ReviewTreatment of Multiple Sclerosis: A Review
Introduction
The autoimmune disease multiple sclerosis (MS) is the leading cause of nontraumatic neurological disability arising in young adults.1,2 MS is characterized by 2 pathological hallmarks: 1) inflammation with demyelination, and 2) astroglial proliferation (gliosis) and neurodegeneration. Tissue damage in MS is restricted to the central nervous system (CNS), sparing the peripheral nervous system. Clinically, MS can follow 2 paths: relapsing or progressive. Most commonly, onset is a relapsing form of MS (RMS), manifested as discrete episodes of neurological dysfunction followed by partial, complete, or no remission. Over time, relapses usually decrease in frequency but a gradual worsening often supervenes, resulting in uninterrupted progression (termed secondary progressive MS [SPMS]) (Figure 1).3 Less than 10% of patients with MS experience progression from onset, a category termed primary progressive MS (PPMS).3 Despite these distinctions, all clinical forms of MS appear to reflect the same underlying disease process. And although inflammation is typically associated with relapses, and neurodegeneration with progression, it is now recognized that both pathologies are present in essentially all patients across the entire disease continuum.
MS is a global problem, and its prevalence is on the rise.4 The prevalence is highest in North America, Western Europe, and Australasia (>100 cases per 100,000 population), and lowest in countries centered around the equator (<30 cases per 100,000 population).4 In the United States, a recent study estimated that nearly 1 million individuals are affected. In RMS, women are affected nearly 3 times more often than men, and the mean age of onset is ~30 years, whereas in PPMS the rates of men and women affected are similar and the mean age of onset is ~40 years.5, 6, 7
The development of increasingly effective therapies for RMS, and partially effective therapy for PPMS and SPMS, represents a profound success that has substantially improved prospects for lives free from disability. For patients with RMS, the mean time to development of SPMS was historically estimated at approximately 19 years after onset, but in the treatment era has been lengthened substantially. On highly effective therapy, relapses are markedly reduced or eliminated. However, control of RMS has uncovered a relapse-independent “silent” progression that was previously obscured by attacks and remissions in RMS.8,9 This recognition has also led to an increasing reliance on highly effective therapies early in the course of MS in order to maximally control both relapses and progression. In this review we summarize recent advances in MS treatment and speculate on future directions.
Section snippets
Clinical Manifestations
MS symptoms vary according to location and severity of lesions occurring within the CNS. Clinical features of RMS may present acutely or subacutely over hours to days, sometimes followed by gradual spontaneous remission over weeks to months. Conversely, PPMS is characterized by slowly progressive symptoms from onset. Table 1 summarizes common clinical and laboratory features of MS. Symptoms may be severe at onset or begin insidiously, sometimes unnoticed for months or years. Once the patient
Advances in Treatment
Current management strategies are focused on treating acute attacks, ameliorating symptoms, and reducing biologic activity through disease-modifying therapies. The approach to treating acute attacks and symptom-based management is summarized in the Appendix (available online).
Approach to Treating Patients With MS
Table 319,22,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 provides an overview of the characteristics and pivotal data associated with approved agents, stratified according to frequency of use and perceived level of efficacy. Given this large array of available therapies, it may be prudent for clinicians to become conversant with a few agents. As such, the following section is focused on detailing MS disease-modifying therapies that are widely used in clinical
Conclusion
Spectacular progress has been made in the treatment of MS as a result of advances in understanding of the pathogenesis and course of this disease. The development of highly effective therapies has produced near-complete control of relapsing disease and focal brain inflammation. However, effective treatment of progression remains an unmet need because current therapies confer only partial protection against the neurodegenerative component of MS. Although natural history studies suggest that the
Acknowledgment
The authors thank Natalie Nwkor for invaluable editorial assistance, and Andrew Barnecut for superb work creating figures and finalizing the manuscript.
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Funding: This work was supported by grants from the National Institute of Neurological Disorders and Stroke (R35NS111644), the National Multiple Sclerosis Society (RR 2005-A-13), and the Valhalla Foundation.
Conflict of Interest: Outside of the submitted work, BACC reports personal fees for consulting from Akili, Alexion, Atara, Biogen, EMD Serono, Novartis, Sanofi, and TG Therapeutics. Outside of the submitted work, SLH reports stock options received for serving on the Board of Directors for Neurona; Scientific Advisory Board for Alector, Annexon, Bionure, and Molecular Stethoscope. He has also received nonfinancial support (travel reimbursement and writing support for anti-CD20-related meetings) from F. Hoffmann-La Roche Ltd and Novartis AG.
Authorship: Both authors contributed equally to the literature search, figures, study design, data collection, data analysis, data interpretation, and writing of this manuscript.