From the Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences and the Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom (P.C.T.); the Rebecca MacDonald Centre, Mount Sinai Hospital, University of Toronto, Toronto (E.C.K.); Leiden University Medical Center, Leiden, the Netherlands (D.H.); Brigham and Women's Hospital, Boston (M.E.W.); Instituto Reumatológico Strusberg, Córdoba, Argentina (L.C.M.); Centro de Investigacion Clinica Especializada, Mexico City (J.R.G.); Ryazan Regional Clinical Cardiology Dispensary, Ryazan, Russia (S.Y.); Eli Lilly, Indianapolis (T.I., S. Beattie, V.A., C.G., T.R., D.S., W.L.M., S. de Bono); and AstraZeneca K.K., Osaka (K.E.), and the First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu (Y.T.) - both in Japan.
N Engl J Med. 2017 Feb 16;376(7):652-662. doi: 10.1056/NEJMoa1608345.
Baricitinib is an oral, reversible inhibitor of the Janus kinases JAK1 and JAK2 that may have therapeutic value in patients with rheumatoid arthritis.
We conducted a 52-week, phase 3, double-blind, placebo- and active-controlled trial in which 1307 patients with active rheumatoid arthritis who were receiving background therapy with methotrexate were randomly assigned to one of three regimens in a 3:3:2 ratio: placebo (switched to baricitinib after 24 weeks), 4 mg of baricitinib once daily, or 40 mg of adalimumab (an anti-tumor necrosis factor α monoclonal antibody) every other week. End-point measures evaluated after adjustment for multiplicity included 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) (the primary end point), the Disease Activity Score for 28 joints (DAS28), the Health Assessment Questionnaire-Disability Index, and the Simplified Disease Activity Index at week 12, as well as radiographic progression of joint damage as measured by the van der Heijde modification of the total Sharp score (mTSS) (range, 0 to 448, with higher scores indicating greater structural joint damage) at week 24.
More patients had an ACR20 response at week 12 with baricitinib than with placebo (primary end point, 70% vs. 40%, P<0.001). All major secondary objectives were met, including inhibition of radiographic progression of joint damage, according to the mTSS at week 24 with baricitinib versus placebo (mean change from baseline, 0.41 vs. 0.90; P<0.001) and an increased ACR20 response rate at week 12 with baricitinib versus adalimumab (70% vs. 61%, P=0.014). Adverse events, including infections, were more frequent through week 24 with baricitinib and adalimumab than with placebo. Cancers were reported in five patients (two who received baricitinib and three who received placebo). Baricitinib was associated with reductions in neutrophil counts and increases in levels of creatinine and low-density lipoprotein cholesterol.
In patients with rheumatoid arthritis who had had an inadequate response to methotrexate, baricitinib was associated with significant clinical improvements as compared with placebo and adalimumab. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358 .).
巴利昔替尼是一种口服、可逆的 Janus 激酶 JAK1 和 JAK2 抑制剂，可能对类风湿关节炎患者具有治疗价值。
我们进行了一项为期 52 周、3 期、双盲、安慰剂对照和活性对照试验，纳入了 1307 例正在接受甲氨蝶呤背景治疗的活动性类风湿关节炎患者，将他们以 3:3:2 的比例随机分配至以下三种治疗方案组之一：安慰剂（24 周后换用巴利昔替尼）、每日 1 次 4mg 巴利昔替尼或每 2 周 1 次 40mg 阿达木单抗（一种抗肿瘤坏死因子 α 单克隆抗体）。经多重调整的终点评估包括：根据美国风湿病学会（ACR）20%缓解标准（主要终点）、28 个关节疾病活动度评分（DAS28）、健康评估问卷残疾指数（HAQ-DI）和简化疾病活动指数（SDAI）的 12 周缓解率，以及第 24 周时 van der Heijde 总 Sharp 评分改良值（mTSS）评估的关节损伤放射学进展（范围：0 至 448，分数越高表示结构关节损伤越严重）。
与安慰剂相比，更多的患者在第 12 周时达到 ACR20 缓解（主要终点：70% vs. 40%，P<0.001）。所有主要次要终点均达到，包括第 24 周时 mTSS 评估的关节损伤放射学进展抑制，与安慰剂相比，巴利昔替尼组的平均基线变化为 0.41，安慰剂组为 0.90（P<0.001），以及与阿达木单抗相比，巴利昔替尼组第 12 周时的 ACR20 缓解率增加（70% vs. 61%，P=0.014）。巴利昔替尼和阿达木单抗治疗组在第 24 周时的感染等不良事件发生率均高于安慰剂组。5 例患者（2 例接受巴利昔替尼治疗，3 例接受安慰剂治疗）报告发生了癌症。巴利昔替尼与中性粒细胞计数降低和肌酐及低密度脂蛋白胆固醇水平升高相关。
在对甲氨蝶呤反应不足的类风湿关节炎患者中，与安慰剂和阿达木单抗相比，巴利昔替尼可显著改善临床疗效。（由礼来和因塞特公司资助；临床试验编号，NCT01710358）。
