Regular Use of Proton Pump Inhibitor and Risk of Rheumatoid Arthritis in Women

A Prospective Cohort Study

Jinqiu Yuan; Changhua Zhang; Jeffrey A. Sparks; Susan Malspeis; Kelvin Kam-Fai Tsoi; Jean H. Kim; Benjamin A. Fisher; Fang Gao; Tim Sumerlin; Yan Liu; Yuxing Liu; Yihang Pan; Yulong He; Joseph J.Y. Sung


Aliment Pharmacol Ther. 2020;52(3):449-458. 

In This Article

Abstract and Introduction


Background: Proton pump inhibitors (PPIs) have a significant impact on the gut microbiome, which in turn, might increase the risk of rheumatoid arthritis (RA).

Aim: To evaluate regular use of PPIs and risk of RA.

Methods: This is a prospective analysis of the US nurses who reported PPI use data, and were free of RA from the Nurses' Health Study (NHS 2002–2014) and NHS II (2003–2015). The exposure was regular use of PPI in the past 2 years, which was repeatedly evaluated in biennial surveys. RA was confirmed by the 1987 or 2010 American College of Rheumatology criteria. We estimated the hazard ratios (HRs) and confidence interval (CIs) with time-dependent Cox regression adjusting for potential confounders.

Results: We documented 421 cases of RA over 1 753 879 person-years of follow-up. Regular PPI users had a 44% higher risk of RA as compared with non-regular users (adjusted HR = 1.44; 95%CI, 1.10–1.89). The risk of RA increased with the total duration of PPI use (P-trend = 0.008). Compared with non-regular users, the adjusted HRs were 1.22 (95%CI, 0.93–1.62) for women with >0 to 4 years' use and 1.73 (95% CI, 1.14 to 2.61) for >4 years' use.

Conclusions: Regular use of PPI was associated with increased risk of RA in women, with a higher risk observed in individuals with a longer duration of PPI use. Due to the observational study design, large prospective trials are still required to confirm our finding.


Proton pump inhibitors (PPIs) are among the top 10 most commonly prescribed medications worldwide,[1] used for a variety of acid-related disorders such as gastro-oesophageal reflux disease, peptic ulcer disease and non-ulcer dyspepsia.[2] Despite the irreplaceable role of PPI in clinical practice, long-term use of PPIs has been linked with a series of health problems including chronic kidney disease, bone fractures, dementia, vitamin and mineral deficiencies.[2,3] Recent studies have observed a large impact of PPIs on the gut microbiome,[4,5] as a possible result of gastric acid suppression on lower gastrointestinal tract environment. On a population level, PPIs may have an even more pronounced effect on gut microbiome than other commonly used drugs such as antibiotics, leading to warnings of PPI over-use and calls for further investigation into the sequelae of long-term PPI consumption.[4]

Rheumatoid arthritis (RA) is a chronic autoimmune joint disease, which has been implicated in cartilage and bone damage.[6] In 2014, the prevalence of RA in the US ranged from 0.53% to 0.55%, leading to a conservative estimate of 1.28–1.36 million patients in this country.[7] The aetiopathogenic mechanisms of RA remain obscure, though possibly involving a combination of infectious, environmental, hormonal and genetic risk factors.[8] Since gut microbiota plays a fundamental role on the maturation and function of the host immune system,[9] research interests have recently been directed at its effects on the pathogenesis of RA.[10,11] In experimental murine models, commensal bacteria can drive autoimmune arthritis by inducing a Th17 response in the intestine.[10,12] Results in humans also suggested that dysbiosis could promote RA progression, and the inflammation that caused by certain intestinal microbes like Prevotella copri, may contribute to the persistence of arthritis.[10] Two resent epidemiological studies also showed that exposure to antibiotics, another class of medicine with a major impact on gut microbiome, was a significant risk factor for RA.[13,14]

Mechanically, long-term use of PPIs may be associated with RA through intestinal dysbiosis; however epidemiological evidence remains unclear. In 2013, a retrospective claims-based cohort study evaluated the association of PPI use with the risk of community-acquired pneumonia. In this study, the risk of RA was also evaluated in the falsification analyses and a positive association with PPI use was observed.[15] This study was limited by potential misclassification of exposures and outcomes, and inadequate control for potential confounders.[15] The Nurses' Health Study (NHS), and NHS II are two large ongoing prospective cohorts which have collected a comprehensive range of data on socio-demographic factors, medications use, lifestyle factors and health conditions such as rheumatologic diseases. These cohorts offer us an opportunity to investigate RA risk factors with adjustment for a wide array of confounding factors or effect modifiers. Using NHS and NHS II datasets, we performed this study to evaluate the association between PPI use and subsequent RA risk among women.