current opinion in neurology - list information€¦ · current opinion in neurology (issn...

Volume 25 bull Supplement 1 bull February 2012

wwwco-neurologycom

Multiple Sclerosis New Goals New Therapies and New Challenges in Patient Management

Guest Editor Aaron E Miller

IMPA

CT F

ACTO

R

502

1

Current Opinion inCurrent Opinion in

NeurologyNeurology


NeurologyNeurology

EDITORIAL BOARDY Agid

Salpeacutetriegravere Hospital France

RL BarchiThomas Jefferson University USA

F Chollet

Purpan Hospital France

DC De Vivo

Columbia University USA

D Eidelberg

North Shore University Hospital USA

S Gilman

University of Michigan USA

P Goadsby

University of California San Francisco USA

H-P Hartung

Heinrich-Heine University Germany

GL Lenzi

University of Rome I Italy

JA Obeso

University of Navarra Spain

J Olesen

University of Copenhagen Denmark

PD Thompson

University of Adelaide Australia

K Toyka

University of Wuumlrzburg Germany

Lord Walton

Founding Editor

C WeillerUniversity Germany

2012 CONTENTSFEBRUARY

Cerebrovascular diseaseEdited by Ralph Sacco and Tatjana Rundek University of Miami USA

Neuro-ophthalmology and neuro-otologyEdited by Jose Sahel and Christine Petit INSERM Paris France

APRIL

Developmental disordersEdited by David Skuse Behavioural and Brain Sciences Unit University College London UK

Seizure disordersEdited by John Stern Department of Neurology UCLA USA

JUNE

Demyelinating diseasesEdited by Ludwig Kappos University Hospital Basel Switzerland

HeadacheEdited by Messoud Ashina University of Copenhagen Denmark

Infl ammatory diseases and infectionEdited by Heinz Wiendl University of Muenster Germany

AUGUST

NeuroimagingEdited by Joe Masdeu National Institute of Mental Health Bethesda USA

Movement disordersEdited by Department of Neurology Baylor College of Medicine Houston Texas USA

OCTOBER

Nerve neuro-muscular junction and motor neuron diseasesEdited by Jean-Marc Leger Consutation de Pathologie Neuro-Musculaire Babinski Building Salpecirctriegravere Hospital Paris France

Neuromuscular diseases muscleEdited by Tom Rando Department of Neurology and Neurological Sciences Stanford University School of Medicine Stanford USA

DECEMBER

Trauma and rehabilitationEdited by Richard Greenwood The Institute of Neurology University College London London

Degenerative and cognitive diseasesEdited by William Seeley University of California San Francisco Memory and Aging Center USA

NeoplasmsEdited by Roger Stupp University of Lausanne Switzerland and Michael Weller University Hospital Zurich Switzerland

Editor-in-Chief Richard SJ Frackowiak Institute of Neurology UK and Deputy Editor John Mazziotta UCLA School of Medicine USA

Literature Scanners P Alison Jones (coordinator) Mark Bower Matthew Griffi n Fareeda Coxon Yaaseen Moosa Patrick Bradley

2010 Journal Citation Reportsreg (Thomson Reuters 2011)

CURRENTOPINION

Current Opinion in Neurology (ISSN 1350-7540)

bull Current Opinion in Neurology (USPS No 003-366) is published bimonthly by Lippincott Williams amp Wilkins and distributed in the US by Mercury Airfreight international Inc 365 Blair Road Avenel NJ 07001 Periodicals postage paid at Rahway NJ USA POSTMASTER send address changes to Current Opinion in Neurology PO Box 1550 Hagerstown MD 21740

bull Advertisements statements or opinions expressed in Current Opinion in Neurology refl ect the views of the advertiser or author(s) and are not the opinion of Lippincott Williams amp Wilkins or the Editorial Board unless so stated Readers are advised that methods and techniques described involving drug usage should be followed only in conjunction with the drug manufacturerrsquos own published literature

Copyright copy 2012 by Wolters Kluwer Health | Lippincott Williams amp Wilkins All rights reserved

Publication Staff Lippincott Williams amp Wilkins

Publisher lan BurgessManaging Editor Leanne BullProduction Editor Dominic HarperProduction Manager Kevin MaycroftDatabase Manager Neelam ShahEditorial Coordinator Edward Newman

Typeset Thomson Digital Noida Special Economic Zone Noida India

Printed and bound Markono Print Media Pte Ltd Singapore on chloine-free recyclable paper from sustainable forests meeting the requirements of ISO 9706 ISO 14001 and ISO 9001

Indexing Current Opinion in Neurology is indexed by Biological Abstracts (BIOSIS) Cumulative Index to Nursing amp Allied Health Literature (CINAHL) Current Awareness in Biological Sciences (CABS) Current Contents EBSCO Online Excerpta Medica (EMBASE) Index Medicus (MEDLINE) JoumalsOvid OCLC ArticleFirst OCLC ContentsFirst PUBMED Research Alert and Scisearch

SUBSCRIPTION

Annual subscription rates United States individuals $392 rest of the world individuals $403 United States institutions $1285 rest of the world institutions $1377 Online only subscriptions for Institutions are available through Ovid (wwwovidcom)

bull The Canadian GST tax of 7 will be added to the subscription price of all orders shipped to Canada Lippincott Williams amp Wilkinsrsquo GST identifi cation Number is 895524239

bull Publications Mail Agreement 0863505 Subscriptions outside United States must be prepaid

bull Prices include handling and shipping but not VAT

Address for subscription information orders or change of address

Permission Please go to the Journal website and click the lsquolsquoPermissionsrsquorsquo link above the title of the paper in the abstract or html window for the relevant article Alternatively send an email to customercarecopyrightcom

Translation Rights amp Licensing queries Please contact Silvia Serra Translations Rights Licensing amp Permissions Manager Wolters Kluwer Health (Medical Research) Ltd 250 Waterloo Road London SE1 8RD UK Phone +44 (0)207 981 0600 SilviaSerrawolterskluwercom

Advertising Enquiries Dick Bower The Point of Difference Tel +44 (0) 20 8542 3200 Fax +44 (0) 20 8543 3810 E-mail dickbowerbtinternetcom

Commercial Reprints Enquiries US amp Canada please contact Vian Holland e-mail VianHollandwolterskluwercom Mexico Argentina Brazil and other Latin American countries please contact Carlos Moreyra e-mail cmoreyrapharmawkhealthcom Europe and Asia Pacifi c you may send your e-mail request to salespharmawkhealthcom

Supplement Enquiries supplementspharmawkhealthcom

USA Europe and others

LWW16522 Hunters Green ParkwayHagerstownMaryland 21740-2116USATel 1-800-638-3030Fax 1-301-223-2320in Maryland tel 301-223-2300

Japan

Wolters Kluwer Health Japan Co Ltd3-23-14 HongoBunkyo-kuTokyo 113-0033JapanTel 81-3-5689-5400Fax 81-3-5689-5402

India Bangladesh Sri Lanka

Nepal and Pakistan

Globe Publication Pvt LtdB-13 3rd FL A BlockShopping ComplexNaraina Vihar Ring RoadNew Delhi 110028 IndiaTel 91-11-579-3211Fax 91-11-579-887

Prices subject to change without notice Copies will be replaced without charge if the publisher receives a request within 90 days

of the mailing date both in the USA and worldwide

Site licences are available to all institutions Visit wwwlwwcomlibrarianshtm to download the site licence most appropriate to your organization For additional information contact Marylou OrsquoConnor tel +1 215 521 8452 In the USA and Canada contact Heidi Alexander tel +1 800 326 1685

Customer Services

Lippincott Williams amp Wilkins16522 Hunters Green ParkwayHagerstownMaryland 21740-2116USA

Publishing Offi ce

Lippincott Williams amp Wilkins250 Waterloo RoadLondonSE1 8RDUK

Contacts


NeurologyNeurology CURRENTOPINION

PURPOSECurrent Opinion in Neurology is one of 24 Current Opinion journals that aims to help clinicians and researchers keep up-to-date in a systematic way with the vast amount of information published in neurology

bull Current Opinion in Neurology guides you through the literature with Review articles by the worldrsquos experts in oncology written in clear concise and accessible language

bull Expert commentary and on the most interesting and relevant papers published in neurology

bull Comprehensive references and bibliographies providing a ready resource

bull Search-enabled full-text web site

EDITORIAL EXPERTISECurrent Opinion in Neurology benefi ts from four levels of editorial participation

bull Editors-in-Chief Richard SJ Frackowiak and Deputy Editor John Mazziotta

bull Editorial Board comprised of neurologists from around the world

bull Section Editors appointed by the Editor-in-Chief and Deputy Editor who are chosen for their expertise

bull Reviewers nominated by the Section Editors are leading authorities on each of the relevant topics

METHODSCurrent Opinion in Neurology is published bimonthly

bull Each issue contains approximately 114 pages

bull The fi eld of neurology is divided into 14 sections each of which is reviewed once a year

bull Each section is assigned to one or two Section Editors leading authorities in that area who identify for review the most important topics at that time

ISSUE CONTENTSEach issue contains the following types of information

bull Review articles concise up-to-date articles written by specialists who provide a personal perspective and overview of the develop ments in the fi eld over the previous year

bull Annotated references the authorsrsquo reference lists offer personal commentary so that you can put the information into context with the text of the article and with the other references

bull Current world literature the end of each issue contains a complete bibliography of all the papers published in the previous year For easy reference the list of papers is organized by subject area

bull Annual contents and cumulative indices the last issue of each volume of Current Opinion in Neurology includes a table of contents for the year as well as cumulative indices organized by both subject and author so that you can easily identify the source of information you need

SCANNING THE LITERATUREbull The journals selected for scanning for Current Opinion in

Neurology are chosen by the Editor-in-Chief and Deputy Editor for their relevance and importance to the fi eld

bull The list published at the end of the current world literature section is reviewed and regularly updated by the Editor-in-Chief Deputy Editor and Editorial Board to ensure that the journals scanned are representative of the fi eld in signifi cance timeliness and accuracy

IN SUMMARYbull Current Opinion in Neurology bridges the gap between the

primary literature and your daily practice

bull It guides you through the vast amount of literature published each month pointing you to the information that is most relevant keeping you up-to-date with personal commentary from the worldrsquos authorities in neurology

bull It provides you with comprehensive well organized reference lists and bibliographies for use throughout the year


NeurologyNeurologyAIMS AND ORGANIZATION


Essential reviews that bridge the gap between primary literature and your daily practice

CURRENTOPINION

MULTIPLE SCLEROSIS NEW GOALS NEW THERAPIES AND NEW CHALLENGES IN PATIENT MANAGEMENT

Guest Editor Aaron E Miller MD

Release date 14 March 2012Expiration date 14 March 2013

FacultyEdward J Fox MD PhDGavin Giovannoni MBBCh PhD FCP (Neurol) FRCP FRCPathRobert W Rhoades PhD

TABLE OF CONTENTS

S1 CME overview and instructions for receiving

CMECE credit

S4 Treatment of relapsing-remitting multiple

sclerosis current approaches and unmet needs

Aaron E Miller and Robert W Rhoades

S11 New treatments and treatment goals for patients

with relapsing-remitting multiple sclerosis

Edward J Fox and Robert W Rhoades

S20 Individualizing treatment goals and interventions

for people with MS

Gavin Giovannoni and Robert W Rhoades


NeurologyNeurology


CURRENTOPINION

This activity is supported by an educational grant from Genzyme a Sanofi Company

Jointly sponsored by Supported by an educational grant from

Target Audience

This activity has been designed to meet the educational needs of physicians registered nurses and other clinicians involved in the management of patients with multiple sclerosis

Release date 14 March 2012Expiration date 14 March 2013Estimated time to complete activity 10 hour

Statement of NeedProgram Overview

Multiple sclerosis (MS) is a chronic infl ammatory disease of the central nervous system with clinical manifestations of demy-elination axonal loss neuronal death and gliosis It is a lifelong disease that once diagnosed requires ongoing treatment Newer therapies have signifi cantly changed the potential benefi t of treatment for patients with MS and clinicians require education to increase awareness of potential advances in treatment While potentially providing improved effi cacy educa-tion is needed as some new treatments may require careful consideration in patient selection and monitoring As persons with MS vary across a wide range of parameters their treatment should be individualized to meet their specifi c characteris-tics and needs The papers comprising this supplement are designed to meet the needs of healthcare providers who care for people with MS by summarizing the benefi ts and risks of both established and emerging therapies and highlighting best practices in partnering with patients in selection of specifi c therapies and overall disease management

Educational Objectives

After completing this activity the participant should be better able tobull Discuss MS management options with the potential to delay disease progression bull Describe MS management options with the potential to improve adherence bull Evaluate emerging data on investigational treatment options and novel therapies for patients with RRMS bull Identify patients at increased risk for adverse events with new MS therapies and manage such events if they occur bull Develop individualized treatment goals and interventions based on patient characteristics bull For registered nurses Provide appropriate care and counsel for patients and their families

Faculty

Aaron E Miller MD (Guest Editor and Chairperson)

Medical DirectorCorinne Goldsmith Dickinson Center for Multiple SclerosisProfessor of NeurologyMount Sinai School of MedicineNew York New York

Gavin Giovannoni MBBCh PhD FCP (Neurol) FRCP FRCPath

Professor and ChairDepartment of NeurologyBarts and the London School of Medicine and DentistryLondon United Kingdom

Edward J Fox MD PhD

DirectorMultiple Sclerosis Clinic of Central TexasClinical Assistant ProfessorUniversity of Texas Medical BranchRound Rock Texas


NeurologyNeurology


CURRENTOPINION

To obtain credit and print your certifi cate of

completion

1 Visit wwwcmeuniversitycom

2 Enter the 4-digit code 8242 in the top search box

3 Complete posttest and evaluation

Robert W Rhoades PhD

Steamboat Springs Colorado

Physician Continuing Medical Education

Accreditation Statement

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accredita-tion Council for Continuing Medical Education through the joint sponsorship of Postgraduate Institute for Medicine and CMEology The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical educa-tion for physicians

Credit Designation

The Postgraduate Institute for Medicine designates this journal-based CME activity for a maximum of 10 AMA PRA Category 1 Credittrade Physicians should claim only the credit commensurate with the extent of their participation in the activity

Nursing Continuing Education

Credit Designation

This educational activity for 10 contact hour is provided by Postgraduate Institute for Medicine


Postgraduate Institute for Medicine is accredited as a provider of continuing nursing education by the American Nurses Credentialing Centerrsquos Commission on Accreditation

Disclosure of Confl icts of Interest

Postgraduate Institute for Medicine (PIM) assesses confl ict of interest with its instructors planners managers and other individuals who are in a position to control the content of CME activities All relevant confl icts of interest that are identifi ed are thoroughly vetted by PIM for fair balance scientifi c objectivity of studies utilized in this activity and patient care recommendations PIM is committed to providing its learners with high-quality CME activities and related materi-als that promote improvements or quality in healthcare and not a specifi c proprietary business interest of a commercial interestThe faculty reported the following fi nancial relationships or relationships to products or devices they or their spouselife partner have with commercial interests related to the content of this CME activity

Name of Faculty or Presenter Reported Financial Relationship

Edward J Fox MD PhD Consulting Fees Bayer Biogen Idec EMD Serono Genzyme Novartis Opexa Teva

Fees for Non-CMECE Services Received Directly from a Commercial Interest or their Agents (eg speakersrsquo bureaus)Bayer Biogen Idec EMD Serono Pfi zer Teva

Contracted ResearchBiogen Idec Genzyme EMD Serono Eli Lilly Novartis Ono Roche Sanofi -aventis Teva


Consulting FeesBayer-Schering Healthcare Biogen Idec Elan Five Prime Therapeutics Genzyme Ironwood Merck Serono Novartis Roche Sanofi -aventis Syn-thon BV UCB Pharma Vertex

Fees for Non-CMECE Services Received Directly from a Commercial Interest or their Agents (eg speakersrsquo bureaus) Genzyme Merck Serono Novartis

Contracted ResearchGW Pharmaceuticals Merck Serono Merz Novartis

Aaron E Miller MD Consulting FeesAcorda Avanir Biogen Idec BioMarin Chelsea Therapeutics Daiichi Sankyo EMD Serono Glaxo Merck Serono Novartis Nuron Biotech Ono LA-SER Sanofi -aventis

Fees for Non-CMECE Services Received Directly from a Commercial Interest or their Agents (eg speakersrsquo bureaus)Acorda Biogen Idec EMD Serono Pfi zer Teva

Contracted ResearchAcorda Biogen Idec Genentech Genzyme Novartis Roche Sanofi -aventis Teva

Robert W Rhoades PhD Nothing to Disclose

The planners and managers reported the following fi nancial relationships or relationships to products or devices they or their spouselife partner have with commercial interests related to the content of this CME activityThe following PIM planners and managers Trace Hutchison PharmD Samantha Mattiucci PharmD Jan Schultz RN MSN CCMEP and Patricia Staples MSN NP-C CCRN hereby state that they or their spouselife partner do not have any fi nancial relationships or relationships to products or devices with any commercial interest related to the con-tent of this activity of any amount during the past 12 monthsThe following CMEology planners and managers Rob Lowney and Ellen Miller hereby state that they or their spouselife partner do not have any fi nancial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months

Method of Participation and Request for Credit

There are no fees for participating and receiving CME credit for this activity During the period 14 March 2012 through 14 March 2013 participants must read the learning objectives and faculty disclosures and study the educational activ-ity

Media

Journal supplement

Disclosure of Unlabeled Use

This educational activity may contain discussion of published andor investigational uses of agents that are not indicated by the FDA PIM CMEology and Genzyme do not recommend the use of any agent outside of the labeled indications The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of PIM CMEology and Genzyme Please refer to the offi cial prescribing information for each product for discussion of approved indications contraindications and warnings

Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development The information presented in this activity is not meant to serve as a guideline for patient management Any procedures medications or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patientsrsquo conditions and possible contraindications on dangers in use review of any applicable manufacturersrsquo product information and comparison with recommenda-tions of other authorities

REVIEW

CURRENTOPINION Treatment of relapsing-remitting multiple sclerosis

current approaches and unmet needs

wwwco-neurologycom

a b


Purpose of review

The aim of this review is to summarize unmet needs for patients with multiple sclerosis (MS) It is importantto understand the current status of these patients and both the benefits and limitations of the most commonlyused MS treatments as new medications with the potential to simplify therapy and improve outcomes maysoon be available

Recent findings

Current treatments for MS decrease the frequency of relapses and slow progressive disability Howevernearly all of these medications require frequent administration and some patients also experience sideeffects In some patients adherence to MS treatment may be less than optimal This may be associatedwith increased risk for relapses and hospitalizations and higher cost of care

Summary

Healthcare providers involved in the treatment of MS must be aware of the unmet needs of theirpatients and intervene as needed to improve adherence andor modify treatment regimens to optimizeoutcomes

Keywords

adherence cost quality of life

aCorinne Goldsmith Dikinson Center for Multiple Sclerosis Mount SinaiSchool of Medicine New York New York and bSteamboat SpringsColorado USA

Correspondence to Dr Aaron E Miller Corinne Goldsmith DickinsonCenter for Multiple Sclerosis Mount Sinai School of Medicine 5 East98th Street 1st Floor New York NY 10029 USA Tel +1 212 2417958 fax +1 212 241 5333 e-mail aaronmillermssmedu

Curr Opin Neurol 2012 25 (suppl 1)S4ndashS10

INTRODUCTION

Multiple sclerosis (MS) is an autoimmune inflam-matory demyelinating disease that attacks thecentral nervous system (CNS) [1] MS generally takesone of four clinical courses a relapsing-remittingcourse characterized by unpredictable exacerbationsof existing symptoms or appearance of new symp-toms [relapsing-remitting MS (RRMS)] an initiallyrelapsing-remitting course that ultimately becomessteadily progressive (secondary progressive MS) aform that is progressive from the onset withoutrelapses (primary progressive MS) and rarely acourse that is progressive from onset but is thenpunctuated by relapses (progressive-relapsing MS)[2] Approximately 85 of patients initially mani-fest a relapsing-remitting course with 10ndash15demonstrating the primary progressive form [1]This article reviews the epidemiology of MS societalcost and patient burden associated with MS thebenefits and limitations of current therapies andunmet patient needs This article complementsa recent review that focuses on advances in MStherapy and predictions regarding treatment by2020 [3]

EPIDEMIOLOGY OF MULTIPLE SCLEROSIS

MS affects about 400 000 people in the UnitedStates and approximately 25 million people world-wide [1] The disease affects persons of all ages butsymptoms are most likely to appear in individuals20ndash50 years of age [4] The prevalence of MS inwomen is approximately two to three times thatin men [1]

SOCIETAL COST OF MULTIPLESCLEROSIS

It has been estimated that the total direct and indi-rect costs of MS in the United States is $28 billioneach year [4] A recent evaluation of healthcare costs

Volume 25 Supplement 1 February 2012

KEY POINTS

MS is a progressive disease associated with higheconomic and patient burden

Patients with MS have an unmet need for interventionsthat will support enhanced adherence and potentiallyimproved outcomes

Stopping or reversing disease progression remains animportant unmet need in patients with MS

Current approaches and unmet needs in MS Miller and Rhoades

for 1411 newly diagnosed patients with MS vs 7055healthy controls indicated that MS patients weresignificantly more likely to be hospitalized (152vs 43) have at least one emergency departmentvisit (255 vs 122) and at least one visit forphysical occupational or speech therapy (237 vs99) over a 1-year follow-up period The meanoverall annual cost of care for a patient with MSwas $18 829 vs 4038 for a healthy control individ-ual excluding MS treatment drugs [5

amp

]Both the direct and indirect costs of MS increase

dramatically as the disease progresses The annualcost for a patient with an Expanded DisabilityStatus Score (EDSS) of 02ndash25 was $5740 and therespective values for patients with scores of 30ndash5560ndash75 and 80ndash95 were $11 114 $26 365 and$46 366 respectively (Fig 1) [6] Another surveycarried out in the United States indicated that thetotal annual per patient cost of MS was $47 215 with53 attributed to direct medical and nonmedicalcosts 37 to production losses and 10 to infor-mal care [7]

The high productivity losses for patients withMS result in large measure from the very highunemployment rate in this group A cross-sectionaland longitudinal investigation of work loss in8867 patients with MS indicated that 56ndash58 of

002ndash25 30ndash55

Change in EDSS score

Annual costincrease (US$)

60ndash75 80ndash95

10 000

20 000

30 000

40 000

50 000

FIGURE 1 Cost of multiple sclerosis increases withExpanded Disability Status Score (Data from Ref [6])

1350-7540 2012 Wolters Kluwer Health | Lippincott Williams amp Wilk

them were not employed and that unemploymentwas associated with a progressive disease courselonger symptom duration and greater level of dis-ability Specific problems in mobility hand func-tion fatigue and cognitive performance were alsoassociated with increased risk for unemployment[8]

The high cost of MS has significant effects onpatients and their families A survey of 983 working-age patients with MS in the United States indicatedthat 164 had considerable difficulty paying forhealthcare 274 put off or postponed seekingneeded healthcare because of costs and 266reported considerable worries about affording suchbasic necessities as food utilities and housing [9]Results from another survey of 411 MS patientsindicated that 37 had experienced a decline intheir standard of living since being diagnosed withthe disease [10]

PATIENT BURDEN

The lesions of MS can occur in many parts of theCNS and result in a wide range of symptoms includ-ing fatigue visual impairment vertigo and sensoryimpairment [1112] MS may be a devastatingdisorder with progressive accumulations of motorsensory and cognitive disabilities and impairedquality of life (QOL) [13ndash18]

Interpersonal relationships and social function-ing are also greatly impaired in patients with MSResults from a cohort of 371 patients with RRMS orprogressive MS indicated that about one-fourth ofthose with relapsing-remitting disease and over 70of those with progressive disease were separated ordivorced following their diagnosis Both friendshipand other family relationships were also affected bythe disease [19] Loneliness is often a poorly recog-nized component of the experience of MS that mayresult from changes in social networks that occurduring the course of chronic illness A survey of 659women with MS indicated that more than 50 feltlonely and this was significantly associated withlow levels of social support increased socialdemands of illness higher functional limitationand lower perceived health status [20]

MS exacts significant physical psychologicaland economic tolls on patientsrsquo families and care-givers and this burden rises as the disease progressesand the patientsrsquo conditions worsen Caregivers mayspend as much as 35 h per day aiding patients withMS and this assistance is viewed as essential for 70of patients [2122] As the MS patientrsquos disease pro-gresses ability for self-care declines and the increas-ing requirement for daily assistance can take arising physical and economic toll on caregivers

ins wwwco-neurologycom S5

New goals in MS treatment

[23] Worsening MS in the patient has been shownto be correlated with declining physical and mentalhealth in the caregiver [24] The impact of MS oncaregiver QOL has been demonstrated in a survey of445 MS patients and their caregivers Care givingwas associated with significant reductions in mentalhealth vitality and general health scores for care-givers vs a normative control group Patient BeckDepression Inventory score was a significant predic-tor of almost all caregiver SF-36 dimension scoresand EDSS disease duration and course and patienttherapeutic characteristics also predicted declines insome dimensions of caregiver QOL [25] Resultsfrom another survey showed that the distress forcaregivers also increased with the emergence ofcognitive and psychiatric conditions in the patientin addition to decline in EDSSs [26]

Evidence also indicates that MS is associatedwith increased mortality and shortened lifespanResults from a cohort of 878 patients with MS indi-cated that median survival after diagnosis was 41 vs49 years for otherwise-matched patients withoutMS The standardized mortality ratio was increased27 fold in the MS patients vs the control individ-uals [27] A review of results from multiple studiesindicated that patients with MS lose 5ndash10 years oflife [28]

DISEASE-MODIFYING THERAPY FORMULTIPLE SCLEROSIS

At present no cure exists for MS and the goals oftreatment are to arrest or slow the progression ofdisability decrease relapse rate manage symptomsslow subclinical disease progression demonstratedby imaging techniques (eg MRI) and maintain orimprove QOL [29ndash31]

The most commonly used MS treatments areimmunomodulating agents interferon (IFN)-b-1aIFN-b-1b glatiramer acetate natalizumab and fin-golimod [32ndash34] These therapies have been dem-onstrated to have efficacy superior to placebo Asummary of prospective randomized head-to-headtrials assessing the comparative efficacy of IFNs andglatiramer acetate is shown in Table 1 [35ndash41]There have been no randomized trials to date thatcompared natalizumab or fingolimod with IFNs orglatiramer acetate

Freedman et al [33] reviewed the efficacy ofthese agents except fingolimod using combinedinformation from randomized placebo-controlleddouble-blind studies and provided informationabout endpoints that included proportion ofrelapse-free patients at 1 and 2 years annualizedrelapse rate at 2 years proportion of progression-freepatients at 2 years and proportion of patients free of

S6 wwwco-neurologycom

gadolinium-enhancing lesions at 1 year or 9 monthsThe results from this analysis support the efficacy ofall of these MS therapies Fingolimod was approvedafter the comparative analysis carried out byFreedman but it has been directly compared withintramuscular (im) IFN-b-1a in a 12-month double-blind double-dummy study The trial included 1292patients with RRMS who had a recent history of atleast one relapse during the previous year or at leasttwo documented relapses during the previous 2 yearsprior to entry Study results showed that the annual-ized relapse rate was significantly lower for fingoli-mod (020 for 125 mgday and 016 for 05 mgday)vs im IFN-b-1a (033 Plt0001) However therewere no significant differences among groups forprogression of disability as measured by EDSSs [34]Adverse events noted among patients receivingfingolimod were systemic herpesvirus infectionsmacular edema and hypertension

UNMET NEEDS IN PATIENTS WITHMULTIPLE SCLEROSIS

Although the agents described in the precedingsection have all been shown to decrease the riskfor relapse and slow disease progression in patientswith RRMS stopping or even reversing disabilityprogression remains an unmet need in manypatients [42ndash45] Further MS is a heterogeneousdisease and some patients may not respondadequately to treatment for reasons that remainto be elucidated [4647]

Adverse events associated with medical treat-ment can negatively impact adherence to therapyacross a wide range of chronic diseases and thisis also the case with MS Adverse events noted forIFN-bs include injection site reactions flu-likesymptoms and depression [48] The most commonsystemic adverse event observed in patients takingIFN-bs is flu-like symptoms These symptoms aremost common during the first few months of treat-ment They usually appear 2ndash6 h after injection andresolve within 24 h [49] Injection site reactions arerelatively common with all the agents delivered bysubcutaneous injection but occur less often for theIFN-b-1a preparation delivered via im injection[48] Liver function abnormalities have been notedin patients taking all IFN-bs and in patients receiv-ing fingolimod [4550] Results from one clinicaltrial indicated that im IFN-b-1a was associated witha significantly lower incidence of abnormal liverfunction test results than subcutaneous IFN-b-1a(9 vs 18 Pfrac140002) [36] Natalizumab is generallywell tolerated but is associated with a small riskfor the development of potentially fatal progres-sive multifocal leukoencephalopathy (PML) an


Table 1 Summary of prospective randomized head-to-head trials of disease-modifying therapies for RRMS

Author (study) Comparison and study duration Annualized relapse rate Relapse free ()Disease progression()

Change inEDSS (mean) Comments

Durelli et al [35](INCOMIN)

IFN b-1a im 30 mg QW (nfrac1492)vs IFN b-1b SC 250 mg EOD(nfrac1496) 24 months

07 vs 05 (Pfrac14003) 36 vs 51 (Pfrac14003) 30 vs 13 (Pfrac140005) 054 vs013 (Plt0004)

Unblinded for clinical outcomesMRI-blinded assessment

Panitch et al [36](EVIDENCE)

IFN b-1a im 30 mg QW (nfrac14338)vs IFN b-1a SC 44 mg TIW(nfrac14339) 48 weeks

065 vs 054(Pfrac14009)

52 vs 62 (Pfrac140009) 14 vs 13 (NS) ND Treating physicians and patientsunblinded to treatment evaluationphysicians and MRI examinersblinded to treatment and outcomes

Etemadifar et al[37]

IFN b-1a im 30 mg QW (nfrac1430)vs IFN b-1b SC 250 mg EOD(nfrac1430) vs IFN b-1a SC 44 mgTIW (nfrac1430) 24 months

12 vs 07 vs 06(Plt0001) for each vsbaseline

20 vs 43 vs 57(Plt005)

ND 01 (NS) vs07 (Plt005)vs 03 (Plt005)

Single center Evaluating physicianblinded patients unblinded totreatment allocation No MRI datareported

Koch-Henriksenet al [38](DMSSG)

IFN b-1a SC 22 mg QW (nfrac14143)vs IFN b-1b SC 250 mg EOD(nfrac14158) 24 months

070 vs 071 (NS) ND 25 vs 21 (NS) ND Physicians and patients unblindedMRI-blinded assessment IFN b-1adosage was 22 mg weeklyadministered SCa

OrsquoConnor et al[39] (BEYOND)

GA SC 20 mg QD (nfrac14448) vsIFN b-1b SC 250 mg EOD(nfrac14897) vs IFN b-1bSC 500 mg EOD (nfrac14899)24 months

034 vs 036 vs033 (NS)b

59 vs 58 vs60 (NS)b

21 vs 27 vs22 (NS)b

ND MRI favored both doses of IFN b-1bvs GA for change in T2 lesionvolume and cumulative new T2lesions (P005 for all)

Mikol et al [40](REGARD)

GA SC 20 mg QD (nfrac14378) vsIFN b-1a SC 44 mg TIW(nfrac14386) 96 weeks

029 vs 030 (NS) 62 vs 62 (NS) 87 vs117 (NS)

ND Physicians and patients unblinded totreatment evaluating physiciansand MRI evaluations blinded

Cadavid et al[41] (BECOME)

GA SC 20 mg QD (nfrac1439) vsIFN b-1b SC 250 mg EOD(nfrac1436) 24 months

033 vs 037 (NS) 72 vs 53 (P valuenot reported)

ND ND Physicians and patients unblindedto treatment

DMSSG Danish Multiple Sclerosis Study Group EDSS Expanded Disability Status Scale EOD every other day GA glatiramer acetate HR hazard ratio im intramuscular IFN interferon ND not determined NSnot significant QD once per day QW once per week SC subcutaneous TIW three times per weekaAt the time of this trial it was thought that IFN b-1a 22mg would have equivalent efficacy whether administered subcutaneously or intramuscularlybNot statistically significant for either IFN b-1b dose vs GA or for comparison of 250 vs 500-mg doses of IFN b-1b

Curre

ntapproachesandunmetneedsin

MS

Miller

andRhoades

1350-7

540

2012

Wolters

Kluw

erH

ealth|

LippincottWilliam

samp

Wilkins

ww

wco

-neu

rolo

gyco

mS7

0 100 200 300 400 500

Time to non-persistence (days)

600 700 800 900 1000

100

075

050

025

000

IM-IFNβ-1a SC-IFNβ-1a

FIGURE 2 KaplanndashMeier failure curve of nonpersistence inmultiple sclerosis patients receiving either intramascular IFN-b-1a or subcutaneous IFN-b1a [57amp] Reprinted from [57amp]with permission from Dove Medical Press Ltd


opportunistic infection of the brain from reactiva-tion of polyomavirus JC Although the risk of PMLwith natalizumab is a concern the ability to identifypatients at risk has advanced with the findings thatantibody to JC virus (JCV) and prior immunosup-pressive therapy are associated with a significantlyincreased risk for PML in patients receiving natali-zumab [51] A serologic test for antibody to JC viruscan identify patients who are seropositive and atelevated risk of PML [52] Risk of PML can be strati-fied by JCV antibody status and immunosuppressiveuse and quantified by duration of natalizumabexposure Current models estimated PML risks torange from 01 per 1000 for those JCV-antibodynegative with no prior immunosuppressive use to81 per 1000 in those JCV-antibody positive withprior immunosuppressive use and over 2 years ofnatalizumab exposure [53]

Women with MS who wish to become pregnantandor breastfeed also need options that will permitthem to stay on treatment and a need remains fortherapies that are approved for use during preg-nancy and during breastfeeding Fortunately therisk for relapses is decreased during pregnancybut is increased postpartum [54]

ADHERENCE TO DISEASE-MODIFYINGTHERAPIES IN PATIENTS WITH MULTIPLESCLEROSIS

A variety of different measures have been used toquantify how well a patient follows a prescribedtreatment regimen Adherence to therapy is definedas the percentage of prescribed medication takenand persistence is defined as continuing to takeprescribed drugs [55]

Failures of persistence with and adherence todisease-modifying therapy are both important prob-lems for patients with MS Results from one studyindicated that one-third of patients taking IFN-binterrupted treatment for more than 1 month over5 years of follow-up and that more than 9 discon-tinued within 6 months [56] Results from a morerecent study of 6680 MS patients receiving disease-modifying treatments indicated that those takingim IFN-b-1a possessed their medication for 77 ofthe days observed vs 70 for subcutaneous IFN-b-1b 72 for glatiramer acetate and 74 for subcu-taneous IFN-b-1a [57

amp

] Time to nonpersistence withim IFN-b-1a and subcutaneous IFN-b-1a is shownin Fig 2 The time for 50 of patients to stoptreatment was about 600 days after the indexprescription [57

amp

] Results from another study of358 patients with MS whose healthcare claims wereevaluated for 1 year indicated persistence rates of603 for im IFN-b-1a 429 for subcutaneous


IFN-b-1b 427 for glatiramer acetate and 45for subcutaneous IFN-b-1a [58]

Patients with MS cite many different reasonsfor discontinuing treatment The most commonreasons for interrupting therapy among patientstaking IFN-bs are perceived lack of efficacy (30)injection site reactions (12) flu-like symptoms(10) depression (9) headache (8) liver func-tion test abnormalities (7) and fatigue (6) [55]Requirement for injection has also been noted as abarrier to adherence in patients with MS takingdisease-modifying therapy [59]

There is no published information about adher-ence to treatment with either natalizumab or fingo-limod outside the setting of controlled clinical trialsHowever patients who discontinue natalizumabmay experience an aggressive return of diseaseactivity shortly after discontinuation that is believedto reflect immune system reconstitution [60]

Poor adherence to disease-modifying therapyfor MS patients is associated with both poorer treat-ment outcomes and increased cost of care Resultsfrom a retrospective cohort study of 1606 MSpatients indicated that those who were adherentto treatment (medication possession on 85 ofdays prescribed) had significantly lower risk forrelapses [risk ratiofrac14089 95 confidence interval(CI)frac14081ndash097] emergency department visits (riskratiofrac14078 95 CIfrac14061ndash099) and hospitaliz-ations (risk ratiofrac14079 95 CIfrac14065ndash098) vsnonadherent patients [61

ampamp

] Results from a secondstudy that included 2446 patients with MS pre-scribed disease-modifying therapy indicated that



596 were adherent to treatment (defined as pos-sessing medication on 80 of days prescribed)Adherent patients were significantly less likely thannonadherent patients to have MS-related hospital-ization [odds ratio (OR)frac14063 95 CIfrac14047ndash083]or MS relapses (ORfrac14071 95 CIfrac14059ndash085) Theaverage cost of care for the adherent patients was$3380 vs 4348 for those who were nonadherent(Pfrac140003) [62

ampamp

]

CONCLUSION

MS is a progressive and highly debilitating diseasethat results in high burdens for both individualpatients and society Current disease-modifyingtherapies for MS are effective for decreasing relapsesand slowing progression but a need for interven-tions that can completely arrest or even reverseprogressive disability in these patients remains

Clinicians should consider treatment goals andcarefully evaluate benefits of and patient adherenceto current therapy Goal assessment and individu-alization of therapy should include consideration ofcurrent disease activity and disability patient life-style and expected longevity patientrsquos preferencefor route of treatment administration patientrsquosability to self-treat or need for therapy to be deliv-ered by a healthcare professional and reproductivestatus and expectations

Acknowledgements

None

Conflicts of interest

AEM has received consulting fees from Acorda AvanirBiogen Idec BioMarin Chelsea Therapeutics DaiichiSankyo EMD Serono Glaxo Merck Serono NovartisNuron Biotech Ono LA-SER and Sanofi-aventis fees fornon-CMECE services directly from a commercial interestor their agents (eg speakersrsquo bureaus) from AcordaBiogen Idec EMD Serono Pfizer and Teva and con-tracted research support from Acorda Biogen IdecGenentech Genzyme Novartis Roche Sanofi-aventisand Teva RR has no conflict of interest

REFERENCES AND RECOMMENDEDREADINGPapers of particular interest published within the annual period of review havebeen highlighted as

amp of special interestampamp of outstanding interest

1 National Multiple Sclerosis Society Fact sheet multiple sclerosis (2011)httpwwwnationalmssocietyorgchaptersmnmmediacenterfactsheetmul-tiplesclerosisindexaspx [Accessed 13 February 2012]

2 Lublin FD Reingold SC Defining the clinical course of multiple sclerosisresults of an international survey National Multiple Sclerosis Society (USA)Advisory Committee on Clinical Trials of New Agents in Multiple SclerosisNeurology 1996 46907ndash911


3 Miller AE Multiple sclerosis where will we be in 2020 Mt Sinai J Med 201178268ndash279

4 Society for Neuroscience Multiple sclerosis (2011) httpwwwsfnorgskinsmainpdfbrssBRSS_Multiple_Sclerosispdf [Accessed 13 February2012]

5amp

Asche CV Singer ME Jhaveri M et al All-cause healthcare utilization andcosts associated with newly diagnosed multiple sclerosis in the UnitedStates J Manag Care Pharm 2010 16703ndash712

This retrospective cohort analysis of the Medstat MarketScan Commercial Claimsand Encounters database provides up-to-date information on the cost of MS in theUnited States6 Multiple Sclerosis Trend Report 2nd ed National Multiple Sclerosis Society

20117 Kobelt G Berg J Atherly D Hadjimichael O Costs and quality of life in

multiple sclerosis a cross-sectional study in the United States Neurology2006 661696ndash1702

8 Julian LJ Vella L Vollmer T et al Employment in multiple sclerosis Exiting andre-entering the work force J Neurol 2008 2551354ndash1360

9 Iezzoni LI Ngo L Health disability and life insurance experiences of working-age persons with multiple sclerosis Mult Scler 2007 13534ndash546

10 Hakim EA Bakheit AM Bryant TNet alThe social impact of multiple sclerosis astudy of 305 patients and their relatives Disabil Rehabil 2000 22288ndash293

11 National Institute of Neurological Disorders and Stroke Multiple sclerosishope through research (2011) httpwwwnindsnihgovdisordersmulti-ple_sclerosisdetail_multiple_sclerosishtm [Accessed 13 February 2012]

12 Miller D Barkhof F Montalban X et al Clinically isolated syndromes sugges-tive of multiple sclerosis part I natural history pathogenesis diagnosis andprognosis Lancet Neurol 2005 4281ndash288

13 Sanchez MP Nieto A Barroso J et al Brain atrophy as a marker of cognitiveimpairment in mildly disabling relapsing-remitting multiple sclerosis Eur JNeurol 2008 151091ndash1099

14 Prakash RS Snook EM Lewis JM et al Cognitive impairments in relapsing-remitting multiple sclerosis a meta-analysis Mult Scler 2008 141250ndash1261

15 Yozbatiran N Baskurt F Baskurt Z et al Motor assessment of upper extremityfunction and its relation with fatigue cognitive function and quality of life inmultiple sclerosis patients J Neurol Sci 2006 246117ndash122

16 Mansson E Lexell J Performance of activities of daily living in multiplesclerosis Disabil Rehabil 2004 26576ndash585

17 Rougier P Faucher M Cantalloube S et al How proprioceptive impairmentsaffect quiet standing in patients with multiple sclerosis Somatosens Mot Res2007 2441ndash51

18 Achiron A Barak Y Rotstein Z Longitudinal disability curves for predicting thecourse of relapsing-remitting multiple sclerosis Mult Scler 2003 9486ndash491

19 Morales-Gonzales JM Benito-Leon J Rivera-Navarro J et al A systematicapproach to analyse health-related quality of life in multiple sclerosis theGEDMA study Mult Scler 2004 1047ndash54

20 Beal CC Stuifbergen A Loneliness in women with multiple sclerosis RehabilNurs 2007 32165ndash171

21 Finlayson M Cho C A descriptive profile of caregivers of older adults withMS and the assistance they provide Disabil Rehabil 2008 301848ndash1857

22 OrsquoHara L De Souza L Ide L The nature of care giving in a community sampleof people with multiple sclerosis Disabil Rehabil 2004 261401ndash1410

23 Buhse M Assessment of caregiver burden in families of persons with multiplesclerosis J Neurosci Nurs 2008 4025ndash31

24 Forbes A While A Mathes L Informal carer activities carer burden and healthstatus in multiple sclerosis Clin Rehabil 2007 21563ndash575

25 Patti F Amato MP Battaglia MA et al Caregiver quality of life in multiplesclerosis a multicentre Italian study Mult Scler 2007 13412ndash419

26 Figved N Myhr KM Larsen JP Aarsland D Caregiver burden in multiplesclerosis the impact of neuropsychiatric symptoms J Neurol NeurosurgPsychiatry 2007 781097ndash1102

27 Grytten Torkildsen N Lie SA Aarseth JH et al Survival and cause of death inmultiple sclerosis results from a 50-year follow-up in Western Norway MultScler 2008 141191ndash1198

28 Ragonese P Aridon P Salemi G et al Mortality in multiple sclerosis a reviewEur J Neurol 2008 15123ndash127

29 Goodin DS Frohman EM Garmany GP Jr et al Disease modifying therapiesin multiple sclerosis report of the Therapeutics and Technology Assessmentof Subcommittee of the American Academy of Neurology and the MS Councilfor Clinical Practice Guidelines Neurology 2002 58169ndash178

30 Becker CC Gidal BE Fleming JO Immunotherapy in multiple sclerosis part1 Am J Health Syst Pharm 1995 521985ndash2000

31 Crayton H Heyman RA Rossman HS A multimodal approach to managingthe symptoms of multiple sclerosis Neurology 2004 63 (Suppl 5)S12ndashS18

32 Wingerchuk DM Current evidence and therapeutic strategies for multiplesclerosis Semin Neurol 2008 2856ndash68

33 Freedman MS Hughes B Mikol DD et al Efficacy of disease-modifyingtherapies in relapsing remitting multiple sclerosis a systematic comparisonEur Neurol 2008 601ndash11

34 Cohen JA Barkhof F Comi G et al Oral fingolimod or intramuscular interferonfor relapsing multiple sclerosis N Engl J Med 2010 362402ndash415



35 Durelli L Verdun E Barbero P et al Every-other-day interferon beta-1b vs once-weekly interferon beta-1a for multiple sclerosis results of a 2-year prospectiverandomised multicentre study (INCOMIN) Lancet 2002 3591453ndash1460

36 Panitch H Goodin DS Francis G et al Randomized comparative study ofinterferon-1a treatment regimens in MS the EVIDENCE Trial Neurology2002 591496ndash1506

37 Etemadifar M Janghorbani M Shaygannejad V Comparison of BetaferonAvonex and Rebif in treatment of relapsing-remitting multiple sclerosis ActaNeurol Scand 2006 113283ndash287

38 Koch-Henriksen N Soslashrensen PS Christensen T et al A randomized study oftwo interferon-beta treatments in relapsing-remitting multiple sclerosis Neu-rology 2006 661056ndash1060

39 OrsquoConnor P Filippi M Arnason B et al 250 g or 500 g interferon beta-1b vs20 mg glatiramer acetate in relapsing-remitting multiple sclerosis a prospec-tive randomised multicentre study Lancet Neurol 2009 8889ndash897

40 Mikol DD Barkof F Chang P et al Comparison of subcutaneous interferonbeta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (theREbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study) amulticentre randomised parallel open-label trial Lancet Neurol 2008 7903ndash914

41 Cadavid D Wolansky LJ Skurnick J et al Efficacy of treatment of MS withIFNb-1b or glatiramer acetate by monthly brain MRI in the BECOME studyNeurology 2009 721976ndash1983

42 Polman CH OrsquoConnor PW Havrdova E et al A randomized placebo-controlled trial of natalizumab for relapsing multiple sclerosis N Engl JMed 2006 354899ndash910

43 Sorensen PS The gap between effect of drugs and effectiveness of treat-ments J Neurol Sci 2007 259128ndash132

44 Goodin DS Biermann LD Bohlega S et al Integrating an evidence-basedassessment of benefit and risk in disease-modifying treatment of multiplesclerosis Curr Med Res Opin 2007 232823ndash2832

45 Kappos L Radue EW OrsquoConnor P et al A placebo-controlled trial of oralfingolimod in relapsing multiple sclerosis N Engl J Med 2010 362387ndash401

46 Cohen BA Khan O Jeffery DR et al Identifying and treating patients withsuboptimal responses Neurology 2004 63 (12 Suppl 6)S33ndashS40

47 Coyle PK Switching algorithms from one immunomodulatory agent toanother J Neurol 2008 255 (Suppl 1)44ndash50

48 Singer B Lucas S Kresa-Reahl K et al Optimizing adherence to multiplesclerosis therapies Managing tolerability and monitoring safety Int J MS Care2008 10113ndash126

49 Langer-Gould A Moses HH Murray TJ Strategies for managing the sideeffects of treatments for multiple sclerosis Neurology 2004 63 (Suppl 5)S35ndashS41

50 Tremlett HL Yoshida EM Oger J Liver injury associated with the beta-interferons for MS a comparison between the three products Neurology2004 62628ndash631


51 Hellwig K Gold R Progressive multifocal leukoencephalopathy and natali-zumab J Neurol 2011 2581920ndash1928

52 Gorelick L Lerner M Bixler S et al Anti-JC virus antibodies implications forPML risk stratification Ann Neurol 2010 68295ndash303

53 Sandrock A Hotemans C Richman S et al Risk stratification for progressivemultifocal leukoencephalopathy (PML) in MS patients role of prior immuno-suppressant use natalizumab-treatment duration and anti-JVC antibodystatus In American Academy of Neurology (AAN) 63rd Annual Meeting9ndash16 April 2011 Honolulu Hawaii Abstract P03248

54 NationalMultipleSclerosisSocietyPregnancyand reproductive issues (2011)httpwwwnationalmssocietyorgliving-with-multiple-sclerosishealthy-livingpregnancyindexaspx [Accessed 13 February 2012]

55 Clowes JA Peel NF Eastell R The impact of monitoring on adherenceand persistence with antiresorptive treatment for postmenopausal osteoporo-sis a randomized controlled trial J Clin Endocrinol Metab 2004 891117ndash1123

56 Tremlett HL Oger J Interrupted therapy stopping and switching of the beta-interferons prescribed for MS Neurology 2003 61551ndash554

57amp

Halpern R Agarwal S Dembek C et al Comparison of adherence andpersistence among multiple sclerosis patients treated with disease-modifyingtherapies a retrospective administrative claims analysis Patient Prefer Ad-herence 2011 573ndash84

This article summarizes adherence and persistence to disease-modifying treat-ments among patients with MS and identifies beneficial outcomes associated withbetter adherence58 Kleinman NL Beren IA Rajagopalan K Brook RA Medication adherence with

disease modifying treatments for multiple sclerosis among US employees JMed Econ 2010 13633ndash640

59 Turner AP Williams RM Sloan AP Haselkorn JK Injection anxiety remains along-term barrier to medication adherence in multiple sclerosis RehabilPsychol 2009 54116ndash121

60 Miravalle A Jensen R Kinkel RP Immune reconstitution inflammatory syn-drome in patients with multiple sclerosis following cessation of natalizumabtherapy Arch Neurol 2011 68186ndash191

61ampamp

Steinberg SC Faris RJ Chang CF et al Impact of adherence to interferons inthe treatment of multiple sclerosis a nonexperimental retrospective cohortstudy Clin Drug Investig 2010 3089ndash100

A retrospective cohort study showing that poor adherence to interferon treatmentincreases the risk for relapses and results in greater healthcare resource utilizationin patients with RRMS62ampamp

Tan H Cai Q Agarwal S et al Impact of adherence to disease-modifyingtherapies on clinical and economic outcomes among patients with multiplesclerosis Adv Ther 2011 2851ndash61

This claims analysis showed that adherence is associated with better clinical andeconomic outcomes including lower risks for MS-related hospitalization MSrelapse and less MS-related medical cost


REVIEW

CURRENTOPINION New treatments and treatment goals for patients


1350-7540 2012 Wolters Kluwer

a b


Purpose of review

The aims of this article are to review emerging therapies for multiple sclerosis (MS) and to consider newapproaches to assessment and achievement of treatment success in patients with this disease

Recent findings

A number of disease-modifying therapies for MS including oral agents are in advanced development andlikely to be available soon Fingolimod has been approved recently by the US Food and DrugAdministration Agents in development include alemtuzumab BG-12 daclizumab teriflunomidelaquinimod and B-cell-targeted monoclonal antibodies ocrelizumab and ofatumumab The advent ofemerging efficacious therapies has set the stage for re-evaluation of treatment goals for patients with MSFreedom from disease defined by the absence of relapses disability progression and radiologic evidenceof disease activity is increasingly seen as the measure of treatment success

Summary

New MS treatments may provide the basis for aggressive early intervention in patients with MS andintensification of treatment when disease is not controlled The availability of therapies that can achievehigher treatment goals may significantly improve long-term outcomes for MS patients

Keywords

alemtuzumab BG-12 daclizumab fingolimod freedom from disease laquinimod multiple sclerosisocrelizumab ofatumumab teriflunomide

aMultiple Sclerosis Clinic of Central Texas University of Texas MedicalBranch Round Rock Texas and bSteamboat Springs Colorado USA

Correspondence to Dr Edward Fox Multiple Sclerosis Clinic of CentralTexas University of Texas Medical Branch 16040 Park Valley Dr BuildingB Suite 100 Round Rock TX 78681 USA Tel +1 512 218 1222 fax+1 512 218 1393 e-mail foxtexmsgmailcom


INTRODUCTION

Patients with relapsing-remitting multiple sclerosis(RRMS) most often receive disease-modifyingtherapy with interferon (IFN)-b or glatiramer acetate[1] These agents are relatively safe and welltolerated and their efficacy is supported by resultsfrom large randomized controlled clinical trials [1]Relapses and disability progression may still occur inpatients receiving disease-modifying therapy andthere is an unmet need for new treatment altern-atives with the potential to improve outcomes inpatients with RRMS [1] The need for new therapiesis underscored by the need to lsquoraise the barrsquo fortreatment success in patients with RRMS Untilrecently treatments for RRMS were consideredeffective if they partially decreased the annualrelapse rate (ARR) and slowed the accumulationof physical disability on the Expanded DisabilityStatus Scale (EDSS) score and this is reflectedin the indication for all currently available MStherapies [1] Advances in MS therapies shouldnot only delay progression but provide freedomfrom disease which has been defined as freedomfrom gadolinium-enhancing T1 or new T2 lesions

Health | Lippincott Williams amp Wilk

detected by MRI freedom from relapses and theabsence of disability progression [2]

Recently approved or investigational agentsin advanced development have the potential tosignificantly improve outcomes for patients withRRMS This review summarizes results from clinicalstudies of these medications and considers theirpotential place in clinical practice

NEW DISEASE MODIFYING AGENTS FORMULTIPLE SCLEROSIS

Several agents for disease modification in MS are inadvanced development and may soon be availableAdditionally agents previously approved for other

ins wwwco-neurologycom

KEY POINTS

Freedom from disease (absence of relapses disabilityprogression and radiologic evidence of diseaseactivity) is increasingly seen as the measure oftreatment success

A number of new disease-modifying agents for MS inadvanced development have set the stage forredefinition of therapy goals

Agents in development include alemtuzumab BG-12daclizumab teriflunomide laquinimod and B-cell-targeted monoclonal antibodies ocrelizumaband ofatumumab

Although potentially providing improved efficacysome new treatments for MS may require carefulconsideration in patient selection and monitoring

Early intervention with the best available therapy and ahigh standard for treatment success has the potential tosignificantly improve long-term outcomes for MS patients


indications are being evaluated for safety andefficacy in MS

Fingolimod

Fingolimod is an oral sphingosine 1-phosphate(S1P) receptor modulator approved for the treat-ment of MS in 2010 in North America and 2011in Europe It is phosphorylated by sphingosinekinase to the active form which binds with highaffinity to S1P receptors (S1PR) of which five sub-types are present on various cells and tissues [3]Binding of phosphorylated fingolimod results ininternalization and degradation of the receptorand downregulation of S1PR mRNA With the result-ing decrease in S1PR on the cell surface lymphocyteegress from lymphoid tissues into the peripheryis inhibited [4] This action is associated withdecreased lymphocyte levels in the blood andcerebrospinal fluid (CSF) and reduced risk for inflam-matory events characteristic of MS pathogenesis[5] Fingolimod significantly reduces progression ofexperimental autoimmune encephalomyelitis (EAE)in experimental models but effectiveness is lost inmice with S1PR defects in S1P1 and S1P5 [67] Thepleiotropic influencesof S1Preceptors in the immuneand central nervous systems may be attributable to acombination of anti-inflammatory and neuroprotec-tive effects

Efficacy

Phase 3 clinical trial results with fingolimod havedemonstrated efficacy in patients with RRMS


The 12-month double-blind TRANSFORMS studyrandomized 1292 patients with RRMS and ahistory of at least one relapse to oral fingolimod(05 or 125 mgday) or intramuscular (im) IFN-b-1a (30 mgweek) The ARR was 016 for 05 mgdayfingolimod 020 for 125 mgday fingolimod and033 for IFN-b-1a (Plt0001 for each fingolimoddose vs IFN-b-1a) Patients in the fingolimod groupshad significantly fewer new or enlarged hyperin-tense T2 lesions and gadolinium-enhancing T1lesions at 12 months compared with those whoreceived IFN-b-1a (all Plt005) There were no sig-nificant differences among groups with respect toEDSS scores [8

amp

] A 1-year extension of TRANS-FORMS compared patients randomized to 05 or125 mg daily fingolimod who remained on theseregimens with those who received IFN-b-1a in thecore study and were randomized to one of the twofingolimod doses in the extension phase Duringthis period investigators knew that participantswere receiving fingolimod but doses remainedblinded Results showed the sustained efficacy offingolimod for the study outcome measures [9]Patients switched from IFN-b-1a to 05 mgdayfingolimod had a reduction in ARR (from 031 to022 Pfrac140049) and those switched to fingolimod125 mgday also had a significant decrease in ARR(from 029 to 018 Pfrac140024) After switchingto fingolimod numbers of new or newly enlargingT2 and gadolinium-enhancing T1 lesions were sig-nificantly decreased compared with the previous12 months of IFN-b-1a therapy (Plt00001 for T2lesions at both doses Pfrac140002 for T1 lesions for05 mgday fingolimod and Pfrac140011 for T1 gadoli-nium-enhancing lesions with 125 mgday fingoli-mod) [9]

The phase 3 FREEDOMS trial was a 24-monthdouble-blind randomized study that included 1272patients with EDSS scores of 0ndash55 and at least onerelapse in the previous year or at least two relapses inthe previous 2 years [10] Patients were randomizedto 05 mgday fingolimod 125 mgday fingolimodor placebo The ARR was 018 for 05 mgday fingo-limod 016 for 125 mgday fingolimod and 040for placebo (Plt0001 for each dose vs placebo)Fingolimod also decreased the risk for disabilityprogression [hazard ratiofrac14070 95 confidenceinterval (CI)frac14052ndash096) for 05 mgday fingolimodand (hazard ratiofrac14068 95 CIfrac14050ndash093) for125 mgday fingolimod vs placebo respectivelyBoth fingolimod doses were associated with a sig-nificant decrease in the number of new or enlargedT2 lesions the number of gadolinium-enhancinglesions change in volume of hypointense T1lesions and brain-volume loss (Plt0001 for allcomparisons at 24 months) [10]


New treatments for patients with RRMS Fox and Rhoades

Safety

In the placebo-controlled phase 3 trial lowerrespiratory tract infections were more common withfingolimod than with placebo (96ndash114 for fin-golimod compared with 6 for placebo) [10] Sevenpatients receiving fingolimod 125 mg were diag-nosed with macular edema Increases in alanineaminotransferase occurred in 85ndash125 of patientsin the fingolimod treatment group compared with17 in the placebo group but returned to thenormal range [10] In the TRANSFORMS trial her-pesvirus infections were diagnosed in 23 patients inthe 125 mgday group (55) nine patients in the05 mgday group (21) and 12 patients in theplacebo group (28) There were two deaths inpatients treated with 125 mgday fingolimod onedue to disseminated primary varicella zoster infec-tion and the other from herpes simplex encephalitis[8

amp

]

Alemtuzumab

Alemtuzumab is a humanized monoclonal antibodyagainst CD52 a glycoprotein antigen found on thesurface of mature lymphocytes and monocytesCD52 is absent from platelets erythroid andmyeloid cells and hematopoietic stem cells Intransgenic mice expressing human CD52 alemtu-zumab depletes peripheral blood lymphocytes witha lesser effect in lymphoid organs [11] Alemtuzu-mab has also been shown to induce production ofneurotrophic factors in reconstituted autoreactiveT cells [12]

Efficacy

Alemtuzumab was studied in CAMMS223 a 3-yearphase 2 rater-blinded trial CAMMS223 included334 patients with RRMS disease duration 3 yearsor less and EDSS 3 or less who were randomizedto subcutaneous (SC) IFN-b-1a (44 mg three timesper week) or annual intravenous (iv) cycles ofalemtuzumab (12 or 24 mgday) for 36 months[13] Alemtuzumab was administered over 5 con-secutive days at the onset and for 3 days at months12 and 24 Only two courses of alemtuzumab wereadministered to most patients due to a hold ondosing detailed below Alemtuzumab was associatedwith a significantly reduced rate of sustained dis-ability accumulation vs IFN-b-1a (90 vs 262Plt0001) The mean EDSS score improved by039 point with alemtuzumab and worsened by038 point with IFN-b-1a (Plt0001) Alemtuzumabsignificantly decreased the ARR (010 vs 036Plt0001) and significantly decreased T2 lesionburden vs IFN-b-1a (Pfrac140005) [13] In a planned


post-hoc analysis significantly more patientsrandomized to alemtuzumab achieved sustainedreduction in disability compared with those receiv-ing IFN-b-1a (hazard ratiofrac14261 95 CIfrac1415ndash44Pfrac1400004) [14] Among patients with no clinicaldisease activity 3 months before treatment or anyclinical or radiologic disease during the trial dis-ability improved after receiving alemtuzumab butnot IFN-b-1a These results suggest that theimprovement in disability seen in the trial wasnot entirely a result of inflammation suppression[12]

Two phase 3 trials of alemtuzumab are ongoing[CARE-MS I (NCT00530348) and CARE-MS II(NCT00548405)] CARE-MS I is a phase 3 compari-son of iv alemtuzumab (12 mgday for 5 daysinitially and for 3 days a year after) vs subcutaneousIFN-b-1a (44 mg three times per week) in 581 patientswith RRMS who had not received prior disease-modifying therapy Results from this study showedthat alemtuzumab treatment resulted in a 55reduction in relapse rate vs IFN-b-1a over 2 years(Plt00001) At 2 years 8 of patients who receivedalemtuzumab and 11 of those treated with IFN-b-1a had a sustained increase in EDSS scores (Pfrac14022)[15]

CARE-MS II is currently comparing alemtuzu-mab with IFN-b-1a subcutaneous in patients withRRMS who relapsed on prior therapy The initialanalysis of results in 840 patients showed a 49reduction in relapse rate in patients receiving alem-tuzumab 12 mg compared with IFN-b-1a subcu-taneous (Plt00001) [16] The coprimary endpointshowed a 42 reduction in the risk of sustaineddisability measured by EDSS (Pfrac140008)

Safety

In the CAMMS223 trial adverse events in the alem-tuzumab vs IFN-b-1a subcutaneous groups includedthyroid disorders (23 vs 3) immune thrombocy-topenic purpura (ITP) (3 vs 1) and infections(66 vs 47) [13] In September 2005 the data andsafety monitoring board (DSMB) recommended sus-pension of the alemtuzumab arm after threepatients developed ITP one of whom died Safetyand efficacy assessments proceeded during thesuspension and those randomized to IFN-b-1a sub-cutaneous continued treatment A program wasestablished for the effective identification andmanagement of ITP and the DSMB lifted the alem-tuzumab dosing suspension in May 2007 [13]

In CARE MS-1 no patient receiving alemtuzu-mab withdrew from the trial due to an adverseevent Eighteen percent of alemtuzumab-treatedpatients developed an autoimmune thyroid-related



adverse event and 08 developed ITP during the2 year study [15] Infections were reported morefrequently in alemtuzumab-treated patients than inpatients receiving IFN-b-1a subcutaneous-treatedpatients (67 vs 46) Infusion associated reactionswere common in alemtuzumab-treated patientsbut were typically controlled with concomitantmedications

There is evidence that the autoimmunityobserved in MS patients receiving alemtuzumabmay be driven by interleukin (IL)-21 Patients whodeveloped secondary autoimmunity during treat-ment with alemtuzumab in the CAMMS223 studyhad more than two-fold greater levels of serum IL-21at baseline than those who did not Assessment ofIL-21 may serve as a biomarker to help identify thoseat higher risk of developing autoimmunity [17]

BG-12 (Dimethyl Fumarate)

BG-12 is a fumaric acid ester with immunomodula-tory properties BG-12 has demonstrated benefits inanimal models of EAE Fumaric acid esters maydecrease leukocyte passage through the bloodndashbrainbarrier and exert neuroprotective properties by theactivation of antioxidative pathways [18]

Efficacy

DEFINE was a phase 3 randomized double-blindplacebo-controlled dose-comparison study of BG-12in 1234 patients [19] Patients with RRMS wererandomized to BG-12 at a dose of either 240 mg twicea day or 240 mg three times a day or to placebo BothBG-12 doses were associated with a significantdecrease in the proportion of patients who relapsedat 2 years compared with placebo (Plt00001) BothBG-12 doses were significantly superior to placebo inreducing ARR the number of new or newly enlargingT2 hyperintense lesions and the number of newgadolinium-enhancing lesions BG-12 was alsosuperior to placebo in slowing the rate of disabilityprogression as measured by EDSS scores at 2 years[19] The reduction in 12-week disability progressionwas 38 and 34 for the twice and three-times dailydoses respectively (Plt005 for both)

Safety

DEFINE results indicated that BG-12 had a safetyprofile comparable to that for placebo [19] Resultsfrom a phase 2b study of BG-12 (120 or 240 mgthree times per day) in 257 patients with RRMSindicated that adverse events occurring more oftenwith BG-12 vs placebo were abdominal pain flush-ing and hot flush [20] Dosing interruptions wereallowed for abnormal results of liver or renal


function tests or lymphopenia and treatment wasdiscontinued in patients with abnormalities persist-ing for 4 weeks Adverse events led to discontinu-ation in 8 11 and 13 of those receiving BG-12doses of 120 mg once daily 120 mg three timesdaily and 240 mg three times daily respectivelyEvents leading to discontinuation included flush-ing elevated alanine aminotransferase nauseadiarrhea and vomiting There was no increased riskof infection associated with BG-12 use

Laquinimod

Laquinimod is an immunomodulator with efficacyin MS Although its mechanism of action is notfully understood laquinimod has been shown topromote anti-inflammatory cytokine profiles inhuman peripheral blood mononuclear cells InEAE models laquinimod effectively reduced inflam-mation demyelination and axonal damage [21]

Efficacy

Laquinimod has been evaluated in the phase 3ALLEGRO trial a 2-year randomized double-blindplacebo-controlled study that included 1106patients with RRMS who were randomized to receive06 mg laquinimod once daily or placebo Theprimary outcome measure was the number ofconfirmed relapses Laquinimod treatment resultedin a 23 reduction in ARR vs placebo (Pfrac1400024)and a 36 decrease in the risk for disability pro-gression as measured by EDSS (Pfrac1400122) Treat-ment with laquinimod was also associated with a33 reduction in progression of brain atrophy vsplacebo (Plt00001) [22]

A second phase 3 study of laquinimod theBRAVO trial is comparing 06 mg laquinimod oncedaily with placebo in patients with RRMS The top-line results of BRAVO showed that the primaryendpoint of reducing ARR was not reached(Pfrac140075) Despite randomization the laquinimodand placebo groups had dissimilar baseline MRIcharacteristics After a preplanned sensitivityanalysis adjusting for baseline MRI laquinimodwas associated with a statistically significantreduction of ARR (213) of risk of disability pro-gression on EDSS (335) and of brain volume loss(275) compared with placebo (all Plt005) [23]

Safety

In ALLEGRO serious adverse events occurredin 222 of laquinimod patients and 162 ofplacebo patients Herpesvirus infection occurredin 17 patients who received laquinimod vs20 patients on placebo with cancers detected ineight vs six patients respectively The most



common adverse event that occurred more oftenwith laquinimod vs placebo was elevation inalanine transaminase (69 with laquinimod vs27 for placebo elevations were more than threetimes the upper limit of normal in 49 and 2 ofthe laquinimod and placebo groups respectively)Transaminase elevations which were transitoryresulted in discontinuation in 13 patients receivinglaquinimod and seven on placebo [22]

Teriflunomide

Teriflunomide is an oral reversible inhibitor of dihy-droorotate dehydrogenase (DHODH) a mitochon-drial membrane protein essential for pyrimidinesynthesis [24] DHODH blocks de-novo pyrimidinesynthesis leading to an inhibition of the prolifer-ation of autoreactive B and T cells In the presenceof teriflunomide replication of hematopoietic andmemory cells is preserved through metabolism ofthe existing pyrimidine pool Teriflunomide hasbeen shown to have additional activities includingmodulation of immunoglobulin class switching IL-2production and IL-2 receptor expression [25]

Efficacy

Teriflunomide (7 or 14 mgday) was compared withplacebo in a 36-week phase 2 trial in 157 patientswith RRMS and 22 patients with secondary progress-ive MS still experiencing relapses The mean valuesfor the primary endpoint of combined unique activelesions per MRI scan were 05 02 and 03 respect-ively for placebo 7 mgday teriflunomide (Plt003vs placebo) and 14 mgday teriflunomide (Plt001vs placebo) Patients who received teriflunomidealso had significantly fewer T1-enhancing lesionsor new or enlarging T2 lesions than those treatedwith placebo (Plt005 all comparisons) Patientsreceiving teriflunomide 14 mgday had significantlyreduced T2 disease burden The proportion ofpatients with increased disability by EDSS at 36 weekswas significantly lower with teriflunomide comparedwith placebo (74 vs 213 Plt004) a relativereduction of 69 [26] Two phase 2 studies evaluatedteriflunomide as adjunctive therapy in persons withMS [2728] In these studies patients receiving glatir-amer acetate (nfrac14120) or a b-IFN (nfrac14116) wererandomized to add placebo or teriflunomide 7 or14 mg daily to their current therapy In both studiesteriflunomide had good safety and tolerability andboth doses were associated with improved diseasecontrol according to reduced number and volumeof T1 gadolinium-enhancing lesions comparedwith placebo

Results from the phase 3 TEMSO study demon-strated significant reduction in ARR and disability


progression with teriflunomide compared withplacebo TEMSO evaluated 1088 patients with relaps-ing forms of MS EDSS scores at least 55 and at leastone relapse in the previous year or at least two relap-ses in the preceding 2 years Patients were random-ized to teriflunomide 7 or 14 mgday or placebo Theadjusted ARRs with teriflunomide 7 and 14 mgdaywere 0370 and 0369 respectively compared with0539 for placebo (Plt0001 for both comparisons)[29] Time to first relapse was increased 244 and281 for the 7 and 14-mg doses compared withplacebo respectively (P001 for both compari-sons) The 14-mgday dose of teriflunomide wasassociated with a 298 reduction in the risk ofsustained disability progression (Pfrac140028)

A key prespecified endpoint of TEMSO was T2burden of disease by MRI Teriflunomide 7 mgdayresulted in a 394 reduction in T2 disease burdenvs placebo (Pfrac14003) and teriflunomide 14 mgdayresulted in a 674 reduction (Plt0001 vsplacebo) The numbers of gadolinium-enhancingT1 lesions and unique active lesions per scan werealso reduced with both teriflunomide doses vsplacebo (Plt0001 for all comparisons) [30]

Teriflunomide is also being evaluated as anadjunctive therapy in combination with IFN-b inthe phase 3 TERACLES study with estimated com-pletion in 2014 Two additional studies are under-way TOWER and TENERE are monotherapy studiescomparing teriflunomide with placebo and IFN-b-1asubcutaneous respectively [31] TOPIC is an ongo-ing phase 3 trial evaluating the efficacy and safety ofonce daily teriflunomide vs placebo in patientswith clinically isolated syndrome [32]

Safety

In the phase 2 study serious adverse events werereported in 19 patients (seven placebo five terifluno-mide 7 mgday and seven teriflunomide 14 mgday)These included elevated hepatic enzymes hepaticdysfunction neutropenia rhabdomyolysis and tri-geminal neuralgia Adverse events that appeared tooccur more often with teriflunomide than placeboincluded nausea paresthesia limb pain diarrheaand arthralgia [26] Teriflunomide was generally welltolerated in the TEMSO trial Adverse events occur-ring at a higher rate in the teriflunomide groups vsplacebo were diarrhea nausea and alanine transfer-ase increases No serious opportunistic infectionsoccurred in patients treated with teriflunomide [26]

B cell depletion

Several treatments are in development for thetherapy of MS that target B cells This therapeuticstrategy is supported by observations that activated



B cells and plasma cells accumulate in MS lesionsand in the CSF of patients with MS B cells maycontribute to MS pathology by production of anti-myelin autoantibodies and by regulating T cellresponses via antigen presentation cytokine releaseand induction of regulatory T cells [33]

Rituximab

Rituximab is a chimeric monoclonal antibody thatdepletes CD20-positive B cells through cell-mediatedand complement-dependent cytotoxic effects andpromotion of apoptosis In a phase II trial in patientswith RRMS rituximab treatment resulted in signifi-cantly decreased numbers of gadolinium-enhancinglesions vs placebo (91 Plt0001) as well as asignificantly decreased risk for relapse (203 vs400 Pfrac14004) [34] Rituximab was associated withinfusion-related reactions and moderately increasedrisk of progressive multifocal leukoencephalopathy(PML) in patients receiving this agent for approvedindications Owing to an impending patent expira-tion and efficacy and safety concerns for use of ritux-imab in patients with MS no phase 3 development ofrituximab in MS is ongoing

Ocrelizumab

Ocrelizumab is a humanized anti-CD20 monoclonalantibody that results in B cell depletion It has beenevaluated in a 48-week phase 2 study that included220 patients with RRMS who were randomized totreatment with iv ocrelizumab (600 or 2000 mgfor the first 24 weeks and 1000 mg for the second24 weeks) im IFN-b-1a (30 mg once weekly)or placebo The mean number of gadolinium-enhancing lesions was reduced by 89 in the low-dose and 96 with high-dose group compared toplacebo At the end of 48 weeks of treatment 80 ofthe patients who received the 600-mg dose and727 of those who received the 20001000-mgdose were relapse-free One patient on ocrelizumabdied at 14 weeks due to brain edema after the occur-rence of a systemic inflammatory response syn-drome No opportunistic infections were reported[35] Phase 3 studies of ocrelizumab for rheumatoidarthritis and lupus were suspended when the respect-ive DSMBs decided the risks outweighed the benefitsin these patient populations [36]

Ocrelizumab is also being evaluated in ORA-TORIO a 120-week phase 3 double-blind random-ized placebo-controlled trial in patients withprimary progressive MS [37] This trial consistsof five treatment cycles of iv ocrelizumab600 mg The primary outcome measure is time toonset of sustained disability progression [34] Twolarge global studies will compare ocrelizumab with


IFN-b-1a subcutaneous (OPERA I and II) in patientswith RRMS [38] These phase 3 double-blinddouble-dummy trials will assess efficacy and safetyin patients randomized to ocrelizumab 600 mg ivevery 24 weeks or IFN-b-1a subcutaneous threetimes weekly Enrollment (Nfrac14800) is projected tobe completed in 2012 with data reported in 2014

Ofatumumab

Ofatumumab is a third anti-CD20 antibody beingdeveloped for the treatment of MS A 24-week phase2 safety and pharmacokinetics study in 38 patientswith RRMS indicated no dose-limiting toxicities andno unexpected safety findings Active treatment alsoresulted in significant reductions in the number ofgadolinium-enhancing T1 lesions and newenlarg-ing T2 lesions in patients treated with ofatumumabvs placebo [39] This agent has not yet proceeded tophase 3 development

Daclizumab

Daclizumab is a humanized monoclonal antibodydirected against the high-affinity IL-2 receptor Thisreceptor is present on activated but not restingT cells Binding of IL-2 to this receptor is necessaryfor clonal expansion and continued viability ofactivated T cells [40] Although the anti-inflamma-tory effects of daclizumab were believed to resultfrom decreased T cell activation it is not associatedwith significant changes in T cell or B cell numbersor the ability of T cells to proliferate It appears thatthe effects of daclizumab may be related to anincrease in immunoregulatory CD56bright naturalkiller cells [41]

Efficacy

Daclizumab was evaluated for the treatment ofRRMS in the phase 2 CHOICE trial It was adouble-blind placebo-controlled study in 230patients with active disease despite IFN-b treatmentPatients were randomized to receive subcutaneousdaclizumab 2 mgkg every 2 weeks subcutaneousdaclizumab 1 mgkg every 4 weeks or placebo for24 weeks as an adjunct to their current IFN-btherapy (46 subcutaneous IFN-b-1a 30 imIFN-b-1a and 24 subcutaneous IFN-b-1b) Theprimary endpoint was the total number of new orenlarged gadolinium-enhancing lesions detectedbetween weeks 8 and 24 The mean number ofnew or enlarged gadolinium-enhancing lesionswas 475 in the IFN-bndashplacebo group vs 132for patients who received IFN-b with high-dosedaclizumab (Pfrac140004) and 358 for those treatedwith IFN-b with low-dose daclizumab (Pfrac14051)



[42] Daclizumab is also being compared with imIFN-b-1a in a phase 3 study in patients with RRMSThe estimated date for completion is 2014 [43]

SELECT is a phase 2b clinical trial that evaluatedtwo doses of daclizumab (150 or 300 mg every4 weeks) in 600 patients with RRMS [44] At 1 yeardaclizumab was associated with 54 and 50reductions in AAR for the 150 and 300-mg dosegroups respectively (Plt0001 vs placebo for bothdoses)

Safety

Safety data from the CHOICE trial indicated similarrates of infection across all treatment groups Theincidence of cutaneous adverse events was higher inthe combined daclizumab groups (34) vs placebo(27) grade 3 cutaneous events included rash(nfrac141) and eczema (nfrac142) in the daclizumab groupA higher incidence of grade-3 or grade-4 infectionsoccurred in those who received daclizumab (46)vs placebo (13) Grade 3 infections occurred in10 patients in the high-dose daclizumab group twoin the low-dose daclizumab group and two in theplacebo groups No opportunistic infections wereobserved and all infections resolved with therapy[42]

Cladribine

Cladribine is an immunosuppressant whose activemetabolite disrupts cellular metabolism inhibitsDNA synthesis and repair and leads to apoptosisof lymphocytes [45] Cladribine has been shown tobe effective for the treatment of RRMS in theCLARITY trial [45] but concerns about sustainedimmunosuppression and associated cancer riskresulted in withdrawal of applications for marketingauthorization in the European Union [46] and dis-continuation of development in the United States[47]

Benefits and limitations of emergingtherapies for multiple sclerosis

The availability of new therapeutic options for dis-ease modification has the potential to expandoptions for persons with MS These new therapieshave the potential to redefine the goals of therapiesin the context of appropriate patient selection andmanagement strategies

Changing the course of disease

A goal for the treatment of MS not yet realized formany patients is freedom from disease activitydefined as a complete absence of relapses MRI


evidence of disease activity and progression ofdisability [2] Freedom from disease activity wasdemonstrated for 295 of patients treated withnatalizumab in the AFFIRM trial [2] which isa reasonable benchmark for assessment of newMS therapies Further 3-year results from theCAMMS223 study indicated alemtuzumab oftendecreased EDSS scores rather than slowing increases[13]

Changing the course of disease in patients withMS is closely linked to the concept of neuropro-tection At present the mechanisms underlyingneurodegeneration in MS and how to promoteneuroprotection are not completely understood[48

ampamp

] Moreover there is no consensus on bio-markers for neuroprotection that could be evaluatedin studies of MS therapies [49] A variety of measureshave been suggested as potential candidates forassessment of neuroprotection in clinical trials[50] It has been proposed that brain volume changeon serial MRI may provide a sensitive overallmeasure of neuroprotection in MS trials [50]However the use of whole-brain atrophy to assessneuroprotection lacks specificity for tissue-relatedprocesses (eg loss of myelin or axons and increasein glial content) Inflammation can also confoundatrophy measurements [51] Prevention of whitematter atrophy may be a practical MRI measurefor assessment of neuroprotective effects of MS treat-ments Loss of white matter reflects axonal damageand subsequent degeneration of neuronal cellbodies and gray matter atrophy [52]

Challenges in patient selection andmonitoring

Although potentially providing improved efficacynew treatments for MS also present challenges inpatient selection and monitoring For example anelectrocardiogram ophthalmologic evaluation formacular edema assessment of pulmonary functionand liver function tests are all recommended priorto initiation of treatment with fingolimod [53]Patients receiving alemtuzumab will also requireclose monitoring for autoimmunity and it ispossible that pretreatment assessment of IL-21 levelsmay be useful for risk stratification with this treat-ment [17] Rituximab requires monitoring of neuro-logic function due to risk for PML in patientsreceiving it for its current indications [54] Thisrequirement may extend to any anti-B-cell antibodyapproved for the treatment of MS Increasingmonitoring of patients for infection or malignancywill be important for many of the new MS treat-ments based on safety results from phase 2 and3 clinical trials



CONCLUSION

The emergence of a large number of new disease-modifying treatments for MS should prompt are-evaluation of our approaches to the long-termmanagement of these patients First and mostimportantly we need to set a higher standard fortreatment success Freedom from disease as definedin preceding sections should be our target It islikely to be achievable in many patients using newertherapies either alone or in combination with cur-rently approved agents Setting a higher standard fortreatment success will result in less tolerance ofrelapses clinical evidence of progression or newlesions detected on MRI Physicians are more likelyto intensify treatment as necessary to recover morecontrol over the disease

Early initiation of disease-modifying therapyis also an important component of advancingtreatment for MS The Multiple Sclerosis TherapyConsensus Group recommends early initiation oftreatment with the goal of terminating inflam-mation and reducing axonal damage [55] Earlyintervention with the best available therapy anda high standard for treatment success has the poten-tial to significantly improve long-term outcomes forMS patients

Acknowledgements

None


EF has received consulting fees from Bayer Biogen IdecEMD Serono Genzyme Novartis Opexa and Teva feesfor non-CMECE services directly from a commercialinterest or their agents (eg speakersrsquo bureaus) fromBayer Biogen Idec EMD Serono Pfizer and Tevaand contracted research support from Biogen IdecGenzyme EMD Serono Eli Lilly Novartis Ono RocheSanofi-aventis and Teva RR has no conflict ofinterest



1 Markowitz CE The current landscape and unmet needs in multiple sclerosisAm J Manag Care 2010 16(8 Suppl)S211S118

2 Havrdova E Galetta S Hutchinson M et al Effect of natalizumab on clinicaland radiological disease activity in multiple sclerosis a retrospective analysisof the Natalizumab Safety and Efficacy in Relapsing-Remitting MultipleSclerosis (AFFIRM) study Lancet Neurol 2009 8254ndash260

3 Mehling M Johnson TA Antel J et al Clinical immunology of the sphingosine1-phosphate receptor modulator fingolimod (FTY720) in multiple sclerosisNeurology 2011 76 (Suppl 1)S20ndashS27

4 Kappos L Antel J Comi G et al Oral fingolimod (FTY720) for relapsingmultiple sclerosis N Engl J Med 2006 3551124ndash1140


5 Kowarik MC Pellkofer HL Cepok S et al Differential effects of fingolimod(FTY720) on immune cells in the CSF and blood of patients with MSNeurology 2011 761214ndash1221

6 Cohen JA Chun J Mechanisms of fingolimodrsquos efficacy and adverse effects inmultiple sclerosis Ann Neurol 2011 69759ndash777

7 Noguchi K Fujii Y Choi JW et al Nervous system and immune system effectsof sphingosine 1-phosphate receptor 5 deletion in mice alters experimentalautoimmune encephalitis progression and the efficacy of fingolimod Programand abstracts of the 5th Joint Triennial Congress of the European andAmericas Committees for Treatment and Research in Multiple Sclerosis(ECTRIMSACTRIMS) 19ndash22 October 2011 Amsterdam The Netherlands

8amp

Cohen JA Barkhof F Comi G et al Oral fingolimod or intramuscular interferonfor relapsing multiple sclerosis N Engl J Med 2010 362402ndash415

A phase 3 randomized trial demonstrating fingolimod to have superior efficacy toIFN b-1a im in patients with early RRMS9 Khatri B Barkhof F Comi G et al Comparison of fingolimod with interferon

beta-1a in relapsing-remitting multiple sclerosis a randomised extension ofthe TRANSFORMS study Lancet Neurol 2011 10520ndash529


11 Hu Y Turner MJ Shields J et al Investigation of the mechanism of action ofalemtuzumab in a human CD52 transgenic mouse model Immunology 2009128260ndash270

12 Jones JL Anderson JM Phuah CL et al Improvement in disability afteralemtuzumab treatment of multiple sclerosis is associated with neuroprotec-tive autoimmunity Brain 2010 1332232ndash2247

13 Coles AJ Compston DA Selmaj KW et al Alemtuzumab vs interferon beta-1a in early multiple sclerosis N Engl J Med 2008 3591786ndash1801

14 Coles AJ Fox E Vladic A et al Alemtuzumab versus interferon beta-1a in earlyrelapsing-remitting multiple sclerosis posthoc and subset analyses of clinicalefficacy outcomes Lancet Neurol 2011 10338ndash348

15 Coles AJ Brinar V Arnold DL et al Efficacy and safety results from CARE-MSI a phase 3 study comparing alemtuzumab and interferon-beta-1a Programand abstracts of the 5th Joint Triennial Congress of the European andAmericas Committees for Treatment and Research in Multiple Sclerosis(ECTRIMSACTRIMS) 19ndash22 October 2011 Amsterdam The Netherlands

16 Jeffrey S Second phase 3 trial positive with alemtuzumab in MS MedscapeMedical News httpwwwmedscapecomviewarticle753502 [Accessed28 December 2011]

17 Jones JL Phuah CL Cox AL et al IL-21 drives secondary autoimmunity inpatients with multiple sclerosis following therapeutic lymphocyte depletionwith alemtuzumab (Campath-1H) J Clin Invest 2009 1192052ndash2061

18 Lee DH Linker RA Gold R Spotlight on fumarates Int MS J 2008 1512ndash18

19 Gold R Kappos L Bar-Or D et al Clinical efficacy of BG-12 an oral therapyin relapsing-remitting multiple sclerosis data from the phase 3 DEFINE trialProgram and abstracts of the 5th Joint Triennial Congress of the Europeanand Americas Committees for Treatment and Research in Multiple Sclerosis(ECTRIMSACTRIMS) 19ndash22 October 2011 Amsterdam The Netherlands

20 Kappos L Gold R Miller DH et al Efficacy and safety of oral fumarate in patientswith relapsing-remitting multiple sclerosis a multicentre randomised double-blind placebo-controlled phase IIb study Lancet 2008 3721463ndash1472

21 Bruck W Wegner C Insight into the mechanism of laquinimod actionJ Neurol Sci 2011 302173ndash179

22 Comi G Oral laquinimod reduced relapse rate and delayed progression ofdisability in ALLEGRO a placebo-controlled phase 3 trial for relapsing remittingmultiple sclerosis Program and abstracts of the American Academy of Neuro-logy (AAN) 63rd Annual Meeting 9ndash16 April 2011 Honolulu Hawaii

23 Consortium of Multiple Sclerosis Centers CMSC INForMS Results of phaseIII Bravo trial (2011) httpbitlyoAuZD6 [Accessed 13 February 2012]

24 Palmer AM Teriflunomide an inhibitor of dihydroorotate dehydrogenase forthe potential oral treatment of multiple sclerosis Curr Opin Investig Drugs2010 111313ndash1323

25 Siemasko KF Chong AS Williams JW et al Regulation of B cell function bythe immunosuppressive agent leflunomide Transplant 1996 27635ndash642

26 OrsquoConnor PW Li D Freedman MS et al A phase II study of the safety andefficacy of teriflunomide in multiple sclerosis with relapses Neurology 200666894ndash900

27 Freedman MS Wolinsky JS Byrnes WJ et al Oral teriflunomide or placeboadded to interferon beta for 6 months in patients with relapsing multiplesclerosis safety and efficacy results Mult Scler 2009 15S273

28 Freedman M Wolinsky JS Frangin GA et al Oral teriflunomide or placeboadded to glatiramer acetate for 6 months in patients with relapsing multiplesclerosis safety and efficacy results Neurology 2010 74A294

29 OrsquoConnor P Wolinsky JS Confavreux C et al A placebo-controlled phase IIItrial (TEMSO) of oral teriflunomide in relapsing MS clinical efficacy and safetyoutcomes In Program and abstracts of the European Committee for Treat-ment and Research in Multiple Sclerosis 13ndash16 October 2010 GoteborgSweden

30 Nelson F Miller A OrsquoConnor P et al Multiple sclerosis monitoring andtreatment Magnetic resonance imaging subgroup analysis from the TEMSOplacebo-controlled phase III trial of oral teriflunomide in multiple sclerosis withrelapses 2011 In Program and abstracts of the European NeurologicalAssociation (ENS) 21st Annual Meeting 28ndash31 May 2011 Lisbon Portugal



31 ClinicalTrialsgov Efficacy and safety of teriflunomide in patients withrelapsing multiple sclerosis and treated with interferon-beta (TERACLES)httpclinicaltrialsgovct2showNCT01252355 [Accessed 13 February2012]

32 ClinicalTrialsgov Phase III study with teriflunomide versus placebo in patientswith first clinical symptom of multiple sclerosis (TOPIC) httpclinicaltrialsgovct2showNCT00622700 [Accessed 13 February 2012]

33 Jones JL Coles AJ New treatment strategies in multiple sclerosis Exp Neurol2010 22534ndash39

34 Hauser SL Waubant E Arnold DL et al B-cell depletion with rituximab inrelapsing-remitting multiple sclerosis N Engl J Med 2008 358676ndash688

35 Kappos L Li D Calabresi P et al Ocrelizumab in relapsing-remitting multiplesclerosis 48 week efficacy and safety results of a phase II randomizedplacebo-controlled multicenter trial In Program and abstracts of theAmerican Academy of Neurology (AAN) 63rd Annual Meeting 9ndash16 April2011 Honolulu Hawaii

36 Thompson Reuters Roche arthritis drug meets goal safety issues linger(2010) httpwwwreuterscomarticle20100420roche-idUSLDE63J04X20100420 [Accessed 13 February 2012]

37 Montalban X Wolinsky J Yin M et al Phase III study of ocrelizumab in patientswith primary progressive MS ORATORIO design Program and abstracts ofthe American Academy of Neurology (AAN) 63rd Annual Meeting 9ndash16 April2011 Honolulu Hawaii

38 Clinical Trialsgov A study of ocrelizumab in comparison with interferon beta-1a in patients with relapsing multiple sclerosis httpclinicaltrialsgovct2showNCT01412333 [Accessed 13 February 2012]

39 Genmab Science and Research 2011 httpbitlypKyDGv [Accessed 13February 2012]

40 Vincenti F Kirkman R Light S et al Interleukin-2-receptor blockade withdaclizumab to prevent acute rejection in renal transplantation DaclizumabTriple Therapy Study Group N Engl J Med 1998 338161ndash165

41 Banwell B Bar-Or A Giovannoni G et al Therapies for multiple sclerosisconsiderations in the pediatric patient Nat Rev Neurol 2011 7109ndash122

42 Wynn D Kaufman M Montalban X et al Daclizumab in active relapsingmultiple sclerosis (CHOICE study) a phase 2 randomised double-blindplacebo-controlled add-on trial with interferon beta Lancet Neurol 20109381ndash390


43 ClinicalTrialsgov Efficacy and safety of daclizumab high yield process versusinterferon b 1a in patients with relapsing-remitting multiple sclerosis (2011)httpclinicaltrialsgovct2showNCT01064401 [Accessed 13 February2012]

44 Business Wire Top-line results from the first registrational trial for daclizumabHYP in relapsing-remitting multiple sclerosis httpwwwbusinesswirecomnewshome20110809005901en [Accessed 27 September 2011]

45 Giovannoni G Comi G Cook S et al A placebo-controlled trial of oralcladribine for relapsing multiple sclerosis N Engl J Med 2010 362416ndash426

46 European Medicines Agency Merck Serono Europe Limited withdraws itsmarketing authorisation application for Movectro (cladribine) (2011) httpbitlyfvtzr1 [Accessed 13 February 2012]

47 Multiple Sclerosis Association of America Merck Serono no longerseeking approval for oral cladribine (2011) httpwwwmsassociationorgnews_centerarticleaspa=_cladribine_not_seeking_approval [Accessed13 February 2012]

48ampamp

Van der Walt A Butzkueven H Kolbe S et al Neuroprotection in multiplesclerosis a therapeutic challenge for the next decade Pharmacol Ther 201012682ndash93

A useful current review summarizing principles of neuroprotection as a considera-tion of current and emerging disease-modifying therapies49 Lisak RP Neurodegeneration in multiple sclerosis defining the problem

Neurology 2007 68 (22 Suppl 3)S5ndashS1250 Barkhof F Calabresi PA Miller DH Reingold SC Imaging outcomes for

neuroprotection and repair in multiple sclerosis trials Nat Rev Neurol 20095256ndash266

51 Lublin FD Emerging strategies for neuroprotection and neuroregeneration inMS Internat J MS Care 2011 131ndash30

52 Sepulcre J Goni J Masdeu JC et al Contribution of white matter lesions togray matter atrophy in multiple sclerosis evidence from voxel-based analysisof T1 lesions in the visual pathway Arch Neurol 2009 66173ndash179

53 Gilenya [package insert] East Hanover NJ Novartis Pharmaceutical Corp2011

54 Rituxan [package insert] South San Francisco CA Genentech Inc 201155 Multiple Sclerosis Therapy Consensus Group (MSTCG) Wiendl H Toyka KV

et al Basic and escalating immunomodulatory treatments in multiple sclerosiscurrent therapeutic recommendations J Neurol 2008 2551449ndash1463


REVIEW

CURRENTOPINION Individualizing treatment goals and interventions

for people with MS

wwwco-neurologycom

a b


Purpose of review

The aim of this article is to consider factors that should be evaluated in the selection of therapy for peoplewith multiple sclerosis (MS) This includes a review of current approaches to treatment selection and how toalign this process with patientsrsquo treatment goals These issues have increased in importance with theavailability of new disease-modifying therapies and will continue to do so as more novel treatments areapproved

Recent findings

The model for decision making in the management of people with MS as well as other chronic diseaseshas evolved from one in which medication is prescribed by the neurologist and the person is expected tocomply with treatment to one in which the neurologist and individual with MS achieve concordance withrespect to both the expectations and goals of therapy and the means to achieve them This shift hasresulted in a requirement for easily understood evidence-based information about the risks and benefits ofdifferent treatment alternatives It has been demonstrated that providing MS sufferers with such informationincreases effective self-management and satisfaction

Summary

Healthcare providers involved in the treatment of MS have an increased responsibility to ensure peoplewith this disease their partners and when appropriate their families are involved in all decisionsregarding care This includes helping to select and adjust therapy on the basis of the individual MSsuffererrsquos characteristics and needs that are likely to evolve as the disease progresses

Keywords

concordance education individualization risk-benefit

aCentre for Neuroscience and Trauma Barts and the London School ofMedicine and Dentistry London UK and bSteamboat Springs ColoradoUSA

Correspondence to Professor Gavin Giovannoni Centre for Neuro-science and Trauma Barts and The London School of Medicine andDentistry 4 Newark Street London E1 2AT UK Tel +44 20 7377 7472fax +44 20 7377 7033 e-mail ggiovannoniqmulacuk


INTRODUCTION

Multiple sclerosis (MS) is a disease in which disabil-ity progresses for many sufferers despite effectivedisease-modifying therapies [12] It cannot be curedwith current therapies As a result the generallyaccepted goals of treatment for MS sufferers are asfollows improve quality of life (QOL) by relievingsymptoms caused by exacerbations and reduce thenumber of these events reduce MRI activity delaythe onset of secondary progressive MS slow orstop the course of disease progression and minimizetreatment-associated adverse events [3] Althoughthese overall goals are generally accepted they alsomay vary substantially from one MS sufferer toanother This article focuses on MS sufferer-relateddisease-related and medication-related factors thatshould be considered in selection of therapy forpersons with relapsing-remitting MS (RRMS) It alsoconsiders the importance of education and com-munication aimed at understanding MS suffererneeds managing expectations and establishing

treatment goals in concordance with the personwith MS and the potential for this approach toimprove adherence to therapy and outcomes

PATIENT-RELATED FACTORS THATSHOULD BE CONSIDERED IN SETTINGTREATMENT GOALS

A very large number of factors should be consideredin tailoring treatment for the person with MS (Fig 1)[4] Characteristics that may influence treatmentgoals and selection of therapy include age culture


KEY POINTS

The majority of patients want to be more involved indecisions about treatment

Encourage persons with MS to discuss their diagnosisand treatment options and to voice any concerns

Help persons with MS access information about theirconditions and recommended therapies

Recognize opportunities to discuss medicationsaddress particular difficulties

Encourage persons with MS to share their feelingsabout their treatment progress

Individualizing MS treatment Giovannoni and Rhoades

education duration of disease and degree of dis-ability desired lifestyle work requirements literacyand health literacy coping skills treatment history(eg inability to tolerate specific agents andoradhere to self-injection regimens) preferences forroute of drugbiologic delivery degree of familysocial support and risk toleranceaversion [56]For example younger and more active MS sufferswith important workfamily responsibilities maywant treatment with the greatest potential to slowdisease progression and may be willing to accept

Individuatreatm

Treatmentstrategy

Increasicompl

environm

Patientrsquostreatment

goals

Patientrsquosriskbenefittolerance

Patiendisease p

and charact

FIGURE 1 Considerations for individualization of treatment in pe


increased risk for adverse events to achieve this goalOlder more sedentary persons with long-standingand slowly progressing disease may be willing toaccept treatments with lower efficacy in order toavoid the potential for rare but potentially seriousadverse events

Consideration of MS sufferer characteristicslisted in the preceding paragraph may influenceboth the treatment selected and route of admi-nistration For example oral disease-modifyingtherapy is now available and many persons withMS may prefer an oral drug However the ultimatechoice of route of treatment administration shouldbe a decision shared by the person with MS and hisor her healthcare providers [7] and within nationalguidelines For example those with a high pro-bability of poor adherence with self-treatmentmay benefit from a therapy delivered at specificvisits in a healthcare setting Conversely MS suffer-ers who are more likely to adhere to their therapiesmay prefer a self-injected or oral medication

ACHIEVING CONCORDANCE IN MULTIPLESCLEROSIS TREATMENT

Achieving concordance with the person with MS isan important initial consideration in individualiz-ing treatment for individuals with MS Concordance

lizedent

nglyex

ent

Economicfactors

Patientrsquos adherenceto monitoring or

drug regimen

Other

trsquosrofileeristics

rsons with multiple sclerosis [4]



is a very different concept from compliance totherapy Compliance is defined as the extent towhich the behavior of the individual being treatedmatches the prescriberrsquos recommendations Itimplies a limited role for the person being treatedin selection of therapy and in deciding whether ornot to take it [8] Adherence is defined as the extentto which the behavior of the person being treatedmatches agreed-upon recommendations from theprescriber It emphasizes that he or she is free todecide whether to adhere to the neurologistrsquosrecommendations and that failure to do so shouldnot be a reason for blame [8] Concordance is abroader concept that includes the consultationprocess in which the neurologist and MS suffereragree upon therapeutic decisions that incorporatetheir respective views and patient support for takingof medications [89

amp

] The differences between thecompliance and concordance approaches for pre-scription and taking of medication are summarizedin Table 1 [81011]

One of the assumptions underlying a concord-ance model for prescribing and taking of medi-cations is that the MS sufferer desires involvementin these decisions [10] Results from surveys of suchindividuals indicate that this is the case One surveyindicated that about 80 of MS sufferers desireautonomous roles in treatment decisions [1213]In another small-scale survey Paterson et al [14]assessed MS sufferersrsquo approaches to everyday self-care decision making These investigators inter-viewed 21 persons with type 2 diabetes HIVAIDSor MS who were identified as lsquoexpert self-care man-agersrsquo by their clinicians Study results indicated thatthese individuals made decisions based on a largenumber of disease-specific elements related to time-liness interpretation of biomarkers interactionwithin a social context the construction of healthpractices and available relevant information The

Table 1 Comparison of the compliance and concordance m

Compliance

Patientrsquos behavior is consistent with the prescriberrsquos recommendation

Aim is to enhance patient adherence to prescribed medication regimen

Patient follows health professionals direction patient may bedeferential or passive

Patient may be reluctant to voice reservations or confide in theirprovider about missed doses or use of complementary therapies

Provider gives patient minimal information about medication andmay not assess patient comprehension


MS sufferers stated that they made numerous self-care decisions every day and that these decisionswere made in view of short-term intermediate-term and long-term consequences [14]

MULTIPLE SCLEROSIS SUFFERERSrsquoASSESSMENTS OF DISEASE ANDTREATMENT RISKS AND BENEFITS

MS sufferersrsquo involvement in decisions regarding MStreatment includes making judgments about theimpact of the disease and the risks and benefits oftreatment There may be substantial differencesbetween patientsrsquo and neurologistsrsquo perceptionsof these issues In one study 42 consecutive MSsufferers attending a neurology outpatient cliniccompleted the SF-36 and EuroQol assessmentsA neurologist measured neurological impairmentusing the Expanded Disability Status Scale andan independent nonclinically qualified assistantadministered the disability questionnaire of theOffice of Population Censuses and Surveys Studyresults indicated that persons with MS and cliniciansdisagreed on which domains of health status weremost important MS sufferersrsquo assessments of theirphysical disability using the physical functioningdomain of the SF-36 were highly correlated with thecliniciansrsquo evaluations and the nonclinical measure-ments However none of the measures of physicaldisability correlated with overall health-related QOLmeasured with EuroQol These investigators con-cluded that persons with MS are less concerned thantheir clinicians about physical disability in theirillness [15]

Persons with MS are also willing to accept sig-nificant risk to achieve their treatment goals andthey may be less risk averse than their neurologistsIn one study 651 MS sufferers chose hypotheticaltreatments from pairs of alternatives with varying

odels [81011]

Concordance

Provider and patient formulate therapeutic decisions thatincorporate their respective views to support medicationtaking

Aim is to optimize health gain from use of medicationscompatible with what the patient desires and can achieve

Agreement between the patient and provider based onshared decision making

Provider respects the beliefs and wishes of the patient indetermining whether when and how their medicine istaken primacy of the patientrsquos decision is recognized

Patient is better informed and a more active participantleading to greater adherence to his or her plan



levels of clinical efficacy and associated risks Studyresults indicated that delay in years to disabilityprogression was the most important factor in treat-ment preferences In return for decreases in relapserates from 4 to 1 and increases in delay in pro-gression from 3 to 5 years persons with MS werewilling to accept a 038 annual risk of death ordisability from progressive multifocal leukoence-phalopathy (PML) a 039 annual risk of deathfrom liver failure or a 048 annual risk of deathfrom leukemia [16] Another study assessed MSsufferersrsquo and neurologistsrsquo perceptions of risksassociated with MS therapy with natalizumab Thistreatment is highly effective but is associated with arare but potentially fatal opportunistic infectionPML [1718] In this study 69 persons with MSreceiving treatment with natalizumab and 66neurologists received an evidence-based informa-tional brochure about the risk of PML and wereasked to fill out an evaluation sheet After readingthe information persons with MS were significantlymore likely than neurologists to continue natalizu-mab treatment and willing to accept higher risks ofPML 49 of neurologists would stop treatment at aPML risk of 2 10 000 or higher whereas only 17 ofMS sufferers would do so at that event rate [19

amp

]Results from another survey of risk acceptance thatincluded results from 5446 persons with MS in theNorth American Research Committee on MultipleSclerosis registry indicated that one-half of the

0

20

40

Patientrespondents ()

60

80

10092

97

31

New oral therapymild riskvigilance

New orasevere ris

FIGURE 2 Results of a survey of relapsing-remitting multiple stherapy (DMT) Patients were administered standardized questiontherapy that was oral or injectable and was associated with mild


respondents would accept a mortality risk morethan 1 in 10 000 for a hypothetical MS cure [20

ampamp

]It has also been shown that MS sufferersrsquo prior

experience with treatment significantly influencesassessment of risk and benefit In a cross-sectionalstudy conducted between 2007 and 2009 ambulat-ory sufferers with RRMS and without significantdepression or cognitive impairment and who hadbeen taking an IFN-b or glatiramer acetate wereasked to respond to a series of questions during aclinic visit [21

ampamp

] They were asked if they wouldconsider switching to a new therapy with mild riskand requiring mild vigilance a new therapy withsignificant risk and requiring significant vigilance anew oral therapy with mild risk and requiring mildvigilance and a new oral therapy with significantrisk and requiring significant vigilance MS suffererswere divided into groups based on duration oftherapy (5 years or gt5 years) with 100 in eachgroup Persons with MS in both groups indicatedthey would favorably consider switching to newtherapies that carry a mild risk and require mildvigilance or treatment monitoring with more than90 in each group indicating they would considerswitching to a new oral therapy with mild riskrequiring mild vigilance (Fig 2) Those with longerdisease duration were significantly more likely toswitch to a new therapy with significant risk andrequiring significant vigilance than MS suffererswith shorter treatment durations More MS sufferers

l therapykvigilance

New therapysevere riskvigilance

New therapymild riskvigilance

59

7884

Disease and DMT lt5 years (n = 100)

Disease and DMT ge5 years (n = 100)

28

63

clerosis patients undergoing self-injected disease modifyingnaires to ask if they would consider switching to a newor severe risk and vigilance [21ampamp]



with longer disease duration (59) than withshorter disease duration (31) said they would con-sider switching to a new oral therapy with signifi-cant risk requiring significant vigilance Personswith MS in both groups (70 for shorter treatmentduration and 91 for longer duration) favored areduction in disability progression over decreasedrelapses as a 10-year treatment outcome [21

ampamp

]All of the results reviewed in this section under-

score the importance of developing validating andimplementing tools to educate persons with MSabout risk and to help align their perceptions of riskwith those of their neurologists

HELPING PERSONS WITH MULTIPLESCLEROSIS MAKE INFORMEDTREATMENT DECISIONS

In the concordance model a major role of theclinician who manages persons with MS is toinform advise and work with them as part of ateam to decide on a course of therapy that best meetstheir needs Morgante et al [22] have describedapproaches to helping persons with MS make betterdecisions about their care The approaches are asfollows

(1)

S24

Establish a collaborative trusting relationship

(2)

Be nonjudgmental (understand the MS suffer-

errsquos perspective)

(3)

Explore MS suffererrsquos health beliefs and values

focusing on ethniccultural differences (egask about previous experiences)

(4)

Assess the MS suffererrsquos support system (familyemployment finances)

(5)

Identify obstacles to MS sufferer participationin decision making (eg cognitive limita-tions)

(6)

Clarify treatment options by explaining therisks and benefits of each therapy

(7)

Identify the MS suffererrsquos priorities

(8)

Listen to the MS suffererrsquos concerns

(9)

Help the person with MS recognize and

achieve personal comfort with decision mak-ing

(10)

Advocate for the person with MS if hisherdecision goes against the teamrsquos consensus

(11)

Help the MS sufferer implement hisherdecision (eg navigate insurance hurdles)

(12)

Evaluate the outcome of the decision

(13)

Realize that decision making is a continuous

process

These investigators noted that newly diagnosedMS sufferers may be compelled to make impor-tant and emotionally charged decisions regarding

wwwco-neurologycom

treatment that may be influenced by fears about thefuture Clinicians should assess the individual MSsuffererrsquos ability and willingness to participate in thedecision-making process and tailor interactionsaccordingly [22] It has been suggested that edu-cation of persons with MS and shared decisionmaking can result in improved treatment satisfac-tion better communication by MS sufferers oftheir values to clinicians and earlier recognitionof ineffective or harmful therapies [23] In additionthese approaches may result in risk-averse MS suffer-ers appropriately initiating immunomodulatorytherapy early in the course of the disease [23]

In counseling individuals about treatment forMS neurologists need to be aware of their ability toinfluence MS sufferersrsquo decisions and the potentialimpact of changing their opinions One recentstudy investigated whether neurologistsrsquo recom-mendations caused persons with MS to change theirtreatment selection This investigation included 101persons with MS who were presented with a hypo-thetical choice between two drugs They selected amedication and then received a fictitious clinicianrsquosrecommendation for the alternative choice Theythen made a final choice between the two agentsOverall 26 of the persons with MS followed theadvice of their neurologist and thus chose the treat-ment option that differed from their initial prefer-ence Those who followed their neurologistrsquos advicewere less satisfied with their decision than patientswho did not [24]

Engaging the person with MS in decision mak-ing regarding his or her MS treatment requires theprovision of evidence-based information This hasbeen defined as information about relevant treat-ment effects communicated in absolute numbers(as absolute risk reductions andor numbers neededto treat) preferably with the use of illustrationsPresentation of relative risk reductions should beavoided as these are not intuitively understood byMS sufferers and usually overestimate treatmenteffects [25] Although absolute risk data may bemore readily comprehended they are derived fromclinical trial data and patients should understandthat their individual situation is unique It has beensuggested that evidence-based patient informationshould also focus on the most relevant outcomes forpersons with MS (eg relapses) with less attentionto surrogate measures (MRI results) [26] Theseapproaches to presentation of information wereimplemented in an education program aimed atinvolving MS sufferers in decisions on relapsemanagement In this study 150 persons with RRMSwere randomized to a single 4-h group session onrelapse management (intervention group) or astandard information leaflet (control group) The



author assumed the group session would increasedecision autonomy The primary outcome measurewas the proportion of relapses treated with self-administered oral corticosteroids or no corticoste-roids (oral or intravenous therapy) as an indicator ofMS sufferer autonomy in treatment decisionmaking Study results indicated that 78 of personswith MS in the intervention group chose to treattheir relapse with oral corticosteroids or nocorticosteroids This was the case for 56 ofthose treating relapses in the control group Intra-venous corticosteroids were administered on aninpatient or outpatient basis to 22 of MS suffer-ers in the intervention group vs 44 of thosein the control group Autonomy of treatmentdecision making in the intervention group wasalso reflected by fewer visits and telephone callsto neurologists to gain assistance in managingrelapses [27]

Although provision of evidence-based decisionaids has gained wide acceptance concerns havebeen raised about delivery of such informationto persons evaluating treatments even in highlysimplified formats It has been noted that more thanone-half of adults have significant difficulty under-standing or applying probabilistic and mathemat-ical concepts and that at least 22 have only themost basic quantitative skills such as countingwhereas another 33 can do only simple arith-metic In addition people may also be biased intheir interpretation of risks They may give exagger-ated importance to small risks or converselyexhibit optimism bias and exaggerate the chancethat they will be among those who benefit fromtreatment [28] All of these concerns underscore theimportance of the neurologist-MS sufferer inter-action in assessing the risks and benefits of alterna-tive treatments in reaching a concordant decisionregarding a therapeutic regimen

EFFECTS OF CONCORDANCE ONADHERENCE TO THERAPY ANDTREATMENT OUTCOMES

Although much has been written about the poten-tial benefits of a concordance approach to treatmentselection in persons with MS there is as yetrelatively little evidence from controlled studies tosupport this approach However studies of individ-uals with other chronic diseases that require signifi-cant decisions regarding treatment have indicatedsubstantial benefits with this model A study ofconcordance during decision making regardingHIV treatment switching and stopping in relationto patient health-related outcomes included 217patients who completed a scale that measured


concordance Concordance was measured betweenthe HIV patientsrsquo and physiciansrsquo opinions regard-ing the change in treatment Higher concordancewas significantly associated with better QOL lesssevere and burdensome symptom experience lowerglobal distress index scores fewer symptomsreported higher CD4 cell count and significantlygreater adherence to treatment [29] The use of aconcordance model has also been shown to beeffective for controlling blood pressure in individ-uals with diabetes Results from a survey of 212 olderpersons with hypertension and diabetes who werebeing treated at a Veterans Administration MedicalCenter indicated that two communication-relatedfactors had independent associations with bloodpressure control as determined by multivariateregression analysis endorsement of a shareddecision-making style and proactive communi-cation with onersquos clinician about abnormal resultsof blood pressure self-monitoring A third factorcliniciansrsquo use of collaborative communicationwhen setting treatment goals also affected hyper-tension via its effects on decision-making style andproactive communication [30]

Although a concordance approach to decisionmaking has not yet been evaluated in personsbeing treated for MS there is evidence thatimproved communication and education enhancesthe response to treatment In one study 120 newlydiagnosed MS sufferers were randomly assignedto diagnosis disclosure (current practice) or currentpractice with an information aid that consisted ofa personal interview with a neurologist using anavigable compact disc and a take-home bookletThe primary composite endpoint was a score in thehighest tertile of MS knowledge and satisfactionwith care questionnaires Other endpoints weresafety treatment adherence extra contactsconsul-tations switching of care center and changes inHospital Anxiety and Depression Scale and ControlPreference Scale scores Study results indicated that50 of MS sufferers who received the interventionand 13 of those in the control group achieved theprimary endpoint However no significant treat-ment effects were seen on secondary outcomes[31] A second study assessed the influence of anevidence-based patient aid on the decision to under-take MS immunotherapy in a group of 297 patientsThe intervention group received the decision aidand a control group received standard informationThe primary outcome measure was the matchbetween the MS suffererrsquos preferred and actual rolesduring consultation with the neurologist A secon-dary outcome was treatment choice There wereno significant between-group differences for theprimary or secondary outcome [32] It has also been



shown that education can alter MS sufferersrsquo expec-tations regarding therapy However these effects arerelatively modest A study that included 99 personswith MS indicated that before educational inter-vention 57 expressed unrealistically optimisticexpectations regarding reduction in attack rateand 34 expressed unrealistically optimistic expec-tations regarding improvement in functional statusthat would result from treatment with IFN-b-1bEducation significantly altered unrealistic expec-tations but 33 of the persons with MS maintainedoverly optimistic expectations regarding reductionin attack rate Posteducation unrealistic expec-tations of improvement in functional status weresignificantly related to discontinuing therapywithin 6 months [33]

In contrast to the modest benefits of the inter-ventions described in the preceding paragraphresults from other studies have indicated that sup-port from healthcare professionals which might beconsidered as a component of the concordancemodel is associated with better adherence to MStherapy Results from a study of 341 persons withRRMS who were being treated with glatirameracetate indicated that 225 were adherent to treat-ment and 116 were not adherent Logistic regressionanalysis revealed that MS sufferersrsquo perceptionsthat the neurologist supported taking medicationas prescribed was significantly associated withadherence [34] Similar results were reported in anevaluation of 199 persons with self-reported pro-gressive forms of MS who were also being treatedwith glatiramer acetate [35]

CONCLUSION

Persons with MS vary across a wide range ofparameters and their treatment should be individ-ualized to meet their specific characteristics andneeds (see Key Points) Individualized treatmentmay change over the course of a MS suffererrsquos diseasedue to variability of symptoms changes in relapsefrequency and treatment tolerability When andhow therapy should be escalated or switched shouldbe part of the treatment plan for each person withMS Optimal treatment regimen and route of admin-istration also may vary across MS sufferers and overthe course of their disease

Decisions regarding whether or not to initiatetreatment and the selected regimen should be madein consultation with the MS sufferer Currentapproaches to optimizing therapy for persons withMS and other chronic diseases have increasinglyfocused on the MS sufferer as a partner in medicaldecision making Studies reviewed in this articleindicate that persons with MS value unbiased


communication of clinical evidence to support theirdecision making and there is a growing body ofevidence that provision of such evidence and aconcordance approach to decision making has thepotential to increase MS sufferer satisfaction andpossibly change behavior As the number of optionsfor disease-modifying therapy in MS grows theneurologistndashMS sufferer partnership in treatmentdecisions will become increasingly important

Acknowledgements

None


GG has received consulting fees from Bayer-ScheringHealthcare Biogen Idec Elan Five Prime TherapeuticsGenzyme Ironwood Merck Serono Novartis RocheSanofi-aventis Synthon BV UCB Pharma and Vertexfees for non-CMECE services directly from a commercialinterest or their agents (eg speakersrsquo bureaus) fromGenzyme Merck Serono and Novartis and contractedresearch support from GW Pharmaceuticals MerckSerono Merz and Novartis RR has no conflict ofinterest



1 Daumer M Neuhaus A Herbert J Ebers G Prognosis of the individual courseof disease the elements of time heterogeneity and precision J Neurol Sci2009 287 (Suppl 1)S50ndashS55

2 OrsquoConnor P Filippi M Arnason B et al 250 microg or 500 microg interferonbeta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiplesclerosis a prospective randomised multicentre study Lancet Neurol2009 8889ndash897

3 National MS Society Treatment (2011) httpwwwnationalmssocietyorgabout-multiple-sclerosiswhat-we-know-about-mstreatmentsindexaspx[Accessed 13 February 2012]

4 Giovannoni G Clinical implications the potential of tailored MS treatmentIn European Neurological Association (ENS) 21st Annual Meeting 28ndash31May 2011 Lisbon Portugal

5 Patti F Optimizing benefit of multiple sclerosis therapy the importance oftreatment adherence Patient Prefer Adherence 2009 41ndash9

6 Rich SJ Managed care considerations in treating multiple sclerosis AdvStudy Pharm 2009 672ndash76

7 Girouard N Soucy N Patient considerations in the management of multiplesclerosis development and clinical utility of oral agents Patient PreferAdherence 2011 5101ndash108

8 Horn R Concordance adherence and compliance in medicine taking Reportfor the National Co-ordinating Centre for NHS Service Delivery and Orga-nisation RampD (NCCSDO) 2005 1ndash309 httpbitlywnBUjf [Accessed 13February 2012]

9amp

Brunton SA Improving medication adherence in chronic disease manage-ment J Family Pract 2011 60 (Suppl)S1ndashS8

Emphasizes the discordance between physiciansrsquo perceptions of their patientsrsquoadherence to medications and the actual level of adherence10 Cushing A Metcalfe R Optimizing medicines management from compliance

to concordance Ther Clin Risk Manage 2007 31047ndash105811 Marinker M Blenkinsopp A Bond C et al From compliance to concordance

achieving shared goals in medicine taking London Royal PharmaceuticalSociety of Great Britain 1997

12 Heesen C Kasper J Kopke S et al Informed shared decision making inmultiple sclerosis-inevitable or impossible J Neurol Sci 2007 259109ndash117



13 Heesen C Kasper J Segal J et al Decisional role preferences risk know-ledge and information interests in patients with multiple sclerosis Mult Scler2004 10643ndash650

14 Paterson B Thorne S Russell C Disease-specific influences on meaning andsignificance in self-care decision-making in chronic illness Can J Nurs Res2002 3461ndash74

15 Rothwell PM McDowell Z Wong CK et al Doctors and patients donrsquot agreecross sectional study of patientsrsquo and doctorsrsquo perceptions and assessmentsof disability in multiple sclerosis BMJ 1997 3141580ndash1583

16 Johnson FR Van Houtven G Ozdemir S et al Multiple sclerosis patientsrsquobenefit-risk preferences serious adverse event risks versus treatmentefficacy J Neurol 2009 256554ndash662



19amp

Heesen C Kleiter I Nguyen F et al Risk perception in natalizumab-treatedmultiple sclerosis patients and their neurologists Mult Scler 2010 161507ndash1512

Study of persons with MS receiving treatment with natalizumab and their neurol-ogists Results showed that persons with MS were three times more likely thanneurologists to accept risks associated with natalizumab20ampamp

Fox R Salter A Alster JM et al Risk tolerance in MS patients survey resultsfrom the NARCOMS registry In American Academy of Neurology (AAN)63rd Annual Meeting 9ndash16 April 2011 Honolulu Hawaii Abstract P06057

Results from this survey of 5446 persons with MS in the North American ResearchCommittee on Multiple Sclerosis (NARCOMS) registry indicated that one-half ofrespondents would accept a mortality risk more than one in 10 000 for ahypothetical MS cure21ampamp

Caon C Memon A Perumal J Khan O Patient response to new diseasemodifying therapies results of a questionnaire study in RRMS patientsreceiving self-injected disease-modifying therapies In American Academyof Neurology (AAN) 63rd Annual Meeting 9ndash16 April 2011 HonoluluHawaii Abstract P01208

This presentation summarized results from a survey of MS patients that assessedrisk perceptions and attitudes related to switching to a new disease-modifyingtherapy


22 Morgante L Hartley G Lowden D et al Decision making in multiple sclerosistheory to practice Int J MS Care 2006 4113ndash120

23 Heesen C Solari A Giordano A et al Decisions on multiple sclerosisimmunotherapy new treatment complexities urge patient engagementJ Neurol Sci 2011 306192ndash197

24 Mendel R Traut-Mattausch E Frey D et al Do physiciansrsquo recommendationspull patients away from their preferred treatment options Health Expect2011 [Epub ahead of print] doi 101111j1369-7625201000658x

25 Bunge M Muhlhauser I Steckelberg A What constitutes evidence-basedpatient information Overview of discussed criteria Patient Educ Couns2010 78316ndash328

26 Kopke S Heesen C Engaging people with MS in decision-making Theconcept of evidence-based patient information Way Ahead 2010 146ndash9

27 Kopke S Kasper J Muhlhauser I et al Patient education program to enhancedecision autonomy in multiple sclerosis relapse management a randomized-controlled trial Mult Scler 2009 1596ndash104

28 Schwartz PH Questioning the quantitative imperative decision aids preven-tion and the ethics of disclosure Hastings Center Report 2011 4230ndash39

29 Clucas C Harding R Lampe FC et al Doctor-patient concordance duringHIV treatment switching decision-making HIV Med 2011 1287ndash96

30 Naik AD Kallen MA Walder A Street RL Jr Improving hypertension control indiabetes mellitus the effects of collaborative and proactive health commu-nication Circulation 2008 1171361ndash1368

31 Solari A Martinelli V Trojano M et al An information aid for newly diagnosedmultiple sclerosis patients improves disease knowledge and satisfaction withcare Mult Scler 2010 161393ndash1405

32 Kasper J Kopke S Muhlhauser I et al Informed shared decision making aboutimmunotherapy for patients with multiple sclerosis (ISDIMS) a randomizedcontrolled trial Eur J Neurol 2008 151345ndash1352

33 Mohr DC Goodkin DE Likosky W et al Therapeutic expectations of patientswith multiple sclerosis upon initiating interferon beta-1b relationship toadherence to treatment Mult Scler 1996 2222ndash226

34 Fraser C Hadjimichael O Vollmer T Predictors of adherence to Copaxonetherapy in individuals with relapsing-remitting multiple sclerosis J NeurosciNurs 2001 33231ndash239

35 Fraser C Hadjimichael O Vollmer T Predictors of adherence to glatirameracetate therapy in individuals with self-reported progressive forms of multiplesclerosis J Neurosci Nurs 2003 35163ndash170



NeurologyNeurology

EDITORIAL BOARDY Agid

Salpeacutetriegravere Hospital France

RL BarchiThomas Jefferson University USA

F Chollet

Purpan Hospital France

DC De Vivo

Columbia University USA

D Eidelberg

North Shore University Hospital USA

S Gilman

University of Michigan USA

P Goadsby

University of California San Francisco USA

H-P Hartung

Heinrich-Heine University Germany

GL Lenzi

University of Rome I Italy

JA Obeso

University of Navarra Spain

J Olesen

University of Copenhagen Denmark

PD Thompson

University of Adelaide Australia

K Toyka

University of Wuumlrzburg Germany

Lord Walton

Founding Editor

C WeillerUniversity Germany

2012 CONTENTSFEBRUARY

Cerebrovascular diseaseEdited by Ralph Sacco and Tatjana Rundek University of Miami USA

Neuro-ophthalmology and neuro-otologyEdited by Jose Sahel and Christine Petit INSERM Paris France

APRIL

Developmental disordersEdited by David Skuse Behavioural and Brain Sciences Unit University College London UK

Seizure disordersEdited by John Stern Department of Neurology UCLA USA

JUNE

Demyelinating diseasesEdited by Ludwig Kappos University Hospital Basel Switzerland

HeadacheEdited by Messoud Ashina University of Copenhagen Denmark

Infl ammatory diseases and infectionEdited by Heinz Wiendl University of Muenster Germany

AUGUST

NeuroimagingEdited by Joe Masdeu National Institute of Mental Health Bethesda USA

Movement disordersEdited by Department of Neurology Baylor College of Medicine Houston Texas USA

OCTOBER

Nerve neuro-muscular junction and motor neuron diseasesEdited by Jean-Marc Leger Consutation de Pathologie Neuro-Musculaire Babinski Building Salpecirctriegravere Hospital Paris France

Neuromuscular diseases muscleEdited by Tom Rando Department of Neurology and Neurological Sciences Stanford University School of Medicine Stanford USA

DECEMBER

Trauma and rehabilitationEdited by Richard Greenwood The Institute of Neurology University College London London

Degenerative and cognitive diseasesEdited by William Seeley University of California San Francisco Memory and Aging Center USA

NeoplasmsEdited by Roger Stupp University of Lausanne Switzerland and Michael Weller University Hospital Zurich Switzerland

Editor-in-Chief Richard SJ Frackowiak Institute of Neurology UK and Deputy Editor John Mazziotta UCLA School of Medicine USA

Literature Scanners P Alison Jones (coordinator) Mark Bower Matthew Griffi n Fareeda Coxon Yaaseen Moosa Patrick Bradley

2010 Journal Citation Reportsreg (Thomson Reuters 2011)

CURRENTOPINION










SUBSCRIPTION













Japan



Nepal and Pakistan





Customer Services


Publishing Offi ce


Contacts

































CURRENTOPINION





TABLE OF CONTENTS


CMECE credit








for people with MS



NeurologyNeurology


CURRENTOPINION



Target Audience







Faculty





Edward J Fox MD PhD



NeurologyNeurology


CURRENTOPINION


completion









Credit Designation



Credit Designation





















Media

Journal supplement



Disclaimer


REVIEW



wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION







KEY POINTS






amp







60ndash75 80ndash95

10 000

20 000

30 000

40 000

50 000





PATIENT BURDEN



























065 vs 054(Pfrac14009)





20 vs 43 vs 57(Plt005)

ND 01 (NS) vs07 (Plt005)vs 03 (Plt005)







034 vs 036 vs033 (NS)b

59 vs 58 vs60 (NS)b

21 vs 27 vs22 (NS)b




029 vs 030 (NS) 62 vs 62 (NS) 87 vs117 (NS)







Curre


MS

Miller

andRhoades

1350-7

540

2012

Wolters

Kluw

erH

ealth|

LippincottWilliam

samp

Wilkins

ww

wco

-neu

rolo

gyco

mS7

0 100 200 300 400 500


600 700 800 900 1000

100

075

050

025

000









amp


amp







ampamp





ampamp

]

CONCLUSION



Acknowledgements

None










5amp

























































57amp






61ampamp






REVIEW




a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION








KEY POINTS








Fingolimod


Efficacy




amp





Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp
































SUBSCRIPTION













Japan



Nepal and Pakistan





Customer Services


Publishing Offi ce


Contacts

































CURRENTOPINION





TABLE OF CONTENTS


CMECE credit








for people with MS



NeurologyNeurology


CURRENTOPINION



Target Audience







Faculty





Edward J Fox MD PhD



NeurologyNeurology


CURRENTOPINION


completion









Credit Designation



Credit Designation





















Media

Journal supplement



Disclaimer


REVIEW



wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION







KEY POINTS






amp







60ndash75 80ndash95

10 000

20 000

30 000

40 000

50 000





PATIENT BURDEN



























065 vs 054(Pfrac14009)





20 vs 43 vs 57(Plt005)

ND 01 (NS) vs07 (Plt005)vs 03 (Plt005)







034 vs 036 vs033 (NS)b

59 vs 58 vs60 (NS)b

21 vs 27 vs22 (NS)b




029 vs 030 (NS) 62 vs 62 (NS) 87 vs117 (NS)







Curre


MS

Miller

andRhoades

1350-7

540

2012

Wolters

Kluw

erH

ealth|

LippincottWilliam

samp

Wilkins

ww

wco

-neu

rolo

gyco

mS7

0 100 200 300 400 500


600 700 800 900 1000

100

075

050

025

000









amp


amp







ampamp





ampamp

]

CONCLUSION



Acknowledgements

None










5amp

























































57amp






61ampamp






REVIEW




a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION








KEY POINTS








Fingolimod


Efficacy




amp





Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp





















































CURRENTOPINION





TABLE OF CONTENTS


CMECE credit








for people with MS



NeurologyNeurology


CURRENTOPINION



Target Audience







Faculty





Edward J Fox MD PhD



NeurologyNeurology


CURRENTOPINION


completion









Credit Designation



Credit Designation





















Media

Journal supplement



Disclaimer


REVIEW



wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION







KEY POINTS






amp







60ndash75 80ndash95

10 000

20 000

30 000

40 000

50 000





PATIENT BURDEN



























065 vs 054(Pfrac14009)





20 vs 43 vs 57(Plt005)

ND 01 (NS) vs07 (Plt005)vs 03 (Plt005)







034 vs 036 vs033 (NS)b

59 vs 58 vs60 (NS)b

21 vs 27 vs22 (NS)b




029 vs 030 (NS) 62 vs 62 (NS) 87 vs117 (NS)







Curre


MS

Miller

andRhoades

1350-7

540

2012

Wolters

Kluw

erH

ealth|

LippincottWilliam

samp

Wilkins

ww

wco

-neu

rolo

gyco

mS7

0 100 200 300 400 500


600 700 800 900 1000

100

075

050

025

000









amp


amp







ampamp





ampamp

]

CONCLUSION



Acknowledgements

None










5amp

























































57amp






61ampamp






REVIEW




a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION








KEY POINTS








Fingolimod


Efficacy




amp





Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp



























TABLE OF CONTENTS


CMECE credit








for people with MS



NeurologyNeurology


CURRENTOPINION



Target Audience







Faculty





Edward J Fox MD PhD



NeurologyNeurology


CURRENTOPINION


completion









Credit Designation



Credit Designation





















Media

Journal supplement



Disclaimer


REVIEW



wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION







KEY POINTS






amp







60ndash75 80ndash95

10 000

20 000

30 000

40 000

50 000





PATIENT BURDEN



























065 vs 054(Pfrac14009)





20 vs 43 vs 57(Plt005)

ND 01 (NS) vs07 (Plt005)vs 03 (Plt005)







034 vs 036 vs033 (NS)b

59 vs 58 vs60 (NS)b

21 vs 27 vs22 (NS)b




029 vs 030 (NS) 62 vs 62 (NS) 87 vs117 (NS)







Curre


MS

Miller

andRhoades

1350-7

540

2012

Wolters

Kluw

erH

ealth|

LippincottWilliam

samp

Wilkins

ww

wco

-neu

rolo

gyco

mS7

0 100 200 300 400 500


600 700 800 900 1000

100

075

050

025

000









amp


amp







ampamp





ampamp

]

CONCLUSION



Acknowledgements

None










5amp

























































57amp






61ampamp






REVIEW




a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION








KEY POINTS








Fingolimod


Efficacy




amp





Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp























Target Audience







Faculty





Edward J Fox MD PhD



NeurologyNeurology


CURRENTOPINION


completion









Credit Designation



Credit Designation





















Media

Journal supplement



Disclaimer


REVIEW



wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION







KEY POINTS






amp







60ndash75 80ndash95

10 000

20 000

30 000

40 000

50 000





PATIENT BURDEN



























065 vs 054(Pfrac14009)





20 vs 43 vs 57(Plt005)

ND 01 (NS) vs07 (Plt005)vs 03 (Plt005)







034 vs 036 vs033 (NS)b

59 vs 58 vs60 (NS)b

21 vs 27 vs22 (NS)b




029 vs 030 (NS) 62 vs 62 (NS) 87 vs117 (NS)







Curre


MS

Miller

andRhoades

1350-7

540

2012

Wolters

Kluw

erH

ealth|

LippincottWilliam

samp

Wilkins

ww

wco

-neu

rolo

gyco

mS7

0 100 200 300 400 500


600 700 800 900 1000

100

075

050

025

000









amp


amp







ampamp





ampamp

]

CONCLUSION



Acknowledgements

None










5amp

























































57amp






61ampamp






REVIEW




a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION








KEY POINTS








Fingolimod


Efficacy




amp





Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp




























Credit Designation



Credit Designation





















Media

Journal supplement



Disclaimer


REVIEW



wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION







KEY POINTS






amp







60ndash75 80ndash95

10 000

20 000

30 000

40 000

50 000





PATIENT BURDEN



























065 vs 054(Pfrac14009)





20 vs 43 vs 57(Plt005)

ND 01 (NS) vs07 (Plt005)vs 03 (Plt005)







034 vs 036 vs033 (NS)b

59 vs 58 vs60 (NS)b

21 vs 27 vs22 (NS)b




029 vs 030 (NS) 62 vs 62 (NS) 87 vs117 (NS)







Curre


MS

Miller

andRhoades

1350-7

540

2012

Wolters

Kluw

erH

ealth|

LippincottWilliam

samp

Wilkins

ww

wco

-neu

rolo

gyco

mS7

0 100 200 300 400 500


600 700 800 900 1000

100

075

050

025

000









amp


amp







ampamp





ampamp

]

CONCLUSION



Acknowledgements

None










5amp

























































57amp






61ampamp






REVIEW




a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION








KEY POINTS








Fingolimod


Efficacy




amp





Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp






























Media

Journal supplement



Disclaimer


REVIEW



wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION







KEY POINTS






amp







60ndash75 80ndash95

10 000

20 000

30 000

40 000

50 000





PATIENT BURDEN



























065 vs 054(Pfrac14009)





20 vs 43 vs 57(Plt005)

ND 01 (NS) vs07 (Plt005)vs 03 (Plt005)







034 vs 036 vs033 (NS)b

59 vs 58 vs60 (NS)b

21 vs 27 vs22 (NS)b




029 vs 030 (NS) 62 vs 62 (NS) 87 vs117 (NS)







Curre


MS

Miller

andRhoades

1350-7

540

2012

Wolters

Kluw

erH

ealth|

LippincottWilliam

samp

Wilkins

ww

wco

-neu

rolo

gyco

mS7

0 100 200 300 400 500


600 700 800 900 1000

100

075

050

025

000









amp


amp







ampamp





ampamp

]

CONCLUSION



Acknowledgements

None










5amp

























































57amp






61ampamp






REVIEW




a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION








KEY POINTS








Fingolimod


Efficacy




amp





Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp























REVIEW



wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION







KEY POINTS






amp







60ndash75 80ndash95

10 000

20 000

30 000

40 000

50 000





PATIENT BURDEN



























065 vs 054(Pfrac14009)





20 vs 43 vs 57(Plt005)

ND 01 (NS) vs07 (Plt005)vs 03 (Plt005)







034 vs 036 vs033 (NS)b

59 vs 58 vs60 (NS)b

21 vs 27 vs22 (NS)b




029 vs 030 (NS) 62 vs 62 (NS) 87 vs117 (NS)







Curre


MS

Miller

andRhoades

1350-7

540

2012

Wolters

Kluw

erH

ealth|

LippincottWilliam

samp

Wilkins

ww

wco

-neu

rolo

gyco

mS7

0 100 200 300 400 500


600 700 800 900 1000

100

075

050

025

000









amp


amp







ampamp





ampamp

]

CONCLUSION



Acknowledgements

None










5amp

























































57amp






61ampamp






REVIEW




a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION








KEY POINTS








Fingolimod


Efficacy




amp





Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp























KEY POINTS






amp







60ndash75 80ndash95

10 000

20 000

30 000

40 000

50 000





PATIENT BURDEN



























065 vs 054(Pfrac14009)





20 vs 43 vs 57(Plt005)

ND 01 (NS) vs07 (Plt005)vs 03 (Plt005)







034 vs 036 vs033 (NS)b

59 vs 58 vs60 (NS)b

21 vs 27 vs22 (NS)b




029 vs 030 (NS) 62 vs 62 (NS) 87 vs117 (NS)







Curre


MS

Miller

andRhoades

1350-7

540

2012

Wolters

Kluw

erH

ealth|

LippincottWilliam

samp

Wilkins

ww

wco

-neu

rolo

gyco

mS7

0 100 200 300 400 500


600 700 800 900 1000

100

075

050

025

000









amp


amp







ampamp





ampamp

]

CONCLUSION



Acknowledgements

None










5amp

























































57amp






61ampamp






REVIEW




a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION








KEY POINTS








Fingolimod


Efficacy




amp





Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp













































065 vs 054(Pfrac14009)





20 vs 43 vs 57(Plt005)

ND 01 (NS) vs07 (Plt005)vs 03 (Plt005)







034 vs 036 vs033 (NS)b

59 vs 58 vs60 (NS)b

21 vs 27 vs22 (NS)b




029 vs 030 (NS) 62 vs 62 (NS) 87 vs117 (NS)







Curre


MS

Miller

andRhoades

1350-7

540

2012

Wolters

Kluw

erH

ealth|

LippincottWilliam

samp

Wilkins

ww

wco

-neu

rolo

gyco

mS7

0 100 200 300 400 500


600 700 800 900 1000

100

075

050

025

000









amp


amp







ampamp





ampamp

]

CONCLUSION



Acknowledgements

None










5amp

























































57amp






61ampamp






REVIEW




a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION








KEY POINTS








Fingolimod


Efficacy




amp





Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp























0 100 200 300 400 500


600 700 800 900 1000

100

075

050

025

000









amp


amp







ampamp





ampamp

]

CONCLUSION



Acknowledgements

None










5amp

























































57amp






61ampamp






REVIEW




a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION








KEY POINTS








Fingolimod


Efficacy




amp





Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp

























ampamp

]

CONCLUSION



Acknowledgements

None










5amp

























































57amp






61ampamp






REVIEW




a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION








KEY POINTS








Fingolimod


Efficacy




amp





Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp















































57amp






61ampamp






REVIEW




a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION








KEY POINTS








Fingolimod


Efficacy




amp





Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp























REVIEW




a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION








KEY POINTS








Fingolimod


Efficacy




amp





Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp























KEY POINTS








Fingolimod


Efficacy




amp





Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp
























Safety


amp

]

Alemtuzumab


Efficacy






Safety









Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp




























Efficacy


Safety




Laquinimod


Efficacy



Safety





Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp

























Teriflunomide


Efficacy







Safety


B cell depletion





Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp

























Rituximab


Ocrelizumab





Ofatumumab


Daclizumab


Efficacy






Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp


























Safety


Cladribine









ampamp






CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp
























CONCLUSION



Acknowledgements

None













8amp













































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp










































48ampamp











REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp























REVIEW


for people with MS

wwwco-neurologycom

a b


Purpose of review


Recent findings


Summary


Keywords





INTRODUCTION






KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp























KEY POINTS








Individuatreatm

Treatmentstrategy

Increasicompl

environm


goals


Patiendisease p

and charact







lizedent

nglyex

ent

Economicfactors


drug regimen

Other






amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp

























amp




Compliance











odels [81011]

Concordance









amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp

























amp


0

20

40


60

80

10092

97

31


New orasevere ris




ampamp



ampamp


l therapykvigilance



59

7884



28

63





ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp

























ampamp





(1)

S24


(2)



(3)



(4)


(5)


(6)


(7)


(8)


(9)



(10)


(11)


(12)


(13)


process


wwwco-neurologycom

















CONCLUSION





Acknowledgements

None













9amp














19amp



































CONCLUSION





Acknowledgements

None













9amp














19amp






























19amp























current opinion in neurology - list information€¦ · current opinion in neurology (issn...

Documents