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Sponsored by Integrity Continuing Education Improving Management Strategies for Patients With Multiple Sclerosis: An Evaluation of Current Practice Supported by an educational grant from Novartis

2 Elizabeth Crabtree, MD Associate Professor of Neurology Director of Patient Education and Support University of California San Francisco MS Center San Francisco, California

Faculty Disclosures3

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 MSMonitor response to therapy as recommended by current treatment guidelines, so that changes in a patient’s treatment plan can be implemented if necessary Learning Objectives4

Multiple Sclerosis Overviewand Unmet Needs5

Chronic inflammatory, neuroimmune, demyelinating, and neurodegenerative disease of the central nervous system (CNS)Characterized by macroscopic and microscopic injury to gray and white matterCommon manifestations are optic neuritis, partial transverse myelitis, and brain stem or cerebellar syndromeProgressive disability occurs over time Exact etiology is unknownMultiple Sclerosis Overview6

Affects ~400,000 people1Major cause of nontraumatic disability2Disease sequelaeMultiple symptoms Disability (cognitive, motor, vocational)Psychological stress3$8,528 to $54,244 per patient/year in direct plusindirect costs4Prevalence and Burden of MS in the United States 7 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.

Clinical Courses of MS 8 Miller AE, et al. Curr Opin Neurol. 2012;25(suppl):S4-S10.

Delay in diagnosis and misdiagnosisLack of biomarkers for disease activityNo curative or reparative/restorative therapy Patient compliance with therapeutic protocolsUnmet Needs in MS9

Pathophysiology of MS10

Immune-mediated mechanisms damage CNS tissueInflammatory 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 MSFamily history (parent or sibling): 1/40 for developing MS1st-degree relative (2%-3% chance; sibling > parent)Underlying Pathophysiology of MS11 Handel​‌ AE, et al. Mult Scler Rel Disord . 2012;1(1):39-42; National MS Society. http :// www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/who-gets-ms/genetics/index.aspx. MHC, major histocompatibility complex.

Focal demyelinated plaques disseminated in CNSEasily visualized in the white matter, but extensive gray matter involvement especially in early MSPredilection for optic nerves, subpial, spinal cord, brain stem, cerebellum and juxtacortical, and periventricular white matter regions Variable degrees of inflammation, gliosis, and neurodegenerationObserved Changes in the CNS in MS12 Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921.

Patients with early RRMS showed significantly lower SDGM, but not cortical volumes compared with patients with CISEvidence that significant SDGM atrophy (not cortical) occurs rapidly during first 4 years in treatment-naïve patientsConfirms that selective regional, but not global, atrophy occurs from clinical onset to conversion to clinically definite MS Evidence for Gray Matter Involvement13Bergsland N, et al. AJNR Am J Neuroradiol. 2012;33:1573–1578.SDGM, subcortical deep gray matter; CIS, clinically isolated syndrome.

Immune-mediated Axonal Injury Mechanisms14 Dutta R, Trapp BD. Prog Neurobiol. 2011;93(1 ):1-12. Transection leads to degeneration of the distal end of the axon and the proximal end forms an ovoid due to accumulation of transported organelles Immune-mediated processes lead to axonal transection

Cortical Demyelination Patterns15 Dutta R, Trapp BD. Prog Neurobiol. 2011;93(1):1-12.

Common and may represent an early and/or initial target of MS disease processMay represent the pathologic substrate of cognitive impairment and seizures in RRMSHighly 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 lesionsInfiltrates are composed of T cells, B cells, and macrophagesCortical Demyelinated Lesions in Early MS: New Insights 16Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921.

MRI of Cortical Onset MS17Popescu et al. Continuum (Minneap Minn) . 2013;19(4):901-921. MRI, magnetic resonance imaging.

Very prominentLess inflammatory than white matter lesionsLack 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 MSAssociated with increased rate of clinical progressionCortical Demyelinated Lesions in Progressive MS: New Insights 18Popescu 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): 2925-2937 .

Cortical Demyelination in SPMS19 Howell OW, et al. Brain. 2011;134(Pt 9):2755-2771.

New Data on Cortical Pathology and SPMS20 Calabrese M, et al. Ann Neurol. 2013;74(1 ):76-83.

Other Studies on Cortical Demyelinating Lesions21New MRI techniques for visualization (DIR, PSIR, T1-weighted 3D FSPGR) and early diagnosis Correlation between gray matter pathology and patient disability and cognitive impairmentEffect of disease-modifying therapy on gray matter pathologyIncreased 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.

Diagnosis of MS22

Recommendations for Diagnosis of MS 23Pohlman CH, et al. Ann Neurol . 2011;69(2):292-302.

No clinical findings are unique to MSDifficulty in patient characterization and physician interpretation of symptomsNumerous differential diagnoses of MS-like symptoms Imaging is not always specific and there may be an overreliance on MRIConfounding comorbidities Unpredictable MS clinical coursesChallenges in the Diagnosis of MS24 Katz S, et al. Continuum (Minneap Minn). 2013;19(4): 922–943.

Typically affects young adults (aged 20-45 years)Patient demonstrates signs and symptoms suggestive of CNS demyelinationAttacks last for at least 24 hours and reach a peak within 2 to 3 weeks No indication of fever, infection, or encephalopathyMany qualify for definitive diagnosis based on 2010 International Panel diagnostic criteriaClinically Isolated Syndrome 25Katz S, et al. Continuum (Minneap Minn). 2013;19(4): 922–943; Lo CP, et al. J Neurol Neurosurg Psychiatry . 2009;80(10):1107-1109.

Steps Toward the Diagnosis of MS 26 Katz S, et al. Continuum (Minneap Minn). 2013;19(4):922–943.

McDonald Criteria: 2010 Revision* 27*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.

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 PPMSApplicability in pediatric, Asian, and Latin American populations 28 Pohlman CH, et al. Ann Neurol . 2011;69(2):292-302.

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 burdenMS must be differentiated from acute disseminated encephalomyelitis (ADEM) or NMO 29 Pohlman CH, et al. Ann Neurol . 2011;69(2):292-302.

Confirmation by:≥2 non–ADEM-like attacks following a first ADEM-like attackOR 1 non-ADEM attack followed by accrual of clinically silent lesionsSerial clinical and MRI observations are required to confirm a diagnosis of MS in childrenAccurate diagnosis of pediatric MS is criticalCriteria for Diagnosis of MS in Pediatric Patients30 Pohlman CH, et al. Ann Neurol . 2011;69(2):292-302.

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 siteIn 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 timeA new T2 and/or Gd-enhancing lesion(s) on follow-up MRI, irrespective of the timing with baseline scanThe development of a second clinical attack Revised MRI Criteria for DIS and DIT31Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302. *Periventricular , juxtacortical, infratentorial, or spinal cord.

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?Clinical Questions32

Imaging in MS33

MS Lesions on MRI34 Katz S, et al. Continuum (Minneap Minn). 2013;19(4):922–943.

MS Lesions on MRI (cont’d)35 Katz S, et al. Continuum (Minneap Minn). 2013;19(4):922–943.

CSF Findings36

CSF findings such as ≥2 oligoclonal bands or elevated IgG index can support:Inflammatory demyelinating nature of the underlying conditionEvaluation of alternative diagnosesPrediction of confirmed diagnosis of MS PPMSSupportive Role for CSF Findingsin MS Diagnosis37 Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302. IgG , immunoglobulin G.

Case Study #1: Kim, 25-year-old Female38

Do you agree with how her physician treated her?Careful history and physical/neurologic examFunduscopic examReferral to neuroophthalmologist What tests do you order?Blood workBrain MRI (with/without contrast, with orbit views)Spinal MRI (cervical, thoracic, and lumbar) Lumbar punctureDoes 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?Clinical Questions 39

Depending on level of clinical suspicion, perform tests to exclude:Autoimmune/demyelinating disordersCollagen vascular disease and other rheumatologic conditionsInfections (ie, Lyme disease, syphilis, HTLV-1, HIV)Endocrine abnormalities (eg, thyroid disease) Vitamin B12 deficiencySarcoidosisOrder specific tests? NMO antibody testCadasil gene test Very long chain fatty acidsOther?Kim’s blood work is normalDiagnosis: CISCase Study #1, Kim, 25-year-old Female: Blood Work40 HTLV-1, human T- lymphotropic virus, type 1; HIV, human immunodefiency virus.

Management of Patients with MS41

Proposed Algorithm 42 Modified from original in Río J, et al. Nat Rev Neurol. 2009;5(10):553-560. Relapse and/or observed progression Consider change in therapy Treatment with disease-modifying agents commences MRI and clinical assessments at 6 to 12 months Negative MRI result Relapses and/or disease progression Active MRI result Consider change of therapy Periodic clinical and MRI assessment Close clinical and MRI monitoring No relapses and no disease progression

10 DMTs to choose from after diagnosis is confirmedNone are curativeNo “one size fits all” empiric treatment (given variability and unpredictability of MS) Disease, drug, patient factorsPrior experience, availability, costRisk-benefit ratioChoosing a Disease-modifying Therapy (DMT) 43Freedman MS. Continuum (Minneap Minn) . 2013;19(4):968-991.

Current disease activity and disabilityDisease prognostic profilePatient lifestyle and expected longevityPreference for route of treatment administration Patient's ability to self-treat Need for therapy to be delivered by a healthcare professional Reproductive status Other expectationsImportant Considerations Before Making Therapeutic Decisions44 Miller AE, et al. Curr Opin Neurol. 2012;25(suppl ):S4-S10.

First-line option involves glucocorticoidsGlucocorticoids may speed up recovery time frame Most common regimen 1000-mg IV methylprednisolone daily for 5 days without an oral taper Excellent bioavailabilityHigh-dose oral could be substitutedSecond-line options involve corticotropin gel, plasma exchange, IVIGRecommendations for Treatment of Acute MS Exacerbations 45Goodin DS, et al. Neurology. 2002;58:169-178. IV, intravenous; IVIG, intravenous immunoglobulin.

First-line Agents Seco nd-line AgentsInterferon beta-1a Interferon beta-1bGlatiramer acetate Oral therapies: Fingolimod Teriflunomide Dimethyl fumarate Mitoxantrone Natalizumab Oral therapies: Fingolimod DMTs Approved for RRMS 46 Río J, et al. Curr Opin Neurol . 2011;24(3):230-237; Coyle PK. CNS Drugs . 2013;27(4):239-247.

ClinicalTrials website. www.clinicaltrials.gov. Accessed December 2, 2013. Safety and efficacy of Siponimod (BAF312) versus placebo for variable treatment durations in patients with SPMSDouble Blind Combination of Rituximab by Intravenous and Intrathecal Injection Versus Placebo in Patients With Low-Inflammatory 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 Current Trials in SPMS 47

Overview of AvailableAgents for MS48

Relapse Response Rate to Interferons49 Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991.INTERFERONS INF β-1 a subcutaneous ‘94 ‘07 INF β-1 a intramuscular ‘93 ‘11 INF β-1 b ‘88 ‘07

Clinical Evidence for Glatiramer Acetate 50Mikol 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. IFN, interferon.

Relapse Response Rate to Therapies51GLATIRAMER ACETATE Freedman MS. Continuum ( Minneap Minn). 2013;19(4):968-991. 19912011

Clinical Evidence for Natalizumab(mAb against leukocyte integrin α4) 52Miller 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; Río J, et al. Curr Opin Neurol . 2011;24(3):230-237. mAb , monoclonal antibody .

Newer Oral Therapies53

Would you switch to a new therapy that was oral or injectable and was associated with mild or severe risk and vigilance?Survey of Patients Taking Self-injected DMT: Route of Administration54 Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27.

Clinical Evidence for Dimethyl Fumarate 55Fox 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.

Practice Recommendations for Dimethyl Fumarate 56National MS Society. http:// www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core-curriculum/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.

Clinical Evidence for Fingolimod 57Kappos 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 .

Adherence with Fingolimod Therapy58Agashivala N, et al. BMC Neurol. 2013;13(1):138. [Epub ahead of print]Naïve disease-modifying therapy users 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Probability of Staying on Index Medication 5 25 45 65 85 105 125 145 165 185 205 225 245 265 285 305 325 345 365 Days Fingolimod Subcutaneous interferon beta-1a Interferon beta-1b Glatiramer acetate Intramuscular interferon beta-1a

Adherence with Fingolimod Therapy (cont’d)59Agashivala N, et al. BMC Neurol. 2013;13(1):138. [Epub ahead of print]Experienced disease-modifying therapy users 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Probability of Staying on Index Medication 1 31 61 91 121 151 181 211 241 271 301 331 361 Days Fingolimod Subcutaneous interferon beta-1a Interferon beta-1b Glatiramer acetate Intramuscular interferon beta-1a

Practice Recommendations for Fingolimod 60Singer BA. Ther Adv Neurol Disord. 2013;6(4):269-275; National MS Society. http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core-curriculum/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 .

Clinical Evidence for Teriflunomide 61O’Connor, et al. N Engl J Med. 2011;365(14):1293-303; Freedman MS. Ther Adv Chronic Dis. 2013;4(5):192-205. po, by mouth.

Comparison of Teriflunomide w ith IFNβ-1a62 Freedman MS. Ther Adv Chronic Dis. 2013;4(5):192-205; Vermersch et al. Mult Scler . 2013 Oct 14. [ Epub ahead of print ].

Practice Recommendations for Teriflunomide 63National MS Society. http:// www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core-curriculum/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.

Superior efficacyEase of administrationGood tolerabilityLong-term safety data Differs from patient to patient (therefore must be individualized based on risk-benefit ratio)Ideal Therapy64 Fox EJ, et al. Curr Opin Neurol. 2012;25(suppl):S11-S19.

Agent Mode of ActionRoute of Administration Promising Outcomes Current Status 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 trials—reduced annual relapse rate Under FDA review Pegylated interferon PEG-IFN beta-1a Subcutaneous Phase 3 trial—reduced annual relapse rate Ongoing phase 3 trials Investigational Agents 65 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 . FDA, US Food and Drug Administration.

Agent Mode of ActionRoute of Administration Promising Outcomes Current Status Daclizumab Humanized monoclonal antibody against IL2-R Subcutaneous SELECT trial—reduction in annual relapse rate Ongoing phase 3 trials Ocrelizumab Recombinant human anti-CD20 monoclonal antibody Intravenous infusion Phase 2 trial—reduction in annual relapse rate Ongoing phase 3 trials BAF312 Selective modulator of sphingosine 1-phosphate receptor types 1 and type 5 Oral BOLD trial—reduction in active lesions Ongoing phase 3 trials Masitinib Tyrosine kinase inhibitor Oral Promising in PPMS and SPMS Ongoing phase 2b/3 trials Investigational Agents (cont’d) 66 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.

Case Study #2: Carl, 40-year-old Male67

New Imaging Results—New Strategy for Treatment?T2-weighted imageRecent scans show multiple new lesionsWhat are the next steps for this patient? 68

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 relapseFrequency of MRI? Image results—one new enhancing lesionCase Discussion69

Considerations for Switching Medications70

Proposed Algorithm71Modified from original in Río J, et al. Curr Opin Neurol. 2011;24(3):230-237. Relapse and/or observed progression Consider change in therapy Treatment with disease-modifying agents commences MRI and clinical assessments at 6 to 12 months Negative MRI result Relapses and/or disease progression Active MRI result Consider change of therapy Periodic clinical and MRI assessment Close clinical and MRI monitoring No relapses and no disease progression

Indication Category Example Intolerable side effects 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 Detection of antibodies JC (John Cunningham) virus antibody positivity Pertinent for natalizumab use Persistent neutralizing antibodies Pertinent for natalizumab and IFN β (high-titer antibodies) Unacceptable breakthrough activity Clinical activity Relapses, disability, cognitive status, transition to progressive disease Neuroimaging activity Brain MRI, spinal cord MRI abnormalities Indications for Switching Therapies 72 Coyle PK. CNS Drugs . 2013;27(4):239-247.

Considerations for Switching Therapies 73Coyle PK. CNS Drugs. 2013;27(4):239-247.

Switching Recommendations 74Coyle PK. CNS Drugs. 2013;27(4):239-247.

Natalizumab to fingolimodJC virus antibody–negative patients Few weeksJC virus antibody–positive patients 4 to 8 weeks after MRI for progressive multifocal leukoencephalopathy lesions Fingolimod to natalizumabJC virus antibody–negative patients Few weeksJC virus antibody–positive patients Until WBC count improvesWashout Considerations75Coyle PK. CNS Drugs. 2013;27(4):239-247.

Individualized Treatment and Patient Education Are Necessary76

Patient’s adherence to monitoring or drug regimen Individualized treatment Roadmap for Individualized Treatment 77 Giovannoni G, et al. Curr Opin Neurol . 2012;25( suppl ):S20-S27. Increasingly c omplex environment Treatment strategy Economic factors Patient’s treatment goals Patient’s risk/benefit tolerance Other Patient’s disease profile and characteristics

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 neuritisRehabilitation (physical and occupational therapy)Surgery as indicated to alleviate symptoms Supportive Treatments78 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.

Encourage patients to discuss diagnosis, voice concerns, and share feelings about treatment progressHelp patients access informationRecognize opportunities to discuss treatment strategies Manage adverse events Facilitate optimal monitoring of disease progressionImproving patient concordancePatient Education 79Giovannoni G, et al. Curr Opin Neurol. 2012;25( suppl):S20-S27.

Improve quality of life by relieving symptoms caused by exacerbations and reduce number of eventsReduce MRI activityDelay/prevent the onset of SPMS Slow or stop the course of disease progressionMinimize treatment-associated adverse eventsTreatment Goals80 Giovannoni G, et al. Curr Opin Neurol. 2012;25( suppl):S20-S27.

Updated diagnostic criteria to facilitate early and accurate diagnosis of MSUnbiased communication of clinical evidence to support decision making and to accommodate patient preferencesEffective strategies to monitor therapeutic progressand switch therapies Individualizing treatment goals and interventions for patients with MSSummary 81

Questions & Answers82

Thank You!83

Revised 2010 McDonald Criteria to Confirm Diagnosis of MS— Reference Slides84

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 Revised 2010 McDonald Criteria to Confirm Diagnosis of MS 85 Pohlman CH, et al. Ann Neurol . 2011;69(2):292-302.

Clinical Attacks Lesions Additional Criteria for Diagnosis 1 Objective clinical evidence of 2 or more lesions 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 Revised 2010 McDonald Criteria to Confirm Diagnosis of MS (cont’d) 86 Pohlman CH, et al. Ann Neurol . 2011;69(2):292-302.

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 MS-typical CNS regions (periventricular, juxtacortical, infratentorial, spinal cord) OR Await further clinical attack implicating a different CNS site Revised 2010 McDonald Criteria to Confirm Diagnosis of MS (cont’d) 87 Pohlman CH, et al. Ann Neurol . 2011;69(2):292-302.

Clinical Attacks Lesions Additional Criteria for Diagnosis 0 (progression from onset) 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 Revised 2010 McDonald Criteria to Confirm Diagnosis of MS (cont’d) 88 Pohlman CH, et al. Ann Neurol . 2011;69(2):292-302.

Back-up89

The defining features of NMO are transverse myelitis and optic neuritis with ≥2 of the following:MRI results nondiagnostic for MSA spinal cord lesion extending over 3 or more vertebral segments (short-segment lesions are typical of MS) A serologic test result positive for NMO-IgGCriteria for Diagnosing NMO and NMO Spectrum Disorders90 Mayo Clinic. Neuromyelitis optica. http://www.mayoclinic.org/medicalprofs/neuromyelitis-optica.html.

Current Trials in PPMSClinicaltrials website. www.clinicaltrials.gov. Accessed December 2, 2013. Fingolimod in Patients With Primary Progressive Multiple Sclerosis (INFORMS) Safety and Efficacy of Rituximab in Adults With Primary Progressive Multiple Sclerosis (OLYMPUS)Ocrelizumab in Patients With Primary Progressive Multiple Sclerosis Idebenone in Patients With Primary Progressive Multiple Sclerosis (IPPoMS) Masitinib for the Treatment of Patients With Primary Progressive or Relapse-free Secondary Progressive Multiple Sclerosis Safety, Tolerability and Activity Study of Ibudilast in Subjects With Progressive Multiple Sclerosis 91