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Background: Microscopic colitis is a relatively new diagnosis that was first described in the 1980s. Patients usually present with chronic watery and non-bloody diarrhea and are typically characterized by an unremarkable gross appearance of the colon on lower endoscopy while having evidence of lymphocytic infiltration of the lamina propria and the epithelium on histology. Two subtypes have been described in the literature: Collagenous colitis, with marked thickening of the subepithelial layer, and Lymphocytic colitis. Multiple risk factors such as female gender, older age and celiac disease have been associated with this entity. A few studies have found an association between microscopic colitis and proton-pump inhibitor (PPI). The aim of our study was to evaluate the risk of developing microscopic colitis and its subtypes for patients who are on PPI therapy., Methods: A validated multicenter and research platform database of more than 360 hospitals from 26 different healthcare systems across the United States from 1999 to September 2022 was utilized to construct this study. Patients aged 18 years and above were included. Individuals who have been diagnosed with any autoimmune disease have been excluded. A multivariate regression analysis was performed to assess risk of developing microscopic, lymphocytic, and collagenous colitis by accounting for potential confounders including female gender, smoking history, and the use of proton pump inhibitor, nonsteroidal anti-inflammatory drugs, and selective serotonin receptor inhibitors. A two-sided P value <0.05 was considered as statistically significant, and all statistical analyses were performed using R version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria, 2008)., Results: 78,256,749 individuals were screened in the database and 69,315,150 were selected in the final analysis after accounting for inclusion and exclusion criteria. The baseline characteristics of patients with microscopic, lymphocytic, and collagenous colitis is seen in table 1. Using a multivariate regression analysis, the risk of developing microscopic, lymphocytic, and collagenous colitis was calculated and illustrated in table 2., Discussion: Our study showed that the risk of microscopic colitis, lymphocytic colitis and collagenous colitis was higher in females and smokers. Although medications like SSRI and NSAIDs showed a positive correlation with colitis, the highest likelihood of developing this disease was associated with PPIs. Lansoprazole has been documented to be associated with microscopic colitis as it is believed to inhibit colonic proton pumps, and subsequently promote diarrhea and inflammation. Interestingly, the prevalence of lymphocytic colitis and collagenous colitis was similar in the cohort of patients treated with PPIs, indicating no specific predisposition to either subtype. This study further confirms the risk factors associated with microscopic colitis. It can help guide physicians to recognize and eliminate these risk factors prior to initiating treatment for this disease. Future studies can focus on identifying the incidence of microscopic colitis with the different types of PPIs in the market.

Microscopic colitis is a chronic inflammatory disorder of the colon characterized by microscopic changes in the intestinal lining. Turmeric, a commonly used spice, is generally regarded as beneficial for digestive and articular health thanks to its anti-inflammatory properties. No cases of microscopic colitis under a food supplement containing turmeric has been previously described in the literature. This article highlights 3 cases where the consumption of a specific turmeric-based supplement caused microscopic colitis. Each of them complained about profuse watery diarrhea shortly after initiating the food supplement containing turmeric. Ileo-colonoscopies with biopsies confirmed the diagnosis of microscopic colitis, with two cases classified as lymphocytic colitis and the third as collagenous colitis. Following the discontinuation of the supplement, all patients experienced a resolution of their symptoms within a few days. Subsequent control biopsies for the three patients confirmed the resolution of microscopic colitis., (© Acta Gastro-Enterologica Belgica.)

Microscopic colitis is part of the differential diagnosis of chronic watery diarrhea. Colonoscopy discloses a normal looking mucosa, therefore its diagnosis is based on histology of colonic biopsies. Two main phenotypes are distinguished: collagenous colitis and lymphocytic colitis. A third entity, incomplete microscopic colitis or unspecified microscopic colitis has been reported in the literature. It affects preferentially women over 60 years of age and its association with certain drugs is increasingly established. In case of suspected drug-induced microscopic colitis, identification of the responsible drug is a key to management. After discontinuation of the suspected drug, the gold standard of treatment is budesonide both for induction and for maintenance in case of clinical relapse, as is often the case after discontinuation. Therapy with immunomodulators, biologics, or surgery is reserved for refractory forms of microscopic colitis after multidisciplinary consultation. Through the clinical case of colitis on olmesartan, we will review the latest recommendations on drug-induced microscopic colitis., Competing Interests: The authors declare that they have no conflict of interest, (© Acta Gastro-Enterologica Belgica.)

Purpose: Immune checkpoint inhibitors (ICIs) are frequently associated with adverse events, often affecting the gastrointestinal tract. We conducted this study to determine the characteristics and outcomes of cancer patients with pre-existing microscopic colitis (MC) who underwent ICI treatment., Methods: In this retrospective study, we identified 10 patients with pre-existing MC who received ICIs at our center 01/2010-06/2020. Clinical characteristics and disease outcomes were recorded., Results: Of 124 screened patients with MC before ICI exposure, 10 had sufficient data to be included in the study. Melanoma (40%) and lung cancer (30%) were the most prevalent cancer types, with 70% of stage IV cancer. Patients received either anti-programmed death 1 regimen (8, 80%) or anti-programmed death ligand 1 agent (2, 20%). Six patients (60%) had collagenous colitis, and 4 (40%) had lymphocytic colitis. The median time from MC diagnosis to ICI initiation was 4 years, with 1 patient on budesonide within 2 months of ICI initiation. Eight patients (80%) developed colitis exacerbations after ICI  and required selective immunosuppression. One patient received a compassionate-use fecal transplantation. The median time from ICI to colitis exacerbation was 14 days, with 40% and 50% of patients experiencing grade 3 diarrhea and grade 2 colitis, respectively, leading to hospitalization in 3 patients. Six patients received steroids and vedolizumab with no colitis recurrence. Of 8 patients who had colitis exacerbation, 6 resumed ICI therapy afterward; with 5 receiving concomitant vedolizumab for secondary prophylaxis., Conclusion: Our findings suggest that ICI exposure increases the risk of exacerbation of underlying colitis necessitating and responding to potent immunosuppression therapy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Pharmacovigilance risk signals have proposed a relationship between the use of acid-suppressive medications and the development of certain autoimmune and immune-mediated inflammatory diseases., Objective: A systematic review and a meta-analysis was performed., Methods: We reviewed MEDLINE (Ovid) and Scopus for comparative observational studies between these diseases and previous exposure to proton-pump inhibitors (PPI), H2-receptor antagonists (H2RA), and antacids. The protocol was registered on the PROSPERO database (CRD42020192715)., Results: From 3,191 citations, 25 articles were eligible and covered 16 diseases. Microscopic colitis (MC) was studied the most (7 studies). In a random-effects meta-analysis, there was low certainty evidence (GRADE approach) of a non-significant relationship between exposure to any PPIs and MC (meta-OR 3.28, 95% CI 0.98-11.0, I2 98.2%, six studies, 4,436 PPI-exposed MC patients). Moderate certainty evidence pointed towards large odds of collagenous colitis after exposure to lansoprazole (meta-OR 14.5, 95% CI 9.37-22.3, I2 10.2%, three studies, 1,725 lansoprazole-exposed patients). After PPI exposure, the risk of rheumatoid arthritis was slightly increased based on low certainty evidence from two cohort studies totaling 475 diagnoses (meta-RR 1.62, 95% CI 1.12-2.34, I2 34.5%)., Conclusions: In patients with MC, it would be reasonable to carefully review the indication of PPI, especially in CC patients using lansoprazole.

Microscopic colitis (MC) is a chronic inflammatory bowel disease that is characterized by nonbloody watery diarrhea. The epidemiology in Japan differs from that in Europe and the United States, but little information is available from epidemiological surveys of MC in Japan. This study aimed to provide a new hypothesis regarding the factors associated with MC by using the Japanese Adverse Drug Event Report (JADER) database. "Colitis microscopic" (preferred term code: 10056979) cases entered into the JADER database between 2004 and 2021 were analyzed. Of the 246,997 cases in the JADER database, 161 cases were observed to be associated with MC. A Weibull analysis revealed that the median onset duration of MC (interquartile range) was 72.5 (36.0‒125.5) days in lansoprazole users and 116.0 (60.3‒1089.0) days in aspirin users. A multiple logistic regression analysis revealed that MC was significantly associated with the female sex, as well as ages ≥ 60 years and drugs including lansoprazole, aspirin, and nicorandil. A subset analysis revealed that MC was positively associated with obesity in female cases. Our study cannot demonstrate a causal inference between MC and each drug; however, the findings suggest that MC was associated with nicorandil as well as with lansoprazole and aspirin., (© 2022. The Author(s).)

Background: Medication consumption has been suggested as a risk factor for microscopic colitis (MC), but studies of varying design have yielded inconsistent results. Our aim was to evaluate the association between medications and MC., Methods: A hybrid cohort of prospectively identified patients undergoing colonoscopy with biopsies for suspicion of MC (N = 144) and patients with MC enrolled within three months of diagnosis into an MC registry (N = 59) were surveyed on medication use. Medication use was compared between patients with and without diagnosis of MC by chi-squared test and binomial logistic regression adjusted for known risk factors of MC: age and gender., Results: In total, 80 patients with MC (21 new, 59 registry) were enrolled. Patients with MC were more likely to be older (p = 0.03) and female (p = 0.01) compared to those without MC. Aspirin and other non-steroidal anti-inflammatory drugs were more commonly used among patients who developed MC (p < 0.01). After controlling for age and gender, these medications remained independent predictors of MC with odds ratio for any non-steroidal anti-inflammatory drug use of 3.04 (95% CI: 1.65-5.69). No association between MC and other previously implicated medications including proton pump inhibitors and selective serotonin reuptake inhibitors was found., Conclusions: In this cohort of patients with chronic diarrhea, we found use of aspirin and non-steroidal anti-inflammatory drugs, but not other implicated medications to be associated with the development of MC. Whether these drugs trigger colonic inflammation in predisposed hosts or worsen diarrhea in undiagnosed patients is unclear. However, we feel that these findings are sufficient to discuss potential non-steroidal anti-inflammatory drug cessation in patients newly diagnosed with MC., (© 2022. The Author(s).)

Background: Microscopic colitis (MC) is associated with several risk factors; however, their relative risk has been variable and not thoroughly evaluated. We aimed to quantify the risk of medical comorbidities and medications associated with MC and treatment offered to these patients., Methods: A population-based retrospective analysis in International Business Machines (IBM) Explorys (1999-2018), a pooled, de-identified database of 63 million patients in the USA, was performed. Odds ratios (OR) were calculated between MC and other diseases/medications. MC patients were also stratified by age to assess trends of MC in different age groups., Results: A total of 1130 patients had MC in the database. Among medications, non-steroidal anti-inflammatory agents (OR, 20.2) and proton pump inhibitors (OR, 12.1) were associated with highest odds of MC. Among medical comorbidities, infectious gastroenteritis (OR, 26.6) and celiac disease (OR, 22.5) had the highest odds of being associated with MC. Tobacco smoking, psoriasis, Sjogren's syndrome, Clostridium difficile infection, and malabsorption syndromes all conferred odds greater than 10., Conclusion: Early identification of MC is critical for minimizing morbidity and mortality. Epidemiologic information can be integrated with current clinical algorithms to more rapidly identify patients at risk., (© 2022. Indian Society of Gastroenterology.)

Secukinumab an interleukin-17 (IL-17) monoclonal antibody inhibitor is currently approved for the treatment of rheumatological conditions, such as psoriasis and ankylosing spondylitis. Lymphocytic colitis, a phenotype of microscopic colitis, is a long-term inflammatory condition, is characterized by relapsing diarrhea. The specific entity of drug-induced lymphocytic colitis has been discussed with numerous individual cases being reported from around the world. Secukinumab has been linked with exacerbation of and de novo cases of inflammatory bowel disease. However, lymphocytic colitis in association with this drug has not been documented. The management of drug-induced lymphocytic colitis is complicated, as patients frequently exhibit spontaneous remission of symptoms. Removal of the offending agent has shown some benefit; however, some patients continue to exhibit symptoms months after drug cessation and washout. Although our patient's lymphocytic colitis was benign and responded to the cessation Secukinumab, it is an important diagnosis to consider in patients with new onset relapsing diarrhea treated with biologics.

Background: Microscopic colitis is an increasingly common cause of watery diarrhoea. Several classes of medications have been associated with microscopic colitis in prior studies., Aims: To determine the association between the use of previously implicated medications and microscopic colitis., Methods: This was a case-control study of patients referred for elective, outpatient colonoscopy for diarrhoea. Patients were excluded for inflammatory bowel disease, C difficile, or other infectious diarrhoea. Colon biopsies were reviewed by the study pathologist and patients were classified as microscopic colitis cases or non-microscopic colitis controls., Results: The study population included 110 microscopic colitis cases and 252 controls. The cases were older, better educated and more likely to be female. Cases reported a greater number of loose, watery, or liquid stools, nocturnal stools, more urgency and weight loss compared to controls. There was no association with proton pump inhibitors (PPIs), adjusted OR (aOR) 0.66, 95% CI 0.38-1.13 or nonsteroidal anti-inflammatory drugs, aOR 0.68, 95% CI 0.40-1.17. Cholecystectomy was less common in cases, aOR 0.33, 95% CI 0.17-0.64, but microscopic colitis cases had more frequent bowel movements following cholecystectomy., Conclusion: Compared to similar patients with diarrhoea, cases with microscopic colitis were not more likely to have taken previously implicated medications. They had more diarrhoea following cholecystectomy, suggesting that bile may play a role in symptoms or aetiology. We conclude that the appropriate choice of controls is crucial to understanding risk factors for microscopic colitis., (© 2021 John Wiley & Sons Ltd.)

Background: Medication use has been implicated in the development of microscopic colitis (MC). However, studies have demonstrated inconsistent findings and there exist variations in design., Aim: To measure the association between medication use and MC., Methods: Patients who underwent a colonoscopy over a 10-year period at two academic medical centres (Columbia University Medical Centre and Mayo Clinic) were identified. Cases were patients with biopsy-proven MC and controls were patients who underwent colonoscopy for evaluation of diarrhoea with biopsies negative for MC. Cases were matched by age, gender and calendar period with up to two controls. Demographics, medication use, smoking history and coeliac disease status were collected. Conditional logistic regression was used with and without adjustment for smoking., Results: A total of 344 patients with MC were matched to 668 controls. After adjusting for smoking, there was an inverse association between MC and use of proton pump inhibitors (PPIs) (OR 0.64; 95% CI 0.47-0.87), H2 blockers (OR 0.46; 95% CI 0.24-0.88) and oral diabetes medications (OR 0.47; 95% CI 0.27-0.81). There was a positive association with nonsteroidal anti-inflammatory drug (NSAID) use and MC (OR 1.63; 95% CI 1.12-2.38)., Conclusions: NSAID use was associated with MC, while use of PPIs, H2 blockers and oral diabetes medications were inversely related to MC. Our use of a control group with diarrhoea, as opposed to healthy controls, may have contributed to these inverse associations. Future studies of drug-induced microscopic colitis should include control groups with diarrhoea, and not only healthy controls., (© 2021 John Wiley & Sons Ltd.)

Background: Microscopic colitis is a form of inflammatory bowel disease characterized by profuse non-bloody watery diarrhea. Macroscopic abnormality is not present on colonoscopy, and it requires biopsy for diagnosis. Few cases have been attributed to levodopa/dopa-decarboxylase inhibitor therapy., Method: A retrospective cohort study of 21 patients on levodopa/benserazide and one patient on levodopa-carbidopa intestinal gel with clinically suspected or biopsy proven microscopic colitis., Results: All 21 patients on oral levodopa/benserazide had resolution of diarrhea with cessation of the medication. Four patients discontinued levodopa permanently. Two were rechallenged with levodopa/benserazide without symptom recurrence. One patient on oral levodopa/carbidopa developed diarrhea only with intermittent dispersible levodopa/benserazide. 14 were switched to levodopa/carbidopa with resolution of diarrhea in 9 but symptom recurrence in 5. One patient on oral levodopa/benserazide developed profuse diarrhea when switched to levodopa-carbidopa intestinal gel. Of 7/22 patients who had colonoscopy and biopsy, 5 had histopathological proven microscopic colitis., Conclusion: levodopa/dopa-decarboxylase inhibitor induced microscopic colitis may be more common than previously suspected, with the potential to affect treatment compliance and therapeutic options., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Enterocolitis is among the leading adverse events associated with immune checkpoint inhibitors (ICIs). There are limited retrospective data regarding the safety of ICIs in patients with inflammatory bowel disease (IBD; ulcerative colitis, Crohn's disease) because they have been generally excluded from clinical trials testing ICIs. Furthermore, there are no outcome data available in patients with microscopic colitis, a leading cause of chronic diarrhea. We aimed to study the safety of ICIs in patients with cancer with pre-existing IBD or microscopic colitis., Methods: We retrospectively reviewed the records of patients with cancer treated at our institution who received at least 1 dose of either a programmed cell death-1 (PD-1)/ PD-1 ligand inhibitor, cytotoxic T-lymphocyte-associated antigen 4 inhibitor, or both between 2011 and 2018. We identified patients with pre-existing IBD or microscopic colitis., Results: Of 548 patients with solid tumor treated with an ICI, we identified 25 with pre-existing colitis (21 IBD; 4 microscopic colitis). An enterocolitis flare occurred in 7 patients (28%): 3 of 4 patients (75%) with microscopic colitis and 4 of 21 (19%) with IBD. All were treated with systemic corticosteroids, 2 required an anti-tumor necrosis factor agent, and one required an anti-integrin agent and colectomy for treatment of refractory colitis. ICI therapy was discontinued in all patients who experienced an enterocolitis flare., Conclusion: In our cohort, exacerbation of enterocolitis occurred in a notable percentage of patients with IBD and a majority of patients with microscopic colitis, leading to discontinuation of ICIs. Although these data suggest that patients with cancer with pre-existing IBD/microscopic colitis may be treated with ICIs, additional studies are needed to validate our results.

Background: During clozapine treatment, diarrhea is a rare but clinically relevant adverse effect. Cases of microscopic colitis and eosinophilic colitis have been previously reported., Procedures: We present 4 patients who developed severe diarrhea in early weeks of clozapine therapy., Findings: Two patients had significant peripheral eosinophilia 1 week after diarrhea symptoms. One of these patients also had Charcot-Leyden crystals in stool afterward, confirming the presence of eosinophils in the gut lumen. One of our patients had a confirmed microscopic colitis and later also neutropenia, which required treatment., Conclusions: Charcot-Leyden crystals in stool may be associated with concurrent diarrhea and eosinophilia during clozapine treatment, which is a previously unreported finding. Occurrence of blood dyscrasias with diarrhea symptoms during clozapine treatment needs further investigation to understand the possible shared mechanisms.

Immune checkpoint inhibitors (ICPis) have revolutionised survival outcomes for cancer patients by bolstering anti-tumour immunity. However, immune activation also occurs in non-cancer tissue, and a significant proportion of patients develop immune-mediated colitis, which can be fatal if not promptly recognised and managed. Diagnosis is often made by inflammation observed during lower gastrointestinal endoscopy. Little is known about microscopic inflammation (histological findings of inflammation in the absence of overt mucosal injury). Management strategies beyond the use of systemic corticosteroids, which incur a high burden of deleterious side effects, have not been extensively explored. We describe the cases of two cancer patients with ICPi-induced colitis who had isolated histoloigical features of colitis in the absence of macroscopic disease. Sustained clinical and histological remission was induced with the topical steroid preparation, beclometasone dipropionate (Clipper), with no adverse effects., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Microscopic colitis is a chronic inflammatory disorder of the colon primarily affecting postmenopausal women. However, the relation between hormonal determinants, including reproductive and menopausal factors, and risk of microscopic colitis has yet to be characterized., Methods: We collected data from 227,766 women who participated in the Nurses' Health Study (NHS) and the NHSII without a baseline history of microscopic colitis. Reproductive and menopausal factors were assessed in 1988 in the NHS and 1989 in the NHSII and updated biennially. Cases of microscopic colitis were confirmed through review of pathology records. We used Cox proportional hazards modeling to estimate hazard ratios and 95% confidence intervals., Results: Through 2014 in the NHS and 2015 in the NHSII, we confirmed 275 incident cases of microscopic colitis over 5,147,282 person-years. Compared with never use, current use of menopausal hormone therapy was associated with increased risk of microscopic colitis (multivariable-adjusted hazard ratio 2.64; 95% confidence interval 1.78-3.90). The risk increased with longer duration of use (P for trend < .0001) and decreased after discontinuation (P for trend = .002). The association did not differ according to disease subtype (P for heterogeneity = .34). Similarly, ever use of oral contraceptives was associated with increased risk of microscopic colitis (multivariable-adjusted hazard ratio 1.57; 95% confidence interval 1.16-2.13). There were no associations between age at menarche, parity, age at first birth, age at menopause, or menopause type and incident microscopic colitis., Conclusions: In 2 large prospective cohort studies, we observed an association between exogenous hormone use and incident microscopic colitis. Further studies are needed to determine the mechanisms underlying these associations., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Eosinophilic colitis is a rare clinical condition that belongs to the group of eosinophilic gastrointestinal disorders. Its occurrence can be primary or secondary to infection, medications, or autoimmune/hematological conditions. We present a case of a young female adult with severe chronic fatigue syndrome, widespread chronic pain, including functional abdominal pain, who developed severe eosinophilic colitis following successive treatments with gabapentin and pregabalin. On both occasions, symptoms manifested as abdominal pain, diarrhea, and eosinophilia and improved upon discontinuation of the medications. Magnetic resonance imaging of the small bowel demonstrated an ascending colon colitis, and endoscopic investigations confirmed florid colitis mainly in the ascending colon with biopsies demonstrating a dense eosinophilic infiltrate with micro-abscesses. Serum eosinophil counts correlated well with the timing of the agents' administration. There was no other organ involvement. Symptoms improved upon discontinuation of the drugs and steroid administration. Eosinophilic colitis is an exceptionally rare entity and its mechanism of action is still unclear. Suspicion of eosinophilic colitis should be raised if a patient presents with abdominal pain, diarrhea, and peripheral eosinophilia following treatment with pregabalin or gabapentin., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: Microscopic colitis (MC) is a chronic inflammatory disease of the colon that is characterized by chronic, watery, nonbloody diarrhea. Concern regarding a potential association between proton-pump inhibitors (PPIs) and MC has recently emerged. We sought to systematically review and summarize the evidence for the potential association between PPIs and MC., Data Sources: We systematically searched EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, and Google Scholar using the terms proton-pump inhibitors (omeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, or esomeprazole), microscopic colitis, collagenous colitis, and lymphocytic colitis., Study Selection: Full-text, English-language reports of case reports/series, observational studies, experimental studies, and systematic reviews/meta-analyses published between January 2000 to August 2016 were included. Bibliographies from pertinent publications were reviewed for additional references. Outcome was defined as the development of biopsy-confirmed MC., Data Extraction/synthesis: A total of 19 publications were identified: 5 case control studies and 14 case reports/series (encompassing a total of 32 cases). All studies were limited by small sample sizes. Risk of MC by dose or specific PPI agent was not investigated in any of the studies. A review of the current body of evidence reveals a possible association between PPIs and MC., Conclusions: There is a need for large observational studies of high quality to examine the differential effect of specific PPIs and whether the magnitude of association is dose dependent. Given their widespread use, clinicians should routinely question whether patients are receiving unnecessary treatment with PPIs and discontinue therapy where appropriate.

A variety of luminal antigens, including a wide range of drugs, have been associated with the still little-known pathophysiology of microscopic colitis (MC), with variable evidence suggesting causality. This article aims to review the aspects related to drugs as potential triggers of MC; to discuss the most commonly identified associations between drugs and MC; and to analyze the limitations of the studies currently available. A literature search was performed in PubMed combining the search terms 'drug exposure', 'drug consumption', and 'risk factors' with 'microscopic colitis', 'lymphocytic colitis', and 'collagenous colitis', with no language restrictions. Reference lists of retrieved documents were also reviewed. A handful of case-control studies have demonstrated significant associations between some commonly used drugs and a higher risk of developing MC. No universally accepted criteria for establishing cause-effect relationships in adverse reactions to drugs are available, but several methods that can be applied to MC, can provide degrees of the likelihood of an association. A high probability imputation in the development of MC as a drug adverse effect has only been demonstrated for individual cases by applying chronological (challenge, de-challenge, and relapse with re-challenge) and semiological criteria. Several case-control studies have shown significant associations between exposure to drugs and MC, but the variability in their design, the reference populations used, and the definitions for drug exposure considered require specific analyses. It can be concluded that drug exposure and MC as a likely cause-effect relationship has only been described for a handful of drugs and in individual cases.

Background: Microscopic colitis (MC) is a chronic bowel disorder characterised by watery diarrhoea. Nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), selective serotonin reuptake inhibitors (SSRIs) and statins have been associated with MC. However, underlying mechanisms remain unclear., Aim: To study the association between exposure to these drugs and MC, with attention to time of exposure, duration, dosage and combined exposure, and to test hypotheses on underlying pharmacological mechanisms., Methods: A case-control study was conducted using the British Clinical Practice Research Datalink. MC cases (1992-2013) were matched to MC-naive controls on age, sex and GP practice. Drug exposure was stratified according to time of exposure, duration of exposure or dosage. Conditional logistic regression analysis was applied to calculate adjusted odds ratios (AORs)., Results: In total, 1211 cases with MC were matched to 6041 controls. Mean age was 63.4 years, with 73.2% being female. Current use of NSAIDs (AOR 1.86, 95% CI 1.39-2.49), PPIs (AOR 3.37, 95% CI 2.77-4.09) or SSRIs (AOR 2.03, 95% CI 1.58-2.61) was associated with MC compared to never or past use. Continuous use for 4-12 months further increased the risk of MC. Strongest associations (fivefold increased risk) were observed for concomitant use of PPIs and NSAIDs. Statins were not associated with MC., Conclusions: Current exposure to NSAIDs, PPIs or SSRIs and prolonged use for 4-12 months increased the risk of MC. Concomitant use of NSAIDs and PPIs showed the highest risk of MC. Acid suppression related dysbiosis may contribute to the PPI effect, which may be exacerbated by NSAID-related side-effects., (© 2016 John Wiley & Sons Ltd.)

Aflibercept is a recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF). This molecule binds to all isoforms of VEGF-A as well as VEGF-B and placental growth factor, preventing them from activating their respective receptors. Aflibercept is used for the treatment of metastatic colorectal cancer (mCRC) in association with irinotecan. For reasons that remain to be elucidated, the addition of aflibercept to irinotecan-based chemotherapy increases the incidence of grade 3-4 diarrhea. We performed systematic colonic biopsies in three patients with grade 3 diarrhea after introduction of fluorouracil, leucovorin, irinotecan and aflibercept treatment for mCRC. For each patient, the diarrhea necessitated treatment discontinuation. Colonoscopy showed normal colonic mucosa. However, histopathological examination of the biopsies performed in these three patients revealed typical features of microscopic colitis. All three patients were treated with budesonide and mesalazine, leading to rapid regression of clinical symptoms. Chemotherapy was reintroduced in all patients, with only mild, grade 1 diarrhea under mesalazine and budesonide treatment. These are the first observations of aflibercept-induced microscopic colitis, and support the use of specific treatment on top of anti-diarrheal treatment in case of important digestive adverse events.

Background: Microscopic colitis has now emerged as a common cause of chronic diarrhoea, but its aetiology remains unknown. Some studies suggest that commonly prescribed drugs and other additional risk factors may be triggers., Aims: To evaluate the effects of drug intake and other risk factors on microscopic colitis patients., Methods: A prospective, case-control study with all consecutive adult patients referred to the Hospital General de Tomelloso (Ciudad Real, Spain) for chronic watery diarrhoea (from 2008 to 2011) was performed. Microscopic colitis was diagnosed following the commonly accepted histopathological criteria., Results: 46 consecutive new cases of microscopic colitis and 317 chronic diarrhoea controls were recruited. Five independent risk factors significantly associated with microscopic colitis were identified: Abdominal pain (OR 3.25; 95%CI, 1.49-7.08), weight loss (OR 2.67; 95%CI, 1.16-6.15), celiac disease (OR 15.3; 95%CI, 3.70-63.5), topiramate intake (OR 13.6; 95%CI, 1.84- 100.8), and older age at diagnosis (OR 1 year increase 1.022; 95%CI, 1.002-1.042). Use of non-steroidal anti-inflammatory drugs was associated with microscopic colitis in the subgroup of patients who fulfilled irritable bowel syndrome criteria (38.5% vs. 10.8%; p < 0.017)., Conclusions: Microscopic colitis is associated with autoimmune disease, an increased age at diagnosis, topiramate intake and only in a sub-group of irritable bowel disease patients with non-steroidal anti-inflammatory drugs.

Objectives: Microscopic colitis (MC) is characterized by chronic watery diarrhea. Recently, several drugs were reported to increase the risk of MC. However, studies lacked a clear exposure definition, did not address duration relationships, and did not take important biases into account. We estimated the risk of MC during drug use., Methods: This is a population-based nested case-control study using a Dutch primary care database (1999-2013). Incident MC cases (aged ≥18 years) were matched to community-based and colonoscopy-negative controls on age, sex, and primary care practice. Drug use was assessed within 1 and 2 years before the index date. Adjusted odds ratios (OR) were calculated by conditional logistic regression., Results: From the source population of 1,458,410 subjects, 218 cases were matched to 15,045 community controls and 475 colonoscopy-negative controls. Current use (≤3 months) of proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors, low-dose aspirin, angiotensin-converting enzyme (ACE) inhibitors and beta-blockers significantly increased the risk of MC compared with never use in community controls. Adjusted ORs ranged from 2.5 (95% confidence interval (CI): 1.5-4.2) for ACE inhibitors to 7.3 (95% CI: 4.5-12.1) for PPIs in the year prior to the index date. After accounting for diagnostic delay, only use of NSAIDs, PPIs, low-dose aspirin, and ACE inhibitors increased the risk of MC. Compared with colonoscopy controls, only use of PPIs (OR-adjusted 10.6; 1.8-64.2) and NSAIDs (OR-adjusted 5.6; 1.2-27.0) increased the risk of MC., Conclusions: NSAIDs and PPIs are associated with an increased risk of MC. The association of MC with use of the other drugs is probably explained by worsening of diarrhea/symptoms rather than increasing the risk of MC itself.

Background: Previous small studies have indicated that commonly prescribed drugs may be associated with microscopic colitis (MC). With an increasing incidence of MC, it is important to explore the association between exposure to proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs, statins, and selective serotonin reuptake inhibitors and MC in a larger setting., Methods: Case-control study based on nationwide Danish registries. The study included all patients with MC diagnosis during the period 2005 to 2011. One hundred sex- and age-matched controls per case were randomly selected among the Danish population. Prescriptions were recorded in a Prescription Register in the year before the first recorded MC diagnosis. Effect measure is the adjusted odds ratio (OR) of collagenous colitis (CC) and lymphocytic colitis (LC) according to prescriptions of PPIs, nonsteroidal anti-inflammatory drugs, statins, and selective serotonin reuptake inhibitors. Within the control group, we identified a subgroup with MC-free colonic biopsies., Results: We identified 3474 patients with CC and 2277 with LC and found a positive association between redemption of prescriptions for PPIs and both CC (OR = 7.04; 95% confidence interval, 6.55-7.56) and LC (OR = 3.37; 95% confidence interval, 3.08-3.69). Among patients with MC-free colon biopsies in the control group, the association between PPIs and CC was strongly positive (OR = 3.47; 95% confidence interval, 3.08-3.89). Adding this parameter to the model attenuated all of the associations, but they remained positive for PPIs versus CC and selective serotonin reuptake inhibitors versus LC., Conclusions: We found positive associations between exposure to all 4 medication classes and MC. Variations in endoscopic frequency by drug category indicate a potential impact of bias.

Microscopic colitis (MC) is diagnosed in up to 13% of patients investigated for chronic diarrhea, particularly in middle-aged and elderly patients. Recent studies have suggested an etiological role for various drugs, including nonsteroidal anti-inflammatory drugs and proton pump inhibitors. To ascertain the potential role for drug exposure in the development of MC, we performed a systematic review based on a MEDLINE search and conducted a meta-analyses on the available data. We also give an overview of the case reports and studies illustrating the role of drugs in inducing MC. A number of hypotheses are formulated with regard to the potential pathophysiological mechanisms in drug-induced MC. However, confirmative evidence is still largely lacking. Considering the high number of drug users and the relatively low incidence of MC, it is more likely that drug-induced cases of MC are the result of an idiosyncratic reaction.

Objective: To report the response to discontinuation of olmesartan, an angiotensin II receptor antagonist commonly prescribed for treatment of hypertension, in patients with unexplained severe spruelike enteropathy., Patients and Methods: All 22 patients included in this report were seen at Mayo Clinic in Rochester, Minnesota, between August 1, 2008, and August 1, 2011, for evaluation of unexplained chronic diarrhea and enteropathy while taking olmesartan. Celiac disease was ruled out in all cases. To be included in the study, the patients also had to have clinical improvement after suspension of olmesartan., Results: The 22 patients (13 women) had a median age of 69.5 years (range, 47-81 years). Most patients were taking 40 mg/d of olmesartan (range, 10-40 mg/d). The clinical presentation was of chronic diarrhea and weight loss (median, 18 kg; range, 2.5-57 kg), which required hospitalization in 14 patients (64%). Intestinal biopsies showed both villous atrophy and variable degrees of mucosal inflammation in 15 patients, and marked subepithelial collagen deposition (collagenous sprue) in 7. Tissue transglutaminase antibodies were not detected. A gluten-free diet was not helpful. Collagenous or lymphocytic gastritis was documented in 7 patients, and microscopic colitis was documented in 5 patients. Clinical response, with a mean weight gain of 12.2 kg, was demonstrated in all cases. Histologic recovery or improvement of the duodenum after discontinuation of olmesartan was confirmed in all 18 patients who underwent follow-up biopsies., Conclusion: Olmesartan may be associated with a severe form of spruelike enteropathy. Clinical response and histologic recovery are expected after suspension of the drug., (Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Frequency of colitis induced by drugs is often under estimated. Antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDS) are usually incriminated. In this study, we classified colitis according to the main responsible drug with a focus on clinical symptomatology, physiopathology, evolution, and complications. We describe colitis due to antibiotics, NSAIDS, laxatives, vasoconstrictive agents, oestroprogestatives, chemotherapy and drugs induced microscopic colitis. The last one represents a particular case; it can be idiopathic, infectious or drugs induced. Its physiopathology is not well known and its diagnosis is based only on histologic criterion. Drug responsibility is easy to determine only for pseudomembranous colitis. In the other cases, chronology is very variable and the clinical, endoscopic and histological elements are rarely specific. Because of the large number of drugs that may induce colitis, it is necessary to search for potentially responsible drugs, especially if there is no obvious cause of the colitis., (© 2010 Société Française de Pharmacologie et de Thérapeutique.)

Goals: The aim of this study was to determine whether proton pump inhibitors other than lansoprazole might be associated with microscopic colitis., Background: Lansoprazole exposure has been associated with diarrhea and microscopic colitis, but this relationship has not been described with other proton pump inhibitors., Study: Cases of microscopic colitis from a consultative gastroenterology practice were collected and reviewed for proton pump inhibitor exposure. Standard clinical, endoscopic, and biopsy findings were analyzed., Results: A case series of 4 patients is described in which subjects developed classic symptoms of lymphocytic-collagenous colitis with typical mucosal histopathology during treatment with omeprazole/esomeprazole. Symptoms promptly stopped and mucosal biopsies returned to normal with drug withdrawal. Disease quickly recurred in 2 patients who were reexposed to the drugs, one with biopsy documented recurrent collagenous colitis., Conclusions: Some cases of microscopic colitis seem to be associated with omeprazole/esomaprazole exposure. These results have epidemiologic, diagnostic, and therapeutic ramifications, which are discussed.

The association of microscopic colitis with celiac disease is rare. A case of microscopic colitis associated with celiac disease and following administration of venlafaxine in a 67-year-old patient is described. The pathophysiologic hypotheses of such an association are discussed.

Diarrhea is a frequent adverse event involving the most frequently antibiotics, laxatives and NSAI. Drug induced diarrhea may be acute or chronic. It may be due to expected, dose dependant properties of the drug, to immuno-allergic or bio-genomic mechanisms. Several pathophysiological mechanisms have been described resulting in osmotic, secretory or inflammatory diarrhea, shortened transit time, or malabsorption. Histopathological lesions sometimes associated with drug induced diarrhea are usually non specific and include ulcerations, inflammatory or ischemic lesions, fibrous diaphragms, microscopic colitis and apoptosis. The diagnosis of drug induced diarrhea, sometimes difficult to assess, relies on the absence of other obvious causes and on the rapid disappearance of the symptoms after withdrawal of the suspected drug.

Both diarrhea and colitis associated with clozapine have been reported. In this article, the authors present a case of clozapine-induced microscopic colitis (MC)-the first reported in the literature. The definitive diagnosis was suggested on colon biopsy, which showed an intraepithelial lymphocytosis (with >20 lymphocytes for every 100 epithelial cells) more striking in the surface epithelium than in the crypts. In addition, there were a mixed inflammatory infiltrate in the lamina propria (with lymphocytes predominating over eosinophils and neutrophils), an architecturally preserved colonic mucosa (particularly in the crypts), and a subepithelial collagen band normally thickened (<10 microm). Clozapine was thought to be the culprit and discontinued. After some days, the patient gradually improved. Diarrhea and spiking fever disappeared within 72 hours. Multiple colon biopsies taken after 7 days from the discontinuation of the clozapine revealed no abnormal histological findings. It is important to clarify the issue of clozapine-induced MC because MC may require the use of expensive or potentially toxic treatments and can occasionally be life-threatening (eg, hypokalemia). Thus, any case of MC that can be cured by withdrawal of the clozapine must be investigated and identified.