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 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.