introduction what is multiple sclerosis? chronic progressive autoimmune disease immune system...
TRANSCRIPT
Introduction
What Is Multiple Sclerosis?• Chronic progressive autoimmune disease • Immune system attacks the myelin sheath on nerve fibers in the
brain and spinal cord (CNS)• May lead to focal areas of damage, axon injury, axon
transection, neurodegeneration, and subsequent scar or plaque formation
Nucleus
Soma
Dendrite
Myelin Sheath (With Axon Through It)
Schwann Cell
Node of Ranvier
Axon Terminal
Graphic by Quasar Jarosz at en.Wikipedia.org
What the Primary Care Clinician Needs to Know About MS
• Common presenting symptoms of demyelinating disease– For example, what is CIS, optic neuritis, brain stem
syndrome, etc
• How the diagnosis of MS is made• Early symptoms that trigger need to refer patient to
neurologist• How to classify MS• How to manage treatment of MS/monitor MS patients
(and what to monitor for)• How to manage treatment side effects
PIK NW Regional Survey (N = 50)Barriers to Diagnosis and Treatment
• Lack of clinician knowledge about MS, its diagnosis, and treatments
• Infrequency of MS in primary care populations• Lack of time, especially since patients have other
complaints to address• Absence of screening tools• Financial/insurance-related obstacles• Side effects of treatment• Patients’ psychosocial status and lack of support• Poor adherence to treatment
Addressing Local Needs• To address the needs identified in the local survey,
this activity provides education regarding the following MS topics:– Risk factors– Pathogenesis– Diagnostic criteria– Role of imaging– Efficacy, safety, and initiation of current therapies– Efficacy and safety of emerging therapies– Monitoring for response, adherence, and tolerability of
therapy– Management of MS symptoms
What Factors Contribute to the Risk for MS?
Compston A, et al. McAlpine’s Multiple Sclerosis, 4th ed. Churchill Livingston; 2006. HauserSL, et al. Multiple Sclerosis. In: Fauci AS, et al. Harrison’s Principles of Internal Medicine. Available at: http://www.accessmedicine.com/content.aspx?aID=2906448. Accessed on: February 19, 2010.
Prevalence~350,000 persons in the United States
Sex distribution ~75% female
Age at onsetTypically 20−40 years,
but can present at any age
Ethnic origin Predominantly Caucasian
MS Epidemiology
MS
Immune Dysregulation
Genetic Predisposition Environmental Factors
Graphic courtesy of Suhayl Dhib-Jalbut, MD.
Multiple SclerosisAn Immunogenetic Disease
Hauser SL, et al. Multiple Sclerosis. In: Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. Available at: http://www.accessmedicine.com/content.aspx?aID=2906445. Accessed on: February 19, 2010. Willer CJ, et al. Proc Natl Acad Sci U S A. 2003;100:12877-12882.
Ap
pro
xim
ate
Pro
ba
bil
ity
of
Dev
elo
pin
g M
S
05
101520253035404550
IdenticalTwin
FraternalTwin
Sibling Parent orHalf-
Sibling
FirstCousin
Spouse NoFamily
Member
25%
5% 3%2%
1% 0.1% 0.1%
Evidence for Genetic Basis of MS
Evidence for Environmental Basis of MS
• No evidence of MS prior to 1822 (~ onset of industrial revolution in Europe)
• Change in the gender ratio over time• These changes (eg, gender ratio, increasing incidence) took
place over ~ 30 years (1–2 generations)—too fast for a genetics cause
• Increased incidence of MS in many regions (especially in women)– When individuals migrate before age 15 from a region of high MS
prevalence to one of low prevalence (or vice versa), they seem to adopt a prevalence similar to that of the region to which they moved
– When they make the same move after age 15, they seem to retain the risk of the region from which they moved
Multiple Sclerosis What Are the Environmental Factors?
• Many environmental factors have been proposed
• Two currently popular candidates for involvement in MS pathogenesis are:– Epstein-Barr virus (EBV) infection– Vitamin D deficiency (sunlight exposure)– Cigarette smoking
• These are hypotheses—not proven facts!– Either, neither, or both may be correct
1. Sumaya, 1980. 2. Bray, 1983. 3. Larson, 1984. 4. Sumaya, 1985. 5. Shirodaria, 1987. 6. Munch, 1998. 7. Myhr, 1998. 8. Wagner, 2000. 9. Ascherio, 2001. 10. Sundström, 2004. 11. Haahr, 2004. 12. Ponsonby, 2005.
Evidence for EBV
• Indirect evidence– Late EBV infection is associated with MS– Symptomatic mononucleosis is associated with MS
• Direct evidence– 10 out of 12 studies found a significantly higher rate of EBV
positivity in MS patients than in controls1-12
– When data from these 12 trials are combined (N = 4155), EBV positivity is found in 99.5% of MS patients vs 94.2% of controls (P <10-23)
1. Munger KL, et al. Neurology. 2004;62:60-65. 2. Van der Mei IA, et al. J Neurol. 2007;254:581-590. 3. Van der Mei IA, et al. BJM. 2003;327:316. 4. Munger KL, et al. JAMA. 2006;296:2832-2838.
Direct Evidence for Vitamin D
• >185,000 women interviewed about their diet: Those in highest quintile of vitamin D consumption had significantly less new-onset MS compared with lowest quintile1
• Study of MS patients and controls from Tasmania found significant negative association between total sun exposure during childhood (especially in those 6–10 years old) and adolescence and the subsequent development of MS2,3
• Evaluation of stored serum samples from 257 MS patients and 514 matched controls (US Military) showed the risk of MS was significantly decreased in those with increased serum vitamin D3 levels4
Cigarette Smoking and MS
• Several cohort and case-control studies have suggested that cigarette smoking nearly doubles the risk of MS1-3
– Risk increases with cumulative smoking “dose”2
• Parental smoking also doubles the risk of MS in children who are passively exposed to the smoke4
• Smokeless tobacco has not been found to increase MS risk1,2
– Implies that non-nicotinic components of cigarette smoke are responsible
1. Carlens C, et al. Am J Respir Crit Care Med. 2010;Mar 4:epub ahead of print. 2. Hedström AK, et al. Neurology. 2009;73:696-701. 3. Riise T, et al. Neurology. 2003;61:1122-1124. 4. Mikaeloff Y, et al. Brain. 2007;130(pt 10):2589-2595.
Risk Factors for MSSummary
• MS is caused by a complex interaction of genetic and environmental factors– In someone with an affected identical twin, risk of MS is
25%, suggesting that genetics play a role in susceptibility but are not the complete story
• Vitamin D insufficiency, EBV infection, and cigarette smoking have shown possible links to MS– This research is thought-provoking, but these factors have
not been definitely proven as causes of MS
Pathophysiology of MS
• Acute Inflammation Relapses
• Neuronal Degeneration Disability
Pathophysiology of MS
1. Dhib-Jalbut S. Neurology. 2007;68:S13-S21. 2. Viglietta V, et al. J Exp Med. 2004;199:971-979.
Immune Dysregulation in MST Cells
• T cells normally recognize specific antigens – CD8+ T cells destroy infected cells – CD4+ T cells release cytokines that mediate inflammatory
and anti-inflammatory responses
• T cells reactive to myelin are found in MS lesions, blood, and cerebrospinal fluid– CD8+ T cells transect axons, induce oligodendrocyte death,
promote vascular permeability1
– There is a cytokine imbalance in MS, favoring secretion of inflammatory (Th1) cytokines
– T cells that normally regulate immune function have reduced activity in MS2
IFN-g, IL-12, TNF IL-4, IL-10, TGFß
Inflammatory Anti-inflammatory
IFN-g, IL-12, TNF
IL-4, IL-10,TGFßInflammatory
Anti-inflammatory
Normal
MS
TH1 TH2
TH1
TH2
Cytokine Imbalance in MS
Graphic courtesy of Suhayl Dhib-Jalbut, MD.
1. Uccelli A, et al. Trends Immunol. 2005;26:254-259.
Immune Dysregulation in MSB Cells
• In some MS patients, ectopic lymphoid follicles have been found in the meninges1
• Mechanisms of B cells in MS may include:– Antimyelin antibody production– Antigen presentation to autoreactive T cells– Proinflammatory cytokine production
Immune Dysregulation in MSOther Involved Cells
• Natural killer (NK) cells– May play opposing roles as both regulators and inducers of disease
relative to cytokine environment and cell:cell contact– NK cell function may be lost during clinical relapse
• Monocytes– Secrete IL-6 (promotes B cell growth) and IL-2 (aids differentiation
of Th1 cells)
• Macrophages– Phagocytic activity may contribute to demyelination
• Microglia– Specialized macrophages in the CNS, also may contribute to T cell
activation
1. Trapp BD, et al. N Engl J Med. 1998;338:278-285. 2. Trapp BD. Neuroscientist. 1999;5:48-57.
Neurodegeneration
• Loss of axons is the main cause of permanent disability in MS• Axonal damage has been shown to occur in acute inflammatory
plaques1 and can lead to brain atrophy– Occurs in white and gray matter– May also produce cognitive impairment
• Axonal damage could be the result of– Cumulative inflammatory damage over time– A parallel degenerative process related to loss of trophic support or
an independent axonal degeneration2
• Can effective immune therapy early in MS prevent worsening disability?
Conclusions
• Pathogenesis of MS involves complex interactions between genetic and environmental factors– Multiple genes are involved– Vitamin D deficiency, EBV infection, and cigarette smoking are
environmental candidates
• MS incidence has increased over the past 30 years due to a change in environmental exposure
• MS pathogenesis involves multiple immune cell types (T cells, B cells, NK cells, others)
• Along with chronic inflammation, MS pathogenesis involves axonal loss– Neurodegeneration is the major source of disability in MS
Challenges in Diagnosing MS
McDonald WI, et al. Ann Neurol. 2001;50:121-127.
What Is an MS “Attack”?
• Neurologic symptoms lasting ≥24 hours but generally longer – Not explained by other conditions – Do not represent recurrent symptoms in
association with increased body temperature or infection (pseudoexacerbations)
• To be considered separate attacks, the interval between episodes must be ≥30 days
Clinical Presentation
• MS symptoms vary widely among individual patients• Numbness, tingling, or weakness in the limbs
– Usually unilateral or only lower half of body
• Tremor, spasticity, incoordination, unsteady gait, imbalance• Vision loss (usually unilateral), pain with eye movement, double
vision• Fatigue, dizziness, cognitive impairment, unstable mood• Urinary and bowel incontinence or frequency• Increased body temperature may trigger or worsen symptoms
RRMSDisability
Time
Time
Disability
SPMS
Disability
Time
PPMS
RPMS
Disability
Time
Four Clinical Subtypes of MS
Fauci AS, et al. In: Harrison's Manual of Medicine, 17th ed. McGraw-Hill Medical; 2009. Reprinted with permission from McGraw-Hill.
Disease Course
• After initial episode, MS patients typically follow a chronic pattern of acute neurologic symptoms (relapses) followed by periods of stability (remission)
• Timing, progression, duration, severity, and specific symptoms are variable and unpredictable
• Typically 2 to 3 relapses per year in untreated patients; treated patients have significantly fewer relapses
• Some symptoms may be ongoing/chronic; these do not represent relapse
• Long-term deficits range from mild to severe
1. Polman CH, et al. Ann Neurol. 2005;58:840-846.
Diagnosis of MS
• Clinically definite MS must meet criteria for1
– Dissemination in space– Dissemination in time
• A single episode of MS-like symptoms (clinically isolated syndrome [CIS]) will not meet these criteria– But if MS is likely based on MRI, it still should be treated like
MS• Delaying treatment may be missing an important window of
opportunity to delay the onset of irreversible disability
– Requires close monitoring over time to confirm diagnosis
Time
Preclinical
MRI Activity
Relapses/Disability
MRI T2 Burden of Disease
Axonal Loss
Dis
abili
ty
CIS
*
Trapp BD, et al. Neuroscientist. 1999;5:48-57. Reprinted with permission from Sage Publications.
Relapsing-Remitting MS
Secondary Progressive MS
Natural History of MSClinical and MRI Measures
0
10
20
30
40
50
60
70
80
90
100
5 (N = 89) 10 (N = 81) 14 (N = 71)
Years Post CIS Diagnosis
% Converting to CDMS
0 lesions
1-3 lesions
4-10 lesions
>10 lesions
Morrissey S, et al. Brain. 1993;116:135-146. O’Riordan J, et al. Brain. 1998;121:495-503. Brex PA, et al. N Engl J Med. 2002;346:158-164.
11%
79%
87%85%
19%
89% 87% 88%
6%
54%
92%
80%
Natural History of CIS (Queen Square)
Risk of Conversion Based on LesionCount at Presentation
Polman CH, et al. Ann Neurol. 2005;58:840-846.
Revised McDonald Criteria
• At least 3 of the following on MRIa:– ≥1 Gd-enhancing brain or spinal cord lesion or ≥9
T2 hyperintense brain and/or spinal cord lesions of ≥3 mm in size if none of the lesions are Gd-enhancing
– ≥1 brain infratentorial lesion or spinal cord lesion ≥3 mm in size
– ≥1 juxtacortical lesion ≥3 mm in size– ≥3 periventricular lesions ≥3 mm in size
aTo meet criteria for dissemination in space
Polman CH, et al. Ann Neurol. 2005;58:840-846.
Revised McDonald Criteria
• At least 1 of the followinga
– A 2nd clinical episode– A Gd-enhancing lesion detected ≥3 months after onset of
initial clinical event• Located at a site different from the one corresponding to the
initial event
– A new T2 lesion detected any time after a reference scan that was performed at least 30 days after the onset of an initial clinical event
• Thus, it is not always necessary to wait for 2 attacks to diagnose MS. A first attack plus changes on MRI may be enough
aTo meet criteria for dissemination in time
A and B: Courtesy of Tracy M. DeAngelis, MD.
Gd-enhancing Corpus Callosum
Typical MRI Lesions in MS
Infratentorial Juxtacortical
C and D: Courtesy of Daniel Pelletier, MD.
Typical MRI Lesions in MS
Spinal Cord Periventricular
E: Courtesy of Daniel Pelletier, MD.F: Courtesy of Tracy M. DeAngelis, MD.
Typical MRI Lesions in MS
Consortium of Multiple Sclerosis Centers. http://www.mscare.org/cmsc/images/pdf/mriprotocol2009.pdf
CMSC MRI Protocol 2009
• Obtain brain MRI at baseline, with contrast• Obtain spinal cord MRI if symptoms pertaining to
spinal cord lesions or no evidence of disease activity in brain
• Repeat scan if:– Unexpected clinical worsening– Need to re-evaluate diagnosis– Starting or modifying treatment
• Consider serial MRI every 1-2 years to evaluate subclinical activity
1. Consortium of Multiple Sclerosis Centers. http://www.mscare.org/cmsc/images/pdf/mriprotocol2009.pdf
Performing Serial MRIs for Follow-up
• A standardized protocol using consistent technology and protocols is essential to serial MRI interpretation– Same magnet strength and slice thickness– Same sequence acquisition– Same patient positioning– Same plane– Section selection should match prior MRIs as closely as
possible
• Radiologists should follow the updated CMSC protocol1 for standardizing MRIs in clinical MS applications
1. Bar-Zohar D, et al. Mult Scler. 2008;14:719-727. 2. Brex PA, et al. N Engl J Med. 2002;346:158-164. 3. Truyen L, et al. Neurology. 1996;47:1469-1476. 4. Miller DH, et al. Brain. 2002;125:1676-1695.
MRI Correlates Poorly With Clinical Outcomes
• T2 lesion volume at a single point in time correlates weakly with clinical disability and is a measure of past attack frequency1– Change in lesion volume over time may be a better
correlate2
• T1-weighted black holes are a better but still imperfect correlate of disability3
• Brain atrophy is a measure of neurodegeneration that may predict disability4
Why MRI Correlates Poorly with MS Disability
• MRI cannot determine extent/nature of tissue damage
• Location of lesion influences its clinical manifestation• MRI cannot distinguish between demyelinated and
remyelinated lesions• MRI cannot detect gray matter lesions or diffuse
damage in normal-appearing white matter• Plasticity of CNS may lead to compensatory use of
alternative neural circuit to circumvent damaged areas
Emerging MRI Technologies
• Measures of CNS atrophy• Magnetization transfer imaging• Proton magnetic resonance spectroscopy• Diffusion tensor imaging• Susceptibility weighted imaging
Other Diagnostic Tools for MSCSF Analysis
• Positive if oligoclonal IgG bands present but absent from corresponding serum sample or IgG index is elevated– Sensitive but not specific: other causes of CNS inflammation
can yield similar findings
• Lymphocytic pleocytosis is rarely >50/mm3• Protein levels rarely exceed 100 mg/dL• Elevated myelin basic protein is not pathognomonic
for MS
Other Diagnostic Tools for MSVisual Evoked Potentials (VEPs)
• Provides evidence of a lesion associated with visual pathways
• Positive if shows delayed but well-preserved wave forms– Abnormal VEP is not specific for MS
• Can help establish dissemination in space
EDSS1
0 1.0 1.52.5
3.54.5
5.5
6.5
7.5
8.5
9.510.0
2.03.0
4.05.0
6.0
7.0
8.0
9.0Normal
neurologic exam
Minimaldisability
Some limitationin walking ability
Need for walking assistance
Restricted to wheelchair
Bedridden
Death
1. Kurtzke JF. Neurology. 1983;33:1444-1452. 2. Confavreux C, et al. Brain. 2003;126:770-782.
Time to EDSS score of 4.0 strongly influenced by relapses in the first 5 years and time to CDMS.2
Residual Disability Sustained After a Relapsea
aIn 224 placebo patients from the NMSS task force on clinical outcome assessment.
Lublin FD, et al. Neurology. 2003;61:1528-1532.
Patients with Residual Disability (%)
Days Since Exacerbation
30−59 Days 60−89 Days 90+ Days
≥0.5 EDSS points 42% 44% 41%
≥1 EDSS points 27% 29% 30%
1. Cree B. Curr Neurol Neurosci Rep. 2008;8:427-433. 2. Lennon VA, et al. J Exp Med. 2005;202:473-477. 3. Lennon V, et al. Lancet. 2004;364:2106-2112. 4. Mayo Medical Laboratories. http://www.mayomedicallaboratories.com/test-catalog/Overview/83185.
1. Cree B. Curr Neurol Neurosci Rep. 2008;8:427-433. 2. Lennon VA, et al. J Exp Med. 2005;202:473-477. 3. Lennon V, et al. Lancet. 2004;364:2106-2112. 4. Mayo Medical Laboratories. http://www.mayomedicallaboratories.com/test-catalog/Overview/83185.
Neuromyelitis Optica (NMO)
• Syndrome of aggressive inflammatory demyelination afflicting the optic nerves and spinal cord1, often associated with severe disability
• Associated with infections and collagen vascular diseases1 – Idiopathic form is considered a variant of MS
• Modern case series indicate that NMO is characterized by1
– Recurrent attacks of optic neuritis and acute transverse myelitis– Multisegmental spinal cord lesion >3 vertebral segments– Initial brain MRI that is often (but not always) normal
• The NMO-IgG antibody recognizes aquaporin-4 (AQP4),2 a water channel expressed on astrocytes– Anti-AQP4 antibody is 73% sensitive and 91% specific for NMO3
– Blood testing is available at Mayo Medical Laboratories4
NMO
Distinguishing NMO from MS
Courtesy of Bruce A.C. Cree, MD, PhD, MCR Courtesy of Tracy M. DeAngelis, MD
MS
Conclusions
• Diagnosis of MS is based on a combination of clinical and radiologic factors– MRI should be performed according to CMSC standardized
protocol
• Revised McDonald criteria are the gold standard for diagnosis
• High-risk CIS should be treated the same as clinically definite MS
• Clinical variants and red flags should be taken into account in formulating differential diagnosis
Achieving Therapeutic Goals with Current Treatments
Therapeutic Goals in MS
• In the absence of a cure for MS, current goals of disease modifying therapy are to– Prevent disability– Prevent relapses– Prevent development of new or enhancing lesions on MRI
• Additional goals in the management of MS are to– Relieve symptoms– Maintain well-being– Optimize quality of life
Treating Acute Relapse
• IV corticosteroids = standard of care– Methylprednisolone 500 to 1000 mg/d IV for 3 to
5 days• May be followed by oral steroid taper
• High-dose oral steroids may be acceptable alternative– Phase III randomized OMEGA trial currently
comparing oral and IV steroids
• Plasmapheresis and IVIG for refractory relapse
Therapeutic Targets in MS
FDA-ApprovedDisease-Modifying Agents
First line:• Interferon beta
– Interferon beta-1b 250 mcg SC QOD (two brands)– Interferon beta-1a 44 mcg SC TIW– Interferon beta-1a 30 mcg IM weekly
• Glatiramer acetate– 20 mg SC QD
Second line:• Mitoxantrone
– 12 mg/m2 over 5 to 15 min q3mo; lifetime max, 144 mg/m2
• Natalizumab– 300 mg IV monthly infusion
Current First-Line MS Therapies
• Interferon beta-1a, interferon beta-1b, glatiramer acetate– Interferons are FDA approved for relapsing forms
of MS– Glatiramer acetate is FDA approved for RRMS
• Similar efficacy for relapse rate reduction ~ 30%
• Generally very safe and well tolerated• All require self-injection
Mechanisms of Action for Interferons
• Reduction of proinflammatory cytokine secretion
• Promotion of anti-inflammatory cytokine secretion
• Stabilization of blood-brain barrier• Enhancement of regulatory T cell activity• Downregulation of antigen presentation to
T cells
Mechanisms of Action for Glatiramer Acetate
• Competitive inhibition of antigen presentation (myelin basic protein) to autoreactive T cells
• Activates regulatory T cells• Promotes Th1 to Th2 cytokine shift
Pantich H, et al. Neurology. 2002;59:1496-1506.
Abbreviations: IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously; TIW, 3 times per week.
Patients Relapse-Free
Difference P Value
IFN beta-1a 30 mcg IM QW
52%
19% in favor of IFN beta-1a 44 mcg SC TIW
<.009
IFN beta-1a 44 mcg SC TIW
62%
Head-to-Head StudyEVIDENCE (IFN beta-1a) Trial,
48 Weeks
Durelli L, et al. Lancet. 2002;359:1453-1460.
Abbreviations: EOD, every other day; IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously.
Patients Relapse-Free
Difference P Value
IFN beta-1b 250 mcg SC EOD
51%
42% in favor of IFN beta-1b
<.036
IFN beta-1a 30 mcg IM QW
36%
Head-to-Head StudyINCOMIN (IFN beta-1b vs beta-1a)
Trial, 104 Weeks
Mikol DD, et al. Lancet Neurol. 2008;7:903-914.
Abbreviations: IFN, interferon; SC, subcutaneously; QD, once daily; TIW, 3 times per week .
Patients Relapse-Free
Difference P Value
Glatiramer acetate 20 mg QD
62%
No difference <.96
IFN beta-1a 44 mcg SC TIW
62%
Head-to-Head StudyREGARD (Glatiramer Acetate vs
IFN beta-1a), 96 weeks
Patients Relapse-
Free
Difference P Value
BECOME1
(18 mo)
GA 20 mg QD 70% 8% in favor of GA
NS
IFN beta-1b 250 mcg SC QOD
62%
BEYOND2
(2 years)
GA 20 mg QD 59% 1% in favor of IFN 500
mcg
NS
IFN beta-1b 250 mcg SC QOD
58%
IFN beta-1b 500 mcg SC QOD
60%
1. Cadavid D, et al. Neurology. 2009;72:1976-1983. 2. O’Connor P, et al. Lancet Neurol. 2009;8:889-897.
Abbreviations: GA, glatiramer acetate; QD, once daily; IFN, interferon; SC, subcutaneously; QOD, every other day; NS, not significant.
Head-to-Head StudiesBECOME and BEYOND
(Glatiramer Acetate vs IFN beta-1b)
Head-to-Head StudiesBottom Line
• Higher-dose subcutaneous interferons are more effective than lower-dose intramuscular interferon
• High-dose subcutaneous interferon formulations and glatiramer acetate probably all offer comparable efficacy
Avonex [package insert]. Cambridge, MA: Biogen Idec; 2006. Betaseron [package insert] Montville, NJ: Bayer HealthCare Pharmaceuticals; 2009. Extavia [package insert]. Montville, NJ: Bayer HealthCare Pharmaceuticals; 2009. Rebif [package insert]. Rockland, MA: EMD Serono; 2009.
Side Effects of Interferons
• Side effects include flu-like symptoms, injection site reactions/necrosis (SC), liver enzyme elevations, lymphopenia, depression
• Pregnancy category C• Warnings: depression/suicide, decreased peripheral
blood counts, hepatic injury, seizures, cardiomyopathy/CHF, autoimmune disease
• Laboratory tests: periodic CBC with differential, liver function profile, thyroid function
Neutralizing Antibodies• Interferon therapies are associated
with production of neutralizing antibodies (NAbs) to the interferon beta molecule1
– NAbs may reduce radiographic and clinical effectiveness of interferon treatment
• NAb testing– Sometimes used when deciding
whether to switch from one interferon to another (usually IM to SC) in a patient with suboptimal response
– There are no guidelines on when to test, which test to use, how many tests are needed, or which cutoff titer to apply1
1. Goodin DS, et al. Neurology. 2007;68:977-984.
45
3124
50
20
40
60
80
100
IFN beta-1b 250 mcg SC QODIFN beta-1a 22 mcg SC TIWIFN beta-1a 44 mcg SC TIWIFN beta-1a 30 mcg IM QW
Pro
babi
lity
of N
Abs
(%
)
Data from prescribing information.
Copaxone [package insert]. Kansas City, MO: Teva Neuroscience; 2009.
Side Effects of Glatiramer Acetate
• Injection-site reactions, vasodilation, rash, dyspnea, chest pain
• Pregnancy category B• Warnings: Immediate postinjection reaction,
chest pain, lipoatrophy, skin necrosis– Postinjection reaction (flushing, chest pain,
palpitations, anxiety, dyspnea, constriction of throat, urticaria) is self-limited; no treatment required
• No lab testing required
Side Effect Management
Flu-like symptoms NSAIDs (eg, naproxen 500 mg 1 h before injection + 12 h later); IFN administration before bedtime; for patients on IFN beta-1a IM, prednisone 10 mg on day of injection; switch to glatiramer acetate
Injection-site reactions and injection-site pain
Rotate injection sites; administer injection without the autoinjector; topical anesthetics; application of ice before injecting; ensure proper product preparation including warming to room temperature
Difficulty self-injecting
Have partner administer injection; if “click” of autoinjector induces anxiety, administer without the autoinjector; call company nurse for retraining; home health agency might administer IFN beta-1a IM; switch to a therapy with less frequent injections
Side Effect Management Tips
Timing of Therapy May Be Key to Preventing Disability
First Clinical Attack
Time (years)
Clinical threshold
Axonal loss
Demyelination
Time window for early treatmen
t
Relapsing-Remitting TransitionalSecondaryProgressive
First Demyelinating
EventPre-
clinical
Inflammation
Rationale for Early Treatment
• Time is ticking…
• What is lost by delaying early therapy is not regained by starting later
Treating CIS
• Treating CIS vs waiting until patient has clinically definite MS (CDMS)– Decrease progression to CDMS– Decrease rate of disability progression– Reduced lesion load on MRI– Fewer and less severe relapses– Most clinicians advocate early treatment BUT not
all CIS will develop MS
Placebo-Controlled Trials of Disease-Modifying Therapy in
CISStudy Treatment N Conversion to CDMS
Follow-
up
On Tx
Placebo P
CHAMPS1 Interferon beta-1a 30 μg IM qwk
383 3 y 35% 50% .002
ETOMS2 Interferon beta-1a 22 μg SC once
weekly
309 2 y 34% 45% .047
BENEFIT3 Interferon beta-1b 250 μg SC q48h
468 2 y 28% 45% <.0001
PreCISe4 Glatiramer acetate 20 mg/d
481 3 y 61% 77% .0005
1. Jacobs LD, et al. N Engl J Med. 2000;343:898-904. 2. Comi G, et al. Lancet. 2001;357:1576-1582. 3. Kappos L, et al. Neurology. 2006;67:1242-1249. 4. Comi G, et al. Lancet. 2009;374:1503-1511.
FDA Approved for CIS
• Interferon beta-1a 30 mcg IM QW• Interferon beta-1b 250 mcg SC QOD• Glatiramer acetate 20 mg SC daily• Interferon beta-1a 44 mcg SC TIW is
sometimes used off-label
Second-Line MS TherapiesNatalizumab
• Inhibits cell adhesion and leukocyte migration across BBB• AFFIRM trial1 of natalizumab vs placebo in RRMS
– 42% reduction in risk of sustained progression of disability in 2 years (P <.001)
– 68% reduction in clinical relapse at 1 year (P <.001)– 83% reduction in new or enlarging T2 lesions over 2 years (P
<.001)– 92% reduction in Gd-enhancing lesions at 1 and 2 years
(P <.001)
1. Polman CH, et al. N Engl J Med. 2006;354:899-910.
Second-Line TherapiesNatalizumab
• FDA approved for relapsing MS• Due to risk of PML, natalizumab is generally reserved for
patients who have not responded to or tolerated alternate therapies– PML (JC virus of brain) leads to severe disability or death; no
known treatment– Available only through very restricted distribution program (TOUCH
Prescribing Program)
• Other warnings: hepatotoxicity, hypersensitivity reactions, immunosuppression
Tysabri [package insert]. Cambridge, MA: Biogen Idec; 2009.
Novantrone [package insert]. Rockland, MA: EMD Serono, and Melville, NY: OSI Pharmaceuticals; 2009.
Mitoxantrone• Antineoplastic in anthracenedione class• FDA approved for SPMS, PRMS, worsening RRMS• Causes cross-links and strand breaks in DNA; inhibits B cell,
T cell, and macrophage proliferation • Due to serious side effects, reserve for patients with rapidly
advancing MS despite other disease-modifying therapies– Cardiomyopathy (LVEF decreased in up to 18%; CHF)– Secondary acute myelogenous leukemia (0.25%)– Elevated liver enzyme and glucose levels– Requires frequent monitoring (CBC, liver function tests, LVEF,
ECG)
• Administration should be performed by an oncologist
Starting an MS Patient on a Disease-Modifying Agent
• Obtain starter kit from local representative
• Complete physician portion of Enrollment Form and have patient complete the patient portion
• Upon receipt of form, company will verify patient’s insurance benefits
• Company will supply medication and send nurse to the patient’s home for training on self-injection and proper needle disposal
• Titrate interferon dose as indicated on the Enrollment Form
Monitoring
• Follow up 4−6 weeks after initiating therapy– Assess injection technique and tolerability
• If stable on therapy, re-evaluate every 3−6 months • Laboratory testing for interferon
– CBC and liver enzyme levels 4–6 weeks after starting treatment, 3 months later, then every 6 months
• No laboratory testing needed for glatiramer acetate• Continue on therapy indefinitely unless clear lack of
benefit, intolerable side effects, or better treatment becomes available
Year 122%
Year 320%
Year 413%
Year 58%
Year 65%
Year 73%
Year 83%
Year 227%
Assess Adherence!Most Patients Who Discontinue
Do So in First 2 Years
Rio J, et al. Mult Scler. 2005;11:306-309.
Cohort of patients who stopped therapy
Assess Adherence by Asking
• Patients typically will not tell you they have been nonadherent if you do not ask
• Ask in nonjudgmental manner that assumes they have missed some doses– For example: How many injections do you think you have
missed in the past 2 months?
• Being asked helps motivate patients to adhere• Assess barriers by asking: What prevents you from
taking your medication? – NOT: Why aren’t you taking it? (Avoid casting blame)
Address Barriers to Adherence
• Difficulty self injecting• Adverse events• Unrealistic expectations of therapy (symptom relief)• Lack of acceptance of MS diagnosis and need for treatment• Financial considerations• “Treatment fatigue”• Depression• Cognitive deficits• Impairment in fine motor skills• Changes to family and support circumstances
Suboptimal Treatment Response
• Worsening clinical status• Radiologic changes (MRI)
– New Gd enhancement and/or new or enlarging T2 lesions are signs of disease activity
• No consensus as to when such findings warrant change in treatment
• Interpret in context of whole clinical picture• If found on repeat scans, even if patient is clinically stable,
probably warrants change in therapy
– Remember: comparison of serial MRI scans requires consistent use of standardized MRI protocol (CMSC protocol)
Suboptimal Response Potential Causes
• Nonadherence• Pharmacogenomics: responsiveness to IFN β
related to genetics1 • Variable pathologies with differing responses to
immune therapies • NAbs• MS subtype (disease modifying agents do not
work in PPMS)
1. Byun E, et al. Arch Neurol. 2008;65:337-344.
Refer or Consult a Neurologist
• When diagnosis is in doubt• If a consult is desired regarding selection of
initial therapy• For patients with poor response or toleration
of first-line therapies• When considering use of natalizumab or
mitoxantrone
Conclusions
• Current MS therapies can reduce relapse rates and disability progression– Interferon beta or glatiramer acetate is first line
• It is best to start treatment as early as possible• Patient education is essential when starting treatment
– Rationale for treatment, injection technique, side effect management, importance of adherence
• After starting treatment, monitor for response, tolerability, and adherence
Emerging MS Therapies
Limitations of Current Therapies
• All are only partially effective • All are injectable or IV and have side effects • Risks vs benefits
– Existing therapies have advantage of long-term safety data
• Difficulty predicting therapeutic response• Goal: Individualized, more effective, safe
medication(s) that are easier to administer
1. Carroll WM. N Engl J Med. 2010;362:456-458.
Two Oral Therapies Have Completed Phase III Studies
• Fingolimod• Cladribine• 3 important questions to ask1
– How do they compare with current therapies?– Are all of the long-term safety issues known?– What do they tell us about MS and our treatment
goals?
Brinkmann V, et al. J Biol Chem. 2002;277:21453-21457. Pinschewer DD, et al. J Immunol. 2000;164:5761-5770. Chiba K, et al. J Immunol. 1998;160:5037-5044.
Fingolimod
• Modulates sphingosine-1-phosphate receptors– Receptors play a role in egress of lymphocytes out of lymph
nodes
• Fingolimod sequesters lymphocytes in lymph nodes• Fingolimod crosses blood-brain barrier and may have
neuroprotective properties• Dosing: once-daily pill• Status: 2 phase III trials completed; pending FDA
review
Kappos L, et al. N Engl J Med. 2010;362:387-401.
Placebo-controlled FREEDOMS II study is ongoing.
No disability progressionat 3 months: 82.3%P = .03 vs placebo
Annualized relapse rate0.18
P < .001 vs placebo
Fingolimod 0.5 mg QDn = 425
No disability progressionat 3 months: 83.4%P = .01 vs placebo
Annualized relapse rate0.16
P < .001 vs placebo
Fingolimod 1.25 mg QDn = 429
No disability progressionat 3 months: 75.9%
Annualized relapse rate0.40
Placebon = 418
N = 1272 RRMS
Fingolimod reduced relapse rate by 54% to 60% vs placebo and reduced risk of disability progression
Fingolimod FREEDOMS, 24-Month Study
No disability progression94.1%
P = .25 vs IFN
Annualized relapse rate0.16
P <.001 vs IFN
Fingolimod 0.5 mg QDn = 429
No disability progression93.3%
P = .50 vs IFN
Annualized relapse rate0.20
P < .001 vs IFN
Fingolimod 1.25 mg QDn = 420
No disability progression92.1%
Annualized relapse rate0.33
IFN beta-1a 30 mcg IM Qn = 431
N = 1292 RRMS randomized
Cohen JA, et al. N Engl J Med. 2010;362:402-415.
Fingolimod reduced relapse rate by 38% to 52% versus IFN beta-1a but was not significantly different with regards to effect on disability
Fingolimod TRANSFORMS, 12-Month Study
Cohen JA, et al. N Engl J Med. 2010;362:402-415. Kappos L, et al. N Engl J Med. 2010;362:387-401.
Fingolimod Safety
• Common: nasopharyngitis, infections, cough/dyspnea, fatigue, headache, back pain, diarrhea, nausea, and elevated ALT levels
• Malignancies (skin cancer, breast cancer)• Bradycardia/atrioventricular block
– Requires 6-hour first-dose monitoring with hourly ECGs– Bradycardia persisting >6 hours requires continued monitoring– Break in therapy >2 days requires repeat first-dose monitoring; therefore,
not good choice for nonadherent patients
• Severe herpes infections (some fatal)• Disseminated Varicella Zoster (fatal)• Macular edema requiring ophthalmology screening• Reduction in FEV1 —PFTs and HRCT required in phase III studies• Lower dose has fewer side effects
Sipe JC. Expert Rev Neurother. 2005;5:721-727.
Cladribine
• Results in selective long-term depletion of CD4+ and CD8+ T cells
• FDA approved for treatment of hairy-cell leukemia• Dosing: given orally for 5 consecutive days for
2 cycles, 1 month apart• Status in MS
– Fast-tracked by the FDA– Phase III study completed– FDA issued “refuse to file” letter Nov. 30, 2009 – NDA will be resubmitted as soon as FDA’s concerns can be
addressed
Giovanni G, et al. N Engl J Med. 2010;362:416-426.
No disability progressionat 3 months: 85.7%P=.02 vs placebo
Annualized relapse rate0.14
P<.001 vs placebo
Cladribine 3.5 mg/kgn = 433
No disability progressionat 3 months: 84.9%
P=.03
Annualized relapse rate0.15
P<.001 vs placebo
Cladribine 5.25 mg/kgn = 456
No disability progressionat 3 months: 79.4%
Annualized relapse rate0.33
Placebon = 437
N = 1326 RRMS
Oral cladribine reduced the relapse rate by 54.5% to 57.6% and the risk of sustained disability progression at 3 months
by about one third compared with placebo.
Oral CladribineCLARITY
Giovanni G, et al. N Engl J Med. 2010;362:416-426.
Cladribine Safety
• Common adverse effects: headache, nasopharyngitis, upper respiratory tract infection, nausea
• Infections/infestations– Herpes zoster– Primary varicella
• Benign uterine leiomyomas• Malignancies (melanoma, pancreatic, ovarian, cervical)• Decreased lymphocyte counts/severe aplastic anemia• Exacerbation of latent tuberculosis
Carroll WM. N Engl J Med. 2010;362:456-458.
Do We Have the Answers to the
Three Questions?• Fingolimod and cladribine are likely to be at least as effective as
available treatments– Fingolimod > IFN beta-1a IM in TRANSFORMS
– IFN beta-1a IM was the least effective of available therapies in prior head-to-head trials
• Fingolimod and cladribine may have greater safety issues– Severe herpes infections, malignancies, lymphocytopenia (both
fingolimod and cladribine)
– Macular edema, bradycardia/AV block (fingolimod)
– Higher discontinuation rates than available therapies
• It is not yet clear whether these therapies can prevent immune-mediated injury
Additional Oral Small-Molecule
MS Therapies in Late-Stage Development
• Fumarate (BG00012)• Teriflunomide• Laquinimod
Emerging Monoclonal Antibodies
• Rituximab• Ocrelizumab• Alemtuzumab• Daclizumab
Conclusions• Oral therapies for MS may soon be available
• Phase III studies have been completed for fingolimod and oral cladribine
– Possibly more effective at reducing relapse rates compared with current therapies, but not clear that they are any better at preventing disability
– Some serious adverse events have been observed Requires patient understanding of risks and need
for close monitoring
• Other small molecules and monoclonal antibodies are in late-stage development for MS
Symptom Management
MS symptoms• Chronic or ongoing indicators of MS lesion damage
to certain areas of the brain or spinal cord
MS relapses• Flare-ups or attacks of new or previously resolved
symptoms that typically evolve over at least 48 hours and last several days to weeks
MS Symptoms vs Relapses
Common MS Symptoms
• Fatigue• Bladder dysfunction• Spasticity• Gait difficulties• Pain• Cognitive impairment• Mood instability• Sexual dysfunction
National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/fatigue/index.aspx
MS Fatigue
• One of the most common (80%) symptoms• One of the most disabling symptoms
– Primary reason to stop working– More likely than other types of fatigue to interfere with daily
responsibilities
• Occurs daily, starts suddenly– Can start early in the morning, even after restful sleep
• Worsens as day progresses, with heat and humidity • Cause unknown
Managing MS FatigueLifestyle Changes
• Physical therapy/exercise• Good nutrition• Enough sleep
– Going to bed on time – Management of other symptoms that interfere with sleep
• Rest breaks• Weight management• Prioritization of tasks; maintaining realistic expectations• Letting others help• Avoidance of excessive caffeine, multitasking, overheating
Managing MS FatiguePharmacologic Strategies
(Off-Label Uses)• Amantadine hydrochloride 100-200 mg/d
early in day– May need additional 100 mg around noon
• Modafanil 100-200 mg/d early in day• Amphetamine-type therapies
– Methylphenidate, can start at 5 mg PO in AM and titrate to effect; 10 mg in AM and around noon or early afternoon is common
– Can use long-acting formulations
National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/bladder-dysfunction/index.aspx and http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/bladder-dysfunction/download.aspx?id=64
Bladder Dysfunction
• Affects 80% of MS patients• Frequency and/or urgency• Hesitancy in starting urination• Nocturia• Incontinence and/or dribbling• Urinary retention, which can lead to UTIs• May interfere with normal activities and cause social
embarrassment
National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/bladder-dysfunction/index.aspx and http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/bladder-dysfunction/download.aspx?id=64
Managing Bladder DysfunctionManagement
• Assessment – Urinalysis/dipstick, culture (UTI) – Postvoid residual urine– Urodynamic studies
• Dietary and fluid management– Do not restrict fluids! 6-8 glasses daily, spread over course of day,
but fewer before bed• Exception: restrict intake ~ 2 hours before activities where no bathroom
will be available
– Limit caffeine, alcohol, citrus juice
• Intermittent self-catheterization• Absorbent pads
National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/bladder-dysfunction/download.aspx?id=64
Managing Bladder DysfunctionPharmacologic Strategies
• Antibiotics if positive for UTI• Anticholinergic agents
– Oxybutynin, propantheline, imipramine, tolterodine, solifenacin succinate, darefenacin, trospium chloride
• Desmopressin acetate nasal spray or tablets (for nocturia)– Need to monitor serum sodium
• Antispasticity agents (to relax sphincter muscle)– Baclofen, tizanidine hydrochloride
• Alpha-adrenergic blockers– Prazosin, terazosin, tamsulosin
National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/spasticity/index.aspx. Kushner S, et al. Spasticity. NMSS Clinical Bulletin. http://www.nationalmssociety.org/download.aspx?id=147
Spasticity
• Velocity-dependent increase in muscle tone, with hyperactive deep tendon reflexes– Clonus: repetitive rhythmic beating of foot or wrist– Difficulty initiating movement– Impaired voluntary muscle control– Difficulty relaxing muscles after movement cessation– Sensation of muscle tightness or pain– Decreased range of motion
• Potential triggers: sudden movements or position changes, fatigue, stress, cold, humidity, tight clothes, tight shoes, constipation, poor posture, infection
• Can be worsened by interferons• Can add to MS fatigue
Kushner S, et al. Spasticity. NMSS Clinical Bulletin. http://www.nationalmssociety.org/download.aspx?id=147
Managing SpasticityNonpharmacologic Strategies
• Daily stretching and exercise (cool environment)– Balance and coordination, strengthening, timing, range of
motion, posture
• Transcutaneous electrical nerve stimulation (TENS)• Thermal (hot and cold)• Biofeedback• Relaxation (yoga, Tai Chi)• Bracing/splinting
Kushner S, et al. Spasticity. NMSS Clinical Bulletin. http://www.nationalmssociety.org/download.aspx?id=147.
Managing SpasticityPharmacologic Strategies
• Baclofen - oral or intrathecal; start low and titrate• Tizanidine• Dantrolene sodium• Diazepam• Other off-label agents sometimes used
– Clonazepam, gabapentin– Botulinum injections for focal spasticity
• Phenol nerve blocks
Kushner S, et al. Spasticity. NMSS Clinical Bulletin. http://www.nationalmssociety.org/download.aspx?id=147
Managing SpasticitySurgery for Intractable Symptoms
• Tenotomy• Neurectomy• Rhizotomy
Ampyra [package insert]. Hawthorne, NY: Acorda Therapeutics; 2010.
Managing Gait Difficulties
• Dalfampridine—previously known as fampridine SR or 4-aminopyridine SR
• FDA approved January 2010• Indication: improve walking speed in patients with MS
– This is not a disease-modifying therapy
• Mechanism: K+ channel blockade– Enhances axonal conduction
• Dose-dependent side effect: seizures
Dalfampridine Phase III Studies
• Dalfampridine 10 mg BID (n = 229) or placebo (n = 72) x 14 weeks
• Response = consistent improvement on timed 25-foot walk
• Walking speed improved by 25% among fampridine responders vs 5% with placebo (Trial 1)
Ampyra [package insert]. Hawthorne, NY: Acorda Therapeutics; 2010. Goodman AD, et al. Lancet. 2009;373:732-738.
35
8
43
9
0
5
10
15
20
25
30
35
40
45
Trial 1 Trial 2
Fampridine
Placebo
Res
pond
ers
(%)
P <.001
Botulinum Toxin for MS Spasticity
Hyman N, et al. J Neurol Neurosurg Psychiatry. 2000;68:707-712.
• N = 74 MS patients with disabling spasticity of the hip adductor muscles of both legs
• Randomized to botulinum toxin 500, 1000, or 1500 U IM injections into hip adductor muscles or placebo
• Botulinum was associated with improved passive hip abduction and distance between the knees
• Botulinum reduced muscle tone, and all groups (including placebo) had reduced frequency of spasms and leg pain
• Nonsignificant trend toward greater efficacy with higher doses but there were twice as many side effects with 1500 U
Managing Other MS SymptomsSymptom Management
Pain Carbamazepine, phenytoin, gabapentin, amitriptyline, duloxetine hydrochloride, pregabalin, baclofen, tizanidine, acetaminophen, NSAIDs, pressure stocking/glove, warm compresses, massage
Cognitive impairment
Referral for cognitive rehabilitation and psychotherapy, memory aids (recordings, lists, mnemonics, etc), assistive technologies (computers, electronic calendars), minimization of distractions, donepezil (if dementia present)
Depression Referral for counseling/psychotherapy, TCAs, SSRIs, SSRNIs, bupropion, mirtazapine
Sexual dysfunction
Consider medication side effects (eg, SSRIs, beta blockers), sildenafil, vardenafil, tadalafil, papaverine, OTC lubricants, alternative means of stimulation, counseling to address relationship issues
National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/pain/index.aspx, http://www.nationalmssociety.org/download.aspx?id=127, http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/treatments/medications/antidepressants/index.aspx, http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/sexual-dysfunction/index.aspx
Conclusions
• Managing MS means thinking about more than just preventing relapse and new lesions
• It is important to address other symptoms that interfere with QOL
• Symptoms need to be recognized in order to treat• Address 1 or 2 symptoms per visit—prioritize• Through counseling and treatment, most symptoms can at least
be reduced• Refer to specialists as needed for optimized symptom control• Expect that many symptoms will never be fully controlled
The Dialogue of MSin Primary Care
Communicating with Patientsand Peers
• There are many resources for clinicians and patients available online
• Social media sites offer resources as well as an opportunity to connect with others
• Some of the information your patients receive over the Internet and via social media sites is more accurate than others– Know what is available– Recommend reputable sites– Ask what they are using
What Your Patients May Be Doing
You Tube
What Your Patients May Be Doing
What Your Patients May Be DoingTwitter
What Your Patients May Be Doing
Blogging
Other Projects In Knowledge MS Enduring Materials
• The Advanced Certificate Program: Multiple Sclerosis Management IIwww.projectsinknowledge.com/cp/1877
• Living Medical Textbook: Multiple Sclerosis Editionwww.livingmedicaltextbook.org/1876