Multiple Sclerosis

Wecht

What is MS?

+characteristics of Disease

Permanent, disabling, unpredictable autoimmune disorder

o Inflammation damages the myelin sheath which breaks down communication between the central nervous system (CNS) and the periphery

Two main characteristics of the disease

o Multiple neurologic symptoms accrue over time

o Plaques and lesions are seen in multiple areas of the brain and spinal cord

MS Pathophysiology

+hypotheses

Exact cause is unknown

Hypotheses include:

• Inflammatory cause

• Autoimmune cause

MS Inflammatory Hypothesis

T Cell Differentiation:

Th1: increase inflammation

• bind inflammation cytokines → BBB breakdown → inflammatory mediators get into CNS → neurodegredation → strips myeline sheets → AND

Th2: decrease inflammation

Th17: increase inflammation

• problem

Treg: regulatory

• problem

• can be pro or anti depending on environment (plascitiy)

  • in MS leads to inflammatory

MS Autoimmune Hypothesis

+offending vriuses

Molecular Mimicry

Viral infection occurs and immune response is generated to the antigen

then

Virus has a similar structure to the protein in the myelin

then

Immune system attacks both the antigen of the virus AND the myelin

Viruses

Epstein barr

CMV and herpes

MS Risk Factors

Having a first degree relative with MS

HLA DRB1*1501 gene

Vitamin D levels < 75 nmol/L

Smoking

High Epstein Barr (EBV) virus antibodies

Living in an environment farther from the equator

• correlates to vitamin D levels?

Caucasian, northern European ancestry

Female

Obesity

Symptoms of MS

+primary, secondary, tertiary + ex for each

Primary: Direct consequence of conduction disturbances

• Caused by the demyelination and axonal damage in the CNS

ex: Visual complaints, Cognitive changes, Gait instability, Pain

Secondary: Complications resulting from primary symptoms

ex: Recurrent UTIs, Depression, Bed sores

Tertiary: Symptoms that relate to the effect of the disease on the patient's life

ex: Financial burden, Emotional burden, Social issues

MS Initial Symptoms

+general, most common, others

Disease of exclusion - vague symptoms

Most common; optic neuritis

Others

• Different types of pain

  • most specific to MS: “MS Hug”

    • squeezing or tightness

    • tingling

    • pins and needles

    • electric shock

Disgnosis of MS

+what to take into consideration → NEEDED?????

S/s

Dissemination in time

Dissemination in space

No other explanation for clinical findings

MS McDonald Criteria

+changes

Relation to dissemination in space and time

Changes

• optic nerve can serve as fifth anatomical location

• dissemination in time (NOT mandatory anymore)

• paramagnetic rim lesions by MRI can be used to diagnose in specific situations

• addition al recommendation should be considered for confirming diagnosis > 50 years with vascular comorbitiies

  • hyperlipidemia

  • diabetes?

MS Imaging and Labs

Imaging

o MRI

Lab

No specific lab tests

CSF evaluation

▪ Oligoclonal bands

▪ Increased IgG

▪ Kappa light chains

Expanded Disability Status Scale (EDSS)

determines disease prognosis for a patient

Disorders that can mimic MS

Lupus

Stroke

Vitamin B12 deficiency

Neoplasms

Syphilis

HIV

Sarcoidosis

Lyme's Disease

Common Phenotypes of MS

Relapse Remitting (RRMS)

most common

Symptom flare ups followed by recovery

• However after each attack, recovery becomes less and less

Patient remains stable between attacks

Secondary progressive MS (SPMS)

o Always begins as RRMS

o Experiences progressive deterioration in function unassociated with acute attacks

o Higher amounts of neurologic disability

Primary progressive MS (PPMS)

o ~males more often; diagnosed later on; more serious form

o Patient don’t experience attacks but show a steady decline in function from disease onset

o Usually occurs in patients diagnosed later in life (>40 years old)

Prognosis Factors: MS

+poor, positive

poor

• male

• older (>40 years) onset

• motor, cerebellar, or splinter symptoms at initial presentation

• more frequent attacks within first 5 years

postitive

• female

• younger onset

• optic neuritis or sensory symptoms at onset

• RRMS

FDA Approved Meds for MS

RRMS/SPMS

• Self Injectives

  • Interferons

  • Glatiramer Acetate

  • Ofatumumab

• Oral

  • Teriflunomide

  • Fumaric Acid Derivatives

PPMS

• ocrelizumab

Interferons

+indication, moa, efficacy, agents - admin and pearls

Indications: RRMS, SPMS

Mechanism of Action: Unknown

• Thought to increase suppressor cell function, reduce and downregulate inflammatory markers

• Increase Treg cells

efficacy: moderate

Interferon-beta 1b

• SubQ every other day

Interferon-beta 1a

• SubQ three times weekly

• pearls

  • prefilled syringe

  • longer stability in fridge

Pegylated interferon-beta 1a

• admin: every 2 weeks (longer t1/2)

• IM or SubQ

Bnenefits of interferons - 1a vs 1b

Benefits of Interferon-beta 1b

o Reduced annual relapse rate

o Decreases burden of disease

o No effect on clinical disability

Benefits of interferon-beta 1a

o Reduced annual relapse rates

o no increase in disability

o Reduction in lesions on MRI

Interferon Monitoring and ADEs

+frequency

Depression - all follow up visits

TFTs - q 6 months

CBS, Paltelets, LFTs - baseline, 1 month, q3 months x1 yr, then q 6 months

ADEs

Injection site reactions

Flu like symptoms

Leukopenia

Hepatotoxicity

Shortness of breath

Tachycardia

Anemia

Major Concern with Interferon use in MS

Antibodies that can reduce the effectiveness of the interferon beta therapies

Rates are variable

o close to half of people will develop neutralizing antibodies

o Depends on specific drug and dosing regimen

Glatiramer Acetate

+indication, moa, admin, pearls, benefits

Indications: RRMS, SPMS

Mechanism of Action: Unknown

• Thought to mimic the antigenic properties of myelin proteins --> inhibits binding of T cells

• Increases Th2 cells

Admin:

• SubQ QD OR SubQ 3 times/week

Pearls

• if using 3 times/week, doses must be separated by at least 48 hours

• longer stability when refrigerated

Benefits:

• Reductions in mean annual relapse rate

• Delays the development of T1 holes on brain MRI

• Slows progression of disability in RRMS

Glatiramer ADEs

+BBW

Injection site reactions

• immediate post injection site reaction

  • One time transient reaction after the first dose of glatiramer is given

    o Symptoms: chest tightness, flushing, shortness of breath

    o Lasts ~20 minutes

    o Usually no treatment is needed

Edema

Nausea

Flu like symptoms

Pruritis/skin rash

Infection

BBW: Anaphylactic reaction

Ofatumumab

+indicaitons, moa, admin, pearls, benefits

indications: RRMS, SPSMS

moa: Immunoglobulin antibody that binds to CD20 on B cells resulting in cellular cytolysis and complement mediated lysis

admin: SubQ once weekly x 3 doses THEN q1 month

pearls

• should be administered into the abdomen, thigh, or upper arm

• stored in refrigerator, first injection should be given in a provider’s office

• pre medications can be given prior to injection

benefits

• Decreased relapse rate

• Decreased active lesions

• Resulted in fewer new or enlarging lesions

• Slowed disability progression

Ofatumuab: Monitoring and ADEs

+frequency, risks

Hep B - baseline

serum iunoglobulins (IgG, IgM) , CBC, CMP - q 6 months

ADEs

• infection s

• Hep B reactivation

• injection site reactions

Risks - PML

*All live vaccines should be given at least 4 weeks prior to the first dose

Progressive Multifocal Leukpencephalopathy (PML)

+description, symtpoms, treatment

RARE but serious side effect

• Fatal disease of the white matter of the brain caused by a viral infection (JC virus)

o Destroys the white matter of the brain and leads to irreversible axon demyelination

• Symptoms: clumsiness, progressive weakness, visual and speech changes

o In severe cases, personality changes

• Treatment: no treatment available

o Remove the offending agent

Comparison of Self-injected medications

Comparison of interferon beta to glatiramer

Similar clinical efficacy at 24 months

However, at 36 months, one study showed higher relapse rates in the group given interferon

• page 51, 52

EDSS

Similar effect on new or enlarging lesions on MRI

Teriflunomide

+indications, moa, amdin, benefits

indications: RMSS, SPMS

Mechanism of Action:

• Inhibits dihydro-orotate dehydrogenase to prevent the proliferation of T and B cells

• Reduces CNS inflammation and demyelination

Admin: qd

Pearls

Inhibits CYP 2C8

Induces CYP 1A2

ADEs: embryofetal toxicity

Benefits:

reduction in relapses

reduction in total lesion volume

reduction in total lesion volume

Teriflunomide: Monitoring and ADEs

+frequency

CBC - baseline, then regular

LFTs - monthly for the first 6 months → every month

Pregnancy - baseline then regularly

ADEs

Alopecia

Headache

Paresthesias

GI Upset

Infection

Leukopenia

Hepatotoxicity

Fumaric Acid Derivatives

+indication, moa, pearls, agents- admin, pearls, benefits

indication: RRMS, SPMS

Mechanism of Action: unknown

• Possible anti-inflammatory and cytoprotective properties via nuclear factor pathway

Dimethyl fumarate

• maintenance : BID

Diroximel fumarate

• maintenance : BID

• lower rate of GI upset

Monomethyl fumarate

• maintenance : BID

• lower rate of GI upset

Benefit so fumaric Acid Derivatives

Reduced annual relapse rates

Reduced number of lesions

Slowed disability progression

Monitoring and ADES: Fumaric Acid Derivates

+risks

CBCs, LFTs → Baseline, then every 6 months for a year, then

annually

ADEs:

Flushing

Pruritus

GI upset

Leukopenia

Elevated LFTs

small risk of PML

Sphigosine 1 - Phosphate Receptor Agonists

+indications, moa, agents - admin, pearls, benefits

-imod

indications: RRMS, SPMS

Mechanism of Action:

• Blocks lymphocytes ability to emerge from lymph nodes, reducing the number of lymphocytes available to cross the blood brain barrier

Benefits - compared to placebo

Decreased relapse rates

New or enlarging lesions reduced over 2 year trial

reduction in 3 month disability progression

Sphigosine 1 - Phosphate Receptor Agonists - NOT DOEN

+agents - admin, pearls, benefits

Agnets

• Fingolimod

  • admin: daily

  • new ODT formualtion

  • pearls

    • pediatrics

      • Contraindicated to take with IA or III anti-

      arrhythmic

      • Good for highly active disease

• Siponimod

• Ozanimod

• Ponesimod

Sphigosine-1-Phosphate Receptor Agonists

+monitoring-freqquecny, ADEs, risks,

CBC, LFTs, EKG - baseline, then regular

Opthaminc exams - anually

ADEs:

First dose bradycardia, AV block

Hypertension

Increased risk of malignancies

Elevated liver enzymes

Macular edema

Infections

small risk of PML

*All live vaccines should be given prior to the first dose of S1P Receptor Agonists

Monitoring: First Dose Bradycardia

+offending agents, parameters

Fingolimod:

• Monitored for 6 hours after the first dose is given

  • Pulse check and blood pressure check every hour

• Continuous EKG monitoring

• For high risk patients, monitoring can be required overnight

  • High risk: QTC prolongation, concomitant medications that slow HR, history of MI or heart failure, risk factor for torsade's

Ponesimod

• Monitored for 4 hours

Siponimod, ozanimod

• Monitoring only required for high risk group

Cladribine

+indications, moa, admin, pearls

indications: RRMs, SPMS

moa: Impairs DNA synthesis --> leading to depletion of B and T lymphocytes

Admin:

• 2 treatment courses

  • Initiate first dose anytime, initiate the

    2nd dose 23-27 days after

    The 2nd course is started 1 year after the first dose is initiated

Pearls

• Maximum lifetime dose is 3.5 mg/kg

• Teratogenic

• Usually saved for patient who have failed other DMTs

Benefits of Cladribine

reduction in relapse rate

remained relapse free after 96 weeks

reduction in new or enlarging T2 lesions

Cladribine: Monitoring and ADEs

+frequency, risk

CBC, LFTs → baseline, ten 3-7 months into tx course

Infection and cancer screening → prior to start of treatment

Pregnancy → baseline, then regularly

ADEs:

Headache

GI upset

Joint pain

Infection

Elevated liver enzymes

Leukopenia

Risk of PML

Alemtuzumab

+indicaiton, moa, admin, pearls

indications: RRMS, SPMS

moa: Humanized monoclonal antibody that targets CD52 which is expressed on T and B lymphocyte

admin: IV infusion

• daily x5 days

  Then 12 months later, 12 mg IV daily x3

  days

pearls:

• REMS program -- high monitoring burden

• Requires premedication prior to giving infusion

• Good for highly active disease

Benfits of Alemtuzumab

reduction in annual relapses

reduction in 6 month disability progression

omitted not stisitclaly significantt

Alemtuzumab: Monitoring and ADEs

+frequency, risk

CBC, LFTs, CMP, UA, TFTs → baseline every 3 months

Infection and cancer screening → prior to start of tx, then regularly

ADEs

Headache

Rash

GI upset

Infusion reactions

Infections (URIs, UTIs)

Immune thrombocytopenia (ITP)

Risk of PML

Ocrelizumab

+indication, moa, admin, pearls

indication: RRMS, SPMS, PPMS

moa:

• Humanized monoclonal antibody that targets CD20 and kills B cells in the immune system

• Prevents B cells from penetrating the blood brain barrier

Admin: IV infusion

• day 1 → 2 weeks later →q6months

Pearls

• Humanized monoclonal antibody –-> lower autoantibody formation, infusion reactions

• Requires pre medication prior to infusion

Benefits of Ocrelizumab

reduced relapses

• Compared to interferon-beta 1a

• Reduced new or enlarging lesions

• Compared to interferon-beta 1a

• When studied specifically for PPMS, patient taking ocrelizumab were less likely to have disability progression

• compared to placebo

Ocrelizumab: Monitoring and ADEs

+frequency

CBC, LFTs, Serum Immunoglobulins (IgG, IgM) → Baseline, then regularly

Hepatitis B → baseline

ADEs

• Infusion reactions

• Inections (URIs, skin infections)

Risk of PML

All live vaccines should be given at least 4 weeks prior to the first dose of

ocrelizumab