Gwen Masclee

Increased risk of microscopic colitis with use of proton pump inhibitors and 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.

Is clostridium difficile associated with relapse of inflammatory bowel disease? results from a retrospective and prospective cohort study in the Netherlands.

Background: Although Clostridium difficile may be associated with exacerbations in inflammatory bowel diseases (IBD), prospective studies identifying the role of C. difficile in disease activity are currently lacking. We examined the prevalence of C. difficile in feces of (1) symptomatic IBD patients retrospectively and (2) consecutive outpatients in relation to disease activity prospectively. Methods: From adult IBD patients with increase of symptoms, fecal samples collected between November 2010 and 2011 were tested for C. difficile, Salmonella, Shigella, Yersinia, and Campylobacter spp. Within a prospective IBD cohort, fecal samples, clinical data, and disease activity scores were collected every 3 months and during relapses. Baseline samples from all subjects (170 Crohn’s disease, 116 ulcerative colitis) and additional samples from patients with changing disease activity during follow-up (57 Crohn’s disease, 31 ulcerative colitis) were tested for C. difficile and when positive for toxin A and B genes by quantitative polymerase chain reaction. Results: From 104 symptomatic patients, 139 fecal samples were analyzed. Toxinogenic C. difficile and Campylobacter jejuni were detected in 3.6% and 1.8%. In the prospective cohort, C. difficile prevalence at baseline was significantly different neither between ulcerative colitis (3.4%) and Crohn’s disease patients (5.9%) nor between active (8.2%) and quiescent (3.3%) disease. In multivariable analysis, C. difficile was not associated with disease activity, disease subtype, gender, antibiotic, and immunosuppressive therapy. Clostridium difficile was also not associated with disease activity within patients with changing disease activity over time (P = 0.45). Conclusions: We found a low prevalence of C. difficile, and our findings indicate that C. difficile is not a common trigger for exacerbations of IBD in clinical practice in the Netherlands.

Enteropathogenic viruses: triggers for exacerbation in IBD? A prospective cohort study using real-time quantitative polymerase chain reaction.

Background:While the role of bacteria as an etiological factor triggering relapse in inflammatory bowel disease (IBD) has been studied extensively, little is known of the role of enteric viruses. We aimed to prospectively study the prevalence and risk factors for common enteropathogenic viruses in IBD patients in relation to disease activity. Methods:IBD patients visiting the outpatient clinic of the Maastricht University Medical Center were included in a prospective cohort with a follow-up of 1 year. Every 3 months and during relapses, fecal samples, demographic, and clinical data were collected and disease activity was scored. A fecal sample from patients at baseline (Crohn’s disease [CD] n = 170, ulcerative colitis [UC] n = 116) and an additional sample from a subgroup with changing disease activity during follow-up (CD n = 57, UC n = 31) were analyzed for the presence of rotavirus, norovirus GI and GII, human astrovirus, and adenovirus using quantitative polymerase chain reaction (qPCR). Results:Overall viral pathogen detection, defined by the detection of at least one of the studied viruses, at baseline was 5.2% and differed neither between CD (6.5%) or UC patients (3.4%) (P = 0.20), nor between active disease (4.7%) and remission (5.5%) (P = 0.79). Within the subgroup of patients with changing disease activity no association was found between overall viral pathogen detection and disease activity (P = 0.39). Using multivariate logistic regression, age, gender, disease subtype, disease activity, medication, and season of sampling were not associated with overall viral pathogen detection. Conclusions:Enteropathogenic viruses are not frequently observed in a consecutive cohort of IBD patients and are not a common trigger for active disease in daily clinical practice.

Incidence of microscopic colitis in relation to the number of colonoscopies over time

itors were associated with an increased risk of MC. As the authors point out, clinical awareness, more liberal use of colonoscopy, and routine random biopsy sampling in normal colonoscopies may have distorted the estimation of the “true” incidence of the disease. Th ese types of detection and diagnostic biases ( 2 ) are, however, diffi cult to account for in incidence studies. A possible solution to give insight in such detection bias is to calculate the incidence of the disease in relation to the number of diagnostic procedures. In a cohort study using data from a primary care database containing electronic medical records of 1.6 million subjects in Th e Netherlands, we identifi ed 210 incident, histologically verifi ed, MC cases between 2003 and 2013. We calculated the rate of MC both over the number of person-years (PY) as most studies do, but also over the number of index To the Editor: We read with great interest the thorough review and meta-analysis by Tong et al. “Incidence, Prevalence, and Temporal Trends of Microscopic Colitis: A Systematic Review and Meta-Analysis” ( 1 ) about microscopic colitis (MC). Th eir study summarizes the evidence from epidemiological studies on MC incidence and drug associations. Th ey report incidence rates from diff erent countries in diff erent time periods. Th ey conclude that the overall incidence of MC increases with age, is higher in females than males and is comparable to the incidence of infl ammatory bowel disease. Diff erences in study settings, geography, source population, and diagnosis verifi cation likely contributed to heterogeneity of the results. Nevertheless, MC incidences appear to have increased over time and proton pump inhibitors as well as selective serotonin re-uptake inhibCONFLICT OF INTEREST Guarantor of the article: Mark E. Gerich, MD. Specifi c author contributions: R.W.I. reviewed the literature and wrote the manuscript. C.B.C. and M.E.G. were involved in editing. Financial support: None. Potential competing interests: None.

812 Synergistic Effects of Concomitant Use of Non-Selective NSAIDs, Coxibs and Low-Dose Aspirin on Risk of Upper Gastrointestinal Bleeding

Aim: Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin (LDA) increases the risk of upper gastrointestinal bleeding (UGIB). Although clinical guidelines suggest to avoid certain drug combinations, little is known about the magnitude of interaction between different NSAIDs and specific drug groups. This is partly due to the need of a large sample for studying drug interactions. Understanding drug synergism is important to develop strategies to minimize the risk of UGIB. Design: A self-controlled case series analysis was performed using data from seven population-based healthcare databases located in three countries (Denmark, Italy, and the Netherlands). UGIB cases were identified based on disease classification codes. Drug exposure was classified into mutually exclusive groups. Interaction of the three main groups (non-selective (ns)NSAIDs, coxibs and LDA) with other drugs was examined. Incidence rate ratios (IRRs) of UGIB during exposure (and corresponding 95% CI) were obtained by Poisson regression modeling. Interaction was assessed on additive (with relative excess risk due to interaction, RERI) and multiplicative scale. Results: In total 114,835 UGIB cases, with corresponding follow-up of 930,888 personyears, were analyzed. Monotherapy with nsNSAIDs was associated with a higher IRR than monotherapy with coxibs or LDA (IRR 4.3; 2.9 and 3.1 respectively). The IRR was highest for concomitant use of nsNSAIDs and steroids (IRR 12.8; 95% CI: 11.2-14.7), which also demonstrated the highest additive interaction (RERI 5.5)(Figure 1). The IRR for nsNSAIDs and aldosterone antagonists was 11.0 (95%CI 8.6 -14.0) and RERI 4.5. Selective serotonin re-uptake inhibitors (SSRIs) and anticoagulants combined with either nsNSAIDs, coxibs or LDA increased the risk of UGIB significantly and also to a greater extent than expected based on the sum of the individual drugs (RERI 1.6;1.9 and 0.5 for SSRIs and 2.4;0.1 and 1.9 for anticoagulants, respectively). Only for the combination of LDA and antiplatelets was apart from additive, also multiplicative interaction observed (IRR 5.4; 95%CI: 4.7-6.4; RERI 1.7). Increasing age was associated with a higher IRR. Stratifying by age showed that for all drugs older persons (.60 years) had a higher IRR compared to younger persons ( ,60 years), except for combinations of nsNSAIDs+anticoagulants and coxibs+steroids. Conclusion: Concomitant use of SSRIs with nsNSAIDs, coxibs or LDA significantly increases the risk of UGIB up to seven-fold. Concomitant use of steroids, anticoagulants or antiplatelets with nsNSAIDs or LDA, but not with coxibs, showed an increased risk of UGIB, up to thirteen-fold. These increased risks were greater than the sum of the risks of individual drugs. This knowledge is of clinical relevance and can help clinicians in tailoring therapy to minimize UGI adverse events.