Heterogeneity between men and women in the influence of the HLA-DRB1 shared epitope on the clinical expression of rheumatoid arthritis

Objective. To test the hypothesis that the influence of the HLA-DRB1 shared epitope (SE) on the clinical manifestations of rheumatoid arthritis (RA) differs between men and women. Methods. We assessed 777 consecutive RA patients for age at disease onset, articular manifestations, subcutaneous nodules, laboratory and radiographic findings, and treatment received. We typed HLA-DRB1 alleles by polymerase chain reaction-sequence-specific primer amplification and categorized the number of SE-containing alleles. We used regression models to adjust comparisons between the sexes for age and clustering by recruitment center, and included SE × sex interaction terms to look for heterogeneity between men and women in the effect of the SE. Results. Among the 777 RA patients, 548 (71%) were women. Men and women differed significantly in the adjusted frequency of SE positivity (women 71.4% versus men 78.4%; P ≤ 0.001). The SE was associated with a younger age at symptom onset and RA diagnosis among men, but not among women. The SE likewise had a significant adverse effect on joint tenderness, swelling, and deformity among men only. The SE was associated with a higher erythrocyte sedimentation rate in women and more frequent positivity for rheumatoid factor among both men and women. Conclusion. There is heterogeneity between men and women in the effect of the SE on RA susceptibility and clinical expression. Further research is needed to understand the mechanism of this heterogeneity.