Evolving Role of Thiopurines in Inflammatory Bowel Disease in the Era of Biologics and New Small Molecules
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REVIEW
Evolving Role of Thiopurines in Inflammatory Bowel Disease in the Era of Biologics and New Small Molecules Anke L. H. Nguyen1,2 · Miles P. Sparrow1,2 Received: 13 September 2020 / Accepted: 6 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract In recent years, with the increasing availability of biologic therapies and due to safety concerns, the role of thiopurines in the management of inflammatory bowel disease has been questioned. While acknowledging that the benefit/risk ratio of biologic therapies is very high, they are expensive and are not required by a majority of patients. Therefore, thiopurines do retain an important role as steroid-sparing and maintenance agents when used as monotherapy, and in combination therapy with biologics due to their clinical and pharmacokinetic optimization of anti-tumor necrosis factor agents in particular. Safety concerns with thiopurines are real but also relatively rare, and with careful pre-treatment screening and ongoing monitoring thiopurine benefits outweigh risks in the majority of appropriately selected patients. Measurement of newer pharmacogenomic markers such as nudix hydrolase 15 (NUDT15), when combined with knowledge of existing known mutations (e.g., thiopurine S-methyltransferase—TPMT), will hopefully minimize the risk of potentially life-threatening leukopenia by allowing for pre-treatment dosing stratification. Further optimization of thiopurine dosing via measurement of thiopurine metabolites should be performed routinely and is superior to weight-based dosing. The association of thiopurines with malignancies including lymphoproliferative disorders needs to be recognized in all patients and individualized in each patient. The decrease in lymphoma risk after thiopurine cessation provides an incentive for thiopurine de-escalation in appropriate patients after a period of prolonged deep remission. This review will summarize the current role of thiopurines in inflammatory bowel disease management and provide recommendations for commencing and monitoring therapy, and when to consider de-escalation. Keywords Inflammatory bowel disease · Thiopurine · Pharmacogenomics · Nudix hydrolase 15 · Thiopurine methyltransferase · Metabolite monitoring
Introduction The inflammatory bowel diseases (IBD) are chronic relapsing and remitting immune-mediated inflammatory diseases, broadly categorized into Crohn’s disease (CD) and ulcerative colitis (UC). Recent decades have brought significant epidemiological changes and therapeutic advances in the management of IBD. The global prevalence and socioeconomic
* Miles P. Sparrow [email protected] Anke L. H. Nguyen [email protected] 1
Department of Gastroenterology, Alfred Health, 55 Commercial Road, Melbourne 3004, VIC, Australia
Monash University, Melbourne, Australia
2
disease burden of these conditions is increasing, driven primarily by an increased incidence in the developing world [1]. The therapeutic armamentarium of medical therapies for IBD has expanded
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