The Relationship Between Thiopurine S-Methyltransferase Genotype/Phenotype and 6-Thioguanine Nucleotide Levels in 316 Patients with Inflammatory Bowel Disease on 6-Thioguanine

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gut. It can be divided into 2 main diseases: Crohn's disease (CD) and ulcerative colitis (UC). In the past 25 years, novel biological therapies have emerged for the treatment of IBD. However, for maintaining remission, conventional thiopurines [azathioprine (AZA) and mercaptopurine (6-MP)] remain important first-line immunosuppressives.1,2 Three to 4 million patients with IBD are known to use thiopurines in daily practice.3 However, approximately 60% of AZA/MP users cease treatment within 5 years mostly because of adverse events or nonresponse.4 Various strategies have been proposed to optimize conventional thiopurine therapies. Common approaches include personalized dosing using the individual geno/phenotype of thiopurine S-methyltransferase (TPMT), reduced dosing with coprescription of allopurinol, and therapeutic drug monitoring (TDM)-directed dosing. The latter approach, that is, TDM, involves measuring 6-thioguanine nucleotides (TGNs), followed by dosing advice.5–7 These approaches are dependent on access to measuring TPMT and TGNs; thus, this could be difficult in countries where such facilities are not readily available. More than 6 decades ago, the Nobel Prize Laureates Elion and Hitchings created thiopurines for the treatment of childhood leukemia,8 heralding the advent of designer drugs. TG was invented before MP and remains part of leukemia treatment regimens.9 The use of TG in IBD started 2 decades ago, and on retrospection, the TG doses, although well tolerated, were markedly high (>120 mg/d) and resulted in high rates of reversible liver injury, limiting its widespread use and potential licensing for IBD.9 With the evolution of analytical chemistry, there is a far better understanding of purine metabolism allowing 6-TGN measurements in erythrocytes, presenting clear benefits such as optimizing TG therapy for leukemia,10 helping determine adherence to thiopurines, and the need for allopurinol co-therapy.11 The enzyme TPMT is responsible for the metabolism of TG and its active TGN metabolites. This results in the formation of inactive methyl-TG and active methyl-TGNs.12 Since its initial use for IBD in 2001, TG has been rediscovered for IBD therapy13 and currently holds a provisional license in the Netherlands.14,15 This has been achieved by administering a lower daily clinical dose of TG in IBD (20 mg/d) than those in initial reports for IBD and leukemia. Similar to other immunosuppressives, adverse events remain an important reason for patients to cease TG treatment in IBD, observed in 11%–20%16,17 of cases; however, these adverse events are reversible with no reported deaths. To further improve safety, TDM and TPMT geno/phenotyping might add value to reduce adverse events if the facility is available at the treatment center. However, to date, no relationship has been identified between 6-TGN levels and abnormal laboratory values.18,19 In this study, we aimed to investigate the role of 6-TGN measurements, TPMT geno/phenotyping, and their mutual relationship with TG therapy in IBD.