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Juvenile idiopathic arthritis: state of the art and

future perspectives
Alberto Martini and Daniel J Lovell
Ann Rheum Dis 2010 69: 1260-1263 originally published online June 4, 2010

doi: 10.1136/ard.2010.133033

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Review 2010

Juvenile idiopathic arthritis: state of the art and future

perspectives
Alberto Martini,1 Daniel J Lovell2
1Dipartimento

di Pediatria,
Universit di Genova, Pediatria
II-Reumatologia, IRCCS G
Gaslini, Genova, Italy
2Cincinnati Childrens Hospital
Medical Center, Cincinnati,
Ohio, USA
Correspondence to
Professor Alberto Martini,
Dipartimento di Pediatria,
Universit di Genova, Pediatria
II Reumatologia, IRCCS G
Gaslini, Largo Gaslini 5, 16147
Genova, Italy;
albertomartini@
ospedale-gaslini.ge.it
Accepted 19 May 2010

ABSTRACT
Juvenile idiopathic arthritis (JIA) is not a disease but
an exclusion diagnosis that includes all forms of chronic
arthritis of unknown origin with onset before 16 years of
age. The current classification identifies several different
categories. While some of them appear to represent
rather homogeneous entities others seem still to include
heterogeneous conditions. The advent of the new
biological treatments has dramatically changed both the
observed responses to treatment and the expectations of
treatments. International research networks of paediatric
rheumatology have contributed to fostering the conduct
of controlled clinical trials and also the development
of validated outcome measures. However, despite a
dramatic advance in the understanding of JIA categories,
pathobiology and treatments, much remains to be done.
Juvenile idiopathic arthritis (JIA) is not a disease
but an exclusion diagnosis that applies to any
arthritis of unknown origin, persisting for more
than 6 weeks and with onset before the age of 16
years.1 The last proposed classication of JIA2 is
intended to represent a work in progress whose
main aim is to nd homogeneous disease groups
suitable for aetiopathogenetic studies. In the past
decade some of the criteria used to classify JIA
have been challenged3 and more information on
the characteristics of the various JIA subsets has
been provided. The picture that now emerges is
that while some JIA subsets identify clearly distinct disease entities, others seem still to include
heterogeneous conditions. The intent was to
develop the JIA categories to more accurately
reect the biological similarities and differences
between groups. This effort will be greatly helped
by the efforts of the Canadian International
Partnership, in which biobanks of samples from
JIA will facilitate the delineation of the biological basis for variation in clinical manifestations
so that phenotypic classication will derive from
biological subtyping.

QUITE WELL CHARACTERISED JIA CATEGORIES

Systemic JIA
Systemic JIA (sJIA) is a disease clearly distinguished from all the other forms of JIA and very
similar to adult-onset Stills disease. It is characterised by prominent systemic features, such as
high spiking fever, and an important elevation of
acute phase reactants. There is a marked activation of the innate immune system,4 witnessed
also by the frequent occurrence (in about 58% of
patients) of a life-threatening complication known
as macrophage activation syndromea form of
1260

haemophagocytic lymphohistiocytosis. The reason for the high rate of occurrence of macrophage
activation syndrome in sJIA remains unknown.5
The hypothesis that interleukin 6 (IL-6) has a
major role in the pathogenesis of sJIA6 has been
conrmed by the efcacy of tocilizumab, an antiIL-6 receptor antibody.7 Anti-IL-1 treatment has
also proved effective, and gene expression analysis in active disease has shown an IL-1 signature.8
Moreover, treatment with anakinra has distinguished two subsets of patients9: one that has a
dramatic response similar to that observed in cryopyrin-associated autoinammatory syndromes
and the other that is resistant or has an intermediate response. The systemic features, the marked
activation of the innate immune system, the lack
of any consistent association with autoantibodies
or human leucocyte antigen (HLA) antigens, and
the response to IL-1 inhibition has led to the categorisation of at least some forms of sJIA as autoinammatory diseases.

Enthesitis-related arthritis
Enthesitis-related arthritis is a form of undifferentiated
spondyloarthropathy. Most patients are HLA-B27
positive and for some, involvement of the sacroiliac
joints develops during the disease course.10

Rheumatoid factor-positive polyarthritis

Rheumatoid factor (RF)-positive polyarthritis is
the same disease as adult RF-positive rheumatoid
arthritis (RA). Indeed, it is also the only form of
JIA with positive antibodies to cyclic citrullinated
peptides.11

Oligoarthritis
The large majority of patients with oligoarthritis
belong to a quite well dened disease which is
typical of children and is not seen in adults. It is
characterised by an asymmetric arthritis affecting
mainly large joints, an early onset (before 6 years
of age), a female predilection, a high frequency of
positive antinuclear antibodies (ANA), a high risk
for developing chronic iridocyclitis and consistent
HLA associations. The International League of
Associations for Rheumatology (ILAR) classication distinguishes two categories of oligoarthritis
based on the number of joints that are involved
after the rst 6 months of disease: persistent oligoarthritis, in which the disease remains conned
to four or less joints, and extended oligoarthritis,
in which arthritis extend to more than four joints
(which may occur in up to 50% of patients).
However, it has been shown that ANA-positive
patients belonging to these two categories share
Ann Rheum Dis 2010;69:12601263. doi:10.1136/ard.2010.133033

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Review 2010
the same characteristics, strongly suggesting that they represent the same disease.12

LESS WELL-CHARACTERISED JIA CATEGORIES

RF-negative polyarthritis
RF-negative polyarthritis is a heterogeneous JIA category. At
least two distinct subsets can be identied: (a) a form that is
similar to adult-onset RF-negative RA and is characterised by
symmetric synovitis of large and small joints, onset in school
age and negative ANA; (b) a form that resembles oligoarthritis,
except for the number of joints affected in the rst 6 months
of disease. These similarities led to the hypothesis that this
second subset of RF-negative polyarticular JIA and early-onset
oligoarthritis are the same disease, the former representing a
rapid arthritis spread in the latter.3 This view has been conrmed by the demonstration that ANA-positive oligoarthritis
(either persistent or extended) shares the same features (asymmetric arthritis, early age at onset, female predominance,
ANA positivity, elevated incidence of chronic iridocyclitis)
as ANA-positive, RF-negative polyarthritis, but not the same
as ANA-negative RF-negative polyarthritis or ANA-negative
oligoarthritis.12 The concept is also supported by the observation that in those countries in which ANA-positive oligoarthritis is rare, ANA-positive, RF-negative polyarthritis is also
seldom seen.3 The heterogeneity of RF-polyarticular JIA has
recently been conrmed also by gene expression studies.13

Psoriatic arthritis
Psoriatic arthritis also does not appear to represent a dened
entity.3 If psoriatic arthritis is dened according to the presence of arthritis and psoriasis or some psoriatic features
(Vancouver criteria) two populations of patients are identied:
(a) one that belong to the enthesitis-related arthritis category
and represent therefore, like adult psoriatic arthritis, a form
of spondyloarthropathy; (b) a second form that is very similar to ANA-positive oligoarthritis with only small differences
such as a more frequent involvement of small joints, a feature
that may well reect the inuence of the psoriatic diathesis
on the ANA-positive oligoarthritis phenotype. Consistently,
most patients who meet the ILAR criteria for psoriatic
arthritis, in which patients with enthesitis are by denition
excluded, have the features of ANA-positive oligoarthritis. So
it appears that the association of psoriasis with arthritis leads
to the identication of two different subsets of patientsone
that is similar to adult psoriatic arthritis and the other that is
overlapping, with only minor differences, with ANA-positive
oligoarthritis.3 14

Undifferentiated arthritis
Undifferentiated arthritis is by denition heterogeneous since
it includes patients who do not full inclusion criteria for any
category or full the criteria for more than one category.

TREATMENT PERSPECTIVES
It was only slightly more than a decade ago that the introduction
of etanercept for the treatment of children with JIA15 began to
dramatically change both the observed responses to treatment
and the expectations of treatments.16 During this same era the
transition from the use of juvenile RA categories to the use of
JIA categories in the determination of eligibility in clinical trials
occurred. Lack of clarity about the efcacy of various biological
treatments in subsets of patients with JIA is a consequence of
both this transition in the use of classication criteria and the
Ann Rheum Dis 2010;69:12601263. doi:10.1136/ard.2010.133033

biological heterogeneity of both the juvenile RA and JIA subgroups as described above.
The performance of these clinical trials has beneted greatly
from several factors. Key non-pharmaceutical supported
studies have been performed by the Pediatric Rheumatology
InterNational Trials Organization (PRINTO) and the Pediatric
Rheumatology Collaborative Study Group (PRCSG) which
have greatly enhanced our ability to study JIA. For example,
the denition of the JIA core set of variables, denitions of
response, denition of inactive disease and clinical remission
states are critically important to the trials that are being
performed currently. The identication in a large randomised
clinical trial of the maximally effective dose of methotrexate
in polyarticular forms of JIA provided a rm understanding
of the most appropriate prebiological treatment approach for
many children with JIA.17 In addition, a validated core set
of clinical measures as well as validated denitions for treatment responsethe Pediatric 30 denition of response18 and
disease are15 19have served to greatly improve both the
scientic validity and efciency of the performance of these
trials.
Furthermore, the trial of etanercept in JIA introduced to paediatric rheumatology the use of the double-blind, randomised
withdrawal study design.19 This treatment design minimises
both the number of children required to demonstrate a signicant difference in clinical effect between an active agent
and placebo and also the time for which children are required
to remain on placebo. Both of these aspects are relevant when
either the efcacy or safety of a new treatment is uncertain
(clinical equipoise). In addition, this trial design allows all
study subjects to be treated with the new active agent and
the status of the individual study subject is the determinant
of the duration that a particular study subject remains in the
double-blind, placebo-controlled part of the study. This study
design has proved to be very well accepted by study participants and their families (user friendly). It has also proved
to be ethically acceptable to investigators and ethics review
committees/institutional review boards since it minimises the
time that a subject experiences active arthritis induced by the
study design. This study design has been sufcient proof to
regulatory agenciesboth the Food and Drug Administration
(FDA) and the European Medicines Agency (EMA)for
them to approve etanercept,15 adalimumab20 and abatacept21
for use in polyarticular forms of JIA. Moreover, PRINTO as
well as the Childhood Arthritis and Rheumatology Research
Alliance are actively engaged in non-industry-supported clinical trials.
Of critical importance to the successful completion of these
studies in JIA has been the existence of two international
research networks of paediatric rheumatology centresPRCSG
and PRINTOthat have worked in a highly integrated and
synergistic fashion on design and performance of preliminary
studies (phase II), pivotal clinical trials (phase III) and clinicaleffectiveness and safety studies (pen label extension and phase
IV). With the exception of etanercept, PRCSG and PRINTO
have collaborated on the testing of all the biological agents used
in children with JIA to date.2123
The Pediatric 30 level of response is seen in over 80% of
the children with polyarticular forms of JIA enrolled in the
clinical trials.15 2025 To provide for more demanding levels
of response, Pediatric 50, 70, 90 and 100 levels of response
have been assessed in the clinical trials.15 2025 More recently,
a validated preliminary denition of clinically inactive disease26 27 has been used as the primary outcome measure in a
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Review 2010
randomised, double-blind trial in children with early JIAthe
National Institutes of Health funded TREAT trial (Wallace PI).
The trial is still continuing but it represents the rst trial to
use inactive disease as the outcome. Increasingly, in clinical
studies we need to focus on higher levels of response and in
the near future, investigator studies are needed to expand
the TREAT trial to see if induction of drug-free remission is
achievable.
Trials of children with sJIA with active systemic features have
demonstrated the efcacy of IL-6 blockade in a phase III study
in Japan.7 International phase III studies are continuing for both
IL-1 and IL-6 blockade.
Safety has been assessed in phase III,7 2023 open-label extension18 24 25 28 and registry studies2932 of biological agents in
children with JIA. To date, no unique safety signals have been
recognised in children that have not already been identied in
adults, with the exception of a possibly increased risk of lymphoma and other types of cancer in children treated with one
of the anti-tumour necrosis factor (TNF) agents. This observation is based on spontaneous adverse event reports (SERS)
in the FDA surveillance system. However, the SERS system
has major limitations, including uncertainty of the completeness of the adverse event reporting (numerator data) and lack
of an internal estimate of the at-risk population (denominator
data). Moreover, the rate of malignancies in children with JIA
not receiving biological treatments is not well established. The
long-term safety of biological agents and of the other drugs
used in JIA needs to be assessed with the use of large international registries.

FUTURE PERSPECTIVES
If more homogeneous groups within JIA have to be identied,
then some classication criteria have to be reconsidered. In
2003 we suggested3 that the number of joints affected and the
presence of psoriasis do not represent suitable classication
parameters to identify homogeneous disease entities and that
children with the same cluster of features that strongly suggest a common background (asymmetric arthritis, early onset,
female predominance, ANA positivity, high risk for iridocyclitis, denite HLA associations) are currently classied into different JIA categories (oligoarticular, polyarticular RF negative
and psoriatic). Moreover, ultrasonography has shown a frequent discrepancy between imaging and clinical examination
in evaluation of the number of affected joints,33 making a classication based on the number of joints involved even more
complicated. We suggested3 that grouping patients according
to other criteria (alone or in combination) such as ANA positivity, age at onset or pace (asymmetrical or symmetrical) of
joint involvement might lead to the denition of more specic
categories. Indeed, as mentioned above, ANA positivity has
been shown to identify a homogeneous subset of patients1 12
and, more recently, it has been shown that a B-cell gene
expression signature can distinguish between early-onset and
late-onset JIA regardless of the number of joints affected.34
So, further renements in the classication criteria are needed
in order to identify more homogeneous entities suitable for
immunological, gene expression and genome-wide association studies.35 36
The potential of imaging has still to be fully exploited in
childhood arthritis. Indeed, methods to evaluate x-ray ndings
have progressed,37 MRI has shown the potential for identifying
bone damage with high sensitivity38 and ultrasonography has
demonstrated its utility in assessing the number of active joints
1262

and in differentiating tendon from articular involvement.33 In

the future, molecular imaging will probably be able to identify bone and cartilage involvement well before morphological damage became apparent. Serum biomarkers (such as S100
proteins) are also showing promise in identifying subclinical
disease and predicting relapse.39 40
Progress in understanding the pathogenesis of RF+ RA and the
spondyloarthropathies will also shed light on their childhood
equivalents.
The efcacy in the various JIA categories of TNF, IL-6 and
IL-1 blockade has provided excellent therapeutic tools and also
helped in unravelling disease pathogenesis. So it can be expected
that the future availability of new drugs with other specic targets will continue to foster this process of reverse translation
(from the bed to the bench side).
Systemic arthritis will represent a precious opportunity to
better understand the role of innate immunity alterations in the
pathogenesis of chronic inammation as well as the factors that
in that context predispose to the development of persistent and
aggressive synovitis.
The fact that an homogeneous disease such as ANA-positive
oligoarthritis can have a more benign (persistent oligo) or a
more aggressive (extended oligo) course offers a useful model
for differentiating factors related to disease aetiology from those
that inuence disease progression. Interesting results have been
indeed achieved for regulatory T cells,41 42 their relationship
with Th17 cells43 and the role of heat shock proteins in modulating the immune response.44 45
Terms such as JIA and onset forms will probably be abandoned in the future since they suggest the misleading concept
that the various forms of chronic childhood arthritis represent
different subsets of a single disease rather than completely different diseases.
Therapeutic trials have already established the efcacy of
anti-TNF agents in children with the polyarticular forms of JIA.
Future studies of additional anti-TNF agents that have established efcacy and safety in adults with RA should only need to
perform dosing and safety studies in patients with polyarticular
forms of JIA. As additional classes of treatment establish efcacy
in children with JIA (eg, IL-1 blockade in sJIA), then fewer efcacy trials will need to be performed.
Current efforts to establish very large multinational longitudinal cohorts of patients with JIA will provide the only realistic approach to assessing the true relative safety of all the
agents used to treat children with JIA, including the various
biological treatments, and to assessing the risk for rare adverse
events. In addition, this effort will be greatly enhanced by the
development of banks of biological specimens obtained from
patients with JIA that have been collected using validated and
standardised techniques for specimen collection, preparation
and storage, such as the Canadian International Partnership
Initiative.
The past decade has brought dramatic advances in the understanding of JIA categories, pathobiology and treatments but
much remains to be done.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.

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