Multiple Sclerosis Disease Overview & Current Management Strategies

Multiple Sclerosis

Disease Overview & Current Management Strategies

Epidemiology

Demographics of MS

Age at onset 15 to 45 years1

Gender 70% women2

US incidence 8,500 to 10,000 new cases per year1

US prevalence 350,0002

1. Jacobsen DL et al. Clin Immunol Immunopathol. 1997;84:223-243.2. Anderson DW et al. Ann Neurol. 1992;31:333-336.

Worldwide Prevalence of MS

Worldwide distribution varies

High prevalence 30+/100,000– Northern United States and Canada

– Most of Europe

– Southern Australia

– New Zealand

– Northern Russia

Kurtzke JF. Neuroepidemiology. 1991;10:1-8.

Pathophysiologyand Diagnosis

Pathology of MS

An immune-mediated disease in genetically susceptible individuals

Demyelination leads to slower nerve conduction

Axonal injury and destruction are associated with permanent neurological dysfunction

Lesions occur in optic nerves, periventricular white matter, cerebral cortex, brain stem, cerebellum, and spinal cord

Trapp BD et al. N Engl J Med. 1998;338:278-285.

Axonal Transection in Acute MS Lesions

64m 45m A BReprinted with permission from Trapp BD et al. N Engl J Med. 1998;338:278-285. Copyright 1998 Massachusetts Medical Society. All rights reserved.

What Causes Demyelinationand Axonal Loss in MS?

Activation of autoreactive CD4+ T cells in peripheral immune system

Migration of autoreactive Th1 cells into CNS

In situ reactivation by myelin autoantigens

Activation of macrophages, B cells

Secretion of proinflammatory cytokines, antibodies

Inflammation, demyelination, axonal transection, and degeneration

Immunopathogenesis of MS

Th1+

RestingT cell

MMP

Activated (+)T cells

Th1+

Th1+

MMP

MMP

BBBBlood CNS

Th1+

TNF- IFN-

Bcell

IL-2

Th1APC APC

Immunopathogenesis of MS

Th1+MMP


Th1+

Th1+

MMP

MMP

Blood

RestingT cell

APC

CNS

TNF- IFN-

Bcell

IL-2

Th1 APC

BBB

Th1+

Disability Progression and Disease Type

Lublin FD, Reingold SC. Neurology. 1996;46:907-911.

Relapsing-remitting

Primary-progressive

Dis

abil

ity

Time

Time

Dis

abil

ity

Secondary-progressive

Progressive-relapsing

Time

Time

Dis

abil

ity

Dis

abil

ity

Adapted from Weinshenker BG et al. Brain. 1989;112:133-146.

Relapsing-remittingPrimary-progressive

Disease Type at Diagnosis Disease Type at 11-15 Years After Diagnosis (Among Those

With RRMS at Diagnosis)

Natural History Over Time

Secondary-progressiveRelapsing-remitting

42%

58%

15%

85%

Progression to Disability: EDSS

Expanded Disability Status Scale (EDSS)

Ordinal scale (range 0-10) measuring disability in increments of 0.5

Most widely accepted measure of disability in patients with MS

Reflects impact of disease on neurological function

Kurtzke JF. Neurology. 1983;33:1444-1452.

0 Normal neurological exam1.0–1.5 No disability2.0–2.5 Minimal disability3.0–3.5 Mild to moderate disability4.0–4.5 Moderate disability5.0–5.5 Increasing limitations in ability to walk6.0–6.5 Walking assistance is needed7.0–7.5 Confined to wheelchair8.0–8.5 Confined to bed/chair; self-care with assistance9.0–9.5 Completely dependent

10.0 Death due to MS

Progression to Disability: EDSS

Natural History

Average is 1 relapse per year, fewer over time1

25% of patients never lose ability to perform activities of daily living1

15% become severely disabled within short time1

Median time to reach EDSS of 6 is 15 years; to reach EDSS of 8 is 46 years2

Mortality from MS as primary cause is low1

1. Compston A, Coles A. Lancet. 2002;359:1221-1231. 2. Weinshenker BG et al. Brain. 1989;112:133-146.

Diagnosis of MS: Basic Principles

Ultimately a clinical diagnosis; no definitive laboratory test

Clinical profile

Laboratory evaluation

Evidence of dissemination of lesions in space and time

Exclusion of other diagnoses

Coyle P. In: Burks J, Johnson K, eds. Multiple Sclerosis, Diagnosis, Medical Management and Rehabilitation. New York: Demos; 2000:81-97.

Most Common Presenting Symptoms

Sensory symptoms in arms/legs1 33% Unilateral vision loss1 16% Multiple symptoms at onset1 14% Slowly progressive motor deficit1 9% Diplopia (double vision)1 7% Acute motor deficit1 5% Others1 16% Rarely seen1

(eg, bladder dysfunction, heat intolerance,pain, movement disorders, dementia)2 <5%

1. Paty DW. In: Burks J, Johnson K, eds. Multiple Sclerosis, Diagnosis, Medical Management and Rehabilitation. New York: Demos; 2000:75-76. 2. Paty DW, Ebers GC (eds.). Multiple Sclerosis. Philadelphia: FA Davis; 1998.

Diagnoses That Mimic MS

Infection– Lyme disease

– Neurosyphilis

– PML, HIV, HTLV-1

Inflammatory– SLE

– Sjögren’s

– Other CNS vasculitis

– Sarcoidosis

– Behçet’s disease

Cohen J, Rensel M. In: Burks J, Johnson K, eds. Multiple Sclerosis Diagnosis, Medical Management and Rehabilitation. New York: Demos; 2000:127-138.

Metabolic

– Vitamin B12 and E deficiencies

CADASIL, other rare familial diseases

CNS lymphoma

Cervical spondylosis

Motor neuron disease

Myasthenia gravis

Use of MRI in Diagnosis

MRI is used to improve confidence in a clinical diagnosis of MS or to make a diagnosis of MS in clinically isolated syndromes1

May show dissemination in space and time(eg, new lesions on follow-up MRI)1

Total lesion load at diagnosis tends to be predictive of future disability2

1. McDonald WI et al. Ann Neurol. 2001;50:121-127.2. Brex PA et al. N Engl J Med. 2002;346:158-164.

MRI Basics in Diagnosing MS

T1-weighted scan– Shows hypointense lesions (black holes)

T2-weighted scan– Indicates total burden of disease– May show new lesions

FLAIR image– Suppresses CSF– Useful for subcortical and cortical lesion

identification

Gadolinium enhancement– Highlights new or active lesions

Costello K et al. American Journal for Nurse Practitioners. October 2000:9-26.Noseworthy JH. N Engl J Med. 2000;343:938-952.

MS Lesions on MRI

T2 BOD

T1/Gd postcontrast

disease activity

T1precontrastblack holes

A B

C

T2-FLAIR

D

McDonald WI et al. Ann Neurol. 2001;50:121-127.

McDonald Diagnostic Criteria

Preserve traditional diagnostic criteria of 2 attacks of disease separated in space and time– Must be no better explanation– Add specific MRI criteria, CSF findings, and

analysis of evoked potentials as means of identifying the second “attack”

Conclude that the outcome of the diagnostic workup should yield 1 of 3 outcomes:– MS – Possible MS – Not MS

McDonald MRI Criteria

Abnormal MRI consistent with MS

– Must have at least 3 of the following:

• 1 Gd-enhancing lesion or 9 hyperintense lesions if no Gd-enhancing lesion

• 1 or more infratentorial lesions

• 1 or more juxtacortical lesions

• 3 or more periventricular lesions

– 1 cord lesion = 1 brain lesion

McDonald WI et al. Ann Neurol. 2001;50:121-127.

Gd-enhancing T2-hyperintense

Juxtacortical Periventricular Spinal Cord

Infratentorial

McDonald MRI Criteria

Reprinted with permission from Rudick RA et al. Neurology. 1999;53:1698-1704.

Brain Atrophy

Secondary-progressiveSecondary-progressive

Relapsing-remittingRelapsing-remittingPreclinicalPreclinical

Disease Progression

Time

Adapted with permission from JS Wolinsky.

Dis

a bi l

i ty

Measures of brain volumeRelapses and impairmentMRI burden of diseaseMRI activity

Disease Management

Goals of Disease Management

Treating relapses

Managing symptoms

Modifying or reducing relapses and delaying progression to disability

Facilitating an acceptable quality of life

Acute MS Relapses

Relapses– Focal disturbances of function >24 hours

– Occur about once a year in untreated patients

– In absence of environmental, metabolic, or infectious processes

Management: high-dose steroids– Common option: methylprednisolone IV for

5 days followed by short course of prednisone

– Oral prednisone, oral methylprednisolone, or dexamethasone

Common MS Symptoms

Fatigue

Depression

Focal muscle weakness

Visual changes

Bowel/bladder/sexual dysfunction

Gait problems/spasticity

Paresthesias

Less Common MS Symptoms

Dysarthria, scanning speech, dysphagia

Lhermitte’s phenomenon

Neuritic pain

Vertigo/ataxia

Cognitive dysfunction

Tremor/incoordination

Rare MS Symptoms

Decreased hearing

Seizures

Tinnitus

Mental disturbance

Paralysis

Sources of Symptoms

Symptoms vary widely in incidence and severity

Sensory symptoms,Lhermitte’sPainProprioception

Optic neuritis

DiplopiaVertigoDysarthriaINO

Tremor,Ataxia

Cognitive loss

Emotional disinhibition

Bladder dysfunction

Symptom Management: Fatigue

75% to 95% of patients with MS have fatigue, which is often debilitating

Rule out possible other causes, such as hypothyroidism, depression, anemia, heat exposure, sleep disorders, pulmonary dysfunction

Shapiro RT, Schneider DM. Fatigue. In: Multiple Sclerosis in Clinical Practice; 1999. MS Council for Clinical Practice Guidelines. Fatigue and Multiple Sclerosis; 1998.

Symptom Management: Fatigue

Management includes:– Lifestyle changes

– Effective energy expenditure

– Pharmacologic interventions• CNS stimulants, eg, amantadine and modafinil• Antidepressants, eg, fluoxetine

Shapiro RT, Schneider DM. Fatigue. In: Multiple Sclerosis in Clinical Practice; 1999. MS Council for Clinical Practice Guidelines. Fatigue and Multiple Sclerosis; 1998.

Symptom Management: Pain

Pain is a complex sensory phenomenon

Multiple causes and types– Neuropathic

– Musculoskeletal

– Optic neuritis

– Spasticity

– Dystonia

Costello K et al, eds. Nursing Practice in Multiple Sclerosis: A Core Curriculum. New York: Demos; 2003.



Nonpharmacologic– Seating

– Posture improvement

– Physical therapy• Gait training• Assistive devices• Muscle strengthening/stretching

Pharmacologic options– Tricyclic antidepressants

• Amitriptyline (Elavil®), nortriptyline (Pamelor®)

– Antiepileptic medications• Carbamazepine (Tegretol®), gabapentin

(Neurontin®), phenytoin (Dilantin®)

– Antispasticity medications• Baclofen, tizanidine (Zanaflex®)• Benzodiazepines, eg, clonazepam (Klonopin®)



Symptom Management: Spasticity

Spasticity can – Limit mobility

– Expend excessive energy

– Cause discomfort

Described as– Tightness

– Pulling

– Tugging

– Aching

Symptom Management: Spasticity

Nonpharmacologic interventions – Stretching

– Positioning

– Seating

– Physical therapy

Surgical Interventions– Baclofen pump

– Rhizotomy

Pharmacologic interventions– Baclofen

– Tizanidine

– Diazepam

– Dantrolene

– Nerve blocks

– Botulinum toxin


Symptom Management: Bladder Dysfunction

Failure to store urine, empty bladder, or both

Symptoms include double voiding, hesitancy, frequency, urgency, incontinence, UTIs

Evaluation: rule out UTI, check post-void residual (ie, amount of urine remaining after voiding bladder)

Management– Antispasmodics – Tricyclic antidepressants– DDAVP (an antidiuretic hormone)– Alpha blockers– Intermittent self-catheterization– Indwelling catheter

Symptom Management: Bowel Dysfunction

Caused by lesions in spinal cord

Symptoms– Constipation is most common– Involuntary bowel – Diarrhea is uncommon

Management– Constipation: fiber, fluids, activity, bowel

training, laxatives, dietary modification– Involuntary bowel: fiber, anticholinergics,

dietary modification


1. Prosiegel M, Michael C. J Neurol Sci. 1993;115:S51-S54.2. Rao SM. Curr Opin Neurol. 1995;8:216-220.

Symptom Management: Cognitive Impairment

Occurs in 45% to 60% of patients1 but results in significant changes in only 15%2

Manifests as short-term memory loss or impaired judgment, learning, word finding, or executive functioning

Management– Neuropsychiatric testing– Compensatory techniques– Cognitive retraining– Disease-modifying therapies

Sexual Dysfunction/Intimacy

Men and women can experience difficulties

Libido

Erection

Frequency of orgasms

Lubrication

Bladder spasticity

Depression


Sexual Dysfunction/Intimacy

Management strategies include– Pharmacologic management

– Treat underlying symptoms

– Adjust medications

– Positioning

– Lifestyle changes

Key to successful management is open communication


Disease-Modifying Therapies

Disease Modification

Aim to alter the natural course of the disease– Decrease relapses

– Delay disability

Two classes of disease-modifying medications:– Immunomodulators

– Immunosuppressants

Noseworthy JH et al. N Engl J Med. 2000;343:938-952.

MS Immunotherapy

Nonspecific immunomodulation– Interferon beta-1b (Betaseron®), Interferon

beta-1a (Avonex®, Rebif®)

Selective immunomodulation– Glatiramer acetate (Copaxone®)

Nonspecific immunosuppression– Corticosteroids– Mitoxantrone (Novantrone®)– Cyclophosphamide (Cytoxan®)*

Experimental therapies*

*These drugs do not have FDA approval for use in MS.

Type Recombinant protein Polypeptide mixture

Indication Reduce relapse frequency in RRMS

Slow Slowaccumulation accumulationof disability of disability

How given 30 g IM 22 or 44 g SC 250 g SC 20 mg SCweekly every other day 3x/week daily

Relapse rate 18% 27%-33% 30% 32%(annualized) (2 years) (5 years) (long-term)

Published data 2 years 4 years 5 years 8+ years

IFN -1a(Rebif®)

Nonselective and Selective Immunomodulatory Treatments

IFN -1a(Avonex®)

IFN -1b(Betaseron®)

GlatiramerAcetate

(Copaxone®)

IFN -1a(Rebif®)

Nonselective and Selective Immunomodulatory Treatments

MRI findings Reduces Reduces Reduces rate Reduces lesions active lesions of new lesions lesions

Reduces risk for Reduces Reduces rate Reduces lossprogression disability of severe of brain tissue

of disability relapses

Common side Mild flulike symptoms, No flulike effects muscle aches, anemia symptoms

No Injection-site reactionsinjection-site

reactions Menstrual Systemicdisorders; mild post-neutropenia and injection

thrombocytopenia; reactionabnormal liver

function

IFN -1a(Avonex®)

IFN -1b(Betaseron®)

GlatiramerAcetate

(Copaxone®)

Mechanisms of Action

Cytokine Imbalance in MS

Normal MS

InflammatoryIFN-IL-12TNF

InflammatoryIFN- IL-12TNF

Anti-inflammatory

IL-4IL-10TGF-

Anti-inflammatory

IL-4IL-10TGF-

Th1 Th2

Th1

Th2

Potential Mechanisms ofAction of IFN- in MS

Antiproliferative effect

Blocking T-cell activation

Apoptosis of autoreactive T cells

IFN- antagonism

Cytokine shifts

Antiviral effect

Does not cross blood-brain barrier

Indirect effects on CNS

IFN-β

MS

InflammatoryTh1 cytokines

Anti-inflammatoryTh2 cytokines

IL-10

IL-12

IFN-β–Induced Cytokine Shift

Th1+

RestingT cell

MMP


Th1+

Th1+

MMP

BBBBlood CNS

Th1+

TNF-α

IFN-γ

IL-2

Th1APC APC

IFN-β

IFN-β

MyelinproteinAntigen

Adapted from Yong VW. Neurology. 2002;59:802-808.

Effects of IFN- at Blood-Brain Barrier

Glatiramer Acetate: Possible Mechanisms of Action

Blocking autoimmune T cells

Induction of anergy

Induction of anti-inflammatory Th2 cells

Bystander suppression

Neuroprotection

Neuhaus O et al. Neurology. 2001;56:702-708.

Th2+

Adapted from Yong VW. Neurology. 2002;59:802-808.

Th2+

GA-inducedT cell

MMP


Th2+

Th2+

MMP

MMP

BBBBlood CNS

IL-4 TGF-β

Bcell

IL-10

Th2APC APC

Glatiramer acetate (GA)

Myelinprotein

• Bystander suppression

Effects of Glatiramer Acetateat Blood-Brain Barrier

Relapse Rates

0.25

0.50

0.75

1.00

1.25

1.50

1 2 3 4 5

PlaceboInterferon -1b, 8 MIU

Mea

n N

um

ber

of

Rel

apse

s 33%*

Study Year

28%†

28%‡

30%‡24%‡

Adapted from IFNB Multiple Sclerosis Study Group. Neurology. 1995;45:1277-1285.

*P < 0.001; †P < 0.05; ‡P = NS.

IFN -1b: Annual Relapse Rates Over 5 Years

Adapted from Jacobs LD et al. Ann Neurol. 1996;39:285-294.

Mea

n N

um

ber

of

Rel

apse

s

00.10.20.30.40.50.60.70.80.91.0

All Patients Patients Treated

2 Years

PlaceboInterferon -1a18%*

32%†

*P < 0.04; †P < 0.002.

Interferon β-1a IM: Annual Relapse Rate

PRISMS Study Group. Neurology. 2001;56:1628-1636.

Placebo/Active

22 g 3/wk

44 g3/wk

Placebo Both IFN -1a Arms

0.720.801.02

1.5 1.5

52%47%32%

P < 0.0001

P < 0.0001

0.0

0.5

1.0

1.5

2.0

Prior to Study Entry

Mea

n N

um

ber

of

Rel

apse

s/P

atie

nt/

Yea

r

At 4 Years

Annual Mean Number of Relapses for IFN -1a SC

Placebo

Glatiramer Acetate: Mean Relapse Rate

Adapted from Johnson KP et al. Neurology. 1998;50:701-708.

Glatiramer Acetate

0.00.20.40.60.81.01.21.41.61.82.0

Mea

n N

um

ber

of

Rel

apse

s

24 Months 24 Months + Extension

29%*

32%†

*P < 0.007; †P < 0.002.

Glatiramer Acetate: 8-Year DataAnnualized Relapse Rate

P = 0.05P = 0.01

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Re

lap

se

Rat

e (

me

an

s)

Entry Placebo-ControlledPhase and Extension

Placebo-ControlledPhase Through

Open-Label Phase

Glatiramer AcetatePlaceboPlacebo/Active

Johnson KP et al. Neurology. 2002;58(suppl 3):A458. P06.079.

Mean Annual Relapse Rates of DMTsNonrandomized, Open-Label Study

Haas J et al. Presented at: AAN, 2003.

INF β-1a IMINF β-1b SCGAINF β-1a 22 μg SC

1.4

1.2

1.0

0.8

0.4

0.6

0.2

0.0Before Study 6 Months 12 Months 24 Months

Mea

n N

um

ber

of

Rel

apse

s

Effects on Disability

ITT progression-free patients: all crossover vs 3 44 g:

P = 0.07

Adapted with permission from PRISMS-4 Study Group. Neurology. 2001;56:1628-1636.

Time (months)0 6 12 18 24 30 36 42 48

1.0

0.8

0.6

0.4

Placebo/44Placebo/22

3 443 22

Pro

po

rtio

n o

f P

ati

ents

IFN -1a SC: Proportion of Patients Free From Progression Over 4 Years

Time to progression:P = 0.096

Patients With Sustained Progression 1 EDSS Step

Placebo 46% (56/122)

IFN -1b 8 MIU 35% (43/122)

Adapted with permission from the IFNB MS Study Group. Neurology. 1995;45:1277-1285.

Pro

bab

ilit

y (%

)

Days

0 180 360 540 720 900 1080 1260 1440 1620 1800

100

90

80

70

60

50

40

30

20

10

0

8 MIUPlacebo1.6 MIU

IFN -1b: Probability of Avoiding Progression Over 5 Years

Johnson KP et al. Mult Scler. 2000;6:255-266.

0 1 2 3 4 5 6 7

Placebo/Active (n = 107)Glatiramer Acetate (n = 101)Time to worsening: P = 0.048

Open-Label PhasePlacebo-Controlled

Phase

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Su

rviv

al D

istr

ibu

tio

n E

stim

ate

Years

Glatiramer Acetate: Time to Worsening by 1.5 EDSS Steps Over 6 Years (Open-Label Cohort)

Glatiramer Acetate: 8-Year DataYearly EDSS Change From Baseline

Ch

ang

e in

ED

SS

Sco

re

Entry 1 2*

3*

4*

5 6 7 8

Year*P < 0.05.

Glatiramer AcetatePlacebo/Active

P = 0.0279 (RMA)

0.8

0.4

0.7

0.6

0.5

0.2

0.3

0.0

0.1

–0.1

Johnson KP et al. Neurology. 2002;58(suppl 3):A458.

Glatiramer Acetate: 8-Year DataCategorical EDSS Change From Randomization

to Last Observation

65.3

50.4

34.7

49.5

0

5

15

25

35

45

55

65

75

Improved/No Change Worsened

Glatiramer AcetatePlacebo/Active

Pat

ien

ts (

%) P = 0.0263

Johnson KP et al. Neurology. 2002;58(suppl 3):A458.

MRI Findings

MRI Endpoints in RRMS TrialsT2 Lesion Burden (Median % Change)*

*Weekly doses reported.1. Paty DW, Li DK. Neurology. 1993;43:662-667.2. Comi G et al. Ann Neurol. 2001;49:290-297.

66 μg

–15 –10 –5 0 5 10 15 20

P < 0.001

P = 0.36

P < 0.0001

IFN β-1b 1

IFN β-1a IM

Placebo

175 μg

875 μg

Placebo

132 μg

30 μg

Placebo

Glatiramer acetate 2

25

PlaceboP = 0.001

140 mg

IFN β-1a SC

IFN -1a IM: Change in Volumeof Black Holes (Total Lesion Load)

0

25

50

75

100

125

150

Placebo IFN β-1a IM

To

tal L

esio

n L

oad

(m

m3),

M

ed

ian

Ch

an

ge

Fro

m B

ase

line

P = 0.065, NS

n = 80 n = 80

Simon JH et al. Neurology. 2000;55:185-192.

Active lesion—new or enlarging T2, new or persistently Gd-enhancing, avoiding double counting. The exact relation between MRI findings and the clinical status of patients is unknown.

Panitch H et al. Neurology. 2002;59:1496-1506.

0

1

2

3

4

5

6

7

8

Week (4-Week MRI Scans)

0 4 8 12 16 20 24

Mea

n C

um

ula

tive

C

U A

ctiv

e L

esio

ns

*P < 0.001 at Week 24

EVIDENCE Trial CU Lesions

IFN β-1a 30 μg qw IM

IFN β-1a 44 μg tiw SC

9.7

7.2

3.4

–6.2

–10

–5

0

5

10

Placebo/22 μgtiw SC(n = 57)

Placebo/44 μgtiw SC(n = 49)

IFN β-1a 22 μgtiw SC

(n = 117)

IFN β-1a 44 μgtiw SC

(n = 111)

IFN β-1a 44 tiw SC vs placebo/44 tiw SCIFN β-1a 22 tiw SC vs placebo/22 tiw SCIFN β-1a 44 tiw SC vs IFN β-1a 22 tiw SC

Med

ian

Per

cen

t C

han

ge

in T

ota

l T2

Les

ion

Are

a

The exact relation between MRI findings and the clinical status of patients is unknown.

PRISMS Study Group. Neurology. 2001;56:1628–1636 [correction in 57:1146].

P = 0.11 P = 0.003 P = 0.009

IFN β-1a SC Long-term Data: MRI T2 Lesions

Adapted with permission from the IFNβ MS Study Group. Neurology. 1995;45:1277-1285.

6.7

21.0

30.2

11.9

18.7

3.6

–0.8–3.8–4.9 –5.6

1 2 3 4 5

Placebo8 MIU

Med

ian

Ch

ang

e A

fter

Bas

elin

e

P = 0.0363

Study Year

P = 0.0012

P = 0.0015

P = 0.0002 P = 0.0055

35

–10

–5

0

5

10

15

20

25

30

IFN -1b: Median Change in MRI-Measured BOD217 Patients Having at Least a Fourth-Year Annual Scan

Stone LA et al. Neurology. 1997;49:862-869.

Months on Study (27 Subjects)

1 2 3 4 5 6 7 8 9 10 11 120

20406080

100120140160

To

tal E

nh

ance

men

ts

80%–90% response

Interferon β-1b initiated

Effect of IFN -1b on Enhancements

Months

Placebo

0

5

Vo

lum

e %

Ch

ang

e (m

edia

n)

1 2 3 4 5 6 7 8 9

Comi G et al. Neurology. 2001;56(suppl 3):A255.

Glatiramer Acetate 9-Month Data:MRI T2 Lesions

25

20

15

10

Glatiramer Acetate

Adapted with permission from Comi G et al. Ann Neurol. 2001;49:290-297. This material is used by permission of John Wiley & Sons, Inc.

Primary Endpoint: Cumulative Numberof Enhancing Lesions (9 Months)

36.8

26.0

0

5

10

15

20

25

30

35

40

45

Les

ion

Nu

mb

er (

mea

n +

SE

)

–29%P = 0.0032

LOCF

PlaceboGlatiramer Acetate

Glatiramer acetate had significant effects on:

Reduction P Value

Total number of enhancing lesions (LOCF) 29% 0.003

Total number of enhancing lesions (as is) 35% 0.001

Total number of new enhancing lesions 33% 0.003

Total number of new T2 lesions 30% 0.003

T2 lesion volume (median, from baseline) 40% 0.001

Relapse rate (9 months) 33% 0.01

Comi G et al. Ann Neurol. 2001;49:290-297.

European/Canadian MRI Trial: Summary

Glatiramer Acetate: Evolution to Black Holes

0

5

10

15

20

25

30

35

7 8

Lesion Age (months)

Les

ion

s E

volv

ing

Into

B

lack

Ho

les

(%)

P = 0.002

P = 0.04 31.4%

15.6%

Filippi M et al. Neurology. 2001;57:731-733.

PlaceboGlatiramer Acetate

50%

Safety and Tolerability

Long-term Safety and Tolerability Issues: IFNs

Flulike syndrome (fever, chills, fatigue) – Experienced by up to 75% of patients taking

an IFN-β

Injection-site reaction and necrosis

Depression

Liver function and bone marrow abnormalities

Neutralizing antibodies

PRISMS Study Group. Lancet. 1998;352:1498-1504.Freedman M. Presented at: The American Academy of Neurology 52nd Annual Meeting; April 29-May 6, 2000; San Diego, Calif.The IFNB MS Study Group. Neurology. 1995;45:1277-1285.

Neutralizing Antibodies

Conflicting evidence regarding role of neutralizing antibodies in treatment failure

38% of patients in the IFN -1b trial developed neutralizing antibodies by the end of the third year1

5% of patients in a recent weekly IFN -1a IM trial who had received drug for at least 1 year developed neutralizing antibodies2

1. The IFNβ Multiple Sclerosis Study Group. Neurology. 1993;43:655-661.2. Avonex® [package insert]. Cambridge, Mass: Biogen, Inc; 2003.

Glatiramer Acetate–Reactive Antibodies

In clinical trials, patients treated with glatiramer acetate developed reactive antibodies that peaked at 3 months and decreased at 6 months1

Development of these antibodies did not correlate with side effects and did not affect therapeutic activity of glatiramer acetate1

Additional recent research confirms that reactive antibodies do not interfere with the biological functions of glatiramer acetate2

1. Brenner T et al. J Neuroimmunol. 2001;115:152-160.2. Teitelbaum D et al. Mult Scler. 2003;9(suppl 1):S37.

Long-term Safety and Tolerability Issues: Glatiramer Acetate

Injection-site reaction

Immediate postinjection reaction

Copaxone® [package insert]. Kansas City, Mo: Teva Marion Partners; 2000.

possibly

no

C

B

noyesyesyesIFN

yesnonoyesGA

Menstrual disorders

Pregnancy category

Post-injection reaction

Flulike symptoms

Lab changes

Injection- site

reaction

Safety and Tolerability Issues

Side Effect Management

Walther EU, Hohlfeld R. Neurology. 1999;53:1622-1627.

Side Effect Management: IFN Flulike Symptoms

Begin 3-6 hours after injection; last up to 24 hours

Management:– Injection at night

– NSAIDs or acetaminophen as comedications

– Dose titration

Not experienced with glatiramer acetate

1. Copaxone® [package insert]. Kansas City, Mo: Teva Marion Partners; 2000.

Side Effect Management:IFN Laboratory Test Abnormalities

Obtain baseline complete blood count and differential and liver function values before initiation of therapy

Monitor laboratory test values at regular intervals after initiation of therapy

Consider dose adjustment or discontinuation of treatment if abnormalities persist

Not indicated with glatiramer acetate1

Side Effect Management: IFN Injection-Site Reactions

Site rotation

Ice to injection site

Use of autoinjector

Local wound care for skin necrosis

Side Effect Management:Glatiramer Acetate Injection-Site Reactions

Site rotation

Ice to injection site

Use of autoinjector

Side Effect Management:Glatiramer Acetate Postinjection Reaction

Occurs immediately after injection and consists of facial flushing, chest tightness, palpitations, anxiety, and shortness of breath

Unrelated to serious sequelae

Treatment steps:– Educate patient about possible occurrence– Reassure patient if reaction occurs– Instruct patient to sit upright in a comfortable

chair– Refer for emergency care if no improvement

in symptom intensity after 15-20 minutes

Quality of Life andAdherence

Facilitating an Acceptable QOL

Quality of life (QOL) is the congruence between actual life conditions and one’s hopes and expectations

MS, with its range of symptoms and its progressive nature, has a profound effect on QOL

Maximizing QOL is an essential component of an optimal management strategy

Includes comprehensive approach

Promoting Adherence

Educate about the critical role of adherence in outcomes

Recognize and address barriers to adherence

Importance of clarifying realistic expectations

Advocacy– Assistance with reimbursement

– Identify resources

– Involve family

Burden of diseaseEnhancing lesions

Disease courseNumber of relapses

Medical PatientConsiderations Considerations

LifestyleExpectationsCapabilities

Support system

Factors That Influence Treatment Decisions

Summary

Summary: Goals of DiseaseManagement in MS

Modifying/reducing relapses and delaying progression to disability

Treating relapses

Managing symptoms

Facilitating an acceptable quality of life

Documents

Multiple Sclerosis Disease Overview & Current Management Strategies