Retrospective Cohort Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 7, 2015; 21(25): 7795-7804
Published online Jul 7, 2015. doi: 10.3748/wjg.v21.i25.7795
Clinical predictors of thiopurine-related adverse events in Crohn's disease
Gordon W Moran, Marie-France Dubeau, Gilaad G Kaplan, Hong Yang, Bertus Eksteen, Subrata Ghosh, Remo Panaccione
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
Gordon W Moran, Nottingham Digestive Diseases Centre, Biomedical Research Unit, University of Nottingham, NG7 2UH Nottingham, United Kingdom
Gilaad G Kaplan, Hong Yang, Community Health Sciences, Cumming School of Medicine, University of Calgary, Alberta T2N 1N4, Canada
Author contributions: Moran GW, Dubeau MF, Kaplan GG, Ghosh S and Panaccione R conceived the study; Moran GW and Dubeau MF extracted the phenotypic data; Moran GW, Dubeau MF, Kaplan GG, Yang H and Eksteen B analysed the data; Moran GW and Dubeau MF drafted the manuscript; Dubeau MF, Kaplan GG, Yang H, Eksteen B, Ghosh S and Panaccione C critically appraised the manuscript; Moran GW prepared the final manuscript; and Dubeau MF, Kaplan GG, Yang H, Eksteen B, Ghosh S and Panaccione R approved the final version.
Ethics approval: The study was approved by the Conjoint Health Research Ethics Board of the University of Calgary.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: Gordon W Moran has received consultancy fees from Abbvie and financial support for educational activities from Abbvie, MSD, Merck Sharp and Dohme Ltd and Ferring. Gilaad G Kaplan has served as a speaker for Merck, Schering-Plough, Jansen, and Abbott. He has participated in advisory board meetings for Abbott, Merck, Schering-Plough, Shire, Jansen, and UCB Pharma. Dr Kaplan has received research support from Abbott, Merck, and Shire. Subrata Ghosh has served as a speaker for Merck, Schering-Plough, Centocor, Abbott, UCB Pharma, Pfizer, Ferring, and Procter and Gamble. He has participated in ad-hoc advisory board meetings for Centocor, Abbott, Merck, Schering-Plough, Proctor and Gamble, Shire, UCB Pharma, Pfizer, and Millennium. He has received research funding from Procter and Gamble, Merck, and Schering-Plough. Remo Panaccione has served as a speaker, a consultant and an advisory board member for Abbott Laboratories, Merck, Schering-Plough, Shire, Centocor, Elan Pharmaceuticals, and Procter and Gamble. He has served as a consultant and speaker for Astra Zeneca. He has served as a consultant and an advisory board member for Ferring and UCB. He has served as a consultant for Glaxo-Smith Kline and Bristol Meyers Squibb. He has served as a speaker for Byk Solvay, Axcan, Jansen, and Prometheus. He has received research funding from Merck, Schering-Plough, Abbott Laboratories, Elan Pharmaceuticals, Procter and Gamble, Bristol Meyers Squibb, and Millennium Pharmaceuticals. He has received educational support from Merck, Schering-Plough, Ferring, Axcan, and Jansen. The remaining authors declare no conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Gordon W Moran, Clinical Associate Professor, Honorary Consultant Gastroenterologist, Nottingham Digestive Diseases Centre, Biomedical Research Unit, University of Nottingham, Queen’s Medical Centre, E floor, West Block, NG7 2UH Nottingham, United Kingdom. gordon.moran@nottingham.ac.uk
Telephone: +44-115-9249924-70608 Fax: +44-115-8231409
Received: October 28, 2014
Peer-review started: October 29, 2014
First decision: December 11, 2014
Revised: January 10, 2015
Accepted: February 11, 2015
Article in press: February 11, 2015
Published online: July 7, 2015
Abstract

AIM: 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.

CONCLUSION: 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.

Keywords: Thiopurines, Azathioprine, Mercaptopurine, Adverse events

Core tip: In Crohn’s disease, adverse events to thiopurines are a common occurrence leading to discontinuation of therapy in 1 in 3 patients in this referral centre cohort. Adverse events leading to discontinuation of the drug were significantly more common in female patients over the age of 40 years at drug prescription. These findings should be replicated in other centres, in other clinical indications for thiopurine use and correlated to thiopurine 6-methyltransferase genotype, activity and thiopurine metabolities.