Protection against severe disease is conferred by DERAA-bearing HLA-DRB1 alleles among HLA-DQ3 and HLA-DQ5 positive rheumatoid arthritis patients

Experimental studies in transgenic mice have suggested that HLA-DQ predisposes to rheumatoid arthritis (RA), but could also modulate disease severity by presenting peptides derived from self-DR molecules. In particular, a short amino acid sequence, 70DERAA 74, in the third hypervariable region of HLA-DRB1 confers protection for the disease, while particular HLA-DQ [DQB1∗0501/DQA1∗01 (DQ5) and DQB1∗03/DQA1∗03 (DQ3)] molecules predispose to the disease. We have therefore analyzed the allelic distribution of HLA-DRB1, DQA1, and DQB1 and the presence of rheumatoid factor and nodules among 199 German RA patients and 196 healthy controls. Our results show that HLA-DQB1∗03/DQA1∗03 (or DRB1∗04) predisposes to RA more than HLA-DQB1∗0501/DQA1∗01 ( i.e., DRB1∗01 and DRB1∗10). Homozygosity for DQ3 confers the strongest genetic risk for RA (OR = 19.79 compared to OR = 10.05 for two doses of shared epitope (SE) positive HLA-DRB1 alleles). Furthermore, patients carrying both predisposing DQ and 70DERAA 74-positive HLA-DRB1 alleles are more often rheumatoid factor (RF) negative than patients carrying predisposing DQ alleles alone. Only one out of 14 patients (7%) with a protective combination (DQ3/ 70DERAA 74 and DQ5/ 70DERAA 74) had rheumatoid nodules compared to 67 out of 144 patients (46.5%) with predisposing DQ alleles alone (OR = 0.12, 95% CI: 0.02–0.72, p = 0.004). These results demonstrate a protective role of 70DERAA 74-positive DRB1 alleles against disease severity among RA patients.