Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody - A multicenter, double-blind, placebo-controlled trial
Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody - A multicenter, double-blind, placebo-controlled trial
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DOI：
10.1002/art.20303
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发表时间：
2004-06-01
影响因子：
--
通讯作者：
Kishimoto, T
中科院分区：
文献类型：
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作者：
Nishimoto, N;Yoshizaki, K;Kishimoto, T
Objective.白细胞介素-6（IL-6）是一种调节免疫应答、炎症和造血的多效性细胞因子。IL-6的过度产生在类风湿性关节炎（RA）中起病理作用，并且IL-6的阻断可能对该疾病具有治疗效果。本研究旨在评估人源化抗IL-6受体抗体MRA在RA患者中的安全性和有效性。在一项多中心、双盲、安慰剂对照试验中，164例难治性RA患者随机接受MRA（4 mg/kg体重或8 mg/kg体重）或安慰剂治疗。MRA每4周静脉注射一次，共3个月。采用美国流变学学会（ACR）标准评估临床反应。MRA治疗以剂量依赖性方式降低疾病活动度。在3个月时，根据ACR标准（ACR 20应答），8 mg组78%的患者、4 mg组57%的患者和安慰剂组11%的患者的疾病活动度至少改善了20%（8 mg组与安慰剂组相比P < 0.001）。8 mg组40%的患者和安慰剂组1.9%的患者达到了ACR 50应答（P < 0.001）。安慰剂组、4 mg组和8 mg组不良事件的总体发生率分别为56%、59%和51%，且不良事件不具有剂量依赖性。在44.0%的患者中观察到血胆固醇升高。还观察到肝功能障碍和白色血细胞计数降低，但这些均为轻度和一过性。抗核抗体或抗DNA抗体未增加。2例患者检测到抗MRA抗体。MRA治疗一般耐受性良好，并显着降低了RA的疾病活动。
Objective. Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL-6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody, MRA, in patients with RA.Methods. In a multicenter, double-blind, placebo-controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria.Results. Treatment with MRA reduced disease activity in a dose-dependent manner. At 3 months, 78% of patients in the 8-mg group, 57% in the 4-mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8-mg group versus placebo). Forty percent of patients in the 8-mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4-mg, and 8-mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti-DNA antibodies. Anti-MRA antibodies were detected in 2 patients.Conclusion. Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.