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性脑炎。通常，这种疾病影响10-50岁的患者，引起明显的精神症状，与意识下降、癫痫发作、运动障碍和危及生命的自主神经异常有关。75%的病例需要重症监护，包括心肺支持。脑脊液中检测抗中枢神经系统NMDAR的IgG自身抗体可确诊。尽管病情严重，但NMDAR脑炎是一种可治疗的神经系统疾病，回顾性病例系列证实了说明书外静脉注射类固醇和免疫球蛋白的益处。这些治疗被认为是通过影响脑脊液中IgG NMDAR自身抗体水平而起作用的，尽管预测治疗反应的前瞻性数据有限。即使得到及时治疗，约50%的患者仍然残疾，需要长期住院。各种说明书外治疗已被提议作为NMDAR脑炎的“二线”治疗。大多数二线治疗针对循环b细胞，具有不同程度的血脑外显率和疗效，对候选药物的时间、剂量和递送途径缺乏共识。需要高质量的证据来指导NMDAR脑炎的治疗。Inebilizumab是一种治疗NMDAR脑炎的有前途的单克隆抗体。这种人源化的抗b细胞表面抗原CD19的单克隆抗体最近被证明在治疗另一种抗体介导的中枢神经系统疾病——视神经脊髓炎谱系障碍中是安全有效的。与其他非标签b细胞消耗疗法（如利妥昔单抗）相比，inebilizumab不仅消耗CD20+ b细胞，而且还消耗CD20-浆母细胞和浆细胞，从而产生强大，广泛和持续的b细胞表达抑制。该试验将随机抽取116名中至重度NMDAR脑炎患者，在一线治疗的基础上接受伊比利珠单抗或安慰剂治疗。采用改进的Rankin量表和公认的安全措施（16周时的主要结果），以及综合的经过验证的神经心理学测试、床边认知筛查工具、生活质量/功能指数和结果预测措施，以标准间隔确定患者的结果。临床数据将与NMDAR自身抗体滴度和与鞘内腔室b细胞活化和抗体产生相关的细胞因子的定量测量相结合，以确定治疗反应，告知结果的生物学因素，并评估生物标志物，这些生物标志物可能作为未来NMDAR脑炎临床试验中有利结果的早期预测因子。熄灭试验的结果将立即影响患者护理，并将促进自身免疫性脑炎患者未来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.