Division of Arthritis and Rheumatic Diseases, Oregon Health and Science University, Portland, OR, USA.
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK; National Institute for Health Research Leeds Musculoskeletal Biomedical Research Centre, Leeds, UK.
Lancet. 2020 Apr 4;395(10230):1115-1125. doi: 10.1016/S0140-6736(20)30265-8. Epub 2020 Mar 13.
Many patients with psoriatic arthritis have an inadequate response to tumor necrosis factor (TNF) inhibitors. Guselkumab, a specific inhibitor of interleukin-23 (IL-23) via IL-23 p19 subunit binding, significantly improved psoriatic arthritis signs and symptoms with an acceptable safety profile in a phase 2 trial.
This multicentre, double-blind, randomised, placebo-controlled, phase 3 trial was done at 86 sites in 13 countries across Asia, Australasia, Europe, and North America and enrolled adults with active psoriatic arthritis (at least three swollen and three tender joints; and C-reactive protein ≥0·3 mg/dL) despite standard therapies. Eligibility criteria included inadequate response to or intolerance of standard treatment, including at least 4 months of apremilast, at least 3 months of non-biologic disease-modifying antirheumatic drugs (DMARDs), or at least 4 weeks of non-steroidal anti-inflammatory drugs for psoriatic arthritis. About 30% of study participants could have previously received one or two TNF inhibitors. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline DMARD and previous TNF inhibitor use) to subcutaneous guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or matching placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 24 in all patients per assigned treatment group using non-responder imputation. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03162796 (active, not recruiting).
From Aug 28, 2017, to Aug 17, 2018, we screened 624 patients, of whom 381 were randomly assigned and treated with guselkumab every 4 weeks (n=128), guselkumab every 8 weeks (n=127), or placebo (n=126). 362 patients continued study treatment up to week 24. The primary endpoint was met: ACR20 at week 24 was achieved by significantly greater proportions of patients in the guselkumab every 4 weeks group (76 [59%] of 128 [95% CI 50-68]) and every 8 weeks group (66 [52%] of 127 [43-61]) than in the placebo group (28 [22%] of 126 [15-30]), with percentage differences versus placebo of 37% (95% CI 26-48) for the every 4 weeks group and 30% (19-41) for the every 8 weeks group (both p<0·0001). Serious adverse events up to week 24 occurred in no patients receiving guselkumab every 4 weeks, four (3%) patients receiving guselkumab every 8 weeks, and five (4%) patients receiving placebo. Up to week 24, one patient in the placebo group died from cardiac failure and two had serious infections; no guselkumab-treated patient died or had serious infections.
Guselkumab demonstrated a favourable benefit-risk profile and might be an effective treatment option for patients with active psoriatic arthritis.
Janssen Research and Development.
许多患有银屑病关节炎的患者对肿瘤坏死因子（TNF）抑制剂的反应不足。古塞库单抗是一种特异性白细胞介素-23（IL-23）抑制剂，通过与 IL-23 的 p19 亚单位结合，在一项 2 期试验中显著改善了银屑病关节炎的症状和体征，且具有可接受的安全性。
这是一项多中心、双盲、随机、安慰剂对照、3 期临床试验，在亚洲、澳大拉西亚、欧洲和北美 86 个地点进行，共纳入了 381 名患有活动性银屑病关节炎（至少 3 个肿胀关节和 3 个触痛关节；C 反应蛋白≥0·3mg/dL）且对标准治疗反应不足或不耐受的成年人。纳入标准包括标准治疗反应不足或不耐受，包括至少 4 个月的阿普米司特、至少 3 个月的非生物性疾病修饰抗风湿药物（DMARDs）或至少 4 周的非甾体抗炎药治疗银屑病关节炎。约 30%的研究参与者之前可能接受过一种或两种 TNF 抑制剂。患者随机分配（1:1:1，计算机生成的置换块；按基线 DMARD 和以前 TNF 抑制剂的使用分层）接受每 4 周皮下注射古塞库单抗 100mg；古塞库单抗 100mg，第 0、4 周，然后每 8 周一次；或匹配的安慰剂。主要终点是所有按治疗组分配的患者在第 24 周时达到美国风湿病学会 20%改善（ACR20），采用无应答者推断。所有接受治疗的患者均进行安全性评估。该试验在 ClinicalTrials.gov 上注册，NCT03162796（活跃，不招募）。
从 2017 年 8 月 28 日至 2018 年 8 月 17 日，我们共筛选了 624 名患者，其中 381 名患者被随机分配并接受古塞库单抗每 4 周治疗（n=128）、每 8 周治疗（n=127）或安慰剂（n=126）。362 名患者继续接受治疗至第 24 周。主要终点达到：古塞库单抗每 4 周组（76[59%]例 128[95%CI 50-68]）和每 8 周组（66[52%]例 127[43-61]）的患者比例显著高于安慰剂组（28[22%]例 126[15-30]），与安慰剂组相比，每 4 周组的差异百分比为 37%（95%CI 26-48），每 8 周组的差异百分比为 30%（19-41）（均 p<0·0001）。至第 24 周，无接受古塞库单抗每 4 周治疗的患者发生严重不良事件，4 名（3%）接受古塞库单抗每 8 周治疗的患者和 5 名（4%）接受安慰剂治疗的患者发生严重不良事件。至第 24 周，安慰剂组 1 例患者死于心力衰竭，2 例患者发生严重感染；没有接受古塞库单抗治疗的患者死亡或发生严重感染。
古塞库单抗显示出有利的风险效益比，可能是治疗活动性银屑病关节炎患者的有效治疗选择。
杨森研发。
