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Multiple Sclerosis


Long-term Experience of Glatiramer Acetate (Copaxone®) in the Treatment of Clinically Isolated Syndrome and Relapsing–Remitting Multiple Sclerosis


Howard Zwibel, MD Founding Medical Director, Emeritus Neuroscience Consultants Comprehensive Care Multiple Sclerosis Center, Coral Gables


Abstract


Multiple sclerosis (MS) is a chronic, disabling condition with severe clinical and social consequences. Glatiramer acetate (GA) has been widely used for more than 15 years as a first-line disease-modifying agent in the treatment of relapsing–remitting MS (RRMS). It appears to have multiple modes of action, including the induction of GA-reactive T-helper 2 (Th2) immunoregulatory cells and the stimulation of neurotrophin secretion in the central nervous system, which may promote neuronal repair. Clinical trial data show that GA reduces the relapse rate in RRMS, can delay or halt disability progression, and brings about improvement in magnetic resonance imaging (MRI) measures of disease activity, including reduction of brain atrophy. Early treatment with GA can reduce the risk of developing clinically definite MS in patients with clinically isolated syndrome. Furthermore, it has an excellent safety and tolerability profile. Recent data from patients treated for 15 years have indicated that more than half of the patients on long-term GA therapy have stable or improved disability scores.


Keywords Glatiramer acetate, relapsing–remitting multiple sclerosis, long-term experience


Disclosure: Howard Zwibel, MD, is or has been a consultant to Acorda Therapeutics, Teva Neuroscience, Bayer, Biogen, Genentech, and EMD Serono, a member of the speakers bureau for Acorda Therapeutics, Teva Neuroscience, Biogen, and EMD Serono, and is a member of the advisory board for WebMD, LLC (Medscape). Acknowledgments: Editorial assistance was provided by James Gilbart, PhD, at Touch Briefings. Received: December 2, 2011 Accepted: January 9, 2012 Citation: US Neurology, 2011;7(2):126–31 Correspondence: Howard Zwibel, MD, 6862 Granada Boulevard, Coral Gables, FL 33146. E: zwibelmdms@aol.com


Support: The publication of this article was funded by Teva Neuroscience. The views and opinions expressed are those of the author and not necessarily those of Teva Neuroscience.


As a chronic disease of the central nervous system (CNS), multiple sclerosis (MS) is characterized by a complex interplay between inflammation, demyelination, remyelination, gliosis, and neuronal injury.1 It continues to be a major cause of acquired neurologic disability in young adults worldwide, particularly in people of northern European origin.2 It affects women with twice the frequency of men and the average age of diagnosis is 37 years.3


The worldwide total estimated prevalence for the past three decades is 83 cases/100,000 population.4


The clinical course of MS is heterogeneous, with variability both between and within patients, and has been categorized as clinically isolated syndrome (CIS), relapsing–remitting MS (RRMS, which accounts for 85 % of MS patients in the initial disease course), primary progressive MS (PPMS), and secondary progressive MS (SPMS).5,6


RRMS is characterized by


relapses, symptoms of which include numbness, blurred vision, difficulty walking, fatigue, and pain. Symptoms are usually temporary and are followed by periods of remission.6


The immunopathogenesis of MS is thought to be heterogeneous; however, the inflammatory demyelinating plaque is characteristic of all forms of MS.7


126


may occur when peptides in myelin attach to the cleft of major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (APCs) including macrophages, monocytes, and dendritic cells.8 Activation of APCs can trigger an immune response against the bound antigen and leads to secretion of pro-inflammatory cytokines and the differentiation of naive CD4+ T cells into T-helper 1 (Th1) and T-helper 17 (Th17) cells, resulting in inflammation and autoimmunity. Th1 and Th17 cells are capable of migration into the CNS and have been identified in active lesions.9,10


Additionally, activated B cells appear to be participants in the creation of myelin lesions by producing antibodies that mediate and promote demyelination.13


Immune-mediated injury to myelin and oligodendrocytes


Th1 cells undergo continued proliferation and secretion of pro-inflammatory cytokines, leading to myelin damage and neuronal loss. Further activation of resident microglia can lead to cross-reactivity, which maintains inflammation and further damage to the myelin sheath.11 Impaired function of regulatory T cells (Tregs), which act against autoimmunity, allows further pathologic activation of autoreactive T cells and exacerbates the feedback loop that causes continual damage to the CNS.12


MS represents a considerable therapeutic challenge, because of its significant heterogeneity and unpredictable clinical course. Glatiramer


© TOUCH BRIEFINGS 2011


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