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Therapeutic Decisions in Multiple Sclerosis Moving Beyond Efficacy

Wolfgang Brück, MD1; Ralf Gold, MD3; Brett T. Lund, PhD4; Celia Oreja-Guevara, MD5; Alexandre Prat, MD6; Collin M. Spencer, BS11; Lawrence Steinman, MD7; Mar Tintoré, MD8; Timothy L. Vollmer, MD9; Martin S. Weber, MD1,2; Leslie P. Weiner, MD4; Tjalf Ziemssen, MD10; Scott S. Zamvil, MD, PhD11,12
[+] Author Affiliations
1Department of Neuropathology, University Medical Centre, Göttingen, Germany
2Department of Neurology, University Medical Centre, Göttingen, Germany
3Research Department of Neuroscience, Neurologische Universitätsklinik, St Josef Hospital, Faculty of Medicine, Bochum, Germany
4Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles
5Department of Neurology, Multiple Sclerosis Unit, Hospital Universitario San Carlos, Madrid, Spain
6Center of Excellence in Neuromics, Centre hospitalier de l’Université de Montréal, Montreal, Quebec, Canada
7Department of Neurology, Stanford University School of Medicine, Stanford, California
8Centre d’Esclerosi Múltiple de Catalunya, Unitat de Neuroimmunologia Clínica, Servei de Neurologia, Hospital Vall d’Hebron, Barcelona, Spain
9Department of Neurology, School of Medicine, University of Colorado Denver, Aurora
10MS Center Dresden, Neuroimmunological Laboratory, Center of Clinical Neuroscience, Department of Neurology, University Clinic Carl Gustavus Carus, Dresden University of Technology, Dresden, Germany
11Department of Neurology, University of California, San Francisco
12Program in Immunology, University of California, San Francisco
JAMA Neurol. 2013;70(10):1315-1324. doi:10.1001/jamaneurol.2013.3510.
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Several innovative disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis have been licensed recently or are in late-stage development. The molecular targets of several of these DMTs are well defined. All affect at least 1 of 4 properties, namely (1) trafficking, (2) survival, (3) function, or (4) proliferation. In contrast to β-interferons and glatiramer acetate, the first-generation DMTs, several newer therapies are imbued with safety issues, which may be attributed to their structure or metabolism. In addition to efficacy, understanding the relationship between the mechanism of action of the DMTs and their safety profile is pertinent for decision making and patient care. In this article, we focus primarily on the safety of DMTs in the context of understanding their pharmacological characteristics, including molecular targets, mechanism of action, chemical structure, and metabolism. While understanding mechanisms underlying DMT toxicities is incomplete, it is important to further develop this knowledge to minimize risk to patients and to ensure future therapies have the most advantageous benefit-risk profiles. Recognizing the individual classes of DMTs described here may be valuable when considering use of such agents sequentially or possibly in combination.

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Figure 1.
Classes of Therapeutic Antibodies

Green indicates protein sequences of murine origin; yellow, protein sequences of human origin; mAb, monoclonal antibody; and MS, multiple sclerosis.

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Figure 2.
Chemical Structure of Sphingosine-1-Phosphate and Fingolimod
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Figure 3.
Methylfumarates Promote Activation of the Nrf2 Pathway via Regulation of Keap1, the Nrf2 Inhibitor

A, Methylfumarates are electrophiles that covalently bind the nucleophilic thiol group (-S-H) of Keap1 residue Cys151.57 Two products can be generated depending on which carbon of the π bond is conjugated. DMF indicates dimethyl fumarate; MMF, monomethyl fumarate. B, In the absence of MMF, Keap1 binds Nrf2, promoting its ubiquitylation and consequent degradation.61 ARE indicates antioxidant response element. C, On covalent binding of MMF to Keap1, interaction between Keap1 and Nrf2 is disrupted. This stabilizes Nrf2, which permits it to bind the ARE and promote gene transcription.

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Figure 4.
Chemical Structure of Linomide and Laquinimod
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Figure 5.
Chemical Structure of Leflunomide and Teriflunomide
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