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


This study included 173 241 women from NHS (n = 78 327) and NHS II (n = 94 914) (Figure 1). Compared with participants who did not use PPIs, regular users tended to be less physically active, had a higher BMI and rate of hypertension, hypercholesterolemia, diabetes, gastric or duodenal ulcer, gastro-oesophageal reflux disease, and were more likely to use NSAIDs and steroids (Table 1). 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.

Figure 1.

Flowchart of participant selection

Over 1 753 879 person-years of follow-up, we observed 421 cases of RA (NHS: 202, NHS II: 219). Of which, 275 were seropositive RA and 146 were seronegative RA. The absolute risk of all RA among PPI regular users of was 0.41 events per 1000 person-years, compared with 0.21 events per 1000 person years among non-regular users. After adjustment for potential confounders and lagging PPI use for 2 years, regular PPI user was associated with 44% increased risk of all RA as compared with non-regular users (HR = 1.44; 95%CI, 1.10- 1.89) (Table 2). We also observed an association between regular PPI use and seropositive RA (HR = 1.50; 95%CI, 1.07- 2.11). For seronegative RA, there was no sufficient evidence of increased risk in PPI users (HR = 1.34; 95%CI, 0.86–2.10) after adjusting for confounders.

We observed that the risk of all RA increased with the duration of regular PPI use (P-trend = 0.008) (Table 3). Compared with non-regular users, the fully adjusted HRs of all RA were 1.22 (95%CI, 0.93–1.62) for women with >0 to 4 years' use of PPIs, and 1.73 (95% CI, 1.14- 2.61) for women with >4 years' use. We observed similar results in the multivariable analyses for seropositive RA (P-trend = 0.008). When compared with current PPI users, the individuals stopping PPIs for >0 to 2 years (HR = 0.59; 95%CI, 0.37–0.95) and for >2 years (HR = 0.70; 95%CI, 0.53–0.94) had lower risk of all RA (Table 4).

In the analysis for H2RA with same method for PPIs, we did not find sufficient evidence of associations between regular H2RA use and risk of all RA (HR = 0.75; 95%CI, 0.48- 1.16), seropositive RA (HR = 0.71; 95%CI, 0.40–1.25), and seronegative RA (HR = 0.83; 95%CI, 0.42–1.66; see Table S1). We also observed no associations between both duration of H2RA use and time-stopping H2RAs with RA risk (Tables S2 and S3). In the falsification analyses for implausible associations, regular PPI use, as expected, was not associated with increased risk of squamous cell skin cancer (HR = 0.99; 95%CI, 0.85–1.15), basal cell skin cancer (adjusted HR = 1.15; 95%CI, 0.77–2.15) and cervical cancer (HR=0.96; 95%CI, 0.73–1.26) (Table S4).

In the subgroup analyses, we did not find sufficient evidence of interaction effects among pre-specified factors such as study (P = 0.42) and age (P = 0.33) (see Table S5). In the sensitivity analysis by lagging the exposure for a time window of 4 years, we still observed an increased risk among regular PPI users (HR = 1.47; 95% CI, 1.10–1.96) (see Table S6). The results were generally unchanged in the sensitivity analyses by two-step pooling method, additionally adjusting for physical examination in the previous 2 years, and adjusting for use of antibiotics. When limited to analyses in women with gastro-oesophageal reflux disease, we observed an even stronger association (HR = 1.52; 95%CI, 1.09- 2.12).