Overview of MS and Strategies for Personalized Treatment

Overview of MS and Strategies for Personalized Treatment
Douglas S. Goodin, MD Professor of Neurology Medical Director Multiple Sclerosis Center University of California, San Francisco San Francisco, California

Multiple Sclerosis Epidemiology
Prevalence 1.0–1.5 per 1,000 population in the United States ~2.5 million cases worldwide Age at onset: 15–45 years 70%–75% of cases are women Increasing worldwide prevalence (especially in women) Ethnic origin: predominantly white, but does occur in other ethnicities as well Goodin DS. Epidemiology of MS. In: Handbook of Clinical Neurology. Philadelphia, PA: Elsevier; Compston A, et al. McAlpine’s Multiple Sclerosis. 4th ed. London, England: Churchill Livingstone; 2006.

Goodin DS. Epidemiology of MS. In: Handbook of Clinical Neurology
Goodin DS. Epidemiology of MS. In: Handbook of Clinical Neurology. Philadelphia, PA: Elsevier; 2012.

Etiology of MS Genetics
Increased risk in persons who have relatives with MS1-3 50–200 susceptibility alleles2,3 Strongest association with HLA DRB1* Environmental factors, current hypotheses History of Epstein-Barr virus infection1,2,4,5 Vitamin D deficiency1,2,6 Smoking2 (active7 or passive8) 1. Goodin DS. PLoS One. 2009;4:e Goodin DS. Epidemiology of MS. In: Handbook of Clinical Neurology. Philadelphia, Pa: Elsevier; Goodin DS. BMC Neurology ;10: Santon A, et al. Mult Scler. 2011;17: Lucas RM, et al. Neurology. 2011;77: Munger KL, et al. Neurology. 2004;62: Handel AE, et al. PLoS One. 2011;6(1):e Hedström AK, et al. Mult Scler J. 2011;17:

Pathophysiology of MS Acute inflammation  demyelination/relapses
Blood-derived lymphocytes and monocytes Breakdown of blood-brain barrier Edema White and grey matter lesions Myelin injury, axonal transection Neurodegeneration  irreversible disability Neuronal loss Brain atrophy Trapp BD, et al. Annu Rev Neurosci. 2008;31:

Subtypes of MS Relapsing-remitting MS (RRMS)
Episodes of acute neurologic dysfunction (attacks) ± recovery Stable disease between attacks Initial diagnosis in ~85% of patients Primary-progressive MS (PPMS) Steady functional decline from onset without attacks ~10% of cases Secondary-progressive MS (SPMS) Steady functional decline ± attacks; always follows RRMS 50%–80% develop SPMS Progressive-relapsing MS (PRMS) Steady functional decline from onset with occasional attacks ~5% of cases Lublin FD, Reingold SC. Neurology. 1996;46: Compston A, et al. McAlpine’s Multiple Sclerosis. 4th ed. London, England: Churchill Livingstone; 2006.

MS Symptoms Common Less Common Vision disturbances Fatigue Numbness
Incoordination Gait impairment Bladder/bowel dysfunction Dizziness and vertigo Pain Cognitive dysfunction Depression Spasticity Speech dysfunction Swallowing difficulties Hearing loss Seizures Respiratory impairment Hauser SL, Goodin DS. Multiple sclerosis. In: Harrison’s Principles of Internal Medicine. New York, NY: McGraw-Hill; 2008:

Revised Diagnostic Criteria Multiple Sclerosis
Dissemination of lesions in space (DIS) ≥1 T2 lesion in ≥2 of 4 CNS areas: periventricular, juxtacortical, infratentorial, spinal cord* Dissemination of lesions in time (DIT) ≥2 clinical attacks, or 1 of the following MRI criteria ≥1 new T2 or gadolinium(Gd)-enhancing lesions not found on baseline scan, irrespective of timing of baseline scan Simultaneous presence of asymptomatic Gd-enhancing and nonenhancing lesions *If brain stem or spinal cord syndrome, the symptomatic lesions are excluded from criteria and do not count toward lesion count. Polman CH, et al. Ann Neurol. 2011;69:

FDA-Approved Disease-Modifying Therapies
Drug Recommended Dose Indication IFN beta-1b (2 brands)1,2 250 mcg SC q2d Relapsing MS, CIS IFN beta-1a3 22 or 44 mcg SC TIW Relapsing MS IFN beta-1a4 30 mcg IM weekly GA5 20 mg SC qd RRMS, CIS Fingolimod6 0.5 mg orally qd Natalizumab7 300 mg IV over 1 h q4wk Relapsing MS (nonresponders/intolerant to alternate therapy) Mitoxantrone8 12 mg/m2 over 5–15 min IV q3mo SPMS, PRMS, worsening RRMS Abbreviations: CIS, clinically isolated syndrome; GA, glatiramer acetate; IFN, interferon; IM, intramuscular; IV, intravenous; SC, subcutaneous. 1. Betaseron [PI]. Montville, NJ: Bayer HealthCare Pharmaceuticals; Extavia [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corp; Rebif [PI]. Rockland, MD: EMD Serono; Avonex [PI]. Cambridge, MA: Biogen Idec; Copaxone [PI]. Kansas City, MO: Teva Neuroscience; Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corp; Tysabri [PI]. Cambridge, MA: Biogen Idec; Novantrone [PI]. Rockland, MD: EMD Serono; 2010.

Comparisons of Therapies

Short-Term Outcomes in MS Establishing Efficacy in MS
Outcome measures: disease activity 1. Clinical assessment (eg, attack rate or attack-free status) 2. Radiologic (MRI) assessment (eg, new T2, Gd+, or combined unique lesions) Outcome measures: disease severity 1. Clinical assessment (eg, confirmed EDSS progression or MSFC) 2. Radiologic (MRI) assessment (eg, T2 burden, T1 black holes, or atrophy) Abbreviations: EDSS, Expanded Disability Status Scale; MSFC, Multiple Sclerosis Functional Composite. 12

Outcome Assessment Relative Risk Risk of illness (exposed or treated)
Risk of illness (unexposed or untreated) Relative risk = Rate of illness (exposed or treated) Rate of illness (unexposed or untreated) RRate = Odds of illness (exposed or treated) Odds of illness (unexposed or untreated) Odds ratio = Bewick V, et al. Critical Care. 2004;8: Courtesy of Douglas S. Goodin, MD. 13

Absolute Risk—NNT/NNH
Outcome Assessment Absolute Risk—NNT/NNH NNT/NNH = 1 | Risk controls – Risk treated | = /ARR NNT/NNH = 1 (Events/Patient) = Patients/Events Abbreviations: ARR, absolute risk reduction; NNH, number needed to harm; NNT, number needed to treat. Courtesy of Douglas S. Goodin, MD. 14

Prospective Randomized Trial
Trial Design Courtesy of Douglas S. Goodin, MD. 15

The Need for Head-to-Head Trials Relative Efficacy (RR)
GA 20 mg qd IFN beta-1a 30 mcg IM qwk IFN beta-1b, 250 mcg SC q2d IFN beta-1a 44 mcg TIW Natalizumab 300 mg/mo Annualized relapse rate -29% -18% -34% -32% -68% Relapse-free (2 years) +42% +36% +100% +57% 3-month sustained progression (≥1 EDSS point) -12% -37% -30% -42% New T2 lesions -38% -36% -83% -78% Gd+ or CU lesions -33% - -88% -92% Goodin DS, et al. Neurology. 2008;71: Courtesy of Douglas S. Goodin, MD. 16

The Need for Head-to-Head Trials Absolute Efficacy (NNT and NNH)
GA 20 mg qd IFN beta-1a 30 mcg IM qwk IFN beta-1b, 250 mcg SC q2d IFN beta-1a 44 mcg TIW Natalizumab 300 mg/mo Annualized relapse rate 4 7 2 Relapse-free (2 years) 15 9 6 Progression- free (%) 33 8 13 New T2 lesions 0.17 1.3 0.34 0.3 0.11 Annualized rate of Gd+ lesions 0.09 1.4 - 0.91 Goodin DS, et al. Neurology. 2008;71: Courtesy of Douglas S. Goodin, MD. 17

INCOMIN Trial 24 Months IFN beta-1a 30 mcg IM qwk IFN beta-1b
250 mcg SC q2d % change P value Relapse-free 36% 51% +42% .036 T2 lesion-free 26% 55% +112% <.003 EDSS progression 30% 13% -44% .005 Gd+ lesion-free 49% 76% +55% .001 Burden of disease +11.7% -2.8% -14.5% .0001 Red indicates primary endpoint. Durelli L, et al. Lancet. 2002;359:

EVIDENCE Trial Final Results
Relative Improvement with IFN beta-1a 44 mcq TIW SC vs 30 mcq IM qwk P value Relapse rate 17% .033 Odds ratio–relapsing 33% .023 Hazard ratio, time to relapse 30% .002 Steroid use 32% .009 T2 lesions 36% <.001 T2 active scans 38% T2 inactive patients 55% Disability progression 6% ns Red indicates primary endpoint. Panitch H, et al. Neurology. 2002;59: Courtesy of Douglas S. Goodin, MD.

REGARD Trial Final Results
IFN beta-1a 44 mcg SC TIW (n = 386) GA 20 mg/d (n = 378) P value Time to first relapse (30th percentile) 495 d 432 d ns Patients free from relapse 62% Annualized relapse rate 0.30 0.29 T2 active lesions 0.67 0.82 Gd-enhancing lesions 0.24 0.41 .0002 CU lesions 0.91 1.22 .010 New T1 hypointense lesions 0.23 Brain volume change -1.240 -1.073 .018 MRI measures reported as lesions per patient per scan. Red indicates primary endpoint. ns = not significant Mikol DD, et al. Lancet Neurol. 2008;7:

BEYOND Trial Final Results
Endpoint BEYOND P Values IFN beta-1b 250 mcg (n = 897) GA (n = 448) Relapse risk ns Relapse rate 0.36 0.34 Progression-free 89% 80% New/Enlarging T2 Lesions 3.3 4.6 0.011 Gd+ Enhancing 0.9 1.2 Change in Brain Volume -0.65% -0.61% Red indicates primary endpoint. O’Connor P, et al. Lancet Neurol. 2009;8: 21

Oral Fingolimod 0.5 mg/d Endpoint TRANSFORMS (Month 12) P Values
IFN beta-1a IM (n = 431) Relapse rate 0.16 0.33 <0.001 Relapse-free 82.6% 69.3% Progression-free 94.1% 92.1% ns New/Enlarging T2 Lesions 1.7 2.6 0.004 Gd+ Lesion Free 90.1% 80.8% Gd+ Enhancing 0.23 0.51 Comparisons all P <.05, except for TRANSFORMS progression-free, P = .25. Abbreviations: TRANSFORMS, Trial Assessing Injectable Interferon vs FTY720 Oral in RRMS. 1. Kappos L, et al. N Engl J Med. 2010;362: Cohen JA, et al. N Engl J Med. 2010;362:

Natalizumab 300 mg/m + weekly IFN beta-1a
Endpoint SENTINAL (Month 24) P Values Natalizumab (n = 589) IFN beta-1a IM (n = 582) Relapse rate 0.34 0.75 <0.001 Progression-free 77% 71% 0.02 New T2 Lesions 0.9 5.4 0.001 Gd+ Lesion Free 96% 75% Rudick RA, et al. N Engl J Med. 2006;354: Red indicates primary endpoint

The Value of Early Treatment

Disease-Modifying MS Therapies Disease Stage and Therapeutic Effects
Potential therapeutic benefit of DMTs Mono-symptomatic MS RR to SP Axonal loss RRMS Natalizumab Fingolimod IFN beta-1a GA IFN beta-1b Therapeutic Benefit Disability threshold IFN beta-1a SPMS NA-SPMS IFN beta-1b Disease stage RRMS SPMS time Abbreviation: NA-SPMS, North American Secondary-Progressive MS Trial. Courtesy of Douglas S. Goodin, MD.

Early Treatment of MS with DMTs
IFN beta-1a 22 mcg SC qwk 30 mcg IM qwk IFN beta-1b 250 mcg SC q2d GA 20 mg SC qd RRMS (reduction in relapse rate vs placebo) 0%1 -18%2 -34%2 -29%2 CIS (reduction in rate of conversion to CDMS vs placebo) -33%3 -44%4 -50%5 -45%6 1. OWIMS Study Group. Neurology. 1999;53: Goodin DS, et al. Neurology. 2008;71: Comi G, et al. Lancet. 2001;357: Jacobs LD, et al. N Engl J Med. 2000;343: Kappos L, et al. Neurology. 2006;67: Comi G, et al. Lancet. 2009;374: Courtesy of Douglas S. Goodin, MD. 26

Long-Term Treatment Outcomes

Propensity-Adjusted Cox PH Model High Exposure to IFN beta-1b
Goodin DS, et al. PLoS One. 2011;6:e22444. 28

IFN beta-1b 21-Year Long-Term Follow-Up Study Design
Vital status of 366 (98.4%) of 372 original RCT participants was identified after 21 years Randomized trial (N = 372) Placebo IFN beta-1b 50 mcg q2d Regular medical care IFN beta-1b 250 mcg q2d 1988 1993 2005 2006 2009 2010 RCT complete 21-year LTF Abbreviations: LTF, long-term follow-up; RCT, randomized controlled trial. Goodin DS, et al. Neurology. 2012;78: Courtesy of Douglas S. Goodin, MD. 29 29 29 29

IFN beta-1b 21-Year Long-Term Follow-Up Results
More deaths were observed among patients originally randomized to placebo than to IFN 78.3% of deaths were from MS-related causes HR of Death Reduction in HR 95% CI P value IFN beta-1b 250 mcg SC q2d vs placebo 0.532 46.8% 0.314–0.902 .0173 IFN beta-1b 50 mcg SC q2d vs placebo 0.540 46.0% 0.318–0.915 .0202 Abbreviations: CI, confidence interval; HR, hazard ratio. Goodin DS, et al. Neurology. 2012;78:

Long-Term Follow-Up in RRMS Glatiramer Acetate
15-year open-label extension of 2-year phase III trial1 Relapses reduced to ~1 every 4 years compared with every year at open-label entry 57% had improved or stable EDSS scores 65% had not progressed to SPMS Mean 5.8-year follow-up of open-label extension of 18-month trial2 Patients taking glatiramer acetate at study onset less likely to need walking aids vs those starting active treatment at extension entry (P = .034) 1. Ford C, et al. Mult Scler. 2010;16: Rovaris M, et al. Mult Scler. 2007;13:

Impact of DMTs on Cognitive Impairment
Likelihood of cognitive impairment was reduced with Early vs delayed IFN beta-1b SC initiation in CIS1 Higher-dose IFN beta-1a SC in RRMS2 IFN beta-1a IM in relapsing MS improved information processing and learning/recent memory3 Cognitive function was preserved in most patients taking glatiramer acetate during 10-year open-label follow-up4 1. Kappos L, et al. Lancet. 2007;370: Patti F, et al. Mult Scler. 2010;16: Fischer JS, et al. Ann Neurol. 2000;48: Schwid SR, et al. J Neurol Sci. 2007;255:57-63.

Safety and Tolerability

Safety of Interferons Side effects: Flu-like symptoms, injection-site reactions, hepatotoxicity (hepatic enzyme elevations), leukopenia, depression (?), headache, thyroid dysfunction Pregnancy: Category C Laboratory tests: Periodic CBC with differential, liver function tests, thyroid function tests Abbreviation: CBC, complete blood count. Betaseron [PI]. Montville, NJ: Bayer HealthCare Pharmaceuticals; Extavia [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corp; Rebif [PI]. Rockland, MD: EMD Serono; Avonex [PI]. Cambridge, MA: Biogen Idec; 2012.

Safety of Glatiramer Acetate
Side effects Injection-site reactions, lipoatrophy Immediate postinjection reaction (flushing, chest pain, palpitations, anxiety, shortness of breath) Self-limited; usually nonrecurrent; no treatment required Pregnancy: Category B Laboratory tests: None required Copaxone [PI]. Kansas City, MO: Teva Neuroscience; 2009.

Safety of Fingolimod Side effects: Headache, liver enzyme elevations, bradycardia, atrioventricular block, severe lymphopenia, macular edema Pregnancy: Category C Drug interactions: QT prolonging drugs, beta-blockers Laboratory tests: CBC with differential, liver enzymes At least 6 hours of cardiovascular observation after 1st dose, with hourly pulse and blood pressure measurement for all patients EKG obtained prior to 1st dose and at end of observation period Cardiovascular monitoring should be extended past 6 hours in patients at higher risk of bradycardia and should include continuous overnight EKG monitoring FDA Drug Safety Communication. May 14, Accessed 5/14/12 at:

Safety of Natalizumab Side effects: Hypersensitivity reactions, fatigue, diarrhea, infections PML/IRIS Pregnancy: Category C Lab tests: JC virus antibody testing prior to/during treatment; antibody testing if persistent antibodies suspected Abbreviations: IRIS, immune reconstitution inflammatory syndrome; PML, progressive multifocal leukoencephalopathy. Tysabri [PI]. Cambridge, MA: Biogen Idec; 2012.

Natalizumab PML Risk Factors
Duration of use1 1–12 months: 0.04 cases/1000 patients 13–24 months: 0.56 cases/1000 patients 25–36 months: 1.93 cases/1000 patients 37–48 months: 1.99 cases/1000 patients JC virus antibodies (JCV Ab) present in ~55%1 FDA-approved screening test now available2 54 cases with samples all JCV Ab positive prior to PML1 3.80–3.87 cases per 1000 patients if JCV Ab positive1 ≤0.09 cases per 1000 patients if JCV Ab negative1 Prior immunosuppressive therapy1 34.5% in PML vs 20.3%–23.5% in all natalizumab users) Risk is further increased if multiple risk factors1 There 212 cases of PML among 99,571 treated (2.1 per 1000 patients) Of the 212 cases worldwide, 46 (22%) died; of the 58 survivors with data on disability/outcomes at ≥6 mo after diagnosis, 23 (40%) had severe disability. Risk in patients with all three risk factors = 11.1 cases per 1000 patients 1. Bloomgren G, et al. N Engl J Med. 2012;366: Stratify JCV [PI]. Cypress, CA: Focus Diagnostics; 2011.

Natalizumab & IRIS IRIS follows PML; in most cases after PE1
Due to rapid restoration of immune function after NTZ clearance2 Typical  PML Sx; days to weeks after PE; may require ICU care3 Corticosteroids: Strike balance between adequate immunosuppression while maintaining effective immune response against JC virus4 Methylprednisolone 1 g/d IV for 5 days followed by oral steroids; repeated courses may be necessary3 In case studies, corticosteroids reduced IRIS and improved EDSS scores in most patients, compared with several deaths3 and worse EDSS scores in patients whose IRIS was untreated5 1. Tysabri [PI]. Cambridge, MA: Biogen Idec; Carson KR, et al. Lancet Oncol. 2009;10: Clifford DB, et al. Lancet Neurol. 2010;9: Berger JR. Neurology. 2009;72: Tan IL, et al. Neurology. 2011;77:

Emerging Disease-Modifying Therapies

Emerging Disease-Modifying Therapies
Small Molecules Monoclonal Antibodies BAF312 Dimethyl fumarate (BG-12) Laquinimod ONO-4641 Teriflunomide Alemtuzumab Daclizumab Ocrelizumab and ofatumumab

Conclusions Early treatment more effective than late
Reduction in relapses, disability progression, MRI Better long-term outcome (physical and cognitive) Recent studies of long-term follow-up show Improved survival/reduced MS-related mortality Good safety track record (GA, IFN) Natalizumab has serious adverse events and requires careful monitoring Fingolimod is probably safe but requires careful monitoring Mitoxantrone Rarely used due to serious adverse events More options expected in the near future

Partnering with Patients to Improve Adherence in MS
Amy Perrin Ross, MSN Neuroscience Program Coordinator Department of Neurosciences Loyola University Chicago Maywood, Illinois

Goals of Treatment with Disease-Modifying Therapy
Reduce frequency and severity of relapses Reduce new/enhancing lesions on MRI Delay disability progression Increase overall quality of life and function Provide therapy that is well tolerated and safe Acceptable benefit vs risk A wellness philosophy is the focal point of comprehensive care 45

The Multiple Sclerosis Team
OUTPUTS Quality of life Adherence Adjustments/ adaptation Patient/Family Neurologist Nurse Urologist Neuropsychologist Speech Therapist Occupational Therapist Social Work/ Counselors Physical Therapist NMSS/MSAA/MSF Ancillary Services Support Staff Recreational Therapist Not a complete picture and individual team members may come in and out of the picture depending on the individuals needs. Abbreviations: MSAA, Multiple Sclerosis Association of America; MSF, Multiple Sclerosis Foundation; NMSS, National Multiple Sclerosis Society. Graphic courtesy of June Halper. 14 46 3

Choosing the Right Treatment for the Individual Patient with MS
Initiation of treatment Which disease-modifying therapy will fit an individual patient? 1st-line medications vs 2nd-line Ability to self-inject – SQ/IM vs oral/IV Lifestyle issues Career/family roles Planning pregnancy Planning trip? Vaccines 47

Decision Making Discussion of pros and cons with patients
Partnership with patients and families Possible use of consent form/contract Future plans and therapies Long-term effects of certain medications Combination of therapies Safety of medications Pregnancy

Adherence vs Compliance
Compliance implies giving in to a request, wish, or demand; it implies a subordinate position to healthcare professionals Versus Adherence is voluntary, active collaborative involvement of the patient in a mutually acceptable course of behavior leading to a desired outcome

Adherence to Therapy Although it is felt to be important
Adherence is difficult Nonadherence estimates are about 50%–70%; this is true for many chronic diseases Many reasons offered as to why Perception that drug is not working Continued MS symptoms Side effects Insurance coverage

Barriers to Adherence Lifestyle issues
Cultural considerations and healthcare literacy Fear of injections Concerns about adverse effects, including injection site reactions that can affect lifestyles Perceived benefits Lack of an effective support system Depression Cost

Barriers to Adherence Progression of disease – hopelessness
Physical impairments – visual disturbances, tremor, weakness Absence of symptoms Fatigue – too tired to inject

Uncover Injection Barriers
What is your schedule for injections? How many injection sites/areas do you use in 1 week? How many injections did you miss in the past month? What were your reasons for missing these injections? Was it because of site reactions, etc? Can you show me the last 3 sites you injected? If needed, would you ask for help with your injections?

Uncover Oral/IV Barriers
What is your schedule for taking pills? How many pills did you miss in the past month? Have you had your follow-up monitoring done? Do you have trouble with IV access? Do you have storage/transportation issues?

Promoting Adherence Educate Identify and address barriers
Develop individualized strategies Encourage realistic expectations Advocate Assist with reimbursement Identify resources Involve family and support system

Fostering Realistic Expectations
For MS patients, realistic expectations are critical to the success of long-term disease management Inform patients that disease-modifying therapies are not curative but that they can: Reduce the rate and frequency of relapses Slow the progression of the disease Having relapses while on treatment does not mean therapy is ineffective; conversely, the lack of relapses when not on treatment does not mean disease is not progressing Improve quality of life

Fostering Realistic Expectations Risk of Not Treating/Delaying Treatment
Compared with no treatment, treatment with disease- modifying therapy (IFN B-1a, IFN B-1b, or glatiramer acetate) Significantly delays the onset of clinically definite MS1,2,3,4 Significantly reduces annualized relapse rates4 Significantly reduces loss of brain volume1 Significantly reduces the number of new or enlarging lesions and gadolinium-enhancing lesions1,4 1. Jacobs LD, et al. N Engl J Med. 2000;343: Kappos L, et al. Lancet. 2007;370: Comi G, et al. Lancet. 2009;374: Comi G, et al. Lancet. 2001;357:

Fostering Realistic Expectations Risk of Not Treating/Delaying Treatment
Early vs delayed treatment Patients receiving early treatment had a significantly reduced risk of progression of disability Patients receiving early treatment performed significantly better on tests of cognitive function than those receiving delayed treatment Kappos L, et al. Lancet. 2007;370:

Provide Balanced Information
Present balanced information about disease-modifying therapies; include pivotal trial data, mechanism of action, potential adverse effects Refer to: National Multiple Sclerosis Society Multiple Sclerosis Association of America Multiple Sclerosis Foundation Consortium of Multiple Sclerosis Centers Direct patients to appropriate websites and provide information kits if available Teach patients to critically evaluate MS educational materials

Strategies to Address Barriers
Medication specifics Develop realistic expectations Discuss dosing and consistent administration Provide tips to minimize side effects, including injection site reactions (eg, medications prior to injection, site rotation, lifestyle, and site of injection) Address side effects Patient/caregiver issues Identify information gaps, provide education Assess patient’s financial status and support wherever possible with resources

Management of Injectable Side Effects
Warm mixed medications to room or body temperature Warm or ice site for 30–60 seconds before injection Inject immediately after a shower Use aerosolized ethyl chloride Apply local anesthetics (lidocaine, benzocaine, etc) For flu-like symptoms, ibuprofen and acetaminophen can be recommended

Injection Mechanics Consider autoinjectors
Modify needle length for body mass index Avoid medication on needle tip Fully penetrate the skin to avoid intradermal infiltration Ensure complete vertical needle penetration into skin surface

Management of Injection Site Reactions
Use topical steroids for postinjection erythema Avoid topical steroids at sites of infection or apparent abscess or necrosis Graphics courtesy of Colleen Harris.

To Be Successful, a Patient…
Must be ready to begin therapy Must believe that therapies can make a difference Must be willing to make a commitment Must be well educated Regarding MS Regarding therapies for MS

Who Can Help? Neurologists Nursing staff Company-sponsored support
Multiple Sclerosis Association of America (MSAA) National Multiple Sclerosis Society (NMSS) Multiple Sclerosis Foundation (MSF) Consortium of Multiple Sclerosis Centers

General Advice for Motivating Patients
MS is lifelong; therapy is a lifelong commitment Take good care of yourself: a wellness approach Rest Eat well Exercise Reduce stress Find a strong support network that includes other people with MS Find and develop a positive relationship with a healthcare provider whom you trust and respect Holland, Murray, Reingold. Multiple Sclerosis: A Guide for the Newly Diagnosed. 2nd ed. New York, NY; Demos Medical Publishing; 2002 Schapiro. Managing the Symptoms of Multiple Sclerosis. 4th ed. New York, NY; Demos Medical Publishing; 2003. 66

Dimensions of Wellness
Intellectual Learning Growth New challenges Environmental Healthy setting Self-protection Physical Nutrition Fitness Lifestyle habits Spiritual Life meaning Purpose Values Wellness Social Respect Relationships Intimacy Tolerance Emotional Stress management Acceptance Expression of feelings Anspaugh D, et al. Wellness: Concepts and Applications. New York: McGraw-Hill; 2008.

The Ultimate Goals in MS Treatment
Prevent accumulation of disability Prevent relapses Improve quality of life—short- and long-term Develop convenient, effective, safe and tolerable treatments Repair damage and restore function Promote realistic hope 68

Translating Science into Practice: Case Studies
Patricia K. Coyle, MD Acting Chair, Department of Neurology Director, MS Comprehensive Care Center Stony Brook University Stony Brook, New York

Case 1 18-Year-Old White Female

History Patient presented with monocular vision loss over 2 days, with right eye pain She has no prior medical history Exam showed diminished right eye vision (20/70), red color desaturation, central scotoma, and afferent pupil Brain/orbit MRI showed enhancement of the right optic nerve only Diagnosis is retrobulbar optic neuritis

Decision Point 1 Which best describes your diagnostic assessment?
Clinically isolated syndrome (CIS) at low risk for multiple sclerosis (MS) CIS at high risk for MS Definite MS

Decision Point 2 Would you encourage this patient to start disease- modifying therapy for MS? Yes No

Additional Nonenhancing Lesions
Suppose the brain MRI, in addition to enhancement of the optic nerve, showed 2 nonenhancing lesions: a 5- mm juxtacortical lesion and a 4-mm periventricular lesion?

Decision Point 3 What is your diagnostic assessment now?
CIS at low risk for MS CIS at high risk for MS Definite MS

Decision Point 4 Would you encourage the patient to start disease- modifying therapy? Yes No

Additional Enhancing Lesions
Suppose the brain MRI, in addition to enhancement of the optic nerve, showed 2 lesions, 1 of which enhanced: a 5-mm enhancing juxtacortical lesion and a 4-mm periventricular lesion?

Decision Point 5 What is your diagnostic assessment?
CIS at low risk for MS CIS at high risk for MS Definite MS

Decision Point 6 What would be your choice of treatment? IFN beta-1a
IFN beta-1b Glatiramer acetate Natalizumab Fingolimod

Case 2 28-Year-Old Lawyer

History Patient was diagnosed with relapsing-remitting MS following 2 attacks over 14 months Her exam is normal She feels well, believes she has benign disease, and is ambivalent about going on anything that can harm her body You counsel her about MS, the damage process, and the benefits of disease-modifying therapy You then discuss individual agents

Interferon Beta Counseling
Adverse reactions include flu-like symptoms, injection reactions, headache/depression Monitoring includes liver function tests, thyroid, complete blood count and differential Therapy initiation involves dose escalation, pre- medication, and possible early evening dosing Blood tests are required every 3 months for 1 year, then every 6 months for higher-dosed interferon beta

Glatiramer Acetate Counseling
Adverse reactions involve injection site reactions, systemic immediate postinjection reaction No routine blood testing is required

Natalizumab Counseling
Associated with the risk of a potentially fatal adverse event (ie, progressive multifocal leukoencephalopathy) Risk stratification (JC virus antibodies, duration of therapy, prior immunosuppression) Monitoring includes liver function test, neutralizing antibodies at 6 months

Fingolimod Counseling
Prescreen patients for exclusion criteria, macular edema, complete blood count and differential, liver function tests (LFTs), IgG/M to VZV, electrocardiogram (EKG) 6-hour initiation dose monitoring with EKG pre and post Repeat ophthalmologic screen, liver function tests at 4 months

Decision Point What would be your treatment choice for this patient?
IFN beta-1a IFN beta-1b Glatiramir acetate Natalizumab Fingolimod

Follow-Up Strategy Regular visits Surveillance brain MRI with contrast
Every 3–4 months on initiation or change in disease- modifying therapy (for 1 year) Every 6–12 months when stable Surveillance brain MRI with contrast At 12 months (6 months if high concern) Annually for the early course, then at the discretion of patient/physician

Suspected Relapse Clarify symptoms and time course Assess adherence
Document objective changes Rule out pseudorelapse Consider whether you want MRI Discuss acute management Consider disease-modifying thrapy implications

General Counseling Stress adherence
Continue close follow-up and reassessments (clinical, MRI) Advise patients to notify of any significant changes Patients often bring up changes months after they occur Let patients know that current expected attack rate 1 every 3–5+ years

Case 3 42-Year-Old Female

History This 42-year-old relapsing-remitting patient has been on therapy with glatiramer acetate for 8 years She has now had her 1st relapse on therapy The relapse involved right leg hypesthesia, with complete recovery

Decision Point 1 Would you change disease-modifying therapy? Yes No

Paraparesis with Incomplete Recovery
Suppose the relapse involved paraparesis with gait ataxia, with incomplete recovery?

Hypesthesia and New Lesions
Suppose the relapse involved hypesthesia with complete recovery? Brain MRI showed 4 contrast lesions, and 10 new lesions from her last MRI a year ago

Paraparesis and Stable MRI
Suppose the relapse involved paraparesis with gait ataxia, with incomplete recovery, and stable MRI?

Switching Disease-Modifying Therapy
Suppose the patient was JC virus antibody negative?

Decision Point 5 What would you recommend? Maintain current therapy
Switch to interferon beta Switch to fingolimod Switch to natalizumab Other

Patient Outcomes Patient was started on IV natalizumab
She does well, feels stronger, and experiences no relapses Brain MRI is completely stable, with no enhancing lesions JC virus antibody is tested every 6 months She continues to do well at 3 years on therapy

JC Virus Antibody Positive
Suppose the patient was JC virus antibody positive?

Decision Point 6 What therapy would you recommend? Interferon beta
Fingolimod Natalizumab Other

Patient Outcomes Patient was started on fingolimod
Total lymphocyte level is below normal limits Since there is no infection issue, she remains on therapy There is no evidence of macular edema at 4 months Brain MRI is stable at 6 and 12 months She continues to do well on fingolimod at 24 months on therapy

Overview of MS and Strategies for Personalized Treatment

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