Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis.
OBJECTIVE
To investigate thiopurine enzyme activities for their possible value in predicting the development of azathioprine (AZA)-related toxicity in patients with rheumatoid arthritis (RA).


METHODS
Patients with longstanding RA (n = 33) were enrolled in a study of treatment with AZA. Before the initiation of AZA treatment and at months 1 and 6 of treatment, we measured activities of the purine key enzymes hypoxanthine guanine phosphoribosyltransferase, 5'-nucleotidase, purine nucleoside phosphorylase, and thiopurine methyltransferase (TPMT). Controls included patients with early RA (n = 24) and healthy volunteers (n = 42).


RESULTS
Fourteen of the 33 patients rapidly developed severe side effects, most frequently gastrointestinal (GI) intolerance. Compared with the other groups, the group with adverse effects had significantly lower TPMT activities (P = 0.004). Seven of 8 patients with reduced ("intermediate") baseline TPMT levels developed toxicity, resulting in a significant relationship (P = 0.005) between toxicity and "intermediate" TPMT activity. Compared with "high" activity, baseline intermediate TPMT activity gave a relative risk of 3.1 (95% confidence interval 1.6-6.2) for the development of severe toxicity with AZA treatment.


CONCLUSIONS
In RA patients, inherited intermediate TPMT activity seems predictive for the development of severe side effects of AZA. Clinicians should consider measuring TPMT prior to treatment initiation to improve the safety of AZA use. We hypothesize that GI intolerance may also be related to a thiopurine metabolic imbalance.
University Hospital Nijmegen, The Netherlands.
J N
JN
Stolk
A M
AM
Boerbooms
R A
RA
de Abreu
D G
DG
de Koning
H J
HJ
van Beusekom
W H
WH
Muller
L B
LB
van de Putte
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology*; D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008780:Methyltransferases / Q000378:metabolism* / Q000633:toxicity; D008875:Middle Aged; D011446:Prospective Studies
D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine