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 Demographics of MS MS is primarily a disease affecting women, although approximately 30% of those with the condition are men.1 Its onset is generally at the prime of life, between the ages of 15 and 45.2 For reasons that are as yet unclear, MS is more common in cooler climates and is increasingly more common with increased distance from the equator.3 The incidence of MS, or the number of new cases per year, is estimated to be between 8,500 and 10,000,2 and the prevalence, or total number of cases, is about 350,000 in the United States.1 1. Anderson DW, Ellenberg JH, Leventhal CM, et al. Revised estimate of the prevalence of multiple sclerosis in the United States. Ann Neurol. 1992;31: 2. Jacobson DL, Gange SJ, Rose NR, Graham NMH. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol. 1997;84: 3. Kurtzke JF. Epidemiologic evidence for multiple sclerosis as an infection. Clin Microbiol Rev. 1993;6: 1. Jacobsen DL et al. Clin Immunol Immunopathol. 1997;84: 2. Anderson DW et al. Ann Neurol. 1992;31:

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 Worldwide Prevalence of MS The prevalence of MS varies with geographic location. Kurtzke developed a classification system based on low prevalence (less than 5 cases per 100,000), intermediate prevalence (5 to 30 per 100,000), and high prevalence (more than 30 per 100,000).1 The prevalence is highest in northern Europe, southern Australia, and northern United States and Canada.2 There is a trend toward increasing prevalence and incidence in southern Europe.3,4 1. Kurtzke JF. Multiple sclerosis: changing times. Neuroepidemiology. 1991;10:1-8. 2. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343: 3. Rosati G, Aiello I, Pirastru MI, et al. Epidemiology of multiple sclerosis in northwestern Sardinia: further evidence for higher frequency in Sardinians compared to other Italians. Neuroepidemiology. 1996;15:10-19. 4. Bufill E, Blesa R, Galan I, Dean G. Prevalence of multiple sclerosis in the region of Osona, Catalonia, northern Spain. J Neurol Neurosurg Psychiatry. 1995;58: Kurtzke JF. Neuroepidemiology. 1991;10:1-8.

Pathophysiology and 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 Pathology of MS Inflammation leads to loss of the myelin sheath, or demyelination, which slows conduction along the nerve axon and leads to neurological symptoms. When the inflammation associated with an acute attack lessens, the symptoms abate. However, there is evidence that the nerve axons are also damaged due to MS, and this damage is associated with permanent neurological dysfunction.1 MS lesions tend to occur in specific areas of the central nervous system (CNS): Optic nerves Periventricular white matter Brain stem Cerebellum Spinal cord The specific type of symptoms a patient experiences is related to the location of the lesions within the CNS. When acute inflammation lessens, symptoms remit, either partially or completely. 1. Trapp BD, Peterson J, Ranshoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338: Trapp BD et al. N Engl J Med. 1998;338:

Axonal Transection in Acute MS Lesions
The slide shows staining of tissue with SMI-32, a mouse anti-nonphosphorylated neurofilament antibody, in the study by Trapp et al.1 The green in both panels of the slide indicates nonphosphorylated neurofilaments; the red in panel B indicates myelin. Panel A shows the center of an active lesion. The arrows point to terminal axonal ovoids (where the axons are transected) with single axonal connections, and the arrowhead points to an axonal ovoid with 2 axonal connections (scale bar equals 64 m). Panel B shows edges of chronic active lesions. In this panel, 3 large, nonphosphorylated neurofilament–positive axons are undergoing active demyelination (arrowheads); the arrow points to an axon ending in a large terminal ovoid (scale bar equals 45 m). Most of the axons with pathologic changes indicated by the SMI-32 reactivity have a normal appearance. 1. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338: 64m 45m A B Reprinted with permission from Trapp BD et al. N Engl J Med. 1998;338: Copyright  1998 Massachusetts Medical Society. All rights reserved.

What Causes Demyelination and 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 What Causes Demyelination and Axonal Loss in MS? The exact cause of the inflammation and the immune response that underlie MS is not known. However, several lines of evidence suggest that immunopathological events, which may be autoimmune in origin, are responsible for the development of MS. Preexisting autoreactive CD4+ T cells in the periphery become activated.1,2 These cells exist in healthy individuals also but become activated only in MS patients and may reflect an immune regulatory defect. Autoreactive Th1 cells (a type of T-helper/CD4+ cell) migrate into the CNS. The blood-brain barrier (BBB) can be breached by lymphocytes if they are in a state of high activation. In situ reactivation of myelin autoantigens stimulates an immune response. Th1 cells secrete proinflammatory cytokines, including interferon- or interleukin-2, which induce inflammation by activating macrophages, other T cells, and B cells.2,3 Increases in Th1 cytokine levels often precede relapses. Demyelination, axonal transection, and degeneration Acute attack is due to demyelination; resolution is due to reduction of inflammation, accompanied by partial remyelination. Axonal loss leads to permanent disability.4,5 1. Benoist C, Mathias D. Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry? Nat Immun. 2001;2: 2. Lang HL, Jacobsen H, Ikemizu S, et al. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat Immunol. 2002;3: 3. Archelos JJ, Storch MK, Hartung HP. The role of B cells and autoantibodies in multiple sclerosis. Ann Neurol. 2000;47: 4. Trapp BD, Ransohoff R, Rudick R. Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr Opin Neurol. 1999;12: 5. Yong VW. Pathology, immunology, and neuroprotection in MS: mechanisms and influence of MS therapeutics. Int J MS Care. 2002;Dec(suppl):4-9.

Immunopathogenesis of MS
Resting T cell MMP Activated (+) T cells BBB Blood CNS TNF- IFN- B cell IL-2 Th1 APC Immunopathogenesis of MS While it remains to be demonstrated conclusively, it appears that the MS pathogenesis has 3 phases1,2: An initial inflammatory phase that meets the criteria for an autoimmune disease A phase of selective demyelination A neurodegenerative phase Inflammatory phase1,2 Proinflammatory T cells in the periphery are activated by antigen-presenting cells (APCs). These activated T cells migrate to and penetrate the BBB. Once in the CNS, these T cells are reactivated by APCs and secrete proinflammatory cytokines, inducing CNS inflammation via activation of macrophages, other T cells, and B cells. Demyelination phase1,2 Macrophages and T cells attack the myelin sheath by cytotoxic mediators, including tumor necrosis factor–, O2 radicals, and nitric oxide; B cells differentiate into plasma cells that secrete demyelinating antibodies. 1. Neuhaus O, Archelos JJ, Hartung H-P. Immunomodulation in multiple sclerosis: from immunosuppression to neuroprotection. Trends Pharmacol Sci. 2003;24: 2. Yong VW. Pathology, immunology, and neuroprotection in MS: mechanisms and influence of MS therapeutics. Int J MS Care. 2002;Dec(suppl):4-9.

Immunopathogenesis of MS
MMP Activated (+) T cells Blood BBB Th1+ CNS TNF- IFN- B cell IL-2 Th1 APC Resting T cell APC Immunopathogenesis of MS While it remains to be demonstrated conclusively, it appears that the MS pathogenesis has 3 phases1,2: An initial inflammatory phase that meets the criteria for an autoimmune disease A phase of selective demyelination A neurodegenerative phase Inflammatory phase1,2 Proinflammatory T cells in the periphery are activated by antigen-presenting cells (APCs). These activated T cells migrate to and penetrate the BBB. Once in the CNS, these T cells are reactivated by APCs and secrete proinflammatory cytokines, inducing CNS inflammation via activation of macrophages, other T cells, and B cells. Demyelination phase1,2 Macrophages and T cells attack the myelin sheath by cytotoxic mediators, including tumor necrosis factor–, O2 radicals, and nitric oxide; B cells differentiate into plasma cells that secrete demyelinating antibodies. 1. Neuhaus O, Archelos JJ, Hartung H-P. Immunomodulation in multiple sclerosis: from immunosuppression to neuroprotection. Trends Pharmacol Sci. 2003;24: 2. Yong VW. Pathology, immunology, and neuroprotection in MS: mechanisms and influence of MS therapeutics. Int J MS Care. 2002;Dec(suppl):4-9.

Disability Progression and Disease Type
Relapsing-remitting Secondary-progressive Disability Disability Time Time Primary-progressive Progressive-relapsing Disability Disability Disability Progression and Disease Type Multiple sclerosis has been divided into 4 subtypes, based on the disease course1: Relapsing-remitting—characterized by relapses of neurological symptoms followed by periods of recovery when symptoms abate, with or without residual disability (50% progress to secondary-progressive) Secondary-progressive—initially has a relapsing-remitting course that changes over time such that patients have fewer relapses and a slower progression of symptoms Primary-progressive—characterized by slow and steady progression of symptoms, without asymptomatic periods Progressive-relapsing—initially has a progressive course, but an exacerbation occurs after establishment of the progressive course 1. Lublin F, Reingold S, for the National Multiple Sclerosis Society Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996;46: Time Time Lublin FD, Reingold SC. Neurology. 1996;46:

Natural History Over Time
Relapsing-remitting Secondary-progressive Primary-progressive Relapsing-remitting 15% 42% 85% 58% Natural History Over Time This slide presents data on the natural history of MS in untreated patients, obtained before the availability of disease-modifying therapies (DMTs). While most patients with MS present with a relapsing-remitting course, as many as 58% of those with an initial diagnosis of relapsing-remitting MS (RRMS) will go on to a secondary-progressive course after having the disease for 11 to 15 years.1 Moreover, the percentage of patients with progressive disease from onset increases with each decade of life; the majority of patients older than 50 years of age at diagnosis have the progressive course.1 1. Weinshenker BG, Bass B, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study. Brain. 1989;112: Disease Type at Diagnosis Disease Type at Years After Diagnosis (Among Those With RRMS at Diagnosis) Adapted from Weinshenker BG et al. Brain. 1989;112:

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 Progression to Disability: EDSS An important assessment of MS progression is the accumulation of disability over time. In other words, during a relapsing-remitting course, acute symptoms may resolve but there is evidence of underlying fixed neurological damage.1 A measure commonly used to quantify the accumulation of fixed disability is the Expanded Disability Status Scale (EDSS).2 Advantages Uses an ordinal scale (range 0-10) to measure disability in increments of 0.5 Is the most widely accepted measure of disability in patients with MS Reflects impact of disease on neurological function Disadvantages3 Not exclusively objective Heavily weighted toward ambulation Insensitive to cognitive and upper limb disabilities 1. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338: 2. Kurtzke JF. Rating neurological impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33: 3. Sharrack B, Hughes RAC. Clinical scales for multiple sclerosis. J Neurol Sci. 1996;135:1-9. Kurtzke JF. Neurology. 1983;33:

Progression to Disability: EDSS
0 Normal neurological exam 1.0–1.5 No disability 2.0–2.5 Minimal disability 3.0–3.5 Mild to moderate disability 4.0–4.5 Moderate disability 5.0–5.5 Increasing limitations in ability to walk 6.0–6.5 Walking assistance is needed 7.0–7.5 Confined to wheelchair 8.0–8.5 Confined to bed/chair; self-care with assistance 9.0–9.5 Completely dependent 10.0 Death due to MS Progression to Disability: EDSS The EDSS is divided into stages that reflect increasing disability1: With an EDSS of <4, the patient can still participate in most activities of daily living (ADL), except in unusual circumstances. With an EDSS of 4.0 to 4.5, some mild disability may become manifest. With an EDSS of 5.0 to 5.5, the patient can walk but may be unable to participate in a full day’s activity. The lower the number, the less disability: With an EDSS of 6.0 to 6.5, assistance is required for walking. With an EDSS of 8.0 to 8.5, the patient is confined to bed. Clinical trials have used this scale to assess whether interventions reduce the progression to disability, by showing movement up a smaller number of steps during a certain time period. 1. Kurtzke JF. Rating neurological impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:

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 Natural History Natural history studies, conducted prior to the availability of immunomodulatory therapy, showed the following: Mortality from MS is low (life expectancy is at least 25 years after diagnosis; most patients die of unrelated conditions1). Average is 1 relapse per year, fewer over time.1 25% of patients never lose ability to perform ADL.1 15% become severely disabled within a short time.1 Median time to reach EDSS of 6 is 15 years; to reach EDSS of 8 is 46 years2 (at EDSS of 6, assistance with walking is needed; at EDSS of 8, patients are confined to bed or chair and perform self-care only with help). 1. Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359: 2. Weinshenker BG, Bass B, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study. Brain. 1989;112: 1. Compston A, Coles A. Lancet. 2002;359: 2. Weinshenker BG et al. Brain. 1989;112:

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 Diagnosis of MS: Basic Principles Ultimately, MS is a clinical diagnosis; no definitive laboratory test exists.1 Clinical profile consists of symptomatic disease, abnormal exam, and white matter involvement, which are consistent with diagnosis.1 Laboratory evaluation includes1: Magnetic resonance imaging (MRI)—imaging to identify lesions (will discuss in more detail) Cerebrospinal fluid (CSF)—evidence of intrathecal inflammation Abnormal CSF includes: – Oligoclonal immunoglobulin G (IgG) bands in CSF and not in serum – Elevated IgG index Evoked potentials—evidence of altered conduction in a pattern consistent with demyelination Evidence of dissemination of lesions in space and time is key to making diagnosis; there must be at least 2 distinct attacks affecting at least 2 areas of the CNS.1 Evaluation should exclude other diagnoses, such as lupus erythematosus, CNS tumors, vasculitis, and endocrine disturbances.1 1. Coyle P. Diagnosis and classification of inflammatory demyelinating disorders. In: Burks J, Johnson K, eds. Multiple Sclerosis, Diagnosis, Medical Management and Rehabilitation. New York: Demos; 2000:81-97. 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/legs % Unilateral vision loss % 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% Most Common Presenting Symptoms The location of the demyelinating lesions influences the types of symptoms patients develop. In a study conducted at the University of British Columbia, Paty et al determined that the initial symptoms in 1721 patients with clinically definite MS were as follows1: Sensory symptoms in arms/legs Unilateral vision loss Slowly progressive motor deficit Acute motor deficit Diplopia Polysymptomatic onset Others Over the disease course, symptoms are highly variable in both frequency and severity. Fatigue is the most common symptom in 80% of patients with MS.2 1. Paty DW, Noseworthy JH, Ebers GC. Diagnosis of multiple sclerosis. In: Paty DW, Ebers GC, eds. Multiple Sclerosis: Contemporary Neurology Series. Philadelphia: FA Davis; 1998. 2. Reingold S. Fatigue and multiple sclerosis. MS News British Multiple Sclerosis Society. 1990;142:30-31 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 Metabolic Vitamin B12 and E deficiencies CADASIL, other rare familial diseases CNS lymphoma Cervical spondylosis Motor neuron disease Myasthenia gravis Diagnoses That Mimic MS Laboratory studies to exclude diseases whose symptoms that may mimic those of MS are advisable before an MS diagnosis is made. These other diseases include1: Metabolic disorders Autoimmune diseases Infectious diseases Vascular disorders Genetic syndrome Lesions of the posterior fossa and spinal cord Psychiatric disorders Neoplastic illnesses Variants of MS 1. Noseworthy JN, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343: Cohen J, Rensel M. In: Burks J, Johnson K, eds. Multiple Sclerosis Diagnosis, Medical Management and Rehabilitation. New York: Demos; 2000:

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 Use of MRI in Diagnosis The expanded diagnostic criteria help clarify the role of MRI in the diagnosis of MS. In general, MRI is used in the diagnosis of MS1: To improve confidence in a clinical diagnosis of MS or to make a diagnosis of MS in clinically isolated syndromes To show dissemination in space and time (eg, new lesions on follow-up MRI) Total lesion load at diagnosis tends to be predictive of future disability: In a study of patients with a clinically isolated lesion followed for 14 years, the number and volume of MRI lesions at presentation and at 5 years were predictive of disability at 14 years, but with low correlation coefficients.2 1. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol. 2001;50: 2. Brex PA, Ciccarelli O, O’Riordan JI, et al. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med. 2002;346: 1. McDonald WI et al. Ann Neurol. 2001;50: 2. Brex PA et al. N Engl J Med. 2002;346:

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 MRI Basics in Diagnosing MS1 T1-weighted scan Shows new or hypointense lesions (ie, black holes) Indicates areas with recent inflammatory demyelination and disruption of the BBB T2-weighted scan: Generally indicates the burden of disease (BOD) Reflects broad spectrum of pathological changes, including inflammation, edema, demyelination, and axonal loss Fluid-attenuated inversion recovery (FLAIR) image The fast FLAIR image improves the ability to detect subcortical and cortical lesions, but it is less optimal in detecting lesions in the posterior fossa or in detecting spinal cord pathology.2 Gadolinium (Gd): Helps identify active lesions, since the contrast medium will enter the CNS only if the BBB has been breached 1. Costello K, Hill CA, Tranter MC. Multiple sclerosis in the primary care setting: key issues for diagnosis and management. American Journal for Nurse Practitioners. October 2000:9-30. 2. Simon JH. Magnetic resonance imaging in the diagnosis of multiple sclerosis, elucidation of disease course, and determining prognosis. In: Burks J, Johnson K, eds. Multiple Sclerosis: Diagnosis, Medical Management, and Rehabilitation. New York: Demos; 2000: Costello K et al. American Journal for Nurse Practitioners. October 2000:9-26. Noseworthy JH. N Engl J Med. 2000;343:

MS Lesions on MRI A B T2 T2-FLAIR C D T1 precontrast
BOD T2-FLAIR C D T1 precontrast black holes T1/Gd postcontrast disease activity MS Lesions on MRI Various MRI metrics are used in assessing MS disease activity: A is a T2-weighted MRI that indicates total BOD. B is a FLAIR image, an MRI technique designed to demonstrate specific aspects of lesions by revealing tissue T2 prolongation with CSF suppression. C is a T1-weighted MRI without Gd contrast that shows black holes—lesions that do not enhance with Gd in subsequent scans and thus are not active lesions. These areas indicate locations of severe axonal damage and permanent CNS damage. D is a T1-weighted MRI with Gd contrast that reflects active lesions, thus showing the level of disease activity. Black holes Are T1-weighted hypointensities Reflect areas of axonal loss Correlate most strongly with the progression of disability Thought to be areas of permanent damage when not associated with a new lesion It should be noted that these representative MRI scans do not come from the same patient. Reference for image A: Miller DH. Magnetic Resonance Imaging in Multiple Sclerosis. Cambridge: Cambridge University Press; 1997. Reference for image B: Noseworthy JH et al. Multiple sclerosis. N Engl J Med. 2000; 343: Reference for images C and D: Courtesy Jerry Wolinsky, MD.

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 Diagnostic Categories In 2002, the International Panel on the Diagnosis of Multiple Sclerosis published revised diagnostic criteria that include the use of new technology.1 The recommendations preserve the traditional criteria of 2 attacks of disease separated in space and time, but add specific MRI, CSF, and evoked potential findings as means of identifying the second attack. Results from these modalities are used in conjunction with previously established clinical criteria to place the patient in 1 of 3 possible categories: Multiple sclerosis, possible multiple sclerosis, or not multiple sclerosis The Poser criteria proposed in 1983 are2: Clinically definite MS: 2 attacks and clinical evidence of 2 separate lesions; 2 attacks, clinical evidence of 1 and paraclinical evidence of another separate lesion Laboratory-supported definite MS: 2 attacks, either clinical or paraclinical evidence of 1 lesion, and CSF immunologic abnormalities; 1 attack, clinical evidence of 2 separate lesions and CSF abnormalities; 1 attack, clinical evidence of 1 and paraclinical evidence of another separate lesion, and CSF abnormalities Clinically probable MS: 2 attacks and clinical evidence of 1 lesion; 1 attack and clinical evidence of 2 separate lesions; 1 attack, clinical evidence of 1 lesion, and paraclinical evidence of another separate lesion Laboratory-supported probable MS: 2 attacks and CSF abnormalities 1. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol. 2001;50: 2. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983;13; McDonald WI et al. Ann Neurol. 2001;50:

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 MRI Criteria For MRI findings to be diagnostic of MS in the proposed criteria, 3 of the following must be met1: 1 Gd-enhancing lesion or 9 T2-hyperintense lesions 1 or more infratentorial lesion 1 or more juxtacortical lesion 3 or more periventricular lesions 1 spinal cord lesion can be substituted for 1 brain lesion in the criteria. 1. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol. 2001;50: McDonald WI et al. Ann Neurol. 2001;50:

McDonald MRI Criteria Gd-enhancing T2-hyperintense Juxtacortical
Periventricular Spinal Cord Infratentorial McDonald MRI Criteria The images on this slide demonstrate certain diagnostic MRI characteristics encompassed by the McDonald criteria1: Gd-enhancing lesions T2-hyperintense lesions Infratentorial lesions Juxtacortical lesions Periventricular lesions Spinal cord lesions 1. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol. 2001;50: Images courtesy of Kathleen Costello.

Brain Atrophy Brain Atrophy This slide illustrates the process of brain atrophy. Panel A is from a 31-year-old healthy man; panel B, a 36-year-old woman with RRMS of 2 years’ duration; and panel C, a 43-year-old woman with secondary-progressive MS (SPMS) of 19 years’ duration.1 Axial cranial MRI scans in 3 individuals show increasing ventricular size with decreasing brain parenchymal fractions (BPFs). 1. Rudick RA, Fisher E, Lee J-C, et al. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology. 1999;53: Reprinted with permission from Rudick RA et al. Neurology. 1999;53:

Measures of brain volume Relapses and impairment Secondary-progressive
Disease Progression Measures of brain volume Relapses and impairment MRI burden of disease MRI activity Secondary-progressive Preclinical Relapsing-remitting Disability Disease Progression This slide presents a graphical representation of the general clinical course of MS. The preclinical phase is characterized by no change in brain volume and no significant impairment, although symptoms may be present and lesions are apparent on MRI. Relapsing-remitting MS is characterized by a gradual reduction in brain volume, increased incidence of relapses and impairment, gradual increase in burden of disease, and ongoing MRI activity. Secondary-progressive MS is characterized by decreased brain atrophy, increased disability, and greatly increased burden of disease. Graphic adapted with permission from JS Wolinsky. Time Adapted with permission from JS Wolinsky.

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 Goals of Disease Management There are 4 main goals for management of MS: Treating relapses Managing symptoms Modifying/reducing relapses and delaying progression to disability Facilitating an acceptable quality of life

Acute MS Relapses Relapses Management: high-dose steroids
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 AcuteMS Relapses Relapses: Are sometimes also referred to as exacerbations, attacks, flare-ups, or acute episodes Are defined as focal disturbance of function, affecting a white matter tract, which lasts more than 24 hours1 Occur in the absence of environmental, metabolic, or infectious processes Generally evolve over a few days, reach a plateau, then resolve to variable degree over weeks or months Occur about once every year in untreated patients2 Management options include high-dose steroids, which accelerate speed but not degree of recovery.3 Options include methylprednisolone, prednisone, prednisolone, betamethasone, and dexamethasone.4 A commonly used option is methylprednisolone IV for 5 days, followed by optional short course of prednisone.5 Oral prednisone is rarely used acutely, since a trial showed increased risk of recurrence in patients with optic neuritis.6 1. Schumacher GA, Beebe G, Kebler RF, et al. Problems of experimental trials of therapy in multiple sclerosis. Ann NY Acad Sci.1965;122: 2. Compston A, Coles A. Multiple sclerosis. Lancet. 2000;359: 3. Leary SM, Thompson AJ. Current management of multiple sclerosis. Int J Clin Pract. 2000;54: 4. Multiple sclerosis: hope through research. National Institute of Neurological Disorders and Stroke. Available at: 5. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343: 6. Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992; 326:

Common MS Symptoms Fatigue Depression Focal muscle weakness
Visual changes Bowel/bladder/sexual dysfunction Gait problems/spasticity Paresthesias Common MS Symptoms MS patients may experience a wide range of symptoms. Symptoms can be described on the basis of the area of the CNS that is involved.1 It is extremely important to address these symptoms promptly and effectively, since they can lead to other problems and can profoundly affect patients’ quality of life. Common MS symptoms can include: Fatigue Depression Focal muscle weakness Visual changes Bowel/bladder/sexual dysfunction Gait problems/spasticity Paresthesias (abnormal touch sensations, such as burning or prickling) 1. Costello K, Hill CA, Tranter MC. Multiple sclerosis in the primary care setting: key issues for diagnosis and management. American Journal for Nurse Practitioners. 2000;October:9-30

Less Common MS Symptoms
Dysarthria, scanning speech, dysphagia Lhermitte’s phenomenon Neuritic pain Vertigo/ataxia Cognitive dysfunction Tremor/incoordination Less Common MS Symptoms Less common MS symptoms can include: Dysarthria, scanning speech, dysphagia Lhermitte’s sign Neuritic pain Vertigo/ataxia Cognitive dysfunction Tremor/incoordination

Rare MS Symptoms Decreased hearing Seizures Tinnitus
Mental disturbance Paralysis Rare MS Symptoms Rare MS symptoms can include: Decreased hearing Seizures Tinnitus (ringing in the ears) Mental disturbance Paralysis

Symptoms vary widely in incidence and severity
Sources of Symptoms Symptoms vary widely in incidence and severity Cognitive loss Emotional disinhibition Tremor, Ataxia Optic neuritis Diplopia Vertigo Dysarthria INO Sources of Symptoms Symptoms can be described on the basis of the area of the CNS that is involved.1 Inflammation of the optic nerve can cause retrobulbar pain, color desaturation, and visual loss. Brain stem lesions may cause changes in eye movement, such as diploplia; can also cause vertigo, dysarthria, dysphagia, and facial weakness. Cerebellar lesions may cause ataxia and tremor. Spinal cord lesions may cause bowel, bladder, and sexual dysfunction, and spastic gait difficulties. Cerebral and corpus callosum lesions, as well as generalized brain atrophy, may cause cognitive dysfunction. Common symptoms in diagnosed MS can include2: Fatigue Pain Spasticity Elimination dysfunctions Cognitive impairment Sexual dysfunction 1. Vollmer T. Multiple sclerosis: the disease and its diagnosis. In: van den Noort S, Holland NJ, eds. Multiple Sclerosis in Clinical Practice. New York: Demos; 1997:7. 2. Costello K, Hill CA, Tranter MC. Multiple sclerosis in the primary care setting: key issues for diagnosis and management. American Journal for Nurse Practitioners. 2000;October:9-30. Sensory symptoms, Lhermitte’s Pain Proprioception 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 Symptom Management: Fatigue One study of patients with MS in Canada found that 88% complained of fatigue, which may be debilitating.1 To determine whether a patient has MS-related fatigue, the physician must rule out possible comorbidities, such as hypothyroidism, depression, anemia, or heat exposure.1,2 1. Shapiro RT, Schneider DM. Fatigue. In: van den Noort S, Holland NJ, eds. Multiple Sclerosis in Clinical Practice. New York: Demos; 1999. 2. MS Council for Clinical Practice Guidelines. Fatigue and Multiple Sclerosis: Evidence-Based Management Strategies for Fatigue in Multiple Sclerosis. Washington, DC: Paralyzed Veterans of America; 1998. 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 Symptom Management: Fatigue Fatigue management in patients with MS requires an integrated multidisciplinary approach of nondrug and drug interventions. Behavioral changes such as energy conservation and improved nutrition can be helpful.1,2 Several medications have been used to treat the fatigue associated with MS, including: Amantadine (Symmetrel®)—antiviral agent3 Pemoline (Cylert®)—CNS stimulant3 Methylphenidate hydrochloride (Ritalin®)—CNS stimulant3 Fluoxetine (Prozac®)—selective serotonin reuptake inhibitor antidepressant1 Modafinil (Provigil®)—CNS stimulant4 1. Shapiro RT, Schneider DM. Fatigue. In: van den Noort S, Holland NJ, eds. Multiple Sclerosis in Clinical Practice. New York: Demos; 1999. 2. MS Council for Clinical Practice Guidelines. Fatigue and Multiple Sclerosis: Evidence-Based Management Strategies for Fatigue in Multiple Sclerosis. Washington, DC: Paralyzed Veterans of America; 1998. 3. Bever CT Jr. Multiple sclerosis: symptomatic treatment. Curr Treat Options Neurol. 1999;1: 4. Rammohan K, Rosenberg J, Pollak CP, et al. Modafinil, efficacy and safety for the treatment of fatigue in patients with multiple sclerosis. Neurology Suppl. 2000;54:A24. 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 Symptom Management: Pain Pain is complex; it is a sensory phenomenon with many potential causes and types.1 Types of pain in MS can include1: Neuropathic Musculoskeletal Hand or arm pain Optic neuritis Spasticity 1. Costello K, Halper J, Harris C, eds. Nursing Practice in Multiple Sclerosis: A Core Curriculum. New York: Demos; 2003:54-56. 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 Symptom Management: Pain Nonpharmacologic treatment includes seating and posture improvement.1 Physical therapy to treat pain may focus on gait training to develop more coordinated movements, advice on use of assistive devices, or stretching and strengthening spastic muscles.1 1. Costello K, Halper J, Harris C, eds. Nursing Practice in Multiple Sclerosis: A Core Curriculum. New York: Demos; 2003:54-56. Costello K et al, eds. Nursing Practice in Multiple Sclerosis: A Core Curriculum. New York: Demos; 2003.

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: Pain Pharmacologic management may include1: Tricyclic antidepressants Amitriptyline (Elavil®) Nortriptyline (Pamelor®) Antiepileptic drugs Carbamazepine (Tegretol®) Gabapentin (Neurontin®) Phenytoin (Dilantin®) Antispasticity medications Benzodiazepines, such as clonazepam (Klonopin®) 1. Costello K, Halper J, Harris C, eds. Nursing Practice in Multiple Sclerosis: A Core Curriculum. New York: Demos; 2003:54-56. Costello K et al, eds. Nursing Practice in Multiple Sclerosis: A Core Curriculum. New York: Demos; 2003.

Symptom Management: Spasticity
Spasticity can Limit mobility Expend excessive energy Cause discomfort Described as Tightness Pulling Tugging Aching Symptom Management: Spasticity Spasticity is common in patients with MS and can limit mobility, use excessive energy, and cause discomfort. There is a wide range of severity—some patients have only mild spasticity, whereas others are significantly disabled.

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: Spasticity Management of spasticity may consist of: Nonpharmacologic interventions Stretching Positioning Seating Physical therapy Surgical interventions Baclofen pump1—centrally acting muscle relaxant, which can be continuously administered by intrathecal infusion via a surgically implanted pump (can also be administered orally; see pharmacologic interventions) Rhizotomy2 Pharmacologic interventions Baclofen (Lioresal®)—centrally acting muscle relaxant, which can be administered orally (can also be administered surgically; see surgical interventions) Tizanidine (Zanaflex®)—centrally acting muscle relaxant Diazepam (Valium®)—centrally acting muscle relaxant Dantrolene (Dantrium®)—peripherally acting muscle relaxant Nerve blocks if refractory—injection of botulinum toxin to treat spasticity affecting limited muscle group3 1. Kamensek J. Continuous intrathecal baclofen infusions. An introduction and overview. Axon ;20:67-72. 2. Halper J, ed. Advanced Concepts in Multiple Sclerosis Nursing Care. New York: Demos; 2001:133. 3. Simpson DM. Clinical trials of botulinum toxin in the treatment of spasticity. Muscle Nerve Suppl. 1997;6:S169-S175.

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: Bladder Dysfunction Bladder dysfunction is present in many patients with MS.1 Symptoms can include hesitancy, frequency, urgency, and incontinence.1 Symptoms are caused by failure to store urine, failure to empty the bladder, or both.1 Evaluation should be done to rule out urinary tract infection (UTI) and check post-void residual (amount of urine remaining after voiding bladder) either via catheterization or bladder ultrasound.1 Management options include1: Antispasmodics Teterodine (Detrol®) Oxybutynin (Ditropan®) Propantheline bromide (Probanthine®) Hyoscyamine (Levsin®, Fevbid®) Flavoxate (Urispas®) Tricyclic antidepressants—imipramine (Tofranil®) DDAVP (an antidiuretic hormone)—desmopressin (DDAVP nasal spray) Alpha blockers Intermittent self-catheterization-bladder Indwelling catheter 1. Costello K, Halper J, Harris C, eds. Nursing Practice in Multiple Sclerosis: A Core Curriculum. New York: Demos; 2003:69-74. Costello K et al, eds. Nursing Practice in Multiple Sclerosis: A Core Curriculum. New York: Demos; 2003.

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 Symptom Management: Bowel Dysfunction Bowel dysfunction is often caused by demyelination in the spinal cord.1 Constipation is the most common bowel symptom; however, involuntary bowel occurs in some patients. Diarrhea is uncommon. When it does occur, it may be a result of fecal impaction.1 Management options include1: Increased dietary fiber, laxatives for constipation Fiber supplements for loose stools or involuntary evacuation Bowel training program for patients with atonia (similar to treatment of patients with spinal cord injuries, with suppositories and planned evacuation) 1. Costello K, Halper J, Harris C, eds. Nursing Practice in Multiple Sclerosis: A Core Curriculum. New York: Demos; 2003:75-80. Costello K et al, eds. Nursing Practice in Multiple Sclerosis: A Core Curriculum. New York: Demos; 2003.

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 Symptom Management: Cognitive Impairment About 50% of patients with MS experience some degree of cognitive impairment, which manifests as short-term memory loss, impaired judgment, impaired executive functioning, or difficulty performing multiple tasks simultaneously.1 Management may include1,2: Items to compensate for impairment, such as drug boxes, lists and portable recorders, and watches with alarms for medication times 1. Prosiegel M, Michael C. Neuropsychology and multiple sclerosis: diagnostic and rehabilitative approaches. J Neurol Sci. 1993;115:S51-S54. 2. Rao SM. Neuropsychology of multiple sclerosis. Curr Opin Neurol. 1995;8: 1. Prosiegel M, Michael C. J Neurol Sci. 1993;115:S51-S54. 2. Rao SM. Curr Opin Neurol. 1995;8:

Sexual Dysfunction/Intimacy
Men and women can experience difficulties  Libido  Erection  Frequency of orgasms  Lubrication  Bladder spasticity  Depression Sexual Dysfunction/Intimacy MS can cause primary, secondary, or tertiary sexual dysfunction.1 Primary sexual dysfunction is the result of physiological changes in the CNS. Secondary sexual dysfunction is the result of physical changes and treatments that affect sexual response indirectly. Tertiary sexual function is the result of psychological, social, or cultural factors that affect sexual response. 1. Costello K, Halper J, Harris C, eds. Nursing Practice in Multiple Sclerosis: A Core Curriculum. New York: Demos; 2003:59-60. Costello K et al, eds. Nursing Practice in Multiple Sclerosis: A Core Curriculum. New York: Demos; 2003.

Sexual Dysfunction/Intimacy
Management strategies include Pharmacologic management Treat underlying symptoms Adjust medications Positioning Lifestyle changes Key to successful management is open communication Sexual Dysfunction/Intimacy Management of primary sexual dysfunction includes medications, lubrication, and body mapping assessment.1 Management of secondary sexual dysfunction includes treatment of underlying symptoms as well as adjustments in positioning.1 Management of tertiary sexual dysfunction includes counseling, treatment of intermittent problems, and culturally sensitive interventions.1 1. Costello K, Halper J, Harris C, eds. Nursing Practice in Multiple Sclerosis: A Core Curriculum. New York: Demos; 2003:59-60. Costello K et al, eds. Nursing Practice in Multiple Sclerosis: A Core Curriculum. New York: Demos; 2003.

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 Disease Modification Disease-modifying agents aim to alter the natural course of the disease, rather than to simply treat symptoms.1 Two classes of disease-modifying medications currently exist: Immunosuppressants, which have been used for over 2 decades to treat MS. Benefits have been modest, however, and side-effects are a concern. Immunomodulators, which have been used since 1993 for the treatment of MS and have been proven in numerous clinical trials to play an important role in modifying and reducing relapses and delaying progression to disability. 1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343: Noseworthy JH et al. N Engl J Med. 2000;343:

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* MS Immunotherapy The available immunosuppressants are nonspecific, whereas the immunomodulators can be classified as nonspecific, selective, or antigen specific. We will focus on the immunomodulators that have been approved by the FDA for treatment of RRMS: 3 interferon drugs, which are nonspecific immunomodulators, and glatiramer acetate, a specific immunomodulator. The only other agent approved for MS is mitoxantrone, which is indicated for secondary-progressive MS, progressive-relapsing MS, and worsening RRMS. There are currently no drugs indicated for primary-progressive MS.1 Experimental therapies being investigated include anticytokine and “immune-deviation” strategies, inhibitors of matrix metalloproteinases, inhibitors of cathepsin B, inhibitors and scavengers of oxygen radicals, and efforts to reverse or reduce the activation of the trimolecular complex.2 1. Wekerle H. Immunology of multiple sclerosis. In: Compston A et al, eds. McAlpine's Multiple Sclerosis. 3rd ed. New York: Harcourt Brace Co; 1998: 2. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343: *These drugs do not have FDA approval for use in MS.

Nonselective and Selective Immunomodulatory Treatments
Glatiramer Acetate (Copaxone®) IFN -1a (Avonex®) IFN -1a (Rebif®) IFN -1b (Betaseron®) Type Recombinant protein Polypeptide mixture Indication Reduce relapse frequency in RRMS Slow Slow accumulation accumulation of disability of disability How given 30 g IM 22 or 44 g SC 250 g SC 20 mg SC weekly 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 Nonselective and Selective Immunomodulatory Treatments This slide compares the 4 approved agents for RRMS. In addition to RRMS, interferon (IFN) -1a IM (Avonex®) is indicated in monosymptomatic patients for delaying the development of clinical MS. These drugs differ in type of immunomodulator, specific indication, route and frequency of injection, dosage, and the length of available long-term data. An extension of the pivotal North American study of IFN -1b SC (Betaseron®) provided placebo-controlled data for up to 5 years (median treatment period 48.0 months).1 More recently, data from the 4-year extension of the PRISMS trial suggest that IFN -1a SC (Rebif®) may be efficacious for up to 4 years.2 No long-term studies (>2 years) have been published describing neurological outcomes following the long-term use of IFN -1a IM (Avonex®) The long-term data that were recently published on glatiramer acetate (Copaxone®)3 involve an 8-year interim analysis of the ongoing 10-year open-label study. This study is now planned to go beyond the 10-year point. 1. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45: 2. PRISMS Study Group. PRISMS-4: long-term efficacy of interferon--1a in relapsing MS. Neurology. 2001;56: 3. Johnson KP, Brooks BB, Ford CC, et al. Results of the long-term (8-year) prospective, open label trial of glatiramer acetate for relapsing multiple sclerosis. Poster presented at: 54th Annual Meeting of the American Academy of Neurology; April 13-20, 2002; Denver, Colo.

Nonselective and Selective Immunomodulatory Treatments
Glatiramer Acetate (Copaxone®) IFN -1a (Avonex®) IFN -1a (Rebif®) IFN -1b (Betaseron®) MRI findings Reduces Reduces Reduces rate Reduces lesions active lesions of new lesions lesions Reduces risk for Reduces Reduces rate Reduces loss progression disability of severe of brain tissue of disability relapses Common side Mild flulike symptoms, No flulike effects muscle aches, anemia symptoms No Injection-site reactions injection-site reactions Menstrual Systemic disorders; mild post- neutropenia and injection thrombocytopenia; reaction abnormal liver function Nonselective and Selective Immunomodulatory Treatments This slide continues the comparison of the 4 approved agents for RRMS.1-4 MRI findings for all 4 agents demonstrate varying rates of reduction of active or new brain lesions at different time points.1-4 Additional MRI findings with the use of different agents correlate with reductions of disability, rates of severe relapses, or brain tissue loss.1-4 The most common side effects in the clinical setting are compared across the 4 agents. 1. PRISMS Study Group. PRISMS-4: long-term efficacy of interferon--1a in relapsing MS Neurology. 2001;56: 2. Stone LA, Frank JA, Albert PS, et al. Characterization of MRI response to treatment with interferon beta-1b: contrast-enhancing MRI lesion frequency as a primary outcome measure. Neurology. 1997;49: 3. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol. 1996;3: 4. Ge Y, Grossman RI, Udupa JK, et al. Glatiramer acetate (Copaxone) treatment in relapsing-remitting MS: quantitative MR assessment. Neurology. 2000;54:

Mechanisms of Action

Cytokine Imbalance in MS
Normal MS Inflammatory IFN- IL-12 TNF Inflammatory IFN-  IL-12 TNF Anti-inflammatory IL-4 IL-10 TGF- Th1 Th2 Cytokine Imbalance in MS The immune system of normal, healthy persons maintains an equilibrium between proinflammatory and anti-inflammatory cytokines. By contrast, persons with MS have an imbalance of cytokines owing to an increased Th1 immune response and a decreased Th2 response. The cytokine shift in persons with MS is characterized predominantly by increased levels of interferon-γ, interleukin-12, and tumor necrosis factor; and decreased levels of interleukin-4, interleukin-10, and transforming growth factor–β.

Potential Mechanisms of Action 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 Potential Mechanisms of Action of IFN- in MS IFN- has the following immune system effects1,2: Inhibition of T-cell proliferation Blocking of T-cell activation Apoptosis of autoreactive T cells Antagonism of IFN-γ Cytokine shifts Reduction of TNF- production Increase in IL-10 production Activates regulatory T cells and stimulates suppressive (Th2) cytokines Reduction of antigen presentation to T cells Reduction of immune cell passage across BBB Because IFN- does not cross the BBB, it produces its effects directly in the peripheral nervous system, but any effects on the CNS are produced indirectly.2 1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med ;343: 2. Yong VW. Differential mechanisms of action of interferon- and glatiramer acetate in MS. Neurology. 2002;59:

IFN-β–Induced Cytokine Shift
MS Inflammatory Th1 cytokines IFN-β IL-12 Anti-inflammatory Th2 cytokines IFN-β–Induced Cytokine Shift In persons with MS treated with IFN-β, a shift in cytokine production is seen. Specifically, treatment with IFN-β results in a reduction in Th1-produced IL-12 and an increase in Th2-produced IL-10. IL-10

Effects of IFN- at Blood-Brain Barrier
BBB CNS IFN-β Th1+ MMP Myelin protein Antigen Th1+ Th1+ Th1 APC APC Effects of IFN- at Blood-Brain Barrier The actions of MS therapies at the level of the BBB translate into the effects observed on Gd-contrast scans IFN- has the following effects at the BBB1: Decreases production of matrix metalloproteinases (MMPs) by T cells Reduces expression of several chemokine receptors Affects adhesion of T cells onto the endothelium Reduces influx of T cells into the CNS Rapid resolution of Gd-enhancing MRI activity 1. Yong VW. Differential mechanisms of action of interferon- and glatiramer acetate in MS. Neurology. 2002;59: MMP Resting T cell Th1+ IL-2 TNF-α IFN-γ Activated (+) T cells IFN-β Adapted from Yong VW. Neurology. 2002;59:

Glatiramer Acetate: Possible Mechanisms of Action
Blocking autoimmune T cells Induction of anergy Induction of anti-inflammatory Th2 cells Bystander suppression Neuroprotection Glatiramer Acetate: Possible Mechanisms of Action The putative mechanism of action of glatiramer acetate incorporates the following steps1: Glatiramer acetate avidly binds to MHC class II molecules on APCs. This complex then competes with myelin basic protein (MBP) and other myelin-associated proteins, such as proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG), for binding to APCs. Binding to the APCs induces activation of glatiramer acetate–specific myelin cross-reactive regulatory T cells (suppressor cells). These activated regulatory T cells can cross the BBB and are reactivated in situ by MBP or other myelin antigens. This reactivation inhibits antigen-specific effector functions, such as proliferation and production of proinflammatory Th1 cytokines. The reactivation also induces a bystander suppressive effect via anti-inflammatory Th2 cytokines. These actions arrest or slow disease activity. 1. Neuhaus O, Farina C, Wekerle H, Hohlfeld R. Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology. 2001;56: Neuhaus O et al. Neurology. 2001;56:

Effects of Glatiramer Acetate at Blood-Brain Barrier
Th2+ Adapted from Yong VW. Neurology. 2002;59: GA-induced T cell MMP Activated (+) T cells BBB Blood CNS IL-4 TGF-β B cell IL-10 Th2 APC Glatiramer acetate (GA) Myelin protein Bystander suppression Effects of Glatiramer Acetate at Blood-Brain Barrier The actions of MS therapies at the level of the BBB translate into the effects observed on Gd-contrast scans. Unlike IFN-, glatiramer acetate does not alter the expression of adhesion molecules, MMP production, or chemokine expression.1 Glatiramer acetate has the following effects at the BBB1: Glatiramer acetate–specific Th2 cells traffic into the CNS to Reduce inflammation Produce bystander suppression Possibly produce neuroprotection 1. Yong VW. Differential mechanisms of action of interferon- and glatiramer acetate in MS. Neurology ;59:

Relapse Rates

IFN -1b: Annual Relapse Rates Over 5 Years
33%* 1.50 Placebo Interferon -1b, 8 MIU 28%† 1.25 1.00 28%‡ 24%‡ Mean Number of Relapses 30%‡ 0.75 IFN -1b: Annual Relapse Rates Over 5 Years The pivotal trial for interferon -1b, which was published in 1995, demonstrated1: A 33% reduction in annual relapse rate from baseline to year 1. About a 30% reduction in annualized relapse rate thereafter, but this difference was only statistically significant for the first 2 years (P < 0.05), probably related to the fact that all groups, including the placebo group, had a gradual reduction in exacerbation rate. An effect on limiting progression of disability, but the results were not statistically significant. A significant increase in lesion burden on MRI scans in the placebo group, but no increase in the 8 MIU group. However, the study was not designed to measure a treatment effect on disease progression. 1. IFNB Multiple Sclerosis Study Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45: 0.50 0.25 1 2 3 4 5 Study Year *P < 0.001; †P < 0.05; ‡P = NS. Adapted from IFNB Multiple Sclerosis Study Group. Neurology. 1995;45:

Interferon β-1a IM: Annual Relapse Rate
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Placebo 32%† 18%* Interferon -1a Mean Number of Relapses Interferon b-1a IM: Annual Relapse Rate In the pivotal trial of IFN b-1a IM1: There was a 32% reduction in annual relapse rate among patients treated for the full 2 years, which was statistically significant (P = 0.002). There was a smaller, although still statistically significant (P = 0.04), reduction seen when data from all patients were analyzed. The primary outcome for the study was not relapse rate but, instead, time to sustained disability progression of at least 1.0 point on the EDSS. There was a statistically significant delay in progression (P = 0.02) with active treatment. In addition, the number and volume of active lesions seen on MRI were reduced with IFN -1a treatment. 1. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol. 1996;39: All Patients Patients Treated 2 Years *P < 0.04; †P < Adapted from Jacobs LD et al. Ann Neurol. 1996;39:

Annual Mean Number of Relapses for IFN -1a SC
0.0 0.5 1.0 1.5 2.0 1.5 1.5 P < 1.02 Relapses/Patient/Year Mean Number of 0.80 0.72 32% 47% 52% Annual Mean Number of Relapses for IFN -1a SC In PRISMS-4, the overall annual relapse rate was assessed after 4 years of treatment for both patients receiving active drug and those who were rerandomized from initial placebo to active drug (placebo/active) at 1 of 2 doses in the IFN -1a SC study. The patients in the placebo/active group switched to active drug at 2 years.1 Over the 4 years of the IFN -1a study, the mean number of relapses/patient were 0.72 in the high-dose IFN -1a group (44 g 3 times weekly) 0.80 in the low-dose group (22 g 3 times weekly) 1.02 in the combined placebo/active groups Both active groups were statistically different from the group that initially received placebo and then was rerandomized to active treatment (P < ). Time to sustained disability progression was significantly prolonged in the high-dose, but not the low-dose, group compared with the crossover group. The study also found a reduced number of new T2-weighted MRI lesions and smaller lesion burden with IFN -1a SC treatment. 1. PRISMS Study Group. PRISMS-4: long-term efficacy of interferon--1a in relapsing MS. Neurology. 2001;56: Placebo Both IFN -1a Arms Placebo/ Active 22 g 3/wk 44 g 3/wk Prior to Study Entry At 4 Years PRISMS Study Group. Neurology. 2001;56:

Glatiramer Acetate: Mean Relapse Rate
Placebo Glatiramer Acetate 32%† 2.0 29%* 1.8 1.6 1.4 1.2 Mean Number of Relapses 1.0 0.8 0.6 Glatiramer Acetate: Mean Relapse Rate The pivotal trial of glatiramer acetate was a placebo-controlled, randomized, double-blind trial for 24 months plus an extension up to 11 months.1 This was followed by an open-label extension study, which has continued to the present, with 8-year data recently published.2 There was a 29% reduction in mean relapse rate during the core study, and a 32% reduction when data from the extension trial are included. This trial continues to accrue data from an open-label phase instituted at 36 months, when placebo recipients were switched to glatiramer acetate. By year 8, the annual relapse rate was 0.16 for patients continuously on glatiramer acetate and 0.23 for those switched from placebo.2 The mean EDSS was more likely to have increased by one level in patients who began active treatment after crossing over (thus after 30 months of placebo) than those continuously on glatiramer acetate.2 A separate trial evaluated MRI metrics and found that glatiramer acetate treatment was associated with a significant reduction in the total number of enhancing lesions and many other secondary endpoints. However, this effect did not reach statistical significance until the third trimester of study.3 1. Johnson KP, Brooks BR, Cohen JA, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology. 1998;50: 2. Johnson KP, Brooks BB, Ford CC, et al. Poster presented at: 54th Annual Meeting of the American Academy of Neurology; April 13-20, 2002; Denver, Colo. 3. Comi G, Filippi M, Wolinsky JS. European/Canadian multicenter, double-blind randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis. Ann Neurol. 2001;49: 0.4 0.2 0.0 24 Months 24 Months + Extension *P < 0.007; †P < Adapted from Johnson KP et al. Neurology. 1998;50:

Glatiramer Acetate: 8-Year Data Annualized Relapse Rate
Placebo Placebo/Active 1.6 1.4 P = 0.01 P = 0.05 1.2 1.0 Relapse Rate (means) 0.8 0.6 Glatiramer Acetate: 8-Year Data Annualized Relapse Rate During the third year of observation, patients from the original placebo group were switched to active treatment as they reached 35 months of blinded, placebo-controlled study.1 Overall, patients remained on assigned treatment for an additional 1 to 11 months (mean of 5.2 additional months for those on glatiramer acetate and 5.9 additional months for those on placebo).1 Relapse rate data for the placebo/active patients in the third year are quite similar to the relapse rate from those who were always on glatiramer acetate, since each placebo patient had a different duration of active therapy during that transitional year.1 By year 8 of the study, relapse rates for group A and group B were similar.1 Annualized relapse rates during the entire 8 years were 0.43 for the glatiramer acetate group and 0.52 for the placebo/active group (P = ; ANCOVA).1 P values (P = and P = ) come from ANCOVA analyses using the following as covariates: baseline EDSS, number of relapses 2 years prior, and days under trial phases.1 1. Johnson KP, et al. Neurology. 2002;58(suppl 3):A458. P 0.4 0.2 0.0 Entry Placebo-Controlled Phase and Extension Placebo-Controlled Phase Through Open-Label Phase Johnson KP et al. Neurology. 2002;58(suppl 3):A458. P

Mean Annual Relapse Rates of DMTs Nonrandomized, Open-Label Study
INF β-1a IM INF β-1b SC GA INF β-1a 22 μg SC 1.4 1.2 1.0 0.8 0.4 0.6 0.2 0.0 Before Study 6 Months 12 Months 24 Months Mean Number of Relapses Mean Annual Relapse Rates of DMTs (Nonrandomized, Open-Label Study) This slide presents data from a nonrandomized, open-label study1 showing the annual relapse rates (arithmetic mean and standard error of mean [SEM]) for the 4 immunomodulators after 6, 12, and 24 months of treatment. The following differences were statistically significant at the P < 0.05 level: For all groups, changes in relapse rates at 6, 12, and 24 months were statistically significantly improved, compared with rates noted prior to the study. After 6 months: No difference between the various treatments (overall comparisons). After 12 months: Glatiramer acetate (GA) >> INF β-1b SC. After 24 months: GA >> INF β-1a IM, GA >> INF β-1b SC, GA >> INF β-1a 22 μg SC. 1. Haas J et al. Onset of clinical benefit of glatiramer acetate (Copaxone) in patients with relapsing remitting multiple sclerosis (RRMS). Presented at: American Academy of Neurology; 2003; Honolulu, Hawaii. Haas J et al. Presented at: AAN, 2003.

Effects on Disability

IFN -1a SC: Proportion of Patients Free From Progression Over 4 Years
1.0 ITT progression-free patients: all crossover vs 3  44 g: P = 0.07 0.8 Proportion of Patients 3  22 3  44 0.6 IFN -1a SC: Proportion of Patients Free From Progression Over 4 Years This slide presents the probability of avoiding disease progression (ie, progression free) in the IFN β-1a SC pivotal trial over 4 years.1 Fewer patients in the high-dose IFN β-1a group than in the other groups exhibited sustained progression of ≥1 EDSS step, but these differences were not significant in the Kaplan-Meier analysis. (Sustained progression had to be maintained for at least 3 months.) Interestingly, a close review of the Kaplan-Meier curve shows that the progression rate during years 3 and 4 was slightly faster for the 44-g arm than for the placebo/44-g arm and for the 22-g arm than for the placebo/22-g arm, but these differences were not significant. In PRISMS-2, 61.7% of patients in the placebo group were free from progression, compared with 70.3% in the 22-g arm and 73.2% in the 44-g arm.2 At the end of the fourth year, 74/161 (46%) patients in the crossover groups, 88/173 (51%) patients in the 22-g group, and 92/164 (56%) patients in the 44-g group remained free from progression.1 These differences were not significant using the ITT sample, although a trend was seen for the 44-g group, compared with the crossover group (P = 0.07). 1. The PRISMS (Prevention of Relapses and Disability by Interferon--1a Subcutaneously in Multiple Sclerosis) Study Group. PRISMS-4: long-term efficacy of interferon--1a in relapsing MS. Neurology. 2001;56: 2. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352: Placebo/44 Placebo/22 0.4 6 12 18 24 30 36 42 48 Time (months) Adapted with permission from PRISMS-4 Study Group. Neurology. 2001;56:

IFN -1b: Probability of Avoiding Progression Over 5 Years
8 MIU Placebo 1.6 MIU Time to progression: P = 0.096 Patients With Sustained Progression 1 EDSS Step Placebo 46% (56/122) IFN -1b 8 MIU 35% (43/122) 100 90 80 70 60 50 40 30 20 10 Probability (%) IFN -1b: Probability of Avoiding Progression Over 5 Years The probability of avoiding disease progression = progression-free (percent of patients). This slide presents the probability of avoiding disease progression in the IFN β-1b pivotal trial. Fewer patients in the high-dose IFN -1b group than in the placebo group exhibited sustained progression of ≥1 EDSS step after a median follow-up of >46 months, but the difference was not significant in this Kaplan-Meier analysis. Median times to progression were 4.79 years in the 8-MIU IFN -1b arm, 4.18 years in the placebo arm, and 3.49 years in the 1.6-MIU IFN -1b group.1 The rates of patients who experienced sustained progression of ≥1 EDSS step for 3 months over the 5 years were 46% (56/122) in the placebo arm and 35% (43/122) in the 8 MIU IFN -1b arm (P = 0.096), which did not definitively establish a therapeutic effect of IFN -1b in decreasing the progression of disability.1 1. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45: 180 360 540 720 900 1080 1260 1440 1620 1800 Days Adapted with permission from the IFNB MS Study Group. Neurology. 1995;45:

Placebo-Controlled Phase Survival Distribution Estimate
Glatiramer Acetate: Time to Worsening by 1.5 EDSS Steps Over 6 Years (Open-Label Cohort) Placebo-Controlled Phase Open-Label Phase 0.7 0.6 0.5 0.4 Survival Distribution Estimate 0.3 Placebo/Active (n = 107) Glatiramer Acetate (n = 101) Time to worsening: P = 0.048 0.2 Glatiramer Acetate: Time to Worsening by 1.5 EDSS Steps Over 6 Years (Open-Label Cohort) This slide shows a Kaplan-Meier analysis of time to worsening by ≥1.5 EDSS steps in the US pivotal trial of glatiramer acetate for the cohort of patients who entered into the open-label phase. As with any Kaplan-Meier analysis, once the patient worsens by a defined amount, he or she is no longer considered; thus, worsening in this analysis may or may not be sustained. The ≥1.5 level of EDSS change was used because of improved observer reliability at that level; however, the curves obtained on analysis of worsening by ≥1 EDSS step were similar.1 EDSS measurements taken during relapses were not removed from these plots. The shaded area between 24 months and 35 months denotes the crossover period when patients who received placebo began to receive glatiramer acetate. The first placebo patient began glatiramer acetate therapy 24 months after randomization, and the final placebo patient began glatiramer acetate therapy at 35 months. Kaplan-Meier analysis of time to worsening by ≥1.5 EDSS steps demonstrated that the lower progression rate in the group always on glatiramer acetate was maintained throughout the study, although the difference between the 2 groups decreased with conversion of the placebo group to active treatment.2 For both groups, the flattening of the curves at later time points indicates a prolongation of time to worsening with increased time on active therapy, emphasizing the benefits of long-term use with glatiramer acetate. The same flattening of curves is observed with the analysis of time to worsening by ≥1 EDSS step (not shown). As the patient’s disability level increases, so do consequent costs, eg, medical expenses, physical assistance aids, and employment time lost. Early treatment appears to provide some protection from disability, particularly over the long term. Patients who started on placebo treatment and later crossed over to active treatment with glatiramer acetate received some of this protective effect; however, their long-term outcomes did not show the same magnitude of benefit as their counterparts who received active treatment from onset. 1. Sharrack B, Hughes RA, Soudain S, Dunn G. The psychometric properties of clinical rating scales used in multiple sclerosis. Brain. 1999;122: 2. Johnson KP, Brooks BR, Ford CC, et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Mult Scler. 2000;6: 0.1 0.0 1 2 3 4 5 6 7 Years Johnson KP et al. Mult Scler. 2000;6:

Glatiramer Acetate: 8-Year Data Yearly EDSS Change From Baseline
0.8 0.4 0.7 0.6 0.5 0.2 0.3 0.0 0.1 –0.1 Glatiramer Acetate Placebo/Active P = (RMA) Change in EDSS Score Glatiramer Acetate: 8-Year Data Yearly EDSS Change From Baseline Another way to look at disability in this long-term trial is to consider the yearly EDSS score change from baseline. In this analysis, significant differences are observed in years 2, 3, and 4. At year 5, the treatment effect has influenced the placebo/active patients enough that the differences are no longer statistically different. The analyses for years 2, 3, and 4 were significant (*) at P < 0.05. Year 1 – GA: n = 101, mean = −0.07; placebo: n = 107, mean = 0.17, P < 0.06 Year 2 – GA: n = 101, mean = −0.01; placebo: n = 107, mean = 0.27, P < 0.04* Year 3 – GA: n = 101, mean = 0.09; placebo: n = 107, mean = 0.42, P < 0.05* Year 4 - GA: n = 97, mean = 0.21; placebo: n = 105, mean = 0.63, P < 0.03* Year 5 – GA: n = 91, mean = 0.23; placebo: n = 93, mean = 0.59, P < 0.07, NS Year 6 – GA: n = 83, mean = 0.14; placebo: n = 86, mean = 0.49, P < 0.10, NS Year 7 – GA: n = 76, mean = 0.29; placebo: n = 76, mean = 0.58, P < 0.24, NS Year 8 – GA: n = 73, mean = 0.38; placebo: n = 71, mean = 0.74, P < 0.16, NS The P value of comes from a repeated measure analysis (RMA) of the continuous change in EDSS scores over trial years. There is a significant difference in the change in EDSS score between the glatiramer acetate–treated and placebo-treated patients across all 8 years. The data from only patients who reached the year were included in the figure and in the analysis. Data on file, Teva Neuroscience/Teva Pharmaceutical Industries, Ltd. Entry 1 2 * 3 * 4 * 5 6 7 8 *P < 0.05. Year Johnson KP et al. Neurology. 2002;58(suppl 3):A458.

Glatiramer Acetate: 8-Year Data Categorical EDSS Change From Randomization to Last Observation
75 Glatiramer Acetate 65.3 Placebo/Active 65 P = 55 50.4 49.5 45 34.7 Patients (%) 35 25 Glatiramer Acetate: 8-Year Data Categorical EDSS Change From Randomization to Last Observation Most patients in both groups improved or remained the same by EDSS score when the last observation was compared with baseline. Patients who received placebo at randomization, thus delaying active treatment for the first 2.5 years, were more likely to have worsened by ≥1 EDSS step compared with those on active treatment since randomization. This graph provides strong evidence for starting therapy with glatiramer acetate. Logistic regression analysis revealed a significant difference (P = ) in the binary variable (improved/no change) vs worsened, because of treatment effects between glatiramer acetate and placebo with baseline EDSS scores and hospitalization as covariates.1,2 1. Johnson KP, Brooks BB, Ford CC, et al. Results of the long-term (8-year) prospective, open-label trial of glatiramer acetate for relapsing multiple sclerosis. Neurology. 2002;58(suppl 3):A458. 2. Data on file, Teva Neuroscience/Teva Pharmaceutical Industries, Ltd. 15 5 Improved/No Change Worsened Johnson KP et al. Neurology. 2002;58(suppl 3):A458.

MRI Findings

MRI Endpoints in RRMS Trials T2 Lesion Burden (Median % Change)*
IFN β-1b 1 Placebo P < 0.001 175 μg 875 μg IFN β-1a IM Placebo P = 0.36 30 μg IFN β-1a SC Placebo P < 66 μg 132 μg MRI Endpoints in RRMS Trials T2 Lesion Burden (Median % Change) Changes in the number of MRI T2-weighted lesions, representing the total lesion burden, were assessed in the pivotal studies of the 3 IFN- products and in a European/Canadian glatiramer acetate trial. In the RRMS IFN β-1b trial, those who received placebo experienced a 16% increase in lesion burden from baseline over the 2-year period. Patients treated with high-dose IFN β-1b experienced a decrease in lesion burden from baseline over the same time period. These differences were significant (P < 0.001). IFN β-1a IM did not significantly affect T2 lesion burden after 2 years. Interestingly, both the placebo and treated groups showed a decrease in lesion burden. This observation may reflect the mild disease (ie, EDSS scores 1.0 to 3.5) in the patient population of this study and their ability to recover from MS-related CNS damage. Patients with RRMS treated with IFN β-1a SC also experienced a significant (P < ) decrease in T2-weighted lesions, compared with placebo-treated patients. Although glatiramer acetate significantly (P = 0.001) reduced T2 lesion burden relative to placebo, these results were for a 9-month period and do not reflect the period of accumulating therapeutic effect (ie, divergence in the accumulation of T2 lesion volume was not significant until months 6 to 9 of the study period). Glatiramer acetate 2 Placebo P = 0.001 140 mg –15 –10 –5 5 10 15 20 25 *Weekly doses reported. 1. Paty DW, Li DK. Neurology. 1993;43: 2. Comi G et al. Ann Neurol. 2001;49:

IFN -1a IM: Change in Volume of Black Holes (Total Lesion Load)
150 P = 0.065, NS 125 100 Total Lesion Load (mm3), Median Change From Baseline 75 50 IFN -1a IM: Change in Volume of Black Holes (Total Lesion Load) A placebo-controlled study of 160 patients with RRMS examined the change in the overall volume of T1 hypointense lesions between 0 and 24 months with IFN -1a IM.1 MRI was performed yearly, and 2-year results are shown here.1 The median volume of T1 hypointensities increased by 40 mm3 (11.8%) in the IFN -1a IM group and by mm3 (29.3%) in the placebo group. The intercohort difference of 59% was not significant (P = 0.065, NS). Because data on acute and chronic black holes were considered in combination, this study did not provide information on the potential effect of treatment on lesion evolution.1 1. Simon JH, Lull J, Jacobs LD, et al. A longitudinal study of T1 hypointense lesions in relapsing MS. MSCRG trial of interferon -1a. Neurology. 2000;55: 25 n = 80 n = 80 Placebo IFN β-1a IM Simon JH et al. Neurology. 2000;55:

EVIDENCE Trial CU Lesions
8 7 6 IFN β-1a 30 μg qw IM 5 Mean Cumulative CU Active Lesions 4 3 IFN β-1a 44 μg tiw SC 2 *P < at Week 24 1 EVIDENCE Trial CU Lesions This randomized, controlled, multicenter trial compared the efficacy and safety of IFN -1a 44 μg SC 3 times weekly and IFN -1a 30 μg IM once weekly in 677 patients with RRMS.1 The principal MRI endpoint in this study was the number of active lesions per patient per scan at 24 weeks.1 Patients returned for follow-up and received MRI scans every 4 weeks. Over 24 weeks, patients treated with IFN -1a 44 μg SC had fewer combined unique (CU), T1, and T2 active lesions per MRI scan than those treated with IFN -1a 30 μg IM. This slide shows the mean cumulative CU active lesions at each MRI assessment time point and the significant net treatment difference between the IFN -1a 44 μg SC group and the IFN -1a 30 μg IM group at week 24 (P < .001). 1. Panitch H, Goodin DS, Francis G, et al, for the EVIDENCE (EVidence of Interferon Dose- response: European North American Comparative Efficacy) Study Group and the University of British Columbia MS/MRI Research Group. Randomized, comparative study of interferon -1a treatment regimens in MS. Neurology. 2002;59: 4 8 12 16 20 24 Week (4-Week MRI Scans) 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:

IFN β-1a SC Long-term Data: MRI T2 Lesions
IFN β-1a 44 tiw SC vs placebo/44 tiw SC IFN β-1a 22 tiw SC vs placebo/22 tiw SC IFN β-1a 44 tiw SC vs IFN β-1a 22 tiw SC 9.7 10 7.2 5 3.4 Median Percent Change in Total T2 Lesion Area –5 –6.2 IFN -1a SC Long-term Data: MRI T2 Lesions The randomized, double-blind, placebo-controlled PRISMS study demonstrated that IFN -1a 22 and 44 μg SC 3 times had significant clinical and MRI benefit, compared with placebo at 2 years.1,2 In the 2-year extension study, reported as PRISMS-4, patients who had been assigned placebo during the initial phase of the study were randomized to receive blinded treatment with either IFN -1a 22 or 44 μg 3 times weekly SC, whereas the other groups continued blinded treatment with their originally assigned dose.3 Patients received annual MRI assessments. BOD, defined as the summed cross-sectional area (in mm2) of lesions in T2 scans, was analyzed as percentage change from baseline. Over 4 years, increases from baseline in BOD were observed in all groups except for those receiving IFN -1a 44 μg SC, who experienced a 6.2% reduction in BOD, compared with increases of 3.4% for the IFN -1a 22-μg SC group (P = vs 44 μg); 7.2% for the placebo/IFN -1a 44-μg SC group (P = vs 44 μg); and 9.7% for the placebo/IFN -1a 22-μg SC group (P = 0.11 vs 44 μg).3 1. PRISMS Study Group. Randomized double-blind placebo-controlled study of interferon-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352: 2. Li DKB, Paty DW, PRISMS Study Group. Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferon-1a in relapsing-remitting multiple sclerosis. Ann Neurol. 1999;46: 3. PRISMS Study Group. PRISMS-4: long-term efficacy of interferon--1a in relapsing MS [published correction appears in Neurology. 2001;57:1146]. Neurology. 2001;56: –10 Placebo/22 μg tiw SC (n = 57) Placebo/44 μg tiw SC (n = 49) IFN β-1a 22 μg tiw SC (n = 117) IFN β-1a 44 μg tiw SC (n = 111) P = 0.11 P = 0.003 P = 0.009 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].

Median Change After Baseline
IFN -1b: Median Change in MRI-Measured BOD 217 Patients Having at Least a Fourth-Year Annual Scan P = 35 Placebo 30.2 8 MIU 30 P = P = 25 21.0 18.7 20 P = 15 P = 11.9 Median Change After Baseline 10 6.7 3.6 5 IFN -1b: Median Change in MRI-Measured BOD 217 Patients Having at Least a Fourth-Year Annual Scan In the pivotal trial of IFN -1b, 217 patients with MS completed 4 or 5 years of the study and had annual MRI scans.1 Analysis of these data showed that the median reduction in MRI-measured burden of disease, compared with baseline, was significantly greater with IFN -1b than with placebo on each of the annual scans. 1. The IFNβ Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45: –0.8 –5 –3.8 –4.9 –5.6 –10 1 2 3 4 5 Study Year Adapted with permission from the IFNβ MS Study Group. Neurology. 1995;45:

Effect of IFN -1b on Enhancements
Months on Study (27 Subjects) 1 2 3 4 5 6 7 8 9 10 11 12 20 40 60 80 100 120 140 160 Total Enhancements 80%–90% response Interferon β-1b initiated Effect of IFN -1b on Enhancements In a study of IFN -1b in MS, patients were evaluated via MR on a monthly basis during a 6- to 7-month baseline (pretreatment) period.1 The patients then received active treatment for 6 months. Data from 27 patients showed that the total number of enhancing lesions on MRI decreased by 80% to 90% during the active treatment period compared with the pretreatment period. 1. Stone LA, Frank JA, Albert PS, et al. Characterization of MRI response to treatment with interferon beta-1b: contrast-enhancing MRI lesion frequency as a primary outcome measure. Neurology. 1997;49: Stone LA et al. Neurology. 1997;49:

Glatiramer Acetate 9-Month Data: MRI T2 Lesions
Placebo 25 Glatiramer Acetate 20 15 Volume % Change (median) 10 Glatiramer Acetate 9-Month Data: MRI T2 Lesions The European-Canadian MRI Study further evaluated the effects of glatiramer acetate on MRI measures of disease activity and burden in patients with RRMS.1 The initial phase was a 9-month, double-blind, placebo-controlled phase of the European-Canadian monthly brain MRI study, in which RRMS patients received glatiramer acetate 20 mg SC daily or placebo.1 This was followed by a 9-month open-label phase in which all patients received glatiramer acetate. In this phase, MRI was performed every 3 months, and the primary endpoint was the total number of enhancing lesions at the end of the 9-month open-label phase. The mean volume of enhancing lesions changed from 1.8 to 0.8 mL in patients initially randomized to placebo (–56%, P < ) and from 1.1 to 0.8 in patients initially randomized to glatiramer acetate (–27%, P = NS). The T2 lesion load remained stable in both arms during the open-label phase. At the final evaluation, the median percentage change of T2 lesion load was 17.4% in patients initially randomized to placebo and 13.0% in patients treated with glatiramer acetate from the onset (P = 0.018). 1. Comi G, Filippi M, Wolinsky JS, for the European/Canadian Glatiramer Acetate Study Group. The extension phase of the European-Canadian MRI Study demonstrates a sustained effect of glatiramer acetate in patients with relapsing-remitting multiple sclerosis [abstract]. Neurology ;56(suppl 3):A255. Abstract P 5 Months Comi G et al. Neurology. 2001;56(suppl 3):A255.

Primary Endpoint: Cumulative Number of Enhancing Lesions (9 Months)
Placebo Glatiramer Acetate 45 36.8 –29% 40 P = 35 26.0 30 25 Lesion Number (mean + SE) 20 Primary Endpoint: Cumulative Number of Enhancing Lesions (9 Months) In the double-blind, randomized phase of the European/Canadian MRI trial, a baseline-adjusted ANCOVA using the LOCF method showed that the mean cumulative number of enhancing lesions on T1-weighted images (the primary endpoint) was 26.0 in the glatiramer acetate group compared with 36.8 in the placebo group, a reduction of 29% at 9 months (P = 0.003).1 When the results were analyzed without carrying missing data forward (“as is” analysis), the results were similar: a 35% reduction in the total number of enhancing lesions with glatiramer acetate compared with placebo (P < 0.001).1 1. Comi G, Filippi M, Wolinsky J, et al. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imagingmeasured disease activity and burden in patients with relapsing multiple sclerosis. Ann Neurol. 2001;49: 15 10 5 LOCF Adapted with permission from Comi G et al. Ann Neurol. 2001;49: This material is used by permission of John Wiley & Sons, Inc.

European/Canadian MRI Trial: Summary
Glatiramer acetate had significant effects on: Reduction P Value Total number of enhancing lesions (LOCF) 29% Total number of enhancing lesions (as is) 35% Total number of new enhancing lesions 33% Total number of new T2 lesions 30% T2 lesion volume (median, from baseline) 40% Relapse rate (9 months) 33% 0.01 European/Canadian MRI Trial: Summary Glatiramer acetate had significant effects on many MRI and clinical parameters in the 9-month randomized, double-blind phase of the European/Canadian MRI trial.1 Compared with placebo, glatiramer acetate reduced the total number of T1-enhancing lesions (the primary endpoint) by 29% (P = 0.003) in an analysis based on LOCF. A significant reduction in this endpoint was also apparent on an “as is” analysis performed without carrying the last observation forward. In addition, glatiramer acetate significantly reduced secondary endpoints, including the total number of new enhancing lesions, the total number of new T2 lesions, the change in T2 lesion volume from baseline, and the relapse rate at 9 months. The magnitude of the effect of treatment on measurements of disease activity mirrored the magnitude of reduction in the relapse rate with glatiramer acetate. 1. Comi G, Filippi M, Wolinsky J, et al. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imagingmeasured disease activity and burden in patients with relapsing multiple sclerosis. Ann Neurol. 2001;49: Comi G et al. Ann Neurol. 2001;49:

Glatiramer Acetate: Evolution to Black Holes
Placebo Glatiramer Acetate Lesion Age (months) Lesions Evolving Into Black Holes (%) P = 0.002 P = 0.04 35 30 31.4% 25 20 50% 15 15.6% 10 Glatiramer Acetate: Evolution to Black Holes The data shown in this slide represent the research done to date on the evolution of black holes in patients treated with glatiramer acetate vs placebo.1 Black holes are defined as new MS lesions that evolved into persistent hypointense lesions on postcontrast T1-weighted images on short-term follow-up. In the European/Canadian glatiramer acetate study, the percentage of black holes on follow-up MRI was lower in the glatiramer acetate group than in the placebo group at each time point.1 This difference achieved statistical significance 7 months after lesion appearance (P = 0.04). Of the 275 new lesions that were identified as T1 hypointense lesions at month 1 and followed for up to 8 months, 21 (15.6%) in the glatiramer acetate group and 44 (31.4%) in the placebo group remained hypointense and could be classified as permanent black holes.1 The difference between treatment groups was statistically significant (P = 0.002). At minimum, these data provide some indication that glatiramer acetate may have a beneficial effect on the development of permanent black holes.1 It is generally recognized that this is an important direction for future additional research. 1. Filippi M, Rovaris M, Rocca MA, et al. Glatiramer acetate reduces the proportion of new MS lesions evolving into “black holes.” Neurology. 2001;57: 5 7 8 Filippi M et al. Neurology. 2001;57:

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 Long-term Safety and Tolerability Issues: IFNs Safety and tolerability are critical issues of concern with any therapy administered, particularly therapies to be given over a long period of time. Although these trials reported on different safety and tolerability variables, the slide contains commonly reported events for the IFNs as a group, because of their similar mechanism of action.1 In the IFN -1b study, which reported laboratory results, laboratory abnormalities were somewhat more common in the high-dose IFN -1b group than in the placebo group over the course of the study.1 Leukopenia, lymphopenia, and neutropenia rates are the percent of patients with grade 2 or higher WBC- (<2,999/mm3), lymphocyte- (<1,499/mm3), or neutrophil- (<1,499/mm3) count toxicity. With regard to clinical adverse effects, the frequency of systemic flulike symptoms decreased in the high-dose group from 52% to 8% during year 1 and persisted in 3% to 8% through year 5.1 The frequency of such symptoms decreased from 18% to 7% in the placebo group and from 19% to 3.5% in the low-dose IFN -1b group in year 2. Injection-site reactions initially occurred in 80% of patients in the high-dose group, and the frequency decreased to 44% to 50% in years 4 and 5. Injection-site necrosis was unusual and varied in frequency from 1% to 3%. The proportions of patients reporting depressive symptoms were increased in active treatment groups compared with the placebo group for the low-dose group in years 3 and 4 and for the high-dose group in years 3 to 5.1 Over the extended follow-up period in the PRISMS trial, IFN -1a treatment at both doses was well tolerated; most of the adverse events were mild in severity.2 The most common were injection-site reactions and flulike symptoms, which were infrequently severe enough to require discontinuation of treatment. Long-term treatment was not associated with an increase in depression or suicide attempts. 1. Walther EU, Hohlfeld R. Multiple sclerosis: side effects of interferon beta therapy and their management. Neurology. 1999;53: 2. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45: PRISMS Study Group. Lancet. 1998;352: 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:

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 Neutralizing Antibodies There is conflicting evidence regarding a role of neutralizing antibodies in treatment failure. However, patients with neutralizing antibodies were more likely to experience relapse and had significantly (P < 0.001) greater BOD as assessed by MRI, compared with patients who did not develop neutralizing antibodies1 38% of patients in the IFN -1b trial developed neutralizing antibodies by the end of the third year.2 5% of patients in a recent weekly IFN -1a IM trial who had received drug for at least 1 year developed neutralizing antibodies.3 1. PRISMS Study Group. PRISMS-4: long-term efficacy of interferon--1a in relapsing MS. Neurology. 2001;56: 2. IFNB Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993;43: 3. Avonex® [package insert]. Cambridge, Mass: Biogen, Inc; 2003. 1. The IFNβ Multiple Sclerosis Study Group. Neurology. 1993;43: 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 Glatiramer Acetate–Reactive Antibodies MS patients treated with glatiramer acetate in 3 well-controlled clinical trials developed glatiramer acetate–reactive antibodies.1 Brenner and colleagues1 reported that levels of glatiramer acetate–reactive antibodies peaked 3 months after initiation of glatiramer acetate therapy, decreasing at 6 months and remaining at low levels thereafter. Analyses of the effects of glatiramer acetate–reactive antibodies in these patients revealed that their development did not correlate with side effects and did not affect the therapeutic activity of glatiramer acetate as measured by disability status.1 Recent research by Teitelbaum and colleagues2 confirms that glatiramer acetate–reactive antibodies do not neutralize any of the humoral or cellular effects of glatiramer acetate therapy in patients with MS. 1. Brenner T, Arnon R, Sela M, et al. Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone. J Neuroimmunol. 2001;115: 2. Teitelbaum D, Brenner T, Abramsky O, Aharoni R, Sela M, Arnon R. Antibodies to glatiramer acetate do not interfere with its biological functions and therapeutic efficacy [abstract]. Mult Scler. 2003;9(suppl 1):S37. Abstract P172. 1. Brenner T et al. J Neuroimmunol. 2001;115: 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 Long-term Safety and Tolerability Issues: Glatiramer Acetate In the glatiramer acetate trial, the most common adverse events were injection-site reactions, which accompanied 4,905 study injections (2.4%) in the initial active treatment group and 1,891 study injections (0.9%) in the placebo/active group.1 No cases of injection-site necrosis occurred. No laboratory value deviations associated with glatiramer acetate were reported. In controlled clinical trials, the most commonly observed adverse events associated with the use of glatiramer acetate and not seen at an equivalent frequency among placebo-treated patients were2: Injection-site reactions Vasodilatation Chest pain Asthenia (loss of strength or energy) Infection Pain Nausea Arthralgia (joint pain) Anxiety Hypertonia (muscle tightness) 1. Johnson KP, Brooks BR, Ford CC, et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Mult Scler. 2000;6: 2. Copaxone® [package insert]. Kansas City, Mo: Teva Marion Partners; 2000. Copaxone® [package insert]. Kansas City, Mo: Teva Marion Partners; 2000.

Safety and Tolerability Issues
possibly no C B yes IFN GA Menstrual disorders Pregnancy category Post-injection reaction Flulike symptoms Lab changes Injection- site reaction Safety and Tolerability Issues Immunomodulating therapies have somewhat different safety and tolerability issues. Injection-site reactions associated with glatiramer acetate are mild, and necrosis is not seen. Interferon treatment is associated with laboratory abnormalities, such as anemia, lymphopenia, neutropenia, and liver function elevations, and necessitates routine laboratory monitoring. Treatment with glatiramer acetate does not require regular laboratory monitoring. Glatiramer acetate does not produce the flulike syndrome associated with the interferons. Glatiramer acetate may produce a transient postinjection reaction characterized by dizziness, sweating, anxiety, and palpitations. However, this has not been associated with serious sequelae. The interferons have been associated with menstrual disorders, such as breakthrough bleeding in some studies. Glatiramer acetate has not been associated with menstrual disorders. The interferons have been shown to be abortifacient and thus are rated Category C. Although none of the available agents are recommended for women who are pregnant, unlike the interferons, glatiramer acetate is not a know abortifacient and is rated Category B.

Side Effect Management

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 Side Effect Management: IFN Flulike Symptoms Flulike symptoms are commonly experienced by patients taking beta interferons. In fact, they affect as many as 75% of patients.1 Symptoms can include fever, myalgia, headache, fatigue. The symptoms generally begin 3-6 hours after injection and last about 24 hours. Management: Recommend injection at night to sleep through symptoms Suggest NSAIDs as comedication—eg, ibuprofen up to 400 mg tid Consider half-dose beta interferon for first 4-6 weeks 1. Walther EU, Hohlfeld R. Multiple sclerosis: side effects of beta therapy and their management. Neurology. 1999;53: Walther EU, Hohlfeld R. Neurology. 1999;53:

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 Laboratory Test Abnormalities IFN  treatment is associated with occasional laboratory test abnormalities, including lymphopenia, neutropenia, leukopenia, and elevated liver aminotransferases. For proper management: 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. A recommended monitoring schedule is to perform lab tests 1 month following therapy initiation and every 3 months thereafter for the first year of treatment and then as appropriate to the clinical scenario. Consider dose adjustment or discontinuation of treatment if abnormalities persist. Not indicated with glatiramer acetate therapy.1 1. Copaxone® [package insert]. Kansas City, Mo: Teva Marion Partners; 2000. 1. Copaxone® [package insert]. Kansas City, Mo: Teva Marion Partners; 2000.

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: IFN Injection-Site Reactions Injection-site reactions can occur with beta interferons and glatiramer acetate. IM route (IFN -1a) generally causes fewer reactions than SC (IFN -1a, IFN -1b). Interferon reactions range from mild irritation to skin necrosis. For mild or moderate reaction: Continue therapy Apply ice before and after injection Allow drug to reach room temperature Use NSAIDs For skin necrosis: Discontinue SC injections; medical intervention if necessary If not infected—sterile covering with antibiotic ointment If infected—surgical intervention and broad-spectrum antibiotics Rare with glatiramer acetate (related to technique)

Side Effect Management: Glatiramer Acetate Injection-Site Reactions
Site rotation Ice to injection site Use of autoinjector Side Effect Management: Glatiramer Acetate Injection-Site Reactions Injection-site reactions can occur with beta interferons and glatiramer acetate. Glatiramer acetate reactions range from mild irritation to (rarely) skin necrosis. For mild or moderate reaction: Continue therapy Apply ice before and after injection Allow drug to reach room temperature Use NSAIDs For skin necrosis: Discontinue SC injections; medical intervention if necessary If not infected—sterile covering with antibiotic ointment If infected—surgical intervention and broad-spectrum antibiotics Rare with glatiramer acetate (related to technique)

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 minutes Side Effect Management: Glatiramer Acetate Postinjection Reaction Occasionally, glatiramer acetate therapy is associated with a postinjection reaction. It occurs immediately following injection and lasts for 30 seconds to 30 minutes. In one trial it occurred in 15.2% of patients treated with glatiramer acetate, compared with 3.2% of patients receiving placebo.1 While the reaction was unrelated to any serious sequelae in clinical trials, it can be very frightening to the patient, and thus patients should be educated about the possibility before beginning treatment. In some patients the postinjection reaction will occur on more than one occasion. The occurrence of the postinjection reaction does not require that the patient stop glatiramer acetate therapy. It is advisable, however, for the patient to administer the next dose of glatiramer acetate in a supervised clinic setting where injection technique can be observed and reassurance can be offered. 1. Johnson KP, Brooks BR, Cohen JA, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology. 1998;50:

Quality of Life and Adherence

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 Facilitating an Acceptable QOL Quality of life (QOL) has been defined as the congruence between actual life conditions and one’s hopes and expectations. MS has a profound effect on QOL: Patients with MS have significantly lower scores on all health dimensions of the SF-36, a commonly used QOL measure, compared with the general population. The difference is especially high in the areas of physical functioning, general health, physical role limitation, vitality, and social functioning.1 QOL assessment is essential for management of MS, since it helps to quantify the effect of MS on the patient as a whole instead of only focusing on a patient’s physical limitations.2 Includes comprehensive approach2: Therapeutic interventions to manage symptoms Coordination with primary care and allied health professionals Evaluation and support of cognitive and emotional status Ongoing patient and caregiver education Promotion and support of adherence 1. Nortvedt MW, Riise T, Muhr KM, Nuland HI. Quality of life as a predictor for change in disability in MS. Neurology. 2000;55:51-54. 2. Multiple Sclerosis Nurse Specialists Consensus Committee. Multiple Sclerosis: Key Issues in Nursing Management: Adherence, Cognitive Function, Quality of Life. Columbia, Md: Medicalliance, Inc; 1998.

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 Promoting Adherence Health care providers can support patient adherence to disease-modifying therapies by1: Providing patient and caregiver education on importance of adherence to success of treatment plan Recognizing and addressing diverse aspects of barriers to adherence, which can include: Communication problems Knowledge deficits Physical impairments Social and cultural variables Financial concerns Emotional distress Psychiatric disorders Cognitive deficits Clarifying realistic expectations regarding treatment: Stress that available drugs are not recovery agents, nor are they cures Involve family members in discussions of expectations Reiterate the benefits and limitations of each treatment Assessing costs Note that differential between the 4 agents is not relevant in treatment decision Investigate sponsored programs for the medically indigent 1. Multiple Sclerosis Nurse Specialists Consensus Committee. Multiple Sclerosis: Key Issues in Nursing Management: Adherence, Cognitive Function, Quality of Life. Columbia, Md: Medicalliance, Inc; 1998.

Factors That Influence Treatment Decisions
Medical Patient Considerations Considerations Burden of disease Enhancing lesions Disease course Number of relapses Lifestyle Expectations Capabilities Support system Factors That Influence Treatment Decisions Treatment decisions in MS are made by weighing the medical considerations along with patient considerations. Treatment decisions must be tailored to take into account the individual patient’s goals and lifestyle. It is also very important to consider not only which treatment will be best for the patient from a clinical standpoint but also which treatment regimen the patient will be able to continue to take over time, since MS is a chronic disease. These decisions are not easy, and they should be made with the patient and his or her family as active participants. Individual patient circumstances must be factored into the equation (eg, employment, schedule, family responsibilities, capabilities, physical assessment). It is also important to maintain balance between side effects and efficacy (risk/benefit ratio) for the chosen regimen. In closing, it is most important that patients realize that disease-altering treatment is available for MS and that it should be initiated early in the disease course to reduce the frequency of relapses and to delay progression of disability.

Summary

Summary: Goals of Disease Management in MS
Modifying/reducing relapses and delaying progression to disability Treating relapses Managing symptoms Facilitating an acceptable quality of life Summary: Goals of Disease Management in MS In conclusion, it is important to keep in mind the 4 main goals of MS management: Modifying/reducing relapses and delaying progression to disability Treating relapses Managing symptoms Facilitating an acceptable quality of life

Multiple Sclerosis Disease Overview & Current Management Strategies

Similar presentations

Presentation on theme: "Multiple Sclerosis Disease Overview & Current Management Strategies"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Multiple Sclerosis Disease Overview & Current Management Strategies

Similar presentations

Presentation on theme: "Multiple Sclerosis Disease Overview & Current Management Strategies"— Presentation transcript:

Similar presentations

About project

Feedback