作者： Genovese MC 翻译 ：徐宁 审校：李常虹

摘要： 本研究是新药2期研究对于Baricitinib这种口服Janus激酶1和2的抑制剂用于既往没有接受过改变病情抗风湿药（DMARDs）的类风湿关节炎患者降低疾病活动度的治疗效果评估。本研究在3期研究中纳入527例对于一个或多个肿瘤坏死因子抑制剂药物治疗临床疗效不好或出现不可接受的副作用的患者，随机分配以1:1:1设立对照研究组，分为baricitinib剂量2mg每日或4 mg每日，或安慰剂组，对于治疗24周后的患者临床特点进行分析。在试验到期时应用美国风湿病学会ACR20评分（主要终点），健康评估问卷残疾指数（HAQ-DI）评分，基于C-反应蛋白水平的28个关节疾病活动度评分（DAS28-CRP），和一个简化疾病活动指数（SDAI）小于或等于3.3分（范围0.1至86，以3.3分或更少的分数指示疾病缓解）。baricitinib剂量2mg每日或4 mg每日组与安慰剂组比较结果提示更多的类风湿关节炎患者在应用baricitinib治疗后比那些接受安慰剂的患者在12周时ACR20更好（55%比27%，P＜0.001）。高剂量的baricitinib组和安慰剂组之间的HAQ-DI评分和DAS28-CRP评分具有显著差异，而 SDAI评分在3.3或以下没有显著差异。通过治疗24周后的患者不良事件发生率情况是baricitinib剂量2mg每日组，4 mg每日，安慰剂组分别是71%、77%和64%，其中包括感染（44%，40%，和31%）。严重不良事件发生率分别为4%、10%和7%。两例黑素瘤皮肤癌和两个主要心血管不良事件，包括致命的中风等情况在高剂量治疗组发生。有患者在治疗后出现血液中性粒细胞水平降低和血清肌酐以及低密度脂蛋白胆固醇水平增加。对于生物制剂DMARDs药物治疗效果不好的难治类风湿性关节炎患者，应用每天4毫克剂量baricitinib进行为期12周的治疗，其研究结果提示具有临床改善作用。

附原文：Background In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs). Methods In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose. Results Significantly more patients receiving baricitinib at the 4-mg dose than those receiving placebo had an ACR20 response at week 12 (55% vs. 27%, P<0 .001). differences between the higher-dose baricitinib group and the placebo group were also significant for the haq-di score and the das28-crp but not for an sdai score of 3.3 or less. adverse-event rates through 24 weeks were higher for patients receiving the 2-mg dose of baricitinib and those receiving the 4-mg dose than for patients receiving placebo (71% and 77%, respectively, vs. 64%), including infections (44% and 40%, vs. 31%). the rates of serious adverse events were 4%, 10%, and 7% in the three groups, respectively. two nonmelanoma skin cancers and two major adverse cardiovascular events, including a fatal stroke, occurred in the higher-dose group. baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholesterol levels. conclusions in patients with rheumatoid arthritis and an inadequate response to biologic dmards, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks. (funded by eli lilly and incyte; clinicaltrials.gov number, nct01721044 .).

引自： Genovese MC1, Kremer J1, Zamani O1, Ludivico C1, Krogulec M1, Xie L1, Beattie SD1, Koch AE1, Cardillo TE1, Rooney TP1, Macias WL1, de Bono S1, Schlichting DE1, Smolen JS1. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med. 2016 Mar 31;374(13):1243-1252.