Lancet Neurol：Eculizumab 治疗视神经脊髓炎谱系疾病初显效

　　IgG自身抗体与水通道蛋白4（AQP4）结合后激活补体被认为是视神经脊髓炎患者中枢神经系统炎症和星形胶质细胞损伤的主要决定因素。一项来自美国的试点研究表明，Eculizumab似乎耐受良好，可以显著降低发作频率，并稳定或改善侵袭性视神经脊髓炎谱系疾病患者的神经失能指标。Eculizumab具有明显疗效，值得进一步进行更大型的随机对照研究。相关论文于2013年4月26日在线发表于《柳叶刀• 神经病学》（The Lancet Neurology）杂志。

　　该研究旨在弄清应用eculizumab（一种能中和补体蛋白C5的治疗性单克隆IgG）治疗视神经脊髓炎谱系疾病的疗效。

　　2009年10月20日到2010年11月3日期间，研究人员招募了来自美国两个中心的患者来参与该项开放标签试验。患者入选标准包括：AQP4-IgG血清阳性，年龄大于等于18岁，患有视神经脊髓炎谱系疾病，既往6个月内至少有过两次发作或既往12个月内至少有3次发作。患者在筛查访问和开始eculizumab治疗后2周接受流脑菌苗注射。患者接受eculizumab静脉注射，每周600 mg ，共4周，第五周900 mg，然后每两周注射一次，每次900 mg，共48周。共同主要终点为有效性（通过发作的次数来计算）和安全性。次要终点为残疾（通过残疾状态调查量表来算），离床活动（奥塞尔评分）和视敏度。在随访中，患者进行了完整的神经系统检查并填写了不良事件调查表。

　　研究共入选14名患者，全部为女性。经eculizumab治疗12个月后，12名患者无复发，2人可能复发。治疗期间，中位发作次数由治疗前的每年3次降至0次（p<0·0001）。无论经哪种转归检测，没有患者发生残疾加重。残疾状态调查量表中位评分从治疗前的4·3改善到治疗期间的3·5（p=0·0078）。奥塞尔评分中2名患者提高了2分，3名患者提高1分；其他患者未记录到改变。在视敏度方面，有4名患者至少单眼提高1分，1名患者单眼提高2分；其他患者未记录到改变。一名患者在首次输注eculizumab后约2个月时发生脑膜炎球菌性和无菌性脑膜炎，但是完全康复后又重新开始了治疗。未发生其他药物相关性严重不良事件。Eculizumab停药后12个月内有5名患者报告有8次发作。

与视神经脊髓炎相关的拓展阅读：

• Eculizumab 治疗视神经脊髓炎谱系疾病初显效
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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.
Funding
Alexion Pharmaceuticals.    

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