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Smoking and HLA Genes in Rheumatoid Arthritis

An analysis from the Swedish EIRA incident rheumatoid arthritis cohort study shows that smoking and HLA-DRB1 exert differential effects on serologically defined rheumatoid arthritis (RA) subsets, but that the strongest influence was seen in double positive (CCP+, RF+) individuals.

These investigators have previously shown that the strong interaction between smoking and HLA-DRB1 shared epitope has been confined to risk of seropositive RA. In this study, they further examined these risks based on RF and anti‐citrulline protein antibodies status.

This cohort study compared incident cases of RA (3,645) and matched controls (5,883) based on the presence or absence of RF and anti-CCP2 antibodies. They assessed the risk for RA using subgroups based on seropositivity, smoking, and the shared epitope.

Key findings showed the highest risk in:

  • Double positive (RF+/anti-CCP2+) patients were most affected as smoking and HLA-DRB1 shared epitope conferred independent disease risks, and there was a strong interaction between the two risk factors
  • RF-/anti-CCP2+ subset: HLA-DRB1 shared epitope conferred an increased risk of RA whereas the independent influence of smoking was less, but there was a significant interaction between HLA-DRB1 and smoking
  • In the RF+/anti-CCP2- subset, there was a smaller increased risk in smokers, only marginally affected by HLA-DRB1 shared epitope
  • Double negative (RF-/anti-CCP2-) subset, neither smoking nor HLA-DRB1SE conferred increased risk of disease

These findings indicate weighted effects of smoking and HLA-DRB1, especially on seropositive RA patients.

Jack Cush, MD, is the director of clinical rheumatology at the Baylor Research Institute and a professor of medicine and rheumatology at Baylor University Medical Center in Dallas. He is the executive editor of A version of this article first appeared on RheumNow, a news, information, and commentary site dedicated to the field of rheumatology. Register to receive their free rheumatology newsletter.