MULTIPLE SCLEROSIS

(MS)
Fall 2021 – 2022
Beirut: Dr. Jihan Safwan – Dr. Marwan Akel
Bekaa: Dr. Samar Younes
School of Pharmacy
Lebanese International University
 Therapeutics I - Fall 2021/2022 2

Learning Objectives
• At the end of the lecture, you will be able to:
• Identify the major differences between the different MS subtypes
• Recognize the place in therapy of the major pharmacological
agents
• Evaluate response to therapy and treatment side effects
 Therapeutics I - Fall 2021/2022 3

Multiple Sclerosis
• Immune-mediated, chronic, inflammatory disease
• Precipitated by unknown environmental factors in genetically
susceptible patients
• Hallmark of MS is inflammatory, demyelinating plaques, and axonal
loss in the CNS
• Plaque formation (sclerosed areas) attributed to immune
mechanisms that are triggered by autoimmune attacks against
antigens in the myelin membrane

• Characterized by relapses and remissions of neurological

symptoms and progression of disability over time
• Most common chronic neurologic disease of young adults
 Therapeutics I - Fall 2021/2022 4

Epidemiology
Worldwide Lebanon

• Approximately 400,000 cases • ~1,500 Lebanese patients

in the US are treated for MS and
• Estimates range from 250,000 to 2,000 with the disease in
500,000 total
• Estimated 2.3 million cases
worldwide • Between 40 and 45
• Higher prevalence with
individuals in every 100,000
northern European ancestry have the disease
• Highest incidence in • >60% of patients develop
Caucasians their first symptoms between
• Higher incidence in woman 20 and 39 years
(≥3:1) • 2/3 cases affected are
• ¾ cases present between ages women (link to sex
15 and 45 hormones: estrogen)
 Therapeutics I - Fall 2021/2022 5

Pathophysiology
• Pathologic hallmarks of MS
• Breakdown of the blood brain barrier
• Multifocal inflammation
• Demyelination & oligodendrocyte loss
• Gliosis
• Axonal degeneration

• Major cause of disability is axonal loss

• MS plaques/lesions are:
• Areas of demyelination
• Followed by partial remyelination and gliotic scarring
• Location of lesions in the CNS dictates the type of clinical deficit
(infiltration of inflammatory cells in brainstem, optic nerves, spinal
cord…)
 Therapeutics I - Fall 2021/2022 6

Pathophysiology
Immune Dysregulation  Autoimmune, neurodegenerative
disease of CNS
• T-cell mediated inflammatory disorder
• CD4-T helper cells become activated in the periphery by unknown
antigen
• Misguided T-cells mistake myelin protein for antigen
• Overproduction of pro-inflammatory cytokines causing inflammation
and damage to myelin and nerves

• B-cells also involved in inflammatory process

• Found in CNS and plaques of MS patients
• Travel with T-cells through the BBB to the CNS
• Produce myelin-specific antibodies
 Therapeutics I - Fall 2021/2022 7

Pathophysiology
Immune Dysregulation  Autoimmune, neurodegenerative
disease of CNS

T‐Cells Myelin sheath Inflammation

Neurologic Nerve fiber

MRI lesions
symptoms scarring/sclerosis
 Therapeutics I - Fall 2021/2022 8

Clinical presentation
• General
– Most patients
• Non-specific complaints
• Vision problems
• Parasthesia

• Symptoms

Primary Signs / Symptoms
•Direct consequence of
conduction disturbances
produced by demyelination
and axonal damage
•Reflect the area of the brain
or spinal cord that is damaged
•Visual complaints/optic
neuritis
•Gait problems
•Paraesthesias
•Pain
•Spasticity
•Weakness
•Ataxia
•Speech difficulty
•Psychological changes
•Cognitive changes
•Fatigue
•Bowel/bladder dysfunction
•Sexual dysfunction
•Tremor
Therapeutics I - Fall 2021/2022 9
Secondary Symptoms Tertiary Symptoms
•Complications resulting •Relate to the effect of
from primary symptoms the disease on the
•Ex: urinary retention (1⁰) patient’s everyday life
 frequent urinary tract
infections (2⁰)
•Recurrent urinary tract •Financial problems
infections •Personal/social
•Urinary calculi problems
•Decubitus ulcer •Vocational problems
•Muscle contractures •Emotional problems
•Respiratory infections
•Poor nutrition
•Depression
 Therapeutics I - Fall 2021/2022 10

Diagnosis
• MS is a diagnosis of exclusion  Diagnosis is mainly clinical
• Requires demonstration of “lesions separated in space and
time”
• Occurrence of at least two episodes of neurologic disturbance,
reflecting distinct sites of damage in the CNS, that cannot be explained
by another mechanism
• MRI
• Detection of MS lesions
• More sensitive compared to computed tomography (CT) scans
• Optic neuritis
• A common first symptom of MS
• Is indicative of a lesion or lesions localized on the optic nerve
• CSF evaluation
• Blood tests
• Evoked potentials
 Therapeutics I - Fall 2021/2022 11

Diagnosis
• McDonald criteria
Attacks Lesions Additional Criteria for MS diagnosis
 Therapeutics I - Fall 2021/2022 12

Clinical course/Classification
• Four categories
1. Clinically isolated syndromes
2. Relapsing-remitting MS
3. Secondary progressive MS
4. Primary progressive MS
 Therapeutics I - Fall 2021/2022 13

Clinical course/Classification
1. Clinically or Radiologically isolated syndromes
(CIS or RIS)
• CIS: is a first symptomatic episode compatible with
demyelination or multiple sclerosis (MS)
• Example: young adult with a single episode of CNS
dysfunction, such as unilateral optic neuritis
2. Relapsing-Remitting MS (RRMS)
• Episodes of acute worsening of neurologic function,
followed by a varying degree of recovery, with a
stable course between attacks; 85 – 90% of
patients at diagnosis

• RIS: an individual presents without overt clinical

symptoms but with MRI findings highly suggestive
of MS
• Example: incidental brain or spinal cord MRI findings that
are highly suggestive of MS
• MRI has been obtained for a completely unrelated
condition such as headaches or trauma

3. Secondary-Progressive MS (SPMS) 4. Primary-Progressive MS (PPMS)

• Initial relapsing-remitting disease course, followed
by progression with or without occasional relapses,
minor remissions, and plateaus; 50% of relapsing-
remitting patients develop secondary progression
within 10 – 20 years
• Gradual, almost continuous worsening with minor
fluctuations but no distinct relapses
• 10% of patients at diagnosis
 Therapeutics I - Fall 2021/2022 14

Clinical course
• Expanded Disability Status Scale (EDSS)
• Measures progression of the disease
• Multiple Sclerosis Functional Composite (MSFC)
• MRI is being used as an index of both disease activity and
progression

• Main factors which lead to a shorter than expected life span

• Development of secondary complications such as pneumonia or
septicemia
• Secondary to aspiration of mouth contents with swallowing difficulties,
decubitus ulcers, or urinary tract infections
• Rapid progression of primary lesions affecting respiratory function

• Suicide
• Suicide rates 7x the general population
• Correlate with progression of disease
 Therapeutics I - Fall 2021/2022 15

Prognostic Indicators in Multiple Sclerosis

Indicator Favorable prognosis Unfavorable prognosis

Age at onset <40 years >40 years

Gender Female Male

Optic neuritis or sensory Motor or cerebellar

Initial symptoms
symptoms symptoms

Attack frequency in
Low High
early disease

Course of disease Relapsing/remitting Progressive

 Therapeutics I - Fall 2021/2022 16

Goals of Disease Management

• Reduce relapses and slow progression
• Treat serious relapses
• Manage symptoms
• Improve QOL
• Hope for the future
 Therapeutics I - Fall 2021/2022 17

Nonpharmacological Treatment
• Occupational therapy may be useful to keep active
• Help improve the ability to complete the activities of daily living or
learn new techniques or tools to accomplish these tasks

• Physical therapy may improve muscle strength to help

patients improve their gait and balance

• Stretching exercises may help reduced muscle spasms or

help patients learn how to use mobility aid such as canes,
or walkers
 Therapeutics I - Fall 2021/2022 18

Treatment
CIS or RIS

RRMS
• Acute Relapses
• DMTs
• Symptomatic Therapy

Progressive MS
• SPMS
• PPMS
 Therapeutics I - Fall 2021/2022 19

Treatment – CIS or RIS

Symptoms consistent with MS
Clinically silent MRI lesions
CIS RIS
 Therapeutics I - Fall 2021/2022 20

Treatment
CIS or RIS

RRMS
• Acute Relapses
• DMTs
• Symptomatic Therapy

Progressive MS
• SPMS
• PPMS
 Therapeutics I - Fall 2021/2022 21

Treatment – RRMS (more common

presentation)
• Treatment of acute attacks
• Shorten the duration and
Acute
Relapses possibly decrease the severity
of the attack
• Disease-modifying therapies
Disease
Modifying • Alter the course of the illness
Therapies • Are most important to diminish
progressive disability over
Symptomatic
time
Therapies • Symptomatic management of
the disease
• Is of greatest importance to
maintain the patient’s quality of
life
 Therapeutics I - Fall 2021/2022 22

Acute Relapses For CS & ACTH 

• Corticosteroids (preferred) Rule out acute infection
• Intravenous methylprednisolone with or without a short prednisone taper
• Dose is 500 mg to 1000 mg/day as 1 dose or divided doses for 3–7 days
• Alternative is Oral prednisone with or without a short prednisone taper
• Dose is 625 to1250 mg/day given for 3 to 7 days
Neurologic recovery is the same with
• Side Effects of CS
or without an oral prednisone taper
• Relatively few side effects in most patients
• Mental status changes, unmasking of infection, and gastric disturbance may occur
• Fractures  Repeated glucocorticoid therapy  baseline and yearly bone density scans are
recommended

• Adrenocorticotropic hormone (ACTH) (alternative)

• Repository corticotropin injection gel IM or SC
• Indication  Patients who cannot tolerate high-dose glucocorticoids or have poor
venous access or prefer self-injection
• 80 units for seven days, 40 units for four days, and 20 units for three days

• PLASMA EXCHANGE (last line)

• May be beneficial in patients with Acute central nervous system (CNS) inflammatory
demyelinating disease who do not respond to glucocorticoid therapy
 Therapeutics I - Fall 2021/2022 23

Disease Modifying Therapy

• OTHER TREATMENTS
• Interferons (IFNs)
• Azathioprine
I. Injectables • Glatiramer acetate
• Daclizumab
• CCSVI treatment
• Cladribine
• Cyclophosphamide
• Fingolimod • Dalfampridine
II. Oral • Teriflunomide
• Dimethyl fumarate
• Glucocorticoids in combination
therapy
• Intravenous immune globulin
• Laquinimod
• Mitoxantrone
• Rituximab
• Natalizumab
III. Intravenous • Alemtuzumab
• Stem cell transplantation

• Ocrelizumab

First Self-injectables Interferons, Glatiramer acetate

Generation
Agents IV Infusion Mitoxantrone

Second Oral Agents Fingolimod, Teriflunomide, Dimethyl fumarate

Generation IV Infusion Natalizumab, Alemtuzumab, Ocrelizumab
Agents Self-injectable Daclizumab
 Therapeutics I - Fall 2021/2022 24

Brand Indicatio Administrat

Drug SE Monitoring Parameters Comments
name n ion
First-generation agents
Self-injectables
Interferon- Avonex® RRMS IM once • Electrolytes, CBC, • Avonex®: Low potency IFN
β1a CIS weekly LFTs, thyroid function, • Rebif® , Plegridy®,
LVEF, depression Betaseron®: High potency
• LFTs at baseline, 1 IFN
Interferon- Rebif® RRMS SC TIW
month, and every 3 • Avoid use in untreated
β1a CIS
months for a year, and severe depression
• Depression, flu- every 6 months • Suicide risk
Pegylated Plegridy® RRMS SC q 14 like sx, thereafter • Can premedicate or
Interferon- CIS days leukopenia, concurrently use an
β1a injection site antipyretic/analgesic for flu-
reactions (more like symptoms
Interferon- Betaseron® RRMS SC QOD • Electrolytes, CBC,
with Betaseron) • Neutralizing antibodies
β1b CIS LFTs, thyroid function,
Extavia® • Develop in some patients
depression
18–24 months after trx
begins
• May disappear even
during continued trx
• Preg. Cat. C
Glatiramer Copaxone® RRMS SC QD or • Injection site • MRI, tissue necrosis, • Chest tightness, urticaria can
acetate CIS SQ TIW reactions, postinjection reaction occur at any dose
infection, • Preg. Cat. B
hypersensitivity,
chest tightness,
urticaria
IV infusion
Mitoxantron Novantrone SPMS IV q 3 • Bone marrow • CBC, ECG, LVEF, • Lifetime dose should not
e ® PRMS months suppression, LFTs exceed 140 mg/m2 due to
Worseni neutropenia, cardiac toxicity
ng cardiotoxicity, • Secondary leukemia
RRMS AML, N, V, D, • Preg. Cat. D
alopecia
 Therapeutics I - Fall 2021/2022 25

Brand Indicati Administr Monitoring

Drug SE Comments
name on ation Parameters
Second-generation agents
Oral agents
Fingolimod Gilenya® RRMS PO QD • Lymphocytopenia, • CBC, ECG, • REMS
macular retinal edema, varicella zoster • Requires first dose observation for
AV block, infection, first antibody, BP, bradycardia at hospital
dose bradycardia, ophthalmic • Contraindicated in patients receiving
headache examination, Class I and III antiarrhythmic drugs and
LFTs those with recent cardiac disease, 2nd
and 3rd degree AV block
• Ketoconazole increases fingolimod
serum concentration (3A4 inhibition)
• Vaccine efficacy may be decreased
• Preg. Cat. C
Teriflunomid Aubagio® RRMS PO QD • Steven–Johnson • CBC, LFTs, BP, • Contraindicated in severe hepatic
e syndrome, liver failure, pregnancy, TB impairment
neutropenia, test • Possibility of TB reactivation
respiratory infection, • Active metabolite of leflunomide
activation of TB, • Preg. Cat. X  CI in pregnancy
alopecia, neuropathy • It is found in semen (transvaginal
absorption)
• Men and women who wish to
conceive a child  SHOULD D/C
teriflunomide and undergo an
accelerated drug elimination
procedure using cholestyramine or
activated charcoal powder for 11
days
Dimethyl Tecfidera® RRMS Delayed • Flushing, rash, pruritus, • CBC, LFTs • Taking with food decreases incidence
fumarate release GI discomfort, of flushing
bid lymphocytopenia, • Preg. Cat. C
increased LFTs,
albuminuria
 Therapeutics I - Fall 2021/2022 26
Brand Indicati Administr Monitoring
Drug SE Comments
name on ation Parameters
Second-generation agents
IV infusion
Natalizuma Tysabri® RRMS IV q 4 • Depression, fatigue, • JCV antibody, • REMS: Risk of PML (progressive
b weeks respiratory infection, infection, MRI, LFTs multifocal leukoencephalopathy)
arthralgia, hepatotoxicity • Risk of IRIS (immune reconstitution
• PML JCV: John inflammatory syndrome) when
• Rapidly progressive viral Cunningham discontinued due to PML
CNS infection by JCV virus  Type • Preg. Cat. C
• Usually results in death or of
permanent disability polyomavirus
Alemtuzum Lemtrad RRMS First trx: IV • Infusion reactions, infections • CBC, thyroid • REMS
ab a® for 5 days (UTI, URI, herpes viral function, antibodies • May premedicate with high-dose CS
infections), thyroid disorders, to varicella zoster (1,000 mg methylprednisolone or
Second trx: • BBW virus, HPV equivalent) immediately before infusion
IV for 3 • Infusion reactions screening, serum for first 3 days
days (12 • autoimmune: immune- creatinine, TB prior • Infection risk
months mediated to trx, infusion • Herpes viral infections 
after first thrombocytopenic purpura reactions, skin prophylactic acyclovir
trx) • Malignancy exams, urinalysis • Pneumocystis jirovecii pneumonia
 prophylactic TMP/SMX
• Contraindicated with HIV infection
• Birth control should be used during trx
and for 4 months after each trx course
• Breastfeeding not recommended
during trx and for 4 months following
each trx course
• Preg. Cat. C
Ocrelizuma Ocrevus RRMS First trx: 2 • Infusion reactions, URTIs, • Screen for hepatitis • REMS
b ® & PPMS IV infusions oral herpes activation, B before each • Risk of PML
separated neoplasms infusion • Preg. Cat.: fetal risk can’t be ruled out
by 2 weeks • Monitor for infusion
Maintenanc reactions throughout
e: IV given infusion and for 1
6 months hour after
after end of completion
1st trx
 Therapeutics I - Fall 2021/2022 27

Brand Indica Administr Monitoring

Drug SE Comments
name tion ation Parameters
Second-generation agents
Self-injectable
Daclizum Zinbryta RRMS SC once • Upper respiratory • LFTs and bilirubin • Live vaccines are not
ab ® monthly tract infection, (prior to trx then recommended during trx
depression, rash, monthly during trx and up to 4 months after
pharyngitis and for 6 months discontinuation
• BBW: Hepatic after the last dose) • Evaluate for tuberculosis
injury (increased prior to trx
ALT) • REMS (monitor LFTs)
• Removed from market in
2018
 Therapeutics I - Fall 2021/2022 28

Disease Modifying Therapy - MOA

Drug MOA

Interferons • ↓ CNS inflammation through inhibition of T-cell activation/proliferation/migration into CNS

Glatiramer acetate • Protects myelin by mimicking myelin proteins and blocking T-cell-mediated damage

Daclizumab • Monoclonal antibody that modulates IL-2-mediated activation of lymphocytes through

receptor antagonism
Dimethyl Fumarate • Exhibits anti-inflammatory and cytoprotective properties through Nrf2 pathway

Fingolimod • ↓ ability of lymphocytes to emerge from lymph nodes

• ↓ migration into CNS
• ↓inflammation
Teriflunomide • Pyrimidine synthesis inhibitor
• ↓ proliferation of activated lymphocytes in CNS
• Primary, active metabolite of leflunomide
Natalizumab • Humanized monoclonal antibody
• Binds a4 integrin to block T-cell migration into CNS
Alemtuzumab • Monoclonal antibody against CD52 on CD4 and CD8 B-cells, eosinophils, macrophages,
monocytes
Ocrelizumab • Anti-CD20 Monoclonal Antibody
STRATEGIES FOR
THERAPY SELECTION
 Therapeutics I - Fall 2021/2022 30

Current MS Treatment Guideline

• Draft proposals have been released by both American
Academy of Neurology (AAN) and European Academy of
Neurology

• WHY NO EXISTING GUIDELINES??

• Diagnosis is complex
• Clinical
• Radiographic
• Substantial variability exists
• Patient presentation
• Disease course
• Limited head-to-head data among FDA-approved medications
 Therapeutics I - Fall 2021/2022 31

Efficacy / Toxicity Illustration

High Natalizumab Alemtuzumab
Efficacy
Ocrelizumab
Fingolimod
Dimethyl
Fumarate Daclizumab
Efficacy
Interferons Teriflunomide

Glatiramer
Low
Efficacy

Low Toxicity High

Toxicity Toxicity
 Therapeutics I - Fall 2021/2022 32

MS Treatment Algorithm

MRI, magnetic resonance imaging; LP, lumbar puncture; MS, multiple sclerosis; CIS, clinically related syndrome; JCV, John Cunningham virus, PML,
Progressive multifocal leukoencephalopathy; RRMS, Relapsing-remitting multiple sclerosis; PPMS, primary progressive multiple sclerosis; SPMS, secondary
progressive multiple sclerosis; Rx, prescription medication.
 Therapeutics I - Fall 2021/2022 33

Symptomatic therapies
• Patients may experience:
• Fatigue
• Spasticity
• Walking impairment
• Urinary incontinence
• Pain
• Depression
• Cognitive impairment
• Fecal incontinence
• Constipation
• Sexual dysfunction
 Therapeutics I - Fall 2021/2022 34

Symptomatic therapies
Fatigue

• Nonpharmacologic  rest, assistive devices, cooling strategies, exercise, stress management

• Pharmacologic  amantadine or methylphenidate

Spasticity: consequence of dysfunction of CNS  characterized by muscle

over activity and high tone spasms

• Therapies must be centrally acting

• First line: Baclofen(skeletal muscle relaxant), tizanidine (short acting muscle relaxant)
• Second line: Dantrolene (skeletal muscle relaxant), diazepam
• Third line: Intrathecal baclofen
• Focal spasticity (impairment & activity limitation in one joint): Botulinum toxin

Walking impairment

• Dalfampridine (Ampyra)
• Indication: improve walking in patients with multiple sclerosis by improving walking speed
• MOA: Potassium channel blocker (prolong action potential)
• Dose: 10 mg orally 2 times/day; extended-release tablets
• Contraindication: patients with a history of seizures or moderate or severe renal impairment
• Adverse effects: Seizures, urinary tract infections, insomnia
 Therapeutics I - Fall 2021/2022 35

Treatment
CIS or RIS

RRMS
• Acute Relapses
• DMTs
• Symptomatic Therapy

Progressive MS
• SPMS
• PPMS
 Therapeutics I - Fall 2021/2022 36

SPMS
Main Recommendation Suboptimal Response

• Treat active SPMS with an • For patients with active SPMS

approach similar to how you who have a suboptimal
treat RRMS response to DMT (evidence of
• Therapeutic options include all ongoing disease activity with
DMTs approved for RRMS attacks (relapses) and/or the
• Evidence from a placebo- development of new MS
controlled randomized trial  lesions)  switching to a
Siponimod was modestly different DMT is a reasonable
effective for reducing disability option
progression at 6 months in • Decision is based upon clinical
SPMS experience and individual patient
• But still no strong rationale for using characteristics, as no randomized
it alone in SPMS, particularly when clinical trials have addressed this
other DMTs may suppress relapses issue
or lesions just as well
N.B.:
Siponimod MOA a sphingosine-1-phosphate (S1P) receptor modulator, binds to sphingosine 1-phosphate receptors
1 and 5. It blocks the lymphocytes' ability to emerge from lymph nodes; therefore, the amount of lymphocytes available
to the CNS is decreased, which reduces central inflammation
 Therapeutics I - Fall 2021/2022 37

PPMS
• Ocrelizumab
• Used in PPMS patients who are ≤55 years or have active disease
on MRI
• Using ocrelizumab in older patients with inactive disease was less
likely to benefit and more likely to experience SE

• Trials of DMTs used in RRMS  NO BENEFIT in PPMS

• Other treatments have been tried for PPMS

• Examples: glucocorticoid pulses, methotrexate, intravenous
immune globulin, mitoxantrone
• Lack convincing clinical trial evidence of effectiveness; most
MS experts do not use these medications for PPMS on a routine
basis
 38

Pregnancy and
MS

Therapeutics I - Fall 2021/2022

 Therapeutics I - Fall 2021/2022 39

FDA APPROVALS
Brand Generic Name Company Approved Type Indications

Ofatumumab August 20, CD20-directed cytolytic RRMS,

Kesimpta® Novartis
(injection) 2020 monoclonal antibody SPMS

Monomethyl
Banner Life
Bafiertam® fumarate (delayed- April 28, 2020 oral fumarate RRMS
Sciences LLC
release capsules)

Bristol-Myers
Ozanimod sphingosine 1-phosphate
Zeposia® Squibb March 25, 2020 RRMS
(capsules) receptor modulator
Company

Diroximel fumarate
October 29,
Vumerity® (delayed-release Biogen oral fumarate RRMS
2019
capsules)

EMD Serono, RRMS,

Mavenclad® Cladribine (tablets) March 29, 2019 purine antimetabolite
Inc. SPMS

sphingosine-1-phosphate RRMS,
Mayzent® Siponimod (tablets) Novartis March 26, 2019
receptor modulator SPMS
THANK YOU…