Is there a change of paradigm towards more effective treatment early in the course of apparent high-risk MS?

Background: Aggressive, highly active, or rapidly evolving severe relapsing-remitting multiple sclerosis (RRMS) is characterized by frequent relapses and active disease on magnetic resonance imaging, ultimately leading to a high risk for rapid disability accumulation. The treatment approach for high-risk patients is evolving into a model of individualized therapy in which early initiation of high-efficacy disease-modifying therapy (DMT), which I refer to as early and strong therapy, is viewed as a rational strategy to prevent the irreversible damage that occurs at disease onset and early in the disease course. This approach uses an individualized benefit-risk assessment to match the level of DMT efficacy with the patient's risk of disease progression and balances it against the risk of drug-related adverse events. It also includes consideration of the patient's risk tolerance and desire for a high-efficacy treatment. This paper discusses the rationale for early treatment, and summarizes the available clinical data on high-efficacy and moderately-high efficacy DMTs in patients with high-risk RRMS. Methods: Literature searches were conducted using search terms aggressive RRMS, highly active RRMS, and severe RRMS alone and in conjunction with the terms natalizumab, fingolimod, alemtuzumab, mitoxantrone, and cyclophosphamide. Studies of drug efficacy in these high-risk populations were reviewed. Results: Subgroup analyses of pivotal trials of natalizumab, fingolimod, and alemtuzumab were available, as well as an independent study of mitoxantrone and a pilot study of cyclophosphamide. In each study, DMT reduced relapses versus either placebo, active comparator, or baseline relapse rate. Conclusion: Data for the high-efficacy DMTs natalizumab and alemtuzumab, and the moderately high-efficacy DMT fingolimod, suggest they are effective in this patient population. Further studies are warranted, and clinical trial data to inform treatment decisions for this high-risk group represent a significant unmet need.