Kappos Ludwig, Kuhle Jens, Gass Achim, Achtnichts Lutz, Radue Ernst-Wilhelm
Department of Neurology, University Hospital, Kantonsspital, 4031, Basel, Switzerland.
J Neurol. 2004 Sep;251 Suppl 5:v57-v64. doi: 10.1007/s00415-004-1509-6.
Disease-modifying treatments (DMTs) for multiple sclerosis (MS) are now widely available, and their beneficial effects on relapse rates, magnetic resonance imaging outcomes and, in some cases, relapse-related disability have been shown in numerous clinical studies. However, as these treatments are only partially effective in halting the MS disease process, the search for improved treatment regimens and novel therapies must continue. Strategies to improve our therapeutic armamentarium have to take into account the different phases or parts of the pathogenesis of the disease. Available treatments address systemic immune dysfunction, blood-brain barrier permeability and the inflammatory process in the central nervous system. Currently, patients who fail to respond adequately to first-line DMTs are often considered as candidates for intensive immunosuppression with cytostatic agents or even autologous stem cell transplantation. However, new approaches are being developed. Combination therapies offer an alternative approach that may have considerable potential to improve therapeutic yield and, although likely to present considerable challenges in terms of trial design, this certainly seems to be a logical step forward in view of the complex pathology of MS. Several new drugs are also being developed with the aim of providing more effective, convenient and/or specific modulation of the inflammatory component of the disease. These treatments include humanised monoclonal antibodies such as the anti-VLA-4 antibody natalizumab, inhibitors of intracellular activation, signalling pathways and T-cell proliferation, and oral immunomodulators such as sirolimus, teriflunomide or statins. There remains, however, an urgent need for treatments that protect against demyelination and axonal loss, or promote remyelination/regeneration. Due to the chronicity of MS, the therapeutic window for neuroprotective agents is wider than that following stroke or acute spinal cord injury, and may therefore allow the use of some drugs that have proven disappointing in other situations. Novel potential neuroprotective agents such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonists and ion-channel blockers will be entering Phase II trials in MS in the near future, and it is hoped that these agents will mark the start of a new era for DMTs for MS.
用于治疗多发性硬化症（MS）的疾病修饰疗法（DMTs）如今已广泛应用，众多临床研究表明，这些疗法对复发率、磁共振成像结果，以及在某些情况下对与复发相关的残疾具有有益效果。然而，由于这些治疗在阻止MS疾病进程方面仅部分有效，因此必须继续寻找改进的治疗方案和新疗法。改善我们治疗手段的策略必须考虑到疾病发病机制的不同阶段或部分。现有治疗针对的是全身免疫功能障碍、血脑屏障通透性以及中枢神经系统的炎症过程。目前，对一线DMTs反应不佳的患者通常被视为使用细胞毒性药物进行强化免疫抑制甚至自体干细胞移植的候选对象。然而，新的方法正在不断开发。联合疗法提供了一种替代方法，可能具有提高治疗效果的巨大潜力，尽管在试验设计方面可能会面临巨大挑战，但鉴于MS复杂的病理学特征，这无疑似乎是向前迈出的合理一步。还在研发几种新药，旨在更有效、方便和/或特异性地调节疾病的炎症成分。这些治疗方法包括人源化单克隆抗体，如抗VLA - 4抗体那他珠单抗、细胞内激活、信号通路和T细胞增殖抑制剂，以及口服免疫调节剂，如西罗莫司、特立氟胺或他汀类药物。然而，仍然迫切需要能够预防脱髓鞘和轴突损失或促进髓鞘再生/修复的治疗方法。由于MS的慢性病程，神经保护剂的治疗窗口比中风或急性脊髓损伤后的治疗窗口更宽，因此可能允许使用一些在其他情况下已证明效果不佳的药物。新型潜在神经保护剂，如α -氨基 - 3 -羟基 - 5 -甲基 - 4 -异恶唑丙酸拮抗剂和离子通道阻滞剂，将在不久的将来进入MS的II期试验，人们希望这些药物将标志着MS的DMTs新时代的开始。
