Sellebjerg Finn, Cadavid Diego, Steiner Deborah, Villar Luisa Maria, Reynolds Richard, Mikol Daniel
Danish Multiple Sclerosis Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Biogen, Cambridge, MA, USA.
Ther Adv Neurol Disord. 2016 Jan;9(1):31-43. doi: 10.1177/1756285615615257.
Multiple sclerosis (MS) is a common and chronic central nervous system (CNS) demyelinating disease and a leading cause of permanent disability. Patients most often present with a relapsing-remitting disease course, typically progressing over time to a phase of relentless advancement in secondary progressive MS (SPMS), for which approved disease-modifying therapies are limited. In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS. In both forms of MS, active brain-tissue injury is associated with inflammation; but in SPMS, the inflammatory response occurs at least partly behind the blood-brain barrier and is followed by a cascade of events, including persistent microglial activation that may lead to chronic demyelination and neurodegeneration associated with irreversible disability. In patients with relapsing forms of MS, natalizumab therapy is known to significantly reduce intrathecal inflammatory responses which results in reductions in brain lesions and brain atrophy as well as beneficial effects on clinical measures, such as reduced frequency and severity of relapse and reduced accumulation of disability. Natalizumab treatment also reduces levels of cerebrospinal fluid chemokines and other biomarkers of intrathecal inflammation, axonal damage and demyelination, and has demonstrated the ability to reduce innate immune activation and intrathecal immunoglobulin synthesis in patients with MS. The efficacy of natalizumab therapy in SPMS is currently being investigated in a randomized, double-blind, placebo-controlled trial.
多发性硬化症（MS）是一种常见的慢性中枢神经系统（CNS）脱髓鞘疾病，也是导致永久性残疾的主要原因。患者最常表现为复发缓解型病程，随着时间的推移，通常会进展为继发进展型多发性硬化症（SPMS）的持续进展阶段，而针对该阶段获批的疾病修正疗法有限。在本综述中，我们总结了SPMS发生发展过程中涉及的病理生理机制，以及那他珠单抗发挥有益作用以减少SPMS中与复发无关的疾病进展的理论依据和临床潜力，那他珠单抗目前已获批用于治疗复发型MS。在两种类型的MS中，活跃的脑组织损伤都与炎症相关；但在SPMS中，炎症反应至少部分发生在血脑屏障之后，并随之引发一系列事件，包括持续的小胶质细胞激活，这可能导致慢性脱髓鞘和与不可逆残疾相关的神经退行性变。在复发型MS患者中，已知那他珠单抗治疗可显著降低鞘内炎症反应，从而减少脑损伤和脑萎缩，并对临床指标产生有益影响，如减少复发频率和严重程度以及减少残疾累积。那他珠单抗治疗还可降低脑脊液趋化因子和鞘内炎症、轴突损伤及脱髓鞘的其他生物标志物水平，并已证明其能够降低MS患者的固有免疫激活和鞘内免疫球蛋白合成。那他珠单抗治疗SPMS的疗效目前正在一项随机、双盲、安慰剂对照试验中进行研究。
