Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease.
OBJECTIVE
Genetic polymorphism in thiopurine methyltransferase (TPMT) activity may influence clinical responsiveness to azathioprine (AZA) therapy. Our aim was to determine if the measurement of erythrocyte TPMT enzyme activity could be used to optimize clinical responsiveness to AZA therapy in patients with inflammatory bowel disease (IBD).


METHODS
A total of 142 consecutive patients were studied. Forty-one patients (32 with Crohn's disease [CD] and 9 with ulcerative colitis [UC]) were enrolled in a 4-month prospective nonrandomized study with AZA, and 101 (65 with CD and 36 with UC) were on either maintenance AZA or 6-mercaptopurine (6-MP). Erythrocyte TPMT activity and AZA metabolite levels were measured blinded to the clinical response.


RESULTS
The response rate after 4 months of continuous AZA therapy was 69% (9/13) in those patients with below-average (</=12 U/mL blood) TPMT activity, and 29% (8/27) in patients with enzyme activity levels >12 U/mL blood (P < 0.001). Patients with TPMT activity </=12 achieved a mean (SEM) erythrocyte 6-thioguanine ribonucleotide (6-TGn) level of 394 +/- 29 pmol/8 x 10(8) red blood cells (RBCs); higher than in patients with TPMT activity >12 (218 +/- 28), despite similar mean (1.6 mg/kg/day) dosages of AZA (P < 0.001). By multivariate logistic regression analysis, patients with a TPMT level <15.3 U/mL blood were 6.2 times more likely to respond to AZA therapy. A 6-TGn level of >292 pmol/8 x 10(8) RBCs was associated with a positive predictive value of clinical response of 85.7%.


CONCLUSIONS
Patients with higher than average TPMT activity (>12) may remain refractory to conventional dosages of AZA, and may require high (>292) 6-TGn levels. Prospective, randomized, controlled trials are needed to determine whether prior TPMT phenotype testing can be used to adjust the dose of AZA effectively to improve clinical response time and rate.
Cuffari
Carmen
C
Department of Pediatrics, The Johns Hopkins University and the Meyerhoff IBD Center at the Johns Hopkins Hospital, Baltimore, Maryland, USA.
Dassopoulos
Themistocles
T
Turnbough
Lisa
L
Thompson
Richard E
RE
Bayless
Theodore M
TM
D000328:Adult; D001379:Azathioprine / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D003424:Crohn Disease / Q000188:drug therapy*; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D006150:Guanine Nucleotides / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016015:Logistic Models; D008297:Male; D015122:Mercaptopurine / Q000378:metabolism; D008780:Methyltransferases / Q000378:metabolism*; D011446:Prospective Studies; D012074:Remission Induction; D013873:Thionucleotides / Q000378:metabolism; D016896:Treatment Outcome
D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine