Age-specific effects of juvenile rheumatoid arthritis-associated HLA alleles

Objective. To define the onset and duration of effect of the HLA alleles th at are associated with disease susceptibility and protection in juvenile rh eumatoid arthritis (JRA) and 2 of its subtypes. Methods. We typed 680 patients with JRA and 254 ethnically matched unrelate d controls for HLA class I and II genes. The frequency of each allele was c alculated for each of the age-at-onset, onset type, and sex categories and plotted against the allele frequency in the control population. Survival an alysis (with onset of disease as the terminating event) was used to calcula te the age by which 50% (S(t)0.5) and 80% (S(t)0.2) of the children with pa rticular alleles and combinations of alleles develop disease. This allele-s pecific survival analysis also allowed for the comparison of the overall su rvival 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 per cent 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 pau ciarticular 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 year s. B27 and DR4 were associated with protection early in life but with incre ased risk later in childhood, with S(t)0.5 values of 7.3 and 6.6 years, res pectively, for pauciarticular JRA and S(t)0.5 values of 10.2 and 10.7 years , respectively, for polyarticular JRA. Sex strongly influenced the age at w hich many of the alleles have their effect. Conclusion. These data define at what age and for how long various HLA alle les 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.