Abstract

ObjectiveJuvenile idiopathic arthritis (JIA) comprises 7 heterogeneous categories of chronic childhood arthritides. Approximately 5% of children with JIA have rheumatoid factor (RF)–positive arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF‐positive polyarticular JIA with those of RA and selected other JIA categories, to more fully understand the pathophysiologic relationships of inflammatory arthropathies.MethodsPatients with RF‐positive polyarticular JIA (n = 340) and controls (n = 14,412) were genotyped using the Immunochip array. Single‐nucleotide polymorphisms were tested for association using a logistic regression model adjusting for admixture proportions. We calculated weighted genetic risk scores (wGRS) of reported RA and JIA risk loci, and we compared the ability of these wGRS to predict RF‐positive polyarticular JIA.ResultsAs expected, the HLA region was strongly associated with RF‐positive polyarticular JIA (P = 5.51 × 10−31). Nineteen of 44 RA risk loci and 6 of 27 oligoarticular/RF‐negative polyarticular JIA risk loci were associated with RF‐positive polyarticular JIA (P < 0.05). The RA wGRS predicted RF‐positive polyarticular JIA (area under the curve [AUC] 0.71) better than did the oligoarticular/RF‐negative polyarticular JIA wGRS (AUC 0.59). The genetic profile of patients with RF‐positive polyarticular JIA was more similar to that of RA patients with age at onset 16–29 years than to that of RA patients with age at onset ≥70 years.Conclusion RF‐positive polyarticular JIA is genetically more similar to adult RA than to the most common JIA categories and thus appears to be a childhood‐onset presentation of autoantibody‐positive RA. These findings suggest common disease mechanisms, which could lead to novel therapeutic targets and shared treatment strategies.

Highlights

  • Juvenile idiopathic arthritis (JIA) is a heterogeneous collection of chronic arthropathies with distinct clinical and laboratory features, but all manifest with arthritis in one or more joints and present before the 16th birthday

  • About 5% of children with JIA demonstrate the presence of rheumatoid factor (RF) and antibodies directed against citrullinated peptides, such as anti-cyclic citrullinated peptide (CCP) antibodies, characteristic biomarkers observed in adults with seropositive rheumatoid arthritis (RA)

  • We provide evidence that this uncommon category of JIA, which is phenotypically similar to adult seropositive RA, is genetically more similar to adult RA than to the most common JIA categories, which lack the characteristic biomarkers (RF and anti-CCP)

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Summary

Introduction

Juvenile idiopathic arthritis (JIA) is a heterogeneous collection of chronic arthropathies with distinct clinical and laboratory features, but all manifest with arthritis in one or more joints and present before the 16th birthday. About 5% of children with JIA demonstrate the presence of RF and antibodies directed against citrullinated peptides, such as anti-cyclic citrullinated peptide (CCP) antibodies, characteristic biomarkers observed in adults with seropositive RA These children and young people tend to present at a later age-of-onset compared to oligoarticular/RF-negative polyarticular JIA, and often tend to have erosive disease with worse long-term outcomes. In contrast to the robust genetic studies that include large cohorts in RA and oligoarticular/RF-negative polyarticular JIA, studies of children with RF-positive polyarticular JIA have been limited to small-scale candidate gene studies. These include investigations of association with the shared epitope encoding HLA-DRB1 alleles as well as several candidate loci associated with RA (5;6). This may provide a greater understanding of the genetic architecture of RF-positive polyarticular JIA

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