Thiopurines in Inflammatory Bowel Disease. How to Optimize Thiopurines in the Biologic Era?

Abstract

Thiopurines have been a cornerstone in the treatment of inflammatory bowel disease (IBD). Although they have been used for more than 50 years, there are still some unsolved issues about their efficacy and, also, some safety concerns, mainly the risk of myelosuppression and life-threatening lymphoproliferative disorders. Furthermore, the development of biological therapy raises the question whether there is still a role for thiopurines in the IBD treatment algorithm. On the other hand, limited cost and wide availability make thiopurines a reasonable option in settings of limited resources and increasing prevalence of IBD. In fact, there is a growing interest in optimizing thiopurine therapy, since pharmacogenomic findings suggest that a personalized approach based on the genotyping of some molecules involved in its metabolism could be useful to prevent side effects. Polymorphisms of thiopurine methyltransferase enzyme (TPMT) that result in low enzymatic activity have been associated with an increased risk of myelotoxicity, especially in Caucasians; however, in Asians it is assumed that the variants of nudix hydrolase 15 (NUDT15) are more relevant in the development of toxicity. Age is also important, since in elderly patients the risk of complications seems to be increased. Moreover, the primo-infection of Epstein Barr virus and cytomegalovirus under thiopurine treatment has been associated with severe lymphoproliferative disorders. In addition to assessing individual characteristics that may influence thiopurines treatment outcomes, this review also discusses other strategies to optimize the therapy. Low-dose thiopurines combined with allopurinol can be used in hypermethylators and in thiopurine-related hepatotoxicity. The measurement of metabolites could be useful to assess compliance, identify patients at risk of adverse events and also facilitating the management of refractory patients. Thioguanine is also a rescue therapy in patients with toxicity related to conventional thiopurine therapy. Finally, the current indications for thiopurines in monotherapy or in combination with biologics, as well as the optimal duration of treatment, are also reviewed.

Classic drugs in the time of new drugs: real‐world, long‐term outcomes of thiopurine monotherapy in 1016 patients with inflammatory bowel disease

“…29,30 The aforementioned observations concerning the benefitrisk balance have also fuelled questioning on the position of thiopurines in the IBD treatment algorithm. 26,31 Interestingly, particularly in the perspective of consensus guidelines, such as the ECCO's, a recent international survey among more than 400 IBD physicians revealed that the majority of physicians still resort to thiopurines in a substantial proportion of patients and believe that thiopurines will still be an important part of the IBD treatment in the future. Moreover, 70% of respondents (strongly) agreed that thiopurines are effective as monotherapy in both CD and UC.…”

Editorial: thiopurines in the multidrug era—time to rescue our memories over half a century of experience. Authors' reply

“…In addition, NUDT15 genotyping may be helpful, specifically in Asian populations. 8 Furthermore, allopurinol co-administration with low-dose thiopurines, or a switch to-or first-line use of thioguanine have also proven valuable in enhancing clinical benefit and tolerability, particularly when metabolic skewing (towards methylation) is present. 9,10 These well documented observations have led to the recent registration of 6-TG for the treatment of IBD in the Netherlands.…”

“…By means of thiopurine methyltransferase testing and therapeutic drug monitoring, improvement of therapeutic success may be achieved. In addition, NUDT15 genotyping may be helpful, specifically in Asian populations 8 . Furthermore, allopurinol co‐administration with low‐dose thiopurines, or a switch to‐ or first‐line use of thioguanine (6‐TG) have also proven valuable in enhancing clinical benefit and tolerability, particularly when metabolic skewing (towards methylation) is present 9,10 .…”

Transmembrane serine protease 2 and angiotensin-converting enzyme 2 anti-inflammatory receptors for COVID-19/inflammatory bowel diseases treatment

“…thiopurine and infliximab) might be an option. Also, monotherapy with natural products may be considered[ 60 , 80 , 81 ]. Vedolizumab (an adversary of α4β7 integrin) is significantly explicit for movement on the gut, hence it is favorable for fundamental or pneumonic responses in COVID-19[ 62 , 82 ].…”