title: Clinical predictors of thiopurine-related adverse events in Crohn's disease.
abstract: OBJECTIVE
  To determine the incidence and predictors of thiopurine-related adverse events.
  
  
  METHODS
  Subjects with Crohn's disease who were followed in the Alberta Inflammatory Bowel Disease Consortium patient database registry were identified. Retrospective chart review was conducted between August 5th, 2010 and June 1st, 2012. We collected data on: age at diagnosis; sex; disease location and behaviour at time of prescribing thiopurine; perianal fistulising disease at or prior to thiopurine prescription; smoking status at time of thiopurine prescription, use of corticosteroid within 6 mo of diagnosis; dosage, age at onset, and cessation of 5-aminosalicyclic acid (5-ASA); anti-tumour necrosis factor medication exposure and intestinal resection before thiopurine prescription. The primary outcome of interest was the first adverse event that led to discontinuation of the first thiopurine medication used. Logistic regression models were used to associate clinical characteristics with outcomes after adjusting for potential confounders. Risk estimates were presented as odds ratios (OR) with 95% CI. Effect modification by age and sex were explored.
  
  
  RESULTS
  Our cohort had a median follow-up duration of 5.8 years [interquartile range (IQR 25th-75th) 2.7-9.1]. Thiopurine therapy was discontinued in 31.3% of patients because of: hypersensitivity reactions (7.1%), acute pancreatitis (6.2%), gastrointestinal intolerance (5.4%), leucopenia (3.7%), hepatotoxicity (3.4%), infection (1.1%) and other reasons (4.3%). A higher incidence of thiopurine withdrawal was observed in patients over the age of 40 (39.4%, P = 0.007). A sex-by-age interaction (P = 0.04) was observed. Females older than 40 years of age had an increased risk of thiopurine discontinuation due to an adverse event (age above 40 vs age below 40, adjusted OR = 2.8; 95%CI: 1.4-5.6). In contrast, age did not influence thiopurine withdrawal in males (age above 40 vs below 40, adjusted OR = 0.9; 95%CI: 0.4-2.1). Other clinical variables (disease location and phenotype, perianal disease, smoking history, history of intestinal resection and prior 5-ASA or corticosteroid use) were not associated with an increased risk an adverse event leading to therapy cessation.
  
  
  CONCLUSIONS
  Thiopurine withdrawal due to adverse events is commoner in women over the age of 40 at prescription. These findings need to be replicated in other cohorts.
authors.affiliation: Gordon W Moran, Marie-France Dubeau, Gilaad G Kaplan, Hong Yang, Bertus Eksteen, Subrata Ghosh, Remo Panaccione, Inflammatory Bowel Disease Clinic, Division of Gastroenterology, Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta T2N 1N4, Canada.
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Moran
authors.affiliation: Gordon W Moran, Marie-France Dubeau, Gilaad G Kaplan, Hong Yang, Bertus Eksteen, Subrata Ghosh, Remo Panaccione, Inflammatory Bowel Disease Clinic, Division of Gastroenterology, Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta T2N 1N4, Canada.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Dubeau
authors.affiliation: Gordon W Moran, Marie-France Dubeau, Gilaad G Kaplan, Hong Yang, Bertus Eksteen, Subrata Ghosh, Remo Panaccione, Inflammatory Bowel Disease Clinic, Division of Gastroenterology, Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta T2N 1N4, Canada.
authors.forename: Gilaad G
authors.initials: GG
authors.lastname: Kaplan
authors.affiliation: Gordon W Moran, Marie-France Dubeau, Gilaad G Kaplan, Hong Yang, Bertus Eksteen, Subrata Ghosh, Remo Panaccione, Inflammatory Bowel Disease Clinic, Division of Gastroenterology, Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta T2N 1N4, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Gordon W Moran, Marie-France Dubeau, Gilaad G Kaplan, Hong Yang, Bertus Eksteen, Subrata Ghosh, Remo Panaccione, Inflammatory Bowel Disease Clinic, Division of Gastroenterology, Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta T2N 1N4, Canada.
authors.forename: Bertus
authors.initials: B
authors.lastname: Eksteen
authors.affiliation: Gordon W Moran, Marie-France Dubeau, Gilaad G Kaplan, Hong Yang, Bertus Eksteen, Subrata Ghosh, Remo Panaccione, Inflammatory Bowel Disease Clinic, Division of Gastroenterology, Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta T2N 1N4, Canada.
authors.forename: Subrata
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Gordon W Moran, Marie-France Dubeau, Gilaad G Kaplan, Hong Yang, Bertus Eksteen, Subrata Ghosh, Remo Panaccione, Inflammatory Bowel Disease Clinic, Division of Gastroenterology, Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta T2N 1N4, Canada.
authors.forename: Remo
authors.initials: R
authors.lastname: Panaccione
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000416:Alberta; D000893:Anti-Inflammatory Agents / Q000009:adverse effects*; D001379:Azathioprine / Q000009:adverse effects*; D003424:Crohn Disease / Q000175:diagnosis / Q000188:drug therapy*; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects*; D006801:Humans; D016015:Logistic Models; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects*; D015999:Multivariate Analysis; D016017:Odds Ratio; D012042:Registries; D012189:Retrospective Studies; D012307:Risk Factors; D012737:Sex Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D015122:Mercaptopurine; D001379:Azathioprine
keywords: Adverse events; Azathioprine; Mercaptopurine; Thiopurines