美国俄勒冈健康与科学大学Atul Deodhar团队在研究中取得进展。他们探索了古塞库单抗治疗TNFα抑制剂无效的活动期银屑病关节炎患者的疗效和安全性。这一研究成果于2020年3月13日发表在《柳叶刀》杂志上。

许多银屑病关节炎患者对肿瘤坏死因子（TNF）抑制剂的应答不足。古塞库单抗是通过IL-23 p19亚基结合的白介素23（IL-23）特异性抑制剂，在临床2期试验中安全改善了银屑病关节炎的体征和症状。

2017年8月28日至2018年8月17日，一项多中心、双盲、随机、安慰剂对照的3期临床试验在亚洲，大洋洲、欧洲和北美的13个国家/地区的86个地点进行，研究组共招募了381名活动期银屑病关节炎的成人患者。这些患者对标准治疗反应不足或不耐受。大约30%的患者以前曾接受过一种或两种TNF抑制剂。

将这些患者按1：1：1随机分组，其中128名接受每4周一次皮下注射古塞库单抗100mg；127名接受第0、4周皮下注射古塞库单抗100mg，之后每8周注射一次；126名接受安慰剂治疗。主要终点为第24周时美国风湿病学院20%改善（ACR20）。

共有362名患者一直治疗至第24周。4周组有59%的患者达到主要终点，8周组有52%，均显著高于安慰剂组（22%）。4周组未发生严重不良事件，8周组严重不良事件发生率为3%，安慰剂组为4%。第24周时，安慰剂组中有1名患者死于心力衰竭，2名患者严重感染；古塞库单抗组中均无患者死亡或严重感染事件。

总之，古塞库单抗治疗活动期银屑病关节炎安全有效。

附：英文原文

Title: Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFα inhibitor treatment (DISCOVER-1): a double-blind, randomised, placebo-controlled phase 3 trial

Author: Atul Deodhar, Philip S Helliwell, Wolf-Henning Boehncke, Alexa P Kollmeier, Elizabeth C Hsia, Ramanand A Subramanian, Xie L Xu, Shihong Sheng, Prasheen Agarwal, Bei Zhou, Yanli Zhuang, Christopher T Ritchlin

Issue&Volume: 2020-03-13

Abstract: BackgroundMany 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.MethodsThis 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).FindingsFrom 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.InterpretationGuselkumab demonstrated a favourable benefit–risk profile and might be an effective treatment option for patients with active psoriatic arthritis.

DOI: 10.1016/S0140-6736(20)30265-8

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30265-8/fulltext