Treatment of Multiple Sclerosis: A Review

Abstract

Multiple sclerosis (MS) is an autoimmune demyelinating and neurodegenerative disease of the central nervous system, and the leading cause of nontraumatic neurological disability in young adults. Effective management requires a multifaceted approach to control acute attacks, manage progressive worsening, and remediate bothersome or disabling symptoms associated with this illness. Remarkable advances in treatment of all forms of MS, and especially for relapsing disease, have favorably changed the long-term outlook for many patients. There also has been a conceptual shift in understanding the immune pathology of MS, away from a purely T-cell-mediated model to recognition that B cells have a key role in pathogenesis. The emergence of higher-efficacy drugs requiring less frequent administration have made these preferred options in terms of tolerability and adherence. Many experts now recommend use of these as first-line treatment for many patients with early disease, before permanent disability is evident.

Keywords: B-cell therapy; MS therapy; Multiple sclerosis.

Figure 1.. The New Natural History of MS

The top half of the figure illustrates the natural history of relapse-onset MS in the pretreatment era. During the relapsing phase, disability accumulation was thought to result from incomplete recovery from relapses, until relapse-independent disability, designated SPMS, supervened. The “new” natural history of MS in the current treatment era is shown in the bottom half. With use of highly effective therapies, attacks are abolished in most patients, but insidious progression independent of relapse activity, termed “silent progression”, is now evident during the relapsing phase. Abbreviations: EDSS, extended disability status score; CIS, clinically isolated syndrome; MS, multiple sclerosis; SPMS, secondary progressive multiple sclerosis.

Figure 2.. Five Distinctive Pathologies Likely Contribute to Progressive MS

(1) Classic inflammatory white matter plaques are typically associated with relapses but also occur in patients who progress gradually without acute attacks. Hallmarks are perivenous inflammation dominated by lymphocytes and macrophages (detected by MRI as gadolinium enhancement indicating blood brain barrier disruption); demyelination associated with activated microglia; sharply demarcated plaques with glial scarring; and axonal loss with secondary retrograde and anterograde degeneration. (2) B cell rich lymphoid aggregates in the meninges, often in deep sulci, with underlying cortical demyelination and neuronal loss. (3) Slowly enlarging lesions due to gradual concentric expansion of chronic plaques, characterized by a rim of activated microglia at the leading edge, astrocytosis, stressed oligodendrocytes and progressive axonal injury. (4) Widespread diffuse microglial inflammation and astrogliosis throughout the CNS white matter, associated with decreased myelin density and ongoing axonal damage. (5) Age-related neurodegeneration. For a more detailed discussion, readers may consult references^– Abbreviations: CNS, central nervous system; MRI, magnetic resonance imaging; MS, multiple sclerosis.

Figure 3.. A Therapeutic Algorithm for Disease-Modifying Therapy Use in MS

A simplified MS treatment algorithm based on the authors’ practice pattern. Several drugs with proven effectiveness for MS are not mentioned, including: diroximel fumarate (presumably comparable to dimethyl fumerate); cladribine (reserved for MS refractory to at least two other treatments); alemtuzumab and mitoxantrone (not generally recommended due to severe toxicities); hematopoietic stem cell transplantation (reserved for severe treatment refractory disease unresponsive to high efficacy treatments); ozanimod (approved but not yet commercially available). Abbreviations: DMT, disease-modifying therapy; JCV, John Cunningham virus; MRI, magnetic resonance imaging; MS, multiple sclerosis.