Improving Management Strategies for Patients With Multiple Sclerosis:

Improving Management Strategies for Patients With Multiple Sclerosis:

Improving Management Strategies for Patients With Multiple Sclerosis: An Evaluation of Current Practice Sponsored by Integrity Continuing Education Supported by an educational grant from Novartis Practitioners Edge is a registered service mark of Integrity Continuing Education, Inc. 2014 Integrity Continuing Education, Inc. Elizabeth Crabtree, MD Associate Professor of Neurology Director of Patient Education and Support University of California San Francisco MS Center San Francisco, California 2 Faculty Disclosures

3 Learning Objectives Apply the most recent evidence-based criteria toward the diagnosis of multiple sclerosis (MS) Implement management strategies that are personalized to the individual needs of patients with MS Describe the risks and benefits of all approved therapies for the management of patients with MS Monitor response to therapy as recommended by current treatment guidelines, so that changes in a patients treatment plan can be implemented if necessary 4 Multiple Sclerosis Overview and Unmet Needs

5 Multiple Sclerosis Overview Chronic inflammatory, neuroimmune, demyelinating, and neurodegenerative disease of the central nervous system (CNS) Characterized by macroscopic and microscopic injury to gray and white matter Common manifestations are optic neuritis, partial transverse myelitis, and brain stem or cerebellar syndrome Progressive disability occurs over time Exact etiology is unknown 6 Prevalence and Burden of MS in the United States Affects ~400,000 people1

Major cause of nontraumatic disability2 Disease sequelae Multiple symptoms Disability (cognitive, motor, vocational) Psychological stress3 $8,528 to $54,244 per patient/year in direct plus indirect costs4 1. Tullman MJ. Am J Manag Care. 2013;19(2, suppl):S15-S20; 2. Miller AE, et al. Curr Opin Neurol. 2012;25(suppl):S4-S10;3. Kalb R. J Neurol Sci. 2007;256(suppl 1):S29-S33; 4. Adelman G, et al. J Med Econ. 2013;16(5):639-647. 7 Clinical Courses of MS Relapsing Remitting (RRMS)

Secondary Progressiv e (SPMS) Progressiv e Relapsing (PRMS) Unpredictable exacerbations of new symptoms or worsening of old symptoms Initially relapsing remitting course that finally

becomes progressive Progressive from onset and is characterized by intermittent relapses Progressive disease from the onset without relapses Initial onset in 85% of cases Usually the natural course

following RRMS Rare Observed in 10% to 15% of cases Miller AE, et al. Curr Opin Neurol. 2012;25(suppl):S4-S10. Primary Progressiv e (PPMS) 8 Unmet Needs in MS Delay in diagnosis and misdiagnosis Lack of biomarkers for disease activity

No curative or reparative/restorative therapy Patient compliance with therapeutic protocols 9 Pathophysiology of MS 10 Underlying Pathophysiology of MS Immune-mediated mechanisms damage CNS tissue Inflammatory response (early vs later, gray vs white matter) B-cell, follicle-like structures in cortical areas Environmental factors (vitamin D, smoking, ultraviolet light) Infectious factors (Epstein-Barr virus) Genetic factors (eg, multiple non-MHC susceptibility genes) No family history: 1/750 for developing MS Family history (parent or sibling): 1/40 for developing MS

1st-degree relative (2%-3% chance; sibling > parent) MHC, major histocompatibility complex. Handel AE, et al. Mult Scler Rel Disord. 2012;1(1):39-42; National MS Society. http://www.nationalmssociety.org/aboutmultiple-sclerosis/what-we-know-about-ms/who-gets-ms/genetics/index.aspx. 11 Observed Changes in the CNS in MS Focal demyelinated plaques disseminated in CNS Easily visualized in the white matter, but extensive gray matter involvement especially in early MS Predilection for optic nerves, subpial, spinal cord, brain stem, cerebellum and juxtacortical, and periventricular white matter regions Variable degrees of inflammation, gliosis, and neurodegeneration Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921. 12

Evidence for Gray Matter Involvement Patients with early RRMS showed significantly lower SDGM, but not cortical volumes compared with patients with CIS Evidence that significant SDGM atrophy (not cortical) occurs rapidly during first 4 years in treatment-nave patients Confirms that selective regional, but not global, atrophy occurs from clinical onset to conversion to clinically definite MS SDGM, subcortical deep gray matter; CIS, clinically isolated syndrome. Bergsland N, et al. AJNR Am J Neuroradiol. 2012;33:15731578. 13 Immune-mediated Axonal Injury Mechanisms Immune-mediated

processes lead to axonal transection Transection leads to degeneration of the distal end of the axon and the proximal end forms an ovoid due to accumulation of transported organelles Dutta R, Trapp BD. Prog Neurobiol. 2011;93(1):1-12. 14 Cortical Demyelination Patterns Dutta R, Trapp BD. Prog Neurobiol. 2011;93(1):1-12. 15

Cortical Demyelinated Lesions in Early MS: New Insights Common and may represent an early and/or initial target of MS disease process May represent the pathologic substrate of cognitive impairment and seizures in RRMS Highly inflammatory and suggests that neuronal and axonal injury in early cortical demyelination occur on a background of inflammation Meningeal inflammation is present in early MS and topographically associated with cortical lesions Infiltrates are composed of T cells, B cells, and macrophages Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921. 16 MRI of Cortical Onset MS

MRI, magnetic resonance imaging. Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921. 17 Cortical Demyelinated Lesions in Progressive MS: New Insights Very prominent Less inflammatory than white matter lesions Lack inflammatory infiltrates, complement deposition, and breakdown of blood-brain barrier Characterized by meningeal inflammatory aggregates (B cell follicle-like structures) in primary as well as secondary progressive MS Associated with increased rate of clinical progression Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921; Popescu BF, Lucchinetti CF. BMC Neurol.

2012;12:11; Howell OW, et al. Brain. 2011;134(Pt 9):2755-2771; Choi SR, et al. Brain. 2012;135(Pt 10):2925- 18 Cortical Demyelination in SPMS Howell OW, et al. Brain. 2011;134(Pt 9):2755-2771. 19 New Data on Cortical Pathology and SPMS Calabrese M, et al. Ann Neurol. 2013;74(1):76-83. 20 Other Studies on Cortical Demyelinating Lesions New MRI techniques for visualization (DIR, PSIR, T1weighted 3D FSPGR) and early diagnosis

Correlation between gray matter pathology and patient disability and cognitive impairment Effect of disease-modifying therapy on gray matter pathology Increased cortical demyelinating lesions can indicate evolution of RRMS to SPMS DIR, double inversion recovery; PSIR, phase-sensitive inversion recovery; 3D, three-dimensional; FSPGR, fast spoiled gradient echo. Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921. 21 Diagnosis of MS 22 Recommendations for Diagnosis of MS Clinical evaluation of history, symptoms, signs,

relapses, and disability progression Supplemented by paraclinical tests, including MRI, evaluation of cerebrospinal fluid (CSF) Exclusion of hereditary, psychological, and other CNS disorders Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302. 23 Challenges in the Diagnosis of MS No clinical findings are unique to MS Difficulty in patient characterization and physician interpretation of symptoms Numerous differential diagnoses of MS-like symptoms Imaging is not always specific and there may be an overreliance on MRI

Confounding comorbidities Unpredictable MS clinical courses Katz S, et al. Continuum (Minneap Minn). 2013;19(4): 922943. 24 Clinically Isolated Syndrome Typically affects young adults (aged 20-45 years) Patient demonstrates signs and symptoms suggestive of CNS demyelination Attacks last for at least 24 hours and reach a peak within 2 to 3 weeks No indication of fever, infection, or encephalopathy Many qualify for definitive diagnosis based on 2010 International Panel diagnostic criteria Katz S, et al. Continuum (Minneap Minn). 2013;19(4): 922943; Lo CP, et al. J Neurol Neurosurg Psychiatry. 2009;80(10):1107-1109.

25 Steps Toward the Diagnosis of MS Medical history and neurological examination usually indicating CIS MRI to confirm presence of macroscopic lesions Katz S, et al. Continuum (Minneap Minn). 2013;19(4):922943.

CSF analysis Blood tests for ruling out differential diagnoses 26 McDonald Criteria: 2010 Revision* Core Requirement: Objective demonstration of dissemination of CNS lesions in both space (DIS) and time (DIT) by MRI Revised criteria simplify DIS and DIT for MS diagnosis

Correct interpretation of clinical signs is critical (Patient-reported symptoms or objectively observed signs typical of an acute inflammatory demyelinating event, duration of at least 24 hours, in the absence of fever or infection) Alternative diagnoses need to be considered and excluded *Please see detailed 2010 Revised McDonald Criteria to confirm a diagnosis of MS in your handout. Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302. 27 Important Considerations in Revised

2010 McDonald Criteria Allows diagnosis of MS in patients with CIS Exclusion of neuromyelitis optica (NMO) and NMO spectrum disorders Diagnosis of PPMS Applicability in pediatric, Asian, and Latin American populations Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302. 28 Pediatric MS >95% of pediatric patients with MS have an initial relapsing-remitting disease course PPMS is exceptional ~80% of pediatric cases, and nearly all adolescent-onset cases, present with attacks typical for adult CIS, with a

similar or greater total T2 lesion burden MS must be differentiated from acute disseminated encephalomyelitis (ADEM) or NMO Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302. 29 Criteria for Diagnosis of MS in Pediatric Patients Confirmation by: 2 nonADEM-like attacks following a first ADEM-like attack OR 1 non-ADEM attack followed by accrual of clinically silent lesions Serial clinical and MRI observations are required to confirm a diagnosis of MS in children Accurate diagnosis of pediatric MS is critical

Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302. 30 Revised MRI Criteria for DIS and DIT DIS can be demonstrated by: 1 T2 lesion in at least 2 of 4 regions of the CNS* Development of further attack implicating different CNS site In patients with brain stem or spinal cord syndromes, symptomatic MRI lesions are excluded from the criteria and do not contribute to lesion count DIT can be demonstrated by: Simultaneous presence of asymptomatic gadolinium (Gd)-enhancing and nonenhancing lesions at any time A new T2 and/or Gd-enhancing lesion(s) on follow-up MRI, irrespective of the timing with baseline scan The development of a second clinical attack *Periventricular, juxtacortical, infratentorial, or spinal cord.

Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302. 31 Clinical Questions How have these revised criteria affected your evaluation of clinical and MRI findings toward a diagnosis of MS? Do you use these criteria to make a diagnosis of MS? If not, what do you use? How many of your patients may have been diagnosed with MS prior to 2010 using the revised criteria? 32 Imaging in MS 33

MS Lesions on MRI Katz S, et al. Continuum (Minneap Minn). 2013;19(4):922943. 34 MS Lesions on MRI (contd) Katz S, et al. Continuum (Minneap Minn). 2013;19(4):922943. 35 CSF Findings 36 Supportive Role for CSF Findings in MS Diagnosis CSF findings such as 2 oligoclonal bands or

elevated IgG index can support: Inflammatory demyelinating nature of the underlying condition Evaluation of alternative diagnoses Prediction of confirmed diagnosis of MS PPMS IgG, immunoglobulin G. Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302. 37 Case Study #1: Kim, 25-year-old Female 38 Clinical Questions

Do you agree with how her physician treated her? Careful history and physical/neurologic exam Funduscopic exam Referral to neuroophthalmologist What tests do you order?

Blood work Brain MRI (with/without contrast, with orbit views) Spinal MRI (cervical, thoracic, and lumbar) Lumbar puncture Does she meet 2010 criteria for CIS? Would you have recommended treatment at the initial visit if her symptoms were still present? Approach to counseling on the risk for MS? 39 Case Study #1, Kim, 25-year-old Female: Blood Work Depending on level of clinical suspicion, perform tests to exclude: Autoimmune/demyelinating disorders Collagen vascular disease and other rheumatologic conditions

Infections (ie, Lyme disease, syphilis, HTLV-1, HIV) Endocrine abnormalities (eg, thyroid disease) Vitamin B12 deficiency Sarcoidosis Order specific tests? NMO antibody test Cadasil gene test Very long chain fatty acids Other? Kims blood work is normal Diagnosis: CIS

HTLV-1, human T-lymphotropic virus, type 1; HIV, human immunodefiency virus. 40 Management of Patients with MS 41 Proposed Algorithm Treatment with disease-modifying agents commences MRI and clinical assessments at 6 to 12 months Relapse and/or observed progression Negative MRI result

Consider change in therapy Periodic clinical and MRI assessment Active MRI result Relapses and/or disease progression No relapses and no disease progression Consider change of therapy Close clinical and

MRI monitoring Modified from original in Ro J, et al. Nat Rev Neurol. 2009;5(10):553-560. 42 Choosing a Disease-modifying Therapy (DMT) 10 DMTs to choose from after diagnosis is confirmed None are curative No one size fits all empiric treatment (given variability and unpredictability of MS) Disease, drug, patient factors Prior experience, availability, cost Risk-benefit ratio Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991. 43

Important Considerations Before Making Therapeutic Decisions Current disease activity and disability Disease prognostic profile Patient lifestyle and expected longevity Preference for route of treatment administration Patient's ability to self-treat Need for therapy to be delivered by a healthcare professional Reproductive status Other expectations Miller AE, et al. Curr Opin Neurol. 2012;25(suppl):S4-S10. 44 Recommendations for Treatment of Acute MS Exacerbations First-line option involves glucocorticoids

Glucocorticoids may speed up recovery time frame Most common regimen 1000-mg IV methylprednisolone daily for 5 days without an oral taper Excellent bioavailability High-dose oral could be substituted Second-line options involve corticotropin gel, plasma exchange, IVIG IV, intravenous; IVIG, intravenous immunoglobulin. Goodin DS, et al. Neurology. 2002;58:169-178. 45 DMTs Approved for RRMS First-line Agents Interferon beta-1a Interferon beta-1b

Glatiramer acetate Second-line Agents Mitoxantrone Natalizumab Oral therapies: Fingolimod Teriflunomide Dimethyl fumarate Oral therapies: Fingolimod Ro J, et al. Curr Opin Neurol. 2011;24(3):230-237; Coyle PK. CNS Drugs. 2013;27(4):239-247. 46 Current Trials in SPMS Safety and efficacy of Siponimod (BAF312) versus placebo for

variable treatment durations in patients with SPMS Double Blind Combination of Rituximab by Intravenous and Intrathecal Injection Versus Placebo in Patients With LowInflammatory Secondary Progressive Multiple Sclerosis (RIVITaLISe) Study of Tcelna (Imilecleucel-T) in Secondary Progressive Multiple Sclerosis (Abili-T) Masitinib for the treatment of patients with PPMS or relapse-free SPMS Safety, Tolerability and Activity Study of Ibudilast in Subjects With Progressive Multiple Sclerosis ClinicalTrials website. www.clinicaltrials.gov. Accessed December 2, 2013. 47 Overview of Available Agents for MS 48

A n n u a liz e d R e la p s e R a te Relapse Response Rate to Interferons INTERFERONS 1.0 0.87 0.84 0.77 0.8 0.67 0.6 0.64

0.54 0.4 0.34 0.36 0.33 0.30 0.27 INF -1a subcutaneous 94 INF -1a intramuscular

07 Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991. 93 BEYOND I N F -b BRAVO TRANSFORM S E V ID E N C E M SCRG REG ARD

C AM M S 223 E V ID E N C E O W IM S 0.0 P R IS M S 0.2 INF -1b 11 88 07

49 Clinical Evidence for Glatiramer Acetate IFN, interferon. Mikol DD, et al. Lancet Neurol. 2008;7(10):903-914; O'Connor P, et al. Lancet Neurol. 2009;8(10):889-897; McGraw CA, et al. Neurotherapeutics. 2013;10(1):2-18. 50 A n n u a liz e d R e la p s e R a te Relapse Response Rate to Therapies GLATIRAMER ACETATE 0.8 0.6

0.59 0.4 0.29 0.34 0.29 0.2 0.0 Johnson REGARD 1991

Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991. BEYOND CONFIRM 2011 51 Clinical Evidence for Natalizumab (mAb against leukocyte integrin 4) mAb, monoclonal antibody. Miller DH, et al. N Engl J Med. 2003;348(1):15-23; Polman CH, et al. N Engl J Med. 2006;354(9):899-910; Ro J, et al. Curr Opin Neurol. 2011;24(3):230-237. 52

Newer Oral Therapies 53 % P a t ie n t s R e s p o n d i n g Y e s Survey of Patients Taking Self-injected DMT: Route of Administration Would you switch to a new therapy that was oral or injectable and was associated with mild or severe risk and vigilance? 100 92 97 84 78

80 63 59 60 40 31 28 20 0 New Oral Therapy Mild Risk/Vigilance

New Oral Therapy Severe Risk/Vigilance Disease and DMT <5 years (n=100) Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27. New Therapy Mild Risk/Vigilance New Therapy Severe Risk/Vigilance Disease and DMT 5 years (n=100) 54 Clinical Evidence for Dimethyl Fumarate

Fox RJ, et al. N Engl J Med. 2012;367:1087-1097; Gold R, et al. N Engl J Med. 2012;367:1098-1107; Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991. 55 Practice Recommendations for Dimethyl Fumarate National MS Society. http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/corecurriculum/managing-ms/comprehensive-care/disease-modification/indications-dosing-etc/index.aspx; http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core-curriculum/managing-ms/ comprehensive-care/disease-modification/warnings-safety-management/index.aspx. 56 Clinical Evidence for Fingolimod Kappos L, et al. N Engl J Med. 2010;362(5):387-401; Cohen JA, et al. N Engl J Med. 2010;362(5):402-415; Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991; Hanson KA, et al. Patient Prefer Adherence. 2013;7:309-318.

57 Adherence with Fingolimod Therapy Probability of Staying on Index Medication Nave disease-modifying therapy users 1.0 0.9 0.8 0.7 0.6 0.5 0.4

5 25 325 45 345 65 365 85 105 125 145

165 185 205 225 245 265 285 305 Days Fingolimod Subcutaneous interferon beta-1a

Interferon beta-1b Glatiramer acetate Agashivala N, et al. BMC Neurol. 2013;13(1):138. [Epub ahead of print] Intramuscular interferon beta-1a 58 Adherence with Fingolimod Therapy (contd) Probability of Staying on Index Medication Experienced disease-modifying therapy users 1.0 0.9 0.8

0.7 0.6 0.5 0.4 1 31 61 91 121 151 181

211 241 271 301 331 361 Days Fingolimod Subcutaneous interferon beta-1a Interferon beta-1b Glatiramer acetate

Agashivala N, et al. BMC Neurol. 2013;13(1):138. [Epub ahead of print] Intramuscular interferon beta-1a 59 Practice Recommendations for Fingolimod Singer BA. Ther Adv Neurol Disord. 2013;6(4):269-275; National MS Society. http://www.nationalmssociety.org/msclinical-care-network/clinical-resources-and-tools/core-curriculum/managing-ms/comprehensive-care/diseasemodification/indications-dosing-etc/index.aspx; http://www.nationalmssociety.org/ms-clinical-care-network/clinicalresources-and-tools/core-curriculum/managing-ms/comprehensive-care/disease-modification/warnings-safetymanagement/index.aspx. 60 Clinical Evidence for Teriflunomide po, by mouth. OConnor, et al. N Engl J Med. 2011;365(14):1293-303; Freedman MS. Ther Adv Chronic Dis. 2013;4(5):192-205.

61 Comparison of Teriflunomide with IFN-1a Freedman MS. Ther Adv Chronic Dis. 2013;4(5):192-205; Vermersch et al. Mult Scler. 2013 Oct 14. [Epub ahead of print]. 62 Practice Recommendations for Teriflunomide National MS Society. http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/corecurriculum/managing-ms/comprehensive-care/disease-modification/indications-dosing-etc/index.aspx; http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core-curriculum/managing-ms/ comprehensive-care/disease-modification/warnings-safety-management/index.aspx. 63 Ideal Therapy

Superior efficacy Ease of administration Good tolerability Long-term safety data Differs from patient to patient (therefore must be individualized based on risk-benefit ratio) Fox EJ, et al. Curr Opin Neurol. 2012;25(suppl):S11-S19. 64 Investigational Agents Route of Administration Promising Outcomes Current

Status Agent Mode of Action Glatiramer acetate Immunomodulatory agent Subcutaneous Results available on double-dose (20 vs 40 mg) administration

Under FDA review Laquinimod Immunomodulatory agent Oral ALLEGRO and BRAVO trials modest outcomes in annual relapse rates Ongoing phase 3 trial

Alemtuzumab Humanized monoclonal antibody against CD52 Intravenous CARE-MS I and II trialsreduced annual relapse rate Under FDA review Pegylated interferon

PEG-IFN beta-1a Subcutaneous Phase 3 trial reduced annual relapse rate Ongoing phase 3 trials FDA, US Food and Drug Administration. Tullman MJ. Am J Manag Care. 2013;19(2, suppl):S21-27; Peru al J, Khan O. Curr Treat Options Neurol. 2012;14(3):256-263; Castro-Borrero et al. Ther Adv Neurol Disord. 2012;5(4):205-220; Clinicaltrials website. www.clinicaltrials.gov. Accessed December 2, 2013. 65 Investigational Agents (contd)

Agent Mode of Action Daclizumab Route of Administration Promising Outcomes Current Status Humanized Subcutaneous monoclonal antibody against IL2R

SELECT trial reduction in annual relapse rate Ongoing phase 3 trials Ocrelizumab Recombinant human Intravenous anti-CD20 infusion monoclonal antibody Phase 2 trial reduction in annual relapse rate

Ongoing phase 3 trials BAF312 Selective modulator of sphingosine 1phosphate receptor types 1 and type 5 Oral BOLD trialreduction Ongoing in active lesions phase 3 trials Masitinib

Tyrosine kinase inhibitor Oral Promising in PPMS and SPMS Tullman MJ. Am J Manag Care. 2013;19(2,suppl):S21-S27; Peru al J, Khan O. Curr Treat Options Neurol. 2012;14(3):256-263; Castro-Borrero et al. Ther Adv Neurol Disord. 2012;5(4):205-220. Ongoing phase 2b/3 trials 66 Case Study #2:

Carl, 40-year-old Male 67 New Imaging ResultsNew Strategy for Treatment? T2-weighted image Recent scans show multiple new lesions What are the next steps for this patient? 68 Case Discussion For this patient with changes on imagery, what is your management strategy: Do you switch medications? If so, to what? What criteria do you use to make this decision?

How many relapses are enough in 1 year to consider switching therapies? How do you monitor disease status/progression following a relapse? Set new baseline MRI at time of relapse Frequency of MRI? Image resultsone new enhancing lesion 69 Considerations for Switching Medications 70 Proposed Algorithm Treatment with disease-modifying agents commences MRI and clinical assessments

at 6 to 12 months Relapse and/or observed progression Negative MRI result Consider change in therapy Periodic clinical and MRI assessment Active MRI result Relapses and/or disease progression No relapses and

no disease progression Consider change of therapy Close clinical and MRI monitoring Modified from original in Ro J, et al. Curr Opin Neurol. 2011;24(3):230-237. 71 Indications for Switching Therapies Indication Intolerable side effects Detection of

antibodies Category Example Adverse reactions Injection site reaction, infusion reaction, infections Persistent symptoms Flu-like symptoms, headache, nausea Significant and persistent laboratory abnormality

Increased liver enzymes, low WBC JC (John Cunningham) virus antibody positivity Pertinent for natalizumab use Persistent neutralizing antibodies Pertinent for natalizumab and IFN (high-titer antibodies) Clinical activity Relapses, disability, cognitive status, transition to progressive disease

Neuroimaging activity Brain MRI, spinal cord MRI abnormalities Unacceptable breakthrough activity Coyle PK. CNS Drugs. 2013;27(4):239-247. 72 Considerations for Switching Therapies Coyle PK. CNS Drugs. 2013;27(4):239-247. 73 Switching Recommendations

Coyle PK. CNS Drugs. 2013;27(4):239-247. 74 Washout Considerations Natalizumab to fingolimod JC virus antibodynegative patients Few weeks JC virus antibodypositive patients 4 to 8 weeks after MRI for progressive multifocal leukoencephalopathy lesions Fingolimod to natalizumab JC virus antibodynegative patients Few weeks JC virus antibodypositive patients

Until WBC count improves Coyle PK. CNS Drugs. 2013;27(4):239-247. 75 Individualized Treatment and Patient Education Are Necessary 76 Roadmap for Individualized Treatment Increasingly complex environment Treatment strategy Patients treatment

goals Economic factors Individualized treatment Patients risk/benefit tolerance Patients adherence to monitoring or drug regimen Other Patients

disease profile and characteristics Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27. 77 Supportive Treatments Pharmacological and nonpharmacological management of symptoms such as: Fatigue, spasticity, bladder problems, bowel problems, cognitive dysfunction, pain, paroxysmal symptoms, sexual dysfunction, tremor, heat intolerance, and optic neuritis Rehabilitation (physical and occupational therapy) Surgery as indicated to alleviate symptoms National MS Society. http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/ core-curriculum/managing-ms/comprehensive-care/symptom-management/index.aspx.

78 Patient Education Encourage patients to discuss diagnosis, voice concerns, and share feelings about treatment progress Help patients access information Recognize opportunities to discuss treatment strategies Manage adverse events Facilitate optimal monitoring of disease progression Improving patient concordance Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27. 79 Treatment Goals Improve quality of life by relieving symptoms caused by exacerbations and reduce number of events Reduce MRI activity

Delay/prevent the onset of SPMS Slow or stop the course of disease progression Minimize treatment-associated adverse events Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27. 80 Summary Updated diagnostic criteria to facilitate early and accurate diagnosis of MS Unbiased communication of clinical evidence to support decision making and to accommodate patient preferences Effective strategies to monitor therapeutic progress and switch therapies Individualizing treatment goals and interventions for patients with MS

81 Questions & Answers 82 Thank You! 83 Revised 2010 McDonald Criteria to Confirm Diagnosis of MS Reference Slides 84 Revised 2010 McDonald Criteria to Confirm Diagnosis of MS Clinical

Attacks Lesions Additional Criteria for Diagnosis 1 Objective clinical evidence of 1 lesion DIS, demonstrated by: 1 T2 lesion in at least 2 MS-typical CNS regions OR Await further clinical attack implicating a different CNS site AND DIT, demonstrated by:

Simultaneous asymptomatic contrast-enhancing and non-enhancing lesions at any time OR New T2 and/or contrast-enhancing lesions(s) on follow-up MRI, irrespective of its timing OR Await a second clinical attack Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302. 85 Revised 2010 McDonald Criteria to Confirm Diagnosis of MS (contd) Clinical Attacks Lesions

Additional Criteria for Diagnosis 1 Objective clinical evidence of 2 or more lesions DIT, demonstrated by: Simultaneous asymptomatic contrast-enhancing and nonenhancing lesions at any time OR New T2 and/or contrast-enhancing lesions(s) on follow-up MRI, irrespective of its timing OR Await a second clinical attack Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.

86 Revised 2010 McDonald Criteria to Confirm Diagnosis of MS (contd) Clinical Attacks Lesions Additional Criteria for Diagnosis 2 or more Objective clinical evidence of 2 or more lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack

None. Clinical evidence alone will suffice; additional evidence desirable but must be consistent with MS 2 or more Objective clinical evidence of 1 lesion DIS, demonstrated by: 1 T2 lesion in at least 2 MStypical CNS regions (periventricular, juxtacortical, infratentorial, spinal cord) OR Await further clinical attack implicating a different CNS site

Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302. 87 Revised 2010 McDonald Criteria to Confirm Diagnosis of MS (contd) Clinical Attacks Lesions 0 (progression from onset) Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302. Additional Criteria for Diagnosis One year of disease progression (retrospective or prospective) AND at least

2 out of 3 criteria: DIS in the brain based on 1 T2 lesion in periventricular, juxtacortical, or infratentorial regions DIS in the spinal cord based on 2 T2 lesions Positive CSF 88

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