Hauser Stephen L, Waubant Emmanuelle, Arnold Douglas L, Vollmer Timothy, Antel Jack, Fox Robert J, Bar-Or Amit, Panzara Michael, Sarkar Neena, Agarwal Sunil, Langer-Gould Annette, Smith Craig H
Department of Neurology, University of California at San Francisco, San Francisco, CA 94143-0114, USA.
N Engl J Med. 2008 Feb 14;358(7):676-88. doi: 10.1056/NEJMoa0706383.
There is increasing evidence that B lymphocytes are involved in the pathogenesis of multiple sclerosis, and they may be a therapeutic target. Rituximab, a monoclonal antibody, selectively targets and depletes CD20+ B lymphocytes.
In a phase 2, double-blind, 48-week trial involving 104 patients with relapsing-remitting multiple sclerosis, we assigned 69 patients to receive 1000 mg of intravenous rituximab and 35 patients to receive placebo on days 1 and 15. The primary end point was the total count of gadolinium-enhancing lesions detected on magnetic resonance imaging scans of the brain at weeks 12, 16, 20, and 24. Clinical outcomes included safety, the proportion of patients who had relapses, and the annualized rate of relapse.
As compared with patients who received placebo, patients who received rituximab had reduced counts of total gadolinium-enhancing lesions at weeks 12, 16, 20, and 24 (P<0.001) and of total new gadolinium-enhancing lesions over the same period (P<0.001); these results were sustained for 48 weeks (P<0.001). As compared with patients in the placebo group, the proportion of patients in the rituximab group with relapses was significantly reduced at week 24 (14.5% vs. 34.3%, P=0.02) and week 48 (20.3% vs. 40.0%, P=0.04). More patients in the rituximab group than in the placebo group had adverse events within 24 hours after the first infusion, most of which were mild-to-moderate events; after the second infusion, the numbers of events were similar in the two groups.
A single course of rituximab reduced inflammatory brain lesions and clinical relapses for 48 weeks. This trial was not designed to assess long-term safety or to detect uncommon adverse events. The data provide evidence of B-cell involvement in the pathophysiology of relapsing-remitting multiple sclerosis. (ClinicalTrials.gov number, NCT00097188 [ClinicalTrials.gov].).
越来越多的证据表明B淋巴细胞参与了多发性硬化症的发病机制，它们可能是一个治疗靶点。利妥昔单抗是一种单克隆抗体，可选择性地靶向并清除CD20+B淋巴细胞。
在一项为期48周的2期双盲试验中，纳入了104例复发缓解型多发性硬化症患者，我们将69例患者分配至在第1天和第15天接受1000mg静脉注射利妥昔单抗，35例患者接受安慰剂治疗。主要终点是在第12、16、20和24周时脑部磁共振成像扫描中检测到的钆增强病灶总数。临床结局包括安全性、复发患者的比例以及年化复发率。
与接受安慰剂的患者相比，接受利妥昔单抗的患者在第12、16、20和24周时钆增强病灶总数减少（P<0.001），同期新出现的钆增强病灶总数也减少（P<0.001）；这些结果持续了48周（P<0.001）。与安慰剂组患者相比，利妥昔单抗组患者在第24周（14.5%对34.3%，P=0.02）和第48周（20.3%对40.0%，P=0.04）时复发的比例显著降低。利妥昔单抗组在首次输注后24小时内发生不良事件的患者比安慰剂组更多，其中大多数为轻至中度事件；第二次输注后，两组的事件数量相似。
单次利妥昔单抗疗程可减少炎性脑病灶并使临床复发减少48周。该试验并非旨在评估长期安全性或检测罕见不良事件。这些数据提供了B细胞参与复发缓解型多发性硬化症病理生理学的证据。（临床试验注册号，NCT00097188 [ClinicalTrials.gov]。）
