Smoking, HLA-genes and serology in rheumatoid arthritis; complex relationships investigated in the Swedish EIRA case-control study.

OBJECTIVES: Smoking is associated with increased risk for subsets of RA defined by the presence of anti-citrulline protein antibodies (ACPA) and rheumatoid factors (RF) and an interaction between smoking and HLA-DRB1 SE has been confined to risk of seropositive RA. We aimed to investigate the interplay between smoking and HLA-DRB1 SE with regard to risk of different RA subsets, based on RF and ACPA status.

METHODS: Incident cases of RA (3645 cases, 5883 matched controls) were divided into four subgroups based on the presence or absence of RF and anti-CCP2 antibodies. The influence of smoking on risk for disease was determined for each RA subgroup, by calculating odds ratios with 95% confidence intervals using logistic regression models. The potential interaction between smoking and HLA-DRB1 SE genes was evaluated by calculating the attributable proportion due to interaction.

RESULTS: In the RF+/anti-CCP2+ subset, both smoking and HLA-DRB1 SE conferred independent disease risks, and there was a strong interaction between the two risk factors. In the RF-/anti-CCP2+ subset, HLA-DRB1 SE conferred an increased risk of RA whereas the independent influence of smoking was limited. However, there was a significant interaction between HLA-DRB1 and smoking. In the RF+/anti-CCP2- subset, there was an increased risk in smokers, which was only marginally affected by presence of HLA-DRB1 SE and no interaction was observed. In the RF-/anti-CCP2- subset, neither smoking nor HLA-DRB1SE conferred increased risk of disease.

CONCLUSIONS: Our findings demonstrate different effects of smoking and HLA-DRB1 in the four serologically defined RA subsets. This article is protected by copyright. All rights reserved.