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Multiple Sclerosis
Nanik “Nayri” Hatsakorzian
Pharm.D/MPH Candidate 2014
Touro University – California
College of Pharmacy
Overview
 Pathophysiology
 Forms of MS
 Hallmark signs and symptoms
 Diagnosis
 Current treatments
Pathophysiology
 Chronic inflammatory demyelinating disorder that mostly affects
Caucasian young women in their reproductive age.
 Massive destruction of myelin. MS lesions, is seen upon extravasation
of activated leukocytes from the peripheral circulation through BBB
into CNS.
 Autoreactive T-cells recognizing self myelin antigens.
 Myelin basic protein (MBP) - primed T-cells. The contact between MBPprimed T-cells and microglia leads to induction of NO
 Excessive NO derived from inducible nitric oxide synthase (iNOS) in
glial cells leading to demyelination
 Persistent oxidative stress is seen even in remission MS patients
Oliveira SR, Kallaur AP, Simao AN, et al. Oxidative stress in multiple sclerosis patients in clinical remission: Association with the
expanded disability status scale. J Neurol Sci. October 15, 2012; 321(1-2):49-53
Rossi B, Angiari S, Zenaro E, et al. Vascular inflammation in central nervous system diseases: adhesion receptors controlling leukocyteendothelial interactions. J Leukoc Biol. April 2011; 89(4):539-56
Oxidative stress evaluated by tert-butyl hydroperoxide-initiated chemiluminescence (CLLOOH) in patients with relapsing/remittent multiple sclerosis.
Oliveira SR, Kallaur AP, Simao AN, et al. Oxidative stress in multiple sclerosis patients in clinical remission: Association with
the expanded disability status scale. J Neurol Sci. October 15, 2012; 321(1-2):49-53
Pathophysiology
 Metalloproteinases (MMPs) & tissue inhibitors of
metalloproteinases (TIMPs)
 MMP/TIMP balance, mRNA stability, and translational
 TIMP-1/MMP-3 ratio imbalance impairs wound healing, arthritis and cancer
metastasis
 MMP levels are low and well controlled in normal resting adult tissue,
and up regulated during development, cell signaling, and remodeling
(i.e. wound healing, ovulation, bone growth, angiogenesis)
 Inflammatory stimuli increase MMP levels leading to tumor invasion
and metastasis, RA, periodontal diseases, and atherosclerosis
Hove VI, Lemmens K, Van de Velde S, et al. Matrix metalloproteinase-3 in the central nervous system: a look on the bright
side. J Neurochem. November 2012; 123(2):203-16
MMP-3: A double edged sword
 MMP-3 is able to degrade MBP and is up-regulated in the brain
prior to the onset of disease, in and around lesions, and in serum
of MS patients
 MMP-3 is highly expressed in astrocytes of corpus callosum
suggesting re-myelination via releasing IGF, and removing myelin
debris.
 Time, space, and cell type specific MMP-3 expression seem to have
dual function. Acute injury might lead to degeneration whereas later
stages of injury up-regulation of MMP-3 might contribute to axonal
sprouting, re-myelination and reactive synaptogenesis.
Hove VI, Lemmens K, Van de Velde S, et al. Matrix metalloproteinase-3 in the central nervous system: a look on the bright
side. J Neurochem. November 2012; 123(2):203-16
Pathophysiology
 Endothelial adhesion molecules detected in relapse MS patients
and have been associated with disease severity and the spreading
of the lesions.
 P – and E – selectin are found in MS lesions and in RR MS patients
 Monocytes were also identified in the CNS parenchyma and it is
believed to play a role in exacerbating MS by providing a source of
pro-inflammatory cytokines.
Rossi B, Angiari S, Zenaro E, et al. Vascular inflammation in central nervous system diseases: adhesion receptors controlling
leukocyte-endothelial interactions. J Leukoc Biol. April 2011; 89(4):539-56
Forms of MS
 Relapsing-remitting MS: Clearly defined relapses with full recovery or
with residual deficit upon recovery. No disease progression during the
periods between disease relapses
 Primary-progressive MS: Disease progression from onset with
occasional plateaus and temporary minor improvements
 Secondary-progressive MS: Initial RR disease course followed by
progression with or without occasional relapses, minor remissions,
and plateaus
 Progressive relapsing MS is characterized by progressive disease
from onset, with clear acute relapses with or without full recovery.
Progression continues during the periods between disease relapses
Barten LJ, Allington DR, Procacci KA, Rivey MP. New approaches in the management of multiple sclerosis. Drug Design,
Development and therapy. 2010:4 343-366
Hallmark signs & symptoms
 Visual disturbances (optic neuritis, optic nerve dysfunction,
diplopia)
 Muscle weakness and bladder and bowel dysregulation
 Trouble with coordination, balance, ataxia
 Numbness
 Pins and needles
 Thinking and memory problem
Barten LJ, Allington DR, Procacci KA, Rivey MP. New approaches in the management of multiple sclerosis. Drug Design,
Development and therapy. 2010:4 343-366
Diagnosis
 McDonald criteria
 Added MRI in 2001, latest update is 2010
 About 5% of patients with clinically defined MS show no
lesions at the time of diagnosis
 Cerebrospinal fluid analysis. Oligoclonal bands seen in 90-95% of
patients with MS
 Visual Evoked Potential (VEP)
 Recording of the nervous system’s electrical impulses. Can
provide evidence of scarring
National Multiple Sclerosis Society. Diagnosing MS. Accessed on October 14, 2012. http://www.nationalmssociety.org/about-multiplesclerosis/what-we-know-about-ms/diagnosing-ms/index.aspx
Treatments
 Anti-inflammatory
 Glucocorticoids IV Methylprednisolone
 Immunomodulatory
 Betaseron (Interferon-β-1b) and Avonex (Interferon-β-1a)
 Copaxone (Glatiramer acetate)
 Tysabri (Natalizumab)
 Gilenya (Fingolimod)
 Anti-neoplastic agents
 Novantrone (Mitoxantrone)
 Novel treatment
 Aubagio (Teriflunomide)
Corticosteroids
IV methylprednisolone
 Acute attacks or exacerbation
 1 gram daily for 3 days, then 21 day tapering oral
treatment
 Pregnancy and lactation
 Enters breast milk
 IVMP exposed Pregnant women can contact OTIS
Autoimmune Diseases Study
Barten LJ, Allington DR, Procacci KA, Rivey MP. New approaches in the management of multiple sclerosis. Drug Design,
Development and therapy. 2010:4 343-366
Ontaneda D, Rae-Grant AD. Management of acute exacerbations in multiple sclerosis. Ann Indian Acad Neurol. Oct 2009;
12(4):264-272
Betaseron (Interferon β-1b)
 Reduce attack rates
 For RRMS and SPMS only
 Beneficial effects are seen on MRI
 MoA is not known exactly, but include enhancement of
suppressor T cell activity, reduction of pro-inflammatory
cytokines, down regulation of antigen presentation, and
reduced trafficking of lymphocytes into the central
nervous system.
Barten LJ, Allington DR, Procacci KA, Rivey MP. New approaches in the management of multiple sclerosis. Drug Design,
Development and therapy. 2010:4 343-366
Goodin DS, Frohman EM, Garmany GP, et al. Disease modifying therapies in multiple sclerosis: Subcommittee of the
American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. January 2002; 58(2); 169178
Clinical pearls
 RRMS: initial 0.0625 mg (0.25 mL) SQ every other day. Gradually
increase dose by 0.0625 mg every 2 weeks
 Target dose: 0.25 mg (1 mL) every other day
 SPMS: initial 0.125 mg (0.5 mL) SQ every other day for 2 weeks.
 Target dose: 0.25 mg every other day
 Reconstituted solution should be used immediately after
reconstitution or within 3 hours if refrigerated
 Caution
 Hepatotoxicity
 Increased risk of infection
 Injection site reaction, necrosis may occur, injection competency should
be evaluated
 Bone marrow suppression
 Neuropsychiatric disorders
 Caution with seizure patients
Copaxone (Glatiramer acetate)
 Reduces attack rates in RRMS patients
 Beneficial effects are seen on MRI
 Pregnancy category B
 MoA: a random polypeptide made up of four amino acids (Lglutamic acid, L-lysine, L-alanine, and L-tyrosine). Antigenically
similar to myelin basic protein; induce and activate T-lymphocyte
suppressor cells specific for a myelin antigen and Interferes with
the antigen-presenting function
Barten LJ, Allington DR, Procacci KA, Rivey MP. New approaches in the management of multiple sclerosis. Drug Design,
Development and therapy. 2010:4 343-366
Goodin DS, Frohman EM, Garmany GP, et al. Disease modifying therapies in multiple sclerosis: Subcommittee of the
American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. January 2002; 58(2);
169-178
Clinical Pearls
 RRMS: 20 mg SQ daily
 Should be refrigerated
 Not for IV administration
 Not for patients with mannitol allergy
 Caution
 Transient chest pain may occur
 Injection site lipoatrophy
 Common post injection systemic reactions include: anxiety,
chest pain, dysphagia, flushing, palpitation, urticaria. Can occur
several months after initiation as well
Tysabri (Natalizumab)
 MoA: Monoclonal antibody against α-4 integrin molecules. It
blocks α4β1 integrin limiting adhesion and transmigration of
leukocytes. It also blocks T-lymphocytes migration into the CNS
 Decrease frequency of relapse and improve measures of disease
severity.
 FDA approval for patients who failed IFNβ or glatiramer therapy
 Combination treatment with IFNβ-1α therapy reduced MRI activity
by 80-90% and clinical activity by 50-70%
 Clinical trials that study combination therapy (three-armed trial)
are not available.
Barten LJ, Allington DR, Procacci KA, Rivey MP. New approaches in the management of multiple sclerosis. Drug Design, Development and
therapy. 2010:4 343-366
Goodin DS, Cohen BA, et al. Assessment: The use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review):
Report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology. Neurology 2008;71;766
Clinical Pearls
 300 mg infused over 1 hour every 4 weeks
 Patient has to be in hospital setting
 Caution
 Patient has to be enrolled in Tysabri Outreach Unified Commitment to
Health (TOUCH) prescribing program due to association with
Progressive Multifocal Leukoencephalopathy PML (a rare demyelinating
neurological disorder caused by the reactivation of the JC virus)
 On January 2012 FDA require patients to test for anti-JC virus
antibodies, risk factor to PML. AND since August 2012, FDA mandates
patients to re-test every 6 months even if the results are negative.
U.S.Food and Drug Administration. Drug Safety Communication: New risk factor for progressive Multifocal
Leukoencephalopathy (PML) associated with Tysabri (natalizumab). Accessed on October 14, 2012.
http://www.fda.gov/drugs/drugsafety/ucm288186.htm
Gilenya (fingolimod)
 Approved for RRMS after interferon and glatiramer
 Reduce frequency of exacerbation and delays disability
 MoA: sphingosine-1- phosphate receptor modulator.
Internalizes S1P on lymphocytes, preventing the egress
from the LN to the peripheral tissue inhibiting
demyelination and neurodegeneration
Goodin DS, Frohman EM, Garmany GP, et al. Disease modifying therapies in multiple sclerosis: Subcommittee of the American
Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. January 2002; 58(2); 169-178
U.S. Food and Drug Administration. Drug Safety Communication: Revised recommendations for cardiovascular monitoring and
use of multiple sclerosis drug Gilenya (fingolimod). Accessed on October 14,2012.
http://www.fda.gov/Drugs/DrugSafety/ucm303192.htm
Clinical Pearls
 0.5 mg PO daily
 Baseline ECG
 Caution
 Bradycardia and AV block; caution with β-blockers and/or Ca
channel blockers
 Infections 72%
 Decrease pulmonary function test
 Increase liver transaminase concentration within 3-4 months
 Most common side effects include: HA, influenza, diarrhea, back
pain, elevation of ALT, and cough
Novantrone (Mitoxantrone)
 Second/third line agents approved for RRMS and SPMS patients
 MoA: Related to anthracyclines; cross links DNA and cause strand
breakage. Inhibits RNA & DNA synthesis. Cell cycle non specific
 12 mg/m2 IV every 3 months
 Maximum lifetime dose due to cardiomyopathy, leukemia,
leucopenia, and infection (140 mg/m2 ; ~ 11 doses)
Barten LJ, Allington DR, Procacci KA, Rivey MP. New approaches in the management of multiple sclerosis. Drug Design, Development
and therapy. 2010:4 343-366
Goodin DS, Frohman EM, Garmany GP, et al. Disease modifying therapies in multiple sclerosis: Subcommittee of the American Academy
of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. January 2002; 58(2); 169-178
Clinical Pearls
 Patients should be in hospital setting
 IV only
 Irritant, and must be diluted
 Caution
 Discontinue when LVEF <50 % or when clinically significant reduction in
LVEF is seen
 Effects of cardiotoxicity may be delayed; it is seen even after completion
of therapy
 Patients undergo annual LVEF evaluation following discontinuation to
monitor delayed cardiotoxicity
 Do not administer when neutrophils < 1500 cells/mm3
 Severe bone marrow suppression
 Increase risk of developing secondary acute myelogenous leukemia
(AML) in patients with cancer or MS
Marriot JJ, Miyasaki JM, Gronseth G, et al. Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of
multiple sclerosis: Report of the therapeutics and Technology Assessment subcommittee of the American Academy of Neurology.
Neurology. 2010; 74;1463
Aubagio (Teriflunomide)
 Significant reduction in active lesions in both RRMS & SPMS
patients
 MoA: inhibits pyrimidine synthesis resulting in
antiproliferative and anti-inflammatory effects. It may reduce
activated lymphocytes in the CNS
 Active metabolites of leflunomide, inhibits T-cell activation by
blocking interaction with antigen-presenting cells
 T ½ life 18-19 days; enterohepatic recycling contribute to
long T ½ life
 7 mg or 14 mg PO daily
Daily Med. Aubagio (teriflunomide) tablet, film coated. Accessed on October 16, 2012.
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4650d12c-b9c8-4525-b07f-a2d773eca155
Clinical pearls
 Caution
 Should discontinue when ALT elevation >3x ULN & administer
 Cholestyramine 8 grams every 8 hours for 11 days
 or activated charcoal 50 grams every 12 hours for 11 days
 Contraindicated with severe hepatic impairment
 Contraindicated in women of childbearing age if non compliant with
contraceptive use
 Pregnancy category X
 Avoid other immunosuppressant medications
 Most common side effects include: HA, elevated ALT,
hypophosphatemia, hyperkalemia, alopecia, neutropenia, influenza,
nausea and vomit.
References 1 of 2
 Barten LJ, Allington DR, Procacci KA, Rivey MP. New approaches in the
management of multiple sclerosis. Drug Design, Development and therapy. 2010:4
343-366
 Daily Med. Aubagio (teriflunomide) tablet, film coated. Accessed on October 16,
2012. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4650d12c-b9c84525-b07f-a2d773eca155
 Goodin DS, Cohen BA, et al. Assessment: The use of natalizumab (Tysabri) for the
treatment of multiple sclerosis (an evidence-based review): Report of the
therapeutics and technology assessment subcommittee of the American Academy
of Neurology. Neurology 2008;71;766
 Goodin DS, Frohman EM, Garmany GP, et al. Disease modifying therapies in
multiple sclerosis: Subcommittee of the American Academy of Neurology and the
MS Council for Clinical Practice Guidelines. Neurology. January 2002; 58(2); 169178
 Hove VI, Lemmens K, Van de Velde S, et al. Matrix metalloproteinase-3 in the
central nervous system: a look on the bright side. J Neurochem. November 2012;
123(2):203-16
 Lexi-Comp, Inc. (Lexi-Drugs TM). Lexi-comp, Inc; October 14, 2012
References 2 of 2
 Marriot JJ, Miyasaki JM, Gronseth G, et al. Evidence Report: The efficacy and safety
of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the
therapeutics and Technology Assessment subcommittee of the American Academy
of Neurology. Neurology. 2010; 74;1463
 National Multiple Sclerosis Society. Diagnosing MS. Accessed on October 14, 2012.
http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-aboutms/diagnosing-ms/index.aspx
 Ontaneda D, Rae-Grant AD. Management of acute exacerbations in multiple
sclerosis. Ann Indian Acad Neurol. Oct 2009; 12(4):264-272
 Oliveira SR, Kallaur AP, Simao AN, et al. Oxidative stress in multiple sclerosis
patients in clinical remission: Association with the expanded disability status scale. J
Neurol Sci. October 15, 2012; 321(1-2):49-53
 Rossi B, Angiari S, Zenaro E, et al. Vascular inflammation in central nervous system
diseases: adhesion receptors controlling leukocyte-endothelial interactions. J
Leukoc Biol. April 2011; 89(4):539-56
 U.S.Food and Drug Administration. Drug Safety Communication: New risk factor for
progressive Multifocal Leukoencephalopathy (PML) associated with Tysabri
(natalizumab). Accessed on October 14, 2012.
http://www.fda.gov/drugs/drugsafety/ucm288186.htm
 U.S. Food and Drug Administration. Drug Safety Communication: Revised
recommendations for cardiovascular monitoring and use of multiple sclerosis drug
Gilenya (fingolimod). Accessed on October 14,2012.
http://www.fda.gov/Drugs/DrugSafety/ucm303192.htm