title: High risk of drug-induced microscopic colitis with concomitant use of NSAIDs and proton pump inhibitors.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Division of Gastroenterology - Hepatology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands.|NUTRIM, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands.
authors.forename: B P M
authors.initials: BP
authors.lastname: Verhaegh
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, The Netherlands.|Clinical Pharmacology & Toxicology, Maastricht University Medical Center+, Maastricht, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: de Vries
authors.affiliation: Division of Gastroenterology - Hepatology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands.|NUTRIM, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands.
authors.forename: A A M
authors.initials: AA
authors.lastname: Masclee
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, The Netherlands.|Division of Digestive Diseases and Nutrition, Rush University, Chicago, IL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Keshavarzian
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: de Boer
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, The Netherlands.
authors.forename: P C
authors.initials: PC
authors.lastname: Souverein
authors.affiliation: Division of Gastroenterology - Hepatology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Pierik
authors.affiliation: Division of Gastroenterology - Hepatology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands.|NUTRIM, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands.
authors.forename: D M A E
authors.initials: DM
authors.lastname: Jonkers
mesh_terms: D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects*; D016022:Case-Control Studies; D046728:Colitis, Microscopic / Q000139:chemically induced*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D012306:Risk; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D054328:Proton Pump Inhibitors; D017367:Selective Serotonin Reuptake Inhibitors