type of study, treatment,

Main results
published number of patients (N)
Genovese 24b week phase II, double blind, 24 week ACR20, mean change from
et al. 2015 placebo-controlled, parallel-group trial. baseline in HAQ-DI, and total SHS
Group 1: 20mg BD PO apremilast (N = results:
82) Group 1: 19.5%, -0.08, 0.34
Group 2: 30mg BD PO apremilast (N = Group 2: 27.6%, -0.23, 1.47
76) Group 3: 24.1%, -0.07, 0.47
Legend: ACR 20 American College of Rheumatology 20% response criteria; BD twice daily; HAQ-DI
health assessment questionnaire damage index; OD once daily; N number of patients; PO oral
administration; SHS -Sharp/van der Heijde score.
SMALL MOLECULE INHIBITORS
JANUS KINASE INHIBITORS [TABLE 6]

Baricitinib is a once-daily, oral, selective Janus kinase (JAK1 and JAK2) inhibitor. The
results of 3 phase III trials have been presented at European and American rheumatology
conferences in 2015, and are due to be formally published in the near future. These studies
have assessed baricitinib to be effective as both monotherapy (RA-BEGIN) [56], and in
combination therapy with csDMARDs (RA-BEACON/BUILD) [57-58], in patient groups
with an inadequate response to csDMARDs [58] or anti-TNF therapies [57], and limited or no
prior csDMARDs or biologics exposure [56]. HAQ-DI questionnaire and total Sharp score
(TSS) were also statistically improved in the active treatment arm. Baricitinib 4mg daily was
more effective than 2mg daily dosing. Preliminary reports stated that in a head to head study,
baricitinib had shown greater efficacy than adalimumab in patients with an inadequate
response to MTX and no prior exposure to biologic therapy (RA-BEAM) [59]. AE rates were
similar between baricitinib treatment groups. Recruitment to a long term extension study is
still in progress (RA-BEYOND) [60].
Table 6. Janus Kinase Inhibitors

Main results
published (N)
Genovese 24 week randomised control trial. 12 week ACR20, and HAQ-
et al. 2015 Group 1: 2mg OD PO baricitinib (N = 174) DI scores
RA-BEACON Group 2: 4mg OD PO baricitinib (N = 177) Group 1: 49%, 59
Group 3: Placebo (N = 176) Group 2: 55%, 67
(P< 0.001)
Group 3: 27%, 43
Dougados 24 week randomised control trial. 12 week ACR20, and HAQ-
et al. 2015 Group 1: 2mg od PO baricitinib DI scores, 24 week mTSS
RA-BUILD (N = 229) Group 1: 66% (P<0.001), 64
Group 2: 4mg od PO baricitinib (P<0.01), 0.33 (P<0.05)
(N = 227) Group 2: 62% (P<0.001), 69
Group 3: Placebo (N = 228) (P<0.01), 0.15 (P<0.01)
Group 3: 40%, 54, 0.7
Fleischmann 52 week randomised control trial. 24 week ACR20 results
et al. 2015 Group 1: methotrexate (N = 210) Group 1: 62%
RA-BEGIN Group 2: 4mg od PO baricitinib (N = 159) Group 2: 77%
Group 3: 4mg od PO baricitinib + methotrexate (N = Group 3: 78%
215)
Fleischmann 12 week randomised, double blind, placebo-controlled, Week 12 ACR20, HAQ-DI
et al. 2015 dose ranging trial. change from baseline results:
Group 1: 25mg decernotinib BD
(N = 41) Group 1: 39%, -0.24
Group 2: 50mg decernotinib BD (N = 41) Group 2: 61.0% (P=0.007), -
Group 3: 100mg decernotinib BD (N = 40) 0.50 (P<0.001)
Group 4: 150mg decernotinib BD (N = 41) Group 3: 65.0% (P=0.002), -
Group 5: Placebo (N = 41) 0.52 (P<0.001)
Group 4: 65.9% (P=0.002), -
0.64 (P<0.001)
Group 5: 29.3%, result not
available
Legend: ACR 20 American College of Rheumatology 20% response criteria; BD twice daily; HAQ-DI health
assessment questionnaire damage index; OD once daily; N number of patients; PO oral administration.
Dercenotinib
Dercenotinib is a Janus kinase inhibitor with a five times increased selectivity for JAK3
compared to other JAKs. A phase IIa 12 week dose-finding RCT of dercenotinib
monotherapy in RA patients with an inadequate response to MTX, have shown a statistically
significant ACR20 response rates in the active treatment group (65% patients responded at
doses of 50-150mg twice daily) [61]. A phase IIb 24 week RCT of dercenotinib therapy in
combination with MTX [62] in patients with similar demographics to the phase IIa study, also
showed similar statistically significant ACR20 responses in the patient groups treated with
150mg daily and 100mg twice daily.
The mean change from baseline in the DAS28-CRP outcome measure for both studies,
and HAQ-DI scores for the IIa study, were also statistically significant in the patient group
treated with higher doses. Overall AEs and SAEs were comparable between groups, with a
slight preponderance for groups taking higher doses. The most common AEs were headache,
nausea, increased infections, liver enzymes and lipids.
Filgotinib
Filgotinib is a selective JAK1 inhibitor. Pharmacokinetic studies have provided evidence

of filgotinib efficacy. Two trials using varying doses of filgotinib were conducted in healthy
male volunteers [63]. Early clinical data suggested the pharmacokinetics of filgotinib was
dose proportional up to 200mg. The maximum pharmacodynamic effect was reached at a
daily dose of 200 mg. Dose finding phase IIB studies of a daily dose range up to 200 mg are
currently under way, assessing the efficacy of this agent as monotherapy (DARWIN2) or in
combination therapy (DARWIN1).
SPLEEN TYROSINE KINASE (SYK) INHIBITORS

Syk is involved in transmitting signals from classical immunoreceptors such as B- and T
cell-receptors on lymphocytes, as well as Fc- and Fc-receptors on myeloid cells and mast
cells. Deletion or inhibition of Syk reduces antibody production and inhibits antibody-
independent functions of B cells, such as B cell-mediated antigen presentation to T cells [64].
Consequently, drugs that inhibit the ATP or the substrate binding P site of Syk have been
developed [65], aiming to reduce the inflammatory responses.
Fostamatinib
A 52 week, phase III RCT into varying doses of fostamatinib in combination with MTX
showed statistically significant improvements in ACR20 responses (44-49%, compared to
34.2% placebo response), but no clinical significance was demonstrated overall [66]. There
were no significant positive radiographic outcomes with fostamatinib. The clinical response
was less than expected as earlier phase II trials had shown ACR20 response rates ranging
from 57% to 72% [67-68]. Other ongoing trials of fostamatinib were subsequently terminated.
A similar side effect profile was shown across the phase II and II trials with the most common
side effects being hypertension, diarrhoea and increased hepatic transaminases.
MITOGEN-ACTIVATED PROTEIN (MAP) KINASES

MAP kinase activation induces the expression of multiple genes that together regulate the
inflammatory response. The isoform of p38 MAP kinase is important in the intracellular
signaling pathway for the generation of TNF and IL1 [69], therefore p38 inhibitors block
the production of TNF and IL1 [70].
Two 12 week RCTs have investigated VX-702, a MAP kinase inhibitor, as a
monotherapy, and in combination with MTX in RA patients with an inadequate response to
MTX. Though ACR20 response rates were numerically superior with VX-702 compared to
placebo, neither study reached statistical significance. Suppression of inflammatory
biomarkers was also not sustained past week 4 indicating that p38 MAPK inhibition may not
provide sustained suppression of inflammation in patients with RA. VX-702 has not been
developed further as a drug to treat RA [71].
BIO-SIMILARS [TABLE 7]
The European Medicines Agency (EMA) defines biosimilars as biological medicinal
products that contain a version of the active substance of an already authorised, original or
reference biological medicinal product.
Evidence on preclinical, pharmacokinetic, pharmacodynamic and clinical data
demonstrating comparable efficacy and safety of the biosimilar; its off-patent reference
biopharmaceutical is required before a biosimilar is made available on the market [72].
Post-translational modification with changes in cell lines and/or manufacturing processes
results in products that are highly similar but not identical to approved reference agents,
hence the term biosimilar rather than bio-identical. Minor modification through the
manufacturing process may alter function and immunogenicity, therefore raising concerns
about switching patients with well controlled disease on reference biologics to biosimilars
[73].
A reference drug that is repeatedly interchanged with a similar biological agent might
elicit immunogenicity that could compromise the efficacy and safety of both medications.
Thus, frequent switching between the original protein product and the biosimilar agent should
be avoided, as even subtle differences, such as impurities introduced during manufacturing,
can trigger an immune response to biosimilar agents [72].
Biomimics or biocopies are versions of mAb or fusion proteins available in countries
where regulation is less stringent [74].
It has been estimated that Germany, France and the UK each stand to save between 2.3
billion and 11.7 billion between 2007 and 2020 in response to the introduction of biosimilars
[75]. These savings have the potential to be used either to increase the number of patients
with access to biologics, or to be diverted into other aspects of care [76].
APPROVED INFLIXIMAB BIOSIMILARS

CT-P13
The efficacy and safety of an infliximab biosimilar (CT-P13) was compared to infliximab
in patients with active disease despite MTX therapy. This phase III randomised controlled
non inferiority study demonstrated similar efficacy in DAS28, ACR and EULAR response
rates, and low disease or remission rates and all other pharmacokinetic and pharmacodynamic
endpoints at week 30. The incidence of drug related AEs was similar to infliximab
(PLANETRA) [77]; however, the study was not sufficiently powered to detect significant
differences in AE rate between the two treatment groups [72].
CT-P13, manufactured by Celltrion Inc., South Korea, is marketed under the trade names
Remsima (Celltrion Inc.) and Inflectra (Hospira Inc., USA). There is also manufacturing
via Egis Pharmaceuticals PLC, Hungary who market the drug as Flammegis. As of May
2015, CT-P13 has been approved for use in approximately 70 countries worldwide [72]. The
South Korean MOFDS and the EMA have both approved CT-P13 for the treatment of RA. A
phase I study showed similar safety and efficacy in patients with ankylosing spondylitis
(PLANETAS) [78], however, both these agencies have allowed extrapolation of indications
for CT-P13 to six additional diseases for which reference infliximab is approved but in which
CT-P13 was not studied, such as psoriatic arthritis and psoriasis.
The first indirect meta-analysis in RA comparing the efficacy and safety of biosimilar-
infliximab to other biologicals found no significant difference in efficacy in ACR20 or
ACR50 response criteria. In regards to safety and tolerability, the infliximab-biosimilar
demonstrated a higher risk than infliximab and other biologics (etanercept, adalimumab,
abatacept) when compared to placebo. However, pairwise comparison did not find any
significant difference in safety [79].
Reports from clinical experience [80] and a long term extension RA study [81] have
shown comparable clinical effectiveness in patient reported outcomes and disease-activity
measures, with no immediate safety signals during one or two years of follow up for patients
switched from reference infliximab to CT-P13.
NOR-SWITCH is a randomised double-blind clinical trial currently in progress in
Norway. It will compare the safety and efficacy of switching from reference infliximab to
CT-P13, with continued treatment with reference infliximab in patients with RA and other
autoimmune conditions. NOR-SWITCH is expected to be completed in the first half of 2016
[82-83].
BOW015
BOW015 is an infliximab biosimilar developed by EPIRUS Biopharmaceuticals, Inc.

(USA) and manufactured by Reliance Life Sciences (India) with a trade name of Infimab.
A phase III, double blind, head-to-head comparison of BOW015 and reference infliximab
showed similar safety and efficacy in ACR20/50/70 scores. The adverse event rate, mostly
infections and infusion reactions, was comparable between treatment groups as was incidence
of immunogenicity [84]. To date BOW015 is approved in India alone with plans to file for
marketing approval in the UK and US in 2017.
APPROVED ETANERCEPT BIOSIMILAR

HD203
HD203 is an etanercept biosimilar with an amino acid sequence identical to that of

reference etanercept product.
A 48 week, phase III randomised controlled, double-blind study of HD203 and reference
etanercept, each administered in combination with MTX, has shown similar safety and
efficacy profiles with low immunogenicity occurrence [85]. HD203 has been approved by the
Korean MOFDS.
Table 7. Biosimilars

Main results
Yoo et al. 2013a 30 week phase III randomised, double blind, Week 30 ACR20 results:
PLANETRA parallel-group study.
Group 1: CT-P13 IV 3mg/kg (N = 302) Group 1: 60.9%
Group 2: Infliximab IV 3mg/kg (N = 304) Group 2: 58.6%
Yoo et al. 54 week phase III randomised, double blind, Week 54 ACR20 results:
2013b parallel group, open label extension trial. Group 1: 76.8%
Group 1: CT-P13 IV maintenance 3mg/kg Group 2 prior to switch: 77.5%
(N = 158) Week 102 ACR20 results:
Group 2: Infliximab to CT-P13 IV switch 3mg/kg Group 1: 72.2%
(N = 144) Group 2 post switch: 71.8%
No statistical differences
Kay et al. 2014 54 week phase III randomised, double blind, Week 16 ACR20 results:
parallel-group trial of 189 patients. Group 1 BOW015: 89.8%%
Group 1: BOW015 IV maintenance 3mg/kg Group 2 Infliximab prior to
Group 2: Infliximab to BOW015 IV switch switch: 86.4%
3mg/kg Week 54 ACR20 results:
Group 2: 72.03%
Bae et al. 2014 48 week phase III randomised, double blind, and Week 24 ACR20 results:
equivalence trial. Group 1: 83.48%
Group 1: HD203 SC 25mg twice weekly Group 2: 81.36%
(N = 147) Week 48 ACR20 results:
Group 2: etanercept SC 25mg twice weekly Group 1: 86.27%
(N = 147) Group 2: 81.90%
Jani et al. 2015 12 week phase III randomised, double blind, Week 12 ACR20 Results:
parallel-group trial. Group 1: 82.0%
Group 1: ZRC-3197 SC 40mg every other week Group 2: 79.2%
(N = 60)
Group 2: Adalimumab SC 40mg every other week
(N = 60)
Legend: ACR 20 American College of Rheumatology 20% response criteria; BD twice daily; IV
intravenously; N number of patients; SC subcutaneously.
APPROVED ADALIMUMAB BIOSIMILAR

ZRC-3197
ZRC-3197 is developed and marketed by Zydus Cadila (India) as Exemptia. The

Cadila Healthcare Laboratory (India) conducted a clinical trial that compared ZRC-3197 and
reference adalimumab, in combination with MTX, in 120 RA patients with an inadequate
response to MTX. The results of this trial have shown similar ACR20 responses between the
2 groups [86]. ZRC-3197 is currently approved in India alone.
Thus far, phase III clinical trials in the above biosimilars have been promising. The range
of biosimilars available on the market will only continue to expand, and the possibility of
significant cost savings to various healthcare systems worldwide is an exciting prospect.
There are concerns however, regarding the long term safety and efficacy of these drugs,
extrapolation to other autoimmune conditions and the right of the physician, over hospital
managers, to choose best which patients are suitable or not to switch onto biosimilars.
RITUXIMAB BIOSIMILAR
PF-05280586
PF-05280586 is a proposed biosimilar to rituximab and marketed by Pzifer. A double-

blind phase I/II pharmacokinetic (PK) similarity trial compared PF-05280586 to rituximab
sourced from the European Union (rituximab-EU) and United States (rituximab-US).
Although not designed to demonstrate similarity for efficacy, mean DAS28-CRP, mean
number of tender and swollen joint counts, and mean high-sensitivity CRP values decreased
over time, and improvement in ACR20/50/70 scores were seen in all groups. All 3 treatments
had similar PD effect on CD19+ B cells. All treatments were generally well-tolerated with
similar AE profiles. These results support continued clinical development of PF-05280586 as
a potential biosimilar to rituximab [87].
CONCLUSION
Impressive advances in the research associated with the aetiopathogenesis of RA led to
the discovery of new molecules and inflammatory pathways, which play an important role in
the disease inflammatory processes and irreversible joint damage. An ever-increasing pool of
potential new cytokine targeted therapies is in development, with some showing promising
data. However, it is too early to determine if all these new biologic agents will be translated
into licensed therapies for RA.
As ever, the cost implications of such treatments can limit which patients have access to
these drugs, especially in countries without free access to healthcare. Biosimilars offer an
exciting chance to reduce the cost of treating RA, but it is important to remember that these
drugs are only similar and not the same as current biologic treatments. Therefore, they should
be used with caution. The patents for many biologic agents currently used in the treatment of
RA will expire by the end of 2018. It is expected that many more biosimilars will be made
available by then. There should still be opportunities for new biologic drugs, as long as they
can demonstrate superior efficacy to current available biologics with acceptable safety
profiles [88]. As highlighted in this chapter, many new therapeutic targets seem promising as
potential new agents for RA treatment, according to data derived from early phase trials, but
they still have to prove their therapeutic potential in larger clinical trials. The landscape of RA
treatment is ever changing and this is definitely an exciting time for research within the field
of RA.
ACKNOWLEDGMENTS
The authors will like to thank to Dr. Maria Leandro, Senior Lecturer and Consultant
Rheumatologist, University College London, Department of Inflammation, Infection and
Immunity (email:maria.leandro@ucl.ac.uk), for reviewing this chapter.
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Chapter 12
BIOLOGICS IN SPONDYLOARTHRITIS
Mediola Ismajli, MRCP* and Maria Leandro, PhD

ABSTRACT
Spondyloarthritis (SpA) represents a heterogeneous group of immune-mediated
inflammatory diseases that share similar pathogenic mechanisms and genetic
predispositions, and are strongly associated with the major histocompatibility complex
(MHC) class I allele, human leucocyte antigen (HLA)-B27. In the last decade, biological
therapies have improved the management of SpA. Tumour necrosis factor (TNF)
inhibitors are effective in patients with axial SpA. Most patients show good response to
TNF blockers; however a proportion of patients lack this response or lose it over time. In
this chapter we focus on some of the reasons for failure of TNF blockers and switching of
TNF therapy in SpA. In this chapter we also discuss new therapeutic agents in
development.
Keywords: ankylosing spondylitis, seronegative spondyloarthritis, biologic treatments, anti

TNF therapy, ustekinumab, sekukinumab, ixekizumab, rituximab, tocilizumab,
apremilast, switching TNF inhibitors
INTRODUCTION
SpA encompasses a group of immune-mediated inflammatory diseases that classically
include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, arthritis
associated with inflammatory bowel disease, and a subgroup of juvenile idiopathic arthritis.
The various clinical forms include spinal (axial) features, peripheral arthritis, enthesopathy,
and extra-articular features such as psoriasis, uveitis, and inflammatory bowel disease. These
Corresponding author: Mediola Ismajli, Department of Rheumatology, University College London Hospital NHS
*
Foundation Trust, 250 Euston Road, London, NW1 2PG, email: mediola.ismajli@uclh.nhs.uk.
284 Mediola Ismajli and Maria Leandro
conditions share similar pathogenic mechanisms and genetic predispositions, and are strongly
associated with the MHC class I allele, HLA-B27 [1]. AS is the most common presentation in
this group of conditions. The incidence and prevalence of SpA vary dependent on the
methodological differences between studies, the definition used to classify disease and on the
prevalence of HLA-B27 in the population studied [2]. A recent systematic review and meta-
analysis studying the prevalence of SpA, showed large variation with a prevalence of 0.20%
in South-East Asia to 1.61% in Northern Artic communities, and the prevalence of AS was
0.02% in Sub-Saharan Africa to 0.35% in Northern Artic communities [3]. A large proportion
of AS patients, at least one third, carry a heavy burden of disease that leads to severe
disability [4].
The modified New York criteria (Table 1) for the diagnosis of AS include clinical as well
as radiographic criteria [5]. Radiographic sacroiliitis has been an essential part of these
criteria. However, radiographic changes may reflect structural damage as a consequence of
ongoing or previous inflammation rather than inflammation itself.
The use of magnetic resonance imaging (MRI) has demonstrated that active inflammation
does occur in the sacroiliac joints prior to the development of changes detectable
radiographically [6].
Table 1. Modified New York criteria for AS [5]
Clinical criteria Radiographic criteria

a) Low back pain and stiffness >3 months Sacroiliitis grade 2 bilaterally
improved by exercise, not relieved by rest Sacroiliitis grade 3-4 unilaterally
b) Lumbar spine limitation of movement in
sagittal and frontal planes
c) Reduced chest expansion relative to normal
values for age and sex
1. Definite AS if radiographic criterion and at least 1 clinical criterion
2. Probable AS if 3 clinical criteria present alone or radiographic criteria present alone
Figure 1. ASAS classification criteria for axial SpA [7].

Biologics in Spondyloarthritis 285
Figure 2. ASAS peripheral SpA classification criteria [8].
The Assessment of SpA International Society (ASAS) has developed new classification
criteria (Figure 1) for axial SpA. These criteria include patients with established radiographic
sacroiliitis (that will be classified as AS) as well as patients with non-radiographic axial SpA.
There is an unmet need for the treatment of the latter group of patients, and the new criteria
might serve as a basis for the use of biologic agents in non-radiographic axial SpA [7]. The
ASAS classification criteria for peripheral SpA are illustrated in Figure 2 [8].
MANAGEMENT OF SPA
Therapeutic options for SpA include non-steroidal anti-inflammatory drugs (NSAIDs)
and physical therapy in the first instance. NSAIDs are usually effective in improving the
symptoms. They might also be effective in reducing the level of acute phase reactants such as
C-reactive protein (CRP) [9]. There is controversy whether NSAIDs reduce radiographic
progression. When taken continuously as a daily dose over 2 years, NSAIDs have been shown
to reduce the radiographic progression of spine disease, compared with an on-demand
treatment schedule [10]. However, results from a randomised multicentre trial (ENRADAS)
in AS patients, showed that continuous diclofenac over 2 years did not reduce radiographic
progression compared to on-demand treatment [11]. In the study by Wanders et al. less
radiographic progression in AS was seen with continuous use of celecoxib, and seemed to
benefit patients with elevated acute phase reactants [10]. In another study in patients with AS
with a high NSAID intake over 2 years demonstrated slowing of new bone formation in the
spine compared with patients with low NSAID intake. This protective effect was nearly
exclusively seen in patients with elevated CRP levels over time and the presence of
syndesmophytes at baseline [12].
Unlike rheumatoid arthritis (RA), axial and entheseal manifestations of SpA do not
respond well to traditional disease modifying anti-rheumatic drugs (DMARDs). There is
limited use of DMARDs, in particular sulfasalazine and methotrexate, in peripheral SpA but
not in axial disease [13]. The introduction of TNF therapy has been a major advance in the
treatment of SpA. The efficacy of TNF blockers has been proven in several randomised
controlled trials as discussed below.
The ASAS consensus for anti-TNF therapy in AS include active disease for 4 or more
weeks with a Bath Ankylosing Spondylitis Disease Activity Score (BASDAI) score of 4,
after having had adequate therapeutic trial of at least 2 different NSAIDs. Patients with
peripheral involvement must have had adequate therapeutic trial of both NSAIDs and
sulfasalazine [14]. The ASAS/EULAR recommendations for the treatment of SpA were
updated in 2010 [15].
ANTI-TNF EFFICACY
The use of anti-TNF agents has revolutionised the treatment of SpA. All of the following
five TNF blockers described below have been licensed for the treatment of AS, whereas
adalimumab, etanercept, certolizumab, and golimumab have also been licensed for the
treatment of non-radiographic axial SpA. The results of meta-analysis showed a consistent
beneficial effect across all five anti-TNF blockers compared to placebo [16].
ETANERCEPT
Etanercept is a recombinant TNF receptor p75 fragment crystallizable (Fc) fusion protein
that acts competitively to inhibit cell surface receptor binding of TNF. The continued safety
and durability of clinical response in patients with AS receiving etanercept, was studied in
277 patients who had participated in a previous randomised, double blind, placebo controlled
24 week trial that continued in an open label extension study for a total of 2 years. In the
etanercept group, 74% achieved an ASsessment in Ankylosing Spondylitis 20% (ASAS20)
response after 96 weeks [17]. The efficacy of etanercept was also demonstrated in early axial
SpA in the ESTHER trial, where 50% of the patients (n = 36) achieved remission in the
etanercept group compared with 19% in the sulfasalazine group at week 48 [18].
The long-term efficacy and safety of etanercept was demonstrated in a 7-year follow-up
study of patients with AS, where 31% of patients were in ASAS partial remission, and 44%
had ASDAS inactive disease [19].
ADALIMUMAB
Adalimumab is a monoclonal, fully human, anti-TNF antibody that binds with high
affinity to TNF. It has also been shown to be effective in the treatment of SpA.
A multicenter, randomised, double-blind, placebo-controlled trial in AS, showed that
adalimumab was well-tolerated during the 24-week study period and was associated with a
significant and sustained reduction in the signs and symptoms of active AS. In this study,
58.2% patients achieved an ASAS20 response in the adalimumab group compared to 20.6%
in the placebo group [20]. Adalimumab has also been shown to be effective in controlling the
disease activity in non-radiographic axial SpA in ABILITY-1 study. ASAS40 response rates
in the adalimumab treated group were 36% compared to 15% in the placebo group [21].
The long-term efficacy of adalimumab has been demonstrated in a 5 year follow-up study
in patients with AS. In this study, 70% of patients achieved an ASAS40 response [22].
INFLIXIMAB
Infliximab is a monoclonal chimeric human anti-TNF antibody that binds with high
affinity to TNF. Treatment with infliximab is effective in patients with active AS. Patients on
infliximab (53% of 34 patients) had a regression of disease activity at week 12 of at least 50%
compared with the placebo group (9% of 35 patients) [23]. The efficacy of infliximab was
also demonstrated in the ASSERT trial, a multicentre, randomised study, where 61.2% of AS
patients in the infliximab group were ASAS20 responders compared with 19.2% of patients
in the placebo group [24].
Infliximab has also been found to be effective in the treatment of non-radiographic axial
SpA, leading to a reduction in disease activity by week 16 [25].
Persistent clinical efficacy and safety of infliximab was demonstrated after 8 years of
follow-up in patients with active AS treated with infliximab, where 24% of the patients were
in partial remission (n = 8) and 64% (n = 21) had low disease activity (BASDAI <3) [26].
GOLIMUMAB
Golimumab is a humanised monoclonal antibody to TNF. In the GO-RAISE study,
golimumab was proven to be effective and well tolerated in a large cohort of patients with
AS. At 14 weeks, about 60% achieved ASAS20 response in the golimumab treated patients
compared to 21.8% in the placebo group [27]. Golimumab has also been shown to be
effective in non-radiographic axial SpA in the GO-AHEAD 16-week study. In this study, the
primary endpoint (ASAS20 at week 16) was achieved by 71.1% patients in the golimumab
group vs. 40.0% in the placebo group [28].
CERTOLIZUMAB
Certolizumab is a PEGylated Fc-free anti-TNF that has been studied in SpA. A phase 3
double-blind, randomised study, evaluated the efficacy and safety of certolizumab in patients
with axial SpA, including patients with AS and non-radiographic axial SpA. At week 12,
ASAS20 response rates were significantly higher in the certolizumab groups (200mg every
other week and 400mg monthly) compared to placebo (57.7 and 63.6 vs 38.3, p 0.004). At
week 24, patients in the certolizumab group showed significant differences in BASDAI,
ASDAS, Bath Ankylosing Spondylitis Functional Index (BASFI), and Bath Ankylosing
Spondylitis Metrology Index (BASMI) scores. The results of this trial demonstrated that
certolizumab led to rapid improvements in clinical signs and symptoms in axial SpA [29].
The efficacy of certolizumab in axial SpA has been demonstrated at 2-year follow-up in
patients with axial SpA including AS and non-radiographic axial SpA [30].
EXTRA-ARTICULAR MANIFESTATIONS OF SPA MANAGEMENT

Even though all five TNF blockers are effective in the treatment of axial disease, the
presence of other associated manifestations of SpA will influence the choice of initial TNF
therapy. Studies have shown that TNF blockers are also efficacious in the treatment of extra-
articular manifestations of SpA [13].
The incidence of uveitis was dramatically reduced with infliximab, whereas it remained
unchanged with etanercept [31]. The recurrence rate of uveitis was significantly decreased in
a study using adalimumab [32].
In a meta-analysis of TNF blockers in AS, it was shown that etanercept and adalimumab
caused increased incidence of flares or new onset of inflammatory bowel disease when
compared with infliximab [33].
RADIOGRAPHIC PROGRESSION
There has been debate on the association between inflammation and new bone formation
in AS. There are two hypothesis regarding inflammation and new bone formation. One claims
that the development of SpA depends on a multi-step process that leads both to chronic or
recurrent inflammation, and to the triggering of new tissue formation, completely or partially
independently of inflammation. The second hypothesis is that inflammation induces
replacement of subchondral bone marrow by (fibrous) repair tissue, which then stimulates
osteoblasts, leading to new bone formation [34].
Despite the good effect on signs and symptoms, CRP and inflammation as detected by
MRI, infliximab did not prevent new bone formation in the spine after 2 years [35]. In another
study, treatment with golimumab over 4 years did not seem to be sufficient to retard
radiographic progression in patients with AS [36].
Other studies on radiographic progression in AS treated with adalimumab [37],
etanercept [38], and infliximab [35] for 2 years, have shown that these TNF blockers do not
appear to inhibit radiographic progression in the spines of patients with AS.
Longer-term data on radiographic progression at 8 years of continuous treatment with
TNF blocker, showed an increase in new bone formation in both patient groups treated with
TNF blocker and those who did not. However, there was less radiographic progression in the
TNF blocker treated group between 4 and 8 years of follow up [39].
A study by Haroon et al. showed that early treatment with TNF blocker before the
manifestation of irreversible structural damage might slow down radiographic progression
[40]. However, this study has methodological issues. The results from various studies suggest
that TNF blockers do not accelerate radiographic progression, but it is yet to be demonstrated
whether TNF blockers have a protective structural effect [41].
SWITCHING
Anti-TNF therapy is effective in the treatment of SpA, however some patients fail to
respond to treatment, some lose efficacy, and some may experience adverse events leading to
discontinuation of treatment.
Studies of anti-TNF drug survival rates have shown favourable persistence of the initial
TNF blocker. In a retrospective study of AS and PsA patients including those with axial
involvement, 69.8% of patients (n = 268) were still receiving their initial therapy after a mean
follow-up of 33.7 months. A longer duration of biologic therapy was observed in the
subgroup of patients with predominantly axial involvement [42].
Similar findings of anti-TNF retention rates were found in a Korean study of AS and RA
patients, where 79% of AS patients were still on the initial TNF blocker after 2 years (the
rates were lower in the RA patients 44% at 1 year). Among the AS patients, 21% (65/310
patients) discontinued anti-TNF therapy due to adverse events (n = 27) and inefficacy (n =
21) [43]. Similar findings were demonstrated from the Spanish register [44] and the Italian
database [45].
A significant proportion, about 20 to 30% of SpA patients discontinued anti-TNF therapy
because of non-response or inadequate response, and 10 to 20% of patients discontinued
treatment due to secondary loss of efficacy or adverse events [46].
Significant differences in the chemical structure and the mechanism of action of the anti-
TNF agents can potentially be of use in switching agents in patients who have failed their first
anti-TNF therapy.
Switching from one anti-TNF to another has been studied in RA, and the data suggest
that this strategy is effective in these patients [47]. There have been no randomised controlled
trials to investigate anti-TNF switching in SpA. However, several observational studies have
shown the benefit of switching TNF blockers in SpA.
The studies that have looked at non-responders to anti-TNF drugs mainly classify the
non-responders due to adverse events or lack of efficacy. Lack of efficacy could be due to
primary lack of efficacy, that is no response at all, or a partial although not sufficient response
as well as secondary loss of efficacy [48].
PRIMARY FAILURE
Primary failure is described as no response or inadequate efficacy in patients following
initiation of treatment with an anti-TNF agent. This has been defined as not responding to
treatment within 3-4 months [49]. Most studies that have looked at anti-TNF switching do not
specify clearly the reasons for discontinuation of anti-TNF, and in most cases both primary
and secondary failure are described in the same study. In this section we identify some of the
studies where the main reason for discontinuation is primary failure of anti-TNF therapy. The
findings of these studies are also summarised in Table 2.
A retrospective cross-sectional study of 15 patients with heterogeneous subtypes (7
patients had AS, 6 had undifferentiated SpA with predominant axial involvement, and 2 had
PsA with peripheral involvement) and follow-up durations, looked at switching infliximab to
etanercept. The reasons for infliximab discontinuation included inadequate efficacy or
adverse events. Nine of 13 patients with SpA and both patients with PsA responded to
etanercept and treatment was well tolerated. Even though this is a small study, the results
suggest that switching to another anti-TNF agent may be appropriate in patients with SpA and
PsA who have not responded or have had adverse effects to another anti-TNF; however,
larger studies are needed [50].
A prospective multicentre longitudinal observational study using the NOR-DMARD,
Norwegian register, looked at 514 patients with AS treated with anti-TNF (including
infliximab, etanercept, and adalimumab), 77 of whom switched to a second anti-TNF agent.
The reason for switching was adverse events in 44 patients (57.1%) and insufficient response
in 30 (38.9%) of the 77 switchers. The insufficient response switchers had been treated with
the first TNF blocker for a median of 294 days, and the adverse event switchers, the treatment
time with the first anti-TNF agent was a median of 171 days. For the first TNF, the 2-year
drug survival rate was 65%, and for the second anti-TNF it was 60%. The 3-month BASDAI
50 and ASAS 40 responses were achieved by 49% and 38% of non-switchers, by 25% and
30% of switchers after the first TNF blocker, and by 28% and 31% after the second TNF
agent. Switching to a second anti-TNF can be an effective approach in AS, with around one-
third of patients showing a good clinical response and more than half of patients continuing
the treatment for more than 2 years [48].
According to a study of 1436 AS patients from the Danish biologics register (DANBIO)
10-year follow-up, 30% of patients switched to a second and 10% switched to a third
biologic. Switchers were more frequently women, had shorter disease duration, and higher
BASDAI/BASFI, visual analogue scale (VAS) scores when they started their first anti-TNF
agent. The main reason for switching was lack of treatment effect in 56% of the patients. In
this study it was not possible to distinguish whether treatment termination was due to lack of
response (primary failure) or loss of effect (secondary failure). After 2 years of treatment, the
response rates and drug survival were lower among switchers; however, 52% of them
achieved response compared to 63% of non-switchers, therefore switching to another anti-
TNF agent should be considered irrespective of the reason for discontinuation of the initial
TNF blocker [51].
Anti-TNF switching was evaluated using the Finnish biologics register (ROB-FIN), in
229 patients with AS treated with biologics including etanercept, infliximab, and
adalimumab. Thirteen patients (7%) discontinued the first biologic due to lack of efficacy,
with 21 patients in whom the reasons for discontinuation were not specified. Fourteen of
these patients switched from infliximab to etanercept or adalimumab. Adverse events
occurred in 11% of the patients receiving their first biologic drug (25 of 229 patients). In this
study the dose of infliximab was increased (from 200mg to 300mg) in more than a quarter of
the patients in an attempt to improve response. There was also an extensive use of
concomitant DMARDs such as methotrexate and sulfasalazine with biologic therapy, due to
peripheral arthritis. The combination of DMARDs and infliximab led to a rapid pain relief
and improvement of patients, and physicians global assessments within six weeks, which
was sustained at two years. A subgroup of AS patients with axial involvement only (n = 46),
had an ASAS20 response in 79%. The authors concluded that switching may be possible;
however, the group of switchers in this study was small (13% of patients, n = 27) [52].
Table 2. Summary of studies evaluating switching between anti-TNF agents in SpA
Study Switching Main reason

Author Study type Response
size from for switching
Lie et al. Prospective 514 AS Etanercept, 33% responded Primary
[48] observational patients infliximab, (ASAS 40 at 3 failure
adalimumab months)
Delaunay et Retrospective 15 Infliximab to 73% responded Primary
al. [50] observational patients etanercept failure
Konttinen et Retrospective 229 AS 13%switched 79% responded Primary
al. [52] observational patients failure
Pradeep et al. Retrospective 108 AS 15%switched 67% responded Primary
[53] observational patients to a 2nd TNF at 6 months failure
and 2% to 3rd 86% at 12
TNF months
Cantini et al. Prospective 23 AS Infliximab to 74% responded Primary
[54] observational patients etanercept failure
Coates et al. Retrospective 113 SpA 13% switched 93% responded Primary and
[55] observational to a 2nd TNF secondary
failure
Conti et al. Prospective 23 AS, Infliximab to 75%responded Primary and
[56] observational PsA etanercept 57.1%responded secondary
patients Etanercept to failure
adalimumab
Glintborg et Retrospective 432 AS 30% switched 52% responded Primary or
al. [51] observational patients to a 2nd TNF secondary
10% switched failure
to 3rd TNF
Haberhauer Retrospective 46 AS, 24% of AS 50% responded Secondary
et al. [49] observational 63 PsA, patients failure
192 RA switched to 2nd
patients TNF, 11% to
3rd TNF
Paccou et al. Retrospective 377 SpA 26% switched 80% responded Primary and
[57] observational patients to 2nd TNF and secondary
7% to 3rd
Legend: AS ankylosing spondylitis; PsA psoriatic arthritis; RA rheumatoid arthritis, SpA
spondyloarthritis; TNF tumour necrosis factor.
A retrospective analysis of 108 severe AS patients treated with anti-TNF therapy

(including infliximab, etanercept, adalimumab), 15% were switched to a second anti-TNF
agent, and two patients were switched to a third anti-TNF agent. Inefficacy was the most
common reason for switching in 67%, followed by adverse events in 28%. At 69 months 86%
of patients who switched to a second anti-TNF drug were continuing treatment. Switching
due to adverse events led to better response than switching due to inefficacy. Sustained
benefit in AS patients treated with a second anti-TNF is similar to the efficacy seen following
the initial anti-TNF therapy [53].
In a 54-week, open-label, prospective study of patients with AS treated with infliximab
who failed to achieve or maintain an ASAS20 clinical response or had adverse events, were
switched to etanercept. At week 54, ASAS20, ASAS50, and ASAS70 response rates were
74%, 61%, and 39% respectively. These figures are similar to the study by Delaunay et al. In
conclusion, switching to etanercept may be a good therapeutic option for patients who do not
respond to infliximab [54].
SECONDARY FAILURE
Some patients do have a good response to anti-TNF treatment initially and over time they
lose this response, hence leading to secondary failure or loss of efficacy. Secondary failure
has been defined as loss of efficacy of anti-TNF agent over time (more than 6 months) [49].
In this section, we have identified some of the studies where secondary failure has been the
main reason for discontinuing or switching TNF therapy. The findings of these studies are
also summarised in Table 2.
In a longitudinal observational prospective study over a 5-year period evaluating the
clinical response after switching from one anti-TNF agent to another in patients with AS and
PsA, were evaluated. A clinical response was seen in 75% of the patients who changed from
infliximab to etanercept, and 57.1% who switched from etanercept to adalimumab. Patients
who switched because of adverse events and lack or loss of efficacy, showed a similar clinical
response, 70% and 61.5% respectively. In this study, 81.3% of patients who had switched
from infliximab to etanercept continued the treatment, compared to only 57.1% of patients
who had changed from etanercept to adalimumab maintained the treatment. Two of the three
patients who stopped adalimumab because of inadequate response had already failed the other
two anti-TNF agents. This observation suggests that the failure of two TNF inhibitors predicts
ineffectiveness to the third, which has been seen in previous data on RA patients. Patients
with SpA with inadequate response or adverse events to one anti-TNF agent may be
successfully treated with another, regardless of the reason for switching [56].
Switching to a second anti-TNF agent was necessary in 24% of the AS patients, and 11%
of AS received a third anti-TNF in an observational study. In this study, secondary failure
was the main reason for switching to a second anti-TNF agent, followed by side effects and
lack of efficacy, whereas the reasons for switching to a third anti-TNF were lack of efficacy,
followed by side effects. As with the previous findings, patients with AS with loss of efficacy
to the first anti-TNF who were switched to a second anti-TNF had an adequate response,
suggesting that switching anti-TNF for secondary failure may be beneficial in this group of
patients [49].
In a cross-sectional study of 467 SpA patients drug survival and the reasons for switching
anti-TNF therapy was studied. Of the 467 patients who started anti-TNF therapy, 28%
switched to a second and 8% switched to a third drug. The mean drug survival did not differ
among the courses of anti-TNF. In this study, the main reasons for switching were lack or
loss of efficacy and adverse events in 40% and 30% of switchers respectively. Switchers were
more frequently women and had higher disease activity parameters (BASDAI, ESR, and
patients visual analogue scale (VAS) for pain and for global state) at the time of the study
than non-switchers [46].
In a retrospective study of 377 SpA patients treated with anti-TNF including AS, PsA,
367 of these had been treated with only one anti-TNF, and 99 patients had stopped receiving
the first anti-TNF due to primary non-response, loss of efficacy (secondary failure) or
occurrence of adverse effects before switching to another anti-TNF (11 patients were lost to
follow up), and of these 28 patients were treated with three anti-TNF agents. The reason for
switching from the first or the second anti-TNF was not predictive of the response.
After failure of the first anti-TNF drug, 80.8% of patients had a satisfactory response to a
second agent, and those who received a third anti-TNF, 82.1% responded.
In the first switch, the reasons for discontinuation were adverse events 39.4%, loss of
efficacy (secondary failure) 39.4%, and primary non-response (primary failure) 21.2%. The
reasons for switching from the second to the third anti-TNF were: adverse events were seen in
32.1%, loss of efficacy in 35.8%, and primary non-response in 32.1% of patients. These
results demonstrate a good treatment response in SpA patients who have switched anti-TNF
therapy [57].
In a retrospective study of 113 patients with AS treated with anti-TNF including
adalimumab, etanercept, infliximab, long term response to biological therapy in AS in a real
life clinical setting was investigated. This study looked at quantifying non-response and
response to switching therapies. At week 12, 88% of the patients responded to their first anti-
TNF. Primary non-response was seen in 13 patients (infliximab n = 10, etanercept n = 3), 7 of
whom were switched to a second anti-TNF, with 6 showing a good clinic response, all to
etanercept. A further 8 patients who initially responded to the initial biologic were also
switched and the reasons were secondary failure to infliximab (n = 2), side effects (n = 2) or
patient choice (n = 4).
The primary and secondary non-response rates were less than 15%. Disease duration,
HLA-B27 status or biologic drug used, did not show any differences in the response rates.
The majority of non-responders had a good response when switched to another anti-TNF,
supporting switching in this group of patients [55].
REASONS FOR PRIMARY ANTI-TNF FAILURE

Several studies have focused on the identification of predictors of response as well as the
retention rates of anti-TNF therapy in AS.
The biological registries have shown that factors associated with clinical response include
raised inflammatory markers, higher ASDAS score, lower BASFI, and younger age at
baseline [51], [58, 59]. According to the Swedish register, apart from the above predictors,
male gender and presence of peripheral arthritis were baseline predictors of continuation of
anti-TNF therapy [60].
Similar findings have also been reported in a large cohort of AS patients treated with
adalimumab. In this study HLA-B27 positivity and anti-TNF naivety were associated with
better response to adalimumab (BASDAI50, ASAS40) [61].
The presence of enthesitis was another predictor of response to TNF in a post hoc
analysis of the ASSERT (patients treated with infliximab, allowed to use concurrent NSAIDs,
but not DMARDS, or systemic corticosteroids) and GO-RAISE (patients treated with
golimumab with or without concurrent NSAIDs, DMARDs, and systemic corticosteroids)
trials [62].
Shorter disease duration [63] and active inflammatory lesions on MRI have also been
shown to predict response to TNF therapy [64].
The use of corticosteroids has been associated with a poor response to infliximab in a
small retrospective study of 70 patients with AS treated with infliximab over a five-year
period. In this study 71.4% patients responded within the first 6 months of treatment [65].
The predictors of switching anti-TNF therapy in AS were evaluated in a retrospective
observational study of 269 Korean patients (who were treated with infliximab, etanercept and
adalimumab over 13 years). In this study 23% of patients had switched to another anti-TNF
drug, and 15.7% switched to a third agent, with the main reason for switching being
inefficacy. The use of adalimumab as the first anti-TNF drug was less likely to lead to
switching. The authors observed that complete ankylosis of the sacroiliac joint when anti-
TNF therapy was initiated, was more likely to lead to switching to anther anti-TNF. This
suggests that patients with advanced disease and severe structural changes do not respond
well to anti-TNF therapy [66].
In a study that looked at switching from infliximab or etanercept to adalimumab, the
chemical structure of the first anti-TNF agent (chimeric monoclonal antibody or recombinant
soluble TNF receptor) was not related to response to the second anti-TNF- drug, a fully
human monoclonal antibody. Patients who fail to respond to a first agent, infliximab or
etanercept respond to adalimumab as a second-line drug irrespective of the reason for
switching [67].
Treatment patterns such as switching between anti-TNF blockers or restarting treatment
after a gap in therapy is not well established. In a study examining treatment patterns in the
first year after initiating anti-TNF therapy, 8454 patients with various inflammatory
conditions were studied, including AS, RA, psoriasis, and PsA. In the first year of starting
anti-TNF therapy most patients have a 45-day treatment gap, and approximately two thirds
of patients were either persistent with their index TNF blocker, or restarted treatment with
their index TNF blocker. In this study, 13% of the patients switched to a different biologic,
and most switches were between the three anti-TNF agents, etanercept, adalimumab, or
infliximab. These findings raise questions whether gaps in anti-TNF treatment influence
effectiveness [68].
Data from the registries have shown that predictors of response include raised
inflammatory markers, lower BASFI, and younger age at baseline [51], [58] whereas male
gender, raised inflammatory markers, low visual analogue scale (VAS) fatigue, and presence
of peripheral arthritis were baseline predictors of longer drug survival [51], [59].
REASONS FOR SECONDARY ANTI-TNF FAILURE

The development of anti-drug antibodies in response to monoclonal antibodies is an
important mechanism underlying secondary failure of anti-TNF treatment. Other mechanisms
may play a role in loss of efficacy of anti-TNFs, as the correlation between loss of efficacy
and anti-drug antibody development has not been observed with etanercept, which is thought
to be less immunogenic [69].
Anti-drug antibodies may be either binding or neutralizing. These antibodies can lead to a
loss of response by altering the pharmacokinetics, resulting in sub-therapeutic levels, or
decreasing efficacy by neutralizing the active component of the molecule [70].
Neutralizing antibodies can be induced by both chimeric and human monoclonal

antibodies, which are known as human anti-chimeric antibodies (HACA) and human anti-
human antibodies (HAMA) respectively [71].
The reported frequency of anti-infliximab and anti-adalimumab antibodies is variable and
could be related to the duration of treatment, or the use of concomitant immunosuppressive
treatment [72]. Anti-drug antibodies can also lead to the formation of immune complexes
involved in the development of infusion-related hypersensitivity reactions, or adverse events
[73].
The presence of neutralizing anti-drug antibodies is associated with lower serum levels of
anti-TNF drug, leading to lower efficacy and higher withdrawal rate [74]. In a small study
patients treated with anti-TNF agents including infliximab, adalimumab, and etanercept for
RA and SpA, PsA or other rheumatic diseases, anti-drug antibodies were demonstrated in
50%, 31%, and 0% respectively. In the SpA group, the improvement in the ASDAS score was
significant in patients without antibodies (3.89 0.82 to 2.22 0.86; P=0.01) but not in those
with anti-drug antibodies (3.40 1.67 to 3.23 1.40; P=0.73) [74].
The clinical relevance of immunogenicity of anti-TNF agents (adalimumab, etanercept,
and infliximab) was evaluated in a study of 62 RA and 81 SpA patients. Patients not
responding to treatment had higher serum anti-adalimumab and anti-infliximab antibody
concentrations. Anti-infliximab antibodies were related to increased risk of infusion related
reactions, switching to another biologic drug, and treatment discontinuation. In this study,
antibodies against adalimumab and infliximab were found in 4% and 24.6% respectively,
with no antibodies against etanercept being detected [75].
In a study of 42 patients with SpA who were commenced on a second anti-TNF after
failing to respond to a first anti-TNF therapy, showed that immunogenicity of the first anti-
TNF determined the outcome of switching to a second anti-TNF therapy. In this study, 26.2%
of the patients developed anti-drug antibody during the first biologic treatment. These patients
were found to have lower disease activity at 6 months [69].
A systematic review and meta-analysis of the immunogenicity of anti-TNF therapy in
RA, SpA, psoriasis and inflammatory bowel disease, showed that anti-drug antibodies reduce
the drug response, which can be attenuated by concomitant immunosuppression [76].
The use of concomitant immunosuppressive therapy in the form of methotrexate in RA
has been shown to reduce the immunogenicity of anti-TNF and increase drug survival [77].
An open label prospective study in 19 patients with active AS to assess the efficacy of
infliximab combined with methotrexate vs. infliximab alone showed that higher ASAS50
responses were achieved in the dual therapy group; however, patients in the combination
group had a shorter disease duration and were younger, factors known to affect drug response
[78].
Three clinical trials [79-81] evaluating infliximab alone or in combination with
methotrexate found no superiority in terms of efficacy and allergic adverse events in the
combination therapy.
All biological drugs can induce an immune response. The structure of the anti-TNF agent
is an important factor in its immunogenicity. However, not all patients treated with anti-TNF
agents develop anti-drug antibodies, therefore immunogenicity is multifactorial associated
with the treatment, the patient and external factors [82].
NEW THERAPIES FOR SPA

Targeting IL23/IL17
While anti-TNF therapy has been a major advance in the treatment of SpA, there are a
group of patients who do not respond, lose efficacy, or have adverse events to anti-TNF,
therefore necessitating the use of different therapies.
IL23/IL17 axis is activated in AS and other SpAs, which can be a therapeutic target.
Ustekinumab, a monoclonal antibody, which blocks the IL23 and IL12 by binding to the
common p40 subunit, has been now approved for the treatment of active PsA [83].
Ustekinumab is also used in plaque psoriasis, and anti-TNF refractory Crohns disease [84].
The efficacy and safety of ustekinumab, has been evaluated in a 28-week, prospective,
open-label study (TOPAS) in patients with AS. At week 24, 65% of the patients achieved
ASAS40 response. There was also significant improvement in active inflammation as
detected by MRI as well as significant reduction of NSAIDs intake. Ustekinumab was well
tolerated and was associated with a reduction of signs and symptoms in active AS [85].
There are ongoing trials assessing ustekinumab in radiographic and non-radiographic
axial SpA.
Secukinumab, an anti-IL17A monoclonal antibody, has been studied in a phase 2 multi-
centre, randomised, double-blind trial of 30 patients with moderate to severe AS. At week 6,
ASAS20 response was achieved in 59% in the secukinumab group (24 patients), vs. 24% in
the placebo group (6 patients). There was one serious adverse event in the secukinumab-
treated group including Staphylococcus aureus subcutaneous abscess. This met its primary
end point; however, it was a small proof of concept study with a short duration of treatment
[86].
The safety and efficacy of secukinumab were evaluated in two double-blind phase III
trials in 590 patients with active AS. Patients who were anti-TNF nave and those who had
previously failed anti-TNF therapy were included. In MEASURE 1 (371 patients), the
ASAS20 response rates at week 16 were 61%, 60% and 29% for subcutaneous secukinumab
at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001). In MEASURE 2 (219
patients), the ASAS20 response rates were 61%, 41%, and 28% for subcutaneous
secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for the
150-mg dose and P=0.10 for the 75-mg dose). The improvements were sustained through 52
weeks. During the entire treatment period, the adverse events in the secukinumab-treated
patients included neutropaenia, candida infection and Crohns disease with incidence rates of
0.7, 0.9, and 0.7 cases per 100 patient-years, respectively [87]. Secukinumab has now been
licensed for use in AS.
Ixekizumab has been shown to be effective in chronic plaque psoriasis [88], and further
studies in psoriasis and PsA are currently ongoing. A phase III trial of ixekizumab in active
AS has been withdrawn.
Several specific inhibitors of IL23 (monoclonal antibodies against the p19 subunit)
including BI 655066, guselkumab and tildrakizumab, are underway in clinical trials in
psoriasis (NCT02203851, NCT02207244 and NCT01729754), PsA (NCT02319759), while BI
655066 in also being currently investigated in a phase II study in AS (NCT02047110) [89].
Targeting IL6
IL6 blockade with tocilizumab, a humanised monoclonal antibody to IL6 receptor, is

effective and licensed for use in RA. Patients with AS have been found to have high serum
levels of IL6 [90]. Also IL6 was found in sacral biopsy samples of patients with AS. These
findings suggest a role for IL6 in AS [91].
There have been case reports suggesting benefit of using tocilizumab in AS patients, who
were refractory to anti-TNF therapy [92], [93]. However, this response was not demonstrated
in BUILDER-1 and BUILDER-2 randomised, placebo-controlled trials. In BUILDER-1 part
1 (duration of 12 weeks), tocilizumab was not effective clinically in AS patients who were
NSAID-inadequate responders and anti-TNF-nave. At week 12, ASAS20 response rates were
37.3% and 27.5% in the tocilizumab and placebo arms, respectively [94].
Sarilumab, a fully human monoclonal antibody against IL6 receptor, was evaluated in the
ALIGN study, a phase 2 randomised placebo-controlled trial of active AS. There was no
statistically or clinically significant effect of sarilumab compared to placebo, suggesting that
the IL6 pathway may not play an essential role in AS [95].
Other Biologics
Biologic agents apart from anti-TNF have been are successfully used in other
inflammatory conditions such as RA. Other biologic agents have been studied in AS patients
with disappointing results. Rituximab, an anti-CD20, B cell depleting monoclonal antibody,
was evaluated in a phase 2 trial of 20 patients with active AS. Rituximab had no therapeutic
effect in 10 patients with AS refractory to anti-TNF therapy, but it showed efficacy in 10
TNF-nave patients [96].
In an open-label study of abatacept, a selective T cell modulator that blocks a co-
stimulatory signal needed to activate T cells, efficacy was demonstrated neither in 15 anti-
TNF-nave patients, nor in 15 active AS patients with inadequate response to TNF-inhibitors
[97].
Anakinra, an IL1 antagonist, did not show convincing results in active AS. In a small
pilot trial of 20 NSAID-refractory patients with AS, anakinra improved spinal symptoms only
in a small subgroup of patients with active AS [98].
Apremilast is an oral phosphodiesterase 4 inhibitor that modulates inflammatory
cytokines. It was evaluated in a double-blind, placebo-controlled, phase II study over 12
weeks, in 38 patients with symptomatic AS with active disease on MRI. This small pilot
study did not meet its primary end point; however apremilast was associated with
improvement in all other clinical assessments, BASDAI, BASFI, and BASMI compared to
placebo. This study supports further research in axial inflammation [99]. A phase III
multicentre, randomised trial studying the efficacy and safety of apremilast in active AS is
currently ongoing (NCT01583374).
Tofacitinib is an oral Janus-kinase (JAK) inhibitor, which has proven to be effective in
RA [100] and potentially might be also effective for AS and axial SpA. A phase II study of
tofacitinib in active AS has completed (NCT01786668), and the results are not as yet
available.
CONCLUSION
Anti-TNF therapy has been a major advance in the management of SpA. The use of MRI
in identifying inflammation in the spine prior to the development of radiographic changes,
will see a change in the management of axial SpA with anti-TNF therapy.
Anti-TNF agents are useful in controlling the symptoms of SpA; however there is debate
whether they prevent structural damage. Most patients benefit from anti-TNF therapy, but
some lose the efficacy with time and some fail to respond. Adverse events are also an issue
for some patients. While switching anti-TNF agents has been investigated in RA, this has not
been evaluated extensively in SpA. Several small retrospective studies support the use of
sequential treatment with TNF blockers in this group of patients.
There has been advancement in therapy in the management of PsA with new agents. IL17
blockade is another major therapeutic target in axial SpA, an addition to the options available
to treat spinal inflammation apart from TNF inhibitors. However there is still a demand for
research and the use of new therapeutic agents in SpA.
ACKNOWLEDGMENTS
The authors would like to thank to Dr. Pedro Machado from Centre for Rheumatology
Research and MRC Centre for Neuromuscular Diseases, University College London, London,
UK for reviewing the chapter (email: p.machado@ucl.ac.uk)
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Chapter 13
ESTABLISHED AND NEW BIOLOGIC THERAPIES

FOR PSORIATIC ARTHRITIS AND PSORIASIS
Benjamin J Thomas1, Sarah Elyoussfi1

and Coziana Ciurtin, PhD FRCP 2,3, *
Medical School, University College London, London, UK

1
2
3
ABSTRACT
Psoriatic arthritis (PsA) is part of the group of seronegative spondyloarthropathies (SpA).
These diseases share common clinical features such as sacroiliitis, spondylitis, enthesitis,
psoriasis, uveitis, and genetic markers. The newly developed biologic treatments aim to target
molecular and cellular abnormalities associated with autoimmunity in PsA and psoriasis.
There are several biologic agents which are currently used, or are under investigation in both
diseases, which creates an opportunity for rheumatologists and dermatologists to share their
expertise for patients benefit. Apart from the large body of evidence for efficacy of the
licensed biologic therapies in psoriasis and PsA, research efforts are currently put into
discovering and testing new molecular targets with therapeutic potential. This chapter will
review all the biologic agents ever tested in these two diseases, stratified based on the level of
evidence regarding their efficacy. As PsA and psoriasis have a diverse clinical phenotype, it is
useful to identify which treatments are effective for a particular clinical manifestation, such as
axial and peripheral arthritis, dactylitis, enthesitis, skin and nail disease. Another aspect of
biologic treatment effectiveness that will be explored in this chapter is the impact of these
*
308 Benjamin J Thomas, Sarah Elyoussfi and Coziana Ciurtin
agents on patients quality of life and functional ability. We propose that by analysing the
patients individual disease phenotype, based on clinical assessments and biomarkers, there is
a huge opportunity to optimise the cost-effectiveness of biologic treatments, by facilitating
tailored treatment options for patients with PsA and psoriasis.
Keywords: psoriatic arthritis, psoriasis, biologic treatment, small molecule inhibitors,

biosimilars, efficacy, safety, cost-effectiveness
INTRODUCTION
PsA is a chronic inflammatory arthropathy, which is characterised by heterogeneous
clinical features, and can effect up to 30% patients with psoriasis. The clinical presentation of
PsA is variable. Frequently, PsA manifests as a mild, oligoarticular disease, which can
progress to a polyarticular arthropathy, developing into a severe, erosive condition in at least
20% of patients [1]. Aggressive disease is associated with poor prognostic factors, such as
polyarticular or erosive arthritis at presentation, additional psoriasis with extensive skin
involvement, strong family history of psoriasis, and disease onset before 20 years of age [1].
The most common clinical manifestation of PsA are: asymmetrical peripheral oligoarthritis,
sacroiliitis, spondylitis, enthesitis (inflammation of the entheses present at the site of the
insertion of ligaments and tendons into the bones), dactylitis (sausage-like swelling of the
fingers and toes), tenosynovitis (inflammation of the tendon sheath), iridocyclitis,
hyperkeratotic and/or pustular rash on the hands and soles (keratoderma blennorrhagica) or
psoriasis [2, 3]. Despite being recognised as a distinct entity, the clinical picture of PsA with
peripheral involvement can be difficult to distinguish from that of rheumatoid arthritis (RA),
which led in the past to a delayed recognition of PsA as a separate disease [4]. In addition,
PsA is associated with increased prevalence of human leucocyte antigen (HLA)-B27 and
positive family history of SpA [5, 6].
Several clinical form of PsA were recognised and classified based on the data from large
cohort studies and clinical trials [7]:
1. Arthritis affecting predominantly the distal interphalangeal joints (DIPs) (10%)

2. Symmetric polyarthritis (5%-20%)
3. Asymmetric oligoarthritis or monoarthritis (70%-80%)
4. Axial disease: predominant spondylitis associated or not with sacroiliitis (5%-20%)
5. Arthritis mutilans (rare)
Several guidelines have been developed to facilitate the diagnosis and tailored treatment
of patients with PsA [8]. Patients experience a decreased quality of life as a consequence of
functional impairment, joint pain, cosmetic implications of skin and nail psoriatic changes,
and (in some cases) secondary to side-effects to therapy [9]. The prevention of irreversible
damage, maintenance of functionality and minimisation of risk of comorbidities are some of
the key long term goals for modern therapy in PsA [10]. The progress made by modern
therapies had significant impact on improving the quality of life of patients with PsA and
psoriasis [11, 12].
Established and New Biologic Therapies for Psoriatic Arthritis and Psoriasis 309
One of the major challenges posed by the disease heterogeneity is that of tailoring
appropriately the available therapeutic options based on patients disease phenotype.
Conventional disease modifying antirheumatic drugs (DMARDS) used in the treatment of
PsA have limited efficacy for certain disease clinical features, such as nail disease, enthesitis
or axial involvement, and some are unable to control moderate to severe peripheral joint and
skin disease [13]. The development and introduction of biologic treatments in the therapeutic
armamentarium of PsA enabled a better control of multiple manifestations of PsA and
psoriasis using a single agent, minimising the need for additional therapies.
DISEASE PATHOGENESIS ASPECTS THAT LED TO

THE DEVELOPMENT OF SPECIFIC BIOLOGIC THERAPEUTIC TARGETS
Despite the recent evidence of differential expression of some biomarkers in patients with
PsA and cutaneous psoriasis [14], the involvement of pro-inflammatory T cell subtypes was
considered equally relevant for the immunopathogenesis of both diseases [15]. The newly
developed biologic treatments aim to target these abnormalities. It was previously identified
that the dermis and epidermis of psoriasis patients is infiltrated with activated cluster of
differentiation (CD) 4+ and CD8+ T cells [16], and also that the synovial fluid aspirated from
patients with active PsA contained high levels of CD8+ T cells [17]. The tumour necrosis
factor (TNF) inhibitors are the most widely used biologic treatment for both diseases, and the
scientific rationale is to target TNF, an inflammatory cytokine released by activated T cells
and keratinocytes, which has additional role in promoting pro-inflammatory signals
associated with psoriasis and PsA pathogenesis [18].
Co-stimulatory molecules have also been explored as potential therapeutic targets, as they
play an important role in the uncontrolled activation of T cells, apoptosis of memory T cells,
inhibition of co-stimulation of T cells, and in the decrease of the inflammatory gene
expression in psoriatic plaques, via a mechanism insufficiently explained [19, 20]. This seems
to be the mechanism of action of alefacept, whilst efalizumab promotes the inhibition of
lymphocyte activation and recruitment into tissues (both are T cell modulator therapies,
which will be discussed in detail below) [21].
The comprehensive interleukin (IL)23/T helper (h)17 axis model of psoriasis, is based
on the role of IL23 (secreted by dermal dendritic cells) in inducing Th17 cell activation and
release of pro-inflammatory cytokines that acts on keratinocytes, which, in turn, produce
more IL23 and other pro-inflammatory cytokines (such as TNF, IL8, S100 molecules), which
all sustain and amplify the chronic inflammatory process [22].
Ustekinumab, a recently approved biologic treatment for psoriasis, also interferes with
the activation of certain types of T cells (mediated by the blockage of p40 subunit of
IL12/23). IL23 is strongly related to the pathogenesis of psoriasis. The intradermal injection
of IL23 or over-expression of IL12/23 p40 subunit in mouse keratinocytes was shown to lead
to skin lesions resembling psoriasis [23]. IL23 was also found to be highly expressed in
human psoriatic skin lesions [24], therefore the use of this therapy is also supported by
immuno-pathogenic evidence. IL23 also plays an important role in the terminal differentiation
of the effector Th17 cells. Th17 cells have a central role in maintaining the skin psoriatic
plaque inflammation, as the plaques are characterised by an abundant Th17 cell infiltrate [25].
Furthermore, the interest in identifying therapies targeting IL17, which is the signature
cytokine of Th17 cells, was supported by the evidence of high levels of expression of IL17
receptor (IL17R) in the synovial tissue of patients with PsA, along with the presence CD4+
IL17+ T cells in their synovial fluid [26]. New therapies targeting IL17A (secukinumab and
ixekinumab) or IL17A receptor (IL17A-R) (brodalumab) have already been proven effective
in both psoriasis and PsA.
A big progress was also achieved with the introduction of the first oral biologic agent,
apremilast, approved by Food and Drug Administration (FDA) in March 2014 for treatment
of adults with active PsA, and in September 2014 for the treatment of moderate to severe
plaque psoriasis. Apremilast inhibits phosphodiesterase 4 (PDE4), which degrades cyclic
adenosine monophosphate (cAMP) into its inactive form AMP, so counteracting the immune
cells ability to produce pro-inflammatory cytokines linked to hyperproliferation and altered
differentiation of keratinocytes, as found in psoriasis.
THE EFFICACY OF BIOLOGIC TREATMENTS AND NEW SMALL

MOLECULES WAS ASSESSED IN NUMEROUS CLINICAL TRIALS,
USING SEVERAL OUTCOME MEASURES
ACR (American College of Rheumatology) response is defined as a different percentage
improvement in the following core set measures (initially defined to assess response in RA
patients) [27]:
1. patient assessment
2. physician assessment
3. pain scale
4. disability/functional questionnaire
5. acute phase reactant (erythrocyte sedimentation rate - ESR or C-reactive protein -
CRP)
ACR20 response is achieved if there is a 20% improvement in tender or swollen joint

counts, as well as a 20% improvement in at least three of the other five criteria (ACR50 has a
positive outcome if there is a 50% improvement, and ACR70 if there is a 70% improvement).
PASI (Psoriasis Area Severity Index) score is an index used to express the severity of
psoriasis, which combines the severity (erythema, induration and desquamation) and
percentage of affected area. PASI75 and 90 define a 75% and 90% respectively reduction of
PASI score from the baseline assessment [28].
NAPSI (Nail Psoriasis Severity Index) is used to assign the nail, nail bed and nail matrix
psoriasis by area of involvement in the nail unit [29].
PsARC (PsA Response Criteria) response is a measurement of response to treatment in
patients with PsA, and includes the following assessments [30]:
66 swollen joint score

68 tender joint score
Patient global assessment (PtGA)
Physician global assessment (PGA)
The PsARC response is defined as improvement in 2 of the 4 tests:
One of which must be the joint tenderness or swelling score

No worsening in any of the four measures
Improvement is defined as a decrease 30% in the swollen or tender joint score and
1 in either of the global assessments.
BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) is a patients reported

outcome questionnaire consisting of a 1 - 10 scale measuring discomfort, pain, and fatigue (1
being no problem and 10 being the worst problem), in response to six questions asked of the
patient pertaining to the five major symptoms of AS:
1. Fatigue
2. Spinal pain
3. Arthralgia (joint pain) or swelling
4. Enthesitis, or inflammation of tendons and ligaments (areas of localised tenderness
where connective tissues insert into bone)
5. Morning stiffness duration
6. Morning stiffness severity
The BASDAI score is calculated as a sum of the five major symptom scores (the average
of the two scores relating to morning stiffness is taken), which is divided by 5 to give a final 0
10 BASDAI score. Scores of 4 or greater suggest suboptimal control of disease [31].
The Functional Assessment of Chronic Illness Therapy (FACIT-F score) is a
collection of collection of health-related quality of life (HRQOL) questionnaires targeted to
the management of chronic illness, which is used along with other patients reported outcome
measures [29].
EQ-5D (Euro Quol group instrument assessing 5 domains) is a standardised instrument
for use of measure of health outcome in 5 domains: mobility, self-care, usual activities,
pain/discomfort and anxiety/depression [32].
DLQI (Dermatology Quality of Life Index) is the first dermatology specific quality of
life 10 question validated questionnaire [32].
Short Form 36 (SF-36) health survey is a 36-item, patient-reported survey of patient
health.
Biologic Therapies for Psoriasis and PsA
Biologic agents have revolutionised the treatment of psoriasis and PsA. Their
introduction began with the various TNF inhibitors that have been proven efficacious,
particularly in those patients who were resistant to conventional DMARDs. Numerous
randomised control trials (RCTs) have shown their efficacy in the various manifestations of
psoriasis, including skin disease, peripheral joint and axial involvement, nail and tendon
involvement, and quality of life (Table 1).
TNF Inhibitors
This group of medications has shown remarkable efficacy across a spectrum of disease
characteristics.
Etanercept
Etanercept was the first TNF inhibitor to be registered for use in patients with
autoimmune diseases. Etanercept is a fusion protein consisting of the p75 receptor bound to
the Fc region of human immunoglobulin G1. Several RCTs have proven its efficacy at 12
weeks for several disease outcome measures in PsA and psoriasis, such as PsARC, ACR20,
50 and 70, and PASI75 response criteria. In addition to improvements in skin and joint
symptoms, there was also an improvement in the quality of life (as assessed by DLQI, SF-36
health survey, EQ-5D scores), patient rating of pruritus and PtGA of psoriasis and PGA [33-
40]. Etanercept was shown to inhibit radiographic progression at 12, and also 24 months [41,
42]. Whilst one study found no improvement in FACIT-F scores [40], another found a
statistically significant improvement at week 12, as well as greater improvement the Hamilton
rating scale for depression (Ham-D) and the Beck depression inventory (BDI) in the active
treatment group compared to placebo [38]. Improvement in fatigue was correlated with
improvement in joint pain in the same study; however improvements in depression had a
weaker correlation.
Efficacy of etanercept has also been demonstrated in the paediatric population with
psoriasis. One study reported that at week 12, significant improvements in PASI75, PASI50,
PASI90 and PGA scores were found [43, 44]. These improvements were maintained up to
week 96 [45]. This is an ongoing study of total duration 264 weeks.
The majority of the clinical trials in patients with psoriasis and PsA have used PASI score
and ACR response measures as primary outcomes. However, the clinicians choice of a
certain biologic therapy in a particular patient may be guided by the biologic agents ability to
tackle specific manifestations of these diseases, such as axial disease, dactylitis, enthesitis and
nail disease.
Etanercept was also found useful in controlling symptoms of AS and led to improvement
in 86% of lesions as detected by serial spinal magnetic resonance imaging (MRI) scan,
demonstrating its possible benefit for patients with PsA and axial disease [46]. An
observational study looking at patients with PsA with axial disease found 72% patients
improved clinically as assessed by the BASDAI score [47].
Etanercept is also effective in patients with PsA and enthesitis and dactylitis. Clinical
benefits were documented at week 12 and week 24 in a multiple dose study [48].
Interestingly, the higher dose had proven no additional efficacy in treating the enthesitis and
dactylitis, but demonstrated improvement of skin lesions.
Nail disease is a common manifestation of PsA causing pain and manual dysfunction, and
reduced quality of life. Placebo controlled trial data are limited, but some trials have reported
nail disease improvement as secondary outcome. Etanercept has been proven effective in
psoriatic nail treatment [49]. Based on the current level of evidence, it has been recommended
by the medical board of the National Psoriasis Foundation for use in different clinical
subtypes of psoriasis and PsA, such as isolated nail disease, skin and nail disease, and nail
and skin and joint disease [50].
The safety of TNF blockers has been broadly investigated in RCT of patients with RA,
SpA (including PsA), and also with psoriasis. The most recognised side-effects, which are
common to TNF inhibitor class as a whole, include infections, malignancies, pancytopenia,
demyelinating disease and autoimmune hepatitis [41, 51]. Injection site reactions can occur
up to approximately 37% of patients [52]. The open label extensions of RCTs and data from
national registries have supported the long-term safety of etanercept treatment [53-55]. These
showed that the incidence of serious adverse events (such as infections, malignancy or
cardiovascular events) did not increase over time. The numbers of adverse events per 100
patient-years of treatment was 96.9 for infections and 0.9 for serious infections, the latter
included bronchitis, cellulitis, fasciitis, diverticulitis, enteritis, and viral meningitis. There
were no reports of opportunistic infections or tuberculosis reactivation in this study,
suggesting an overall acceptable safety of long-term therapy with etanercept. The rate for
malignancies was similar to the general population and did not increase with continued
exposure to etanercept [53].
The anti-TNF group of medications have found to be safe and effective in numerous
rheumatologic and dermatological autoimmune conditions. Etanercept has also been reported
to reduce the risk of myocardial infarct (MI) when used in patients with psoriasis in a
retrospective cohort study [56]. Patients with PsA or psoriasis were observed for a median of
4.3 years, and grouped in three cohorts: patients treated with anti-TNF for at least two months
(n = 1673), patients treated with other systemic treatments or phototherapy (n = 2097), and
patients prescribed only topical treatments (n = 5075). The incidence rates for MI was lowest
in the anti-TNF cohort, and after adjusting for MI risk factors, the etanercept group had a 50%
lower risk of MI compared with the cohort using only topical treatments. Further research is
needed to assess the benefits of anti-TNF therapy for the overall cardiovascular risk of
patients with psoriasis and PsA as several studies reported controversial results with regard of
the increased cardiovascular risk in this patient population [57-59].
Adalimumab
Adalimumab, a human monoclonal antibody with a high affinity for TNF, which is
licensed for use in adults with severe psoriasis and PsA, in whom conventional therapies have
failed or are not tolerated.
The benefits of this therapy are well-recognised. In the phase III REACH trial, 71%
patients achieved PASI75 score in the treatment arm vs. 7% in the placebo arm [60]. Further
studies have shown similar efficacy at week 12 and 16 for ACR20, ACR50, ACR70, and
PsARC response criteria, HAQ and the SF-36 health survey, DLQI score, Mental Component
Summary Score and FACIT fatigue scale [61-64]. Radiographic progression, as measured by
the modified total Sharp score at weeks 24 and 48 was lower in those in treated with
adalimumab, irrespective of whether they were receiving methotrexate (MTX) at baseline
[61, 64].
With regards to conventional treatments, adalimumab has demonstrated its superiority in
multiple RCTs. In a study comparing adalimumab and MTX alongside placebo, PASI75
score was reached by 79.6% in the adalimumab group, which was significantly increased
compared to 35.5% in the MTX group and 18.9% in the placebo group [65]. Adalimumab and
cyclosporine showed similar efficacy in treating skin lesions but when these drugs were
combined they showed superiority to monotherapy [66].
Adalimumab has been compared with other TNF inhibitors (infliximab, etanercept and
golimumab) in patients with PsA, all of which have demonstrated similar outcomes with
regards to ACR measures [67-69]. In addition, some studies reported additional benefit when
switching from one anti-TNF drug to another, in case of inadequate response [70, 71].
The ACCLAIM trial reported significant improvement of clinical features of dactylitis
and enthesitis in patients treated with adalimumab [72]. One RCT and three observational
studies have shown effectiveness of adalimumab in controlling nail disease [65, 73, 74]. The
National Psoriasis Foundation has recommended the use of adalimumab in patients with nail
disease alone, skin and nail disease, or for patients with a combination of nail, skin and joint
disease [50]. Adalimumab was ranked with the highest enthusiasm compared to all other
drugs recommended for nail psoriasis.
Data regarding the efficacy of adalimumab in axial disease is available from the AS
clinical trials [75, 76]; however a recent meta-analysis assessing the efficacy of adalimumab
in AS didnt report any data on patients with concomitant psoriasis or axial PsA [77]. An
open label study of adalimumab on patients with AS improved axial disease, regardless of a
history of psoriasis [78], demonstrating that axial disease, classified as both AS or PsA with
axial involvement, is equally responsive to adalimumab.
In summary, adalimumab has shown clear benefits in joint and skin disease. Studies have
shown a clear reduction in disability and increase of quality of life [79, 80]. Adalimumab may
also be the drug of choice for patients with dactylitis, enthesitis and nail disease. It may also
be of use in patients in whom MTX is ineffective or other TNF blockers have failed, or in
combination with cyclosporine [81].
The precautions relating to its use are similar to those relating to etanercept, as detailed
above. The long term safety of adalimumab has been confirmed through open label extension
studies [82] and registries [83]. The adverse event rate during the extension was consistent
with that in the initial REVEAL trial, with the rate of side-effects declining through the study
period [82].
Infliximab
Infliximab is a chimeric monoclonal antibody against TNF, which has demonstrated
benefits in treating psoriasis and PsA. With regard to treatment of psoriasis, the EXPRESS
trials showed significant results at 10 weeks, where PASI75 response at week 10 was 80% vs.
3% for placebo (P<0.0001) [37]. Significant results were also found for the treatment of nail
disease at week 24 [84], and were maintained up to 1 year for skin and nail disease [85].
However, 27% of patients developed antibodies to infliximab by week 66 [37]. In addition,
continuous therapy maintained better PASI responses than intermittent therapy as assessed at
week 50 in a separate trial for psoriasis [86].
Infliximab has also demonstrated efficacy in treating PsA. In the IMPACT trials,
infliximab was efficacious at treating joint disease demonstrated by significant ACR20,
ACR50, ACR70 responses vs. placebo at week 24 [87], with responses maintained through 1
year of treatment [88]. Significant findings for the treatment of other manifestations of PsA
have also been shown in these trials for enthesitis and dactylitis [87, 88], as well as
demonstrating significant radiographic progression of total joint disease in the PsA-modified
van Der Heijde - Sharp (vDH-S) score (developed to score radiographic abnormalities in the
hands and feet of patients with PsA) at week 24 [89]. Improvements in quality of life were
seen, as evidenced by significantly improved HAQ scores and SF-36 questionnaire at week
14 [90].
Infliximab also demonstrated significant results in other patient demographics, as it
significantly improved the PASI75 responses in Chinese patients with psoriasis [91], and the
ACR20 responses of Japanese patients with PsA [92].
The benefit of infliximab was translated in a significantly greater PASI75 response when
compared with MTX (78% in the active group vs. 42% in the MTX group at week 16) [93].
Similar positive results were reported for joint disease (ACR20) and dactylitis in the
RESPOND study [94]. In the PSUNRISE trial, 65.4% of patients who had an inadequate
response to etanercept had a PGA score of 0 or 1 (demonstrating clear or almost clear nail
disease) at week 10, upon switching to infliximab [95].
Concerning safety, infliximab has many of the same common adverse effects as the other
TNF blockers mentioned above. Serious adverse events were present in 6% of patients on
infliximab at week 24 in the EXPRESS trial [37], and in a slightly higher proportion when
compared to MTX in the RESTORE trial (7% vs. 3%) [93]. In patients switching from
etanercept to infliximab, a proportion of 3.7% experienced a severe adverse event [95].
Patients with PsA tolerated well infliximab, whilst adverse events were often higher than
placebo, the incidence of serious adverse events was similar [87, 88, 92, 94]. In the IMPACT-
2 study, 11.5% of patients had experienced a serious adverse event, and 8.4% stopped
treatment due to adverse events, as assessed at week 54 [88].
Whilst infusion-related reactions were found in 16% patients treated with infliximab, it
was observed that patients who are concurrently treated with further immunosuppressive
agents, such as MTX or azathioprine, were likely to have lower incidence of infusion-related
reactions [52]. Most infusion reactions were of mild-moderate nature [86]. Granulomatous
infections were more common in patients on infliximab than etanercept; it has been reported
at a prevalence of 239 cases of infection per 100,000 patients treated with infliximab, of
which tuberculosis was the most common (144 per 100,000). In addition, candidiasis,
coccidioidomycosis, histoplasmosis, listeriosis, nocardiosis and nontuberculous mycobacteria
infections were significantly more frequent in patients treated with infliximab. The risk of a
granulomatous infection, whilst still very low in absolute terms, is 3.25 times greater in
patients on infliximab compared to etanercept [96], a proportion of which are attributed to be
reactivation of latent granulomatous infection [97].
The major long-term observational study for infliximab for the treatment of psoriasis: P-
SOLAR included 12095 patients, who have been followed up for a combined 31818 patient-
years. This study reported that, compared to non-biological therapy, the use of biologic agents
was not a significant predictor of MACE (Mortality and Major Adverse Cardiac Events),
malignancy or death; and no new safety concerns were found when the results were reported
in 2013 [98].
Certolizumab
Certolizumab pegol is a PEGylated Fab fragment from a humanised TNF-inhibitor
monoclonal antibody. Initial benefits were found in treating psoriasis, as patients had
significantly greater PASI75 responses at week 12 for multiple doses (75% 200mg, 83%
400mg) of certolizumab, when compared with placebo (7%), P<0.001 [99].
The RAPID trials demonstrated the efficacy of certolizumab in treating joint

manifestations associated with PsA, and reported as a significant ACR20 response vs. placebo
at week 12 (for multiple active treatment doses and regardless of prior TNF blocker
exposure). Some patients experienced significant improvement as early as week 1 of
treatment [100], and the response rates were maintained up until week 48 [101]. Significant
positive results were also found for dactylitis, enthesitis, and nail disease at week 24 [100].
Radiographic analyses also demonstrated significant inhibition of progression of joint disease
vs. placebo at week 24 [102].
Patient reported outcomes were also improved by treatment with certolizumab, as proven
by significant improvement of the PGA scores at week 12 in the active treatment arm
compared to placebo [99], as well as significant improvement in physical function, as
measured by the HAQ-DI scores at week 24 [103]. In addition, the RAPID trial analysed the
changes in productivity in the work-place and at home, and found significant productivity
improvement as early as week 4, maintained until week 24. The treatment also improved the
patients domestic, family, social and leisure activities, regardless of employment status at
week 24 [104].
With respect to the safety of certolizumab in psoriasis, there was no clinically meaningful
differences of treatment-emergent adverse events between treatment groups, and most side
effects were of mild/moderate severity, with nasopharyngitis, headache and pruritus being the
most common [99]. Serious adverse events occurred in 3% of patients on 200 mg
certolizumab, in 5% of those on 400 mg certolizumab and in 2% of patients on placebo over
24 weeks [99]. The RAPID-PsA trial reported similar serious adverse events and treatment
discontinuation rates at 24 weeks [100]. At week 48, 9.9% of patients had experienced a
serious adverse event [101], and by week 96, 17.0% of patients had experienced a serious
adverse event, based on the results of the same trial. The most common adverse events were
pneumonia, HIV, erysipelas and urinary tract infection, which had led to 9.2% of patients
withdrawing from the study by week 96 [105]. Injection site reactions at 24 weeks were
reported by 2.2% patients on placebo vs. 4.3% for 200 mg certolizumab, and 9.6% for 400
mg certolizumab groups [100]. A Cochrane review has found statistically significant increase
in serious infections and serious adverse events for certolizumab compared to the control
groups [106], but this analysis looked at the data on biologic treatments across many
autoimmune conditions, rather than just psoriasis or PsA, and was made on indirect
comparisons.
Golimumab
Golimumab is another monoclonal antibody against TNF, originally engineered from a
transgenic model in mice. The GO-REVEAL series of trials showed that this treatment was
effective in treating PsA, as assessed by ACR20 responses (48% in the treatment arm vs. 9%
in the placebo group, P<0.001) [107]. These benefits were sustained, as reported at different
time points: at 1 year [108], 2 years [109], and 5 years [110], with a proportion of 31% of
patients discontinuing the treatment with golimumab after 5 years. There was also a
significant benefit in controlling symptoms of enthesitis and dactylitis, but this was only seen
in the higher dose (100mg) golimumab arm when compared to placebo at week 24 [111].
These benefits, along with significant radiographic response, were maintained through 1 year
[108], 2 years [109] and 5 years [110].
Similarly to other biologics, quality of life improvements were demonstrated with

golimumab as well, as early as week 24 [107] and as far as 5 years into treatment. A
proportion of 52% of patients had a clinically meaningful decrease in their HAQ-DI scores
(>0.3) [110].
One of the studies looking at the long-term follow up of patients treated with golimumab
demonstrated that 6% from the total number of patients developed antidrug antibodies at 5
years. A higher proportion of these patients were on golimumab monotherapy (10.0% vs.
1.8% for those who had received baseline MTX treatment) [110].
Through the first 24 weeks of golimumab treatment in the GO-REVEAL study, there was
a similar incidence of adverse events for golimumab vs. placebo, of which nasopharyngitis
and upper respiratory tract infections (URTI) were the most common. At 24 weeks, 3% of
patients taking golimumab and 4% of placebo patients discontinued treatment due to adverse
events [107]. At 1 year, 4% of patients taking golimumab had discontinued due to adverse
events [108], and this proportion increased 6% at 2 years. However, by this point there had
been no serious injection site reactions requiring treatment or resulting in discontinuation of
the study medication, and there was no significant increase in the risk of serious infections,
MACE, malignancy or mortality [109]. After 5 years of treatment, 21.1% of patients had
experienced a significant adverse event, with 12.4% discontinuing the treatment due to the
adverse event. The most common significant adverse events were basal cell carcinoma
(BCC), MI and cholelithiasis [110]. This indicates that golimumab is well tolerated during
long-term treatment.
Cost-effective ness of TNF- Inhibitors for the Treatment of PsA

Systematic reviews and meta-analyses have assessed the cost-effectiveness of biologics
in the treatment of PsA and psoriasis, with emphasis on TNF agents as they are the most used
[112, 113]. The National Institute of Health and Care Excellence (NICE), which is the main
UK regulatory body that provides national guidance and advice to improve health,
recommended etanercept, infliximab, adalimumab and golimumab for the treatment of active
and progressive PsA. These recommendations were bases on published studies assessing
clinical effectiveness and on economic evaluations [114]. On the basis of the numerous
RCTs, it was concluded that there was sufficient evidence with regards to the effectiveness of
these therapies for cost-effective treatment of PsA and psoriasis. They noted that all the anti-
TNF agents can be used interchangeably, as there is not enough evidence at the moment to
indicate differences between the individuals TNF inhibitors.
The committee responsible for the appraisal considered the results of a base case model
[114]. This ranked the costs and quality-adjusted life-year (QALY) associated with the TNF
inhibitors compared with palliative care. Acquisition costs for etanercept and adalimumab
were similar. Infliximab has additional administration costs. Infliximab was the most
effective for controlling joint and skin disease, followed by etanercept and adalimumab.
Infliximab was found to be the most expensive, again followed by etanercept then
adalimumab. Etanercept had the highest probability of being cost-effective (44% probability,
if the maximum acceptable amount to pay for an additional QALY was 20,000, and 48% if
the maximum acceptable amount to pay for an additional QALY was 30,000) [114].
However, these cost-effectiveness assessments are based on indirect comparisons rather
than head to head studies of all the anti-TNF agents. Furthermore, in clinical practice these
drugs are used interchangeably. For this reason, NICE recommends that the most cost-
effective practice is to start with the least expensive drug, based on local variation and
administration costs [114].
A separate analysis looking at golimumab, which was introduced in clinical practice
more recently, recommended the use of golimumab under the same circumstances as the other
three drugs [115]. Based on the results of RCTs, the committee concluded that golimumab is
clinically effective and cost-effective when compared to placebo. Golimumab was similarly
effective as other anti-TNF agents with regard to PsARC and PASI responses. The NICE
appraisal concluded that golimumab was not cost-effective when compared to etanercept, but
cost-effective when compared with adalimumab and infliximab. Golimumab is thus
recommended for use in active and progressive PsA, providing that the manufacturer offers
the 100 mg dose of golimumab at the same cost as the 50 mg dose. There is also evidence that
the TNF blockers are considered cost-effective for treatment of psoriasis in other countries as
well [116]. Depending on the health system regulations in different countries, the licensing of
these biologic agents depends on their cost-effectiveness analysis. A similar real-life cost
analysis in the United States showed that etanercept is the most cost-effective anti-TNF
therapy in autoimmune rheumatic diseases, with the exception of psoriasis, for which
adalimumab was the most cost-effective [117].
Anti-Interleukin Biologic Therapies
Ustekinumab
Ustekinumab is a human monoclonal antibody directed against the p40 subunit of
IL12/23. The PHOENIX1 and PHOENIX2 RCTs recruited patients with psoriasis and both
showed significantly greater PASI75 responses at week 12 vs. placebo [118, 119], with
responses maintained until week 76. These studies also reported significant benefit in nail
disease at week 12, as evidenced by NAPSI scores improvement [120].
Ustekinumab demonstrated efficacy in treating PsA initially in phase II RCTs which
showed significant ACR20 response vs. placebo at 12 weeks [121]. This positive outcome
was then replicated in the larger PSUMMIT1 and PSUMMIT2 trials, which showed
significantly increased ACR20 response at 24 weeks [122, 123], which was maintained
through 2 years [124], alongside significant increases in the ACR50 and ACR70 responses
[122, 123]. Ustekinumab is also efficacious for treating other manifestations of PsA. Both
PSUMMIT1 and PSUMMIT2 RCTs showed significant benefits for enthesitis [122, 123], but
only PSUMMIT1 showed significant improvement in the dactylitis scores and spondylitis (as
measured by the BASDAI score at week 24) [122], as well as inhibition of radiographic
progression (as measured by the PsA-modified vDH-S score at week 24) [125].
Patient reported outcomes have also improved following treatment with ustekinumab as
assessed by DLQI and HAQ-DI scores at week 12 [126], and clinically meaningful HAQ-DI
scores of 0 or 1, which were maintained up until 2 years of treatment [124].
Ustekinumab is effective in treating patients from diverse demographic backgrounds, as
similar results were reported by the LOTUS RCT which included Chinese patients [127], and
the PEARL RCT which recruited Taiwanese and Korean patients with psoriasis [128].
Ustekinumab has been compared to etanercept in a head-to-head, the ACCEPT trial,
which found a non-significant increase in PASI75 response in ustekinumab (67.5% for 45mg,
73.8% for 90mg) vs. etanercept (56.8%) at week 12. In addition, whilst the incidence of
adverse events and proportion of participants discontinuing the trial were similar, there was a
significantly increased amount of injection site reactions in the etanercept vs. ustekinumab
groups, which the authors suggested that could be explained by the difference in the
frequency of subcutaneous administrations [129].
In all the RCTs assessing patients with psoriasis, ustekinumab was generally well
tolerated [118, 119, 129, 130], including in the Chinese [127] and Taiwanese and Korean
[128] populations. In the PHOENIX-1 trial, the most common serious adverse events were
infections, malignancy and cardiovascular events, including MI and stroke [118], as assessed
at 3 years. A proportion of 7.9% of patients on 45 mg and 10.1% of patients on 90 mg
ustekinumab had suffered a serious adverse event, with 6.9% and 6.4% of patients
respectively discontinuing study participation due to an adverse event [130]. Injection site
reactions were rare: the PHOENIX-2 study reported them in 1.0% of ustekinumab treated
patients at week 52. At the same time point, 5.4% of patients had developed antibodies to
ustekinumab [119].
Similarly, ustekinumab has been well-tolerated by patients with PsA [121, 122], and all
injection site reactions reported in the P-SUMMIT-1 trial at week 24 were mild. The P-
SUMMIT-2 trial found 1.3% of patients with ustekinumab had experienced a serious adverse
event by week 24, with 2.1% of patients discontinuing treatment due to an adverse event
[123]. Long-term safety data for ustekinumab was reported by the PSOLAR registry [98],
which found that ustekinumab had a lower unadjusted rate of serious infection of 0.93/100
patient years compared to 2.91/100 patient years for infliximab, and 1.91/100 patient years for
other biologics. Also, ustekinumab was not associated with increased risk of malignancy,
MACE, or mortality [131].
Ustekinumab is recommended in the treatment of severe psoriasis (which is appreciated
as having significant impact on patients quality of life), but only in patients who have failed
to get their disease controlled with other treatments such as Psoralen and long wave
ultraviolet radiation (PUVA), cyclosporine and MTX [132].
Ustekinumab has also been recommended for the treatment of patients with active PsA,
in which TNF inhibitors were not suitable or effective (after a trial period of 24 weeks). Due
to the introduction of the patient access scheme, the treatment with ustekinumab is now
considered to be cost-effective. Incremental cost-effectiveness ratio per QALY compared to
conventional treatment was calculated by NICE at 21,900 for patients who had not had TNF
inhibitors before (not considered cost-effective); 25,400 for people who have had TNF
inhibitors and for whom subsequent TNF inhibitors would be appropriate, and 25,300 for
people who have failed TNF inhibitors [133].
Secukinumab
Secukinumab is a monoclonal antibody against IL17A, which was shown to be effective
for psoriasis, as proven by significantly increased PASI75 responses vs. placebo at 12 weeks
in the ERASURE trial [134], JUNCTURE trial [135] and FEATURE trial [136], as well as
demonstrating a significant increase in PASI75 response at week 12 in a head-to-head study,
in which it was compared to etanercept.
Early phase IIa RCT data showed a significant ACR20 response at week 6 vs. placebo,
but non-significant difference when compared to placebo for the ACR50 and ACR70
response criteria [137]. The FUTURE1 and FUTURE2 trials are still pending publication;
however, conference proceedings showed a significant improvement in ACR20 response vs.
placebo at week 12 [138, 139], alongside achievement of secondary endpoints, which

included dactylitis, enthesitis, DAS28-CRP, ACR50, ACR50, PASI75 and PASI90 responses
(regardless of prior anti-TNF treatment) [138, 139]. This was maintained up to week 52 in the
FUTURE 1 RCT [138].
Significantly less radiographic progression from baseline was achieved by secukinumab
when compared to placebo, as assessed at week 24 [140].
Secukinumab is well tolerated in patients who received this treatment for psoriasis [134-
136], with the most common adverse events being nasopharyngitis, headache, URTI [134]
and diarrhoea [135]. In the FIXTURE-1 trial there were less injection site reactions for
secukinumab (0.75%) compared to etanercept (11.1%), and more patients treated with
etanercept discontinued their participation in the study because of side-effects. There are also
no clinically apparent differences in the types of significant adverse events among various
study groups [134].
For the treatment of PsA, rates and types of infection were similar for secukinumab arm
vs. placebo [137]. The early reports of side-effects in the FUTURE-1 RCT found that they
affected only 8.6% of patients who had received 75mg SC secukinumab and 9% of patients
who had received 150mg at any point in the study [138]. The FUTURE-2 trial reported that
the overall incidence of adverse events up to week 16 was similar across all the secukinumab
arms, and also were similar to the placebo arm: overall, 3.3% of patients treated with
secukinumab experienced severe adverse events compared to 2.0% for patients on placebo
[139].
Secukinumab is recommended in the treatment of patients with severe psoriasis, with
impact on their quality of life, and in patients who have failed to respond to other treatments
for psoriasis, such as PUVA, cyclosporine and MTX. The cost for secukinumab was 52,760
per QALY gained (incremental costs 20807 compared with best supportive care) [141].
Brodalumab
Brodalumab is a monoclonal antibody against IL17A, IL17F and IL23. Brodalumab is
effective for treatment of psoriasis. A phase II RCT demonstrated significantly improved
PASI75 responses vs. placebo at week 12, as well as significantly increased PASI90 scores at
higher doses (140 mg and 210 mg), when compared to baseline and with the placebo arm
[142]. PASI responses were maintained during the open label extension of the study, up to
120 weeks [143].
Brodalumab has also shown efficacy in treating joint disease in patients with PsA. In a
phase II RCT, there was significant increase in the ACR20 response at week 12 when
compared to placebo; however there was no significant difference in the enthesitis or
dactylitis scores secondary to treatment [144]. In addition, BASDAI scores were significantly
improved in the brodalumab group, indicating potential benefits for axial involvement in
patients with PsA.
Brodalumab was generally well tolerated. In the RCTs of psoriatic patients, the most
common reported adverse events were nasopharyngitis, URTI, arthralgia and erythema [142].
The analysis of the open-label extension study after 120 weeks of treatment reported that
8.3% of patients treated with brodalumab had suffered serious adverse events, with 6.2% of
patients discontinuing study participation due to adverse events [143]. For the treatment of
PsA, the proportion of serious adverse events was similar to placebo (brodalumab 3% vs.
placebo 2%) at week 12, and upon analysing the open-label extension study, it was found that
6% of patients taking brodalumab had experienced a serious adverse event by week 52 [144].
Ixekizumab
Ixekizumab is another monoclonal antibody against IL17A, which has demonstrated
efficacy in treating psoriasis, as seen by significantly greater PASI75 score improvement
compared to placebo at doses of 25mg, 75mg and 150mg at 12 weeks [145], as well as
significant improvement in nail disease vs. placebo at the higher doses of 75mg and 150mg
[146].
Ixekizumab was well tolerated over 20 weeks, with no patients reporting a serious
adverse event. The most common adverse events were nasopharyngitis, URTI, injection-site
reaction (only mild-moderate) and headache [145].
Tocilizumab
A randomised trial of tocilizumab in AS showed no clinical efficacy, despite being
effective in decreasing the CRP levels [147]. No further clinical trials are planned.
T Cell Modulatory Therapies
Abatacept
Abatacept, a T cell co-stimulation inhibitor, is a fusion protein that binds to CD80 and
CD86 interfering with T cell signalling and activation, and hence reducing the inflammatory
response.
Abatacept has shown efficacy at 6 months (as assessed by the ACR20, SF-36, psoriatic
target lesion response and PASI scores), particularly at a dose of 10mg/kg in an early phase
RCT [148]. The treatment with abatacept was associated with additional improvements in
radiographic progression, appearance of osteitis, joint synovitis and function, as assessed by
HAQ, and was associated with sustained ACR and skin responses at 12 months [148].
Patients in the placebo group, who had switched to abatacept, exhibited similar responses.
However, skin response was inconsistent, and TNF nave patients showed greater responses
than those previously treated with anti-TNF medication. This study showed promise for the
use of a new biologic agent in the treatment of psoriasis and PsA. Additional case reports
provided evidence that abatacept can be a suitable treatment option for refractory cases of
PsA and psoriasis [149, 150].
Abatacept has failed to show efficacy in AS in a 24 week open label study [151]. There
has been no data to support its use in PsA with axial involvement, dactylitis, enthesitis or nail
disease.
The only RCT of abatacept in PsA reported similar safety profile for the 3, 10 and 30/10
mg/kg doses. There were two cases of infection, which was considered drug related, but
overall it was reported to be a well-tolerated and safe drug [148].
Apremilast
Apremilast is a phosphodiesterase inhibitor. It acts by targeting PDE4, thereby increasing
levels of cAMP which results in decreased levels of pro-inflammatory cytokines.
Treatment with apremilast was shown effective in controlling the symptoms of PsA, as
assessed by the ACR20 response in several RCTs [152, 153]. The PALACE studies, a group
of large phase III trials, have demonstrated its efficacy by achieving the primary outcome, the
ACR20 response at week 16, which was maintained at week 52 in patients treated with 20 mg
twice daily (BD) dose [153]. Apremilast was also effective in improving joint function, and
symptoms and signs of enthesitis and dactylitis. The level of efficacy of apremilast is
comparable to that of TNF inhibitors as assessed in clinical trials, although, it is of note that
TNF inhibitors achieved similar results in almost half the time. Axial disease was not
investigated in the RCTs of apremilast in PsA.
Apremilast was also proven effective for treatment of psoriasis [154-156]. The multi dose
phase IIb RCT of apremilast in psoriasis reported significant improvement in the PASI75
score at week 16 and 32 in both, the 20 mg and 30 mg BD treatment groups [157]. There
were also improvements in pruritus, DLQI and physician global assessment of psoriasis. This
trial data also supported the role of apremilast in the treatment of nail disease, with a
NAPSI50 response index achieved at both week 16 and 32 [157]. Apremilast is recommended
by the National Psoriasis Foundation in skin and nail disease, and skin, nail and joint disease,
but with less enthusiasm and a lower ranking then adalimumab and etanercept [50]. The
treatment with apremilast was recently approved by FDA for use in PsA and psoriasis [158].
Long-term trials have reported apremilast as safe and well tolerated. In a 52-week RCT
of apremilast in PsA, the most common adverse effects were diarrhoea and nausea; these
were highest within the first 2 weeks of medication administration and most resolved within a
month of continued treatment. The incidence of significant adverse events was comparable
across all treatment groups [159]. The treatment with apremilast 30 mg BD in patients with
moderate-severe psoriasis was also well tolerated in a 52 week RCT, most side-effects being
mild or moderate. Their incidence did not increase with longer apremilast exposure [156].
There were no cases reporting reactivation of tuberculosis.
There was recent interest in assessing the cost-effectiveness of apremilast treatment in
different health systems in the UK, Spain and Italy [160-162].
Alefacept
Alefacept is a dimeric fusion protein that consists of the extracellular portion of the
human leukocyte function antigen-3 (LFA-3) linked to the Fc portion of human IgG1, which
acts as a T cell modulator. Multiple clinical trials have shown efficacy at week 12 for PASI75
and DLQI scores compared to placebo [163-166]. When used in combination with MTX, the
treatment was superior in achieving ACR20 and PASI50 responses at week 24 compared to
MTX plus placebo [167]. There was also an improvement in HAQ at 12 weeks, but not at 24
weeks. As of yet there is no data to support the efficacy of this treatment in controlling axial
disease, dactylitis, enthesitis or nail disease.
Alefacept is safe and well tolerated, with a similar incidence of adverse events reported in
the treatment and placebo groups. The most common adverse events were mild and included
headache, infection, injection site reactions. There was no evidence of any adverse
immunosuppression caused by the treatment with alefacept [164].
Efalizumab
Efalizumab is a recombinant humanised monoclonal antibody, which binds to the CD11a
subunit of lymphocyte function-associated antigen 1, and acts as an immunosuppressant by
inhibiting lymphocyte activation and cell migration out of blood vessels into tissues.
Efalizumab failed to prove superiority in treating PsA when compared with placebo [168]. A
large multicentre RCT of efalizumab in patients with moderate-severe psoriasis established
initially this treatment efficacy [169], and was followed by numerous other RCTs with similar
results [170-172]. Despite the fact that initially the treatment with efalizumab was considered
safe in clinical trials [173], further reports showed that efalizumab was associated with
serious adverse events such as infections, malignancy and haemolytic anaemia [174, 175].
Some patients experienced worsening of their psoriasis [176]. Progressive multifocal
leukoencephalopathy was observed in 3 patients who had exposure greater than 3 years [177,
178]. Efalizumab drug was withdrawn in 2009 in Europe and the United States due to these
risks.
B Cell Depletion Therapies
Rituximab
Rituximab consists of a chimeric monoclonal antibody against CD20, which has not
demonstrated any significant benefit in treating psoriasis or PsA and its manifestations in a
small, open label trial, despite being well-tolerated [179].
Small Molecule Inhibitors
Tofacitinib
Tofacitinib is a Janus-Kinase inhibitor, taken orally, which has shown to be effective in
treating psoriasis, with significantly higher PASI75 responses at week 12 when compared to
placebo [180], as well as having significantly better PASI responses for body regions graded
separately at week 12 [181].
Tofacitinib was well tolerated by patients with psoriasis: severe adverse events were
reported in 2.0% (2mg BD), 4.1% (5mg BD), 0% (15mg BD) tofacitinib in comparison with
10.0% in the placebo patients. Discontinuation rates due to adverse events were 2.0%, 4.1%,
6.1% respectively for tofacitinib different dose regimens compared to 6.0% in patients on
placebo, as reported at week 12 [180].
Biosimilars
Biologics have revolutionised the treatment and changed the lives of patients around the
world. As their patents are soon to expire, biosimilars, biotechnologically processed drugs
designed to have the same active properties as those previously licensed, are set to add to the
repertoire of affordable biologic medications. Whilst clinicians and governing bodies
welcome biosimilar substitution, there are risks and uncertainties associated with them,
largely due to the limited long-term data.
Biologics cannot be replicated exactly, as the molecules are derived from cells using
recombinant DNA technology; therefore the biosimilars are not chemically identical. The
National Psoriasis Foundation supports the use of biosimilars and has provided a set of
recommendations guiding their use [184]. These include ensuring patients are fully informed
and educated, ensuring the biosimilar intended for use have been approved as interchangeable
by the FDA following adequate documentation of their safety and efficacy. Adequate
evidence of their bio-equivalence including their clinical efficacy and safety must be obtained
before we can fully take advantage of the economic benefits without compromising clinical
care [185]. Whilst there have been studies reporting positive results of the use of biosimilars
in RA and AS, there are no studies to date to assess their efficacy in PsA and psoriasis [186,
187]. The biologic therapeutic armamentarium for psoriasis and PsA is rapidly expanding, as
proven by the large number of biologic agents and small molecule inhibitors available at
present. Even if initially, the majority of these medications were assessed for efficacy in
psoriasis, recent data showed that many of them are useful for PsA patients as well.
Table 1. Biologic treatments used in PsA and psoriasis
Duration, type of study, treatment, number

Authors Main results
of patients (N)
Anti-TNF treatments
Mease 24-week RCT of adalimumab vs. placebo At week 12, 58% of the adalimumab-treated
et al. 2005 [61] (N = 151 + 162). patients achieved an ACR20 response,
compared with 14% of the placebo-treated
patients (P<0.001). 59% adalimumab-treated
patients achieved a 75% PASI response at 24
weeks, compared with 1% of the placebo
group (P<0.001).
Gladman 48-week open label trial of adalimumab At week 48, patients had achieved ACR20,
et al. 2007 vs. placebo in PsA ACR50, and ACR70 response rates of 56%,
[182] (N = 151). 44%, and 30%, respectively. The PASI50,
PASI75, PASI90, and PASI100 response rates
were 67%, 58%, 46%, and 33%, respectively.
Menter 52-week, RCT of adalimumab vs. placebo At week 16, 71% of adalimumab and 7% of
et al. 2008 [60] in psoriasis patients placebo-treated patients achieved greater than
(N = 1212) or equal to 75% improvement in the PASI
score (P<0.001).
Sauret 16-week RCT of adalimumab (N = 108), At week 16, 79.6% of adalimumab-treated
et al. 2008 [65] oral MTX (N = 110) and placebo (N = 53) patients achieved PASI 75, compared with
(1:1:1). 35.5% for MTX (P<0001) and 18.9% for
placebo (P<0001 vs. adalimumab).
Mease 12-week RCT trial of etanercept in PsA At 12 weeks, the ACR20 was achieved by
et al. 2000 [33] (25 mg twice-weekly subcutaneous 73% etanercept-treated patients compared with
injections) or placebo (N = 60). 13% placebo-treated patients (P<0.0001).
Gottlieb 24-week RCT of etanercept vs. placebo in At week 12, 30% of the etanercept patients
et al. 2003 [34] patients with psoriasis and 2% of placebo-treated patients achieved
(N = 112). PASI75% (P<0.001), 56% of etanercept
patients and 5% of placebo patients at week 24
(P<0.001).
Leonardi et al. 24-week RCT of etanercept low dose (25 At week 12, there was an improvement from
2003 [35] mg once weekly), medium dose (25 mg base line of PASI75 in 4% of the patients in
twice weekly), or high dose (50 mg twice the placebo group, 14% of those in low-dose
weekly) vs. placebo. etanercept group, 34% in the medium-dose
etanercept group, and 49% in the high-dose
etanercept group (P<0.001 for all three).
At week 24, PASI75 was achieved in 25% of
the patients in low-dose group, 44% in
medium-dose group, and 59% in high-dose
group.
Mease 24-week RCT of etanercept vs. placebo in At 12 weeks, 59% of etanercept patients met
et al. 2004 [41] PsA (N = 205). the ACR20 compared with 15% of placebo
patients (P<0.0001).

of patients (N)
Anti-TNF treatments
Tyring 24-week RCT of 50 mg twice-weekly At week 12, 47% of patients achieved PASI75
et al. 2006 etanercept or placebo (N = 618). compared with 5% (P<0.0001).
[38]
Reich et al. 46-week RCT of infliximab vs. placebo in At week 10, a significant greater PASI 75 and
2005 [37] patients with psoriasis. (N = 378). PASI 90 response in Infliximab vs. placebo
was found: 80% vs. 3%, (P<0.0001), and
57% vs. 1%, (P<0.0001), respectively.
At week 24: PASI75 and PASI90 responses
were maintained in the active group: 82% vs.
4% (P<0.0001), and 58% vs. 1%, (P<0.0001),
respectively.
Rich et al. 50-week RCT of Infliximab vs. placebo in At week 24, there was a significantly greater
2008 [84] patients with psoriasis. nail disease clearance in the infliximab group
(N = 305). vs. placebo: 26.2% vs. 5.1%, (P<0.001) and at
week 10, significant greater NAPSI %
improvement in infliximab vs. placebo: 26.8%
vs. -7.7% (P<0.001) was also noted.
Antoni 50-week RCT of Infliximab vs. placebo in At week 16, significantly greater ACR20
et al. 2005 patients with psoriasis and PsA (N = 104). response in infliximab vs. placebo groups:
[87] 65% vs. 10%, (P<0.001), and significantly
greater improvement in dactylitis score from
baseline in the Infliximab vs. placebo groups:
85% vs. 29%, (P<0.001) were found.
Similarly, significant lower proportion of
enthesitis (14% vs. 31%, P=0.021) and
significant greater PASI75 response (68% vs.
0%, P<0.001) in the infliximab vs. placebo
groups were found at week 16.
Reich et al. 12-week RCT of certolizumab 200mg, At week 12, significantly greater PASI75
2012 [99] 400mg vs. placebo in patients with response in certolizumab vs. placebo groups
psoriasis (N = 176). was noted: 75% (200mg) vs. 83% (400mg) vs.
7% (placebo), P<0.001.
Also, at week 12, significantly greater PGA
score of clear/almost clear psoriasis was found
in the active medication groups: 53% (200mg)
vs. 72% (400mg) vs. 2% (placebo).
Mease et al. 24-week RCT of certolizumab 200mg, At week 12, the ACR20 response was
2014 [100] 400mg vs. placebo in patients with significantly increased in the certolizumab vs.
psoriasis and PsA (N = 409). placebo arms: (58.0% (200mg) vs. 51.9%
(400mg) vs. 24.3% (placebo), P<0.001.
At week 24, significantly greater PASI75
response was encountered in the certolizumab
group vs. placebo: 62.2% (200mg) vs. 60.5%
(400mg) vs. 15.1% (placebo), P<0.001; there
were similar findings for enthesitis
improvement: -2.0 (200mg). vs. -1.8 (400mg)
vs. -1.1 (placebo) (P<0.01, P<0.03,
respectively) and dactylitis improvement: -
40.7 (200mg) vs. -53.5 (400mg) vs. -22.0
(placebo) (P=0.02 and P<0.01, respectively)
Kavanaugh 24-week RCT of golimumab 50mg, At week 24, there was a significant decrease in
and Mease, 100mg vs. placebo in patients with PsA-modified MASES enthesitis score in the
2012 [111] psoriasis and PsA (N = 405). active medication group: 46% (50mg),
P<0.001. vs. 52% (100mg), P<0.001. vs. 13%
(placebo), and difference in dactylitis score:
66% (50mg), P=0.09. vs. 82% (100mg),
P<0.001. vs. 28% (placebo).

IL12/IL23 Inhibition
Leonardi 76-week RCT of ustekinumab 45mg, At week 12, significantly greater PASI75 score
et al. 2008 90mg vs. placebo in patients with was recorded in the ustekinumab vs. placebo
[118] psoriasis (N = 766). groups: 67.1% (45mg) vs. 66.4% (90mg) vs.
3.1% (placebo), P<0.0001
PASI75 score was better maintained at 1 year in
the treatment arm, (P<0.0001).
Rich et al. 76-week RCT of ustekinumab 45mg, At week 24, significantly greater NAPSI score
2014 [120] 90mg vs. placebo in patients with was found in the ustekinumab vs. placebo
psoriasis (N = 766). groups: 26.7% (45mg) vs. 24.9% (90mg) vs.
11.8% (placebo), (P<0.001).
Young 12-week RCT of ustekinumab 45mg, At week 12, PASI75 response improved
et al. 2011 90mg vs. etanercept in patients with significantly in the ustekinumab vs. etanercept
[129] psoriasis (N = 903). groups: 67.5% (45mg) vs. 73.8% (90mg) vs.
56.8% (etanercept).
McInnes, 52-week RCT of usekinumab 45mg, At week 24, a significantly greater proportion of
et al. 2013 90mg vs. placebo in patients with patients achieved ACR20 response in the
[122] psoriasis and PsA (N = 615). ustekinumab vs. placebo groups: 42.4% (45mg),
49.5% (90mg) vs. 22.8% (placebo), (P<0.0001).
At the same time point, there was significant
decreased in dactylitis score: 56.6% (45mg) vs.
76.1% (placebo), P=0.005, and 55.8% (90mg)
vs. 76.1% (placebo), P=0.0038; significant
decrease in enthesitis scores: 68.6% (45mg) vs.
81.0% (placebo), P=0.019. 60.8% (90mg) vs.
81.0% (placebo), P<0.0001; and significantly
higher proportion of PASI75 response: 57.2%
(45mg), 62.4% (90mg) vs. 11.0% (placebo),
(P<0.0001).
T cell co-stimulatory blockade
Mease 6-month RCT of abatacept vs. placebo at At week 24, ACR20 response was achieved by
et al. 2011 doses of 3 mg/kg, 10 mg/kg, or 30/10 19%, 33%, 48%, and 42% in the placebo, the
[148] mg/kg (2 initial doses of 30 mg/kg, abatacept 3 mg/kg (P=0.121), 10 mg/kg
followed by 10 mg/kg). (P=0.006), and the 30/10 mg/kg (P=0.022)
groups respectively.
Phosphodiesterase 4-Inhibitors
Schett 12-week RCT of apremilast 20 mg BD, At week 12, 43.5% of patients receiving
et al. 2012 40 mg OD vs. placebo, followed by a apremilast 20 mg (P<0.001) and 35.8%
[152] 12-week treatment-extension phase. receiving 40 mg (P=0.002) achieved an ACR20
response vs. placebo (11.8%).
Kavanuagh et 24-week RCT of apremilast 20 mg BD At week 16, 31% of apremilast 20 mg BD group
al. 2013 [153] or 30 mg BD vs. placebo (N=504). (31%), and 40% of the apremilast 30 mg BD
group achieved ACR20 vs. placebo (19%)
(P<0.001).
IL17 Inhibition
Langley 52-week RCT of secukinumab 300mg, At week 12, a significantly greater proportion of
et al. 2014 150mg vs. placebo in patients with patients achieved PASI75 score in the
[134] psoriasis. N = 738. secukinumab group vs. placebo: 81.6%
52-week RCT of secukinumab 300mg, (300mg), 71.6% (150mg) vs. 4.5% (placebo),
150mg vs. etanercept in patients with (P<0.001).
psoriasis (N = 1306). At week 12, a significantly greater proportion of
patients achieved PASI75 score in the
secukinumab vs. etanercept group: 77.1%
(300mg), 67.0% (150mg) vs. 44.0%
(etanercept).

of patients (N)
Mease 52-week RCT of secukinumab 75mg, At week 24, a significant greater proportion of
et al. ACR 150mg vs. placebo in patients with patients fulfilled the ACR20 response criteria in
2014 [138] psoriasis and PsA (N = 606). the secukinumab vs. placebo groups: 50.5%
(75mg), 50.0% (150mg) vs. 17.3% (placebo),
(P<0.0001).
Papp et al. 12-week RCT of brodalumab 70mg, At week 12, more patients achieved PASI75
2012 [142] 140mg, 210mg vs. placebo in patients response in the brodalumab groups vs. placebo:
with psoriasis (N = 198). 45.0% (70mg), 85.9% (140mg), 86.3% (210mg)
vs. 16.0% (placebo), (P<0.001).
Mease 12-week RCT of brodalumab 140mg, At week 12, more patients achieved ACR20
et al. 2014 280mg vs. placebo in patients with responses in the brodalumab groups vs. placebo:
[144] psoriasis and PsA (N = 168). 37% (140mg), vs. 18% (placebo), P=0.03. 39%
(280mg) vs. 18% (placebo), P=0.02. However,
at week 12, there was no significant difference
in the enthesitis and dactylitis scores.
At week 12, the Psoriasis Symptom Inventory,
BASDAI, SF-36 physical component scores
significantly improved in the brodalumab group
(280mg) vs. placebo.
Leonardi et al. 12-week RCT of ixekizumab 10mg, At week 12, a greater proportion of patients
2012 [145] 25mg, 75mg, 150mg vs. placebo in achieved PASI75 score in the ixekizumab vs.
patients with psoriasis and PsA placebo groups, except for lowest (10mg) dose:
(N = 142). 82.1% (150mg), 82.8% (75mg), 76.7% (25mg)
vs. 7.7% (placebo), P<0.001
Similarly, at week 12, a significantly greater
PASI90 score was noted for the 25mg, 75mg,
150mg ixekizumab doses vs. placebo.
Langley 20-week RCT of ixekizumab 10mg, At week 20, scalp psoriasis had significantly
et al. 2015 25mg, 75mg, 150mg vs. placebo in improved from baseline for the ixekizumab 25
[146] patients with nail psoriasis (N = 58), in and 75 and 150mg groups vs. placebo.
patients with scalp psoriasis (N = 105). Similarly, NAPSI scores improved significantly
in the ixekizumab 75mg and 150mg groups vs.
placebo.
IL6 Inhibition
Sieper 12-week RCT of tocilizumab vs. placebo At week 12, the ASAS20 response rates were
et al. 2012 in AS (N = 102). 37.3% and 27.5% in the tocilizumab group vs.
[147] placebo (P=0.2823).
T-Cell Modulators
Krueger 24-week RCT of alefacept 7.5 mg IVS. At week 24, PASI 75 score was achieved by
et al. 2002 or placebo in patients with psoriasis 28% of alefacept-treated and 8% of placebo-
[163] (N = 553) treated patients (P<0.001).
Lebwohl 24-week RCT of 10 mg or 15 mg of At week 24, PASI 75 score improved
et al. 2003 alefacept once weekly for 12 weeks vs. significantly (P<0.001) in patients receiving 15
[164] placebo, followed by 12 weeks of mg of alefacept (33%) or 10 mg of alefacept
observation. (28%), compared to the placebo group (13%).
Mease 24-week RCT of alefacept and MTX (N At week 24, 54% of patients in the alefacept
et al. 2006 = 123) or placebo and MTX plus MTX group achieved an ACR20 response,
[167] (N =62) in patients with psoriasis. compared with 23% of patients in the placebo
plus MTX group (P<0.001).
Gordon 24-week RCT of 12 weekly At week 24, 27% of efalizumab-treated patients
et al. 2003 subcutaneous efalizumab, 1 mg/kg achieved PASI-75 score vs. 4% of the placebo
[169] (N = 369) vs. placebo (N = 187) group (P<0.001).
Menter 12-week RCT of efalizumab At week 12, efalizumab-treated patients showed
et al. 2004 1.0 mg/kg/week vs. placebo in patients significant improvement in patient-reported
[183] with psoriasis. outcomes, as measured by DLQI
(P<0.001), psoriasis severity (P<0.001),
psoriasis frequency (P<0.001), and psoriasis itch
(P<0.001) scores.

Papp et al. 24-week RC of efalizumab 1 mg/kg At week 12, 28% of efalizumab-treated patients
2007 [168] weekly or placebo for 12 weeks, achieved ACR-20 response, compared with 19%
followed by 12 additional weeks of of placebo patients (P=0.27).
open-label efalizumab in PsA patients
(N = 115).
Janus Kinase Inhibitors
Papp et al. 12-week RCT of tofacitinib 2mg, 5mg, At week 12, a significant higher PASI75
2012 [180] 15mg vs. placebo in patients with response was achieved for all active treatment
psoriasis (N = 197). groups vs. placebo: 25.% (2mg), 40.8% (5mg),
66.7% (15mg), 2.0% (placebo), (P<0.0001).
Menter et al. 12-week RCT of tofacitinib 2mg, 5mg, At week 12, a significantly greater proportion of
2014 [181] 15mg vs. placebo in patients with patients achieved PASI scores in all active
psoriasis (N = 197). treatment groups vs. placebo in all body regions
(head/neck, upper limbs, trunk, lower limbs),
(P<0.001).
Anti-CD20
Jimenez-Boj et 6-month open label study of rituximab in At week 24, 56% patients achieved the primary
al. 2012 [179] patients with psoriasis and PsA endpoint, which was 30% improvement by
(N = 9). PsARC, 33% of patients achieved ACR20
response criteria, 44% improved their dactylitis
scores, but there was no improvement in the
enthesitis, and also there was no significant
difference in the BASDAI score compared to
baseline: 6.3+/-2.2; 5.9+/-3.0, (P=0.57).
Legend: ACR20,50,70 American College of Rheumatology response criteria; AS ankylosing spondylitis; BASDAI
Bath Ankylosing Spondylitis Disease Activity Index; BD twice daily; DLQI Dermatology Quality of Life Index;
MTX methotrexate; NAPSI Nail Psoriasis Severity Index; PASI Psoriasis Area Severity Index; PGA
physician global assessment; PsA psoriatic arthritis; PsARC Psoriatic Arthritis Response Criteria; RCT
General Considerations
Clinicians have many therapeutic options at present and data about direct comparisons
between all these agents are relatively lacking. However, as discussed above, there is
evidence from head-to-head RCTs that secukinumab and ustekinumab had greater efficacy
than etanercept in treating psoriasis. Alefacept induced sustained treatment benefit for a drug-
free follow-up period of 12 weeks in patients with psoriasis (suggesting the possibility of
intermittent treatment regimens), and itolizumab (a humanised anti CD6 monoclonal antibody
tested only in psoriasis, but no in PsA) was associated with very prolonged drug-free
remission [188].
An indirect comparison between the percentage of patients achieving ACR20 response
criteria when treated with different biologic agents showed the following figures:
ustekinumab 90 mg, 42%; secukinumab 300 mg, 54%; brodalumab 280 mg, 64%: abatacept
10 mg/kg, 48%; apremilast 20 mg daily, 43.5%, which is comparable to infliximab 5 mg/kg,
65%; certolizumab 200 mg e.o.w., 58%; golimumab 100 mg monthly, 61%; adalimumab
58%, etanercept 25 mg twice weekly, 59%). TNF inhibitors, ustekinumab and secukinumab
have been effective in controlling symptoms of dactylitis and enthesitis. Patients with PsA
and axial involvement also responded to therapy with ustekinumab and secukinumab (in
addition to TNF inhibitors), and the nail involvement associated with psoriasis also improved
with treatment with apremilast and sekukinumab (along with all the licensed TNF inhibitors).
The need to optimise the therapy of patients who failed TNF inhibitors is one of the main
challenges that clinicians face. In order to maximise their chance to respond to subsequent
biologic therapies, different strategies of doses optimisation were employed in clinical trials
(e.g., in a clinical trials with secukinumab, the intravenous loading dose and use of the 300
mg monthly dose was associated with best response in PsA patients who failed TNF
inhibitors).
Recent data from the NOR-DMARD cohort showed that the response to the second TNF
inhibitor, in patients with PsA who failed the first anti-TNF, is significantly lower [70]. In
consequence, it was hypothesised that switching to another biologic treatment with a
completely different mechanism of action is a more suitable option. In comparison with RA,
and in both AS and PsA, the retention rates of first anti-TNF treatment and the response to the
second TNF inhibitor are higher, although these are decreased compared to the first anti-TNF
[189]. Therefore, the switch to the second TNF might therefore be recommended in most
cases when no other (biologic) treatments are available.
Table 2 includes a summary of evidence of efficacy of different biologic treatments for

different clinical manifestations in PsA and psoriasis. The data is presented using the Oxford
Centre of Evidence-based Medicine classification:
1a Systematic reviews (with homogeneity) of randomised controlled trials

1b Individual randomised controlled trials (with narrow confidence interval)
1c All or none randomised controlled trials
2a Systematic reviews (with homogeneity) of cohort studies
2b Individual cohort study or low quality randomised controlled trials (e.g., <80%
follow-up)
2c Outcomes Research; ecological studies
3a Systematic review (with homogeneity) of case-control studies
3b Individual case-control study
4 Case-series (and poor quality cohort and case-control studies)
5 Expert opinion without explicit critical appraisal, or based on physiology, bench
research or first principles
Table 2. Biologic treatments effectiveness in relation to various disease manifestations

(* = level of evidence)
Skin psoriasis
involvement
Sacroiliitis
Peripheral
and spinal
Enthesitis
Dactylitis
arthritis
disease
Nail
Treatment
ABATACEPT NO (*1b) YES (*1b) YES

Only AS (*1b)
studies
ADALIMUMAB YES (*1a) YES (*1a) YES
(*1a)
Table 2. (Continued).
Peripheral arthritis
Nail involvement
Sacroiliitis and
Skin psoriasis
spinal disease
Enthesitis
Dactylitis
Treatment
ALEFACEPT YES
(*1a)
APREMILAST YES (*1a) YES (*1b) YES (*1b) YES (*1b) YES
(*1a)
BRODALUMAB YES (*1b) YES (*1b) NO (*1b) NO (*1b)
CERTOLIZUMAB YES (*1a) YES (*1a) YES (*1a) YES (*1a) YES (*1a) YES
(*1a)
EFALIZUMAB NO (*1b) YES
(withdrawn) (*1a)
ETANERCEPT YES (*1a) YES (*1a) YES (*1a) YES (*1a) YES (*1a) YES
(*1a)
GOLIMUMAB YES (*1a) YES (*1a) YES (*1a) YES (*1a) YES (*1a) YES
(*1a)
INFLIXIMAB YES (*1a) YES (*1a) YES (*1a) YES (*1a) YES (*1a) YES
(*1a)
ITOLIZUMAB Planned Planned Planned Planned Planned YES
studies studies studies studies studies (*1b)
IXEKIZUMAB Ongoing Ongoing Ongoing Ongoing YES
(*1a)
RITUXIMAB NO (*1b) NO (*1b) YES (*1b)
SECUKINUMAB YES (*1a) YES (*1a) YES (*1a) YES (*1a)
TOCILIZUMAB NO (*1b) YES (*4) YES
(*4)
TOFACITINIB Ongoing Ongoing Ongoing Ongoing YES
(in AS) (*1a)
USTEKINUMAB YES (*1b) YES (*1a) YES (*1b) YES (*1b) YES
(*1a)
CONCLUSION
In summary, this chapter highlighted that the number of biologic treatments for PsA and
psoriasis increased significantly in the recent years. Also the small molecule inhibitors might
be the next treatments licensed for PsA, taking into consideration their cost and oral
administration. Given the heterogeneity of clinical features of both PsA and psoriasis,
clinician should tailor the treatment options based on local policies and assessment of
individual patient cases. Further research into both prognostic biomarkers and patient
stratification is required to allow clinicians the possibility to make better use of the various
biologic treatment options available.
ACKNOWLEDGMENTS
The authors would like to thank Dr. Sanziana Micu, Rheumatologist, Centre Hospitalier
de Sens, France, for reviewing the chapter (email: sinziana.micu@gmail.com)
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Chapter 14
BIOLOGICS IN JUVENILE IDIOPATHIC ARTHRITIS
Charalampia Papadopoulou1 and Nicola Ambrose, PhD2,*

1Institute of Child Health, University College London, UK
2Department of Rheumatology, University College London Hospital, and Arthritis
Research UK Centre for Adolescent Rheumatology, University College London, UK
ABSTRACT
The advent of biological drugs has revolutionised the management of paediatric
rheumatologic diseases, primarily juvenile idiopathic arthritis (JIA). The general
treatment goals of JIA now include remission or low disease activity, and normalization
of joint function, to preserve normal growth and development, and to prevent long-term
joint damage and deformities. While efficacy is established, our knowledge of possible
long-term risks of these treatments is still lacking. This chapter summarises the evidence
for current and some possible future biologics for the treatment of JIA.
Keywords: juvenile idiopathic arthritis, biologic therapy, clinical trials
INTRODUCTION
Juvenile idiopathic arthritis (JIA) is the most common type of chronic arthritis in
childhood with an incidence of 2 to 20 cases per 100,000 children and a prevalence of 16 to
150 cases per 100,000 children worldwide [1]. The term JIA was introduced in 1994 and has
largely replaced the older terms juvenile rheumatoid arthritis (JRA, used commonly in the
United States) and juvenile chronic arthritis (JCA, preferred in Europe). JIA is a diagnosis of
exclusion, which is defined by the International League of Associations for Rheumatology
(ILAR) as arthritis with no apparent cause that begins before the age of 16 years, and persists
*
Corresponding author: Dr. Nicola Ambrose, Consultant Rheumatologist, Department of Rheumatology, 3rd Floor
Central, 250 Euston Road, University College London Hospital, London, NW1 2PG, UK, email:
nicola.ambrose@uclh.nhs.uk.
348 Charalampia Papadopoulou and Nicola Ambrose
for at least 6 weeks [2-4]. Although some types of JIA share similarities with adult-onset
arthritis, JIA is a distinct entity with distinct genetics, clinical course and co-morbidities [5].
JIA occurs in the context of the growing and developing child and can disrupt growth,
and adversely affect the joints resulting in permanent joint damage and long-term functional
limitation and disability [1]. The disease can be active years after onset, and in at least 60% of
cases, it persists into adulthood, dispelling the notion that children can outgrow JIA [6, 7].
JIA is a wide term, which covers a number of different subtypes. Seven mutually
exclusive subtypes of JIA are recognised with differences in clinical presentation, course,
prognosis, and response to treatment with disease-modifying drugs (DMARDs): systemic
arthritis, oligoarthritis, polyarthritis (rheumatoid factor negative), polyarthritis (rheumatoid
factor positive), psoriatic arthritis, enthesitis related arthritis, and undifferentiated arthritis [8,
9] (Table 1). As the understanding of the pathophysiology of childhood arthritis remains
limited, by necessity the JIA classification was based largely on clinical findings, family
history, and in some cases, information from specific laboratory tests (rheumatoid factor, anti-
nuclear antibodies, HLA-B27). Drug therapy is dependent upon the number and type of joints
involved, as well as the presence of any systemic symptoms and extra-articular
manifestations.
Definitions
To understand results from clinical trials, it is important to understand the term

American College of Rheumatology Pediatric (ACR Pedi) responses (30, 50, 70 or 90),
which are used in most trials. They are defined as at least a 30, 50, 70, or 90% improvement
from baseline in 3 out of any 6 core set variables, with no more than one of the remaining
variables worsening by >30, 50, 70 or 90%, respectively. Despite being used in clinical trials,
these core sets have not been adopted into clinical practice [10].
Table 1. Subtypes of JIA
Subtype % of all female: male Features Peak onset, years

Oligoarticular ~50 3:1 4 joints in first 6 months 2-6
Persistent Oligoarticular
Remains 4 joints
Extended Oligoarticular
Extends to > 5 joints after 6 months
Poly-articular ~30 3:1 5 joints in first 6 months, 6-7
RF negative RF negative
Poly-articular ~10 9:1 5 joints in first 6 months, 8-12
RF positive RF positive
Enthesitis-related ~10 1:7 Enthesitis, HLA-B27 in 8-12
Arthritis approximately 50%
Psoriatic Arthritis ~10 2:1 Psoriasis/dactylitis; Two peaks; 3-5
psoriasis in first degree and 10-12
relative
Systemic Arthritis ~10 1:1 Rash, fever, other organ 2-4
involvement
Legend: HLA human leucocyte antigen; RF Rheumatoid factor.
Biologics in Juvenile Idiopathic Arthritis 349
A major recent advance is the definition and clinical validation of disease activity in
children with JIA [11, 12]. Disease activity in JIA includes the following categories:
remission off medication, remission on medication, clinical inactive disease (CID), minimal
disease activity, acceptable symptom state and active disease (Table 2). The Wallace criteria
define CID in the absence of active joints, uveitis and systemic symptoms with a normal C-
reactive protein (CRP) and erythrocyte sedimentation rate (ESR), a physician global
assessment of 0 and morning stiffness for less than 15min [11]. Recently, the 3-variable
version of the Juvenile Arthritis Disease Activity Score (JADAS) was introduced based on
which the states of inactive disease (ID) and low disease activity (LDA or minimal disease
activity), moderate disease activity (MDA), and high disease activity (HDA) were defined
[12-15]. It is worth noting that the adult disease activity score (DAS) underestimates disease
activity in JIA as it does not include the temporomandibular joint [16].
Several treatment targets were developed to assess the efficacy of different treatments in
JIA (Table 2).
Table 2. Defining treatment targets in JIA
Clinically inactive disease (Wallace criteria)

No joints with active arthritis
No fever, rash, serositis, splenomegaly or generalised lymphadenopathy attributable to JIA
No active uveitis according to standardization of uveitis nomenclature criteria
ESR or CRP level within normal limits
Best possible score on PGA of disease activity
Duration of morning stiffness <15 min
Clinical remission on medication (Wallace criteria)
Clinically inactive disease for 6 months on therapy
Clinical remission off medication (Wallace criteria)
Clinically inactive disease for 12 months off therapy
Clinical remission (JADAS)
JADAS cut-off = 1
Minimal disease activity (JADAS)
Oligoarthritis: JADAS cut-off = 2
Polyarthritis: JADAS cut-off = 3.8
Acceptable symptom state (JADAS)
Oligoarthritis: JADAS cut-off = 3
Polyarthritis: JADAS cut-off = 4.3
Low disease activity (ACR)
One or no active joints
ESR or CRP level normal
PGA of overall disease activity score <3 on a scale of 010
Patient or parent global assessment of overall well-being score <2 on a scale of 010
Adapted from [17]
Legend: ACR - American College of Rheumatology; CRP - C-reactive protein; ESR - erythrocyte
sedimentation rate (mm/h); JADAS - Juvenile Arthritis Disease Activity Score; JIA - juvenile
idiopathic arthritis; PGA - physician global assessment
Aim of Treatment
Studies in adults with rheumatoid arthritis (RA) have shown that patient outcomes are
improved when aiming for minimal levels of disease activity by frequently adjusting therapy
according to quantitative indices (treat to target) [18, 19]. Moreover, the strategy of tight
control, aiming for remission, appears more important than the therapeutic agent itself [20].
Improved outcomes have been therefore demonstrated, when aggressive treatment is started
early in the disease course [21-23]. Many rheumatologists believe there is a window of
opportunity early in the disease during which aggressive therapy has a profound long-term
effect.
Based on those findings, the paediatric rheumatology community has recently considered
whether this also applies to JIA. In recent studies, an early response to methotrexate (MTX) at
6 months predicted better long-term outcome [24], while achieving inactive disease at least
once within 5 years from disease onset also predicted less joint damage [25]. The Aggressive
Combination Drug Therapy in Very Early poly-JIA (ACUTE-JIA) trial published in 2011
demonstrated greater efficacy of infliximab plus MTX than MTX alone. Among the most
clinically important findings were striking differences in the time spent in an inactive versus
an active state of disease when early biological therapy was compared with that of a DMARD
combination [26]. Similarly, the Trial of Early Aggressive Therapy in poly-JIA trial (TREAT)
found that the only predictor of achievement of CID was disease duration at onset of
treatment, while subsequent analysis suggested that more aggressive therapy result in a higher
probability and longer duration of CID in patients with poly-JIA [27, 28].
Treatment
The aim of drug therapy in patients with JIA is to induce and maintain remission or low
disease activity, to allow a child to achieve normal growth, development, and allow full
participation in school, career, sport and all other aspects of normal life. While most children
do very well overall with this condition, quality of life can be significantly affected, as a
consequence of associated joint damage that can results in pain and disruption of daily tasks
and activities, and as a consequence of the bio-psycho-social aspects of being a child with a
chronic illness. Early pharmacological and non-pharmacological treatment of the disease is
imperative for the prevention of irreversible soft tissue and joint damage [29, 30].
Pharmacological interventions for JIA include non-steroidal anti-inflammatory drugs
(NSAIDs), DMARDs, biologics, and glucocorticoids (GCs) (as both systemic treatment and
now more commonly through intra-articular injection) [30]. Non-pharmacological
interventions, such as physiotherapy interventions (e.g., therapeutic exercises, massage),
podiatrist and occupational therapist input when required, may help patients maintain their
joint range of motion and functional status while also contributing to maintenance of an
increase in bone mineral density, and ultimately to the prevention of osteopenia [31, 32]. This
combined multi-disciplinary approach to care is essential for overall better management of
symptoms and leads to better ultimate outcomes.
Intra-articular corticosteroid (IAC) injections are widely used in the management of JIA
to induce rapid relief of symptoms of active synovitis, particularly pain and functional
impairment, and to obviate the need for regular systemic therapy [1, 33, 34]. This mode of
therapy is generally considered for the treatment of children with arthritis affecting a small
number of joints, particularly large joints, or in children with a poly-articular course who are
responding to systemic therapy but have a few joints that remain actively inflamed. Currently,
many paediatric rheumatologists use IACs as their first approach in oligo-articular JIA [35-
39]. In recent years, the strategy of performing IAC injections in multiple joints has been
advocated in children with poly-articular JIA with the aim of inducing prompt remission of
synovitis, while simultaneously initiating therapy with DMARDs and/or biologic agents [40-
42].
Methotrexate (MTX) has been the first conventional DMARD with marked efficacy in
several categories of JIA [43] for over 30 years. Despite the recent advances in
pharmacotherapy, MTX remains an important cornerstone of therapy for JIA and is used
extensively both as mono- and combination therapy worldwide, while sulfasalazine has been
proven effective in HLA-B27-associated enthesitis-related arthritis patients. In general, for
children with JIA, MTX therapy is started at a dose of 1015 mg/m2/week. A proportion of
6075% of patients with JIA benefit significantly from MTX therapy, with the maximum
therapeutic effect usually becoming apparent 46 months after the beginning of treatment,
while another 3545% of patients fail to respond [28, 44]. MTX is possibly not that effective
for the treatment of enthesitis-related arthritis, where axial arthritis is a prominent feature,
although this has not been proven through trials [45].
Biologic Treatments
Since 1999, the treatment of JIA has been extended with a new category of drugs called
biologic agents. Biologic agents are genetically engineered drugs designed to target specific
areas of the immune system and selectively block inflammatory pathways implicated in
disease processes. They include monoclonal antibodies, soluble cytokine receptors and
recombinant receptor antagonists (summarised in Table 3).
In JIA, the efficacy of biologic therapies has been shown in a number of clinical trials
made possible through multicentre international collaboration. In addition, there are several
reports of the safety and efficacy of biologics in a range of other inflammatory conditions.
Biologic therapies while demonstrating significant efficacy, have also been linked to rare
but severe adverse events such as lymphoma, serious infections, demyelination and
hepatotoxicity. Young people may have different susceptibility to such effects, given the
changes occurring during childhood and adolescence, with rapid growth and development.
All biological agents currently are administered by subcutaneous injection or intravenous
infusion, having particular implications for paediatric use.
The evidence for many of the treatments used in paediatric rheumatology and especially
in adolescents is incomplete and further research is needed. There are no studies of
withdrawal of biological therapies and most use is long-term highlighting the importance of
registries to document long-term safety. Moreover, the majority of the clinical trials have
been limited to include only patients with systemic and polyarticular JIA and thus findings
may not be relevant to those with other subtypes.
Table 3. Biologic agents currently used in paediatric rheumatology
Biologic Agent Mode of action Administration Doses Current indications Licensed indications
Abatacept Humanised IV infusion over 30 10mg/kg at 0,2,4 weeks, Polyarticular-JIA; JIA In USA and EU for moderately
selective min. then every 4 weeks, max associated uveitis to severely active JIA 6 years
T cell co- dose 1gr
stimulatory
modulator
Adalimumab Humanised soluble SC 24mg/m2 up to 40 every 2 Polyarticular-JIA4 years, EMA licensed for refractory
anti-TNF weeks JIA associated uveitis, polyarticular-JIA in 2-17 years
monoclonal systemic vasculitis, age
antibody CRMO/SAPHO
Anakinra Humanised anti-IL1 SC 2mg/kg daily SoJIA, CAPS, In USA for NOMID
receptor antagonist CRMO/SAPHO
Canakinumab Human anti-IL1 SC 2-4mg/kg 8-weekly CAPS EMA licensed for CAPS 2
monoclonal 4mg/kg 4-weekly, SJIA SoJIA years. In USA also for SoJIA
antibody 2 years
Etanercept Human tumour SC 0.4mg/kg twice a week or Polyarticular-JIA, ERA, PsA, NICE approval
necrosis factor 0.8mg/kg once a week extended oligo JIA, Systemic
(TNF) receptor p75 max. dose 50mg/week vasculitis, CRMO/SAPHO Licensed for >2 years in EU
Fc fusion protein and USA
Infliximab Chimeric human- IV infusion 6 mg/kg at 0, 2, 6 weeks, Polyarticular-JIA, JIA Off label
murine anti-TNF then every 4-8 weeks associated uveitis, refractory
IgG1 monoclonal according to response JDM, Kawasaki disease,
antibody Systemic vasculitis, PsA,
ERA, CRMO/SAPHO
Rilonacept Dimeric fusion SC Initially 4.4 mg/kg, up to a CAPS 12 years In EU and USA for CAPS
protein of IL1R1 maximum of 320 mg. SoJIA 12years
and IL1RAcP Dosing should be continued
linked in-line to the with a once-weekly
Fc portion of human injection of 2.2 mg/kg, up
IgG1 to a maximum of 160 mg
Biologic Agent Mode of action Administration Doses Current indications Licensed indications
Rituximab Chimeric anti-CD20 IV infusion 750mg/m2 on day 0-14 JSLE, SoJIA, Off label
monoclonal (given with 100mg Refractory polyarticular-JIA,
antibody methylprednisolone and Systemic vasculitis,
often cyclophosphamide) Refractory JDM
Tocilizumab Humanised IV infusion 30 kg: 8 mg/kg once SoJIA, refractory FDA and EMA approved for
recombinant anti- every 2 weeks, polyarticular-JIA SoJIA and refractory
IL-6 receptor BW <30 kg: 12 mg/kg polyarticular-JIA 2years
monoclonal once every 2 weeks
antibody NICE approved for
SoJIA2years
Phase III clinical trials
Certolizumab Polyethylene 10 to < 20 kg: Polyarticular-JIA Not currently available in UK
glycol-lated Fab loading dose = 100 mg
fragment of a every 2 weeks;
humanised anti- treatment dose = 50 mg
TNF antibody every 2 weeks
20 to < 40 kg:
loading dose = 200 mg
every 2 weeks;
treatment dose = 100 mg
every 2 weeks
40 kg:
loading dose = 400 mg
every 2 weeks;
treatment dose = 200 mg
every 2 weeks
Golimumab Humanised SC 30 mg/m2 every 4 weeks Refractory Polyarticular-JIA Not currently available in UK
monoclonal anti-
TNF antibody
Legend: IV - intravenous; SC - subcutaneous; JIA - Juvenile Idiopathic Arthritis; EU - European Union; TNF - Tumour Necrosis Factor; CRMO/SAPHO - Chronic Recurrent
Multifocal Osteomyelitis/Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis syndrome; EMA - European Medicines Agency; IL - Interleukin; SoJIA - Systemic onset
Juvenile Idiopathic Arthritis; CAPS Cryopyrin associated Periodic Syndromes; NOMID - Neonatal Onset Multisystem Inflammatory Disease; ERA - Enthesitis Related
Arthritis; PsA - Psoriatic Arthritis; JDM - Juvenile Dermatomyositis; IL1R1 - IL1 receptor type 1; IL1RAcP - IL1 receptor accessory protein; JSLE - Juvenile Systemic
Lupus Erythematosus; FDA - Food and Drug Administration; NICE - The National Institute for Health and Care Excellence. Adapted from [46].
It has been identified that adolescents with JIA face challenges when transitioning from
paediatric to adult. It is important when transferring patients to adult care that a clear plan is
in place including for the chosen biologic agent to ensure that there will be no interruption in
the provision of established treatment.
Selecting Patients for Treatment
The choice of biologic agent may be customised for every patient to include
considerations of co-morbidities or the need for concomitant drug treatment. Some of the
factors that influence the choice of biologic therapy include age of the patient; disease type;
patient characteristics and comorbidities; previous therapies and adherence; drug availability;
potential for self-administration by the young person or their parents/carers; and the familys
level of social support and their home circumstances.
There are currently several possible alternative options for licensed biologic therapies
(see Table 3). The UK the National Institute for Health and Clinical Excellence (NICE) have
provided guidance on the use of etanercept and tocilizumab biologic agents in JIA. It is
important however, to acknowledge that in practice, many patients in the UK under the age of
16 are being treated with other biologic therapies such as adalimumab, abatacept, infliximab
and rituximab, all of which are currently used as unlicensed drugs.
Initiation of treatment with biologics should only be undertaken at a specialist centre, and
should always involve a consultant paediatric/adolescent rheumatologist and a
paediatric/adolescent-trained Clinical Nurse Specialist (CNS). Management will also involve
a paediatric ophthalmologist for screening for and treatment of uveitis.
Tumour Necrosis Factor (TNF) Inhibitors
TNF was first described by Lloyd Old et al. in 1975 as an endotoxin-induced

glycoprotein, which caused haemorrhagic necrosis of solid tumours [47]. TNF is released as
a soluble cytokine after being enzymatically cleaved from its cell-surface-bound precursor by
TNF-converting enzyme. TNF is produced by numerous cell types, including immune cells
(B cells and T cells, basophils, eosinophils, dendritic cells, natural killer cells, neutrophils and
mast cells), non-immune cells (astrocytes, fibroblasts, glial cells, granuloma cells and
keratinocytes) and many kinds of tumour cells [48, 49].
TNF is a potent inducer of the inflammatory response, a key regulator of innate
immunity, and plays an important role in the regulation of Th1 immune responses against
intracellular bacteria and certain viral infections [50, 51]. However, dysregulated TNF can
also contribute to numerous pathological situations.
The biological activity of TNF is triggered by binding to one of two structurally distinct
receptors: TNF receptor type I (TNFRI) and TNF receptor type II (TNFRII). TNFRI and
TNFRII are present in all cell types, except erythrocytes. The binding of TNF to its receptor
ultimately leads to activation of transcription factors that cause production of inflammatory
mediators and anti-apoptotic proteins. Once TNF was identified as a key player in the
spreading of inflammatory diseases, potential therapeutic implications of its blockade became

apparent. In 1998, the US Food and Drug Administration (FDA) announced the approval of a
new biologic agent, called etanercept, for the treatment of adults with rheumatoid arthritis.
This was the beginning of the biologics era in the treatment of rheumatological diseases in
both adults and children as followed by the development of other biologic agents.
The two modalities used for TNF inhibition involve soluble receptors (etanercept) and
antibodies (infliximab, adalimumab, golimumab, and certolizumab). Etanercept and
adalimumab are currently the only TNF inhibitors that are approved for use in JIA. Others
that are commonly used, and approved for use in adults with rheumatoid arthritis (RA), are
infliximab, golimumab and certolizumab as well as the biosimilars drugs.
In the 2011 ACR recommendations for JIA treatment, TNF inhibitors were recommended
in a number of situations: for patients with 4 or fewer active joints who had received
glucocorticoid joint injections and 3 months of methotrexate at the maximum tolerated
suggested dose and had moderate or high disease activity, and features of poor prognosis; for
patients who had received IACs and 6 months of MTX and had high disease activity even
without features of poor prognosis; for patients specifically with enthesitis-related arthritis
who had received IACs injections if appropriate and an adequate trial of sulfasalazine
(without prior MTX) and had moderate or high disease activity, irrespective of prognostic
features [52]; for polyarticular JIA in those who had received MTX or leflunomide for 3
months at the maximum tolerated typical dose and had moderate or high disease activity,
irrespective of poor prognostic features; and also for patients who have received methotrexate
or leflunomide for 6 months and still have high disease activity [5].
Switching from one TNF inhibitor to another is recommended as one treatment approach
for patients who have received a TNF inhibitor for 4 months and have ongoing moderate or
high disease activity.
Etanercept
Etanercept is a human tumour necrosis factor receptor p75 Fc fusion protein produced by
recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian expression
system. Etanercept is a dimer of a chimeric protein, genetically engineered by fusing the
extracellular ligand-binding domain of human tumour necrosis factor receptor-2
(TNFR2/p75) to the Fc domain of human IgG1. It binds to circulating TNF-a, preventing its
interaction with the cell surface receptor and subsequent activation of the inflammatory
cascade.
In May 1999, it was the first biologic agent to be FDA-approved for use in children 2
years old with moderate to severe polyarticular JIA [in 2000, the European Medicines
Evaluating Agency (EMA) followed]. This approval was based on a multicenter, double
blind, randomised controlled trial (RCT) of etanercept to have been conducted in children to
date [53]. In that withdrawal study, patients 4 to 17 years old received 0.4 mg of etanercept
per kilogram of body weight subcutaneously twice weekly for up to three months in the
initial, open-label part of the multicenter trial. Those who responded to treatment then entered
a double-blind study and were randomly assigned to receive either placebo or etanercept for
four months or until a flare of the disease happened. At the end of the open-label study, 74%
of patients achieved at least an ACR Pedi 30 while in the double-blind study, 81% of the
patients who received placebo withdrew because of disease flare compared with 28% of the
patients who received etanercept (P = 0.003). Moreover, those who continued on etanercept
had significantly longer time with no disease flare than those on placebo (median: 116 vs 28
days; p < 0.001) [53]. Several other studies also demonstrated the efficacy of etanercept in
JIA [54-56].
Since the above mentioned RCT included only patients with Poly-JIA, two other trials
investigated the efficacy of etanercept in patients with three JIA subtypes (oligo-extended,
enthesitis-related arthritis (ERA) and psoriatic arthritis (PsA), CLIPPER study) [57] and more
recently in ERA [58]. The CLIPPER study included 127 patients for evaluation of efficacy of
etanercept treatment in three JIA categories including extended oligoarticular JIA, ERA and
PsA. In both studies, etanercept proved effective.
Etanercept is a subcutaneous injection given at a dose of 0.8 mg/kg/week or 0.4 mg/kg
twice weekly (maximum 50 mg/week), with both having similar efficacy [59]. There is little
evidence regarding when to stop etanercept in JIA. A recent report based on data from 19 JIA
patients followed in the Dutch National Study suggested careful tapering of etanercept, and
that subsequent discontinuation should be considered in JIA patients who have been in
clinical remission on medications [60] for at least 1.5 years [61].
Adalimumab
Adalimumab is the recombinant IgG1 human monoclonal antibody consisting of 1330

amino acids. The drug is manufactured by recombinant DNA technology. It binds to p55 and
p75 receptors of soluble and membrane associated TNF. Adalimumab can activate the
complement system that results in lysis of cells with superficially located TNF. The drug
alters the levels of adhesion molecules that contribute to leukocytes migration (ELAM-1,
VSAM-1, and ICAM-1). Thus, it has increased efficacy due to both antibody and complement
dependent cytotoxicity.
Adalimumab was FDA approved in 2008 for use in poly-JIA based on a withdrawal study
of 190 active poly-JIA patients who had previously received NSAIDs with or without
methotrexate [62]. All patients received 24 mg/m2 (maximum 40 mg) of adalimumab
subcutaneously every other week for 16 weeks. Responders, those who achieved at least an
ACR Pedi 30 response, were randomised to continue adalimumab or subcutaneous placebo
for up to 32 weeks or until a flare of the disease. After 100 weeks of the open-label extension,
ACR Pedi 50 and 70 responses were achieved in 86% and 77% of patients, respectively.
Furthermore, 40% of patients achieved an ACR Pedi 90 at 16 weeks with a sustained
response at up to 170 weeks of follow-up. Adverse events were not common and usually
considered mild, such as infection and reactions at the injection site. Serious adverse events
probably related to adalimumab were present in 14 patients, including viral infections,
pharyngitis, and pneumonia.
In 2015, the results of a multicenter, randomised double-blind study in patients aged 6
to <18 years with ERA treated with adalimumab were published [63]. Forty-six patients were
randomised (31 adalimumab/15 placebo). The change in the number of active joints was
greater in the adalimumab group compared to the placebo group (P = 0.039) while there was
also significant improvement in other secondary variables suggesting that adalimumab
reduced signs and symptoms of ERA, with improvement sustained through week 52.
Despite its efficacy for treatment of arthritis, adalimumab is valuable also for chronic
recurrent anterior uveitis, which emerged in about 20% of JIA patients especially in
oligoarticular JIA, seronegative polyarthritis, and juvenile psoriasis arthritis. In an open trial,
16 of 18 patients with uveitis who had all failed systemic steroids, cyclosporine, MTX,
leflunomide, etanercept, or infliximab had good responses to adalimumab [64]. In another
retrospective study on 20 patients with chronic uveitis, of whom 19 were previously treated
with infliximab or etanercept, 7 showed improved activity, 1 worsening, while in 12 patients
there was no change in the activity of uveitis [65, 66]. These studies suggest that adalimumab
is a treatment option in JIA-associated uveitis. Up to now, only open uncontrolled trials have
indicated clinical usefulness while controlled trials are still ongoing [67].
Adalimumab is administered subcutaneously once every 2 weeks; the elimination half-
life of the drug is 2 weeks. The dosing is weight based: 10 mg for children weighing 10 to
<15 kg, 20 mg for children weighing 15 to <30 kg and 40 mg for children weighing 30 kg.
The frequency can sometimes be increased to weekly dosing for continued improvement. The
dosing is different in the EU. For children aged 212 years with polyarticular JIA, the dosing
is 24 mg/m2 (maximum dose of 20 mg for children aged <4 years and 40 mg for children of
age 412 years) given every other week. For children aged 1317 years, the dosing is 40 mg
given every other week. For children with ERA, the dosing is 24 mg/m2 (maximum dose 40
mg) given every other week [68].
Infliximab
Infliximab is a chimeric human-murine IgG1 monoclonal antibody produced in murine

hybridoma cells by recombinant DNA technology. It was marketed first for treatment of
rheumatoid arthritis in the late 90s. Despite the fact that infliximab has been shown to be an
effective drug in adult RA [69, 70], it is still not approved for the treatment of JIA.
In 2007, a multicenter, double blind, placebo-controlled study in poly-JIA did not reach
primary end point and therefore did not demonstrate superiority for treatment with infliximab
over placebo [71]. In this trial, patients were randomised to receive infliximab (3 or 6 mg/kg)
or intravenous placebo for 14 weeks, after which all patients received infliximab through
week 44. Patients were randomised to either one of two groups. Patients in Group 1 received
MTX plus infliximab through week 44. Patients in Group 2 received MTX plus placebo for
14 weeks, followed by MTX plus infliximab (6 mg/kg) through week 44. Although the
difference in ACR Pedi 30 at week 14 between placebo and 3 mg/kg infliximab was not
statistically significant (63.8% and 49.2%, respectively), after the 1 year open-label treatment
with infliximab, ACR Pedi 50 and 70 responses were achieved in 70% and 52% of patients,
respectively [71]. As infliximab did not achieve a statistically significant difference in its
primary endpoint of an ACR Pedi 30 at week 14 versus placebo, it did not receive FDA
approval for JIA.
A more recent study, in which children were randomised to receive either infliximab plus
MTX, or combination therapy of three conventional DMARDs, did favour infliximab therapy
[26]. The reasons for the discrepancy are unclear, although it could relate to the low numbers,
short trial duration, or low dosage used in the unsuccessful study, as well as the unusually
high placebo response rate in that study. Thus, all three of these TNF inhibitors are consider
viable options [72]. Furthermore, a recent systematic review showed that infliximab and
adalimumab provide similar benefits in the treatment of refractory chronic uveitis, and both
are superior to etanercept [73].
Doses of 610 mg/kg are recommended for children with JIA which is higher than doses
used in adults. It has recently been demonstrated that doses as high as 20 mg/kg/dose every
two weeks can be safely administered to children with JIA [74]. Concurrent use of MTX or
another DMARD is recommended to prevent the development of human antichimeric
antibodies, which appear to correlate with infusion reactions and decreased effectiveness [75].
Certolizumab Pegol
Certolizumab pegol is a recombinant, humanised antibody Fab' fragment against TNF

expressed in Escherichia coli and conjugated to polyethylene glycol (PEG). The purpose of
pegylation is to increase the drugs half-life. However, since it lacks an Fc portion, it does not
induce cell-mediated cytotoxicity, complement activation or apoptosis, like the other
monoclonal antibodies [76]. It is currently indicated for the treatment of moderate to severe
RA, axial spondylarthritis and psoriatic arthritis in adults with or without the concomitant use
of methotrexate. A multicenter, open-label study to assess the pharmacokinetics, safety and
efficacy of certolizumab pegol in children and adolescents with moderately to severely active
polyarticular-course JIA is still ongoing.
Golimumab
Golimumab is a completely humanised monoclonal anti-TNF antibody for subcutaneous

application binding both soluble and membrane-bound forms of TNF [77]. So far it is
approved for the treatment of rheumatoid arthritis and adult ankylosing spondylitis, while a
controlled multicentre trial in JIA (GoKids) is still ongoing. Some children, teenagers, and
young adults who received golimumab injection and similar concomitant medications
developed severe or life-threatening cancers including lymphoma. Some of them developed
hepatosplenic T cell lymphoma (HSTCL). Most of the people who developed HSTCL were
being treated for Crohn's disease or ulcerative colitis with golimumab along with azathioprine
or 6-mercaptopurine.
INHIBITION OF THE COSTIMULATORY PATHWAY

Abatacept
Abatacept is a soluble fusion protein consisting of the Cytotoxic T cell Lymphocyte

Antigen-4 (CTLA-4) fused with the Fc region of human IgG [78]. It competitively binds to
CD80/86 on antigen presenting cells with higher avidity than to CD28 on T cells, thereby
preventing the second signal required for T cell activation. This concept proved to be
effective for the treatment of rheumatoid arthritis [79]. So far, only one double-blind
randomised placebo-controlled study involving abatacept in children with JIA has been
published [80]. All children initially received intravenous abatacept (10 mg/kg) during the 4-
month open-label period, in addition to their prior stable dose of methotrexate. Children who
achieved an ACR Pedi 30 were randomised to abatacept or placebo for the following 6
months or until disease flare. Patients on abatacept had fewer flares of arthritis than placebo,
20% and 53%, respectively. At 4 months, ACR Pedi 50 and 70 were achieved in 50% and
28% of patients. Abatacept had clinical benefits for patients, irrespective of JIA subtype
(excluding children with systemic juvenile idiopathic arthritis and active systemic
manifestations in the previous 6 months). Because of this trial, abatacept received FDA-
approval for JIA in 2008, while in 2009 was also approved by the EMA for use in children
with JIA.
Abatacept is an intravenous infusion given at a dose of 10 mg/kg in patients under 75 kg.
A trial of abatacept administered subcutaneously is still ongoing.
B CELL INHIBITION
Rituximab
Rituximab is a chimeric monoclonal antibody directed against the human cluster of

differentiation (CD) 20 receptor, which is present only on B cells. Rituximab is a well-
established therapeutic option in adult RA. There are no trials to date in JIA. Therefore, data
is limited to case reports and one case series, which have largely been positive [81, 82].
Current guidelines suggest the use of rituximab for patients with arthritis in five or more
joints (extended oligoarthritis, RF-negative polyarthritis, RF-positive polyarthritis, PsA, ERA
and undifferentiated arthritis, excluding those with systemic arthritis or active sacroiliac
arthritis), with persistent high disease activity despite receiving a TNF inhibitor and
abatacept, especially in patients who are RF positive [52] [83].
Systemic Onset Juvenile Idiopathic Arthritis (SoJIA)
Systemic onset juvenile idiopathic arthritis (SoJIA, formerly called Still's disease) is
classified as a subset of JIA, but the pathophysiology is most consistent with an
autoinflammatory disease with interleukin-1 (IL1) and interleukin-6 (IL6) found to play a
pivotal role [84, 85]. Furthermore, approximately 10% of children with SoJIA develop
macrophage activation syndrome (MAS), a life-threatening condition characterised by fever,
organomegaly, cytopenias, hyperferritinaemia, hypofibrinogenaemia, hypertriglyceridaemia
and coagulopathy. Until recently, the treatment algorithms in SoJIA included mainly
corticosteroids and MTX, while autologous stem cell transplantation has been used in patients
with particularly severe disease that failed response to any other treatment. However, MTX
seems to be less effective for SoJIA than for other JIA categories, while long lasting steroid
treatment is related with severe side effects, mainly growth failure and osteoporosis. With
advancing knowledge on disease pathogenesis, two cytokines have been the target of modern
biologic treatment of SoJIA, and clinical experience has now shown us that biologics
blocking IL1 and IL6 are very effective.
IL1 INHIBITORS
Anakinra
Anakinra is a human, recombinant IL1 receptor antagonist that competitively binds to the
IL1 receptor on cell surfaces, thereby preventing its interaction with IL1 and subsequent cell
signalling. The effectiveness of anakinra in SoJIA was first reported in 2004 in an abstract
presented at the American College of Rheumatology (ACR) [86] summarizing the
experiences of seven patients from five centres, which reported overall improvements in
inflammatory markers and arthritis. Since then, several other studies demonstrated
effectiveness of anakinra in SoJIA with improvement in both clinical and laboratory
parameters in patients with refractory SoJIA [85, 87, 88]. However, the first multicentre,
randomised, double-blind placebo-controlled trial was published in 2011 [89]. In that trial, the
primary objective was to compare the efficacy of a one-month treatment with anakinra (2
mg/kg subcutaneously daily, maximum 100 mg) to a placebo between 2 groups of 12 patients
each. Response was defined by a 30% improvement of paediatric ACR core-set criteria for
JIA, in addition to resolution of fever and systemic symptoms, and a decrease of at least 50%
of both C-reactive protein and erythrocyte sedimentation rate. Secondary objectives included
tolerance and efficacy assessment over 12 months, pharmacokinetic analyses, treatment effect
on blood gene expression, anti-pneumococcal response, serum amyloid A and ferritin levels,
and percentage of glycosylated ferritin. At one month, there was a significant difference in the
response rate between patients treated with anakinra and placebo. The number of adverse
events, mainly pain related to injections, was similar between both groups. Ten patients from
the placebo group switched to anakinra at month 1, and nine were responders after two
months [89].
Anakinra may be more effective if used early in the disease course, rather than as
rescue therapy, once other therapies have failed. One international group gathered 46
patients who had received anakinra as part of initial therapy for SoJIA, including 10 treated
with anakinra without glucocorticoids or other DMARDs [90]. Many patients were able to
avoid glucocorticoid therapy altogether, and chronic arthritis did not develop in almost 90%
of these patients followed for more than six months (compared with 30 to 50% among
historical controls). Results from a subsequent prospective case series are consistent with the
previous study [91]. Moreover, several cases of SoJIA-associated MAS with a dramatic
response to anakinra (after partial response to corticosteroids and cyclosporine) have now
been reported [92, 93]. IL1 may not be the absolute defining factor in all patients with
SoJIA. A study by Gattorno and colleagues [94] suggested a clinical SoJIA subset likely to
respond to IL1 blockade (45%), characterised by a lower number of active joints and an
increased absolute neutrophil count (in contrast to the non-responders group).
Anakinra is a daily subcutaneous injection given at a dose of 12 mg/kg/day (maximum
100 mg/day), which is noted to be painful. Higher doses may be required in some cases for
better control of, especially, systemic symptoms. The need for daily subcutaneous injections
can be a problem, particularly in the younger group of children affected. Injection site
reaction can be as common as 40%, which usually subside after 2-3 weeks of ongoing
treatment. Anakinra is the only IL1 inhibitor NICE approved at the moment for children with
MAS secondary to SoJIA (Table 4).
Canakinumab
Canakinumab is a human monoclonal anti-human IL1b antibody of the IgG1/k isotype. It

binds selectively and with high affinity to human IL1b, neutralizing its biological activity (by
blocking its interaction with IL1 receptors), thereby preventing IL1b-induced gene activation
and inflammatory mediator production. Canakinumab does not bind to IL1a or the IL1
receptor antagonist [95].
The efficacy of subcutaneous canakinumab in patients aged 219 years with active SoJIA
was evaluated in two double blind, placebo-controlled, multinational, phase III studies [96].
In the first trial, 84 children aged 2 to 19 years with active SoJIA including both systemic
features (fever) and arthritis were randomly assigned to a single dose of canakinumab (4
mg/kg subcutaneously) or placebo. Concurrent treatment with another biologic agent was not
allowed, but patients on background therapy with glucocorticoids, NSAIDs, and/or MTX
were also enrolled. There was a significant difference in the proportion of patients with an
adapted JIA ACR 30 response between the canakinumab group and the placebo group (84%
versus 10%, respectively). Two serious adverse events were reported in each group (MAS
and varicella in the canakinumab group, and MAS and gastroenteritis in the placebo group).
The second trial included patients from the first trial (canakinumab responders and
placebo-group patients) plus additional patients (100 in total), and had an initial open-label
phase in which all patients were treated with canakinumab every four weeks for 12 to 32
weeks. In the randomised withdrawal phase, patients who had a sustained adapted JIA ACR
30 response or better, and who were not on glucocorticoids or had been tapered to a stable
glucocorticoid dose, were either continued on canakinumab or placed on placebo. The rate of
flares was significantly lower in the canakinumab group compared with the placebo group
(26% versus 75%, respectively). In addition, inactive disease rates were higher at the end of
the withdrawal phase in the canakinumab group, compared with placebo (62% versus 34%).
Four cases of MAS were reported in the open-label phase and two in the withdrawal phase.
Two patients with MAS died, one in the open-label phase, and one from the placebo group in
the withdrawal phase. The report of MAS as an adverse event (AE) in both clinical trials
prompted the formation of an independent MAS Adjudication Committee (MASAC), to
assess the impact of canakinumab on MAS incidence [97], which concluded that the IL1
inhibition has little if any effect on MAS, not only in the possibility of contributing to its
development, but also in its clinical manifestations and response to treatment. Developing
MAS should be considered and closely monitored in all patients with worsening SoJIA, and
adjustments to treatment to be made in a timely way.
The recommended dose of canakinumab for children with a body weight of more than 7.5
kg is 4 mg/kg (up to a maximum of 300 mg), administered subcutaneously, every 4 weeks.
Rilonacept
Rilonacept is a fusion protein consisting of human cytokine receptor extracellular

domains of both receptor components required for IL1 signaling with the Fc portion of human
IgG1. Rilonacept binds IL1a and IL1b with picomolar affinity, but potentially can bind to
IL1R antagonist [98]. It is available in the United States for treatment of autoinflammatory
diseases, but its use in patients with SoJIA is still investigated.
In a trial of 24 patients with refractory SoJIA randomly assigned 2:1 to rilonacept (2.2
mg/kg in cohort 1 and 4.4 mg/kg in cohort 2, given subcutaneously on days 3, 7, 14, or 21) or
placebo, no significant differences in efficacy, based upon ACR Pediatric 30, 50, and 70
scores, were observed during the blinded phase [99]. However, systemic features (fever and
rash) completely resolved by three months in the 23 patients who received rilonacept during
the open-label phase. More than half of these patients maintained their response, and more
than 90% were able to reduce or discontinue glucocorticoids, although 13 of the 23 patients
withdrew from the study during the open-label phase before 24 months. Additionally, a
randomised trial in 71 children with active SoJIA that had a four-week initial placebo-
controlled phase, followed by a 20-week treatment phase for all patients, showed that the time
to response was shorter in the rilonacept arm compared with the placebo arm. Response at
week 4 was 57% in the rilonacept arm compared with 27% in the placebo arm [100].
Rilonacept was given as a loading dose of 4.4 mg/kg followed by 2.2 mg/kg weekly.
Treatment was well tolerated.
Rilonacept is a subcutaneous injection given as a loading dose of 4.4 mg/kg (maximum
320 mg), followed by a weekly maintenance dose of 2.2 mg/kg (maximum 160 mg/week).
IL6 INHIBITORS
Tocilizumab
Tocilizumab is a humanised monoclonal antibody to IL6 receptor. In 2011, FDA

approved tocilizumab for the treatment of SoJIA in children after the age 2 years, and EMA
followed. NICE guidance recommends tocilizumab for the treatment of SoJIA in children and
young people aged 2 years and older whose disease has responded inadequately to NSAIDs,
systemic corticosteroids and MTX (Table 4).
Results from a phase III clinical trial in SoJIA were published in 2008 [101]. In this
study, 56 children with SoJIA were treated with tocilizumab open-label at 8 mg/kg every
other week for six weeks. A number of 43 patients reached the responder criteria, and were
enrolled into the 12-week long double-blind withdrawal phase; 17% patients in the placebo
group maintained an ACR Pedi 30 response and a CRP concentration of less than 15 mg/L
compared with 80% in the tocilizumab group (p < 0.0001). By week 48 of the open-label
extension phase, ACR Pedi 30, 50, and 70 responses were achieved by 47 (98%), 45 (94%),
and 43 (90%) of 48 patients, respectively [101]. Similar findings were demonstrated in
another trial that randomised 112 children (age 217) with active SoJIA to tocilizumab (12
mg/kg if <30 kg or 8 mg/kg if 30 kg) or placebo intravenously every 2 weeks for 12 weeks
[102]. At week 12, a significantly bigger number of patients who received tocilizumab than
those who received placebo met the primary endpoint of a JIA ACR 30 response and an
absence of fever (85% vs. 24%, P < 0.001). At week 52, 80% of the patients who received
tocilizumab had at least 70% improvement with no fever, including 59% who had 90%
improvement; in addition, 48% of the patients had active arthritis, and 52% were able to
discontinue oral steroids.
Tocilizumab is also approved for the treatment of polyarticular JIA in children 2 years
old but in a different recommended dose. In a Phase III, randomised, double-blind withdrawal
trial, 188 patients received tocilizumab. 163 of enrolled patients were randomised to either
continue tocilizumab or switch to placebo [103]. JIA flare occurred in 25.6% of patients who
continued tocilizumab versus 48.1% of patients who received placebo (p = 0.0024).
Tocilizumab is administered as an intravenous infusion over 1 hour and treatment is
repeated at 2-week intervals. The recommended dose is 8 mg/kg in patients weighing 30 kg or
more, and 12 mg/kg in patients weighing less than 30 kg. For Poly-JIA, tocilizumab is given
at a dose of 8 mg/kg in patients weighing 30 kg or more, and 10 mg/kg in patients weighing
less than 30 kg and is given at 4-week intervals. Tocilizumab as a subcutaneous injection is
currently investigated not only for the treatment of JIA, but also for the treatment of
refractory chronic uveitis.
Other agents targeting IL6 such as sarilumab are entering clinical trial phases in JIA.
Specific JIA Subtypes
Psoriatic JIA (PsJIA)

PsJIA, or alternately juvenile psoriatic arthritis (JPsA), is a condition that can range
widely in presentation and severity. Frank cutaneous psoriasis is not always evident, and the
extent of articular involvement may vary from mild enthesitis to polyarticular involvement of
multiple axial (spine and sacroiliac joints) and peripheral joints. PsJIA has a high incidence of
dactylitis, long recognised as a distinguishing feature from other subtypes of JIA. In adults,
the psoriatic rash appeared to precede the onset of arthritis, but in children, the occurrence of
arthritis or psoriasis as the first symptom seemed to be divided evenly [104]. It remains
debatable whether this subtype represents a clearly defined entity. Treatment
recommendations for PsJIA are derived mainly from trials in other JIA subtypes and from
adult psoriatic arthritis (PsA). Treatment of paediatric patients is complicated by limited
approved treatments and the lack of evidence from randomised, controlled trials available for
this population [57, 105, 106].
Recently, a new biologic agent has been approved for adult PsA. Ustekinumab is a
monoclonal antibody that acts as a cytokine inhibitor by targeting interleukin 12 (IL12) and
interleukin 23 (IL23), preventing its interaction with the IL12 receptor b1 subunit of the IL12
and IL23 receptor complexes. IL23 inhibits Th17 cells. Ustekinumab has been proven to be
safe and effective treatment for moderate-to-severe psoriasis in adult patients. In the
PHOENIX trials, ustekinumab effectively reduced psoriasis signs and symptoms in adults
[107, 108]. In CADMUS trial, ustekinumab was evaluated in adolescent patients with active
psoriasis (age 12-17 years) [109], with a good response. Moreover, in a Phase III, multicenter,
placebo-controlled trial in adults with active PsA, 43.8% of patients who received
ustekinumab achieved ACR20 at week 24, compared to patients who received placebo [110].
Improvement was observed in those previously treated with TNF inhibitors and was
sustained. It proved to be effective for most PsA manifestations, including peripheral arthritis,
skin disease, enthesitis, dactylitis, quality of life and radiographic progression in patients
failing traditional DMARDs and TNF inhibitors [111].
Enthesitis-Related Arthritis (ERA)

The enthesitis-related arthritis (ERA) JIA category describes a clinically heterogeneous
group of children. Axial disease is common in children with established ERA. Until recently,
treatment was including NSAIDs, local corticosteroid injections, and exercise. MTX and
Sulfasalazine have also been used for peripheral arthritis while TNF inhibitors are used to
treat refractory enthesitis and sacroiliitis. Almost two third of patients with ERA have
persistent disease, and often have significantly decreased quality of life.
Infliximab [112] and etanercept [57, 58, 113] have shown improvement in arthritis and
enthesitis, reduction in inflammatory markers and pain, and better physical function in open-
label trials in ERA. In addition, adalimumab treatment was associated with promising results
in a double blind, randomised placebo-controlled study in patients with ERA [114]. Emerging
data suggests that TNF inhibitors retard radiographic progression of axial disease in ERA
[115]. Other biologic agents such as rituximab, anakinra, abatacept, tocilizumab and
secukinumab have not been systematically studied in patients with ERA [116].
Biosimilars
The high cost of biologics has become an important issue in the battle concerning ever-
increasing healthcare costs. A biosimilar is a biological agent that has a molecular structure
and biological properties highly similar to the reference product that has been approved by
regulatory agencies, such as the EMA and the United States FDA. In addition, there are no
clinically meaningful differences between the biosimilar and reference product in terms of
safety, purity, and potency. The advent of biosimilars comes at a particularly important time
given global efforts to increase focus on treatment outcomes and reduction of healthcare
costs. The EMA was the first drug regulatory body to develop and publish guidelines for the
development of biosimilars. Since then, the EMA has approved biosimilars, including the
biosimilar infliximab. While there appears to be great potential in how biosimilar monoclonal
antibodies may affect the treatment landscape and benefit patients, a number of concerns and
obstacles must be addressed.
Based on the available evidence regarding the efficacy of biologic treatments for JIA, the
following algorithm is proposed (Table 4).
Table 4. Suggested treatment flow-chart for JIA. Adapted from [83]

CONCLUSION
The major new revolution in managing childhood rheumatic diseases has been the advent
of biological therapies, developed to block specific targets of the inflammatory response.
While their efficacy is well established, our knowledge about the possible long-term risks of
these treatments is lacking. However, the potential risk versus benefit for each biologic needs
to be individualised for each patient and their disease. Patients should be evaluated carefully
for the risk or presence of infection, tuberculosis and other serious adverse events by regular
visits, careful clinical assessments, and an assiduous, high index of suspicion for these rare
events.
ACKNOWLEDGMENTS
The authors would like to thank to Dr. Corinne Fisher, Department of Rheumatology,
University College London, London, UK (email: c.fisher@ucl.ac.uk) for reviewing the
chapter.
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MISCELLANEA
Chapter 15
BIOLOGIC DISEASE MODIFYING

ANTI-RHEUMATIC DRUGS IN PREGNANCY
AND BREAST-FEEDING PERIOD
Hanh Nguyen1,2 and Ian Giles, PhD FRCP1,2,*

Centre for Rheumatology Research, Rayne Institute,
1

2
ABSTRACT
Inflammatory rheumatic diseases (IRD) have a predilection for women of
reproductive age; hence, many women with IRD have disease that has been controlled
through treatment with standard and/or biologic disease modifying anti-rheumatic drugs
(DMARDs) and are increasingly considering pregnancy. Historically, inflammatory
rheumatic diseases such as rheumatoid arthritis (RA) were considered to spontaneously
improve in most patients during pregnancy. Modern prospective studies however, have
shown less than half of all patients with RA objectively improve during pregnancy and
have a significant risk of disease flare post-partum. In addition, adverse pregnancy
outcomes have been linked with increased disease activity in various IRD, such as RA
and systemic lupus erythematosus (SLE). Therefore, adequate control of disease activity
both immediately before, during and after pregnancy with medications that are
compatible with pregnancy are essential, and the use of biologic (b)DMARDs to maintain
disease control is increasingly being considered in pregnancy. There are however,
potential concerns as to the safety of these drugs in pregnancy and breastfeeding because
current reports on their use in this situation are limited to often inadvertent exposures
described retrospectively in case reports/series or population registries. Adequately
controlled studies with long term follow-up of infants exposed to these drugs in utero are
lacking. Significantly, many bDMARDs have a similar structure to maternal IgG that can
Corresponding author: Dr Ian Giles, Department of Rheumatology, University College London, Room 411, Rayne
*
Institute, 5 University Street, London, WC1E 6JF, UK, email: i.giles@ucl.ac.uk.

378 Hanh Nguyen and Ian Giles
cross the placenta by active transport from 16 weeks of pregnancy onwards; hence many
bDMARDs share this ability of placental transfer during organogenesis in pregnancy. In
contrast, certain bDMARDs with different structures undergo appreciably less placental
transfer. Therefore, knowledge of biologic structure is important when considering
current evidence with regard to their potential effects upon pregnancy. The aim of this
chapter is to summarise current information regarding structure, compatibility and use of
various biologics for women with IRD at conception, during pregnancy, breastfeeding
and consider their impact on longer term infant outcomes.
Keywords: rheumatic disease, pregnancy, biologic, disease modifying anti-rheumatic drugs,

breast feeding
INTRODUCTION
IRD include autoimmune rheumatic diseases (ARD) - such as SLE, RA and
antiphospholipid syndrome (APS) - and other inflammatory arthropathies, such as psoriatic
arthritis (PsA) and spondylarthropathies (SpA). Many of these conditions have a predilection
for women and an appreciable overall prevalence, with RA and PsA alone estimated to affect
2-3% of the population [1, 2]. Consequently, many women of childbearing age with these
conditions have disease that has been controlled through treatment with standard and/or
bDMARDs, and are increasingly considering pregnancy. Arguably, the advent of biologic
therapies to better control disease activity has meant that more patients, even those with more
severe disease manifestations are now becoming pregnant; thus contributing to the modern
finding that pregnancy itself has a less beneficial effect than previously believed on many
IRDs.
REPRODUCTIVE ISSUES ARE COMMON IN PATIENTS WITH

INFLAMMATORY RHEUMATIC DISEASE
Management of rheumatic patients during pregnancy is complicated by several factors
including an increased burden of pregnancy morbidity that has been clearly linked with
increased disease activity in several IRDs. Therefore, it is paramount to maintain adequate
control of disease activity with medications that are compatible with pregnancy. Prescription
however, of many anti-rheumatic drugs in pregnancy is complicated by safety concerns, with
obvious risks being identified with some drugs and a great deal of uncertainty existing for
many others. Given that biologic therapies are now well established in the management of
many IRDs the question of whether they may be given in pregnancy and breastfeeding is
increasingly being asked. Therefore, this chapter will summarise the growing body of
evidence regarding the potential use of biologics in this reproductive setting.
Biologic Disease Modifying Anti-Rheumatic Drugs in Pregnancy 379
INCREASED INFLAMMATION ASSOCIATED WITH RHEUMATIC

DISEASES IS LINKED WITH ADVERSE PREGNANCY OUTCOMES
Many IRD (particularly SLE) have an increased burden of adverse pregnancy outcomes
(APO) including hypertensive disorders of pregnancy (13-23%) and foetal growth restriction
(5%) that are associated with poor placentation, as well as increased rates of pregnancy loss,
premature delivery and caesarean delivery compared with the general population [3-6]. There
are clear links between increased disease activity immediately prior to and during pregnancy
and APO in RA [7] and SLE [8, 9], and certain autoantibodies are clearly associated with
APO, particularly anti-phospholipid antibodies (aPL) in APS and anti-Ro/La antibodies in
neonatal lupus [10].
Historically pregnancy has been considered to have a beneficial effect upon RA disease
activity in pregnancy, with 60-90% of mothers reportedly improving. These findings
however, were from mostly retrospective studies, which lacked objective measures of disease
activity [11]. Modern prospective studies using validated measures of disease activity reveal
less impressive ameliorative effects of pregnancy on inflammatory disease activity, such that
only 48% of women with active RA reportedly improved during pregnancy and 39% had a
disease flare-up within six months of delivery [12]. Similarly, cohort studies have yielded
conflicting results of the impact of pregnancy on SLE activity with many studies identifying
between 35 70% of all pregnancies in patients with SLE having some form of measurable
disease activity and 15 30% having a moderate to severe flare in pregnancy, reviewed in
[8]. The risk of lupus flare during pregnancy is increased in patients with: active disease
within 4 6 months of pregnancy [13-14]; active disease at conception [15-16]; a history of
highly active disease in the years prior to pregnancy and discontinuation of
hydroxychloroquine [17-18]. Whilst the factors specific to pregnancy that determine
inflammatory rheumatic disease remission or relapse remain poorly characterised, it is clear
that adequate control of inflammatory disease activity is required to reduce APO.
MANAGEMENT OF INFLAMMATORY
RHEUMATIC DISEASE IN PREGNANCY
Immunosuppressive therapies, standard and/or bDMARDs are required to control
inflammatory rheumatic disease activity. The use however, of many of these drugs in
pregnancy, such as methotrexate (MTX) and mycophenolate mofetil (MMF), is
contraindicated because exposure increases the risk of congenital malformations and
spontaneous abortion. The situation regarding use of bDMARDs in pregnancy is rapidly
evolving. For instance, early consensus recommendations regarding anti-tumour necrosis
factor (TNF) inhibitor drugs advised avoidance of etanercept, infliximab and adalimumab in
pregnancy and breastfeeding due to a lack of evidence rather than evidence of harm [19, 20].
Increasing evidence however, from mostly first trimester exposure to these drugs, has shown
compatibility with pregnancy, such that a gastroenterology consensus statement in 2011
considers TNF inhibitor (TNFi) drugs for treatment of inflammatory bowel disease (IBD) to
be low risk in the first and second trimester of pregnancy [21].
Rheumatologists are increasingly questioned about the suitability of bDMARDs use in

pregnancy. Therefore, the British Society of Rheumatology (BSR) has recently published a
two-part guideline specifically on prescribing anti-rheumatic drugs in pregnancy and
breastfeeding period [22]. These guidelines expand and update previous consensus
recommendations [19, 20] and systematically review all current evidence on use of various
anti-rheumatic drugs before/during pregnancy and breastfeeding in patients with rheumatic
disease. They provide guidance for all healthcare professionals to ensure uniformity in routine
prescribing of compatible bDMARDs in clinical practice across different specialist centres.
Ideally, management of these patients should involve a collaborative multidisciplinary
approach between rheumatologists and obstetric healthcare professionals to provide optimal
management before, during and post-pregnancy. This approach ensures an appropriate risk
assessment and provision of an individualised treatment plan for antenatal and postnatal
management for these high-risk patients to help enhance the chances of successful pregnancy
outcomes.
EVIDENCE FOR USE OF BIOLOGIC THERAPIES IN PREGNANCY

Evidence of compatibility of bDMARDs in pregnancy and breastfeeding arises from
animal data, as well as human studies that are mostly retrospective, uncontrolled and
observational. Although these studies help to inform experience, there remains an urgent need
for more robust adequately controlled human studies to provide reliable evidence about
compatibility of bDMARDs in pregnancy. In particular, when interpreting reports of the
effect of a drug on adverse pregnancy events, it is important to consider factors such as: the
potential effects of the underlying disease itself upon pregnancy; and the incidence of adverse
outcomes in otherwise healthy pregnancies. Unfortunately, appropriate controls are lacking
from most studies.
TRANS-PLACENTAL PASSAGE OF MONOCLONAL ANTIBODIES

DURING PREGNANCY
Biologic drugs are recombinant proteins; most commonly monoclonal immunoglobulin

(Ig) G1 class antibodies directed against specific targets or fusion proteins containing the
fragment crystallisable (Fc) portion of IgG1 joined to receptor-blocking proteins, shown in
Figure 1. These drugs share similar structure with maternal Ig G, which are large proteins
(~150 kDa) that are unable to cross the placenta via simple diffusion. Active trans-placental
transfer of maternal IgG takes place via neonatal fragment of crystallisable component/Fc
receptors (FcRn), present on syncytiotrophoblast [23-25] and occurs rapidly from 16 weeks of
pregnancy onwards, shown in Figure 2. An exception is anakinra that is a recombinant form
of human IL1 receptor antagonist that has a high molecular weight but does not contain any
Ig structure, hence lacks the Fc region, and has not been found to cross ex-vivo full-term
human placenta [26]. Therefore, it is important to consider carefully both, the structure and
timing of bDMARD exposure during pregnancy.
Different rates of placental transfer have been demonstrated amongst the TNFi drugs. In
particular, certolizumab pegol, an antigen binding (Fab) fragment of an anti-TNF antibody
that has been conjugated with the polymer polyethylene gycol (PEG) in a process known as
PEGylation, has been shown to have the lowest rates of placental transfer compared with
other TNFi, consistent with its structure that lacks the Fc region [29, 30].
Few studies have examined rates of maternal transfer of TNFi to cord and/or infant
blood, shown in Table 1. A study of 31 pregnant women with IBD receiving infliximab (n =
11), adalimumab (n = 10), or certolizumab (n = 10) throughout pregnancy found that
concentrations of infliximab and adalimumab, but not certolizumab, were higher in blood
from infants at birth and their cord blood than in maternal blood. The median level of
infliximab in the cord was 160% that of the mother, the median level of adalimumab in the
cord was 153% that of the mother, and the median level of certolizumab in the cord was 3.9%
that of the mother [31]. This study also found that differences in half-life and bioavailability
altered the elimination time of the biologics in infant blood on follow-up. The median time
from last dose to delivery was: 35 days for infliximab, which then took up to 7 months for
infant levels to become undetectable; 5.5 weeks for adalimumab, which took up to 11 weeks
to become undetectable in the infant; and 19 days for certolizumab. This study provided clear
evidence that infliximab and adalimumab are transferred across the placenta and can be
detected in infants at birth for up to 7 months afterwards in the case of infliximab. In contrast,
certolizumab had the lowest levels of placental transfer of the three drugs tested [29-32].
Interestingly, two case studies have also reported low rates of placental transfer of etanercept
administered throughout pregnancy, with cord levels at delivery of 3.6% and 7.4% those of
maternal blood [33, 34].
Legend: CH constant region, heavy chain of the antibody, CTLA4 cytotoxic T lymphocyte-
associated protein 4; Fab antigen binding domain of the antibody; Fc heavy chain constant
region; PEG polyethylene glycol; VH variable domain (heavy chain) of the antibody, VL
variable domain (light chain) of the antibody.
Figure 1. Diagram of molecular structures of different bDMARDs (Adapted from: [27-29]).
These different rates of placental transfer mean that these drugs may be present in infant
blood at the time of birth if they are given later on in pregnancy. This finding is relevant
because a case of fatal tuberculosis (TB) like disease has been reported post Bacillus
Calmette-Gurin (BCG) in an infant who was not breastfed, but was exposed to infliximab
throughout pregnancy [35]. Therefore, if TNFi therapy is given in the third trimester, live
vaccines should be avoided in the infant until they are at least six months of age to ensure the
clearance of biologic drug. Information regarding placental transfer of other biologic drugs is
currently lacking. Given that many biologic drugs share an IgG1 structure or contain an Fc
region (Figure 1), it is reasonable to assume that placental transfer of such drugs will not
occur until 16 weeks of pregnancy onwards.
Legend: FcRn - crystallisable component/Fc receptors; Ig G - immunoglobulin G
Figure 2. Diagram showing foetal acquisition of maternal IgG via transcytosis. Maternal IgG can be
transported across the placental barrier by active binding to FcRn to form an IgG/FcRn complex, which
subsequently crosses syncytiotrophoblast and enters foetal blood circulation (Adapted from [24]).
Table 1. Summary of studies of maternal transfer of TNFi
Ratio of drug levels reported

Biological drug Pregnancy exposure time points in mothers compared to
cord/infant [31]
Infliximab 1st, 2nd and 3rd trimesters Levels of infliximab present in cord blood
levels showed higher than maternal drug levels
(160%). Infliximab levels reported as
undetectable in new-born blood from 28 weeks
Adalimumab 1st, 2nd and 3rd trimesters At birth, new-borns drug levels showed much
higher compared to mothers levels (153%). At
post-partum, drug levels detectable up 11
weeks.
Etanercept 1st, 2nd and 3rd trimesters Very low drug levels in cord blood reported
compared to maternal drug levels (7%) [34].
Ratio of drug levels reported
Biological drug Pregnancy exposure time points in mothers compared to
cord/infant [31]
Certolizumab pegol At conception/1st, 2nd and/or 3rd Very low/undetectable drug levels detected in
trimesters new-borns (3.9%)
Golimumab At pre-conception (within 2 Not studied.
months), conception, 1st trimester
and during pregnancy.
Adapted from: [31]
USE OF BIOLOGIC DMARDS IN PREGNANCY

AND BREASTFEEDING
The developments of biologic drugs have improved the outcomes for patients with
different forms of IRD and they are commonly prescribed to treat conditions such as; SLE,
RA, PsA, juvenile onset arthritis (JIA) and ankylosing spondylitis (AS). Currently, nine
biologic drugs are licensed to treat various IRD as second line agents when standard
DMARDs alone have failed. Increasing use of treat to target regimes has led to rapid
escalation of therapies, to achieve disease remission such that many women with IRD are
established on maintenance, often combination therapy with standard and/or bDMARDs
when they are considering pregnancy.
For these patients adequate control of disease activity remains the priority throughout
pregnancy. If this disease control has been achieved through combination therapy with
standard as well as biologic DMARDs, it is vital at the pre-pregnancy planning stage to alter
standard DMARDs and stop any known teratogens, such as MTX in advance of pregnancy.
Consideration should then be given to switching/continuing DMARDs, such as
hydroxychloroquine or sulfasalazine that are compatible with pregnancy [22].
The growing body of evidence demonstrating compatibility of many bDMARDs,
particularly TNFi, in pregnancy comes from human data that is limited to inadvertent
exposure described in case reports/series and population registries. There remains however, a
paucity of evidence relating to many bDMARDs in pregnancy and breastfeeding, so not all of
the currently available bDMARDs can be recommended in these situations. Recent BSR
guidelines on prescribing anti-rheumatic drugs in pregnancy have systematically reviewed
information up to December 2013 to update previous reviews [20, 36] and produce evidence-
based recommendations. They are discussed below in relation to different bDMARDs.
Prescribing recommendations for TNFi reported in the BSR 2016 guidelines have been
summarised in Table 2 in this chapter [22].
USE OF TNFI DRUGS IN PREGNANCY AND BREASTFEEDING

In the UK, there are five TNFi drugs (etanercept, adalimumab, infliximab, certolizumab
and golimumab) approved for treatment of RA, PsA, AS, JIA and other conditions, including
psoriasis, IBD such as Crohns disease (CD) and ulcerative colitis (UC). As described above,
these drugs have different structures (shown in Figure 1), half-lives, bioavailability and rates
of placental transfer that are relevant when considering their potential use in pregnancy.
Currently there remains a limited number of human pregnancy studies reported to address
the safety of biological treatments and no controlled studies published, but there is a growing
body of collective evidence available surrounding inadvertent exposure to bDMARDs in
case-reports, cohort studies, pregnancy registries and pharmaco-vigilance databases. The
majority of these reports are for mothers exposed to infliximab, adalimumab and etanercept
during conception and the first trimester but increasing evidence is emerging of their use later
in pregnancy.
Table 2. Summary of licensed TNFi function and prescribing recommendations

according to current UKs full BSR 2016 guidelines for pregnant women with IRD [22]
Current UK national BSR 2016 guideline summary of

bDMARD type bDMARD function
biologic drug exposure/use during pregnancy [22]
Etanercept A fusion protein of the TNF May continue etanercept until the end of 2nd trimester
receptor joined to the Fc to ensure low/no levels of drug in cord blood at
region of IgG1 which binds delivery. Etanercept should be avoided in the 3 rd
and inhibits TNF. trimester because of theoretical increased infection
Additionally, it also binds risk in new-borns. If etanercept is continued into later
to TNF and circulating stages of the pregnancy (to treat active disease), then
TNFs. live vaccinations should be avoided in the infant until
seven months of age.
Infliximab A chimeric human-murine Infliximab may be continued until 16 weeks
monoclonal IgG1 which gestation.
binds and inhibits TNF. To ensure that no/low levels of infliximab are present
in cord blood at delivery, this drug should be stopped
at 16 weeks, because of a theoretical increased
infection risk in new-born babies. If infliximab needs
to be continued later in pregnancy (to treat active
disease), then live vaccines should be avoided in the
infant until seven months of age.
Adalimumab A fully humanised Adalimumab may be continued until the end of 2nd
monoclonal IgG1 which trimester. To ensure that low/no levels of drug to be
binds and inhibits TNF. present in cord blood at delivery adalimumab should
be avoided in the 3rd trimester because of a theoretical
increased infection risk in new- born. If drug is
continued later in pregnancy (to treat active disease),
then live vaccines should be avoided in the infant
until seven months of age.
Golimumab A fully humanised No published evidence currently available to provide
monoclonal IgG1 which any recommendation of golimumab use in pregnancy.
binds and inhibits TNF. However, it is deemed unlikely to cause harm if
mothers are exposed to golimumab in the 1st
trimester.
Certolizumab A PEGylated humanised Limited body of evidence shows that certolizumab is
pegol antigen binding Fab` compatible with pregnancy during all three trimesters
fragment of a monoclonal during pregnancy. It has reduced placental transfer
anti-TNF antibody, which compared with other TNFi.
lacks an Fc region therefore
cannot bind to human
FcRn.
(Adapted from BSR 2016 guideline [22])
The BSR 2016 guideline [22] identified: 5 cohort studies [37-41], 8 case-series [32, 42-
48] and 1 case report [49] of (n = 265) infliximab exposed pregnancies; 3 cohort studies [37,
38, 50], 3 case-series [44, 51, 52] and 4 case reports [33, 34, 53, 54] of (n = 100) etanercept
exposed pregnancies; 4 cohort [38, 39, 50, 55], 5 case series [31, 34, 47, 48, 56], and 3 case
reports [49, 57, 58] of (n = 89) adalimumab exposed pregnancies; and a case series of 10
certolizumab exposed pregnancies [31]. In addition, 2 cohort studies [55, 59], one case-series
[60] and one case-control [61] reported combined outcomes from (n = 201) pregnancies
exposed to etanercept, infliximab, adalimumab and/or certolizumab. All of these studies

examined TNFi use in patients with rheumatic disease or IBD.
These studies reported on outcomes from (n = 706) TNFi exposed pregnancies of patients
with predominantly IBD but also rheumatic disease and two studies of non-autoimmune
mediated recurrent spontaneous miscarriage compared with (n = 399) disease and (n = 170)
healthy control pregnancies [22]. These studies mostly reported first and second trimester
exposures. Despite multiple confounders of concomitant therapies (including MTX,
leflunomide -LEF and MMF) and active inflammatory disease, no consistent adverse effects
of any TNFi were observed on maternal or foetal outcomes. In particular, although various
major malformations were described there were no consistent patterns of abnormalities and
the incidence were not increased compared to the control groups [61-64].
Whilst no journal articles citing human pregnancy and breast feeding exposure to
golimumab have been published, two different groups have recently reported pregnancy
outcomes of RA patients exposed to golimumab alone and golimumab with concomitant
MTX exposure in abstract form [65, 66]. These authors collected and analysed pregnancy
outcome information reported to biologic registries, manufacturer repository, and clinical
studies. Strangfeld et al. [66] reported one case of RA patient being exposed to golimumab at
conception from a total of 95 pregnancies which were exposed to other bDMARDs including;
ETA (n = 26), adalimumab (n = 10), tocilizumab (n = 4), certolizumab (n = 4), rituximab (n =
3), abatacept (n = 2), and infliximab (n = 1) [66]. Over 37% of patients exposed to bDMARD
around conception were reported to be receiving combination treatment regime of a biologic
agent with corticosteroids (>/= to 10 mg/daily) during latter course of pregnancy. Overall, this
study concluded that there was no increased risk of congenital defects or spontaneous
abortion in these patients with RA exposed to various bDMARDs, including golimumab
during conception [66].
Lau et al. [65] evaluated pregnancy outcomes reported by women with IRD or IBD
exposed to golimumab within two months of conception and during pregnancy. Information
was collected in a retrospective (n = 12) and prospective (n = 35) manner. A total of 47
patients were analysed, of which 30 had RA, 1 had PsA, 5 had AS and 11 had UC. Notably,
concomitant treatment with MTX was given in 12 RA pregnant patients treated with
golimumab. There were a total of 13 spontaneous abortions (27.7%), of which 4 cases
(30.8%) occurred in women exposed to golimumab and concomitant MTX. Other pregnancy
outcomes reported included; 55.3% live births (n = 26 cases of whom 5 mothers were
exposed to MTX), 14.9% induced abortion (n = 7 cases), and only 2.1% of ectopic pregnancy
(n = 1 case). An un-specified congenital anomaly was reported in one patient treated with
both golimumab and MTX, and this pregnancy resulted in intra-uterine death and consequent
induced abortion [65]. Although this study lacked a direct comparison group, the reported
rates of adverse pregnancy outcomes in patients taking golimumab alone were consistent with
general background rates.
Table 3. Summary of studies reporting TNFi drug levels found in breast milk of mothers exposed to drug prior to conception,
during pregnancy, post-partum and lactation periods
TNFi level in
TNFi drug Diagnosis Timing of TNFi exposure Adverse event References
breast milk
Infliximab IBD Drug was received at pre-conception, 1 ,st
Undetected [43] None. Ben Horin et al. [45]
during 2nd and 3rd trimesters, post-partum Minute (<1/200th of maternal All new-borns delivered Kane et al. [43]
and breastfeeding in patients. serum levels) amount detected [45]. were healthy [43]. Vasiliauskas et al. [67]
Drug detected at 34th week post- Fritzsche
partum (1/20th maternal serum 3 out of 4 new-borns et al. [48]
level); 2% of maternal serum level were healthy at delivery. Stengel and Arnold [72]
detected at 5th day post infliximab One new-born presented Madahaven et al. [32]
administration (approximately at 16 with polydactyly left Zelinkova
weeks post-partum) [48]. hand (mother was et al. [46]
Drug level detected within 24-48 exposed to MTX at pre- Steenholdt et al. [73]
hours in breast milk samples after conception for 2 months) Matro et al. [30]
dosing, with a maximum titre 90- [46].
591 ng/ml [30].
Adalimumab IBD Drug received at pre-conception, 1st, Drug was undetectable in breast None. All new-borns Fritzsche
during 2nd and 3rd trimesters, post-partum milk samples [30]. delivered were healthy. et al. [48]
and breastfeeding in patients. Drug detected at 21 weeks where in Madahaven et al. [32]
foetal blood (<1/1000th of maternal Matro et al. [30]
serum levels); at 8th week post-
partum <1/10th of maternal serum
level detected [48].
Etanercept RA, AS Drug received at pregnancy, continued Drug received prior to pregnancy, None. Murishima et al. [33]
throughout pregnancy and breast feeding during pregnancy, post-partum and A healthy new- born was Keeling and Wolbin [54]
in patient. breast feeding in patient (n = 1) delivered. Berthelsen et al. [34]
[34]. Ostensen and Eigenmann
Drug was re-introduced to patient [74]
(n=1) at post-partum and continued
throughout breast feeding [54].
Certolizumab IBD Drug received at preconception, 1st, during Drug was undetectable in breast None. Madahaven et al. [32]
2nd and 3rd trimesters, post-partum and milk samples. All new-borns delivered Matro et al. [30]
breastfeeding in patients. were healthy.
Legend: AS ankylosing spondylitis; IBD inflammatory bowel disease; MTX methotrexate; RA rheumatoid arthritis.
BREASTFEEDING AND POST-PARTUM PREGNANCY OUTCOMES

WITH TNFI EXPOSURE
Several studies have found little/no TNFi in breast-milk with no adverse effects
detectable in any breast-fed infants [31, 33, 34, 43, 45, 48, 54, 67] summarised in Table 3.
The BSR guideline [22] identified long-term follow-up studies of pregnant patients
treated with the following TNFi: ETA administered up to 9 months resulted in 12 healthy
new-born babies [33, 34, 44, 52, 54]. Another study of a case series of 11 children, whose
mothers were treated with etanercept up to 7 month during pregnancy, reported hand-foot-
mouth syndrome in one infant and upper respiratory tract infections in two other [31]. Other
studies followed up the outcome of pregnancy exposure to adalimumab (for 14-15 months)
[48] and certolizumab (for one month) [31], and reported no complications.
Additional data has been published (in journal articles and conference abstracts) since the
systematic reviewed was included in the BSR guideline. A study of (n = 56) first trimester
exposures to TNFi (etanercept, infliximab and adalimumab) did not identify any significant
increase in adverse pregnancy outcomes in women with chronic autoimmune disease,
compared with those who received TNFi before but not during pregnancy [62].
Clowse et al. [29] recently reported on n = 625 pregnancies exposed to certolizumab for
Crohns disease (n = 192) and rheumatic diseases (n = 118 with rheumatic diseases) from the
UCB Pharma safety database. The majority of cases analysed were receiving certolizumab
within the first trimester and one third of cases were exposed to certolizumab during the
second and/or third trimesters, and 59.5% (n = 372) pregnancies outcomes were recorded,
including maternal (n = 339) and paternal exposure cohorts (n = 33). The pregnancy
outcomes (post certolizumab exposure of one of the biologic parents), were as follows:
281 live births (maternal group n = 254, paternal group n = 27);

56 miscarriages (maternal group n = 52, paternal group n = 4);
33 induced abortions (maternal group n = 32, paternal group n = 1);
12 congenital abnormalities;
1 case of foetal death, and 2 still birth deliveries (one still birth reported in each
group) [29].
Overall, this study results concurred with previous reassuring reports and concluded that
certolizumab treatment received at very early stages or later stages of pregnancy does not
inflict major adverse effects on pregnancy outcomes [29, 30, 68, 69].
In addition, two recent prospective European studies have reported TNFi exposed
pregnancy outcomes with conflicting findings. A large study, which collected data from 11
centres from nine countries (collaborating within the European Network of tetralogy
Information Services) followed up a large number of pregnancies exposed to various TNF
inhibitors: 172 were exposed to adalimumab, 168 to infliximab, 140 to etanercept, 7 to
certolizumab, 3 to golimumab, and 5 pregnancies were double-exposed (3 to both
adalimumab and etanercept; 2 to adalimumab and infliximab). Thus, the study compared in
total 495 TNFi exposed and 1532 non-TNFi exposed pregnancies in patients without
rheumatic disease [70]. The proportion of underlying pathology in the exposed group was as
follow: IBD (n = 238, 48.1%), RA (n = 133, 26.9%), AS (n = 68, 13.7%), Ps/PsA (n = 39,
7.9%) and others (n = 17, 3.4%). The risk of major birth defects was increased in the exposed
(5.0%) compared with the non-exposed group (1.5%; adjusted odds ratio (ORadj 2.2, 95% CI
1.0, 4.8). The risk of preterm birth was increased (17.6%; ORadj 1.69, 95% CI 1.1, 2.5), but
not the risk of spontaneous abortion (16.2%; adjusted hazard ratio [HRadj] 1.06, 95% CI 0.7,
1.7). Birth weights adjusted for gestational age and sex were significantly lower in the
exposed group compared to the non-exposed cohort (P = 0.02). The study authors
acknowledged that the lack of an inflammatory disease non-TNFi exposed group in
pregnancy signified that the effects of poorly controlled inflammatory diseases themselves
upon pregnancy outcomes (such as miscarriage, pregnancy duration and birthweight) cannot
be distinguished from those that may be related to the TNFi. Therefore, they concluded that
TNFi may carry a risk of adverse pregnancy outcomes, but acknowledged that certain TNFi
remain a treatment option in pregnancy in poorly controlled inflammatory disease refractory
to other immunomodulatory treatments. A recent smaller Italian study of TNFi exposed
pregnancies (56 to etanercept, 13 to adalimumab, 3 to infliximab, 2 to certolizumab and 1
pregnancy exposed to golimumab), which lacked a direct comparator group, did not identify
an increase in adverse pregnancy outcomes that could be attributed to the TNFi [71].
The BSR 2016 guideline [22] made several recommendations regarding TNFi use in
pregnancy, summarised in Table 2. TNF may be continued until 16 weeks, and etanercept and
adalimumab may be continued until the end of the second trimester. To ensure low/no levels
of drug in cord blood at delivery, etanercept and adalimumab should be avoided in the third
trimester and infliximab stopped at 16 weeks. If these drugs are continued later in pregnancy
to treat active disease, then live vaccines should be avoided in the infant until seven months
of age. Certolizumab is compatible with all three trimesters of pregnancy, and has reduced
placental transfer compared with other TNFi; golimumab is unlikely to be harmful in the first
trimester. Women should not be discouraged from breastfeeding on TNFi but caution is
recommended until further information is available [22].
RITUXIMAB
Rituximab is a chimeric (human-murine) monoclonal IgG which targets the B cell surface
antigen, cluster of differentiation 20 (CD20) and depletes B cells [75-77]. Given its structure,
active placental transfer of rituximab can occur from 16 weeks onwards at organogenesis
stage in pregnancy. It has a maximum half-life of 35 days, which is another important factor
when considering its potential impact upon pregnancy, given its ability to interact with foetal
B cells and potential for B cell depletion in utero [78, 79]. This B cell depletion therapy was
initially developed for use in certain haematological malignancies and is used to treat a
variety of rheumatic diseases including RA, SLE and certain forms of vasculitis [25].
Due to the limited evidence of human pregnancy experience with rituximab treatment,
use of this drug in pregnancy has previously been discouraged. The BSR 2016 guidelines
identified; 3 cohort studies [38, 80, 81], 1 case series [82] and 4 case reports [83-86] on (n =
173) pregnancies in women exposed to rituximab [22]. Most of these exposed cases have
been included in a large study reported by Chakaravaty et al. [87]. This group reported the
largest cohort study outcomes of pregnancies exposed to rituximab using a global drug safety
database, and they have revealed 153 pregnancies with known outcomes [87].
Concomitant medications use with rituximab was not always recorded and time points of
rituximab exposure varied in this study. This study included; 8 pregnancies exposed to
rituximab at pre-conception (6-22 months), 6 pregnancies exposed to rituximab at 0-3 weeks
pre-conception, and a total of 72 pregnancies were exposed to rituximab throughout
pregnancy. There were a wide range of maternal indications, such as malignancies (non-
Hodgkins lymphoma), serious haematological disorders and different types of non-
autoimmune rheumatic diseases. This group reported known pregnancy outcomes as follows:
live births occurred in n = 90 (59%), spontaneous miscarriages in n = 33 (22%), one foetal
death occurring at 6 weeks and 28 patients deciding to have elective terminations of their
pregnancy (18%).
Furthermore, 24 infants were born prior to 37 weeks gestation but none at less than 30
weeks. One case of maternal death occurred due to pre-existing autoimmune
thrombocytopenia, and congenital abnormalities were reported in two cases; one twin infant
suffered a clubfoot and a singleton birth suffered cardiac malformation. This group
additionally reported haematological abnormalities in 11 neonates at birth, comprising
transient neonatal lymphopenia, neutropenia, thrombocytopenia, anaemia and B cell
depletion. None of these neonates experienced any infection correlating to their
haematological abnormalities, and recovered within weeks and months spontaneously. Lastly,
four cases of infection were reported [87].
There have been case reports published reporting outcomes of rituximab exposure at pre-
conception and during pregnancy in a majority of women with a non-rheumatologic disease.
These published reports included women with SLE exposed to rituximab ranging from 22
months before pregnancy [82], and up until the third trimester in idiopathic thrombocytopenia
purpura (ITP) [88]. A total of 24 infants exposed to rituximab were healthy at birth, and 8
babies were delivered prematurely. Premature births were reported in a total of 5 cases
including; SLE (n = 1), immune thrombocytopenic purpura (n = 1) and non-Hodgkin
lymphoma (n = 2) women exposed to rituximab at pre-conception and during second and
third trimesters, although it is unclear whether this effect was directly attributable to
rituximab or to the underlying disease. Amongst these case reports, there were a total of 3
congenital malformations cases identified (one infant presented with oesophageal atresia and
a couple of twins with a clubfoot and transient erythema toxicum neonatorum) [82, 86].
Ostensen et al. [89] reported on 3 women with SLE who received rituximab prior to
conception at 12, 6 and 4 months. Two of these patients delivered a healthy infant, however
one mother chose to undergo therapeutic abortion. Rituximab-exposed pregnancy case reports
have been summarised in Table 4.
Overall, the rituximab exposed pregnancy studies published so far have provided some
reassuring pregnancy outcomes. However, it is important to note that reports have concluded
in 6 out of 11 infants whom B cells levels were tested, were found to have depleted B cell
counts at birth. Five infants whom had low B cells were found to have been exposed to
rituximab during pregnancy (in second/third trimester). In a review conducted by Hyrich et al.
[25], 6 infants with rituximab exposure at pre-conception or during the 1st trimester of
pregnancy were deemed to have normal B cell levels [25].
Table 4. Summary of case reports reporting rituximab exposure at pre-conception or during pregnancy
B cell count in Offspring

Reported neonatal
Reference Diagnosis Exposure time point offspring at response
condition
birth to vaccination
Ostensen et al. SLE (n = 3) Preconception (12, 6 and 4 Two healthy (one - -
[20] months) premature birth) and
one termination
Sangle SLE (n = 3) Preconception (8, 10, 22 Healthy term - -
et al. [82] months)
Sangle SLE (n = 2) Preconception (12 and 18 Premature births, with -
et al. [82] months) oesophageal atresia
and low birth weight
Sangle GPA (n = 1) Preconception (10 months) Healthy term - -
et al. [82]
Alkaabi SLE/thrombocytopenia (n = 1) 2nd trimester Premature - -
et al. [83]
Ojeda-Uribe Thrombotic thrombocytopenia Pre-conception (9 weeks) Healthy term Normal -
et al. [85] purpura (n = 1)
Ojeda-Uribe et al. RA (n = 2) 1st trimester (2nd and 4th Healthy term - -
[85] week)
Ton et al. [86] RA (n = 1) Preconception (6 weeks) Twin births (one Normal -
clubfoot)
Gall et al. [90] ITP (n = 1) 2nd trimester (26 weeks) Healthy term Low -
Martinez- ITP (n = 1) 2nd trimester Premature birth Absent -
Martinez et al.
[91]
Klink et al. [88] ITP (n = 1) 3rd trimester Healthy term Absent Normal
Pellkofer et al. Neuromyelitis optica (n = 1) Pre-conception (1 week) Healthy term Normal Normal
[92]
B cell count in Offspring
Reported neonatal
Reference Diagnosis Exposure time point offspring at response
condition
birth to vaccination
Ng et al. [93] In vitro fertilisation, positive Pre-conception (6 months) Healthy term - -
autoantibodies (n = 1)
Ponte and Lopes Dermatitis (n = 1) 1st trimester Healthy term Normal -
[94]
Daver Hairy cell leukaemia (n = 1) 2nd trimester Healthy term - -
et al. [95]
Kimby NHL (n = 2) Pre-conception and 1st Healthy term Low Normal
et al. [96] trimester
Rey et al. [97] NHL (n = 1) 2nd trimester Premature birth - -
Herold NHL (n = 2) 2nd and 3rd trimester Healthy term (35 - -
et al. [98] weeks)
Freidrichs et al. NHL (n = 2) 2nd and 3rd trimester Healthy term Absent Normal
[99]
Decker NHL (n = 2) 2nd and 3rd trimester Healthy term (33 Low Normal
et al. [100] weeks)
Perez NHL (n = 2) 2nd and 3rd trimester Premature - -
et al. [101]
Legend: GPA granulomatosis with polyangiitis; SLE systemic lupus erythematosus; RA rheumatoid arthritis; ITP Idiopathic thrombocytopenic
purpura; NHL Non-Hodgkins lymphoma.
Due to insufficient evidence, rituximab cannot be deemed as being compatible with

pregnancy. Therefore the BSR 2016 guidelines [22] recommend that it should be stopped 6
months prior to conception. Rituximab has not been shown to be teratogenic from the limited
evidence reported, and has been shown to be associated with neonatal B cell depletion only in
those cases of second/third trimester exposures. Thus, inadvertent rituximab exposure at early
stages of pregnancy/within the first trimester is unlikely to cause major adverse effect on
neonates. Currently, no human breastfeeding data studies have been reported [22]. The UK
BSR prescribing recommendations for rituximab and other biologics in pregnancy have been
summarised in Table 5.
Table 5. Summary of other licensed biologics function and prescribing

recommendations according to current UKs full BSR 2016 guidelines for pregnant
women with IRD [22]
Current UK national BSR 2016 guideline

bDMARD bDMARD function
summary of biologic drug exposure/use during
type
pregnancy [22]
Rituximab A chimeric-murine monoclonal IgG1 There remains insufficient evidence to be
which binds to CD20 protein confident that rituximab is compatible with
expressed on B cells, which depletes pregnancy and it should be stopped 6 months
B cells. prior to conception. Limited evidence however,
has not shown rituximab to be teratogenic and
only 2nd/3rd trimester exposure is associated
with neonatal B cell depletion. Therefore
unintentional rituximab exposure at the 1st
trimester is unlikely to be harmful.
Tocilizumab A humanised IgG1, which binds to There remains insufficient data and tocilizumab
soluble and membrane bound IL6 should be stopped at least 3 months prior to
receptor, which hinders IL6 from conception. Unintentional exposure early in the
exerting its pro-inflammatory effects. 1st trimester period is unlikely to be harmful.
Anakinra A recombinant human IL1 receptor Due to limited evidence on which to base a
antagonist that lacks the Fc region, recommendation for Anakinra in pregnancy.
which blocks the biological activity However, unintentional exposure during 1st
of IL1. trimester is unlikely to cause harm.
Abatacept A fusion protein containing Fc region Due to limited evidence on which to base a
of IgG1 fused with extracellular recommendation for abatacept in pregnancy.
CTLA-4 domain which can bind to However, unintentional exposure during 1st
CD80 and CD86 molecules trimester is unlikely to cause harm.
expressed on APCs. Consequently,
abatacept stops APC from delivering
co-stimulatory signal required for T
cell activation.
Belimumab A fully humanised monoclonal IgG1 There remains insufficient data to recommend
directed against BAFF which belimumab in pregnancy, hence no specific
depletes B cells. recommendations can be made. However,
unintentional exposure in the 1st trimester is
unlikely to be harmful.
(Adapted from BSR 2016 guideline [22])
Legend: APC antigen presenting cell; BAFF B cell activating factor; CD cluster of differentiation;
CTLA-4 cytotoxic T lymphocyte-associated protein 4; Ig G1 immunoglobulin G1; IL1 interleukin
1; IL6 interleukin 6.
TOCILIZUMAB
Tocilizumab is a humanised monoclonal IgG which binds and inhibits the interleukin (IL)
6 receptor. Currently, there are very limited reports of the effects of tocilizumab exposure in
human pregnancies. The BSR 2016 guideline did not identify any full-length publications and
cited only one abstract. This abstract reported 33 tocilizumab exposed pregnancies in 32
patients with RA, of whom 26 patients were also taking concomitant MTX, a further 6
patients were exposed to tocilizumab monotherapy or to concomitant DMARD (which was
not MTX) [102]. The reported pregnancy outcomes were the following: n = 13 cases of
elective termination of pregnancy; n = 7 spontaneous abortions (where n = 5 were exposed to
concomitant MTX at conception); n = 11 healthy term deliveries (n = 2 with single drug
tocilizumab exposure and n = 9 with concomitant MTX). One infant died of respiratory
distress syndrome 3 days after emergency caesarean section for intrapartum feto-maternal
haemorrhage due to placenta praevia. The outcome was unknown for two pregnancies [102].
Therefore, the BSR 2016 guideline recommends that tocilizumab should be stopped for at a
minimum of three months pre-conception, but unintentional exposure to tocilizumab in the
first trimester is unlikely to be harmful. There were no data upon which to base a
recommendation for use of tocilizumab in breastfeeding [22].
Subsequently, Ishikawa et al. [103] have reported in abstract form pregnancy outcomes in
n = 7 tocilizumab exposed patients with RA. Pregnancy outcomes included: n = 5 full term
live births; n = 1 spontaneous abortion; and n = 1 premature delivery, for which the
pregnancy duration was not specified. One patient received tocilizumab throughout
pregnancy and five patients became pregnant after the drug was stopped (biologic free time
frame range was from 2-11 months). Notably, in the spontaneous abortion case, the mother
presented with high disease activity throughout pregnancy. Worsened disease activity was
reported in four patients post-partum and in three cases throughout pregnancy [103].
ANAKINRA
Anakinra is a recombinant form of human IL1 receptor antagonist that lacks the Fc
region, and has not been found to cross ex-vivo full-term human placenta [26]. The BSR 2016
guidelines identified n = 5 pregnancies exposed to anakinra in a cohort [38], case series [104]
and a case report [105]. Fischer-Betz et al. [104] and Berger et al. [105] reported on n = 3
patients with adult onset stills disease (AOSD) exposed to anakinra, in whom no appreciable
adverse effects of the drug on pregnancy were observed [104, 105]. A cohort study by Kuriya
et al. [38] identified n = 393 RA pregnancies from 34,169 women of childbearing age. In this
study, one patient in the elective abortion group (n = 37) was receiving anakinra, compared to
another one in the successful live birth group (n = 281), and this finding was not considered
significant to prove drug toxicity [38]. No human breastfeeding data was found. Due to this
limited evidence, the BSR 2016 guidelines [22] were unable to provide recommendations for
anakinra in pregnancy: however, unintentional exposure to this drug during the first trimester
is unlikely to be harmful.
ABATACEPT
Abatacept is a fusion protein containing the Fc region of IgG1 fused to the extracellular
domain of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) (shown in Figure 1). Thus,
it is capable of transferring across the placental barrier from the sixteenth week onwards.
Currently, there is very little evidence relating to exposure of human pregnancy to abatacept.
The BSR 2016 guideline [22] identified one case series [106] and one case report [85],
totaling n = 3 pregnancies exposed to abatacept in the first trimester, which were all
confounded by concomitant MTX. The outcomes were two (one spontaneous and one
elective) first trimester miscarriages [106], and one full-term healthy infant, who was
followed to 3.5 years of age with no observed complications [85].
Pham et al. [107] have published a review article reporting pregnancy outcomes from n =
8 patients participating in double-blind and open-label clinical studies of abatacept [107]. All
patients were taking concomitant MTX (n = 7) or LEF (n = 1). Three patients experienced a
spontaneous first trimester abortion, although two of them had a previous history of
spontaneous abortion, and other two patients had an elective abortion. The remaining three
patients were still pregnant at the time of the study report. This review article also reported a
delivery of a healthy new-born from a spouse of a male patient receiving abatacept treatment
[107].
Therefore, the BSR 2016 guidelines were unable to provide specific recommendations
regarding use of abatacept in pregnancy or breastfeeding, they do state however that
inadvertent exposure to abatacept in the first trimester is unlikely to be harmful. No
breastfeeding recommendations can be provided at this current time due to the lack of
evidence [22].
BELIMUMAB
Belimumab is a fully humanised monoclonal IgG1 (Figure 1) which inhibits a soluble B
lymphocyte stimulator (BLyS) also known as B cell activating factor (BAFF), which is an
important cytokine required for B cell differentiation and survival. It is the only biologic to be
approved for treatment of SLE [108, 109]. It is licensed for use in the UK, but does not have
National Institute for Health and Clinical Excellence (NICE) approval. Currently published
data on belimumab exposure in human pregnancies are limited to reports in review and
abstract articles. Further knowledge regarding this biologics safety, tolerability and potential
impact on human pregnancy and neonatal outcomes remains to be fully elucidated.
Review articles have summarised outcomes of human pregnancies from unplanned
pregnancies reported during manufacturers placebo controlled phase 2 and 3 studies of
belimumab in patients with SLE. In these studies, patients received belimumab and
concomitant therapy with immuno-suppressants, corticosteroids, anti-malarials or, non-
steroidal anti-inflammatory drugs (NSAIDs) [110]. All study patients who became pregnant
had their treatment with belimumab stopped immediately, and were removed from the clinical
trial. A total of 83 known pregnancy outcomes were reported, consisting of; 42% live births;
27.7% spontaneous abortions; 24% elective terminations; and 3.6% (n = 3) cases of
congenital anomalies of which one was a chromosomal translocation also detected in the
mother and therefore unrelated to belimumab exposure.
The belimumab pregnancy registry prospective study has been set up to collect pregnancy
outcome information (by voluntary reporting) from pregnant women who received
belimumab within 4 months prior to/and or during pregnancy. This study also aims to obtain
follow up long-term follow-up information on exposed infants (http://clinicaltrials.gov/
show/NCT01532310). The BSR 2016 guideline obtained unpublished pregnancy outcome
data from the belimumab registry (up to 08/09/2014) from (n = 118) SLE pregnancies, with
the following reported outcomes: 37.3% healthy live births; 28.8% spontaneous abortions and
28% elective terminations, all with no apparent congenital anomaly; and 4.2% live births with
congenital defects lacking any specific pattern [111].
A recent abstract published has described pregnancy outcomes for SLE patients who
conceived during their participation in clinical research studies which involved administration
of belimumab via two different ways, including intravenous and sub-cutaneous injections
[112]. A total of 66 pregnancies with known outcomes were reported in women who were
exposed to belimumab, and 6 women were receiving placebo drug. Out of 66 pregnancies
exposed to belimumab, foetal loss was reported to have occurred in 18 pregnancies (27%). In
contrast, out of a total of 6 pregnancies exposed to placebo drug, there were 3 cases (50%) of
foetal loss reported. A total of 33 live births out of 66 pregnancies (50%) were reported in
belimumab exposed group. There were 3/33 live births associated with congenital defects
which included: Dandy Walker syndrome (n = 1), bilateral enlarged kidneys in a pregnancy
which was also exposed to an unnamed teratogenic medication (n = 1), and an unbalanced
trans-location involving chromosomes number 11 and 13 (linked to mother). Lastly, in the
SLE patients receiving belimumab, anti-cardiolipin (aCL) antibodies were detected at
baseline in 7/33 (21%) patients who had a live birth, and 8/18 (44%) of these aCL patients
had foetal loss [112].
Due to insufficient evidence, the BSR 2016 guideline was unable to make any specific
recommendations regarding associated risk, safety and use of belimumab in human pregnancy
and breastfeeding, although unintentional exposure to belimumab in the first trimester is
unlikely to be harmful [22].
CONCLUSION
It is important to maintain control of IRD activity in pregnancy to ensure optimum
pregnancy outcomes. Increasingly, bDMARDs are being considered in this situation, and
there is growing evidence to support their compatibility in pregnancy. This chapter reviewed
the current evidence and recommendations from the BSR 2016 guidelines, which provides
medical practitioners with the necessary tools to facilitate optimum prescribing of bDMARDs
and other anti-rheumatic drugs in their patients considering and during pregnancy, thus
avoiding the unnecessary withdrawal of potentially beneficial medication in this situation.
ACKNOWLEDGMENTS
The authors would like to thank Dr Chee-Seng Yee, Consultant Rheumatologist,
Doncaster Royal Infirmary, Doncaster, UK (email: csyee@ymail.com) for reviewing the
chapter and providing very helpful comments.
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Chapter 16
BIOLOGIC THERAPY IN OSTEOPOROSIS:

Maria Mouyis, MRCP1 and Judith Bubbear, PhD2,*

Department of Rheumatology, Northwick Park Hospital, London, UK
1
2
Department of Rheumatology, Whipps Cross University Hospital, London, UK
ABSTRACT
Osteoporosis is a significant healthcare problem with a disabling impact on patients,
families and societies. This chapter provides a definition of osteoporosis, briefly explains
its pathogenesis and further explores the new biologic agents in the treatment of
osteoporosis. Treatments can be classified into anti-resorptive and anabolic agents.
Anti-resorptive agents include bisphosphonates, selective oestrogen receptor analogues
(SERMs), RANK-L inhibitors (denosumab), cathepsin K inhibitors and integrin
antagonists. Anabolic agents include parathyroid hormone (PTH) analogues
(teriparatide), anti-sclerostin antibodies and DKK-1 antibodies. Oral bisphosphonates
have been the mainstay of treatment for osteoporosis for many years due to the low cost
of these drugs, but compliance is limited due to side effects. In comparison, the biologic
agents are more expensive. The cost analysis of both licensed biologic agents
(teriparatide and denosumab) has shown cost-effectiveness compared to oral
bisphosphonates in long term treatment. One of the advantages of the biologic agents is
that of adherence, although this is also the case with intravenous zoledronate given
annually. Denosumab is only administered 6 monthly, which increases compliance and
therefore decreases long term cost. The treatment of osteoporosis has come a long way
from oestrogen therapy to biologics. Trials are still underway for the more recent biologic
agents identified as potentially useful in the treatment of osteoporosis. Denosumab has
proven effective for up to 8 years, and teriparatide has also been in use for a number of
Corresponding author: Dr. Judith Bubbear. Consultant Rheumatologist, Whipps Cross University Hospital,
*
London, UK (email: judith.bubbear@bartshealth.nhs.uk).

406 Maria Mouyis and Judith Bubbear
years. The place of newer biologic agents still needs to be determined; however, they can
provide viable alternatives for patients who are intolerant of bisphosphonates or who
have further fractures despite treatment. Despite the advances in bone research, one must
still take a holistic approach to treating patients, focusing on both non-pharmacological
and pharmacological therapeutic options.
Keywords: osteoporosis, denosumab, biologic therapy, teriparatide, sclerostin inhibitors,

cathepsin K inhibitors, integrin antagonists
INTRODUCTION
Osteoporosis is a condition of reduced bone mass and changes in architecture of bone
tissue. The National Institute of Health defines osteoporosis as a skeletal disorder
characterised by compromised bone strength predisposing to an increased risk of fracture.
Bone strength reflects the integration of two main features: bone density and bone quality.
Bone density is expressed as grams of mineral per area or volume, and in any given
individual is determined by peak bone mass and amount of bone loss. Bone quality refers to
architecture, turnover, damage accumulation (e.g., microfractures) and mineralization. A
fracture occurs when a failure-inducing force (e.g., trauma) is applied to osteoporotic bone.
Thus, osteoporosis is a significant risk factor for fracture, and a distinction between risk
factors that affect bone metabolism and risk factors for fracture must be made [1].
Worldwide, a bone fracture happens almost every 3 seconds, resulting in 8.9 million fractures
annually. An increased number of women worldwide are affected by osteoporosis (200
million), highlighting this condition as an important public health concern, therefore the
importance in understanding and treating osteoporosis. Men are also affected, with at least
one in four men having an osteoporotic fracture in their lifetime. In the US alone, men
accounted for 29% of total fractures in 2005 [2]. In terms of financial burden, osteoporosis is
comparable to other chronic conditions such as asthma, hypertensive heart disease or
rheumatoid arthritis [3].
PATHOGENESIS OF OSTEOPOROSIS
The pathogenesis of osteoporosis is not fully understood; although in the last few years
there have been some developments leading to new treatments of bone loss. These advances
are based on the interactions and effects of bone mediators and pro-inflammatory pathways in
the bone micro environment. Figure 1 is a schematic presentation of the pathogenesis of
osteoporosis and the mechanisms described below.
The balance between osteoclast activity and osteoblast activity leads to bone homeostasis.
Osteoclastogenesis causes bone loss, whereas the osteoblast activity promotes bone
formation. Tissue loss occurs when osteoclast activity is greater than osteoblast activity. This
is commonly seen in the post-menopausal female, when bone resorption increases by 50%
[4].
Low oestrogen levels alter bone remodelling due to increased production of tumour
necrosis factor alpha (TNF) and increased sensitivity to interleukin 1 (IL1). Both these
Biologic Therapy in Osteoporosis 407
cytokines act on pre-osteoblasts to secrete IL6, macrophage - colony stimulating factor (M-
CSF), IL11, and transforming growth factor beta (TGF).
Osteoclast activity is controlled through receptor activator of nuclear factor kappa-B
ligand (RANK-L), which is produced by osteoblasts and binds to the RANK receptor on
osteoclasts, stimulating osteoclast maturation, and thereby bones resorption. Oestrogen causes
a decrease in RANK [3][4]. Pro-inflammatory cytokines (IL1, IL6, IFN, and TNF) are also
thought to affect this process, and therefore bone resorption [5][6]. Osteoblasts are stimulated
by the parathyroid hormone to secrete M-CSF, which acts on osteoclasts which leads to bone
resorption. This is reflected by raised serum calcium levels. Osteoclast activation is only one
way of causing bone resorption, the other two mechanisms include increased expression of
the receptor of RANK-L and inhibition of osteoblast function whilst the osteoclast function is
promoted [8]. The homeostatic process is influenced by oestrogen, parathyroid hormone,
vitamin D and cytokines.
More recent studies have shown another signalling pathway involved in bone formation
is called the wingless-type (Wnt) signalling pathway [8]. This pathway is inhibited by
sclerostin, which is produced by osteocytes and Dickkopf-1 (DKK-1) (a protein secreted in
bone). These bind to the co-receptors low-density lipoprotein receptor related protein (LRP) 5
and 6, inhibiting the Wnt pathway and bone formation. The better understanding of this
signalling pathway has led to the discovery of new biologic agents, as illustrated in Figure 1.
These biologic agents are expanded on in the text as well as summarised in Table 1, where we
also included the treatment doses currently used or under investigation in clinical trials.
Legend: DKK-1 Dickkopf-1; PTH parathyroid hormone; PTHrP parathyroid hormone related
protein; RANKL receptor activator of nuclear factor kappa-B ligand.
Figure 1. Schematic presentation of target therapy for osteoporosis.

TREATMENTS OF OSTEOPOROSIS
Treatments can be classified into anti-resorptive or anabolic agents (Table 1). Anti-
resorptive agents include bisphosphonates, SERMs, RANK-L inhibitors (denosumab),
cathepsin K inhibitors and integrin antagonists. Anabolic agents include PTH analogues
(teriparatide), anti-sclerostin antibodies and DKK-1 antibodies.
Anabolic Agents
The parathyroid gland secretes parathyroid hormone (PTH), an 84 amino acid

polypeptide, in response to changes in serum calcium, thus regulating calcium and phosphate
homeostasis. To maintain calcium homeostasis, PTH acts on the renal tubules to increase
calcium reabsorption and acts on bone to increase bone resorption [9].
PTH and PTH-related protein receptor (PTHrP) is a protein coupled receptor in bone,
cartilage and kidney. The complex is referred to as PTHR1 [10]. The PTHR1 binds to several
cells stimulating intracellular pathways activated by PTH or PTHrP. Although they both act
on the same receptor their effect is different: PTH is involved in calcium homeostasis,
whereas PTHrP acts on the skeletal growth plate, regulating cell differentiation and
proliferation [11].
Teriparatide
Teriparatide is PTH 1-34, a PTH analogue. It causes bone formation and remodelling and
is therefore considered an anabolic agent [11]. It is approved both by the Food and Drug
Administration (FDA) and the European Medical Agency (EMA), and is a daily subcutaneous
(SC) injection given for a maximum of 24 months at a dose of 20 g a day.
Mechanism of Action
Pre-osteoblasts mature into osteoblasts which then lay down collagen and mineralise
matrix to lead to bone formation. This is done under the influence of PTH [12]. Activated pre-
osteoblasts also release cytokines to increase osteoclast activity leading to bone resorption. In
addition, PTH blocks sclerostin in the Wnt signalling pathway increasing bone formation
[10].
Efficacy
Bone formation will begin immediately and can be seen within the first month and peaks
in the first 9 months [13]. There is a 13% increase in bone mineral density (BMD) of the
female spine over a 3 year period [14]. There is particularly an increase in the density of
trabecular bone, which allows for an increase tensile strength and reduction of fractures,
although cortical bone also increases. This is why PTH is particularly considered for the
treatment of osteoporosis with vertebral fractures, as vertebrae have predominantly trabecular
bone [14], [15]. The Fracture Prevention Trial (FPT) confirmed the effect of PTH therapy in
the treatment of osteoporosis. It included 1637 post-menopausal women with a history of
vertebral fractures who were assigned to receive 20g PTH SC injection daily, 40g PTH SC
injection daily or placebo. BMD levels were assessed after 18 months of treatment, and there
was an improvement in BMD in the 20g group by 9% in lumbar spine and 13% in the 40g
group. Treatment with the licensed dose of 20g of teriparatide leads to a 65% reduction in
vertebral fractures. The 40g dose was also associated with 69% reduction of vertebral
fractures. The effect of PTH was considered to be independent of age, baseline BMD and
baseline vertebral fractures [16].
One of the clinical disadvantages of teriparatide is that as soon as treatment stops, bone
mass/BMD starts to decline, and an alternative agent needs to be initiated. This depends on
the patient and the clinical setting. This therapeutic aspect was explored in a phase II study.
After 12 months of treatment with teriparatide, patients were divided into 3 groups: to
continue with teriparatide, to receive no treatment, or to receive raloxifene. Lumbar spine
BMD was assessed at the end of 24 months. The teriparatide group continued to show
improvement in bone density (10.7%), the raloxifene group did not show a significant change
(7.9%), and the no treatment group showed a loss in bone density [17]. This study highlights
the fact that post teriparatide treatment, anti-resorptive agents are needed (denosumab is a
suitable option). The DATA extension study (denosumab and teriparatide transitions in
postmenopausal osteoporosis) enrolled women who were on teriparatide in the original trial
and treated them with denosumab, women who were on denosumab initially were given
teriparatide, and women who had been treated with both denosumab and teriparatide were
maintained on denosumab only. BMD was assessed at 6 monthly intervals from 6 months to
24 months. BMD at the hip increased the most in the denosumab after combination therapy
group (8.6%), followed by the teriparatide switched to denosumab group (6.6%), and then the
denosumab switched to teriparatide group (2.8%) The lumbar spine BMD increased by 18.3%
at 48 months in the teriparatide switched to denosumab group, but only 14% in the
denosumab switched to teriparatide group, and 16% in the combination to denosumab group.
Denosumab is therefore a potential treatment option after completion of teriparatide
treatment.
Safety Profile
Side effects of 20 g teriparatide include headache (6.9%), hypercalcaemia (4.3%),

arthralgia (8%) and nausea (12.4%-20 g), although these are usually short term side effects,
and more frequent in the first year of treatment [17]. Hypercalcaemia and nausea are more
common at the higher dose (40 g), therefore the current licensed dose is 20 g. At this dose,
only 3% of patients had persistent hypercalcaemia. It is commonly transient and tends to
occur at the onset of treatment. Although urinary calcium is increased the incidence of
hypercalcuria does not increase [16]. Patients with renal stones should not be treated with
PTH, although there are no reported cases of nephrocalcinosis secondary to PTH treatment.
Rarely some patients may experience hypotension with the first few injections [16]. There
have also been reports of increased serum uric acid levels and gout attacks [18]. In terms of
long term exposure, there have been case reports regarding the development of osteosarcoma,
although there is no clear cut causal relationship, as stated by a 7 year study (there
is a possible correlation with previous radiotherapy) [19]. The concern related to the
osteosarcoma risk have been developed from rat studies. Fischer rats were given 30-4500 g
(human dose equivalent) PTH1-34 from 8 weeks to 2 years, and a high proportion developed
osteosarcoma; although it seems to be dose, duration and age dependent. Adult rats did not
seem to develop osteosarcoma [20]. Teriparatide should be avoided in patients at high risk for
sarcoma, i.e., Paget disease or history of prior skeletal radiation therapy, and also in children
or those with unfused epiphyses.
Abaloparatide
This is a synthetic analogue of parathyroid hormone-related protein: PTHrp 1-34. It binds

to the PTH1 receptor, and is also given as a daily SC injection.
Efficacy
The ACTIVE trial (abaloparatide versus teriparatide) was a study of 222 post-
menopausal woman assigned to receive 24 weeks of treatment with daily SC injections of
placebo, abaloparatide, 20, 40, or 80 g, or teriparatide, 20 g. At 24 months, abaloparatide
showed an increase in BMD comparable to teriparatide, but also an improved in bone density
at the hip. Pro-inflammatory cytokines (IL1, IL6, IFN, and TNF) are also thought to affect
this process, respectively. Lumbar spine BMD increased by 5.5% with teriparatide versus 2.9,
5.2, and 6.7% in the abaloparatide, 20g, 40g, and 80g treatment groups. In the all
treatment groups the BMD values were higher than placebo, which showed an increase of
only 1.6% [21].
Abaloparatide and teriparatide have also been compared in a phase III active randomised
controlled trial, which enrolled 2463 post-menopausal women. They received daily SC
injections of 20g teriparatide, 80g of abaloparatide or placebo for a total of 18 months.
Calcium and vitamin D supplements were also continued. A number of 1901 patients
completed the trial. Changes in BMD and fracture rate were assessed. Teriparatide showed a
decrease in vertebral fracture risk of 80% compared to placebo. Abaloparatide showed a
reduction in the incidence of new vertebral fractures by 86% compared to placebo (4.2%) (P
< 0.001 in both cases). Non vertebral clinical fractures were reduced by 43% in the
abaloparatide group compared to 28% in teriparatide (P = 0.049). In terms of BMD, both
groups showed an increase at the spine, femoral and hip levels compared to placebo. At
18 months, however, abaloparatide showed a more significant increase at the hip and femoral
neck (P = 0.0003). Abaloparatide caused lower levels of serum C-terminal cross-linking
telopeptide (CTX), a marker of bone resorption, with levels 46-69% lower in the
abaloparatide group than the teriparatide group [22]. Overall, abaloparatide seemed to have a
number of advantages when compared to teriparatide with greater fracture risk reduction of
non-vertebral, as well as a better side effect profile. The phase III trial is ongoing, with
patients receiving alendronate after stopping abaloparatide, and full results are awaited. At the
time of writing, abaloparatide is not licensed for use in osteoporosis treatment.
Safety Profile
In the ACTIVE trial the most commonly reported side effects were dizziness (9%),
headache (13%, which is similar to the incidence reported for teriparatide). Transient
hypercalcaemia was present in 11% of cases who received abaloparatide 80 g, which is less
than teriparatide (40%) at 4 hours<0.001, but there was no significant difference at 24 hours
[21]. Injection site reactions were considered to be mild. A proportion of 4% patients had a
serious side effect, including influenza, ovarian cancer (abaloparatide 20g), back or chest
pain, bronchitis, arthralgia and ascites. There was also a severe case of diverticulitis in a
patient on abaloparatide 80 g. Interestingly, there is also a risk of anti-abaloparatide
antibody formation. This was seen in 12% patients at end of 24 week study period, although
this did not correlate with an increase in side effects or immune related effects [2,18-19].
SCLEROSTIN INHIBITORS: ROMOSOZUMAB AND BLOSOZUMAB

Mechanism of Action
Sclerostin is a glycoprotein which inhibits bone formation through the Wnt pathway as
described above, therefore by inhibiting the action of sclerostin one can increase bone
formation.
Efficacy
Romosozumab is an anti-sclerostin anti-body which has been shown in both phase I and
II trials to increase bone density [24], [25]. In the phase I trial, patients received intravenous
AMG 785 (1 or 5mg/kg) SC, AMG 785 (0.1, 0.3, 1, 3, 5, or 10 mg/kg) or placebo. Patients
were assessed on day 85 and found to have a 5.3% increase in BMD at the lumbar spine
compared to placebo. The drug was also thought to be well tolerated [25]. The phase II trial
was of 419 postmenopausal women assigned into 4 groups: anti-sclerostin (romosozumab) at
monthly doses of 70 mg, 140 mg or 210 mg, or 3 monthly at doses of 140 mg or 210 mg;
alendronic acid (70mg weekly), teriparatide (20 g daily) or placebo. Analysis at 12 months,
showed an increase in BMD from baseline with 11.3% at the lumbar spine, 4.1% at the total
hip level, and 3.7% at the femoral neck level in patients receiving 210 mg romosuzumab. This
was significantly greater than the changes seen in both the teriparatide (7.1% at the lumbar
spine) and alendronic acid (4.1% at lumbar spine) groups. The pooled romosozumab group
showed a statistical improvement compared to placebo regardless of the dose (P < 0.001) [5],
[26], [27]. The changes in BMD were further reflected by an increase of pro-collagen type I
N-terminal pro-peptide (PINP), which is a marker of bone formation compared to baseline, as
well as a decrease in CTX of 50%. Changes in bone markers are transient and maximal at 1
month. A recent press release of the FRAME study, which is the phase III study currently
underway, indicated that there was a 73% reduction of vertebral fractures compared to
placebo [28].
Similarly, a phase II trial with blosozumab (another anti-sclerostin anti-body) showed

significant benefit, as high as a 17.7% BMD improvement at the spine and 6.2% at the hip
level, with a dosing regimen of 270 mg every 2 weeks for a one year period. The results were
considered to be significant compared to placebo, P < 0.001 [29].
Safety Profile
Injection site reactions (erythema) are commonly reported. Symptoms of back pain,
headache, nasopharyngitis arthralgia, and dizziness were also reported in phase I and phase
III studies [28]. One case of hepatitis has been documented as well, which resolved rapidly
with no adverse outcomes. Transient hypercalcaemia was noted at the onset of the study due
to a transient increase in PTH [5], [25]. In the phase III study 5.2% of patients reported an
injection site reaction. There was a report of one atypical femoral fracture (after 3 months of
treatment), and two reports of osteonecrosis of the jaw (after 12 months of treatment).
Sclerostin inhibitors are not yet approved by any regulatory body or yet licensed for use.
DKK-1 ANTIBODIES
These are antibodies to the DKK-1 related protein 1. This protein binds to LPR5 and
LPR6 to reduce bone formation. By blocking or inhibiting the DKK related protein 1 this
should lead to an increase in bone formation. There are currently phase I clinical trials in
multiple myeloma patients but no specific trials in osteoporosis at the time of writing this
chapter. This may be an area for development in the future.
ANTI-RESORPTIVE AGENTS
Denosumab
Denosumab is a human monoclonal antibody that binds to RANK-L, thereby inhibiting

osteoclast activity on bone. RANK-L binds to the RANK receptor which is found on pre-
osteoclasts and osteoclasts. Activation of osteoclasts through this mechanism leads to bone
resorption. Denosumab in binding to RANK-L blocks this process, decreasing osteoclast
maturation and bone resorption [5].
Efficacy
There have been several trials assessing the efficacy of this drug. We will focus on the
FREEDOM trial, which compared denosumab to placebo. Denosumab has been approved by
the FDA for the use of both male and post-menopausal female osteoporosis, as well as by the
EMA.
The FREEDOM trial randomised 7868 woman with osteoporosis to treatment with SC
denosumab 60 mg, every 6 months or placebo. After 3 years, there was an increase of 4% in
BMD of the lumbar spine versus no improvement in the placebo group. The trial was
extended for a further 5 years (8 years in total), showing an increase of BMD at the lumbar
spine of 18.4% over 8 years. After 3 years, both placebo and treatment groups received
denosumab. The trial also indicated that denosumab reduced fracture rate.
In comparison to placebo, there was a lower vertebral fracture rate of 2.3% versus 7.2%
(P < 0.001); therefore a 68% risk reduction. There was also a lower rate of non-vertebral
fractures 0.7 versus 1.2% (P = 0.04), which equates to 40% risk reduction and hip fractures of
6.5% respectively versus 8.5% in the placebo group (P = 0.01), which is 20% risk reduction
[30][32].
Optimal treatment duration is not yet known. There is safety data from the patients in the
FREEDOM study for 8 years [30]. Unfortunately, the effect of denosumab is not sustained;
once stopping treatment the BMD begins to fall but will improve again with retreatment. The
action of denosumab is reflected in the trend of the bone markers. At the onset of treatment,
CTX and P1NP fall in the first month, and the bone marker levels stay low whilst the patient
is on denosumab. On stopping denosumab, CTX and P1NP increased above baseline within 3
and 6 months respectively, but returned to baseline by month 48, highlighting that the
treatment effect is not sustainable on discontinuation of treatment [33].
Safety Profile
Side effects are reported in approximately 10% of patients and can be multisystemic.
They include upper respiratory tract infection (24%) arthralgia (19%), back pain (16%),
nausea (11%), hypertension, (10.5%), headache (10.5%), dyspepsia (10.5%), influenza
(10.5%), cystitis/UTI (10.5%), diarrhoea (8%), dermatitis/eczema (3%). Rare side effects
include cellulitis, atypical femoral fractures (1 per 10 000 years) and osteonecrosis of the jaw
(ONJ) (4.2 per 10 000 years), which is in fact similar to bisphosphonates (20 cases per 10 000
in patients on oral bisphosphonates for more than 4 years) [27], [31], [34], [35]. Post
marketing studies still favoured a positive risk profile. There are reports of 4 atypical femoral
fractures and 32 cases of ONJ amongst 1,252,566 patient-year [36]. There is no renal
excretion for denosumab; therefore, no dose adjustments are necessary in patients with
impaired renal function. However, it should be used with caution in patients with a
glomerular filtration rate of less than 30ml/min due to the increased risk of hypocalcaemia
post treatment. The treatment efficacy did not appear dependent on the glomerular filtration
rate level [37]. Transient hypocalcaemia was not noted in women with normal renal function.
The risk of infections may be related to RANK-L functions on the immune system. There
have been reported infections requiring hospitalisation such as significant cellulitis,
pneumonia, appendicitis and diverticulitis [38][40].
CATHEPSIN K INHIBITORS: ODANACATIB

Cathepsin K is a protease enzyme, metabolised by CYP3A4, which causes breakdown of
bone. It is released by osteoclasts and degrades type 1 collagen and bone matrix. Cathepsin K
inhibitors prevent this process, which leads to an improvement in BMD. Odanacatib inhibits
cathepsin K, therefore preventing bone resorption [41][43].
Efficacy
Initial phase 1 trials on postmenopausal women showed an improvement in BMD, which

was dose dependent. Doses of 50 mg, oral, weekly administration, showed an increased in
lumbar spine BMD of 5.5%, with a safety profile similar to placebo [41], [42], [44]. These
results were confirmed in phase II trials. A double blind trial randomised 214 postmenopausal
women to receive placebo or odanacatib (50mg weekly). At the end of one year, an increase
BMD of 3.5% in the lumbar spine was noted. Bone markers indicative of bone resorption
were also reduced compared to placebo (P < 0.001) [42]. A further extension study, which
followed patients up for other additional 3 years echoed similar results. In the first 2 years, a
dose-ranging regimen was assessed (10, 25, or 50mg of odanacatib once weekly) and showed
a dose dependent increase in BMD). From the 3rd year onwards, patients were randomised
into continuing with placebo or odanacatib 50mg weekly. Patients who received a total of 5
years of odanacatib treatment had an increase in BMD of 11.9% at the lumbar spine and 8.5%
at the hip in comparison with those who were placebo, who experienced a reduction of BMD
back to baseline.
One of the potential advantages of odanacatib is that through inhibiting cathepsin K it
interferes with osteoclast function, but does not reduce the number of active osteoclasts, as is
the case with bisphosphonates [45]. The largest trial to date is the Phase III Long Term
Odanacatib Trial (LOFT), whereby 6,713 participants were recruited. The study was
terminated early due to positive outcome results, and ethical issues of continuing with placebo
treatment [43], [46]. In terms of fracture efficacy, there was a 54% risk reduction in the rate
of new radiological vertebral fractures,73% risk reduction in clinical vertebral fractures and
23% risk reduction in clinical non vertebral fractures [47].
Safety
Reported side effects include atrial fibrillation at an incidence of 1.1%, atypical femoral
fractures (0.1%) and morphea like skin lesions in 0.1%. A 3.8% incidence of cerebrovascular
events was noted but this is under ongoing review [45] [48].
INTEGRIN ANTAGONISTS
Osteoclasts bind to the bone surface through integrins. Integrin alpha V beta 3 (V3) is
needed for bone resorption. Integrin antagonists may therefore prevent bone resorption, by
preventing osteoclast binding to the bone surface. In a double blind randomised placebo
controlled phase II trial of this integrin antagonist, 227 post-menopausal women were
assessed over a 12 month period. The patients were randomised to receive either placebo, 100
mg once daily, 400mg once daily or 200 mg L-000845704 (a V3 integrin antagonist) twice
daily. Although there was not an increase in total BMD, there was an increase of BMD at the
lumbar spine level (2.1%, 3.1% and 3.5% at doses of 100 mg, 400 mg or 200 mg twice daily,
respectively. P < 0.01). The 200 mg twice daily dosing also demonstrated an increase in
BMD at the hip level (1.7%, P < 0.03). This drug may therefore be a potential for the future
treatment of osteoporosis, but further studies are required to support these preliminary data
[49].
Safety
The study data reported adverse events in 6 patients: headache, decreased appetite, hot
flushes and arthralgia (although this was not considered to be a drug effect). There also
seemed to be an increase incidence in dermatitis, pruritus, rash, and urticarial [49]. It is
difficult to comment further on safety as the study included only a small numbers of patients
for a short period of time.
HEALTH ECONOMICS
The prevalence of osteoporosis increases with age, and is higher in post-menopausal
women than men. Across 27 countries in the European Union, the prevalence is
approximately 27.6 million in 2010 [50]. In the United States (US) 10 million people over the
age of 50 have osteoporosis [51].
One of the concerns with osteoporosis is the impact it has on society secondary to direct
and indirect costs, not to mention the impact on patients and their families. Direct costs relate
to acute fractures and the treatment thereof, followed by rehabilitation. Indirect costs are
related to acquired health problems, such as hospital acquired infections or venous thrombo-
embolism [50].
There were 8.9 million fractures across the world in the year 2000 secondary to
osteoporosis [3]. Common fracture sites include the forearm, hip and spine. Hip fractures may
lead to significant morbidity and mortality. They are associated with falls, which increase in
the elderly one third of elderly individuals falling per year and less than 50% of patients with
hip fractures achieving the same level of function post operatively. In the UK, the cost of hip
fractures is 2 billion pounds per year with the cost of treatment equalling 13,000 in the first
year [52].
These figures are only expected to increase in light of the ageing population. Vertebral
fractures are also common but the prevalence is difficult to estimate due to difficulties with
detection and reporting [50]. Both vertebral and hip fractures are associated with an increase
in morbidity and mortality. Apart from pain, vertebral fractures also lead to loss of height and
kyphosis. These changes in body shape can lead to a loss of self-confidence, respiratory
problems and a reduction in ability to self-care which will then impact on social services. In
the US up to 20% patient will require nursing home care [51].
Table 1. Summary of biologic treatments of osteoporosis
% Fracture risk
Drug Trade name MOA Dose Side Effects Comments
reduction
Teriparatide Forsteo/ Recombinant 20g/day SC Nausea 6.9% 65%-80% vertebral Decrease in BMD
Forteo PTH analogue Headache 13% fracture after stopping
PTH 1-34 Hypercalcaemia 40% (4hr) 28% non-vertebral treatment.
rhPTH 1-34 Hypotension fractures
Abaloparatide PTHrp 1-34 80g/day/SC Dizziness 9% 86% vertebral Currently not
Headache 14% fractures licensed for use in
Hypercalcaemia 11% (4hr) 43% non-vertebral osteoporosis.
Arthralgia (<4%) fractures
Back pain (<4%)
URTI (<4%)
Denosumab Prolia Anti-RANK-L 60mg SC 6 URTI (24%) 68% vertebral Decrease in BMD
monthly Arthralgia (19%) fractures after stopping
Back pain (16%) 20% non-vertebral treatment
Nausea (11%) fractures
Hypertension, (10.5%)
Headache (10.5%)
Dyspepsia (10.5%)
Influenza (10.5%)
Cystitis/UTI (10.5%)
Diarrhoea (8%)
Dermatitis/eczema (3%)
Osteonecrosis of the jaw (rare)
Atypical femoral fractures (rare)
Romosuzumab Sclerostin 210mg monthly Injection site reaction 73% reduction in Phase III clinical
inhibitors Headache vertebral fractures trial
Nasopharyngitis
Back pain
Report hepatitis
% Fracture risk
Drug Trade name MOA Dose Side Effects Comments
reduction
Blosozumab Sclerostin 270mg every 2 Injection site reaction No fracture data Phase II trials
inhibitors weeks available at the
time of writing this
chapter
Odanacatib Cathepsin K 50mg weekly PO Cerebrovascular events 72% vertebral Trial terminated due
inhibitors Morphea like skin reactions fractures to positive results.
UTI 23% non-vertebral
AF fractures
Integrin L-000845704 Integrin alpha V 100mg od Headache No fracture data

antagonists beta 3 400mg od Decreased appetite available at the time
antagonist 200mg bd Hot flushes of writing this
chapter
Legend: AF atrial fibrillation; bd twice daily; BMD bone mineral density; od once daily; MOA mechanism of action; PO per os; SC subcutaneous; URTI
upper respiratory tract infection; UTI urinary tract infection.
NB: Studies are not head to head and study populations vary between studies
DALYs (Disability-Adjusted Life Years) are used to assess the global burden of
osteoporosis. In 2000, there was a loss of 5.8 million DALYs, which is 0.83% of global
burden of non-communicable disease. This is secondary to 9 million fractures in the year
2000. In Europe alone this is 1% of all DALYs per annum [50].
The National Institute for Health and Care Excellence (NICE) in the UK provides a care
pathway for osteoporosis. They advocate that people presenting to any healthcare
environment should have a fragility fracture risk assessment, depending on their age and risk
factors. Thereafter, primary or secondary prevention should be carried out in post-menopausal
women. NICE advocate that oral alendronate should be used as first line in both primary and
secondary prevention of osteoporotic fractures. Other bisphosphonates, raloxefine and
strontium ranelate would be considered as a potential second line treatment, although due to
cardiovascular and thromboembolic risk, the use of strontium ranelate was limited.
Denosumab is suggested as second line treatment in those patients who have fractured during
bisphosphonate treatment. In primary prevention, denosumab use is limited to those patients
at higher risk of fractures, with concomitant lower T-scores (NICE technology appraisal
TA204). In the UK, teriparatide is restricted to those patients who are unable to tolerate or
have had an unsatisfactory response to a bisphosphonates, have a low BMD with a T-score of
at least -3.5 and multiple fractures.
The rationale for oral bisphosphonates as first line treatment is the reduced cost of these
drugs compared to newer agents. A cost-effectiveness analysis of teriparatide as a first line
treatment compared to alendronic acid in the treatment of glucocorticoid induced osteoporosis
and post-menopausal osteoporosis was undertaken in Sweden. A micro simulation model was
used analysing fracture risks, fracture costs, and a treatment period of 18 months with either
bisphosphonate, teriparatide or no treatment. The threshold for cost-effectiveness was set at
50 000 Euros/QALY (Quality adjusted life year). Teripartide was found to be cost effective at
this threshold in 74% of the replications simulated in both the teriparatide and bisphosphonate
groups [53].
Another study in Sweden looked at the cost-effectiveness of denosumab. A health
economics model was used (the Markov Cohort model). Patients were followed in 6 monthly
cycles from the baseline point of initiation of treatment to 100years/death, and the cost-
effectiveness of medication was assessed over a 5 year period. Results showed that
denosumab was the most expensive treatment when compared to either no treatment or
treatment with alendronate, but had a larger gain in QALY and morbidity cost savings.
Adherence was also found to be higher in the denosumab group: at 1-year, discontinuation
rates were double in the alendronate group versus denosumab group. (20.2% versus 10.3%, P
= 0.0492). The incremental cost-effectiveness ratio (ICER) was close to 60,000 per QALY.
Comparing denosumab to alendronate the cost per QALY gained was 27,090.
In the US the cost of denosumab versus bisphosphonates was also looked at using the
same Markov model. This study noted that in a post-menopausal population a total lifetime of
cost for alendronate was $US 64,400 versus $US 67,400 in the denosumab group. Total
QALYs were $US 82,804 compared to $US 83,155. Overall, treatment with denosumab
despite its cost is considered cost-effective especially in high risk groups [54].
Other biologic agents have yet to be priced as most of them have been only used in
clinical trials. Biologic agents in the treatment of osteoporosis do not yet have a clearly
Biologic Therapy in Osteoporosis: New Developments, Clinical Uses 419
defined role, and will need to be assessed in comparatively in different health systems. The
way the new biologic drugs will be placed in a treatment algorithm will depend on local
economic and demographic factors.
There are predictions that life expectancy will increase over time. A larger elderly
population implies an increased rate of osteoporosis and fractures, and ultimately economic
burden. Perhaps the key lies in prevention and controlling of as many variables associated
with osteoporosis risk as possible, such as regular exercise, adequate calcium and vitamin D
levels, healthy diet and falls education. Another aspect to consider is that of adherence.
Improving treatment adherence can improve cost-effectiveness by reducing the number of
fractures. This was seen with both zoledronic acid and denosumab treatments, although this
may be partly related to the dosing regimens of these drugs [50], [55], [56].
CONCLUSION
The treatment of osteoporosis has come a long way from the use of oestrogen therapy to
the development of biologic agents. Despite the new therapeutic advances, one must still take
a holistic approach to treating the patient, focusing on non- pharmacological and
pharmacological treatments. Due to cost-effectiveness, the bisphosphonates remain the first
line pharmacological intervention in osteoporosis, as they are inexpensive and have proven
anti- fracture efficacy. In terms of cost-effectiveness, biologics are starting to supersede the
anti-resorptives, and may be considered in patients with refractory disease, intolerant of
bisphosphonates and previous treatment failure. Biologics are a suitable alternative for
patients who are intolerant of bisphosphonates or who have further fractures despite
treatment. Trials are still underway for the more recent biologic agents, but there is already
long term efficacy data for both denosumab and teriparatide.
ACKNOWLEDGMENTS
The authors would like to thank to Dr Richard Keen, Consultant Rheumatologist with
interest in metabolic bone diseases, from Royal National Orthopaedic Hospital, Stanmore,
UK (email: richard.keen@ucl.ac.uk) for reviewing this chapter.
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Chapter 17
BIOLOGIC TREATMENTS FOR PULMONARY

INVOLVEMENT IN RHEUMATIC DISEASE
Helen S. Garthwaite1,2 and Joanna C. Porter, PhD FRCP1,2*

Centre for Interstitial Lung Disease, UCLH and 2Leukocyte Trafficking Laboratory
1
Centre for Inflammation and Tissue Repair, University College London, London, UK
ABSTRACT
Interstitial lung disease (ILD) is a common complication of many autoimmune

rheumatic diseases and has significant morbidity and mortality implications. Despite this,
there is a lack of robust evidence to support treatment decisions, with many assumptions
extrapolated from clinical trials in systemic sclerosis, or based on experience of treating
other immune mediated inflammatory disorders. Treatment to date has typically been
with steroids and synthetic disease modifying drugs, including mycophenolate and
cyclophosphamide, with clinical response being variable and thus, often unpredictable.
An increased understanding of the molecular pathways responsible for propagating
inflammation in connective tissue diseases (CTDs) has led to the development of targeted
biologic agents. These drugs have transformed the management of many autoimmune
diseases and represent a key treatment strategy, particularly for patients with severe and
or non-responsive disease. Since on-going inflammation in progressive CTD-ILD is
likely to be due to activation of the same pathways and cytokines, there has been
increasing interest in using these treatments in patients with pulmonary disease refractory
to other therapies. In this chapter, the evidence relating to the efficacy of biologics in
treating CTD-ILD will be reviewed. Concerns around the safety of these agents will also
be discussed, reflecting reports that they may indeed, on occasion, cause new ILD or
accelerate pre-existing disease.
*
Corresponding author: Dr. Joanna Porter, Centre for Interstitial Lung Disease, Rayne Institute, University College
London, 5 University Street, London, UK, email: Joanna.porter@ucl.ac.uk.
426 Helen S. Garthwaite and Joanna C. Porter
INTRODUCTION
Interstitial lung disease (ILD) is an umbrella term used to describe a collection of
conditions where the tissue network that supports the alveoli is affected. These disorders are
characterised by microscopic inflammation or fibrosis or both, resulting in impaired
ventilation and in severe cases, respiratory failure. The various diseases covered by the term
ILD, have common clinical, radiological and histopathological features. They are globally
classified as either idiopathic interstitial pneumonias (IIP) or those secondary to specific
occupations, recreational exposures, drugs, or as discussed here, in the context of connective
tissue disease (CTD).
The frequency of CTD associated ILD varies between individual autoimmune rheumatic
diseases (Table 1), with reported rates for each disease also varying significantly. This
reflects a lack of consensus about how ILD is defined, particularly as in some cases it may be
diagnosed incidentally, without being clinically significant. Equally, ILD can occur as the
initial, predominant or even, the only manifestation of an immune mediated inflammatory
disease; a condition referred to as interstitial pneumonitis with autoimmune features (IPAF)
[1]. In addition, specific CTDs are associated with particular histopathological patterns with
characteristic corresponding radiological features, such that a lung biopsy is infrequently
necessary (Table 2).
Table 1. Incidence of interstitial lung disease and relative incidence of histopathological

subgroups in connective tissue disease (least frequently observed (-) to most (++++)
Rheumatic Frequency of clinically

UIP NSIP OP LIP DAD
conditions significant ILD
Systemic sclerosis 50% [2] but with some ++ ++++ + - +
(SSc) studies quoting up to
80%
Polymyositis/ 45-75% [3][5] ++ +++ ++ - +
dermatomyositis
(PM/DM)
Rheumatoid arthritis 18-50% [6], [7] +++ ++ + - +
(RA)
Primary Sjgrens 25% [8] + + + +++ -

Syndrome (SS)
Systemic lupus 3-8% [9], [10] + + + - ++
erythematosus
(SLE)
Legend: UIP usual interstitial pneumonitis; NSIP non specific pneumonitis; OP organising
pneumonia; LIP lymphocytic interstitial pneumonitis; DAD diffuse alveolar damage.
Biologic Treatments for Pulmonary Involvement in Rheumatic Disease 427
Table 2. Description of radiological features that correspond

to histopathological diagnoses
Pulmonary involvement Radiological features

UIP Reticular change associated with traction bronchiectasis
(Usual Interstitial With or without honeycombing
Pneumonitis) Subpleural basal predominant distribution
Lobar volume loss
Minimal ground glass opacification (i.e., not the dominant feature)
often in areas of reticular change
NSIP Ground glass opacification more dominant feature
(Non Specific Interstitial Combined with reticular opacities
Pneumonitis) Subpleural but may lack an apico-basilar gradient
Typically no honeycombing although architectural distortion (traction
bronchiectasis) may be present
OP Patchy, multifocal consolidation
(Organising Pneumonia) Predominantly basal, subpleural or peri-bronchovascular distribution
Perilobular pattern may be seen
Ill defined peribronchial or peribronchiolar nodules and bands with air
bronchograms can occur
Co-existing architectural distortion can occur i.e., traction
bronchiectasis
LIP Scattered thin walled cysts typically subpleural or perivascular
(Lymphocytic Interstitial Ground glass opacification
Pneumonitis) Interstitial thickening
Small centrilobular or subpleural nodules
Mid to lower lobe predominance
DAD Acutely - diffuse ground glass opacification and consolidation in a
(Diffuse Alveolar dependent distribution
Damage) In the organising phase fibrotic change (including honeycombing) can
develop
There is increasing recognition that pulmonary disease is a major determinant of

morbidity and mortality in CTD. In systemic sclerosis (SSc) for example, pulmonary
complications (referring to ILD and pulmonary hypertension) have surpassed renal
involvement as the leading cause of death [11]. Despite this, the heterogenicity of ILD
coupled with the relative rarity of these diseases, means the evidence base for treatment is
limited. The lack of a reliable biomarker, the difficulty in predicting the natural history of the
disease and disagreement over suitable primary end points in clinical trials, are just some of
the challenges facing researchers. Corticosteroids typically form the basis of initial treatment,
with SSc the notable exception. Immunosuppressive agents including azathioprine,
mycophenolate and cyclophosphamide are added to therapy in those requiring unacceptably
high doses of steroid for maintenance, or for those who progress in spite of steroids; however,
some patients demonstrate refractory disease. In reality, SSc associated ILD is the only
condition for which good quality clinical trial data is available, such that treatment choices
are often based on logical assumptions reflecting what is known about disease
pathophysiology, together with expert opinion based on case reports/series and registry data.
The increasing use, availability and success of biologic therapies to treat various
autoimmune mediated diseases has led to a growing interest in the use of these drugs to treat
CTD-ILD. Although the clinical manifestations of immune mediated diseases vary, there are
many shared themes. There is definite evidence for a genetic component with different
autoimmune diseases existing with increased frequency in certain families, as well as
repeated reporting of similar environmental precipitating factors. Furthermore, the different
diseases share common pathophysiological themes with certain target inflammatory cells and
cytokine pathways repeatedly implicated.
As well as the predictable challenges of studying drug efficacy in orphan diseases,
progress in this area has been further complicated by the emergence of autoimmune
phenomena (including ILD) in response to some biologic agents. In this chapter, current
experience of using these treatments in CTD-ILD, including the possible development of new
or worsening ILD in response to therapy will be covered.
The biologic treatments discussed fall into two broad categories; lymphocyte targeted
therapies or cytokine inhibitors. The former refers to the anti CD20 B cell depleting
monoclonal antibody, rituximab and anti T cell activation agent, abatacept, whilst the latter
includes tumour necrosis factor (TNF) blockers, IL6 receptor monoclonal antibodies and IL1
receptor antagonists.
PATHOGENESIS OF CTD-ILD
The pathogenesis of ILD due to autoimmune disease is complex and involves cellular and
biologic players from both the innate and adaptive immune responses. The lung pathology is
characterised by degrees of inflammation and fibrosis that vary, not only between diseases,
but also between individuals with the same disease. The events that lead to ILD can be
considered in three phases illustrated schematically in Figure 1. In an initiating phase, there is
lung endothelial or epithelial damage. This may result from autoimmunity, such as antibody
mediated cellular toxicity (Type II hypersensitivity) or deposition of antigen-antibody
complexes and activation of complement (Type III hypersensitivity); or by an environmental
stimulus such as severe infection or a systemic/inhaled toxin. In each of these scenarios, a
complex interplay between host and environmental factors results in a vigorous inflammatory
response.
There is an increasing interest in the role of neutrophils in driving the subsequent
adaptive immune response. T cells produce cytokines, IL4, IL10 and IL13, which drive
monocytes, recruited from the blood, and lung resident macrophages towards an alternatively
activated macrophage (AAM) phenotype that produce, amongst other cytokines, high levels
of IL6 and TGF. In this inflammatory phase the key mediators are TNF (produced by the
epithelium and AAMs) and IL6 (neutrophils, T cells and AAMs). There is loss of the normal
lung architecture and disruption of the basement membrane across which gas exchange takes
place. With further epithelial damage and apoptosis, comes up-regulation of epithelial
integrins such as v6. This robust inflammatory response overlaps with a reparative phase
in which resolution of inflammation and fibroproliferative repair dominate driven by high
levels of TGF. Released in an inactive form, this cytokine requires an activation step
facilitated by integrins that bind the RGD motif of pro-TGF and promote its cleavage and
activation. Locally activated TGF drives the recruitment of fibroblasts and a feed-forward
cycle of further TGF production. Under these conditions, fibroblasts differentiate into
myofibroblasts that express high levels of integrin v6, are resistant to apoptosis and lay
down collagen matrix. Once collagen has been laid down in the lung, where the architecture
is already distorted, gas exchange is no longer efficient. There is a change in the vasculature
of the lung parenchyma with both fall-out of blood vessels and neoangiogenesis driven by
local production of vascular endothelial growth factors. Although this is a simplification of a
complex series of events, it is clear that early interruption of the abnormal mechanisms at play
may allow a return of the lung architecture to normal; once the inflammation and fibrosis
have continued unchecked and irreversible fibrosis ensues the chances of full recovery are
reduced (Figure 1). At this stage the clinical aim is merely to prevent further loss of lung
function.
Attempts to interrupt this cycle of inflammation and fibro-proliferative repair form the
basis of the therapies considered in this chapter and shown in Figure 2. Those shown in
orange boxes are considered in the chapter below; those shown in hatched boxes, although
theoretically beneficial, have yet to be proven in a clinical setting. They include the anti-IL13
agent lebrikizumab, the TGF resolimumab and metelimumab, and the anti-fibrotic
pirfenidone, whose mode of action, though not well understood, appears to, amongst other
things, prevent the effects of TGF on fibroblasts.
Figure 1. Pathological mechanisms involved in ILD in the context of autoimmune rheumatic diseases.
Figure 2. Drug targets in ILD associated with autoimmune rheumatic diseases.
INDIVIDUAL BIOLOGIC AGENTS

Evidence for individual biologic agents is described in the following part of this chapter.
The greatest amount of data exists for rituximab and results of that data are also presented in
Table 3.
RITUXIMAB
Rituximab is a chimeric monoclonal antibody with a high affinity for the CD20 surface
antigen expressed on B and pre B lymphocytes, and results in B cell depletion. It is derived
from a mouse monoclonal antibody following replacement of the heavy and light chain
constant regions with their equivalent from the human IgG1 monoclonal antibody. It was
originally developed and used to successfully treat lymphomas, but now has proven efficacy
in treating the articular manifestations of rheumatoid arthritis (RA) as well as having a role in
the management of ANCA vasculitis and idiopathic thrombocytopenic purpura (ITP).
Excess B cell accumulation in lung biopsies of ILD patients has been described in several
pre clinical studies. One group demonstrated increased CD20+ B cell infiltrates in lung
biopsies from 35 patients with RA-ILD [12] compared to 21 patients with idiopathic
interstitial pneumonias and 11 non ILD cases. The RA-ILD samples showed marked
formation of peri-bronchiolar B cell follicles, diffuse tissue infiltration with plasma cells and
increased B cell cellularity. Equally, in SSc B cells have been repeatedly implicated as having
a pathogenic role. In one animal model, B cells demonstrated chronic hyperactivity and
augmented CD19 signaling, an important regulator of B cell maturation, with CD19
deficiency attenuating skin fibrosis [13]. Furthermore, in patients with SSc, peripheral blood
B cells specifically overexpress CD19 and are chronically activated [14] with lung biopsies
from these patients also demonstrating excess B cell infiltration arranged in lymphoid
aggregates [15].
Two uncontrolled studies have explored the potential clinical efficacy of rituximab in
SSc, although the primary endpoints were related to skin manifestations. In the first, skin
fibrosis clinically and histologically improved significantly [16]. In the second although no
overt clinical benefit was observed, skin biopsies did show a reduction in the myofibroblast
score, and patients were clinically stable [17]. In these studies, lung function was documented
pre and post treatment and shown to be stable at 24 weeks, although significant ILD was one
of the exclusion criteria and only 50% of patients (across both groups) had any ILD, all of
which was mild.
When specifically considering SSc associated interstitial lung disease (SSc-ILD), several
case reports have shown success in otherwise refractory disease [18], [19]. Furthermore, in a
case controlled trial [20] the effects of rituximab in 14 patients with SSc-ILD was evaluated.
All the patients had a predictable autoantibody profile (Scl 70 positive), diffuse cutaneous
disease and significant ILD on the basis of high resolution CT (HRCT) appearances and
pulmonary function tests (PFTs). They were then randomised to receive either four weekly
pulses of rituximab (repeated at 6 months) or placebo in addition to any established
medication (predominantly mycophenolate). At 1 year there was a significant increase in
forced vital capacity (FVC) and diffusing capacity of carbon monoxide (DLCO) from
baseline in the rituximab group whilst no change was seen in the control arm. In addition,
direct comparison of FVC change showed significant improvement in the treatment group
when compared to standard therapy (P = 0.002). In an extension study [21] 8 of the original
patients received further courses of rituximab at 12 and 18 months, completing a total of 2
years of follow up. The lung function tests of these patients demonstrated a linear
improvement over time with interestingly the most striking response seen in the two
individuals with the shortest disease duration.
There have also been several reports describing the successful use of rituximab for ILD
associated with anti synthetase syndrome, a form of polymyositis/dermatomyositis where 70-
80% of patients have ILD. In one retrospective case series [22], 11 patients with severe ILD
were treated with rituximab. In this cohort the lung function prior to treatment (where
available) demonstrated a definite deterioration, with 64% of the patients achieving a greater
than 10% improvement in FVC and/or a greater than 15% improvement in DLCO 6 months
after therapy. Amongst the remaining patients, 2 still improved but by a less convincing
categorical percentage change, whilst 2 deteriorated in spite of treatment and 1 died
secondary to pneumocystis jirovecii infection. In a follow on study [23] of the same patients,
plus a further 13 treated at the same centre, there were significant improvements in lung
function over more than 4 years of follow up. Again the most pronounced improvements were
seen in those who received treatment within 12 months of diagnosis.
Similarly, Marie et al. [24] described 7 patients with deteriorating anti synthetase
syndrome associated ILD refractory to steroids, cytotoxics and/or intravenous
immunoglobulins, who were then treated with rituximab. In these patients, there was a
significant improvement in median FVC and DLCO 1 year after rituximab therapy as well as
a universal improvement in symptoms and imaging, that at follow up, was either stable (n =
2) or improved (n = 5).
Finally, in a retrospective case series of 50 patients with severe progressive immune
mediated ILD, rituximab was shown to be a viable rescue therapy [25]. The patients in this
report had a variety of underlying diseases, including 33 with a defined CTD. These patients
had severe lung disease as defined by a median FVC of 44%, median DLCO of 24.5% and
resting hypoxia, with 4 being mechanically ventilated at the time of rituximab administration.
In these patients, there was a demonstrable deterioration in lung function, in spite of treatment
with cyclophosphamide or mycophenolate, prior to rituximab. Paired pulmonary function
tests 6-12 months following one course of treatment (1g at baseline repeated at 14 days)
showed an improvement in FVC with stabilisation of DLCO. It is worth noting that, similar to
the previous series, the response to treatment was unsurprisingly not universal; whilst 85% of
CTD-ILD patients responded, 5 patients continued to deteriorate in spite of treatment. The
authors evaluated possible predictors of response and discovered that a lesser decline in FVC
prior to treatment and a trend towards a better preserved FVC were positive predictors of
response, perhaps hinting yet again that earlier intervention with biologic therapy is more
likely to result in a positive clinical outcome.
There clearly remains a need for further, more robust data in support of rituximab,
however these studies do suggest a potential role for its use in specifically treating CTD-ILD,
irrespective of extra-thoracic disease activity. Moreover, these are patients with severe and
progressive disease in whom treatment options are extremely limited. For these patients lung
transplant may be the only remaining option, but in reality is only possible for a few highly
selected patients. The currently recruiting RECITAL study comparing cyclophosphamide and
rituximab as treatments for CTD-ILD (NCT01862926) will potentially provide more data on
the subject.
It is worth considering that whilst the current studies suggest B cells may be important, it
is unlikely that this is simply related to blocking autoantibody production. There is data, for
instance from systemic lupus erythematous, that these cells have a role in regulating T cell
behaviour and that the B cell line that repopulate following successful depletion tend to be
antigenically inexperienced, and hence, there may be a mechanism by which the immune
dysregulation that characterises these diseases, is effectively reset. Should rituximab become
an established treatment option in the future, the timing of repeat treatments will need to be
considered. B cell depletion (based on peripheral blood measures) in patients receiving
rituximab (for other indications) persists for 6-9 months after dosing; however, it is not
consistent across all patients and does not always correspond to clinical disease activity,
perhaps adding weight to the concept of immune system resetting. These observations
make standardised treatment protocols difficult to determine and it is likely significant
resources will need to be deployed to detect any suggestion of disease reactivation or
relapse.
Table 3. Studies assessing the efficacy of rituximab in CTD-ILD
Connective tissue Endpoint or measured

Clinical Trial Study design Outcome/Comments
disease studied parameters
Daoussis et al. [10] Open label, randomised Systemic sclerosis (1) change in PFTs Significant increase in FVC with RTX; 68.13% +/-19.69 at
controlled; rituximab (n = (baseline, 24 weeks and 1 year) baseline vs. 75.63%+/- 19.73 at 1 year; P = 0.0018.
8) vs. standard therapy (n = (2) modified Rodnan skin score Significant increase in DLCO with RTX; 52.25%+/-20.71 at
6) at baseline and 1 year. baseline vs. 62+/-23.21 at 1 year; P = 0.017).
Median improvement in FVC was 10.25% with RTX vs. a mean
deterioration of -5.04% in the control group.
Significant improvement in HAQ at 1 year vs. baseline in RTX
group; no change in the standard therapy group.
Daoussis et al. [11] Extension study of the 8 Systemic sclerosis Lung function parameters. Significant increase in FVC at 2 years compared to baseline
original patients who 77.13% (+/-7.13) vs. 68.13% (+/-6.96), P < 0.0001
received rituximab (10) Median percentage improvement in FVC at 2 years was 12.79%
Two additional cycles (8.76-25.12%)
given at 12 and 18 months Early disease (n = 2) had the most striking response with increases
with follow up at 2 years in FVC of 27.94% and 29.03%
Significant increase in DLCO 63.13% (+/-7.65) vs. baseline of
52.25% (+/-7.32), P < 0.001
Median percentage improvement in DLCO at 2 year 19.47%
(3.81-27.15).
Sem et al. [12] Retrospective case series (n Anti-synthetase Lung function at baseline, 3 and In the 8 patients with gradual onset ILD, 5 displayed a >10%
= 11) syndrome 6 months. HRCT Serum anti Jo- improvement FVC and >15% DLCO, 2 improved but by a lesser
1 (or anti-PL-12) and serum degree and 1 demonstrated a decline in FVC
creatine kinase. In the 3 with acute onset ILD (< 1 month) FVC improved by
>10% in 1, however1 worsened and the 1 patient died.
Andersson et al. (13) Retrospective cases series Anti synthetase Lung function. HRCT. Median percentage predicted FVC increased from 58% (15-60) to
(n = 24) syndrome Median follow up 52 months. 72% (38-105), P < 0.018
Median percentage predicated DLCO increased from 41% (15-
60%) to 48% (15-84%)
7 of the 24 had >30% increase in all PFTs
Most pronounced effects in those with disease duration < 12
months.
Extent of ILD on HRCT decreased in the majority of patients
21% (7 out of 34) died during the observation period with the
most common adverse event infection although mortality rate
across whole patient cohort was 32%.
Connective tissue Endpoint or measured

Clinical Trial Study design Outcome/Comments
disease studied parameters
Marie et al. [14] Retrospective case series of Antisynthetase Change in FVC and DLCO prior Significant improvement in FVC (P = 0.03) and DLCO (P =
patients with ILD refractory syndrome to RTX and 6 and 12 months 0.00002).
to standard therapy after treatment Median FVC at baseline 66% (35-76%) increasing to 74% (57-
108%) and median DLCO from 39% (20-57%) to 59% (49-72%).
Clinical resolution/improvement of ILD allowed a tapering of the
daily steroid dose from a median daily dose of 20mg (range 7-
30mg) at baseline to 9mg (range 3-15mg) at 1 year (P = 0.015).
Allenbach Open label prospective Anti-synthetase Primary endpoint was muscular Improvement in ILD as measured by PFTS in 50% of patients (N
et al. multi-centre phase II trial in syndrome with involvement = 5),
patients refractory to myoisits and ILD Secondary endpoints (1) CK 4 demonstrated stabilisation and 1 declined
prednisolone and at least 2 levels (2) FVC and or DLCO (3) 6 out of 10 were able to reduced immunosuppression.
immunosuppressants (n = decreased need for
10) immunosuppressive therapy at
12 months following 1st of 2
cycles 6 months apart
Keir et al. [16] Retrospective assessment CTD-ILD (33); Change in paired pulmonary Median decline in FVC of -13.3% (-47.2 to 4.5%) and DLCO of -
of case series of patients Idiopathic function data at 6-12 months 18.8% (-47.8 to 0%) prior to RTX
with severe progressive inflammatory Patients defined as responders In the 6-12 months following RTX FVC improved by 8.9% (-
ILD (n=50) myopathy (10) (stable or categorical 9.1% to 45.5%) and DLCO stabilised (median change of 0%,
SSc (8) improvement) or non responders range -24% to 76.2%; P < 0.01).
UCTD (9) (continued categorical decline or 28 (85%) patients were classified as responders; 18 with
MCTD (2) death) stabilisation of PFTs and 10 with a categorical improvement.
RA (2) SLE (1) Strongest response in ILD associated with idiopathic
Sjogrens (1) inflammatory myopathy
RECITAL Randomised double blind Severe or Primary endpoint of absolute Currently recruiting
(NCT01862926) controlled trial comparing progressive CTD- change in FVC over 48 weeks.
rituximab against ILD; SSc, PM.DM Secondary endpoints; change in
intravenous or MCTD (1) DLCO (2) health related
cyclophosphamide quality of life scores (3) global
disease activity score (4)
progression free survival using a
composite endpoint of mortality,
transplant, treatment failure or
decline in FVC >10%
Legend: CK creatine kinase; DLCO diffusing capacity of the lungs for carbon monoxide; DM dermatomyositis; FVC forced vital capacity; HAQ health assessment questionnaire; HRCT high resolution CT;
MCTD mixed connective tissue disease; RA rheumatoid arthritis; PFTs pulmonary function tests; PM polymyositis; RTX rituximab; SSc systemic sclerosis; SLE systemic lupus erythematosus; UCTD
undifferentiated connective tissue diseases.
ABATACEPT
CTLA-4 is expressed on T cells and is a physiological antagonist of the T cell co-
stimulatory molecule CD28. CTLA-4 competes with CD28 for binding to CD80/86 on
antigen presenting cells, and prevents delivery of the necessary second signal for T cell
activation. Abatacept is a fully human soluble fusion protein made up of cytotoxic T
lymphocyte antigen 4 (CTLA-4) and the Fc portion of IgG1 (CTLA4-Ig) It acts as a high
affinity ligand for CD80/CD86 on APCs, preventing the engagement of CD28 and the
subsequent T cell activation, resulting in immunological anergy.
Abatacept therapy already has an established role in treating the articular features of RA
where CD28 expression is increased, with a mean expression greatest in patients with
clinically active disease [26]. Its role in treating CTD- ILD is not fully established but would
seem logical given that excess, activated T cells in ILD may promote fibrosis and endothelial
damage through cytotoxic effects and through the production of soluble mediators. Certainly,
activated T cells are increased in the lung interstitium and bronchoalveolar fluid from SSc
patients with active ILD [27]. Furthermore, serum CTLA-4 levels have been shown to be
elevated in patients with diffuse cutaneous systemic sclerosis (dcSSc), and are associated with
greater frequency and severity of pulmonary fibrosis in this cohort [28].
In the pre clinical setting animal data has provided further evidence, with a CD28
deficient mouse model demonstrating markedly reduced fibrosis with decreased production of
relevant chemokines and cytokines [29]. As previously intimated, CTD-ILD knowledge
frequently evolves from similar diseases: e.g., in hypersensitivity pneumonitis, a form of non
CTD-ILD, there is an up-regulated expression of CD86 (B7-2) on alveolar macrophages,
accompanied by an influx of activated T cells. In a mouse model of this disease,
administration of CTLA4-Ig markedly decreased lung inflammation, leading to significantly
fewer inflammatory cells in the bronchoalveolar lavage fluid and lung tissue, coupled with
decreased production of IL-4, IL-10, and IFN-gamma [30], [31].
In terms of clinical experience of using abatacept in CTD-ILD, only case reports exist,
with the majority commenting on safety rather than efficacy, reflecting concerns about the use
of alternative biologic agents in patients with ILD. Mera-Varela et al. [32] presented their
experience with the drug in 4 patients who either developed ILD or had progression of
underlying ILD whilst receiving TNF blockers. In all cases, a switch to abatacept resulted in
significant improvement in their joint disease, and no further progression of respiratory
disease measured both objectively (with lung function and imaging) and in terms of
symptoms. A further case report of a 62 year old male with treatment refractory sero-negative
RA has been published, which suggested that treatment with abatacept not only halted
progression of lung function deterioration, but in fact resulted in some parameters improving
[33]. The paucity of similar positive results, in other words cases where there is an
improvement rather than a lack of deterioration, underpins one of the key messages when
managing CTD-ILD. Unlike articular disease the goal of treatment is often to induce stability,
and whilst improving function is desirable, it is not realistic when established fibrosis is
present. The currently recruiting ASSET study will potentially provide more insight into the
efficacy of abatacept in CTD-ILD. It is a phase II study comparing abatacept with placebo in
dcSSc with one of the secondary outcomes measures being change in per cent predicted FVC
from baseline to 52 weeks (NCT02161406).
TUMOUR NECROSIS FACTOR BLOCKERS

A longstanding interest in TNF as a target reflects no shortage of evidence indicating
that expression of this master cytokine is increased in the lungs of ILD patients, localising
particularly to the epithelium and macrophages. A causative role for it in the pathogenesis of
pulmonary fibrosis is strengthened by observations that blocking TNF signalling attenuates
bleomycin induced fibrosis [34][37] in a murine model.
Several case reports of CTD-ILD (RA, SSc and DM) have demonstrated a sustained
improvement in respiratory symptoms with stabilisation of lung function tests [38], [39], or
even an improvement in some physiological parameters [40], [41] when using infliximab. In a
retrospective case series of 14 patients with DM associated ILD, 71.4% demonstrated an
increase in motor strength, reduced rashes and an improvement in lung CT appearances with
adalimumab [42]. The remaining 4 patients, however, died of respiratory failure, although
they all had more severe hypoxaemia compared to the responders, suggesting that earlier
intervention may be associated with a greater chance of response.
Despite these reports, the role of TNF blockers as a therapy for ILD has been
significantly hampered by numerous reports of new or worsening ILD as a response to these
agents, an observation discussed in more detail elsewhere in this chapter.
TOCILIZUMAB
Tocilizumab is a fully humanised monoclonal antibody that binds to and inhibits IL6
receptors. IL6 has been implicated in the disease pathogenesis of various autoimmune
diseases with a wealth of data demonstrating that it is both pro-inflammatory [43][45] and
pro-fibrotic with an increase in collagen and glycosaminoglycan production from human
dermal fibroblasts induced by IL6 [46].
In SSc patients, IL6 has been shown to be overexpressed in skin, serum [47] and
bronchoalveolar lavage fluid. Serum levels positively correlate with severity of skin disease
[48]. Furthermore, IL6 inhibition has been associated with prevention and reversal of skin
fibrosis in a murine scleroderma model [49]. A positive correlation between IL6 and HRCT
scores [50] has also been demonstrated, suggesting that IL6 induced inflammation is
associated with more aggressive pulmonary disease. De Santis et al. [51] reported similar
findings with elevated IL6 levels predictive of a decline in FVC and/or DLCO within the first
year and of death within 30 months.
The clinical experience of using the drug to treat ILD is, however, scarce. In a published
case report [52] a 15 year old girl with an undifferentiated systemic inflammatory condition
associated with progressive interstitial lung disease, refractory to steroids, synthetic disease
modifying drugs, TNF blockers and anakinra, was then treated with tocilizumab. This led to
an improvement in respiratory symptoms, oxygenation and a reduction in ground glass
opacification on CT, which was then sustained for 2.5 years. In another case report,
experience of using tocilizumab to treat organising pneumonia associated with Sjgrens was
reported [53]. A 55 year old man with clinical findings consistent with the disease was
initially treated with oral prednisolone, demonstrating a rapid improvement in respiratory
symptoms and infiltrates on CT imaging; however, as the dose was reduced both
methotrexate and rituximab were ineffective at controlling both pulmonary and arthritis
symptoms. At this stage tocilizumab was added to prednisolone and methotrexate with a rapid
improvement in symptoms, normalisation of lung function tests and successful reduction in
steroid dose.
In a more recent proof of concept study, the use of tocilizumab in SSc was investigated
[54]. Eighty seven patients with active diffuse cutaneous disease and elevated acute phase
reactants (in this instance platelets and C reactive protein) were randomised to receive
subcutaneous tocilizumab or placebo for 48 weeks. At the mid point evaluation there was a
numerically favourable effect on the modified skin scores favouring tocilizumab, an effect
which was even greater at 48 weeks. Over the course of the study 27% of patients in the
placebo arm showed a decline of more than 10% in FVC compared with 3.3% in the
tocilizumab group (P = 0.009). Adverse events were high for both groups (88.4% of the
treatment arm and 90.9% of the placebo group), with infections more commonly associated
with tocilizumab (n = 6 versus 1). One episode of severe pulmonary infection resulted in
death, whilst non-infectious side effects were more frequently observed with placebo (n = 10
versus 5 in the tolicizumab group). As a result of these findings a confirmatory phase III
clinical trial assessing benefit on skin, but also evaluating pulmonary disease response is
underway (NCT01532869).
ANAKINRA
Anakinra is a recombinant interleukin 1 receptor antagonist, blocking the activity of IL1,
a cytokine produced in response to inflammatory stimuli. It has proven efficacy in RA
articular disease, reducing radiological progression [55], and providing greater benefit than
traditional DMARDs alone [56], [57].
In an animal model of pulmonary fibrosis, administration of an IL1 receptor antagonist
completely prevented collagen deposition after instillation of a profibrotic drug and globally
decreased the proportion of damaged lung on histopathological samples [58].
In humans, IL1 inhibitory activity has been shown to be diminished in healthy smokers,
patients with sarcoidosis and idiopathic pulmonary fibrosis, when compared with healthy
nonsmokers, suggesting that this may be relevant in other chronic inflammatory lung diseases
[59]. Furthermore, in other forms of ILD, namely asbestosis and silicosis, Nalp3
inflammasome activation has been shown to lead to IL1 secretion, and Nalp3 knockout mice
demonstrate reduced production of this cytokine with diminished recruitment of
intrapulmonary inflammatory cells [60]. At present, there is minimal clinical experience of
using this agent except for a case report demonstrating partial response [52], however, the
rationale underpinning its potential may result to further use in the future.
NEW OR WORSENING ILD IN RESPONSE TO BIOLOGIC THERAPY

Autoimmune disease appearing in response to the use of biologic agents was first
described in RA patients treated with a TNF blocker [61]. Since then the number and
diversity of autoimmune diseases triggered by biologic agents has accumulated in line with
their increasing use. Cases of new ILD in association with all the first generation TNF
blockers have been reported [62], [63]. Results from post marketing surveillance for the three
TNF blockers in common use are presented in Table 4.
There are also a considerable number of case reports describing new onset or worsening
of pre-existing ILD in response to biologic treatments with an alternative mechanism of
action, including tocilizumab, rituximab and abatacept [67][73]. The sometimes serious
nature of these reactions were highlighted by Ostor et al. [74] who reported four fatalities
from sudden deterioration of previously present, but asymptomatic ILD, soon (3-10 weeks)
after receiving infliximab. How exactly these treatments might cause such serious respiratory
complications is not known, but theories include causing idiosyncratic drug reactions,
modifying a pre-existing ILD into a more injurious phenotype, or by increasing susceptibility
to infection which potentially leads to an exuberant inflammatory host defence. In the case of
the TNF blockers, experimental studies have shown that TNF may have both pro and anti-
fibrotic effects, and potentially it is the balance or rather imbalance of these two opposing
roles that may result in either prevention or acceleration of pulmonary inflammation.
In an analysis of registry data from the BIOGEAS project, Ramos-Casals et al. [75]
reviewed 800 cases of autoimmune disease (all forms, not just pulmonary) documented after
the use of biologic agents. Amongst all the cases, in 118 patients ILD was reported,
predominantly following infliximab and etanercept. The mean time of developing ILD after
starting the therapy was 14.7 weeks, with the majority manifesting within 6 weeks of
initiating treatment. In all cases, the biologic agent was stopped, and over 80% of patients
were then treated with steroids or an alternative immunosuppressant, with subsequent
resolution in just over a third. A proportion of 78% of the recorded deaths were due to ILD (N
= 14 of a total of 18 deaths), 12% of the total number of patients developing ILD as a
complication of their treatment. Perhaps, even more importantly death was predominantly
seen in patients with pre-existing ILD (11 of the 14 who died).
One difficulty with appraising the currently available data, with regard ILD risk, is that
these observations are from case reports or registry data and bias is likely to exist. Since
safety signals have been published in relation to TNF blockers and RA-ILD in 2004,
clinicians are less inclined to prescribe these drugs in patients with pre-existing pulmonary
fibrosis. Indeed, ILD has been included as an undesirable effect on the specific product
characteristics (SPC) for the three TNF blocking agents. This has potentially resulted in more
patients with ILD receiving standard therapy and since the presence of ILD is a major
contributor of death, the mortality rate in this cohort will have risen.
Table 4. Incidence of new ILD from post surveillance of the TNF blockers
Number of RA Number/%
TNF blocker Reference
patients evaluated developing ILD
Infliximab 5000 25/0.5% Takeuchi T et al.
[64]
Etanercept 7091 42/0.6% Koike T et al. [65]
Adalimumab 3000 17/0.6% Koike T [66]
Indeed, several authors have presented evidence suggesting that there is no increased risk
of ILD with biologics. Wolfe et al. [76] were unable to associate the use of biologic
treatments with hospitalisation for ILD, with only one case in their cohort (a total of 260 per
100,000 patient years) demonstrating a possible temporal association with the administration
of infliximab. What is more clear is that ILD itself is a strong predictor of increased all-cause
mortality in RA patients (mortality odds ratio 2.12) irrespective of the treatment given [77].
An observational study using data from the BSRBR (British Society for Rheumatology
Biologics Register) examined the influence of TNF blockers on mortality in patients with
established RA-ILD [77]. Of the 13883 patients identified, 367 had pre-existing ILD as
identified by their physician; 68 were then treated with standard therapy, whilst 299 were
treated with anti TNF therapy (biologic nave). The mortality rate in the group with pre
existing ILD treated with a biologic was 23% versus 21% in those who received standard
treatment (median follow up 3.8 and 2.1 years respectively). Amongst these patients, ILD was
cited as the cause of death in 21% of the patients who died and were treated with TNF
blockers compared with 7% in the DMARD group. For patients who had no pre-existing ILD,
ILD was given as the cause of death in 14 patients treated with TNF blockers (2% of deaths,
0.13% of the total number treated) versus 2 patients in the comparison group (1% of the
deaths, 0.05% of the total number of patients in this cohort). After adjustment for age, gender
and other potential cofounders the adjusted mortality rate ratio was 0.81 (0.38 to 1.73) for the
TNF treated cohort, suggesting no increased mortality in this group.
Curtis et al. [78] evaluated the ILD incidence and exacerbation of pre-existing disease
amongst users of abatacept, rituximab and tocilizumab compared with anti TNF agents in a
cohort of RA patients. These patients had previously discontinued a different biologic agent,
and hence represented a group with more refractory disease. They used two different methods
to define ILD, one with a high specificity and the other with a high sensitivity,
acknowledging the inherent difficulties in diagnosing ILD. Overall ILD incidence rates
ranged from 1.8 to 6.4 per 1000 patient years. The authors concluded that there was no
significant difference in the risk of ILD incidence between patients exposed to TNF blocking
agents compared to biologics with an alternative mechanism of action. The proportion of
patients with newly diagnosed ILD ranged from 0.1% to 0.4%; whilst the frequency of ILD
exacerbations in patients with pre-existing ILD ranged from 4.1-8.4% at rates between 65.8
and 127.7 per 1000 patient-years.
Similarly Herrinton et al. [79] identified 38 cases of newly diagnosed ILD amongst 8417
patients with autoimmune diseases. Of those patients treated with a TNF blocker, 0.5% were
diagnosed with ILD over follow up, versus 0.3% of those who received standard treatment.
Nearly all the cases of ILD occurred in patients with RA where the incidence rate was 7 times
higher than for the other autoimmune diseases, however the adjusted hazard ratio (1.03; 95%
CI [0.512.07]) did not suggest any increased risk with TNF blockers compared to standard
treatment with methotrexate. It is worth remembering however, that existing ILD patients
were not included in this analysis and observations from other authors would suggest that it is
these individuals where the risk is greatest.
Ultimately, whilst there are reports of both new ILD and progression of pre existing
disease in response to all currently licenced biologics, making firm conclusions is not
possible based on current evidence, particularly for diseases other than RA. These outcomes
are rare and generally based on observational or retrospective data where there is no formal,
matched comparator arm. Since ILD is a complication of these diseases it is of course feasible
that the new ILD cases may have occurred irrespective of the treatment. Equally, the natural
history of existing ILD is often unpredictable and it is difficult to know whether observed
progression is related to treatment or indeed disease activity.
CONCLUSION
There are many considerations when determining a management plan for a patient with
CTD-ILD. The first is whether indeed the disease requires treatment. Given that a significant
number of patients will have subclinical, or minimally significant disease, the decision to treat
will be informed by the course of the disease, as well as non-pulmonary, patient factors. In
some cases, reassurance combined with sequential long-term observation is appropriate.
Therapy is generally given to those with either significant, severe disease at diagnosis or to
those with a progressive phenotype based on the severity of functional impairment indicated
by symptoms, lung physiology measures/FVC decline, HRCT appearances, and in some
cases, BAL cytology. In the absence of strong trial evidence, it would seem most appropriate
to appraise each patient on a case by case basis taking into consideration these various factors,
as well as the presence of articular disease and response to previous therapies. A potential
algorithm for managing these patients is summarised in Figure 3.
At present, if the pulmonary disease is the dominant clinical problem it is likely treatment
with more conventional, non biologic therapy will remain first line, with mycophenolate or
azathioprine, or alternatively cyclophosphamide (+/- methylprednisolone) if the disease is
severe or rapidly progressive. The use of biologics will be reserved for those patients who fail
to respond to these treatments or in those who have co-existing severe articular disease.
Having said this, some of the current data hints that earlier intervention, when function is
better preserved, might result in more impressive outcomes and the results of future studies
may well add weight to this argument, such that biologic agents will be used sooner and more
frequently. In terms of selecting specific agents, currently the largest evidence base is for
rituximab, however, it is feasible that as new evidence emerges drugs with alternative
mechanisms of action may be increasingly used.
In addition, combination therapy (to include a biologic agent or agents) may become
more commonplace with physicians adopting an approach more akin to oncology, focussing
on multiple mediators and pathways, and simultaneously targeting them. ILD pathogenesis
shares common themes with cancer biology including response to growth signals, abnormal
fibroblast behaviour and altered cellular signalling and communication. In both disease
groups, multiple pathways are implicated in propagating disease and in pulmonary fibrosis
the balance of these potentially varies between individuals, providing a possible explanation
for the different histological patterns, range of clinical manifestations and response to
treatments that we see in clinical practice. Personalised medicine, already used to treat some
cancers, would allow for individualised treatment on the basis of a patients predominant
pathogenic pathway. This may become possible as our understanding of pathogenesis
improves and with the availability of validated and commercially available biomarkers.
Legend:
1
Moderate disease defined as FVC 60-80% predicted.
2
Progressive disease should include exclusion of infection or other potential cause for lung function
decline.
HRCT high resolution CT; DLCO diffusion capacity of lungs; FVC forced vital capacity; MMF
mycophenolate mofetil; CYC cyclophosphamide; PFTs pulmonary function tests.
Figure 3. Potential treatment algorithm for managing CTD-ILD.
In the future predicting response to treatments using these tools and applying
pharmacogenomics may drastically alter our approach to treatment. There will, however, need
to be careful consideration in terms of maintaining effective host defence particular if
combination therapy is used.
There remains controversy about the safety of TNF blockers or indeed other biologic
agents in the presence of pre-existing ILD. It is the authors view that if a patient has severe
debilitating disease, either thoracic or extra thoracic, biologic agents should not, on the basis
of current evidence, be withheld due to concerns about causing exacerbations. Put simply, if it
is felt that the disease left untreated will have significant morbidity or mortality implication,
treatment should be undertaken but with careful, specialist directed monitoring. The greatest
body of evidence for potential harm relates to TNF blockers in patients who have established
ILD, thus one might postulate that where alternatives are available, it would seem ideal to use
a non TNF agent in these patients. Having said this, the absence of evidence does not have the
same meaning as evidence of no harm and the same close monitoring for adverse events is
recommended irrespective of the drug used.
ACKNOWLEDGMENTS
The authors would like to thank Dr Maria Leandro, Consultant Rheumatologist and
Honorary Senior Lecturer at University College London Hospitals/University College
London for reviewing the chapter (email: maria.leandro@ucl.ac.uk).
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Chapter 18
ADDITIONAL BENEFITS OF TUMOUR NECROSIS

FACTOR INHIBITOR THERAPIES
Angela Pakozdi, PhD and Vanessa Morris, MD*

ABSTRACT
Tumour necrosis factor (TNF) inhibitors have been shown to possess a wide range of
beneficial effects other than reducing inflammation. Most of those have been recognised
indirectly during observational and clinical trials that studied the anti-inflammatory
effects of the drugs. Patients appreciate greatly when fatigue and depression improve
once treatment commences. Both fatigue and depression, however, seem to strongly
relate to disease activity and their independent assessment in clinical trials has been
challenging. However, reports on the positive impact of TNF blockers on fatigue and
depression have been consistent. Both cachexia and anaemia seem to improve after the
initiation of TNF inhibitor treatment. Reduced bone loss has been observed in RA
patients taking TNF blockers in several studies; although this effect may be explained by
better disease control. TNF inhibitors may reduce the risk of atherosclerosis and
cardiovascular (CV) co-morbidity. In this chapter we aim to highlight the most important
extra-articular benefits of TNF inhibitor treatment.
Keywords: TNF blockers, fatigue, depression, cardiovascular risk, cachexia, anaemia,

fertility
INTRODUCTION
Controlling inflammation is a very necessary part of treating patients with arthritis. TNF
inhibitors have revolutionised the way inflammatory diseases, such as rheumatoid arthritis
(RA), seronegative inflammatory arthritis and ankylosing spondylitis (AS) are managed.
Correspondence to: Dr Vanessa Morris, Department of Rheumatology, University College London Hospital NHS
*
Foundation Trust, 250 Euston Road, London, NW1 2PG, email: vanessa.morris@uclh.nhs.uk.
450 Angela Pakozdi and Vanessa Morris
Introducing these drugs early on in the disease course reduces morbidity and as a result
improves the quality of the patients life. Patients not only suffer from joint pain and stiffness,
but also symptoms of severe lethargy and depression. The active inflammatory condition may
lead to cachexia and weight loss. Inadequately treated arthritis patients often go on to lead a
life of disability thus making it harder for them to work.
The disease not only impacts on the patients, but also their relatives and friends, and the
society as a whole. Up to a third of RA patients stop working in the first few years of
developing arthritis and require state support. With better disease control, patients can
continue to live a life of normality and employability. These drugs, although expensive, are
cost effective as they reduce long-term disability and the need for joint replacement surgery,
incapacity and the need for financial support. TNF inhibitors may improve fertility, not only
by improving general health, but also by modulating the immune system. Whether TNF
inhibitors exhibit actions beyond controlling inflammatory activity remains debatable and in
this chapter we review the evidence for these possible additional beneficial effects.
FATIGUE
Fatigue is an overwhelming symptom in RA, and patients consider the management of
fatigue to be a critical outcome of medical treatment [1]. OMERACT 8, an international
initiative to improve outcome measurement in rheumatology clinical trials, long recognised
that measuring fatigue in addition to the core set of outcome measures in RA clinical trials
should be aimed for [2]. Whether fatigue is directly related to the inflammatory disease
activity or rather correlates with pain and disability is still debated. Sickness behavior in
animals is mediated by pro-inflammatory cytokines including TNF alpha () [3] and is
characterised by loss of appetite, decreased activity and withdrawal from social interactions.
Fatigue in human therefore could be considered as a coping mechanism.
Crucially, patients with RA report improvement of fatigue after commencing TNF
inhibitor therapy [4-7], with the largest improvement being gained in the first 6 months of
treatment [6]. In three large randomised controlled trials (RCT) of adalimumab vs. placebo
plus methotrexate or placebo plus standard anti-rheumatic therapies; fatigue was significantly
and consistently reduced in adalimumab treated patients with moderate to severe RA [7]. The
ARMADA trial (Anti-TNF Research study program of the Monoclonal antibody
Adalimumab in Rheumatoid Arthritis), a 6-month placebo controlled, phase II/III study,
measured the effect of adalimumab against placebo in patients with active RA on concomitant
methotrexate treatment [8]. Fatigue was measured using the 13-item FACIT Scale (Functional
Assessment of Chronic Illness Therapy) with scores ranging from 0-52, with greater scores
indicating less fatigue. There were significant improvements in fatigue scores from baseline
in all treatment arms. At week 24, fatigue scores had improved by 11 points in the
adalimumab 80 mg group (p<0.001), by 10 points in the adalimumab 40 mg group (p<0.001),
by 8 points in the adalimumab 20 mg group (p<0.001), and by 6 points in the placebo group
(p=0.017). Similar results were observed in the DE019 study at 24 weeks, where FACIT
scores had improved by 8 and 9 points in RA patients treated with adalimumab 40 and 20 mg,
respectively, compared to 6 points in patients treated with placebo [9]. In a long-term
observational cohort of 2652 participants in the British Society for Rheumatology Biologics
Additional Benefits of Tumour Necrosis Factor Inhibitor Therapies 451
Register for RA, inflammatory disease activity was not directly related to the level of fatigue,
whilst improvement in pain, disability and depression was [10].
Similarly in patients suffering from psoriatic arthritis and AS, TNF inhibitors reduce
fatigue [11, 12]. In the ATLAS study (Adalimumab Trial evaluating Long-term safety and
efficacy for Ankylosing Spondylitis), treatment effects on fatigue occurred rapidly, within 2
weeks adalimumab-treated AS patients reported significant improvement in fatigue compared
with placebo-treated subjects. Fatigue scores (Bath Ankylosing Spondylitis Disease Activity
Score - BASDAI fatigue) improved by 2.2 points in adalimumab treated patients compared to
0.7 points in placebo-treated ones by week 12, and this reduction was maintained through
week 24 in the adalimumab treated group [11]. However, it has been highlighted that the level
of fatigue is strongly correlated with the level of pain in AS and not surprisingly,
commencing on TNF blockers reduces both [13].
DEPRESSION
The prevalence of depression in RA is 13-20%, approximately twice that seen in the
general population. The obvious reason for this is that the disease and its consequences may
be risk factors for depression. Pain and disability are important predictors of depression;
however a history of clinical depression also predicts reports of pain. The link between these
makes it difficult to assess them independently in trial settings [14]. Nevertheless, many
clinical trials involving patients with rheumatologic and non-rheumatologic conditions
concluded that TNF inhibitors have a beneficial effect on depression. RA patients receiving
TNF inhibitors are less likely to suffer from depression [15]. Interestingly, there are gender
differences in the response to treatment. In a recent Japanese study, although both female and
male patients improved on biologic drugs, there were sex differences in the improvement of
depression. All eight items of the SF-36 improved significantly in female patients, whilst no
improvement was observed in any items in men [16].
Neuro-inflammation plays a role in the pathogenesis of major depressive disorders with
pro-inflammatory cytokines, including TNF being implicated in the pathophysiology.
Plasma levels of TNF and its soluble receptors p55 and p75 are increased in acutely
depressed patients [17]. TNF has been shown to affect the serotonergic homeostasis by
acutely mediating serotonin uptake in both rat embryonic raphe cell line and in mouse
midbrain and striatal synaptosomes [18]. The plasma concentration of tryptophan, the
precursor of serotonin, has been found to be low in depression [19]; moreover, experimental
depletion of tryptophan reverses the therapeutic effects of antidepressant medication [20].
TNF can not only acutely stimulate serotonin neurotransmission but also reduce the
production of serotonin by stimulating the enzyme indoleamine 2, 3-dioxygenase (IDO),
which converts tryptophan, the precursor of serotonin, into kynurenine. Overstimulation of
IDO leads to depletion of the circulating tryptophan resulting in reduced serotonin synthesis
in the brain [21]. The link between TNF and the serotonergic system is further proven by the
recent discovery that circulating TNF is highly correlated with the brainstem serotonin
transporter availability and treatment with etanercept results in its significant reduction [22].
In animals, induction of depressive behavior by TNF can be reversed with anti-TNF
antibody [23], moreover, etanercept treatment has also been shown to have significant anti-
depressant effects [24].
On the other hand, a randomised controlled trial has assessed the efficacy of infliximab in
treatment resistant depression, and has failed to show any beneficial effect of infliximab on
depression scores. However, an exploratory analysis revealed that patients with high baseline
inflammatory markers responded better to infliximab than placebo, and the baseline
concentration of TNF and its soluble receptors were significantly higher in responders
compared to non-responders to infliximab [25].
In the COMET trial (COmbination of Methotrexate and ETanercept in Active Early
Rheumatoid Arthritis), patients who achieved clinical remission were less likely to maintain
symptoms of depression or anxiety compared with non-remitters. Both fatigue and pain had
impact on changes in depression status [26]. The addition of etanercept to conventional
methotrexate treatment demonstrated better efficacy and improved depression in an open
labeled study [27].
Infliximab has been shown to improve depression scores in AS, and this effect was
observed as early as after the second infusion, where change in disease activity scores and
inflammatory markers did not correlate with the change in depression scores [28].
Furthermore, a recent systematic review concluded that both adalimumab and etanercept
reduced depression symptoms scores in patients with moderate-to-severe psoriasis [29].
WORK DISABILITY
Work disability is a major issue for people with early RA, with up to a third of patients
stopping work within the first few years of diagnosis, often before they are referred to a
specialist or started on a disease modifying anti-rheumatic drug [30]. Older age at diagnosis
[31], Health Assessment Questionnaire (HAQ) disability [30, 32, 33], physically demanding
employment [32-34], increased bodily pain [35, 36] and low vitality [36] are all predictors of
work disability; whilst risk factors for benefits claims include disease activity, greater
disability and the presence of extra articular disease [36].
Taking biologic therapy is associated with increased workforce participation. Results
from the Stockholm anti-TNF follow-up registry have shown that commencing TNF
inhibitors significantly improved the number of hours worked per week as early as at 6
months (+2.4 hours), which continued to increase up to 5 years (+6.6 hours). After 5 years of
treatment, the expected indirect cost gain corresponded to 40% of the annual TNF inhibitor
drug cost in patients continuing treatment [37]. In contrast, in a large US RA cohort, TNF
blocking treatment did not seem to offer any protection against employment loss, although
there was some beneficial effect in patients with shorter disease duration (<11 years) [38].
CACHEXIA
Rheumatoid cachexia is associated with increased disability, morbidity and mortality.
TNF plays an important role in the development of cachexia. TNF induces anorexia by
increasing resting energy expenditure, stimulates lipolysis in adipocytes [39], and causes
muscle loss by stimulation of muscle protein breakdown. The effect of pharmacological

treatments on body composition has been controversial. Whilst significant weight gain has
been reported in patients taking TNF inhibitors [40-46], no effect on weight was noticed in
patients taking other biologic treatments such as ustekinumab, efalizumab or tocilizumab [47-
49]. In a retrospective study, 73% of RA patients gained a mean of 4.17 kg weight in the first
year of TNF inhibitor treatment, of whom one fifth gained more than 6 kg [41]. A recent
study indicated that etanercept-induced weight gain occurred without a change in appetite
scores in RA patients, and suggested an important role for gut hormones and leptin in the
patho-mechanism [42]. Infliximab therapy has also been shown to induce weight gain in RA
patients, with an effect that is not achieved with combination methotrexate, sulphasalazine
and hydroxychloroquine therapies despite similar reduction in disease activity [43].
A recent study demonstrated that 60% of psoriatic arthritis patients gained weight after
24 months of treatment, and this weight increase involved both fat and lean muscle mass [44].
Similarly, patients with spondyloarthritis (SpA) receiving TNF blockers have an increase in
fat mass. A study examined the effect of TNF inhibitor therapy on body mass index, waist
circumference, fat and lean mass, and visceral and subcutaneous adipose tissue in 85 patients
with SpA [45]. There were significant increases from baseline in body mass index (BMI),
waist circumference, and visceral and subcutaneous adipose tissue areas after two years of
TNF blocking therapy. A two-year prospective study from the same group, revealed not only
fat but also lean mass gain, as well as an increase in bone mineral densities in SpA patients
receiving TNF inhibitor therapy [46].
BONE MINERAL DENSITY (BMD)

Patients suffering from chronic inflammation have a more rapid bone loss, and
subsequently higher risk of fractures. It seems that inflammatory mediators such as TNF
play a major role in it. TNF not only promotes bone resorption via osteoclast activation [50,
51], but suppresses osteoblast proliferation [52, 53] and induces their apoptosis [54]. In the
BeSt trial (Behandel Strategieen), comparing combination synthetic disease modifying anti-
rheumatic drugs (DMARDs) to combination of synthetic DMARD and infliximab in RA,
hand bone loss was less apparent in those receiving initial combination infliximab treatment,
however, the difference disappeared upon adjusting on disease activity, suggesting that TNF
inhibitors are likely to control bone loss through arresting inflammatory activity [55, 56].
Furthermore, we learnt from the PREMIER trial that combination therapy with adalimumab
and methotrexate slowed down hand bone loss compared to monotherapy with any of the two
agents [57].
Spinal bone loss has also been investigated in clinical trials, however the results are
conflicting. Various observational studies claimed the beneficial effect of TNF blockers on
arresting spinal and hip bone loss in RA [58-61]. Some claimed that infliximab treatment
reduced BMD loss at the femoral neck and total hip, but had no effect on hand and spine of
RA patients [62], whilst others found benefits of infliximab on spinal BMD as well [63]. The
BeSt trial did not find any association between changes in BMD and treatment regimens,
again suggesting that the preservation of BMD by infliximab is related to disease control
rather than a direct effect [55]. A large population-based Canadian cohort study of over
sixteen-thousand RA patients concluded that the risk of osteoporotic non-vertebral fracture

was indifferent in those receiving synthetic DMARDs only or in combination with TNF
inhibitors [64].
Inconsistent results have been published on TNF inhibitor related BMD changes in SpA
as well. Some reported marginal benefit only when bisphosphonates are co-administered [65,
66], whilst some described a clear positive effect [67-69].
CARDIOVASCULAR RISK
The increased prevalence of cardiovascular disease (CVD) in RA is mainly driven by
chronic inflammation. TNF has been implicated in the development of atherosclerosis by
mediating endothelial dysfunction, plaque formation and rupture and promotion of
prothrombotic state [70]. TNF can also induce insulin resistance and dyslipidaemia [71, 72].
TNF inhibitors therefore may reduce the progression of atherosclerosis and the risk of CVD.
Evidence suggests that methotrexate treatment is associated with a reduced risk of CVD in
RA [73], and in many studies, TNF antagonists also appear to reduce the likelihood of CVD
[74]. In a recently published retrospective study on more than one hundred thousand RA
patients, therapy with TNF inhibitors was associated with a 13% CV risk reduction in patients
aged 50 and over, which mostly included myocardial infarction, unstable angina and heart
failure. Longer cumulative exposures to TNF blockers were associated with greater levels of
risk reduction, up to 51% after 3 years of treatment [75].
The findings of visceral fat increase by TNF antagonist treatment could suggest that
treatment may induce changes in body composition by increasing abdominal fat. This fat
redistribution raises concerns regarding CV risk. Increased fat mass, especially abdominal
obesity increases the risk for diabetes and CVD, important risk factors of mortality in RA
[76]. Infliximab therapy does not seem to have a significant influence on lipid profile [77],
and the infliximab-induced fat gain is not associated with an atherogenic lipid profile either
[43]. Furthermore, TNF inhibitor treatment has been shown to improve insulin resistance and
pancreatic beta cell function [78, 79], and reduce the expression of endothelial cell activation
markers [80-82], contributing to a lower CV co-morbidity.
ANAEMIA OF CHRONIC DISEASE

Anaemia is the most frequent extra-articular manifestation of RA [83] and can also occur
in AS patients. This can contribute to the patients feeling of lethargy. TNF plays an
important role in the development of anaemia via inhibition of bone marrow erythropoiesis
[84], induction of apoptosis of bone marrow erythroid cells [85] and modulation of
macrophage iron metabolism [86]. Serum levels of TNF strongly correlate with the degree
of anaemia [87], and TNF blockers increase hemoglobin levels in RA patients [88]. Similarly
in AS patients, TNF inhibition provides significant improvement in hemoglobin levels [89-
91]. One study assessed the effect of different TNF blockers on haemoglobin levels and found
that whilst infliximab and adalimumab improved haemoglobin levels, etanercept had no effect
[89].
INFERTILITY
A recently proposed way of managing recurrent miscarriages involves the use of TNF
blockers, which may not only suppress the maternal-foetal immune system related to the Th1
cytokine profile, but also enhance maternal tolerance via regulatory T cells. There have been
case reports describing successful pregnancies in women with history of miscarriage after
TNF inhibitor treatment [92, 93]. A controlled study evaluated the use of adalimumab and/or
intravenous immunoglobulin (IVIG) to improve success of in vitro fertilization (IVF) [94].
Women with high Th1/Th2 cytokine ratio and more than two IVF failures were divided into 4
groups by treatment regimen: both IVIG and adalimumab 40 mg fortnightly (group 1), IVIG
only (group 2), adalimumab only (group 3), standard treatment (group 4). The implantation
rates were 59%, 47%, 31% and 0% for groups 1 through 4, respectively. The clinical
pregnancy rate (foetal heart activity) was 80%, 57%, 50% and 0% for groups 1 through 4,
respectively. Although the results seem encouraging, there is a lack of published data on the
use of TNF inhibitors in recurrent miscarriages, therefore further evidence needs to be
collected before firm conclusions could be drawn and treatment could be offered to sub-fertile
women.
There have been conflicting reports on the effect of TNF inhibitors on male fertility.
TNF has been shown to promote cell survival during spermatogenesis in rats, and this effect
is reversed by infliximab [95]. However, human sperm motility studies have shown that high
levels of TNF reduce sperm motility and membrane integrity, and are toxic to testicular
somatic and germ cells [96].
Two studies compared semen sample qualities in AS patients with or without TNF
blocking treatment. One found that sperm of patients not taking TNF inhibitors had poorer
motility and vitality than found in patients on longstanding treatment with TNF blockers,
however sperm concentration and morphology was similar in the two groups [97]. Another
study however, described comparable sperm qualities in patients with active AS before and
after TNF blocking therapies and in healthy controls [98]. A recent systematic literature
review was inconclusive regarding the impact of TNF inhibitors on male sperm
characteristics; however, the review overall suggested that TNF blockers might improve
sperm motility and vitality, which could be the result of the improvement in disease activity
rather than a direct effect [99].
CONCLUSION
In summary, there is growing evidence that TNF inhibitors offer additional benefits,
which are extra-articular and may help the individual patient in many different and
unrecognised ways.
ACKNOWLEDGMENTS
The authors would like to thank Dr. David Rees (david.rees@wvt.nhs.uk), Consultant
Rheumatologist at Hereford County Hospital, UK for reviewing the chapter and providing
very helpful comments.
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Chapter 19
INFECTION AND BIOLOGICS
Maria Krutikov and Jessica Manson, PhD FRCP*

ABSTRACT
Biologic agents are being increasingly used in the treatment of autoimmune
disorders, particularly in rheumatology. However, as they target the host immune system,
this treatment predisposes the patient to infections. These can be life-threatening, and it is
important that appropriate screening and monitoring is undertaken. Each group of drugs
increases the risk of different infections. More is known about the risk profile of TNF
blockers and CD20 inhibiting drugs, as these have been in use the longest. However,
there is growing evidence of infection relating to use of interleukin 6 (IL6) blockers and
newer biologic agents. Prior to commencing any biologic agent, it is recommended that a
careful history detailing exposure to infections should be undertaken. Screening for latent
tuberculosis (LTB) can be carried out using several algorithms. Screening for hepatitis B
and C, human immunodeficiency virus (HIV) and varicella is also recommended. If
positive, patients must undergo further testing and referral to a specialist. Vaccination is
recommended annually, and prior to treatment. Clinicians must exercise care when
treating patients with biologic agents. Prompt management of the unwell patient using a
broad differential and thorough investigation is prudent.
Keywords: rheumatic diseases, infection risk, biologic disease modifying anti-rheumatic

drugs, tuberculosis, chronic hepatitis, HIV
INTRODUCTION
Biologic agents are used increasingly in the treatment of autoimmune conditions across
all medical specialties, including rheumatology. Agents that target different immune cells and
Correspondence to: Dr. Jessica Manson, Department of Rheumatology, University College London Hospital NHS
*
Foundation Trust, 250 Euston Road, London, NW1 2PG, email: jessica.manson@uclh.nhs.uk.
466 Maria Krutikov and Jessica Manson
cytokines involved in host-defense predispose patients to particular infections. The

introduction and continued use of biologic agents must be done cautiously, and should be
coordinated by specialists. Prior to commencing treatment, patients must be screened for
latent infection using risk stratification and screening tests when available. This is to reduce
the risk of reactivation of infection once established on immunomodulatory therapy. There
are many published guidelines on this, particularly in the context of tuberculosis (TB). It is
important to consider the patients country of origin, family and travel history when making
these decisions. Clinicians managing these patients should be aware of the wider differential
of all acute presentations, investigate accordingly, and have a low threshold for treatment
escalation and for seeking expert, particularly infectious disease, input. Moreover, patients
with rheumatoid arthritis (RA) suffer 1.52fold higher rates of hospitalised infections
independent of therapy [1]. This is true for other rheumatic diseases particularly if there is
prior immunosuppression with non-biologic agents, like corticosteroids. This means that
these patients have a poorer immune response to infection at baseline and this risk of
infection is increased with biologic therapy.
This chapter will discuss the particular infectious risks associated with biologic drugs
widely used in rheumatology, grouping them together where appropriate. It will aim to
outline recommendations for the clinician in screening and management of patients.
Drugs That Inhibit Tumour Necrosis Factor (TNF)
Tumour necrosis factor alpha (TNF) is a cytokine produced by monocytes,

macrophages, lymphocytes and fibroblasts. TNF plays an important role in both innate and
adaptive immune responses, with numerous effects that include; activation of vascular
endothelium causing increased vascular permeability, up-regulation of class II major
histocompatibility molecules and activation of T- and B-lymphocytes and platelets. TNF is
also key to macrophage activation and recruitment of neutrophils for granuloma formation,
thus playing an important role in defense against intracellular organisms in particular.
Infliximab was the first TNF inhibitor to be adopted into routine rheumatology practice.
We now have approximately 15 years of clinical experience with TNF inhibitors, and it is
therefore for this group of drugs that we have the largest body of evidence about adverse
effects, particularly relating to infection. Currently there are five drugs in routine use, 4 anti-
TNF antibodies (infliximab, adalimumab, golimumab, certolizumab), and one soluble TNF
receptor (etanercept).
Studies have shown that infection risk is greatest in the first 90 days of treatment. After
this, the infection risk becomes similar to baseline risk of infection, which is higher in
patients with rheumatoid arthritis (RA) and systemic lupus erythematosus than in the general
population. A German study looked at over 5000 patients enrolled into the national biologics
register. Of these patients, 392 had serious infections, but the rate of these declined over the
first three years from 4.8 to 2.2 per 100 patient years. This was likely due to treatment
termination and steroid sparing effect, as well as likely depletion of susceptible patients and
survivor bias over time. Patients with particularly increased risk were those older than 60
years with chronic lung or renal disease, low functional capacity, treatment with
glucocorticoids dose greater than 15 mg /day or a history of serious infections [1].
Infection and Biologics 467
Multiple studies support the observation that infection risk associated with biologic use is
further increased by concurrent use of corticosteroids. Steroids are often needed to achieve
rapid disease control, particularly during flares, or while patients are just starting biologic
therapy. However, once established on treatment, corticosteroids can often be stopped when
good disease control is achieved. The dose of corticosteroids appears to be important. Patients
on less than 5 mg / day have a 1.5 times greater risk, as opposed to those on greater than 20
mg who have a 4 fold increase, as shown in recent meta-analysis of 42 observational studies
[2-3].
Looking at multiple drugs in multiple diseases, population based studies have varied in
their conclusions in relation to the detail and magnitude of the risk of infection with TNF
inhibiting treatment. A large study in the United States (US) assembled multiple patient
registries and was able to show an incidence of serious infection to be 5-10 per 100 person
years, depending on underlying diagnosis. This was greater in those with inflammatory bowel
disease and RA than psoriasis or spondylarthropathies. A proportion of 53% of these
infections were soft tissue and skin infections or pneumonia. In particular, patients on
infliximab had a 25% greater risk of infection when compared with etanercept (adjusted
hazard ratio [(aHR) = 1.26)] or adalimumab (aHR = 1.23) [4]. However, this may be because
of more frequent use of concurrent methotrexate with infliximab than with other TNF
inhibitors.
TNF INHIBITORS AND BACTERIAL INFECTIONS

Patients treated with TNF inhibitor therapy, especially those with RA, have an increased
risk of invasive skin or soft tissue infections, particularly invasive Staphylococcal infections,
although it has not been established whether these are related to indwelling intravenous lines
[5]. In many studies, this is the most frequently occurring infection. This may be because this
group of patients have high baseline rates of colonization due to their underlying pathology
i.e., RA or psoriasis [6]. Septic arthritis was seen twice as often in those on TNF inhibitor
therapy when compared to RA patients on disease modifying anti-rheumatic drugs
(DMARDs), and was most commonly caused by Staphylococcus aureus (57%) [7].
Other atypical bacterial infections are also more frequently seen in patients treated with
TNF inhibitors. Listeria monocytogenes is a gram-positive intracellular organism that causes
a granulomatous infection in the host. In the US between 2004 and 2011, there were 266
cases of listeria infection associated with biologic therapy; of these 77.1% were in patients
taking infliximab. Out of all of the infected patients, 47.7% were receiving biologic agents for
treatment of rheumatologic diseases. However, 73% were receiving concomitant drugs,
mainly steroids and methotrexate. The median time of onset of infection was 184 days from
drug initiation [8].
A study, using the Food and Drug Agency (FDA) reporting system in the US, identified
fifteen patients with listeriosis who were on infliximab or etanercept. All of these patients had
a septic arthritis or meningitis and had received a median number of 2.5 doses of drug [9].
A French registry published data on ten cases of legionella pneumonia in 2004; six cases
on adalimumab, two cases on etanercept and two patients on infliximab. Eight of these
patients were being treated for RA, one for pyoderma gangrenosum and one for cutaneous
psoriasis, with a median treatment duration of 38.5 weeks. However, eight patients (80%)
were receiving concomitant treatment with corticosteroid and six with methotrexate. This
study found a relative risk for legionella infection of 16.5-21.0 compared with that of the
French population overall [10].
TNF Inhibitors and Mycobacterial Infections
One of the key concerns relating to TNF inhibitor treatment is of reactivation of LTB. In
a recent systematic review of 40 randomised controlled trials (RCTs) looking at the infection
risk on TNF inhibitor therapy, the rate of TB reactivation on TNF inhibitor was 0.26%
compared with 0% in the placebo group. This risk was higher in those on non-biologic
DMARDs, particularly methotrexate or azathioprine [11]. Some studies have found a 1.6
25% risk of TB reactivation depending on country of origin [12]. Occupation may also be a
risk factor a study from our department showed that over a 10 year period treating 703
patients there were five cases of active TB [13]. Four out of those five cases were born in
areas of high TB prevalence, and two were healthcare workers. Figure 1 shows the chest
radiograph of one of these patients who developed pulmonary TB after 3 months treatment
with adalimumab.
Figure 1. Chest radiograph of a 60-year-old nurse who developed pulmonary TB after 3 months
treatment with adalimumab. Initial management was for presumed community acquired pneumonia, but
symptoms and signs did not resolve with treatment.
In the general population, 85% of TB infections are pulmonary however in those treated
with TNF inhibitor, extra-pulmonary TB is about 50% more common [3]. Rates in the UK
have been shown as 56 per 100,000 patients, although this figure was prior to the advent of
widespread TB screening [5].
The risk of TB is different between the agents. Reactivation of TB was shown to be 3 to 4
times higher in those on adalimumab and infliximab than those on soluble TNF receptor
antagonists (etanercept) [14].
In a case-control analysis looking at exposure to infliximab or adalimumab vs. etanercept,
the risk of TB was increased, with an OR of 13.3 [95% CI, 2.669.0] and 17.1 [95% CI, 3.6
80.6], respectively [15]. This difference in risk for these drugs has not been fully explained,
but is thought to be due to differential granuloma penetration, reduced antimicrobial-
producing CD8 effector cells and down-regulation of antigen-stimulated interferon gamma
[15]. The rate of TB infection was reduced significantly with the implementation of screening
recommendations. This was shown in a study that looked at a Spanish registry, which found
that the risk of active TB was reduced by 78% when using a screening programme. It also
showed that the probability of developing active infection was seven times higher if
recommendations were not followed [16].
Figure 2. Actions of TNF in antibacterial and inflammatory responses to Mycobacterium tuberculosis

infection. Adapted from [17].
The role of TNF in modulating the anti-bacterial and inflammatory responses relevant for the TB
infection is explained by the following cellular and molecular interactions (Figure 2): A) The TNF
produced by macrophages acts as a co-stimulus for T cells. B) The TNF released by T cells primes
macrophages for mycobactericidal activity. C) TNF released by macrophages and T cells (with
interferon (IFN)- and chemokines) recruits and organises mononuclear cells into highly structured
granulomas. TNF and IFN- also regulate excessive inflammation by inducing apoptosis of T cells.
D) TNF antagonist therapy results in granuloma breakdown and dissemination of mycobacteria.
A pathogen that is much less frequently discussed is non-tuberculous mycobacterium.

This includes Mycobacterium avium complex (MAC), Mycobacterium abscessus,
Mycobacterium chelonae and Mycobacterium marinum. In a survey of infectious diseases
physicians in the US, cases of non-tuberculous mycobacterium were seen twice as often as
TB in patients on TNF inhibitor treatment. Although the nature of this study meant that there
was no known denominator for the patients reported, case notes could not be reviewed and
there was the potential for significant reporting and recall bias resulting in under or over
reporting [6].
There have been concerns raised that TNF inhibitors increase the risk of immune
reconstitution syndrome (IRIS). IRIS has been widely described in patients with HIV starting
antimicrobial and antiretroviral treatment simultaneously, and is mainly seen in the context of
TB treatment. IRIS is due to an excessive inflammatory response to the existing infection in a
newly reconstituted immune system. This can cause worsening of existing symptoms with
fever and inflammation. The mainstay of treatment for this is moderate doses of
corticosteroid.
So far, there have been six reports of IRIS associated with TB treatment in patients on
adalimumab and eleven in patients on infliximab. Eleven of these cases had disseminated
disease involving the CNS. Two of these patients did not respond to steroid treatment
developing life- threatening illness with lung and CNS cavities, which required re-
administration of TNF inhibiting agents in an attempt to suppress the TNF-mediated
inflammatory response.
This may be an important consideration in patients with clinical deterioration despite
appropriate anti-TB treatment, and may warrant stricter screening guidelines to look for
evidence of extra-pulmonary disease [18].
TNF Inhibitors and Fungal / Endemic Infections
There is increasing evidence that patients treated with TNF inhibitors are at a greater risk
of developing endemic or fungal infections. These can often present atypically and patients
can go on to develop life-threatening disseminated disease [19]. In a recent case-control study
that looked at over 30,000 patients in the US, those prescribed prednisolone as well as TNF
inhibitors, were twice as likely to develop a fungal infection. Of the cases of infection, 60%
developed histoplasmosis, 10% coccidiomycosis, 3% cryptococcosis and 2% pneumocystosis
[20]. Histoplasmosis is the most frequent invasive fungal infection and can result in mortality
rates of up to 20% [21]. In a survey of US clinicians, it caused serious infections in three
times more patients on TNF inhibiting therapy than TB. The immune response to
Histoplasma capsulatum is thought to be macrophage mediated, inhibited by TNF blockade.
It often presents with fever, cough, fatigue, and can cause hepatosplenomegaly that can often
resemble TB [22]. There have also been reports of histoplasmosis presenting with scaly,
papular, cutaneous lesions [23].
In 2008, the US FDA issued a black box warning of the risk of endemic fungal infections
in patients on TNF inhibitor therapy. They reported 240 cases of histoplasmosis, mainly in
the Ohio and Mississippi river valleys where the fungus is endemic. Twelve of these patients
died [24]. There have also been a few reports of invasive aspergillosis in patients on TNF
inhibitors [21].
Nocardia is a gram-positive actinomycete found in soil that causes granulomatous

disease in the infected host. It can present with cutaneous infection like cellulitis or
abscess, with lymphocutaneous sporotrichoid disease, or with subcutaneous infection like
actinomycetoma. Pulmonary disease is found in two thirds of affected patients, particularly in
patients on TNF inhibitors or in profoundly immunosuppressed patients. It can present with
disseminated disease and abscesses in the brain and meninges. A recent review of published
cases of nocardiasis associated with TNF inhibiting therapy, reported eleven cases. Of these
cases, nine were on infliximab, two on adalimumab, seven had inflammatory bowel disease
(IBD) and four had other rheumatologic conditions. Three patients presented with
disseminated disease, four with lung involvement, one hepatic and three with cutaneous
disease [25].
Leishmania is a parasite that lives within phagocytes. In its cutaneous form, characteristic
skin lesions are seen with occasional muco-cutaneous involvement. The visceral form has a
chronic presentation with anaemia, fever, weight loss and eventually massive splenomegaly.
The main tests for these are skin scrapings or bone marrow trephines with characteristic
intracellular amastigotes on microscopy.
There have been several case reports of leishmaniasis, few visceral cases but
predominantly cutaneous. The median duration of treatment with TNF inhibitors prior to
infection was 60 months. However, as these cases were all reported in endemic countries, this
may have been the result of reactivation of latent infection or incident infection after a TNF
inhibitor [26].
TNF INHIBITORS AND VIRAL INFECTIONS

Herpes
Varicella Zoster
Reactivation of varicella zoster infection has been well described in the
immunosuppressed and elderly population, occasionally causing disseminated disease with
life-threatening outcomes. In the total population of patients with RA, the risk of herpes
zoster virus (HZV) has been described as 2-3 times higher than that of the baseline population
[27].
A large prospective cohort trial in Germany showed an increased risk of zoster with
monoclonal antibodies, adalimumab and infliximab (HR, 1.82 [95% CI, 1.053.15]), but not
with etanercept (HR, 1.36 [95% CI, .732.55]) [28]. In a further study that looked at 20,000
US veterans, etanercept (HR 0.62) and adalimumab (HR 0.53) had a protective association,
with a non-significant risk elevation for infliximab (HR 1.32) [29].
However, in subgroup analyses of the large US based SABER (Safety Assessment of
Biologic thERapy) trial that included 32,208 patients looking at new users of biologics, there
was no difference in risk of developing infection with varicella zoster between different TNF
inhibitors or with DMARDs. The use of corticosteroids was associated with an increased risk
[adjusted HR 2.13 (1.64, 2.75)], as was older age, female sex and overall health status. Of the
patients that were hospitalised with disseminated disease, a similar proportion were in the
TNF inhibitor group (6%) as in the DMARD group (5.5%). This raises the possibility that
those that develop HZV while on TNF inhibitors are at no greater risk of hospitalization.
Patients on TNF inhibitors who develop zoster infections should be treated with antivirals
(i.e., acyclovir or valacyclovir), and TNF inhibiting treatment should be withheld until
vesicles have resolved. As the HZV vaccine is a live-attenuated vaccine, there have been
concerns regarding the safety of using it in patients on immunosuppression [30]. However,
there have been studies that have shown that vaccination of patients with RA while on TNF
inhibitors has not led to increased risk of disseminated disease [31].
Primary varicella infection is of concern in patients on TNF inhibiting therapy. Several
case reports have highlighted issues that can complicate management. These include patients
reporting childhood infections that do not match with serological testing and atypical
presentation of skin manifestations. In case of contact, immunity should be re-checked, and
patients should receive prophylactic treatment if inadequate immunity is demonstrated [32].
Ebstein-Barr virus (EBV)

Latent and primary Ebstein-Barr virus (EBV) infections have been linked to lymphoma,
mainly in the IBD patient group. This has clearly been described in the post-transplant
population, as EBV viral load is related to risk of lymphoproliferative disease; therefore,
monitoring with pre-emptive treatment is routinely performed. Serological monitoring of
patients on TNF inhibitor treatment has not showed a correlation between viral load and
disease risk. Therefore, there are currently no clear guidelines for surveillance of patients on
biologic drugs, and it is unclear whether this would be beneficial [33-34].
Human papilloma virus (HPV) is associated with increased risk of cervical and
anogenital dysplasia. HPV carriage is increased in post-transplant and HIV positive patients.
This has also been shown in patients on TNF inhibitors and immunomodulators. Cases of
anogenital condylomata and abnormal cervical smears in IBD patients have been reported.
Therefore annual cervical smears and HPV vaccination for all young girls is recommended
[35].
Other Herpes Infections

There have been a few case reports of herpes simplex virus (HSV) infection including
one of HSV oesophagitis, in patients on TNF inhibiting treatment; these have all responded
well to antiviral treatment [30]. Although there have been a few case reports of
cytomegalovirus (CMV) infection with hepatitis, retinitis and haemophagocytic syndrome on
infliximab, prospective studies using CMV-PCR in patients with Crohns disease, showed no
evidence of CMV reactivation following infliximab infusion [31].
Viral Hepatitis
Hepatitis B virus (HBV) induced hepatic injury is mediated by cytotoxic T cells. Pro-
inflammatory cytokines like TNF and IL6 are part of the innate immune system that
suppresses viral replication within cells. Hepatitis B and C reactivation in patients on TNF
inhibiting therapy is becoming of increasing concern since the first case report in 2004.
Studies show that 20-50% of hepatitis B virus (HBV) carriers that undergo
immunosuppression will reactivate their disease. This figure is lower for hepatitis C virus
(HCV) carriers, however if reactivation occurs, it can lead to serious complications like
fulminant hepatic failure [36].
Hepatitis B
In a review of 87 cases with chronic HBV infection (HBsAg positive), 38% of patients
reactivated on TNF inhibiting treatment. Of these 50% were on infliximab, 33% on etanercept
and 17% on adalimumab. Of the cases with viral reactivation, 75% had an increase in
aminotransferase levels and 25% had been on prophylactic antiviral treatment (compared with
62% in the non-reactivation group) [37]. Prospective studies have shown that prophylactic
treatment of these patients with antivirals like Lamivudine can prevent relapse in more than
90% of patients [38].
By contrast, for the patient group with resolved HBV infection (HBsAg negative, anti-
HBc positive), there is evidence that these patients do not reactivate their hepatitis. This has
been shown in several prospective studies, however all patients had an undetectable HBV
viral load at the start of treatment [38]. A larger review that included 468 patients showed a
reactivation rate of 1.7%, all of which had a satisfactory outcome [39].
The HBV vaccine is a recombinant deoxyribonucleic acid (DNA) vaccine that is usually
given in three booster injections to induce immunity in high-risk groups. There have been
some concerns recently that the vaccine can lead to autoimmune adverse effects like Guillain-
Barre syndrome, multiple sclerosis and autoimmune inflammatory syndrome. This has been
of particular interest when considering patients already affected by autoimmune diseases.
However, the benefit of pre-emptively vaccinating a patient who will be immunosuppressed
seems clear, especially if their individual risk is high. This must be a discussion between the
clinician and the patient [38].
Hepatitis C
Due to the role that TNF plays in the signaling pathway for apoptosis of infected
hepatocytes, introduction of TNF inhibiting therapy has raised concerns regarding
progression of HCV infection and hepatic damage. However, data from other
immunosuppressed patient groups such as those post chemotherapy or post bone marrow
transplantation have not demonstrated flares of HCV during these periods [40].
A review of 216 cases of HCV infected patients on TNF inhibiting therapy in the
published literature from 2000-2013, showed only three cases of drug withdrawal due to
clinical suspicion of exacerbation of HCV liver disease. However, none of these patients
demonstrated an increase in viral load and it can be difficult to be certain that these flares
were not just part of the usual HCV disease course.
The different side-effect profile of TNF inhibitors has led to the preferential use of
etanercept in HCV infected patients. In 2004, a warning was issued for infliximab causing
severe hepatic reactions following the diagnosis of autoimmune hepatitis in a few cases. Of
four patients with toxic hepatitis on infliximab, when switched to etanercept or adalimumab,
there was no transfer of toxicity [38, 41].
Furthermore because of the role of TNF in hepatocyte function, there is even a
suggestion that TNF inhibition may be helpful in the treatment of hepatitis C. TNF is
produced by hepatocytes of patients chronically infected with HCV and may be involved with
inhibition of viral replication [42]. Often patients with high titres of TNF prior to treatment
with interferon have a worse response to treatment than those with low TNF levels.
Therefore, there has been a suggestion that concurrent treatment with TNF inhibitors and
interferon could lead to better outcomes. This is due to the role that TNF plays in viral
replication and also stabilization of concurrent autoimmune disease, which can often be
exacerbated during treatment with interferon [43].
This suggestion was strengthened by Zain et al. in 2005, [44] who conducted the only
RCT to date, assessing the effects of etanercept as an adjuvant treatment to interferon and
ribavirin for patients with chronic hepatitis C. The 19 patients treated with etanercept suffered
fewer side effects associated with ribavirin and interferon treatment, and had a higher rate of
sustained virological response. This also raises the possibility that inhibition of TNF can
restore TNF-induced CD4 cell impairment that is required to block HCV replication [45].
Screening for HCV in patients commencing immunosuppressive therapy should be
carried out using anti-HCV antibodies. Patients who are positive should have further HCV-
ribonucleic acid (RNA) levels, depending on which they may need HCV genotype and
cryoglobulins, alongside referral to a hepatologist for staging of disease with liver imaging.
TNF inhibition is not contraindicated in patients with hepatitis C who have no signs of
liver decompensation, however close monitoring on a quarterly basis should be conducted. In
cirrhotic patients, extreme caution should be exercised as there is a high risk of fatal disease.
Those exhibiting signs of reactivation should be referred to a hepatologist for further
management [46].
HIV
TNF has been found to participate in HIV infection by increasing cellular spread of the
virus and can stimulate viral replication [47]. There have been reports of HIV infected
patients with RA treated with etanercept. They all had CD4 cell counts > 200 m/l and low
HIV viral load < 60,000 copies / mm3, and five received concomitant highly active
antiretroviral therapy. There were no reports of opportunistic infections or increased viral
replication [48-49].
RITUXIMAB
Rituximab is a monoclonal antibody against the CD-20 molecule expressed on pre-B and
mature B-lymphocytes. It was initially developed as a chemotherapy agent, and is still used as
part of the R-CHOP [rituximab, cyclophosphamide, doxorubicin (hydroxydaunomycin),
vincristine (Oncovin ) and prednisolone] treatment regimen for B cell lymphoma.
Treatment with rituximab causes a reduction in B cells. Rituximab can induce
immunosuppression through neutrophil inhibition, followed by T cell and eventually long-
term B cell depletion. This has accounted for the increased risk of viral infections
like hepatitis B. In addition, there have been reports of progressive multifocal
leukoencepahlopathy (PML), which is caused by JC virus.
Studies have varied in their outcomes regarding rates of serious infection following
rituximab treatment. Two RCTs (DANCER and REFLEX) found an increased rate of serious
infections compared with the placebo, however a meta-analysis of three RCTs showed no
increase in serious infection [50]. In an analysis of 3194 patients over 9.5 years, the most
frequently occurring infections were upper respiratory tract infections, nasopharyngitis,
urinary tract infections, bronchitis, sinusitis, influenza and gastroenteritis; serious infections
were most often lower respiratory tract. However, there was no increase in the risk of serious
infections compared to placebo in these studies [51].
A French study looked at 1681 patients with RA treated with rituximab from 99 centres
over 4 years. There were 82 severe infections, which required hospitalization and / or
intravenous antibiotics in the twelve months following rituximab administration. There was
only one opportunistic infection (gonococcal septic arthritis) and no TB infections. The
infection was most likely to occur in the first six months from treatment and after the first
cycle. These findings were similar to those reported in clinical trials. Independent risk factors
for developing infection were low immunoglobulin (Ig) G levels before starting rituximab,
lung and cardiac disease and extra-articular disease [52-54].
The effects of rituximab on Ig levels have been well described. Studies have varied but
have shown a decrease below the lower limit of serum IgM in 10 22.4% of patients; the
more courses the patient had the more likely this was to occur. For IgG, this was 3.5 5.9%
and showed a similar pattern [51, 55].
These studies found no increase in infection rate in those with low Ig during the treatment
period; however, serious infection was higher in those with low IgG than those who had
maintained normal IgG levels. This was also identified as an independent risk factor for
serious infection in the French registry described above.
For this reason, it is advised that Ig levels are checked prior to and throughout treatment
with rituximab. Those with low IgG should consider alternative treatment options. Switching
should be considered for patients whose levels drop during treatment particularly if they have
other risk factors for infection like older age, other co-morbidities and concomitant
glucocorticoid use [50].
Those that suffer serious infections with hypogammaglobulinaemia may benefit from
intravenous immunoglobulins (IVIg) [56], and in some cases, IVIg can be used to maintain
levels for rituximab treatment.
TB
There is no evidence so far of any increased risk of TB infection in patients with

autoimmune rheumatic diseases on rituximab. In a long-term safety report of patients with
RA, there were two cases of pulmonary TB, none extra-pulmonary or atypical [51]. There
have also been other studies reporting incidence of TB on rituximab [6]. A study in Taiwan
reported no cases of TB reactivation after one year. They included 13 patients with either
latent or previous TNF inhibitor associated TB and recorded serial interferon-gamma levels
using the Quantiferon TB Gold test (IGRA), which they found did not change after a year of
rituximab treatment. However, this result is difficult to interpret as it is unclear whether
changes in interferon levels are associated with risk of reactivation [57].
Hepatitis B
Due to the action of rituximab on B cells as well as T cells, rituximab use can speed up
HBV replication.
Rates of hepatitis B reactivation in patients treated with rituximab vary depending on
serology. In HbsAg positive patients, literature has suggested rates are 27-80% in those not
receiving antiviral prophylaxis. In the HBsAg negative / anti-HBc positive group, these rates
are 3-25% and are slightly higher in those who are also anti-HBs negative. Of the chronic
hepatitis B group (HBsAg positive), those who receive antiviral prophylaxis have a
reactivation rate of 0-13%. There have also been a few reported cases of fulminant hepatitis
[38].
The Medicines and Healthcare products Regulatory Agency (MHRA) issued a warning in
2013 to advise clinicians to screen for hepatitis B prior to treatment. Those with active
hepatitis B should not be treated with rituximab [58].
HBV vaccination is recommended for at risk groups prior to commencing rituximab. If
the patient is already established on treatment, the vaccine should be given at least 6 months
after the start and 4 weeks before the next course is due [59].
In the HBsAg negative / anti-HBc positive group of patients, pre-emptive antiviral
treatment should be given regardless of HBV-DNA levels and they should be monitored by a
specialist for reactivation [38].
Hepatitis C
Data from the haemato-oncology cohort of patients has shown an increased risk of HCV
reactivation and flare on rituximab. These studies have looked at rituximab given in
conjunction with other chemotherapy agents in the R-CHOP regimen used for lymphoma
treatment. As rituximab induces profound immunosuppression, it can increase HCV
expression in hepatic cells, which can cause a flare of HCV disease. Most of the evidence is
from case reports and there are few studies that have specifically looked into this [60]. A few
individual cases have been described of hepatitis C reactivation in patients treated with
rituximab for RA but no formal, good quality studies are available [61].
Progressive Multifocal Leukoencehalopathy (PML)
PML is caused by replication in the brain of JC (John Cunningham) virus. This leads to
progressive inflammation and multifocal demyelination of brain white matter. Treatment is
only supportive and the disease progresses rapidly over a year to eventual death. The virus
asymptomatically infects a large number of adults, but PML only occurs in those who are
profoundly immunosuppressed. In patients with HIV, treatment with highly active
antiretroviral therapy (HAART) has shown some reduction in the speed of progression with
restoration of anti-JCV T cell immunity, but there is a risk of associated IRIS with the
reconstituting immune system.
PML has also been described in patients on rituximab. This suggests that B cells are
involved in the immunity against JC virus. The incidence of this has been described as
2/8,000 in patients with systemic lupus erythematosus (SLE) and 1/25,000 in those with RA
on rituximab [62]. It has been suggested that B cells act as a viral reservoir, disseminating the
virus in the brain and act within the adaptive immune response to control JC virus [63].
The few case reports of PML occurring in patients on rituximab have been in patients on
longstanding immunosuppressive therapies; some had lymphopenia and cancer prior to
starting rituximab treatment. In a Swedish registry of 66,278 patients with RA, risk of PML
was increased when compared with the general population, but this risk did not increase with
exposure to rituximab with a rate of 2.3/100,000 person-years [64, 65].
TOCILIZUMAB
Tocilizumab is a monoclonal antibody directed against IL6 receptors. IL6 is a cytokine
that is secreted by T cells and macrophages and is involved in B and T cell differentiation.
C-reactive protein (CRP) is often measured in serum to monitor the patients
inflammatory response. As IL6 is involved in the acute-phase response, it plays a large role in
the production of CRP in the liver. As a result, patients on tocilizumab often have a normal
serum CRP even in the face of a significant infection, which may lead to delayed detection
[66].
The infection risk associated with tocilizumab has been found to be dose-dependent. A
systematic review and meta-analysis of RCTs using tocilizumab for treatment of RA
compared 4mg/kg dose with 8mg/kg dose in terms of adverse events. They found a
significantly higher risk of infection in those on the higher dose (OR 1.30; 95% CI 1.07, 1.58)
with no change in risk of hepatitis or TB reactivation [67].
A meta-analysis from 2012 found no increased risk of serious infection compared with
the general population. However a study in Japan that looked at 601 RA patients treated with
tocilizumab and compared them with age- and sex-standardised RA patients, found an
increased incidence of serious infection, mainly affecting the respiratory tract, which they felt
was comparable with the reported risk with TNF inhibitors [68, 69].
A cohort study from Germany suggested that the rate of serious infection in tocilizumab -
treated RA patients was higher than the clinical trials suggested and was comparable to TNF
inhibitors. 23.2% of their cohort developed infections within a median time of five months
from the start of treatment. Serious infections were seen in 7.1%, 75% of these had a rise in
CRP and there was one death from pneumonia, 50% had gastrointestinal complications [70].
There is likely to be a risk of TB reactivation in patients on tocilizumab. A review
looking at rates of TB in patients on newer biologic agents found 8 cases of active TB on
tocilizumab for RA, in 21 trials. However most of these cases occurred in TB endemic
countries. This was backed up by an analysis of 3881 patients in Japan that found a similar
incidence rate of TB as with TNF inhibitors, although in this study TB screening and
treatment of latent TB was undertaken [71, 72].
There is little data on risk of hepatitis reactivation. A retrospective study found two cases
of rise in HBV-DNA out of 18 HBsAg negative / anti-HBc positive patients, who did not
have pre-emptive antivirals. However, this reverted to undetectable within 3-6 months, and
there was no change to the liver transaminase levels. Case reports have described patients
with chronic hepatitis B being given tocilizumab with good disease outcomes [73]. This
suggests that tocilizumab is a safe treatment option in patients who are at risk of hepatitis
reactivation or live in endemic areas.
Screening guidelines for infection prior to treatment are similar for tocilizumab and TNF
inhibiting therapy.
ANAKINRA
Anakinra is an IL1 receptor antagonist. Although initially developed for the management
of RA, anakinra was not shown to be an effective treatment for RA. However, it is used for
treatment of auto-inflammatory conditions like adult onset Stills disease and occasionally
gout.
In a recent review, Cantini et al. found no cases of active TB on anakinra [74].
Controlled trials have found stable rates of serious infection over 3 years. There have
been some rare cases of fungal, viral opportunistic and mycobacterial infections and
concurrent use of anakinra with TNF inhibiting agents has not been recommended [75].
ABATACEPT
This is a T cell co-stimulatory modulator. Abatacept carries a labelled warning regarding
risk of pulmonary infection in patients with chronic obstructive pulmonary disease. This was
shown in a randomised controlled trial using abatacept and usual treatment regime that
included a biologic agent or DMARD and placebo. Subsequently, it has been contra-indicated
to prescribe abatacept with other biologics due to the increased risk of infection [76].
A recent review of available literature on patients treated with non-TNF inhibiting
biologics for RA found no cases of active TB in patients on abatacept [71].
In terms of hepatitis B, there is little data on safety, but the conclusions drawn so far are
that abatacept may be safe to use in chronically infected or asymptomatic HBV carriers, as
long as viral prophylaxis is given [38]. This has been shown in several retrospective studies
looking at patients with RA treated with abatacept. In a study of eight patients, four did not
receive prophylaxis and they all experienced viral reactivation [77].
The incidence of serious infection was higher in patients treated with intravenous
abatacept than with subcutaneous. The incidence rate was also found to be higher in the first
six months of therapy and declined thereafter [78].
RECOMMENDATIONS FOR SCREENING PRIOR TO BIOLOGIC THERAPY

Hepatitis B
There are few prospective studies looking at screening for hepatitis B in rheumatology
patients starting biologic therapy, therefore recommendations are based on best practice.
Studies have shown that only 69% of US rheumatologists screen for HBV prior to
commencing biologic agents [79].
All patients should be screened before starting treatment; the testing should include
HBsAg, anti-HBc and anti-HBs antibodies. Those found to be positive on core or surface
antigen need to have liver function tests, HBV-DNA levels checked, and a hepatologist
should be consulted to determine whether antiviral treatment or prophylaxis is necessary.
Vaccination is recommended for those at risk of acquiring HBV infection. This includes
healthcare professionals, travelers, and those with infected family members with absent levels
of protective antibodies. In others patient groups, a careful risk-benefit analysis should be
made in discussion with the patient. This vaccine can be administered during the use of TNF
inhibitors but should be given before administration of rituximab.
Treatment with a nucleoside analogue is recommended for those found to have active
disease. This should be commenced one month before treatment and continue for six months
after the end of treatment [38].
Chronic Infection (HBsAg Positive)
A recent retrospective study showed that 5 out of 8 untreated chronically infected patients
had reactivation of disease as opposed to none out of ten on prophylaxis [80].
If the treatment course is to continue for longer than 12 months, newer antivirals such as
entecavir and tenofovir are recommended as prophylaxis, as a lower risk of drug resistance
has been observed with these agents. However, they have a larger side effect profile when
compared with lamivudine. Patients with HBV-DNA < 2000 IU/ml with short-term
immunosuppression should have lamivudine as prophylaxis. They require frequent
monitoring of HBV-DNA levels and immunosuppressive treatment should not be commenced
until HBV-DNA levels are undetectable [38].
Resolved Infection (HBsAg Negative / Anti-HBc Positive)
For these patients the benefit of prophylaxis is not so clear. A baseline assessment
including HBV-DNA levels and additional risk factors should be undertaken. Those with
undetectable viral levels, negative anti-HBs or strong immunosuppression can be monitored
with regular blood tests. For those on rituximab, more caution should be taken and pre-
emptive treatment considered regardless of HBV-DNA levels.
If reactivation is detected, it is vital to stop immunosuppressive therapy and start
treatment with antivirals. In addition, patients who develop positive HBV-DNA during
lamivudine treatment should change to tenofovir, as it is very likely that they are infected
with a lamivudine-resistant virus (cross-resistance has been reported between lamivudine and
entecavir) [38].
Hepatitis C
As the effect of TNF inhibition on hepatitis C is unclear, patients with hepatitis C can still
be treated with TNF inhibitors. Screening for hepatitis is recommended prior to treatment.
TB
In 2005, the British Thoracic Society published guidelines for screening for LTB in
patients commencing TNF inhibiting therapy [81], which was updated in 2008 by the
American College of Rheumatology (ACR) [82]. It is important to establish the individuals
risk of Mycobacterium tuberculosis infection, using travel history, past exposure and
confounding risk factors like underlying lung disease. Individuals should be screened for
latent infection using interferon-gamma release assays (IGRAs). The tuberculin skin test
(TST) is an inadequate test as it can have poor sensitivity in immunocompromised individuals
(including those on steroids or DMARDs) and has poor specificity in those with prior BCG
vaccinations [83], as shown in data comparing TST with IGRA in the DMARD population. In
paediatric practice, the concomitant use of both is still recommended. Chest radiographs
should be performed to assess for evidence of previous or current infection. Those with
positive findings should be investigated for active TB with sputum microscopy and culture
for acid-fast bacilli and bronchoscopy if indicated. Patients should also be assessed for extra-
pulmonary involvement. The risk of TB development is low when the initial infection
occurred more than seven years before [84].
Patients with positive results should be referred to a specialist clinic for treatment. The
start of treatment with TNF inhibiting therapy must be delayed by at least 2 months until the
drug-susceptibilities of the organism are available. Anti-TB medications should be started,
and once it is clear that the patient is able to tolerate these without significant side effects and
has a good treatment response, restarting TNF inhibiting therapy can be considered. Those
patients with latent TB infection can be treated with a choice of either 3 months of isoniazid
and rifampicin, or 6 months of isoniazid alone. The choice of treatment may depend on other
drugs taken and their interaction with rifampicin [12, 81].
Before treatment
Screen patients prior to starting therapy for active infection

Caution when considering biologic therapy in those with recurring/chronic infection,
underlying conditions that can predispose to infection, travel or work in high risk
areas
Hold therapy in patients with active infection until infection is managed
Educate patients about signs and symptoms of infection and to contact healthcare
professionals if they suspect an infection
During treatment
Be vigilant for signs of infection and consider atypical sites or presentations
After treatment
Monitor patients until the drug is eliminated

Figure 3. Treatment algorithm according to ACR recommendations (adapted from [82]).

Recommendations for preventing and diagnosing infections in patients receiving biologic agents.
Recommendations for Vaccination
It is advised that at their first visit, the patients vaccination profile is assessed. This
includes establishing side effects experienced to previous vaccines and antibody status to
infections like varicella.
Vaccination is recommended during stable disease and prior to immunosuppression.
Although there have been case reports describing flares in disease following vaccine
administration, a few controlled prospective studies did not confirm this [85].
Non-Live Vaccines
This group includes influenza, pneumococcal, hepatitis B, tetanus toxoid and

haemophilus influenzae B vaccines. These vaccines are safe and recommended for all patients
on biologic drugs. Some studies have shown that the response in those on TNF inhibiting
drugs is reduced. In addition, rituximab reduces the response to influenza and pneumococcal
vaccines. In patients given the tetanus toxoid, a response was seen 24 weeks after B cell
depletion [86].
The findings of this study suggest that those with life-threatening tetanus should be given
tetanus immunoglobulin as immunity has only be shown 24 weeks after rituximab
administration. It is recommended that vaccines are administered prior to B cell depletion. In
addition, studies have shown a reduced persistence of antibody response [59].
Influenza Vaccine
Influenza vaccine is recommended for all patients with chronic diseases, which include
rheumatic conditions as they reduce the rate of hospitalization from serious respiratory
infection. Two studies looking at a single trivalent H1N1 influenza vaccine; one in just RA
patients using tocilizumab and one in vasculitis, spondylarthropathies and connective tissue
disease found good results. There were good rates of seroprotection and no serious adverse
events. There was a slightly reduced response in those on methotrexate, abatacept and
rituximab; however, it was still adequate. In addition, the duration of antibody response was
shorter than for the general population [87, 88].
In conclusion, annual influenza vaccine is safe and recommended in the rheumatic
disease population on biologics and a single dose can be sufficient for appropriate protection
[85].
Pneumococcal Vaccine
The 7-valent conjugate pneumococcal vaccine is recommended in the autoimmune

rheumatic disease group. A study comparing those on TNF inhibitors with other drug
treatments showed that use of methotrexate and greater age were associated with a worse
antibody response to vaccine [89]. A further study followed patients up for 1.5 years post
vaccine. This found that in patients with RA, TNF inhibiting treatment was related to a
shorter duration of protective antibody levels. This, however, was not the case in the
spondylarthropathy group. This raises the question of whether booster vaccines are necessary
[90].
Human Papilloma Virus Vaccine
HPV vaccine is recommended in most countries in young women to prevent development

of premalignant lesions leading to cervical cancer.
Several studies have shown that SLE patients are more likely to be infected with HPV
[91] and therefore have higher rate of squamous intraepithelial lesions, but these have not
shown an increased rate of cervical cancer [85]. The European League against Rheumatism
(EULAR) have recommended HPV vaccine for all female SLE patients under the age of 25
[59].
Live Attenuated Vaccines
EULAR have recommended that these are avoided in the immunosuppressed group of
patients as there is a risk of severe infection. There have been a few studies, which have
looked at using live attenuated vaccines i.e., measles, mumps and rubella (MMR) or
varicella in the paediatric population [59].
Hepatitis A and B Vaccine
It is recommended that these are given to patients with autoimmune rheumatic disease,
particularly those on biologic therapy who are at risk of acquiring these infections. There is a
question over how effective this vaccine is this patient group [59].
Vaccinations in Paediatric Population
Children with paediatric rheumatic disease have an increased risk of infection when
compared with a healthy paediatric population, which can be prevented with appropriate
vaccination.
The efficacy and safety of vaccines is difficult to study, as high power and long duration
of follow up is required to assess persistence of immune response. As a result,
immunogenicity is the outcome measure that most studies use which looks at the vaccine
specific antibody titres combined with the humoral / cellular response to each pathogen.
A review of 15 studies looking at vaccines in patients on biologics, found that most
patients reached protective antibody concentrations after vaccination, however these were
lower than in the non-biologic group and declined more rapidly over time. This means that
these patients require booster vaccinations to maintain protective antibody levels [92].
Following a case report of the death of a three month old baby born to a mother on
infliximab for Crohns disease, who developed vaccine induced mycobacterial infection
following BCG, it has been recommended that BCG vaccines are not given to patients using
biologics [93].
There have been no vaccine induced infections associated with MMR or VZV booster
vaccination in patients with juvenile idiopathic arthritis or juvenile SLE, and it has been
suggested that these are given to patients in the biologic and the non-biologic group of
patients [92].
Summary of Vaccine Recommendations in Patients on Biologics
Assess vaccination status of all patients in initial consultation

Administer vaccinations during stable disease if possible, before commencing
therapy
Response to vaccine is likely to have shorter duration than in non-imunosuppressed
Avoid BCG vaccine
Non-live vaccines should be administered before starting rituximab if possible, but

can be given during DMARD and TNF inhibiting therapy
Consider influenza and pneumococcal vaccine
Avoid live-attenuated vaccines
Consider booster vaccines
Consider hepatitis A and B vaccines
HPV vaccines are recommended in females under 25, this is also recommended in
males in certain countries
If contaminated wound and received rituximab less than 24 weeks prior, give tetanus
immunoglobulin
CONCLUSION
Biologic therapies have revolutionised the management of autoimmune rheumatic
diseases. However, they are associated with specific infection risks according to the agent
used. Prior to commencing these treatments, clinicians must make a thorough, relevant risk
assessment and perform appropriate screening. Vaccinations should be given during stable
disease, if at all possible, and before the start of immunosuppressive therapy. The clinician
must consider a wider differential of infections when faced with these patients. In addition,
early consultation with infectious disease specialists is advisable. Although most well known
infection risk is associated with TNF inhibiting drugs, this is likely to be because these drugs
have been available for longer and as a result, there is a large amount of published literature
from clinical experience. As other drugs become more widely used, it is important to continue
to publish case reports in relation to infection in order to inform the scientific community.
Many agents are currently in clinical trial phase and their infection risk in clinical practice
will need to be characterised further.
Recommendations
TNF Inhibitors / tocilizumab

Infections Screening
Mycobacterium typical / atypical Interferon gamma assay / TST
+/- chest radiograph and sputum
Hepatitis B HBV serology, baseline blood tests
Hepatitis C HCV serology +/- HCV RNA
Varicella Zoster Varicella serology
Bacterial skin / soft tissue / joint infection n/a
Endemic infections Baseline serology
Rituximab
Infections Screening
Bacterial infections Baseline Immunoglobulin levels
Hepatitis B rituximab not recommended
Hepatitis C HCV serology +/- HCV RNA
PML n/a
Anakinra / Abatacept
Little known data, however avoid concurrent use with other biologic agents
Legend: HCV hepatitis C virus; HCV RNA hepatitis C virus ribonucleic acid (viral
copies); TST tuberculin skin test.
Summary Points
TNF inhibiting drugs are associated with an increased risk of mycobacterial

infections; both typical and atypical. Consider extrapulmonary and disseminated
infection and take a travel history. It is crucial to screen patients with a chest
radiograph and IGRA before commencing treatment.
In endemic areas, systemic fungal infection can occur on TNF inhibitors
Consider deep seated soft tissue infection on TNF inhibitors
Infliximab is associated with a greater risk of infection than etanercept and
adalimumab
Consider IRIS in patients that are not improving on anti-microbial therapy,
immunosuppression may need to be continued
Patients with chronic HBV infections should be given anti-viral prophylaxis while on
biologic treatment
There may be an increased risk of PML for rheumatic patients on rituximab
Avoid rituximab in patients with chronic HBV due to serious risk of reactivation
CRP may not rise in patients on tocilizumab during acute infection
Tocilizumab has a similar infection risk profile to TNF inhibitors
Little is known about infection risk with abatacept and anakinra, but clinical trials
have shown a low rate of infection
Ensure patients are up to date with vaccinations prior to commencing biologics and
have regular boosters
ACKNOWLEDGMENTS
The authors would like to thank to Dr Kevin Winthrop MD MPH, Oregon Health and
Science University (email: winthrop@ohsu.edu) and Dr Michael Brown FRCP PhD, London
School of Hygiene and Tropical Medicine (michael.brown@uclh.nhs.uk), for reviewing this
chapter.
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systemic lupus erythematosus, Rheumatol Int, vol. 33, pp. 335-40, 2013.
[92] N. Groot, M. W. Heijstek, and N. M. Wulffraat, Vaccinations in Paediatric

Rheumatology: an Update on Current Developments, Curr Rheumatol Rep, vol. 17, p.
46, 2015.
[93] K. Cheent, J. Nolan, S. Shariq, L. Kiho, A. Pal, and J. Arnold, Case Report: Fatal case
of disseminated BCG infection in an infant born to a mother taking infliximab for
Crohn's disease, J Crohns Colitis, vol. 4, pp. 603-5, 2010.
Chapter 20
PARTICIPANT INFORMATION SHEETS

IN CLINICAL RESEARCH: COMPROMISING
THE ETHICS OF INFORMED CONSENT?
Andra F. Negoescu1,, Leslie Gelling2,3

and Andrew J. K. str, PhD1,4
Department of Rheumatology, Addenbrookes Hospital, Cambridge, UK
1
Faculty of Health, Social Care and Education, Anglia Ruskin University,

2
Cambridge, UK
3
Chair, Cambridge South Research Ethics Committee,
National Research Ethics Service (NRES), UK
4
Director, Rheumatology Research Unit, Addenbrookes Hospital, Cambridge, UK
ABSTRACT
Clinical research forms the foundation on which rest the advancement of medical
knowledge and improvement in patient experience and outcomes. In order to obtain
accurate information, as well as to protect research participants and ensure their safety, it
is crucial that potential participants go through a meaningful informed consent process,
and they understand what they are engaging to and what is expected of them. The
progress recently achieved in the implementation of new biologic therapies across many
rheumatic disorders depended on the information provided by clinical trials. The current
way of delivering information about a biologic drug in a clinical trial is in the form of A4
sheets, with participant information sheet (PIS) sometimes exceeding thirty pages. We
are concerned that in these circumstances participants feel overwhelmed, which can lead
to poor quality and, in some cases, even unethical research. The unfriendliness of both
the language and length of the PIS is a perfect recipe for failure to engage people in
clinical research. Even more worryingly, individuals may be participating in research
without truly understanding what their participation will involve. Here we discuss the
Correspondence to: Dr. Andra F Negoescu, Department of Rheumatology, Addenbrookes Hospital, Cambridge,
UK. Email: andra.negoescu@addenbrookes.nhs.uk.
496 Andra F. Negoescu, Leslie Gelling and Andrew J. K. str
ethical implications of informing patients about new therapies available through clinical
trials.
Keywords: informed consent, patient information sheet; clinical trials, ethical aspects of
informed consent
INTRODUCTION
Clinical research forms the foundation on which rest the advancement of medical
knowledge and improvement in patient experience and outcomes. The discovery of biologic
treatments was associated with a large number of clinical trials which aimed at establishing
the safety and toxicity profile of these drugs. As such, governments have encouraged and
supported clinical research and in certain countries desire exists to include every patient in
some form of health research [1]. Achieving this goal however is challenging, as study
participants usually represent a homogenised group, due to strict inclusion and exclusion
criteria, and are not representative of the general group of patients with a particular condition.
This has certainly been true for patients suffering from rheumatoid arthritis where, following
a frenzy of research and implementation of new biologic treatments over the last decade,
recruitment into trials has become increasingly difficult [2].
A change in the treatment paradigm has been partly responsible as individuals do well on
available therapies and, therefore, are not severe enough to meet trial inclusion criteria. In a
climate where study recruitment is complex, meeting ethical requirements regarding informed
consent can create additional hurdles. We argue that the PIS, a central part of the informed
consent process, has now become unethical and is hindering the conduct of clinical research
and implementation of new therapies.
PATIENT INFORMATION SHEETS AND INFORMED CONSENT

Until recently, research ethics committees insisted that the PIS should not exceed one A4
page. Over the last decade, however, efforts have been made to improve the quality of
informed consent for research purposes. Investigators have become increasingly aware of the
need to ensure that participants understand why research is being conducted, and what is
expected of them once they do consent. Simultaneously, a requirement has developed to
obtain ultimate completeness, no doubt driven by a desire to avoid the legal implications of
omitting important information from the PIS. As a result, the PIS has become increasingly
dense and overwhelming often exceeding thirty A4 pages. In a society where the sound bite
rules and communication exchange is often limited to 140 characters, the appropriateness of
the PIS in its current form is questionable. It is our belief that the requirement to generate all-
inclusive PISs has created a situation where the process of seeking informed consent is
compromised and may even be described as unethical.
It has been estimated that an adult reads 200-250 words per minute (for non-technical
material) therefore two minutes is required to read an average A4 page of text. This
coupled with a mean attention span of 20 minutes, should be of great concern as a 30-
Participant Information Sheets in Clinical Research 497
page PIS would take over 60 minutes to read. This will inevitably impact on
comprehension and retention of information, especially as much of the data is new to the
reader and may contain technical or simplified scientific material. In this context, it is
worrying that individuals are deciding whether to participate in research with, for example, a
pharmaceutical agent that has not been tested in substantial numbers of patients or any at all.
How many research participants genuinely provide informed consent prior to engaging in
clinical studies? A cross-sectional survey of cancer trial patients showed that 90% of patients
who had recently been enrolled in a clinical trial were satisfied with the informed consent
process and most considered themselves to be well informed. Nevertheless, many did not
recognise the concept of non-standard treatment (74%), the potential for incremental risk
from participation (63%), the unproven nature of the treatment (70%), the uncertainty of
benefits to self (29%) or that trials are generally conducted to benefit future patients (25%)
[3]. This raises the dilemma if a distinction exists between believing oneself to be adequately
informed and actually being appropriately informed.
Whilst verbal description of research is an important part of obtaining informed consent,
the PIS remains the predominant means of imparting information with potential research
participants. Who should decide however the level of data required for a potential research
participant to receive in order to make an informed decision? Currently, in the UK, the
National Research Ethics Service (NRES) offers guidance on what information should be
included but it is the research ethics committee (REC) that ultimately decides if the PIS is
complete. Is this appropriate or should researchers, lawyers, trial sponsors and end users
also have influence over the content?
The PIS is a legal document requiring an element of contract but of superior importance
is to ensure that researchers meet the needs of patients and potential research participants.
Those responsible for a patients clinical care may be ideally placed to understand the needs
of their patients. Alternatively, patients, users and consumers may have a greater
understanding of what information is required to make an informed decision. Overall RECs
do include a wide and varied membership, often including doctors, nurses and lay members,
but RECs are still constrained by the expectations of NRES.
At present it is difficult to establish what could be removed from the PIS without
impacting on the process of obtaining informed consent. Perhaps a more useful approach
would be to alter the way information is delivered. Currently RECs place considerable
emphasis on reviewing the information provided in the PIS and less on how verbal
information might be provided. Surprisingly, no evidence based guidelines exist regarding the
optimal way to deliver information to research participants. Currently, the preferred, but
possibly archaic, way to deliver information is in the form of white A4 sheets of paper. This
does not take into consideration that the average reading age in the UK is 12, attention spans
are limited and that, in many parts of the world, illiteracy rates are high. More effective ways
of delivering information must be developed that maintain attention and interest, thus
increasing the amount of information retained such as a short video or animated DVD.
Furthermore, a short quiz could be incorporated into the consenting process to make the
process patient friendly, more engaging and less overwhelming. These could help in the
ultimate goal of obtaining truly meaningful informed consent for research.
In a personal view article Richard Wassersug highlighted that consent forms, including
the PIS, are written in unfriendly language. His perspective is valuable as he is both a cancer
researcher and patient. The unfriendliness of both the language and length of the PIS are a
498 Andra F. Negoescu, Leslie Gelling and Andrew J. K. str
perfect recipe for failure to engage people in clinical research. Even more worryingly,
individuals may be participating in research without truly understanding what their
participation will involve.
Currently RECs insist that the PIS should be written in simple, neutral language. This
appears sensible however can we be sure that 30-pages of simple, neutral language is either
read or understood prior to enrolment in a clinical trial? There are three possible scenarios
related to a PIS of such length. One: the potential participant reads the PIS but is swamped by
the vast amount of information and decides not to take part; two: the potential participant
doesnt read the PIS at all (as it requires a significant amount of time and concentration) and
doesnt take part; three: the potential participant doesnt read the PIS properly and decides to
take part. This third situation is not only dangerous but also contravenes the fundamental
ethical principle that a participant is able to freely make an autonomous decision. Research
undertaken in such circumstances could be deemed unethical.
Unfortunately scant literature exists regarding the degree of understanding of research
participants about what their participation will involve following completion of the consent
process. A wealth of information however does exist regarding individuals estimation of risk,
which overall is poor [4-5].
CONCLUSION
Fully informed consent for all participants is unobtainable ideal as so many variables
exist and most individuals are unlikely to understand all the information given to them during
the consenting process. Thus there is no gain, especially to potential research participants, in
formulating a PIS which does not fulfil its intended purpose. Would it not be better to focus
on the information that is truly relevant for the participant? The first step may be to simply
ask them. A web-based survey on the preferred size of the participant information sheet in
research showed that brief information provided in the first instance was sufficient, with 77%
of participants choosing to access the first level of information only (those that corresponded
to the average reading times). A sizeable minority of the participants chose not to access any
information at all [6].
The primary and underpinning principle of the Nuremberg Code, the Declaration of
Helsinki and all subsequent codes of research ethics has been that those involved in research
have first been able to make an autonomous decision about their participation. For many now
invited to participate in clinical research, this principle has become a challenge not always
achieved.
ACKNOWLEDGMENTS
The authors would like to thank Dr. Natasha Jordan PhD, Consultant Rheumatologist and
Deputy Director Rheumatology Clinical Research Unit, Addenbrookes Hospital, Cambridge,
UK (Email: natasha.jordan@ addenbrookes.nhs.uk) for reviewing the chapter.
Participant Information Sheets in Clinical Research 499
REFERENCES
[1] Department of Health, Best Research for Best Health, A New Natl. Heal. Res. Strateg.
NHS Contrib. to Heal. Res. England., vol. 17, no. Suppl.1, pp. 11-315, 2006.
[2] Thoma A., Farrokhyar F., Mcknight L., and Bhandari M., How to optimize patient
recruitment, Can. J. Surg., vol. 53, no. 3, pp. 205-210, 2010.
[3] Joffe S., Cook E. F., Cleary P. D., Clark J. W., and Weeks J. C., Quality of informed
consent in cancer clinical trials: a cross-sectional survey., Lancet, vol. 358, no. 9295,
pp. 1772-1777, 2001.
[4] Shankar J., Patients memory for medical information., J. R. Soc. Med., vol. 96, no.
10, p. 520, 2003.
[5] Turner P. and Williams C., Informed consent: Patients listen and read, but what
information do they retain?, N. Z. Med. J., vol. 115, no. 1164, 2002.
[6] Antoniou E. E., Draper H., Reed K., Burls A., Southwood T. R., and Zeegers M. P.,
An empirical study on the preferred size of the participant information sheet in
research, J. Med. Ethics, vol. 37, no. 9, pp. 557-562, 2011.
Chapter 21
BIOLOGIC TREATMENT:
THE YOUNG PATIENTS PERSPECTIVE
Nicola Daly*
Department of Rheumatology, University College London
ABSTRACT
This commentary explores the benefits of biologic treatments for autoimmune
rheumatic diseases from the perspective of young patients (16-25 years old). In addition,
the role of the rheumatology specialist nurse in managing young patients throughout the
long journey of getting their disease under control is explained using concrete examples
of patient - nurse interactions.
Keywords: adolescent rheumatologic patients, specialist nurse perspective
INTRODUCTION
As discussed in the previous chapters of this book, biologics are becoming more
commonly used throughout the juvenile and young adult population. The outlook and
prognosis for children with severe arthritis is much improved over the last 10 years [1]. We
have excellent data to show that biologics have been hugely successful in treating the various
forms of juvenile idiopathic arthritis (JIA). But what about the patients themselves, how do
they feel? How have biologics impacted on their quality of life? As a nurse who works
closely with these young people, I hope to speak on their behalf and answer some of these
questions. Through my day to day interaction with this group of patients, I get to witness
Correspondence to: Nicola Daly, Department of Rheumatology, University College London Hospital NHS
*
Foundation Trust, 250 Euston Road, London, NW1 2PG, email: nicola.daly@uclh.nhs.uk.
502 Nicola Daly
positive responses to life-altering treatment in many cases, but I also see the road to that goal,
the ups and downs, the uncertainty and worry from not just the patients but their whole
support network. Working with adolescents brings with it not just the patient themselves but
also their wider network i.e., parents, guardians, grandparents, siblings and friends. When
working with young people the road is not always clear or straight. I will be using some
scenarios in my main discussion to emphasise in more detail the challenges of having arthritis
and coping with the complexities of the adolescent life.
CHALLENGES OF MANAGING CHRONIC RHEUMATIC CONDITIONS

IN ADOLESCENTS AND YOUNG ADULTS
For the older adolescent (16-19 years old) and the young adult (20-25 years old), life in
general is fraught with decisions on a day to day basis. Throw into the mix living with a long-
term condition and being asked to make life altering decisions about your long term health
and wellbeing to get the full picture of the difficulties of being an adolescent or a young
person with arthritis [2].
The management of inflammatory arthritis or JIA in this case has in recent decades
moved towards earlier and more aggressive intervention with the use of biologics. For an
adolescent or young person whose disease has not been adequately controlled or lost response
to conventional disease modifying anti rheumatic drugs (DMARDs), the next therapeutic step
is the initiation of biologic treatment. People above the age of 16 can make decisions about
their care. This burden of responsibility may coincide with a period of rapid physical,
cognitive, psychological, social, educational and vocational development, and all the while,
relationships with parents/carers and health professionals are changing [3]. There is evidence
that health professional support during this period is valuable. In a recent study, the
implementation of a transition programme as a brief intervention improved the perceived
health and quality of life of adolescents with JIA during the transition process, as well as the
parenting behaviours of their parents [4]. Also, the health professionals support could not be
replaced by additional information sources, such as health-related internet sites providing
information about medication use and aspects of JIA relating to social life, according to
another study [5]. This recent research showed that young people need to be supported in
making decisions about their care by their health professionals, peers and families, and
understanding the role of their therapy plays in their disease management is central to this
process.
The short term benefits of using biologic agents in JIA are were documented and
comprise a reduction in joint pain and damage, and additional improved mobility; there are
also well-recognised short term risks, such as increased vulnerability to infection. But what
about the long term consequences (e.g., malignancy, fertility and more acute infections)? An
older adult would worry about longer term affects and need reassurance about some of those
issues. In my experience, most but not all young people worry less about the distant future
they worry much more about the here and now. My view is that young people have a different
outlook on life in general, they worry about things somebody older than them wouldnt even
contemplate, and for that reason it is essential the health care professionals working with
them have insight into that and tailor the advice, guidance, information and understanding to
Biologic Treatment: The Young Patients Perspective 503
their specific needs. Only when we recognise and understand those specific needs, we can
truly treat this group of patients in the most effective way.
Young people who are offered biologic therapy are confronted with decisions that may
have profound consequences at a point when their disease is at its worst and their wider lives
are characterised by change and uncertainty. Health care professionals play an important role
as providers of information and advice for patients generally.
When we think of young people and treatment in the same sentence, one word probably
springs to our minds adherence. Biologic treatments, as we know, are expensive and
offered only after conventional treatments failed to control adequately the disease. Once a
decision has been made to start a biologic treatment, one would think that is the hard part
done, but unfortunately the process of managing a young person on a biologic treatment is not
that straightforward. Again, not in all, but in a large cohort of our young patients there are a
number of contributing factors as to why some find it difficult to adhere to their treatment. As
I mentioned previously, young people think about things differently.
To demonstrate my point, I will discuss below a few patient scenarios, which I have
encountered personally as a rheumatology clinical specialist nurse who works with young
people.
Patient A
He is 16 years old and is due his fortnightly tocilizumab infusion. He lives not far from
where he receives his treatment. It is a nice sunny day so all of his friends are going to play
football in the park after school. He feels fine, his joints have not been painful at all recently,
and he cant remember the last time he had a bad flare. He feels like he actually doesnt even
need the treatment now; anyway, so missing one course of medication is not going to make
much of a difference.
Patient B
She is 20 years old and is studying at university away from home. She is due her 8
weekly infliximab infusion. Her 2nd year finals are coming up, she is really stressed and has
been staying up late most nights to keep on top of things. She is typing on her laptop for a
much longer period that normal. She knows she needs her infusion, as she has been feeling
much stiffer particularly in the morning and her wrists are really starting to hurt and become
swollen. But it is a two hours train journey to the hospital for her treatment; firstly she cant
afford the train ticket and secondly, she would miss a whole day studying and really needs to
stay focused. She decides she will just try and get through this month by taking some extra
painkillers and deal with her arthritis and infusion after her exams are over. She gets on well
with the nurses in the infusion clinic and is confident that they will book her in if she calls in
few weeks time.
504 Nicola Daly
Patient C
She is 18 years old she is due to have her rituximab course in the following week. She
has never had it before, her consultant and specialist nurse told her that as part of the
treatment she will receive pre-medication to prevent infusion reactions. This pre-medication
includes intravenous steroids. She is flaring badly which is why she was switched to
rituximab from adalimumab. As the rituximab takes at least 2-3 months to fully take effect,
her consultant has recommended that she have a larger dose of steroids than the normal pre-
med dose, to help get things under control. She remembers having steroids when she was first
diagnosed with arthritis, and at the time she was only 10 years old and very unwell, so her
mum made the decisions about her treatment. But she remembers that the steroids made her
feel really angry and down, and they also made her face really big, she put on weight and her
hair also fell out a little bit. Her specialist nurse explained that a different steroid dose than
before would be used and only as a one off infusion, but she doesnt agree with the treatment
as she is not going to take any risks of having similar side-effects. She refuses to have
rituximab as it involves having additional steroids. She is worried that her new boyfriend will
think she is ugly if she put on weight and loses her hair.
Patient D
He is 14 years old and has humira injections every two weeks for his enthesitis-related
arthritis (ERA), which doesnt bother him too much. He recently had some scans which
showed that he had significant inflammation in his lower back and some damage to his hips.
The doctor told him that in order to take away the inflammation and slow down the rate of
damage, he needs to continue with having his humira injections, as prescribed. But the
injection really hurts and stings every single time it is administered, and he dreads having it
every two weeks. His mum was doing the injections but he has now learned to do it himself.
He missed some injections and he fights with his mum all the time because she says he needs
it and it will stop him having irreversible damage in his joints when he is older. He does not
see the point of having such a painful injection when he is not even feeling unwell or in pain
because of his arthritis. He decides that maybe if he just has it now and again, his mother will
be happy then.
These are just some examples to emphasise my point that young people have different
needs and worries to that of a younger child or an adult. However, this is cant be generalised
to any adolescent or young person having arthritis, but there are challenges that a
rheumatology nurses encounters frequently. At some point, all our young patients have tough
decisions to make, decisions that can affect their educational, social, physical and general
wellbeing.
For example, young people with swollen and painful joints have difficulties going to
school on a daily basis, cannot see their friends or sit their exams, go on holiday or go to that
important job interview, or maybe even need their parent or partner to help them wash and
dress, as they are feeling so tired all the time. Once you address the barriers to treatment
success, such as adherence, once they are ready to accept they have arthritis and they need to
take responsibility for their health and long term future, only then can they make the informed
decision to start and adhere to treatment.
Biologic Treatment: The Young Patients Perspective 505
I have heard the statements: the biologic treatment has changed my life, I never want
to go back to how I was, and I feel so much happier and more energised. For most young
people, that time will come when they realise that we are here to help them and that the
treatments we offer are going to make a difference to their quality of life in the longer term.
Some come to that conclusion earlier than others and some others (but only a very small
number) never come to that conclusion. All we can do for our patients is continue to support
and guide them, and be ready to overcome some barriers on the road to where they need to be.
Lastly, I want to briefly touch on the role of the rheumatology specialist nurse in this
whole process. As we all know, the medical team faces the hard task of diagnosing these
chronic autoimmune conditions and commencing the right treatment for that individual
patient or young person, and all the while ensuring that person is as well as they can be. The
patients, and to a lesser extent their support network, cope with the everyday struggle of
living with a chronic or long term condition, endless hospital visits, blood tests, scans and
medication. So where does the nurse fit into this picture? The extensive use of biologic agents
for the treatment of rheumatic conditions in recent years has required a steep learning curve
for the specialist nurses who manage and work in this specialty, as despite biologic treatments
many young patients continue to have active disease [6]. Since 2002, rheumatology specialist
nurses have taken more of an active role in managing patients on biologic treatments,
including patients screening and education, treatment administration, prescription
coordination for home drug delivery, patient support, monitoring and data collection.
As an adolescent and young persons rheumatology specialist nurse, my role is to act as
an advocate for both doctors and patients and bridge the gap between them. It is essential that
specialist nurses provide support, understanding, flexibility, compassion and above all else, a
high standard of care for their young patients. It is also important that these young people
have a voice and feel heard, it is vital that the things which are most important to them at that
specific time in their life are recognised and acknowledged, to ensure they are not living a life
that is tinged with too much uncertainty, struggle and sacrifice because of their disease.
CONCLUSION
In summary, the use of biologics for treatment of juvenile forms of arthritis and other
autoimmune conditions expanded in the last 10-15 years. The use of these therapies in JIA
has been associated with a positive outcome for a large number of young people with arthritis.
But we are still uncertain of the longer term outcomes and potential side-effects of using
biologics in young population. There is still so much we are yet to learn and discover. But
what we do know is that these treatments have changed the face of arthritis and for the most
part of our patients for the better. As we continue to gain further understanding of the
challenges and obstacles that coincide with working with this particular cohort of patients,
then the already high standard of care we all struggle to offer to our patients, will be
maintained and improved further.
506 Nicola Daly
ACKNOWLEDGMENTS
Nicola Daly would like to thank Samantha Moore, Rheumatology Clinical Nurse
Specialist, University College London Hospitals NHS Trust (email: samantha.moore@uclh.
nhs.uk) for reviewing this commentary.
REFERENCES
[1] J. Guzman, K. Oen, L. B. Tucker, A. M. Huber, N. Shiff, G. Boire, et al., The
outcomes of juvenile idiopathic arthritis in children managed with contemporary
treatments: results from the ReACCh-Out cohort, Ann Rheum Dis, vol. 74, pp. 1854-
60, Oct 2015.
[2] E. J. Coulson, H. J. Hanson, and H. E. Foster, What does an adult rheumatologist need
to know about juvenile idiopathic arthritis?, Rheumatology (Oxford), vol. 53, pp.
2155-66, Dec 2014.
[3] R. I. Hart, H. E. Foster, J. E. McDonagh, B. Thompson, L. Kay, A. Myers, et al.,
Young people's decisions about biologic therapies: who influences them and how?,
Rheumatology (Oxford), vol. 54, pp. 1294-301, Jul 2015.
[4] D. Hilderson, P. Moons, K. Van der Elst, K. Luyckx, C. Wouters, and R. Westhovens,
The clinical impact of a brief transition programme for young people with juvenile
idiopathic arthritis: results of the DON'T RETARD project, Rheumatology (Oxford),
vol. 55, pp. 133-42, Jan 2016.
[5] P. A. van Pelt, C. H. Drossaert, A. A. Kruize, J. Huisman, R. J. Dolhain, and N. M.
Wulffraat, Use and perceived relevance of health-related Internet sites and online
contact with peers among young people with juvenile idiopathic arthritis,
Rheumatology (Oxford), vol. 54, pp. 1833-41, Oct 2015.
[6] K. L. Vidqvist, M. Malin, T. Varjolahti-Lehtinen, and M. M. Korpela, Disease activity
of idiopathic juvenile arthritis continues through adolescence despite the use of biologic
therapies," Rheumatology (Oxford), vol. 52, pp. 1999-2003, Nov 2013.
Chapter 22
STRATEGIES AND SAFETY NETS:

NURSE-LED CARE OF THE PATIENT
ON BIOLOGICS
Pauline Buck and Victoria Howard*

Rheumatology Department, University College London Hospital,
London, UK
ABSTRACT
Nurse-led interventions are often associated with positive outcomes in the
management of patients on biologic treatment for chronic conditions. Nursing input
provides holistic care and support that is well reported to benefit the patient. The
diagnosis of a rheumatological condition can be life changing and affect patients in a host
of different ways. Many patients have benefited since the advent of biologics and it
effectiveness in treating the diseases process. In this chapter, we present two case studies
and discuss the interventions and strategies used, including those implemented by the
clinical nurse specialist (CNS). We present the case of a 20-year-old female patient with
ankylosing spondylitis (AS) and a 47-year-old man with rheumatoid arthritis (RA). Both
these patients embark on a journey of biological therapy that ultimately successfully
controlled their disease. The role of the CNS deploys a proverbial safety net for patients
and their families, along with the medical team helps to develop coping strategies and
plans to support patients through the disease process.
Keywords: clinical nurse specialist, holistic management of patients with arthritis,

management of rheumatic patients on biologics
Correspondence to: Victoria Howard, Department of Rheumatology, University College London Hospital NHS
*
Foundation Trust, 250 Euston Road, London, NW1 2PG, email: victoria.howard@uclh.nhs.uk.
508 Pauline Buck and Victoria Howard
INTRODUCTION
A safety net can be defined as a net put below people performing at a great height
(Cambridge Dictionaries 2016). The role of a CNS is a privileged position and patients may
often feel they are balancing at a great height when diagnosed with a chronic illness suffering
and learning to cope with a whole swarm of symptoms. Since the advent of biologics in 1999,
patients treatment options have increased. Patients who are on biologics often need a lot of
support both physically and emotionally, and part of the CNS role is to coordinate this care
and provide a safety net. Indeed, there is regular contact between patients and the nurses and
often a trust develops between the two. This regular contact can entitle nurses to a greater
insight into patients life and struggles. Nurses may be perceived as more approachable; thus,
sensitive issues are often discussed. Educating and informing patients can be key to
developing trust when looking at treatment options or counseling about initiation of new
therapies. A study by Barlow et al. suggested that patients found individual sessions with
nurses helpful in educating them about their disease [1]. Education and knowledge help to
give patients a much better understanding of the disease process, and therefore a sense of
responsibility, which can be a safety net in itself.
The CNS and additional nursing team also provide another dimension: a holistic support.
Holistic care involves looking after the whole of the person. Under this approach, not only
patients physical needs, but also psychological, social and cultural aspects are considered [2].
Naturally, all healthcare professionals often can provide this comprehensive care, particularly
those spending significant time with individual patients. However, nurses training is
underpinned by this approach and therefore they are often at the forefront of care. This is
especially relevant for the CNS role.
The high-level work of the CNS can be broken down into four areas, which are
applicable to all specialist nursing skills including those of the rheumatology CNS (adapted
from [3]).
1) Using and applying technical knowledge of rheumatologic conditions to oversee and

co-ordinate services, personalise the patient pathway, handle complex information
about patients and their disease, and support the needs of patents and their families.
2) Acting as a contact or the multidisciplinary team, undertake proactive case-
management and use clinical knowledge to reduce the risk to patient from treatment
or disease.
3) Using empathy, knowledge and experience to assess and alleviate the psychosocial
suffering of a rheumatologic condition, referring to other health care professionals or
agencies as appropriate.
4) Using technical knowledge and insight from patient experience to lead service
redesign in order to make improvements and make the service responsive to the
patients needs.
The care for rheumatology patients can begin from an early age, if they are diagnosed
with arthritis or other autoimmune condition in the childhood. The CNS is pivotal in
providing the right support and treatment at various stages during the patient care journey.
There are a few central skills required for providing optimal patients support:
Strategies and Safety Nets 509
1) Communication - the CNS needs to be able to communicate to the patient about the
care is needed, but sensitively enough so that the patient feels they are listened to and
that they have a choice. It is important to gauge patient understanding, repeating
salient points and providing written information where appropriate. The CNS should
be aware of any barriers to understanding, such as language, cultural diversity and
beliefs or disability, and be able to use interpreting services and get the family
members on board where necessary.
2) Collaboration - caring for the patient receiving treatment with a biologic agent
requires collaboration form all the members of the clinical team, but especially
between the nurse and the patient. An honest approach provides optimal results.
Collaboration also comes in the form of up-to-date and accurate medical records-
especially when other professionals are involved in care.
3) Education - is key in looking after any patient. Education provides the CNS with the
knowledge and skills to manage each patient well. Although not all patients wish to
know the science underpinning the rationale for the treatment chosen, it is vital the
nurse has this knowledge in order to understand the need for treatment, the
monitoring required and aftercare. An informed patient who links in with the
collaborative aspect of holistic nursing care, it is often supported by co-operation and
understanding. Teaching the patient how to take their medicines correctly (tablets,
injections or infusions), is paramount in achieving an optimal disease control and
compliance. Education provides patient with knowledge, which in turn and can be
empowering for patients. This may lead to self-help, acceptance, independence and a
greater understanding of their individual disease.
4) Care planning - it is highly important to set achievable goals when looking after
patients on biologic treatments. The mode of administrating the drug should be
considered-for example infusion vs. self-injection. The patient also needs to know
how to manage acute disease flares and when they can contact the CNS for advice.
5) Emotional wellbeing - The CNS needs to consider a gamut of emotions that the
patient may be experiencing: anger at diagnosis; frustration with impact of disease on
daily activities; sadness at difficulties that may have arisen in personal relationships,
to highlight but a few. The CNS should be able to provide support but also to know
when to refer to other healthcare professionals and escalate to the medical team as
necessary.
6) Physical wellbeing - aside from the impact of disease, the CNS should encourage a
healthy lifestyle, provide advice against poor lifestyle choices, and assist in matters
such as weight loss and smoking cessation, non-judgmentally.
7) Medication - a CNS must be well informed about each biologic drug that may be
prescribed. They need to advise on the benefits and possible risks of each individual
drug, monitor blood results effectively, particularly as biologic drugs can often cause
neutropenia and liver function abnormalities, and where appropriate, to share
relevant information with their patients.
8) Dignity - Each patient is an individual, and although all patients share the common
feature of having a rheumatic disease, they will present and cope differently;
therefore, it is important that the CNS is mindful of this aspect when providing
holistic care.
Medication is a crucial aspect of a patients care. Side effects are common, up to 77% as
reported by a Cochrane review from 2010 [4]. Providing counselling about therapy and
advice about how to manage a patient who experienced side effects is an important part of the
CNS role. One of the commonest problems encountered in patients on conventional and
biologic treatments is altered blood biochemistry and haematology readings [5]. Regular
blood monitoring should be undertaken for this purpose. Drugs may need to be reduced in
frequency of administration or dose, in order to overcome and minimize side effects. If
symptoms worsen, infections develop or indeed side effects prevail, there will be a discussion
about stopping the current treatment and using of alternative therapies [6].
Patients perception of the benefits and potential toxicity of biologic therapies is an
important factor in patients well-being and compliance. In a qualitative study, Marshall et al.
showed that patients generally had a positive experience of anti TNF therapy [7]; however,
many had such high expectations and the study reported these were not always met. Having
already failed to respond to a number of drugs, patients were happy to have an increase in
options. Patients reported serious side effects in 127/ 1000 cases compared with 118/ 1000
that were taking placebo [4]. The side effects and safety profile of biologics are certainly a
key factor in patients decision making. The short term safety profile of these treatments is
well known; however, given that biologic agents are less than two decades old, the long-term
profile is yet to be attained.
Pregnancy is an important aspect of patients lives and part of the CNS role is to listen to
patients wishes and act as an advocate as well as assisting with drug counselling and
supporting patients throughout the process of getting their disease under controls whilst
trying to lead as a normal life as possible. Rheumatic diseases are associated with changes in
the immune responses [8], and in some cases, patients notice a significant improvement of
symptoms. In RA, for example 48-75% patients report improvement of disease activity.
Conversely, in ankylosing spondylitis (AS) pregnancy does not appear to have an effect on
the disease activity.
Katz et al. conducted telephone interviews of 411 married RA patients and concluded that
there were lower birth rates in women with RA [9]. It was concluded that this might be
related to patient choice, for example, concerns regarding managing families whilst suffering
with a chronic disease, concerns regarding inheritance of the disease or having problems with
sexual intercourse because of pain associated with RA. Moreover, Ostensen et al. showed that
poor control of rheumatologic disease could result in poor outcomes in pregnancy, including
babies being premature and or having a low birth weight [8]. However, positive outcomes for
most women could be achieved; carefully elaborated care plans during pregnancy and a better
understanding of disease pathogenesis, currently permit the majority of women to have
positive pregnancy outcomes.
In male patients, it is just as essential to create an environment where patients feel
comfortable to discuss fertility questions and aspects surrounding medication and disease.
There are fewer examples of men and fertility issues reported. One case study discussed a
male patient with AS who had low sperm count and a 20-year history of infertility [10]. As
TNF can be increased in semen during periods of inflammation, using a TNF blocker could
have additional benefits in addressing fertility issues. This patient was started on etanercept
and consequently, his partner had a successful pregnancy. Whilst one example in isolation is
too small to be considered significant, if appropriate, discussing these issues with patients can
be important.
CASE STUDY PRESENTATION

Case Study 1
A healthy 20-year-old woman presented in the rheumatology clinic with uveitis and
lower back pain. The diagnosis of ankylosing spondylitis was confirmed, based on the
evidence of sacroiliitis on imaging and extra-articular symptoms. Her lower back and hip pain
responded well to diclofenac 50 mg thrice daily; however, she continued to suffer with
frequent episodes of uveitis lasting for weeks at a time. Given the severity of the uveitis, it
was decided she should start infliximab 5mg/kg every eight weeks.
Her first and second infusions were uneventful; however, at the third infusion she felt her
throat tighten and felt hot and clammy, consistent with a mild allergic response. Observations
showed hypertension. This resolved with chlorphenamine, together with monitoring and
reassurance from the medical and nursing teams in the daycare unit. Subsequent infusions
were uneventful. She responded well to infliximab and remained in full time employment.
Her Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score [12], which
measures the disease activity, remained below 2.0 (suggesting well-controlled disease) for
two years and at this point, the patient concluded that she would like to start a family. This
was discussed with the medical team and CNS and the patient was referred to the combined
obstetric/ rheumatology clinic where it was decided that she should remain on infliximab until
she conceived. At this point, she stopped infliximab, and had no recurrent episodes of uveitis
and remained well during pregnancy. Towards the end of the third trimester, the patient
presented with lower back pain and elected for a caesarian section. The medical team felt this
back pain was mechanical rather than a flare of her sacroiliitis. After the birth of her baby,
infliximab was reinstated and the patient remained in clinical remission. Two years later, the
patient conceived again and instigated an infliximab holiday until the birth of her baby. She
did not have any flare ups of sacroiliitis or uveitis during her second pregnancy.
Unfortunately, following this pregnancy, she did develop a severe allergic response and
treatment with infliximab was discontinued. She was counselled by the CNS and started
on adalimumab afterwards (as per the decision of the medical team). During the treatment
she had an infection and developed allergic reactions to multiple antibiotics. The
clinical immunologists evaluated her, and a diagnosis of idiopathic angioedema/anaphylaxis
syndrome was made. The patient was concerned that she may be allergic to adalimumab; an
immunology test was negative and treatment was advised to continue. She continued to have
angioedema associated with her treatment and finally, she decided to stop the treatment with
adalimumab; unfortunately, the allergic symptoms continued despite ceasing the drug.
Following discontinuation of both infliximab and adalimumab, the patient has remained off
biologic treatment and is currently managing her disease with non-steroidal anti-
inflammatories (NSAIDs).
In summary, over the time span of six years, the patient had two successful pregnancies
and was able to breast feed, remained in employment and no suffered no longstanding flares.
Case Study 2
A 47-year-old male with type 1 diabetes mellitus and chronic urticarial, was referred to
the rheumatology department for review of increasing bilateral foot pain and swelling.
Preliminary findings were suggestive of gout, superimposed inflammatory arthritis or
neuropathy. At his first consultation with the rheumatologist a month later, it became
apparent that the problem had also extended to his left ankle and his proximal interphalangeal
(PIP) joints. A diagnosis of new onset seronegative RA was made.
In conjunction with consultant input, the patient was also seen by the CNS in the disease-
modifying anti-rheumatic drugs (DMARD) clinic and counselled with a view to be started on
hydroxychloroquine, methotrexate, and shortly afterwards to commence sulfasalazine
treatment. The CNS was responsible for blood monitoring at regular intervals and acting upon
any abnormal results. His initial response to treatment, which included an intramuscular
steroid (methylprednisolone) injection, was good, but unfortunately, his arthritis became
active afterwards, this time extending to his right ankle and further PIP joints. Six months
later, the decision to add a biologic treatment (certolizumab) was made. Synovitis had also
extended to his elbow by this time. Despite an excellent initial response, the effect was
short lived and following emergency review, patients treatment was switched to weekly
etanercept injections a further six months later. Once again, response was short lived and
treatment to rituximab was proposed; however, because of an adjuvant diagnosis of
hypogammaglobulinaemia, tocilizumab became the drug of choice at this stage. His first
infusion was given almost two years after his initial referral and diagnosis with RA. Regular
contact with both his named nurse specialist and nursing staff within the infusion clinic
provided the advice and support that was necessary during a period of personal upheaval.
Overall treatment was well tolerated and the patient was been able to return to work, albeit on
a voluntary basis.
Discussion
Patient perception and understanding of biologic treatment are important for compliance
issues and well-being of patients with rheumatic conditions [11]. It is important that patients
have choice when it comes to their care, and medication is a major part of this. In the first
case study, the patient had an allergic reaction directly related to infliximab, she then
responded well to adalimumab, although stopped regarding concerns of allergy. Patient two
waivered in response to anti TNF therapy and developed hypogammaglobulinaemia (low
levels of gamma globulins which may result increase risk of infection) on rituximab.
A Cochrane review found that 770/1000 patients treated with biologics reported side
effects compared with 724/1000 patients on placebo, representing a 5% risk of harm
associated with the use of biologic agents [12]. Patient one experienced an acute reaction to
infliximab. Hansel et al. hypothesised that an allergic reaction to biologic therapy could be
due to a variety of reasons, although likely to be an IgE mediated reaction where the body
creates an antibody against the drug. Given the patients diagnosis of anaphylactic syndrome,
this may be a suitable explanation. Interestingly, whilst clearly evoking a reaction against
infliximab, the situation with adalimumab was different. In the clinic, acute reactions are
often pre-empted by the premedication given [13]. After being reviewed by the immunology
team, it was recommended premedication with an antihistamine drug to minimise the risk of
allergic reaction to adalimumab.
Anaphylaxis to biologics remains rare, accounting for only 0.1-0.2% allergic reactions
encountered by patients on biologics [14]; however, due to continued anaphylactic reactions
of unknown cause, the patient decided to discontinue adalimumab. The patient remained
under the care of the clinical team and in regular contact with the nurse specialist for support
and holistic care and advice. Patient two had a different experience, as he actually lost
response to anti TNF therapy. Whilst the official figure is difficult to ascertain, a small study
(sample size 34) by Radstake et al. showed that nearly half of patients had a good response to
TNF blockage, 8% had a moderate and 29% were in the non-responder category [15]. Patients
need a lot of support during times of non-response because they are often understandably
disappointed, and frequently the outcome is different from what is expected. Unfortunately,
the patient developed hypogammaglobulinaemia to rituximab, which has been found in up to
39% patients treated with rituximab according to a study [16]; however, he was started on
tocilizumab and responded well to this treatment.
Nursing interventions were paramount in supporting patient two through the many drugs
that were initiated to manage his disease. A good patient/nurse relationship enables the patient
to report when disease is not responding to treatment in order to find a suitable alternative by
highlighting issues and problems as they go along. Support was also important when
treatment with tocilizumab was initiated and the disease can take up to six months to respond
effectively to treatment. Nursing interventions and support assisted the patient whilst disease
control was attained.
In our case study one, the patient elected to have a caesarian section because of concerns
regarding lower back pain. This is consistent with an extended report of a Swedish cohort,
which found that 28.9% patients with AS had caesarian sections compared with 16.4% in the
control group. The study proposes that flares in symptoms may not just be of inflammatory
nature but could be related to inflammatory changes. Normal inflammatory markers may be
partly reassuring that the lower back pain may not be of an inflammatory nature, given that
during the previous flares this patient experienced, the inflammatory markers were raised. In
some cases, it is recognised that localised inflammation is not always associated with
systemic inflammatory response. In addition, certain alterations of the pelvic ligaments
because of hormonal changes prenatally could be a contributing factor to the pain experienced
by some patients. About half of patients report lower back pain in pregnancy; although in the
case of patients with history of sacroiliitis, there would be a low threshold for considering an
arthritis flare, and the presence of symptoms may account for a higher proportion of elective
caesarean sections amongst AS patients.
Overall, the rheumatology CNS is a central player in the process of managing and caring
for the patients on biologic treatments. They provide the link between primary and secondary
care, between the physician and the patient, and a liaison with other health care professionals.
CNSs also provide support and advice for patients. A holistic nursing approach is
recommended, to allow for all areas of the patients needs to be considered in the complex
process of optimally managing their disease [17].
The figures below summarize the patient generic journey (Figure 1), and individualised
examples of patient journey based on the previously discussed cases (Figures 2 and 3).
Figure 1. The Patient journey template.
Figure 2. Patient journey - case study 1.
Figure 3. Patient journey case study 2.
Employment is one aspect that can be significantly affected by poor disease control,
limited understanding about the impact of disease from either employers or the employees
lack of transparency about disease [19]. The CNS can be a useful source in pointing the
patient in the right direction with regard to providing information for employers, advising on
suitability of certain jobs and providing information for social benefits when employment is
no longer an option. However, it should be remembered that the vast majority of patients on a
biologic therapy who responded to treatment are probably employed with part- or full-time
work, as the effectiveness of biologic agents in maintaining overall function is well
recognised.
A report discussing employment opportunities for those with chronic conditions
concluded that individuals have a higher risk of unemployment and fewer opportunities for
having a job [18]. The report cited the following obstacles posed by employers: poor
understanding of disease, perceived poor productivity levels, and eventual additional costs to
the enterprise (sick leave, adaptions to the workplaces). Workers themselves can face hurdles
in needing time off work for hospital appointments and treatments, needing to adopt
flexible/personalised solutions to working, facing time, and mobility limitations. A study
explained the importance of going beyond the routine when providing support for patients,
and concluded that this occurs when the medical team and the patient work well together [19].
Both patients discussed in the case studies remained in employment, which was
encouraging given their disease pattern. Patient two struggled with full time employment
initially due to poor disease control but did manage to work voluntarily. Patients require
support from their rheumatology team. Encouraging patients with chronic diseases to work
and enabling them to work can increase self-esteem [1]. Both case studies highlighted the
journey, through a number of life changing events, undertaken by patients diagnosed with a
chronic rheumatic disease and underlined the role of the CNS in supporting them through the
complex process of adjusting to the life changes imposed by their medical condition.
CONCLUSION
The link between the two cases of patients journeys through a number of biologics
treatments and the process of living with a chronic disease is clearly depending on the
availability of care as well as trust that developed over time and dozens of appointments and
conversations between the patients and medical teams. The day care and support given by the
health professionals through the disease process whilst the patients continued carrying with
their normal lives, working, conceiving and raising a family as, as well as trying to cope with
the challenges of having a chronic disease, were highlighted in these two cases as a model of
team approach.
Side effects, queries and concerns around employment, pregnancy and other sensitive
issues are inevitable. As a nurse, it is a privilege to be involved in such important
conversations alongside the medical teams, and, despite time restraints, nurses always make
themselves available to their patients and listen to their concerns. Implementing strategies and
providing safety nets (as illustrated in Figure 4) can give a comfort blanket for the patient
managing chronic inflammatory disease.
Figure 4. The Safety Net.
ACKNOWLEDGMENT
The authors would like to thank Samantha Moore, Rheumatology Clinical Nurse
Specialist, University College London Hospitals NHS Trust (email:
samantha.moore@uclh.nhs.uk) for reviewing this chapter.
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[2] C. E. Zimmern, Medical-Surgical Nursing - Concepts and Clinical-Practice -
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[6] T. Ding, J. Ledingham, R. Luqmani, S. Westlake, K. Hyrich, M. Lunt, et al., BSR and
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[7] N. J. Marshall, G. Wilson, K. Lapworth, and L. J. Kay, Patients' perceptions of
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ABOUT THE EDITORS
Dr. Coziana Ciurtin, PhD FRCP

Consultant Rheumatologist,
Principal Research Investigator - Clinical Trials in Inflammatory Arthritis
University College London/University College London Hospital,
London, London, UK
Email: c.ciurtin@ucl.ac.uk
Coziana Ciurtin trained in Bucharest (Romania) and Oxford (UK). She is Director of
Medicine Studies Portfolio at University College London and is currently leading the clinical
trials activity within the Department of Rheumatology. Her research interests are in the study
of immunological abnormalities associated with Sjgrens syndrome and the role of
musculoskeletal ultrasound in inflammatory arthritis. She has won several national and
international research awards during her training, and has published papers and book chapters
in the field of Sjgrens syndrome, inflammatory arthritis and clinical trials.
Prof. David A. Isenberg, MD FRCP FAMS

ARC Diamond Jubilee Professor
Academic Director of Rheumatology, Professor of Rheumatology
University College London/University College London Hospital,
London, London, UK
Email: d.isenberg@ucl.ac.uk
Professor Isenberg trained in London and Boston acquiring major research interests in
the development of activity and damage indices for several of the major autoimmune
rheumatic diseases, including lupus and myositis and in the structure, function, origin and
pathogenicity of anti-dsDNA and anti-cardiolipin antibodies. He is a past president of the
British Society for Rheumatology, past chair of the Systemic Lupus International
Collaborating Clinics group and current chair of the British Isles Lupus Assessment Group.
He is on the Executive Boards of Arthritis Research UK and The Royal National Orthopaedic
Hospital in Stanmore and chairs the research committee for LUPUS UK. He was the first
non-North American to win the Hess prize (2010) for contributions to lupus research and the
522 About the Editors
Rodger Demers prize (2012) for contribution to international rheumatology. He has published
nearly 800 original and review articles and authored/edited 18 previous books. He is firmly
committed to improving the education and training in rheumatology. His alter ego leads a
band, Lupus Dave and The Davettes and he has known much pain as a long term supporter of
Tottenham Hotspurs.
INDEX
albumin creatinine ratio (ACR), 18, 20, 38, 40, 44,

A 49, 58, 84, 99, 112, 118, 126, 138, 152, 159, 160,
161, 204, 206, 207, 208, 209, 210, 211, 213, 214,
abatacept, 8, 19, 29, 30, 49, 55, 57, 58, 64, 68, 77,
231, 232, 234, 236, 237, 238, 240, 242, 243, 245,
83, 89, 97, 105, 113, 125, 138, 158, 160, 164,
260, 261, 263, 264, 268, 269, 271, 273, 310, 312,
175, 223, 229, 230, 233, 234, 235, 236, 237, 238,
314, 321, 327, 328, 332, 340, 342, 348, 349, 355,
239, 241, 250, 251, 252, 257, 272, 297, 306, 321,
356, 357, 359, 360, 361, 362, 403, 421, 480, 481,
326, 328, 342, 343, 352, 354, 358, 359, 364, 370,
492
385, 392, 394,402, 403, 428, 435, 438, 439, 444,
alefacept, 57, 64, 78, 309, 322, 327, 328, 332, 344
447, 448, 478, 479, 482, 485, 491
alemtuzumab, 26, 50, 56, 83, 89, 113, 125, 133, 138,
ACR20 response, 206, 211, 212, 214, 237, 239, 261,
177, 188, 260, 262, 276
264, 266, 267, 269, 270, 273, 310, 315, 316, 318,
American College of Rheumatology, 18, 38, 44, 58,
319, 320, 321, 324, 325, 326, 327, 328
71, 84, 99, 101, 112, 161, 167, 170, 204, 207,
activated macrophage (AAM) phenotype, 428
209, 211, 213, 214, 220, 221, 231, 232, 236, 240,
adalimumab, 48, 54, 106, 113, 124, 131, 137, 142,
242, 245, 250, 260, 261, 264, 265, 268, 269, 273,
143, 151, 159, 174, 180, 181, 182, 183, 184, 185,
310, 328, 348, 349, 360, 366, 368, 480, 492
187, 192, 193, 194, 196, 199, 203, 205, 208, 209,
American College of Rheumatology Pediatric (ACR
215, 216, 220, 222, 223, 225, 226, 231, 232, 234,
Pedi), 348, 355, 356, 357, 359, 362
237, 239, 243, 244, 245, 246, 248, 249, 252, 258,
anaemia, 8, 36, 230, 323, 389, 449, 454, 463, 471
268, 272, 273, 282, 286, 287, 288, 290, 291, 292,
anakinra, 49, 50, 55, 113, 130, 141, 154, 181, 229,
293, 294, 295, 300, 301, 303, 313, 314, 317, 318,
230, 242, 243, 256, 257, 297, 306, 352, 360, 364,
322, 324, 328, 335, 336, 337, 340, 345, 352, 354,
371, 380, 392, 393, 403, 436, 437, 446, 478, 485
355, 356, 357, 358, 364, 369, 373, 379, 381, 382,
ANCA-associated vasculitis (AAV), 109, 110, 111,
383, 384, 385, 386, 387, 388, 399, 400, 436, 438,
112, 113, 114, 115, 116, 117, 118, 119, 121, 122,
445, 447, 450, 451, 452, 453, 454, 455, 456, 457,
123, 124, 125, 126, 127, 133, 136, 137, 153, 156,
460, 462, 466, 467, 468, 469, 470, 471, 473, 474,
158
485, 487, 504, 511, 512, 513, 519
anifrolumab, 17, 18, 19, 29
adalimumab biosimilar, 273
ankylosing spondylitis, 25, 35, 271, 281, 283, 291,
adherence, 9, 157, 354, 405, 419, 503, 504
298, 299, 300, 301, 302, 303, 304, 305, 306, 328,
adhesion molecule targeted therapies, 64
333, 334, 336, 337, 342, 343, 345, 358, 368, 373,
adolescents, 33, 34, 35, 36, 37, 38, 39, 40, 41, 43,
383, 386, 449, 457, 458, 461, 462, 463, 507, 510,
334, 351, 354, 358, 367, 368, 502
511, 519
albumin, 18, 20, 38, 40, 44, 49, 58, 84, 99, 112, 118,
anti synthetase syndrome, 431
126, 138, 152, 159, 160, 161, 204, 206, 207, 208,
anti-citrullinated protein antibodies (ACPAs), 200
209, 210, 211, 213, 214, 231, 232, 234, 236, 237,
anti-complement therapies, 20
238, 240, 242, 243, 245, 260, 261, 263, 264, 268,
anti-glomerular basement membrane (GBM) disease,
269, 271, 273, 310, 312, 314, 321, 327, 328, 332,
110, 111, 112, 132, 133, 144
340, 342, 348, 349, 355, 356, 357, 359, 360, 361,
anti-interferon alpha (IFN), 3, 6, 8, 17, 18, 29, 39,
362, 403, 421, 480, 481, 492
50, 62, 66, 179, 183, 185
anti-La/SSB, 58
524 Index
anti-Ro/SSA, 58 BASDAI (Bath Ankylosing Spondylitis Disease

anti-TGF, 90, 97 Activity Index), 286, 287, 290, 292, 297, 303,
anti-thymocyte globulin (ATG), 90, 105 311, 312, 318, 320, 327, 328, 451, 511
anti-TNF, vi, 24, 35, 48, 54, 65, 69, 91, 92, 99, 137, basiliximab, 89, 96, 105
143, 146, 151, 152, 153, 156, 164, 170, 171, 174, Beck depression inventory (BDI), 312
177, 179, 180, 181, 182, 183, 184, 185, 187, 188, belimumab, 4, 6, 7, 9, 10, 14, 15, 16, 17, 21, 23, 27,
189, 192, 193, 194, 195, 196, 202, 204, 205, 212, 36, 38, 43, 57, 58, 62, 63, 68, 76, 113, 123, 137,
213, 215, 216, 217, 218, 219, 220, 221, 222, 225, 156, 173, 392, 394, 395, 403
226, 227,228, 229, 230, 233, 234, 235, 237, 238, bevacizumab, 183, 184, 193
239, 240, 241, 243, 254, 266, 268, 278, 286, 287, biologic agents, ix, 3, 4, 6, 9, 10, 12, 20, 33, 34, 35,
289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 36, 40, 41, 62, 67, 68, 69, 70, 134, 151, 152, 163,
301, 302, 303, 304, 313, 314, 317, 318, 320, 321, 164, 177, 183, 184, 193, 202, 215, 218, 229, 230,
324, 325, 329, 339, 340, 345, 352, 353, 358, 368, 232, 238, 246, 248, 252, 259, 260, 274, 285, 297,
381, 384, 399, 400, 448, 450, 451, 452, 456, 459, 307, 315, 318, 324, 328, 351, 354, 355, 364, 405,
460, 461, 462, 463, 466, 486, 487, 488, 489, 492, 407, 418, 419, 425, 428, 430, 435, 437, 438, 440,
519 441, 447, 465, 466, 467, 478, 479, 481, 485, 492,
anti-TNF agents, 91, 92, 99, 156, 184, 187, 188, 205, 502, 505, 512, 517
215, 216, 217, 225, 286, 289, 291, 292, 293, 294, biologic therapy(ies), ix, 3, 4, 6, 8, 40, 43, 51, 57, 62,
295, 298, 302, 317, 318 64, 69, 70, 83, 88, 100, 109, 112, 134, 145, 153,
anti-TNF therapy, 65, 146, 170, 171, 182, 183, 184, 157, 163, 164, 179, 180, 182, 183, 201, 216, 225,
189, 195, 204, 212, 215, 216, 217, 230, 240, 243, 226, 229, 230, 246, 259, 260, 268, 278, 289, 290,
286, 289, 291, 292, 293, 294, 295, 296, 297, 298, 307, 312, 329, 338, 347, 351, 354, 378, 406, 427,
301, 302, 303, 304, 313, 318, 448, 486, 487, 492, 432, 440, 452, 466, 467, 479, 481, 483, 486, 495,
519 503, 506, 512, 517
anti-TNF targeted therapies, 65 biologics, v, vi, vii, ix, 9, 19, 33, 34, 35, 36, 40, 42,
apremilast, 179, 191, 260, 268, 279, 280, 283, 297, 45, 51, 109, 112, 117, 126, 128, 134, 162, 164,
306, 310, 321, 322, 326, 328, 343 166, 170, 175, 177, 179, 180, 181, 182, 185, 186,
ASAS classification criteria, 284, 285 188, 189, 191, 195, 202, 205, 216, 218, 225, 226,
atacicept, 7, 9, 14, 16, 28, 38, 43, 62, 63, 76 228, 232, 233, 237, 241, 245, 249, 256, 257, 261,
autoimmunity, 21, 22, 27, 33, 35, 50, 56, 86, 200, 262, 264, 267, 268, 271, 272, 274, 283, 290, 297,
250, 307, 368, 428, 443, 490 302, 303, 304, 317, 319, 323, 334, 336, 337, 339,
axial and peripheral arthritis, 307 340, 347, 350, 351, 354, 355, 359, 364, 371, 378,
axial SpA, 283, 284, 285, 286, 287, 288, 297, 298 381, 392, 400, 401, 402, 405, 419, 425, 439, 440,
azathioprine, 4, 39, 101, 116, 120, 136, 147, 177, 448, 450, 456, 457, 458, 465, 466, 472, 478, 482,
179, 180, 181, 182, 184, 185, 187, 188, 189, 315, 483, 484, 486, 487, 491, 492, 501, 502, 505, 507,
358, 427, 440, 468 508, 510, 512, 513, 517, 518, 519
biosimilars, vi, 4, 9, 10, 35, 41, 200, 259, 260, 271,
273, 274, 281, 282, 308, 323, 345, 355, 364
B bispecific monoclonal antibodies, 13
blisibimod, 7, 17, 28, 29, 123
B cell activating factor (BAFF), 5, 6, 7, 14, 15, 17, bone mineral density (BMD), 350, 408, 409, 410,
27, 28, 29, 37, 38, 43, 51, 62, 63, 65, 69, 70, 75, 411, 412, 413, 414, 415, 416, 417, 418, 420, 421,
76, 79, 122, 123, 137, 156, 173, 392, 394 422, 423, 424, 453, 454, 460, 461
B cells, ix, 3, 5, 6, 8, 10, 11, 13, 14, 15, 16, 17, 19, breastfeeding, 377, 378, 379, 380, 383, 386, 388,
20, 21, 27, 33, 35, 36, 38, 39, 46, 52, 57, 60, 61, 392, 393, 394, 395, 397, 398, 399, 401
62, 64, 67, 74, 87, 88, 103, 117, 123, 131, 135, British Society of Rheumatology (BSR), 117, 118,
156, 161, 200, 201, 203, 230, 238, 246, 252, 253, 135, 187, 204, 216, 227, 228, 380, 383, 384, 387,
259, 261, 270, 274, 354, 359, 388, 389, 392, 431, 388, 392, 393, 394, 395, 397, 519
432, 443, 475, 476, 477 brodalumab, 264, 265, 266, 278, 310, 320, 327, 328,
B lymphocyte stimulator (BLyS), 5, 7, 14, 15, 16, 342
27, 35, 37, 38, 43, 62, 63, 76, 113, 122, 394
BAFF (B lymphocyte activating factor), 37
BAFF/BLyS, 7, 62, 75
baricitinib, 268, 269, 280
Index 525
denosumab, 405, 406, 408, 409, 412, 413, 418, 419,

C 421, 422, 423, 424
depression, 16, 311, 312, 333, 449, 450, 451, 452,
cachexia, 449, 450, 452, 459
457, 458
canakinumab, 113, 130, 142, 154, 172, 181, 192,
Dercenotinib, 269
352, 361, 371, 372
dermatomyositis, 29, 45, 46, 52, 53, 54, 55, 56, 426,
cardiovascular risk, 313, 335, 449, 454
431, 434, 442, 445
cathepsin K inhibitors, 405, 406, 408
dermatomyositis (PM/DM), 426
certolizumab, 199, 203, 211, 212, 215, 217, 223,
diffuse alveolar damage (DAD), 426, 427
224, 225, 233, 286, 287, 288, 300, 315, 316, 325,
disease modifying antirheumatic drugs (DMARDS),
328, 338, 339, 355, 358, 381, 383, 384, 385, 387,
97, 98, 99, 151, 231, 293, 309
388, 397, 398, 401, 466, 512
certolizumab pegol, 203, 220, 224, 315, 358, 370,
382, 384 E
clinical inactive disease (CID), 349, 350, 366
clinical nurse specialist (CNS), 354, 470, 507, 508, eculizumab, 20, 31, 39, 125
509, 510, 511, 512, 513, 517 education, 9, 419, 421, 495, 505, 508, 509, 522
connective tissue disease (CTD)-associated ILD, 88 efalizumab, 64, 78, 309, 322, 327, 328, 332, 344,
corticosteroids, 28, 37, 43, 45, 46, 48, 101, 103, 112, 345, 453
126, 127, 128, 130, 131, 132, 181, 182, 183, 185, employment, 9, 316, 452, 458, 511, 517
186, 187, 188, 191, 192, 233, 293, 294, 359, 360, enthesitis, 150, 293, 307, 308, 309, 312, 314, 316,
362, 367, 385, 394, 397, 427, 443, 466, 467, 472 318, 320, 321, 322, 325, 326, 327, 328, 339, 348,
cost of biologic therapies, 9 351, 355, 356, 363, 364, 369, 373, 504
cost-effectiveness, ix, 9, 199, 200, 215, 226, 229, enthesitis-related arthritis (ERA), 210, 351, 352, 353,
230, 234, 238, 241, 249, 252, 256, 260, 308, 317, 355, 356, 357, 359, 363, 364, 369, 373, 504
318, 319, 322, 340, 369, 405, 418, 419, 424 Eosinophilic Granulomatosis with Polyangiitis
C-reactive protein, 230, 285, 299, 310, 349, 360, (Churg Strauss Syndrome), 112
445, 477 epratuzumab, 7, 13, 14, 27, 38, 61, 68, 75
creatinine, 18, 20, 38, 40, 44, 49, 58, 84, 99, 112, EQ-5D (Euro Quol group instrument assessing 5
118, 126, 138, 152, 159, 160, 161, 204, 206, 207, domains), 311, 312, 333
208, 209, 210, 211, 213, 214, 231, 232, 234, 236, erythrocyte sedimentation rate, 62, 68, 161, 232,
237, 238, 240, 242, 243, 245, 260, 261, 263, 264, 262, 310, 349, 360
268, 269, 271, 273, 310, 312, 314, 321, 327, 328, etanercept, 48, 54, 65, 68, 78, 79, 91, 99, 106, 107,
332, 340, 342, 348, 349, 355, 356, 357, 359, 360, 113, 124, 128, 129, 131, 137, 141, 142, 151, 156,
361, 362, 403, 421, 480, 481, 492 159, 160, 170, 173, 180, 181, 183, 184, 185, 191,
Cryoglobulinaemic Vasculitis, 112, 131 192, 193, 194, 199, 203, 205, 208, 209, 210, 211,
CTLA-4, 19, 55, 64, 77, 235, 252, 358, 370, 392, 215, 216, 217, 220, 223, 224, 225, 226, 234, 239,
394, 435, 444 243, 249, 257, 272, 273, 282, 286, 288, 289, 290,
cyclophosphamide, 4, 6, 8, 37, 39, 43, 73, 74, 85, 95, 291, 292, 293, 294, 295, 299, 301, 302, 303, 312,
96, 101, 102, 103, 112, 116, 120, 135, 136, 139, 313, 314, 315, 317, 318, 319, 320, 322, 324, 326,
151, 153, 179, 185, 186, 187, 188, 194, 239, 353, 328, 331, 333, 334, 335, 336, 338, 340, 341, 352,
425, 427, 432, 434, 440, 441, 475 354, 355, 356, 357, 358, 364, 368, 369, 379, 381,
cytokines, 5, 22, 35, 36, 51, 52, 56, 65, 67, 73, 78, 382, 383, 384, 386, 387, 388, 398, 399, 400, 401,
80, 87, 100, 117, 146, 150, 151, 153, 154, 170, 438, 446, 447, 451, 452, 453, 454, 458, 459, 461,
172, 177, 179, 191, 199, 200, 201, 202, 219, 230, 463, 466, 467, 469, 471, 473, 474, 485, 487, 489,
234, 244, 245, 259, 267, 268, 297, 309, 310, 321, 510, 512, 519
359, 368, 398, 407, 408, 420, 425, 428, 435, 450, etanercept biosimilar, 272, 282
451, 457, 466, 473 EULAR Sjgrens syndrome disease activity index
(ESSDAI), 60, 63, 68, 73
EULAR Sjgrens syndrome patient reported index
D (ESSPRI), 60, 63, 68, 73
European League against Rheumatism (EULAR),
dactylitis, 307, 308, 312, 314, 315, 316, 318, 320,
59, 68, 73, 84, 86, 102, 134, 135, 152, 166, 167,
321, 322, 325, 326, 327, 328, 339, 348, 363
170, 179, 184, 186, 191, 204, 211, 220, 232, 238,
526 Index
243, 250, 260, 271, 286, 299, 331, 442, 443, 483, IL6, 6, 8, 19, 20, 30, 35, 46, 49, 57, 63, 66, 69, 87,
490 91, 124, 150, 152, 153, 154, 156, 157, 158, 159,
EXPLORER, 6, 11, 24, 36 160, 161, 163, 164, 170, 171, 175, 177, 179, 184,
Extra-Articular Manifestations of SpA, 288 186, 201, 229, 230, 231, 233, 244, 260, 297, 327,
359, 362, 363, 392, 407, 428, 436, 465, 473, 477
IL6 receptor monoclonal antibodies, 428
F ILD, 86, 88, 89, 91, 92, 94, 95, 98, 99, 101, 217,
425, 426, 427, 428, 429, 430, 431, 432, 433, 434,
FACIT-F score, 311, 312 435, 436, 437, 438, 439, 440, 441
fatigue, 57, 58, 61, 62, 63, 64, 66, 80, 96, 161, 181, imaging, 13, 115, 146, 148, 149, 153, 158, 160, 164,
241, 245, 294, 311, 312, 313, 333, 449, 450, 451, 168, 185, 187, 219, 250, 284, 298, 300, 304, 312,
452, 456, 457, 471 432, 435, 436, 474, 511
fibrosis, 7, 65, 86, 87, 88, 90, 91, 99, 102, 104, 107, in vitro fertilization (IVF), 455
108, 121, 426, 428, 429, 431, 435, 436, 444 increased risk of infection, 9, 148, 162, 215, 478,
filgotinib, 270, 280 483
fostamatinib, 270, 280 infertility, 34, 118, 455, 510, 519
fresolimumab, 90, 97 infliximab, 48, 54, 65, 68, 78, 91, 99, 106, 107, 113,
118, 119, 120, 123, 127, 128, 129, 131, 136, 137,
G 140, 141, 142, 143, 151, 156, 159, 161, 169, 170,
171, 173, 176, 177, 179, 180, 181, 182, 183, 184,
gastrointestinal involvement, 107, 184 185, 186, 187, 188, 191, 192, 194, 195, 196, 199,
gevokizumab, 154, 160, 172, 183, 193 202, 203, 205, 206, 207, 208, 215, 216, 217, 219,
glucocorticoids, 36, 37, 38, 52, 116, 118, 120, 127, 220, 221, 222, 223, 224, 225, 226, 228, 235, 237,
129, 132, 136, 139, 146, 159, 161, 166, 167, 176, 239, 251, 253, 271, 272, 273, 281, 282, 287, 288,
179, 180, 350, 360, 361, 362, 466 289, 290, 291, 292, 293, 294, 295, 300, 301, 302,
golimumab, 182, 186, 193, 199, 204, 211, 213, 214, 303, 304, 314, 315, 317, 318, 319, 325, 328, 333,
215, 223, 224, 225, 233, 263, 286, 287, 288, 293, 336, 337, 338, 340, 345, 350, 352, 354, 355, 357,
300, 301, 314, 316, 317, 318, 325, 328, 336, 339, 364, 370, 379, 381, 382, 383, 384, 385, 386, 387,
340, 353, 355, 358, 370, 382, 383, 384, 385, 387, 388, 398, 399, 401, 436, 438, 439, 445, 447, 452,
388, 400, 463, 466 453, 454, 455, 458, 459, 460, 461, 462, 463, 466,
granulomatosis with polyangiitis (Wegeners 467, 469, 470, 471, 473, 474, 484, 485, 487, 489,
granulomatosis), 112 493, 503, 511, 512, 519
infliximab biosimilars, 271
informed consent, 495, 496, 497, 498, 499
H integrin antagonists, 405, 406, 408
interferon , 92
Hamilton rating scale for depression (Ham-D), 312 interferon , 5, 92
health-related quality of life (HRQOL), 13, 27, 49, interstitial lung disease, ix, 86, 95, 98, 99, 103, 104,
169, 237, 255, 311, 331, 333, 337, 341, 344 106, 107, 165, 217, 425, 426, 431, 436, 442, 443,
human leucocyte antigen (HLA)-B27, 59, 283, 308, 444, 445, 446, 447, 448
348 interstitial pneumonitis with autoimmune features
HuMax-IL15, 264 (IPAF), 426
hyperimmune caprine serum, 100, 108 intravenous immunoglobulins (IVIg), 46, 48, 66, 83,
92, 113, 126, 128, 129, 138, 431, 475
ixekinumab, 310
I ixekizumab, 264, 266, 296, 321, 342
idiopathic inflammatory myopathies, 45, 46, 54
IFN and Anti-IFN Targeted Therapies, 65 J
IgA Vasculitis (IgAV) (HenochSchnlein Purpura),
130 Janus kinase inhibitors, 243, 244, 268, 269, 328
IL1 receptor antagonists, 428 Juvenile Arthritis Disease Activity Score (JADAS),
IL23/IL17, 296 349, 366
Index 527
juvenile idiopathic arthritis (JIA), 20, 35, 337, 347, 245, 247, 248, 254, 257, 261, 262, 264, 268, 269,
348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 270, 280, 314, 317, 333, 335, 338, 393, 453
358, 359, 360, 361, 362, 363, 364, 365, 367, 370, mucocutaneous involvement, 180
371, 383, 501, 502, 505 mycophenolate, 4, 8, 24, 36, 43, 85, 105, 122, 147,
juvenile SLE, 33, 44, 484 189, 379, 400, 425, 427, 431, 432, 440, 441
mycophenolate mofetil, 4, 8, 24, 36, 43, 85, 105,
122, 147, 379, 400, 441
K myositis, ix, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,
55, 56, 60, 89, 93, 521
Kawasaki disease, 111, 113, 128, 140, 141, 142, 352
keratoderma blennorrhagica, 308
N
L NAPSI (Nail Psoriasis Severity Index), 310, 318,
325, 326, 327, 328, 333
large vessel vasculitis, ix, 112, 124, 145, 146, 158, National Institute for Health and Clinical Excellence
166, 168, 171, 174 (NICE), 354, 394
LUNAR, 6, 11, 19, 36 National Institute of Clinical Excellence (NICE),
lung biopsy, 426 204, 234
lymphocytic interstitial pneumonitis (LIP), 426, 427 National Institute of Health and Care Excellence
(NICE), 317
M neurological involvement, 185
NNC0109-0012, 267
MACE (Mortality and Major Adverse Cardiac non specific interstitial pneumonitis, 427
Events), 315, 317, 319 non-radiographic axial SpA, 285, 286, 287, 288, 296
management of SpA, 283, 285, 298 NSAIDs, 152, 233, 285, 286, 293, 296, 299, 350,
MAP kinase inhibitor, 270 356, 361, 362, 364, 394, 511
mavrilimumab, 260, 263, 277 NSIP, 426, 427
metelimumab, 90, 97, 429
methotrexate, 4, 8, 26, 28, 48, 54, 75, 76, 85, 97, 98,
O
99, 101, 102, 116, 122, 123, 147, 156, 166, 167,
177, 181, 182, 184, 185, 186, 187, 188, 189, 192, ocrelizumab, 7, 12, 26, 39, 61, 75, 261
204, 207, 209, 210, 211, 213, 214, 219, 221, 222, ocular disease, 181, 182, 183
223, 224, 225, 226, 231, 232, 236, 240, 242, 247, ofatumumab, 6, 7, 12, 25, 26, 39, 44, 61, 75, 121,
248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 137, 260, 275
258, 260, 269, 275, 276, 277, 278, 280, 281, 282, older adolescent, 502
285, 290, 295, 304, 306, 313, 328, 335, 338, 342, organising pneumonia (OP), 426, 427, 436, 446
344, 350, 351, 355, 356, 358, 359, 366, 367, 368, osteoporosis, ix, 4, 147, 170, 359, 405, 406, 407,
369, 370, 379, 386, 403, 437, 439, 446, 450, 452, 409, 410, 412, 413, 415, 416, 418, 419, 420, 421,
453, 454, 456, 458, 461, 467, 468, 482, 488, 492, 422, 423, 424
512 otelixizumab, 65, 78
microscopic polyangiitis, 46, 110, 112, 113, 120, other potential biologic therapies, 66
135, 138, 139
modified Rodnan skin score, 83, 84, 95, 96, 97, 98,
99, 433 P
monoclonal antibodies (mAb), 17, 19, 26, 27, 36, 38,
39, 52, 60, 61, 62, 64, 65, 66, 67, 77, 121, 177, PASI (Psoriasis Area Severity Index) score, 310,
182, 194, 199, 203, 204, 219, 231, 260, 261, 262, 312, 314, 318, 320, 321, 323, 324, 325, 327, 328,
263, 264, 267, 271, 276, 294, 295, 296, 304, 351, 333
358, 364, 471, 519 patient scenarios, 503
monotherapy, 30, 128, 132, 134, 152, 153, 157, 161, patient/nurse relationship, 513
183, 185, 205, 208, 209, 210, 212, 214, 216, 222, Paulus response, 262
223, 224, 232, 234, 237, 238, 239, 240, 241, 242,
528 Index
polyarteritis nodosa (PAN), 111, 112, 113, 126, 127, recurrent oral ulceration, 178, 180, 185
128, 134, 138, 139, 140, 163 relaxin, 93, 108
polymyositis, 29, 45, 46, 52, 53, 54, 55, 56, 431, research ethics, 496, 497, 498
434, 442 rilonacept, 154, 352, 361, 362, 372
polymyositis/, 426 rituximab, 4, 6, 9, 10, 11, 13, 14, 21, 23, 24, 25, 27,
pralnacasan, 267, 279 36, 37, 38, 39, 40, 42, 43, 45, 46, 47, 48, 51, 52,
pregnancy, vi, ix, 8, 93, 203, 220, 377, 378, 379, 53, 54, 57, 58, 60, 61, 62, 68, 69, 70, 73, 74, 75,
380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 76, 81, 83, 88, 89, 94, 95, 103, 104, 105, 108,
390, 392, 393, 394, 395, 396, 397, 398, 399, 400, 113, 116, 117, 118, 119, 120, 121, 122, 123, 127,
401, 402, 403, 455, 463, 510, 511, 513, 517, 519 128, 129, 130, 131, 132, 133, 136, 137, 139, 142,
primary failure, 289, 290, 293 143, 144, 161, 188, 196, 205, 221, 229, 230, 233,
Primary Sjgrens Syndrome (SS), 57, 58, 59, 60, 61, 234, 238, 239, 240, 241, 242, 252, 253, 254, 255,
62, 63, 64, 65, 66, 67, 69, 70, 71, 73, 79, 80, 249, 256, 257, 260, 261, 274, 275, 282, 283, 297, 305,
426 323, 328, 345, 353, 354, 359, 364, 370, 371, 385,
PsA-modified van Der Heijde - Sharp (vDH-S) 388, 389, 390, 392, 401, 402, 403, 428, 430, 431,
score, 314 432, 433, 434, 437, 438, 439, 440, 443, 444, 447,
PsARC (PsA Response Criteria), 310 448, 475, 476, 477, 479, 480, 482, 484, 485, 489,
psoriasis, ix, 64, 65, 66, 78, 142, 154, 179, 188, 196, 490, 492, 504, 512, 513, 519
227, 272, 278, 279, 283, 294, 295, 296, 305, 307, rituximab biosimilar, 274
308, 309, 310, 311, 312, 313, 314, 315, 316, 317, role of the rheumatology specialist nurse, 501, 505
318, 319, 320, 321, 322, 323, 324, 325, 326, 327, rontalizumab, 8, 17, 18, 29, 66
328, 329, 330, 331, 332, 333, 334, 335, 336, 337,
338, 340,341, 342, 343, 344, 345, 348, 357, 363,
372, 373, 383, 400, 452, 458, 459, 460, 462, 467, S
468
psoriatic arthritis, ix, 35, 179, 272, 283, 291, 301, sacroiliitis, 284, 298, 300, 307, 308, 364, 511, 513
302, 304, 307, 308, 328, 331, 332, 333, 334, 335, safety net, 507, 508, 517
336, 337, 338, 339, 340, 341, 342, 343, 344, 345, sclerostin inhibitors, 406
348, 356, 358, 363, 369, 372, 373, 378, 396, 451, secondary failure, 289, 290, 291, 292, 293, 294
453, 457, 463 secukinumab, 177, 183, 193, 260, 264, 265, 266,
psoriatic JIA (PsJIA), 363 277, 278, 296, 305, 310, 319, 320, 326, 327, 328,
puberty, 34 329, 341, 342, 364
pulmonary fibrosis, 16, 51, 83, 84, 101, 106, 435, seronegative spondyloarthritis, 283, 302
436, 437, 438, 440, 445, 446, 447 seronegative spondyloarthropathies, ix, 307
pulmonary hypertension, 84, 427 Short Form 36 (SF-36), 311
sifalimumab, 8, 17, 18, 29, 50, 55, 66
sirukumab, 19, 20, 30, 31, 44, 158, 160, 164
Q skin and nail disease, 307, 313, 314, 322
small vessel vasculitis, 109, 110, 112, 113, 123, 129,
quality-adjusted life years (QALYs), 215, 234, 238, 134
418 SpA, 283, 285, 286, 287, 288, 289, 291, 292, 293,
295, 296, 298, 307, 308, 313, 378, 453, 454
Spleen Tyrosine Kinase (Syk) Inhibitors, 270
R spondyloarthritis, vi, 283, 291, 298, 299, 300, 301,
303, 304, 305, 333, 336, 459, 463
radiographic progression, 208, 209, 210, 212, 237, SRI-5, 15, 17
241, 242, 261, 285, 288, 299, 301, 312, 314, 318, STAT, 244
320, 321, 334, 338, 341, 342, 363, 364, 373 switching, 156, 180, 194, 205, 220, 221, 229, 240,
radiographic sacroiliitis, 285 248, 254, 271, 272, 282, 283, 289, 290, 291, 292,
randomised control trials (RCTs), 6, 13, 15, 34, 36, 293, 294, 295, 298, 302, 303, 314, 315, 329, 336,
38, 59, 66, 70, 118, 132, 152, 179, 185, 200, 202, 355, 383, 475, 491
208, 209, 230, 232, 233, 238, 239, 240, 241, 242, switching anti-TNF therapy, 205, 292, 294
243, 245, 259, 270, 311, 312, 313, 317, 318, 319, systemic lupus erythematosus (SLE), ix, 3, 4, 5, 6, 7,
320, 321, 322, 328, 468, 475, 477 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
Index 529
22, 23, 24, 25, 26, 27, 28, 29, 30, 33, 34, 35, 36, transforming growth factor- (TGF), 51, 87, 90,
37, 38, 39, 40, 41, 42, 43, 44, 60, 62, 63, 64, 66, 407, 428, 429
76, 103, 112, 118, 121, 123, 129, 156, 256, 377, trans-placental passage, 380
378, 379, 383, 388, 389, 390, 391, 396, 397, 402, treat to target, 350, 383
403, 426, 434, 442, 443, 447, 466, 477, 492 tregalizumab, 260, 262, 276
systemic onset juvenile idiopathic arthritis (SoJIA), tuberculosis (TB), 3, 8, 24, 157, 163, 175, 189, 216,
352, 353, 359, 360, 361, 362 226, 234, 313, 315, 322, 365, 381, 465, 466, 469,
systemic sclerosis (SSc), 83, 84, 85, 86, 87, 88, 89, 480, 487, 490, 492
90, 91, 92, 93, 95, 97, 98, 99, 100, 101, 102, 103, tumour necrosis factor (TNF) blockers, 261, 428
106, 426, 427, 431, 433, 434, 435, 436, 437 tumour necrosis factor (TNF) inhibitors, 46, 91, 229,
283, 309, 354, 449
tumour necrosis factor alpha, 466
T tumour necrosis factor alpha (TNF) inhibitors, 202
tumour necrosis factor blockers, 436
T cell targeted therapies, 63 type I interferon, 35, 50
T cells, 5, 6, 14, 15, 19, 22, 35, 36, 42, 46, 49, 50,
52, 59, 60, 62, 63, 65, 67, 72, 76, 80, 87, 90, 103,
105, 133, 151, 152, 154, 155, 160, 179, 191, 201, U
226, 234, 246, 262, 267, 270, 276, 297, 309, 332,
354, 358, 428, 435, 455, 470, 473, 476, 477 urticarial vasculitis, 112, 113, 129, 130, 141, 142
tabalumab, 7, 14, 15, 16, 28 ustekinumab, 188, 196, 260, 264, 277, 283, 296, 304,
teriparatide, 405, 406, 408, 409, 410, 411, 418, 419, 305, 309, 318, 319, 326, 328, 340, 341, 363, 372,
420, 421, 424 373, 453, 460
the functional assessment of chronic illness therapy, usual interstitial pneumonitis (UIP), 426, 427
311
TNF inhibitors, 28, 48, 89, 91, 107, 128, 131, 180,
199, 200, 203, 205, 212, 215, 216, 217, 218, 229, V
230, 233, 243, 246, 261, 283, 292, 298, 302, 311,
314, 317, 319, 322, 328, 329, 336, 355, 357, 363, vaccination, 126, 390, 391, 465, 472, 476, 479, 482,
364, 387, 449, 450, 451, 452, 453, 454, 455, 456, 483, 484, 488, 490, 492
466, 467, 470, 471, 472, 474, 477, 478, 479, 480, vascular disease, 106, 186, 445
482, 485, 491 veltuzumab, 10, 13, 121, 260, 261, 276
TNF, 5, 48, 59, 62, 65, 69, 87, 91, 113, 123, 124,
128, 131, 151, 169, 177, 179, 181, 182, 188, 194, W
201, 314, 315, 316, 354, 356, 358, 384, 406, 420,
428, 436, 451, 452, 453, 454, 455, 466, 469, 470, work disability, 452, 458, 459
473, 474, 491
tocilizumab, 8, 19, 30, 49, 66, 91, 106, 113, 124,
157, 158, 159, 160, 161, 162, 164, 166, 171, 172, Y
174, 193, 195, 230, 231, 232, 233, 234, 247, 248,
249, 305, 321, 353, 362, 363, 392, 393, 403, 436, young adult, 358, 501, 502
446, 477, 485
tofacitinib, 229, 230, 244, 245, 246, 257, 258, 297,
323, 328, 345

tolerance to human Type I collagen, 93
v6, 428

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Biologics in Rheumatology New Developments, Clinical Uses and Health Implication 2016

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NEW DEVELOPMENTS IN MEDICAL RESEARCH

Additional books in this series can be found on Novas website

Additional eBooks in this series can be found on Novas website

NEW DEVELOPMENTS, CLINICAL USES

COZIANA CIURTIN, PHD FRCP

NOTICE TO THE READER

Library of Congress Cataloging-in-Publication Data

ISBN: 978-1-63485-302-6 (e-book)

Published by Nova Science Publishers, Inc. New York

Biologic Treatments in Autoimmune Rheumatic Diseases 1

Biologic Treatments in Chronic Inflammation Arthritides 197

Chapter 22 Strategies and Safety Nets:

Dr. Coziana Ciurtin, PhD FRCP

Prof. David A. Isenberg, MD FRCP FAMS

Maria Mouyis1, MRCP,

lymphoma and anti-drug or autoimmune antibody formation. Despite their toxicity

Keywords: systemic lupus erythematosus, biologic treatments, safety, efficacy, biosimilars

Legend: APRIL - a proliferation-inducing ligand; BAFF B cell activating factor; BlyS - B

Figure 1. Schematic presentation of targeted therapy of SLE.

Table 1. An overview of biologic therapy in SLE

Biologic Trial Mechanism of Side effects Dosage Organ specific

Biologic Trial Mechanism of Side effects Dosage Organ specific

Biologic Trial Mechanism of Side effects Dosage Organ specific

Advantages and Disadvantages

and cyclophosphamide, which are contraindicated in pregnancy. The biggest disadvantage of

Biologic Therapies Affecting B Cells

Mechanism of Action and Dosage

Efficacy and Side Effect Profile

Mechanism of Action and Dosage

Efficacy and Side Effect Profile

Mechanism of Action and Dosage

Efficacy and Side Effect Profile

Mechanism of Action and Dosage

Bispecific Monoclonal Antibodies

Mechanism of Action and Dosage

Epratuzumab is considered to reduce on average only 35% of circulating B cells in

Side Effect Profile

Anti B Cell Activating Factors

Mechanism of Action and Dosage

Efficacy and Side Effect Profile

Mechanism of Action and Dosage

Mechanism of Action and Dosage

Efficacy and Side Effect Profile

encountered included haemophilus influenzae pneumonia, legionella pneumonia and bacillus

Mechanism of Action and Dosage

Efficacy and Side Effect Profile

Anti-Interferon Alpha (IFN)

Efficacy and Side Effect Profile

Mechanism of Action and Dosage

Efficacy and Side Effect Profile

Mechanism of Action and Dosage

Efficacy and Side Effect Profile

Efficacy and Side Effect Profile

Blockade of T Cell Activation

Mechanism of Action and Dosage

Efficacy and Side Effect Profile

Mechanism of Action and Dosage

Efficacy and Side Effect Profile

FUTURE TREATMENT OPTIONS

Complement activation is strongly involved in the pathogenesis of SLE. The function of

[24] P. Panopalis, M. Petri, S. Manzi, D. A. Isenberg, C. Gordon, J. L. Senecal et al., The

[40] B. Bonavida, Rituximab-induced inhibition of antiapoptotic cell survival pathways:

severe hepatitis C virus-related vasculitis: a long-term followup study of thirty-two

radionuclides pretargeted with a new anti-CD20 bispecific antibody, Leukemia, vol.