Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, Netherlands; Free University (VU) Amsterdam, Amsterdam, Netherlands; Amsterdam Rheumatology and Immunology Center, Amsterdam, Netherlands.
University of California Los Angeles, Los Angeles, CA, USA.
Lancet. 2018 Oct 13;392(10155):1330-1339. doi: 10.1016/S0140-6736(18)32167-6. Epub 2018 Sep 21.
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.
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, and 520 mg for patients weighing >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.
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.
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.
Janssen Research & Development, LLC.
乌司奴单抗是一种靶向白细胞介素（IL）-12 和 IL-23 的单克隆抗体，已获批准用于治疗斑块状银屑病、银屑病关节炎和克罗恩病。IL-12 和 IL-23 与系统性红斑狼疮有关。我们旨在评估乌司奴单抗在常规治疗下仍有中度至重度疾病活动的系统性红斑狼疮患者中的疗效和安全性。
这是一项多中心、双盲、随机、对照的 2 期临床试验，在阿根廷、澳大利亚、德国、匈牙利、墨西哥、波兰、西班牙、中国台湾和美国的 44 家私人诊所和学术中心进行。合格的成年患者为患有活动性、血清阳性系统性红斑狼疮的患者，年龄 18-75 岁，体重至少 35 公斤，在接受研究药物首次给药前至少 3 个月诊断为系统性红斑狼疮。符合条件的患者被随机分配（3:2）至乌司奴单抗或安慰剂组，使用具有分层的交互式网络响应系统，分层因素为皮肤活检、狼疮肾炎存在、基线系统性红斑狼疮药物和系统性红斑狼疮疾病活动指数 2000（SLEDAI-2K）评分组合因子、地点、地区和种族。患者和研究者对治疗分配均不知情。患者接受乌司奴单抗静脉输注（体重 35-55 公斤的患者为 260 毫克，体重 >55 公斤且 ≤85 公斤的患者为 390 毫克，体重 >85 公斤的患者为 520 毫克），随后每 8 周皮下注射乌司奴单抗 90 毫克，或在第 0 周接受静脉输注安慰剂，随后每 8 周皮下注射安慰剂，均在标准治疗的基础上进行。主要终点是在第 24 周时达到 SLEDAI-2K 应答指数-4（SRI-4）应答的患者比例。在接受至少一次（部分或完全，静脉或皮下）随机分配的研究治疗的改良意向治疗人群中进行疗效分析。安全性分析在接受至少一次研究治疗的所有患者中进行，无论分组情况如何。这项研究在 ClinicalTrials.gov 注册，编号为 NCT02349061。
2015 年 10 月 6 日至 2016 年 11 月 30 日期间，共有 166 名患者接受了筛查，其中 102 名患者被随机分配接受乌司奴单抗（n=60）或安慰剂（n=42）。在第 24 周时，乌司奴单抗组的 60 名患者中有 37 名（62%）和安慰剂组的 42 名患者中有 14 名（33%）达到了 SRI-4 应答（百分比差异 28%[95%CI 10-47]，p=0.006）。在第 0 周至第 24 周期间，乌司奴单抗组的 60 名患者中有 47 名（78%）和安慰剂组的 42 名患者中有 28 名（67%）至少发生了一次不良事件。感染是最常见的不良事件类型（乌司奴单抗组 27 例[45%]，安慰剂组 21 例[50%]）。在第 0-24 周期间，没有死亡或治疗后出现的机会性感染、带状疱疹、结核病或恶性肿瘤。
与安慰剂相比，乌司奴单抗联合标准治疗在治疗活动性系统性红斑狼疮方面的疗效更好，其安全性与乌司奴单抗治疗其他疾病的安全性一致。这项研究的结果支持乌司奴单抗作为一种新的系统性红斑狼疮治疗方法的进一步发展。
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