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Passive smoking among women during childhood and/or adulthood was associated with an increased risk for the development of rheumatoid arthritis (RA), according to a French prospective study.

This risk is particularly notable among patients who are positive for anti-citrullinated protein antibodies and those who carry the HLA-DRB1 shared epitope alleles, said Yann Nguyen, MD, of Université Paris Sud in Villejuif, France, at the European League Against Rheumatism virtual congress.

Citrullination of proteins -- with the conversion of the amino acid arginine to citrulline -- at the airway mucosal surface is recognized as one of the earliest events leading to RA.

RA is a systemic, multifactorial autoimmune disease thought to result from an interaction between genetics and environment. Active smoking has been the most consistently reported risk factor for RA, with reported relative risks of 1.3 to 2.1.

Despite the clear connection with active smoking, few studies have considered the risks associated with passive smoking, and the available data have been conflicting.

To further explore this possible link, Nguyen and colleagues analyzed data from the E3N-EPIC prospective cohort study that has been investigating environmental factors associated with chronic diseases. This cohort has followed almost 100,000 healthy French women since 1990, and RA cases were identified with questionnaires and medication reimbursements.

Women were considered to have been exposed to passive smoking if they reported being in a smoky room for several hours a day during childhood or at least 1 hour a day during adulthood.

In , the French researchers for the first time identified a nonsignificant trend towards a positive association between RA and passive smoking (HR 1.43, 95% CI 0.97-2.11). However, that analysis included only 371 validated cases and may have been underpowered, Nguyen noted.

The database now includes 964 validated cases of RA, including 698 incident cases, which were stratified according to active smoking ever among those exposed to passive smoke.

Mean age at baseline was 49, and mean age at the time of RA diagnosis was 65.2 years. Fourteen percent reported exposure to passive smoking during childhood, 54% during adulthood, and 8% reported both.

Among those exposed to passive smoking during childhood, the hazard ratio for RA was 1.24 (95% CI 1.01-1.51), and was highest among women who themselves were never smokers (HR 1.40, 95% CI 1.06-1.86).

Among those who were exposed to passive smoking as adults, the hazard ratio for RA was 1.19 (95% CI 1.02-1.40), and again was higher among women who were never smokers (HR 1.27, 95% CI 1.02-1.57).

In the overall analysis, the risks were highest among women who had been exposed to passive smoking and themselves were ever smokers, with a hazard ratio of 1.50 (95% CI 1.22-1.84).

An additional observation was that the age at RA onset was also influenced by passive and active smoking. For those who had never smoked and had no exposure to passive smoking, the mean age at RA diagnosis was 66.5 years, whereas for those who had ever smoked and had been exposed to passive smoking during childhood, the mean age at diagnosis was 60.6 years.

"In this large prospective cohort, passive smoking in childhood or adulthood was associated with an increased risk of RA. Moreover, RA may occur earlier with passive smoking exposure during childhood. We hypothesize that passive smoking could favor citrullination in genetically predisposed individuals, even years before the first symptoms," Nguyen concluded.

A limitation of the study was its inclusion of only French women.

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