Treatment of Multiple Sclerosis 2/13/18

Key Things That Haven’t Changed: MS is best diagnosed by a clinician with MS-related expertise with support of imaging and other tests. Dissemination of lesions in the nervous system in space and time are required, but the revisions provide additional avenues for obtaining supporting evidence of dissemination. The need to ensure there is no better explanation for the individual’s symptoms remains an essential consideration. The McDonald Diagnostic Criteria apply to individuals experiencing a typical clinically isolated syndrome -- CIS. (CIS is a first episode of neurologic symptoms typical of an MS relapse in a person not known to have MS.)

What Are the Key Changes? In individuals with typical CIS: CSF oligoclonal bands -- Positive findings of oligoclonal bands in the spinal fluid can substitute for demonstration of dissemination of lesions in time in some settings. Types of lesions – Both asymptomatic and now symptomatic MRI lesions can be considered in determining dissemination in space or time. (This does NOT include MRI lesions in the optic nerve in a person presenting with optic neuritis.) Site of lesions – Cortical lesions have been added to juxtacortical lesions for use in determining MRI criteria for dissemination of lesions in space.

Why do we need to treat MS? Progressive disease Patients acquire significant disability over time 50% of all individuals diagnosed with MS will need at least a unilateral aid to walk 15 years after the onset of illness

Which patients need treatment? Clinically Isolated Syndrome with MRI findings Relapsing-Remitting MS Secondary Progressive MS with activity Primary Progressive MS with activity

“Predicting the course” of MS Clinical features at onset Motor worse than sensory Polyregional worse than monosymptomatic Early bladder involvement, poor prognosis Incomplete recovery from initial attack Short interval between attacks

Strategies for use of DMT Step Therapy Start with more potent therapy Induction therapy

DMT Self-injected Oral Intravenous

Self-injected Interferon beta-1b (Betaseron) Interferon beta-1a (Avonex) Glatiramer acetate (Copaxone) Interferon beta-1a (Rebif) Peginterferon beta-1a (Plegridy) Daclizumab (Zinbryta) Avonex is IM weekly Rebif is SC three times weekly Glatiramer acetate (Copaxone)

Interferons PROS CONS Moderate Effectiveness Long safety record Fewer injections than GA (sometimes) CONS Moderate effectiveness Tolerability (Flu-like symptoms, mood changes, blood monitoring) Neutralizing antibodies

Glatiramer acetate (Copaxone) PROS Long safety record Better tolerated than interferons Moderate efficacy No neutralizing antibodies (**on RITE) CONS Daily injection or three times weekly Injection site reactions Less reduction of MRI lesions

Daclizumab (Zinbryta) MOA IL-2 receptor blocking antibody IL-2 is a cytokine signaling molecule in the immune system. IL-2 discriminates b/t “foreign” and “self.” Il-2 mediates its affects by binding to IL-2 receptors on lymphocytes Therefore by blocking this receptor, there is reduced inflammatory lymphocyte proliferation

Daclizumab (Zinbryta) PROS Once monthly SC injection CONS Hepatic injury Immune-mediated disorders Increased risk of infections Generally need to have failed to other MS medications

Oral Fingolimod (Gilenya) Terifulnomide (Aubagio) Dimethyl fumarate (Tecfidera)

Fingolimod (Gilenya) RITE!!- Fingolimod is a sphingosine-1 phosphate-receptor modulator approved for oral therapy for relapsing remitting multiple sclerosis. Activating the first subtype of the sphingosine-1 phosphate-receptor reduces lymphocyte recirculation from the lymph nodes resulting in functional immunosuppression. Activating the third subtype of the sphingosine-1 phosphate-receptor reduces heart rate and prolongs the PR interval. The cardiac effects of fingolimod are maximal after the first dose but persist for about 14 days

Fingolimod (Gilenya) PROS CONS Moderate to high efficacy 50% better than weekly IFNB-1a Daily oral capsule CONS Infections (PML, Crypto, Herpes) Cardiovasular Macular edema Monitoring requirements

Terifulnomide (Aubagio) Metabolite of leflunomide (used in RA) inhibit dihydroorotate dehydrogenase (DHODH), a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway required by rapidly dividing cells. Has a cytostatic effect on rapidly dividing T and B lymphocytes in the periphery (so therefore can’t get into CNS)

Aubagio moa

Terifulnomide (Aubagio) PROS Moderate effectiveness Once daily oral medication Statistically significant reduction in disability progression in 2 trials Lefllunomide has an extensive good safety record CONS Pregnancy category X Hair loss Liver monitoring monthly x 6

Dimethyl fumarate (Tecfidera) MOA Unknown thought to constrain immune cells and prevent them from attacking the body’s nervous system Promotes anti-inflammatory and cytoprotective activities mediated by Nrf2 pathway

Dimethyl fumarate (Tecfidera) PROS Moderate to high effectiveness Oral medication CONS Twice daily doing Side effects (flushing, GI symptoms) Risk of PML

Intravenous Mitoxantrone (Novantrone) Natalizumab (Tysabri) Alemtuzumab (Lemtrada) Ocrelizumab (Ocrevus)

Mitoxantrone (Novantrone) Disrupts DNA synthesis and repair Inhibits B cell, T cell, and macrophage proliferation Impairs antigen presentation

Mitoxantrone (Novantrone) PROS Effective CONS Cardiotoxicity Blood cancer Pregnancy Category D

Natalizumab (Tysabri) MOA Monoclonal antibody Binds to α4 integrin(common on all white blood cells, except neutrophils), thus reducing trafficking of lymphocytes into the CNS This prevents autoreactive leukocytes from exiting blood vessels and entering target organs to cause inflammation.

Natalizumab (Tysabri) PROS Highly effective Well tolerated Intravenous infusion every 4 weeks CONS Progressive multifocal leukoencephalopathy (PML) Infusion is 3 hours every 4 weeks Rebound activity 3-4 months after stopping

Alemtuzumab (Lemtrada)

Alemtuzumab (Lemtrada) PROS Once per year infusion x 2 (hopefully) Showed RRR for disability at 2 years compared with Rebif Significant percentage remaining relapse free at year 2 compared with Rebif CONS Infusion reactions (common: skin rash, fever, headache, muscle aches) Usually reserved for patients that have failed 2 or more DMT Risk of autoimmunity (thyroid, ITP, glomerular nephropathies Risk of malignancy (thyroid, melanoma, lymphoproliferative) Annual skin exams Monthly labs until 48 months after last treatment Available only through REMS

Ocrelizumab precise mechanism of action is not known but is presumed to involve binding to CD20, a cell surface antigen on pre-B and mature B lymphocytes, causing antibodydependent and complementmediated cytolysis

Ocrevus Side Effects infusion reactions (potentially life-threatening) -infections -possible increased risk of malignancies (including breast cancer, which occurred in 6 of 781 treated patients and no placebo patients)

Disability in PPMS mean change [improved performance] in 25ft walk performance baseline to week 120: 55.1% placebo; 38.9% treated: relative reduction 29.3% (p=0.04)