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2138 www.thelancet.com Vol 377 June 18, 2011

Lancet 2011; 377: 213849
See Comment page 2067
This is the third in a Series of
three papers about arthritis
Centre for Molecular and
Cellular Intervention,
Department of Paediatrics,
University Medical Centre
Utrecht, Netherlands
(Prof B Prakken MD);
Translational Research
Laboratory, Inammatory and
Infectious Diseases Center,
Sanford-Burnham Medical
Research Institute, La Jolla, CA,
USA (Prof S Albani MD);
Department of Paediatrics,
University of Genova and
Pediatria II, Institute G Gaslini,
Genova, Italy
(Prof A Martini MD)
Correspondence to:
Prof Alberto Martini,
Department of Paediatrics,
University of Genova and
Pediatria II, Institute G Gaslini,
Largo G Gaslini 5,
16147 Genova, Italy
albertomartini@ospedale-
gaslini.ge.it
Arthritis 3
Juvenile idiopathic arthritis
Berent Prakken, Salvatore Albani, Alberto Martini
Juvenile idiopathic arthritis is a heterogeneous group of diseases characterised by arthritis of unknown origin with
onset before age of 16 years. Pivotal studies in the past 5 years have led to substantial progress in various areas,
ranging from disease classication to new treatments. Gene expression proling studies have identied dierent
immune mechanisms in distinct subtypes of the disease, and can help to redene disease classication criteria.
Moreover, immunological studies have shown that systemic juvenile idiopathic arthritis is an acquired
autoinammatory disease, and have led to successful studies of both interleukin-1 and interleukin-6 blockade. In
other forms of the disease, synovial inammation is the consequence of a disturbed balance between proinammatory
eector cells (such as T-helper-17 cells), and anti-inammatory regulatory cells (such as FOXP3-positive regulatory
T cells). Moreover, specic soluble biomarkers (S100 proteins) can guide individual treatment. Altogether these new
developments in genetics, immunology, and imaging are instrumental to better dene, classify, and treat patients
with juvenile idiopathic arthritis.
Introduction
Juvenile idiopathic arthritis is not a single disease, but a
term that encompasses all forms of arthritis that begin
before a patient is aged 16 years that persist for more
than 6 weeks and are of unknown origin.
1,2
It is the most
common childhood chronic rheumatic disease and
causes much disability. In high-income countries it has a
yearly incidence of 220 cases per 100 000 population and
a prevalence of 16150 cases per 100 000 population.
1
In
this Seminar we focus on developments in the
understanding of pathogenesis and in the diagnosis and
treatment, and discuss how translational research and
new imaging modalities and biomarkers are expected to
improve diagnostic and treatment options.
Clinical manifestation and classication
Disorders described by the term juvenile idiopathic
arthritis have been grouped on the basis of clinical and
laboratory features to try and identify homogeneous,
mutually exclusives categories.
3
Clinical and laboratory
ndings have improved the understanding of the
dierent forms of chronic childhood arthritis.
46
Although
some categories identify denite disease entities, others
still include heterogeneous disorders.
7
Well-characterised categories
Systemic juvenile idiopathic arthritis is characterised by
prominent systemic features, such as fever, rash, and
serositis, and is much like adult-onset Stills disease.
1

Pronounced activation of a patients innate immune
system and the absence of any consistent association
with autoantibodies or human leucocyte antigen (HLA)
have led to the hypothesis that this systemic form of
disease is a polygenic autoinammatory syndrome.
8

Findings from previous studies suggesting a major
pathogenic role for interleukin-6
9
in the disease have
been substantiated by the reported eectiveness of
treatment with tocilizumab, an anti-interleukin 6 receptor
antibody.
10,11
Moreover, the nding that anti-interleukin 1
treatment can also be eective
12
has led to the subsequent
delineation of two subpopulations of this form of
disease:
13
one with a pronounced, complete response to
interleukin-1 blockade (much the same as seen in
cryopyrin-associated autoinammatory syndromes) and
another that is resistant to treatment or has an
intermediate response. These two subpopulations do not
dier in interleukin-1 in vitro production or in serum
cytokine concentrations, but only in the number of joints
aected and in neutrophil counts; patients with fewer
joints aected or with a higher neutrophil count have an
increased probability of responding to anti-interleukin-1
treatment. Thus, systemic juvenile idiopathic arthritis
can be stratied into at least two subgroups on the basis
of responsiveness to inhibition ofand therefore
possible pathogenic relevance ofinteleukin-1. Once the
ndings from a phase 3 trial of canakinumab (an anti-
interleukin-1 antibody; NCT00889863) and a second
phase 3 trial of tocilizumab (NCT00642460) are available,
the pattern of response might provide new clinical or
laboratory biomarkers useful to further understand the
Search strategy and selection criteria
We searched PubMed for papers with the search terms
juvenile arthritis, systemic, polyarticular,
oligoarticular, psoriasis, spondylarthropathy, therapy,
pathogenesis, immunology, genetics, cytokines, and
T cells. We gave preference to papers published between
2005 and 2010, without excluding key references from earlier
years. We also gave preference to original studies published in
peer-reviewed journals, but also searched for, and if
appropriate included, abstracts from the main paediatric
rheumatology conferences during the past 3 years. We aimed
to include the most recent publications while also referring to
the rst original publication on a given subject.
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www.thelancet.com Vol 377 June 18, 2011 2139
heterogeneity between these two subgroups and the
reciprocal roles of interleukin-1 and interleukin-6 in
disease pathogenesis.
Rheumatoid factor positive polyarthritis, a small
subcategory of juvenile idiopathic arthritis (aecting 5%
of patients), is thought to be much like adult rheumatoid
factor (RF)-positive rheumatoid arthritis; indeed, it is the
only form of juvenile idiopathic arthritis with positive
antibodies to cyclic citrullinated peptides.
14
Major
dierences with the adult form of disease are in the eect
that the disease can have on a growing skeleton, leading
to either general growth retardation or accelerated growth
of an aected joint.
Enthesitis-related arthritis is a form of undierentiated
spondyloarthropathy.
15
Most patients are HLA-B27
positive, and, in about 3040% of patients, the disease
can progress to aect sacroiliac joints. Although the
category oligoarthritis, as a whole, is probably
heterogeneous, most patientsat least in developed
countrieshave a well-dened disease that is seen only
in children.
16
Arising more often in girls than in boys,
oligoarthritis has early onset (before 6 years of age), has
consistent HLA associations, and is characterised by
asymmetric arthritis that aects mainly large joints.
Patients have high concentrations of positive antinuclear
antibodies (ANA) and a high risk of developing chronic
iridocyclitis. Juvenile idiopathic arthritis classication
criteria
3
distinguish two categories of oligoarthritis:
persistent oligoarthritis, in which the disease aects four
joints or fewer, and extended oligoarthritis, in which
more than four joints are aected after the rst 6 months
of disease. However, patients with either persistent or
extended oligoarthritis who test positive for ANA have
similar clinical characteristics (eg, age at onset, sex ratio,
asymmetry of articular involvement, and frequency of
iridocyclitis), which strongly suggests that these two
categories of oligoarthritis are the same disease, diering
only in severity.
17,18
Less well-characterised categories
Rheumatoid factor-negative polyarthritis is a hetero-
geneous category of juvenile idiopathic arthritis. At least
two subsets can be identied: one that is similar to adult-
onset RF-negative rheumatoid arthritis, characterised by a
symmetric synovitis of large and small joints, onset at
school age, and the absence of ANA expression, and
another that resembles oligoarthritis, apart from the
number of joints aected in the rst 6 months of disease.
Similarities between this second subset and early-onset
oligoarthritis led to the hypothesis that they are the same
disease, with a more rapid spread of arthritis in the second
subset than in early-onset arthritis.
16
This view has been
lent support by the nding that ANA-positive oligoarthritis
share the same features with ANA-positive RF-negative
polyarthritis, but not with ANA-negative RF-negative
polyarthritis or with ANA-negative oligoarthritis.
17
The
view is also lent support by the fact that ANA-positive
RF-negative polyarthritis is seldom seen in countries in
which ANA-positive oligoarthritis is rare.
16
If psoriatic arthritis is dened according to the
presence of arthritis and psoriasis or some psoriatic
features (as it is in the Vancouver criteria
19
), two disease
entities exist:
16,20,21
one in the enthesitis-related arthritis
category, which is therefore, like adult psoriatic arthritis,
a form of spondyloarthropathy, and a second that is very
similar to ANA-positive oligoarthritis with only small
dierences such as it aects small joints more often
than large joints, a feature that could be attributable to
psoriatic diathesis in the ANA-positive oligoarthritis
phenotype. The association of psoriasis with arthritis
seems to lead to the identication of two subsets of
patientsone with disease that is similar to adult
psoriatic arthritis and another with disease that has only
minor dierences with ANA-positive oligoarthritis.
16

Indeed, most patients who meet the present classication
criteria for psoriatic arthritis, in which patients with
enthesitis are by denition excluded, have features of
ANA-positive oligoarthritis.
Perspectives for a new classication
To improve our understanding of the cause and
development of the various forms of childhood chronic
arthritis and nd more suitable treatments, the
identication of categories that, at least from a clinical
point of view, seem as homogeneous as possible is
essential to enable immunological, gene expression, and
genome-wide association studies. If more homogeneous
groups within juvenile idiopathic arthritis are to be
identied, which seems likely in view of the heterogeneity
within the present subcategories, then some classication
criteria need to be reconsidered.
In 2003, we suggested
16
that the number of joints aected
and the presence of psoriasis are not suitable criteria with
which to identify homogeneous disease entities, and that
children with clinical features that are strongly suggestive
of a common cause (eg, asymmetric arthritis, early onset,
sex ratio, ANA positivity, high risk for iridocyclitis) are
wrongly classied into three dierent disease categories
oligoarthritis, RF-negative poly arthritis, and psoriatic
arthritis. We postulated that the grouping of patients into
these three categories according to criteria (alone or in
combination) such as ANA positivity, age at disease onset,
or pace (asymmetrical or symmetrical) at which the disease
aects joints could lead to the denition of more
homogeneous categories.
The analysis of gene expression proles has conrmed
the heterogeneity of polyarticular juvenile idiopathic
arthritis.
22
Moreover, Barnes and colleagues
23
recorded a
B-cell signature that characterises patients with early-
onset arthritis independently from the number of joints
aected. Their study accords with previous ndings
showing that plasma cell inltration of the synovium was
more common in the early phase of joint inammation
but not related to disease activity or severity.
24
Additionally,
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2140 www.thelancet.com Vol 377 June 18, 2011
high-resolution HLA class I and class II typing has shown
similarities between early-onset polyarticular and
oligoarticular forms of disease.
25
All these ndings
corroborate the suggestion that ANA-positive, early-onset
arthritis is a homogeneous entity that is classied into
dierent disease categories because of dierences in the
spread of arthritis or the association with psoriasis or
psoriatic features.
Ultrasonography has shown much discrepancy between
imaging and clinical examination in the assessment of
the number of aected joints,
26
making a classication
on the basis of the number of joints aected even more
complicated. However, ultrasonography allows better
dierentiation between tendon and articular involvement,
thus providing information that could also be of relevance
for classication purposes.
27
Because in children, as in adults, several dierent
diseases exist that all cause chronic arthritis, the terms
juvenile idiopathic arthritis and juvenile idiopathic
arthritis onset-forms will probably become outdated as
more is learnt about each disease. These terms wrongly
suggest that juvenile idiopathic arthritis is a single
disease (as was thought many years ago) and that the
various onset-forms (or categories) are only pheno-
typic variants.
Cause and pathogenesis
One of the most intriguing questions in the study of
human autoimmune diseases is what determines the
phenotype and organ specicity of a disease. In juvenile
idiopathic arthritis, for example, the occurrence of
uveitis is related to explicit risk factors, such as age at
disease onset, sex, the presence of ANA auto-antibodies,
and the subtype of juvenile idiopathic arthritis.
2830

Despite these associations, the immune pathogenesis
underlying the link between arthritis and uveitis is
unknown. However, studies done in the past 5 years
have provided information about the immune
pathogenesis of juvenile idiopathic arthritis, conrming,
among other things, that the systemic form is a dierent
disease from other types of juvenile idiopathic arthritis,
with a distinct immune pathogenesis, and should be
treated as would an acquired autoinammatory disease.
Genetic susceptibility
Despite the heterogeneity of juvenile idiopathic arthritis,
a specic genetic overlap might exist between subtypes
since they share joint inammation as the most
prominent disease feature.
31
The concordance rate and
similarity in disease phenotype between monozygotic
twins (2040%) also suggests a strong genetic component
of the disease.
32,33
Indeed, ndings from several studies
suggest that specic genetic susceptibility genes can be
identied, which can be broadly divided into two
groupsHLA genes and non HLA-related genes. The
non HLA-related genes include cytokines and other
immune genes.
34
The association of juvenile idiopathic
arthritis with both HLA class I (HLA A-2, and HLA B27)
and HLA class II (HLADRB1 and HLA DP) alleles has
been reported and substantiated in various studies,
underscoring the supposed importance of the role of
T cells in the disease course.
35
Many non-HLA candidate
genes have been studied for associations with juvenile
idiopathic arthritis, including various cytokine genes, but
only a few candidate genes including PTPN22, MIF,
SLC11A6, WISP3, and tumour necrosis factor (TNF)
could be independently conrmed.
36,37
Instead of
searching for specic candidate genes, doing genome-
wide association studies are an attractive alternative.
38

This approach has led to the successful identication of
new genes and immune pathways in other autoimmune
diseases. Because the eects of individual genes in a
complex autoimmune disease such as juvenile idiopathic
arthritis are probably very small, international
collaborations will be necessary for su ciently powered
studies. As discussed in the Treatment section of this
Seminar, such international collaborations are indeed
actively pursued in paediatric rheumatology.
Gene expression proling
In addition to searching for susceptibility genes, gene
expression proling can identify any genes for which
expression patterns change during the course of disease,
providing a disease signature that can lead to the
identication of unique biomarker patterns. Although
this approach has disadvantages (such as the high costs,
the complexity of the composition of the DNA
microarrays, and the analysis of the results), its potential
is underscored by various studies in patients with juvenile
idiopathic arthritisstudies of patients with dierent
forms of disease showed a consistent, though not fully
elucidated, association with interleukin-10-regulated
genes in all forms of the disease.
3941
Also, peripheral
blood mononuclear cells from patients with recent-onset
disease have a dierent gene expression prole dependent
on their subtype.
41
In another study, researchers compared early samples
of either peripheral blood mononuclear cells or synovial
uid mononuclear cells from patients who developed
either persistent or widespread oligoarticular disease and
identied patterns that were dierent between both
groups.
42
However, the most striking nding was an
increased CD4 to CD8 ratio in patients with remitting
disease, underscoring the important part played by T cells
in disease course.
42
Also, as discussed above, gene
expression proles in peripheral blood mononuclear
cells of patients with recent-onset juvenile idiopathic
arthritis identied expression patterns that diered with
age of onset but not with the numbers of joints aected,
suggesting dierent biological mechanisms in patients
with either early-onset and late-onset disease.
22,23
Gene expression patterns in systemic juvenile
idiopathic arthritis are dierent from those of other
subtypes, and include upregulation of genes related to
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www.thelancet.com Vol 377 June 18, 2011 2141
innate immunity and complement systems, and of a
group of mostly haemopoietic genes.
43
The next challenge
will be to relate these molecular proles to specic
immune pathways and the clinical manifestations to
individual pathways. Thus gene expression proling can
provide a basis for a novel molecular method of
classication of patients at disease onset, which could
help to better predict treatment response and thus guide
individual treatment regimens.
4,44
Environmental triggers
In a healthy immune system, eector and regulator
mechanisms are kept in balance, assuring a tailor-made
response that adequately protects against an invading
pathogen while preventing unwarranted damage to an
individual and preserving immune tolerance. To achieve
this balance, the innate and adaptive immune systems
closely interact. Much the same as with most human
autoimmune diseases, the cause of juvenile idiopathic
arthritis is assumed to be multifactorial. A genetically
susceptible individual might develop a deleterious and
uncontrolled response towards a self-antigen on exposure
to an unknown environmental trigger.
32
This response
causes a self-perpetuating loop of activation of both
innate and adaptive immunity that causes tissue damage.
In juvenile idiopathic arthritis, infections and vaccinations
have been suggested as two candidate triggers, but
neither has been conrmed as a trigger because of a
scarcity of proper controlled, prospective studies.
4,32,45
A
prospective study did not show a relation between
vaccination with meningococcus C
46
and disease
exacerbation in juvenile idiopathic arthritis, and a
retrospective analysis did not show any association with
measles, mumps, and rubella vaccination and disease
exacerbation.
47
Patients with polyarticular disease,
however, showed an increased proinammatory immune
response towards vaccine antigens after vaccination with
meningococcus C, suggesting a potential risk for
aggravating inammation.
48
Again, much larger studies
including both genetic susceptibility and up-to-date
immunological analysis will be needed to dene the role
of environmental triggers in juvenile idiopathic arthritis.
Balancing tolerance and inammation
The autoreactive immune response in juvenile idiopathic
arthritis is assumed to be initially triggered by an adaptive
(T cell or B cell) response towards a self-antigen. This
assumption is underscored by the fact that joint
inammation in juvenile idiopathic arthritis is
characterised by selective accumulation of activated
memory T cells in the synovium, which are clustered
around antigen-presenting (dendritic) cells.
24,49,50
However,
soon after the initial autoreactive insult, almost all the
immune system is taking part in the immune response
(gure 1).
5153
Therefore, the question of what initially
triggers the disease is of minor importance. Even if in
individual patients such a disease-causing antigen could
be identied, at the time the patient has developed
juvenile idiopathic arthritis, the inammatory process
would have has already spread and both innate and
adaptive immunity would have been activated.
24,5359
Moreover, human autoimmune diseases such as
juvenile idiopathic arthritis are complex genetic diseases
with a combination of genetic susceptibility and largely
unknown environmental triggers leading to disease.
Such complexity hinders the study of the underlying
immunological mechanisms that contribute to such
diseases. However, unlike other autoimmune diseases,
juvenile idiopathic arthritis has distinct subtypes,
including subtypes with a remitting form of arthritis,
which allows the comparison not only between subtypes,
but also of immune responses at dierent stages of
disease (in active disease and during remission).
The idea that juvenile idiopathic arthritis can have a
remitting course has led to speculation about whether so-
called regulatory T cells play a part in the disease.
Regulatory T cells (Tregs), rst described by Sakaguchi,
60,61

are part of a unique population of T cells that can specic-
ally suppress other immune cells. They express the
transcription factor FoxP3 and are crucial for the regu-
lation of inammation and the maintenance of immune
tolerance in both animals and people.
61,62
Although most
information about the role of Tregs in autoimmunity
comes from animal studies, they are probably important
for the regulation of inammation in human autoimmune
diseases. The rst description of the role of Tregs in people
comes from studies in juvenile idiopathic arthritis,
showing increased numbers of Tregs in remitting disease
and after autologous stem cell transplantation,
63,64
and co-
expression of CD27 or CD39 in the synovial uid of patients
with juvenile idiopathic arthritis.
6569
Both natural Tregs
(those directly derived from the thymus) and antigen-
induced Tregs are present in increased numbers in the
synovial uid and peripheral blood of patients with
remitting forms of juvenile idiopathic arthritis, with heat
shock proteins (heat shock proteins (hsp)60 and dnaJ)
being the most well-dened antigens.
65,7075
Because Tregs are present in increased numbers at the
site of inammation not only in juvenile idiopathic
arthritis, but also in other autoimmune disease such as
rheumatoid arthritis, questions have been has raised as
to whether they are insu cient in quality, quantity, or
both, to aect disease
76,77
Alternatively, the eector
response could be simply too strong to be counter-
regulated by regulatory T cells
5,68
T-helper (Th)17 cells have also been recorded in the
joints of patients with juvenile idiopathic arthritis.
78

These cells are characterised by the expression of
transcription factor RORc and have a reciprocal relation
with FOXP3-positive Tregs that could prove crucial for
the regulation of joint inammation.
79
Growing evidence
suggests that the dierent subtypes of T cells in the
synovial uid (not only Tregs and Th17, but also, for
example, Th1, Th2, and T regulatory-1 cells) should not
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2142 www.thelancet.com Vol 377 June 18, 2011
be thought of as separate entities, but as a community
of T-cell subsets that are in a constantly changing,
dynamic balance. If this suggestion holds true, future
treatment options should not focus on only cytokines,
Tregs, or Th17 cells, but perhaps on all potential targets.
Causes and pathogenesis of systemic disease
Prominent systemic clinical features, the absence of
auto-antibodies, and a relation with HLA alleles have led
to the realisation that systemic juvenile idiopathic
arthritis is a specic disease entity, with more similarities
with autoinammatory diseases than with classic
autoimmune diseases.
8,80,81
This realisation is emphasised
by the fact that patients with the systemic form of disease
have a much less favourable response to anti-TNF
treatment than have patients with other forms of the
disease, despite also having raised concentrations of
TNF in synovial uid.
58,82,83
Systemic juvenile idiopathic arthritis is related to an
overproduction of the proinammatory cytokine
interleukin-6,
9,84
which is the basis of successful treatment
with toculizimab.
10,85
Pascual and co-workers
12
made major
steps forward thanks to well-designed studies
86,87
of the
biological and transcriptional eects of a patients serum
on healthy blood cells. Altogether, these studies showed
that patients with systemic disease have a unique
interleukin-1 signature.
12,86,87
Interleukin-1 concentrations
are not clearly raised when directly measured in plasma
or even in synovial uid of patients with systemic juvenile
idiopathic arthritis, but this signature becomes clear after
incubation of mononuclear cells with plasma from such
patients. Identication of this signature has led to
successful clinical trials with interleukin-1 blockade.
12,13,88

Whether early treatment with anti-interleukin-1 drugs
can prevent the involvement of adaptive immunity and
the onset of severe arthritis is unknown.
The cytokine expressed most abnormally in plasma or
synovial uid is neither interleukin-6 or interleukin-1,
but interleukin-18.
58
Interleukin-18 is in the same family
as interleukin-1, and is essential for natural killer cell
activation, which is compromised in patients with
systemic juvenile idiopathic arthritis because of an
Figure 1: The balance between tolerance and inammation in juvenile idiopathic arthritis
In a genetically susceptible individual, an environmental trigger leads to local tissue damage, the expression of auto-antigens (such as heat shock proteins), and
inammation, which activates a range of innate and adaptive immune responses that can either down-regulate (blue arrows) or promote (red arrows) local
inammation. DAMPs=damage-associated molecular pattern molecules. HSP=heat-shock protein. TGF=tumour growth factor. TNF=tumour necrosis factor.
Release DAMPs:
(S100 proteins)
Release cytokines:
(TNF, interferon, interleukin-6)
Neutrophil
activation
HSP-specic T cells
Genetic susceptibiity
Antigen-specic
T cell
Environmental trigger
Tissue damage
and expression of
auto-antigens
HSP expression
CD25
CD27
FOXP3+
CD39+ FOXP3+
T cells
CD30
TGF
Interleukin-10
CD39+ FOXP3T cells
(interferon, interleukin-17)
Auto-antigen-specic T-cells:
(T-helper-17, T-helper-1 cells)
?
+
+
Natural tregs
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www.thelancet.com Vol 377 June 18, 2011 2143
interleukin-18-receptor signalling defect.
89
Another
distinctive feature of the systemic form of disease is the
strong association with macrophage activation syn-
drome,
81,90
a major and life-threatening complication that
occurs in 510% of patients with juvenile idiopathic
arthritis.
90
Macrophage activation syndrome has strong
resemblance with either genetic-haemophagocytic or
acquired-haemophagocytic lympho histiocytosis. Gen etic
(familial) disease is associated with mutations in the
perforin gene and MUNC genes. Despite the absence of
gene mutations in either gene in systemic juvenile
idiopathic arthritis, there are clear indications of an
association with acquired functional or genetic defects
in the perforin and MUNC genes in the disease.
80,91,92
Another major step forward in the understanding and
management of systemic juvenile idiopathic arthritis was
the identication of phagocyte-specic S100 proteins as
biomarkers for disease and treatment response.
6,93
These
proteins belong to a novel group of so-called damage-
associated molecular pattern molecules (DAMP), and are
also known as myeloid-related proteins (MRPs). They
have clear proinammatory eects on other immune cells
and can act as endogenous activators of toll-like receptor 4.
Several well-designed studies have shown that two of these
proteins, MRP-8 (S100A8) and MRP-14 (S100A9), are
excellent biomarkers in several autoimmune and inam-
matory diseases, especially systemic juvenile idio pathic
arthritis.
93,94
Indeed, the concentration of MRP-8 and
MRP-14 is greatly increased in the serum of patients with
systemic disease, and can distinguish such patients in an
early phase not only from healthy individuals, but also
from patients with infections or malignant disease.
6,94

Increased concentrations of MRP-8 or MRP-14 are even
helpful as biomarkers to predict disease relapse after
stopping methotrexate treatment.
9496
Because they are
closely related to disease activity, these molecules can also
be attractive targets for immunological treatment of
arthritis. Thus, this group of calcium-binding proteins can
have both benets and disadvantages in juvenile idiopathic
arthritis. They can be biomarkers for the disease and are
potential targets for immune treatment. More generally,
experience with S100 proteins as biomarkers and the
growing insight in the mechanisms of disease should help
in the design of phase 0 studies aimed at understanding
the mechanisms of disease and the basis for response to
treatment (gure 2).
Imaging
Imaging has not been used to its full potential in
childhood arthritis.
9799
Findings from studies in adults
are not applicable to children because of the unique
features of the growing skeleton, such as age-related
variations in the thickness of the articular cartilage,
incomplete ossication, and bone growth anomalies
induced by the disease. Indeed, for conventional
radiology, scoring systems specic for juvenile idiopathic
arthritis has been devised.
100102
As well as being useful in the assessment of subclinical
synovitis
26
and in the dierentiation of tendon from
articular involvement,
27
ultrasonography can be used to
assess cartilage thickness, although more data are needed
for the normal thickness of cartilage in children of dierent
ages. In patients with juvenile idiopathic arthritis,
ultrasonography is as good as or better than conventional
radiology for the detection of cortical erosions in
sonographically accessible areas.
103
Therefore, although
more data for reproducibility and sensitivity to change are
needed, important information will be acquired in the near
future when serial ultrasonography is used to supplement
clinical assessment in the monitoring of disease activity
and in the assessment of response to treatment.
Despite the great diagnostic potential of MRI, few
studies of juvenile idiopathic arthritis, all of which have
diering methodologies, have been done.
98,104
Figure 2: Established and emerging immunological treatments
Intervention are targeted at T cells in a specic (1) or non-specic (24) way, B cells (5), cytokines (6), and other
soluble mediators (78). TNF=tumour necrosis factor. HLA=human leucocyte antigen. TNF=tumour necrosis
factor. MMP=matrix metalloproteinase.
Cartilage
Joint
Erosion
Osteoclast
6. Cytokines 5. B-cell
Antibody
T-cell
4. Adhesion molecules
2. T-cell receptor
1. Peptide
HLA
4. Adhesion molecules
Antigen-presenting cell
Antigen-presenting cell
6. TNF
6. Interleukin-1
6. Interleukin-6
7
7
7
7
7
8
8
8
MMP
Fibroplasts
1. Antigen-specic immunotherapy
2. Anti-CD3 antibody
3. CTLA-4 TRAP
4. Interference with lymphocyte migration
5. Anti-CD20 or anti-CD22 antibodies
6. Anti-TNF, anti-interleukin 6, interleukin 1-TRAP,
anti-interleukin-17
7. Proteolytic molecules
8. Kinase inhibitors
3. Co-stimulatory
molecules
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2144 www.thelancet.com Vol 377 June 18, 2011
The feasibility of a quantitative measurement of
synovial volume and of dynamic contrast-enhanced MRI
to provide a quantitative assessment of inammation
on the basis of analysis of the time course of signal
changes after gadopentetic acid injection has been
reported.
105
These approaches could provide useful
information to assess responsiveness to treatment and
predict joint destruction, as already reported in adult
rheumatoid arthritis.
106
The prognostic value of bone
marrow oedema has not been established for juvenile
idiopathic arthritis, but studies done in adults with
rheumatoid arthritis strongly suggest that its assessment
would also be very useful in children.
MRI can also detect cartilage damage; dedicated studies
are needed to dene the variation of cartilage volume
with age in healthy individuals to better understand the
importance of changes in cartilage volume over time in
patients with juvenile idiopathic arthritis. In the near
future, molecular imaging could also provide information
on cartilage injury before morphological damage is
apparent. For instance, delayed gadolinium-enhanced
MRI cartilage imaging (gure 3) is a sensitive technique
to assess cartilage proteoglycan content with the negative
charge of the paramagnetic MRI contrast agent, which
distributes into the cartilage, inversely to the xed charge
density of negatively charged glycosaminoglycans.
107

Finally, consistent with the results of studies in adults,
the ndings of a pilot multi-imaging study
105
have shown
that MRI is the most sensitive imaging modality for the
detection of bone erosions in wrists of patients with
juvenile idiopathic arthritis, detecting more than twice as
many erosions as did conventional radiography
or ultrasonography.
In the near future, ultrasonography and MRI are
therefore likely to provide much essential new
information useful for disease management, including
the early identication of patients at high risk of erosive
disease. Indeed, at present, even within a given category
of juvenile idiopathic arthritis, di culties exist in the
identication of patients at risk for a poor outcome early
enough to allow aggressive treatment at disease onset.
Treatment
The management of juvenile idiopathic arthritis is
based on a combination of pharmacological inter-
ventions, physical and occupational therapy, and
psychosocial support. Until a decade ago, very few
randomised controlled trials (RCT) were done in
children with this disease. This situation changed
completely with the implementation of the so-called
paediatric rule by the Food and Drug Administration
(FDA) and the European Medicines Agency (EMA).
According to this rule, a company that wishes to
register a new treatment for a given disease in adults
has to also test their product in children if there is a
paediatric counterpart of the illness. The paediatric
rule opens the door for more targeted studies, which
are crucial for the safety of paediatric patients such as
those with juvenile idiopathic arthritis.
108110
Paediatric
rheumatologists were able to quickly take advantage of
this rule thanks to the existence of two very large
networks that have worked in a highly integrated and
synergistic way, the Pediatric Rheumatology Collab-
orative Study Group (PRCSG) in North America and
the Paediatric Rheumatology International Trial Organ-
isation (PRINTO) in Europe and the rest of the world.
111

Moreover, these two networks had already dened
validated criteria to assess response to treatment in
juvenile idiopathic arthritis.
112
In the past decade, great advances have been made in
the treatment of juvenile idiopathic arthritis, which will
probably greatly improve the long-term prognosis of the
disease and alleviate some of the heavy burden it
imposes on children, their parents, and society.
113,114
The
widespread use of intra-articular triamcinolone
hexacetonide joint injections has played an important
part in the prevention of deformities secondary to joint
contractures, and the dose of methotrexate with the
greatest eectiveness has been established in a
randomised trial.
115
Although results from a trial have
shown that leunomide is an eective treatment for
polyarticular juvenile idiopathic arthritis, clinical
experience with this drug in children is scarce.
116,117
The e cacy of several anti-TNF drugs
118120
and of
abatacept
121,122
has been shown in randomised controlled
trials in the polyarticular form of diseasea controlled
trial with tocilizumab (NCT00642460) is taking place
and is due to end in October, 2014. As mentioned above,
anti-interleukin-6 and anti-interleukin-1 treatments
have shown much e cacy in the treatment of systemic
juvenile idiopathic arthritis
1013,123
a disease that has
little sensitivity to anti-TNF drugs. Once the results of
the phase 3 trials that are in progress are reported, these
Figure 3: Imaging of recent-onset juvenile idiopathic arthritis
Delayed gadolinium-enhanced MRI cartilage imaging in a 9-year-old patient,
showing early cartilage degradation in their radiolunate, lunocapitate, and
capitate third metacarpal base joints. T1 mapping shows the concentration of
gadolinium (diethylene triamine pentaacetic acid), which is anionic and distributes
in articular cartilage inversely to the concentration of negatively charged
glycosaminoglycans. Areas with glycosaminoglycan loss have a higher
concentration of gadolinium and a shorter T1 relaxation time (seen in red).
150 433
T1 (ms)
716 1000
Series
www.thelancet.com Vol 377 June 18, 2011 2145
two therapeutic approaches, if their safety is conrmed
with long-term follow-up, will probably substantially
change the treatment of systemic juvenile idiopathic
arthritis and its long-term prognosis.
In uveitis, early diagnosis is essential for the success of
treatment.
1
Topical corticosteroids and mydriatics are
eective in most cases. In patients with resistant disease,
periocular and systemic corticosteroids are indicated. In
moderate-to-severe uveitis, several drugs have been
claimed to be eective, including methotrexate,
ciclosporin, mycophenolate mofetil, and alkylating
agents.
1
However, no controlled trials have been done.
The eectiveness of etanercept is controversial, whereas
iniximab, adalimumab, and abatacept have been
anecdotally reported to be of benet.
124
The eectiveness of biological agents has also changed
physicians expectations; much improved treatment
response is now needed to show e cacy in clinical trials.
Furthermore, denitions of minimum disease activity
125

and remission
126
have been established. Treatment
stategies for patients in clinical remission, including the
withdrawal of treatment, will probably be guided in the
future not only by clinical data, but also by imaging
assessment of residual synovitis and normalisation of
those biomarkers (such as gene expression patterns or
serum proteins), the presence of which might prove to be
associated with a risk of relapse.
44,51,96
Biological agents seem to have a good safety
prole.
121,122,127131
The most consistent experience is with
anti-TNF agents and is congruent with ndings in adults
with the only exception of a possible small increased risk
of lymphoma and other types of cancer in children.
132

However, a clear causal relation cannot be established
because of the concomitant use of immunosuppressive
drugs and the absence of information on the potential
risk of malignant disease when used with or without
methotrexate.
In a population-based cohort study done in Sweden,
133

children diagnosed with juvenile idiopathic arthritis
between 1969 and 2007 did not have an increased risk of
cancer. However, when the analysis was restricted to
children who were diagnosed from 1987 onwards, those
with juvenile idiopathic arthritis were more than twice as
like to have a malignant disease and more than four
times as likely to have a lymphoproliferative malignant
disease than were children without juvenile idiopathic
arthritis. This increased risk could not be explained by
the introduction of biological treatment because the
association was similar in analyses ending in 1999.
However, use of methotrexate for the treatment of
juvenile idiopathic arthritis was rst reported in 1986.
134
Safety is assessed through passive surveillance of
adverse events, which substantially underestimates the
incidence rate of adverse events, or through product-
specic observational registries done by pharmaceutical
companies, which result in competing and duplicate
eorts to gather similar information from small
populations of patients.
135
Future collaboration between
regulatory agencies, industry, and research networks could
provide an opportunity to set up larger and more eective
international pharmacovigilance registries. Such registries
will be implemented by the Paediatric Rheumatology
European Society (PRES) and PRINTO in Europe and by
the PRCSG and the Childhood Arthritis Rheumatology
Research Alliance (CARRA) in North America.
In most randomised controlled trials of juvenile
idiopathic arthritis, the use of the double-blind,
randomised withdrawal study design proposed by
Giannini and Lovell
120
has been very useful. According to
this design, all children are treated with the active drug
and the responders are then randomly allocated to receive
either the active drug or a placebo (double-blinded phase);
patients who have a pre-dened denition of disease
worsening (eg, are) are withdrawn from the double-
blind withdrawal phase and usually unmasked and given
the experimental treatment. An added benet of this
design is that it keeps the time that children are exposed
to placebo to a minimum.
Researchers designing future randomised trials of
treatments for juvenile idiopathic arthritis will face
challenges because of both the heterogeneity of the
disorder and the availability of eective drugs.
136,137
Parallel
trials with an active comparator (the available eective
treatment) could be the design of choice, but would need
a very large population of patients to show a signicant
dierence. If only patients for whom a previous biological
treatment had failed are included, the number of available
individuals will be much reduced. This problem, as with
any rare disease or rare subcategories of common
disorders, will need to be solved with the improvement of
methodologies for randomised controlled trials in small
populations and the identication of sensitive imaging
techniques that can quickly assess the disease-modifying
potential of new drugs, and will take advantage of the
existence of PRCSG and PRINTO.
However, once the e cacy and safety of a class of drugs
(eg, anti-TNF agents) have been established for the
treatment of juvenile idiopathic arthritis, then approval
for use in children of a new drug in that class could need
proof of safety and e cacy in adults only, with
pharmacokinetic and pharmacodynamic dose-nding
studies in a small sample of patients with juvenile
idiopathic arthritis, followed by adequate phase 4
registries to assess safety and eectiveness.
136
Future perspectives
Major advances during the past 5 years have led to a novel
outlook for the care of patients with juvenile idiopathic
arthritis. Thanks to pivotal genetic and molecular-
immunology studies, immune pathogenesis can be
much better linked with clinical phenotypes of disease,
which should led to a revision of the original disease
classication criteria. Moreover, these studies have led to
novel treatment strategies for systemic juvenile idiopathic
Series
2146 www.thelancet.com Vol 377 June 18, 2011
arthritis and the identication of immune biomarkers.
The next challenge will be to combine genetic and
immunological mechanistic studies with new imaging
modalities to better dene subgroups of patients,
individual risk proles, and response to treatment. This
should lead to the next generation of clinical trials that
aim to restore the immune balance in patients with
juvenile idiopathic arthritis while restricting potential
long-term side-eects of treatment.
Contributors
BP, SA, and AM designed the paper. BP and AM wrote the paper. SA
provided critical input and composed gure 1 and gure 2.
Conicts of interest
We declare that we have no conicts of interest.
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