Department of Medicine, University of Queensland, Rheumatology Research Unit, Sunshine Coast, QLD, Australia.
Guy's and St Thomas' NHS Foundation Trust, London, UK.
Lancet. 2017 Jun 10;389(10086):2317-2327. doi: 10.1016/S0140-6736(17)31429-0. Epub 2017 May 24.
Patients who have had inadequate response to tumour necrosis factor inhibitors have fewer treatment options and are generally more treatment refractory to subsequent therapeutic interventions than previously untreated patients. We report the efficacy and safety of ixekizumab, a monoclonal antibody that selectively targets interleukin-17A, in patients with active psoriatic arthritis and previous inadequate response to tumour necrosis factor inhibitors.
In this double-blind, multicentre, randomised, placebo-controlled, phase 3 study (SPIRIT-P2), patients were recruited from 109 centres across ten countries in Asia, Australia, Europe, and North America. Patients were aged 18 years or older, had a confirmed diagnosis of psoriatic arthritis for at least 6 months, and had a previous inadequate response, distinguished by being refractory to therapy or had loss of efficacy, or were intolerant to tumour necrosis factor inhibitors. Patients were randomly assigned (1:1:1) by a computer-generated random sequence to receive a subcutaneous injection of 80 mg ixekizumab every 4 weeks or every 2 weeks after a 160 mg starting dose or placebo. The primary endpoint was the proportion of patients who attained at least 20% improvement in the American College of Rheumatology response criteria (ACR-20) at week 24. This study is registered with ClinicalTrials.gov, number NCT02349295.
Between March 3, 2015, to March 22, 2016, 363 patients were randomly assigned to placebo (n=118), ixekizumab every 4 weeks (n=122), or ixekizumab every 2 weeks (n=123). At week 24, a higher proportion of patients attained ACR-20 with ixekizumab every 4 weeks (65 [53%] patients; effect size vs placebo 33·8% [95% CI 22·4-45·2]; p<0·0001) and ixekizumab every 2 weeks (59 [48%] patients; 28.5% [17·1-39.8]; p<0·0001) than did patients with placebo (23 [20%] patients). Up to week 24, serious adverse events were reported in three (3%) patients with ixekizumab every 4 weeks, eight (7%) with ixekizumab every 2 weeks, and four (3%) with placebo; no deaths were reported. Infections were reported in 47 (39%) patients with ixekizumab every 4 weeks, 47 (38%) with ixekizumab every 2 weeks, and 35 (30%) with placebo. Three (2%) serious infections, all in patients in the ixekizumab every 2 weeks group, were reported.
Both the 2-week and 4-week ixekizumab dosing regimens improved the signs and symptoms of patients with active psoriatic arthritis and who had previously inadequate response to tumour necrosis factor inhibitors, with a safety profile consistent with previous studies investigating ixekizumab.
Eli Lilly and Company.
与从未接受过治疗的患者相比，肿瘤坏死因子抑制剂治疗反应不足的患者的治疗选择较少，并且通常对后续治疗干预的反应更差。我们报告了选择性靶向白细胞介素-17A 的单克隆抗体依奇珠单抗在肿瘤坏死因子抑制剂治疗反应不足的活动性银屑病关节炎患者中的疗效和安全性。
在这项双盲、多中心、随机、安慰剂对照、3 期研究（SPIRIT-P2）中，从亚洲、澳大利亚、欧洲和北美的 109 个中心招募了患者。患者年龄在 18 岁或以上，确诊为银屑病关节炎至少 6 个月，并且之前的治疗反应不足，表现为对治疗有抵抗力或疗效丧失，或不耐受肿瘤坏死因子抑制剂。患者通过计算机生成的随机序列以 1:1:1 的比例随机分配接受皮下注射 80mg 依奇珠单抗，每 4 周一次或在 160mg 起始剂量后每 2 周一次。主要终点是在第 24 周时达到美国风湿病学会反应标准（ACR-20）至少 20%改善的患者比例。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT02349295。
2015 年 3 月 3 日至 2016 年 3 月 22 日，363 名患者被随机分配至安慰剂组（n=118）、依奇珠单抗每 4 周组（n=122）或依奇珠单抗每 2 周组（n=123）。在第 24 周时，更多接受依奇珠单抗每 4 周治疗的患者达到 ACR-20（65 [53%] 名患者；与安慰剂相比，效果大小为 33.8% [22.4-45.2]；p<0.0001）和依奇珠单抗每 2 周治疗（59 [48%] 名患者；28.5% [17.1-39.8]；p<0.0001）。在第 24 周之前，接受依奇珠单抗每 4 周治疗的患者中有 3 名（3%）、接受依奇珠单抗每 2 周治疗的患者中有 8 名（7%）和接受安慰剂治疗的患者中有 4 名（3%）报告了严重不良事件；没有死亡报告。接受依奇珠单抗每 4 周治疗的患者中有 47 名（39%）、接受依奇珠单抗每 2 周治疗的患者中有 47 名（38%）和接受安慰剂治疗的患者中有 35 名（30%）报告了感染。报告了 3 例（2%）严重感染，均发生在依奇珠单抗每 2 周治疗组的患者中。
依奇珠单抗每 2 周和每 4 周的治疗方案均改善了肿瘤坏死因子抑制剂治疗反应不足的活动性银屑病关节炎患者的体征和症状，且安全性与先前研究中调查依奇珠单抗的结果一致。
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