Edwards Jonathan C W, Szczepanski Leszek, Szechinski Jacek, Filipowicz-Sosnowska Anna, Emery Paul, Close David R, Stevens Randall M, Shaw Tim
University College London, London, United Kingdom.
N Engl J Med. 2004 Jun 17;350(25):2572-81. doi: 10.1056/NEJMoa032534.
BACKGROUND: An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis. To confirm these observations, we conducted a randomized, double-blind, controlled study. METHODS: We randomly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments: oral methotrexate (> or =10 mg per week) (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined according to the criteria of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) were assessed at week 24 (primary analyses) and week 48 (exploratory analyses). RESULTS: At week 24, the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria, the primary end point, was significantly greater with the rituximab-methotrexate combination (43 percent, P=0.005) and the rituximab-cyclophosphamide combination (41 percent, P=0.005) than with methotrexate alone (13 percent). In all groups treated with rituximab, a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria (65 to 76 percent vs. 38 percent, P< or =0.025) or had EULAR responses (83 to 85 percent vs. 50 percent, P< or =0.004). All ACR responses were maintained at week 48 in the rituximab-methotrexate group. The majority of adverse events occurred with the first rituximab infusion: at 24 weeks, serious infections occurred in one patient (2.5 percent) in the control group and in four patients (3.3 percent) in the rituximab groups. Peripheral-blood immunoglobulin concentrations remained within normal ranges. CONCLUSIONS: In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in disease symptoms at both weeks 24 and 48.
背景：一项开放标签研究表明，使用利妥昔单抗选择性清除B细胞可使类风湿关节炎患者的临床症状持续改善。为证实这些观察结果，我们进行了一项随机、双盲、对照研究。 方法：我们将161例尽管接受甲氨蝶呤治疗仍患有活动性类风湿关节炎的患者随机分配，接受以下四种治疗之一：口服甲氨蝶呤（每周≥10 mg）（对照组）；利妥昔单抗（第1天和第15天各1000 mg）；利妥昔单抗加环磷酰胺（第3天和第17天各750 mg）；或利妥昔单抗加甲氨蝶呤。根据美国风湿病学会（ACR）和欧洲抗风湿病联盟（EULAR）的标准定义的反应在第24周（主要分析）和第48周（探索性分析）进行评估。 结果：在第24周时，根据主要终点ACR标准，疾病症状改善50%的患者比例，在利妥昔单抗-甲氨蝶呤联合治疗组（43%，P = 0.005）和利妥昔单抗-环磷酰胺联合治疗组（41%，P = 0.005）显著高于单用甲氨蝶呤组（13%）。在所有接受利妥昔单抗治疗的组中，根据ACR标准，疾病症状改善20%的患者比例显著更高（65%至76%对38%，P≤0.025），或有EULAR反应的患者比例更高（83%至85%对50%，P≤0.004）。利妥昔单抗-甲氨蝶呤组在第48周时所有ACR反应均得以维持。大多数不良事件发生在首次输注利妥昔单抗时：在24周时，对照组有1例患者（2.5%）发生严重感染，利妥昔单抗组有4例患者（3.3%）发生严重感染。外周血免疫球蛋白浓度保持在正常范围内。 结论：对于尽管接受甲氨蝶呤治疗仍患有活动性类风湿关节炎的患者，单次疗程的两次输注利妥昔单抗，单独使用或与环磷酰胺或继续使用甲氨蝶呤联合使用，在第24周和第48周时均能显著改善疾病症状。
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