Aj. Black et al., THIOPURINE METHYLTRANSFERASE GENOTYPE PREDICTS THERAPY-LIMITING SEVERE TOXICITY FROM AZATHIOPRINE, Annals of internal medicine, 129(9), 1998, pp. 716-718
Background: Substantial hematologic toxicity limits the use of azathio
prine. Objective: To evaluate 1) polymorphic inactivation of azathiopr
ine by thiopurine methyltransferase and 2) clinical toxicity. Design:
Prospective cohort study. Setting: Two rheumatology units. Patients: 6
7 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 beca
use of toxicity. Results: Six of 67 patients (9%) were heterozygous fo
r mutant thiopurine methyltransferase alleles. Five of the 6 patients
discontinued therapy within 1 month of starting treatment because of l
ow leukocyte counts. The sixth patient did not adhere to treatment. Pa
tients with wild-type thiopurine methyltransferase alleles received th
erapy 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 m
ethyltransferase genotype is a quick way to identify patients at risk
for acute toxicity from azathioprine.