Rheumatoid arthritis: Another reason to be wary of long-term PPI use?

Regular users of proton pump inhibitors (PPIs) risk developing rheumatoid arthritis (RA), and the risk increases proportionally with the duration of use, according to a study.

“As PPIs have been linked with other health problems, such as fractures and gastric cancer, our study once again suggested the importance of carefully evaluating the need for long‐term, continuous use of PPIs,” the investigators said. [Gastroenterology 2017;152:706-715; Mayo Clin Proc 2018;93:240-246]

“Mechanically, long‐term use of PPIs may be associated with RA through intestinal dysbiosis… while intestinal dysbiosis has been linked with autoimmune mechanisms which are involved in the development of RA,” they pointed out. [Gut 2016;65:749-756; Digestion 2018;97:195-204; J Immunol Res 2017;2017:4835189; Arthritis Rheumatol 2016;68:35-45]

In their study, the investigators documented 421 RA cases over 1,753,879 person‐years of follow‐up among 173,241 PPI users. The incidence rate was higher among regular than non-regular users: 0.41 vs 0.21 events per 1,000 person‐years. [Aliment Pharmacol Ther 2020;doi:10.1111/apt.15834]

In multivariable Cox regression models, regular PPI use conferred a 44-percent increased risk of RA compared with non-regular use (hazard ratio [HR], 1.44, 95 percent confidence interval [CI], 1.10– 1.89). This held true for seropositive (HR, 1.50, 95 percent CI, 1.07–2.11) but not for seronegative RA.

Furthermore, the longer the duration of PPI use, the greater the risk of RA (p_trend=0.008). The risk was 22-percent higher among women who reported >0 to 4 years of use (adjusted HR, 1.22, 95 percent CI, 0.93–1.62) and 73 percent higher among those who reported >4 years of use (adjusted HR, 1.73, 95 percent CI, 1.14–2.61) relative to non-regular users.

On a positive note, discontinuing PPIs was protective, such that the risk of RA was lower by 41 percent among women who had stopped using the drugs for >0 to 2 years (HR, 0.59, 95 percent CI, 0.37–0.95) and by 30 percent among those who had stopped using for >2 years (HR, 0.70, 95 percent CI, 0.53–0.94).

“These associations were largely unchanged in a series of sensitivity analyses. By contrast, we did not observe an increased risk of RA among women who used H2 receptor antagonists, which are less potent acid suppressors than PPI,” the investigators noted.

The analysis included 78,327 PPI users from the Nurses’ Health Study and 94,914 from the NHS II, among whom 4,150 and 4,538 reported regular PPI use in the past 2 years. This group of women tended to be less physically active, have a higher body mass index (BMI), use nonsteroidal anti-inflammatory drugs and steroids, and have hypertension, hypercholesterolaemia, diabetes, gastric or duodenal ulcer, gastro‐oesophageal reflux disease as compared with non-regular users.

“Some of these factors, such as BMI and physical activity, were known risk factors for RA. Whether other RA risk factors, such as infection history, were balanced between groups is unclear, and we could not adjust in multivariable analysis, because these data were not available,” the investigators said.

“One concern with our findings could be that the positive association between PPI use and RA was due to reverse causation, whereby subclinical RA symptoms may be related to [the antireflux drug] use,” they pointed out.

More studies are needed to confirm the present data, as well as to investigate the underlying mechanisms, according to the investigators.