Impracticalities of thiopurine-S-methyltransferase determination in daily inflammatory bowel disease practice: authors' reply


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Sirs It is interesting to learn about the limited current use of thiopurine methyltransferase (TPMT) screening prior to initiating thiopurine treatment in inflammatory bowel disease patients in Holland. However, it is also instructive to read that 45% of clinicians would prefer in the future to use some form of toxicity screening in addition to the standard of care, which is haematological monitoring alone.

To the best of our knowledge, no similar questionnaire studies have been reported in the UK, but we would be surprised if the uptake of TPMT screening was as low as 5% given the greater availability of phenotype and genotype analyses in the UK.

The three major criticisms of a TPMT screening strategy identified by the questionnaire are that despite screening: (i) frequent monitoring of the blood count remains mandatory; (ii) the majority of cases of leucopenia are reported in patients with normal TPMT activity; and (iii) the delay in commencing thiopurine treatment while waiting for a TPMT result is unacceptable. We appreciate these observations, but still maintain that a TPMT screening strategy is superior to haematological monitoring alone.

Although only 3% of patients will suffer significant leucopenia and only one-third of these cases will be related to TPMT deficiency, screening allows detection of the one in 300 patients who are homozygous for defective mutations. We have previously stated our concerns that these patients with homozygous deficiency may develop early, severe leucopenia despite frequent blood count monitoring. This puts them at risk of an iatrogenic death, which would have been preventable had thiopurines been avoided. Identification of these high-risk patients as the sole aim of screening makes TPMT testing cost effective.1

Another potential benefit of TPMT screening is that a priori knowledge of a patient's ability to metabolize thiopurines may optimize dosage and response to therapy. Patients with intermediate activity of this enzyme can often be managed effectively at lower doses, while individuals who have high activity can be safely treated with higher doses earlier, reducing time to remission. Dubinsky et al.2 performed a cost effectiveness analysis comparing four different strategies of initiation of thiopurine therapy. Compared with standard haematological monitoring, the TPMT-guided model was not only more cost effective but also resulted in a shorter ‘time to response’ to treatment, achieving satisfactory disease control almost 4 weeks earlier. This observation offsets the argument that the brief delay in initiating thiopurine treatment while waiting for a TPMT result is detrimental to disease control.

Cost effectiveness analyses can justly be criticized because they are theoretical models of practice and not clinical studies in real patients. However, when considering some clinical problems, theoretical models are the only feasible way of finding an answer. TPMT screening in thiopurine therapy is one such area. Prospective randomized studies comparing standard monitoring with a TPMT-based strategy are unlikely to be forthcoming because of the large patient numbers required. Based on the current literature, we would advocate that investing in laboratory services to permit TPMT analysis (whether phenotype or genotype) is likely to be beneficial in the management of inflammatory bowel disease.