Thiopurine Methyltransferase Genotype Predicts Therapy-Limiting Severe Toxicity from Azathioprine

Thiopurine Methyltransferase Genotype Predicts Therapy-Limiting Severe Toxicity from Azathioprine

Alison J. Black, MB, ChB;
Howard L. McLeod, PharmD;
Hillary A. Capell, MB, ChB, MD, FRCP;
Robert H. Powrie, BSc;
Lloyd K. Matowe, MSc;
Stuart C. Pritchard, MSc;
Elaina S.R. Collie-Duguid, PhD; and
David M. Reid, MB, ChB, MD, FRCP

From the University of Aberdeen and Aberdeen Royal Hospitals Trust and Glasgow Royal Infirmary, Glasgow, United Kingdom. Acknowledgments: The authors thank research nurse Rosemary Hampson. Grant Support: In part by the Wellcome Trust (046607) and the Beit Trust. Dr. Reid is also supported by the Arthritis Research Campaign. Requests for Reprints: Howard L. McLeod, PharmD, Department of Medicine & Therapeutics, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, United Kingdom; e-mail, h.l.mcleod@abdn.ac.uk. Current Author Addresses: Dr. Black: The Osteoporosis Research Unit, Aberdeen Royal Hospitals Trust, Aberdeen AB25 2ZD, United Kingdom.

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.

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.