title: Risk factors for serious adverse effects of thiopurines in patients with Crohn's disease.
abstract: OBJECTIVE
  Thiopurines are effective in attaining and maintaining remission in patients with inflammatory bowel diseases (IBD). The major drawback of these drugs are their serious adverse effects (SAE), highlighting the importance of preemptive identification of patients at risk. We aimed to examine whether gene polymorphisms in GSTM1, GSTT1 and TPMT, combined with various clinical parameters, can predict thiopurine induced SAE.
  
  
  METHODS
  A retrospective cohort of 176 Crohn's Disease (CD) patients treated with thiopurines (131 with 6MP and 45 with azathioprine) was genotyped for common polymorphisms in GSTM1, GSTT1 and TPMT. Clinical data including SAE, age, ethnicity, gender and smoking status were extracted from patient charts. SAEs evaluated were myelosuppression, hepatotoxicity and pancreatitis. Associations between demographic, clinical, and genetic variables and thiopurine induced SAE were assessed.
  
  
  RESULTS
  Twenty-four patients (14%) developed SAE, revealing a significant association between thiopurine induced SAE and GSTM1-null genotype (P=0.05), older age (P=0.016) and active smoking status (P=0.043) and SAE. On multi-variant analysis, past or current smokers were at increased risk for developing thiopurine related SAE (OR 2.915, CI 95%: 1.199- 7.084), specifically pancreatitis (p<0.001). No association was found between TPMT or GSTT1 polymorphisms and the development of SAE.
  
  
  CONCLUSIONS
  Active smoking and GSTM1-null genotype appear to be risk factors for thiopurine induced SAEs (i.e. myelosuppression, hepatotoxicity and pancreatitis) in patients with CD. Corroboration of these associations in larger cohorts is warranted.
authors.affiliation: Gastroenterology Department, Rambam Health Care Campus, Haifa, Israel. y_mazor@rambam.health.gov.il
authors.forename: Yoav
authors.initials: Y
authors.lastname: Mazor
authors.forename: Eduard
authors.initials: E
authors.lastname: Koifman
authors.forename: Hela
authors.initials: H
authors.lastname: Elkin
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Chowers
authors.forename: Norberto
authors.initials: N
authors.lastname: Krivoy
authors.forename: Amir
authors.initials: A
authors.lastname: Karban
authors.forename: Edna
authors.initials: E
authors.lastname: Efrati
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000209:etiology; D015331:Cohort Studies; D003424:Crohn Disease / Q000188:drug therapy*; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics; D015999:Multivariate Analysis; D010195:Pancreatitis / Q000139:chemically induced / Q000453:epidemiology; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D012907:Smoking / Q000009:adverse effects; D055815:Young Adult
chemical_list: D005982:Glutathione Transferase; D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D008780:Methyltransferases; C488629:azathiopurine; C022745:thiopurine methyltransferase; C413545:glutathione S-transferase T1