Rheumatoid arthritis (RA) is a systemic autoimmune disease of multifactorial aetiology, which preferentially affects women. To date, active smoking has been the most reproducibly reported risk factor for anti-citrullinated protein antibodies (ACPA) positive RA, particularly persons who carry the HLA-DRB1-shared epitope (SE) alleles.

Objectives: We aimed to investigate the relationships between passive smoking in childhood (PSc) or in adulthood (PSa), and the risk of incident RA in a large prospective cohort of healthy French women.

Methods: The E3N-EPIC (Etude Epidémiologique auprès des femmes de la Mutuelle générale de l’Education Nationale) is a French prospective cohort study that investigates environmental factors associated with chronic diseases. It follows 98,995 healthy French women since 1990 covered by a national health insurance primarily involving teachers. RA cases have been previously identified with specific questionnaires and medication reimbursement database. Women were considered exposed to PSc if they self-declared staying in a smoky room several hours a day during childhood, and to PSa if they self-declared being exposed at least one hour a day to passive smoking while adults. We used Cox multivariable regression models with age as the timescale (model 1), adjusted on smoking status (never, current, or former smoker) and on the two types of passive smoking (model 2), and on educational level, and BMI (model 3). Stratified analyses were conducted depending on the active smoking status (never or ever-smoker).

Results: 79,806 women were included in the study. Mean (± SD) age at cohort entry was 49.0 (± 6.4) years. Among them, 698 incident RA cases were identified, diagnosed after a mean of 11.7 (± 5.8) years after baseline. In the whole cohort, 10,810 (13.5%) women were exposed to PSc, 42,807 (53.6%) to PSa, 6,581 (8.25%) were exposed to both, and 47,036 (58.9%) were exposed to either.

In the whole population, PSc was positively associated with the risk of RA in all three models (HR 1.24; 95% CI [1.01 to 1.51] in Model 3). In stratified analyses on smoking status, PSc was associated with RA among never-smoking women (HR 1.42; 95% CI [1.07 to 1.88]), but not among ever-smoking women (HR 1.10; 95% CI [0.83;1.46]).

In the whole population, PSa was also positively associated with the risk of RA in all three models (HR 1.19; 95% CI [1.02 to 1.40] in Model 3). In stratified analyses on the smoking status, PSa was associated with an increased RA risk only among never-smoking women (HR 1.27; 95% CI [1.02 to 1.57]) and not among ever-smoking women (HR 1.16; 95% CI [0.93;1.44]).

Conclusion: In this large population-based prospective cohort study of French women, we reported that passive exposure to smoking during childhood or adulthood increased the risk of RA. The association was principally observed among never smoking women. These results suggest that smoking by-products, whether actively or passively inhaled absorbed, could generate autoimmunity, at least towards antigens involved in RA pathogenesis.