A Phase-2b, Double-Blind, Randomized Controlled Trial to Evaluate the Activity and Safety of Inebilizumab in Anti-N-methyl-D-aspartate receptor (NMDAR) Encephalitis and Assess Markers of Disease

N-甲基-D-天冬氨酸受体(NMDAR)脑炎是自身免疫性脑炎最常见的原因之一，在工业化国家的患病率超过疱疹病毒性脑炎。通常，这种疾病影响10-50岁的患者，导致明显的精神症状，与意识下降、癫痫发作、运动障碍和危及生命的自主神经障碍有关。75%的病例需要重症监护，包括心肺支持。通过检测脑脊液中抗中枢神经系统NMDAR的Ig G自身抗体来确认诊断。尽管病情严重，NMDAR脑炎是一种可治疗的神经疾病，回顾病例系列证实了标签外静脉注射类固醇和免疫球蛋白的好处。这些治疗被认为是通过影响脑脊液中的Ig G、NMDAR自身抗体水平而起作用的，尽管提供治疗反应预测因素的前瞻性数据有限。即使及时治疗，约50%的患者仍有残疾，需要延长住院时间。各种非标签疗法已被提议作为NMDAR脑炎的“二线”疗法。大多数二线治疗针对的是循环B细胞，具有不同程度的血脑透过率和有效性，对候选药物的给药时机、剂量和途径缺乏共识。需要高质量的证据来指导NMDAR脑炎的治疗。Inebilizumab是一种很有前途的治疗NMDAR脑炎的治疗性单抗。这种人源化的抗B细胞表面抗原CD19的单抗最近被证明在治疗视神经脊髓炎光谱障碍方面是安全有效的，这是另一种抗体介导的中枢神经系统疾病。与其他标签外的B细胞耗竭疗法，如利妥昔单抗相比，inebilizumab不仅耗尽CD20+B细胞，还可耗尽CD20-浆母细胞和浆细胞，导致对B细胞表达的强劲、广泛和持续的抑制。这项消除试验将随机选择116名患有中到重度NMDAR脑炎的参与者，除一线治疗外，还接受inebilizumab或安慰剂治疗。患者结果将按标准间隔使用修改的兰金评分和公认的安全措施(16周后的主要结果)，以及全面的经过充分验证的神经心理测试、床边认知筛查工具、生活质量/功能指数和结果预测措施来确定。临床数据将与鞘内B细胞激活和抗体产生所涉及的NMDAR自身抗体滴度和细胞因子的定量测量相结合，以确定治疗应答者，告知影响结果的生物因素，并评估可能作为未来NMDAR脑炎临床试验有利结果的早期预测因素的生物标志物。ELANLISH试验的结果将立即影响患者的护理，并将促进未来针对自身免疫性脑炎患者的临床试验的设计和实施。

N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most common causes of autoimmune encephalitis, with prevalence exceeding herpes encephalitis in industrialized nations. Typically, the disease affects patients age 10-50 causing prominent psychiatric symptoms, associated with declining consciousness, seizures, movement disorders and life-threatening dysautonomia. Intensive care, including cardiorespiratory support is required in 75% of cases. The diagnosis is confirmed by detection of IgG autoantibodies against central nervous system NMDAR in the cerebrospinal fluid. Despite the severity of the illness, NMDAR encephalitis is a treatable neurological disease, with retrospective case series establishing the benefit of off- label intravenous steroids and immunoglobulins. These treatments are presumed to work through effects on IgG NMDAR autoantibody levels in the CSF, although prospective data informing predictors of treatment responses are limited. Even with prompt treatment, ~50% of patients remain disabled, requiring prolonged hospital admissions. Various off-label therapies have been proposed as “second-line” treatments in NMDAR encephalitis. The majority of second-line treatments target circulating B-cells with various degrees of blood brain penetrance and efficacy, and poor consensus on the timing, dose and route of delivery of candidate agents. High-quality evidence is needed to inform the treatment of NMDAR encephalitis. Inebilizumab is a promising therapeutic monoclonal antibody for the treatment of NMDAR encephalitis. This humanized monoclonal antibody against the B-cell surface antigen CD19 was recently shown to be safe and efficacious in the treatment of neuromyelitis optica spectrum disorder—another antibody-mediated disorder of the central nervous system. Compared to other off label B-cell depleting therapies, such as rituximab, inebilizumab not only depletes CD20+ B-cells, but also CD20- plasma blasts and plasma cells, resulting in robust, broad and sustained suppression of B-cell expression. The Extinguish Trial will randomize 116 participants with moderate-to-severe NMDAR encephalitis to receive either inebilizumab or placebo in addition to first-line therapies. Patient outcomes will be ascertained at standard intervals using the modified Rankin scale and accepted safety measures (primary outcomes at 16 weeks), together with comprehensive well-validated neuropsychological tests, bedside cognitive screening tools, quality of life/ functional indices, and outcome prediction measures. Clinical data will be combined with quantitative measures of NMDAR autoantibody titers and cytokines implicated in B-cell activation and antibody production within the intrathecal compartment to identify treatment responders, inform the biologic contributors to outcomes, and evaluate for biomarkers that may serve as early predictors of favorable outcomes in future clinical trials in NMDAR encephalitis. The results of the Extinguish Trial will immediately impact patient care and will facilitate the design and implementation of future clinical trials in patients with autoimmune encephalitis.