Multiple Sclerosis Update. Bridget A. Bagert, MD, MPH Director, Ochsner Multiple Sclerosis Center

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1 Multiple Sclerosis Update Bridget A. Bagert, MD, MPH Director, Ochsner Multiple Sclerosis Center

2 None Disclosures

3 First of All. Why is my talk in the Neurodegenerative hour? I respectfully object!

4 Case 1 21 y/o woman developed left hemi-numbness and double vision in July She then developed weakness of arms and legs that rapidly progressed. MRI with several demyelinating lesions in the brainstem, gad+; also several non-enhancing lesions in corpus callosum; LP: 5 OCB, 1 WBC IV solumedrol did not help Lesions would not remit Patient remained in hospital for 8 weeks

5 Case 1 Transferred to Ochsner November 2011 Exam revealed severe ophthalmoparesis and dysarthria; severe ataxia in all 4; unable to walk Social History: Single mother to 3 year-old boy Labs: NMO negative, all mimics negative Rescue Therapy: PLEX improved, and left hospital with walker DMT: Natalizumab 5 years year later: Pt working full time and has normal PE.

6 Multiple Sclerosis: Overview and Impact Commonest, disabling disease of young adults Affects 400,000 people in the US Affects 4,000 people in Louisiana

7 MS: Pathogenesis Autoimmune attack on Myelin in Brain and Spinal Cord Prevailing Theory: Viral exposure (? EBV) in setting of certain genetic (HLA DR15) and environmental (vitamin D deficiency) factors leads to aberrant immune response to virus (molecular mimicry) which leads to Auto-reactive T cells that cross the blood brain barrier, and Attack myelin in the brain and spinal cord

8 The Multiple Sclerosis Plaque Frohman EM et al. N Engl J Med 2006;354:

9 A Revolution in MS Care over Past Two Decades Ransohoff et al. Nat Rev Neurol.2015 March; 11(3):

10 Immunotherapy for Multiple Sclerosis New Era of Treatment for MS Treat early Consider the individual situation Goal of treatment: Prevent Disability and minimize risk of immunotherapy Comprehensive Care approach

11 MS: Disease Modifying Therapies Interferon beta-1b, subcutaneous (Betaseron)-1993 Interferon beta-1a, intramuscular (Avonex) Glatiramer acetate, sq (Copaxone) Mitoxantrone IV (Novantrone) Interferon beta-1a, subcutaneous (Rebif) Natalizumab IV (Tysabri) Interferon beta-1b (Extavia) Fingolimod (Gilenya) Teriflunomide (Aubagio) Dimethyl Fumarate (Tecfidera) Peginterferon beta-1a (Plegridy) Alemtuzumab (Lemtrada)--2014

12 New Ideas in MS Care MS is highly treatable in most patients, especially if treated early; Concept of NEDA, No Evidence of Disease Activity Progressive MS is treatable in many patients Vitamin D is a critical component of immunotherapy in MS Concept of Shared Decision Making

13 Case 1--Lesson MS is highly treatable in most patients, especially if treated early; Modern DMT can not only control the disease but can even restore function in some In certain cases, aggressive treatment makes a difference

14 New Ideas in MS Care MS is highly treatable in most patients, especially if treated early; Concept of NEDA, No Evidence of Disease Activity Progressive MS is treatable in many patients Vitamin D is a critical component of immunotherapy in MS

15 Case 2 31 y/o man diagnosed with MS in 2008 Relapsing course Treated with interferon but had elevated LFTs Treated with GA, but had persistent gadolinium enhancement on MRI and frequent relapses Social History: Accountant, married, 1 child JCV Ab negative, Natalizumab started No further relapses, MRIs stable JCV Ab status checked every 1 month; No Evidence of Disease Activity, NEDA after 4 years

16 New Ideas in MS Care MS is highly treatable in most patients, especially if treated early; Concept of NEDA, No Evidence of Disease Activity Progressive MS is treatable in many patients Vitamin D is a critical component of immunotherapy in MS Concept of Shared Decision Making

17 Case 3 34 y/o woman presents with 3 year history of progressive gait ataxia History of optic neuritis 1998 MRIs with 9 enhancing brain lesions Mimics negative; LP deferred; JCV Ab negative Social HX: practicing attorney, engaged to be married DX: SPMS Natalizumab started as initial DMT 1 year later, 25 foot timed walk improved from 6s to 3.6s Progressive MS is treatable in many patients

18 Case 4 52 y/o woman developed progressive difficulty climbing stairs in 2012 Brain MRI with a few lesions typical of MS, and CSF with 12 oligoclonal bands isolated to CSF Diagnosed with Primary Progressive MS, started on Copaxone She worsened rapidly, and 25 foot timed walk increased from 8.0 seconds in 2014 to 15 seconds in She was switched to Rituxan in November of 2015, and her timed walk improved to 9.0 seconds with cane 1 month after first Rituxan dose.

19 Case 5 45 y/o man diagnosed with RRMS in 2009; had significant initial relapse with brainstem involvement; Started on Rebif, and developed SPMS within first year of diagnosis, with progressive spasticity and gait disturbance; 25 foot timed walk 4.7 seconds in 2012; switched to Tecfidera in 2013; timed walk slowed to 7.8 seconds in Switched to Rituxan in early 2014, and 25 foot timed walk improved dramatically to 4.8 seconds

20 B-Cells in MS B cells matter in MS (not just a T cell disease) B cell follicles present in the meninges of individuals with longstanding MS Anti-B cell therapy is effective in MS

21 Ocrelizumab in PPMS ORATORIO study: 720 patients with PPMS Ocrelizumab vs Placebo Primary Outcome: time to onset of confirmed disability progression (CDP) sustained for at least 12 weeks Data presneted at ECTRIMS October 2015 Ocrelizumab group: 25% reduction in the risk of CDP at 24 weeks reduction in whole brain volume loss by 17.5 percent (week 24 to week 120).

22 New Ideas in MS Care MS is highly treatable in most patients, especially if treated early; Concept of NEDA, No Evidence of Disease Activity Progressive MS is treatable in many patients Vitamin D is a critical component of immunotherapy in MS Concept of Shared Decision Making

23 Vitamin D Vitamin D deficiency is a risk factor for MS Vitamin D receptor exists on lymphocytes Vitamin D shifts from Th1 to Th2 cytokines Sun exposure is the best source of vitamin D, but excess sun is also associated with skin cancer risk

24 Munger et al. JAMA Dec 20;296(23): Prospective, nested case control study 257 cases, 500 controls, vitamin D levels measured, all samples drawn before MS onset Results: vitamin D levels categorized into quintiles Individuals in highest quintile if vitamin D had 63% lower odds of developing MS than those in the lowest quintile.

25 Vitamin D as Immunotherapy in MS Vitamin D levels measured in MS patients in BENEFIT study (interferon beta 1a in early MS) Ascherio et al. JAMA Neurol Mar;71(3) Vit D levels measured at baseline, 6, 12, 24 months in this study 468 patients in this study had vitamin D measurements Results: a 20ng/mL increment in average serum vitamin D level predicted: 57% reduction in new active lesions 25% lower yearly increase in T2 lesion volume 57% lower relapse rate

26 Vitamin D3 Impossible to get significant doses of vitamin D from foods Oral supplementation is the only way 5,000-10,000 IU units/day

27 Future Directions Biomarkers need to be defined to help individualize therapy Combination therapy needs to be explored Immune tolerance strategies Remyelination strategies

28 My Two Cents Treat the individual MS is highly variable from one patient to another Use the clinical trial information to guide you, but treat the individual patient Consider: Baseline disability, frequency and severity of exacerbations, black holes on MRI, atrophy on MRI, co-morbidities Goal: strike best balance between safety and efficacy Push vitamin D3 Many patients who are not stable on first line therapy become stable when vitamin D is aggressively supplemented

29 Safety first My Two Cents Orals DMTs may be more convenient and appealing for patient, but they are systemically immunosuppressive Injectable DMTs have best safety profile Many patients will respond to first line therapy (interferon or glatiramer acetate); 30% reduction of relapse rate is an average response Comprehensive care model important for many patients

30 Our Team

31 Thank you