Robarts Clinical Trials, Inc., London, ON, Canada.
IBD Center, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
J Crohns Colitis. 2020 Aug 1;14(Supplement_2):S725-S736. doi: 10.1093/ecco-jcc/jjaa014.
Inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are chronic inflammatory disorders of the gastrointestinal tract which are characterised, in part, by an imbalance in the production of several pro- and anti-inflammatory cytokines. Although various agents are effective for inducing and maintaining remission, approximately 20% of patients are treatment-refractory and require surgery. Parenterally administered monoclonal antibody-based biologics are associated with adverse effects resulting in treatment discontinuation and/or immunogenicity, leading to loss of response to therapy. Approximately 50% of patients who initially respond to treatment with tumour necrosis factor antagonists lose response to therapy within the 1st year of treatment. Incidence of immunogenicity tends to decrease over time, but once present can persist for years, even after treatment discontinuation. Nonimmunogenic oral small molecule therapies, including Janus kinase inhibitors, are currently being developed and have demonstrated efficacy in early phase clinical trials, which has already led to regulatory approval of tofacitinib for the treatment of patients with moderate-to-severe ulcerative colitis. Differentiation of T cells into T helper cells, which are mediators of the inflammatory response in inflammatory bowel disease, is mediated by the Janus kinase signal transducer and activator of the transcription signalling pathway. Absorption and distribution of Janus kinase inhibitors occurs at the site of action in the gastrointestinal tract, and newer compounds are being developed with limited systemic absorption, potentially reducing the risk of adverse effects. The current review describes the clinical pharmacology of approved Janus kinase inhibitors, as well as those in clinical development for the treatment of inflammatory bowel disease.
炎症性肠病，包括溃疡性结肠炎和克罗恩病，是胃肠道的慢性炎症性疾病，其特征部分是几种促炎和抗炎细胞因子的生产失衡。虽然各种药物对诱导和维持缓解有效，但约 20%的患者对治疗无反应，需要手术。肠外给予基于单克隆抗体的生物制剂与不良反应相关，导致治疗中断和/或免疫原性，导致对治疗的反应丧失。最初对肿瘤坏死因子拮抗剂治疗有反应的约 50%的患者在治疗的第 1 年内对治疗失去反应。免疫原性的发生率随时间推移而降低，但一旦出现，即使在治疗停止后也可能持续多年。目前正在开发非免疫性口服小分子疗法，包括 Janus 激酶抑制剂，已在早期临床试验中证明有效，这已经导致托法替尼获得批准用于治疗中度至重度溃疡性结肠炎患者。T 细胞分化为辅助性 T 细胞，这是炎症性肠病炎症反应的介质，是由 Janus 激酶信号转导和转录激活因子信号通路介导的。Janus 激酶抑制剂的吸收和分布发生在胃肠道的作用部位，并且正在开发具有有限全身吸收的新型化合物，这可能降低不良反应的风险。本综述描述了已批准的 Janus 激酶抑制剂以及正在开发用于治疗炎症性肠病的 Janus 激酶抑制剂的临床药理学。
