New approaches in the management of multiple sclerosis

Abstract

Multiple sclerosis (MS) is a central nervous system chronic inflammatory disease that is characterized by an extensive and complex immune response. Scientific advances have occurred in immunology, pathophysiology, and diagnostic and clinical assessment tools, and recent discovery of unique therapeutic targets has spurred numerous Phase II and Phase III clinical trials. Reductions in MS relapse rates and improvements in T₂ or gadolinium-enhancing lesion burdens have been reported from Phase III trials that include fingolimod, alemtuzumab, cladribine, and rituximab. Promising Phase II trial data exist for teriflunomide, daclizumab, laquinimod, and fumarate. The optimism created by these favorable findings must be tempered with evaluation of the adverse effect profile produced by these new agents. Given the discovery of progressive multifocal leukoencephalopathy with the use of natalizumab, ongoing vigilance for rare and life-threatening reactions due to new agents should be paramount. Patients with MS often experience difficulty with ambulation, spasticity, and cognition. Recent clinical trial data from two Phase III dalfampridine-SR trials indicate certain patients receive benefits in ambulation. This article provides an overview of data from clinical trials of newer agents of potential benefit in MS.

Keywords: Phase II trials; Phase III trials; monoclonal antibody; multiple sclerosis; progressive multifocal leukoencephalopathy.

Figure 1

Natural history of MS. Four clinical patterns are recognized by international consensus. Approximately 85% of patients experience RRMS, characterized by the abrupt start of symptoms and acute episodes of worsening (exacerbations or relapses) with complete or partial recovery. Between these episodes, patients may be clinically stable, may experience gradual progression of disability, or may undergo a combination of both. Approximately 50% of patients with RRMS convert to SPMS within 10 years of disease onset. The secondary progressive phase is characterized by gradual progression of disability with or without superimposed relapses. In contrast, patients with PPMS (~10% of patients with MS) experience gradual progression of disability from onset without superimposed relapses. Patients with progressive relapsing MS experience gradual progression of disability from disease onset, later accompanied by one or more relapses; this clinical pattern affects ~5% of patients. An important conceptual development in the understanding of MS pathogenesis has been the compartmentalization of the mechanistic process into two distinct but overlapping and connected phases, inflammatory and neurodegenerative. Axonal loss begins most likely at disease onset and accumulates. Conversion of relapsing– remitting to secondary progressive occurs once axon loss surpasses the capacity of the CNS to compensate for loss of function. Copyright © 2006, Elsevier. Adapted with permission from Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006;52(1):61–76. Abbreviations: CNS, central nervous system; RRMS, relapsing–remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis; PPMS, primary progressive multiple sclerosis.

Figure 2

Possible mechanisms of injury and repair in MS. Genetic and environmental factors (including viral infection, bacterial lipopolysaccharides, superantigens, reactive metabolites, and metabolic stress) may facilitate the movement of autoreactive T cells and demyelinating antibodies from the systemic circulation into the CNS through disruption of the BBB. In the CNS, local factors (including viral infection and metabolic stress) may upregulate the expression of endothelial adhesion molecules, such as ICAM-1, VCAM-1, and E-selectin, further facilitating the entry of T cells into the CNS. Proteases, including matrix metalloproteinases, may further enhance the migration of autoreactive immune cells by degrading extracellular-matrix macromolecules. Proinflammatory cytokines released by activated T cells, such as IFN-γ and TNF-β, may upregulate the expression of cell-surface molecules on neighboring lymphocytes and antigen-presenting cells. Binding of putative MS antigens, such as myelin basic protein, myelin-associated glycoprotein, MOG, proteolipid protein, αβ-crystallin, phosphodiesterases, and S-100 protein, by the trimolecular complex – the TCR and class II MHC molecules on antigen-presenting cells – may trigger either an enhanced immune response against the bound antigen or anergy, depending on the type of signaling that results from interactions with surface costimulatory molecules (eg, CD28 and CTLA-4) and their ligands (eg, B7-1 and B7-2). Downregulation of the immune response (anergy) may result in the release of anti-inflammatory cytokines (IL-1, IL-4, and IL-10) from CD4⁺ T cells, leading to the proliferation of anti-inflammatory CD4⁺ Th2 cells. Th2 cells may send anti-inflammatory signals to the activated antigen-presenting cells and stimulate pathologic or repair-enhancing antibody-producing B cells. Alternatively, if antigen processing results in an enhanced immune response, proinflammatory cytokines (eg, IL-12 and IFN-γ) may trigger a cascade of events, resulting in the proliferation of proinflammatory CD4⁺ Th1 cells and ultimately in immune-mediated injury to myelin and oligodendrocytes. Multiple mechanisms of immune-mediated injury of myelin have been postulated: cytokine-mediated injury of oligodendrocytes and myelin; digestion of surface myelin antigens by macrophages, including binding of antibodies against myelin and oligodendrocytes (ie, antibody-dependent cytotoxicity); complement-mediated injury; and direct injury of oligodendrocytes by CD4⁺ and CD8⁺ T cells. This injury to the myelin membrane results in denuded axons that are no longer able to transmit action potentials efficiently within the CNS (loss of saltatory conduction). This slowing or blocking of the action potential results in the production of neurologic symptoms. The exposed axon segments may be susceptible to further injury from soluble mediators of injury (including cytokines, chemokines, complement, and proteases), resulting in irreversible axonal injury (such as axonal transection and terminal axon ovoids). There are several possible mechanisms of repair of the myelin membrane, including resolution of the inflammatory response followed by spontaneous remyelination, spread of sodium channels from the nodes of Ranvier to cover denuded axon segments and restore conduction, antibody-mediated remyelination, and remyelination resulting from the proliferation, migration, and differentiation of resident oligodendrocyte precursor cells. Copyright © 2000, Massachusetts Medical Society. All rights reserved. Adapted with permission from Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343(13):938–952. Abbreviations: ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular-cell adhesion molecule 1; CNS, central nervous system; TNF-β, tumor necrosis factor-β; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; TCR, T-cell receptor; MHC, major-histocompatibility-complex; Th1, type 1 helper T; Th2, type 2 helper T; BBB, blood-brain barrier.

Figure 3

Classification of MS lesion pattern. Various cellular (macrophages and activated microglia) and humoral (antibodies and complement) immune components are dominating in Pattern I and II lesions. In contrast, Pattern III and IV are mainly characterized by a primary oligodendropathy with less inflammation. Type III lesions barely remyelinate and are similar to lesions found after hypoxic and/or toxic brain injury. Type IV lesions differ from lesion Pattern II by increased oligodendrocyte apoptosis due to metabolic dysfunction. Copyright © 2007, Bentham Science Publishers. Adapted with permission from Kleinschnitz C, MEuth SG, Kieseier BC, Wiendl H. Immunotherapeutic approaches in MS: update on pathophysiology and emerging agents or strategies 2006. Endocr Metab Immune Disord Drug Targets. 2007;7(1):35–63. Abbreviations: CD8, CD8 T cell; MF, macrophage; MOG, myelin oligodendrocyte glycoprotein; ROS, reactive oxygen species; T, T cell; TNF, tumor necrosis factor.

Figure 4

New MS drug mechanisms of action. Schematic depiction of putative targets for the new MS treatment modalities. In lymphoid organs in the periphery, autoreactive T cells interact with APC and B cells and, after activation, are able to cross the BBB. In the CNS, reactivation of autoreactive T cells results in production of effector cytokines such as IFN-γ, TNF-α, and IL-17, attraction of macrophages and microglia, antibody production by plasma cells, and attack by CD8⁺ T cells. In concert, these mechanisms lead to demyelination and axonal injury. Interactions of immune cells are shown with black arrows and transmigration over the BBB is displayed with yellow arrows. Red arrows indicate therapeutic interactions with pointed arrows standing for targeting of specific cell types or molecules, T-shaped lines in red indicate blocking of pathways or receptors. Hypothetic mechanisms not proven in vivo are depicted with a question mark. Copyright © 2008, Elsevier. Adapted with permission from Linker RA, Kieseier BC, Gold R. Identification and development of new therapeutics for multiple sclerosis. Trends Pharmacol Sci. 2008;29(11):558–565. Abbreviations: APC, antigen-presenting cell; B, B cell; BBB, blood–brain barrier; CNS, central nervous system; IL, interleukin; INF-γ, interferon-γ; NK, natural killer cell; NO, nitric oxide; PC, plasma cell; S1P-R, sphingosine-1-phosphate receptor; Th, T-helper cell; TNF-α, tumour necrosis factor-α; VCAM, vascular cell adhesion molecule-1.