Antibodies against cyclic citrullinated peptide are associated with HLA-DR4 in simplex and multiplex polyarticular-onset juvenile rheumatoid arthritis.

OBJECTIVE: Anti-cyclic citrullinated peptide (anti-CCP) antibodies have been detected in patients with juvenile rheumatoid arthritis (JRA), particularly in those with polyarticular, rheumatoid factor (RF)-positive JRA. Our objectives were to determine whether anti-CCP antibodies are associated with HLA-DR4 in children with polyarticular JRA, whether anti-CCP antibodies are associated with clinical features of disease, and whether affected sibling pairs (ASPs) with JRA are concordant for this antibody. METHODS: Stored serum samples obtained from 230 HLA-typed patients with JRA (77 with polyarticular-onset disease and 153 with pauciarticular- or systemic-onset disease), 100 JRA ASPs, and 688 healthy children were tested for anti-CCP antibodies and RF. RESULTS: Thirteen percent of the patients with polyarticular-onset JRA and 2% of the other JRA patients exhibited anti-CCP antibodies, compared with only 0.6% of the controls. Fifty-seven percent of RF-positive patients with polyarticular-onset JRA had anti-CCP antibodies. HLA-DR4-positive patients with polyarticular-onset JRA were more likely to have anti-CCP antibodies than were those without HLA-DR4 alleles (odds ratio [OR] 5.20, 95% confidence interval [95% CI] 1.30-20.9). Anti-CCP antibodies were associated with polyarticular onset (OR 7.46, 95% CI 1.99-28.0), a polyarticular disease course (OR 9.78, 95% CI 1.25-76.7), and erosive disease (OR 14.3, 95% CI 3.01-67.9). Concordance rates for anti-CCP antibodies among ASPs were statistically significant. CONCLUSION: These data demonstrate increased anti-CCP antibody formation in HLA-DR4-positive patients with polyarticular-onset JRA. The overall prevalence of anti-CCP antibodies in JRA is low, but a substantial proportion of RF-positive patients with polyarticular-onset JRA have these antibodies. Anti-CCP antibodies in JRA are associated with polyarticular onset, a polyarticular course, and erosive disease.

Juvenile rheumatoid arthritis affected sibpairs: extent of clinical phenotype concordance.

OBJECTIVE: To investigate the clinical phenotypes and demographic characteristics of 183 affected sibling pairs (ASPs) with juvenile rheumatoid arthritis (JRA) and to determine whether there are differences between the clinical phenotypes of the ASP cohort compared with patients with sporadic disease and whether there is greater sharing of specific clinical features within versus between sibpairs. METHODS: Details of the JRA Affected Sibpair Registry operations have been described previously. The frequencies of phenotypes in the 2 cohorts were tabulated, summary statistics were determined, and comparisons were made by chi-square test or t-test. Sibling risk, sibling risk ratios (lambda(s)), and odds ratios were calculated to assess familial aggregation of several different clinical manifestations. RESULTS: The most common onset type among the 164 nontwin ASPs was pauciarticular (65% overall). Fifty-three percent of the ASPs were concordant for pauciarticular-onset JRA; 19% were concordant for a polyarticular disease onset. Among subjects with polyarticular-onset disease, significantly more joints were involved at onset in simplex patients than in ASPs (P = 0.008). The difference in age at JRA onset within sibpairs (sibling 1 versus sibling 2) was not significantly different. ASPs developed disease at a mean real-time difference of 5.1 years apart. Familial aggregation was found for tenosynovitis (lambda(s) 29.5), leukocytosis (lambda(s) 25), rheumatoid factor (lambda(s) 11.0), anemia (lambda(s) 1.7), and antinuclear antibodies (lambda(s) 1.3). CONCLUSION: This study confirms the findings of earlier studies showing that a high proportion of ASPs overall show concordance of disease-onset type, except for the subset of patients with systemic disease, and that nontwin ASPs do not develop disease at the same point in real time. We conclude that JRA and its clinical manifestations do not differ substantially between ASPs and the simplex population. The exception is the number of affected joints at JRA onset among patients with polyarticular-onset disease. Familial aggregation of clinical features among ASPs adds strong evidence for a genetic background in this disease.

The -174G allele of the interleukin-6 gene confers susceptibility to systemic arthritis in children: a multicenter study using simplex and multiplex juvenile idiopathic arthritis families.

OBJECTIVE: Levels of interleukin-6 (IL-6) have been shown to correlate with the fever and disease activity of systemic juvenile idiopathic arthritis (JIA). In a previous case-control study, a significant association between the IL-6 -174 nucleotide variant and systemic JIA was noted, and HeLa cell transfection assays show functional differences in levels of transcription of the IL-6 -174 alleles. The present study was undertaken to confirm the previous findings and to assess possible association with variations of the A(n)T(n) tract in the promoter. METHODS: We studied a cohort of JIA families from 3 countries, using transmission disequilibrium testing. Genotyping of the -174 nucleotide variant was done by restriction fragment length polymorphism, heteroduplex analysis, or allelic discrimination. The A(n)T(n) tract at -392 to -373 was typed using DNA sequencing. Statistical analysis was performed using the programs Transmit and EHplus. RESULTS: There was a significant excess transmission of the -174G allele in the systemic JIA families (P = 0.041). The excess transmission was only to systemic JIA patients with age at onset >5 years (P = 0.007). No significant association with the other subtypes was found. No A(n)T(n) alleles or -174/A(n)T(n) haplotypes were significantly associated with systemic JIA. CONCLUSION: This study confirms that the IL-6 -174 nucleotide variant is significantly associated with systemic JIA. The significant excess transmission to patients with age at onset >5 years but not to those with age at onset < or =5 years suggests that there may be genetic heterogeneity between the 2 groups.

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

OBJECTIVE: Juvenile rheumatoid arthritis (JRA) represents a heterogeneous group of disorders with a complex genetic component. A genome scan was performed to detect linkage to JRA in 121 families containing 247 affected children in North America (the JRA Affected Sibpair [ASP] Registry). METHODS: Genotype data collected for HLA-DR and 386 microsatellite markers were subjected to multipoint nonparametric linkage analysis. Following analysis of the entire set of families, additional analyses were performed after a priori stratification by disease onset type, age at onset, disease course, and selected HLA-DRB1 alleles. RESULTS: Linkage of JRA to the HLA region was confirmed (logarithm of odds [LOD] score 2.26). Additional evidence supporting linkage of JRA was observed at 1p36 (D1S214; LOD 1.65), 19p13 (D19S216; LOD 1.72), and 20q13 (D20S100; LOD 1.75). For early-onset polyarticular disease, evidence of linkage was found at chromosome 7q11 (D7S502; LOD 3.47). For pauciarticular disease, evidence supporting linkage was observed on chromosome 19p13 (D19S216; LOD 2.98), the same marker that supported linkage to the "JRA" phenotype. Other regions supporting linkage with JRA disease subtype included 20q13, 4q24, 12q24, and Xp11. Stratification of families based on the presence of the HLA-DR8 allele in affected siblings resulted in significant linkage observed at 2p25 (D2S162/D2S305; LOD 6.0). CONCLUSION: These data support the hypothesis that multiple genes, including at least 1 in the HLA region, influence susceptibility to JRA. These findings for JRA are consistent with findings for other autoimmune diseases and support the notion that common genetic regions contribute to an autoimmune phenotype.