Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine.
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.
Black
A J
AJ
University of Aberdeen and Aberdeen Royal Hospitals Trust, United Kingdom.
McLeod
H L
HL
Capell
H A
HA
Powrie
R H
RH
Matowe
L K
LK
Pritchard
S C
SC
Collie-Duguid
E S
ES
Reid
D M
DM
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*
D018501:Antirheumatic Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine