“No one knows if this is due directly to hormonal changes caused by the pill, or whether it is due to avoiding pregnancy whilst on the pill, or whether the pill acts as a marker for some other lifestyle factors that are what is really protective,” said Dr. Symmons. Women who take the pill may also have better healthcare insurance or access to better medical care for other confounding factors.
Other pregnancy-related factors may affect RA risk too, said Dr. Symmons. As women enter menopause and no longer take oral contraceptives, they may be more at risk. Another large-scale study, the European Prospective Investigation of Cancer, Norfolk Arthritis Register (EPIC-2-NOAR), showed that women who have two or more children have a higher risk of RA, while women who have one child have no increased risk, she said.4 Adverse pregnancy outcomes, such as miscarriage or terminated pregnancies, were also associated with a higher risk of RA in women.
According to the Nurses’ Health Study data, breastfeeding offers no protective effect if done for a short period, but does lower risk of RA if a woman breastfeeds for two or more years, said Dr. Symmons.
Danger to the Lungs
Among all the modifiable triggers of RA development, smoking is one of the worst and most consistent culprits, said Dr. Symmons and her fellow panelists. There is strong evidence that autoimmunity in patients with RA often initiates in their lungs’ mucosal lining, said V. Michael Holers, MD, head of the division of rheumatology at University of Colorado Denver and co-founder of the Study of the Etiology of RA (SERA).
“Think how big the lung surface is. If you stretched it out, it’s almost the length of a football field,” Dr. Holers said in a post-conference interview. Exposure to factors in the environment, such as tobacco smoke, bacteria or viruses, triggers the development of antibodies that set autoimmunity in motion. Smoking leads to the citrullination of proteins in the lungs’ mucosal tissue. Individuals who have one or more copies of a key shared epitope then develop anti-citrullinated protein antibodies (ACPAs). Smoking likely triggers or speeds up citrullination in people who are ACPA positive, including a 23-fold-higher RA risk in people who have both copies of the allele and also smoke, said Dr. Symmons.
Smoking affects different population groups more than others as an RA risk factor, and for particular reasons, said Dr. Symmons.
“Smoking is a stronger risk factor in men than women because of a dose-dependent effect,” she said. Male smokers have a fivefold risk of developing RA, while females’ risk is increased but less significant. “There’s probably no increased risk from smoking until a person reaches 10 pack-years, and then it rises progressively thereafter. Many women do not smoke as heavily as that.” Passive smoking also increases risk among those who live with smokers or work in a smoke-filled environment, said Dr. Symmons.
