Evolving Role of Thiopurines in Inflammatory Bowel Disease in the Era of Biologics and New Small Molecules

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.

Low-Dose Azathioprine in Combination with Allopurinol: The Past, Present and Future of This Useful Duo

“…While thiopurines have not been able to demonstrate equivalent effectiveness when compared to biologics, such as anti-tumour necrosis factor (anti-TNF) agents, used alone or in combination with immunomodulators, they do have several advantages [7][8][9][10][11]. The most obvious benefits of thiopurines are reduced cost, ease of administration and simpler storage.…”

“…Patients with low or absent TPMT activity are at risk of bone marrow suppression from the high levels of 6-TGN relative to the dose received [46,47]. TPMT testing, by phenotype or genotype, is now recommended in all patients prior to commencing a thiopurine [8,47]. More recently, polymorphisms of Nudix NUDT15 have also been associated with myelotoxicity, especially in Asian ethnicities.…”