Gargallo-Puyuelo Carla J, Laredo Viviana, Gomollón Fernando
Department of Gastroenterology, University Clinic Hospital Lozano Blesa, Zaragoza, Spain.
Department of Medicine, Psychiatry and Dermatology, University of Zaragoza, Zaragoza, Spain.
Front Med (Lausanne). 2021 Jul 16;8:681907. doi: 10.3389/fmed.2021.681907. eCollection 2021.
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.
硫嘌呤一直是治疗炎症性肠病（IBD）的基石。尽管它们已被使用了50多年，但关于其疗效仍存在一些未解决的问题，同时也存在一些安全问题，主要是骨髓抑制风险和危及生命的淋巴增殖性疾病风险。此外，生物治疗的发展引发了一个问题，即硫嘌呤在IBD治疗方案中是否仍有作用。另一方面，成本有限且广泛可得使得硫嘌呤在资源有限且IBD患病率不断上升的情况下成为一个合理的选择。事实上，人们对优化硫嘌呤治疗的兴趣日益浓厚，因为药物基因组学研究结果表明，基于参与其代谢的某些分子的基因分型的个性化方法可能有助于预防副作用。硫嘌呤甲基转移酶（TPMT）的多态性导致酶活性降低与骨髓毒性风险增加有关，尤其是在白种人中；然而，在亚洲人中，人们认为Nudix水解酶15（NUDT15）的变体在毒性发展中更具相关性。年龄也很重要，因为老年患者并发症的风险似乎更高。此外，硫嘌呤治疗期间爱泼斯坦-巴尔病毒和巨细胞病毒的初次感染与严重的淋巴增殖性疾病有关。除了评估可能影响硫嘌呤治疗结果的个体特征外，本综述还讨论了优化治疗的其他策略。低剂量硫嘌呤与别嘌呤醇联合可用于高甲基化者和硫嘌呤相关的肝毒性。代谢物的测量有助于评估依从性、识别有不良事件风险的患者以及促进难治性患者的管理。硫鸟嘌呤也是传统硫嘌呤治疗相关毒性患者的挽救疗法。最后，还综述了硫嘌呤单药治疗或与生物制剂联合治疗的当前适应证以及最佳治疗持续时间。
