Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine

Ann Intern Med. 1998 Nov 1;129(9):716-8. doi: 10.7326/0003-4819-129-9-199811010-00007.


Background: Substantial hematologic toxicity limits the use of azathioprine.

Objective: To evaluate 1) polymorphic inactivation of azathioprine by thiopurine methyltransferase and 2) clinical toxicity.

Design: Prospective cohort study.

Setting: Two rheumatology units.

Patients: 67 patients for whom azathioprine was prescribed as second-line therapy for rheumatic disease.

Measurements: 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).

Conclusion: Analysis of thiopurine methyltransferase genotype is a quick way to identify patients at risk for acute toxicity from azathioprine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antirheumatic Agents / adverse effects*
  • Azathioprine / adverse effects*
  • Female
  • Hematologic Diseases / chemically induced*
  • Heterozygote
  • Humans
  • Male
  • Methyltransferases / genetics*
  • Middle Aged
  • Point Mutation*
  • Prospective Studies
  • Rheumatic Diseases / drug therapy*


  • Antirheumatic Agents
  • Methyltransferases
  • thiopurine methyltransferase
  • Azathioprine