Background/Purpose : Rheumatoid arthritis (RA) has been associated with increased risk for chronic obstructive pulmonary disease (COPD) and asthma, but these findings may have been confounded by smoking behaviors occurring before and after RA diagnosis. Citrullination of proteins in the airways is important in both RA and COPD etiology so may link these diseases beyond smoking. Marginal structural modeling (MSM) is a statistical method to control for factors, such as smoking, on the causal pathway for an outcome, such as COPD or asthma. We investigated whether RA increases risk for COPD or asthma using MSM to adjust for smoking occurring before RA onset or mediating these respiratory morbidities after RA diagnosis.

Methods : Within the prospective NursesÕ Health Study (n=121,701 women; 1976-2014), we identified an incident RA cohort and matched each woman with RA to 10 non-RA comparators by age and year of RA diagnosis (index date). All RA cases met the 1987 ACR classification criteria. We excluded women with prevalent COPD or asthma at baseline. Data were obtained through biennial questionnaires and medical records. We used MSM to determine the independent effect of RA on incident self-reported COPD or asthma, adjusting for time-varying covariates by inverse probability weighting. Smoking was categorized as fixed pre-index intensity/duration (0, >0 to 10, 10.1 to 20, or >20 pack-years) and time-varying post-index status (never, past, or current). In subgroup analyses, we separately investigated seropositive RA and seronegative RA for risk of COPD or asthma.

Results : We identified 843 women with incident RA during 38 years of follow-up in the NHS, matched to 8,399 comparators without RA. Mean age was 59.8 years and mean follow-up after index date was 18.6 years (SD 9.0) for RA and 18.8 years (SD 9.5) for comparators. During 173,484 person-years of follow-up after index date, we identified 68 (8.1%) incident COPD and 40 (4.7%) asthma cases among women with RA, and 459 (5.5%) COPD and 268 (3.2%) asthma cases among comparators. RA was associated with increased risk of COPD (HR 1.52, 95%CI 1.17-1.97, Table) and asthma (HR 1.55, 95%CI 1.11-2.16) compared to comparators matched to age and year at index date. After adjustment for time-varying covariates, including smoking before and after index date, RA was significantly associated with COPD (HR 1.68, 95%CI 1.36-2.07), but not asthma (HR 1.11, 95%CI 0.59-2.09), compared to non-RA. Women with seropositive RA (HR 1.74, 95%CI 1.36-2.23) and seronegative RA (HR 1.62, 95%CI 1.09-2.40) had similar increased risk for COPD compared to comparators.

Conclusion : In this large prospective cohort study with time-varying measures throughout long-term follow-up, RA was associated with increased risk for incident COPD, but not asthma, independent of smoking and other lifestyle factors. These results provide rationale to investigate the effect of RA-specific factors beyond smoking on COPD risk.