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• W1946135013 abstract "Sirs, We were interested to read the letter by Stocco et al. which draws attention to two key issues: (i) the lack of concordance between thiopurine-S-methyltransferase genotype and activity demonstrated in our study and (ii) the potential use of pre-treatment genotyping to tailor azathioprine dose with the aim of limiting toxicity and improving therapeutic response. Overall concordance between genotype and activity has been noted to vary between 76% and 100% and is poorest when analysing the relationship between intermediate metabolizer phenotype and heterozygotes for TPMT.1 The concordance between those groups in our study was 65%, which is similar to previous reports from Bulgaria2 and Argentina.3 Schaffeler et al. have demonstrated that screening for a wider range of rare mutant TPMT alleles improves concordance in this group from 86% to 89%.1 It is therefore likely that most cases of intermediate TPMT activity discordant to genotype occur secondary to other genetic influences, including genetic variation in the MTHFR gene.4 The use of HapMap resources to identify other genes influencing TPMT activity appears promising and we await further studies in this area with interest.5 Retrospective studies have indicated that intermediate metabolizers achieve a good clinical response at lower thiopurine doses,6, 7 but this has not been tested prospectively. Although our retrospective analysis did not demonstrate a correlation between intermediate activity and toxicity,8 there is accumulating evidence from larger prospective studies that intermediate metabolizers suffer significantly more adverse events when treated with azathioprine at a dose of 2–2.5 mg/kg.9, 10 This observation therefore lends weight to the argument for initial dosing tailored according to TPMT status, although no prospective studies have compared this treatment model with weight-based dosing. We agree with Stocco et al. that thiopurine dosing according to TPMT status may be logical and advantageous. However, the primary purpose of TPMT testing prior to thiopurine therapy is to identify patients completely deficient in TPMT and therefore at high risk of profound neutropaenia. For this reason we advocate initial screening by measuring enzyme activity, rather than genotype, to avoid missing those patients who are compound heterozygotes for rare mutations. Patients who then exhibit intermediate TPMT activity (11%) may either have a normal genotype or be heterozygous. Studies of dose-response and 6-thioguanine nucleotide levels in these patients are still needed. There is a risk of inappropriate use of suboptimal therapy if all such patients are currently treated with a modified dosage. The decision to use lower thiopurine doses may be further supported by the additional finding of a heterozygous genotype. Therefore, there may be a case for genotyping individuals with intermediate range TPMT activity to identify genetic carriers of a TPMT mutation who may benefit from reduced dose of azathioprine or mercaptopurine. Studies are required to explore these hypotheses." @default.
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• W1946135013 date "2007-07-20" @default.
• W1946135013 modified "2023-09-24" @default.
• W1946135013 title "TPMT genotype and the response to azathioprine in inflammatory bowel disease: authors’ reply" @default.
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• W1946135013 doi "https://doi.org/10.1111/j.1365-2036.2007.03448.x" @default.
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