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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.


Advances in the Management and Treatment of Multiple Sclerosis


GOAL
To provide neurologists with up-to-date information on the treatment and management of patients with multiple sclerosis.

TARGET AUDIENCE
This activity is designed for neurologists. No prerequisites required.

LEARNING OBJECTIVES
At the conclusion of this activity, the participant should be able to:

  • Discuss the biology of demyelination, axonal degeneration, and neuronal cell death in multiple sclerosis (MS).
  • Summarize the clinical course and prognosis of patients with MS.
  • Develop a rationale for the selection of disease-modifying therapy in patients with MS.
  • Identify noninvasive imaging techniques for the assessment and monitoring of neurodegeneration in patients with MS.
  • Describe current and emerging therapeutic strategies designed to promote neuroprotection in MS.

The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.

ACCREDITATION STATEMENT
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The estimated time to complete this educational activity: 2 hours.

After reading this monograph, participants may receive credit by completing the CME test, evaluation, and receiving a score of 70% or higher.

Release date: May 15, 2008. Expiration date: May 15, 2010.

DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine name implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an educational grant from Pfizer Inc.

Full Disclosure Policy Affecting CME Activities:
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Course Director and Participating Faculty reported the following:

COURSE DIRECTOR

Arun Venkatesan, MD, PhD
Assistant Professor
The Johns Hopkins University School of Medicine
Department of Neurology
The Johns Hopkins Hospital
Baltimore, Maryland
Dr Venkatesan reports having no significant financial or advisory relationships with corporate organizations related to this activity.

PARTICIPATING FACULTY

Bruce A. Cohen, MD
Professor, Davee Department of Neurology
Feinberg School of Medicine
Northwestern University
Director, Northwestern Comprehensive Multiple Sclerosis Program
Chicago, Illinois
Dr Cohen reports serving as a consultant for Bayer, Biogen-Idec, EMD Serono, Genentech, Inc, Pfizer Inc, and Teva Neuroscience; being a stock shareholder in Abbott Laboratories, Inc and CVS-Caremark; receiving honoraria from Bayer, Biogen-Idec, EMD Serono, Genentech, Inc, Novartis, Pfizer Inc, and Teva Neuroscience; and serving on the speakers' bureau for Bayer, Biogen-Idec, EMD Serono, Pfizer Inc, and Teva Neuroscience.

Michael K. Racke, MD
Professor and Chairman of Neurology
The Helen C. Kurtz Chair in Neurology
The Ohio State University Medical Center
Columbus, Ohio
Dr Racke reports receiving grants/research support from Bayer, the National Institutes of Health, and the National Multiple Sclerosis Society; serving as a consultant for Genentech, Inc, Peptimmune, Inc, and Teva Neuroscience; and serving on the speakers' bureau for Bayer, Serono, and Teva Neuroscience.

Notice: The audience is advised that an article in this CME activity contains reference(s) to unlabeled or unapproved uses of drugs or devices.

Dr Cohen–alemtuzumab, daclizumab, fingolomid, fumaric acid ester derivative BG-12, laquinimod, oral cladribine, rituximab, teriflunamide, and vaccination approaches.

All other faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.

Johns Hopkins Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Johns Hopkins Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Advances in the Management and Treatment of Multiple Sclerosis
Arun Venkatesan, MD, PhD*

Multiple sclerosis (MS) is the most common disabling neurologic condition among young adults, affecting approximately 400 000 people in the United States and more than 2.5 million worldwide.1,2 The first disease-modifying therapy for MS–interferon (IFN) b-1b–was introduced only 15 years ago, in 1993.3 Since then, considerable progress has been made in understanding the pathogenesis of MS, developing new neuroimaging techniques to identify and characterize MS lesions, refining diagnostic criteria, and developing new MS management strategies. Indeed this is an exciting time to study MS and to treat patients, as a number of novel treatment options are currently in development.

Although MS has traditionally been described as an autoimmune disease mediated primarily by CD4+ T lymphocytes, recent research has revealed that MS lesions are created and maintained by complex interactions among numerous cell populations, including several T-cell subsets, B lymphocytes, macrophages/ microglia, and astrocytes.4,5 An important recent development has been the recognition that the chronic, progressive disability of MS is closely associated with axonal transection, neurodegeneration, and brain atrophy, and that these processes begin early in the course of MS and accumulate as the disease progresses.6,7

New imaging techniques are helping to reveal alterations in brain structure, chemical composition, and function that are caused by MS in both white matter and gray matter, and to characterize the effects that are produced by MS therapies. Observations such as these have highlighted the importance of the early initiation of disease-modifying therapy for patients with MS, and several recent studies have confirmed that initiation of treatment at the time of a first demyelinating event suggestive of MS (ie, a clinically isolated syndrome) significantly slows the rate of progression to definite MS.8-10 New diagnostic criteria have also been developed that incorporate radiologic and laboratory findings to permit the diagnosis of MS at earlier stages.11

There are now 6 US Food and Drug Administration-approved medications for MS. First-line treatment options include 3 formulations of IFNb (IFNb-1a for subcutaneous administration 3 times/week; IFNb-1a for intramuscular administration once/week; and IFNb-1b for subcutaneous administration every other day) and glatiramer acetate. Natalizumab and mitoxantrone are generally reserved for patients who are not responding to or cannot tolerate a first-line disease-modifying agent. All the approved disease-modifying therapies have been shown to produce a number of beneficial effects in patients with MS, including reductions in relapse rates, improvements in magnetic resonance imaging measures of disease activity, and reduced long-term disability. However, many important issues in MS management and treatment are not well defined. It is currently not possible to predict which subset of patients will experience a benign disease course. In addition, all of the medications that are currently available primarily target central nervous system (CNS) inflammation, and they do not directly prevent the axonal loss and degeneration that are now believed to underlie progressive MS and permanent neurologic disability. None of the available medications are approved for patients with primary progressive MS, who make up approximately 10% to 15% of all patients with MS.12 Many patients who use IFNb eventually develop neutralizing antibodies to IFN, which has been associated with a diminished treatment response. The optimal approach to testing for neutralizing antibodies (NAbs) during IFN therapy and for modifying a treatment regimen for patients who develop NAbs is currently not well defined. Finally, adherence to treatment is often a challenge for patients because of adverse effects of therapy and the need for frequent injections.

This issue of Johns Hopkins Advanced Studies in Medicine provides an update on MS research and treatment for neurologists who treat patients with MS. Michael K. Racke, MD, of The Ohio State University Medical Center, reviews recent research examining the immunologic processes that are thought to cause MS. Dr Racke also describes new approaches to neuroimaging and biomarker development that permit detailed analysis of structural and functional CNS changes in patients with MS. Bruce A. Cohen, MD, of Northwestern University, discusses the clinical course of MS, important prognostic factors, and treatment strategies for patients with MS. Two case studies illustrate some of the practical issues that are important in the management of patients with early MS (presented by Dr Racke) or those who are not responding adequately to treatment (presented by Dr Cohen). Participants in this activity will be able to better discuss the biology of MS, the clinical course and prognosis, the use of noninvasive imaging techniques in MS research and treatment, and emerging strategies to reduce neurodegeneration and prevent progressive disability. In addition, participants will develop a rationale for the selection of disease-modifying therapies to treat patients with MS.

REFERENCES

1. Murray TJ. Diagnosis and treatment of multiple sclerosis. BMJ. 2006;332:525-527.
2. National MS Society. Who Gets MS? Available at: http://www.nationalmssociety.org/about-multiple-sclerosis/who-gets-ms/index.aspx. Accessed April 10, 2008.
3. Connelly JF. Interferon b for multiple sclerosis. Ann Pharmacother. 1994;28:610-616.
4. Agrawal SM, Yong VW. Immunopathogenesis of multiple sclerosis. Int Rev Neurobiol. 2007;79:99-126.
5. Prat A, Antel J. Pathogenesis of multiple sclerosis. Curr Opin Neurol. 2005;18:225-230.
6. Rudick RA, Fisher E, Lee JC, et al. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology. 1999;53:1698-1704.
7. Paolillo A, Piattella MC, Pantano P, et al. The relationship between inflammation and atrophy in clinically isolated syndromes suggestive of multiple sclerosis: a monthly MRI study after triple-dose gadolinium-DTPA. J Neurol. 2004;251:432-439.
8. Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357:1576-1582.
9. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon b-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000;343:898-904.
10. Kinkel RP, Kollman C, OÕConnor P, et al. IM interferon b-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology. 2006;66:678-684.
11. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50:121-127.
12. Boissy A, Fox RJ. Current treatment options in multiple sclerosis. Curr Treat Options Neurol. 2007;9:176-186.

*Assistant Professor, The Johns Hopkins University School of Medicine, Department of Neurology, The Johns Hopkins Hospital, Baltimore, Maryland.
Address correspondence to: Arun Venkatesan, MD, PhD, Assistant Professor, The Johns Hopkins University School of Medicine, Department of Neurology, The Johns Hopkins Hospital, Pathology 509, 600 North Wolfe Street, Baltimore, MD 21287. E-mail: avenkat2@jhmi.edu.

The content in this monograph was developed with the assistance of a staff medical writer. Each author had final approval of his article and all its contents.





Johns Hopkins Advanced Studies in Medicine (ISSN-1558-0334), is published by Galen Publishing, LLC, d/b/a ASiM, PO Box 340, Somerville, NJ 08876. (908) 253-9001. Copyright ©2012 by Galen Publishing. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, without first obtaining permission from the publisher. ASiM is a registered trademark of The Healthcare Media Group, LLC.