ITPA genotyping test does not improve detection of Crohn's disease patients at risk of azathioprine/6-mercaptopurine induced myelosuppression

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Abstract
Since the identification of the molecular basis of inosine triphosphate pyrophosphatase (ITPAse) deficiency,1 a clinically benign condition characterised by abnormal accumulation of inosine triphosphate in erythrocytes, the possibility of a correlation between thiopurine toxicity and ITPAse deficiency has been raised. Complete ITPase deficiency was found to be associated with a homozygous missense 94C>A mutation that encodes a Pro32Thr exchange, whereas an intronic IVS2+21A>C polymorphism was shown to have a less severe effect, homozygotes retaining 60% ITPAse activity. It was then postulated that in ITPAse deficient patients treated with thiopurine drugs, a 6-thio-ITP metabolite could accumulate resulting in toxicity.1 A recent study in 62 patients with inflammatory bowel disease reported a significant association between the ITPA 94C>A polymorphism and AZA related adverse effects, specifically flu-like symptoms, rash, and pancreatitis.2 No correlation was observed with occurrence of neutropenia but only 11 patients were studied. We previously reported TPMT genotype analysis in 41 Crohn’s disease (CD) patients who had experienced leucopenia during AZA/6-MP therapy.3 Even though this study confirmed the efficiency of TPMT genotyping in identifying patients at risk of developing myelosuppression, it also highlighted its limitations, as only 27% of patients carried mutant alleles of the TPMT gene that were associated with enzyme deficiency. This prompted us to investigate the occurrence of ITPA mutations in this series of patients in order to evaluate whether genotyping of the ITPAse gene could improve the detection rate of patients at risk of thiopurine myelotoxicity.