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.

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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

Facebook

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