Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease
Article first published online: 4 JUL 2008
© 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd
Alimentary Pharmacology & Therapeutics
Volume 28, Issue 8, pages 973–983, October 2008
How to Cite
ANSARI, A., ARENAS, M., GREENFIELD, S. M., MORRIS, D., LINDSAY, J., GILSHENAN, K., SMITH, M., LEWIS, C., MARINAKI, A., DULEY, J. and SANDERSON, J. (2008), Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease. Alimentary Pharmacology & Therapeutics, 28: 973–983. doi: 10.1111/j.1365-2036.2008.03788.x
- Issue published online: 20 SEP 2008
- Article first published online: 4 JUL 2008
- Publication data Submitted 31 May 2008 First decision 17 June 2008 Resubmitted 27 June 2008 Accepted 29 June 2008 Epub Accepted Article 4 July 2008
Background One-third of patients with inflammatory bowel disease (IBD) receiving azathioprine (AZA) withdraw treatment due to side effects or lack of clinical response.
Aim To investigate whether pharmacogenetic loci or metabolite concentrations explain clinical response or side effects to AZA.
Methods Patients with IBD were given 2 mg/kg of AZA without dose escalation or adjustment. Serial clinical response, thiopurine methyl transferase (TPMT) activity and thioguanine nucleotide (TGN) concentrations were measured over 6 months. All patients were genotyped for inosine triphosphatase (ITPase) and TPMT. Clinical response and side effects were compared to these variables.
Results Two hundred and seven patients were analysed. Thirty-nine per cent withdrew due to adverse effects. Heterozygous TPMT genotype strongly predicted adverse effects (79% heterozygous vs. 35% wild-type TPMT, P < 0.001). The ITPA 94C>A mutation was associated with withdrawal due to flu-like symptoms (P = 0.014). A baseline TPMT activity below 35 pmol/h/mg/Hb was associated with a greater chance of clinical response compared with a TPMT above 35 pmol/h/mg/Hb (81% vs. 43% respectively, P < 0.001). Patients achieving a mean TGN level above 100 were significantly more likely to respond (P = 0.0017).
Conclusions TPMT testing predicts adverse effects and reduced chance of clinical response (TPMT >35 pmol/h/mg/Hb). ITPase deficiency is a predictor of adverse effects and TGN concentrations above 100 correlate with clinical response.