HLA-DR1, DR4, and DRB1 disease related subtypes in rheumatoid arthritis. Association with susceptibility but not severity in a city wide community based study

Objective. To determine the relationship of DR1, DR4, and DR4 subtypes with disease severity in patients with rheumatoid arthritis (RA). Methods. We studied a cohort of 103 Caucasian patients with an onset of disease in 1985, and 6 to 7 years of disease at the time of the study. All rheumatologists in Edmonton participated in the city wide study which included hospital and community based patients with mild and severe disease. HLA status was determined using polymerase chain reaction amplification and amplified fragment length polymorphism typing. Outcome measures included joint counts, radiological scores, and physical functional status. Results. Fifty-six patients (54%) were DR4 positive, (OR = 2.3, 95% CI 1.4-3.6, compared to controls). This association was only statistically significant for seropositive patients (OR = 2.8 in seropositive patients and OR = 1.5 in seronegative patients). A higher risk was observed for DR1/DR4 heterozygotes (OR = 6.8 in seropositive patients and OR = 1.7 in seronegative patients). No significant differences were observed in disease activity, joint counts, radiological scores, or functional status among patients carrying 1, 2 or no disease related alleles, although the prevalence of rheumatoid factor (RF) showed a linear association with allele dose (0, 1, or 2). Conclusion. DR4 and in particular DR1/DR4 heterozygosity were related to susceptibility to RA only in seropositive patients. RF was a better predictor of severity than disease related HLA subtypes. These findings suggest that the effect of these alleles on severity may be related to seropositivity, or that perhaps, seropositive and seronegative RA are genetically distinct entities. The results of our study suggest that in community based settings, which include patients with milder disease, DR1 and DR4 disease related alleles increase susceptibility for RA, but are not clinically useful as predictors of longer term outcome.