Lancet Neurol：依库珠单抗明显改善视神经脊髓炎患者的临床症状

补体与水孔蛋白4（AQP4）IgG自身抗体结合后而激活被认为是造成视神经脊髓炎中枢神经系统炎症和星形胶质细胞损伤的主要机制。来自美国梅奥临床中心的Sean J Pittock等医生评估了依库珠单抗对视神经脊髓炎的治疗作用，结果发表在2013年6月的Lancet Neurology杂志上。该项研究的目的是探索应用依库珠单抗--与补体蛋白C5特异性结合的IgG单克隆抗体--治疗视神经脊髓炎疾病谱疾病的疗效。研究显示：依库珠单抗明显改善视神经脊髓炎临床症状。

2009年10月20日至2010年11月3日期间，在美国两个治疗中心招募患者进入开放标签的临床试验。招募的患者为年龄均超过18岁的，血清水孔蛋白4抗体阳性，诊断为视神经脊髓炎疾病谱的患者，这些患者在之前的6个月至少有两次发作，或在之前12个月至少有三次疾病发作。在对患者进行初始评估时注射脑膜炎双球菌疫苗，并与2周后开始依库珠单抗治疗。使用方法为初始四周内，每周静脉使用依库珠单抗600mg；在第五周时给予900mg；之后48周内，，每两周给予900mg。联合的主要终点事件为有效性及安全性，有效性通过发作次数评估，即新发的神经功能障碍加重超过24小时并排除其他可能的原因。次要终点事件为残疾程度评估（使用扩展残疾状态量表），下床活动性（Hauser评分）及视力评估。在随访期内（治疗后6周、3月、6月、9月及12月，终止使用后3月及12月），均进行完整的神经系统检查及不良反应的调查问卷。

该研究共招募14例患者，均为女性。在使用依库珠单抗治疗12月后，12为患者症状未在复发，2例可疑发作。每年的平均发作次数从治疗前的3次（范围为2到4次）降到治疗期间发作0次（范围为0到1此）(p<0·0001)。所有患者的预后评估都没有残疾程度的加重。扩展残疾状态量表的平均评分从治疗前的4.3分（范围为1.0-8.0）改善到治疗期间的3.5分（范围为0到8分）(p=0·0078)。Hauser评分显示，两例患者改善2分，3例患者改善1分，其他患者没有变化。视觉清晰度检查至少4例患者单眼改善1分，1例患者改善2分，其他患者没有变化。1例患者在首次使用依库珠单抗2月后出现脑膜炎双球菌败血症和无菌性脑膜炎，但在治疗后完全恢复。没发现其他药物相关的严重不良反应。停止使用依库珠单抗12个月内，五例患者发生8次疾病发作。

研究显示，依库珠单抗有良好的耐受性，可明显降低具有视神经脊髓炎疾病谱患者的反复发作，，稳定或改善神经功能。依库珠单抗的良好疗效需要样本量更大的随机对照试验来验证。

Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study.
BACKGROUND
Complement activation after binding of an IgG autoantibody to aquaporin 4 (AQP4) is thought to be a major determinant of CNS inflammation and astrocytic injury in neuromyelitis optica. The aim of this study was to investigate the use of eculizumab-a therapeutic monoclonal IgG that neutralises the complement protein C5-in neuromyelitis optica spectrum disorders.
METHODS
Between Oct 20, 2009, and Nov 3, 2010, we recruited patients from two US centres into an open-label trial. Patients were AQP4-IgG-seropositive, aged at least 18 years, had a neuromyelitis optica spectrum disorder, and had at least two attacks in the preceding 6 months or three in the previous 12 months. Patients received meningococcal vaccine at a screening visit and 2 weeks later began eculizumab treatment. They received 600 mg intravenous eculizumab weekly for 4 weeks, 900 mg in the fifth week, and then 900 mg every 2 weeks for 48 weeks. The coprimary endpoints were efficacy (measured by number of attacks [new worsening of neurological function lasting for more than 24 h and not attributable to an identifiable cause]) and safety. Secondary endpoints were disability (measured by expanded disability status scale), ambulation (Hauser score), and visual acuity. At follow-up visits (after 6 weeks and 3, 6, 9, and 12 months of treatment; and 3 and 12 months after discontinuation), complete neurological examination was undertaken and an adverse event questionnaire completed. This trial is registered with ClinicalTrials.gov, number NCT00904826.
FINDINGS
We enrolled 14 patients, all of whom were women. After 12 months of eculizumab treatment, 12 patients were relapse free; two had had possible attacks. The median number of attacks per year fell from three before treatment (range two to four) to zero (zero to one) during treatment (p<0·0001). No patient had worsened disability by any outcome measure. Median score on the expanded disability status scale improved from 4·3 (range 1·0-8·0) before treatment to 3·5 (0-8·0) during treatment (p=0·0078). Two patients improved by two points and three improved by one point on the Hauser score; no change was recorded for the other patients. Visual acuity had improved in at least one eye by one point in four patients, and by two points in one patient; no change was recorded for other patients. One patient had meningococcal sepsis and sterile meningitis about 2 months after the first eculizumab infusion, but resumed treatment after full recovery. No other drug-related serious adverse events occurred. Eight attacks in five patients were reported within 12 months of eculizumab withdrawal.
INTERPRETATION
Eculizumab seems to be well tolerated, significantly reduce attack frequency, and stabilise or improve neurological disability measures in patients with aggressive neuromyelitis optica spectrum disorders. The apparent effects of eculizumab deserve further investigation in larger, randomised controlled studies.