Background and Objectives: Microscopic colitis (MC) is a chronic inflammatory bowel disease characterized by watery diarrhoea and a normal radiological and endoscopic appearance. Concern regarding a potential association between drug exposure and MC has recently emerged. We sought to systematically review and summarize the evidence for the potential association. Methods: A systematic review and meta-analysis were performed to evaluate the incidence of MC associated with exposure to drug. The PubMed and Embase databases were searched to identify potential studies for inclusion. Results: Twelve case-control studies were included in the meta-analysis. The results showed exposure to NSAID (OR, 1.64; 95% CI: 1.14–2.37; p < 0.001), PPI (OR, 2.36; 95% CI: 1.59–3.52; p < 0.001), SSRI (OR, 2.16; 95% CI: 1.5–3.13; p < 0.001), or aspirin (OR, 2.84; 95% CI: 1.4–5.76; p < 0.001) was related to the incidence of MC; however, such relationships in PPI and SSRI may be modulated by the selection of controls. Furthermore, we did not found a positive association with other drug exposure and MC. Conclusion: This meta-analysis indicated that NSAID, PPI, SSRI, or aspirin consumption may increase the risk for MC. Further studies exploring drug-induced microscopic colitis should include control groups with diarrhoea and not only healthy controls.

Microscopic colitis (MC) is a chronic inflammatory bowel disease characterized by watery diarrhoea and a normal radiological and endoscopic appearance, but microscopic abnormalities in the colon [1]. This disease includes collagenous colitis and lymphocytic colitis, which are clinically indistinguishable [2, 3]. The two separate entities share histopathological features such as a marked increase in the intraepithelial CD8+ T-lymphocyte count; collagenous colitis is additionally characterized by a thickened (10 μm or more) subepithelial collagen band [4]. Despite its low prevalence, the incidence of MC has increased in recent decades, but its aetiology is unknown [5]. Identification of the risk factors for MC may help prevent the disease and could also inform appropriate interventions.

Environmental risk factors, such as drugs, have been suggested to be associated with the MC incidence [1]. Several cases of MC have been identified after oral use of a statin or selective serotonin reuptake inhibitor, but MC was alleviated after discontinuation of these drugs, implying a causal relationship between the drug exposure and MC [6‒9]. Some epidemiological studies [10‒16] examined the potential risk of MC after drug exposure, with mixed results. A 2015 meta-analysis [17] summarized these associations and reported that four common drug exposures increase the risk of MC. The most recent systematic review [18] investigated this association but did not provide an overall estimation of the effect of proton pump inhibitors (PPIs) on MC. Additional studies [19‒23] have been published since these two systematic reviews, enabling a more detailed analysis of the association between drug exposure and MC risk. These studies also investigated the effects of other common drugs, but the results were inconsistent. We reviewed epidemiology studies of patients taking these drugs, compared with unexposed people, and assessed the risk of MC. The aim was to evaluate the risk of MC after drug exposure for the purposes of designing evidence-based practice guidelines and informing future research.

This meta-analysis was conducted following guidance provided by the Meta-Analysis of Observational Studies in Epidemiology Group to maintain a high quality level (online suppl. Table S1; see www.karger.com/doi/10.1159/000526809 for all online suppl. material) [24] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (online suppl. Table S2). Two investigators from different subspecialities were involved in all steps of the literature search, selection, quality assessment, and data extraction. Disagreements were resolved by discussion with a third author.

Literature Review

A comprehensive literature search of the PubMed and Embase databases was performed up to August 2021 for relevant studies. The following synonymous terms were used to develop the search strategy: statin, nonsteroidal anti-inflammatory drug (NSAID), aspirin, antidepressant, selective serotonin reuptake inhibitor (SSRI), benzodiazepine (BDZ), β-blocker, angiotensin-converting enzyme inhibitors (ACEI), PPI, H2 antagonists, acid-suppressive medication, diuretic AND lymphocytic colitis, collagenous colitis, and microscopic colitis. The reference lists of reports identified were used to find additional publications.

Selection Criteria

Observational studies examining the association between drug exposure and the risk of MC were included in the meta-analysis. A study was considered eligible if it was (1) a cohort or case-control study, (2) included drug exposed versus unexposed participants, (3) evaluated the association between drug use and the risk of MC, and (4) provided adequate data to extract the risk estimates.

Data Extraction and Quality Assessment

All data were extracted independently by 2 authors using scheduled electronic data extraction, and a third author resolved any discrepancies before the final analysis. The following information was collected from each study: author, study time period/year of publication, data source, ascertainment of drug exposure, total number of participants in each group, outcome assessed, and study quality. As recommended by the Cochrane Collaboration, we evaluated the methodological quality of the studies based on the Newcastle-Ottawa scale [25], which was developed to assess the quality of observational studies in meta-analyses. Studies with scores greater than 7 were considered high quality.

Statistical Analysis

We used Stata SE version 13.0 software (StataCorp, College Station, TX, USA) for statistical analysis. The Cochran Q χ2 test and the Higgins I2 statistic were used to assess heterogeneity among studies [26]. Negative values of I2 were set at zero; the I2 results are between 0 and 100%. An I2 value >50% was considered to indicate substantial heterogeneity [26]. The random-effects model (DerSimonian and Laird method) was applied to combine the risk estimates and 95% confidence intervals (CIs) reported in individual studies; this model is considered to give more generalized results as it incorporates potential heterogeneity. We evaluated the publication bias of the studies included in the final analysis using a Begg funnel plot [27]. Publication bias was not assessed because the meta-analysis included fewer than 10 studies [28].

Search Results

Using the keywords, 898 potentially eligible articles were identified. Of these, 720 articles, as well as 126 duplicates, were excluded after reading the titles and abstracts; 40 citations remained for full-text screening. Of these, 3 studies [22, 29, 30] used the Danish Pathology Register; therefore, only the latest and largest study [22] was included. However, the study by Bonderup et al. [20] included a subgroup analysis based on individual PPIs. Finally, 12 studies involving approximately 16,633 MC cases were included in the analysis. Figure 1 presents the number of articles excluded at each stage of the eligibility assessment, together with the reasons for exclusion.

Fig. 1.

Flow chart of the studies considered and finally selected for review.

Fig. 1.

Flow chart of the studies considered and finally selected for review.

Close modal

Characteristics of the Included Studies

The characteristics of the included studies and participants are listed in Table 1. The earliest and most recent studies were published in 1992 and 2021, respectively. Four studies were population-based studies, and the remaining were hospital-based studies. Three studies were performed in the USA, and 9 were performed in Europe. There was heterogeneity in the type of drug exposure among the studies, including NSAIDs, PPIs, aspirin, SSRIs, statins, ACEIs, BDZs, β-blockers, diuretics, and H2 antagonists. Two control groups were considered in our included studies: (1) random controls: healthy controls from the source population; and (2) colonoscopy or diarrhoea controls: those who had undergone a colonoscopy without MC or patients with diarrhoea. We excluded case reports and series, animal studies, editorials, and reviews. The Newcastle-Ottawa scale scores (maximum possible score, 9) in the 12 studies ranged from 4 to 8 (median, 6.6) (online suppl. Table S3).

Table 1.

Summary of observational studies evaluating MC risk with drug exposure

 Summary of observational studies evaluating MC risk with drug exposure
 Summary of observational studies evaluating MC risk with drug exposure

Meta-Analysis

Nonsteroidal Anti-Inflammatory Drugs

The results of all meta-analyses are presented in Table 2. Nine studies with 10 estimates involving 16,504 MC cases reported the risk of MC in relation to NSAID exposure; the combined OR for MC was 1.79 (95% CI: 1.41–2.27; p < 0.001; I2 = 72.5%; Fig. 2). In subgroup analyses according to type of control, a significant association was observed in studies using a random control (OR, 1.7; 95% CI: 1.3–2.22; p < 0.001; I2 = 74.8%) or a colonoscopy or diarrhoea control (OR, 2.55; 95% CI: 1.16–5.6; p = 0.02; I2 = 68.6%).

Table 2.

Meta-analysis for studies included in the analysis

 Meta-analysis for studies included in the analysis
 Meta-analysis for studies included in the analysis
Fig. 2.

NSAID exposure and the risk of MC.

Fig. 2.

NSAID exposure and the risk of MC.

Close modal

Proton Pump Inhibitors

Ten studies with 12 estimates including 16,340 MC cases reported the risk of MC in relation to PPI exposure; the combined OR for MC was 2.34 (95% CI: 1.64–3.35; p < 0.001; I2 = 85.9%; Fig. 3). In subgroup analyses according to type of control, a significant association was observed in studies using a random control (OR, 2.93; 95% CI: 1.9–4.51; p < 0.001; I2 = 94.3%) but not in those using a colonoscopy or diarrhoea control (OR, 1.66; 95% CI: 0.6–4.61; p = 0.332; I2 = 88.9%). After grouping the studies according to the individual PPI, a significant association was observed for omeprazole (OR, 2.49; 95% CI: 1.82–3.43; p < 0.001; I2 = 67.9%) and lansoprazole (OR, 9.57; 95% CI: 4.69–19.49; p < 0.001; I2 = 96.6%).

Fig. 3.

PPI exposure and the risk of MC.

Fig. 3.

PPI exposure and the risk of MC.

Close modal

Selective Serotonin Reuptake Inhibitors

Ten studies with 12 estimates involving 16,466 MC cases reported the risk of MC in relation to SSRI exposure; the combined OR for MC was 2.34 (95% CI: 1.64–3.35; p < 0.001; I2 = 85.9%; Fig. 4). In subgroup analyses according to type of control, a significant association was observed in studies using a random control (OR, 2.95; 95% CI: 1.87–4.67; p < 0.001; I2 = 87.7%) but not in those using a colonoscopy or diarrhoea control (OR, 1.02; 95% CI: 0.76–1.36; p = 0.91; I2 = 0%).

Fig. 4.

SSRI exposure and the risk of MC.

Fig. 4.

SSRI exposure and the risk of MC.

Close modal

Statins

Seven studies with 9 estimates including 16,230 MC cases reported the risk of MC in relation to statin exposure; the combined OR for MC was 1.12 (95% CI: 0.9–1.38; p = 0.31; I2 = 67.5%). In subgroup analyses according to type of control, no significant association was observed in studies using a random control (OR, 1.19; 95% CI: 0.95–1.49; p = 0.13; I2 = 62.9%) or a colonoscopy or diarrhoea control (OR, 0.9; 95% CI: 0.68–1.2; p = 0.49; I2 = 0%).

Other Drugs

Four studies with 7 estimates including 526 MC cases reported the risk of MC in relation to aspirin exposure; the combined OR for MC was 2.84 (95% CI: 1.4–5.76; p < 0.001; I2 = 51.3%). We also evaluated the association of other drug exposures with MC, which was reported by several of the studies. Exposure to ACEIs (OR, 1.52; 95% CI: 0.91–2.52; p = 0.11; I2 = 55.6), BDZs (OR, 1.04; 95% CI: 0.73–1.49; p = 0.83; I2 = 0%), β-blockers (OR, 2; 95% CI: 0.95–4.2; p = 0.07; I2 = 75.3%), diuretics (OR, 0.95; 95% CI: 0.71–1.28; p = 0.74; I2 = 0%), or H2 antagonists (OR, 1.31; 95% CI: 0.44–3.95; p = 0.63; I2 = 86.2%) was not associated with an increased risk of MC.

MC is an ageing-associated disease that appears more often in the elderly. Epidemiological study has shown that age over 65 years is associated with a significantly increased risk of MC [17]. Drug consumption is considerably more frequent in this age group than in younger people. Our meta-analysis of 12 case-control studies suggested a significant association between the use of some drugs and MC. As considerable heterogeneity was observed in the marked study, we can be less certain about this result.

NSAIDs are some of the most commonly used medications in patients requiring analgesic, antipyretic, and anti-inflammatory therapies and are reportedly associated with intestinal mucosal inflammation, perforation, and bleeding [31]. In addition, NSAIDs may exacerbate preexisting inactive inflammatory bowel disease [32]. Therefore, it is reasonable to speculate that exposure to NSAIDs may induce MC by decreasing the synthesis of prostaglandins, which have important immunosuppressive properties [33]. Although there were 2 previous meta-analyses demonstrating a role for NSAIDs in MC, we conducted an updated pooled analysis with larger sample sizes. Our results using a colonoscopy or diarrhoea control group, which were more representative of the general population, agree with these data. This association between NSAID use and MC should be interpreted with caution due to the high heterogeneity. It also should be noted that the OR for MC was less than 2; therefore, further studies are still needed to verify this association.

The most recent systematic review identified only 5 observational studies with 6,321 MC cases but did not provide an overall estimation of the effect of PPIs on MC [18]. The authors recommended that a history of PPI use should be viewed as a potential risk factor for MC. However, the mechanism is unclear. Proton pump inhibition by PPIs induces pH changes that alter the intraluminal environment and bacterial flora, leading to small-intestinal bacterial overgrowth [34]. Furthermore, PPIs can induce transmucosal leakage in the upper GI tract [35, 36], which is associated with a higher frequency of mucosal defects. Our result was consistent with a previous meta-analysis, which found a substantially increased risk of MC induced by PPIs. However, the subgroup analysis did not show that patients with MC did not consume more PPI medications compared with the colonoscopy or diarrhoea control. The inconsistent findings may be due to the type of PPI or sample size. The strength of the association was high for lansoprazole because the OR values obtained were ≥9. It has been hypothesized that lansoprazole and/or its metabolites have a direct toxic effect on colonocytes [37].

Diarrhoea is a common adverse event associated with SSRI use and is more severe with sertraline [38]. The mechanism by which SSRIs cause diarrhoea is unknown. One hypothesis is that SSRIs increase serotonin release via stimulation of enterochromaffin cells [39]. However, the intestinal immune balance could be modulated by serotonin in diarrhoea patients with inflammatory diseases [40, 41]. The findings were inconsistent in our subgroup based on type of control. Therefore, future studies of SSRI-induced MC should include control groups with diarrhoea and not only healthy controls.

The strength of our meta-analysis lies in its large sample size and comprehensive search, which allowed detailed examination of the association. In addition, unlike the previous meta-analysis, we conducted a further analysis using colonoscopy or diarrhoea as the control. However, the meta-analysis also has several limitations. The most important limitation was the residual number of unknown confounders. Further well-designed studies considering more covariates, such as smoking status, concomitant drug use, and autoimmune disorders, are required to examine the association between drug consumption and MC. Second, there were sparse data on the time and dose of the drug used in the included studies; therefore, we could not draw robust conclusions on the exposure parameters potential associated with MC risk. Fourth, varying definitions of MC were used among the studies. Finally, the number of eligible studies and the sample size of patients on other drugs (such as ACEIs and BDZs) were small, which might have influenced the accuracy of the results.

In conclusion, our results suggest that exposure to NSAIDs, PPIs, SSRIs, or aspirin may be associated with the risks of MC. There is a need for large observational studies of high quality with appropriate controls to examine the effects of individual NSAIDs, PPIs, SSRIs, or aspirin and whether the association is dose or time dependent. Given their widespread use, clinicians should routinely question whether patients are receiving unnecessary treatment with NSAIDs, PPIs, SSRIs, or aspirin and to discontinue therapy where appropriate.

An ethics statement is not applicable because this study is based exclusively on published literature.

The authors declare no competing interest.

This research received no external funding.

Guarantor of article and manuscript drafting: Dan Chen. Study concept and study supervision: Shao-Wen Zhang and Dan Chen. Study design: Shao-Wen Zhang. Data collection and/or data interpretation: all the authors. Data analysis: Ru-hu Xu. Manuscript edition and final approval: all authors. All the authors identified above have critically reviewed the paper and approved the final version of this paper, including the authorship statement.

The data and materials associated with this study are not deposited in any repositories. It will be available from the corresponding author upon the proper request.

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Additional information

Shao-Wen Zhang and Ru-hu Xu contributed equally to this work.