Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy - Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks
Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy - Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks
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DOI：
10.1002/art.22025
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发表时间：
2006-09-01
影响因子：
--
通讯作者：
Totoritis, Mark C.
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文献类型：
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作者：
Cohen, Stanley B.;Emery, Paul;Totoritis, Mark C.
目的：确定利妥昔单抗联合甲氨蝶呤（MTX）治疗对抗肿瘤坏死因子（抗TNF）疗法反应不佳的活动性类风湿关节炎（RA）患者的疗效和安全性，并探究利妥昔单抗在该人群中的药代动力学和药效学。
方法：我们评估了参与利妥昔单抗治疗类风湿关节炎长期疗效随机评估（REFLEX）试验的患者在24周时的主要疗效和安全性。这是一项为期2年、多中心、随机、双盲、安慰剂对照的利妥昔单抗治疗Ⅲ期研究。患有活动性RA且对1种或多种抗TNF药物反应不佳的患者被随机分配接受静脉注射利妥昔单抗（1个疗程，包括2次每次1000mg的输注）或安慰剂，两组均同时使用MTX作为基础治疗。主要疗效终点是在24周时达到美国风湿病学会20%改善标准（ACR20）的反应。次要终点是在24周时达到ACR50和ACR70改善标准、28个关节的疾病活动评分以及欧洲抗风湿病联盟（EULAR）反应标准的反应。其他终点包括在24周时慢性疾病治疗功能评估 - 疲劳（FACIT - F）、健康评估问卷（HAQ）残疾指数（DI）和简表36（SF - 36）量表的评分，以及Genant改良Sharp放射学评分。
结果：被分配到安慰剂组（n = 209）和利妥昔单抗组（n = 311）的患者患有活动性、长期存在的RA。在第24周，利妥昔单抗治疗组达到ACR20（51%对18%）、ACR50（27%对5%）和ACR70（12%对1%）反应以及中到良好EULAR反应（65%对22%）的患者明显多于安慰剂治疗组（P < 0.0001）。利妥昔单抗治疗组的所有ACR反应参数均显著改善，在疲劳、残疾和健康相关生活质量方面也有临床意义的改善（分别由FACIT - F、HAQ DI和SF - 36评分证明），并且在放射学终点方面显示出进展减缓的趋势。利妥昔单抗耗竭外周CD20 + B细胞，但平均免疫球蛋白水平（IgG、IgM和IgA）仍在正常范围内。大多数不良事件发生在第一次利妥昔单抗输注时，严重程度为轻到中度。利妥昔单抗组的严重感染率为每100患者 - 年5.2例，安慰剂组为每100患者 - 年3.7例。
结论：在24周时，单疗程利妥昔单抗联合MTX治疗为对1种或多种抗TNF疗法反应不佳的活动性、长期存在的RA患者的疾病活动提供了显著且具有临床意义的改善。
Objective. To determine the efficacy and safety of treatment with rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to anti-tumor necrosis factor (anti-TNF) therapies and to explore the pharmacokinetics and pharmacodynamics of rituximab in this population.Methods. We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the Randomized Evaluation of Long-Term Efficacy of Rituximab in RA (REFLEX) Trial, a 2-year, multicenter, randomized, double-blind, placebo-controlled, phase III study of rituximab therapy. Patients with active RA and an inadequate response to 1 or more anti-TNF agents were randomized to receive intravenous rituximab (1 course, consisting of 2 infusions of 1,000 mg each) or placebo, both with background MTX. The primary efficacy end point was a response on the American College of Rheumatology 20% improvement criteria (ACR20) at 24 weeks. Secondary end points were responses on the ACR50 and ACR70 improvement criteria, the Disease Activity Score in 28 joints, and the European League against Rheumatism (EULAR) response criteria at 24 weeks. Additional end points included scores on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire (HAQ) Disability Index (DI), and Short Form 36 (SF-36) instruments, as well as Genant-modified Sharp radiographic scores at 24 weeks.Results. Patients assigned to placebo (n = 209) and rituximab (n 311) had active, longstanding RA. At week 24, significantly more (P < 0.0001) rituximab-treated patients than placebo-treated patients demonstrated ACR20 (51% versus 18%), ACR50 (27% versus 5%), and ACR70 (12% versus 1%) responses and moderate-to-good EULAR responses (65% versus 22%). All ACR response parameters were significantly improved in rituximab-treated patients, who also had clinically meaningful improvements in fatigue, disability, and health-related quality of life (demonstrated by FACIT-F, HAQ DI, and SF-36 scores, respectively) and showed a trend toward less progression in radiographic end points. Rituximab depleted peripheral CD20+ B cells, but the mean immunoglobulin levels (IgG, IgM, and IgA) remained within normal ranges. Most adverse events occurred with the first rituximab infusion and were of mild-to-moderate severity. The rate of serious infections was 5.2 per 100 patient-years in the rituximab group and 3.7 per 100 patient-years in the placebo group.Conclusion. At 24 weeks, a single course of rituximab with concomitant MTX therapy provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more anti-TNF therapies.