Thiopurine methyltransferase (TPMT) activity and adverse effects of azathioprine in inflammatory bowel disease: long-term follow-up study of 394 patients.
OBJECTIVE
To prospectively evaluate whether a relationship between thiopurine methyltransferase (TPMT) activity and incidence of adverse effects (especially myelotoxicity) exists, in a long-term follow-up study of a large group of patients with inflammatory bowel disease treated with azathioprine.


METHODS
TPMT activity in red blood cells (RBC) was measured by a radiochemical method in 394 consecutive patients with Crohn's disease (238) or ulcerative colitis (156) starting treatment with azathioprine. The relationship among several variables and TPMT values was assessed, and the correlation between such levels and the incidence of adverse effects was evaluated.


RESULTS
Mean TPMT value was 18.6 +/- 4 U/mL RBCs (range 9.4-33.7). No patient had low levels (<5), 7.1% had intermediate levels (5-13.7), and 92.9% had high levels (>13.8). Differences (P < 0.001) were demonstrated in TPMT activity depending on the type of inflammatory bowel disease, but not on the remaining variables (including treatment with 5-aminosalycilates). Adverse effects were reported in 74 patients (18.8%), the most frequent being gastrointestinal intolerance (9.1%) and myelotoxicity (4.3%). No patient having adverse effects had low TPMT levels. However, mean TPMT activity was lower in those with adverse effects (16.6 +/- 3 vs 19.1 +/- 4 U/mL, P < 0.001). Moreover, the probability of suffering myelotoxicity in the high TPMT group was only 3.5%, compared with 14.3% in the TPMT intermediate group (95% CI = 1.37-14.9; OR = 4.5).


CONCLUSIONS
The strategy of determining TPMT activity in all patients prior to initiating treatment with azathioprine could help to minimize the risk of myelotoxicity, as patients with intermediate TPMT activity had fourfold more risk than high TPMT activity patients.
Gisbert
Javier P
JP
Gastroenterology Unit, Hospital Universitario de la Princesa, Universidad Autónoma, Madrid, Spain.
Niño
Pilar
P
Rodrigo
Luis
L
Cara
Carlos
C
Guijarro
Luis G
LG
D000328:Adult; D001379:Azathioprine / Q000008:administration & dosage / Q000009:adverse effects*; D001855:Bone Marrow Diseases / Q000139:chemically induced; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000201:enzymology*; D008297:Male; D008780:Methyltransferases / Q000097:blood*; D008875:Middle Aged; D011446:Prospective Studies
D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine