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MULTIPLE SCLEROSIS IN A PRIMARY CARE SETTING:
Employing Strategies for Early Diagnosis & Improved Patient Outcomes
Victor M. Rivera, MD, Sr, FAAN
Distinguished Emeritus Professor of Neurology
Founding Director, Maxine Mesinger MS Comprehensive Care Center
Department of Neurology, Baylor College of Medicine
Houston, Texas
Regina R. Berkovich, MD, PhD
Assistant Professor, Clinical Neurology Principal Investigator
ACTH Vs MP Trial Department
Neurology Keck School of Medicine of USC
Los Angeles, California
May 1, 2013
10:45am—12:15pm
Anaheim Convention Center
EDUCATION PARTNER
Session 3: Multiple Sclerosis in a Primary Care Setting:
Employing Strategies for Early Diagnosis and Improved Patient Outcomes
Learning Objectives
1.
2.
3.
4.
Recognize early multiple sclerosis (MS) symptoms and facilitate accurate diagnosis according to recommended MS diagnostic
and imaging criteria.
Be familiar with strategies for managing the symptoms and complications of MS in the primary care setting.
Outline the risks and benefits of currently available disease modifying therapies in the treatment of patients with MS.
Monitor MS patients on disease modifying therapies for effectiveness and safety.
Faculty
Regina R. Berkovich, MD, PhD
Assistant Professor, Clinical Neurology Principal Investigator
ACTH Vs MP Trial Department
Neurology Keck School of Medicine
University of Southern California
Los Angeles, California
Dr Regina Berkovich is an assistant professor of Clinical Neurology at the Comprehensive MS Care Center of the Keck School of
Medicine, University of Southern California (USC). She has specific training and expertise in Multiple Sclerosis and is one of the key
opinion leaders in her field. The USC MS Center is the largest in Southern California; serving over 2500 patients with MS. She has a large
clinical practice where she consults and follows up with MS patients on a regular basis.
Dr Berkovich also carries out extensive clinical research in MS and has participated in many multicenter clinical trials in the capacity of
principal investigator (PI) and co-PI. She developed several investigator initiated protocols and has been awarded research grants for
originally designed Investigator Initiated Studies (IIS) from National Multiple Sclerosis Society, Questcor, and Teva Pharmaceutical. The
Investigational New Drug Application (IND) was granted to her by the FDA for potential new indicator for the adrenocorticotropic
hormone. Her recent American Academy of Neurology (AAN) poster was included in official 65th AAN Press release.
Over years of working in clinical trials, Dr Berkovich developed close professional relationships with top scientists in the MS field. She
designed and carried on collaborative ancillary studies, such as the Immunology study of ACTH in collaboration with Professor
Lawrence Steinman, MD at Stanford University and MRI metrics of monthly ACTH in collaboration with Professor Rohit Bakshi, MD, PhD
at Harvard University.
In 2010, Dr Berkovich was awarded the Top Doctors Certificate by the Pasadena Magazine. She is a member of Los Angeles Society of
Neurologists, Association of California Neurologists, American Neurology Association (ANA), and American Academy of Neurology
(AAN).
Victor M. Rivera, MD, Sr, FAAN
Distinguished Emeritus Professor of Neurology
Founding Director, Maxine Mesinger MS Comprehensive Care Center
Department of Neurology
Baylor College of Medicine
Houston, Texas
Dr Victor M. Rivera is the distinguished emeritus professor of Neurology at Baylor College of Medicine, adjunct professor of Research at
the University of Houston, senior member and fellow of the American Academy of Neurology. He is also the founder of the Mexican
Academy of Neurology and the Latin American Committee for Treatment and Research in MS (LACTRIMS); serving as its president for
two consecutive terms. He is also the founder and first director of the Maxine Mesinger Multiple Sclerosis Comprehensive Care Center &
Clinic of Baylor College of Medicine at The Methodist Hospital in Houston, Texas.
Session 3
Faculty Financial Disclosure Statements
The presenting faculty reports the following:
Dr Berkovich served as a consultant for Acorda, Avanir, Bayer, Biogen Idec, Genzyme, Questcor, Teva.
Dr Rivera has no financial relationships to disclose.
Education Partner Financial Disclosure Statement
The content collaborators at Horizon CME have report the following:
Brian Lee, PharmD, Elizabeth Wilkerson, CHES, Cara Williams, PharmD, and Arianna Sunford, BHA, have no financial relationships to
disclose.
Acronym List
Acronym
CDMS
CIS
DMT
EDSS
IPIR
ITP
JCV
Definition
Clinically Definite Multiple Sclerosis
Clinically Isolated Syndrome
Disease Modifying Therapy
Expanded Disability Status Scale
Immediate Postinjection Reaction
Idiopathic Thrombocytopenia Purpura
John Cunningham Virus
Acronym
PML
PPMS
RRMS
SPMS
VEP
Definition
Progressive Multifocal Leukoencephalopathy
Primary Progressive Multiple Sclerosis
Relapsing-Remitting Multiple Sclerosis
Secondary Progressive Multiple Sclerosis
Visual Evoked Potentials
Suggested Reading List
Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med.
2010;362(5):402–415.
Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study.
Lancet. 2001;357(9268):1576–1582.
Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with
clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet. 2009;374(9700):1503–1511.
Comi G, Jeffery D, Kappos L, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366(11):1000–1009.
Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple
sclerosis. CHAMPS Study Group. N Engl J Med. 2000;343(13):898–904.
Kappos L, Polman CH, Freedman MS. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in
patients with clinically isolated syndromes. Neurology. 2006;67(7):1242–1249.
Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med.
2010;362(5):387–401.
Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol.
2005;58(6):840–846.
Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol.
2011;69(2):292–302.
PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis.
PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet.
1998;352(9139):1498-1504.
Vollmer T, Soelberg Sorensen P, Arnold DL, et al. A placebo-controlled and active comparator phase III trial (BRAVO) for relapsing
remitting multiple sclerosis. Paper presented at: 5th Joint triennial congress of the European and Americas Committees for Treatment
and Research in Multiple Sclerosis; October 22, 2011; Amsterdam, The Netherlands; Abstract 148.
Session 3
Presenter Disclosure Information
SESSION 3
10:45 AM – 12:15 PM
The following relationships exist related to this presentation:
• Dr Berkovich served as a consultant for Acorda, Avanir, Bayer, Biogen
Idec, Genzyme, Questcor, Teva.
Multiple Sclerosis in a Primary Care
Setting: Employing Strategies for
Early Diagnosis and Improved
Patient Outcomes
• Dr Rivera has no financial relationships to disclose.
Off-Label/Investigational Discussion
SPEAKERS
• In accordance with pmiCME policy, faculty have been asked to
disclose discussion of unlabeled or unapproved use(s) of drugs or
devices during the course of their presentations.
Regina R. Berkovich, MD, PhD
Victor M. Rivera, MD, Sr, FAAN
Learning Objectives
Multiple Sclerosis in a Primary
Care Setting:
• Recognize early MS symptoms and facilitate
accurate diagnosis according to recommended
MS diagnostic and imaging criteria
• Be familiar with strategies for managing the
symptoms and complications of MS in the
primary care setting
• Outline the risks and benefits of currently
available disease modifying therapies in the
treatment of patients with MS
• Monitor MS patients on disease modifying
therapies for effectiveness and safety
Employing Strategies for Early Diagnosis
and Improved Patient Outcomes
Demographic Question
?
Outcomes Question #1
Which of the following criteria are required
for a diagnosis of MS?
How many patients with multiple sclerosis do
you see each week?
1.
2.
3.
4.
5.
1. A single clinical episode and characteristic visual
evoked potential (VEP) findings
2. A single clinical episode and evidence of a
plaque anywhere in the CNS
3. Evidence of plaques in at least two different
locations in the CNS and evidence that plaques
occurred at different points in time
4. Evidence of plaques in at least two different
locations in the CNS regardless of when they
developed
None
1-10
11-20
21-30
Over 30
1
?
Outcomes Question #2
?
Outcomes Question #3
When should disease-modifying MS
therapies be initiated?
Which of the following signs indicate MS
disease progression and/or the need to
adjust disease-modifying therapy?
1. After a first attack
2. At definite diagnosis of MS with active,
relapsing disease
3. For acute exacerbations
4. For incomplete remission from acute
exacerbations
1. New T2 lesions on MRI
2. Gadolinium-negative lesions on MRI
3. No improvement in Expanded Disability
Status Scale (EDSS)
4. No decrease in frequency of relapse
Drug List
Drug List
Generic Drug Name US Trade Name Generic Drug Name US Trade Name
Generic Drug Name
US Trade Name ACTH (corticotrophin)
H.P. Acthar Gel
Alprostadil
Caverject, Muse
Desmopressin
DDAVP
dimethyl fumarate (BG‐12) oral
Tecfidera
Amantadine
Symmetrel
Diazepam
Valium
fingolimod (oral)
Gilenya
Amitriptyline
Elavil
Docusate
Colace
glatiramer acetate (injection)
Copaxone
Baclofen
Lioresal, Gablofen
Duloxetine HCl
Cymbalta
interferon β‐1a (intramuscular)
Avonex
Bisacodyl
Dulcolax
Fluoxetine
Prozac
interferon β‐1a (subcutaneous)
Rebif
Bupropion
Wellbutrin
Gabapentin
Neurontin
interferon β‐1b (subcutaneous)
Betaseron
Carbamazepine
Tegretol
Glycerin
Glycerin
methylprednisolone acetate (injection)
Solumedrol
Clonazepam
Klonopin
Isoniazid
Nydrazid
mitroxantrone (injection)
Novantrone
Dalfampridine
Ampyra
Milk of Magnesia
Mineral oil
Antivert
natalizumab (injection)
Tysabri
Dantrolene
Dantrium
Magnesium Hydroxide
Mineral oil
teriflunomide (oral)
Aubagio
Darifenacin
hydrobromide
Enablex
Meclizine HCl
Drug List
Generic Drug Name US Trade Name
Generic Drug Name US Trade Name Modafinil
Provigil
Sildenafil
Viagra
Nortriptyline HCl
Aventyl, Pamelor
Vesicare
Cialis
Flomax
Onabotulinumtoxin A
Botox
Solifenacin
succinate
Tadalafil
Oxybutynin
Ditropan
Tamsulosin HCl
Papaverine
Papacon, Pavacot
Terazosin
Hytrin
Paroxetine HCl
Paxil
Tixanidine
Zanaflex
Phenytoin
Dilantin
Trospium Cl
Sanctura
Propantheline
bromide
Psyllium hydrophilic
mucilloid
Sertraline
Pro‐Banthine
Vardenafil HCl
Levitra, Staxyn
Metamucil
Venlafaxine HCl
Effexor
EPIDEMIOLOGY & ETIOLOGY
Zoloft
2
?
Epidemiology of MS
Cause of MS is Unknown
• Inflammatory, demyelinating and
degenerative disease of the CNS
• About 350,000 people in the US, 2.5
million worldwide
• Incidence is rising
• MS is the leading cause of chronic
neurologic disability in young adults
(1:1000)
• Female : male ratio is 2:1
• Average age of diagnosis is 32, but can
occur at any age (generally 20-40);
increasingly recognized in children
Genetic
Predisposition
Environmental
Trigger
Autoimmunity
Loss of myelin
& nerve fibers
Cleveland Clinic. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis/
Accessed April 8, 2013. Noseworthy JH, et al. Multiple Sclerosis. N Engl J Med. 2000;343(13):938–952.
Cleveland Clinic. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis/ Accessed April 8, 2013. Noseworthy JH, et al. Multiple Sclerosis. N Engl J Med. 2000;343(13):938–952. Demyelination and Axonal Damage
Sources of Inflammation in MS
• Immune mechanisms most likely start in the
periphery, rather than in the CNS
• Myelin-specific immune response in T cells
involves
– T and B Lymphocytes, NK cells, Macrophages,
Neutrophils, mast cells
• Immune cells gain entry to the CNS via several
mechanisms involving
– integrins, adhesion molecules, chemokines
– dynamic changes in the blood brain barrier
• Activation of microglia, astrocytes and production
of their inflammatory mediators also occur
http://health.howstuffworks.com/diseases‐conditions/musculoskeletal/multiple‐sclerosis1.htm
Frohman EM, Racke MK, Raine CS. Multiple Sclerosis‐The plaque and its pathogenesis. N Eng J Med 2006;354:942‐955.
Summary
• MS is an inflammatory, demyelinating and degenerative
disease of the CNS
– Incidence rising; leading cause of chronic neurologic disability in
young adults
DIAGNOSIS OF MULTIPLE SCLEROSIS: SYMPTOMS, MRI & PARACLINICAL FINDINGS
– Cause is unknown
• Genetic predisposition + environmental trigger  autoimmune response
– Autoimmune response
• T-cells and demyelinating antibodies from systemic circulation
enter CNS
• Release proinflammatory cytokines, stimulate other
proinflammatory mediators, trigger enhanced immune attack of
myelin
• Results in loss of myelin (demyelination) and damaged axons
(poor transmission of action potentials)
3
Clinically Isolated Syndrome
Common Symptoms of MS
• Sensory disturbances
• Most common presentations as the very first event
– Optic Neuritis
• Usually unilateral ocular/orbital pain; Blurred or total loss
of vision; Central scotoma; RAPD; Dyschromatopsia
– Myelitis
• Sensory disturbance involving affected dermatome(s);
paralysis may develop if motor pathways involved;
spasticity with abnormal reflexes; gait affected; sphincter
control difficulties may occur
• Vision impairment
• Cognitive problems
• Sexual dysfunction
• Vertigo & dizziness
• Speech problems
• Spasticity
• Fatigue
• Muscular weakness
• Bladder & bowel
problems
• Tremor
• Gait & balance
problems
– Brain Stem/Cerebellar Syndrome
• Double vision; nystagmus; ophthalmoplegia; facial
numbness and/or facial weakness; dysarthria;
dysphagia; ataxia.
• Ambulation difficulties
RAPD=relative afferent pupillary defect.
Miller D, et al. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. The Lancet Neurology. 2005;4(5):281–288.
How is MS Diagnosed?
Mimics of MS
• Multiple Sclerosis is a clinical diagnosis
•
•
•
•
•
•
– Signs and symptoms
– Medical history
– Laboratory tests
• Requires dissemination in space and time
– Space: evidence of plaques in at least two different
locations in the CNS
– Time: evidence that plaques occurred at different
points in time
• There is no other explanation for the symptoms
Neuromyelitis optica
Acute disseminated encephalomyelitis (ADEM)
Systemic Lupus Erythematosus
Lyme disease
Neurosarcoidosis
Adrenoleukodystrophy and metachromatic
dystrophy
– Differential diagnosis to rule out other diseases and
radiographic mimics.
Noseworthy JH, et al. Multiple Sclerosis. N Engl J Med. 2000;343(13):938–952.
Coyle PK. Adv Stud Med. 2006;6(7D):s681‐s686.
Confirming the Diagnosis
Magnetic Resonance Imaging • What tests are used?
– Magnetic Resonance Imaging (MRI)
• Approximately 10% of MS cases show a normal MRI upon first presentation in
the clinic
– Visual evoked potentials (VEPs)
– Lumbar puncture (CSF)
• Clinically Isolated Syndrome (CIS) or Clinically Definite Multiple
Sclerosis (CDMS)?
– With single clinical episode and minimal MRI changes the condition is likely
to be called CIS
– CIS may also be diagnosed if there is a single clinical episode and
characteristic VEP or CSF findings (ie, presence of oligocloncal bands in
the CSF but not the serum)
– More than one episode of neurological dysfunction, “disseminated in space
and time” define Clinically Definite Multiple Sclerosis (CDMS)
Gadoliniumenhancing lesion:
breakdown of bloodbrain barrier, active
inflammation
MTR=magnetization transfer ratio.
FLAIR/T2: all lesions”
(edema, inflammation,
demyelination, axonal
loss)
National Multiple Sclerosis Society. http://www.nationalmssociety.org/ms‐clinical‐care‐network/clinical‐resources‐and‐
tools/publications/clinical‐bulletins/index.aspx. Accessed April 19, 2013.
Miller DH, et al., The Lancet Neurology. 2012;11(2):157–169. Miller D, et al., Multiple Sclerosis. 2008;14(9):1157–1174.
Bagnato, F, et al. Expert Opin. Biol. Ther 2007;7(7):1079‐1091.
4
T1 hypointense:
axonal loss, tissue
destruction
MTR
Cerebrospinal Fluid (CSF) Tap
Visual Evoked Potentials (VEPs)
• CSF testing can provide evidence of chronic
CNS inflammation
– The CSF is tested for oligoclonal bands
found in 90% to 95% of patients with definite
MS
• VEPs can be used to reveal otherwise
asymptomatic demyelination
– The brain of a person with MS often responds
less actively to stimulation of the optic and
sensory nerves
• Combined with MRI and clinical data, the
presence of oligoclonal bands in the CSF but
not the serum helps facilitate a diagnosis of MS
• In conjunction with other tests, VEPs can
help elucidate the overall nerve
involvement required for a definitive
diagnosis of MS
Noseworthy JH, et al. Multiple Sclerosis. N Engl J Med. 2000;343(13):938–952.
National Multiple Sclerosis Society. http://www.nationalmssociety.org/ms‐clinical‐care‐network/clinical‐resources‐and‐
tools/publications/clinical‐bulletins/index.aspx
Noseworthy JH, et al. Multiple Sclerosis. N Engl J Med. 2000;343(13):938–952.
National Multiple Sclerosis Society. http://www.nationalmssociety.org/ms‐clinical‐care‐network/clinical‐resources‐and‐
tools/publications/clinical‐bulletins/index.aspx
Diagnostic Criteria
for Clinically Definite MS
2010 Revised McDonald Diagnostic Criteria
• The criteria for a diagnosis of MS have evolved over
time
• Poser criteria (19831)
– 2 attacks and evidence of separate lesions
• McDonald criteria (2001, 20052, 20103)
– Incorporated MRI, neurological history, examination,
and paraclinical laboratory examinations into
diagnosis
• Over time, changes in diagnostic criteria have
incorporated clinical advances and improvements in
imaging technology to allow for earlier diagnosis and
treatment
Clinical presentation
≥2 attacks; objective
clinical evidence of ≥2
lesions
≥2 attacks; objective
clinical evidence of 1
lesion
1 attack; objective
clinical evidence of ≥2
lesions
1 attack; objective
clinical evidence of 1
lesion
(monosymptomatic
presentation; CIS)
Insidious neurologic
progression suggestive
of MS
Additional data needed for MS diagnosis
None
Dissemination in space, demonstrated by:
• MRI or ≥2 detected lesions consistent with MS plus positive
CSF or Await future clinical attack implicating a different site
Dissemination in time, demonstrated by:
• MRI or Second clinical attack
Dissemination in space, demonstrated by:
• MRI or ≥2 detected lesions consistent with MS plus positive
CSF and
Dissemination in time, demonstrated by:
• MRI or second clinical attack
1 year of disease progression (retrospectively or prospectively
determined) and 2 of the following:
• Positive brain MRI (9 T2 lesions or 4 or more T2 lesions with
positive VEP), Positive spinal cord MRI (2 focal T2 lesions)
• Positive CSF
1. Poser C, et al. et al. Ann Neurol. 1983;13(3):227–231. 2. Polman CH, et al. Ann Neurol. 2005;58:840‐846. 3. Polman CH, et al. Ann Neurol. 2011;69(2):292–302.
Polman CH, et al. 2010 Revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302.
Clinical Types of MS
and Natural History
Multiple Slcerosis
Clinical Types
CIS
85-88%
will be CDMS
Primary
progressive MS
(PPMS)
15%
RRMS
80%
at onset
Relapsing-remitting
MS (RRMS)
SPMS
50%
of RRMS
Secondary
progressive MS
(SPMS)
PPMS
10-15%
PRMS
5%
85%
Disease type at
diagnosis
RRMS = Relapsing‐remitting multiple sclerosis; SPMS = Secondary‐progressive MS; PPMS = Primary‐progressive MS
PRMS = Progressive‐relapsing MS.
Fieschi C, et al. Int MS J. 2005;12(1):21‐31. Wegner C. Int MS J. 2005;12(1):13‐19. Kappos L, et al. The Lancet 2007;370 (9585):389‐397. Lublin FD, Reingold SC. Neurology 1996;46:907‐911. Brex PA, et al. J Neurol Neurosurg Psychiatry 2010;70:390‐393. 42%
58%
Disease type 11-15 years
after diagnosis among
patients with RRMS at
diagnosis
Weinshenkder BG, et al. Brain. 1989;112:133‐146.
http://www.nationalmssociety.org/ms‐clinical‐care‐network/clinical‐resources‐and‐tools/publications/clinical‐
bulletins/index.aspx
5
The EDSS: Assessing the Course of Disease
Disease Progression
Relapse Remitting
Secondary Progressive
10.0 = Death due to MS
9.0‐9.5 = Completely dependent
8.0‐8.5 = Confined to bed/chair; self‐care with help
7.0‐7.5 = Confined to wheelchair
Clinical
disability
6.0‐6.5 = Walking assistance is needed
Clinical
threshold
5.0‐5.5 = Increasing limitation in ability to walk
4.0‐4.5 = Impairment is relatively severe
Brain
volume
3.0‐3.5 = Impairment is mild to moderate
Inflammation
2.0‐2.5 = Impairment is minimal
1.0‐1.5 = No impairment
0 = Normal neurologic exam
Time
EDSS = Expanded Disability Status Score
Kurtzke JF. Neurology. 1983;33:1444‐1452.
Adapted from Ziemssen T. J Neurol 2005;252(suppl 5):V/38‐V/45.
EDSS = Expanded Disability Status Scale
Summary
• Multiple Sclerosis is a clinical diagnosis
• Confirming diagnosis
– Magnetic Resonance Imaging (MRI)
– Visual evoked potentials (VEPs) used to reveal otherwise
asymptomatic demyelination
TREATMENT STRATEGIES
– Lumbar puncture (oligoclonal bands in CSF)
• 2010 Revised McDonald Diagnostic Criteria
– Requires dissemination in space and time
• Progressive disease over time
– Relapsing-remitting (RRMS)  Secondary-progressive (SPMS)
– Increasing disability (EDSS)
– Episodic inflammation
Acute MS Exacerbations (MS Relapse)
What are the Treatment Strategies?
• New neurologic symptom that last >24 hours in the absence
of a fever or infection
• Worsening of a neurologic symptom that had previously been
stable for ≥30 days
• Exacerbations can last days, weeks, or months
• At least 80% of patients with MS have an acute exacerbation
during the course of the disease
• Average acute exacerbation rate of 0.5 to 1.0 per year in the
US
• Incomplete remission from an exacerbation may result in
permanent neurologic deficit
1. Treatment of relapses (aka exacerbations,
flare-ups, attacks—that last at least 24 hours)
2. Symptom management
3. Disease modification
4. Rehabilitation (maintain/improve function)
5. Psychosocial support
Thrower BW. Neurologist. 2009;15(1):1‐5. Polman CH, et al. In: Multiple Sclerosis: The Guide to Treatment and Management. 2006:11‐20. McDonald WI, et al. Ann Neurol. 2001;50(1):121‐127. Sliwa JA. Arch Phys Med Rehabil. 2000;81(3 suppl 1):S3‐S12. Lublin FD, et al. Neurology. 2003;61(11):1528‐1532.
6
Patients Own Report of Symptoms MS Relapse Treatment
(n=300)
• IV methylprednisolone at a dose of 1000 mg/day
for 3 to 7 days with or without rapid oral tapering,
could be a safe and effective protocol.
Fatigue
Spasticity
Difficulty Walking
Depression
Bladder/Bowel sx
Pain
Paroxysmal sx
None
• Alternatively, IM or SQ ACTH 80 Units (1 cc/day)
can be given for 7-10 days.
• Cost difference may be substantial
ACTH=corticotropin; IM = intramuscular; SQ = subcutaneous.
58%
37%
35%
35%
33%
29%
24%
5%
Medications
available
Rivera VM. The Nature of Multiple Sclerosis. IOMSN/SiSalud, Mexico City, March 31, 2013.
Berkovich, R. Neurotherapeutics. 2013;10(1):97‐105.
Management of Primary Symptom
Management of Primary Symptoms
Symptom
Drug
Symptom
Vertigo & dizziness
Drug
Fatigue
amantadine, fluoxetine, and modafinil
Tremor
clonazepam, isoniazid
Spasticity
onabotulinumtoxin A, dantrolene, baclofen,
diazepam, tizanidine
Constipation
Ambulation difficulties
docusate, mineral oil, bisacodyl, psyllium
hydrophilic mucilloid, magnesium hydroxide,
glycerin
dalfampridine
Gait & balance problems
physical therapy and rehabilitation procedures
Depression
venlafaxine, paroxetine, fluoxetine, bupropion,
sertraline
Vision impairment
low vision clinics; prism to correct diplopia
Cognitive problems
computer-based cognitive retraining
Sexual dysfunction
papaverine, tadalafil, vardenafil, alprostadil,
sildenafil
Speech problems
speech therapy
Muscular weakness
physical therapy, strengthening exercises,
rehabilitation
Bladder dysfunction
desmopressin, oxybutynin, darifenacin, alpha
blockers (tamsulosin, terazosin, etc…),
propantheline bromide, trospium chloride,
solifenacin succinate
Pain and sensory
dysesthesias or
paresthesias
duloxetine hydrochloride, phenytoin, amitriptyline,
gabapentin, nortriptyline, carbamazepine
National MS Society. Clinical Bulletins. Symptom management. http://www.nationalmssociety.org/ms‐clinical‐care‐
network/clinical‐resources‐and‐tools/publications/clinical‐bulletins/index.aspx Accessed April 22, 2013. Stuifbergen A, et al. Int J MS Care. 2011; 13(4):189‐198. http://ijmsc.org/doi/pdf/10.7224/1537‐2073‐14.S3.1. Accessed April 15, 2013.
National MS Society. Clinical Bulletins. Symptom management. http://www.nationalmssociety.org/ms‐clinical‐care‐
network/clinical‐resources‐and‐tools/publications/clinical‐bulletins/index.aspx Accessed April 22, 2013
Disease Modifying Therapy
General Secondary Symptoms
Treatment Recommendations for Physicians
“Initiation of treatment with an interferon beta
medication or glatiramer acetate should be
considered as soon as possible following a definite
diagnosis of MS with active, relapsing disease, and may
also be considered for selected patients with a first
attack who are at high risk of MS.”
• Prevention and Management
–
–
–
–
meclizine
Vitamin D3
Cease smoking
Involvement in physical activities
Support Groups
• Overall fewer patients with advanced disability
—National Clinical Advisory Board of the National Multiple Sclerosis Society (NMSS),
Treatment Recommendations for Physicians, Disease Management Consensus
Statement, 2008.
– Wheel-chair bound  bed ridden (EDSS 7.0 – 9.5)
• Skin care and usual DVT prophylaxis indicated in these
cases.
In 2008, only interferon and glatiramer acetate were available for a first
attack. This statement applies to Disease Modifying Therapy in general.
National Clinical Advisory Board of the National Multiple Sclerosis Society (NMSS), Treatment Recommendations for Physicians, Disease Management Consensus Statement 2008. http://www.nationalmssociety.org/ms‐clinical‐care‐
network/clinical‐resources‐and‐tools/publications/expert‐opinion‐papers/index.aspx
EDSS=expanded disability status scale.
Milo R, Kahana E. Autoimmun Rev. 2010;9(5):A387‐94. Handel AE, et al. PLoS One. 2011;6(1):e16149. 7
Currently Available Disease Modifying Therapies
Glatiramer Acetate
Natalizumab
Disease Modifying Therapies
Dimethyl Fumarate
(BG 12)
Mitoxantrone
IFNβ-1b
1990
Fingolimod
1995
IFNβ-1a
2000
IFNβ-1a
(SQ)
2005
2010
2015
Teriflunomide
Drug
Dose
Route
Frequency
Low-dose IFNβ-1a
30 mcg
IM
Weekly
High-dose IFNβ-1b
250 mcg
SC
Every other day
High-dose IFNβ-1a
22 mcg or 44
mcg
SC
3x weekly
Glatiramer acetate
20 mg
SC
Daily
Natalizumab
300 mg
IV
Monthly
Mitoxantrone
12 mg/m2
IV
Every 3 months
Fingolimod
0.5 mg
Oral
Daily
Teriflunomide
7 mg or 14 mg
Oral
Daily
Dimethyl fumarate (BG 12)
240 mg
Oral
Twice daily
Drugs@FDA. FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm Efficacy of Disease Modifying Therapies
Drug
Annualized Relapse Rates (ARR)
Placebo
0.41 – 1.382
Low-dose IFNβ-1a (IM)
0.333 – 0.704
High-dose IFNβ-1b
0.365 – 0.846
High-dose IFNβ-1a (44 mcg)
0.307 – 0.888
Glatiramer acetate
0.297 – 0.819
Natalizumab
0.2610
Mitoxantrone
0.4211
Fingolimod
0.181
Teriflunomide
0.3712
Dimethyl fumarate (BG 12)
0.1713
Efficacy – MRI
Dimethyl fumarate (BG12)
Note: ARRs have decreased over the last decade in both treatment & placebo groups.14
Placebo
Natalizumab
INFβ-1a SQ*
INFβ-1a IM
Glatiramer acetate
Fingolimod
0
1. Kappos L, et al. N Engl J Med. 2010;362:387‐401. 2. Bornstein MB, et al. N Engl J Med. 1987;317:408‐414. 3. Cohen JA, et al. N Engl J Med. 2010;362:402‐415. 4. Durelli L, et al. Lancet. 2002;359:1453‐1460. 5. O’Connor P, et al. Lancet Neurol. 2009;8:889‐897. 6. IFNB Multiple Sclerosis Study Group. Neurology. 1993;43:655‐661. 7. Mikol DD, et al. Lancet Neurol. 2007;7:903‐914. 8. PRISMS Study Group. Lancet. 1998;352:1498‐1504. 9. Comi G, et al. Ann Neurol. 2001;49:290‐297. 10. Polman C, et al. N Engl J Med. 2006;354:899‐910. 11. Hartung HP, et al. Lancet. 2002;360:2018‐25. 12. O’Connor P, et al. N Engl J Med. 2011;365:1293‐1303. 13. Gold R, et al. N Engl J Med. 2012;367:1098‐107. 14. Inusah S, et al. Mult
Sclerosis. 2010;16:1414‐1421.
0.5
1
1.5
2
2.5
3
Mean (*Median) Number of Enhancing Lesions
Kappos L, et al. N Engl J Med. 2010;362:387‐401.
Rovaris M, et al. Mult Sclerosis. 2007;13:502‐508. Jacobs LD, et al. Ann Neurol. 1996;39:385‐394.
Li DKB, et al. Ann Neurol. 1999;46:197‐206.
Treatment of the First Clinical Event Suggestive of MS
Polman C, et al. N Engl J Med. 2006;354:899‐910.
O’Connor P, et al. N Engl J Med. 2011;365:1293‐1303.
Hartung HP, et al. Lancet. 2002;360:2018‐25.
Gold R, et al. N Engl J Med. 2012;367:1098‐107. MOA of Interferon β
and Glatiramer Acetate
• Multicenter, double-blind, placebo-controlled, randomized
trials of DMTs in CIS
•
•
•
•
Active
Mitoxantrone
Teriflunomide 14 mg
CHAMPS1 – IFNβ-1a IM
ETOMS2 – IFN β -1A SQ
BENEFIT3 – IFN β -1b
PreCISe Study4 – GA
Agent
Drug Class
IFNβ
Immune
Modulation
Glatiramer
Acetate
Immune
Modulation
Mechanism of Action (MOA)
 Reduces proinflammatory
cytokine levels and increases levels of
anti-inflammatory mediators
 Induces a shift from TH1 to TH2 cells
• Efficacy of DMTs on the rate of conversion to CDMS has
been evaluated.
• The IFNβ-1a IM, IFNβ-1b and GA are approved for the CIS
indication.
DMT=disease modifying therapy
CIS=clinically isolated syndromes
GA=glatiramer acetate
IFN=interferon
CDMS=clinically definite multiple sclerosis. TH1 = proinflammatory T‐cells; TH2 = antiinflammatory T‐cells.
1. Jacobs LD, et al. N Engl J Med. 2000;343(13):898–904. 2. Comi G, et al. The Lancet. 2001;357(9268):1576–1582. 3. Kappos L, et al. Neurology. 2006;67(7):1242–1249.
4. Comi G, et al. The Lancet. 2009;374(9700):1503–1511.
Drugs@FDA. FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Kieseier BC. CNS Drugs. 2011;25(6):491‐502. Blanco Y, et al. Neurosci Lett. 2006;406(3):270‐275; Weber MS, et al. Neurotherapeutics. 2007;4(4):647‐653. Aharoni R, et al. Proc Natl Acad Sci USS. 2008;105(32):11358‐11363; Sarchielli P, et al. Mult Scler. 2007;13(3):313‐331.
8
Safety Considerations Glatiramer Acetate and Interferon β
Agent
IFNβ-1a
Common Side Effects
Pregnancy
Category
Liver
Monitoring
Laboratory
Monitoring
Depression, decreased
peripheral blood counts,
anaphylaxis, hepatic injury, flulike symptoms, asthenia, anemia,
headache, gastrointestinal upset
C
+
Required
Glatiramer acetate (n=101)
90%
90%
78%
80%
High dose IFNβ-1a/ High
dose IFNβ-1b (n=93)
67%
70%
60%
50%
C
+
Required
21%
20%
10%
10%
B
_
1.7%
1%
0%
Not
required
Low dose IFNβ-1a (n=79)
40%
40%
30%
Injection-site and post-injection
reactions, vasodilatation, chest
pain, asthenia, pain, nausea,
infections, arthralgia, anxiety,
hypertonia
Glatiramer
Acetate
Results from an open-label study conducted by chart review and
interviews of patients receiving MS therapies over 5 years
100%
Depression, injection-site
necrosis, anaphylaxis, hepatic
injury, injection-site reactions, flulike symptoms, hematologic
abnormalities
IFNβ-1b
Injection‐Site Reactions
Local ISRs
Lipoatrophy
1.7%
Skin Necrosis
FDA-approved labeling includes up to 3 years of clinical data.
ISRs = injection site reactions
This study included an analysis of additional adherence factors. Caon C, et al. Mult Scler. 2008;14(suppl 1):S36.
Drugs@FDA. FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
MOA of Other
Disease Modifying Therapies
Agent
Drug Class
Mechanism of Action (MOA)
Natalizumab
Cell Trafficking
Fingolimod
Cell
Sequestration
 Strongly reduces proinflammatory cell
recruitment to the CNS
 Significantly decreases the number of
lymphocytes from leaving the lymph nodes
and entering the bloodstream and CNS
compartment
Teriflunomide
Immune
Modulation
 An immunomodulatory agent with
anti-inflammatory properties that inhibits
“de novo” pyrimidine synthesis
Dimethyl fumarate Immune
(BG 12)
Modulation
Natalizumab – Safety
• Most common side effects:
– Headache, fatigue, arthralgia, UTI, lower respiratory
tract infection, gastroenteritis, vaginitis, abdominal
discomfort, diarrhea NOS, and rash
• Hepatotoxicity
• Risk of progressive multifocal
leukoencephalopathy (PML)
 Inhibits the expression of adhesion
molecules and proinflammatory cytokines
– Opportunistic viral infection of the brain that usually
leads to death or severe disability
– Only available through a restricted distribution
program (TOUCH® Program)
 Induces a shift from TH1 to TH2 cells
TH1 = proinflammatory T‐cells; TH2 = antiinflammatory T‐cells.
Drugs@FDA. FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Lopez‐Diego RS, et al. Nat Rev Drug Discov. 2008;7(11):909‐920. Kappos L, et al. N Engl J Med. 2010;362(5):387‐401.
Claussen MC, Korn T. Clin Immunol. 2012;142(1):49‐56. Kappos L, et al. Lancet. 2008;372:1463‐1472. Gold R, et al. Presented at WCTRIMS, Montréal, Canada, September 17‐20, 2008. [P50] Gasperini C, et al. Expert Opin Emerg Drugs.
2008;13:465‐477.
UTI=urinary tract infections; NOS=not otherwise specified
Drugs@FDA. FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.
Incidence of PML Related to Natalizumab
Safety Considerations
Stratified by Known Risk Factors
ANTI‐JCV ANTIBODY POSITIVE
No prior IS use
Agent
Common Side Effects
Natalizumab
PML, infections,
hypersensitivity reactions,
hepatotoxicity/ headache,
fatigue, arthralgia, UTIs,
gastroenteritis, vaginitis,
depression, others
<2 years
<1/1000
2/1000
>2 years
>2 years
4/1000
11/1000
JCV=John Cummings Virus; IS=immunosuppressant
Safety Precautions
C
 Monitor for signs of PML and
infection
 Monitor liver enzymes
Fingolimod
Skin malignancies, cardiac
arrythmia, macular edema,
HTN, Herpes infections,
leukopenia, headaches,
increased liver enzymes,
diarrhea
C
 VZV vaccination in antibody-negative
patients before treatment initiation
 During initiation of treatment
monitoring for alterations of cardiac
rhythm
 Monitor for signs of infection, macula
edema and dermatological changes
 Regular blood monitoring, including
liver enzymes
Teriflunomide
Potential hepatototicity,
teratogenicity, hair thinning,
GI symptoms, paresthesia,
UTIs, neutro- & lymphopenia
X
 Regular blood monitoring, including
liver enzymes.
 Monitoring for signs of infection.
Dimethyl Fumarate
(BG12)
Lymphopenia, GI symptoms,
flushing, pruritus
C
 CBC baseline and once a year
 Monitor for signs of infections
With prior IS use
<2 years
Pregnancy
Category
VZV=varicella‐zoster virus
Drugs@FDA. FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Clifford DB, et al. The Lancet Neurology. 2010;9(4):438–446. Drugs@FDA. FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
9
Indication for Use of
Disease Modifying Therapies
Indication for Use of
Disease Modifying Therapies
Agent
Indication
Comments
Agent
Indication
Comments
IFNβ
Reduce frequency of relapses in
RRMS
 First-line therapy
Mitoxantrone
Reduce frequency of
relapses in RRMS and
slow neurologic disability
 Not generally considered a first-line
therapy
Glatiramer Acetate
Reduce frequency of relapses in
RRMS
 First-line therapy
Natalizumab
Reduce frequency of relapses in
RRMS and slow physical disability
 Not considered first line unless
patient has severe disease
Fingolimod
 Dose is titrated up over a few
weeks
Reduce frequency of relapses in
RRMS and slow physical disability
 Avoid use in MS patients with liver
dysfunction
 First-line therapy
Teriflunomide
 Avoid in patients with recent
(≤6 months) MI, UA, stroke,
TIA, decompensated HF
requiring hospitalization or
Class III/IV HF
Dimethyl
fumarate (BG 12)
RRMS = relapsing‐remitting multiple sclerosis; MI = myocardial infarction; UA = unstable angina; TIA = transient ischemic attack; HF = heart failure.
Drugs@FDA. FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Wells, B. (2011). Neurological Disorders: Multiple Sclerosis. In LR Talbert, JT DiPiro, et al, Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY:McGraw‐Hill; National Multiple Sclerosis Society. Disease Management Consensus Statement. 2008, http://www.nationalmssociety.org. Accessed April 28, 2013. – 718 patients treated with either IFN-β-1b or placebo for 3 years
– Primary outcome = time to progression in disability*
• Significant difference in time to progression favoring IFN-β-1b
(p=0.0008)
• Other trials with IFN-β-1b, IFN-β-1a or Glatiramer Acetate
failed to confirm this
• Existing and new DMTs are being studied
Treatment Considerations Evolving
Medical History/
Comorbidities
•
•
•
•
•
•
•
•
•
•
Hepatic/renal
dysfunction
Depression
Diabetes
Cardiovascular
disorders
Other autoimmune
diseases
(including thyroid)
Infections
Varicella history
Hematologic
disorders
Current/prior
cancers
Prior
immunosuppressive
treatment
Pulmonary
disorders
Safety/
Tolerability
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Flu-like symptoms
Depression
Hepatic injury
ISRs
Lipoatrophy
PML
IPIRs
Immunosuppression
Opportunistic
infections
Malignancies
Bradycardia
Macular edema
Pulmonary function
Autoimmune
thyroiditis
ITP
Lifestyle
Considerations
Monitoring
•
•
•
•
•
•
•
•
•
•
Liver function tests
Thyroid function
Signs of hepatic
injury
Cardiac evaluations
Blood cell counts
Pulmonary
evaluations as
clinically indicated
Blood pressure
tests
Ophthalmologic
evaluations
JCV antibody status
MRI
•
•
•
•
•
•
•
 Favorable side-effect profile and improved
efficacy makes it an appealing alternative
to current first-line agents
Drug
Dose
IFNβ-1a (Avonex®)
30 mcg IM once per week
Cost per Month
 $3,745
IFNβ-1a (Rebif®)
22 mcg or 44 mcg SC 3x per
week
 $3,500
IFNβ-1b (Bestaseron® or Extavia®)
0.25 mg SC every other day
 $3,500-$3,740
Glatiramer Acetate (Capaxone®)
20 mg SC once daily
 $4,000
Mitoxantrone (Novantrone®)
12 mg/m2 IV every 3 months
 $1,500
Natalizumab (Tysabri®)
300 mg IV every 4 weeks
 $3,800
 $4,400
Fingolimod (Gilenya®)
0.5 mg PO once daily
Teriflunomide (Aubagio®)
7 mg or 14 mg PO once daily
 $3,400
Dimethyl Fumarate (Tecfidra®)
120mg PO twice daily x 7 days;
then 240mg PO twice daily
 $5,000
Monitoring DMT Safety and Efficacy Safety in MS Patients
Snapshot:
•
Reduce frequency of
relapses in RRMS
 Favorable side-effect profile offers an
alternative to current first-line agents
IM = intramuscular; SC = subcutaneous; PO = by mouth.
Drugs@FDA. FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Hester SA. Drug Treatments for Multiple Sclerosis. Pharmacist Letter. November 2012.
*defined as a 1.0 increase in EDSS from baseline or 0.5 increase if baseline EDSS was 6.0 or 6.5
Kappos L. and European Study Group on Interferon beta‐1b in Secondary Progressive MS. The Lancet. 1998;352(9139):1491–1497.
CIS
RRMS
Disease severity
EDSS
Lesion load/location
Level of cognitive
impairment
 Comparable efficacy to IFNβ
Cost Considerations
• The effects of IFN-β or Glatiramer Acetate in secondary
progressive multiple sclerosis are controversial.
• The European Study Group on IFN-β-1b in Secondary
Progressive MS trial
•
•
•
•
•
•
Reduce frequency of
relapses in RRMS
RRMS = relapsing‐remitting multiple sclerosis; LVEF = left ventricular ejection fraction.
Drugs@FDA. FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Thöne J, Ellrichmann G. Drug Healthc Patient Saf. 2013;5:37‐47. Treatment of progressive multiple sclerosis
Disease Stage
 Cumulative lifetime dose=140 mg/m2 due
to potential cardiac effects such as
decreased in LVEF
• Safety
Age
Weighing impact of
side effects
Childbearing
potential
Employment status
Support system
Finances
Compliance
–
–
–
–
–
–
–
–
–
–
CIS=clinically isolated syndrome; EDSS=Expanded Disability Status Scale; ISR=injection‐site reaction; PML=progressive multifocal leukoencephalopathy; IPIR=immediate postinjection reaction; ITP=idiopathic thrombocytopenic purpura; JCV=John Cunningham virus; MRI=magnetic resonance imaging.
1. COPAXONE® prescribing information. Teva Neuroscience, Inc. 2. Avonex® prescribing information. Biogen Idec Inc. 3. Betaseron® prescribing information. Bayer HealthCare Pharmaceuticals Inc. 4. Rebif® prescribing information. EMD Serono, Inc. 5. Tysabri® prescribing information. Biogen Idec Inc. 6. Extavia® prescribing information. Novartis Pharmaceuticals Corporation. 7. Gilenya® prescribing information. Novartis Pharmaceuticals Corporation. 8. Marrie RA, et al. Mult Scler. 2008;14(8):1091‐1098. 9. Kieseier BC, et al. Nat Rev Neurol. 2011;7(5):255‐262. 10. Hartung H‐P, et al. Expert Rev Neurother. 2011;11(3):351‐362.
Liver function tests
Thyroid function
Signs of hepatic injury
Cardiac evaluations
Blood cell counts
Pulmonary evaluations as
clinically indicated
Blood pressure tests
Ophthalmologic evaluations
JCV antibody status
MRI
• Efficacy
– Relapse frequency
– Changes in EDSS
– MRI findings
JCV=John Cummings Virus; MRI=magnetic resonance imaging; EDSS= Expanded Disability Status Score
10
Monitoring of DMT
Monitoring of DMT Cont’d
Agent
Laboratory Tests
Frequency
Glatiramer Acetate
None Required
NA
IFNβ-1a
Liver
Thyroid
1, 3, and 6 months initially and then periodically
Every 6 months in pts with hx of thyroid dysfunction
IFNβ-1b
CBC
Liver
1, 3, and 6 months initially and then periodically for: CBC
with differential WBC and platelet counts; blood
chemistries, and liver function tests
Agent
Fingolimod
Baseline MRI and JCV antibody every 6 months;
Evaluate the patient 3 months after 1st infusion, 6 months
after 1st infusion, and every 6 months thereafter.
PML Monitoring
Natalizumab
Liver
Teriflunomide
Monthly liver panel for 12 months, quarterly indefinitely in
pts with normal liver panel,
Discontinue drug if AST/ALT ≥3x ULN or total bilirubin ≥2x
ULN; Monthly liver panel indefinitely for patients with
elevated AST/ALT or bilirubin but with values below the
threshold (AST/ALT <3x ULN and billirubin <2x ULN)
Dimethyl
Fumarate
(BG12)
Laboratory
Tests
Frequency
Comments
ECG for bradycardia ≥6 hrs after 1st
dose, overnight continuous ECG in pts
at high risk of bradycardia, heart block,
or prolonged QTc interval at baseline;
baseline CBC; baseline eye exam and
another 3-4 months after initiating
therapy; Baseline liver panel
Women of childbearing
potential should use
effective contraception
during and for 2 months
after stopping drug
Liver; CBC; BP
Baseline liver transaminase and bilirubin
levels within 6 mon prior initiating drug;
Baseline CBC; Baseline BP
Monitor renal function
and potassium;
Pregnancy Category X –
women of childbearing
potential should use
effective contraception
CBC
CBC baseline and once a year
May cause lymphopenia
ECG; CBC; Eye;
Liver
JCV=John Cunningham virus. Drugs@FDA. FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Department of Veterans Affairs ‐ Multiple Sclerosis Center of Excellence. Natalizumab and Hepatotoxicity with Multiple Sclerosis. Wallin, M and Whitham. Available at:
http://www.va.gov/ms/articles/Natalizumab_and_Hepatotoxicity_with_Multiple_Sclerosis.asp. Accessed April 16, 2013. Drugs@FDA. FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Response to Disease Modifying Therapy
Predictors of Disability Progression
MRIs annually vs. ”treat the patient not the scan”
MRI Activity
Clinical Activity
Frequency
of relapse
Is it >1/yr ?
Is the EDSS >4?
Is there sustained
increase in EDSS?
MRI:
Are there
Gd+ lesions?
MRI:
MRI:
MRI:
Are there
new T2 lesions?
Are there new
black holes?
Is there increase
in brain atrophy?
Frequency of relapse
If the answer is No – the treatment is adequate.
However, if Yes ‐ consider and discuss alternative DMT
EDSS=expanded disability status scale.
Confavreux C, et al. Brain. 2003;126:770‐782.
Brex PA, et al. N Engl J Med. 2002;346:158‐164.
Tomassini V, et al. J Neurol. 2006;253:287‐293.
Tintore M, et al. Neurology. 2006;67:968‐972.
Paolillo A, et al. J Neurol. 2004;251:432‐439.
Rudick RA, et al. Ann Neurol. 2006;60:236‐242.
Time to CDMS
T1 T2 Gd+ Brain lesions lesions black atrophy
holes
Physical Disability Progression
Weinshenker BG, et al. Brain. 1989;112:1419‐1428.
Fisher E, et al. Neurology. 2002;59:1412‐1420. National MS Society Website. Magnetic Resonance Imaging. http://www.nationalmssociety.org/about‐multiple‐
sclerosis/what‐we‐know‐about‐ms/diagnosing‐
ms/magnetic‐resonance‐imaging‐mri/index.aspx. Accessed
April 18, 2013.
CDMS = clinically definite multiple sclerosis.
Confavreux C, et al. Brain. 2003;126:770‐782. Brex PA, et al. N Engl J Med. 2002;346:158‐164.
Tomassini V, et al. J Neurol. 2006;253:287‐293.
Tintore M, et al. Neurology. 2006;67:968‐972. Summary
Patient Cases
• MS is a common neurological disorder with approximately 200 new
cases diagnosed each week
• Diagnosis of MS involves assessment of neurological symptoms, MRI
evidence, and/or laboratory tests
• Over time, diagnostic criteria have evolved to allow for earlier
diagnosis and treatment
• Because it is impossible to predict how any individual MS patient will
progress over time, initiation of treatment with an approved first-line
therapy should be considered as soon as possible following a
definitive diagnosis of MS
• Treatment response should be assessed regularly – both clinically and
radiologically
• Awareness of suboptimal response and treatment failure signs is
paramount for optimal management of MS patients
• New DMTs, including oral, are emerging. Safety considerations remain
very important in choosing DMT strategy
11
Paolillo A, et al. J Neurol. 2004;251:432‐439.
Rudick RA, et al. Ann Neurol. 2006;60:236‐242.
Weinshenker BG, et al. Brain. 1989;112:1419‐1428.
Fisher E, et al. Neurology. 2002;59:1412‐1420.
Case 1 Continued
Case 1
• 33-year-old woman, housewife and mother of 2 children ages
4 years and 14 months, was previously healthy until June
2011 when she experienced Optic Neuritis affecting the right
eye (blurred vision, right ocular and frontal pain). She was
seen by an ophthalmologist. Symptoms dissipated gradually
without treatment in about 3 weeks.
• Since the uneventful birth of her second child in
March 2012, she has experienced unusual and
persistent overwhelming fatigue. Patient denied
bladder, bowel or sexual dysfunction.
• She was worked in by her Family Physician
(PCP) to be seen next morning. Blood work was
performed and referred immediately to a
neurologist in the same building .
• In June 2012 she acutely developed a “strange” feeling
around the neck and tingling of the legs. Although she felt a
little unsteady while walking, there was no overt motor
weakness of the lower extremities. There was no fever,
malaise or any other associated symptom.
Case 1 Continued
Case 1 Continued
• Social: Worked briefly as accountant until she got pregnant with her first
child.
• Medical History: good health., no surgical antecedents. She recalls having had Infectious Mononucleosis during adolescence. • Habits: Smokes ½ pack of cigarettes/day since College. Quit
intermittently during pregnancies. No drugs or alcohol abuse.
• PE:
• Medications: Oral contraceptive and multivitamins. – BP 120/70 mm Hg
Wt. 158 lbs., Height 5’5 (BMI =26.5)
– General Examination = Unremarkable. Neurological Examination:
Mental Status, Cranial Nerves and Speech normal. Decreased
sensation to light touch and pinprick from upper chest down to legs.
Reflexes slightly hyperactive in LE’s. Gait normal but tandem
walking is unsteady.
• Labs: CBC, Chemistry, RA Factor, ANA, ACE, Sjögren’s antibodies all
normal or negative.
RA=rheumatoid arthritis ANA=antinuclear antibody ACE=angiotensin converting enzyme
Case 1 – Question 1
?
MRI STUDIES
This patient has experienced two separate
neurological events and has objective findings to
examination. In this clinical setting what tests
are indicated to make the appropriate
diagnosis?
1.
2.
3.
4.
5.
Brain MRI and MRA of neck vessels
Brain and Spinal Cord MRI, CSF and VEP
Spinal cord MRI and Electromyography of legs
Only spinal cord MRI or CT scan of spine
Only brain MRI
CSF study showed 5 Oligoclonal Bands.
VEP showed slowing of conduction on right Optic Nerve.
12
Case 1 – Question 2
?
Case 1 Cont’d
•
How should this patient be treated for this
acute relapse?
•
•
•
1. Epidural methylprednisolone acetate suspension
injections in upper neck
2. The patient should simply be observed (no Rx)
3. Intravenous methylprednisolone pulses (1000 mg
each) for three days with or without oral taper with
methylprednisolone or prednisone
4. Oral low-dose chemotherapy
5. Extensive physical therapy without medications
Case 1 – Question 3
•
The patient has no cardiac, liver, or laboratory
abnormalities that are concerns for treatment of
her MS with chronic therapy.
The patient plans to quit smoking.
She is not sure if she will have more children.
She expressed substantial phobia to needles
and would decline injectable therapies.
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Case 2
• 45-year-old male, trial lawyer, single. Was diagnosed
with Relapsing/Remitting MS at age 39 after he had an
episode of vertigo, double vision and ataxia. Brain MRI
showed 9 T2 lesions at that time, some enhancing after
intravenous contrast. CSF showed 3 Oligoclonal Bands.
VEP was normal. After IV steroids he was initiated on
interferon beta 1-a high dose with poor tolerance due to
persistent side effects (flu-like symptoms) leading to lack
of adherence.
Which of the treatment options is most
appropriate for the patient at this time?
1. She is a good candidate for oral fingolimod
2. Traditionally a SC interferon should be tried first
3. Occasional intramuscular injections of interferon could
be considered until the fear to needles is overcome
4. Once a month Intravenous natalizumab could be
offered as alternative
5. The patient can wait until next attack then use
glatiramer acetate
• He had a relapse at age 41 with significant leg weakness
and residual spastic gait (EDSS 3.5). His daily activities
have been substantially affected since. MRI showed
more lesions in brain and 2 in the thoracic spinal cord.
He received intravenous steroids and was switched to
glatiramer acetate daily injections.
Case 2
Last MRI Study ‐ EDSS 4.5
• Despite treatment with glatiramer acetate and
adequate adherence, the patient has continued
to have relapses about one per year with
increasing EDSS (4.5) and MRI burden of
disease. His neurologist suggests natalizumab
as second line therapy. JC Virus antibody test
ordered. The patient never has been exposed to
immunosuppressive agents.
Gd-enhancing
T2-hyperintense
Increased burden of disease
Active lesions
JC=John Cunningham virus
13
Case 2 Continued
Case 2 Continued
• Social: Voluntary work with the NMSS
• Habits: None
• PE:
– BP 130/78 mm Hg Wt.178 lbs. Height 5’9 (BMI=26.3)
– Normal mental status and speech.
– Mild horizontal nystagmus without diplopia. Spastic
paraparesis 4/5 with abnormal gait. Exaggerated reflexes
and bilateral Babinski signs. Decreased vibration sense
in toes.
• Labs: Periodic CBC and general chemistry with liver
function tests = normal. JC Virus Antibody test = positive.
• Medical History: Unremarkable. He had a
concussion playing football in College.
Vitamin D level was low in two separate
occasions.
• Medications: Glatiramer acetate 20 mg SC
daily; Baclofen 10 mg tid for spasticity;
Fampridine 10 mg bid for walking;
Vitamin D3 2000 IU daily.
Case 2 – Question 1
•
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Case 2 – Question 2
The patient is considered for natalizumab
therapy. All of the following are reasons to
use natlizumab for second line (rescue)
therapy except:
The patient is considered for natalizumab therapy. He never
received chemotherapy but he is JCV antibody positive.
The discussion regarding risk for Progressive
Multifocal Encephalopathy (PML) should include:
1.
2.
3.
4.
Failure to tolerate a first line therapy
Failure to respond to a first line therapy
Persistent relapsing disease
Increasing disability and burden of disease
by worsening MRI
5. Absence of JCV antibodies
Case 2 – Question 3
?
1.
2.
3.
4.
Risk of > 100/1000
Risk of <1/1000
Natalizumab is generally contraindicated in this setting
The patient can be treated but therapy should be for
less than a year then resume glatiramer acetate
5. Natalizumab could be added to glatiramer acetate as
combination therapy
?
Outcomes Question #1
Which of the following criteria are required
for a diagnosis of MS?
The patient is considered for natalizumab therapy. He
never received chemotherapy but he is JCV
positive. The discussion regarding PML risk should
include which of the following?
1. A single clinical episode and characteristic visual
evoked potential (VEP) findings
2. A single clinical episode and evidence of a
plaque anywhere in the CNS
3. Evidence of plaques in at least two different
locations in the CNS and evidence that plaques
occurred at different points in time
4. Evidence of plaques in at least two different
locations in the CNS regardless of when they
developed
1. Risk increases after 25 infusions therefore closer
follow-ups and MRIs are in order
2. Current predictive data is not reliable
3. Natalizumab is the only MAB that causes PML
4. Natalizumab beneficial effects last 24 months
14
?
Outcomes Question #2
?
Outcomes Question #3
When should disease-modifying MS
therapies be initiated?
Which of the following signs indicate MS
disease progression and/or the need to
adjust disease-modifying therapy?
1. After a first attack
2. At definite diagnosis of MS with active,
relapsing disease
3. For acute exacerbations
4. For incomplete remission from acute
exacerbations
1. New T2 lesions on MRI
2. Gadolinium-negative lesions on MRI
3. No improvement in Expanded Disability
Status Scale (EDSS)
4. No decrease in frequency of relapse
Question & Answer
15
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