Edited by: Betty Diamond, Feinstein Institute for Medical Research, United States
Reviewed by: Vita Golubovskaya, University of Oklahoma Health Sciences Center, United States; Amira Kamil Mohammed, Physiology and Pharmacology Department, Iraq
*Correspondence: Chi-Ching Chang,
This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology
†These authors have contributed equally to this work
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Previous study revealed proton pump inhibitors (PPIs) have an effect on gut microbiota. Alteration of the microbiome causes changes of the host immune system and then induces the development of autoimmune diseases (ADs). This study aimed to explore the possible association between PPIs use and ADs.
This study was conducted using data from the Taiwan National Health Insurance Research Database in the period between 2002 and 2015. We performed multivariate and stratified analysis through the Kaplan-Meier method and Cox proportional hazard models to estimate the association between proton pump inhibitor use and the risk of autoimmune diseases.
Of the 297,099 patients treated with PPI identified, the overall mean (SD) age was 49.17 (15.63) years and 56.28% of the subjects was male. As compared with the non-PPI group, the adjusted hazard ratio (aHR) were higher for incident organ specific ADs such as Graves disease (aHR=3.28), Hashmoto thyroiditis (aHR=3.61), autoimmune hemolytic anemia (aHR=8.88), immune thrombocytopenic purpura (aHR=5.05) Henoch-Schonlein pupura (aHR=4.83) and Myasthenia gravis (aHR=8.73). Furthermore, the adjusted hazard ratio (aHR) were also higher for incident systemic ADs such as ankylosing spondylitis (aHR=3.67), rheumatoid arthritis (aHR=3.96), primary Sjogren syndrome (aHR=7.81), systemic lupus erythemtoasus (aHR=7.03). systemic vasculitis (aHR=5.10), psoriasis (aHR=2.57), systemic scleroderma (aHR=15.85) and inflammatory myopathy (aHR=37.40). Furthermore, we observed no dose-dependent effect between PPI use and the risk of ADs.
Our retrospective population-based cohort study showed that the prescription of proton pump inhibitors is associated with a higher risk of ADs.
Proton pump inhibitors (PPIs), for gastric acid related disorders including gastroesophageal reflux disease and peptic ulcers, are one of the most prescribed medications around the world. These drugs also prevent peptic ulcer diseases in critical patients (
Autoimmune diseases (ADs) comprise disorders caused by an imbalance of the immune system, which leads to damage to individual tissues. ADs consist of systemic conditions, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome, as well as single-organ conditions, such as autoimmune thyroid diseases and autoimmune hepatitis. The mechanism underlying the development of ADs remains unknown. Multiple factors (e.g., genetic and environmental factors) affect the risk of ADs. The administration of medications is one of the most important factors in the induction of ADs.
Some medications change the composition of the gastrointestinal microbiota, which may influence human health and cause the development of many diseases (
The host–microbiota interaction plays an essential role in the host immune system (
Our data were obtained from the Taiwan National Health Insurance Research Database (NHIRD). In brief, the single-payer mandatory Taiwan National Health Insurance (NHI) program currently covers >99% of the 23 million residents in Taiwan (
This cohort study was retrospectively conducted using the NHIRD. We identified all individuals in the database from January 1, 2002, to December 31, 2015. The entry date was the day when the patients were included to our study, such as the date of the first PPI prescription in PPI users. We identified patients without prescriptions of PPIs during the entire study period as the control group. Patients were followed up from the entry date to the development of AD, death, or the end of the study.
The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes were used for the definition of basic characteristics and events of ADs. The Anatomical Therapeutic Chemical (ATC) Classification codes were used for the definition of PPIs, anti-bacterial, antiviral, antifungal, and antituberculosis drugs.
We excluded patients who (1) had unknown general data or unknown follow-up time; (2) were less than 20 years old; (3) were diagnosed with ADs before the cohort entry date; (4) had received previous antibiotic, antifungal, anti-tuberculosis, or antiviral agents; and/or (5) had a history of
In Taiwan, when applying for reimbursement under the NHI program for PPIs, patients are required to have a diagnosis of reflux esophagitis or peptic ulcer disease through upper gastrointestinal endoscopy or a barium study. In this study, the duration of PPI use was determined according to prescription information contained in NHI claims data. We recorded the drug name, dosage, and start and withdrawal dates of each prescription claim. The PPIs included omeprazole, pantoprazole, lansoprazole, rabeprazole, and esomeprazole (ACT code A02BC), all of which are covered by the NHI program in Taiwan. Dosage of PPIs was presented as the defined daily dose (DDD), which has been established by the World Health Organization as the average maintenance dose per day for a drug used for its main indication in adults. Exposures of PPIs (cumulative dose during follow-up time) were analyzed by treatment continuation determined by the redeemed prescriptions, and the estimated doses were grouped into different cumulative defined daily doses (cDDDs) to assess dose–response effects on hazard ratios and the effects of long-term use on the risks of ADs. The cDDDs was estimated during the study period based on redeeming prescriptions. Furthermore, we divided the patients into four subgroups stratified by cDDDs, as follows: 1–21 DDDs, 22–42 DDDs, 43–98 DDDs, and ≥99 DDDs.
We determined potential confounders, associating a given covariate with PPI use on basis of the literature and direct or indirect association with other conditions, such as comorbidities and concomitant medications. According to the literature, these comorbidities and concomitant medications may induce changes in gut microbiota, such as liver cirrhosis (
The outcomes of systemic and organ-specific ADs were analyzed (see
Patients’ baseline characteristics, including age, sex, coexisting medical conditions, and PPIs doses, were collected. We categorized age in 10-year intervals. Baseline characteristics were compared between PPIs users and nonusers using the chi-square test for categorical variables and the
All statistical analyses were performed using SAS for Windows version 9.4 software (SAS Institute, Cary, NC), and a two-sided P value <0.05 was considered statistically significant.
Study flow chart. NHI, nation health insurance; PPI, proton pump inhibitor.
Baseline characteristic of PPI and non-PPI users.
PPI (n = 297,099) | non-PPI (n = 3,125,594) | P-Value | |||
---|---|---|---|---|---|
n | % | n | % | ||
|
0.0043 | ||||
Female | 129,900 | 43.72% | 1,375,250 | 43.99% | |
Male | 167,199 | 56.28% | 1,750,692 | 56.01% | |
|
<.0001 | ||||
20–30 | 37,209 | 12.52% | 623,753 | 19.95% | |
31–40 | 57,072 | 19.21% | 690,853 | 22.10% | |
41–50 | 68,021 | 22.90% | 720,217 | 23.04% | |
51–60 | 66,238 | 22.29% | 568,056 | 18.17% | |
61–70 | 38,407 | 12.93% | 276,260 | 8.84% | |
71–80 | 20,248 | 6.82% | 149,150 | 4.77% | |
≥81 | 9,904 | 3.33% | 97,653 | 3.12% | |
Mean (SD) | 49.17 (15.63) | 45.38 (16.02) | <.0001 | ||
Median (IQR) | 49 (23) | 44 (22) | <.0001 | ||
|
|||||
Cancer | 13,150 | 4.43% | 50,087 | 1.60% | <.0001 |
Diabetes Mellitus | 28,708 | 9.66% | 128,694 | 4.12% | <.0001 |
End-Stage Renal Disease | 4,507 | 1.52% | 11,550 | 0.37% | <.0001 |
Cirrhosis of Liver | 5,677 | 1.91% | 4,397 | 0.14% | <.0001 |
Autoimmune Disorders | |||||
Overall | 2926 | 0.98% | 7592 | 0.24% | <.0001 |
Systemic | 1858 | 0.63% | 4635 | 0.15% | <.0001 |
Organ-specific | 1075 | 0.36% | 2973 | 0.1% | <.0001 |
PPI, proton pump inhibitors.
In the baseline analyses, there were 2926 events in the PPI users and 7592 events in nonusers during the follow-up period of 12 months. The incident rates of ADs were 1219.94 and 274.67 per 100,000 person-years in the PPI users and nonusers, respectively (see
Risk of autoimmune disorders between PPI and non-PPI users.
Types of Autoimmune Disorders | Event | IR | IRR | Adj. HR | 95% C.I. for adj. HR |
---|---|---|---|---|---|
Overall | |||||
non-PPI | 7592 | 274.67 | ref. | ref. | |
PPI | 2926 | 1219.94 | 4.440 | 3.640*** | 3.484–3.804 |
Systemic | |||||
non-PPI | 4635 | 167.65 | ref. | ref. | |
PPI | 1858 | 772.14 | 4.606 | 4.335*** | 4.103–4.580 |
Organ-specific | |||||
non-PPI | 2973 | 107.38 | ref. | ref. | |
PPI | 1075 | 445.97 | 4.148 | 2.750*** | 2.558–2.957 |
PPI, proton pump inhibitors. Adj HR, adjusted hazard ratio was adjusted by gender, age, comorbidities. IR, incidence rate was incidences of per 100,000 person-year. CI, confidence intervals. ***P-Value < 0.001.
Cumulative incidence of autoimmune diseases in PPI and non-PPI users.
No significant relationship was observed between the PPI dose and AD risk in the PPI users.
The dose response between PPI and autoimmune diseases.
Types of Autoimmune Disorders | Event | IR | IRR | Adj. HR | 95% C.I. for adj. HR |
---|---|---|---|---|---|
Overall | |||||
0 | 7592 | 274.67 | ref. | ref. | |
1–21 | 768 | 1071.64 | 3.901 | 3.317*** | 3.078–3.573 |
22–42 | 774 | 1353.25 | 4.925 | 4.284*** | 3.977–4.614 |
43–98 | 894 | 1442.01 | 5.249 | 4.219*** | 3.932–4.527 |
≥99 | 490 | 999.32 | 3.637 | 2.690*** | 2.451–2.952 |
Systemic | |||||
0 | 4635 | 167.65 | ref. | ref. | |
1–21 | 483 | 672.06 | 4.009 | 3.789*** | 3.449–4.163 |
22–42 | 484 | 843.00 | 5.028 | 4.775*** | 4.346–5.245 |
43–98 | 579 | 930.66 | 5.552 | 5.193*** | 4.758–5.668 |
≥99 | 312 | 635.17 | 3.789 | 3.522*** | 3.135–3.956 |
Organ-specific | |||||
0 | 2973 | 107.38 | ref. | ref. | |
1–21 | 289 | 401.41 | 3.734 | 2.688*** | 2.380–3.035 |
22–42 | 292 | 507.33 | 4.721 | 3.549*** | 3.144–4.005 |
43–98 | 316 | 506.60 | 4.712 | 2.999*** | 2.665–3.375 |
≥99 | 178 | 361.96 | 3.366 | 1.817*** | 1.558–2.120 |
PPI, proton pump inhibitors. Adj. HR, adjusted hazard ratio was adjusted by gender, age, comorbidities. IR, incidence rate was incidences of per 100,000 person-year. CI, confidence intervals. ***P-Value < 0.001.
In
Risk of organ-specific and systemic autoimmune diseases between PPI and non-PPI users.
Event | Incidence Rate | IRR | ADJ. HR | 95% CI. | |
---|---|---|---|---|---|
Systemic autoimmune disease | |||||
Ankylosing spondylitis | |||||
non-PPI | 3211 | 116.13 | 1.000 | 1.000 | |
PPI | 1051 | 435.87 | 3.753 | 3.670*** | 3.418–3.941 |
Rheumatoid arthritis | |||||
non-PPI | 809 | 29.25 | 1.000 | 1.000 | |
PPI | 324 | 134.16 | 4.587 | 3.968*** | 3.482–4.523 |
Sjögren syndrome | |||||
non-PPI | 307 | 11.09 | 1.000 | 1.000 | |
PPI | 236 | 97.68 | 8.804 | 7.810*** | 6.569–9.285 |
Systemic lupus erythematosus | |||||
non-PPI | 182 | 6.58 | 1.000 | 1.000 | |
PPI | 116 | 47.98 | 7.296 | 7.029*** | 5.520–8.952 |
Systemic vasculitis | |||||
non-PPI | 49 | 1.77 | 1.000 | 1.000 | |
PPI | 27 | 11.16 | 6.305 | 5.099*** | 3.162–8.225 |
Psoriasis | |||||
non-PPI | 47 | 1.70 | 1.000 | 1.000 | |
PPI | 12 | 4.96 | 2.922 | 2.568** | 1.348–4.891 |
Systemic Sclerosis | |||||
non-PPI | 33 | 1.19 | 1.000 | 1.000 | |
PPI | 53 | 21.92 | 18.380 | 15.851*** | 10.190–24.660 |
Inflammatory myopathy | |||||
non-PPI | 15 | 0.54 | 1.000 | 1.000 | |
PPI | 52 | 21.50 | 39.674 | 37.397*** | 20.920–66.870 |
Organ-specific autoimmune disease | |||||
Graves’ disease | |||||
non-PPI | 152 | 5.49 | 1.000 | 1.000 | |
PPI | 44 | 18.19 | 3.313 | 3.280*** | 2.335–4.608 |
Hashimoto’s thyroiditis | |||||
non-PPI | 1160 | 41.95 | 1.000 | 1.000 | |
PPI | 382 | 158.25 | 3.773 | 3.606*** | 3.206–4.057 |
Autoimmune hemolytic anemia | |||||
non-PPI | 67 | 2.42 | 1.000 | 1.000 | |
PPI | 82 | 33.91 | 14.008 | 8.877*** | 6.293–12.520 |
Immune thrombocytopenic purpura | |||||
non-PPI | 137 | 4.95 | 1.000 | 1.000 | |
PPI | 71 | 29.36 | 5.932 | 5.048*** | 3.745–6.803 |
Henoch-Schonlein purpura | |||||
non-PPI | 98 | 3.54 | 1.000 | 1.000 | |
PPI | 47 | 19.44 | 5.489 | 4.829*** | 3.383–6.886 |
Myasthenia gravis | |||||
non-PPI | 56 | 2.02 | 1.000 | 1.000 | |
PPI | 43 | 17.78 | 8.788 | 8.733*** | 5.836–13.070 |
PPI, proton pump inhibitors. Adj. HR, adjusted hazard ratio was adjusted by gender, age, comorbidities. IR, incidence rate was incidences of per 100,000 person-year. CI, confidence intervals. **0.001 ≤ P-Value < 0.01, ***P-Value < 0.001.
A Kaplan–Meier analysis revealed the cumulative incidence of ADs and subgroup ADs development in those PPI and non-PPI users (
According to our review of the relevant literature, this study is the first nationwide population-based work to evaluate the relationship between PPIs and ADs. In the present study, the incidence rate of overall ADs was 3.9 times higher in the PPI users than in non-PPI users, with an adjusted HR of 3.32 after adjustment for age, sex and comorbidity. Furthermore, we found that PPI users also had an increased risk of organ-specific and systemic ADs, respectively.
Our study indicated an association between PPI and the risk of ADs, including systemic and single-organ ADs. The possible mechanism of the association of the prescription of PPIs and the development of ADs is hypothesized to be an alteration of the gut microbiome by PPIs, which leads to AD development. The effect of the host microbiota on the immune system has been identified (
The prescription of antibiotics altered the microbiota of the host, giving rise to the development of ADs, such as rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease (
Our study data was derived from a real-world database, the Taiwan NHIRD, and investigated that PPIs can induce an elevated risk of ADs. However, the development of ADs is affected by many factors. The microbiota play a role in the pathogenesis of ADs (
Several previous studies described the risk of several ADs is increased by PPIs. Polymyositis was found in patients treated with PPIs in the World Health Organization adverse drug reactions database (VigiBase) (
The etiology of ADs remains unknown. We have described new potential medical factors leading to induction of ADs. Using PPIs will increase the risk of ADs. In previous studies, the prescription of PPIs had a low risk for users. Inappropriate prescription of PPIs was declared previously (
The limitation of our study was that we did not use a matched sample. We used nonmatching to compare data to explain a high risk of ADs in patients with PPI use in real-world settings. Difference in baseline characteristics exists between PPI users and nonusers. However, the high aHR would direct the real elevated risk for developing ADs in patients receiving PPIs. Another limitation of our study was that we cannot exclude all the possible factors affecting the gut microbiota. Although we excluded patients receiving antibiotics, antiviral agents, and antituberculosis agents, the microbiota will also be affected by a variety of host and environmental factors. We also excluded patients with major organ dysfunction diseases, including diseases of the liver and kidney. We tried to eliminate possible confounding factors by our established exclusion criteria. In addition, we could not confirm the exact time when a prescription of PPIs induced alteration of the gut microbiome. Furthermore, we could not predict the time when using PPIs induces the development of ADs. Therefore, the development of ADs was recorded as the event immediately after the prescription of PPIs in our study.
In conclusion, in the findings of our study, PPIs was associated with higher risk of the development of ADs. Therefore, it is recommended that awareness of increased risk of ADs in patients with PPI treatment is very important for clinician. Furthermore, the mechanism of PPIs inducing ADs needs further research to elucidate.
The original contributions presented in the study are included in the article/
The present research was approved by the Institutional Review Board of Taipei Medical University (TMU JIRB-N201908055). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.
Conception and design of the study: S-HL, J-HC, and C-CC. Analysis and interpretation of data: Y-CL and J-HC. Drafting of article or revising it critically for important intellectual content: S-HL, Y-SC, T-ML, L-FH, T-YH, H-CH, P-IK, W-SC, Y-CL, J-HC, and C-CC. All authors contributed to the article and approved the submitted version.
This study was supported by research grants from Taipei Medical University(TMU106-AE1-B02).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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