Clinical utility of ustekinumab in Crohn's disease.
Clinical utility of ustekinumab in Crohn's disease.
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DOI：
10.2147/jir.s157358
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发表时间：
2018
影响因子：
4.5
通讯作者：
Panaccione R
中科院分区：
文献类型：
--
作者：
Kotze PG;Ma C;Almutairdi A;Panaccione R
抗肿瘤坏死因子（TNF）治疗的引入标志着中重度克罗恩病（CD）治疗的一个重要里程碑。然而，对于原发性无应答、继发性应答丧失或对常规治疗和TNF拮抗剂产生不可耐受的副作用的患者，仍然迫切需要替代治疗选择。优特克单抗（UST）是一种全人源IgG 1 κ单克隆抗体，可抑制促炎细胞因子白细胞介素（IL）-12和-23共享的p40亚基。这种阻断导致炎性级联反应和炎性T细胞的分化的抑制。CD中UST的临床开发项目包括剂量探索II期（克罗恩氏诱导用优特克单抗白细胞介素-12/23应答评价[CERTIFI]）和关键III期（UNITI）试验，这些试验证明了抗TNF初治和抗TNF暴露患者的临床疗效和安全性。现实世界的证据进一步确定了UST在CD管理中的作用。在这篇综述中，我们讨论了UST的作用机制，描述了该药物的随机对照试验结果，并回顾了观察队列的真实疗效和安全性数据。最后，我们确定了IL-12/23炎症通路的未来研究领域，并讨论了这种新的治疗选择在CD治疗算法中的定位。
The introduction of anti-tumor necrosis factor (TNF) therapy marked an important milestone in the management of moderate-to-severe Crohn’s disease (CD). However, there remains a pressing demand for alternative therapeutic options for patients with primary nonresponse, secondary loss of response, or intolerable side effects to conventional treatment and TNF antagonists. Ustekinumab (UST) is a fully human IgG1κ monoclonal antibody that inhibits the p40 subunit shared by the proinflammatory cytokines, the interleukin (IL)-12 and -23. This blockade leads to dampening of the inflammatory cascade and differentiation of inflammatory T cells. The clinical development program for UST in CD includes dose finding Phase II (Crohn’s Evaluation of Response to Ustekinumab Anti-Interleukin-12/23 for Induction [CERTIFI]) and the pivotal Phase III (UNITI) trials that demonstrated both the clinical efficacy and safety in anti-TNF-naive and anti-TNF-exposed patients. Real-world evidence has further defined the role of UST in CD management. In this review, we discuss the mechanism of action of UST, describe the results of the randomized controlled trials with this agent, and review the real-world efficacy and safety data from observational cohorts. Finally, we identify areas of future research in the IL-12/23 inflammatory pathway and discuss the positioning of this novel therapeutic option in CD treatment algorithms.