Simpson Alexandra, Mowry Ellen M, Newsome Scott D
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD USA.
Division of Neuroimmunology and Neurological Infections, Johns Hopkins Hospital, 600 North Wolfe St., Pathology 627, Baltimore, MD 21287 USA.
Curr Treat Options Neurol. 2021;23(7):19. doi: 10.1007/s11940-021-00677-1. Epub 2021 May 15.
This review presents a comprehensive analysis of the current high-efficacy disease-modifying therapies (DMTs) available for treatment of multiple sclerosis (MS). We discuss the existing approved and emerging therapeutics in patients with relapsing and progressive forms of MS using data from clinical trials and observational studies. Treatment considerations in pediatric and pregnant populations are also reviewed. Finally, we discuss the treatment paradigms of the escalation and early aggressive approaches to treatment of MS, with review of ongoing clinical trials to compare these approaches.
Natalizumab has shown promising data on efficacy in not only randomized trials but also observational studies when compared with placebo, the injectable DMTs, and fingolimod. The anti-CD20 B cell depleting therapies (rituximab, ocrelizumab, and ofatumumab) have also demonstrated superiority in randomized clinical trials compared to their comparator group (placebo, interferon, and teriflunomide, respectively) and rituximab has shown in observational studies to be more effective than older injectable therapies and some of the oral therapies. Alemtuzumab has shown good efficacy in randomized controlled trials and observational studies yet has several potentially severe side effects limiting its use. Mitoxantrone has similarly demonstrated significant reduction in new disease activity compared to placebo but is rarely used due to its severe side effects. Cladribine is an oral DMT often grouped in discussion with other higher efficacy DMTs but may be slightly less effective than the other therapies described in this review. Many emerging targets for therapeutic intervention are currently under investigation that may prove to be beneficial in early aggressive MS, including autologous hematopoietic stem cell transplantation.
Traditionally, MS has been treated with an escalation approach, starting patients on a modestly effective DMT and subsequently escalating to a higher efficacy DMT when there is evidence of clinical and/or radiologic breakthrough activity. With the development of higher efficacy therapies and emerging data showing the potential positive long-term impact of these therapies when started earlier in the disease course, many clinicians have shifted to an early aggressive treatment approach in which patients are initially started on a higher efficacy DMT. Two clinical trials, the TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) trial and the Determining the Effectiveness of earLy Intensive Versus Escalation approaches for the treatment of Relapsing-remitting MS (DELIVER-MS) trial, aim to directly compare these treatment strategies and their impact on clinical and radiologic outcomes.
本综述对目前可用于治疗多发性硬化症（MS）的高效疾病修正疗法（DMTs）进行全面分析。我们利用临床试验和观察性研究的数据，讨论复发型和进展型MS患者中现有的已获批和新兴治疗方法。还对儿科和妊娠人群的治疗考量进行了综述。最后，我们讨论MS治疗的升级和早期积极治疗方法的治疗模式，并对比较这些方法的正在进行的临床试验进行综述。
与安慰剂、注射用DMTs和芬戈莫德相比，那他珠单抗不仅在随机试验中，而且在观察性研究中均显示出有前景的疗效数据。抗CD20 B细胞清除疗法（利妥昔单抗、奥瑞珠单抗和奥法木单抗）在随机临床试验中也显示出优于各自的对照治疗组（分别为安慰剂、干扰素和特立氟胺），并且利妥昔单抗在观察性研究中显示比旧的注射疗法和一些口服疗法更有效。阿仑单抗在随机对照试验和观察性研究中显示出良好疗效，但有几种潜在的严重副作用限制了其使用。米托蒽醌与安慰剂相比同样显示新疾病活动显著减少，但由于其严重副作用很少使用。克拉屈滨是一种口服DMT，在讨论中常与其他高效DMT归为一类，但可能比本综述中描述的其他疗法效果稍差。目前正在研究许多新兴的治疗干预靶点，这些靶点可能被证明对早期积极治疗的MS有益，包括自体造血干细胞移植。
传统上，MS采用升级治疗方法，开始让患者使用适度有效的DMT，随后当有临床和/或放射学突破性活动证据时升级到更高疗效的DMT。随着更高疗效疗法的发展以及新数据表明这些疗法在疾病病程早期开始使用时可能产生积极的长期影响，许多临床医生已转向早期积极治疗方法，即最初让患者使用更高疗效的DMT。两项临床试验，即MS的传统与早期积极治疗（TREAT-MS）试验和确定复发缓解型MS的早期强化与升级治疗方法的有效性（DELIVER-MS）试验，旨在直接比较这些治疗策略及其对临床和放射学结果的影响。
