Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease

A. Ansari, M. Arenas, S. M. Greenfield, D. Morris, J. Lindsay, K. Gilshenan, M. Smith, C. Lewis, A. Marinaki, J. Duley, J. Sanderson

Research output: Contribution to journalArticlepeer-review

161 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)973-983
Number of pages11
JournalAlimentary Pharmacology and Therapeutics
Volume28
Issue number8
DOIs
StatePublished - Oct 2008
Externally publishedYes

Fingerprint

Dive into the research topics of 'Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease'. Together they form a unique fingerprint.

Cite this