sclerosis - كلية الطب · 2019-03-06 · slide 18 of 26 clinically isolated syndrome (cis)...
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SCLEROSIS
DR.Sadik AL-Ghazzwi
Consultant Neurologist
MRCP,FRCP UK
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1396: Earliest Recorded Case of MS
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• 1868—Jean-Martin Charcot describes the disease and finds MS plaques (scars) on autopsy.
• 1878—Louis Ranvier describes the myelin sheath (the primary target of MS in the central nervous system).
“Multiple sclerosis is often one of the most difficult problems in clinical medicine.” (Charcot, 1894)
“When more is known of the causes and…pathology of the disease… more rational methods may brighten the therapeutic
prospect.” (Gowers, 1898)
• 1981—1st MRI image of MS is published.
HISTORY
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What is Multiple Sclerosis (MS)?
• CHRONIC Autoimmune demyelination
disease of
CNS:
- brain
-optic nerve
- and spinal cord
• Affects 2.3 million people in the world
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What is the epidemiology of MS?
• Geographic distribution
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What are the possible risk factors?
• Infections : viral ,bacterial, fungal.
• Age: 15yr.-45yr.
• Gender :female: male 3:1
• Genetic Factors
– DR15 haplotype
• Autoimmune diseases
• Race
• Climate
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What are the possible triggers of MS?
• Epstein-Barr Virus
• Smoking
• Vitamin-D deficiency
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What is the genetic factor?
• The risk of getting MS is approximately:
– 1/750 for the general population (0.1%)
– 1/40 for person with a close relative with MS (3%)
– 1/4 for an identical twin (25%)
• 20% of people with MS have a blood relative with MS
The risk is higher in any family in which there are several family
members with the disease (aka multiplex families)
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What RISKS OF MS?
Genetic
Predisposition
Environmental
Trigger
Autoimmunity
Loss of myelin
& nerve fiber
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What happens in MS?
...cross the blood-brain barrier…
…launch attack on myelin & nerve fibers...
“Activated” T cells...
…to obstruct nerve signals.
myelinated nerve fibermyelinated nerve fiber
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How are myelin autoreactive T-cells activated?
• Myelin-reactive T-cells
– Myelin basic protein (MBP)
• T-cell activation
– Autoantigens
– Molecular mimicry
• Immune cell recruitment
– CD8+ cells
– B cells
– Granulocytes
– Monocytes
– Mast cells
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What happens once across the BBB?
• Reactivation of CD4+ cells
– Proinflammatory cytokines
• Microglial and astrocyte activation
– Myelin phagocytosis
• Humoral response
• B cell co-stimulation
• Demyelination
– Type II hypersensitivity
https://michellepetersen76.files.wordpress.com/2015
/05/discovery-of-a-treatment-to-block-the-
progression-of-multiple-sclerosis-
neuroinnovations.jpg
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What causes neuronal degeneration?
• MS lesions
– Active lesions
– Inactive, chronic lesions
• Demyelination
• Immune mechanisms cause:
– Oligodendrocyte damage
– Injury and loss of axon
– Gliosis
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Slide 14 of 26Lublin et al, 2014
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Relapsing-Remitting MS
• Subacute repeated onset of CNS dysfunction with
resolution ( sometimes incomplete , over days to
weeks)
• Revised McDonald criteria
• MRI: Periventricular, brainstem, juxtacortical
prominent T2, often Gad enhancing lesions, T1
hypointense (black holes)
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Secondary Progressive MS
• Majority of RRMS many years following onset
• Progressive impairment (spastic gait disturbance) between or in
absence of attacks
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Primary Progressive MS
• Presents with progressive myelopathic gait, cerebellar ataxia or cognitive impairment without clear history of any clinical attacks
• Clinical progression must be for at least 1 year and accompanied by a combination of brain spinal abnormalities and/or CSF abnormalities consistent with MS
• Lack of clinical attacks/ relative paucity of MRI lesions
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Clinically Isolated Syndrome (CIS)
• A first neurologic event suggestive of demyelination
• Individuals with CIS are at high risk for developing clinically
definite
MS if the neurologic event is accompanied by
•
multiple, clinically silent (asymptomatic) lesions on MRI
typical of MS
18
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Radiologically Isolated Syndrome (RIS)
– No typical symptoms of CNS demyelination
– No formally accepted diagnostic criteria
– MRI : Typical MS lesions
– CSF abnormalities
– Clinical MS Attack:
– 35% over 5 years
– MRI progression:
• 59-83% in 2 years
Okuda DT et al, Neurology2011:76()8, 686-692
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What are the symptoms of MS?
• Early symptoms
• Daily effects
• Age range
• Characteristics of symptoms
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Cycle of MS Symptoms:Related and Interdependent
Sleep
Fatigue
Depression
Bladder
& Bowel
problems
Sexuality
issues
Spasticity
Constipation
Cognitive
function
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Features Consistent With MS
• Relapses and remissions
• Age Onset between ages 15 and 50
• Optic neuritis
• Lhermitte's sign
• Internuclear ophthalmoplegia (INO)
• Fatigue
• Uhthoff's phenomenon
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How is MS diagnosed?
• MS is a clinical diagnosis
– Medical history
– SIGNS And symptoms
– Laboratory tests
• Requires dissemination in time and space:
– Space: Evidence of scarring (plaques) in at least two separate areas of the CNS (space)
– Time: Evidence that the plaques occurred at different points in time
• There must be no other explanation
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Diagnosis of MS
• No single test for diagnosing MS
• Usually diagnosed when all other possibilities ruled out
• Many tests
– Medical history
– Nervous system functioning
– MRI McDonald criteria
– Evoked potential tests, spinal tap
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INITIAL SYMPTOMS
• ascending numbness
starting in the feet;-
bilateral hand numbness;-
hemiparesthesia;-
dysesthesia in one of the
above distributions;-
generalized heat
intolerance
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• Sensory systems:
• -Lhermitte's sign-
dysesthetic pain-
paresthesia-
numbness-dorsal
column signs
(i.e.,. severe
decrease or loss
of vibratory sense
and
proprioception,
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• Ongoing Symptoms and Signs
•
Motor system:-
• weakness (variable severity mono- and
paraparesis, hemiparesis, quadriparesis)-
• increased spasticity resulting in spastic gait
• -pathologic signs (Babinski's, , Hoffmann,, etc.)
-dysarthria
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• Cerebellar signs
• incoordination (dysdiadochokinesia,
problems with heel-to-shin test)-slowing
• of rapid repeating movements-cerebellar
ataxia (ataxic gait)
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Expanded Disability Status Scale
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What tests may be used to help confirm the diagnosis?
• Magnetic resonance imaging
(MRI)
• Visual evoked potentials (VEP)
• Lumbar puncture
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McDonald Diagnostic CriteriaMRI-High Specificity & Sensitivity for MS
• Typical MS demyelinating lesions meeting at least 3 of the
following 4 criteria:
– At least 1 Gd lesion or at least 9 T2 lesions
– At least one infratentorial lesion
– At least one juxtacortical lesion
– At least 3 periventricular lesions
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McDonald Diagnostic CriteriaMRI-Dissemination in Time
• If the first MRI is performed 3 months after the clinical
• event, 1 of the 2 below must be found:
– > 1 Gd lesion not at site of original attack; or
– MRI 3 months later showing a new T2 or Gd lesion
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If the first MRI is performed < 3 months after the clinical event,then a
second MRI done 3 months after the attack provides
evidence for 1 of the 2 below must be found:
New Gd lesion on the second MRILater MRI showing new T2 or Gd lesion
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Case : MRI Brain
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Case 2: MRI Spine
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Case 1: Fundoscopy
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© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What role does lumbar puncture play in
diagnosis?
Spinal fluid can reveal signs of MS
Unique oligoclonal bands in spinal fluid by isoelectric
focusing (in 90%-95% of patients with MS)
Elevation of IgG index (in 50%-75%)
Mild pleocytosis (in ≈50%)
Negative CSF result alone doesn’t rule out MS
But when clinical and radiologic suspicion is low, a normal
CSF result reassures patients they probably don’t have MS
For RRMS diagnosis
Criteria don’t require confirmation by CSF testing
For PPMS diagnosis
Test CSF if MRI features don’t meet criteria for dissemination
in space
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Case : CSF Oligoclonal bands
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© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What are the differential diagnoses?
Other demyelinating diseases
Acute disseminated encephalomyelitis
Neuromyelitis optica (Devic disease)
Idiopathic transverse myelitis
Systemic inflammatory disease
Systemic lupus erythematosus
The Sjögren syndrome
Sarcoidosis
The Behçet syndrome
Metabolic disorders
Adult-onset leukodystrophy
Vitamin B12 deficiency
Copper deficiency
Zinc toxicity
Vitamin E deficiency
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© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
Infections
HIV, Lyme disease, syphilis
Human T-lymphotropic virus
Vascular disorders
Sporadic and genetic stroke syndromes
CNS vasculitis
Dural arteriovenous fistula
Migraine
Neoplasia (i.e., primary CNS neoplasm (glioma or lymphoma)
or metastatic disease)
Paraneoplastic syndromes
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An Overview of Treatment Strategies
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How is MS treated?
• There is no cure for MS
• Treatments FOR:
– MS attacks or acute relapse.
– Immune Modify agents
to prevent progression and reduce activity
Of the disease.
• Treatment of symptoms
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HOW SHOULD CLINICIANS CHOOSE THERAPY FOR PATIENTS WHO ARE HAVING AN ACUTE RELAPSE?
• Relapse: new or worsening neurologic symptoms lasting ≥24h
without clear underlying triggers of pseudo-relapse
Standard treatment: high-dose corticosteroids
IV infusion methylprednisolone, 1g/d for 3-5 days .
OTHER treatment if relapse doesn’t respond to steroids
Plasma exchange
5 days of IM or SC adrenocorticotrophic hormone .
Pulse-dose IV cyclophosphamide
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Disease-Modifying Drugs for RRMS
• All reduce attack frequency and severity, reduce lesions
on MRI, and probably slow disease progression.
• These medications are not designed to:
– Cure the disease
– Make people feel better
– Alleviate symptoms
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How is the disease course treated?
• Thirteen disease-modifying therapies are
FDA-approved for relapsing forms of MS:– glatiramer acetate (Copaxone®; Glatopa™ - generic equivalent) [inj.]
– interferon beta-1a (Avonex®, Plegridy™, Rebif®) [inj.]
– interferon beta-1b (Betaseron® and Extavia®) [inj.]
– dimethyl fumarate (Tecfidera™) [oral]
– fingolimod (Gilenya™) [oral]-MELLIOR ORAL
– teriflunomide (Aubagio®) [oral]
– alemtuzumab (Lemtrada™) [Inj.]
– natalizumab (Tysabri®) [inf]
– mitoxantrone (Novantrone®) [inj.]
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Treatment AMildly effective, mildly toxic
Disease active
Escalation Strategy
Disease suppressed Disease still active
Treatment BMore effective, more toxic
Disease suppressed Disease still active
Treatment CMost effective, most toxic
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Incr
eas
ing
eff
icac
y
Increasing burden of treatment(worse safety, more difficult administration)
Interferon-beta
NatalizumabJC+
Mitoxantrone
FingolimodDimethyl fumarate
Autologous stem cell transplantation
Glatiramer
First, second and third line therapies
Laquinimod
Alemtuzumab
NatalizumabJC neg
Rituximab / ocrelizumab
Teriflunomide
Third line
Second line
First line
Daclizumab
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Incr
eas
ing
eff
icac
y
Increasing burden of treatment(worse safety, more difficult administration)
Interferon-beta
NatalizumabJC+
Mitoxantrone
FingolimodDimethyl fumarate
Autologous stem cell transplantation
Glatiramer
High and low risk treatments
Daclizumab
Laquinimod
Alemtuzumab
NatalizumabJC neg
Rituxmab / ocrelizumab
Teriflunomide
“Dangerous”
“Aggressive”
“Safe”
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IFNβ-1b SC qod
GA
SC qd
IFNβ-1a IM qwk
Mitox
IV q 90
d wks
IFNβ-1a SC tiw
Natalizuma
b
IV q 4 wks Fingolim
od
0.5 mg gd
Teriflun
PO qd
Laquin
PO
Daclizum
ab
SC
BG-12
PO
bid
Alemtu
z
IV
The Changing Landscape of MS Disease Modifying Treatment
Of Approved and Emerging Therapies
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FDA-approved disease modifying agents
• Interferon beta
– Interferon beta-1b (Betaseron®) 250 mcg qod
– Interferon beta-1a (Rebif®) 44 mcg SC TIW
– Interferon beta-1a (Avonex®) 30 mcg IM weekly.
– Commn side effects: inj.site reactions,flu like symptoms,abdominal pain,depression,abn.liver function
• Glatiramer acetate (Copaxone®)
– 20 mg\ml SC \day or 40mg\ml 3 times\week.
– Side effects: vasodilatation,rash,sob,chest pain,anexiety.
• Mitoxantrone (Novantrone®)
– 12 mg/m2 q3mo: lifetime max, 144 mg/m2
– Side effects: nausea,hair thinning,bladder infection.low wbc,and
platletes
• Natalizumab (Tysabri®)
– 300 mg IV monthly infusion
Side effects: UTI,RTI,DIAREA,PML,ENCEPHALITIS
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• Continue disease modifying drugus
• Parenteral (IV) drugs
– Monoclonal antibodies: rituximab/ocrelizumab, alemtuzumab,
daclizumab
• Oral Drugs
– Fingolimod, teriflunomide,Dymethyl fumarate, laquinimod
• Symptomatic therapies
– Fampridine (4-AP), nerispirdine
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Glatiramare acetate(copaxon)
• Glatiramer acetate, the active ingredient of COPAXONE,
consists of the acetate salts of synthetic polypeptides
• containing four naturally occurring amino acids: L-
glutamic acid, L-alanine, L-tyrosine, and L-lysine with an
average molar fraction of 0.141, 0.427, 0.095, and 0.338,
respectively. The average molecular weight of glatiramer
acetate is 5,000 – 9,000 daltons. Glatiramer acetate is
identified by specific antibodies.
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COPAXON
• COPAXONE 20 mg per mL: administer once per day
• or
• COPAXONE 40 mg per mL: administer three times per
week
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Rituximab• Mechanism of action
– Chimeric human/murine mAb to CD20
– Depletes circulating B-cells
• Dosing
– 2 doses given 2 weeks apart IV: 1 g on days 1 and 151
• Side effects
– Infusion reactions, infections, hepatitis B reactivation, cases of progressive multifocal leukoencephalopathy in systemic lupus erythematosus/cancer population
Approved by FDA for lymphomas, rheumatoid arthritis
• HERMES phase II study for RRMS1
• Randomized, 48 weeks, 104 patients with RRMS
– Rituximab 1 g IV vs placebo on days 1 and 15
– 91% decrease in mean total Gd+ lesions
Rituximab 0.5 ± 2.0; placebo 5.5 ± 15 (P <.0001)
– Relapses at 24 weeks
Rituximab 14.5% vs placebo 34.3% (P = .02)
• Neuromyelitis optica/Devic’s open-label study2
• OLYMPUS trial phase II/III in PPMS – ineffective3
1. Hauser S, et al. N Engl J Med. 2008;358:676-688.
2. Cree BA, et al. Neurology. 2005;64:1270-1272.
3. Hawker KS, et al. Mult Scler. 2008;14:S299. Abstr 78.
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Alemtuzumab• Mechanism of action
– Anti-CD52 mAb to receptor on surface of T- and B-cells
FDA approved for chronic lymphocytic leukemia
– Given 12mg\day IV for 5days (60mg) followed by 12mg\day for 3days 12monthes later.
• Alemtuzumab CAMSS223 Phase II trial 1
– 334 early RRMS patients randomized to alemtuzumab vs interferon beta-1a
2-year follow-up results
– Alemtuzumab group: 75% reduction in relapse rate vs interferon beta-1a
– Significant reduction of risk of sustained disability
3-year follow-up
– Maintained 71% and 74% reduction in risk of sustained disability and relapse rate, respectively, vs interferon beta-1a
2 phase III trials (CARE-MS, CARE-MS2) now enrolling
• Serious adverse events
– Infusion reactions
– Idiopathic thrombocytopenic purpura (3%): total of 6 cases – 1st case was fatal
– Grave’s disease – autoimmune thyroiditis (20%)
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Daclizumab• Mechanism of action
– Anti-CD25 mAb targeting α chain of IL-2 receptor (IL-2Rα)
– Blocks the IL-2 “proinflammatory, ie, bad” cytokine receptor
– Prevents activation of sensitized T-cells
• Dosing
– IV infusion every 2 weeks (high dose) or every 4 weeks (low dose)
Side effects – infections, cutaneous reactions
• FDA approved for graft versus host disease/kidney transplant rejection
– CHOICE Trial – phase II results1
Randomized double-blind controlled trial
Add-on to interferon in 230 patients with RRMS
3 arms: 2 doses of daclizumab and placebo added to interferon
– Results
Decrease in new MRI lesions with higher dose vs interferon alone
No significant difference in relapse rate
5.2% with significant infections, none life-threatening
– SELECT: phase II trial of daclizumab monotherapy – Ongoing
1. Montalban X, et al. Mult Scler. 2007;13:S7-S273. Abstr 50.
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Teriflunomide( Aubagio)
• Mechanism of action
– Inhibits pyrimidine (DNA) synthesis in T-cells resulting in destruction of immune cells
• Dosing
– Once-daily 7mg or 14mg\day
• Side effects: alopecia,diarrhea,flu,liver injury,renal failure
• Results of phase II trial1: 36 weeks in 179 patients
– Teriflunomide (high dose and low dose) vs placebo
– Significant (>61%) decrease in new MRI lesions in both doses
– Decrease in disease progression (in high dose)
– Trend towards lower relapse rate in high-dose group
.
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FINGOLIMOD
Sphingosine-1-Phosphate (S1P) Receptor
Agonist
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LN
T-cell FTY720-P
Prevents T-cell
invasion of central
nervous system
S1P receptor
Sphingosine-1-phosphate (S1P) receptor modulator
Internalises S1P1, blocks
lymphocyte egress from lymph
node (LN) while sparing
immune surveillance by
peripheral memory T-cells
FTY720 traps
circulating
lymphocytes in
peripheral lymph
nodes
Multiple sclerosis
FTY720
Fingolimod: Mechanism of Action
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Fingolimod
• Treatment with fingolimod 0.5 mg:
– Significant benefits on relapse-related
outcomes within first 3 months and on volume
loss over 6 months compared with PBO in
FREEDOMS and FREEDOMS II studies;
concordant results from 2 large phase 3 trials,
along with phase 2 data, allow better definition
of expectations regarding time lag between
initiation and effects of fingolimod treatment
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Injectable therapiesOral therapies
Consider side
effects
BG 12
Fingolimod0,5mg\
day
DIMETHYL
FUMARATE
Terflunomide
Natalizumab 300MG
I.V inj.\month
Glatirame
r
Interferon
β
Relapsing inflammatory MS clinical course
First lineFirst
line?
Severe relapsing
inflammatory
MS/JCV negative
Inadequate
response/inj
intolerance
Inadequate
response/oral
intolerance
Parallel switch
Inadequate
response/JCV
negative
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Dimethyl Fumarate
(TECFIDERA)(sclera)
: A New Small Molecule Disease-
Modifying Drug for Multiple Sclerosis
120 mg PO BID initially; after 7 days,
increase to maintenance dose of
240 mg BID
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Dimethyl fumarate (TECFIDERA) is
an orally administered fumarate ester FDA
approved for first-line monotherapy of multiple
sclerosis in 2013. Because it is rapidly and
completely hydrolyzed by esterases before
reaching the systemic circulation, the
pharmacologic activity of dimethyl fumarate is due
to its active metabolite, monomethyl fumarate
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Although the precise mechanism of action is
incompletely characterized, monomethyl
fumarate is thought to exert neuroprotective
effects in patients with multiple sclerosis by
activating the nuclear erythroid 2-related factor
2 (nuclear factor erythroid-derived 2-like
2; Nrf2) transcriptional pathway. Using a model
of endogenous neuronal oxidative stress
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Proposed Mechanism of Action of Dimethyl Fumarate.
Abbreviations used: ARE, antioxidant response element;
GCLC, glutamate-cysteine ligase; GSH, glutathione;
GstA2, glutathione S-transferase A2; HO-1, heme-
oxygenase-1; Nqo1, NADPH quinone oxidoreductase 1;
MMF, monomethyl fumarate; Nrf2, nuclear factor
erythroid-derived 2-related factor 2.
Comments
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What is the prognosis?
• One hallmark of MS is its unpredictability.
– Approximately 1/3 will have a very mild course
– Approximately 1/3 will have a moderate course
– Approximately 1/3 will become more disabled
• Certain characteristics predict a better outcome:
– Female
– Onset before age 35
– Sensory symptoms
– Monofocal rather than multifocal episodes
– Complete recovery following a relapse
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Slide 70 of 26
Who is on the MS “Treatment Team”?
• Neurologist
• Urologist
• Nurse
• Physiatrist
• Physical therapist
• Occupational therapist
• Speech/language pathologist
• Psychiatrist
• Psychotherapist
• Neuropsychologist
• Social worker/Care manager
• Pharmacist
• Primary care physician
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What is the prognosis?
• One hallmark of MS is its unpredictability.
– Approximately 1/3 will have a very mild course
– Approximately 1/3 will have a moderate course
– Approximately 1/3 will become more disabled
• Certain characteristics predict a better outcome:
– Female
– Onset before age 35
– Sensory symptoms
– Monofocal rather than multifocal episodes
– Complete recovery following a relapse
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Slide 72 of 26
So what do we know about MS?
• MS is a chronic, unpredictable disease
• The cause is still unknown
• MS affects each person differently; symptoms vary widely
• MS is not fatal, contagious, directly inherited, or always disabling
• Early diagnosis and treatment are important
– Significant, irreversible damage can occur early on
– Available treatments reduce the number of relapses and may slow
progression
• Treatment includes: attack management, symptom management,
disease modification, rehab, emotional support
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Slide 73 of 26
•QUESTIONS
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Slide 75 of 26
THANK YOU