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Individuals who quit smoking and maintained their nonsmoking status over a long duration of time had a decreased risk of developing seropositive rheumatoid arthritis (RA), an analysis of two large prospective cohorts found.
Compared with recent quitters -- those who stopped less than 5 years ago -- women who quit smoking 30 years ago or more had a 37% decreased risk of being diagnosed with RA (HR 0.63, 95% CI 0.44-0.90), according to Jeffrey A. Sparks, MD, of Harvard Medical School in Boston, and colleagues.
Nonetheless, a "modestly elevated" risk was still present 30 years after stopping smoking, with a hazard ratio of 1.25 (95% CI 1.02-1.53) for all RA and 1.30 (95% CI 1.01-1.68) for seropositive RA, which suggests that "in some individuals, the immune system may be permanently altered perhaps with resultant autoimmunity established once a threshold of smoking is reached and progression to RA occurring many years later," they wrote online in Arthritis Care & Research.
Smoking has been recognized as a potentially important risk factor for RA, and particularly for seropositive disease, meaning the presence of rheumatoid factor or anti-cyclic citrullinated peptide antibodies. Smoking's influence may result from local inflammation in the lung, promotion of citrullination, impaired T-cell function, and the induction of proinflammatory cytokines, although the precise mechanisms have not been identified.
However, whether smoking cessation can influence the risk of subsequent RA has been less certain.
To address this question, Sparks and colleagues analyzed data from the Nurses' Health Study (1976-2014), which included 117,182 women, and the Nurses' Health Study II (1989-2015), which included 113,550. Participants completed biennial questionnaires on multiple aspects of sociodemographics, health, and lifestyle (including smoking).
They identified 1,528 incident cases of RA, of which 63.4% were seropositive, during more than 6 million person-years of follow-up, or up to 38 years.
There were more smokers in the earlier cohort (18.8% current, 35.8% former) than in the later group (13.4% current, 21.3% former). In both groups, smokers reported more alcohol consumption and sedentary behavior.
After adjustment for multiple factors including age, cohort, body mass index, physical activity, parity/breastfeeding, and income, the overall hazard ratio for RA was 1.36 (95% CI 1.22-1.53) for past smokers and 1.46 (95% CI 1.26-1.70) for current smokers.
The intensity of smoking also influenced risk. Compared with never smokers, those currently smoking 25 or more cigarettes per day had a 92% increased risk for seropositive RA (HR 1.92, 95% CI 1.39-2.66).
No increased RA risk was seen for women whose smoking history was less than 10 pack-years, but those with 10 to 20 pack-years of smoking were at elevated risk for all RA (HR 1.38, 95% CI 1.17-1.64) and seropositive RA (HR 1.54, 95% CI 1.25-1.89), although not for seronegative RA.
Those whose smoking history exceeded 40 pack-years had a greater risk for all RA (HR 1.83, 95% CI 1.52-2.20) and a twofold greater risk for seropositive RA (HR 2.25, 95% CI 1.80-2.82). Again, there was no increased risk for seronegative disease, "suggesting that seropositive and seronegative RA may be distinct phenotypes with distinct risk factors," the investigators noted.
"In this large prospective study of women, we observed that sustained smoking cessation reduced seropositive RA risk compared to recent quitters, suggesting that this behavior change can delay or even prevent the onset of seropositive RA," they wrote.
A smoking cessation intervention study could therefore be worthwhile to see whether the formation of autoantibodies could be prevented among individuals at risk or whether disease progression could be modified among smokers, they suggested.
Limitations of the study included its inclusion of primarily white, well educated women and the self-report of smoking.
The study was funded by the National Institutes of Health.
The authors reported no financial conflicts.