Multiple Sclerosis Treatment

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1 Special Supplement September 2014 Volume 16, Supplement 5 The Official Publication of the Consortium of Multiple Sclerosis Centers Optimizing Efficacy and Adherence to Multiple Sclerosis Treatment 2014 istockphoto.com/nadla/henrik5000 This continuing medical education activity is provided by This activity is supported by an educational grant from Teva Pharmaceuticals ijmsc.org

2 Optimizing Efficacy and Adherence to Multiple Sclerosis Treatment PROVIDER STATEMENT This continuing education activity is provided by SUPPORT STATEMENT This activity is supported by an educational grant from Teva Pharmaceuticals. Education activities are distinguished as separate from endorsement of commercial products. When commercial products are displayed, participants will be advised that accredited status as a provider refers only to its continuing education activities and does not imply ANCC Commission on Accreditation endorsement of any commercial products. TARGET AUDIENCE The intended audience for this activity is neurologists, multiple sclerosis nurses, nurse practitioners, and other health care professionals involved in the treatment of patients with multiple sclerosis. PURPOSE/LEARNING OBJECTIVES At the conclusion of this activity, participants should be able to: Compare the mechanisms of action and efficacy of currently available and emerging MS treatments in order to better individualize patient treatment plans. Review evidence-based medicine about the safety and efficacy of early and effective treatment of CIS and MS to aid in clinical decision-making and management strategies. Tailor multiple sclerosis therapy to optimize and achieve adherence and compliance in individual patients. COURSE CHAIR Introduction Edward J. Fox, MD, PhD Director, MS Clinic of Central Texas Clinical Assistant Professor University of Texas Medical Branch Round Rock, TX FACULTY Relevance of MOA in MS Treatment Efficacy Thomas P. Leist, MD, PhD Professor of Neurology Chief, Division of Clinical Neuroimmunology Director, Comprehensive Multiple Sclerosis Center Jefferson University Philadelphia, PA Early and Effective Treatment of Clinically Isolated Syndrome and Multiple Sclerosis Fred D. Lublin, MD, FAAN, FANA Saunders Family Professor of Neurology Director, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis Co-Chief Editor, Multiple Sclerosis and Related Disorders Icahn School of Medicine at Mount Sinai New York, NY Adherence and Compliance: Applying Concepts to Practice to Improve Outcomes Megan R. Weigel, DNP, ARNP-c, MSCN Advanced Registered Nurse Practitioner Baptist Neurology Beaches Division Jacksonville Beach, FL CME INFORMATION Provider Statement: This continuing medical education activity is provided by Vindico Medical Education. Accreditation Vindico Medical Education is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Credit Designation Vindico Medical Education designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurse practitioners can apply for AMA PRA Category 1 Credit(s) through the American Academy of Nurse Practitioners (AANP). AANP will accept AMA PRA Category 1 Credit(s) from organizations accredited by Accreditation Council for Continuing Medical Education. Nurse practitioners can also apply for credit through their state boards. 2

3 CNE INFORMATION Provider Statement: This continuing nursing education activity is provided by Vindico Medical Education. Accreditation: Vindico Medical Education, LLC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center s Commission on Accreditation. Contact Hour Statement: Vindico Medical Education will provide 1.5 contact hours for nurses. Vested Interest Statement: The speakers/authors disclose that they do have significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support. This enduring material is approved for 1 year from the date of original release, September 15, 2014 to September 15, HOW TO PARTICIPATE IN THIS ACTIVITY AND OBTAIN CME/CNE CREDIT To participate in this CME activity, you must read the objectives and articles, complete the CME posttest, and complete and return the registration form and evaluation. Provide only one (1) correct answer for each question. A satisfactory score is defined as answering 70% of the posttest questions correctly. Upon receipt of the completed materials, if a satisfactory score on the posttest is achieved, Vindico Medical Education will issue an AMA PRA Category 1 Credit(s) certificate within 4 to 6 weeks. PLANNING COMMITTEE AND FACULTY: Edward J. Fox, MD, PhD Fred D. Lublin, MD, FAAN, FANA Thomas P. Leist, MD, PhD Megan R. Weigel, DNP, ARNP-c, MSCN REVIEWERS: Benjamin M. Greenberg, MD, MHS Barbara Niedz, PhD, RN, CPHQ MEDICAL WRITER: Valerie Zimmerman, PhD DISCLOSURES In accordance with the Accreditation Council for Continuing Medical Education s Standards for Commercial Support, all CME providers are required to disclose to the activity audience the relevant financial relationships of the planners, teachers, and authors involved in the development of CME content. An individual has a relevant financial relationship if he or she has a financial relationship in any amount occurring in the last 12 months with a commercial interest whose products or services are discussed in the CME activity content over which the individual has control. Planning Committee and Faculty members report the following relationship(s), which are accurate at the time of original content release (May 30, 2014): Edward J. Fox, MD, PhD Consultant: Bayer, Biogen Idec, EMD Serono, Genzyme, Novartis, Teva Pharmaceuticals Speaker s Bureau: Acorda, Bayer, Biogen Idec, EMD Serono, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals Fees for Non-CE Services Received Directly from a Commercial Interest: Acorda, Bayer, Biogen Idec, Eli Lilly, EMD Serono, Genzyme, GlaxoSmithKline, Novartis, Opexa, Roche, Sanofi-Aventis, Teva Pharmaceuticals Contracted Research: Biogen Idec, Eli Lilly, EMD Serono, Genzyme, GlaxoSmithKline, Novartis, Opexa, Roche, Sanofi-Aventis, Teva Pharmaceuticals Thomas P. Leist, MD, PhD Consultant: Biogen Idec, EMD Serono, Genzyme, Novartis, Pfizer, Roche Speakers Bureau: Novartis, Pfizer, Teva Pharmaceuticals Fred D. Lublin, MD, FAAN, FANA Consultant/Advisory Board: Acorda, Actelion, Bayer, Biogen Idec, Bristol-Myers Squibb, Celgene, Coronado Bioscience, EMD Serono, Inc., Forward Pharma, Genentech, Genzyme, Johnson & Johnson, Med- Immune, Novartis, Questcor, Receptos, Revalesio, Roche, Sanofi-Aventis, Teva Pharmaceuticals, to-bbb technologies, Xenoport Contracted Research: Acorda, Biogen Idec, Celgene, Genzyme, NIH, NMSS, Novartis, Sanofi, Teva Pharmaceuticals Stocks/Ownership: Cognition Pharmaceuticals, Inc. Other: Co-Chief Editor of Multiple Sclerosis and Related Diseases 3

4 Megan R. Weigel, DNP, ARNP-c, MSCN Consultant: Genzyme, Questcor Speaker s Bureau: Acorda, Bayer, Biogen Idec, EMD Serono, Genzyme, Novartis, Pfizer, Questcor, Teva Pharmaceuticals Fees for Non-CE Services Received Directly from a Commercial Interest: PRIME, Inc Reviewers reports the following relationship(s): Benjamin M. Greenberg, MD, MHS Consultant: Novartis Contracted Research: Acorda Therapeutics, Biogen Idec Barbara Niedz, PhD, RN, CPHQ No relevant financial relationships to disclose Medical Writer reports the following relationship(s): Valerie Zimmerman, PhD No relevant financial relationships to disclose Vindico staff report the following relationship(s): No relevant financial relationships to disclose. Signed disclosures are on file at Vindico Medical Education, Office of Medical Affairs and Compliance. OVERVIEW Multiple sclerosis (MS) is a chronic disease characterized by inflammation, axonal damage, and demyelination. Over 400,000 individuals in the United States and over 2.5 million worldwide are affected by MS. With no cure for MS, the goals of disease management include stopping disease relapses, delaying or preventing disability, and improving quality of life. For clinicians who manage patients with MS, it is important to keep up-to-date with the latest treatment advances, their benefits, limitations, and optimal use so that they can provide the best outcomes for their patients. Topics to be covered in the monograph include the mechanisms of action, the efficacy of currently available and emerging MS treatments, the evidence-based medicine about the safety and efficacy of early, effective evaluation and treatment of clinically-isolated syndrome in addition to MS, as well as how to tailor MS therapy to optimize and achieve adherence and compliance. UNLABELED AND INVESTIGATIONAL USAGE The audience is advised that this continuing education activity may contain references to unlabeled uses of FDA-approved products or to products not approved by the FDA for use in the United States. The faculty members have been made aware of their obligation to disclose such usage. All activity participants will be informed if any speakers/authors intend to discuss either non-fda approved or investigational use of products/devices. COPYRIGHT STATEMENT Created by Vindico Medical Education, 6900 Grove Road, Building 100, Thorofare, NJ Telephone: ; Fax: Printed in the USA. Copyright 2014 Vindico Medical Education. All rights reserved. No part of this publication may be reproduced without written permission from the Consortium of MS Centers (CMSC), Delaware Media Group, LLC or Vindico Medical. The material presented at or in any of Vindico Medical Education continuing medical education activities does not necessarily reflect the views and opinions of Vindico Medical Education or the publisher. Neither Vindico Medical Education, the CMSC, the publisher, nor the faculty endorse or recommend any techniques, commercial products, or manufacturers. The faculty/authors may discuss the use of materials and/or products that have not yet been approved by the US Food and Drug Administration. All readers and continuing education participants should verify all information before treating patients or utilizing any product. CME QUESTIONS? Contact us at cme@vindicomeded.com 4

5 FACULTY COURSE CHAIR Edward J. Fox, MD, PhD Director, MS Clinic of Central Texas Clinical Assistant Professor University of Texas Medical Branch Round Rock, TX Thomas P. Leist, MD, PhD Professor of Neurology Chief, Division of Clinical Neuroimmunology Director, Comprehensive Multiple Sclerosis Center Jefferson University Philadelphia, PA Fred D. Lublin, MD, FAAN, FANA Saunders Family Professor of Neurology Director, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis Co-Chief Editor, Multiple Sclerosis and Related Disorders Icahn School of Medicine at Mount Sinai New York, NY Megan R. Weigel, DNP, ARNP-c, MSCN Advanced Registered Nurse Practitioner Baptist Neurology Beaches Division Jacksonville Beach, FL Publishers Joseph J. D Onofrio Frank M. Marino De laware Me dia Group 66 S. Map le Ave Ridge wood, NJ p hone jdonofrio@delmedgroup.com September 2014 Vol. 16, Supplement 5 Optimizing Efficacy and Adherence to Multiple Sclerosis Treatment 7 Relevance of MOA in MS Treatment Efficacy 11 Early and Effective Treatment of Clinically Isolated Syndrome and Multiple Sclerosis 15 Case Scenario #1 17 Adherence and Compliance: Applying Concepts to Practice to Improve Outcomes 24 Case Scenario #2 26 Q&A 30 Post-test 31 Evaluation Form Art Director James Ticchio Published by Consortium of MS Centers and Delaware Media Group, LLC. Created by Vindico Medical Education, 6900 Grove Road, Building 100, Thorofare, NJ Telephone: ; Fax: Printed in the USA. Joint Copyright 2014 Vindico Medical Education and IJMSC. All rights reserved. No part of this publication may be reproduced without written permission from the CMSC, publisher or Vindico Medical. The material presented at or in any of Vindico Medical Education continuing medical education activities does not necessarily reflect the views and opinions of Vindico Medical Education. Neither Vindico Medical Education, the CMSC, Delaware Media Group, LLC nor the faculty endorse or recommend any techniques, commercial products, or manufacturers. The faculty/authors may discuss the use of materials and/or products that have not yet been approved by the US Food and Drug Administration. All readers and continuing education participants should verify all information before treating patients or utilizing any product. 5

6 Optimizing Efficacy and Adherence to Multiple Sclerosis Treatment Despite the significant advancements that have been made in multiple sclerosis (MS) management in the last few decades, it remains an incurable, lifelong disease. The availability of disease modifying therapies has had a major impact on exacerbations and disability, while research efforts aimed at developing a cure continue, performed in parallel with research to advance our knowledge of the pathophysiology of the disease. Effective management of MS requires establishing a strong teamwork relationship between health care professionals and the patients they manage. Practitioners must have competent knowledge of the risks and benefits of the available agents, and establish a communication milieu conducive to effectively educating the patient and maintaining adequate followup of the consequences of the treatment choice. Practitioners must also understand the limitations of the clinical trials supporting the approval of the available therapeutic agents, and be alert for characteristics of the individual patient that can affect not only treatment safety and effectiveness in the real world, but also adherence to the treatment. Many factors influence medication adherence, and in addition to striving to overcome those that are modifiable, the practitioner must have good interpersonal skills and should provide motivational support to encourage adherence. A continuous educational process is essential, and it must provide appropriate, accurate information at a level of detail suitable for each patient. To provide essential knowledge that can facilitate optimizing efficacy of and adherence to MS treatment, Vindico Medical Education organized a team of experts to share their expertise and experience, and discuss case examples that exemplify some of the essential considerations that contribute to choosing among the treatment options. The mechanisms of action among the available therapies was discussed; the evidence supporting early treatment was provided, consideration was given to the latest definitions for the clinical course of MS; and concepts that can be put into practice to improve medication adherence were reviewed. I thank the participants for their contribution to the discussion and to the development of this monograph. Readers can expect to enhance their familiarity with the current evidence base that can assist with choosing the most appropriate treatment for these patients, increasing the understanding of the comprehensive teamwork necessary to assure adherence and optimize outcomes. Edward J. Fox, MD, PhD Course Chair 6

7 Relevance of MOA in MS Treatment Efficacy Thomas P. Leist, MD, PhD Multiple sclerosis (MS) is an incurable, life-long disorder that requires long-term medical management. Clinical trials assess shorter-term, generally 1 to 3 years, efficacy and safety against controls in select patient groups. Trials do not directly answer questions regarding long-term efficacy and safety. In addition to the limitations of assessing short-term outcomes in a life-long disease, applicability of clinical trial data is also affected by often stringent subject eligibility criteria, making only a small number of patients with MS eligible for a given study. Inclusion criteria define specific patient eligibility characteristics, and patients with comorbid diseases are often excluded. Factors not addressed in clinical trials may affect the effectiveness and safety of, as well as adherence to, treatment in practice. Clinical trials assess treatment efficacy, that is, they investigate performance of the intervention under controlled conditions. Effectiveness is the ability of the intervention to achieve desired outcomes in real clinical practice. Effectiveness can be influenced by many factors that often are not controlled in efficacy trials, including comorbid conditions, other treatments, patient perspective, adherence, genetic factors, and long-term safety. These limitations are applicable to clinical trials across most therapeutic areas. Several constraints specifically impact the applicability of clinical trial efficacy data to general MS practice. Endpoints focus on relapses, disability, and MRI activity and changes. Confirmed disability progression in clinical trials is often assessed using Kaplan-Meyer survival analysis. This analysis does not allow consideration of improved function beyond the confirmation timeframe for disability progression and does not capture additional episodes of functional deterioration. The Expanded Disability Status Scale (EDSS) has been a widely used primary or secondary outcome in clinical trials since Validity was established, and a strong correlation was shown with other measures. Good comparability among studies was observed, and the EDSS is fairly robust for longitudinal measurements. However, when compared with patientreported outcomes, correlation ranged from moderate to none. This may, in part, be driven by the fact that the EDSS is not a linear scale and does not adequately assess cognition and memory. MRI has changed how MS is viewed and diagnosed. Yet, despite the benefits and importance of MRI investigations in MS, imaging of gray matter lesions remains challenging in the trial setting and essentially absent in practice, and cord lesions, while a significant source of clinical complaints, are usually not assessed in trials. Despite these limitations, significant advancements during the last 30 to 40 years have brought the life expectancy of persons with MS very close to that of the general population. In a database of commercially insured patients, annual mortality rates from 1996 to 2009 were 899/100,000 for patients with MS, compared with 446/100,000 for comparator patients without MS. 2 Median life expectancy in MS is about 6 years less than that of persons without MS. MS is most frequently diagnosed in young women in their early 30s. Using the Social Security life-expectancy table, a 30-year-old woman s life expectancy is approximately 85.8 years. 3 Taking into account the effect of MS on longevity, a newly diagnosed 30-year-old woman has a good chance of living with the disease for half a century. Therefore, a person with MS may require disease modifying treatment approaches for a very long time, representing a challenge as the understanding of long-term effect of therapeutic interventions is rather limited. In addition to the physical and mental comorbidities and adverse health risks that are common in MS, these patients can be expected to develop agerelated and other comorbidities. 4 These comorbidities and lifestyle factors may delay diagnosis of MS, affect disability progression, have a negative impact on the health-related quality of life (QOL) and, in general, increase the complexity of MS management. Universal Treatment Goals in MS The first-order treatment goals in MS are reducing the number and severity of relapses, preventing and slowing disability progression, reducing the number of brain lesions as evident on magnetic resonance imaging (MRI), and reducing the rate of brain atrophy. 7

8 Table 1. Proportions of Patients Converting to Clinically Definite Multiple Sclerosis in Major Trials* CHAMPS ETOMS REFLEX BENEFIT PreCISe TOPIC ORACLE Interferon beta-1a Interferon beta-1a Interferon beta-1a Interferon beta-1b Glatiramer acetate Teriflunomide Cladribine N Dose 30 μg weekly 22 μg weekly 44 μg 1 or 3 times per week 250 μg every other day 20 mg daily 7 or 14 mg daily 3.5/5.25 mg/ kg Administration IM SC SC SC SC Oral Oral Steroid Treatment Mandatory Elective Elective Elective Elective Elective Elective Monosymptomatic only Yes No No No Yes No No Conversions, %: Treatment Group 35% 34% ~21% 28% 25% 24%-28% ~14% Placebo Group 50% 45% 38% 45% 43% 36% 34% *All studies except ORACLE (development suspended by manufacturer) were of currently approved therapies for MS SOURCE: Jacobs LD, et al. N Engl J Med. 2000;343: Comi G, et al. Lancet. 2001;357: ; Kappos, L, et al. Neurology. 2006;67: ; Comi G, et al. Lancet. 2009;374: ; Comi G, et al. Lancet Neurology. 2012;11:33-41; Miller A, et al. 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 3, 2013; Copenhagen, DK; Leist TP, et al. Lancet Neurology. 2014;13: Targeting these goals is an important part of long-term disease management, which also must consider patient safety. Effective management requires active participation of the patient in treatment selection and followup. A robust relationship is more likely to encourage patient adherence to their medications, and assure accurate reporting of difficulties and adverse effects that may be associated with their treatment. Major advances have been made in disease modifying therapies (DMT) for the treatment of patients with relapsing-remitting MS. Five interferon beta formulations, including a recently approved pegylated interferon beta-1a formulation, as well as glatiramer acetate have been approved for self-injection. Fingolimod, dimethylfumarate, and teriflunomide and approved for oral dosing. Natalizumab is approved for infusion. Seven pivotal trials using interferon preparations, glatiramer acetate, teriflunomide, or cladribine (cladribine is currently not licensed for treatment of MS) which enrolled patients 3 weeks to 3 months after a first demyelinating event showed that treatment is most effective when started early All trials, which had up to 3 years of follow-up, showed a 35% to 65% reduction in conversion to clinically definite multiple sclerosis (CDMS) in intervention group patients compared with placebo groups (Table 1). 12 In 2 of the trials patients were followed for 5 years. 13 The proportion of patients converting to CDMS was lower in the earlytreated patients when compared to those who switched to active treatment after initially being randomized to the control groups. Treatment initiation of these crossover patients was delayed by 2 to 3 years. Although these data were limited by the effects of dropouts and sampling errors, they suggest that delayed treatment is associated with a significantly increased risk of conversion to CDMS in early years after the first clinical presentation. 14 Multiple Sclerosis Therapy All current treatments are directed against or work with the immune system to decrease relapse rate and delay accumulation of brain lesions shown on MRI. 15 Several characteristics, which may have dynamic borderlines, are essential when considering a DMT (Table 2). Patient characteristics may influence the relative weight given to these therapy-centered considerations. DMTs approved for treatment of MS have distinct mechanisms of action and are viewed as interacting with the pathophysiologic processes in MS in distinct ways (Table 3; Figure 1) This may guide a change of treatment due to suboptimal effectiveness. 8

9 Table 2. Immune-centered Treatment Considerations in Multiple Sclerosis Immunomodulation Short-lasting treatment effect Pleotropic treatment effects No drug interactions Short drug half-life / Elimination Safer Moderate treatment efficacy None or minimal therapy monitoring No treatment legacy vs. Immunosuppression vs. Enduring / irreversible effect vs. Targeted treatment effect vs. Drug interactions vs. Long drug half-life vs. Riskier vs. Higher treatment efficacy vs. Required therapy monitoring vs. Treatment legacy The mechanisms of action of these MS DMTs are not completely understood, some remain unknown, and some of these medications have pleiotropic immune effects. Practitioners should be aware of the scope of the mechanisms of action as well as the pharmacokinetics, including distribution, of each treatment option to guide treatment decisions. Familiarity with the prescribing information for these agents is essential. Monoclonal antibodies can act through blocking, depleting, or modulating an immune response. The blocking anti-vla-4 monoclonal antibody, natalizumab, has been approved for the treatment of MS. However, it is available only to patients enrolled in a restricted distribution risk minimization plan (TOUCH Prescribing Program) that includes close monitoring for progressive multifocal leukoencephalopathy (PML), an adverse event that has been associated with longer-term natalizumab treatment beyond 24 infusion in patients who test positive for JC antibodies. 18 Phase III trials are underway or have been completed for other monoclonal antibodies, including the IL-2 modulating antibody daclizumab, and the depleting antibodies alemtuzumab and ocrelizumab. 9 Table 3. Approved Treatments for Multiple Sclerosis: Class and Mechanism of Action Class Approved Agent Administration Immunosuppressive anti-neoplastic Immunomodulator Mitoxantrone 1 Intravenous Monoclonal antibody Natalizumab Intravenous Ala-glu-lys-tyr Glatiramer acetate Self-injection copolymer 2 Cytokine Interferon beta-1a and -1b, pegylated interferon beta-1a Nrf2 pathway activator Dimethyl fumarate Oral S1P receptor antagonist Fingolimod Oral Pyrimidine synthesis inhibitor Teriflunomide Self-injection Oral 1 Indicated for secondary progressive, progressive relapsing, or worsening relapsing-remitting MS 2 Ala alanine, glu glutamic acid, lys lysine, tyr tyrosine; antigenically similar to myelin basic protein Summary In summary, MS is a long-term disorder that is not yet curable, although it may be manageable. The data provided by clinical trials is important; however, effectiveness data from the real world are also necessary to allow interpretation of treatment risks and benefits in an expanded population that has characteristics not studied in clinical trials. Medical management should continually optimize effectiveness and safety of what is usually life-long treatment for these patients. Effectiveness is closely associated with the specific characteristics of individual patients. The patient must be part of the Figure 1. Purported Main Effects of Multiple Sclerosis Therapies SOURCE: Leist TP. 2014

10 treatment plan, as their involvement can have a significant impact on overall treatment effectiveness. o References 1. Meyer-Moock S, Feng YS, Maeurer M, et al. Systematic literature review and validity evaluation of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) in patients with multiple sclerosis. BMC Neurol. 2014;14: Kaufman DW, Reshef S, Golub HL, et al. Survival in commercially insured multiple sclerosis patients and comparator subjects in the U.S. Mult Scler Relat Disord. 2014;3: Social Security. Retirement Survivors Benefits Life Expectancy Calculator. Accessed July 26, Marrie R, Horwitz R, Cutter G, et al. Comorbidity, socioeconomic status and multiple sclerosis. Mult Scler. 2008;14: Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000;343: Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, doubleblind, placebo-controlled trial. Lancet. 2009;374: Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357: Comi G, De Stefano N, Freedman MS, et al. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurology. 2012;11: Kappos L, Polman CH, Freedman MS, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinicall isolated syndromes. Neurology. 2006;67: Leist TP, Comi G, Cree BAC, et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurology. 2014;13: Miller A, Wolinsky J, Kappos L, et al. TOPIC main outcomes: efficacy and safety of once-daily oral teriflunomide in patients with clinically isolated syndrome. 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 3, 2013; Copenhagen, DK. 12. Brownlee WJ, Miller DH. Clinically isolated syndromes and the relationship to multiple sclerosis. J Clin Neurosci. 2014:DOI: /j. jocn Marcus JF, Waubant EL. Updates on clinically isolated syndrome and diagnostic criteria for multiple sclerosis. Neurohospitalist. 2013;3: Calabresi PA, Kieseier BC, Arnold DL, et al. Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3 double-blind study. Lancet Neurol. 2014;13(7): Olek M. Treatment of relapsing-remitting multiple sclerosis in adults. UpToDate. 2014; Accessed July 26, Broadley SA, Barnett MH, Boggild M, et al. Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 1 Historical and established therapies. J Clin Neurosci. Jun :DOI: /j. jocn Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc. 2014;89: TYSABRI [Package insert]. Cambridge, MA: Biogen Idec Inc.;

11 Early and Effective Treatment of Clinically Isolated Syndrome and Multiple Sclerosis Fred D. Lublin, MD, FAAN, FANA The basic diagnostic criterion for multiple sclerosis (MS) is evidence of central nervous system (CNS) involvement that occurs at more than one time point and in more than one location; hence, the word multiple in multiple sclerosis. The clinical course of MS, described in 1996 based on expert opinion from the U.S. National Multiple Sclerosis Society (NMSS) Advisory Committee on Clinical Trials in Multiple Sclerosis, comprised 4 clinical subtypes: relapsing-remitting, primary progressive, secondary progressive, and progressive relapsing. 1 Since then, clinical and magnetic resonance imaging (MRI) data have allowed categorization of other demyelinating events and situations. The Committee reconvened and in 2013 released revisions to the earlier MS clinical course definitions. 2 They believed clarifying terminology for the disease or disability progressing/worsening was needed. Progressing has been used for worsening from multiple attacks or poor recovery from a severe attack, as well as for the beginning of the progressive phase of the disease. They suggested that progression should be reserved for patients who are in the progressive phase, independent of relapse activity, with worsening used, more generally, as warranted to describe patients with relapsing forms of the disease with step-wise worsening and those who are truly progressing (in a progressive phase of the illness). The committee urged caution when using the terms benign and malignant MS, as these terms are often misunderstood and, accordingly, misused. They are intended to describe disease severity over time, and theoretically can be observed in any of the MS phenotypes. Importantly, these terms should only be used as a retrospective determination. An important change to the classification scheme was the addition of clinically isolated syndrome as a separate MS phenotype. Although the Committee recommended that patients with radiologically isolated syndrome be monitored prospectively, it was not included as a distinct MS phenotype. Clinically Isolated Syndrome / Radiologically Isolated Syndrome A first attack of inflammatory demyelinating disease that was consistent with MS, but which had not yet fulfilled criteria of dissemination in time and/or space, became known as clinically isolated syndrome (CIS). Clinical trials of MS therapies in CIS typically aim to determine if the intervention, initiated after a first attack, can delay onset of a second attack. Regulatory agencies accepted intervention data supporting treatment that delayed conversion to a confirmed diagnosis of MS, which contributed to establishing CIS as an MS phenotype. 2 If, however, patients with a single episode also fulfill the single scan criterion for dissemination in time and space, based on the 2010 revisions to the McDonald MS diagnostic criteria, they are diagnosed with MS at the time of the first attack. 3 Common CIS presentations include optic neuritis, brainstem or cerebellar syndromes, and acute partial myelitis. 4 The event must last at least 24 hours, and is distinguished from radiologically isolated syndrome (RIS), where incidental MRI findings are consistent with MS in the absence of clinical signs and symptoms. 2,5 Patients with CIS and MRI lesions have been estimated to have an 80% long-term (within 10 to 20 years) probability of developing MS, while patients with a normal baseline MRI have an approximate 20% risk of eventually meeting diagnostic criteria for MS. 4 Data on progression from RIS to CIS and MS are limited, although persons with RIS are at risk of MS, and patients with MRI lesions that are suggestive of demyelinating pathology have an increased likelihood of developing MS clinical symptoms. 2 MS Classification and Treatment Availability Relapsing-remitting Relapsing-remitting MS (RRMS) represents 85% to 90% of disease cases at onset. 6 Most clinical trials investigate agents for this pattern, which have pro- 11

12 duced 10 FDA-approved therapies. After an initial CIS, this phenotype is characterized by clearly-defined relapses with either full recovery or recovery with sequelae and residual deficits. 1 Many patients eventually reach the secondary progressive phase of MS, which typically occurs 1 to 3 decades after disease onset. 7 Secondary Progressive Secondary progressive MS (SPMS) is characterized by an initial RRMS disease course that is followed by gradual worsening. 2,6 Relapses, minor remissions, and plateaus may or may not occur. There are no criteria to define the transition to SPMS, making it a retrospective determination. However, it usually occurs 10 to 20 years after disease onset. Emerging data suggest that persons with less recovery after an initial attack are more likely to develop secondary progressive MS. 8 The antineoplastic agent, mitoxantrone, was approved by the FDA in 2000 for reducing neurologic disability and/or the frequency of relapses in patients with secondary progressive, progressive relapsing, or worsening RRMS. 9 Mitoxantrone was shown to have significant efficacy; however, long-term treatment has been associated with cardiac dysfunction in approximately 12% of patients, and treatment-related acute leukemias in almost 1% of patients. A black box warning was added to the label in 2008 regarding these potential serious adverse events. 10 Primary Progressive Patients with primary progressive MS (PPMS) have disease progression from onset, with occasional plateaus, temporary minor improvements, and no acute relapses. 6 Although PPMS follows a different course, characterized by the absence of exacerbations prior to clinical progression, the pathophysiological features of PPMS are most likely similar to those of SPMS. 2 PPMS typically has an onset at a later age, has more even gender distribution, and may be associated with worse ultimate disability compared with patients with RRMS. There are currently no agents approved to treat PPMS. 6 Early Treatment Initiation Advocates of treating at the first attack cite clinical trial data that show reduced attacks, with lesser accumulation of damage seen on MRI, and less risk of short-term disability development. There is no evidence supporting waiting to start treatment. Choosing Therapies Considerations related to choosing MS therapies include: 1) efficacy, and where known, relative efficacy; 2) safety; and 3) convenience. Briefly, clinical research outcomes provide the most up-to-date therapeutic information. Monitoring frequency for patients with relapsing MS should be done at least annually, and should include a clinical exam and an MRI. Changes in either assessment comprise activity. With disease modifying agents (DMA), the primary interest is in the drug s efficacy. However, safety and adverse effects are also very important, as they can have a major effect on patient acceptance and medication adherence. Choosing therapies should be done in collaboration with the patient. This should be an ongoing discussion. As more therapeutic choices become available, the discussion will continue to get longer. Practitioners should partner with the patient to assure they have a good understanding of what to expect in terms of efficacy, safety, and convenience. Patients should be familiar with the various routes and schedules of administration, and any follow-up monitoring that is required. The importance of adhering to the regimen and the consequences of failing to take the treatments as prescribed should be emphasized to all patients. Practitioners should remember the caveat that despite all the research, MS is a very difficult disease to prognosticate. When changes are observed, it is not inevitable that changes will continue to develop. The effectiveness of MS treatment may be related to the agent s mechanism of action. However, depending on the patient s status, the mechanism of action may cause detrimental interactions. Comorbidities and other medical issues affecting the patient can affect the treatment response, including diabetes, smoking, and vascular disease. Adequate knowledge is necessary to allow appropriate sequencing of therapies, and agents used previously can have an impact on the effectiveness of subsequent treatment. For example, a patient who starts natalizumab after prior experience with immunosuppressive agents has an increased risk of developing progressive multifocal leukoencephalopathy, a serious and often fatal viral infection of the brain that has been associated with natalizumab use. 11 Special consideration is necessary for young women in their reproductive years; that is, the population pri- 12

13 marily affected by MS. Working closely together, the practitioner and patient must determine how to incorporate family planning into medication choices. Some agents may have consequences that occur in the future, which may require monitoring for several years. The likelihood of losing contact with the patient, without making an appropriate referral, should be considered and efforts made to avoid a gap in appropriate medical care. Strategies for Starting Therapy Three main approaches are used to start treatment. If the patient does not do well on the first-line treatment, a potentially more potent agent may be used or escalation therapy may be chosen, when a safe and effective agent is used to initiate treatment. Alternatively, with induction therapy, the patient can be started on an intensive regimen, which may be tapered off with time, depending on outcomes. Finally, there are still some practitioners who continue to do nothing; however, this number is getting smaller as the importance of providing early treatment is being more universally acknowledged. Clinical Trials of Disease Modifying Therapies for CIS Clinical trial data supporting the use of various disease modifying therapies (DMTs) were obtained from patients who had experienced a first attack that was consistent with CIS. (Table 1). 12 Primary outcomes were reported as a decreased likelihood of having another attack within a specified interval, or as time to clinically definite multiple sclerosis. In all disciplines, the importance of head-to-head trials to determine relative efficacy among agents is acknowledged. This is particularly important in MS trials, where trends in patient and disease characteristics and trial eligibility over time have had a significant impact on outcomes. Annualized relapse rates (ARR) in both placebo and treatment groups were shown to decrease over time in one study that compiled data on 32 RRMS trials, and reported a significant negative association between year of publication and ARR (P=.001). 13 In a systematic review of 56 studies, ARR in placebo groups decreased among time epochs, from 1.16 in studies performed between 1982 and 1994 to 0.41 in studies performed from 2010 to Head-to-head Trials of DMTs for Relapsing MS Results are available from a few head-to-head trials of DMTs, and data from ongoing studies are expected to provide additional information in the future. The EVIDENCE trial compared weekly, low-dose interferon beta-1a to thrice weekly, high-dose interferon beta-1a. The proportion of patients remaining relapse free after 48 weeks was significantly greater and active MRI lesions were significantly fewer in the high-dose/ high-frequency group compared with the low-dose/ low-frequency group. 15 Injection site reactions, asymptomatic liver enzyme abnormalities, and altered leukocyte counts were more frequent in the more intense treatment group. The BEYOND study compared 2 doses of interferon beta-1b (250 or 500 μg sc every other day) with glatiramer acetate (20 mg subcutaneously daily). 16 Similar relapse risk, progression, lesion volume, and brain volume after 2 to 3.5 years of followup were reported. Although overall tolerability between agents was similar, flu-like symptoms were significantly more common in patients treated with interferon, while injection site reactions were significantly more common in the glatiramer group. The CombiRx study compared low-dose/low frequency interferon beta-1a (30 μg IM weekly) and glatiramer acetate (20 mg sc daily) given in combination with the agents given individually. 17 Both the Table 1. Major Trials of Available Disease Modifying Agents for CIS Agent CHAMPS ETOMS REFLEX BENEFIT PreCISe TOPIC Interferon beta-1a Interferon beta-1a Interferon beta-1a Interferon beta-1b Glatiramer acetate Teriflunomide N Dose 30 μg weekly 22 μg weekly 44 μg 1 or 3 times per week 250 μg every other day 20 mg daily 7 or 14 mg daily Administration IM SC SC SC SC Oral SOURCE: Brownlee WJ, et al. J Clin Neurosci

14 combination and single agent glatiramer acetate had significantly reduced relapse rates compared with single-agent interferon. The combination group had less new lesion activity and accumulation of total lesion volume. However, a significant clinical benefit, measured by lessening of confirmed Expanded Disability Status Scale (EDSS) progression or change in Multiple Sclerosis Functional Composite (MSFC) scores, was not observed over 3 years. The 12-month TRANSFORMS study compared oral fingolimod (0.5 or 1.25 mg daily) with intramuscular interferon beta-1a (30 μg weekly), and showed a significantly lower ARR in both fingolimod groups compared with the interferon group. 18 MRI outcomes were also superior in the fingolimod groups. Proportions of patients with adverse events were similar among groups, although fingolimod was associated with distinct adverse events including a transient, dosedependent bradycardia. Subsequent pivotal Phase III trials of fingolimod led to FDA approval recommending the 0.5-mg dose, noting higher doses are associated with a greater incidence of adverse events without additional clinical benefit. 19 High-dose/high-frequency interferon beta-1a (dose ascending to 44 μg sc 3 times/week) was compared with 2 doses of oral teriflunomide (7 or 14 mg daily) in the TENERE study. 20 The study was completed 48 weeks after the last patient was randomized, for a median exposure duration of 64 weeks, and a maximum of 115 weeks. The primary outcome, time-to-failure, was similar among groups; however, the ARR was significantly higher with teriflunomide 7 mg. At 48 weeks, Treatment Satisfaction Questionnaire for Medication (TSQM) scores were significantly higher in both teriflunomide groups compared with the interferon group. Summary In summary, increased understanding of MS allowed reclassification of the disease course, and excellent clinical trial evidence supports the benefits of early treatment of patients with CIS/MS. Data from ongoing head-to-head trials are expected to provide more evidence on the comparative efficacy and safety of approved agents. o References 1. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46: Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology. 2014;83: Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69: Olek M. Clinically isolated syndromes suggestive of multiple sclerosis. UpToDate. 2014; Accessed August 3, Marcus JF, Waubant EL. Updates on clinically isolated syndrome and diagnostic criteria for multiple sclerosis. Neurohospitalist. 2013;3: Olek M. Clinical course and classification of multiple sclerosis. UpTo- Date. 2014; Accessed August 3, Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc. 2014;89: Novotna M, Tutuncu M, Soldan M, et al. Early relapse-recovery impacts progressive disease course in multiple sclerosis (S34.006). 66th Annual Meeting of the American Academy of Neurology; April 30, 2014; Philadelphia, PA. 9. NOVANTRONE [Package insert]. Rockland, MA: EMD Serono, Inc.; Martinelli Boneschi F, Vacchi I, Ravaris M, et al. Mitoxantrone for multiple sclerosis. Cochrane Database of Systematic Reviews. 2013(5):DOI: / CD pub TOUCH On-Line. TYSABRI (natalizumab) is available only through the TOUCH Prescribing Program, which stands for TYSABRI Outreach: Unified Commitment to Health. 2014; Accessed August 5, Brownlee WJ, Miller DH. Clinically isolated syndromes and the relationship to multiple sclerosis. J Clin Neurosci. 2014:DOI: /j. jocn Inusah S, Sormani MP, Cofield SS, et al. Assessing changes in relapse rates in multiple sclerosis. Mult Scler. 2010;16: Steinvorth SM, Rover C, Schneider S, et al. Explaining temporal trends in annualised relapse rates in placebo groups of randomised controlled trials in relapsing multiple sclerosis: systematic review and metaregression. Mult Scler. 2013;19: Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology. 2002;59: O Connor P, Filippi M, Arnason B, et al. 250 μg or 500 μg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurology. 2009;8: Lublin FD, Cofield SS, Cutter GR, et al. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol. 2013;73: Cohen J, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362: GILENYA [Package insert]. East Hanover, NJ: Novartis; Vermersch P, Czlonkowska A, Grimaldi LM, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler. 2014;20:

15 Case Scenario #1 A 25-year-old woman presented with optic neuritis in her right eye. Her visual acuity was 20/200 OD, and she had loss of color distinction and painful movement of that eye. She had no past medical or neurological history. She was engaged to be married, and hoped to start a family within the next few years. Her family history was remarkable for autoimmune thyroiditis, rheumatoid arthritis, and ulcerative colitis. Physical examination revealed an inflamed right optic disc with pseudopapilledema. Her neurologic examination was normal. Laboratory data showed normal complete blood count (CBC) and comprehensive metabolic panel (CMP). MRI-orbits revealed her prechiasmal right optic nerve was swollen and enhanced with gadolinium. MRI-brain revealed 5 lesions, including an asymptomatic gadolinium-enhancing lesion in the corpus callosum. A lumbar puncture was not performed. Fred D. Lublin, MD, FAAN, FANA: This patient has had a single episode of optic neuritis. Review of the full MRI information would most likely show that she meets MRI criteria for dissemination in time, and most likely space as well (Table 1). 1,2 Therefore, despite this being her first attack, she is probably diagnosable as having multiple sclerosis. If not, she would be diagnosed as clinically isolated syndrome (CIS). Table 1. Clinically Isolated Syndrome: 2010 McDonald MRI Criteria for Dissemination in Space and Time Dissemination in Space Dissemination in Time 1 T2 lesion in at least 2 of 4 areas:* Periventricular Juxtacortical Infratentorial Spinal cord Either: A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI, OR Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time *If symptoms are referable to the brainstem or spinal cord, these sites do not contribute to dissemination in space SOURCE: Brownlee WJ, et al. J Clin Neurosci. 2014;doi: /j. jocn [Epub ahead of print] Considerations that may influence the choice of disease modifying therapy for this patient include: 1) the type of relapse that has occurred; 2) her age and childbearing potential; 3) recovery from this first clinical event; 4) opinion regarding acceptance of the treatment risk; and 5) desirability of optimal tolerance of therapy. All of these considerations are important. With regard to type of relapse, optic neuritis has a somewhat better prognosis over time compared with brain-stem cerebellar lesions or spinal cord lesions. The patient is young and approaching the time when she will want to start a family; yet she will be on medication for the long term. When discussing options with the patient, it would be appropriate to suggest that she and her husband consider having a child as soon as possible, deferring the start of therapy, and being optimistic that she will be spared another attack in the meantime. The patient can be told that the risk of flare-up during pregnancy decreases with each trimester, which may assist her with her decision. If she chooses to start a family first, the practitioner should be prepared to discuss when therapy should be initiated after delivery, and educate her on breast-feeding issues as well. The mechanism of action of the drug choices can also influence the treatment selection decision. Clinical trial data have shown that treatments currently available begin having a statistically meaningful effect after approximately 2 months; therefore, the rapidity of effect is not substantially different among agents. Factors related to the mechanism of action that may be relevant to choice of treatment include: 1) reversibility of the treatment; 2) level of immunosuppression achieved; 3) likelihood of causing blood-work abnormalities; and 4) worsening of extant symptoms. Thomas P. Leist, MD, PhD: For this patient, her desire to become pregnant and other individual characteristics should be considered with regard to the possible impact of these factors. Acceptance of treatment risk and optimal therapy tolerance are important discussions to have with all patients. Partnering with the patient requires detailed discussions that help making an informed choice as part of an optimal treatment plan. There are no reliable prognostication utilities that 15

16 can be used early in the course of MS to guide selecting between induction or escalation treatment strategies. If criteria are eventually defined that allow identification of patients who warrant being treated aggressively, outcomes may be improved in those patients. In this case, the patient chose to start treatment. She had a partial response to steroids, after which she agreed to start a disease modifying therapy (DMT). During treatment, several characteristics can be monitored, which have varying value in identifying resumed disease activity: 1) new or enlarging lesions on MRI; 2) gadolinium enhancing lesions on MRI; 3) T1 hypointensity development on MRI; 4) clinical evidence of a new relapse; and 5) worsening of the previous symptoms. Megan R. Weigel, DNP, ARNP-c, MSCN: During the first year of treatment, new or enlarging lesions, gadolinium-enhancing lesions, and clinical evidence of a new relapse are all important indicators of response to disease modifying therapy, especially within the second half of the year. These investigations can help determine if the patient should stay on the therapy. Importantly, the patient should be educated about pseudo exacerbations, and understand that worsening of old symptoms may not indicate she is having a relapse. o References 1. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69: Brownlee WJ, Miller DH. Clinically isolated syndromes and the relationship to multiple sclerosis. J Clin Neurosci. 2014;doi: /j. jocn [Epub ahead of print] 16

17 Adherence and Compliance: Applying Concepts to Practice to Improve Outcomes Megan R. Weigel, DNP, ARNP-c, MSCN Multiple sclerosis (MS) creates a complicated environment for making treatment decisions. Individualized disease modifying therapy (DMT) selection is based on the state of MS, other medical conditions and medications, the patient s psychosocial and physical needs, and financial concerns. Practitioners must establish a successful partnership with their patients, and assure the management plan and its changes over time is completely understood, with shared ownership of the plan by the patient. Treatment adherence is of primary importance to the success of any management plan. Adherence can be affected by drug factors, including complexity and efficacy of treatment regimen, drug cost, expectations of therapy, and adverse events. Patient-related factors, including psychosocial attitudes and perceptions, physical factors including convenience and ability to administer medication, system access and financial considerations also significantly impact adherence. Adherence research is an important aspect of MS management, and provides data that are used to develop strategies to affect these factors and improve outcomes. Adherence versus Compliance The terms compliance and adherence are frequently used synonymously. 1 However, nuances in their definitions may differentiate between the 2 by ascribing a power relationship to compliance, and an active, voluntary, and collaborative relationship to adherence (see box). Compliance versus Adherence* Compliance: Doing what you have been asked or ordered to do Adherence: Steady or faithful attachment * Adherence and the U.S. Health Care System A recent review of medication adherence by persons with chronic diseases reported that nonadherence accounts for $100 to $300 billion of avoidable health care costs yearly. 2 A study of 2446 patients with MS taking DMT revealed significantly lower medical costs for patients who were at least 80% adherent to their medication compared with patients who were nonadherent (P=.003). 3 However, medical cost savings may not offset increased pharmacy expenditures that can accompany increased adherence. 4 Self-administration Medication Adherence in Multiple Sclerosis The abundant research that has been performed on adherence is limited by inconsistent methodology and lack of generalizability due to study sample characteristics. Common methods of adherence monitoring include discontinuation rates, proportion of days covered, and medication possession ratios (MPR). A review of 24 studies reported adherence ranging from 41% to 88% across the 4 injectable DMTs evaluated and among studies of the same DMT. 5 Six different measures of adherence were used in the reviewed studies, including 2 variations of the MPR. Interferon beta and glatiramer acetate adherence has been reported to range from approximately 60% to 80% or more during 2 to 5 years of treatment. 6,7 Treatment discontinuation usually occurs during the first 2 years of treatment. 6,8 The Global Adherence Project, an observational study that evaluated real-world adherence to DMTs in 179 sites in 22 countries, reported 25% nonadherence in 2646 patients treated for at least 6 months, with a median time on treatment of 32 months. 9 Several studies have shown that adhering to the prescribed timing, dosing, and frequency of injectable DMT regimens is associated with a lower risk of relapse, and results in improved self-reported quality of life compared with patients who discontinue or are nonadherent. 5,10 Review of data representing 2388 patients in a national managed care database explored an association between medication (IM interferon beta-1a, SC interferon beta-1a/b, and glatiramer acetate) gaps and risk of relapse over a 24-month inter- 17

18 Drug-related Factors Perceived Lack of Efficacy Adverse Events Cost Decreased Adherence Reduced Efficacy Figure 1. Factors Leading to Poor Adherence to MS DMT KEY: DMT disease-modifying therapy, MS multiple sclerosis val. 11 During that period, 8.1% of patients had at least 1 severe relapse, defined as an MS-related hospitalization or emergency room visit. When compared with patients who had no or shorter gaps, medication gaps 90 days were significantly associated with a higher risk of severe MS relapse. The majority of factors that affect treatment adherence in MS can be categorized as drug-related or patient-related (Figure 1). Practitioners should be aware of the status of factors that contribute to reduced adherence, which can be incorporated into individual patient management plans. Drug-Related Factors and Adherence Patient-related Factors Education Psychosocial Physical System Access Perceived Lack of Efficacy Nonadherence due to a perceived lack of efficacy varies among reports. A perceived lack of efficacy was the cause of suspended therapy in 29% of 225 interferon patients during a mean followup of 4.2 ± 2.7 years. 12 Most (95%) of these patients were switched to another DMT and the majority was able to continue treatment at the end of followup. In another study, approximately half (52%) of the 17% of patients who discontinued treatment during 47 ± 29 months of followup reported lack of efficacy. 8 In a recent study of data from the North American Research Committee on Multiple Sclerosis (NARCOMS) database, almost 2000 patients with MS answered discontinuation questionnaires; lack of efficacy, which included no perceived benefit or worsening MS symptoms or disability, was the most frequent reason given. 10 Proportions 18 stopping for lack of efficacy varied among agents, from 27% for SC interferon beta-1a, to 40%, 41%, and 46% for SC interferon beta- 1b, IM interferon beta-1a, and SC glatiramer acetate. After adjusting for baseline age, gender, disease duration, and patient-determined disease steps (PDDS) score, patients were significantly more likely to stop treatment with glatiramer compared with each of the other 3 agents. Adverse Effects/Adverse Events Among injectable DMTs, adverse events (AEs) account for 14% to 51% of treatment discontinuations. 6 The most common AEs leading to clinical intervention, including treatment discontinuation, in interferon beta clinical trials were flu-like symptoms, depression, injection-site reactions, and elevated liver enzymes. Similar AEs, including flu-like symptoms (23%), depression (21%), fatigue (16%), and injection site reactions (16%), were responsible for treatment discontinuation in a retrospective study of 394 patients treated for up to 8 years. In glatiramer clinical trials, 3% to 5% of subjects discontinued because of an AE. 13 Injection site reactions, vasodilation, tachycardia, tremor, and depression were the most common AEs leading to intervention. In the NARCOMS database discontinuation study, injection stress was a reason for discontinuation in similar proportions of patients taking each of the injectable DMT agents (Table 1). 10 Considerable variation among agents was reported by discontinuing patients for injection pain (6% to 44%) and skin reac- Table 1. Patient-reported Tolerability Reasons for Treatment Discontinuation IM IFN beta-1a (n=271) Discontinued, No. (%) SC IFN beta-1a (n=86) SC IFN beta-1b (n=143) SC GA (n=172) Injection stress 42 (15) 10 (12) 17 (12) 24 (14) Skin reaction 10 (4) 23 (27) 44 (31) 67 (39) Injection pain 15 (6) 38 (44) 25 (17) 44 (26) Fever 214 (79) 23 (33) 72 (50) 29 (17) Palpitations* 40 (23) *Palpitations in interferon were defined as a safety issue KEY: GA glatiramer acetate, IFN - interferon SOURCE: Fox, RJ et al. Int J MS Care. 2013;15:

19 tion (4% to 39%). Fever was the reason for discontinuation in 17% to 79% of patients among the 4 agents. Glatiramer acetate was associated with a typically spontaneously resolving post-injection reaction that includes at least 2 of the following symptoms: flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria. This reaction was observed in approximately 16% of patients in the 5 placebocontrolled trials of the 20-mg dose, compared with 4% of placebo patients. 13 In a placebo-controlled trial of the 40-mg dose, this rate in glatiramer and placebo patients was 2% and none. This usually occurred several months after starting treatment, and can be frightening to patients and lead to discontinuation in some cases. Although realistic expectations of the risks and benefits of their treatment is important for patients to have, the AEs listed on the prescribing information may cause hesitation in some patients. Patients often fear AEs such as effects on blood count, liver abnormalities, hair thinning, cardiac problems, infections, GI issues, and flushing. Risk Management Obligations The potential for serious AEs that may be associated with some agents requires more time spent educating patients and more patient self-responsibility, which can also affect adherence. Certain agents require frequent laboratory monitoring, and careful patient selection based on the ability to fulfill these monitoring requirements may improve adherence, as well as decrease the risk of AEs. Treatment with the intravenously administered monoclonal antibody natalizumab increases the risk of developing progressive multifocal leukoencephalopathy (PML), a serious and usually fatal AE. 14 The risk is increased in patients who have undergone longer treatment, particularly for more than 2 years. Prior treatment with an immunosuppressant also increases the risk of PML when taking natalizumab. These risks have resulted in natalizumab being restricted to distribution only through the TOUCH program. Prior exposure to the John Cunningham virus (JCV) increases the risk for the development of PML. Therefore, a means to screen patients for the presence of anti-jcv antibodies is warranted. In 2012, the FDA allowed marketing of an antibody ELISA test, which can help determine the risk for developing PML in patients for whom natalizumab is being considered. 15 This test is recommended every 6 months while on therapy, and can be triggered by TOUCH recertification. The prescribing information for the oral drug fingolimod includes specific monitoring information for bradycardia after the first dose. 16 A minimum of 6 hours of observation includes hourly pulse and blood pressure measurements, and ECG before dosing and at the end of the observation period. Prior to starting fingolimod, a complete blood count, liver function testing, ophthalmologic evaluation, and varicella zoster virus antibody testing is recommended, as well. Teriflunomide, one of the other oral agents, has a boxed warning for hepatotoxicity in its prescribing information, which requires obtaining transaminase and bilirubin levels within 6 months of starting Teriflunomide, as well as screening for tuberculosis exposure. 17 During treatment, ALT levels should be determined at least monthly for 6 months. Before treatment with oral dimethyl fumarate, a complete blood count within 6 months of drug start should be done, as well as at least annually following therapy start. 18 Cost Economic feasibility plays an important role in any treated medical condition, including MS. 19,20 Patient insurance status, and burden of the medication cost on the patient can affect adherence. Increased drug copayments have been shown to be associated with decreased adherence, 21 although some patients have coinsurance that can reduce copayments. Office visit copays can affect adherence in the setting of increased appointment frequency with the newer DMTs. Similarly, more laboratory and ancillary testing required with the newer DMTs can affect willingness and ability to adhere to a treatment if the patient must bear some financial responsibility for the testing. Patient-related Factors Education Patient education is critical for maximizing adherence. 19 Patients who understand their condition, the need for treatment, and potential treatment benefits may be less likely to abandon a treatment regimen, and empowering patients by giving them an active role in treatment decisions can enhance motivation. 22 Patients with MS who understand their disease know 19

20 they will have periods of relapse and remission, and it is important that they know these will be uncertain and unpredictable. Patients with stable disease, however, can become complacent, and have been shown to have poorer adherence and more missed appointments. 23 In addition, patients often have unrealistic expectations of DMTs. 24 If patients have a relapse while on medication, they may believe that they failed or did something wrong, or that the drug failed. Psychosocial Several psychosocial factors can impact patient adherence. Education level, underlying mood disorders, support system availability, baseline quality of life, daily schedule, and expectations of therapy are a few of the important characteristics practitioners should become and remain familiar with about their patients. Patients should be nurtured to acquire a greater sense of control over their disease. This can be enhanced by improving patient self-efficacy, which has been defined as the ability to organize and implement a course of action, to initiate coping mechanisms for an unfavorable task, persist in the behavior, and set goals to encourage persistence. 24 In a survey study that enrolled a convenience sample of 108 patients who began treatment with glatiramer acetate, the Multiple Sclerosis Self-Efficacy Scale (MSSE) was a significant predictor of adherence, while the Herth Hope Index, Performance Scales, previous use of immunomodulatory therapy, and level of perceived support were without predictive value. 25 A larger study explored self-efficacy in 556 persons with MS, including 124 men and 432 women with relapsing-remitting MS and progressive MS. 26 Women had a significantly greater belief in their ability to function with MS compared with men, and a nonsignificantly greater belief in their ability to control their MS. Within gender groups, persons with a relapsing form of MS had significantly higher levels of self-efficacy in both control and function subscales. The authors concluded that strategies to increase selfefficacy are warranted, and can include skill training for self-management, educating and supporting the patient and family, providing a role model for the patient, encouraging physical reconditioning, and referring to a support group that addresses individual needs. Cognitive dysfunction also affects adherence. Similar to results observed across all therapeutic areas, 2 many studies have reported forgetfulness as the main cause of missed treatments by persons with MS. 6 In a survey study of 798 patients taking DMT, slightly more than one-third missed at least one injection. 27 Forgetting to administer the medication was the most common (58%) explanation for missing injections. Similarly, the Global Adherence Project, which reported nonadherence in 25.3% of 2646 patients treated with DMT, found forgetting to administer the treatment was the most common reason, reported by 50.6% of participants. 9 Depression is highly prevalent in patients with MS. The Therapy Optimization in MS (TOP MS) study, a large, prospective, 2-year survey study exploring associations between compliance with DMT and health outcomes, reported over half (55.2%) of almost 3000 participants screened positively for major depression. 28 Depression was an important factor in adherence in an 8-week study that reported MS patients with mood or anxiety disorders were approximately 5 times more likely to have adherence problems compared with patients with no psychiatric diagnosis. 29 Depression, memory difficulties, neuroticism, and low conscientiousness were also associated with low adherence. In addition to self-reports and medication diaries, this study used an electronic monitoring device that recorded needle disposal to track adherence. Practitioners should be alert for signs of depression, and be prepared to initiate the discussion, as these patients may be reluctant to discuss their emotional health. The TOP MS study included communications that were sent to treating physicians when severe fatigue or new or worsening depression was reported by patients taking the online survey. 28 Persons with MS face considerable challenges coping with disease-related life changes. Other life changes that emerge may also interfere with medication adherence. The stress associated with role changes, marriage, pregnancy, and the effects of other chronic illnesses can have an impact on disease management; however, any form of instability can affect adherence. 20 Fear of needles and injection anxiety can play a major role in adherence. Patients may perceive that they are doing something to themselves, rather than for themselves. A telephone survey study including baseline assessment and monthly followup for 6 months enrolled 89 subjects who had been using DMT 20

21 for 3.4 ± 3.3 years. 30 Baseline injection anxiety was an independent predictor of lower adherence at 4 and 6 months after controlling for demographics, MS disability, type of DMT, and time on DMT. Treatment requirements may be burdensome. After the FORTE study showed equivalence between the approved 20-mg daily dose of glatiramer and a 40-mg dose given 3 times per week, 31 the GALA study provided pivotal data that resulted in the January 2014 FDA approval of the reduced dosing regimen. 32 The longer half-life of the recently approved pegylated interferon beta-1a was investigated in the ADVANCE study in patient groups following 2- and 4-week dosing regimens, with data supporting superiority of the 2-week schedule after 2 years A single use autoinjector assessed in a subset of patients in ATTAIN, an extension of the ADVANCE study, was found to be convenient and easy to use. 36 Administration regimens should be suited to the individual, with regard to dosing frequency and monitoring required. Patients should understand requirements for refrigerated storage, including those that allow specific intervals of room temperature storage. 20 This can be particularly important when a patient plans to travel. Physical Factors Physical factors may affect a patient s ability to inject medication, concomitantly affecting adherence. In a study of 632 patients with MS for a mean followup of 47 ± 29 months, the Expanded Disability Status Score at entry was the main factor that predicted treatment interruption. 8 Weakness, sensory loss, visual disturbance, ataxia, and tremor can all affect patient dexterity and contribute to impaired self-injection. In addition, for some patients the safety of the home environment may not be adequate to allow them to optimize their limited capabilities. System Access A patient s level of trust in health care providers can also impact adherence. This trust should be established at the time of diagnosis, which is a life-altering event for the patient. 20 Practitioners should clearly show their willingness to take the necessary time, and calmly explain the condition while maintaining eye contact with the patient. If subsequent care requires long waits and difficulties making appointments, adherence may decrease. Therefore, appointments should be scheduled at reasonable, regular intervals to reinforce treatment plan and provide patients adequate time to discuss current issues, even during periods of disease quiescence. Reliable pharmacy access should also be assured. Opportunities to Improve Adherence Although some constraints to adherence are permanent, many are modifiable. 20,37 More frequent patient contact improves adherence. Offices should be readily accessible to patients, particularly for timely management of AEs. Nurse contact can be provided from pharmaceutical patient support programs as well as from the office. 38,39 A retrospective cohort study of the impact of a specialty care management program was introduced into a large commercial insurance program in 2005, and includes mailing both medication and disease-specific patient education directly to patients; nurse-managed assessment calls upon enrolling, at 3, 6, and 12 months during the first year and annually thereafter; and refill reminder calls during which the patient s status is also discussed. 4 During a 12-month study, medication adherence was significantly greater in participating patients (86%) compared with nonparticipating patients (64%; P<.001). Multivariate analysis controlling for pre-baseline characteristics, including baseline adherence, continued to support an average 18% superior adherence in participants compared with nonparticipants. In the 12 months prior to the study, hospitalization rates were similar for participant and nonparticipant groups (9.6% vs. 10.1%; P=.64), while in the 12-month study period, participants had a significantly lower hospitalization rate compared with nonparticipants (7.1% vs. 12.0%; P<.001). Patient education should provide realistic expectations for DMT therapy; however, they should also be encouraged to have hope in the future of MS therapies. The Health Beliefs Model (HBM) was tested for its ability to predict adherence in 89 patients with MS who completed telephone surveys at baseline and monthly for 6 months. 40 Of the 4 HBM constructs (perceived susceptibility, severity, benefits, and barriers to DMT adherence and satisfaction), perceived benefits uniquely predicted both adherence and satisfaction outcomes at several time points in this sample, where >80% of patients had 80% adherence during followup. The authors concluded that focus on perceived benefits of ongoing DMT therapy may be a valuable component of the patient/provider interaction. 21

22 Poor communication has been shown to be associated with poor adherence in several studies of many chronic diseases. For example, a meta-analysis showed a small but statistically significant positive association was observed between health literacy and medication adherence in several therapeutic areas. 41 The more patients know about the drugs they are given, the greater their adherence to their treatment plan. The importance of communication was supported in a meta-analysis of 127 studies of several conditions that showed that poor communication was associated with a 19% higher risk of nonadherence. 42 In MS, ineffective communication can be expressed as lack of awareness of their patients medication adherence. In an international survey study of 280 physicians and 331 patients with MS currently being treated with a DMT, almost twice as many patients admitted taking a treatment holiday (31%) compared with the proportion estimated to do so by physicians (17%). 43 Although the study was limited because the patients were not necessarily being treated by the responding physicians, the authors concluded that improvements in dialogue between the patient and health care professional could be used to increase DMT adherence and improve outcomes. To improve communication with patients, health care providers may use techniques such as motivational interviewing, and tools such as the MS-TAQ, to collaboratively develop treatment plans. 44 The injection technique may require re-training, or use of autoject devices. 20,45 When justified, DMTs with less frequent dosing should be used. 46 Regimens should be simplified when possible, and medications should be auto-filled when appropriate to the risk strategy. Opportunities should be provided for reducing costs. 2 Summary The primary reasons reported for not adhering to DMT often vary among studies. This exemplifies the importance of having a strong relationship with patients, and being aware not only of their medication adherence, but of their reasons for missing or stopping treatment. Drug- and patient-related factors that can affect adherence may be managed by assessing and responding to the patient s social and psychological situation, creating individualized treatment plans, educating the family and care partners in addition to the patient, and improving the patient-provider-office relationship. o References 1. Cramer J, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. Value Health. 2008;11: Iuga AO, McGuire MJ. Adherence and health care costs. Risk Manag Healthc Policy. 2014;7: Tan H, Cai Q, Agarwal S, et al. Impact of adherence to disease-modifying therapies on clinical and economic outcomes among patients with multiple sclerosis. Adv Ther. 2011;28: Tan H, Yu J, Tabby D, et al. Clinical and economic impact of a specialty care management program among patients with multiple sclerosis: a cohort study. Mult Scler. 2010;16: Menzin J, Caon C, Nichols C, et al. Narrative review of the literature on adherence to disease-modifying therapies among patients with multiple sclerosis. J Manag Care Pharm. 2013;19(1-a):S24-S Costello K, Kennedy P, Scanzillo J. Recognizing nonadherence in patients with multiple sclerosis and maintaining treatment adherence in the long term. Medscape J Med. 2008;10: Reynolds MW, Stephen R, Seaman C, et al. Persistence and adherence to disease modifying drugs among patients with multiple sclerosis. Curr Med Res Opin. 2010;26: Rio J, Porcel J, Tellez N, et al. Factors related with treatment adherence to interferon beta and glatiramer acetate therapy in multiple sclerosis. Mult Scler. 2005;11: Devonshire V, Lapierre Y, MacDonnell R, et al. The Global Adherence Project A multicentre observational study on adherence to diseasemodifying therapies in patients suffering from relapsing-remitting multiple sclerosis. 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September, 26, 2006, Madrid, Spain. 10. Fox RJ, Salter AR, Tyry T, et al. Treatment discontinuation and disease progression with injectable disease-modifying therapies: findings from the north american research committee on multiple sclerosis database. Int J MS Care. 2013;15: Al-Sabbagh A, Bennet R, Kozma C, et al. Medication gaps in diseasemodifying drug therapy for multiple sclerosis are associated with an increased risk of relapse: findings from a national managed care database. Abstract th meeting of the European Neurological Society; June 7, 2008, Nice, France. 12. Portaccio E, Zipoli V, Siracusa G, et al. Long-term adherence to interferon beta therapy in relapsing-remitting multiple sclerosis. Eur Neurol. 2008;59: COPAXONE [Package insert]. Overland Park, KS: TEVA Neuroscience, Inc; TYSABRI [Package insert]. Cambridge, MA: Biogen Idec Inc.; FDA. FDA permits marketing of first test for risk of rare brain infection in some people treated with Tysabr. FDA News Release 2012; ucm htm. Accessed August 7, GILENYA [Package insert]. East Hanover, NJ: Novartis; AUBAGIO [Package insert]. Cambridge, MA: Genzyme Corporation; Sempere AP, Gimenez-Martinez J. Safety considerations when choosing the appropriate treatment for patients with multiple sclerosis. Expert Opin Drug Saf. 2014;1-3. [Epub ahead of print] 19. Dor A, Lage M, Tarrants M, et al. Cost sharing, benefit design, and adherence: the case of multiple sclerosis. Adv Health Econ Health Serv Res. 2010;22: Saunders C, Caon C, Smrtka J, et al. Factors That Influence Adherence and Strategies to Maintain Adherence to Injected Therapies for Patients With Multiple Sclerosis. J Neurosci Nurs. 2010;42(Supplement): S10-S Lafata JE, Cerghet M, Dobie E, et al. Measuring adherence and persistence to disease-modifying agents among patients with relapsing remitting multiple sclerosis. J Am Pharm Assoc. 2008;48: Patti F. Optimizing the benefit of multiple sclerosis therapy: the importance of treatment adherence. Patient Prefer Adherence. 2010;4: Hancock LM, Bruce JM, Lynch SG. Exacerbation history is associated with medication and appointment adherence in MS. J Behav Med. 2011;34:

23 24. Caon C, Saunders C, Smrtka J, et al. Injectable Disease-Modifying Therapy for Relapsing-Remitting Multiple Sclerosis. J Neurosci Nurs. 2010;42(Supplement):S5-S Fraser C, Morgante L, Hadjimichael O, et al. A prospective study of adherence to glatiramer acetate in individuals with multiple sclerosis. J Neurosci Nurs. 2004;36: Fraser C, Polito S. A comparative study of self-efficacy in men and women with multiple sclerosis. J Neurosci Nurs. 2007;39: Treadaway K, Cutter G, Salter A, et al. Factors that influence adherence with disease-modifying therapy in MS. J Neurol. 2009;256: Coyle PK, Cohen BA, Leist T, et al. Therapy optimization in multiple sclerosis: a prospective observational study of therapy compliance and outcomes. BMC Neurol. 2014;14: Bruce JM, Hancock LM, Arnett P, et al. Treatment adherence in multiple sclerosis: association with emotional status, personality, and cognition. J Behav Med. 2010;33: Turner A, Williams R, Sloan A, et al. Injection anxiety remains a longterm barrier to medication adherence in multiple sclerosis. Rehabil Psychol. 2009;54: Comi G, Cohen JA, Arnold DL, et al. Phase III dose-comparison study of glatiramer acetate for multiple sclerosis. Ann Neurol. 2011;69: Khan O, Rieckmann P, Boyko A, et al. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol. 2013;73: Keller D. Peg-interferon beta-1a reduces MS relapses and progression. Medscape. 2014; Accessed August 10, Calabresi PA, Kieseier BC, Arnold DL, et al. Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurology. 2014;13: Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc. 2014;89: Seddighzadah A, Hung S, Selmaj K, et al. Single-use autoinjector for peginterferon-β1a treatment of relapsing-remitting multiple sclerosis: safety, tolerability and patient evaluation data from the Phase IIIb ATTAIN study. Expert Opin Drug Deliv. 2014;Ahead of print July 29, (doi: / ). 37. Viswanathan M, Golin C, Jones C, et al. Interventions to improve adherence to self-administered medications for chronic diseases in the United States. Ann Intern Med. 2012;157: Schapiro R. Adherence to interferon beta-1b: Beta Nurse Program. 18th Annual Meeting of the Consortium of Multiple Sclerosis Centers; June 3, 2004; Toronto, CA. 39. Kennedy P, Bowling A, Saunders C, et al. Partnership between shared solutions and MS office nurses: adherence enhancement program. Paper presented at: 21st Annual Meeting of the Consortium of Multiple Sclerosis Centers; June 1, 2007; Washington, DC. 40. Turner A, Kivlahan D, Sloan A, et al. Predicting ongoing adherence to disease modifying therapies in multiple sclerosis: utility of the health beliefs model. Mult Scler. 2007;13: Zhang NJ, Terry A, McHorney CA. Impact of health literacy on medication adherence: a systematic review and meta-analysis. Ann Pharmacother. 2014;48: Zolnierek KB, Dimatteo MR. Physician communication and patient adherence to treatment: a meta-analysis. Med Care. 2009;47: Rinon A, Buch M, Holley D, et al. The MS Choices Survey: findings of a study assessing physician and patient perspectives on living with and managing multiple sclerosis. Patient Prefer Adherence. 2011;5: Harris C, Halper J, Kennedy P, et al. Moving forward: adherence to therapy and the role of nursing in multiple sclerosis. Retrieved online: Lugaresi A. Addressing the need for increased adherence to multiple sclerosis therapy: can delivery technology enhance patient motivation? Expert Opin Drug Deliv. 2009;6: Srivastava K, Arora A, Kataria A, et al. Impact of reducing dosing frequency on adherence to oral therapies: a literature review and metaanalysis. Patient Prefer Adherence. 2013;7:

24 Case Scenario #2 A 54-year-old woman with a history of multiple sclerosis (MS) for 26 years complains of worsening in her balance over the past month, with an increase in spasticity and bladder symptoms. Her original presentation was with loss of sensation in the left arm, and she has been on 3 injectable medications over the last 15 years. She is married, with 2 grown children, and is employed full-time in the financial services market, which requires multitasking. She has a history of migraine headaches, hyperlipidemia, and hypertension. She admits adherence to her current medication is poor due to perceived drug ineffectiveness. On physical examination, she has a slowed gait with bilateral proximal and distal loss of strength in the legs. Sensory loss is greater in the legs than in the arms, with increased tone at rest. The left arm has reduced sensation to pinprick and temperature. The patient s height is 5 4 and her weight is 185 pounds. CBC is normal. CMP reveals mildly elevated transaminases (AST: 55 U/L; ALT 85 U/L), and is otherwise normal. A urinalysis is done to rule out a pseudo-relapse. There are a few WBC, nitrate and cultures are negative. Fred D. Lublin, MD, FAAN, FANA: This patient appears to be having a relapse, despite the long duration of her illness. The most common cause of a flareup in someone on a disease modifying therapy (DMT) is failure to take the medication. Several studies have shown that forgetfulness is the primary reason for nonadherence to injectable medications. Further investigation of why she is not taking her therapy is warranted. It is important to discuss her nonadherence and its causes in more detail before considering switching her medication. Although the patient said she had poor adherence, she had not been counseled to track her adherence and her statement was without definition. The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Medication Compliance and Persistence Special Interest Group defines adherence as the percentage of prescribed doses taken as prescribed over a set period of time. 1 They argue that, although an arbitrary threshold differentiating good from poor compliance is often set at 80%, this usually is not supported by research documenting its validity for a specific medication class or disease. However, the 80% may have some validity in MS adherence. One study of adherence in a medical and pharmacy claims administrative database included 2446 patients with MS who were taking a DMT. 2 Medication possession ratio (MPR: the ratio of days the subject had drug to take at the prescribed frequency [syringe counts] compared to the number of days in the interval) was used to estimate adherence, with 80% defining an adherent patient. Using this cutoff, 60% of patients were adherent, and adherent patients were significantly less likely to have relapses and MS-related hospitalizations, but not ER visits, compared with nonadherent patients. Megan R. Weigel, DNP, ARNP-c, MSCN: Obviously, we strive for 100% compliance in the clinic, and encouraging our patients to share this goal can help motivate their adherence. The TOP MS study also recently reported an association between adherence and relapse incidence, based on data from approximately 2000 patients. 3 That study combined patient reporting and medication possession ratio (MPR) tracking to assess adherence over the 2-year study interval. MPR was calculated from shipment dates for study participants, which were uploaded to the study database by participating specialty pharmacies. Selfreporting of missed doses were similar to MPR data. During the 2-year follow-up, MPR exceeded 80% for 63% of 1912 participants who remained on the same therapy during the study. However, relapses, defined as physician confirmed and/or treatment with corticosteroids, were significantly reduced (61%; P=.038) when patients had an MPR over 90% compared with patients in the <50% category. Thomas P. Leist, MD, PhD: The practitioner should devise a strategy for this patient to resolve her chronic nonadherence. Unless there is a medication tolerance issue affecting her adherence, if she is given a change in administration route or dosing frequency either for this medication or with a different medication, her nonadherence pattern may simply carry over to the new regimen. 24

25 Family reinforcement of the importance of drug adherence can be very effective. A person who is close to the patient, often a spouse, can check on the medication supply and comment if the refrigerator or medicine cupboard contains unused medication. Medication reminders can also be established with family members. Patients have many different support networks, and the practitioner should determine who in their network has the most influence. This person could be invited to come with the patient on her clinic visits. Contact with the care team also can be effective. Appointment frequency can be increased to review adherence. o References 1. Cramer J, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. Value Health. 2008;11: Tan H, Cai Q, Agarwal S, et al. Impact of adherence to disease-modifying therapies on clinical and economic outcomes among patients with multiple sclerosis. Adv Ther. 2011;28: Leist T, Zwibel H, Markowitz C, et al. Ethnicity and Patient Outcomes in the TOP MS Study. Annual Meeting of the Consortium of Multiple Sclerosis Centers; May 31, 2013; Orlando, FL. 25

26 Q&A What is the best test for monitoring a patient who is already on therapy? Megan R. Weigel, DNP, ARNP-c, MSCN: For a clinically stable patient with infrequent visits who is doing well on disease modifying therapy (DMT), MRI is the best test, as it may detect disease activity that can warrant a change in management. What factors are associated with more aggressive MS? Thomas P. Leist, MD, PhD: Although prognosticating future behavior is difficult in MS, significant lesion load, lesions in the brain stem and cerebellum, and incomplete recovery are disease characteristics that can contribute to a worsened prognosis. Life choices, such as smoking, and comorbidities, such as diabetes, can also have an impact on MS. Is radiologically isolated syndrome (RIS) asymptomatic MS? Fred D. Lublin, MD, FAAN, FANA: Some of it is asymptomatic MS. There is little question that some of these people will progress to symptomatic MS. MRI can be more sensitive than clinical examination, so it is not surprising when RIS is incidentally observed. Decades ago, these investigations were done at autopsy, and approximately 1 in 1000 brains showed pathological changes of MS without a documented history of a neurologic event. A higher level of suspicion is warranted if there are gadolinium-enhancing lesions. Spinal cord lesions also increase the risk of progressing to MS. If they fulfill the MRI criteria, their risk is also increased. These people should be followed over time, to assure timely identification of any changes in their status. What interval is required before a person can be said to have benign MS? Dr. Weigel: One definition has been that 10 years of no EDSS progression is consistent with benign MS. However, we all see patients who have no disease activity for 10 years, after which relapses occur. This is supported in the literature, as well. 1 One 30-year observational study of almost 900 patients showed that favorable 10-year disability scores were not predictive of a long-term benign course. 2 With each of the 2 subsequent decades included in the study, almost half of the patients were no longer benign. What is the best way to optimize treatment effectiveness? What endpoints are the most important to determine if a patient is on optimal treatment? Dr. Leist: The ultimate goal is for an individual with a diagnosis of MS to lead a life that approximates the potential of a person without MS. This is a comprehensive consideration that is often not fully appreciated. For example, a person may not have had a considerable shift in his EDSS, which can produce a retrospective designation of benign MS. However, cognitive effects may have required that the person quit his job, and may have seriously affected all aspects of his quality of life. I call these patients the walking wounded. When they come to the clinic, although their EDSS has not undergone a large change, interaction with these patients has deteriorated from being an elaborate discussion to a simple monosyllabic conversation. Accordingly, an important goal is to have cognitive and motoric preservation. In many patients we fall short of this goal, which exemplifies that we need better and more effective approaches to inhibiting the disease process. Dr. Lublin: My next goal is having no evidence of disease activity. That requires a therapy with which there are no relapses, no changes in the MRI at least by T2 and gadolinium-enhancing lesions, and no progression. No agent currently available achieves this in even 50% of patients after 2 years. In addition, that is just the tip of the iceberg, because cognitive and other progressive effects should also be prevented. What is the best way to communicate with the patient to assure they have reasonable expectations, yet know that a high standard is being established? Dr. Weigel: One of the first things I say to all my patients is that although we are choosing a therapy together, it has to be a therapy that they are willing to 26

27 take, that they are willing to assume the risk of taking, and that they are willing to accept responsibility for taking it as prescribed. If these acceptances are in place, I have confidence they will have a better course regardless of the medication they have chosen. The reality is, if we have an idea of what is best for them, and they do not share our opinion, there is a high likelihood that they will be nonadherent. We have very effective medications available, so we should worry less about the numbers from the clinical trials and be more concerned about what we are doing in the life of a patient to help them remain 100% active across all domains that are affected by MS. Is it expected to be possible in the future to reverse existing deficits? Edward J. Fox, MD, PhD: In the present, when we talk about optimizing efficacy, we are talking about stabilization. We all hope that in future years, demyelination and restoration of neurologic function will be possible. Dr. Leist: When we assess if a patient has become disease activity-free, we are not acquiring all of the inputs. There are areas we do not sample with our MRI, and we have disability outcomes that may not be captured consistently. Recovering function in patients with MS is the next frontier. This recovery will be easier if we consider acute deficits and well-established long-term deficits initially. An underlying concern is that the MS lesions lead to inflammatory damage, with secondary injuries potentially occurring if mitochondrial injury or other factors play a role in secondary degeneration. In that case, there may be fewer reversible effects than what are desirable. Dr. Lublin: A couple of early-phase studies are looking at repair. This is an area that is just getting started, and will be interesting research to follow. Dr. Weigel: The National Multiple Sclerosis Society s research webpage ( Research) lists the research they are funding. Repairing and restoring is currently a huge initiative for them. References 1. Sayao A, Devonshire V, Tremlett H. Longitudinal follow-up of benign multiple sclerosis at 20 years. Neurology. 2007;68: Leray E, Coustans M, Le Page E, et al. Clinically definite benign multiple sclerosis, an unwarranted conceptual hodgepodge: evidence from a 30-year observational study. Mult Scler. 2013;19:

28 Educational Tool 1: Available Disease-modifying Agents Generic name Brand name Dosage Warnings (partial list) Teriflunomide Aubagio Every day; pill taken orally; 7 mg or 14 mg Interferon beta-1a Interferon beta-1b Avonex Rebif Betaseron; Extavia Once a week; intramuscular injection; 30 µg 3 times a week; subcutaneous injection; 22 µg or 44 µg Every other day; subcutaneous injection; 0.25 mg (250 µg) Glatiramer acetate Copaxone Every day; subcutaneous injection; 20 mg (20,000 µg) Liver damage, birth defects, increased risk of infections, peripheral neuropathy, renal failure/ elevated potassium, increased blood pressure Depression, seizure disorder, cardiac problems, liver abnormalities, anemia, allergic reactions Depression, seizure disorder, liver abnormalities, anemia, allergic reactions Depression, seizures, allergic reactions, injectionsite reactions Permanent depressions under the skin at injection sites; skin damage; a post-injection reaction that includes at least 2 of the following: flushing, chest pain, palpitations, anxiety, shortness of breath, constriction of the throat, and transient skin eruptions; these symptoms generally disappear spontaneously after about 15 minutes and have no known long-term effects Fingolimod Gilenya Every day; capsule taken orally; 0.5 mg Bradycardia, increased blood pressure, reduction in blood lymphocyte counts, herpetic infections, respiratory dysfunction, macular edema, liver enzyme elevations Mitoxantrone Novantrone 4 times a year by IV infusion in a medical facility (12 mg/m 2 ). Lifetime cumulative dose limit of approximately 8-12 doses over 2-3 years (140 mg/m 2 ) Dimethyl fumarate Tecfidera Twice a day; capsule taken orally; 120 mg for 1 week and 240 mg thereafter Natalizumab Tysabri Every 4 weeks by IV infusion in a registered infusion facility; 300 mg Acute myelogenous leukemia (AML); heart damage Reduction in blood lymphocyte counts; nausea; vomiting; diarrhea; abdominal pain; flushing Increased risk of progressive multifocal leukoencephalopathy (PML); not recommended for persons with weakened immune systems For more specific recommendations regarding warnings and monitoring, consult prescribing information for each drug. Source: Hilas O, et al. Open Neurol J. 2010;4:

29 Educational Tool 2: Adherence & Compliance: Applying Concepts to Practice to Improve Outcomes Opportunities to Improve Adherence Individualized DMT selection based on state of MS ± other medical conditions/medications and Psychosocial needs Level of education, underlying mood disorder, support system, baseline quality of life, daily schedule, expectations of therapy Physical needs Dexterity, safety of home environment Financial concerns Is therapy affordable? What patient and copayment assistance programs are available? More frequent contact improves adherence Nurse contact from office, from pharmaceutical patient support programs Make office accessible to patients, particularly if concerned about adverse events Education Realistic expectations of DMT Injection technique, even re-training, use of autoject devices Use of DMTs with less frequent dosing, if appropriate Provide hope about future of MS therapies In a meta-analysis of adherence to oral therapies in chronic disease, daily dosing schedules were associated with higher adherence Educate patients about goals of therapy and risk management to improve health literacy Poor communication = 19% greater risk of nonadherence. COMMUNICATE. Use dose titration, autoject devices, engage social network, simplify regimen, auto-refill meds when appropriate to risk strategy, and provide opportunities for reduced cost References: Saunders C, et al. J Neurosci Nurs. 2010;42(5 Suppl):S10-S18. Kennedy P. (2007). Presented at the 21st Annual Meeting of the Consortium of MS Centers, May 30-June 2, Washington, DC. Schapiro, R. International Journal of MS Care. 2004;6:66. Lugarese A. Expert Opin Drug Deliv. 2009;6(9): Srivastava K, et al. Patient Prefer Adherence. 2013;7: Zhang NJ, et al. Ann Pharmacother. Epub ahead of print 2014 Mar 11. Iuga AO, et al. Risk Manag Healthc Policy. 2014;7: Viswanathan M, et al. Ann Intern Med. 2012;157(11):

30 Consortium of Multiple Sclerosis Centers Annual Meeting ª Join world renowned thought leaders and experts in the field of MS for plenary sessions, workshops and symposia at the largest North American educational meeting on MS care. ª Hear from physicians, researchers and leaders in comprehensive care as they share information about cutting edge research findings, basic and translational sciences, clinical advances and new treatment strategies, emerging practice patterns, evolving healthcare delivery models, and specific advocacy issues impacting access to care. ª Enjoy networking opportunities, organized meals, awards ceremonies, poster sessions, platform presentations, research interest groups, and exhibits with the latest products and services- all included in your registration fee! ª Earn continuing education credit from our fully accredited program that includes credit for physicians, nurses, pharmacists, social workers and psychologists. May JW Marriott Hotel Indianapolis, Indiana