RHEUMATOID

ARTHRITIS
(RA)
Dr. I Nyoman Suarjana, SpPD-KR
SMF Ilmu Penyakit Dalam
RSUD Ulin/FK UNLAM

Pre test
1. Laboratory examination to support
diagnosis of RA is follows, except :
a. C-reactive protein
b. Rheumatoid factor
c. Anticyclic citrullinated peptide
antibody (anti-CCP)
d. Anti-RA 33
e. Anti-ds DNA

Pre test
2. If diagnosis of RA was established, the
basic therapy must be given
immediately :
a. Steroide
b. Non steroide antiinflammatory
drugs (NSAIDs)
c. Disease modifying antirheumatic
drugs (DMARDs)
d. Calcium
e. Physioterapy

Introduction
RA is a common chronic inflammatory joint
condition
multifactorial aetiology
variable course with exacerbations and
remissions of activity
inflammation leads to joint damage
(erosions)
can result in severe disability

Rheumatoid Arthritis: Definition

Progressive, systemic, inflammatory
disorder
Unknown etiology
Characterized by
Symmetric synovitis
Joint erosions
Multisystem extra-articular manifestations

The Importance of Early

Diagnosis
RA is progressive, not benign
Structural damage/disability occurs within
first
2 to 3 years of disease
Slower progression of disease linked to
early treatment

History

Rheumatoid first used in 1859 by Garrod

Little evidence for RA prior to 16th Century
Possibly earlier in New World
In contrast to OA and Gout

Epidemiology
Incidence
1.4/10000 male, 3.6/10000 females

Prevalence 0.5-2 %
male:female 1:3
Worldwide distribution
higher in native Americans
absent in some parts of Africa

Onset any age but maximum

40 - 70 years in women
60 - 70 years in men

Etiology of Rheumatoid Arthritis

Autoimmunity Normal antibodies become
autoantibodies and attack the tissue.
Infectious agents
Genetic Factor
Gender Female : Male ( 2:1- 4:1)
Endocrine (CRH, estrogen synthase)
Stressful events
Smoking

Possible Infectious Causes of RA

Infectious Agent
Mycoplasma
Parvovirus B19
Retroviruses
Enteric bacteria
Mycobacteria
EBV
Bacterial cells wall

Potential Pathogenic Mechanism

Direct synovial infection, superantigens
Direct synovial infection
Direct synovial infection
Molecular mimicry (QKRAA)
Molecular mimicry (QKRAA, proteoglyc.)
Immunostimulatory DNA
Molecular mimicry (QKRAA)
Macrophage activation

Q = glutamine, K = leucine, R = arginine, A = alanine

HLA-DR4 amino acids sequence 70 - 74

Potential Autoantigens in RA

Cartilage antigens
Type II collagen, gp39, Cartilage link protein,
Proteoglycans, Agrecan
Citrullinated peptides
Glucose-6-phosphoisomerase
HLA-DR (QKRAA)
Heat-shock proteins
Heavy-chain binding protein (BiP)
hnRNP-A2
Immunoglobulin (IgG)

Genetic factors
Small increased risk in siblings
Monozygotic twins
15% concordance

Dizygotic twins
4% concordance

HLA DR4

Clinical features
Symmetrical deforming polyarthritis
affects synovial lining of joints, bursae and tendons
more then just joint disease

Presentation

Variable
Gradual or acute/subacute
Palindromic
Monoarticular
Symmetrical, diffuse small joint involvement

RA Is Characterised by Synovitis and

Joint Destruction
NORMAL

RA
Inflamed
synovial
membrane

Synovial
membrane

Pannus
Cartilage

Major cell types:

T lymphocytes
macrophages
Minor cell types:
fibroblasts
plasma cells
endothelium
dendritic cells

Synovial
fluid

Capsule

Cartilage thinning
Adapted from Feldmann M, et al. Annu Rev Immunol. 1996;14:397-440.

Major cell type:

neutrophils

Progression of joint involvement

Spread occurs within months to years to other
joints
Almost any joint may be involved
Spontaneous remission can occur (after acute onset)
Poor prognosis factors exist

Symptoms
Of inflammation
stiffness, pain, swelling, warmth, redness

Pattern of joint involvement

symmetrical
small joints of hands - DIP spared
characteristic features

Boutonniere
Swan neck
Z thumb
Volar subluxation
Ulnar deviation

Functional impairment
related to underlying disease activity
and
joint damage due to previous activity

Extra articular disease

nodules
eye
lung
kidney
vasculitis
nerves
Feltys

Investigations
Haematology
Hb, wcc, plts, ESR

Biochemistry
U+E, LFT, CRP

Immunology
RhF, ANA

Microbiology
viral titres

Radiology
XR, bone scan, MRI

Differential diagnosis

Post viral (parvo, rubella)

Reactive arthritis
SLE
Polyarticular Gout
Polyarticular OA

ACR 1987 Criteria for Diagnosis

Four or more of the following criteria must
be present:

Morning stiffness > 1 hour

Arthritis of > 3 joint areas
Arthritis of hand joints (MCPs, PIPs, wrists)
Symmetric swelling (arthritis)
Serum rheumatoid factor
Rheumatoid nodules
Radiographic changes

First four criteria must be present for 6

weeks or more

Management
Education
Physical therapies
Drugs
analgesics
NSAIDs
DMARDs
Immunotherapies
Steroids ia, po, im, iv
Surgery

Rheumatoid Arthritis:Treatment
Principles
Confirm the diagnosis
Determine where the patient stands in the
spectrum of disease
When damage begins early, start aggressive
treatment early
Use the safest treatment plan that matches the
aggressiveness of the disease
Monitor treatment for adverse effects
Monitor disease activity, revise Rx as needed

Goals of Therapy
Control disease activity
Alleviate pain
Maintain function for essential daily
activities
Maximize quality of life
Slow progression/rate of joint damage

Non-Pharmacological Management
of Rheumatoid Arthritis
Rest
Exercise
Flexibility/stretching
Muscle conditioning
Cardiovascular/aerobic
Diet/weight control
Physical/occupational therapy

Pharmacological treatment of RA can be

divided into :

Disease-modifying antirheumatic
drugs (DMARDs)
Anti-inflammatory agents
Analgesics

Anti-inflammatory agents and analgesics

Anti-inflammatory agents include:
Glucocorticoids
Non-steroidal anti-inflammatory drugs
(NSAIDs, most also act as analgesics)
Analgesics include:
Acetaminophen
Opiates
Diproqualone
Lidocaine topical

DMARDs can be further subdivided into :

- Traditional small molecular mass drugs synthesised
chemically
- Newer 'biological' agents produced through genetic
engineering.
Traditional small molecular mass drugs:

Azathioprin
Ciclosporin (cyclosporine A)
D-penicillamine
Gold salt
Hydroxychloroquine
Leflunomide
Methotrexate (MTX)
Minocycline
Sulfasalazine (SSZ)

Biological agents :
Tumor necrosis factor (TNF) blockers : etanercept (Enbrel), infiximab
(Remicade), adalimumab (Humira), Certolizumab pegol (Cimzia)sc
(CDP-870)
Anti-B cell (CD20) antibody : rituximab (Rituxan, MabThera),
Ocrelizumab
Interleukin-1 blockers : anakinra (Kineret)
Blockers of T cell activation (costimulation blockers) : abatacept
(Orencia)
Anti-Blys antibody : Belimumab
Anti-IL-6 receptor MAb : Tocilizumab (ActemraTM)
Protein tyrosine kinase inhibitor : Imatinib (Gleevec)
CPH82 (influences the cell cycle & cell proliferation) : Reumacon

 Combination therapy is well tolerated and

associated with no significant increase in the
rate of adverse events compared with
monotherapy.
Methotrexate-sulfasalazine,
Methotrexate-chloroquine,
Methotrexate- ciclosporin,
Methotrexate-leflunomide,
Methotrexate-intramuscular-gold
Methotrexate-doxycycline
are effective combination regimens.
Nat Clin Pract Rheumatol. 2007; 3(8):450-458.

 Triple DMARD therapy is better than

various DMARD monotherapy and dual
therapy regimens.
Methotrexate and hydroxychloroquine
may have synergistic anti-inflammatory
properties.
Clinical trial evidence to support the use of
other methotrexate and sulfasalazine
combinations is often weak or lacking.
Nat Clin Pract Rheumatol. 2007; 3(8):450-458.

Disease-Modifying antirheumatic Drugs (DMARDs)

Drug

Mechanisms
of action

Injectable gold
Aurothioglucose
Gold sodium
thiomalate
Oral gold
Auranofin
Antimalarials
Hydroxychlorqn
Chlorqn phosphat

Inhibits: macorphg, Mucocutan.eruptions 50 mg/wk i.m to total

angiogenesis,prot. Proteinuria
dose of 1000 mg then
kinase C
Thrombocytopenia
50 mg i.m q 2-4 wk

D-Penicillamine

Common
adverse effects

Inhibits: macrophg, Diarrhea, Mucocutan.

PMN function
eruptions

Usual
Dosing regimens

3 mg p.o.b.i.d

Inhibits: cytokine Diarrhea, mucocutan. 400 mg p.o.,q.d

secretion,lysoso- eruptions
250 mg p.o.,q.d
mal enzymes, ma
crophg.function
Inhibits: helper T Mucocutan.eruptions 500-1000 mg p.o.,q.d
cell function, angio Proteinuria
genesis
Thrombocytopenia

Disease-Modifying antirheumatic Drugs (DMARDs)

Drug
Sulfasalazine

Methotrexate

Leflunomide

Mechanisms
of action

Common
adverse effects

Usual
Dosing regimens

Inhibits: B cell
Nausea, abd.pain,
1000 mg p.o.,b.i.d
responses, angiodiarrhea, rash
or t.i.d
genesis
Dihydrofolate
Mucocutan.eruptions
7.5-25 mg/wk p.o.
reductase inhibitor, Bone marrow
(may also be admiAntiinflammatory via Nausea, diarrhea,
nistered parenteinduction of adeno- Hepatic abnormalities
rally SC or IM)
sine release,inhibits
chemotaxis
Inhibits pyrimidine
Hepatic abnorm.
20 mg/day p.o.
synthesis
Diarrhea,nausea
(initial loading dose
of 100 mg/day for
3 days

Disease-Modifying antirheumatic Drugs (DMARDs)

Drug

Mechanisms
of action

Common
adverse effects

Usual
Dosing regimens

Anakinra

IL-1 receptor
antagonist

Injection site
reactions,
Infections

100 mg s.c.
injection daily

Adalimumab

TNF antibody
(human)

40 mg s.c. inj.
q. 14 days

Infiximab

TNF antibody
(chimeric)

Injection site
reaction,
Opportunistic
infections
Infusion reactions
Opportunistic
infection
Injection site
reactions
Opportunistic
infections

Etanercept

Soluble TNF
receptor

3 mg/kg i.v. slow

infusion wk 0,2,6,
then every 8 wk
25 mg s.c. inj.
twice weekly or
50 mg/wk s.c.

Disease-Modifying antirheumatic Drugs (DMARDs)

Drug

Mechanisms
of action
Cyclosporine
Inhibits: synthesis
of IL-2 & other T
cell cytokines
Azathioprine
Inhibits DNA
synthesis
Mycophenolate Inhibits lymphocyte
Mofetil
proliferation
Cyclophosphamide

Crosslinks DNA
& inhibits cellular
proliferation

Common
Usual
adverse effects
Dosing regimens
Hypertension
2.5-4 mg/kg p.o.
Renal insuff.
q.d.
Hirsutism
Bone marrow
1-2 mg/kg p.o,q.d
supprression
GI, leukopenia
1.0-1.5 g p.o,b.i.d
nausea,hepatic
abnormalities
Nausea, emesis
1-2 mg/kg p.o,q.d
Bone marrow
suppression
Ovarian failure
Hemorrhagic cystitis
risk of cancer

Disease-Modifying antirheumatic Drugs (DMARDs)

Drug
Minocycline

Rituximab

Mechanisms
Common
Usual
of action
adverse effects
Dosing regimens
Inhibits biosynDiarrhea,nausea
100 mg p.o, b.i.d
thesis & activity
Photosensitivity
of MMPs
Anti-CD20 mono- Hypotension
1 g IV q.14 days
clonal antibody
Hypertension
(chimeric)
RA exacerb.

STEM CELL THERAPY

Hematopoietic stem cells may be beneficial as a
treatment for rheumatoid arthritis
Bingham SJ, Moore JJ. Stem cell transplantation for autoimmune
disorders. Rheumatoid arthritis. Best Pract Res Clin Haematol 2004;
17(2): 263-76.
Hematopoietic stem cell transplantation is being investigated as a
treatment for patients with severe refractory rheumatoid arthritis that
is unresponsive to conventional therapies. The stem cells are well
tolerated in patients with rheumatoid arthritis. The authors review
the research and suggest future protocols for treatments.

Prognosis
Life expectancy reduced by
7 years in men
3 years in women
Severe morbidity
sudden onset do better than gradual
early knee involvement bad
Bad RA has a worse prognosis than
IHD or Hodgkins

Risk Factors for Increased Morbidity

and Mortality in RA
Social factors

Low socioeconomic status

Lack of formal education
Psychosocial stress
Low HAQ scores

Physical factors

Extra-articular manifestations
Elevated CRP and ESR
High titers of RF
Erosions on x-ray
Duration of disease

Rheumatoid Arthritis:
Treatment Plan Summary
A variety of treatment options are available
Treatment plan should match

The current disease activity

The documented and anticipated pace of joint
destruction

Consider a rheumatology consult to help

design a treatment plan