Letter: TPMT – not all that glitters is gold; authors’ reply

Abstract

We appreciate the interest shown in our paper1 by Dr Gonzalez-Lama and Professor Gisbert.2 We agree that there are several aspects of the thiopurine metabolism pathway that are unexplained despite the large volume of research in this area. In particular, the cause or causes of preferential 6-MMP production is/are not yet clear, and we have shown that thiopurine methyltransferase (TPMT) enzyme activity is not the main determinant of this. However, knowledge of TPMT activity in patients is still important to predict some of the cases of severe bone marrow suppression and to help predict final metabolite concentrations, and therefore final doses.3 We agree that if more clinical data had been available to us, then more conclusions and recommendations could have been drawn from the study. Indeed, the limitations raised were already described in our discussion section. However, in response to the suggestion of possible bias due to selective measurements taken in patients with certain characteristics, TPMT determination prior to thiopurine therapy is routine in New Zealand, and so these results should not be subjected to selection bias. Moreover, the TPMT enzyme activity distribution and mean TPMT activity did not differ from that found in our previous studies among inflammatory bowel disease (IBD) patients.4, 5 In parts of New Zealand, thiopurine metabolite monitoring is now routine for all IBD patients, and in other centres, metabolites are measured only when there is nonresponse to treatment or suspected toxicity. This may have resulted in an over-representation of preferential 6-MMP production patients in our study, as we discussed in the paper. However, if anything this should have enhanced our ability to show a clinically relevant difference in TPMT enzyme activity between those with a high vs. low 6-TGN/6-MMP ratio. We demonstrated, with large patient numbers, that there was no such difference. Declaration of personal and funding interests: None.