Nodular disease in rheumatoid arthritis: Association with cigarette smoking and HLA-DRB1/TNF gene interaction

Objective. To investigate the association of nodular disease in rheumatoid arthritis (RA) with smoking, seropositivity, and polymorphisms at HLA-DRB1 and TNF loci. Methods. Consecutive patients with RA (n = 420) attending a hospital clinic were examined for the presence of subcutaneous nodules. Rheumatoid factor (RF) status and HLA-DRB1 genotype were determined on every patient, and their smoking history was recorded. TNFa microsatellite polymorphisms were examined in a subgroup of 144 patients. The relationships between smoking, RF status, HLA-DRB1 genotype, TNFa microsatellite polymorphism, and the presence of nodules were examined using chi-square tests and logistic regression analyses. Results. Current smokers were more likely to have nodular disease than those who had never smoked (OR 1.8, 95% CI 1.0-2.9). An association was also found between RF positivity and nodular disease (OR 2.2, 95% CI 1.2-3.8) that remained significant after correction for current smoking. A combination of current smoking and seropositivity increased the risk of nodular disease (OR 3.9, 95% CI 1.7-9.1). Analysis of HLA-DRB1 genotypes in this RA population revealed that only DRBI*0401 homozygotes were associated with nodular disease, and that this was independent of the influence of smoking and seropositivity. Individual TNFa microsatellite alleles were not associated with the presence of nodules, but an interactive effect was found between the TNF a6 allele and homozygosity for DRB1*040 1. Conclusion. Our data indicate that nodular disease in RA is independently associated with current cigarette smoking, seropositivity, and homozygosity for HLA-DRB1*0401. The latter association involves a possible interaction with the TNF a6 microsatellite allele.