Introduction

What Is Multiple Sclerosis? Chronic progressive autoimmune disease Immune system attacks the myelin sheath on nerve fibers in the brain and spinal cord (CNS) May lead to focal areas of damage, axon injury, axon transection, neurodegeneration, and subsequent scar or plaque formation Nucleus Soma Dendrite Myelin Sheath (With Axon Through It) Schwann Cell Node of Ranvier Axon Terminal Graphic by Quasar Jarosz at en.Wikipedia.org

What the Primary Care Clinician Needs to Know About MS Common presenting symptoms of demyelinating disease For example, what is CIS, optic neuritis, brain stem syndrome, etc How the diagnosis of MS is made Early symptoms that trigger need to refer patient to neurologist How to classify MS How to manage treatment of MS/monitor MS patients (and what to monitor for) How to manage treatment side effects

PIK NW Regional Survey (N = 50) Barriers to Diagnosis and Treatment Lack of clinician knowledge about MS, its diagnosis, and treatments Infrequency of MS in primary care populations Lack of time, especially since patients have other complaints to address Absence of screening tools Financial/insurance-related obstacles Side effects of treatment Patients’ psychosocial status and lack of support Poor adherence to treatment

Addressing Local Needs To address the needs identified in the local survey, this activity provides education regarding the following MS topics: Risk factors Pathogenesis Diagnostic criteria Role of imaging Efficacy, safety, and initiation of current therapies Efficacy and safety of emerging therapies Monitoring for response, adherence, and tolerability of therapy Management of MS symptoms

What Factors Contribute to the Risk for MS? 8

MS Epidemiology Prevalence ~350,000 persons in the United States Sex distribution ~75% female Age at onset Typically 20−40 years, but can present at any age Ethnic origin Predominantly Caucasian Compston A, et al. McAlpine’s Multiple Sclerosis, 4th ed. Churchill Livingston; 2006. Hauser SL, et al. Multiple Sclerosis. In: Fauci AS, et al. Harrison’s Principles of Internal Medicine. Available at: http://www.accessmedicine.com/content.aspx?aID=2906448. Accessed on: February 19, 2010. 9

Multiple Sclerosis An Immunogenetic Disease Environmental Factors Genetic Predisposition Immune Dysregulation MS Graphic courtesy of Suhayl Dhib-Jalbut, MD. 10

Evidence for Genetic Basis of MS 50 45 40 35 Approximate Probability of Developing MS 30 25% 25 20 15 10 5% 2% 3% 5 1% 0.1% 0.1% Identical Fraternal Sibling Parent or First Spouse No Twin Twin Half- Cousin Family Sibling Member Hauser SL, et al. Multiple Sclerosis. In: Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. Available at: http://www.accessmedicine.com/content.aspx?aID=2906445. Accessed on: February 19, 2010. Willer CJ, et al. Proc Natl Acad Sci U S A. 2003;100:12877-12882. 11

Evidence for Environmental Basis of MS No evidence of MS prior to 1822 (~ onset of industrial revolution in Europe) Change in the gender ratio over time These changes (eg, gender ratio, increasing incidence) took place over ~ 30 years (1–2 generations)—too fast for a genetics cause Increased incidence of MS in many regions (especially in women) When individuals migrate before age 15 from a region of high MS prevalence to one of low prevalence (or vice versa), they seem to adopt a prevalence similar to that of the region to which they moved When they make the same move after age 15, they seem to retain the risk of the region from which they moved 12

Multiple Sclerosis What Are the Environmental Factors? Many environmental factors have been proposed Two currently popular candidates for involvement in MS pathogenesis are: Epstein-Barr virus (EBV) infection Vitamin D deficiency (sunlight exposure) Cigarette smoking These are hypotheses—not proven facts! Either, neither, or both may be correct 13

Evidence for EBV Indirect evidence Direct evidence Late EBV infection is associated with MS Symptomatic mononucleosis is associated with MS Direct evidence 10 out of 12 studies found a significantly higher rate of EBV positivity in MS patients than in controls1-12 When data from these 12 trials are combined (N = 4155), EBV positivity is found in 99.5% of MS patients vs 94.2% of controls (P <10-23) 1. Sumaya, 1980. 2. Bray, 1983. 3. Larson, 1984. 4. Sumaya, 1985. 5. Shirodaria, 1987. 6. Munch, 1998. 7. Myhr, 1998. 8. Wagner, 2000. 9. Ascherio, 2001. 10. Sundström, 2004. 11. Haahr, 2004. 12. Ponsonby, 2005. 14

Direct Evidence for Vitamin D >185,000 women interviewed about their diet: Those in highest quintile of vitamin D consumption had significantly less new-onset MS compared with lowest quintile1 Study of MS patients and controls from Tasmania found significant negative association between total sun exposure during childhood (especially in those 6–10 years old) and adolescence and the subsequent development of MS2,3 Evaluation of stored serum samples from 257 MS patients and 514 matched controls (US Military) showed the risk of MS was significantly decreased in those with increased serum vitamin D3 levels4 1. Munger KL, et al. Neurology. 2004;62:60-65. 2. Van der Mei IA, et al. J Neurol. 2007;254:581-590. 3. Van der Mei IA, et al. BJM. 2003;327:316. 4. Munger KL, et al. JAMA. 2006;296:2832-2838. 15

Cigarette Smoking and MS Several cohort and case-control studies have suggested that cigarette smoking nearly doubles the risk of MS1-3 Risk increases with cumulative smoking “dose”2 Parental smoking also doubles the risk of MS in children who are passively exposed to the smoke4 Smokeless tobacco has not been found to increase MS risk1,2 Implies that non-nicotinic components of cigarette smoke are responsible 1. Carlens C, et al. Am J Respir Crit Care Med. 2010;Mar 4:epub ahead of print. 2. Hedström AK, et al. Neurology. 2009;73:696-701. 3. Riise T, et al. Neurology. 2003;61:1122-1124. 4. Mikaeloff Y, et al. Brain. 2007;130(pt 10):2589-2595.

Risk Factors for MS Summary MS is caused by a complex interaction of genetic and environmental factors In someone with an affected identical twin, risk of MS is 25%, suggesting that genetics play a role in susceptibility but are not the complete story Vitamin D insufficiency, EBV infection, and cigarette smoking have shown possible links to MS This research is thought-provoking, but these factors have not been definitely proven as causes of MS

Pathophysiology of MS 18

Pathophysiology of MS Acute Inflammation Relapses Neuronal Degeneration Disability 19 19

Immune Dysregulation in MS T Cells T cells normally recognize specific antigens CD8+ T cells destroy infected cells CD4+ T cells release cytokines that mediate inflammatory and anti-inflammatory responses T cells reactive to myelin are found in MS lesions, blood, and cerebrospinal fluid CD8+ T cells transect axons, induce oligodendrocyte death, promote vascular permeability1 There is a cytokine imbalance in MS, favoring secretion of inflammatory (Th1) cytokines T cells that normally regulate immune function have reduced activity in MS2 1. Dhib-Jalbut S. Neurology. 2007;68:S13-S21. 2. Viglietta V, et al. J Exp Med. 2004;199:971-979. 20

Cytokine Imbalance in MS IFN-g, IL-12, TNF IL-4, IL-10, TGFß Inflammatory Anti-inflammatory IL-4, IL-10,TGFß Normal MS TH1 TH2 Graphic courtesy of Suhayl Dhib-Jalbut, MD. 21 21

Immune Dysregulation in MS B Cells In some MS patients, ectopic lymphoid follicles have been found in the meninges1 Mechanisms of B cells in MS may include: Antimyelin antibody production Antigen presentation to autoreactive T cells Proinflammatory cytokine production 1. Uccelli A, et al. Trends Immunol. 2005;26:254-259. 22

Immune Dysregulation in MS Other Involved Cells Natural killer (NK) cells May play opposing roles as both regulators and inducers of disease relative to cytokine environment and cell:cell contact NK cell function may be lost during clinical relapse Monocytes Secrete IL-6 (promotes B cell growth) and IL-2 (aids differentiation of Th1 cells) Macrophages Phagocytic activity may contribute to demyelination Microglia Specialized macrophages in the CNS, also may contribute to T cell activation 23

Neurodegeneration Loss of axons is the main cause of permanent disability in MS Axonal damage has been shown to occur in acute inflammatory plaques1 and can lead to brain atrophy Occurs in white and gray matter May also produce cognitive impairment Axonal damage could be the result of Cumulative inflammatory damage over time A parallel degenerative process related to loss of trophic support or an independent axonal degeneration2 Can effective immune therapy early in MS prevent worsening disability? 1. Trapp BD, et al. N Engl J Med. 1998;338:278-285. 2. Trapp BD. Neuroscientist. 1999;5:48-57. 24

Conclusions Pathogenesis of MS involves complex interactions between genetic and environmental factors Multiple genes are involved Vitamin D deficiency, EBV infection, and cigarette smoking are environmental candidates MS incidence has increased over the past 30 years due to a change in environmental exposure MS pathogenesis involves multiple immune cell types (T cells, B cells, NK cells, others) Along with chronic inflammation, MS pathogenesis involves axonal loss Neurodegeneration is the major source of disability in MS 25

Challenges in Diagnosing MS

What Is an MS “Attack”? Neurologic symptoms lasting ≥24 hours but generally longer Not explained by other conditions Do not represent recurrent symptoms in association with increased body temperature or infection (pseudoexacerbations) To be considered separate attacks, the interval between episodes must be ≥30 days McDonald WI, et al. Ann Neurol. 2001;50:121-127. 28

Clinical Presentation MS symptoms vary widely among individual patients Numbness, tingling, or weakness in the limbs Usually unilateral or only lower half of body Tremor, spasticity, incoordination, unsteady gait, imbalance Vision loss (usually unilateral), pain with eye movement, double vision Fatigue, dizziness, cognitive impairment, unstable mood Urinary and bowel incontinence or frequency Increased body temperature may trigger or worsen symptoms 29

Four Clinical Subtypes of MS RRMS Disability Time Disability Time PPMS Time Disability SPMS RPMS Disability Time Fauci AS, et al. In: Harrison's Manual of Medicine, 17th ed. McGraw-Hill Medical; 2009. Reprinted with permission from McGraw-Hill. 30

Disease Course After initial episode, MS patients typically follow a chronic pattern of acute neurologic symptoms (relapses) followed by periods of stability (remission) Timing, progression, duration, severity, and specific symptoms are variable and unpredictable Typically 2 to 3 relapses per year in untreated patients; treated patients have significantly fewer relapses Some symptoms may be ongoing/chronic; these do not represent relapse Long-term deficits range from mild to severe 31 31

Diagnosis of MS Clinically definite MS must meet criteria for1 Dissemination in space Dissemination in time A single episode of MS-like symptoms (clinically isolated syndrome [CIS]) will not meet these criteria But if MS is likely based on MRI, it still should be treated like MS Delaying treatment may be missing an important window of opportunity to delay the onset of irreversible disability Requires close monitoring over time to confirm diagnosis 1. Polman CH, et al. Ann Neurol. 2005;58:840-846. 32

Natural History of MS Clinical and MRI Measures Relapses/Disability MRI Activity MRI T2 Burden of Disease Axonal Loss Secondary Progressive MS Preclinical Relapsing-Remitting MS CIS * Disability Time Trapp BD, et al. Neuroscientist. 1999;5:48-57. Reprinted with permission from Sage Publications. 33

Natural History of CIS (Queen Square) Risk of Conversion Based on Lesion Count at Presentation 11% 79% 87% 85% 19% 89% 88% 6% 54% 92% 80% Morrissey S, et al. Brain. 1993;116:135-146. O’Riordan J, et al. Brain. 1998;121:495-503. Brex PA, et al. N Engl J Med. 2002;346:158-164. 34 34

Revised McDonald Criteria At least 3 of the following on MRIa: ≥1 Gd-enhancing brain or spinal cord lesion or ≥9 T2 hyperintense brain and/or spinal cord lesions of ≥3 mm in size if none of the lesions are Gd-enhancing ≥1 brain infratentorial lesion or spinal cord lesion ≥3 mm in size ≥1 juxtacortical lesion ≥3 mm in size ≥3 periventricular lesions ≥3 mm in size aTo meet criteria for dissemination in space Polman CH, et al. Ann Neurol. 2005;58:840-846. 35

Revised McDonald Criteria At least 1 of the followinga A 2nd clinical episode A Gd-enhancing lesion detected ≥3 months after onset of initial clinical event Located at a site different from the one corresponding to the initial event A new T2 lesion detected any time after a reference scan that was performed at least 30 days after the onset of an initial clinical event Thus, it is not always necessary to wait for 2 attacks to diagnose MS. A first attack plus changes on MRI may be enough aTo meet criteria for dissemination in time Polman CH, et al. Ann Neurol. 2005;58:840-846. 36

Typical MRI Lesions in MS Gd-enhancing Corpus Callosum A and B: Courtesy of Tracy M. DeAngelis, MD. 37

Typical MRI Lesions in MS Infratentorial Juxtacortical C and D: Courtesy of Daniel Pelletier, MD.

Typical MRI Lesions in MS Periventricular Spinal Cord E: Courtesy of Daniel Pelletier, MD. F: Courtesy of Tracy M. DeAngelis, MD.

CMSC MRI Protocol 2009 Obtain brain MRI at baseline, with contrast Obtain spinal cord MRI if symptoms pertaining to spinal cord lesions or no evidence of disease activity in brain Repeat scan if: Unexpected clinical worsening Need to re-evaluate diagnosis Starting or modifying treatment Consider serial MRI every 1-2 years to evaluate subclinical activity Consortium of Multiple Sclerosis Centers. http://www.mscare.org/cmsc/images/pdf/mriprotocol2009.pdf 40

Performing Serial MRIs for Follow-up A standardized protocol using consistent technology and protocols is essential to serial MRI interpretation Same magnet strength and slice thickness Same sequence acquisition Same patient positioning Same plane Section selection should match prior MRIs as closely as possible Radiologists should follow the updated CMSC protocol1 for standardizing MRIs in clinical MS applications 1. Consortium of Multiple Sclerosis Centers. http://www.mscare.org/cmsc/images/pdf/mriprotocol2009.pdf 41

MRI Correlates Poorly With Clinical Outcomes T2 lesion volume at a single point in time correlates weakly with clinical disability and is a measure of past attack frequency1 Change in lesion volume over time may be a better correlate2 T1-weighted black holes are a better but still imperfect correlate of disability3 Brain atrophy is a measure of neurodegeneration that may predict disability4 1. Bar-Zohar D, et al. Mult Scler. 2008;14:719-727. 2. Brex PA, et al. N Engl J Med. 2002;346:158-164. 3. Truyen L, et al. Neurology. 1996;47:1469-1476. 4. Miller DH, et al. Brain. 2002;125:1676-1695. 42

Why MRI Correlates Poorly with MS Disability MRI cannot determine extent/nature of tissue damage Location of lesion influences its clinical manifestation MRI cannot distinguish between demyelinated and remyelinated lesions MRI cannot detect gray matter lesions or diffuse damage in normal-appearing white matter Plasticity of CNS may lead to compensatory use of alternative neural circuit to circumvent damaged areas 43

Emerging MRI Technologies Measures of CNS atrophy Magnetization transfer imaging Proton magnetic resonance spectroscopy Diffusion tensor imaging Susceptibility weighted imaging 44

Other Diagnostic Tools for MS CSF Analysis Positive if oligoclonal IgG bands present but absent from corresponding serum sample or IgG index is elevated Sensitive but not specific: other causes of CNS inflammation can yield similar findings Lymphocytic pleocytosis is rarely >50/mm3 Protein levels rarely exceed 100 mg/dL Elevated myelin basic protein is not pathognomonic for MS 45

Other Diagnostic Tools for MS Visual Evoked Potentials (VEPs) Provides evidence of a lesion associated with visual pathways Positive if shows delayed but well-preserved wave forms Abnormal VEP is not specific for MS Can help establish dissemination in space 46

EDSS1 Bedridden Restricted to wheelchair Death Need for walking assistance Some limitation in walking ability 10.0 9.5 Minimal disability 9.0 Normal neurologic exam 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 Time to EDSS score of 4.0 strongly influenced by relapses in the first 5 years and time to CDMS.2 3.0 2.5 2.0 1.0 1.5 1. Kurtzke JF. Neurology. 1983;33:1444-1452. 2. Confavreux C, et al. Brain. 2003;126:770-782. 47 47

Residual Disability Sustained After a Relapsea Patients with Residual Disability (%) Days Since Exacerbation 30−59 Days 60−89 Days 90+ Days ≥0.5 EDSS points 42% 44% 41% ≥1 EDSS points 27% 29% 30% aIn 224 placebo patients from the NMSS task force on clinical outcome assessment. Lublin FD, et al. Neurology. 2003;61:1528-1532. 48 48

Neuromyelitis Optica (NMO) Syndrome of aggressive inflammatory demyelination afflicting the optic nerves and spinal cord1, often associated with severe disability Associated with infections and collagen vascular diseases1 Idiopathic form is considered a variant of MS Modern case series indicate that NMO is characterized by1 Recurrent attacks of optic neuritis and acute transverse myelitis Multisegmental spinal cord lesion >3 vertebral segments Initial brain MRI that is often (but not always) normal The NMO-IgG antibody recognizes aquaporin-4 (AQP4),2 a water channel expressed on astrocytes Anti-AQP4 antibody is 73% sensitive and 91% specific for NMO3 Blood testing is available at Mayo Medical Laboratories4 1. Cree B. Curr Neurol Neurosci Rep. 2008;8:427-433. 2. Lennon VA, et al. J Exp Med. 2005;202:473-477. 3. Lennon V, et al. Lancet. 2004;364:2106-2112. 4. Mayo Medical Laboratories. http://www.mayomedicallaboratories.com/test-catalog/Overview/83185. 49 49

Distinguishing NMO from MS Courtesy of Bruce A.C. Cree, MD, PhD, MCR Courtesy of Tracy M. DeAngelis, MD

Conclusions Diagnosis of MS is based on a combination of clinical and radiologic factors MRI should be performed according to CMSC standardized protocol Revised McDonald criteria are the gold standard for diagnosis High-risk CIS should be treated the same as clinically definite MS Clinical variants and red flags should be taken into account in formulating differential diagnosis 51

Achieving Therapeutic Goals with Current Treatments 53

Therapeutic Goals in MS In the absence of a cure for MS, current goals of disease modifying therapy are to Prevent disability Prevent relapses Prevent development of new or enhancing lesions on MRI Additional goals in the management of MS are to Relieve symptoms Maintain well-being Optimize quality of life 54

Treating Acute Relapse IV corticosteroids = standard of care Methylprednisolone 500 to 1000 mg/d IV for 3 to 5 days May be followed by oral steroid taper High-dose oral steroids may be acceptable alternative Phase III randomized OMEGA trial currently comparing oral and IV steroids Plasmapheresis and IVIG for refractory relapse 55

Therapeutic Targets in MS 56

FDA-Approved Disease-Modifying Agents First line: Interferon beta Interferon beta-1b 250 mcg SC QOD (two brands) Interferon beta-1a 44 mcg SC TIW Interferon beta-1a 30 mcg IM weekly Glatiramer acetate 20 mg SC QD Second line: Mitoxantrone 12 mg/m2 over 5 to 15 min q3mo; lifetime max, 144 mg/m2 Natalizumab 300 mg IV monthly infusion 57

Current First-Line MS Therapies Interferon beta-1a, interferon beta-1b, glatiramer acetate Interferons are FDA approved for relapsing forms of MS Glatiramer acetate is FDA approved for RRMS Similar efficacy for relapse rate reduction ~ 30% Generally very safe and well tolerated All require self-injection 58

Mechanisms of Action for Interferons Reduction of proinflammatory cytokine secretion Promotion of anti-inflammatory cytokine secretion Stabilization of blood-brain barrier Enhancement of regulatory T cell activity Downregulation of antigen presentation to T cells 59

Mechanisms of Action for Glatiramer Acetate Competitive inhibition of antigen presentation (myelin basic protein) to autoreactive T cells Activates regulatory T cells Promotes Th1 to Th2 cytokine shift 60

Head-to-Head Study EVIDENCE (IFN beta-1a) Trial, 48 Weeks Patients Relapse-Free Difference P Value IFN beta-1a 30 mcg IM QW 52% 19% in favor of IFN beta-1a 44 mcg SC TIW <.009 IFN beta-1a 44 mcg SC TIW 62% Abbreviations: IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously; TIW, 3 times per week. Pantich H, et al. Neurology. 2002;59:1496-1506. 61

Head-to-Head Study INCOMIN (IFN beta-1b vs beta-1a) Trial, 104 Weeks Patients Relapse-Free Difference P Value IFN beta-1b 250 mcg SC EOD 51% 42% in favor of IFN beta-1b <.036 IFN beta-1a 30 mcg IM QW 36% Abbreviations: EOD, every other day; IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously. Durelli L, et al. Lancet. 2002;359:1453-1460. 62

Patients Relapse-Free Head-to-Head Study REGARD (Glatiramer Acetate vs IFN beta-1a), 96 weeks Patients Relapse-Free Difference P Value Glatiramer acetate 20 mg QD 62% No difference <.96 IFN beta-1a 44 mcg SC TIW Abbreviations: IFN, interferon; SC, subcutaneously; QD, once daily; TIW, 3 times per week. Mikol DD, et al. Lancet Neurol. 2008;7:903-914. 63

Patients Relapse-Free Head-to-Head Studies BECOME and BEYOND (Glatiramer Acetate vs IFN beta-1b) Patients Relapse-Free Difference P Value BECOME1 (18 mo) GA 20 mg QD 70% 8% in favor of GA NS IFN beta-1b 250 mcg SC QOD 62% BEYOND2 (2 years) 59% 1% in favor of IFN 500 mcg 58% IFN beta-1b 500 mcg SC QOD 60% Abbreviations: GA, glatiramer acetate; QD, once daily; IFN, interferon; SC, subcutaneously; QOD, every other day; NS, not significant. 1. Cadavid D, et al. Neurology. 2009;72:1976-1983. 2. O’Connor P, et al. Lancet Neurol. 2009;8:889-897. 64

Head-to-Head Studies Bottom Line Higher-dose subcutaneous interferons are more effective than lower-dose intramuscular interferon High-dose subcutaneous interferon formulations and glatiramer acetate probably all offer comparable efficacy 65

Side Effects of Interferons Side effects include flu-like symptoms, injection site reactions/necrosis (SC), liver enzyme elevations, lymphopenia, depression Pregnancy category C Warnings: depression/suicide, decreased peripheral blood counts, hepatic injury, seizures, cardiomyopathy/CHF, autoimmune disease Laboratory tests: periodic CBC with differential, liver function profile, thyroid function Avonex [package insert]. Cambridge, MA: Biogen Idec; 2006. Betaseron [package insert] Montville, NJ: Bayer HealthCare Pharmaceuticals; 2009. Extavia [package insert]. Montville, NJ: Bayer HealthCare Pharmaceuticals; 2009. Rebif [package insert]. Rockland, MA: EMD Serono; 2009. 66

Neutralizing Antibodies Interferon therapies are associated with production of neutralizing antibodies (NAbs) to the interferon beta molecule1 NAbs may reduce radiographic and clinical effectiveness of interferon treatment NAb testing Sometimes used when deciding whether to switch from one interferon to another (usually IM to SC) in a patient with suboptimal response There are no guidelines on when to test, which test to use, how many tests are needed, or which cutoff titer to apply1 Probability of NAbs (%) Data from prescribing information. 1. Goodin DS, et al. Neurology. 2007;68:977-984. 67

Side Effects of Glatiramer Acetate Injection-site reactions, vasodilation, rash, dyspnea, chest pain Pregnancy category B Warnings: Immediate postinjection reaction, chest pain, lipoatrophy, skin necrosis Postinjection reaction (flushing, chest pain, palpitations, anxiety, dyspnea, constriction of throat, urticaria) is self-limited; no treatment required No lab testing required Copaxone [package insert]. Kansas City, MO: Teva Neuroscience; 2009. 68

Side Effect Management Tips Flu-like symptoms NSAIDs (eg, naproxen 500 mg 1 h before injection + 12 h later); IFN administration before bedtime; for patients on IFN beta-1a IM, prednisone 10 mg on day of injection; switch to glatiramer acetate Injection-site reactions and injection-site pain Rotate injection sites; administer injection without the autoinjector; topical anesthetics; application of ice before injecting; ensure proper product preparation including warming to room temperature Difficulty self-injecting Have partner administer injection; if “click” of autoinjector induces anxiety, administer without the autoinjector; call company nurse for retraining; home health agency might administer IFN beta-1a IM; switch to a therapy with less frequent injections 69

Timing of Therapy May Be Key to Preventing Disability First Demyelinating Event Secondary Progressive Pre- clinical Relapsing-Remitting Transitional Time window for early treatment First Clinical Attack Axonal loss Clinical threshold 1841 CMSC Slide Demyelination Inflammation Time (years) 70

Rationale for Early Treatment Time is ticking… What is lost by delaying early therapy is not regained by starting later 1841 CMSC Slide 71

Treating CIS Treating CIS vs waiting until patient has clinically definite MS (CDMS) Decrease progression to CDMS Decrease rate of disability progression Reduced lesion load on MRI Fewer and less severe relapses Most clinicians advocate early treatment BUT not all CIS will develop MS 72 72

Placebo-Controlled Trials of Disease-Modifying Therapy in CIS Study Treatment N Conversion to CDMS Follow- up On Tx Placebo P CHAMPS1 Interferon beta-1a 30 μg IM qwk 383 3 y 35% 50% .002 ETOMS2 Interferon beta-1a 22 μg SC once weekly 309 2 y 34% 45% .047 BENEFIT3 Interferon beta-1b 250 μg SC q48h 468 28% <.0001 PreCISe4 Glatiramer acetate 20 mg/d 481 61% 77% .0005 1. Jacobs LD, et al. N Engl J Med. 2000;343:898-904. 2. Comi G, et al. Lancet. 2001;357:1576-1582. 3. Kappos L, et al. Neurology. 2006;67:1242-1249. 4. Comi G, et al. Lancet. 2009;374:1503-1511. 73

FDA Approved for CIS Interferon beta-1a 30 mcg IM QW Interferon beta-1b 250 mcg SC QOD Glatiramer acetate 20 mg SC daily Interferon beta-1a 44 mcg SC TIW is sometimes used off-label 74

Second-Line MS Therapies Natalizumab Inhibits cell adhesion and leukocyte migration across BBB AFFIRM trial1 of natalizumab vs placebo in RRMS 42% reduction in risk of sustained progression of disability in 2 years (P <.001) 68% reduction in clinical relapse at 1 year (P <.001) 83% reduction in new or enlarging T2 lesions over 2 years (P <.001) 92% reduction in Gd-enhancing lesions at 1 and 2 years (P <.001) 1. Polman CH, et al. N Engl J Med. 2006;354:899-910. 75

Second-Line Therapies Natalizumab FDA approved for relapsing MS Due to risk of PML, natalizumab is generally reserved for patients who have not responded to or tolerated alternate therapies PML (JC virus of brain) leads to severe disability or death; no known treatment Available only through very restricted distribution program (TOUCH Prescribing Program) Other warnings: hepatotoxicity, hypersensitivity reactions, immunosuppression Tysabri [package insert]. Cambridge, MA: Biogen Idec; 2009.

Mitoxantrone Antineoplastic in anthracenedione class FDA approved for SPMS, PRMS, worsening RRMS Causes cross-links and strand breaks in DNA; inhibits B cell, T cell, and macrophage proliferation Due to serious side effects, reserve for patients with rapidly advancing MS despite other disease-modifying therapies Cardiomyopathy (LVEF decreased in up to 18%; CHF) Secondary acute myelogenous leukemia (0.25%) Elevated liver enzyme and glucose levels Requires frequent monitoring (CBC, liver function tests, LVEF, ECG) Administration should be performed by an oncologist Novantrone [package insert]. Rockland, MA: EMD Serono, and Melville, NY: OSI Pharmaceuticals; 2009. 77

Starting an MS Patient on a Disease-Modifying Agent Obtain starter kit from local representative Complete physician portion of Enrollment Form and have patient complete the patient portion Upon receipt of form, company will verify patient’s insurance benefits Company will supply medication and send nurse to the patient’s home for training on self-injection and proper needle disposal Titrate interferon dose as indicated on the Enrollment Form 78

Monitoring Follow up 4−6 weeks after initiating therapy Assess injection technique and tolerability If stable on therapy, re-evaluate every 3−6 months Laboratory testing for interferon CBC and liver enzyme levels 4–6 weeks after starting treatment, 3 months later, then every 6 months No laboratory testing needed for glatiramer acetate Continue on therapy indefinitely unless clear lack of benefit, intolerable side effects, or better treatment becomes available 79

Assess Adherence! Most Patients Who Discontinue Do So in First 2 Years Cohort of patients who stopped therapy Rio J, et al. Mult Scler. 2005;11:306-309. 80

Assess Adherence by Asking Patients typically will not tell you they have been nonadherent if you do not ask Ask in nonjudgmental manner that assumes they have missed some doses For example: How many injections do you think you have missed in the past 2 months? Being asked helps motivate patients to adhere Assess barriers by asking: What prevents you from taking your medication? NOT: Why aren’t you taking it? (Avoid casting blame)

Address Barriers to Adherence Difficulty self injecting Adverse events Unrealistic expectations of therapy (symptom relief) Lack of acceptance of MS diagnosis and need for treatment Financial considerations “Treatment fatigue” Depression Cognitive deficits Impairment in fine motor skills Changes to family and support circumstances 82

Suboptimal Treatment Response Worsening clinical status Radiologic changes (MRI) New Gd enhancement and/or new or enlarging T2 lesions are signs of disease activity No consensus as to when such findings warrant change in treatment Interpret in context of whole clinical picture If found on repeat scans, even if patient is clinically stable, probably warrants change in therapy Remember: comparison of serial MRI scans requires consistent use of standardized MRI protocol (CMSC protocol) 83

Suboptimal Response Potential Causes Nonadherence Pharmacogenomics: responsiveness to IFN β related to genetics1 Variable pathologies with differing responses to immune therapies NAbs MS subtype (disease modifying agents do not work in PPMS) 1. Byun E, et al. Arch Neurol. 2008;65:337-344. 84

Refer or Consult a Neurologist When diagnosis is in doubt If a consult is desired regarding selection of initial therapy For patients with poor response or toleration of first-line therapies When considering use of natalizumab or mitoxantrone

Conclusions Current MS therapies can reduce relapse rates and disability progression Interferon beta or glatiramer acetate is first line It is best to start treatment as early as possible Patient education is essential when starting treatment Rationale for treatment, injection technique, side effect management, importance of adherence After starting treatment, monitor for response, tolerability, and adherence 86

Emerging MS Therapies 88

Limitations of Current Therapies All are only partially effective All are injectable or IV and have side effects Risks vs benefits Existing therapies have advantage of long-term safety data Difficulty predicting therapeutic response Goal: Individualized, more effective, safe medication(s) that are easier to administer 89

Two Oral Therapies Have Completed Phase III Studies Fingolimod Cladribine 3 important questions to ask1 How do they compare with current therapies? Are all of the long-term safety issues known? What do they tell us about MS and our treatment goals? 1. Carroll WM. N Engl J Med. 2010;362:456-458. 90

Fingolimod Modulates sphingosine-1-phosphate receptors Receptors play a role in egress of lymphocytes out of lymph nodes Fingolimod sequesters lymphocytes in lymph nodes Fingolimod crosses blood-brain barrier and may have neuroprotective properties Dosing: once-daily pill Status: 2 phase III trials completed; pending FDA review Brinkmann V, et al. J Biol Chem. 2002;277:21453-21457. Pinschewer DD, et al. J Immunol. 2000;164:5761-5770. Chiba K, et al. J Immunol. 1998;160:5037-5044. 91

Fingolimod FREEDOMS, 24-Month Study Fingolimod reduced relapse rate by 54% to 60% vs placebo and reduced risk of disability progression Placebo-controlled FREEDOMS II study is ongoing. Kappos L, et al. N Engl J Med. 2010;362:387-401. 92

Fingolimod TRANSFORMS, 12-Month Study Fingolimod reduced relapse rate by 38% to 52% versus IFN beta-1a but was not significantly different with regards to effect on disability Cohen JA, et al. N Engl J Med. 2010;362:402-415. 93

Fingolimod Safety Common: nasopharyngitis, infections, cough/dyspnea, fatigue, headache, back pain, diarrhea, nausea, and elevated ALT levels Malignancies (skin cancer, breast cancer) Bradycardia/atrioventricular block Requires 6-hour first-dose monitoring with hourly ECGs Bradycardia persisting >6 hours requires continued monitoring Break in therapy >2 days requires repeat first-dose monitoring; therefore, not good choice for nonadherent patients Severe herpes infections (some fatal) Disseminated Varicella Zoster (fatal) Macular edema requiring ophthalmology screening Reduction in FEV1 —PFTs and HRCT required in phase III studies Lower dose has fewer side effects Cohen JA, et al. N Engl J Med. 2010;362:402-415. Kappos L, et al. N Engl J Med. 2010;362:387-401. 94

Cladribine Results in selective long-term depletion of CD4+ and CD8+ T cells FDA approved for treatment of hairy-cell leukemia Dosing: given orally for 5 consecutive days for 2 cycles, 1 month apart Status in MS Fast-tracked by the FDA Phase III study completed FDA issued “refuse to file” letter Nov. 30, 2009 NDA will be resubmitted as soon as FDA’s concerns can be addressed Sipe JC. Expert Rev Neurother. 2005;5:721-727. 95

Oral Cladribine CLARITY Oral cladribine reduced the relapse rate by 54.5% to 57.6% and the risk of sustained disability progression at 3 months by about one third compared with placebo. Giovanni G, et al. N Engl J Med. 2010;362:416-426. 96

Cladribine Safety Common adverse effects: headache, nasopharyngitis, upper respiratory tract infection, nausea Infections/infestations Herpes zoster Primary varicella Benign uterine leiomyomas Malignancies (melanoma, pancreatic, ovarian, cervical) Decreased lymphocyte counts/severe aplastic anemia Exacerbation of latent tuberculosis Giovanni G, et al. N Engl J Med. 2010;362:416-426. 97

Do We Have the Answers to the Three Questions? Fingolimod and cladribine are likely to be at least as effective as available treatments Fingolimod > IFN beta-1a IM in TRANSFORMS IFN beta-1a IM was the least effective of available therapies in prior head-to-head trials Fingolimod and cladribine may have greater safety issues Severe herpes infections, malignancies, lymphocytopenia (both fingolimod and cladribine) Macular edema, bradycardia/AV block (fingolimod) Higher discontinuation rates than available therapies It is not yet clear whether these therapies can prevent immune-mediated injury Carroll WM. N Engl J Med. 2010;362:456-458. 98

Additional Oral Small-Molecule MS Therapies in Late-Stage Development Fumarate (BG00012) Teriflunomide Laquinimod 99

Emerging Monoclonal Antibodies Rituximab Ocrelizumab Alemtuzumab Daclizumab 100

Conclusions Oral therapies for MS may soon be available Phase III studies have been completed for fingolimod and oral cladribine Possibly more effective at reducing relapse rates compared with current therapies, but not clear that they are any better at preventing disability Some serious adverse events have been observed Requires patient understanding of risks and need for close monitoring Other small molecules and monoclonal antibodies are in late-stage development for MS 101

Symptom Management 103

MS Symptoms vs Relapses Chronic or ongoing indicators of MS lesion damage to certain areas of the brain or spinal cord MS relapses Flare-ups or attacks of new or previously resolved symptoms that typically evolve over at least 48 hours and last several days to weeks

Common MS Symptoms Fatigue Bladder dysfunction Spasticity Gait difficulties Pain Cognitive impairment Mood instability Sexual dysfunction 105

MS Fatigue One of the most common (80%) symptoms One of the most disabling symptoms Primary reason to stop working More likely than other types of fatigue to interfere with daily responsibilities Occurs daily, starts suddenly Can start early in the morning, even after restful sleep Worsens as day progresses, with heat and humidity Cause unknown National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/fatigue/index.aspx 106

Managing MS Fatigue Lifestyle Changes Physical therapy/exercise Good nutrition Enough sleep Going to bed on time Management of other symptoms that interfere with sleep Rest breaks Weight management Prioritization of tasks; maintaining realistic expectations Letting others help Avoidance of excessive caffeine, multitasking, overheating 107

Managing MS Fatigue Pharmacologic Strategies (Off-Label Uses) Amantadine hydrochloride 100-200 mg/d early in day May need additional 100 mg around noon Modafanil 100-200 mg/d early in day Amphetamine-type therapies Methylphenidate, can start at 5 mg PO in AM and titrate to effect; 10 mg in AM and around noon or early afternoon is common Can use long-acting formulations 108

Bladder Dysfunction Affects 80% of MS patients Frequency and/or urgency Hesitancy in starting urination Nocturia Incontinence and/or dribbling Urinary retention, which can lead to UTIs May interfere with normal activities and cause social embarrassment National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/bladder-dysfunction/index.aspx and http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/bladder-dysfunction/download.aspx?id=64 109

Managing Bladder Dysfunction Management Assessment Urinalysis/dipstick, culture (UTI) Postvoid residual urine Urodynamic studies Dietary and fluid management Do not restrict fluids! 6-8 glasses daily, spread over course of day, but fewer before bed Exception: restrict intake ~ 2 hours before activities where no bathroom will be available Limit caffeine, alcohol, citrus juice Intermittent self-catheterization Absorbent pads National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/bladder-dysfunction/index.aspx and http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/bladder-dysfunction/download.aspx?id=64 110

Managing Bladder Dysfunction Pharmacologic Strategies Antibiotics if positive for UTI Anticholinergic agents Oxybutynin, propantheline, imipramine, tolterodine, solifenacin succinate, darefenacin, trospium chloride Desmopressin acetate nasal spray or tablets (for nocturia) Need to monitor serum sodium Antispasticity agents (to relax sphincter muscle) Baclofen, tizanidine hydrochloride Alpha-adrenergic blockers Prazosin, terazosin, tamsulosin National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/bladder-dysfunction/download.aspx?id=64 111

Spasticity Velocity-dependent increase in muscle tone, with hyperactive deep tendon reflexes Clonus: repetitive rhythmic beating of foot or wrist Difficulty initiating movement Impaired voluntary muscle control Difficulty relaxing muscles after movement cessation Sensation of muscle tightness or pain Decreased range of motion Potential triggers: sudden movements or position changes, fatigue, stress, cold, humidity, tight clothes, tight shoes, constipation, poor posture, infection Can be worsened by interferons Can add to MS fatigue National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/spasticity/index.aspx. Kushner S, et al. Spasticity. NMSS Clinical Bulletin. http://www.nationalmssociety.org/download.aspx?id=147 112

Managing Spasticity Nonpharmacologic Strategies Daily stretching and exercise (cool environment) Balance and coordination, strengthening, timing, range of motion, posture Transcutaneous electrical nerve stimulation (TENS) Thermal (hot and cold) Biofeedback Relaxation (yoga, Tai Chi) Bracing/splinting Kushner S, et al. Spasticity. NMSS Clinical Bulletin. http://www.nationalmssociety.org/download.aspx?id=147 113

Managing Spasticity Pharmacologic Strategies Baclofen - oral or intrathecal; start low and titrate Tizanidine Dantrolene sodium Diazepam Other off-label agents sometimes used Clonazepam, gabapentin Botulinum injections for focal spasticity Phenol nerve blocks Kushner S, et al. Spasticity. NMSS Clinical Bulletin. http://www.nationalmssociety.org/download.aspx?id=147. 114

Managing Spasticity Surgery for Intractable Symptoms Tenotomy Neurectomy Rhizotomy Kushner S, et al. Spasticity. NMSS Clinical Bulletin. http://www.nationalmssociety.org/download.aspx?id=147 115

Managing Gait Difficulties Dalfampridine—previously known as fampridine SR or 4-aminopyridine SR FDA approved January 2010 Indication: improve walking speed in patients with MS This is not a disease-modifying therapy Mechanism: K+ channel blockade Enhances axonal conduction Dose-dependent side effect: seizures Ampyra [package insert]. Hawthorne, NY: Acorda Therapeutics; 2010. 116

Dalfampridine Phase III Studies Responders (%) P <.001 Dalfampridine 10 mg BID (n = 229) or placebo (n = 72) x 14 weeks Response = consistent improvement on timed 25-foot walk Walking speed improved by 25% among fampridine responders vs 5% with placebo (Trial 1) Ampyra [package insert]. Hawthorne, NY: Acorda Therapeutics; 2010. Goodman AD, et al. Lancet. 2009;373:732-738. 117

Botulinum Toxin for MS Spasticity N = 74 MS patients with disabling spasticity of the hip adductor muscles of both legs Randomized to botulinum toxin 500, 1000, or 1500 U IM injections into hip adductor muscles or placebo Botulinum was associated with improved passive hip abduction and distance between the knees Botulinum reduced muscle tone, and all groups (including placebo) had reduced frequency of spasms and leg pain Nonsignificant trend toward greater efficacy with higher doses but there were twice as many side effects with 1500 U Hyman N, et al. J Neurol Neurosurg Psychiatry. 2000;68:707-712. 118

Managing Other MS Symptoms Management Pain Carbamazepine, phenytoin, gabapentin, amitriptyline, duloxetine hydrochloride, pregabalin, baclofen, tizanidine, acetaminophen, NSAIDs, pressure stocking/glove, warm compresses, massage Cognitive impairment Referral for cognitive rehabilitation and psychotherapy, memory aids (recordings, lists, mnemonics, etc), assistive technologies (computers, electronic calendars), minimization of distractions, donepezil (if dementia present) Depression Referral for counseling/psychotherapy, TCAs, SSRIs, SSRNIs, bupropion, mirtazapine Sexual dysfunction Consider medication side effects (eg, SSRIs, beta blockers), sildenafil, vardenafil, tadalafil, papaverine, OTC lubricants, alternative means of stimulation, counseling to address relationship issues National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/pain/index.aspx, http://www.nationalmssociety.org/download.aspx?id=127, http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/treatments/medications/antidepressants/index.aspx, http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/sexual-dysfunction/index.aspx 119

Conclusions Managing MS means thinking about more than just preventing relapse and new lesions It is important to address other symptoms that interfere with QOL Symptoms need to be recognized in order to treat Address 1 or 2 symptoms per visit—prioritize Through counseling and treatment, most symptoms can at least be reduced Refer to specialists as needed for optimized symptom control Expect that many symptoms will never be fully controlled 120

The Dialogue of MS in Primary Care

Communicating with Patients and Peers There are many resources for clinicians and patients available online Social media sites offer resources as well as an opportunity to connect with others Some of the information your patients receive over the Internet and via social media sites is more accurate than others Know what is available Recommend reputable sites Ask what they are using

What Your Patients May Be Doing You Tube

What Your Patients May Be Doing Facebook

What Your Patients May Be Doing Twitter

What Your Patients May Be Doing Blogging

Other Projects In Knowledge MS Enduring Materials The Advanced Certificate Program: Multiple Sclerosis Management II www.projectsinknowledge.com/cp/1877 Living Medical Textbook: Multiple Sclerosis Edition www.livingmedicaltextbook.org/1876