Lecture 72, 73 Multiple Sclerosis Tremlett

DIAGNOSIS OF MS:

• Should be made by an MS neurologist

• Requires a careful clinical history

• Diagnostic criteria modified overtime (current = McDonald 2010) o Evidence of CNS lesions

▪ Dissemination in time and space ▪ Multiple plaques in the CNS occurring at different times

o No better explanation (rule out other things) ▪ Vitamin B12 deficiency, lupus, SLE, tumor, HIV, HTLV-1,

Lyme disease …

WHAT COMES FIRST?

PATHOLOGY AND PATHOGENESIS OF MS:

• Damage to myelin sheaths, oligodendrocytes

• Demyelination of neurons demyelinated plaque (lesion)

• Active plaques = inflammation & edema associated with relapses

• Plaques occur in CNS, including spinal cord

• BBB compromised

• Re-myelination can occur

• Damage to axons can occur early associated with irreversible disability

• White AND grey matter affected

• Diffuse damage in CNS can be present, not just focal lesions

GENETICS OF MS:

• Less common in non-caucasians?

• MS identical twin 30% chance of also developing MS

• MS 1st degree relative < 5% chance of developing MS o 20-40x risk of general population

• Multiple interacting genes = “a genomic map”

EPIDEMIOLOGY:

• Prevalence/incidence increases proportionally with increasing distance from the equator o Sunlight (vit D) play a role?

• Epidemic in Faroe Islands (1940) after occupation by British Troops o Due to infection?

• Increased incidence in farming communities, reduced incidence in fishing communities (Norway) o Dietary differences (saturated vs. polyunsatured fats?)

SYMPTOMS OF MS:

• Visual disturbances – optic neuritis, nystagmus

• Incontinence and constipation

• Fatigue

• Spasticity, tremor, mobility problems

• Paroxysmal sx (neuralgia, itching)

• Pain, temperature sensitivity

• Depression

• Cognitive impairment

• Speech & word finding difficulties

• Mood changes: euphoria, emotional lability

• Sexual dysfunction

• Recurrent UTIs

• Pressure sores

MS DISEASE COURSE (OR PHASES):

• Relapsing remitting (RRMS) (85%): episodes of worsening (relapses) with recovery and stable course between relapses o Secondary progressive (SPMS): gradual

neurologic deterioration with or without superimposed relapses in pt who previously had RRMS (70% of RRMS SPMS)

• Primary progressive (PPMS) (10%): gradual, nearly continuous neurologic deterioration from onset of sx

• Progressive relapsing (PRMS (5%)

PROGNOSIS = UNCERTAIN

• MS = very variable disease (no 2 pts are the same) o Monozygotic twins can have different disease courses

• Disease progresses more slowly than earlier studies showed o Unrelated to specific drug treatments

• 15 years after onset, approx.: o 20% required a cane to walk

▪ 30 years from RRMS at onset to cane ▪ 13 years from PPMS at onset to cane

o 5% were wheelchair-bound

• Men do not necessarily have worse outcomes (old literature) o Females more likely to develop MS, present clinically

at an earlier age o Both men and women required a cane to walk at

around the same age

PROBLEMS WITH DRUG DEVELOPMENT AND CLINICAL TRIALS IN MS:

• Animal models of MS are inadequate (ex// experimental autoimmune encephalomyelitis EAE)

• Rational drug targeting? Drug development is difficult because we don’t yet understand the cause/pathogenesis/immunology

• Manipulation of immune system can results in unpredictable adverse events o Ex// natalizumab progressive multifocal leukoencephalopathy (PML)

• No single “test” to measure severity of MS o How do you measure effectiveness of a new drug in a fluctuating disease that can

spontaneously improve?

• Placebo effect: masking/blinding is VERY important, but can be difficult, especially with ADEs o Ex// 50% of placebo-taking MS pts in fatigue clinical trials will report improvement o Ethical consideration in placebo-controlled trials

• MS is a life-long, slowly progressing disease but clinical trials usually last 2 years

• MS course can affect drug response (RR, SP, PP) must be defined

• Statistically significant ≠ medically significant o Ex// new drug showed 0.2 pt improvement on EDSS (SS) BUT most pts only notice a

>0.5 point worsening (not medically significant)

• Outcome measures o Expanded Disability Status Scale (EDSS):

Advantages Disadvantages

• Gold standard

• Well-recognized & understood

• Heavily reliant on ability to walk

• Does not capture fatigue, cognition

• Inter & intra-rator variability

• Ordinal scale (progression not steady along scale)

o Relapse rates ▪ Pseudo-relapses common

• Confirmed by neurologist? ▪ Reliant on memory (past relapses can be forgotten)

• More frequent assessments more relapses recalled/ recorded ▪ Regression to the mean periods of high relapse rates often followed

by periods of low relapse rates ▪ Relapse rates ↓ with time and at different rates, according to pt’s age

and disease duration o Paraclinical measures: MRI

▪ Remains an unvalidated biomarker

• Relationship with disability in MS is not defined ▪ Should be secondary outcome measure

• Maybe primary in short-term phase II studies ▪ MRI machine to machine variation

• Scan each pt on same machine ▪ Gadolinium-enhanced MRI affected by corticosteroids

MANAGEMENT OF MS:

• Non-drug treatment (PT, OT, exercise, etc)

• Disease modifying drugs: reduce risk of relapses, uncertainty over long-term benefits o 1st-line (in BC): beta-interferon, glatiramer acetate,

dimethyl fumerate, teriflunomide o 2nd line (in BC): typically have to fail 1st-line drug:

natalizumab, fingolimod, alemtuzemab, mitoxantrone, daclizumab (not in BC yet)

• Treat acute relapse: accelerate recovery from relapse o Corticosteroids

• Symptomatic control: alleviate sx of MS o Antidepressants o Baclofen (spasticity) o Oxybutynin (urinary incontinence) o Carbamazepine (trigeminal neuralgia, paroxysmal sx)

Lecture 72, 73 Multiple Sclerosis Tremlett

FIRST-LINE DRUGS FOR MS: Interferons (IFN) IFNB-1a 22 mcg or 44 mcg sc x 3 weekly or 30 mcg IM wkly PEG IFNB-1a 125 mcg sc every 2 wks IFNB-1b 250 mcg sc alt days

Description • Naturally occurring cytokines (proteins) produced in response to viruses, bacteria

• IFNB-1a vs. b structural differences: glycosylation (IFNB-1a), amino-acid sequencing, neutralizing Abs (NAbs) production differs

MOA • Not fully understood; not thought to enter CNS

• Shift from TH1 TH2 cytokine production (pro anti inflammatory) by downregulating TH1

• Active at BBB to decrease production of: o Matrix metalloproteinases (MMP) by T cells o Vascular cell adhesion molecule-1 (VCAM-1) by endothelium cells

AEs Very common (>5%)

• Injection site reactions or necrosis o PREVENTION: rotate injection sites; warm injection to room temperature; use ice-packs before injection

• Flu-like symptoms (fever, chills, myalgia) o PREVENTION: dose-titration (full dose within 3-5 weeks); ibuprofen and/or acetaminophen before & after injections;

inject at bed-time

• Elevated liver test results, decreased lymphocytes, leucopenia, neutralizing antibodies to IFNB o MONITOR: CBC & liver tests before & during treatment (1,3,6 months, periodically thereafter)

• Menstrual disorders, migraines, increased spasticity, sweating, hypertension

Less common (<5%)

• Liver failure

• Depression

• Anaphylaxis

Glatiramer acetate (GA) 20 mg sc daily

Description • Synthetic polypeptide analogue of myelin basic protein (L-amino acids: glutamic acid, alanine, lysine, tyrosine)

• Developed to induce EAE but instead prevented EAE

MOA • Not fully understood, not thought to enter CNS

• Shift from TH1 TH2 cytokine production (pro anti inflammatory) by promoting TH2

AEs Very common (>5%)

• Chest pain, dyspnea (breathing difficulties), flushing, palpitations, anxiety – lasting 15 mins

• Tachycardia, nausea, arthralgia, migraine, tremor, sweating, menstrual disorders

• Injection site reactions (pain & erythema); lipoatrophy

Less common (<5%)

• Syncope, nystagmus, lymphadenopathy

• Treatment with GA may undermine body’s defenses against infections and tumor surveillance

Monitoring • Routine laboratory monitoring not required

IFNBs and GA efficacy

RRMS • Reduce relapse rate by 18 to 30% (IFNB vs. GA similar efficacy) o What does this mean? If a person was going to have 3 relapses over 3 years, by going on drug they would have 2 relapses over 3 years

(prevent 1 relapse) ▪ Drug cost = $20,000 per year = $60,000 to prevent one relapse = COST EFFECTIVE?

• Major beneficial effect on MRI (main reason for FDA license)

• Longer-term benefits unclear (trials too short to measure disability progression)

SPMS • Findings unimpressive; probably only effective if pt still experiencing relapses

PPMS • Few trials; none have been positive

Clinically isolated syndrome

• Delay conversion to clinically definite MS in high-risk parents

• Do not impact disability (5-year follow-up)

Natalizumab Monthly infusion 300 mg

Description • A monoclonal antibody, specifically inhibits alpha-4 integrin prevents adhesion of lymphocytes and monocytes to vascular endothelium limits infiltration into CNS

Efficacy • Versus placebo o Beneficial on MRI and decrease relapse rates in RRMS (by 68%), not SPMS o Rate of disability progression reduced, sustained for 3 months, by 42% over 2 years – caution with this result

• Addition of IFNB o Not useful, also associated with PML

• No head-to-head comparisons with IFNB or GA

AEs Very common (> 5%)

• Neutralizing antibodies to natalizumab reduced efficacy and increased infusion reactions (occurs b/w 2-6 months after initiation)

Less common (<5%)

• Infections (URTI, influenza, UTI)

• Hypersensitivity (within 2 hours infusion): urticaria, dizziness, fever, flushing, hypotension, dyspnea, chest pain

• Anaphylaxis, depression, headache

PML (1/300) • PML white matter demyelination

• Risk factors: JC virus, previous exposure to immunosuppressant, >2 year exposure to natalizumab o Early detection (on MRI, pre-sx onset): 1/30 risk of death o Late detection (after sx appear): ¼ in death, high risk of disability in survivors

• Sx: progressive weakness on one side of the body; disturbance of vision; changes in thinking/memory/orientation; confusion and personality changes

o Can progress over days to week o Pts being treated with natalizumab OR ANY of the newer 2nd line MS drugs should report any new neurological S/S

Dimethyl fumarate 120 mg bid x 7 days, then 240 mg bid (delayed release) – swallow whole, w/ or w/o food

Description • Methyl ester of fumaric acid; delayed-release capsules: 120 mg bid x 7 days, then 240 mg bid

AEs • PML reported

• Lymphopenia: baseline CBC and every 6-12 months thereafter

• Flushing (40%) – taking after food, non-enteric coated aspirin might help

• Abdominal pain, diarrhea, nausea

Efficacy • Phase III trials: relapses reduced by 50% (vs. placebo); impact on EDSS inconclusive

Teriflunomide 14 mg oral daily (w/ or w/o food)

Description • Active metabolite of leflunomide; median half-life 19 days

MOA • Immunomodulatory; blocks rapidly dividing T-cells (blocks mitochondrial enzyme inhibits de novo pyrimidine synthesis) fewer T-cells enter CNS?

AEs • Hepatotoxicity: liver tests pre-treatment, monthly or 6 months, 6 months thereafter

• Teratogenic: men & women to avoid pregnancy for TWO years after stopping o Consider wash-out: cholestyramine or activated charcoal

• HTN, decreased WBC (periodic CBC)

Efficacy • Phase III trials: relapses reduced by 30% (vs. placebo); impact on EDSS unimpressive

• Less effective than other 1st line MS drugs

Lecture 72, 73 Multiple Sclerosis Tremlett

SECOND-LINE AND OFF-LICENSED DRUGS USED IN MS: all are for RRMS patients (typically 2 relapses in last 2 years) & failure 1st line drug. NONE are for PPMS. Fingolimod 0.5 mg daily

Description • First oral drug for MS

• Metabolite of the fungus Isaria sinclairii

MOA • Prodrug: phosphorylated sphingosine-1-phosphate receptor modulator; binds to lymphocytes stuck in lymph nodes cannot enter CNS

Efficacy • Reduces annual relapse rate BUT > 50% patients had NO relapses (placebo or drug group)

• Marginal (but SS) effect on disability

• Superior to IFNB-1a (IM) in a 2-year head-to-head RCT BUT effectiveness of blinding not reported in any RCT

Monitoring Before starting • If never exposed to chickenpox & VZV ab negative vaccinate & wait 1 month before starting fingolimod

• Avoid immunosuppressants & CV meds (anti-arrhythmic, BBs, CCBs)

• Obtain an ECG & CBC

After 1st dose • Observe patients for at least 6 hours for bradyarrhythmia (slow heart rate)

• Obtain ECG at 6 hours

• Measure blood pressure & liver test results regularly

• Ophthalmic evaluation at 3-4 months for macular edema

Report sx of • Infection (including up to 2 months after stopping)

• Heart problems (e.g. chest pain, slow, irregular heartbeat, feeling dizzy)

• Visual disturbances

• PML

Safety • PML case

• Deaths reported: reactivation of latent herpes/varicella zoster; CV related; or sudden and unexplained

• Long half-life (6-9 days); PD effects last 2 months (e.g. reduced WBC)

Alemtuzemab Description • Humanized monoclonal antibody

• Depletes circulating T and B cells binds to CD52 shifts T & B cell subtypes (permanently?)

Dose • IV infusion (each takes 4+ hours); 2 courses o Course #1: 12 mg/day IV for 5 consecutive days (60 mg total) o Course #2: 12 months after course #1, 1 mg/day IV for 3 consecutive days (36 mg total)

• Corticosteroids/antihistamines/acetaminophen before first 3 infusions suggested

Monitoring • Blood and urine before, during, and 4 years after last dose MONHLY

• ECG before starting

Serious AEs • Thyroid disorders (hyper- or hypo-) – very common (1/10)

• Immune thrombocytopenic purpura (low platelets); infections – common (1/100)

• Kidney disorders (anti-glomerular basement membrane disease) – uncommon (1/1000)

Other AEs • Infusion reactions: headache, rash, nausea, fever

• No PML reported (YET)

Contra-indications

• HIV, TB, immunosuppressants

Pregnancy & lactation

• Avoid for ≥ 4 months after last dose

Efficacy • Phase III: reduced relapses by 55% vs. IFNB-1a (BUT ≥ 59% were relapse-free in both groups)

• One trial NSS change in disability (EDSS); one trial showed SS change in EDSS (clinically relevant??)

Daclizumab 150 mg SC monthly Not available in BC yet

Description • Humanized monoclonal antibody against CD52 on IL-2 receptor

• Terminal half-life 21 days

MOA • Unknown, but decreases T-cell response

Safety • Biochemical liver tests: monthly and up to 6 months after stopping

• Hepatic injury

• Immune-mediated disease (skin, lymphadenopathy)

Efficacy • Phase III trials: relapses reduced by 45% vs. IFNB; 54% vs. placebo (although 65% in placebo group had NO relapses)

• Impact on EDSS inconclusive

Mitoxantrone 12 mg/m2 every 3 months

Description • Licensed in USA for SPMS and worsening RRMS

• Cytotoxic antibiotic – anthracycline derivative

• Structurally related to doxorubicin

Safety • Cardiotoxic, max dose allowed = 140 mg/m2, although decreased LVEF can occur before max dose is reached

Monitor • LVEF, biochemical liver tests, neutrophil count

AEs • Nausea, hair loss, amenorrhea, therapy-related acute leukemia (TRAL)

DRUG INTERACTIONS:

• Virtually no formal drug interaction studies for the MS disease-modifying drugs (first or second line)

• Some interactions identified: o Natalizumab: avoid other immunomodulatory drugs

(12-week wash-out recommended) o Fingolimod: avoid drugs lowering HR o Teriflunomide: warfarin (↓INR by 25%); inhibits OAT3

transported so caution with substrates

SAFETY IN PREGNANCY AND LACTATION:

• FDA B: animal studies no fetal risk = GA

• FDA C: animal studies show fetal risk = IFNB, natalizumab, fingolimod, alemtuzemab, dimethyl fumarate

• FDA D: evidence of human fetal risk: mitoxantrone

• X: fetal malformations in animals: teriflunomide

• Lactation: generally avoid (unknown if excreted)

USE OF MS DISEASE-MODIFYING DRUG CANNOT BE JUSTIFIED DURING PREG/LACT given current limited knowledge

DRUG-TREATMENT OF RELAPSE:

• Short course of corticosteroids can accelerate recovery from relapse (no long-term benefits) o IV methylprednisolone (IVMP) 1 g OD x 3 o Oral corticosteroids likely as effective as IV (at an equivalent dose)

• Risk of continuous corticosteroids would out-weigh any potential benefits

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