3Demographics of MS Age at onset 15 to 45 years1 Gender 70% women2 US incidence 8,500 to 10,000 new cases per year1US prevalence 350,0002Demographics of MSMS 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 45.2For reasons that are as yet unclear, MS is more common in cooler climates and is increasingly more common with increased distance from the equator.3The 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.11. 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:
4Worldwide Prevalence of MS Worldwide distribution variesHigh prevalence 30+/100,000Northern United States and CanadaMost of EuropeSouthern AustraliaNew ZealandNorthern RussiaWorldwide Prevalence of MSThe 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).1The prevalence is highest in northern Europe, southern Australia, and northern United States and Canada.2There is a trend toward increasing prevalence and incidence in southern Europe.3,41. 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.
6Pathology of MSAn immune-mediated disease in genetically susceptible individualsDemyelination leads to slower nerve conductionAxonal injury and destruction are associated with permanent neurological dysfunctionLesions occur in optic nerves, periventricular white matter, cerebral cortex, brain stem, cerebellum, and spinal cordPathology of MSInflammation 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.1MS lesions tend to occur in specific areas of the central nervous system (CNS):Optic nervesPeriventricular white matterBrain stemCerebellumSpinal cordThe 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:
7Axonal 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;338:64m45mABReprinted with permission from Trapp BD et al. N Engl J Med. 1998;338: Copyright 1998 Massachusetts Medical Society. All rights reserved.
8What Causes Demyelination and Axonal Loss in MS? Activation of autoreactive CD4+ T cells in peripheral immune systemMigration of autoreactive Th1 cells into CNSIn situ reactivation by myelin autoantigensActivation of macrophages, B cellsSecretion of proinflammatory cytokines, antibodiesInflammation, demyelination, axonal transection, and degenerationWhat 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.1,2These 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.2,3Increases in Th1 cytokine levels often precede relapses.Demyelination, axonal transection, and degenerationAcute attack is due to demyelination; resolution is due to reduction of inflammation, accompanied by partial remyelination.Axonal loss leads to permanent disability.4,51. 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.
9Immunopathogenesis of MS Resting T cellMMPActivated (+) T cellsBBBBloodCNSTNF-IFN-BcellIL-2Th1APCImmunopathogenesis of MSWhile 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 diseaseA phase of selective demyelinationA neurodegenerative phaseInflammatory phase1,2Proinflammatory 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 phase1,2Macrophages 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.
10Immunopathogenesis of MS MMPActivated (+) T cellsBloodBBBTh1+CNSTNF-IFN-BcellIL-2Th1APCResting T cellAPCImmunopathogenesis of MSWhile 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 diseaseA phase of selective demyelinationA neurodegenerative phaseInflammatory phase1,2Proinflammatory 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 phase1,2Macrophages 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.
11Disability Progression and Disease Type Relapsing-remittingSecondary-progressiveDisabilityDisabilityTimeTimePrimary-progressiveProgressive-relapsingDisabilityDisabilityDisability Progression and Disease TypeMultiple 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 symptomsPrimary-progressive—characterized by slow and steady progression of symptoms, without asymptomatic periodsProgressive-relapsing—initially has a progressive course, but an exacerbation occurs after establishment of the progressive course1. 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:TimeTimeLublin FD, Reingold SC. Neurology. 1996;46:
12Natural History Over Time Relapsing-remittingSecondary-progressivePrimary-progressiveRelapsing-remitting15%42%85%58%Natural History Over TimeThis 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.1Moreover, 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.11. Weinshenker BG, Bass B, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study. Brain. 1989;112:Disease Type at DiagnosisDisease Type at YearsAfter Diagnosis (Among Those With RRMS at Diagnosis)Adapted from Weinshenker BG et al. Brain. 1989;112:
13Progression to Disability: EDSS Expanded Disability Status Scale (EDSS)Ordinal scale (range 0-10) measuring disability in increments of 0.5Most widely accepted measure of disability in patients with MSReflects impact of disease on neurological functionProgression to Disability: EDSSAn 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.1A measure commonly used to quantify the accumulation of fixed disability is the Expanded Disability Status Scale (EDSS).2AdvantagesUses an ordinal scale (range 0-10) to measure disability in increments of 0.5Is the most widely accepted measure of disability in patients with MSReflects impact of disease on neurological functionDisadvantages3Not exclusively objectiveHeavily weighted toward ambulationInsensitive to cognitive and upper limb disabilities1. 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:
14Progression to Disability: EDSS 0 Normal neurological exam1.0–1.5 No disability2.0–2.5 Minimal disability3.0–3.5 Mild to moderate disability4.0–4.5 Moderate disability5.0–5.5 Increasing limitations in ability to walk6.0–6.5 Walking assistance is needed7.0–7.5 Confined to wheelchair8.0–8.5 Confined to bed/chair; self-care with assistance9.0–9.5 Completely dependent10.0 Death due to MSProgression to Disability: EDSSThe 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:
15Natural History Average is 1 relapse per year, fewer over time1 25% of patients never lose ability to perform activities of daily living115% become severely disabled within short time1Median time to reach EDSS of 6 is 15 years; to reach EDSS of 8 is 46 years2Mortality from MS as primary cause is low1Natural HistoryNatural 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.125% of patients never lose ability to perform ADL.115% become severely disabled within a short time.1Median 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:
16Diagnosis of MS: Basic Principles Ultimately a clinical diagnosis; no definitive laboratory testClinical profileLaboratory evaluationEvidence of dissemination of lesions in space and timeExclusion of other diagnosesDiagnosis of MS: Basic PrinciplesUltimately, MS is a clinical diagnosis; no definitive laboratory test exists.1Clinical profile consists of symptomatic disease, abnormal exam, and white matter involvement, which are consistent with diagnosis.1Laboratory evaluation includes1:Magnetic resonance imaging (MRI)—imaging to identify lesions (will discuss in more detail)Cerebrospinal fluid (CSF)—evidence of intrathecal inflammationAbnormal CSF includes:– Oligoclonal immunoglobulin G (IgG) bands in CSF and not in serum– Elevated IgG indexEvoked potentials—evidence of altered conduction in a pattern consistent with demyelinationEvidence 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.1Evaluation should exclude other diagnoses, such as lupus erythematosus, CNS tumors, vasculitis, and endocrine disturbances.11. 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.
17Most 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 SymptomsThe 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/legsUnilateral vision lossSlowly progressive motor deficitAcute motor deficitDiplopiaPolysymptomatic onsetOthersOver the disease course, symptoms are highly variable in both frequency and severity.Fatigue is the most common symptom in 80% of patients with MS.21. 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;142:30-311. 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.
18Diagnoses That Mimic MS InfectionLyme diseaseNeurosyphilisPML, HIV, HTLV-1InflammatorySLESjögren’sOther CNS vasculitisSarcoidosisBehçet’s diseaseMetabolicVitamin B12 and E deficienciesCADASIL, other rare familial diseasesCNS lymphomaCervical spondylosisMotor neuron diseaseMyasthenia gravisDiagnoses That Mimic MSLaboratory 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 disordersAutoimmune diseasesInfectious diseasesVascular disordersGenetic syndromeLesions of the posterior fossa and spinal cordPsychiatric disordersNeoplastic illnessesVariants of MS1. 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 Managementand Rehabilitation. New York: Demos; 2000:
19Use of MRI in DiagnosisMRI is used to improve confidence in a clinical diagnosis of MS or to make a diagnosis of MS in clinically isolated syndromes1May show dissemination in space and time (eg, new lesions on follow-up MRI)1Total lesion load at diagnosis tends to be predictive of future disability2Use of MRI in DiagnosisThe 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 syndromesTo 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.21. 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:
20MRI Basics in Diagnosing MS T1-weighted scanShows hypointense lesions (black holes)T2-weighted scanIndicates total burden of diseaseMay show new lesionsFLAIR imageSuppresses CSFUseful for subcortical and cortical lesion identificationGadolinium enhancementHighlights new or active lesionsMRI Basics in Diagnosing MS1T1-weighted scanShows new or hypointense lesions (ie, black holes)Indicates areas with recent inflammatory demyelination and disruption of the BBBT2-weighted scan:Generally indicates the burden of disease (BOD)Reflects broad spectrum of pathological changes, including inflammation, edema, demyelination, and axonal lossFluid-attenuated inversion recovery (FLAIR) imageThe 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.2Gadolinium (Gd):Helps identify active lesions, since the contrast medium will enter the CNS only if the BBB has been breached1. 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:
21MS Lesions on MRI A B T2 T2-FLAIR C D T1 precontrast BODT2-FLAIRCDT1 precontrastblack holesT1/Gd postcontrastdisease activityMS Lesions on MRIVarious 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 holesAre T1-weighted hypointensitiesReflect areas of axonal lossCorrelate most strongly with the progression of disabilityThought to be areas of permanent damage when not associated with a new lesionIt 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.
22McDonald Diagnostic Criteria Preserve traditional diagnostic criteria of 2 attacks of disease separated in space and timeMust be no better explanationAdd 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:MSPossible MSNot MSMcDonald Diagnostic CategoriesIn 2002, the International Panel on the Diagnosis of Multiple Sclerosis published revised diagnostic criteria that include the use of new technology.1The 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 sclerosisThe 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 lesionLaboratory-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 abnormalitiesClinically 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 lesionLaboratory-supported probable MS: 2 attacks and CSF abnormalities1. 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:
23McDonald 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 lesion1 or more infratentorial lesions1 or more juxtacortical lesions3 or more periventricular lesions1 cord lesion = 1 brain lesionMcDonald MRI CriteriaFor 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 lesions1 or more infratentorial lesion1 or more juxtacortical lesion3 or more periventricular lesions1 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:
24McDonald MRI Criteria Gd-enhancing T2-hyperintense Juxtacortical PeriventricularSpinal CordInfratentorialMcDonald MRI CriteriaThe images on this slide demonstrate certain diagnostic MRI characteristics encompassed by the McDonald criteria1:Gd-enhancing lesionsT2-hyperintense lesionsInfratentorial lesionsJuxtacortical lesionsPeriventricular lesionsSpinal cord lesions1. 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.
25Brain AtrophyBrain AtrophyThis 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.1Axial 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:
26Measures of brain volume Relapses and impairment Secondary-progressive Disease ProgressionMeasures of brain volumeRelapses and impairmentMRI burden of diseaseMRI activitySecondary-progressivePreclinicalRelapsing-remittingDisabilityDisease ProgressionThis 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.TimeAdapted with permission from JS Wolinsky.
28Goals of Disease Management Treating relapsesManaging symptomsModifying or reducing relapses and delaying progression to disabilityFacilitating an acceptable quality of lifeGoals of Disease ManagementThere are 4 main goals for management of MS:Treating relapsesManaging symptomsModifying/reducing relapses and delaying progression to disabilityFacilitating an acceptable quality of life
29Acute MS Relapses Relapses Management: high-dose steroids Focal disturbances of function >24 hoursOccur about once a year in untreated patientsIn absence of environmental, metabolic, or infectious processesManagement: high-dose steroidsCommon option: methylprednisolone IV for 5 days followed by short course of prednisoneOral prednisone, oral methylprednisolone, or dexamethasoneAcuteMS RelapsesRelapses:Are sometimes also referred to as exacerbations, attacks, flare-ups, or acute episodesAre defined as focal disturbance of function, affecting a white matter tract, which lasts more than 24 hours1Occur in the absence of environmental, metabolic, or infectious processesGenerally evolve over a few days, reach a plateau, then resolve to variable degree over weeks or monthsOccur about once every year in untreated patients2Management options include high-dose steroids, which accelerate speed but not degree of recovery.3Options include methylprednisolone, prednisone, prednisolone, betamethasone, and dexamethasone.4A commonly used option is methylprednisolone IV for 5 days, followed by optional short course of prednisone.5Oral prednisone is rarely used acutely, since a trial showed increased risk of recurrence in patients with optic neuritis.61. 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:
30Common MS Symptoms Fatigue Depression Focal muscle weakness Visual changesBowel/bladder/sexual dysfunctionGait problems/spasticityParesthesiasCommon MS SymptomsMS patients may experience a wide range of symptoms.Symptoms can be described on the basis of the area of the CNS that is involved.1It 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:FatigueDepressionFocal muscle weaknessVisual changesBowel/bladder/sexual dysfunctionGait problems/spasticityParesthesias (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
31Less Common MS Symptoms Dysarthria, scanning speech, dysphagiaLhermitte’s phenomenonNeuritic painVertigo/ataxiaCognitive dysfunctionTremor/incoordinationLess Common MS SymptomsLess common MS symptoms can include:Dysarthria, scanning speech, dysphagiaLhermitte’s signNeuritic painVertigo/ataxiaCognitive dysfunctionTremor/incoordination
32Rare MS Symptoms Decreased hearing Seizures Tinnitus Mental disturbanceParalysisRare MS SymptomsRare MS symptoms can include:Decreased hearingSeizuresTinnitus (ringing in the ears)Mental disturbanceParalysis
33Symptoms vary widely in incidence and severity Sources of SymptomsSymptoms vary widely in incidence and severityCognitive lossEmotional disinhibitionTremor,AtaxiaOptic neuritisDiplopiaVertigoDysarthriaINOSources of SymptomsSymptoms can be described on the basis of the area of the CNS that is involved.1Inflammation 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:FatiguePainSpasticityElimination dysfunctionsCognitive impairmentSexual dysfunction1. 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’sPainProprioceptionBladder dysfunction
34Symptom Management: Fatigue 75% to 95% of patients with MS have fatigue, which is often debilitatingRule out possible other causes, such as hypothyroidism, depression, anemia, heat exposure, sleep disorders, pulmonary dysfunctionSymptom Management: FatigueOne study of patients with MS in Canada found that 88% complained of fatigue, which may be debilitating.1To determine whether a patient has MS-related fatigue, the physician must rule out possible comorbidities, such as hypothyroidism, depression, anemia, or heat exposure.1,21. 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.
35Symptom Management: Fatigue Management includes:Lifestyle changesEffective energy expenditurePharmacologic interventionsCNS stimulants, eg, amantadine and modafinilAntidepressants, eg, fluoxetineSymptom Management: FatigueFatigue 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.1,2Several medications have been used to treat the fatigue associated with MS, including:Amantadine (Symmetrel®)—antiviral agent3Pemoline (Cylert®)—CNS stimulant3Methylphenidate hydrochloride (Ritalin®)—CNS stimulant3Fluoxetine (Prozac®)—selective serotonin reuptake inhibitor antidepressant1Modafinil (Provigil®)—CNS stimulant41. 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.
36Symptom Management: Pain Pain is a complex sensory phenomenonMultiple causes and typesNeuropathicMusculoskeletalOptic neuritisSpasticityDystoniaSymptom Management: PainPain is complex; it is a sensory phenomenon with many potential causes and types.1Types of pain in MS can include1:NeuropathicMusculoskeletalHand or arm painOptic neuritisSpasticity1. 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.
37Symptom Management: Pain NonpharmacologicSeatingPosture improvementPhysical therapyGait trainingAssistive devicesMuscle strengthening/stretchingSymptom Management: PainNonpharmacologic treatment includes seating and posture improvement.1Physical 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.11. 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.
38Symptom Management: Pain Pharmacologic optionsTricyclic antidepressantsAmitriptyline (Elavil®), nortriptyline (Pamelor®)Antiepileptic medicationsCarbamazepine (Tegretol®), gabapentin (Neurontin®), phenytoin (Dilantin®)Antispasticity medicationsBaclofen, tizanidine (Zanaflex®)Benzodiazepines, eg, clonazepam (Klonopin®)Symptom Management: PainPharmacologic management may include1:Tricyclic antidepressantsAmitriptyline (Elavil®)Nortriptyline (Pamelor®)Antiepileptic drugsCarbamazepine (Tegretol®)Gabapentin (Neurontin®)Phenytoin (Dilantin®)Antispasticity medicationsBenzodiazepines, 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.
39Symptom Management: Spasticity Spasticity canLimit mobilityExpend excessive energyCause discomfortDescribed asTightnessPullingTuggingAchingSymptom Management: SpasticitySpasticity 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.
40Symptom Management: Spasticity Nonpharmacologic interventionsStretchingPositioningSeatingPhysical therapySurgical InterventionsBaclofen pumpRhizotomyPharmacologic interventionsBaclofenTizanidineDiazepamDantroleneNerve blocksBotulinum toxinSymptom Management: SpasticityManagement of spasticity may consist of:Nonpharmacologic interventionsStretchingPositioningSeatingPhysical therapySurgical interventionsBaclofen 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)Rhizotomy2Pharmacologic interventionsBaclofen (Lioresal®)—centrally acting muscle relaxant, which can be administered orally (can also be administered surgically; see surgical interventions)Tizanidine (Zanaflex®)—centrally acting muscle relaxantDiazepam (Valium®)—centrally acting muscle relaxantDantrolene (Dantrium®)—peripherally acting muscle relaxantNerve blocks if refractory—injection of botulinum toxin to treat spasticity affecting limited muscle group31. 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.
41Symptom Management: Bladder Dysfunction Failure to store urine, empty bladder, or bothSymptoms include double voiding, hesitancy, frequency, urgency, incontinence, UTIsEvaluation: rule out UTI, check post-void residual (ie, amount of urine remaining after voiding bladder)ManagementAntispasmodicsTricyclic antidepressantsDDAVP (an antidiuretic hormone)Alpha blockersIntermittent self-catheterizationIndwelling catheterSymptom Management: Bladder DysfunctionBladder dysfunction is present in many patients with MS.1Symptoms can include hesitancy, frequency, urgency, and incontinence.1Symptoms are caused by failure to store urine, failure to empty the bladder, or both.1Evaluation 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.1Management options include1:AntispasmodicsTeterodine (Detrol®)Oxybutynin (Ditropan®)Propantheline bromide (Probanthine®)Hyoscyamine (Levsin®, Fevbid®)Flavoxate (Urispas®)Tricyclic antidepressants—imipramine (Tofranil®)DDAVP (an antidiuretic hormone)—desmopressin (DDAVP nasal spray)Alpha blockersIntermittent self-catheterization-bladderIndwelling catheter1. 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.
42Symptom Management: Bowel Dysfunction Caused by lesions in spinal cordSymptomsConstipation is most commonInvoluntary bowelDiarrhea is uncommonManagementConstipation: fiber, fluids, activity, bowel training, laxatives, dietary modificationInvoluntary bowel: fiber, anticholinergics, dietary modificationSymptom Management: Bowel DysfunctionBowel dysfunction is often caused by demyelination in the spinal cord.1Constipation 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.1Management options include1:Increased dietary fiber, laxatives for constipationFiber supplements for loose stools or involuntary evacuationBowel 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.
43Symptom Management: Cognitive Impairment Occurs in 45% to 60% of patients1 but results in significant changes in only 15%2Manifests as short-term memory loss or impaired judgment, learning, word finding, or executive functioningManagementNeuropsychiatric testingCompensatory techniquesCognitive retrainingDisease-modifying therapiesSymptom Management: Cognitive ImpairmentAbout 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.1Management may include1,2:Items to compensate for impairment, such as drug boxes, lists and portable recorders, and watches with alarms for medication times1. 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:
44Sexual Dysfunction/Intimacy Men and women can experience difficulties Libido Erection Frequency of orgasms Lubrication Bladder spasticity DepressionSexual Dysfunction/IntimacyMS can cause primary, secondary, or tertiary sexual dysfunction.1Primary 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.
45Sexual Dysfunction/Intimacy Management strategies includePharmacologic managementTreat underlying symptomsAdjust medicationsPositioningLifestyle changesKey to successful management is open communicationSexual Dysfunction/IntimacyManagement of primary sexual dysfunction includes medications, lubrication, and body mapping assessment.1Management of secondary sexual dysfunction includes treatment of underlying symptoms as well as adjustments in positioning.1Management of tertiary sexual dysfunction includes counseling, treatment of intermittent problems, and culturally sensitive interventions.11. 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.
47Disease Modification Aim to alter the natural course of the disease Decrease relapsesDelay disabilityTwo classes of disease-modifying medications:ImmunomodulatorsImmunosuppressantsDisease ModificationDisease-modifying agents aim to alter the natural course of the disease, rather than to simply treat symptoms.1Two 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:
48MS Immunotherapy Nonspecific immunomodulation Interferon beta-1b (Betaseron®), Interferon beta-1a (Avonex®, Rebif®)Selective immunomodulationGlatiramer acetate (Copaxone®)Nonspecific immunosuppressionCorticosteroidsMitoxantrone (Novantrone®)Cyclophosphamide (Cytoxan®)*Experimental therapies*MS ImmunotherapyThe 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.1Experimental 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.21. 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.
49Nonselective and Selective Immunomodulatory Treatments Glatiramer Acetate(Copaxone®)IFN -1a(Avonex®)IFN -1a(Rebif®)IFN -1b(Betaseron®)Type Recombinant protein PolypeptidemixtureIndication Reduce relapse frequency in RRMSSlow Slow accumulation accumulationof disability of disabilityHow given 30 g IM 22 or 44 g SC 250 g SC 20 mg SC weekly every other day 3x/week dailyRelapse rate 18% 27%-33% 30% 32%(annualized) (2 years) (5 years) (long-term)Published data 2 years 4 years 5 years 8+ yearsNonselective and Selective Immunomodulatory TreatmentsThis 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.
50Nonselective and Selective Immunomodulatory Treatments Glatiramer Acetate(Copaxone®)IFN -1a(Avonex®)IFN -1a(Rebif®)IFN -1b(Betaseron®)MRI findings Reduces Reduces Reduces rate Reduceslesions active lesions of new lesions lesionsReduces risk for Reduces Reduces rate Reduces loss progression disability of severe of brain tissue of disability relapsesCommon 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 functionNonselective and Selective Immunomodulatory TreatmentsThis slide continues the comparison of the 4 approved agents for RRMS.1-4MRI findings for all 4 agents demonstrate varying rates of reduction of active or new brain lesions at different time points.1-4Additional MRI findings with the use of different agents correlate with reductions of disability, rates of severe relapses, or brain tissue loss.1-4The 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:
52Cytokine Imbalance in MS NormalMSInflammatory IFN- IL-12 TNFInflammatory IFN- IL-12 TNFAnti-inflammatory IL-4 IL-10 TGF-Th1Th2Cytokine Imbalance in MSThe 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.
53Potential Mechanisms of Action of IFN- in MS Antiproliferative effectBlocking T-cell activationApoptosis of autoreactive T cellsIFN- antagonismCytokine shiftsAntiviral effectDoes not cross blood-brain barrierIndirect effects on CNSPotential Mechanisms of Action of IFN- in MSIFN- has the following immune system effects1,2:Inhibition of T-cell proliferationBlocking of T-cell activationApoptosis of autoreactive T cellsAntagonism of IFN-γCytokine shiftsReduction of TNF- productionIncrease in IL-10 productionActivates regulatory T cells and stimulates suppressive (Th2) cytokinesReduction of antigen presentation to T cellsReduction of immune cell passage across BBBBecause 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.21. 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:
54IFN-β–Induced Cytokine Shift MSInflammatory Th1 cytokinesIFN-βIL-12Anti-inflammatory Th2 cytokinesIFN-β–Induced Cytokine ShiftIn 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
55Effects of IFN- at Blood-Brain Barrier BBBCNSIFN-βTh1+MMPMyelin proteinAntigenTh1+Th1+Th1APCAPCEffects of IFN- at Blood-Brain BarrierThe actions of MS therapies at the level of the BBB translate into the effects observed on Gd-contrast scansIFN- has the following effects at the BBB1:Decreases production of matrix metalloproteinases (MMPs) by T cellsReduces expression of several chemokine receptorsAffects adhesion of T cells onto the endotheliumReduces influx of T cells into the CNSRapid resolution of Gd-enhancing MRI activity1. Yong VW. Differential mechanisms of action of interferon- and glatiramer acetate in MS. Neurology. 2002;59:MMPResting T cellTh1+IL-2TNF-αIFN-γActivated (+) T cellsIFN-βAdapted from Yong VW. Neurology. 2002;59:
56Glatiramer Acetate: Possible Mechanisms of Action Blocking autoimmune T cellsInduction of anergyInduction of anti-inflammatory Th2 cellsBystander suppressionNeuroprotectionGlatiramer Acetate: Possible Mechanisms of ActionThe 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:
57Effects of Glatiramer Acetate at Blood-Brain Barrier Th2+Adapted from Yong VW. Neurology. 2002;59:GA-induced T cellMMPActivated (+) T cellsBBBBloodCNSIL-4TGF-βBcellIL-10Th2APCGlatiramer acetate (GA)Myelin proteinBystander suppressionEffects of Glatiramer Acetate at Blood-Brain BarrierThe 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.1Glatiramer acetate has the following effects at the BBB1:Glatiramer acetate–specific Th2 cells traffic into the CNS toReduce inflammationProduce bystander suppressionPossibly produce neuroprotection1. Yong VW. Differential mechanisms of action of interferon- and glatiramer acetate in MS. Neurology ;59:
59IFN -1b: Annual Relapse Rates Over 5 Years 33%*1.50PlaceboInterferon -1b, 8 MIU28%†1.251.0028%‡24%‡Mean Number of Relapses30%‡0.75IFN -1b: Annual Relapse Rates Over 5 YearsThe 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;45:0.500.2512345Study Year*P < 0.001; †P < 0.05; ‡P = NS.Adapted from IFNB Multiple Sclerosis Study Group. Neurology. 1995;45:
60Interferon β-1a IM: Annual Relapse Rate 0.10.20.30.188.8.131.52.80.91.0Placebo32%†18%*Interferon -1aMean Number of RelapsesInterferon b-1a IM: Annual Relapse RateIn 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 PatientsPatients Treated 2 Years*P < 0.04; †P <Adapted from Jacobs LD et al. Ann Neurol. 1996;39:
61Annual Mean Number of Relapses for IFN -1a SC 0.00.51.01.52.01.51.5P <1.02Relapses/Patient/YearMean Number of0.800.7232%47%52%Annual Mean Number of Relapses for IFN -1a SCIn 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.1Over the 4 years of the IFN -1a study, the mean number of relapses/patient were0.72 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 groupsBoth 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:PlaceboBoth IFN -1a ArmsPlacebo/ Active22 g 3/wk44 g 3/wkPrior to Study EntryAt 4 YearsPRISMS Study Group. Neurology. 2001;56:
62Glatiramer Acetate: Mean Relapse Rate PlaceboGlatiramer Acetate32%†2.029%*184.108.40.206.2Mean Number of Relapses1.00.80.6Glatiramer Acetate: Mean Relapse RateThe 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.2There 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.2The 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.2A 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.31. 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;49:0.40.20.024 Months24 Months + Extension*P < 0.007; †P <Adapted from Johnson KP et al. Neurology. 1998;50:
63Glatiramer Acetate: 8-Year Data Annualized Relapse Rate PlaceboPlacebo/Active1.61.4P = 0.01P = 0.051.21.0Relapse Rate (means)0.80.6Glatiramer Acetate: 8-Year Data Annualized Relapse RateDuring 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.1Overall, 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).1Relapse 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.1By year 8 of the study, relapse rates for group A and group B were similar.1Annualized 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).1P 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.11. Johnson KP, et al. Neurology. 2002;58(suppl 3):A458. P0.40.20.0EntryPlacebo-ControlledPhase and ExtensionPlacebo-ControlledPhase Through Open-Label PhaseJohnson KP et al. Neurology. 2002;58(suppl 3):A458. P
64Mean Annual Relapse Rates of DMTs Nonrandomized, Open-Label Study INF β-1a IMINF β-1b SCGAINF β-1a 22 μg SC1.41.21.00.220.127.116.11.0Before Study6 Months12 Months24 MonthsMean Number of RelapsesMean 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.
66IFN -1a SC: Proportion of Patients Free From Progression Over 4 Years 1.0ITT progression-free patients: all crossover vs 3 44 g: P = 0.070.8Proportion of Patients3 223 440.6IFN -1a SC: Proportion of Patients Free From Progression Over 4 YearsThis 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/44Placebo/220.4612182430364248Time (months)Adapted with permission from PRISMS-4 Study Group. Neurology. 2001;56:
67IFN -1b: Probability of Avoiding Progression Over 5 Years 8 MIUPlacebo1.6 MIUTime to progression: P = 0.096Patients With Sustained Progression 1 EDSS StepPlacebo 46% (56/122)IFN -1b 8 MIU 35% (43/122)100908070605040302010Probability (%)IFN -1b: Probability of Avoiding Progression Over 5 YearsThe 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.1The 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.11. 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;45:18036054072090010801260144016201800DaysAdapted with permission from the IFNB MS Study Group. Neurology. 1995;45:
68Placebo-Controlled Phase Survival Distribution Estimate Glatiramer Acetate: Time to Worsening by 1.5 EDSS Steps Over 6 Years (Open-Label Cohort)Placebo-Controlled PhaseOpen-Label Phase0.70.60.50.4Survival Distribution Estimate0.3Placebo/Active (n = 107)Glatiramer Acetate (n = 101)Time to worsening: P = 0.0480.2Glatiramer 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;6:0.10.01234567YearsJohnson KP et al. Mult Scler. 2000;6:
69Glatiramer Acetate: 8-Year Data Yearly EDSS Change From Baseline 0.80.40.70.18.104.22.168.00.1–0.1Glatiramer AcetatePlacebo/ActiveP = (RMA)Change in EDSS ScoreGlatiramer Acetate: 8-Year Data Yearly EDSS Change From BaselineAnother 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 < 0.06Year 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, NSYear 6 – GA: n = 83, mean = 0.14; placebo: n = 86, mean = 0.49, P < 0.10, NSYear 7 – GA: n = 76, mean = 0.29; placebo: n = 76, mean = 0.58, P < 0.24, NSYear 8 – GA: n = 73, mean = 0.38; placebo: n = 71, mean = 0.74, P < 0.16, NSThe 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.Entry12*3*4*5678*P < 0.05.YearJohnson KP et al. Neurology. 2002;58(suppl 3):A458.
70Glatiramer Acetate: 8-Year Data Categorical EDSS Change From Randomization to Last Observation 75Glatiramer Acetate65.3Placebo/Active65P =5550.449.54534.7Patients (%)3525Glatiramer Acetate: 8-Year DataCategorical EDSS Change From Randomization to Last ObservationMost 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.1,21. 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.155Improved/No ChangeWorsenedJohnson KP et al. Neurology. 2002;58(suppl 3):A458.
72MRI Endpoints in RRMS Trials T2 Lesion Burden (Median % Change)* IFN β-1b 1PlaceboP < 0.001175 μg875 μgIFN β-1a IMPlaceboP = 0.3630 μgIFN β-1a SCPlaceboP <66 μg132 μgMRI Endpoints in RRMS TrialsT2 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 2PlaceboP = 0.001140 mg–15–10–5510152025*Weekly doses reported.1. Paty DW, Li DK. Neurology. 1993;43:2. Comi G et al. Ann Neurol. 2001;49:
73IFN -1a IM: Change in Volume of Black Holes (Total Lesion Load) 150P = 0.065, NS125100Total Lesion Load (mm3), Median Change From Baseline7550IFN -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.1MRI was performed yearly, and 2-year results are shown here.1The 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.11. 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;55:25n = 80n = 80PlaceboIFN β-1a IMSimon JH et al. Neurology. 2000;55:
74EVIDENCE Trial CU Lesions 876IFN β-1a 30 μg qw IM5Mean Cumulative CU Active Lesions43IFN β-1a 44 μg tiw SC2*P < at Week 241EVIDENCE Trial CU LesionsThis 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.1The 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;59:4812162024Week (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:
75IFN β-1a SC Long-term Data: MRI T2 Lesions IFN β-1a 44 tiw SC vs placebo/44 tiw SCIFN β-1a 22 tiw SC vs placebo/22 tiw SCIFN β-1a 44 tiw SC vs IFN β-1a 22 tiw SC9.7107.253.4Median Percent Change in Total T2 Lesion Area–5–6.2IFN -1a SC Long-term Data: MRI T2 LesionsThe 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.1,2In 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).31. 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:–10Placebo/22 μgtiw SC(n = 57)Placebo/44 μgtiw SC(n = 49)IFN β-1a 22 μgtiw SC(n = 117)IFN β-1a 44 μgtiw SC(n = 111)P = 0.11P = 0.003P = 0.009The 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].
76Median Change After Baseline IFN -1b: Median Change in MRI-Measured BOD 217 Patients Having at Least a Fourth-Year Annual ScanP =35Placebo30.28 MIU30P =P =2521.018.720P =15P =11.9Median Change After Baseline106.73.65IFN -1b: Median Change in MRI-Measured BOD 217 Patients Having at Least a Fourth-Year Annual ScanIn the pivotal trial of IFN -1b, 217 patients with MS completed 4 or 5 years of the study and had annual MRI scans.1Analysis 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:–0.8–5–3.8–4.9–5.6–1012345Study YearAdapted with permission from the IFNβ MS Study Group. Neurology. 1995;45:
77Effect of IFN -1b on Enhancements Months on Study (27 Subjects)12345678910111220406080100120140160Total Enhancements80%–90% responseInterferon β-1b initiatedEffect of IFN -1b on EnhancementsIn 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:
78Glatiramer Acetate 9-Month Data: MRI T2 Lesions Placebo25Glatiramer Acetate2015Volume % Change (median)10Glatiramer Acetate 9-Month Data: MRI T2 LesionsThe European-Canadian MRI Study further evaluated the effects of glatiramer acetate on MRI measures of disease activity and burden in patients with RRMS.1The 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 P5MonthsComi G et al. Neurology. 2001;56(suppl 3):A255.
79Primary Endpoint: Cumulative Number of Enhancing Lesions (9 Months) PlaceboGlatiramer Acetate4536.8–29%40P =3526.03025Lesion Number (mean + SE)20Primary 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).1When 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).11. 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 imagingmeasured disease activity and burden in patients with relapsing multiple sclerosis. Ann Neurol. 2001;49:15105LOCFAdapted with permission from Comi G et al. Ann Neurol. 2001;49: This material is used by permission of John Wiley & Sons, Inc.
80European/Canadian MRI Trial: Summary Glatiramer acetate had significant effects on:Reduction P ValueTotal 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% 0.01European/Canadian MRI Trial: SummaryGlatiramer acetate had significant effects on many MRI and clinical parameters in the 9-month randomized, double-blind phase of the European/Canadian MRI trial.1Compared 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 imagingmeasured disease activity and burden in patients with relapsing multiple sclerosis. Ann Neurol. 2001;49:Comi G et al. Ann Neurol. 2001;49:
81Glatiramer Acetate: Evolution to Black Holes PlaceboGlatiramer AcetateLesion Age (months)Lesions Evolving Into Black Holes (%)P = 0.002P = 0.04353031.4%252050%1515.6%10Glatiramer Acetate: Evolution to Black HolesThe 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;57:578Filippi M et al. Neurology. 2001;57:
83Long-term Safety and Tolerability Issues: IFNs Flulike syndrome (fever, chills, fatigue)Experienced by up to 75% of patients taking an IFN-βInjection-site reaction and necrosisDepressionLiver function and bone marrow abnormalitiesNeutralizing antibodiesLong-term Safety and Tolerability Issues: IFNsSafety 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.1In 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 5.1Over 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:
84Neutralizing Antibodies Conflicting evidence regarding role of neutralizing antibodies in treatment failure38% of patients in the IFN -1b trial developed neutralizing antibodies by the end of the third year15% of patients in a recent weekly IFN -1a IM trial who had received drug for at least 1 year developed neutralizing antibodies2Neutralizing AntibodiesThere 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 antibodies138% of patients in the IFN -1b trial developed neutralizing antibodies by the end of the third year.25% of patients in a recent weekly IFN -1a IM trial who had received drug for at least 1 year developed neutralizing antibodies.31. 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.
85Glatiramer Acetate–Reactive Antibodies In clinical trials, patients treated with glatiramer acetate developed reactive antibodies that peaked at 3 months and decreased at 6 months1Development of these antibodies did not correlate with side effects and did not affect therapeutic activity of glatiramer acetate1Additional recent research confirms that reactive antibodies do not interfere with the biological functions of glatiramer acetate2Glatiramer Acetate–Reactive AntibodiesMS patients treated with glatiramer acetate in 3 well-controlled clinical trials developed glatiramer acetate–reactive antibodies.1Brenner 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.1Recent 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.
86Long-term Safety and Tolerability Issues: Glatiramer Acetate Injection-site reactionImmediate postinjection reactionLong-term Safety and Tolerability Issues: Glatiramer AcetateIn 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.1No 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 reactionsVasodilatationChest painAsthenia (loss of strength or energy)InfectionPainNauseaArthralgia (joint pain)AnxietyHypertonia (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.
87Safety and Tolerability Issues possiblynoCByesIFNGAMenstrual disordersPregnancy categoryPost-injection reactionFlulike symptomsLab changesInjection- site reactionSafety and Tolerability IssuesImmunomodulating 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.
89Side Effect Management: IFN Flulike Symptoms Begin 3-6 hours after injection; last up to 24 hoursManagement:Injection at nightNSAIDs or acetaminophen as comedicationsDose titrationNot experienced with glatiramer acetateSide Effect Management: IFN Flulike SymptomsFlulike symptoms are commonly experienced by patients taking beta interferons. In fact, they affect as many as 75% of patients.1Symptoms 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 symptomsSuggest NSAIDs as comedication—eg, ibuprofen up to 400 mg tidConsider half-dose beta interferon for first 4-6 weeks1. Walther EU, Hohlfeld R. Multiple sclerosis: side effects of beta therapy and their management. Neurology. 1999;53:Walther EU, Hohlfeld R. Neurology. 1999;53:
90Side Effect Management: IFN Laboratory Test Abnormalities Obtain baseline complete blood count and differential and liver function values before initiation of therapyMonitor laboratory test values at regular intervals after initiation of therapyConsider dose adjustment or discontinuation of treatment if abnormalities persistNot indicated with glatiramer acetate1Side Effect Management: IFN Laboratory Test AbnormalitiesIFN 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.11. Copaxone® [package insert]. Kansas City, Mo: Teva Marion Partners; 2000.1. Copaxone® [package insert]. Kansas City, Mo: Teva Marion Partners; 2000.
91Side Effect Management: IFN Injection-Site Reactions Site rotationIce to injection siteUse of autoinjectorLocal wound care for skin necrosisSide Effect Management: IFN Injection-Site ReactionsInjection-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 therapyApply ice before and after injectionAllow drug to reach room temperatureUse NSAIDsFor skin necrosis:Discontinue SC injections; medical intervention if necessaryIf not infected—sterile covering with antibiotic ointmentIf infected—surgical intervention and broad-spectrum antibioticsRare with glatiramer acetate (related to technique)
92Side Effect Management: Glatiramer Acetate Injection-Site Reactions Site rotationIce to injection siteUse of autoinjectorSide Effect Management: Glatiramer Acetate Injection-Site ReactionsInjection-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 therapyApply ice before and after injectionAllow drug to reach room temperatureUse NSAIDsFor skin necrosis:Discontinue SC injections; medical intervention if necessaryIf not infected—sterile covering with antibiotic ointmentIf infected—surgical intervention and broad-spectrum antibioticsRare with glatiramer acetate (related to technique)
93Side Effect Management: Glatiramer Acetate Postinjection Reaction Occurs immediately after injection and consists of facial flushing, chest tightness, palpitations, anxiety, and shortness of breathUnrelated to serious sequelaeTreatment steps:Educate patient about possible occurrenceReassure patient if reaction occursInstruct patient to sit upright in a comfortable chairRefer for emergency care if no improvement in symptom intensity after minutesSide Effect Management: Glatiramer Acetate Postinjection ReactionOccasionally, 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.1While 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:
95Facilitating an Acceptable QOL Quality of life (QOL) is the congruence between actual life conditions and one’s hopes and expectationsMS, with its range of symptoms and its progressive nature, has a profound effect on QOLMaximizing QOL is an essential component of an optimal management strategyIncludes comprehensive approachFacilitating an Acceptable QOLQuality 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.1QOL 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.2Includes comprehensive approach2:Therapeutic interventions to manage symptomsCoordination with primary care and allied health professionalsEvaluation and support of cognitive and emotional statusOngoing patient and caregiver educationPromotion and support of adherence1. 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.
96Promoting AdherenceEducate about the critical role of adherence in outcomesRecognize and address barriers to adherenceImportance of clarifying realistic expectationsAdvocacyAssistance with reimbursementIdentify resourcesInvolve familyPromoting AdherenceHealth care providers can support patient adherence to disease-modifying therapies by1:Providing patient and caregiver education on importance of adherence to success of treatment planRecognizing and addressing diverse aspects of barriers to adherence, which can include:Communication problemsKnowledge deficitsPhysical impairmentsSocial and cultural variablesFinancial concernsEmotional distressPsychiatric disordersCognitive deficitsClarifying realistic expectations regarding treatment:Stress that available drugs are not recovery agents, nor are they curesInvolve family members in discussions of expectationsReiterate the benefits and limitations of each treatmentAssessing costsNote that differential between the 4 agents is not relevant in treatment decisionInvestigate sponsored programs for the medically indigent1. Multiple Sclerosis Nurse Specialists Consensus Committee. Multiple Sclerosis: Key Issues in Nursing Management: Adherence, Cognitive Function, Quality of Life. Columbia, Md: Medicalliance, Inc; 1998.
97Factors That Influence Treatment Decisions Medical PatientConsiderations ConsiderationsBurden of diseaseEnhancing lesionsDisease courseNumber of relapsesLifestyleExpectationsCapabilitiesSupport systemFactors That Influence Treatment DecisionsTreatment 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.
99Summary: Goals of Disease Management in MS Modifying/reducing relapses and delaying progression to disabilityTreating relapsesManaging symptomsFacilitating an acceptable quality of lifeSummary: Goals of Disease Management in MSIn conclusion, it is important to keep in mind the 4 main goals of MS management:Modifying/reducing relapses and delaying progression to disabilityTreating relapsesManaging symptomsFacilitating an acceptable quality of life