From Emerging Agents to Biomarkers: Integrating Scientific Advances into MS Management

Transcription

1 Special Supplement December 2013 Volume 15, Supplement 2 The Official Publication of the Consortium of Multiple Sclerosis Centers From Emerging Agents to Biomarkers: Integrating Scientific Advances into MS Management 6 Improving Early Diagnosis and Assessment in MS 12 Individualizing Disease-Modifying Therapy to Improve Adherence 17 Current and Evolving Biomarkers in MS 19 Summary 22 Post-test This supplement is supported by an independent educational grant from Teva Neuroscience Release Date: December 15, 2013 Expiration Date: December 15, 2014 Estimated time to complete this activity is 1.25 hours. ijmsc.org

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3 From Emerging Agents to Biomarkers: Integrating Scientific Advances into MS Management CME Release Date: 12/15/2013; Valid for credit through 12/15/2014 SUPPLEMENT SUMMARY MS is a chronic, progressive, inflammatory, and neurodegenerative disease of the central nervous system that leads to significant disability. The push towards ever earlier diagnosis and treatment of MS and the rapid emergence of novel agents are causing considerable changes to the management of the disease. The decisions regarding when to initiate treatment and which agents to use, along with deliberations on long-term management, are all increasingly difficult, with adherence issues continuing to negatively impact outcomes and add to the intricacy of MS treatment. The emerging data on biomarker research, aimed at increasing diagnostic accuracy and aiding in management, adds to the complexity of decision-making in MS. This program provides neurologists and MS specialists with updates on the latest advances in MS diagnosis and management, so that they can optimize outcomes for their patients with MS. TARGET AUDIENCE This activity is intended for neurologists, nurses, and other health care providers actively involved in the care of patients with multiple sclerosis. LEARNING OBJECTIVES At the conclusion of this activity, participants should be able to demonstrate the ability to: Describe the mechanisms of action and efficacy and safety profiles of current and emerging DMD therapies in MS Select and initiate effective DMD therapies earlier in the course of MS Provide patient-tailored therapy to optimize adherence, increase effectiveness, and improve patient outcomes Apply improved MRI measures and diagnostic biomarkers to allow for earlier diagnosis of MS Assess the clinical utility of MRI measures and biomarkers to monitor disease activity and response to DMD therapy DISCLOSURE INFORMATION Potomac Center for Medical Education (PCME) adheres to the policies and guidelines, including the Standards for Commercial Support, set forth to providers by the Accreditation Council for Continuing Medical Education (ACCME) and all other professional organizations, as applicable, stating those activities where continuing education credits are awarded must be balanced, independent, objective, and scientifically rigorous. All persons in a position to control the content of a continuing medical education program sponsored by PCME are required to disclose any relevant financial relationships with any commercial interest to PCME as well as to learners. All conflicts are identified and resolved by PCME in accordance with the Standards for Commercial Support in advance of delivery of the activity to learners. The content of this activity was vetted by an external medical reviewer to assure objectivity and that the activity is free of commercial bias. 3

4 The faculty/steering committee reported the following relevant financial relationships that they or their spouse/ partner have with commercial interests: Name of Faculty Suhayl Dhib-Jalbut, MD Clyde E. Markowitz, MD Aaron E. Miller, MD Reported Financial Relationship Consultant: Bayer, Biogen Idec, EMD Serono, Teva; Speaker: Teva; Primary Investigator: Teva Consultant: Acorda, Bayer, Biogen Idec, Genentech, Novartis, Questor, Sanofi-Genzyme, Teva Consultant: EMD Serono, GlaxoSmithKline, Nuron Biotech, Ono Pharmaceutical, Teva Neuroscience; Consultant/Research: Acorda, Biogen Idec, Genzyme/Sanofi-Aventis, Novartis Non-faculty Content Contributors: Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Matthew Horn, MD; P. Susan Jordan, PharmD; Paula Larson; Blair St. Amand; Jay Katz, CCMEP; Ashley Marostica, MSN, RN; Amanda Glazar, PhD, Dana Simpler, MD; provided editorial assistance or served as content and/or editorial reviewers: All have disclosed no relevant financial relationships. Editorial assistance was provided by P. Susan Jordan, PharmD. FDA DISCLOSURE The contents of some CME/CE activities may contain discussions of non-approved or off-label uses of some agents mentioned. Please consult the prescribing information for full disclosure of approved uses. ACCREDITATION STATEMENTS Physicians: This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Potomac Center for Medical Education and Rockpointe. The Potomac Center for Medical Education is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Nurses: Global Education Group is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center s Commission on Accreditation. DESIGNATION STATEMENT Physicians: The Potomac Center for Medical Education designates this enduring activity for a maximum of 1.25 AMA PRA Category I credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. For questions regarding this activity, please contact@rockpointe-pcme.com. Nurses: This educational activity for 1.25 contact hours is provided by Global Education Group. Nurses should claim only the credit commensurate with the extent of their participation in the activity. For questions, please contact Global at inquire@globaleducationgroup.com or INSTRUCTIONS FOR PARTICIPATION AND CREDIT This activity is designed to be completed within the time designated; clinicians should claim only those credits that reflect the time actually spent in the activity. In order to obtain credit for this activity: 1. Complete the online post-test at: 2. Earn a score of 70% or higher 3. Complete the program evaluation Certificates will be available online after completion. There are no fees for participating in or receiving credit for this educational activity. Jointly Sponsored by: Co-provided by: 4

5 FACULTY December 2013 Vol. 15, Supplement 2 ACTIVITY CHAIR Suhayl Dhib-Jalbut, MD Professor and Chairman Department of Neurology Rutgers-Robert Wood Johnson Medical School Chief, Neurology Service Robert Wood Johnson University Hospital New Brunswick, NJ Clyde E. Markowitz, MD Chief, MS Section Director, MS Center Associate Professor of Neurology Perelman School of Medicine University of Pennsylvania Philadelphia, PA Aaron E. Miller, MD Professor of Neurology Medical Director, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis Mount Sinai Medical Center New York, NY From Emerging Agents to Biomarkers: Integrating Scientific Advances into MS Management 6 Improving Early Diagnosis and Assessment in MS 12 Individualizing Disease-Modifying Therapy to Improve Adherence 17 Current and Evolving Biomarkers in MS 19 Summary 22 Post-test Publishers Joseph J. D Onofrio Frank M. Marino Delaware Media Group 66 S. Maple Ave Ridgewood, NJ phone jdonofrio@delmedgroup.com Art Director James Ticchio Copyright 2013 by the Consortium of Multiple Sclerosis Centers and Rehabilitation in Multiple Sclerosis. All rights reserved. None of the contents of this publication may be reproduced without prior written permission from the publisher. Statements and opinions in this publication are solely those of the authors and contributors and not of the publisher, sponsor, or Editorial Board. ISSN

6 From Emerging Agents to Biomarkers: Integrating Scientific Advances into MS Management Ongoing advances in the science of multiple sclerosis (MS) are contributing to improvements in the care of patients by slowing disease progression and disability. Advances in understanding the immunopathogenesis of MS are leading towards earlier diagnosis, better treatment, and the development of biomarkers of disease activity. As the inflammatory processes involved in MS have been defined, more biomarkers with potential clinical utility have been identified. The emergence of oral therapies and less frequent dosing schedules for injectable drugs are also changing the management of MS. These changes in treatment show promise for improving adherence to therapy; thus, lessening the negative impact on outcomes associated with poor adherence. However, with all these advances, decisions regarding when to initiate treatment and which agents to use, along with deliberations on long-term management, are increasingly complex and difficult for physicians. This supplement discusses the advances in the science of MS and their application in the complex clinical decision-making process to provide better patient management and optimize outcomes. IMPROVING EARLY DIAGNOSIS AND ASSESSMENT IN MS The importance of early diagnosis of MS is best appreciated by an understanding of the natural history of untreated disease. One goal of the early diagnosis and treatment of MS is to prevent patients with clinically isolated syndrome (CIS), who have experienced their first clinical event, from progressing to clinically definite (CD) MS (Figure 1). Progression to CDMS is characterized by greater degenerative changes and increased disease burden and brain atrophy on MRI. MS is currently considered to have three basic components: inflammation, demyelination, and axonal loss (Figure 2). 1-4 Axonal loss (a correlate of disability) and brain 6 atrophy occur early in the MS disease process and are due to an inflammatory process. Initially, the loss of axons may be completely asymptomatic. However, each attack contributes to greater axonal loss, leading to chronic functional impairment and permanent neurological deficit, resulting in greater Figure 1. Disease type and disability progression. 47 Reprinted from Weiner HL. The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease? Ann Neurol. 2009;65: with permission of John Wiley and Sons American Neurological Association. Published by Wiley-Liss, Inc., through Wiley Subscription Services.

7 Figure 2. The immunopathogenesis of multiple sclerosis involves inflammation early in the disease process that leads to demyelination and axonal loss. Initiating treatment early in the disease process can limit axonal loss, a correlate of disability. disability, fatigue, and cognitive impairment, as well as depression and other psychiatric symptoms in some cases. 5, 6 For patients with untreated MS, 30% to 50% will have a worsening by 1.0 unit on the Expanded Disability Status Scale (EDSS) within 2 to 3 years, with relapsing MS leading to secondary progressive (SP) MS after 10 years in 50% of patients. 7, 8 Patients with MS express concerns about loss of mobility and cognitive function: up to 44% will need an assistive device for walking within 5 years, and 45% to 65% experience cognitive impairment that affects their employment, social life, and daily functioning. 9, 10 Currently, there is no routine screening tool for assessing cognitive function in the clinic. Several risk factors have been identified as contributors to more aggressive disease and predictors of the course of MS (Table 1). 11 Patients are classified into risk groups based on the number of risk factors present: low risk, 0 to 1 risk factor; medium risk, 2 to 3 risk factors; and high risk, 4 to 6 risk factors. The type of symptoms at onset affects outcome: cerebellar and motor symptoms are associated with a worse prognosis than are sensory symptoms. Patients who experience symptoms while on therapy or have significant residual deficits after each attack also have a worse prognosis since their disease course may be more aggressive. The 7 incidence of MS is higher in women and the ratio in women compared with men is increasing and may now be as high as 3:1 or 4:1. Men, however, have a higher risk of poor outcomes. Diagnostic Considerations A case presentation is used to facilitate the discussion of early diagnosis and treatment of MS. Case Presentation DM is a 27-year-old woman who presents to the neurologist s office with complaints of blurry vision in the left eye for the past 2 days and an aching feeling around the left eye that is worse with eye movements. She has no other neurological complaints currently or in the past. Past medical, family, and social histories are not significant. Her neurologic exam showed normal mental status. Her visual fields were full, and visual acuity was normal in the right eye (20/20) but 20/100 in the left eye. She had an afferent pupillary defect with decreased red saturation in the left eye; her eye movements were intact; her other cranial nerves were normal. Her motor exam showed normal bulk, tone, and strength, as well as intact coordination; gait was narrow based with no Table 1. Risk factors that contribute to more aggressive disease and predict the course of multiple sclerosis. 11 Age at onset Symptoms at onset MRI status (at onset and at diagnosis of CDMS) Interval between first and second attack Attack frequency in first 2 years (relapse rate) Completeness of recovery from initial attacks Sex (from post-hoc analysis) Females: higher incidence of MS (approximately 2:1) Males: higher risk of poor outcomes Abbreviations: CDMS = clinically definite multiple sclerosis; MRI = magnetic resonance imaging; MS = multiple sclerosis

8 ataxia and normal tandem; sensation was normal to light touch, pin, temperature, and vibration; reflexes were normal. DM underwent an MRI of the brain that showed several non-enhancing periventricular white matter lesions and a single juxtacortical lesion. Can one make a diagnosis of MS based on the information presented for DM or should further testing be considered? Some neurologists may obtain blood tests for vasculitis, antinuclear antibody, rheumatoid factor, erythrocyte sedimentation rate, retroviral infections, and levels of vitamin D, folate, and vitamin B12, as these all may be helpful in ruling out other conditions that mimic MS. If the results of these tests are negative, one could classify the patient as having a first demyelinating event and consider treatment for MS. An additional test to consider before initiation of treatment is a cervical spine MRI, as it would provide a baseline for the patient and might be diagnostic for neuromyelitis optica (NMO) or an NMO spectrum disorder. Others, however, may not consider additional testing since the patient has classic optic neuritis with a brain MRI that is typical for MS. Since she does not meet the criteria for a definite diagnosis of MS, a test for NMO antibody may be helpful to rule out NMO. In the past, a visual evoked potential test may have been considered to determine if there were additional lesions in the opposite eye. However, since the MRI shows multiple lesions in a location different from that responsible for her clinical symptomatology, a visual potential is not necessary. The reliance on MRI findings also has lessened the need for a spinal tap. Patient DM did undergo additional testing as summarized below. Case Presentation Continued All of the blood work for DM was within normal limits, including a recent complete blood count and liver function test results. Analysis of cerebral spinal fluid found elevated protein (55), positive oligoclonal bands, and elevated IgG synthesis. A follow-up MRI of the brain showed new gadolinium-enhancing lesions consistent with MS. DM was diagnosed with left optic neuritis that was treated for 3 days with intravenous methylprednisolone 1 g. Her vision improved after 2 weeks. The question is whether to initiate treatment in DM with disease-modifying therapy. Her initial MRI of the brain showed multiple lesions in 2 different areas of the brain, fulfilling the criterion for dissemination in space, but she did not meet the criterion for dissemination in time. While she may have CIS and not definitive MS at this point, treatment should probably be considered for DM. Diagnostic Criteria The diagnostic criteria for MS have changed over time. Historically, the clinical diagnosis of MS required dissemination in space and time of lesions as described by the McDonald criteria (Table 2). 12 Increasingly, patients present following their first event, and the diagnosis of MS is made based on the results of the Table 2. Clinically definite multiple sclerosis by the McDonald criteria. Clinical Presentation 2 relapses with objective evidence 2 relapses with objective evidence of 1 lesion Additional Data Needed None 1 relapse with objective evidence of 2 lesions DIT by MRI or second relapse DIS by MRI or 2 lesions with positive CSF or another relapse 1 relapse with evidence of 1 lesion (e.g. CIS) DIS by MRI or 2 MRI lesions with positive CSF and DIT by MRI or second relapse Insidious progression suggesting MS 1 year progression and 2 of the following: (A) MRI with 9 T2 or 4 T2 and positive CSF (B) Positive spinal cord MRI (2 focal T2 lesions) (C) Positive CSF Abbreviations: CIS = clinically isolated syndrome; CSF = cerebrospinal fluid; DIS = dissemination in space; DIT = dissemination in time; MRI = magnetic resonance imaging; MS = multiple sclerosis. 8

9 initial workup and brain MRI. A 2010 revision of the McDonald criteria allows the diagnosis of MS based on a single MRI scan to obtain dissemination in time (Table 3) CIS, a precursor to MS, is the initial presentation in 90% of patients with MS. It is defined as a first neurologic episode that lasts at least 24 hours. It can be monofocal or multifocal (multiple areas of the central nervous system [CNS] involved at one time point) and is caused by inflammation/demyelination in the CNS. 15 Common CIS presentations include spinal cord syndrome (50% of patients with MS), optic neuritis (25%), and brainstem syndrome (15%). Various factors/presentations determine the risk of progressing from CIS to CDMS, including optic neuritis (30% to 75%), brainstem syndrome (47%), and spinal cord syndrome (39%). 16 The risk of progressing from CIS to MS is greatest in the first 5 years, but continues for many years, and is greater in patients with abnormal baseline MRIs. Follow-up MRI scans in patients with an initial flair after CIS, but no new symptoms, often show multiple lesions, fulfilling the criteria of dissemination in space and dissemination in time. A follow-up scan for patient DM demonstrates that she meets the MAGNIMS 2010 criteria for MS, as she has at least one lesion in more than two characteristic locations (Figure 3). Examination of the cerebrospinal fluid (CSF) potentially provides additional information regarding risk of CIS progression. A study that followed 52 patients with CIS for 6 years examined the CSF for oligoclonal bands using isoelectric focusing. 17 A higher percentage of patients who were oligoclonal band positive progressed to a second event and a diagnosis of MS compared with those who were oligoclonal band negative (32% vs. 3%). The study had high sensitivity and specificity (91% and 94%, respectively). Table 3. Evolution of diagnostic criteria for multiple sclerosis: application of magnetic resonance imaging) McDonald Criteria 2001 McDonald Criteria 2005 McDonald Criteria 2010 Dissemination in Space (either baseline or follow-up MRI) 3 of the following 3 of the following 1 lesion in each of 2 characteristic locations 9 T2 lesions of 1 Gd-enhancing lesion 9 T2 lesions 1 Gd-enhancing lesion Periventricular 3 Periventricular lesions 3 Periventricular lesions Juxtacortical 1 Juxtacortical lesion 1 Juxtacortical lesion Posterior fossa 1 Posterior fossa lesion 1 Posterior fossa lesion Spinal Cord 1 Cord lesion can replace 1 brain lesion Dissemination in Time (1) 1 Gd-enhancing lesion 3 months after CIS onset (if not related to CIS) (2) New T2 lesion with reference to a prior scan obtained 3 months after CIS Any number of lesions included in lesion count (1) 1 Gd-enhancing lesion 3 months after CIS onset (if not related to CIS) (2) New T2 lesion with reference to a prior scan obtained 30 days after CIS All lesions in symptomatic regions excluded in brain stem & spinal cord syndromes (1) Simultaneous presence of asymptomatic Gd-enhancing & non-enhancing lesions at any time (2) New T2 and/or Gd-enhancing lesion on follow-up MRI irrespective of timing of baseline scan Abbreviations: CIS = clinically isolated syndrome; Gd = gadolinium; MRI = magnetic resonance imaging. Reprinted from Neurology, Montalban X, Tintore M, Swanton J, et al. MRI criteria for MS in patients with clinically isolated syndromes;74(5): , Copyright 2010, with permission from Elsevier. 9

10 Figure 3. By the MAGNIMS 2010 Criteria for multiple sclerosis, patient DM has the disease. Images courtesy of Omar Khan, MD. A less well understood potential precursor to MS is radiologically isolated syndrome (RIS), which may represent MS before the onset of symptoms. In a study of 44 patients who had an initial MRI scan performed for reasons other than suspected MS (e.g. migraine, vertigo, trauma, familial aneurysm history) and showed ovoid, well-circumscribed, homogeneous lesions (T2 hyperintensities >3 mm that fulfilled 3 of 4 Barkhof criteria for dissemination in space, and CNS white matter abnormalities that were not typical of a vascular pattern), radiological progression occurred in 59% (24/41) of patients as evidenced by new T2 lesions, gadolinium enhancement, or enlargement of preexisting T2 lesions. This was after a median follow-up period of 2.7 years (range, 0.1 to 26.0 y). 18 Of the 41 patients administered gadolinium at baseline, 10 had at least one contrast-enhancing lesion. Examination of the CSF at baseline showed that 18/27 patients had oligoclonal bands or an elevated IgG index, a profile suggestive of MS. Of the 18 patients with positive CSF findings at baseline, 11 (61%) experienced radiologic progression, and 8 (44%) developed clinical symptoms. For the 30 patients from whom clinical follow-up data were obtained, 30% progressed to either CIS or clinically definite MS (median time to first clinically defining event, 5.4 y). Although the 10 radiological findings from this study were strongly suggestive of MS at baseline, a definitive diagnosis of MS could not be made until the patients developed symptoms, since MS is a clinical diagnosis. This study of the natural history of MS did demonstrate that patients with RIS are at increased risk of developing clinical symptoms of MS or experiencing radiologic progression. Patients with RIS pose a challenge regarding whether to make an early diagnosis of MS based on the MRI results and whether to initiate treatment. Current consensus urges caution with respect to initiating treatment based on the findings from an initial scan as, over time, disease processes other than MS might emerge in some patients while others might develop benign MS. Such patients should be followed for clinical progression and with serial MRIs, as well as an assessment of cognitive impairment. The goal is to prevent patients with preclinical RIS from progressing to CDMS (Figure 1). MRI Diagnostics Several MRI techniques are available for detecting and quantitating MS disease activity. Among the standard techniques are pre- and post-gadolinium enhanced T1-weighted scans that demonstrate breakdown of the blood-brain barrier, the initiating event in MS, which is indicative of acute inflammatory activity in the CNS. 19 Other standard techniques are proton density and T2 hyperintense weighted imaging, which represent the cumulative burden of disease and identify heterogeneous lesions, such as prior inflammatory events, demyelination, gliosis, and axonal loss. 19 T1 hypointense MRI scans identify black holes, which are indicative of serious brain injury and provide better correlation with progression of disability in SPMS than do T2 hyperintense-identified lesions. 19 Fluidattenuated inversion recovery (FLAIR) also is a conven-

11 tional MRI technique that identifies 28% more lesions than conventional SE T2 sequences, 73% of which are subcortical. 20 FLAIR detects fewer lesions in the posterior fossa and spinal cord compared with other MRI techniques. In addition, there are a number of newer MRI techniques for distinguishing MS lesions. Magnetization transfer imaging is useful for characterizing lesion types and distinguishing them from other white matter lesions. A 3% to 5% reduction in the magnetization transfer ratio (MTR) indicates edema and inflammation, while greater reductions are associated with demyelination, axonal loss, and disruption of the structural integrity of tissues. 21 The MTR shows an inverse correlation with clinical disability, 22 and quantification of the MTR in normal-appearing white matter can predict the evolution of MS. 23, 24 Another newer technique is diffusion-weighted imaging, which measures the diffusion properties of water in brain white matter. 25 It is the most sensitive MRI method for diagnosing ischemic brain infarcts. Limited data in patients with MS suggest that there is an increase in the apparent diffusion coefficient in MS plaques and normal appearing white matter compared with controls. A technique that can identify plaques in cortical gray matter of patients with MS is ultra-high field strength MRI. Functional MRI (fmri) is an investigational technique that has been used in several studies of patients with MS. During performance of a simple motor task, brain areas with significant activations are detected on fmri. Patients with MS have more significant activations during task performance indicating compensation for structural damage compared with healthy volunteers. 26 Findings to date suggest that fmri may be a sensitive method for identifying reversible vs. irreversible functional deficits in patients with MS and that it also may be useful for testing cognitive function. Magnetic resonance spectroscopy, which measures the biochemical changes that occur in tissue metabolites in the normal-appearing white matter of patients with MS, provides insights into the biochemical nature of structural changes. A decrease in N-acetylaspartate (NAA), a specific neuronal marker, a may reflect axonal dysfunction or degeneration. The typical measure in magnetic resonance spectroscopy is the NAA:creatinine ratio, which is decreased in MS lesions and in the normal-appearing white matter in MS patients. 27 Treatment Considerations Conventional wisdom regarding MS holds that it is most often a progressive disease in which most patients acquire significant disability over time. 7 Fifteen years after the onset of MS, 50% of patients will require at least a unilateral aid to walk. Patients with any relapsing form of MS (e.g. relapsing-remitting MS, SPMS with relapses, and progressive-relapsing MS) should be treated with a disease modifying therapy. The goals/ benefits of therapy are to reduce the number and severity of MS relapses, delay disease progression by clinical measures, reduce the number of new lesions on MRI (gadolinium-enhancing and T2), reduce brain atrophy, and slow cognitive decline. In addition, many trials indicate that treating patients with CIS (who have at least 2 lesions on brain MRI) can reduce the percentage of patients converting to definite MS over the next 2 years; therefore, many experts recommend such patients be offered treatment. Whether the goals/benefits of therapy in MS patients are being met should be assessed clinically on a regular basis, not just when patients experience relapses. Ideally, patients are assessed clinically every 3 to 4 months for the first 2 years after MS is diagnosed and when changes in treatment occur. Each visit should include a thorough neurological exam and documentation of relapses when they occur. Repeat MRI testing should be performed periodically (many experts suggest annually). These evaluations provide valuable information for assessing how a patient is doing on a particular drug. Other factors to be considered in an assessment of therapy are the occurrence of side effects, clinical symptoms/changes such as fatigue, declining cognition, and depression, and patient perceptions of how well/ poorly they are doing. Several factors can aid clinicians in predicting the course of MS and whether a patient will develop more aggressive disease. Table 1 lists many of these factors. In addition, approximately 80% of CIS patients, with >1 T2 lesion on the initial MRI, progressed to clinically definite MS by 20 years, and nearly 50% of patients with 10 T2 lesions will have a median EDSS score of 6 at 20 years. 28 A short interval between the first two attacks of MS indicates a more negative prognosis. 11

12 INDIVIDUALIZING DISEASE- MODIFYING THERAPY TO IMPROVE ADHERENCE Disease-modifying drug therapies for MS have been available for nearly two decades. The initially available injectable agents, such as interferon-β and glatiramer acetate, are generally safe and modestly effective, reducing the relapse rate by 30% to 35%. 29, 30 Significant reductions in progression to clinically definite MS in patients with CIS was demonstrated with interferon-β treatment: a 44% (P=0.002) reduction at 37 months was shown in the CHAMPS trial, using intramuscular interferon β-1a, and a 52% (P=0.0004) reduction at 2 years was shown in the REFLEX trial, using subcutaneous interferon β-1a. 31, 32 A 45% (P<0.0001) reduction in the 2-year probability of progression was shown in the BENEFIT trial of interferon β-1b treatment. 33 In addition, the 2-year probability of conversion to MS by the 2010 McDonald criteria was reduced by 85% (P< ) with interferon β-1b treatment. A 2-year study of glatiramer acetate demonstrated a 29% reduction in the relapse rate compared with placebo, and disability improved in a significantly greater proportion of patients as measured by the EDSS. 34 Natalizumab, a more recent agent that is administered by intravenous infusion, was approved by the FDA in 2004 for relapsing forms of MS. It is a monoclonal antibody that blocks entry of lymphocytes into the CNS by inhibiting the interaction between VLA-4, a selective adhesion molecule on the surface of lymphocytes and VCAM-1, a receptor on the vascular endothelial wall. 35, 36 In the placebo-controlled AFFIRM trial, one-year of natalizumab treatment significantly lowered the annualized relapse rate by 68% (0.81 vs. 0.26, placebo vs. natalizumab, P<0.0001), which was maintained at 2 years. 37 Although natalizumab probably is more effective than earlier therapies for MS, this reduction in relapse rate does not provide insight into its effectiveness relative to other active therapies, since no head-to-head comparison studies have been done. The primary concern with natalizumab therapy is the risk of developing progressive multifocal leukoencephalopathy (PML). The observed incidence of PML in clinical trials was 1.00 per 1000 in patients who received a mean of 17.9 monthly doses. A post-marketing analysis found the rate to be 2.63 per 1000 (from 1 dose up to 60 monthly doses) based on 224,718 patient-years of natalizumab exposure. 38 The risk of MS patients developing PML has been stratified by known risk factors, including history of immunosuppressant therapy (e.g. cyclophosphamide, methotrexate, azathioprine) and the presence of polyomavirus JC virus (JCV) antibodies. Exposure to JCV is common, with antibodies present in a majority of people; but, it is generally harmless in those without lowered immune defenses. The risk of developing PML in MS patients receiving natalizumab who are JCV antibody positive and have received immunosuppressant therapy in the past increases from 1.2 per 1000 (95% confidence interval [CI], ) in months 1 to 24 of therapy to 7.8 per 1000 (95% CI, ) in months 25 to The risk is much less in antibody positive patients who have not had prior immunosuppressant therapy: 0.35 per 1000 (95% CI, ) in months 1 to 24 and 2.5 per 1000 (95% CI, ) in months 25 to 48. The risk of PML in those who are JCV antibody negative is thought to be even lower. A point of note in assessing studies of newer vs. older drugs for MS is that the annualized relapse rate with placebo has shown a marked reduction in studies conducted after 2002 from those completed in the 1990s. This difference probably reflects that patients with less active or less aggressive disease are now included in clinical trials. Overview of Oral Therapies Although the injectable therapies for MS are effective, many patients would prefer an alternative route of administration. In the last several years, newer oral therapies have emerged, and a number are in development in phase II and phase III trials (Figure 4). The mechanisms of action and efficacy and safety profiles of selected newer therapies are discussed briefly (Table 4). 40 Fingolimod. Fingolimod is an orally administered agent, approved by the FDA in 2010 for relapsing forms of MS. It is a fungus-derived immunomodulator of the sphingosine 1-phosphate receptor (S1PR) that traps circulating lymphocytes in peripheral lymph nodes. 41 Trapping of lymphocytes inhibits their recirculation and potentially prevents invasion of pathogenic cells into the CNS. Immune surveillance by circulating memory T cells is spared. Fingolimod also readily enters the CNS and has multiple effects on neural cells, which express S1PRs. 12

13 also demonstrated significantly better MRI outcomes in patients with relapsing MS. 41, 42 In a 12-month comparative trial of patients with relapsing MS (TRANSFORMS), the annualized relapse rate was significantly lower with oral fingolimod 0.5 mg compared with intramuscular interferon β-1a (0.16 vs. 0.33; P<0.001), and MRI outcomes were significantly better with oral fingolimod. 43 Figure 4. Existing and emerging therapies for multiple sclerosis. There are several potentially serious side effects with fingolimod therapy. One In the placebo-controlled FREEDOMS clinical trial, fingolimod 0.5 mg significantly reduced the is lymphopenia, which may be profound and results annualized relapse rate by 54% (P<0.001) and disability progression by 30% (P=0.024) (Figure 5). It Experience to date has not shown that the from trapping of lymphocytes in the lymph nodes. lymphope- Table 4. Comparison of selected oral agents for relapsing multiple sclerosis. 40 Drug Mechanism of Action Outcomes Side Effects Safety/Monitoring Fingolimod Modulation of SIPR Inhibition of lymphocyte egress from lymph nodes into CNS Reductions in ARR, disability progression, Enlarging or new T2 hyperintense lesions, Gad-enhancing lesions, brain atrophy Lymphopenia Macular edema Increased liver enzyme GI disturbances Infections Close vaccination gaps (eg, Varicella zoster) CBC, Liver enzymes Ophthalomologic exam Signs of infection Cardiac rhythm Teriflunomide Downregulation of T- and B-cell proliferation by suppressing pyrimidine synthesis Reductions in ARR, disability progression, Enlarging or new T2 hyperintense lesions, Gad-enhancing lesions Neutropenia Lymphopenia Increased liver enzymes GI disturbances UTI CBC, Liver enzymes Signs of infection Dimethyl fumarate Modulation of secretion of proinflammatory cytokines Downregulation of inflammatory cell infiltration into CNS Neuroprotection via Nrf2 antioxidant pathway Reductions in ARR, disability progression, Enlarging or new T2 hyperintense lesions, Gad-enhancing lesions, brain atrophy, new T1 hypointense lesions Lymphopenia GI disturbances Flushing CBC, Liver enzymes Signs of infection Abbreviations: ARR = annualized relapse rate; CBC = complete blood count; CNS = central nervous system; Gad = gadolinium; GI = gastrointestinal. 13

14 Figure 5. Efficacy results for fingolimod from the placebo-controlled FREEDOMS trial. 42 MRI: decreased number of new and enlarging T2H and Gad+ lesions (p<0.001) 14 nia is associated with emergence of opportunistic infections other than Varicella zoster Another potential adverse event is bradycardia that requires observation of patients for 6 hours following the first dose. 44 Other potentially serious side effects of fingolimod include macular edema and liver function abnormalities. Before initiating treatment with fingolimod, patients should have a baseline complete blood count (CBC), hepatic panel, and ophthalmological examination, and have their cardiac status and Varicella immune status checked. 44 Before administration of the first dose and during the observation period, blood pressure, heart rate, and electrocardiogram should be monitored while observing for symptoms such as dizziness and tiredness. If a potentially serious bradyarrhythmia occurs during the initial observation period, additional monitoring is required until the heart rate increases. If a patient stops taking fingolimod for >14 days and treatment is restarted, the first-dose monitoring needs to be redone. During treatment, the CBC and hepatic panel should be repeated approximately every 3 months, blood pressure should be checked at each visit, and an ophthalmological exam be performed after the first 3 to 4 months of treatment and then annually. Teriflunomide. Teriflunomide, an orally administered drug, is the active metabolite of leflunomide, which is indicated for the treatment of rheumatoid arthritis. 45 Teriflunomide was approved for use by the FDA in 2012 for relapsing forms of MS. It acts primarily by inhibiting dihydroorotate dehydrogenase (DHODH), which is involved in the synthesis of pyrimidines in rapidly proliferating cells. By blocking pyrimidine, teriflunomide reduces the activity of T- and B-lymphocytes, which likely attenuates the inflammatory response to autoantigens in MS. It does not affect resting or homeostatically proliferating hematopoietic cell lines as pyrimidine pools in these cells are generated through a different salvage pathway. Lymphocytes are, therefore, still available for immune surveillance. In a placebo-controlled study of patients with relapsing MS (TEMSO), teriflunomide doses of 7 mg and 14 mg significantly reduced the annualized relapse rate by approximately 31% (P=0.0002, 7-mg dose; P=0.0005, 14-mg dose). 46 The proportion of patients with confirmed disability progression was lower with teriflunomide (7 mg: 23.7%, P=0.0835; 14 mg: 31.5%, P=0.0279) than with placebo (27.3%). In addition, teriflunomide was superior to placebo for endpoints measured by MRI. For the key MRI endpoint, burden of disease or increase in total lesion volume, the increase after 108 weeks was 39.4% (P=0.0317) lower for the 7-mg dose and 67.4% (P=0.0003) lower for the 14-mg dose compared with placebo (Figure 6). 47 A second placebo-controlled study found a greater difference in efficacy between the two teriflunomide doses: reduction in the annualized relapse rates compared with placebo were 22.3% (P=0.02) and 36.3% (P<0.0001) for the 7-mg and 14-mg doses, respectively. 48 For the 14-mg dose, there was a significant 31.5% reduction in the risk of 12-week sustained disability accumulation compared with placebo (P=0.04); whereas, the reduction with the 7-mg dose was not significant. Teriflunomide is generally well tolerated. Side effects, which are usually mild to moderate, include diarrhea, nausea, dizziness, paresthesia, alopecia, elevated liver enzymes, neutropenia, and lymphopenia. 40, 45 Safety monitoring guidelines recommended by the FDA include baseline CBC and liver function tests, screening for latent tuberculosis with a tuberculin skin

15 Figure 6. Increase in total lesion volume with teriflunomide therapy compared with placebo in the TEMSO study of patients with relapsing multiple sclerosis. 47 * = relative change from placebo Wolinsky JS et al. Mult Scler Feb 27. [Epub ahead of print]. Reprinted by Permission of SAGE. test (based on risk of reactivation of tuberculosis with leflunomide, the parent compound), and blood pressure measurement. 45 Additional monitoring includes monthly liver function tests for the first 6 months and periodically thereafter at the physician s discretion, periodic monitoring of CBC when there are signs of hematologic toxicity, and periodic blood pressure measurements. Teriflunomide has a long plasma half-life and is cleared from the body slowly. Because of the teratogenic potential of teriflunomide, women who wish to become pregnant or men who wish to father a child should undergo an elimination procedure with cholestyramine or activated charcoal after discontinuation of teriflunomide. 45 BG-12/Dimethyl Fumarate. BG-12 or dimethyl fumarate is another oral drug for relapsing MS approved by the FDA in It has several anti-inflammatory effects including modulation of the secretion of proinflammatory cytokines, downregulation of infiltration of inflammatory cells into the CNS, and an influence 15 on inflammatory cascades, as well as neuroprotective effects, via the Nrf2-mediated antioxidative path- 40, 49 ways. The placebo-controlled DEFINE trial demonstrated significant reductions in annualized relapse rates of 53% (P<0.0001) with twice daily and 48% (P<0.0001) with thrice daily doses of 240 mg of BG-12 compared with placebo. 50 There was also a significant relative risk reduction in the time to 12-week confirmed disability progression of 38% (P=0.005) with the twice daily and 34% (P=0.0128) with the thrice daily dose (Figure 7). In addition, MRI endpoints were significantly better in BG-12-treated patients. A second placebo-controlled trial, CONFIRM, also demonstrated significant reductions in the annualized relapse rate (44% twice daily dosing, 51% thrice daily dosing; P<0.001, both regimens), but the reductions in 12-week confirmed disability progression were not significant (21% and 24%, twice and thrice daily dosing, respectively). 51 Figure 7. Time to 12-week confirmed disability progression with BG-12 in the placebo-controlled DEFINE trial. 50 Gold R et al. N Engl J Med. 2012;367: Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

16 Figure 8. Treatment decisions require consideration of many factors related to the benefits and risks of any given therapy. BG-12 was well-tolerated in clinical trials. The most commonly reported adverse effects included flushing, gastrointestinal complaints (nausea, diarrhea), decreased lymphocyte counts, which may be significant, and elevated liver enzymes. 50, 51 There were no reports of malignant neoplasms or opportunistic infections. The recommended monitoring for BG-12 is a baseline CBC repeated at least yearly. However, it may be prudent to repeat the CBC more frequently (e.g. every 3 months), since significant lymphopenia may occur, and to monitor liver function test results. Since BG-12 is administered twice daily, adherence with therapy should also be monitored. 16 Therapy Considerations The increasing number of drugs available for the treatment of MS provides more options for patients, but also complicates treatment decisions. Physicians and patients must weigh the benefits and risks of each therapy, including the patient s goals for therapy and lifestyle, to insure optimum adherence to a treatment regimen (Figure 8). An example of a decision tree for starting a new patient on disease-modifying therapy for MS is illustrated in Figure 9. Good communication with patients is essential for selecting and ensuring success with therapy. The first key to good communication is to establish a relationship of trust with patients. Physicians must be cognizant of the fact that patients have access to multiple and conflicting sources of information, which is particularly important for discussions of risks vs. benefits of therapy, and clinicians must also be sensitive to the psychological and social factors that influence how patients respond to risk information. 52 Successful risk communication involves several steps: provide simple, relevant information that is responsive to the needs and values of the patient; allow for a twoway exchange of information, opinions, and values to maximize trust; recognize potential need for a series of consultations; be truthful knowing that uncertainties will remain; and acknowledge uncertainties and accept patient decisions. Practices by physicians that will aid in minimizing the risk of miscommunication and maximizing adherence with therapy are summarized in Table 5. Figure 9. Decision tree for selection of therapy in a patient about to start disease-modifying treatment for multiple sclerosis. Abbreviations: AB = antibody; Fingo = fingolimod; GA = glatiramer acetate; IFN =interferon; JCV = polyomavirus JC; NTZ = natalizumab; Teri = teriflunomide.

17 Table 5. Physician practices to minimize risks of and maximize adherence with therapy. Educate, educate, educate! See patients at regularly scheduled visits (patients should leave office with next visit scheduled) Do not order refills for longer than the time to the next scheduled appointment Adhere to recommended monitoring guidelines for drug prescribed Inquire about patient s adherence with medication regimen in a nonthreatening manner Ask about use of complementary therapie Maximizing Adherence with Injectable Therapies Less frequent administration regimens for injectable MS drugs could improve acceptance by patients, as well as adherence to therapy. Results from two placebo-controlled studies show promise for injectable therapies being administered less frequently. The GALA trial assessed the efficacy of glatiramer acetate 40 mg administered subcutaneously three times a week in patients with relapsing remitting MS. 53 There was a significant 34.4% (P<0.0001) reduction in the annualized relapse rate with glatiramer acetate 40 mg three times weekly compared with placebo. In addition, there were significant (P<0.0001) reductions in the cumulative number of gadolinium-enhancing lesions (44.8%) and in the cumulative number of new or enlarging T2 lesions (34.7%). The overall safety profile of the 40 mg three times a week regimen was consistent with that of 20 mg per day glatiramer acetate regimen. Injection-site reactions were reported more often by patients treated with glatiramer acetate than by those receiving placebo. The ADVANCE trial assessed the efficacy of 125 mcg of pegylated interferon β-1a administered subcutaneously every 2 weeks and every 4 weeks in patients with relapsing remitting MS. 54 Although efficacy results for both pegylated interferon β-1a regimens were significant, the every 2 week regimen was better overall: the reductions in the annualized relapse rate were 35.6% (P<0.001) and 27.5% (P<0.02) and the number of new or enlarging T2 lesions was reduced by 67% (P<0.001) and 28% (P<0.001) for the every 2- and 4-week regimens, respectively. Both regimens reduced the 12-week confirmed disability progression by 38% (P<0.04). The safety and tolerability profiles were favorable with both pegylated interferon β-1a regimens, and the overall incidence of adverse events, including serious events, was similar in the pegylated interferon β-1a and placebo groups. The most commonly reported adverse events with pegylated interferon β-1a treatment were redness at the injection site and flu-like symptoms. Returning to the case of the 27-year-old woman presented earlier (see box), what MS therapy would you consider? While many physicians may still opt for injectable MS therapies because of greater experience with their use, patients are now more likely to request one of the newer oral therapies or perhaps a less frequent injectable dosing regimen. Decision trees (such as the one illustrated in Figure 9) are helpful tools for physicians in selecting therapy for a specific patient. Counseling regarding risks and benefits of all of the therapy options and good communication with the patient are increasingly important strategies for selecting MS therapy. CURRENT AND EVOLVING BIOMARKERS IN MS The objectives for identifying biomarkers in MS are to predict and monitor response to therapy and to predict the risk of developing adverse events with prolonged therapy. Since MS is a heterogeneous disease that is both inflammatory and degenerative in nature, identifying biomarkers is more complex. An understanding of its immunopathogenesis and its course provide clues for potential biomarkers. In the future, genetics might supplement the current best predictor of conversion from CIS to clinically definite MS the presence of lesions on MRI at baseline. 55 The HLA DRBI*1501 genotype, which is present in approximately 50% of Caucasians, is associated with increased brain inflammatory processes at the clinical onset of MS; but, a definitive association with MRI findings has not been shown. 55 Therefore, the clinical utility of HLA DRBI*1501 genotyping is limited at present. Additional studies may better define whether early HLA DRBI*1501 genotyping will identify patients at risk for developing CDMS. 17

18 Table 6. Outcome measures with recombinant interferon-β1a 44 mcg thrice weekly treatment stratified by neutralizing antibody status. 60 Outcome Measure Relapse Rate (years 3 and 4) T2 Active Lesions (median number) Neutralizing Antibody Negative Neutralizing Antibody Positive P= P<0.001 Burden of Disease 8.5% +17.6% P<0.001 Biomarkers in MS There are two approaches to identifying biomarkers in MS: (1) large-scale array analyses and (2) testing of molecules involved in a drug s mechanism of action to determine if they have predictive value for response to treatment or development of adverse events. Findings using the latter method are discussed for selected drugs. Interferon-β. Poor response to interferon-β1a is well correlated with new MRI lesions and early relapses during treatment New gadolinium-enhancing lesions and relapse within the first 6 to 12 months of interferon-β1a treatment are likely indicators of treatment failure. Another indicator of potential interferon-β treatment failure, particularly high-dose treatment, is the induction and persistence of neutralizing antibodies, which can reduce or abolish interferon-β bioavailability. 59 The reduced efficacy of recombinant interferon-β1a 44 mcg administered thrice weekly in neutralizing antibody positive patients was shown in an analysis of outcomes by neutralizing antibody status in the PRISMS-4 study (Table 6). 60 The utility of the findings from neutralizing antibody assays is illustrated by the decision tree in Figure 10. Potential laboratory biomarkers for MS include the interleukins, specifically the IL-7/IL-27 ratio and IL-10, as well as interferon-β activity at baseline and molecular signatures There is some indication that modulation of these cytokines may predict response to interferon-β therapy. However, their role in the disease process of patients with MS requires evaluation before they can be considered clinically useful biomarkers. In summary, the findings regarding predictors of response to interferon-β treatment are the following: there are no validated laboratory markers; persistent active MRI lesions at 6 months predict clinical activity; and persistent high titers of neutralizing antibodies could be a reason to switch a patient to a non-interferon treatment. 56 Glatiramer acetate. The mechanism of action of glatiramer acetate involves its binding to major histocompatibility complex (MHC) class II molecules leading to perturbation in T cell-antigen reactivity and induction of anti-inflammatory cells and regulatory T cells. 65 Several potential biomarkers for glatiramer acetate treatment have been identified (Figure 11). 66 Those with statistical correlation to glatiramer acetate response are: an increase in IL-4/interferon-gamma ratio, increase in IL-10, and reduction in IL-18 and caspace-1. The strongest data are for human lympho- Figure 10. Clinical decision tree for neutralizing antibody assay results for patients who are not responding clinically to interferon-β treatment. Figure 11. Potential biomarkers for glatiramer acetate treatment of multiple sclerosis