Aetiology

The exact aetiology is unknown. JIA is thought to be an autoimmune disorder, initiated and sustained by environmental factors in genetically susceptible individuals.[12]

However, direct and indirect evidence points to the role of aberrant immune responses, suggesting that JIA is an autoimmune disorder.

Monozygotic twin concordance is 25% to 40%.[13][14] The prevalence of JIA probands among siblings is 15 to 30 times higher than the population prevalence.[14][15][16] Affected sibling pairs have a high concordance of onset age and subtype, which also supports theories of genetic predispositions.[17][18] There is no association between birth order and JIA.[19]

In one study of 110 families of JIA probands, 74% had at least one relative with autoimmunity compared with only 33% of families of control probands.[20] First- and second-degree relatives of children with JIA have a threefold increase in the prevalence of autoimmunity, particularly autoimmune thyroid disease.[20] This increase appears to be more pronounced in female relatives of mothers compared with that of fathers.[21]

Polymorphisms in the genes encoding human leukocyte antigens have been associated with different JIA subtypes.[12] In the class I human leukocyte antigen (HLA) region, HLA A2 is associated with early-onset JIA.[22][23] HLA B27 allele is associated with enthesitis-related JIA.[24] Oligoarticular JIA is associated with alleles HLA DRB1*01, DRB1*08, DRB1*11, DRB1*13, DPB1*02, and DQB1*04.[22][23][25][26][27][28] Alleles HLA DRB1*04 and DRB1*07 appear to be protective against oligoarticular JIA.[23][28] Polyarticular rheumatoid factor (RF)-negative JIA is associated with alleles DRB1*08 and DPB1*03.[27][28] Polyarticular RF-positive JIA, which is phenotypically similar to adult rheumatoid arthritis, is associated with alleles DRB1*04, DQA1*03, and DQB1*03.[27][28] Fewer confirmed associations between HLA polymorphisms and psoriatic arthritis or systemic-onset juvenile idiopathic arthritis have been reported.

Variants in the genes encoding PTPN22, TNFA, MIF have also been shown to be associated with JIA.[12]

Environmental factors that may influence JIA development include infection in genetically susceptible individuals (no specific infectious agent has been conclusively identified), exposure to antibiotics in childhood, and maternal smoking during pregnancy (one study suggested an increased risk of inflammatory polyarthritis in female offspring, but this has not been confirmed by other studies).[29][30][31]

Pathophysiology

Chronic inflammation of the synovium (manifested by accumulation of synovial fluid and thickening of the synovial lining) is common to all JIA subtypes.

Synovial tissue contains various inflammatory cells including neutrophils, plasma cells, dendritic cells, and a high proportion of activated T-cells.[32][33][34] Recruitment of pro-inflammatory cells into the synovium is believed to be mediated by chemokines that selectively attract type 1 helper T cells. This is characterised by the production of pro-inflammatory cytokines such as interleukin (IL)-2, interferon-gamma, and tumour necrosis factor (TNF)-alpha.[35][36][37] Several studies have demonstrated that Th1 cytokines also predominate in the synovial tissue and synovial fluid of children with JIA.[38][39][40][41] Pro-inflammatory cytokines, including IL-1beta, IL-6, TNF-alpha, IL-2R, IL-8, and sCD154, are significantly elevated in sera of affected children.[42] These observations support the use of biological agents directed against TNF-alpha, IL-1, and IL-6 to treat JIA. IL-17 is an inducer of a potent pro-inflammatory cytokine cascade and of the cytokine RANKL. RANKL is present in elevated amounts in the synovium of children with JIA and has been associated with bone resorption and cartilage damage.[43][44][45]

Classification

International League of Associations for Rheumatology (ILAR) classification of juvenile idiopathic arthritis[1]

Seven subtypes are recognised, some of which share clinical and pathological features with other chronic autoimmune disorders:

  • Systemic arthritis

  • Oligoarthritis

  • Polyarthritis (RF-negative)

  • Polyarthritis (RF-positive)

  • Psoriatic arthritis

  • Enthesitis-related arthritis

  • Undifferentiated arthritis.

American College of Rheumatology criteria for juvenile rheumatoid arthritis[2]

  • Pauciarticular arthritis

  • Polyarticular arthritis

  • Systemic-onset arthritis.

The European League Against Rheumatism criteria for juvenile chronic arthritis[3]

  • Systemic arthritis

  • Polyarticular arthritis

  • Juvenile rheumatoid arthritis

  • Pauciarticular arthritis

  • Juvenile ankylosing spondylitis

  • Juvenile psoriatic arthritis.

The Pediatric Rheumatology International Trials Organization proposed classification[4]

This classification is proposed as a successor to the ILAR classification.

  • A. Systemic JIA

  • B. RF-positive JIA

  • C. Enthesitis/spondylitis-related JIA

  • D. Early-onset antinuclear antibody-positive JIA

  • E. Other JIA

  • F. Unclassified JIA

Use of this content is subject to our disclaimer