Complex Relationships of Smoking, HLA-DRB1 Genes, and Serologic Profiles in Patients With Early Rheumatoid Arthritis: Update From a Swedish Population-Based Case-Control Study

Arthritis Rheumatol. 2019 Sep;71(9):1504-1511. doi: 10.1002/art.40852. Epub 2019 Jul 24.


Objective: Smoking is associated with an increased risk of rheumatoid arthritis (RA) in subsets of patients defined according to the presence or absence of anti-citrullinated protein antibodies (ACPAs) and rheumatoid factors (RFs). Moreover, an interaction between smoking and the HLA-DRB1 shared epitope (SE) has been demonstrated to be a risk factor for seropositive RA. The aim of this study was to investigate the interplay between smoking and the HLA-DRB1 SE with regard to risk of RA in different patient subsets based on ACPA and RF status.

Methods: Incident cases of RA (3,645 cases, 5,883 matched controls) were divided into 4 subgroups based on the presence or absence of RF and anti-cyclic citrullinated peptide 2 (anti-CCP2) antibodies. The influence of smoking on the risk of disease was determined in each RA subgroup, using logistic regression models with calculation of odds ratios and 95% confidence intervals (95% CIs). The potential interaction between smoking and HLA-DRB1 SE genes was evaluated by calculating the attributable proportion due to interaction (AP).

Results: In the RF+/anti-CCP2+ subset of RA patients, both smoking and the presence of the HLA-DRB1 SE conferred independent disease risks, and there was a strong interaction between the 2 risk factors (AP 0.4, 95% CI 0.3, 0.5). In the RF-/anti-CCP2+ patient subset, the HLA-DRB1 SE conferred an increased risk of RA, whereas the independent influence of smoking was limited. However, there was a significant interaction between the HLA-DRB1 SE and smoking (AP 0.2, 95% CI 0.02, 0.5). In the RF+/anti-CCP2- patient subset, there was an increased risk of disease among smokers, which was only marginally affected by the presence of the HLA-DRB1 SE, and no interaction between the 2 factors was observed (AP 0.002, 95% CI -0.3, 0.3). In the RF-/anti-CCP2- patient subset, neither smoking nor the presence of the HLA-DRB1 SE conferred an increased risk of RA.

Conclusion: These findings demonstrate different effects of smoking and HLA-DRB1 in the 4 serologically defined RA subsets.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Anti-Citrullinated Protein Antibodies / blood
  • Arthritis, Rheumatoid / blood*
  • Arthritis, Rheumatoid / epidemiology
  • Arthritis, Rheumatoid / genetics*
  • Case-Control Studies
  • Epitopes / blood
  • Epitopes / immunology
  • Female
  • HLA-DRB1 Chains / blood*
  • Humans
  • Incidence
  • Logistic Models
  • Male
  • Middle Aged
  • Rheumatoid Factor / blood
  • Risk Factors
  • Smoking / adverse effects
  • Smoking / blood*
  • Smoking / genetics*
  • Sweden / epidemiology


  • Anti-Citrullinated Protein Antibodies
  • Epitopes
  • HLA-DRB1 Chains
  • Rheumatoid Factor