Multiple Sclerosis for the
Non-Specialist
Keith Cushing, M.D.
Board Certified, Neurology
JWM Neurology
Disclosures:
None
Topic Outline: Multiple Sclerosis
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Epidemiology and Demographics
Pathophysiology
Diagnosis and Differential
Treatment Options
MS: A brief history
first described by French
neurologist Charcot in 1868:
“la sclérose en plaques
disséminées”
named for the scattered,
firm, sclerotic plaques
seen post-mortem in the
brain and spinal cord
Epidemiology and Demographics
more common in women than men
mean age of onset 30 years
peak age of onset 5 years earlier in women
than men
Source: Up-to-Date,” Epidemiology and clinical features of multiple sclerosis in adults”
Epidemiology and Demographics
incidence and prevalence varies geographically
● high prevalence areas
○ all of Europe, including Russia
○ southern Canada
○ northern U.S.
○ New Zealand
○ southeast Australia
● lowest risk
○ people of Asian, African, or American Indian origin
● supposed latitudinal gradient of MS incidence has been recently
challenged
Epidemiology and Demographics
no association between vaccines and MS
though many viruses, including EBV, have
been linked, there is no specific evidence
linking them directly to the development of
MS
Epidemiology and Demographics
Genetic factors appear to contribute to the pathogenesis
of MS, particularly variation involving the HLA-DRB1
locus
Chronic cerebrospinal venous insufficiency has been
reported in some patients with MS but its relationship to
MS is controversial
Source: Up-to-Date,” Epidemiology and clinical features of multiple sclerosis in adults”
Natural History
● Progression of disability due to MS is highly variable,
but accumulating evidence suggests that progression in
most patients with MS is slow.
● At the extreme ends of the severity spectrum, there are
benign and malignant forms of MS.
Natural History
● Benign MS refers to disease in which the patient
remains fully functional in all neurologic systems 15
years after the disease onset.
● Malignant MS refers to disease with a rapid progressive
course, leading to significant disability in multiple
neurologic systems or death in a relatively short time
after disease onset
Source: Up-to-Date,” Epidemiology and clinical features of multiple sclerosis in adults”
MS Pathophysiology
MS: Pathophysiology
the precise etiology of MS has not yet been determined
pathologic hallmark is multiple focal areas of myelin loss
within the CNS
it is these areas that are referred to as plaques or lesions
Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of
Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.
Pathophysiology
myelin loss is typically accompanied by gliosis
and inflammation and by relative preservation
of the axons
Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of
Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.
Pathophysiology
active MS lesions are
infiltrated by
macrophages containing
myelin debris
Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of
Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.
Pathophysiology
lymphocytic inflammatory infiltrates in MS are
composed mainly of CD8+ cytotoxic T cells
less so, CD4+ helper T cells, B cells, and
plasma cells
Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of
Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.
Pathophysiology
Gadolinium MRI enhancement
characterizes lesions with a
damaged blood-brain barrier,
which enables the infiltration
of inflammatory cells into the
CNS
Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of
Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.
Pathophysiology: Heterogeneity
active lesions show a profound pathologic
heterogeneity and can be classified into four
immunopatterns, suggesting that the targets
of injury and the mechanisms of
demyelination are distinct in different disease
subgroups
Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of
Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.
Pathophysiology: Axonal Injury
● Although demyelination appears to be the dominant
process, axonal injury occurs in multiple sclerosis and is
most pronounced during active inflammatory
demyelination
● acute axonal injury occurring in early multiple sclerosis
lesions likely contributes to the relapse-related disability
observed predominantly during the inflammatory
disease phases
Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of
Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.
Pathophysiology
● neurodegeneration is present in demyelinated lesions
and is invariably associated with inflammation
● in chronic inactive lesions from aged patients with longstanding progressive multiple sclerosis where the
inflammatory process has died out, the
neurodegeneration is also reduced to levels seen in
control patients.
Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of
Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.
Pathophysiology
Extensive remyelination, illustrated by the presence of
newly formed myelin sheaths and oligodendrocyte
precursor cells, is frequently encountered within active
plaques of early multiple sclerosis.
Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of
Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.
Pathophysiology
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Cortical demyelinated lesions are present and common
in early multiple sclerosis
these lesions are highly inflammatory
they may represent the pathologic substrate of cognitive
impairment and epilepsy in relapsing-remitting multiple
sclerosis.
Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of
Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.
Pathophysiology
•
•
The presence of inflammatory cortical demyelination in
early multiple sclerosis argues against a primary
neurodegenerative process at this stage of disease
this process suggests that neuronal and axonal injury in
early cortical demyelination occur on a background of
inflammation.
Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of
Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.
Pathophysiology
● Meningeal inflammation is present in early multiple
sclerosis and topographically associated with cortical
lesions
● it may drive the cortical demyelination but also set the
stage for subsequent subcortical white matter
inflammation and demyelination.
Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of
Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.
MS: Diagnostic Subtypes
● relapsing-remitting
● primary progressive
● secondary progressive
Diagnosis and Differential
The majority of patients diagnosed with
multiple sclerosis (MS) (80% to 85%) follow
an initial relapsing-remitting course
characterized by episodes with fairly rapid
onset of new or recurrent neurologic deficits
followed by partial or complete recovery.
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Diagnosis and Differential: The Bible
McDonald Criteria
● first published in 2001
● 2005 revision
● 2010 revision
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Diagnosis and Differential
● All recent formulations of the diagnostic criteria begin
with an initial clinical presentation that includes
symptoms typical for a multiple sclerosis attack (also
called a relapse or exacerbation)
● This initial presentation has been termed the “clinically
isolated syndrome” (CIS)
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Diagnosis and Differential
The McDonald 2010 panel defined an attack as:
● patient-reported symptoms or objectively observed
signs typical of an acute inflammatory demyelinating
event in the CNS
● current or historical
● with duration of at least 24 hours
● in the absence of fever or infection
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Diagnosis and Differential
For paroxysmal symptoms (such as
paroxysmal dysarthria, tonic spasms, or
paroxysmal sensory symptoms) to be
considered an attack, symptoms must be
recurrent over at least 24 hours.
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Diagnosis and Differential
Once multiple sclerosis has been established as the most
likely etiology of the symptoms, the clinician must
evaluate for evidence of:
● dissemination in space, which requires involvement of
multiple areas of the CNS
● dissemination in time, which requires ongoing disease
activity over time.
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Diagnosis and Differential
DIS criteria may be satisfied on clinical grounds alone if
the patient has:
● objective clinical evidence of involvement of at least two
CNS sites
● or objective clinical evidence of one lesion with
reasonable historical evidence of another site being
affected.
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Diagnosis and Differential
Objective clinical evidence may include:
● findings on neurologic examination
● abnormal visual evoked potentials in a
patient with a history of visual loss
● evidence of a demyelinating lesion on MRI
that would explain prior symptoms.
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Diagnosis and Differential
● If there is only objective clinical evidence of one lesion, DIS may be
established by applying the MRI criteria.
● The revised McDonald 2010 DIS MRI criteria are based on
recommendations from the European multicenter collaborative
research network that studies MRI in MS (MAGNetic Resonance In
Multiple Sclerosis, or MAGNIMS)
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Diagnosis and Differential
Dissemination-in-space MRI criteria now require at minimum only two
lesions: at least one T2 lesion in at least two of the four sites
typically affected by multiple sclerosis (periventricular, juxtacortical,
infratentorial, or spinal cord).
Diagnosis and Differential
● DIT criteria may be satisfied on clinical
grounds alone if the patient has a history of
at least two attacks
● If the patient has a history of one attack, MRI
criteria may be applied to establish DIT.
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Diagnosis and Differential
● Under the 2010 criteria, DIT can be
established with the development of a new
T2 lesion at any time, compared to a
baseline scan performed at any time
● In certain cases, DIT can actually be
established with a single MRI scan
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Diagnosis and Differential
•
Dissemination in time can be demonstrated with a
single MRI if simultaneous asymptomatic gadoliniumenhancing and nonenhancing lesions are present.
Diagnosis and Differential
Primary progressive multiple sclerosis:
● characterized by the insidious onset of symptoms
followed by gradual deterioration over time
● Clinical disease in these patients typically presents as a
progressive myelopathy, and less frequently as a
brainstem or cerebellar syndrome.
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Diagnosis and Differential
Secondary progressive multiple sclerosis:
● diagnosed when, after an initial relapsingremitting course, a patient demonstrates
disease progression independent of relapses
for at least 6 months.
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Diagnosis and Differential
Radiologically isolated syndrome:
diagnosed when a patient is incidentally found
to have imaging findings suggestive of
multiple sclerosis, which are not better
explained by another medical condition, in
the absence of clinical symptoms.
Diagnosis and Differential
if any element of the:
● clinical history
● examination
● imaging
is atypical, additional testing to exclude other etiologies is warranted.
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
There are no clinical
findings that are unique to
MS, but some are highly
characteristic of the disease
Diagnosis and Differential
A classic presentation of a brainstem
syndrome suggestive of clinically isolated
syndrome is diplopia due to internuclear
ophthalmoplegia, which is often bilateral.
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Diagnosis and Differential
Patients with optic neuritis
related to underlying multiple
sclerosis typically present with
painful, subacute, unilateral
visual loss that manifests as
visual blurring or a scotoma.
Diagnosis and Differential
Patients with a spinal cord syndrome
suggestive of clinically isolated syndrome
characteristically present with a partial
transverse myelitis, which is usually
dominated by sensory symptoms.
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Diagnosis and Differential
On MRI, spinal cord lesions due to multiple sclerosis are
typically peripheral, with the dorsolateral cord being the
most common plaque location. Multiple sclerosis lesions
are usually less than two vertebral segments in length
and occupy less than half of the cross-sectional cord
area.
Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.
Lhermitte sign
electric shock-like sensations that run
down the back and/or limbs upon
flexion of the neck
Uhthoff phenomenon
● small increases in the body temperature can
temporarily worsen current or preexisting
signs and symptoms
● This phenomenon is presumably the result
of conduction block developing in central
pathways as the body temperature increases
MS Therapies: Interferon beta
● available since 1993
● four preparations now available
○ Rebif (subcutaneous interferon beta 1a, 3x/week)
○ Betaseron (subcutaneous interferon beta 1b, every other
day)
○ Avonex (intramuscular interferon beta 1a, once a week)
○ Extavia (subcutaneous interferon beta 1b, every other
day)
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Interferon beta
Mechanism of Action:
● modulates T-cell and B-cell function
● decreases expression of matrix
metalloproteinases
● reverses blood-brain barrier disruption
● alters expression of a number of cytokines
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple
Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Interferon beta
Evidence:
A series of phase 3 studies in relapsing MS
support the benefit of IFN-β in
● reducing relapses (by approximately 30%)
● disability progression
● MRI lesion activity and accrual
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Interferon beta
Side Effects:
● flulike symptoms (eg, fever, chills, malaise, myalgia)
after injection
● sometimes with concomitant worsening of preexisting
neurologic symptoms
● These symptoms usually last from several to 24 hours
after injection and are worse with the initiation of
therapy
● In most cases they attenuate over time
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
MS Therapies: Interferon beta
Side Effects (continued):
● injection-site reactions
● rare skin necrosis
● depression
● leukopenia
● liver abnormalities
● thyroid disorders
● patients with preexisting headache syndromes or spasticity may
experience a worsening of these symptoms with IFN-β therapy
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Glatiramer Acetate
Mechanism of Action:
● complex mixture of random synthetic polypeptides
● probably functions as an altered peptide ligand for the
major histocompatibility complex (MHC) class II
molecules
● may also stimulate neuroprotective or repair
mechanisms
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Glatiramer Acetate
Evidence:
● Two phase 3 studies demonstrated that GA 20 mg/d
administered by subcutaneous injection reduced annualized
relapse rate (ARR) with a reduction of approximately 30% in
the second study
● A separate randomized controlled trial demonstrated a
benefit in MRI measures, including gadolinium-enhancing
lesions, new T2 lesions, and the proportion of lesions
evolving into T1-hypointense “black holes.”
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Glatiramer Acetate
Side Effects:
● injection-site tenderness
● pruritus
● erythema
● induration
● Lipoatrophy (loss of subcutaneous fat with scarring)
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
MS Therapies: Glatiramer Acetate
Side Effects:
● occasionally causes a postinjection systemic reaction
comprising various combinations of flushing,
diaphoresis, chest tightness, dyspnea, palpitations, and
anxiety
● begins within minutes of injection and resolves
spontaneously in 1 to 30 minutes
● reaction typically occurs once or at most a few times in
a given patient and does not recur with continued
dosing
MS Therapies: Glatiramer Acetate
In contrast to IFN-β, GA is not associated with
● constitutional side effects
● depression
● liver enzyme abnormalities
● low blood counts
● worsening headaches
● spasticity
● neutralizing antibodies
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
MS Therapies: Natalizumab
Mechanism of Action:
● a humanized monoclonal antibody
● binds α4-integrin and blocks interaction of α4β1-integrin
on leukocytes with vascular cell adhesion molecules
and connecting segment-1 (CS-1) on fibronectin sites
on vascular endothelial cells
● As a result, migration of leukocytes from the blood into
the CNS is inhibited
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Natalizumab
Evidence:
phase 3 trial showed that monthly IV infusions of 300 mg
natalizumab
● reduced ARR by 68% over 2 years
● disability progression by 42%
● MRI gadolinium-enhancing lesion number by 92%,
relative to the study placebo group
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Natalizumab
A second phase 3 study supported these results, showing
that natalizumab combined with IFN-β-1a IM was more
effective than IFN-β-1a IM plus placebo infusions
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Natalizumab
Natalizumab is generally considered for:
● patients who have relapsing MS and continued disease
activity despite use of one or more of the standard
disease therapies or who are intolerant of the standard
agents
● It also can be considered for patients with disease
characteristics that suggest high risk of disability and for
whom a more potent although potentially more risky
agent is felt to be appropriate
MS Therapies: Natalizumab
Side Effects:
● anxiety
● fatigue
● pharyngitis
● sinus congestion
● peripheral edema
● infusion-related symptoms (headache, flushing,
erythema, nausea, fatigue, and dizziness).
MS Therapies: Natalizumab
Allergic hypersensitivity reactions, including anaphylaxis,
urticaria, pruritus, and anaphylactoid syndromes,
occurred in 4% of natalizumab-treated patients and were
serious in 1%.
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Natalizumab
● key safety concern is an increased
risk for PML, a concern that did not
surface during the course of the original
trials
● This is a serious, often fatal
opportunistic infection of oligodendrocytes
caused by reactivation of latent
John Cunningham (JC) polyomavirus
MS Therapies: Natalizumab
● MRI is performed before treatment and intermittently
during natalizumab therapy
● Manifestations that suggest PML include subacutely
worsening visual, motor, or cognitive changes and/or
gradually enlarging T2 hyperintensities with minimal or
no gadolinium enhancement
● If PML is suspected, natalizumab treatment should be
suspended, MRI obtained, and CSF examination
performed, including PCR for JC virus.
Recently Introduced Oral Therapies
● Fingolimod (Gilenya)
● Teriflunomide (Aubagio)
● Dimethyl Fumarate (Tecfidera)
MS Therapies: Fingolimod
the first oral drug to receive North American
and European regulatory approval to reduce
relapses in patients with relapsing MS.
MS Therapies: Fingolimod
Mechanism of Action:
● sphingosine-1-phosphate receptor (S1P1) modulator
that has immunoregulatory features
● inhibits the migration of T cells from lymphoid tissue into
the peripheral circulation and target organs, including
the CNS
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Fingolimod
Evidence:
● (FTY720 Research Evaluating Effects of Daily Oral Therapy in
Multiple Sclerosis [FREEDOMS], a placebo-controlled 24-month
trial
● Trial Assessing Injectable Interferon versus FTY720 Oral in
Relapsing-Remitting Multiple Sclerosis [TRANSFORMS]
○ a 12-month head-to-head trial with comparator IFN-β-1a IM)
demonstrated that orally administered fingolimod (0.5 mg/d)
was effective and superior to IFN-β-1a IM at reducing ARR and
MRI activity in patients with relapsing MS
MS Therapies: Fingolimod
Although fingolimod is generally well tolerated, specific
safety issues have been identified:
● first-dose bradycardia
● the possible risk of herpes virus dissemination
● macular edema
● long-term consequences of elevated blood pressure)
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Fingolimod
● Further long-term data are needed to assess the safety
profile of fingolimod
● Of clinical concern is a patient started on fingolimod
who died on the second day of treatment
● Further analysis of this and other cases led to a more
stringent set of criteria for fingolimod therapy and more
careful first-dose observation
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Teriflunomide
Mechanism of Action:
● Derived directly from leflunomide
● an antimetabolite that interferes with the de novo synthesis of
pyrimidines, sparing the salvage pathway, by inhibiting the
mitochondrial enzyme dihydro-orotate dehydrogenase
● This has the effect of blocking cell replication in rapidly dividing
cells, but the exact mechanism by which this translates into efficacy
for MS is unknown
● Typically, the cells that are more involved in mediating autoimmune
processes will be more susceptible to the antimetabolite effects of
teriflunomide.
MS Therapies: Teriflunomide
Evidence:
● (the Teriflunomide Multiple Sclerosis Oral [TEMSO]
trial)
● showed a significant effect on the primary outcome of
relapse rate
● secondary outcomes on MRI and disability (Expanded
Disability Status Scale [EDSS] progression) also
reached statistical significance over placebo
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
MS Therapies: Teriflunomide
Other Teriflunomide Studies:
● The Teriflunomide Oral in People with RelapsingRemitting Multiple Sclerosis (TOWER)
● A Study Comparing the Effectiveness and Safety of
Teriflunomide and Interferon-β-1a in Patients with
Relapsing Multiple Sclerosis (TENERE)
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Teriflunomide
Side Effects and Safety:
● Hair thinning
● gastrointestinal upset
● The potential for teratogenicity has come from preclinical studies,
which is of particular concern in women of childbearing potential
● A specific washout program using cholestyramine or activated
charcoal can be used to remove teriflunomide from the system;
however, without this washout, teriflunomide may remain in the
system for months after the last dose
● Careful counseling is therefore recommended in women of
childbearing age contemplating teriflunomide.
MS Therapies: Dimethyl Fumarate
● fumaric acid ester that can be taken orally and is immediately
hydrolyzed by esterases to its metabolite monomethyl fumarate
(MMF)
● DMF is better tolerated than MMF, as it is associated with lower
gastrointestinal side effects
● BG-12 is a formulation of DMF manufactured as an enteric-coated
microtablet to improve gastrointestinal tolerability
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Dimethyl Fumarate
● The exact mechanism by which it exerts its positive anti-inflammatory
effects is unknow
● It may act on the major transcription factor known as nuclear factor
erythroid 2–related factor 2 (Nrf-2), which is released from binding to kelchlike ECH-associated protein 1 (Keap-1) via the activity of DMF
● In turn, Nrf-2 upregulates an array of antioxidative pathways, such as
increased glutathione levels
● Nrf-2 pathway activation also leads to an inhibition of the translocation of
nuclear factor-κB into the nucleus, which would normally turn on the
expression of a cascade of inflammatory cytokines, chemokines, and
adhesion molecules
MS Therapies: Dimethyl Fumarate
● Determination of the Efficacy and Safety of Oral Fumarate in
Relapsing-Remitting Multiple Sclerosis (DEFINE)31 was one of two
large phase 3 studies comparing two doses of BG-12 to placebo
● 1234 patients with relapsing MS and EDSS scores of 5.0 or lower
were randomized to receive placebo (n = 408) or 240 mg of BG-12
twice a day (n = 410) or 3 times a day (n = 416)
● clinic visits were every 12 weeks
● MRI studies were performed at baseline, 24, 48, and 96 weeks in a
subgroup of patients (n = 540).
MS Therapies: Dimethyl Fumarate
● The primary outcome was the proportion of patients relapsing at 2
years
● the difference in ARR and the risk for disability progression
(measured by EDSS scores) were considered secondary outcome
measures in this study
● Both doses of BG-12 reduced the proportion of patients relapsing
by nearly 50% (P<.001)
● Whereas 46% of placebo patients relapsed, only 27% of the
patients dosed with BG-12 twice a day and 26% of those dosed 3
times a day had at least one relapse by 2 years (P<.001 for both
comparisons).
MS Therapies: Dimethyl Fumarate
● BG-12 twice a day reduced the ARR relative to the placebo population by
53% and BG-12 3 times a day by 48% (P<.001 for both comparisons)
● EDSS progression confirmed at 12 weeks was also reduced by both
dosing regimens: whereas 27% of patients treated with placebo
progressed, only 16% of those treated twice a day with BG-12 and 18% of
those treated 3 times a day with BG-12 did so, a relative reduction of 38%
and 34%, respectively
● New or newly enlarging MRI lesions were also substantially reduced by
both doses: 85% and 74% for BG-12 twice a day and 3 times a day,
respectively, versus placebo (P<.001 for both comparisons).
MS Therapies: Dimethyl Fumarate
Potential negative aspects include
● the twice a day dosing
● initial gastrointestinal and flushing symptoms
● Fumaderm or its generic equivalent, a combination of
fumaric acid esters, has been available in Germany and
Europe but only recently was associated with a few
cases of PML in patients treated mainly for psoriasis.33
Whether BG-12 will turn out to have similar problems
remains to be determined.
MS Therapies: Other Therapies
● Laquinimod
● Alemtuzumab
● Daclizumab
● Ocrelizumab
MS Therapies: Caveats
● Experience with interferon-β and glatiramer acetate
over several decades has assured us of their relative
safety in the general public of unselected patients with
multiple sclerosis
● The same cannot be said of all of the newer agents
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Caveats
Safety in a carefully selected study set of
patients cannot predict how a diseasemodifying drug will do when given more
generally to unselected patients
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Caveats
Although all agents are tested primarily for
their ability to reduce relapses, in populations
with low relapse rates, supportive effects are
also sought from efficacy on other metrics
such as MRI and Expanded Disability Status
Scale progression
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Caveats
Given how few head-to-head trials have been
conducted, comparing efficacy among
disease-modifying drugs is difficult, so the
indication (first- or second-line) comes from
the risk profile, with riskier agents relegated
to a higher tier
Freedman, Mark S. MSc, MD, FAAN, FANA, FRCP(C). Present and Emerging Therapies for Multiple Sclerosis.
CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 968-991.
MS Therapies: Caveats
● Although newer agents appeal because of convenience
(eg, oral dosing) or the perception that they
demonstrate superior efficacy to long-standing
interferon-β or glatiramer acetate, few data support this
● Recent studies show annualized relapse rates for
interferon-β or glatiramer acetate in the same range as
some of the newer agents.
MS Therapies: Caveats
● Not all patients present with the same amount of
disease or carry the same risk of progression
● Risk factors such as disease course, type of relapse
and residual disability, MRI burden of disease, or even
response to previous disease-modifying drugs must be
taken into account when considering a choice for
therapy.