Thiopurine S-methyl transferase (TPMT)

• assessment of TPMT is useful in the treatment of patients with thiopurine drugs such as azathioprine, mercaptopurine and 6-thioguanine
  • 0.3 % of the population do not have this enzyme and can build up toxic levels of the active metabolites. Another 10% have a medium activity and may also need a lower dose than other patients
  • the strategy of determining TPMT activity in all patients prior to initiating treatment with azathioprine could help to minimize the risk of myelotoxicity, as patients with intermediate TPMT activity had fourfold more risk than high TPMT activity patients (1)
• TPMT can be induced to some extent by thiopurine drugs and results from patients on treatment need careful interpretation. Patients who have had a blood transfusion may give misleading results.
  • this is important as patients who may have had adverse affects due to azathioprine may well have had blood transfusions

A study found patients with an ACKR1 variant (rs2814778-CC) had a higher risk of azathioprine discontinuation due to haematopoietic toxicity (3.92 per 100 person-years vs 1.34 for TT or TC genotype; HR 2.92; 95% CI 1.57 to 5.41]), that remained significant after adjustment for race (2)

Reference:

1. Gisbert JP et al. Thiopurine Methyltransferase (TPMT) Activity and Adverse Effects of Azathioprine in Inflammatory Bowel Disease: Long-Term Follow-Up Study of 394 Patients. Am J Gastroenterol. 2006 Oct 6.
2. Alyson L. Dickson, Laura L. Daniel, Elise Jackson, et al; Race, Genotype, and Azathioprine Discontinuation: A Cohort Study. Ann Intern Med. [Epub 21 June 2022]. doi:10.7326/M21-4675