Department of Neurosciences, Neurology Unit, University of Padova, Padova, Italy.
Department of Medicine, Hematology Unit, University of Padova, Padova, Italy.
Neurotherapeutics. 2022 Apr;19(3):874-884. doi: 10.1007/s13311-022-01222-x. Epub 2022 Mar 28.
Autoimmune diseases of the peripheral nervous system have so far been treated mainly with exogenous high-dose intravenous immunoglobulins (IVIg), that act through several mechanisms, including neutralization of pathogenic autoantibodies, modulation of lymphocyte activity, interference with antigen presentation, and interaction with Fc receptors, cytokines, and the complement system. Other therapeutic strategies have recently been developed, in part to address the increasing shortage of IVIg, prime among which is the use of B cell depleting monoclonal antibodies, or small molecule inhibitors targeting the B-cell specific kinases. Rituximab, a chimeric monoclonal antibody against CD20 + B lymphocytes, is currently the most used, especially in anti-MAG antibody neuropathy and autoimmune neuropathies with antibodies to nodal/paranodal antigens that are unresponsive to IVIg. After several reports of its efficacy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), rituximab is currently under investigation in three Phase 2 trials in CIDP. In addition, the possible role of complement activation in the pathogenesis of chronic autoimmune neuropathies has brought into consideration drugs that can block the complement cascade, such as eculizumab, a monoclonal antibody already assessed in acute polyradiculoneuropathies, and approved for myasthenia gravis. Preliminary data on eculizumab in multifocal motor neuropathy have been published, but randomized controlled studies are pending. Moreover, the neonatal Fc receptor, that recycles IgGs by preventing their lysosome degradation, is an important and attractive pharmacological target. Antibodies against FcRn, which reduce circulating IgG (both pathogenic and non-pathogenic) have been developed. The FcRn blocker efgartigimod, a humanized IgG1-derived Fc fragment, which competitively inhibits the FcRn, has recently been approved for the treatment of myasthenia gravis and is currently under investigation in CIDP. In addition, the anti-human FcRn monoclonal antibody rozanolixizumab is currently being assessed in phase 2 trials in CIDP. However, none of the abovementioned monoclonal antibodies is currently approved for treatment of any immune-mediated neuropathies. While more specific and individualized therapies are being developed, the possibility of combined treatments targeting different pathogenic mechanisms deserves consideration as well.
自身免疫性周围神经病的治疗方法主要是采用外源性大剂量静脉注射免疫球蛋白（IVIg），其作用机制包括中和致病性自身抗体、调节淋巴细胞活性、干扰抗原呈递以及与 Fc 受体、细胞因子和补体系统相互作用。最近还开发了其他治疗策略，部分原因是为了应对 IVIg 的日益短缺，其中主要包括使用 B 细胞耗竭单克隆抗体或针对 B 细胞特异性激酶的小分子抑制剂。利妥昔单抗是一种针对 CD20+B 淋巴细胞的嵌合单克隆抗体，目前应用最广泛，特别是在抗 MAG 抗体神经病和对 IVIg 无反应的抗结节点/神经周围抗原自身免疫性神经病中。在几项关于其在慢性炎症性脱髓鞘性多发性神经根神经病（CIDP）中的疗效的报告之后，利妥昔单抗目前正在 CIDP 的三项 2 期临床试验中进行研究。此外，补体激活在慢性自身免疫性神经病发病机制中的可能作用促使人们考虑使用能够阻断补体级联的药物，例如已经在急性多神经根神经病中评估并批准用于重症肌无力的依库珠单抗。依库珠单抗在多灶性运动神经病中的初步数据已经公布，但仍有待随机对照研究。此外，新生儿 Fc 受体通过防止 IgG 溶酶体降解来回收 IgG，是一个重要且有吸引力的药理靶点。已经开发出针对 FcRn 的抗体，可减少循环 IgG（包括致病性和非致病性）。FcRn 阻断剂 efgartigimod 是一种人源化 IgG1 衍生的 Fc 片段，可竞争性抑制 FcRn，最近已被批准用于治疗重症肌无力，目前正在 CIDP 中进行研究。此外，抗人 FcRn 单克隆抗体 rozanolixizumab 目前正在 CIDP 的 2 期临床试验中进行评估。然而，上述单克隆抗体均未被批准用于治疗任何免疫介导的神经病。虽然正在开发更特异和个体化的治疗方法，但联合针对不同发病机制的治疗方法也值得考虑。
