Elsevier

The Lancet

Volume 377, Issue 9783, 18–24 June 2011, Pages 2138-2149
The Lancet

Series
Juvenile idiopathic arthritis

https://doi.org/10.1016/S0140-6736(11)60244-4Get rights and content

Summary

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 classification to new treatments. Gene expression profiling studies have identified different immune mechanisms in distinct subtypes of the disease, and can help to redefine disease classification criteria. Moreover, immunological studies have shown that systemic juvenile idiopathic arthritis is an acquired autoinflammatory disease, and have led to successful studies of both interleukin-1 and interleukin-6 blockade. In other forms of the disease, synovial inflammation is the consequence of a disturbed balance between proinflammatory effector cells (such as T-helper-17 cells), and anti-inflammatory regulatory cells (such as FOXP3-positive regulatory T cells). Moreover, specific soluble biomarkers (S100 proteins) can guide individual treatment. Altogether these new developments in genetics, immunology, and imaging are instrumental to better define, 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 2–20 cases per 100 000 population and a prevalence of 16–150 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.

Section snippets

Clinical manifestation and classification

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 findings have improved the understanding of the different forms of chronic childhood arthritis.4, 5, 6 Although some categories identify definite disease entities, others still include heterogeneous disorders.7

Perspectives for a new classification

To improve our understanding of the cause and development of the various forms of childhood chronic arthritis and find more suitable treatments, the identification 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 identified, which seems likely in view of the heterogeneity within the

Cause and pathogenesis

One of the most intriguing questions in the study of human autoimmune diseases is what determines the phenotype and organ specificity 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.28, 29, 30 Despite these associations, the immune pathogenesis underlying the link between arthritis and uveitis is

Imaging

Imaging has not been used to its full potential in childhood arthritis.97, 98, 99 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 ossification, and bone growth anomalies induced by the disease. Indeed, for conventional radiology, scoring systems specific for juvenile idiopathic arthritis has been devised.100, 101, 102

As well as being

Treatment

The management of juvenile idiopathic arthritis is based on a combination of pharmacological interventions, 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

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 classification criteria. Moreover, these studies have led to novel treatment strategies for systemic juvenile idiopathic arthritis and the identification of immune

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,

References (137)

  • A Ravelli et al.

    Juvenile idiopathic arthritis

    Lancet

    (2007)
  • A Martini et al.

    Juvenile idiopathic arthritis: state of the art and future perspectives

    Ann Rheum Dis

    (2010)
  • RE Petty et al.

    International league of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001

    J Rheumatol

    (2004)
  • BJ Prakken et al.

    Using biology of disease to understand and guide therapy of JIA

    Best Pract Res Clin Rheumatol

    (2009)
  • K Nistala et al.

    Th17 and regulatory T cells: rebalancing pro- and anti-inflammatory forces in autoimmune arthritis

    Rheumatology (Oxford)

    (2009)
  • M Frosch et al.

    New insights in systemic juvenile idiopathic arthritis—from pathophysiology to treatment

    Rheumatology (Oxford)

    (2008)
  • S Thompson et al.

    Heterogeneity in JIA, impact of molecular profiling based on DNA polymorphism and gene expression patterns

    Arthritis Rheum

    (2010)
  • SL Masters et al.

    Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*)

    Annu Rev Immunol

    (2009)
  • F De Benedetti et al.

    Is systemic juvenile rheumatoid arthritis an interleukin 6 mediated disease?

    J Rheumatol

    (1998)
  • S Yokota et al.

    Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial

    Lancet

    (2008)
  • F De Benedetti et al.

    Efficacy and safety of tocilizumab in patients with systemic juvenile idiopathic arthritis (sJIA): 12-week data from the phase 3 tender trial

    Ann Rheum Dis

    (2010)
  • V Pascual et al.

    Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade

    J Exp Med

    (2005)
  • M Gattorno et al.

    The pattern of response to anti-interleukin-1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis

    Arthritis Rheum

    (2008)
  • M van Rossum et al.

    Anti-cyclic citrullinated peptide (anti-CCP) antibodies in children with juvenile idiopathic arthritis

    J Rheumatol

    (2003)
  • RA Colbert

    Classification of juvenile spondyloarthritis: enthesitis-related arthritis and beyond

    Nat Rev Rheumatol

    (2010)
  • A Martini

    Are the number of joints involved or the presence of psoriasis still useful tools to identify homogeneous disease entities in juvenile idiopathic arthritis?

    J Rheumatol

    (2003)
  • A Ravelli et al.

    Patients with antinuclear antibody-positive juvenile idiopathic arthritis constitute a homogeneous subgroup irrespective of the course of joint disease

    Arthritis Rheum

    (2005)
  • A Ravelli et al.

    Antinuclear antibody positive patients should be grouped as a separate category in the classification of juvenile idiopathic arthritis

    Arthritis Rheum

    (2011)
  • TR Southwood et al.

    Psoriatic arthritis in children

    Arthritis Rheum

    (1989)
  • ML Stoll et al.

    Comparison of Vancouver and International League of Associations for rheumatology classification criteria for juvenile psoriatic arthritis

    Arthritis Rheum

    (2008)
  • ML Stoll et al.

    Patients with juvenile psoriatic arthritis comprise two distinct populations

    Arthritis Rheum

    (2006)
  • TA Griffin et al.

    Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets

    Arthritis Rheum

    (2009)
  • MG Barnes et al.

    Biological similarities based on age at onset in oligoarticular and polyarticular subtypes of juvenile idiopathic arthritis

    Arthritis Rheum

    (2010)
  • A Gregorio et al.

    Lymphoid neogenesis in juvenile idiopathic arthritis correlates with ANA positivity and plasma cells infiltration

    Rheumatology (Oxford)

    (2007)
  • JA Hollenbach et al.

    Juvenile idiopathic arthritis and HLA class I and class II interactions and age-at-onset effects

    Arthritis Rheum

    (2010)
  • S Magni-Manzoni et al.

    Comparison of clinical versus ultrasound-determined synovitis in juvenile idiopathic arthritis

    Arthritis Rheum

    (2009)
  • ME Rooney et al.

    Ankle disease in juvenile idiopathic arthritis: ultrasound findings in clinically swollen ankles

    J Rheumatol

    (2009)
  • RK Saurenmann et al.

    Risk factors for development of uveitis differ between girls and boys with juvenile idiopathic arthritis

    Arthritis Rheum

    (2010)
  • RK Saurenmann et al.

    Risk of new-onset uveitis in patients with juvenile idiopathic arthritis treated with anti-TNFalpha agents

    J Pediatr

    (2006)
  • RK Saurenmann et al.

    Prevalence, risk factors, and outcome of uveitis in juvenile idiopathic arthritis: a long-term followup study

    Arthritis Rheum

    (2007)
  • P Woo et al.

    An overview of genetics of paediatric rheumatic diseases

    Best Pract Res Clin Rheumatol

    (2009)
  • DN Glass et al.

    Juvenile rheumatoid arthritis as a complex genetic trait

    Arthritis Rheum

    (1999)
  • S Prahalad et al.

    Twins concordant for juvenile rheumatoid arthritis

    Arthritis Rheum

    (2000)
  • S Prahalad et al.

    Juvenile rheumatoid arthritis: linkage to HLA demonstrated by allele sharing in affected sibpairs

    Arthritis Rheum

    (2000)
  • S Prahalad et al.

    A comprehensive review of the genetics of juvenile idiopathic arthritis

    Pediatr Rheumatol Online J

    (2008)
  • S Prahalad

    Genetics of juvenile idiopathic arthritis: an update

    Curr Opin Rheumatol

    (2004)
  • P Rosen et al.

    Non-HLA gene polymorphisms in juvenile rheumatoid arthritis

    Clin Exp Rheumatol

    (2003)
  • SD Thompson et al.

    A genome-wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage

    Arthritis Rheum

    (2004)
  • MS Fife et al.

    Novel IL10 gene family associations with systemic juvenile idiopathic arthritis

    Arthritis Res Ther

    (2006)
  • EM Ogilvie et al.

    Specific gene expression profiles in systemic juvenile idiopathic arthritis

    Arthritis Rheum

    (2007)
  • MG Barnes et al.

    Subtype-specific peripheral blood gene expression profiles in recent-onset juvenile idiopathic arthritis

    Arthritis Rheum

    (2009)
  • PJ Hunter et al.

    Biologic predictors of extension of oligoarticular juvenile idiopathic arthritis as determined from synovial fluid cellular composition and gene expression

    Arthritis Rheum

    (2010)
  • N Fall et al.

    Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome

    Arthritis Rheum

    (2007)
  • N Knowlton et al.

    The meaning of clinical remission in polyarticular juvenile idiopathic arthritis: gene expression profiling in peripheral blood mononuclear cells identifies distinct disease states

    Arthritis Rheum

    (2009)
  • B Andersson Gare

    Juvenile arthritis–who gets it, where and when? A review of current data on incidence and prevalence

    Clin Exp Rheumatol

    (1999)
  • E Zonneveld-Huijssoon et al.

    Safety and efficacy of meningococcal c vaccination in juvenile idiopathic arthritis

    Arthritis Rheum

    (2007)
  • MW Heijstek et al.

    Safety of measles, mumps and rubella vaccination in juvenile idiopathic arthritis

    Ann Rheum Dis

    (2007)
  • Ronaghy A, de Jager W, Zonneveld-Huijssoon E, et al. Vaccination leads to an aberrant FOXP3 T cell response in...
  • LR Wedderburn et al.

    Divergence in the degree of clonal expansions in inflammatory T cell subpopulations mirrors HLA-associated risk alleles in genetically and clinically distinct subtypes of childhood arthritis

    Int Immunol

    (2001)
  • LR Wedderburn et al.

    Selective recruitment of polarized T cells expressing CCR5 and CXCR3 to the inflamed joints of children with juvenile idiopathic arthritis

    Arthritis Rheum

    (2000)

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