Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis - A randomized, double-blind, placebo-controlled, dose-escalation trial
Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis - A randomized, double-blind, placebo-controlled, dose-escalation trial
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DOI：
10.1002/art.10623
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发表时间：
2002-12-01
影响因子：
--
通讯作者：
Panayi, GS
中科院分区：
文献类型：
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作者：
Choy, EHS;Isenberg, DA;Panayi, GS
objective.目的：探讨重组人抗白细胞介素-6（IL-6）受体单克隆抗体（MRA）治疗类风湿关节炎（RA）的安全性和有效性。一项随机、双盲、安慰剂对照、剂量递增试验在45例活动性RA患者中进行，活动性RA的定义由美国风湿病学会（ACR）修订标准确定。患者依次接受0.1、1、5或10 mg/kg MRA或安慰剂单次静脉给药。主要疗效终点为治疗后2周达到ACR 20%应答标准。治疗组间的人口统计学特征相似。在第2周，在5 mg/kg MRA和安慰剂之间观察到显著的治疗差异，MRA队列中有5例患者（55.6%），安慰剂队列中无患者实现ACR 20%改善。第2周时，其他3个MRA队列与安慰剂之间的ACR 20%应答无统计学显著差异。接受5 mg/kg和10 mg/kg MRA的患者第2周的平均疾病活动评分分别为4.8和4.7（方差分析P <0.001和P <0.001）。这些平均评分在统计学上显著低于0.1和1 mg/kg MRA和安慰剂队列（分别为6.4、6.2和7.0）。5和10 mg/kg MRA队列的红细胞沉降率和C反应蛋白值显著下降，并在治疗后2周恢复正常。17例患者（安慰剂、0.1、1、5和10 mg/kg MRA队列中分别有5、4、6、2和0例患者）在研究结束前因活动性疾病需要皮质类固醇或病情缓解抗风湿药物治疗。他们从接受这些治疗时起被视为无应答者。腹泻是最常见的不良事件，8%的患者发生。7例患者（15.6%）报告了重度不良事件（安慰剂、0.1、1和10 mg/kg MRA队列中分别有3、1、2和2例患者）。未发生与研究药物相关的严重不良事件。这是第一个随机对照试验表明，抑制IL-6显着改善RA的体征和症状，并使急性期反应物正常化。需要进一步研究多次给药以确定最合适的RA治疗方案。
Objective. To investigate the safety and efficacy of MRA, a recombinant human anti-interleukin-6 (anti-IL-6) receptor monoclonal antibody of the IgG1 subclass that inhibits the function of IL-6, in patients with established rheumatoid arthritis (RA).Methods. A randomized, double-blind, placebo-controlled, dose-escalation trial was conducted in 45 patients with active RA, as defined by the American College of Rheumatology (ACR) revised criteria. Patients were sequentially allocated to receive a single intravenous dose of either 0.1, 1, 5, or 10 mg/kg of MRA or placebo. The primary efficacy end point was meeting the ACR 20% response criteria at week 2 after treatment.Results. Demographic features were similar between treatment groups. At week 2, a significant treatment difference was observed between the 5 mg/kg of MRA and placebo, with 5 patients (55.6%) in the MRA cohort and none in the placebo cohort achieving ACR 20% improvement. There was no statistically significant difference in the ACR 20% response between the other 3 MRA cohorts and placebo at week 2. The mean disease activity score at week 2 in those who received 5 mg/kg and 10 mg/kg of MRA was 4.8 and 4.7 (P < 0.001 and P < 0.001 by analysis of variance), respectively. These mean scores were statistically significantly lower than those in the 0.1- and 1-mg/kg MRA and the placebo cohorts (6.4, 6.2, and 7.0, respectively). The erythrocyte sedimentation rate and C-reactive protein values fell significantly in the 5- and 10-mg/kg MRA cohorts and normalized 2 weeks after treatment. Seventeen patients (5, 4, 6, 2, and 0 patients in the placebo, 0.1-, 1-, 5-, and 10-mg/kg MRA cohorts, respectively) required corticosteroid or disease-modifying antirheumatic drug treatment because of active disease before study end. They were regarded as nonresponders from the time they received these treatments. Diarrhea was the most common adverse event, occurring in 8% of patients. Seven patients (15.6%) reported a severe adverse event (3, 1, 2, and 2 patients in the placebo, 0.1-, 1-, and 10-mg/kg MRA cohorts). There were no serious adverse events that were thought to be related to the study drug.Conclusion. This is the first randomized controlled trial showing that inhibition of IL-6 significantly improved the signs and symptoms of RA and normalized the acute-phase reactants. Further research with multiple dosing is necessary to define the most appropriate therapeutic regimen of MRA in RA.