Lack of association of the HLA–DRB1 shared epitope with rheumatoid nodules: An individual patient data meta-analysis of 3,272 Caucasian patients with rheumatoid arthritis

Objective The objective of this individual patient data (IPD) meta-analysis was to examine the relationship of rheumatoid nodules to the HLA–DRB1 shared epitope (SE) and to individual SE genotypes. Methods English-language studies that enrolled adult non-Hispanic Caucasian patients with rheumatoid arthritis (RA) were identified by searches of Medline and Embase, and by manual searches of medical journals. All authors were contacted for IPD. Metaanalysis was performed to assess the association of SE presence, dose, and genotype with rheumatoid nodules. Meta-analyses adjusted for disease duration and cumulative meta-analyses were also performed to assess the influence of RA duration and year of study publication on the results. Results A total of 24 studies and 3,272 patients were available for analysis. IPD were obtained for 22 of the studies. There was a nonsignificant association between the presence of the SE (i.e., 1 or 2 alleles versus 0 alleles) and rheumatoid nodules (summary odds ratio [OR] 1.3, 95% confidence interval [95% CI] 0.97–1.6). Analysis by SE genotype, however, demonstrated a weak relationship with inheritance of a single DRB1*0401 SE allele (OR 1.4, 95% CI 1.1–1.8). No other genotypes achieved statistical significance in the adjusted or unadjusted analyses. Conclusion The presence of the HLA–DRB1 SE does not appear to significantly increase the risk of rheumatoid nodules among Caucasian patients with RA. Analysis by DRB1 SE genotype was uninformative, suggesting only a potential (and at most modest) role of the DRB1*0401 SE allele. Results from this IPD meta-analysis implicate other genetic, stochastic, and/or environmental factors in the susceptibility to rheumatoid nodules.