难治性自身免疫性脑炎的免疫治疗研究进展

Advances in Immunotherapy of Refractory Autoimmune Encephalitis

摘要: 自身免疫性脑炎是一种由自身免疫反应介导的中枢神经系统疾病，早期开始免疫治疗已被证明可以改善临床结果并减少其复发。其免疫治疗有一线治疗，二线治疗，升级治疗，添加治疗，以及长程维持治疗。一线治疗包括静脉注射糖皮质激素、静脉注射免疫球蛋白和血浆置换，在比较严重的病例中可以联合使用。在无反应的病例中，可以采用二线免疫治疗如利妥昔单抗或者环磷酰胺。但少数患者仍然对其没有反应，因此这是一个重大的临床挑战，且治疗策略存在争议。现针对难治性自身免疫性脑炎提出了三种治疗方法，包括(1) 基于细胞因子的药物：托珠单抗、低剂量IL-2、巴利昔单抗、阿那白滞素和托法替尼；(2) 浆细胞耗竭剂：硼替佐米、达雷木单抗；(3) 针对鞘内免疫细胞或能通过血脑屏障的药物：鞘内注射甲氨蝶呤、那他珠单抗。这些药物的疗效证据大多来自于病例报告系列，很少有高质量的随机对照临床研究进行报道。所以对当前难治性自身免疫性脑炎的免疫治疗研究进展进行综述。

Abstract: Autoimmune encephalitis is a disease of the central nervous system mediated by an autoimmune response, and early initiation of immunotherapy has been shown to improve clinical outcomes and reduce its recurrence. Immunotherapy includes first-line therapy, second-line therapy, escalation therapy, add-on therapy, and long-term maintenance therapy. First-line treatment includes intra-venous glucocorticoids, intravenous immunoglobulin, and plasma exchange, or a combination in more severe cases. In nonresponsive cases, second-line immunotherapy such as rituximab or cy-clophosphamide can be used. However, a minority of patients still do not respond to it, making it a major clinical challenge and a therapeutic strategy controversial. Three approaches have been proposed for the treatment of refractory autoimmune encephalitis, including (1) Cytokine-based drugs: tocilizumab, low-dose IL-2, basiliximab, anakinra, and tofacitinib; (2) Plasma cell depleting agents: bortezomib and daratumumab; (3) Drugs that target intrathecal immune cells or can cross the blood-brain barrier: intrathecal methotrexate, natalizumab. Most evidence for the efficacy of these agents comes from case report series, and few high-quality randomized controlled clinical studies have been reported. Therefore, the current research progress of immunotherapy for re-fractory autoimmune encephalitis is reviewed.