Karolinska Institute, Stockholm.
N Engl J Med. 2012 Aug 9;367(6):508-19. doi: 10.1056/NEJMoa1112072.
Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis.
In this 12-month, phase 3 trial, 717 patients who were receiving stable doses of methotrexate were randomly assigned to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of adalimumab once every 2 weeks, or placebo. At month 3, patients in the placebo group who did not have a 20% reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily; at month 6, all patients still receiving placebo were switched to tofacitinib in a blinded fashion. The three primary outcome measures were a 20% improvement at month 6 in the American College of Rheumatology scale (ACR 20); the change from baseline to month 3 in the score on the Health Assessment Questionnaire-Disability Index (HAQ-DI) (which ranges from 0 to 3, with higher scores indicating greater disability); and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity).
At month 6, ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) than among those receiving placebo (28.3%) (P<0.001 for all comparisons). There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28-4(ESR) below 2.6 at month 6 in the active-treatment groups than in the placebo group. Adverse events occurred more frequently with tofacitinib than with placebo, and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group. Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts.
In patients with rheumatoid arthritis receiving background methotrexate, tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy. (Funded by Pfizer; ORAL Standard ClinicalTrials.gov number, NCT00853385.).
托法替尼（CP-690,550）是一种新型的口服 Janus 激酶抑制剂，目前正在研究用于治疗类风湿关节炎。
在这项为期 12 个月的 3 期试验中，717 名正在接受稳定剂量甲氨蝶呤治疗的患者被随机分配接受托法替尼 5mg 每日 2 次、10mg 每日 2 次、40mg 阿达木单抗每 2 周 1 次或安慰剂治疗。在第 3 个月，未达到基线时肿胀和触痛关节数减少 20%的安慰剂组患者以盲法方式转换为托法替尼 5mg 或 10mg 每日 2 次；在第 6 个月，所有仍接受安慰剂治疗的患者以盲法方式转换为托法替尼。3 项主要终点指标为：第 6 个月时美国风湿病学会（ACR）20 改善率（ACR 20）；从基线到第 3 个月时健康评估问卷残疾指数（HAQ-DI）评分的变化（范围为 0 至 3，分数越高表示残疾程度越高）；以及第 6 个月时疾病活动评分（DAS28-4[ESR]）小于 2.6 的患者比例（评分范围为 0 至 9.4，分数越高表示疾病活动度越高）。
在第 6 个月时，接受托法替尼 5mg 或 10mg 治疗的患者（分别为 51.5%和 52.6%）和接受阿达木单抗治疗的患者（47.2%）的 ACR 20 应答率均高于接受安慰剂治疗的患者（28.3%）（所有比较均 P<0.001）。在第 3 个月时，HAQ-DI 评分的降低幅度更大，在第 6 个月时 DAS28-4（ESR）小于 2.6 的患者比例在活性治疗组中也高于安慰剂组。与安慰剂相比，托法替尼治疗组更常发生不良事件，并且在接受 10mg 托法替尼治疗的 2 例患者中发生了肺结核。托法替尼可增加低密度脂蛋白胆固醇和高密度脂蛋白胆固醇水平，并降低中性粒细胞计数。
在接受背景甲氨蝶呤治疗的类风湿关节炎患者中，托法替尼显著优于安慰剂，在疗效方面与阿达木单抗相当。（由辉瑞公司资助；ORAL Standard 临床试验.gov 编号，NCT00853385）。
