Multiple Sclerosis Lecture Note

Van – Multiple Sclerosis Tuesday, February 25, 2025 11:00 AM Risk Factors • • • • Gender Specific Ethnicity Genes: genetic variation accounts for approx. 30% of overall disease risk Environmental factors ○ Cigarette smoking ○ Viruses: Epstein-Barr virus (EBV) ○ Vitamin D deficiency low sun exposure ○ Childhood/adolescence obesity ○ Geographic gradient MS Classifications • Relapsing – Remitting MS ○ Dx at early ages ○ clearly defined attacks/relapses of new or increasing neurologic symptoms ○ Followed by periods of partial or complete recovery (remissions) • Secondary – Progressive MS ○ Follows an initial relapsing-remitting course ○ progressive worsening of neurologic function (accumulation of disability) over time • Primary – Progressive MS ○ Dx at later age ○ worsening neurologic function (accumulation of disability) from the onset of symptoms, without early relapses or remissions Diagnosis Criteria • Revised McDonald Criteria ○ At least 2 separate areas of CNS ▪ Brain, Spinal Cord, Optic Nerves ○ AND Damage occurred 1 month apart ○ AND Rule out other possible diagnosis Diagnostic tool: MRI (Gold-Standard) • CSF • "Spinal Tap" findings • Visual evoked Potential (VEP) Disease-Modifying Therapies (DMTS) ** EXAM MUST KNOW: • Interferon Brands only, all generics • Route Category Drug Injectables Interferon beta-1a • Avonex • Rebif Indication Relapsing forms of MS Route & Frequency • Avonex – IM Qweekly • Rebif – SQ 3x/week • DO NOT shake • Store in refrigerator, allow to warm to RT before use Interferon beta-1b • Betaseron • Extavia • SQ qod Peginterferon beta-1a (Plegridy) • SQ every 14 days • Must be used immediately after reconstitution if not used immediately, can refrigerate up to 3 hours • DO NOT shake ADRs Monitoring • Thyroid function tests • CBC w/ diff, transaminase levels • LFT every 6 months for Avonex • CMP • sx of autoimmune disorders • s/sx of psychiatric disorder (e.g. depression and/or suicidal ideation) • s/sx of new onset/worsening cardiovascular disease Notes • Pregnancy Category C • C/I • Human albumin (albumin-containing formulations only) • CMP • Pregnancy Category C • CBC w/ diff. • C/I • LFTs at 1, 3, and 6 months w/ initiation and prn • Human albumin thereafter • Thyroid function q6month w/ history thyroid dysfunction or clinically necessary • flu-like symptoms • allergic or anaphylactic reactions • injection site reactions • worsening of cardiac symptoms (in heart failure patients) • s/sx of depression Oral Glatiramer acetate (Copaxone) • Best evidence for safe use in pregnancy • SQ daily • SQ 3x/week (higher dose) • Lipoatrophy (may not resolve) • Pregnancy Category B • Contains mannitol (C/I in mannitol allergy) Ofatumumab (Kesimpta) • SQ once monthly • Infections (URTI, UTI, etc.) • • • • Store in original container at 2°C to 8°C (36°F to 46°F) Do not shake Protect from light C/I: active hep B virus infection MitoXANtrone (Novantrone) Relapsing-remitting MS or secondary progressive MS (not indicated: primary progressive MS) • IV ONLY • Max lifetime cumulative dose: 140 mg/m2 Natazlizumab (Tysabri) • REMS drug: TOUCH Prescribing Program Relapsing forms of MS • IV Alemtuzumab (Lemtrada) • REMS drug Relapsing remitting MS • IV and active secondary • Premedicate w/ methylprednisolone progressive multiple before infusion first 3 days sclerosis • Herpes viral prophylaxis on day 1 and continue for at least 2months after completion of tx pf until CD4+ count ≥ 200 cells/mm3 • Infusion rxns Ocrelizumab (Ocrevus) • Only med indicated for primary progressive MS • Multiple sclerosis, relapsing • Primary progressive • IV • Hepatitis B virus screening in all patients prior to therapy initiation • infusion reactions • C/I • history of life-threatening infusion reaction to ocrelizumab • active hepatitis B virus (HBV) infection Fingolimod (Gilenya) Relapsing forms of MS and delay disability progression • PO once daily • When initiating 1st treatment dose for all patients: • Monitor: ○ Signs/symptoms of bradycardia for at least 6 hours ○ Hourly pulse and BP measurement • High risk pts: Extended cardiovascular monitoring (> 6 hrs-overnight) • Decreases in HR • Ophthalmologic exam: Macular edema • Infections • Respiratory function • C/I • Baseline QTc interval ≥ 500 msec • Concurrent use of a class Ia or III antiarrhythmic – DDI ○ Class 1a – lidocaine, flecainide ○ Class III – amiodarone • Within 6 months prior to treatment initiation ○ MI ○ Unstable angina ○ Stroke ○ TIA ○ Decompensated heart failure (requiring hospitalization)/ NYHA class III/IV HF • Avoid live vaccines during treatment and 2 months after • Pregnancy: • Elimination takes 2 months; should wait 2 months before becoming pregnant Teriflunomide (Aubagio®) Relapsing forms of MS • PO once daily • • • • • • C/I • Concomitant use w/ leflunomide (Arava) ○ Teriflunomide is the active metabolite of leflunomide • Pregnancy Category X • BBW: hepatotoxicity, embryofetal toxicity • Medication can stay in blood for up to 2 years after stopping use • Drug elimination procedure (to speed elimination process) ○ Cholestyramine: 8 g Q8H for 11 days ○ Alternative: Activated charcoal Dimethyl fumarate (Tecfidera®) • Last resort • D/C use w/ LVEF < 50% • BBW • DO NOT use if neutrophil count < 1500 cells/mm3 • Myocardial toxicity + HF • ↑ risk of secondary AML • Blue-green coloration of secretions and eyes • May persist 24 hours post infusion • Pregnancy Category D • Warning/Precaution • Infusion-related reactions (HYPERSENSITIVITY) • Premedication needed prior to each infusion • PO BID • Flushing • May take peanut butter or yogurt to ↓ flushing • S/Sx of hepatotoxicity, infection, depression • C/I: • S/Sx of hypersensitivity during infusion and 1 • Hypersensitivity hour post infusion • Current or history of progressive multifocal leukoencephalopathy • S/Sx suggestive of PML (weakness in one side (PML) of the body, vision disturbance, changes in ○ Viral brain infection (can be fatal) memory or thinking) during treatment and for 6 • BBW: increase risk of PML months after discontinuation • Pregnancy Category C CBC LFT blood pressure (may cause HTN) pregnancy TB (risk) • CBC • LFT • C/I • • • BBW • • • • • HIV infection Active infection Fatal autoimmune conditions Bone marrow suppression Infusion rxns Malignancies Stroke • Can give aspirin 10 mins prior • Dalfampridine (Ampyra) FDA approved: improve walking in all forms of MS • PO Q12h • C/I • History of seizures (FDA alert in July 2012) • CrCl ≤ 50 mL/min • Pregnancy Category C Cladribine (Mavenclad) Relapsing forms of MS (relapsing-remitting; active secondary progressive) • PO (divided into 2 yearly tx courses) • C/I • Pregnancy • Men or women of reproductive potential who do not plan to use effective contraception during therapy and for 6 months after the last dose in each treatment course • Breastfeeding Siponimod (Mayzent) Relapsing forms of MS • PO daily • Based on CYP2C9 genotype ○ Must be determined before initiation • • • • HA Hypertension peripheral edema bradycardia Algorithm ○ Dimethyl fumarate, fingolimod, siponimod, teriflunomide, glatiramer acetate, interferon beta 1a and 1b, ofatumumab, natalizumab, ocrelizumab = has indication for CIS ▪ CIS: condition characterized by a single episode of neurological symptoms that are consistent with multiple sclerosis (MS) but do not meet the diagnostic criteria (McDonald Criteria) for MS Low risk High Risk No MRI signs consistent w/ MS demyelination pattern → continue diagnostic workup and follow MRI signs consistent w/ MS → treat w/ DMT • ○ Treat acute or refractory relapse ▪ Ocrelizumab (only FDA approval for primary progressive MS) ▪ Alemtuzumab ▪ Natalizumab • Minimize PML risk: ○ JCV negative ○ ≤ 2 years therapy ○ No prior immunosuppressive use ○ Switching DMTs ▪ Suboptimal response to therapy: • ≥ 1 relapse in 12 month period • At least 1 enhancing lesion or at least 2 T2 lesions in 1 year • Significant relapse w/ poor recovery/permanent disability • Sustained objective worsening of disability ▪ DMTs take 3 to 6 months to be fully effective ▪ Washout period ▪ When switching for breakthrough activity → higher efficacy, different MOA DMT ▪ Lowest to highest efficacy: • Injectable therapies (interferons and glatiramer acetate) → lower to mid-level efficacy • Orally administered agents → mid- to higher level efficacy • IV monoclonal antibody therapies (natalizumab, ocrelizumab, and alemtuzumab) → highest efficacy category ○ Alemtuzumab – highest efficacy of monoclonal categories (depends on patient profile if suitable or not) ○ Stopping DMTs ▪ Relapsing MS w/ prolonged inactive disease ▪ CIS w/ prolonged inactive period ▪ SPMS, distant from relapsing phase ▪ Pregnancy in some cases ▪ Age > 60 years Pregnancy and DMTs Drug Recommendations for use during pregnancy Recommendations for use during breastfeeding No May be considered for use during pregnancy Probably compatible with breastfeeding Glatiramer acetate (Copaxone, Glatopa) No ✅ Best evidence for safe Probably compatible with breastfeeding Interferon beta (class) Washout prior to planned pregnancy? use during pregnancy Ofatumumab (Kesimpta) 6 months after last dose AVOID Probably compatible • First dose monitoring for 6 hours recommended for patients with: • sinus bradycardia (HR <55 bpm) • first- or second-degree AV block, or • a history of MI or heart failure • C/I: CYP2C9*3/*3 genotype Mitoxantrone (Novantrone) 6 months AVOID Natalizumab (Tysabri) Avoid washout period before pregnancy to reduce pregnancy relapse risks May be considered for use AVOID during pregnancy in case of highly active disease/high relapse risk AVOID Alemtuzumab (Lemtrada) 4 months AVOID AVOID Ocrelizumab (Ocrevus) 4-6 months washout AVOID AVOID Fingolimod (Gilenya) 2-month washout recommended in labeling Not recommended AVOID Teriflunomide (Aubagio) Discontinue and accelerated elimination Do not use before or during pregnancy AVOID Dimethyl fumarate (Tecfidera) No Not recommended AVOID Dalfampridine (Ampyra) N/A AVOID AVOID Cladribine (Mavenclad) 6 months after the last course C/I C/I Siponimod (Mayzent) N/A AVOID AVOID Non-Pharmacological Treatment • Occupational therapy: improve ability to complete activities of daily living or learn new techniques or tools to accomplish these tasks • Physical therapy: improve muscle strength to help patients improve their gait and balance • Stretching exercises: help reduced muscle spasms or help patients learn how to use mobility aid such as canes, or walkers Treatment Options • Treatment of acute attacks/exacerbations ○ Shorten the duration and possibly decrease the severity of the attack • Disease-modifying therapies (DMTs) ○ Alter the course of the illness, and diminish progressive disability over time • Symptomatic treatment ○ Maintain the patient’s quality of life MS Exacerbations • True exacerbation: ○ MUST last at least 24 hours ○ MUST be at least 30 days from previous attack • Rule out other causes prior to treatment • Treatment ○ Mild exacerbations → NO treatment required ○ Moderate-severe exacerbations (functional ability is affected) → High-dose corticosteroids (methylprednisolone or prednisone) ▪ IV methylprednisolone shown to shorten duration of exacerbations • Initiated within 2 weeks of symptom onset • Short-term use ADRs: ○ Sleep disturbance ○ a metallic taste in mouth, and, rarely, Gl upset ○ Pts with DM → elevation of BG → requiring insulin • Long-term use of ADRs: ○ Acne, weight gain ○ fungal infections ○ Mood alteration ○ Rarely, Gl hemorrhage (especially in hospitalized patients or in those taking aspirin) ▪ Steroids have NOT been shown to affect disease progression Symptomatic Management • Gait Difficulties and Spasticity ○ Spasticity ▪ Preferred: Baclofen (Lioresal) • Should not be d/c abruptly (to avoid possible seizures) • AVOID if pt on dialysis, CrCl < 30 mL/min ▪ Tizanidine (Zanaflex) • Efficacy comparable to baclofen • Can be added in small dosages to baclofen ▪ If unable to tolerate neither of medications above: • Consider diazepam, clonazepam, or dantrolene sodium → but are less effective ▪ Mild spasticity may respond to moderately high doses of gabapentin ▪ Pregabalin may also be considered ○ Additional gait disruptions ▪ Dalfampridine shown to improve walking speed in patients with MS • Fatigue ○ Most common complaint in MS pts ○ Ginkgo biloba possibly effective for reducing fatigue in MS ○ Medications ▪ Amantadine ▪ CNS stimulants • Modafinil (Provigil) • Armodafinil (Nuvigil) • Methylphenidate (Ritalin) • Dextroamphetamine (Dexedrine) ▪ Pts suffering from both depression and fatigue → fluoxetine