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


In this prospective study of 173 241 women with over 1.7 million person-years of follow-up, we observed that regular PPI use was associated with increased risk of overall RA and seropositive RA. Our results also showed that the risk of RA increased with the duration of PPI use, while stopping PPIs was associated with reduced risk as compared with current users. 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 H2RAs, which are less potent acid suppressors than PPI.

Our results were in line with a previous retrospective claims-based cohort study (26 436 PPI users and 28 054 non-users) from the US.[15] The primary objective of this study was to evaluate the association of PPI use with risk of community-acquired pneumonia. The risk of RA was evaluated in the falsification analyses and a positive association with PPI use was observed (PPI group: 85 cases/10 000 persons per year, control group: 68 cases/10 000 persons per year, P < 0.001).[15] The authors considered the association between PPI and RA was implausible and concluded that the observed associations between PPI use and community-acquired pneumonia may be confounded. RA might be used as an implausible association in 2013 when this study was carried out, but the association is no longer implausible now. A lot of studies published after 2013 suggested PPIs have a major impact on gut microbiome, which in turn, may increase the risk of rheumatoid arthritis.[4,5,10] A comprehensive literature search did not identify any other epidemiological studies investigating this association.

The mechanisms underlying the observed association between PPIs use and RA remain unclear. A possible explanation is that gut microbiota may mediate their association. Strong evidence showed that PPIs could result in intestinal dysbiosis,[4,5] while intestinal dysbiosis has been linked with autoimmune mechanisms which are involved in the development of RA.[10,11] Certain bacteria, such as Escherichia coli, maybe involved in the disease process of RA. In a combined analysis of three cohorts of 1815 adult individuals, PPI users showed a significant increase in the abundance of pathogenic species E. coli.[4] In a cohort of 246 patients, IgM antibodies to E. coli were associated with early RF+ rheumatoid arthritis, suggesting E. coli alteration appear to be an early event in the disease course of seropositive RA.[29] Further investigation suggested that RF+ patients were more commonly colonised with phylogenetic Group D E. coli, whereas RF−patients were more commonly colonised with phylogenetic Group B2 E. coli.[30] How the E. coli infection or the antibodies, or both, contribute to the disease process of RA is still unresolved. Furthermore, PPIs may increase RA risk through hampering the transforming growth factor beta (TGF-β) function by alkalisation of PH.[31,32] Increased TGF-β function is one of the key ways to restore joint homeostasis in RA.[33,34] Future research is still required to investigate the underlying mechanisms.

We analysed H2RAs with the same methods as PPIs, because H2RAs have similar applications in clinical practice but are much less potent than PPI in terms of gastric acid suppression. Such analysis would be helpful to reduce unmeasured factors that may confound the causal relationship (such as protopathic bias and imbalance in the underlying diseases for acid suppressants use). Our finding that only PPIs were associated with increased RA risk suggested that PPIs may increase RA risk through their effects on gastric acid secretion. This was in line with a previous study finding that PPIs were associated with greater risk of Salmonella, Campylobacter and other enteric infections than H2RAs.[35] However, the results should be interpreted with caution because (a) the estimated HRs were not precise as the number of cases was small in regular H2RA users; (b) such analysis provided additional evidence, but was unable to prove the casual relationship between PPI use and RA.

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 PPI use. In the primary analysis, we lagged the exposure for a time window of 2 years, allowing the participants with subclinical RA symptoms to progress and be diagnosed with RA. Additional lagging exposure for even longer time showed similar results. In addition, we excluded individuals with RA confirmed by rheumatologists as well as those with self-reported RA. Self-reported RA in this setting has been shown to lack specificity and included participants with subclinical RA symptoms but did not fulfil the RA classification criteria. Last, H2RAs may also be related to subclinical symptoms in the same way as PPIs, but no increased risk was observed in H2RA users. Another concern in pharmacoepidemiological studies is immortal time bias, however, the risk is low in our study since PPI use was determined before the start of follow-up.[36] In addition, the association between PPI and RA maybe interacted by NSAIDs as these two medicines are often prescribed together. In this study, the crude risk ratios of RA by PPI use were similar between regular NSAID users and non-NSAID users (Table S7). Subgroup analysis by NSAIDs also showed no interaction effect (P = 0.87).

Strengths and Limitations of This Study

One of our strengths is that this study was based on two well-established prospective cohorts with large sample sizes and over 12 years of follow-up. Data on exposures and most covariates data were collected with biennial questionnaires and potential time-varying effects were adjusted. The participants were nurses who were able to provide complete and accurate health information. Additionally, we comprehensively controlled for established RA risk factors, which minimised potential confounding effects. Last, robust sensitivity analyses and the clear dose-response relationship additionally increased our confidence in the results.

This study has limitations. First, as an observational study, this study could not confirm the causal-relationship between PPI use and RA risk. Despite our careful adjustment for potential confounders, residual confounding effects may still exist. Genetic factors, such as major histocompatibility complex (MHC) gene, may confound the effect but we were unable to fully control the influence as these data were not collected. However, we controlled family history of RA and the results were not changed. Second, we did not collect detailed PPI usage data, including dosage, frequency, duration, type or brand, and the reasons for using PPIs, so more specified evaluation of the effects for PPI could not be performed. Third, the association between PPI use and RA may be confounded by the indications for using PPI. In this study, regression analyses adjusting for common indications (gastro-oesophageal reflux disease, gastric or duodenal ulcer) showed almost no change in the estimated effect. Analyses limiting the participants in women with gastro-oesophageal reflux disease indicated an even stronger association. Fourth, all the included participant were female nurses who may have different characteristics as general population, such as gender, education, income and lifestyles. Our findings may not be generalisable to general population. The subgroup analyses by age, BMI, family history of RA, menopausal status, breastfeeding time and smoking did not found sufficient evidence of effect modification. Fifth, the number of cases may not be enough for seronegative RA and subgroup analyses. However these analyses were not for the primary objective of this study, and would not influence our conclusion. The number of cases were small so the confidence intervals were wide, which might not be able to provide precise estimates of effects. Sixth, for the lagged analysis, we cannot determine the most appropriate lagging time based on solid evidence as current research about PPI use and RA risk is sparse. In the primary analysis, we lagged the exposure for 2 years, which was widely used in other NHS analyses. Additionally lagging exposure for 4 years showed similar results. Last, pharmacoepidemiologic research based on Nurses Health Studies are also limited by left truncation, interval data and reliance on self-report.