Thiopurine methyl-transferase activity influences clinical response to azathioprine therapy in patients with IBD

Abstract

Background: Genetic polymorphisms in Thiopurine methyl-transferese (TPMT) enzyme activity are well known to influence clinical responsiveness to anti-metabolite therapy in patients with leukemia (J Clin Onco11989;7:1816). Patients with high TPMT activity shunt azathioprine(AZA)metabolism away from the production of its active 6-thioguanine (6-TG) metabolitas, and remain refractory to standard doses of therapy. We hypothesize that inherent differences in TPMT phenotype present in the general population may influence clinical responsiveness to AZA therapy in patients with IBD. Methods: Thirty-one consecutive patients with IBD (Crohn's Disease,22;UC,9) on long-term AZA therapy (>4months) had TPMT activity measured as per Weinshilboum et al (Clin Chem Acta 1978;85:323). E~hrocyta 6-TG metabolita levels were measured by HPLC (342nm) and were correlated with clinical response as defined by either symptomatic improvement, fistula closure, or the ability to wean off of corticostaruid therapy. Patients were divided into 4 groups based on TPMT activity and erythrocyte 6-TG levels. Group 1A: TPMT - 250; Group 1B: TPMT - 16.0, 6-TG 16.0, ~-TG >250. ~esoits: See Table 1. Group 1 had significantly higher erythrocyte 6-TG levels [248(70-440)] compared to Group 21121(51-674)] despite similar AZA dosing (p<O.O5).Group 1 also achieved an improved clinical response. Conclusions: TPMT phenotype influences clinical responsiveness in patients on AZA therapy. Future prospective controlled trials are in progress to determine whether TPMT phenotype testing performed prior to commencing AZA therapy would be helpful.