Overlapping and distinct mechanisms of action of multiple sclerosis therapies
Overlapping and distinct mechanisms of action of multiple sclerosis therapies
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DOI：
10.1016/j.clineuro.2010.05.002
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发表时间：
2010-09-01
影响因子：
1.9
通讯作者：
Dhib-Jalbut, S.
中科院分区：
文献类型：
--
作者：
Graber, J. J.;McGraw, C. A.;Dhib-Jalbut, S.
在过去的二十年中，多发性硬化症已经从一种仅需要对症治疗的特发性疾病转变为一种具有更好的病理生理学基础和多种基于特定作用机制改变其长期病程的治疗方法的疾病。现在 FDA 批准了几种疾病发作时的治疗方案，并且已经开始讨论为个体患者选择最佳治疗方案以及对当前治疗失败的患者下一步选择什么方案。许多研究已经开始强调，中枢神经系统损伤的潜在病理学在不同的患者亚群中可能有所不同，这增加了一些患者可能对针对“他们的”多发性硬化症的作用机制的治疗产生反应的可能性。具有不同作用机制的众多新药和一些联合疗法的试验正在进行中。更好地了解每种疗法的作用原理可以指导以更合理的方式启动、组合或改变疗法的决策，以改善患者的治疗结果。对患有“相同”疾病的不同患者的潜在疾病机制的进一步了解可能会导致更有针对性的治疗，预测临床治疗反应的生物标志物也会产生这种效果。对多发性硬化症中使用的各种药物的作用的研究揭示了重叠和不同的作用机制，这些机制可能与其在个体患者中的疗效和副作用有关。然而，重要的是要记住，大多数药物的批准是基于其在短时间内减少 MRI 病变和复发率的情况。这些指标仅与长期残疾相关，而长期残疾可能是多发性硬化症患者最相关的临床结果。固定性残疾需要数年时间才能显现出来，而且缺乏针对慢性结果的生物标志物的大型研究。此外，很少有大型研究将对治疗的反应与认知结果联系起来，而认知结果是慢性残疾的主要原因。本次综述将尝试在正在进行的联合治疗临床试验的背景下总结当前 FDA 批准的多发性硬化症治疗的作用机制的临床相关知识，并提出对怀疑对其当前治疗“无反应”的患者改变治疗的合理方法。 (C) 2010 Elsevier B.V. 保留所有权利。
In the last two decades MS has changed from an idiopathic condition with only symptomatic treatments to a disease with better characterized pathophysiologic underpinnings and several treatments that modify its long-term course based on specific mechanisms of action. There are now several FDA approved options for therapy at the onset of disease, and discussions have begun on choosing the best treatment in individual patients and what option to choose next in patients who are failing their current treatment. Numerous studies have begun to highlight that the underlying pathology of CNS damage may be different in subsets of patients, raising the possibility that some may respond to a treatment with a mechanism of action that is targeted to 'their' MS. Trials are ongoing of numerous new agents with different mechanisms of action and some combination therapies. A better understanding of how each therapy works may guide decisions on initiating, combining or changing therapy in a more rational way to improve patient outcomes. Further knowledge of underlying mechanisms of disease in different patients with 'the same' disease may lead to more targeted therapies, as will biomarkers that predict clinical response to therapy. Studies of the effects of various agents used in MS reveal both overlapping and distinct mechanisms of actions that may be relevant to their efficacy and side effects in individual patients. However, it is important to remember that most agents are approved based on their reduction of MRI lesions and relapse rates over a short time frame. These measures only partially correlate with long-term disability, which may be the most relevant clinical outcome for people with MS. Fixed disability requires years to become apparent, and there is a lack of large studies of biomarkers for chronic outcomes. In addition, few large studies correlate response to therapy with cognitive outcomes, which are a major cause of chronic disability.This review will attempt to summarize clinically relevant knowledge of the mechanisms of action of current FDA approved therapies for MS in the context of ongoing clinical trials of combination therapy and address rational approaches to changing therapy in a patient suspected to be 'unresponsive' to their current treatment. (C) 2010 Elsevier B.V. All rights reserved.