Thiopurine‐S‐methyltransferase genotype and the response to azathioprine in inflammatory bowel disease

We read with interest the paper by Winter et al. about the evaluation of thiopurine-S-methyltransferase (TPMT) activity and genotype to predict myelosuppression following azathioprine. This study shows that myelosuppression induced by azathioprine in the treatment of inflammatory bowel disease (IBD) is not associated with variant alleles of TPMT, generally related to a reduced enzymatic activity. Interestingly, however, in this study just 11 of the 17 patients with a reduced TPMT activity presented with one of the considered variant TPMT alleles, a clear indication that other factors, both genetic and non-genetic, can influence TPMT activity in patients. In this regard, a relevant genome-wide study recently published has ranked 17542 genes as predictors of TPMT activity, identifying haplotypes of 96 genes that ranked better than TPMT in predicting the TPMT activity; more studies should be performed to clarify mechanisms and clinical utility of the associations detected. Moreover, we want to underline that among IBD patients treated with azathioprine and with a dose escalating approach, those with a variant TPMT allele, associated with reduced enzymatic activity, respond to lower doses compared with patients with a normal TPMT gene. In our experience, patients with a variant TPMT allele, even if treated with standard doses of azathioprine, present high concentrations of the active metabolites (Table 1), generally above