Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study
Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study
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DOI：
10.1016/s0140-6736(18)32167-6
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发表时间：
2018-10-13
期刊：
影响因子：
168.9
通讯作者：
Rose, Shawn
中科院分区：
文献类型：
--
作者：
van Vollenhoven, Ronald F.;Hahn, Bevra H.;Rose, Shawn
背景Ustekinumab是一种针对IL-12和IL-23的单抗，被批准用于治疗斑块型牛皮癣、牛皮癣关节炎和克罗恩病。IL-12和IL-23与系统性红斑狼疮有关。我们的目的是评估ustekinumab在常规治疗的基础上对中到重度疾病活动期的系统性红斑狼疮患者的疗效和安全性。方法这是一项多中心、双盲、2期随机对照试验，在阿根廷、澳大利亚、德国、匈牙利、墨西哥、波兰、西班牙、台湾和美国的44个私人诊所和学术中心进行。符合条件的成年人年龄为18-75岁，体重至少35公斤，在首次服用研究药物前至少3个月被诊断为系统性红斑狼疮。符合条件的患者被随机分配到ustekinumab组或安慰剂组(3：2)，使用交互式网络响应系统，根据皮肤活检、狼疮性肾炎的存在、系统性红斑狼疮药物的基线和综合因素、地点、地区和种族的评分，将其分为ustekinumab组或安慰剂组。患者和调查人员被蒙面进行治疗分配。患者接受ustekinumab静脉注射(体重35-55公斤的患者为260 mg，体重为55 kg和85 kg的患者为390 mg)，然后每8周皮下注射ustekinumab 90 mg，或在第0周静脉注射安慰剂，然后每8周皮下注射一次安慰剂，这两项都是除了标准护理治疗之外的。主要终点是在第24周达到SLEDAI-2K反应者指数4(SRI-4)反应的患者的比例。疗效分析是在一个改良的意向治疗人群中进行的，这些患者接受了至少一个剂量(部分或全部，静脉或皮下)的随机分配研究治疗。对所有接受了至少一剂研究治疗的患者进行了安全性分析，而不考虑分组。这项研究在ClinicalTrials.gov上注册，编号NCT02349061。在2015年10月6日至2016年11月30日期间，对166名患者进行了筛查，其中102人被随机分配接受ustekinumab(n=60)或安慰剂(n=42)。在第24周，ustekinumab组60名患者中的37名(62%)和安慰剂组42名患者中的14名(33%)实现了SRI-4应答(百分比差异28%[95%可信区间10-47]，p=0.006)。在第0周到第24周期间，ustekinumab组60名患者中有47名(78%)和安慰剂组42名患者中有28名(67%)至少有一次不良事件。感染是最常见的不良事件类型(ustekinumab组27例(45%)，安慰剂组21例[50%])。没有死亡或治疗--在0-24周内发生紧急机会性感染、带状疱疹、结核病或恶性肿瘤。解释：在标准护理治疗中加入ustekinumab在治疗活动性系统性红斑狼疮方面的临床和实验室参数方面比安慰剂更有效，并且在其他疾病中的安全性与ustekinumab疗法一致。这项研究的结果支持Ustekinumab作为系统性红斑狼疮的一种新疗法的进一步发展。版权所有(C)2018爱思唯尔有限公司。保留所有权利。
Background Ustekinumab is a monoclonal antibody targeting interleukin (IL)-12 and IL-23 and is approved for the treatment of plaque psoriasis, psoriatic arthritis, and Crohn's disease. IL-12 and IL-23 have been implicated in systemic lupus erythematosus. We aimed to assess the efficacy and safety of ustekinumab for the treatment of systemic lupus erythematosus in patients with moderate-to-severe disease activity despite conventional treatment.Methods This was a multicentre, double-blind, phase 2, randomised, controlled trial of adult patients with active, seropositive systemic lupus erythematosus, done at 44 private practices and academic centres in Argentina, Australia, Germany, Hungary, Mexico, Poland, Spain, Taiwan, and the USA. Eligible adults were aged 18-75 years, weighed at least 35 kg, and had a diagnosis of systemic lupus erythematosus at least 3 months before the first administration of study drug. Eligible patients were randomly assigned (3:2) to the ustekinumab or placebo group using an interactive web response system with stratification by skin biopsy, lupus nephritis presence, baseline systemic lupus erythematosus medications and systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) score combined factor, site, region, and race. Patients and investigators were masked to treatment allocation. Patients received an intravenous infusion of ustekinumab (260 mg for patients weighing 35-55 kg, 390 mg for patients weighing >55 kg and 85 kg) followed by subcutaneous injections of ustekinumab 90 mg every 8 weeks or intravenous infusion of placebo at week 0 followed by subcutaneous injections of placebo every 8 weeks, both in addition to standard-of-care therapy. The primary endpoint was the proportion of patients achieving a SLEDAI-2K responder index-4 (SRI-4) response at week 24. Efficacy analyses were done in a modified intention-to-treat population of patients who received at least one dose (partial or complete, intravenous or subcutaneous) of their randomly assigned study treatment. Safety analyses were done in all patients who received at least one dose of study treatment, regardless of group assignment. This study is registered at ClinicalTrials.gov, number NCT02349061.Findings Between Oct 6, 2015, and Nov 30, 2016, 166 patients were screened, of whom 102 were randomly assigned to receive ustekinumab (n=60) or placebo (n=42). At week 24,37 (62%) of 60 patients in the ustekinumab group and 14 (33%) of 42 patients in the placebo group achieved an SRI-4 response (percentage difference 28% [95% CI 10-47], p=0.006). Between week 0 and week 24,47 (78%) of 60 patients in the ustekinumab group and 28 (67%) of 42 patients in the placebo group had at least one adverse event. Infections were the most common type of adverse event (27 [45%] in the ustekinumab group vs 21 [50%] in the placebo group). No deaths or treatment-emergent opportunistic infections, herpes zoster, tuberculosis, or malignancies occurred between weeks 0-24.Interpretation The addition of ustekinumab to standard-of-care treatment resulted in better efficacy in clinical and laboratory parameters than placebo in the treatment of active systemic lupus erythematosus and had a safety profile consistent with ustekinumab therapy in other diseases. The results of this study support further development of ustekinumab as a novel treatment in systemic lupus erythematosus. Copyright (C) 2018 Elsevier Ltd. All rights reserved.