摘要
TNF antagonists have revolutionized the treatment of IBD. Nevertheless, between 30 and 45% of patients discontinue infliximab and other TNF antagonists over a 2- to 6-year period due to nonresponse, loss of response, or adverse events. Accordingly, the need for novel therapies grows each year. Recent studies have demonstrated the promise of new drugs with distinct modes of action for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). These include agents targeting leukocyte trafficking, therapies directed against IL-12/23 and Janus kinases (JAK), and antibodies against the classic inflammatory cytokine, IL-6. The anti-α4-integrin antibody, natalizumab, was the first effective antitrafficking agent for CD; however, its use has been greatly limited by the risk of progressive multifocal leukoencephalopathy. Therefore, second-generation antitrafficking agents have focused on restricting leukocyte blockade to the intestine through mechanisms interfering with α4β7-integrin and its interaction with mucosal addressin cellular adhesion molecule 1. IL-23 is a cytokine central to the adaptive immune responses that characterize IBD. Ustekinumab, targeting the p40 subunit of IL-12 and IL-23, and the oral JAK inhibitor tofacitinib have proven to be effective in phase 2 trials in CD and UC, respectively. In addition, antibodies targeting the proinflammatory cytokine IL-6 are being studied in CD. Each of the approaches described have promise as well as limitations, so it is likely that the search for novel agents in IBD will continue.
摘要译文
TNF拮抗剂彻底改变了IBD的治疗方法。然而，由于无反应，反应丧失或不良事件，在2至6年内有30％至45％的患者停用英夫利昔单抗和其他TNF拮抗剂。因此，对新疗法的需求每年都在增长。最近的研究表明，具有独特作用方式的新药有望用于治疗溃疡性结肠炎（UC）和克罗恩病（CD）。这些药物包括针对白细胞运输的药物，针对IL-12 / 23和Janus激酶（JAK）的疗法，以及针对经典炎症细胞因子IL-6的抗体。抗α4-整联蛋白抗体那他珠单抗是第一种有效的抗CD贩运药物。然而，由于进行性多灶性白质脑病的风险极大地限制了其使用。因此，第二代抗人口贩运活动的重点是通过干扰α4β7-整联蛋白及其与细胞粘附分子1的粘膜地址相互作用的机制来限制白细胞对肠道的阻滞。IL-23是适应性免疫反应的核心细胞因子，其表征IBD。乌斯替单抗靶向IL-12和IL-23的p40亚基，口服JAK抑制剂托法替尼已被证明分别在CD和UC的2期试验中有效。另外，正在CD中研究靶向促炎细胞因子IL-6的抗体。所描述的每种方法都有希望和局限性，因此可能会继续在IBD中寻找新型药物。
Sands B.E.. New Drugs on the Horizon for IBD[J]. Digestive Diseases, 2014,32: 74-81