Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease.
BACKGROUND
Azathioprine therapy is discontinued in one-third of patients with inflammatory bowel disease because of toxicity or a lack of clinical response. Patients with thiopurine methyltransferase (TPMT) deficiency are intolerant to azathioprine, whilst carriers are at increased risk of side-effects.


OBJECTIVE
To evaluate the importance of TPMT activity in the management of azathioprine therapy in inflammatory bowel disease.


METHODS
Clinical response, adverse effects and haematological parameters were determined and correlated with TPMT enzyme activity and genotype in 106 patients with inflammatory bowel disease.


RESULTS
Ninety-six patients had high TPMT activity, and 10 had intermediate activity. Nineteen patients (18%) were intolerant to azathioprine. Fifteen (16%) of those with high TPMT activity were intolerant, compared with five (50%) with intermediate activity [odds ratio (OR), 5.4; 95% confidence interval (CI), 1.5-19.8]. Complete remission was achieved in 63% of cases, and complete or partial remission in 79%. Interestingly, very high TPMT activity (> 14 units/mL red blood cells) was significantly associated with non-response, irrespective of the time on azathioprine (OR, 0.21; 95% CI, 0.07-0.68). TPMT gene mutations correlated with TPMT activity.


CONCLUSIONS
Inflammatory bowel disease patients with intermediate TPMT activity have an increased risk of azathioprine toxicity. Conversely, very high TPMT activity predicts treatment failure. TPMT genotype predicted TPMT phenotype in this study.
Ansari
A
A
Department of Public Health Medicine, GKT School of Medicine, London, UK.
Hassan
C
C
Duley
J
J
Marinaki
A
A
Shobowale-Bakre
E-M
EM
Seed
P
P
Meenan
J
J
Yim
A
A
Sanderson
J
J
D000328:Adult; D001379:Azathioprine / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000201:enzymology; D007958:Leukocyte Count; D016015:Logistic Models; D008297:Male; D008780:Methyltransferases / Q000097:blood* / Q000235:genetics; D008875:Middle Aged; D016017:Odds Ratio; D012189:Retrospective Studies; D017211:Treatment Failure
D015415:Biomarkers; D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine