We're unable to sign you in at this time. Please try again in a few minutes.
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Review |

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.
Text Size: A A A
Published online

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.

Figures in this Article

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?


Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Chemical Structure of Sphingosine-1-Phosphate and Fingolimod
Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.
Chemical Structure of Linomide and Laquinimod
Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.
Chemical Structure of Leflunomide and Teriflunomide
Graphic Jump Location




Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.


Some tools below are only available to our subscribers or users with an online account.

22 Citations

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles