Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population.

Most of the genetic risk for rheumatoid arthritis (RA) is conferred by 'shared epitope' (SE), encoding alleles of HLA-DRB1. Specific North American Native (NAN) populations have RA prevalence rates of 2-5%, representing some of the highest rates estimated worldwide. As many NAN populations also demonstrate a high background frequency of SE, we sought to determine whether other genetic factors contribute to disease risk in this predisposed population. RA patients (n=333) and controls (n=490) from the Cree/Ojibway NAN population in Central Canada were HLA-DRB1 typed and tested for 21 single-nucleotide polymorphisms (SNPs) that have previously been associated with RA, including PTPN22, TRAF1-C5, CTLA4, PADI4, STAT4, FCRL3, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, KIF5A-PIP4K2C, IL2RB, TNFAIP3, IL10-1082G/A and REL. Our findings indicate that SE is prevalent and represents a major genetic risk factor for RA in this population (82% cases versus 68% controls, odds ratio=2.2, 95% confidence interval 1.6-3.1, P<0.001). We also demonstrate that in the presence of SE, the minor allele of MMEL1-TNFRSF14 significantly reduces RA risk in a dominant manner, whereas TRAF1-C5 increases the risk. These findings point to the importance of non-HLA genes in determining RA risk in a population with a high frequency of disease predisposing HLA-DRB1 alleles.

Epidemiology of chronic arthritis in childhood.

This study was performed to review reports of the descriptive epidemiology of chronic arthritis in childhood and to analyze the factors that may explain differences in its reported frequency. Articles were retrieved by searching MEDLINE and EMBASE under the following index terms: juvenile rheumatoid arthritis (JRA), juvenile chronic arthritis (JCA), spondyloarthropathy, epidemiology, prevalence, and incidence. For reports published between 1977 to 1982, the Index Medicus was used. All original articles that provided prevalence or incidence rates, population size, or number of cases, were reviewed and entered into the analysis. Variables analyzed were disease prevalence and incidence. Modifier variables investigated were diagnostic criteria, source population, geographic origin of the report (Europe or North America), duration of the study, and race of the population studied. Diagnostic criteria had no effect on reported prevalence or incidence rates. Prevalence per 100,000 at risk obtained from population studies (132, 95% CI: 119, 145) was significantly higher than values derived from practitioner- (26, 95% CI: 23, 29) or clinic-based studies (12, 95% CI: 10, 15) (P = .02). North American clinic-based studies had higher prevalence values compared with European reports (32, 95% CI: 26, 38 versus 8, 95% CI: 5, 11, P = .009). None of the factors analyzed accounted for the variability in reported incidence rates. An effect of race was detected only in the distribution of patients among onset subsets. Thus, the percentage of patients with pauciarticular JRA was highest in series of North American and European caucasian patients (58, 95% CI: 56, 60) compared with series of East Indian (25, 95% CI: 20, 31), native North American Indian (26, 95% CI: 15, 37), or other races (31, 95% CI: 28, 35) (P = .001). In contrast, the percentage of patients with polyarticular JRA was lowest in the former (27, 95% CI: 25, 28) compared with the other racial groups (East Indian, 61, 95% CI: 55, 66; native North American Indian, 64, 95% CI: 53, 76; other races, 34, 95% CI: 30, 38) (P = .004). Although an effect of source population on reported prevalence was confirmed, the effect of geographic origin suggests that environmental or ethnic differences also may influence the prevalence of chronic arthritis in children. Differences in the percentages of patients with pauciarticular and polyarticular JRA may reflect racial differences in the prevalence of these conditions.

The relationship between ocular and articular disease activity in children with juvenile rheumatoid arthritis and associated uveitis.

The onset patterns and disease courses of children with juvenile rheumatoid arthritis and uveitis were reviewed to establish correlations. Results indicated that although the disease activity of arthritis and uveitis may at times run a parallel course, it is more common for the activities to be independent.

SEA syndrome revisited: a longterm followup of children with a syndrome of seronegative enthesopathy and arthropathy.

Thirty-six of the 39 children originally described with the syndrome of seronegative enthesopathy and arthropathy, followed for a mean of 11 years after symptom onset, were found to have had a widely varied clinical course. Twelve of the 23 patients (52%) who originally did not have a seronegative spondyloarthropathy developed definite (6) or possible (6) seronegative spondyloarthropathies. The development of a seronegative spondyloarthropathy was associated with HLA-B27 (p = 0.0004) and the presence of arthritis (rather than arthralgia only) at the time of the original report (p = 0.05). For patients with arthritis, the development of a seronegative spondyloarthropathy was associated with arthritis onset after 5 years of age (p = 0.01).

Rheumatic diseases in Western Canadian Indian children.

For both genetic and environmental reasons the prevalences and characteristics of the rheumatic diseases affecting North American Indian children might be expected to differ from those of similarly affected non-Indian children. We reviewed 34 Western Canadian Indian children with rheumatic disorders. For comparison a group of Caucasian children with chronic arthritis was also evaluated. The prevalence of clinic attendance by Indian children (.059%) was substantially but not significantly more common than attendance by non-Indian children (.034%). When compared to the seronegative spondyloarthropathies (SSA), juvenile rheumatoid arthritis (JRA) was relatively less common in the Indian population (1.2:1) than in the Caucasian children (5.4:1). Of the children with JRA, polyarticular onset type, positive tests for rheumatoid factor and HLA-AW24 were significantly more common in the Indian population (p less than .05). The characteristics of Indian and of non-Indian children with SSA did not differ significantly. Even though an increased prevalence of HLA-B27 may account for the relative increase of SSA in the Indian population, this study indicates that childhood rheumatic diseases other than B27 associated SSA should be recognized as occurring frequently in Indian children.

Seasonal onset of systemic-onset juvenile rheumatoid arthritis.

OBJECTIVE: This study was undertaken to investigate the recent finding of a seasonal difference in the onset of systemic-onset juvenile rheumatoid arthritis (SoJRA). We hypothesized that a seasonal onset pattern might implicate on infectious agent as a cause of SoJRA. METHODS: The date of onset was collected from the records of all patients with SoJRA from 1980 to 1992 at presentation to pediatric rheumatology clinics across Canada. The onset pattern of SoJRA was then compared with incidence data on viral infections obtained for the same period. RESULTS: Across Canada the onset of SoJRA was constant across the seasons. However, in the Prairie region there was a statistically significant seasonal pattern, with peaks in autumn and early spring. We could find no evidence that viral incidence correlated with disease incidence either throughout Canada or in the Prairie region. CONCLUSIONS: If a seasonal infectious agent causes SoJRA, then it is likely only one of several causes and may act only in certain regions. Future studies should be carried out in those areas where SoJRA does have a seasonal onset pattern.