Respiratory Diseases as Risk Factors for Seropositive and Seronegative Rheumatoid Arthritis and in Relation to Smoking

Objective The link and interplay between different airway exposures and rheumatoid arthritis (RA) risk are unclear. This study was undertaken to determine whether respiratory disease is associated with development of RA, and specifically to examine this relationship by RA serostatus and smoking exposure. Methods Using data from the Epidemiological Investigation of Rheumatoid Arthritis study, this analysis included 1,631 incident RA cases and 3,283 matched controls recruited from 2006 to 2016. Linking these individuals to the National Patient Register provided information on past diagnoses of acute or chronic upper or lower respiratory disease. For each disease group, we estimated adjusted odds ratios (ORadj) with 95% confidence intervals (95% CIs) for RA, using logistic regression models adjusted for age, sex, residential area, body mass index, and education level both overall and stratified by anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF) status and by smoking status. Results Respiratory disease diagnoses were associated with risk of RA, with an ORadj of 1.2 (95% CI 0.8-1.7) for acute upper respiratory disease, 1.4 (95% CI 1.1-1.9) for chronic upper respiratory disease, 2.4 (95% CI 1.5-3.6) for acute lower respiratory disease, and 1.6 (95% CI 1.5-3.6) for chronic lower respiratory disease. These associations were present irrespective of RF or ACPA status, though the association was somewhat stronger for ACPA-positive or RF-positive RA than for ACPA-negative or RF-negative RA. The association between any respiratory disease and RA was stronger for nonsmokers (ORadj 2.1 [95% CI 1.5-2.9]) than for smokers (ORadj 1.2 [95% CI 0.9-1.5]). Conclusion Respiratory diseases increase the risk for both seropositive and seronegative RA, but only among nonsmokers. These findings raise the hypothesis that smoking and airway disease are associated with RA development through partly different mechanisms.