Department of Gastroenterology, IDIBAPS, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
Nat Rev Gastroenterol Hepatol. 2020 Jun;17(6):323-337. doi: 10.1038/s41575-020-0273-0. Epub 2020 Mar 19.
Cytokines are involved in intestinal homeostasis and pathological processes associated with inflammatory bowel disease (IBD). The biological effects of cytokines, including several involved in the pathology of Crohn's disease and ulcerative colitis, occur as a result of receptor-mediated signalling through the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) DNA-binding families of proteins. Although therapies targeting cytokines have revolutionized IBD therapy, they have historically targeted individual cytokines, and an unmet medical need exists for patients who do not respond to or lose response to these treatments. Several small-molecule inhibitors of JAKs that have the potential to affect multiple pro-inflammatory cytokine-dependent pathways are in clinical development for the treatment of IBD, with one agent, tofacitinib, already approved for ulcerative colitis and several other agents with demonstrated efficacy in early phase trials. This Review describes the current understanding of JAK-STAT signalling in intestinal homeostasis and disease and the rationale for targeting this pathway as a treatment for IBD. The available evidence for the efficacy, safety and pharmacokinetics of JAK inhibitors in IBD as well as the potential approaches to optimize treatment with these agents, such as localized delivery or combination therapy, are also discussed.
细胞因子参与肠道稳态和与炎症性肠病（IBD）相关的病理过程。细胞因子的生物学效应，包括与克罗恩病和溃疡性结肠炎病理相关的几种细胞因子，是通过 Janus 激酶（JAK）和信号转导和转录激活因子（STAT）DNA 结合蛋白家族的受体介导信号传递而产生的。尽管针对细胞因子的治疗方法彻底改变了 IBD 的治疗方法，但它们在历史上一直针对个别细胞因子，对于那些对这些治疗方法无反应或失去反应的患者，仍然存在未满足的医疗需求。有几种潜在的小分子 JAK 抑制剂正在开发用于治疗 IBD，这些抑制剂可能会影响多种促炎细胞因子依赖的途径，其中一种药物托法替尼已被批准用于溃疡性结肠炎，还有几种其他药物在早期临床试验中显示出疗效。这篇综述描述了 JAK-STAT 信号通路在肠道稳态和疾病中的当前认识，以及将该通路作为治疗 IBD 的一种方法的原理。还讨论了 JAK 抑制剂在 IBD 中的疗效、安全性和药代动力学的现有证据，以及优化这些药物治疗的潜在方法，例如局部给药或联合治疗。
