Jn. Stolk et al., REDUCED THIOPURINE METHYLTRANSFERASE ACTIVITY AND DEVELOPMENT OF SIDE-EFFECTS OF AZATHIOPRINE TREATMENT IN PATIENTS WITH RHEUMATOID-ARTHRITIS, Arthritis and rheumatism, 41(10), 1998, pp. 1858-1866
Objective. To investigate thiopurine enzyme activities for their possi
ble 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 w
ith AZA, Before the initiation of AZA treatment and at months 1 and 6
of treatment, me measured activities of the purine key enzymes hypoxan
thine guanine phosphoribosyltransferase, 5'-nucleotidase, purine nucle
oside 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 sid
e effects, most frequently gastrointestinal (GI) intolerance. Compared
with the other groups, the group,vith adverse effects had significant
ly 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 ''inte
rmediate'' TPMT activity. Compared with ''high'' activity, baseline in
termediate TPMT activity gave a relative risk of 3.1 (95% confidence i
nterval 1.6-6.2) for the development of severe toxicity with AZA treat
ment, Conclusion. In RA patients, inherited intermediate TPMT activity
seems predictive for the development of severe side effects of AZA. C
linicians should consider measuring TPMT prior to treatment initiation
to improve the safety of AW use. We hypothesize that GI intolerance m
g also be related to a thiopurine metabolic imbalance.