title: Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine.
abstract: BACKGROUND
  Substantial hematologic toxicity limits the use of azathioprine.
  
  
  OBJECTIVE
  To evaluate 1) polymorphic inactivation of azathioprine by thiopurine methyltransferase and 2) clinical toxicity.
  
  
  METHODS
  Prospective cohort study.
  
  
  METHODS
  Two rheumatology units.
  
  
  METHODS
  67 patients for whom azathioprine was prescribed as second-line therapy for rheumatic disease.
  
  
  METHODS
  Polymerase chain reaction-based assays were used to detect mutations in thiopurine methyltransferase. The primary end point was discontinuation of azathioprine therapy because of toxicity.
  
  
  RESULTS
  Six of 67 patients (9%) were heterozygous for mutant thiopurine methyltransferase alleles. Five of the 6 patients discontinued therapy within 1 month of starting treatment because of low leukocyte counts. The sixth patient did not adhere to treatment. Patients with wild-type thiopurine methyltransferase alleles received therapy longer than did patients with mutant alleles (median duration of therapy, 39 weeks [range, 6 to 180 weeks] and 2 weeks [range, 2 to 4 weeks], respectively; P = 0.018).
  
  
  CONCLUSIONS
  Analysis of thiopurine methyltransferase genotype is a quick way to identify patients at risk for acute toxicity from azathioprine.
authors.affiliation: University of Aberdeen and Aberdeen Royal Hospitals Trust, United Kingdom.
authors.forename: A J
authors.initials: AJ
authors.lastname: Black
authors.forename: H L
authors.initials: HL
authors.lastname: McLeod
authors.forename: H A
authors.initials: HA
authors.lastname: Capell
authors.forename: R H
authors.initials: RH
authors.lastname: Powrie
authors.forename: L K
authors.initials: LK
authors.lastname: Matowe
authors.forename: S C
authors.initials: SC
authors.lastname: Pritchard
authors.forename: E S
authors.initials: ES
authors.lastname: Collie-Duguid
authors.forename: D M
authors.initials: DM
authors.lastname: Reid
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000009:adverse effects*; D001379:Azathioprine / Q000009:adverse effects*; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008875:Middle Aged; D017354:Point Mutation; D011446:Prospective Studies; D012216:Rheumatic Diseases / Q000188:drug therapy*
chemical_list: D018501:Antirheumatic Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine