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Objective: To define the onset and duration of effect of the HLA alleles that are associated with disease susceptibility and protection in juvenile rheumatoid arthritis (JRA) and 2 of its subtypes., Methods: We typed 680 patients with JRA and 254 ethnically matched unrelated controls for HLA class I and II genes. The frequency of each allele was calculated for each of the age-at-onset, onset type, and sex categories and plotted against the allele frequency in the control population. Survival analysis (with onset of disease as the terminating event) was used to calculate the age by which 50% (St0.5) and 80% (St0.2) of the children with particular alleles and combinations of alleles develop disease. This allele-specific survival analysis also allowed for the comparison of the overall survival functions for the various JRA subtype and sex categories., Results: Certain alleles are strongly associated with early susceptibility to pauciarticular JRA, including HLA-A2, DR8, DR5, and DPB1*0201. Fifty percent of the children carrying at least 1 of these alleles had disease onset prior to their third birthday. Among children who carried HLA-A2 and any 2 HLA-DR alleles (DR3, DR5, DR6, or DR8), the median age at the onset of pauciarticular disease was 2.7 years. Combinations of A2 and DPB1*0201 and one DR allele narrowed the window further to a median age at onset of 2.4 years. B27 and DR4 were associated with protection early in life but with increased risk later in childhood, with St0.5 values of 7.3 and 6.6 years, respectively, for pauciarticular JRA and St0.5 values of 10.2 and 10.7 years, respectively, for polyarticular JRA. Sex strongly influenced the age at which many of the alleles have their effect., Conclusion: These data define at what age and for how long various HLA alleles influence susceptibility and protection (window-of-effect) in patients with JRA. In addition, these data establish more clearly the boundaries of ages-at-onset for 2 of the subtypes of the disease.

Objective: To determine if HLA class I and II alleles previously found to be associated with (or protective against) pauciarticular-onset juvenile rheumatoid arthritis (pauci-onset JRA) in population-association studies are transmitted from heterozygous parents to an extent different from the expected 50%., Methods: One hundred one Caucasian North American families that had a child with pauci-onset JRA and at least 1 parent who was heterozygous for the allele of interest were available for analysis. Both biologic parents and all children (affected and unaffected) were typed for HLA class I and II alleles. The transmission disequilibrium test (TDT) was used to determine if affected offspring received the disease-associated (or protective) allele more (or less) frequently than its alternate allele. In families in which an unaffected sibling was available, the unmatched chi-square test was used to determine if a meiotic segregation distortion bias existed., Results: HLA class I alleles A2, B27, and B35 showed a significantly higher than expected frequency of transmission to affected offspring, as did class II alleles DR5 and DR8. HLA-DR4 was found to be transmitted significantly less frequently than expected to affected, but not unaffected, offspring. All alleles that showed an excess transmission to affected offspring were transmitted to unaffected offspring at expected rates. When the data were stratified by age and sex, the likelihood of transmission of some of the alleles was strongly influenced by these variables. For example, excess transmission of HLA-DR5 was found exclusively in female patients who were younger at the time of disease onset., Conclusion: Results from these family-based studies rule out the possibility that HLA disease associations found in earlier studies were a result of population stratification and establish linkage and association between the major histocompatibility complex and pauci-onset JRA.

Alpha HLA-DR4 extended haplotypes have been established by family studies in children and adults with chronic arthritis, the children having polyarticular juvenile rheumatoid arthritis and the adults rheumatoid arthritis. These diseases are probably the same disorder presenting at different ages. The results demonstrate age-related differences in the frequency of HLA-DR4 extended haplotypes between the two groups of patients. The childhood onset was associated with the presence of the HLA-B44, SC30, DR4 extended haplotype, whereas the adult form was more strongly associated with the HLA-Bw62, SC33, DR4 haplotype. These results suggest that differences in the age at onset are influenced by the MHC in addition to the presence of the HLA DR4 gene itself.

Two genetic markers, HLA-Bw35 and HLA-B8, are found to be associated with "febrile" or "systemic" onset juvenile rheumatoid arthritis (JRA). Evidence is presented that JRA patients are probably heterogeneous with respect to these antigens.

Recent immunogenetic studies of JRA patients have both helped to clarify subdivision into distinctive subtypes and identified those subtypes which may be related to adult rheumatic disease. Despite the variability of HLA associations from different geographic sources, a consensus appears to be emerging as to the most important associations. In addition to the HLA-DR locus, distinct associations with the HLA-DP and HLA-DQ loci have been described. Family studies have suggested an increased risk with certain haplotypes, particularly in the EOPA JRA population. Although inheritance patterns remain to be defined, recent studies with monoclonal antibodies, alloreactive T cell clones, and DNA have identified the existence of specific epitopes encoded by a variety of Ia molecules which may be more directly related to disease susceptibility. The concept of an epitope dose effect is put forward to account for the variable HLA association with disease, particularly with regard to EOPA JRA. Further developments in the definition of micropolymorphisms of Ia molecules at the genomic level as well as the possible involvement of other genetic loci, in particular T cell receptor variable gene products, should help clarify our understanding of the role of genetic factors in the aetiology of JRA. The studies of the last two decades indicate that inferences made by Carter (1969) on the 'polygenic, weakly penetrant genetic effect' in autoimmune disease are indeed applicable to JRA.

Analysis of sex ratio in 301 siblings of 150 patients with early-onset pauciarticular juvenile rheumatoid arthritis revealed a male-to-female ratio of 1:2.00 in sibships with an HLA-B44+ proband, compared with a ratio of 1:1.05 in other sibships (G2 = 6.07, df = 1, p = 0.014). The siblings had a sex ratio of 1:0.8, when the HLA-B44 antigen was present in either parent but not transmitted to the proband. The capacity to distort the sex ratio was limited therefore to disease-associated HLA-B44 haplotypes.

The following four points are discussed in this study: (1) Human leukocyte antigen (HLA) genes are associated with all groups of juvenile rheumatoid arthritis patients to varying degrees. (2) These HLA associations are similar to those of some adult inflammatory arthropathies (rheumatoid arthritis and ankylosing spondylitis), but distinct in others. (3) Predisposition commonly involves a contribution from both of a subject's HLA haplotypes. (4) Unusual immunogenetic aspects include a HLA-DP association, independent of linkage disequilibrium with other class II genes, and a HLA-associated mechanism increasing the relative proportion of girls in the involved sibships.

Fifty-nine patients with HLA-B27 positive ankylosing spondylitis were HLA genotyped to look for immunogenetic differences between patients with associated peripheral arthritis and those with disease limited to the axial skeleton. An association was found between the peripheral arthropathy and 2 antigens, HLA-A11 and HLA-DR7 at the p less than 0.05 level. Complementation between these 2 alleles and HLA-B27 occurred in both the cis and trans positions. Four patients with peripheral arthritis had a rare HLA-B27 haplotype (HLA-B27, HLA-DR7) which was not found in the group with axial disease alone.