2015 ACR/ARHP Annual Meeting: Research Offers Clues to Environmental Triggers of RA

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SAN FRANCISCO—Research is revealing more clues about the environmental factors that likely play a role in triggering rheumatoid arthritis (RA) in patients who are susceptible—or that may even protect them from autoimmunity.

Large-scale, lengthy population studies conducted at institutions worldwide provide in-depth data from which to identify potential triggers and protective factors for RA, from tobacco smoke to oral contraceptives.

By lifting the curtain on how and why these factors act on the immune system in certain individuals, rheumatologists may one day be able to identify who is most at risk for such diseases as RA, suggest interventions to interrupt disease onset or develop better, more targeted therapies that delay or disrupt bone and joint damage years before it begins, panelists said in November 2015 at the 2015 ACR/ARHP Annual Meeting. In addition to environmental and infectious triggers of autoimmunity, other factors may offer some protection from autoimmunity, offering rheumatologists more tools to fight rheumatic diseases before they can begin to do harm to tissue.

In diseases such as RA, persistent inflammation is the result of dysregulated on and off switches, said Stephen Young, PhD, senior lecturer in rheumatology at the University of Birmingham in the United Kingdom and one of the moderators of the conference. It’s not just a rheumatologic problem: Research published in the American Journal of Psychiatry in 2015 revealed that patients with schizophrenia had signs of neuroinflammation on positron emission tomography (PET) scans, he said.¹

“Inflammation is everywhere, and acute inflammation is part of our normal immune response,” said Dr. Young. Out-of-control inflammation may occur when certain alleles make a patient susceptible, then risk factors like smoking, dietary habits or reproductive hormones set it in motion.

Genetics Set the Stage

Genetic factors account for about 50% of the susceptibility to develop RA according to the latest estimates, said Deborah Symmons, MD, professor of rheumatology and musculoskeletal epidemiology at the University of Manchester in the U.K. Over just the past eight years, more than 108 RA risk loci have been identified, she said. But no combination of genetic factors is sufficient to develop RA, so researchers think environmental triggers are the key to moving a person from the potential to have autoimmunity to actually having it.

“Obviously, genes are present from birth. So a person’s genetic risk of RA, which will vary between individuals, is constant throughout their lifetime,” said Dr. Symmons in a follow-up interview after the conference. “It is true that the more susceptibility genes someone has, then the earlier in life they are likely to develop RA. But nevertheless, at least one environmental trigger is required in everyone to set the process going. We know this because there is a relatively low concordance for RA in identical twins who share their genetic susceptibility.”

Dr. Symmons and her fellow panelists spoke about four phases of RA that each person moves through: Genetic risk, autoimmunity but asymptomatic, early symptoms of articular disease and active disease with synovitis.

RA Rising & Falling

To learn more about RA incidence rates and the identification of potential triggers and protective factors, researchers glean data collected from large studies, such as the Rochester Epidemiology Project at the Mayo Clinic, the Karolinska Institute of Sweden’s Epidemiological Investigation of Rheumatoid Arthritis (EIRA) and Harvard Medical School Channing Laboratory’s Nurses’ Health Study, said Dr. Symmons. These extensive, long-term data show intriguing trends in RA that help focus future research in the right directions.

Although RA is more common in women, men’s risk rises with aging, said Dr. Symmons. The Mayo Clinic data show that “the incidence of RA fell progressively in men and women between around 1955 and 1995.² It started to rise again from 1995 to 2005. We don’t know yet what happened in the next decade,” she said.

Clues for the rise or fall in RA cases may be in well-known triggers. Some of these triggers are modifiable, such as smoking, obesity, diet and exposure to reproductive hormones. Other factors, such as aging or gender, are not modifiable, and some people may be exposed to environmental triggers, such as silica particles in the air or secondhand smoke, with little ability to control it.

Pregnancy hormones are a potential risk factor for developing RA, so the availability of oral hormonal contraceptives in the U.S. from the 1960s onward may have affected RA incidence rates in women. In addition, the hormonal concentration of oral birth control pills was higher in the 1960s than in later decades, which may have affected users’ RA risk, according to the Mayo Clinic data.

“One reason for the fall may be the protective effect of the pill in women. It was also felt that this was part of a natural change in disease incidence,” Dr. Symmons said. “No one really knows why. Some of the rise since 1995 may be due to increased prevalence of obesity, which is an environmental risk factor.”

Scientists stumbled on the pill’s potentially protective aspect in RA by accident, said Dr. Symmons. The Royal College of General Practitioners Oral Contraception Study, which collected data on 46,112 women over 39 years, looked into the health impact of the widely used medicine.³ One of the findings showed that RA risk was less than half in those who took the pill compared with those who had never taken it, she said. But researchers still aren’t sure exactly why these hormones offer this protection.

“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.

Exposure to respirable crystalline silica in sand, rock or soil also is associated with lung fibrosis and increased RA risk. Findings from the EIRA population study showed that men who work in professions where they have high exposure to silica, such as drilling or crushing stone, had double the RA risk of men with lower exposure.⁵ Prevalence is as much as five times higher among men who work in such settings and also smoke, Dr. Symmons said.

Diet’s Role

Obesity is a known risk factor for developing RA, because adipocytes are not inert, but produce adipokines, cytokines, chemokines and other pro-inflammatory proteins and hormones, said Dr. Symmons. Data from the Mayo Clinic study suggest that recent increases in prevalence of RA may be due to simultaneous increases in obesity among Americans, she said.

Obesity increases RA risk in women who are either ACPA seropositive or seronegative according to the Nurses’ Health Study data, but other data show it may be somewhat protective for men.⁶ The Swedish EIRA study showed that obesity in men was associated with a decreased risk for seropositive RA, but not in women.

Sugar-sweetened beverages, such as soft drinks, may be associated with higher RA risk in women according to recent prospective studies, she said. Consumption of these drinks may also be a factor in obesity.

Does vitamin D intake through sunlight exposure or diet also serve as a protective factor for RA? Data from the Nurses’ Health Study suggest that levels of ultraviolet B light exposure may be related to RA risk in women, said Dr. Symmons. The connection is still inconclusive based on the available evidence, so potential interventions with dietary supplementation of vitamin D or increased UVB exposure are a long way off.

“Even with regard to RA prevention, one can only say that if a susceptible person is found to be vitamin D deficient, then advising more sunlight exposure and so restoring vitamin D levels may be helpful, although there is no evidence to support this approach. It’s just a conclusion from the risk factor data,” she said. Some research shows that obese participants have lower vitamin D levels than non-obese ones, and also typically exercise less, so RA risk may be due to a mixture of factors, she said.

Other modifiable dietary risk factors could either help trigger RA or offer some protection. “You’ll be pleased to know that alcohol is not a risk factor for rheumatoid arthritis,” Dr. Symmons told the audience. According to the Nurses’ Health Study data, daily intake of less than 10 g of alcohol a day offered some protection, while higher intake offered no protection, so only mild consumption is helpful.

Susan Bernstein is a freelance medical journalist based in Atlanta.

References

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