CURRENT AND
`EMERGING MULTIPLE
`SCLEROSIS THERAPEUTICS
`
`Benjamin M. Greenberg, Bhupendra O. Khatri, John F. Kramer
`
`ABSTRACT
`
`For a disease whose cause remains elusive, there has been a paradoxical growth in
`multiple sclerosis (MS) therapeutics. During the past 17 years, six therapeutic drugs for MS
`were brought to market. All of these disease-modifying therapies (DMTs) have shown a
`beneficial effect in reducing the number of exacerbations in double-blind placebo-
`controlled trials, and three drugs (subcutaneous [SCM interferon beta-1a, natalizumab)
`have been shown to reduce relapses, decrease MRI activity, and reduce the risk of
`sustained disability after 2 years of treatment. No controlled studies exist to show long-
`term benefit with any of the current DMTs. Immunosuppressive drug (ISD) therapies
`continue to play a role in the management of patients who fail to respond to
`immunomodulatory agents. These agents, however, have shown mixed data in terms of
`efficacy and put patients at higher risk for the development of secondary cancers. Plasma
`exchange for severe relapses not responsive to corticosteroid therapy has regained
`interest in the past few years. Furthermore, six new agents that will dramatically impact
`ourability to prevent disability in patients with MSare in late-stage or have completed
`phase 3 clinical development. Determining the risk-benefit calculations that we will need
`to employ toward these new drugs and the algorithms for switching therapies will be
`critical issues in the next 5 years. This article highlights the clinical efficacy of the current
`DMTS/SDs and discusses the current treatment options for clinically isolated syndrome,
`relapsing-remitting MS (RRMS), and exacerbations of RRMS.It also addresses the
`management of a suboptimal response to the DMTs; discusses the challenge of primary
`progressive MS; and presents an overview of emerging therapeutic options.
`
`Continuum Lifelong Leaming Neurol 2010; 16(5):58-77.
`
`Note: Text referenced in the Quintessentials Preferred Responses, which appear
`later in this issue, is indicated in yellow shading throughoutthisarticle.
`
`
`
`multiple sclerosis (RRMS). Interferon
`DISEASE-MODIFYING
`beta-1b (Betaseron) was approvedin
`THERAPIES
`1993, glatiramer acetate (Copaxone) in
`The decade of the 1990s brought forth
`1996,
`IM interferon beta-la (Avonex)
`the first US Food and Drug Administra-
`in 1997, and subcutaneous (SC) inter-
`tion (FDA)-approved disease-modifying
`therapies (DMTs) for relapsing-remitting_feron beta-la (Rebif) in 2002 (Table 3-1).
`
`Relationship Disclosure: Dr Greenberg has received personal compensation for activities with Biogen Idec;
`DioGenix.
`Inc.
`EMD Serono,
`Inc.; and Teva Neuroscience. Dr Khatri has received personal compensationfor
`consulting, speaking. and advisory boardactivities from Bayer; Biogen Idec; EMD Serono,Inc.; Pfizer Inc; and
`Teva Neuroscience. Dr Khatri has received research support from Bayer; Biogen Idec, Covidian; Medtronic
`Inc.;
`Novartis: Pfizer
`Inc;
`and Teva Neuroscience. Mr Kramer has received personal compensation for
`speaking engagements from Bayer; Biogen Idec; EMD Serono, Inc.: Pfizer Inc; and Teva Neuroscience
`Unlabeled Use of Products/Investigational Use Disclosure: Dr Greenberg discusses the investigational use
`of multiple agents, including alemtuzumab, BGO0012, daclizumab, FTY720, laquinimod. andteriflunomide.
`Dr Khatri and Mr Krimer have nothing to disclose
`
`Merck 2008
`TWi Vv Merck
`« 2010, American Academy of Neurology. All nghts reserved
`Copyright
`Copyright © American Academy of Neurology. Unauthorized reproduction ofthis article is prohibited. IPR2023-00049
`
`
`Merck 2008
`TWi v Merck
`IPR2023-00049
`
`

`

`CURRENT AND
`EMERGING MULTIPLE
`SCLEROSIS THERAPEUTICS
`
`Benjamin M. Greenberg, Bhupendra O. Khatri, John F. Kramer
`
`ABSTRACT
`
`For a disease whose cause remains elusive, there has been a paradoxical growth in
`multiple sclerosis (MS) therapeutics. During the past 17 years, six therapeutic drugs for MS
`were brought to market. All of these disease-modifying therapies (DMTs) have shown a
`beneficial effect in reducing the number of exacerbations in double-blind placebo-
`controlled trials, and three drugs (subcutaneous [SCM interferon beta-1a, natalizumab)
`have been shown to reduce relapses, decrease MRI activity, and reduce the risk of
`sustained disability after 2 years of treatment. No controlled studies exist to show long-
`term benefit with any of the current DMTs. Immunosuppressive drug (ISD) therapies
`continue to play a role in the management of patients who fail to respond to
`immunomodulatory agents. These agents, however, have shown mixed data in terms of
`efficacy and put patients at higher risk for the development of secondary cancers. Plasma
`exchange for severe relapses not responsive to corticosteroid therapy has regained
`interest in the past few years. Furthermore, six new agents that will dramatically impact
`ourability to prevent disability in patients with MSare in late-stage or have completed
`phase 3 clinical development. Determining the risk-benefit calculations that we will need
`to employ toward these new drugs and the algorithms for switching therapies will be
`critical issues in the next 5 years. This article highlights the clinical efficacy of the current
`DMTS/SDs and discusses the current treatment options for clinically isolated syndrome,
`relapsing-remitting MS (RRMS), and exacerbations of RRMS.It also addresses the
`management of a suboptimal response to the DMTs; discusses the challenge of primary
`progressive MS; and presents an overview of emerging therapeutic options.
`
`Continuum Lifelong Leaming Neurol 2010; 16(5):58-77
`
`Note: Text referenced in the Quintessentials Preferred Responses, which appear
`later in this issue, is indicated in yellow shading throughoutthisarticle.
`
`
`
`multiple sclerosis (RRMS). Interferon
`DISEASE-MODIFYING
`beta-1b (Betaseron) was approvedin
`THERAPIES
`1993, glatiramer acetate (Copaxone) in
`The decade of the 1990s brought forth
`1996,
`IM interferon beta-la (Avonex)
`thefirst US Food and Drug Administra-
`in 1997, and subcutaneous (SC) inter-
`tion (FDA)-approved disease-modifying
`therapies (DMTs) for relapsing-remitting—_feron beta-la (Rebif) in 2002 (Table 3-1).
`
`Relationship Disclosure: Dr Greenberg has received personal compensation for activities with Biogen Idec;
`DioGenix.
`Inc.
`EMD Serono,
`Inc.; and Teva Neuroscience. Dr Khatri has received personal compensationfor
`consulting, speaking, and advisory boardactivities from Bayer; Biogen Idec; EMD Serono,Inc.; Pfizer Inc; and
`Teva Neuroscience. Dr Khatri has received research support from Bayer; Biogen Idec, Covidian; Medtronic
`Inc.;
`Novartis: Pfizer Inc;
`and Teva Neuroscience. Mr Kramer has received personal compensation for
`speaking engagements from Bayer; Biogen Idec; EMD Serono, Inc.; Pfizer Inc; and Teva Neuroscience
`Unlabeled Use of Products/Investigational Use Disclosure: Dr Greenberg discusses the investigational use
`of multiple agents, including alemtuzumab, BGO0012, daclizumab, FTY720, laquinimod., and teriflunomide.
`Dr Khatri and Mr Kramer have nothing to disclose
`
`Copyright © American Academy of Neurology. Unauthorized reproduction ofthis article is prohibited.
`
`Copyright
`
`© 2010, American Academy of Neurology. All rights reserved
`
`

`

`KEY POINT
`
`Moresimilarities than differences exist
`termine whetherthere is a long-term
`among these agents, andall four re-
`therapeutic benefit. With the known
`duce the numberof relapses by ap-
`biases of retrospective analyses in mind,
`exist among
`/
`:
`the injectable
`the long-term data showthat certain
`proximately 30% (somewhat lower in
`
`the intent-to-treat analysis of the piv-—subsets ofpatients in each ofthe pivotal disease-modifying
`
`otal IM interferon beta-la trial). Two—trials do well on continuous therapy. therapies for
`drugs, SC and IMinterferon beta-1la,
`In general, the injectable DMTsare
`multiple sclerosis
`showeda reduction in the risk of sus-
`safe and well
`tolerated (Table 3-1).
`(MS), and all
`taineddisability at 2 years.'* Research-
`For patients on interferon therapy, he-
`four reduce
`ers have retrospectively attempted to matologic abnormalities, including leu-
`the number
`glean long term-data from population
`kopenia, thrombocytopenia, andliver
`of relapses by
`subsets in these pivotal
`trials to de-
`enzymeelevation, are well documented —
`
`@ Moresimilarities
`than differences
`
`Current US Food and Drug Administration-Approved Disease-Modifying
`Therapies for Relapsing-Remitting Multiple Sclerosis
`
`Dru
`
`Dosin
`
`Modeof Action
`
`Adverse Effects
`
`Precautions
`
`Pregnancy
`)
`
`Interferon beta-1a
`
`(Avonex)
`
`30 yg IM
`once a
`week
`
`Promotes
`Ty1—Ty2 shift
`
`Leukopenia
`LFT abnormalities
`
`Obtain baseline
`and periodic LFTs
`and complete
`blood cell count
`
`
`
`(Rebif) LFT abnormalities|Obtain baseline44 11g SC Promotes
`
`
`3timesa
` 1Ty1—Ty2 shift
`and periodic LFTs
`week
`and complete
`blood cell count
`
`Interferon beta-1b
`
`(Betaseron/
`Extavia)
`
`Has antiviral/
`8mIUSC
`every other anti-inflammatory
`day
`properties
`
`LFT abnormalities
`
`
`
`Obtain baseline
`and periodic LFTs
`and complete
`blood cell count
`Glatiramer 20 mg SC_Promotes suppressor Injection site B
`
`
`acetate
`every day
`cells of Ty2
`reactions
`(Copaxone)
`Bystander suppression
`Possibly promotes
`brain-derived
`neurotrophic factor
`production
`
`Mitoxantrone 12 mg/m?__—Antineoplastic- Leukemia Preexisting x
`
`maximum anthracenedione
`(0.44%-0.67%)
`heart failure or
`dose
`class
`;
`immunodeficiency
`Congestive heart
`140. mg/m
`failure
`
`
`
`
`
`2
`
`
`
`Natalizumab 300 mg IV_Prevents 1:1000 risk of HIV-positive c
`
`
`
`
`
`(Tysabri) activatedTcellsmonthly progressive status or other
`
`from crossing the
`multifocal
`immunodeficiency
`blood-brain barrier
`leukoencephalopathy
`
`SC = subcutaneous; LFT = liver function test; T41 = helper T cell type 1; T42 = helper T cell type 2
`
`Copyright © American Academy of Neurology. Unauthorized reproductionof this article is prohibited
`
`Continuum Lifelong Learning Neuro! 2010; 16(5)
`
`€
`

`

`CONTINUUM
`
`» CURRENT AND EMERGING THERAPEUTICS
`
`KEY POINT
`
`A paucity of data
`regarding the
`long-term
`safety of the
`disease-modifying
`therapies in
`open-label
`trials beyond
`16 years
`is available.
`
`in na-
`and are commonly transient
`ture. For these reasons, routine blood
`studies,
`including a complete blood
`cell count andliver function tests, are
`necessary in patients receiving treat-
`mentwith interferons. In patients who
`develop abnormal
`laboratory values,
`general practice guidelines indicate
`either dose reduction or suspension
`before a second attempt at redosing
`is made. Patients should be counseled
`to restrict or abstain from alcohol con-
`sumption as that can independently
`cause hepatic injury. The SC prepara-
`tions of interferon can have associated
`site reactions andrarely thyroid func-
`tion abnormalities. In contrast, glatir-
`ameracetate does not require regular
`blood monitoring. The most common
`side effects with glatiramer acetate are
`injection site reactions, bruising, itch-
`ing, and lipoatrophy. Approximately
`10% of patients will develop infrequent
`episodes ofa self-limited idiosyncratic
`systemic reaction characterized by one
`or more of the following: chest pain,
`palpitations, anxiety, dyspnea, urticaria,
`flushing, and throat constriction thatis
`not cardiopulmonaryin nature, andusu-
`ally develops within 15 minutes of the
`injection andusually occurs after several
`monthsof treatment.
`A paucityof data regarding the long-
`term safety of the DMTs in open-label
`trials beyond 16 years is available. Two
`recent articles have raised the issue of
`a relationship between the develop-
`ment of cancer and the prolonged use
`of interferon therapy. A population-
`based studyof Israeli patients with MS
`on glatiramer acetate showeda slightly
`increased risk of breast cancer.** Al-
`though notstatisticallysignificant, this
`concern warrants further investigation.
`The exact mechanismsof the interfer-
`on therapies andglatiramer acetate are
`not known. In general, the injectable
`DMTs have an anti-inflammatoryeffect
`on the immune system, shifting from a
`proinflammatorystate (helperT cell type
`
`Continuum Lifelong Learning Neuro! 2010; 16(5)
`
`[Ty1]}) to a more anti-inflammatory
`1
`(helper T cell type 2 [T,42]) cytokine
`profile. Earlier clinical trials showeda su-
`perior effect of high-dose/high-frequency
`interferon over lower-dose interferon.*°
`More recent comparator trials of in-
`terferon beta-1b versus glatiramer ace-
`tate. and interferon beta-la_ versus
`glatiramer acetate” showed nosignifi-
`cant clinical differences between glatir-
`ameracetate and the high-dose/high-
`frequencyinterferons.
`
`SECOND-GENERATION DISEASE-
`MODIFYING THERAPIES
`
`Natalizumab represents thefirst second-
`generation DMT for MS. A selective ad-
`hesion molecule inhibitor, natalizumab
`prevents autoreactive T cells from cross-
`ing the blood-brain barrier by blocking
`the binding of verylate antigen-4, which
`is expressed on all white blood cells ex-
`cept neutrophils, to vascular cell adhe-
`sion molecule 1, which is expressed on
`the surface of vascular endothelium. In
`the monotherapy pivotal trial of natalizu-
`mab, the relative relapse reduction rate
`was 67% over 2 years compared to
`placebo.” A 42% reduction occurred in
`sustained disability as measured by the
`Expanded Disability Status Scale (EDSS)
`at 3 months and a 54% reduction at
`6 months. Both of the aforementioned
`outcomes were highly statistically signifi-
`cant. Although natalizumab’s efficacy re-
`lative to placebo is numerically greater
`than that of the interferons and glatir-
`amer acetate, in the absence of head-to-
`head comparative data,
`it
`is uncertain
`whether natalizumab has superior effi-
`cacy or whether the apparently greater
`reductions in relapses and disability are
`due to recruitment of more benign MS
`patients with less disease activity.'” Given
`the intense reduction in the number of
`gadolinium-enhancing lesions, natalizu-
`mab is an attractive drug for use in pa-
`tients, such as the one in Case 3-1, who
`continue to have enhancing lesions de-
`spite the use of an appropriate platform
`
`Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
`
`

`

`KEY POINT
`
`Natalizumab was
`
`only studied at
`a standard dose
`
`of 300 mg IV
`every month;
`further
`
`investigations
`are underway
`to determine
`whether
`
`temporary drug
`discontinuation
`will reduce the
`risk of
`
`progressive
`multifocal
`
`leukoencephalopathy.
`
`Case 3-1
`A 34-year-old woman was diagnosed with RRMS. Her presenting symptoms
`were left facial, arm, and chest numbness; left leg weakness; and bladder
`frequency;all of which resolved over a period of 3 months. MRI of the brain
`showed multiple areas of abnormalsignal change throughout the corpus
`callosum, posterior fossa, and subcortical white matter that was typical of
`demyelinating plaques. CSF analysis was consistent with MS. Cervical cord
`imaging was normalat the time of diagnosis. High-dose interferon therapy
`was started. Repeat MRI of the brain and cervical cord 1 year later to assess
`drug efficacy showed a single new lesion of increased signalintensity in the
`brain and four new spinalcord lesions, all of which were nonenhancing.
`She remained clinically stable. During that same year, she went off therapy
`in June and became pregnant in November. Over the next 2 years, after
`resuming high-dose interferon therapy, she had two episodes of intermittent
`paresthesias that resolved without additional treatment. During an office
`visit, she admitted to not taking her injection therapy at least once a week.
`The next year, she developed dizziness, tinnitus, and hearing loss.
`A neuro-otology workup was negative, and the symptoms were attributed
`to an MS exacerbation. Repeat brain MRI showed one new lesion in the
`deep white matter but was otherwise unchanged. She was encouraged
`to consider natalizumab treatment, but she wished to continue with
`high-dose interferon therapy. Two years later she developed an odd
`abdominal sensation radiating into her right leg. Brain MRI showed at
`least four new lesions, three of which enhanced after gadolinium.
`Because of her continuing relapses, MRI changes, injection fatigue, and
`noncompliance, natalizumab was started. After 6 months of natalizumab
`treatment, MRI of the brain was repeated and wasstable without any
`areas of enhancement compared to the prior study.
`Comment. This case illustrates an appropriate change to a patient's
`DMT in the setting of injection fatigue, breakthrough disease on
`MRI, and persistent relapses.
`
`therapy.'' Theinitial enthusiasm regard-
`ing natalizumab was dampenedbythe
`discovery of three cases of progressive
`multifocal
`leukoencephalopathy (PML)
`in the clinical trial population. All three
`cases were seen in patients on con-
`comitant DMT or immunosuppressive
`drug (ISD) therapy(two on IMinterferon
`beta-la and one on azathioprine in a
`separate trial for Crohn disease). Natali-
`zumab was voluntarily withdrawn from
`the market in 2005 andreintroducedin
`2006, as no cases of PML were detected in
`the monotherapytrial.'* Subsequently, as
`of May 2010, more than 50 cases of PML
`have occurred in patients on natalizumab
`monotherapy. The risk of PML rises with
`duration of exposure to the drug.'? No
`standard treatment for PML exists, butit is
`
`well knownfromotherdisease states that
`reconstituting the immune systemis cru-
`cial for good patient outcomes. A recent
`pharmacokinetic study showedthat rap-
`id, high-volumeplasma exchange (PLEX)
`therapy can effectively remove natalizu-
`mab from the circulation, desaturate the
`lymphocytes, and reestablish the traffick-
`ing of lymphocytes across the blood-brain
`barrier within 11 days'* comparedto ap-
`proximately 90 days for normal drug eli-
`mination. Steroids are sometimes added
`to the regimen to prevent immune recon-
`stitution inflammatory syndrome (IRIS).
`Natalizumab wasonlystudied as monthly
`dosing, and further investigations are
`underway to determine whether tem-
`porary drug discontinuation will
`re-
`duce the risk of PML.
`
`Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
`
`Continuum Lifelong Learning Neuro! 2010; 16(5)
`
`

`

`CONTINUUM }& CURRENT AND EMERGING THERAPEUTICS
`
`KEY POINT
`
`B At this time,strict
`guidelines do not
`exist for clinicians
`
`treating patients
`with MS who
`become
`
`neutralizing
`antibody
`positive while
`on interferon
`
`therapy.
`
`NEUTRALIZING ANTIBODIES
`
`One of the thorniest issues in the treat-
`ment of MS todayis the debate over the
`importance of neutralizing antibodies
`(NAbs) with interferon therapy. NAbs
`by definition have the potential to par-
`tially or completely block the intended
`drug effect. Numerous studies provide
`evidence to support the view that per-
`sistent high titers (greater than 100) of
`NAbs renders interferon biologically in-
`active.’ At this time,strict guidelines do
`not exist for clinicians treating patients
`with MS who become NAb positive
`while on interferon therapy. The con-
`troversy continues because of a number
`offactors that include lack of consensus
`on the definition of NAb seropositivity;
`possible reversion to NAb-negative sta-
`tus; variability of testing from laboratory
`to laboratory; and varying degrees of
`immunogenicity among the interferon
`products. The immunogenicityof the in-
`terferons in descending orderis: SC in-
`terferon beta-1b, SC interferon beta-la,
`andIM interferon beta-la.
`
`In contrast, the implication of the
`presence of NAbs during treatment with
`natalizumab is more straightforward.If
`a patient develops persistent NAbs (de-
`fined as twopositive titers separated by
`42 days),'® thentheclinical effect of the
`drugis similar to placebo. Patients who
`develop an anaphylactic/anaphylactoid
`reaction while on natalizumab, most of
`whom are anti-natalizumab seroposi-
`tive, should avoid subsequentinfusions.
`The incidence of persistent NAb sero-
`positivity (6%) is lower for natalizumab
`compared tothe high-dose interferons.
`
`CLINICALLY ISOLATED
`SYNDROME
`
`Clinically isolated syndrome (CIS) is de-
`finedasaninitial demyelinating event such
`as optic neuritis, brainstem/cerebellar
`syndrome, or incomplete transverse mye-
`litis. Longitudinal natural history data
`support the fact that patients with CIS
`andan abnormal MRI scan of the brain
`have an 85%chance of developingclini-
`cally definite MS within 10 years.'” One
`
`Case 3-2
`A 30-year-old man presented to the neurology clinic with a 1-month
`history of pain in his neck associated with left distal upper extremity
`numbness and tingling. He had no incontinence of bowel/bladder,
`visual disturbance, lateralized weakness, easy fatigability, or cognitive
`problems. He could not remember having any of the above symptoms in
`the past. Heinitially had seen an orthopedic surgeon, who gave him
`hydrocodone for the pain and ordered an MRI of the cervicalspine.
`The patient's past medical history was otherwise unremarkable. His
`paternal grandmother had a history of MS. He occasionally drank alcohol
`but did not smoke.His review of systems was unremarkable. His neurologic
`examination, including detailed sensory examination, was normal.
`The MRIscan of the cervical spine showed two lesions in the cervical
`cord at levels C4-C5 and C6-C7. The cord lesion at C6-C7 demonstrated
`mild enhancement after the administration of gadolinium. Further diagnostic
`workup, including MRI of the brain and CSF studies, was ordered. MRI of
`the brain showed three periventricular lesions that were are. His
`CSF analysis was unremarkable.
`Comment. This case provides a good example of a patientwho would meet
`the criteria for recent clinical trials in patients with CIS. Placebo-controlled
`trials of patients with CIS show a significant delay in the time between the first
`and secondclinical episodes in patients initiated on DMT.
`
`Continuum Lifelong Learning Neuro! 2010; 16(5)
`
`Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited
`
`

`

`of the quandaries regarding MS thera-
`peutics is when to initiate treatment
`The fact that demyelination, axonal loss,
`and brain atrophy occur early in thedis-
`ease process’ supports therationalefor
`initiating preventive treatment sooner
`rather than later in appropriate patients
`with CIS, such as thepatient in Case 3-2.
`
`Becauseofthis early pathologic process,
`increased cortical
`recruitment
`signifi-
`cantly increases in patients who may
`not show overt signs ofdisability, sug-
`gesting a compensatory neuronal pro-
`cess as shown in Figure 3-1."”
`Does the treatment of CIS affect the
`
`long-term outcome of MS? Randomized
`
`Increased cortical activation in patients with relapsing-remitting multiple
`sclerosis (/eft) during finger-tapping exercises compared to healthy controls.
`From Rocca M,Falini A, Colombo 8, et al. Adaptive functional changes in the cerebral cortex of patients with nondisabling
`MScorrelate with the extent of brain structure damage. Ann Neurol 2002;51(3):330-339. Reprinted with permission
`
`ontinuum Lifelong Learr
`
`ng Neuro! 2010;16(5
`
`The fact that
`
`demyelination,
`axonal!
`|0ss, and
`
`brain atrophy
`occur earlyin
`the disease
`process
`supports the
`rationale for
`
`initiating
`preventive
`treatment
`sooner rather
`than later in
`appropriate
`patients with
`clinically isolated
`syndrome
`
` KEY POINT
`
`Copyright©American Academyof Neurology
`Unauthorized reproduction of this article is prohibited
`
`

`

`CONTINUUM
`
`» CURRENT AND EMERGING THERAPEUTICS
`
`longer and not
`secondary to
`another medical
`condition
`
`(ie, infection,
`fever, heat
`exhaustion).
`
`TREATMENT OF
`EXACERBATIONS
`
`An exacerbation is defined as a new
`or worsening symptomof MS, usually
`lasting 24 hours or longer, and not
`secondary to another medical condition
`(ie, infection, fever, heat exhaustion). If
`the same symptomrecurs within 30 days
`
`42.4% increase 0.5 or more
`
`i 2
`
`0.100 inesenes | or mages
`
`Numberofsubjects
`
`esSsse2S3888
`
`KEY POINT
`placebo-controlled trials with—interfe-
`oftheinitial relapse, it is consideredpart
`= Anexacerbation is
`of the same relapse. Exacerbations are
`ron beta-1b, IM interferon beta-la, and
`defined as a new
`glatiramer acetate showeda significant
`importantfor several reasons:(1) exacer-
`or worsening
`delay in the time to the next relapse,sig-
`bations are a markerfor clinical disease
`symptom of MS,
`nifying conversion to clinically definite MS
`activity; (2) the numberof exacerbations
`usually lasting
`in patients who were treated initially af-
`that occur early in the disease process
`24 hours or
`tera demyelinating event compared to the
`has some predictive value in determin-
`group thatinitially received placebo”?
`ing disease Outcome and therefore can
`These CIS trials have included open-label
`help with treatmentselection; but (3)all
`exacerbations are not equal. A study of
`extensions that suggest treating patients
`with DMTsafter the diagnosis ofCIS alters
`224 patients showedthat 42% ofsubjects
`the course ofof MS. Further complicating
`hada residual deficit of 0.5 on EDSS and
`the issue about when to start treatment
`28% of patients had greater than 1.0
`change on EDSSat an average of42 days
`is the recently termed radiologically iso-
`after an exacerbation (Figure 3-2).**~°
`lated syndrome,’ which aptly describes
`patients who have a brain MRI performed
`This implies that relapses pose a sig-
`nificant
`risk for
`the development of
`for reasons other than a demyelinating
`sustaineddisability. In addition, the eco-
`~ event and havelesions highly suggestive
`nomic impact of exacerbationsis signifi-
`of demyelination. No controlledtrials ex-
`amining the value of treating patients
`cant. The average cost per relapse is
`estimatedto be $4682.7° Treatments for
`with radiologically isolated syndrome
`acute exacerbations vary depending on
`have been done.
`the clinical presentation. If the patient's
`symptomsare mild (eg, paresthesias), a
`watchful waiting period is usually ap-
`propriate. More significant exacerbation
`symptoms (eg, motor weakness, vision
`loss) warrant the use of high-dose corti-
`costeroid therapy. Corticosteroids remain
`the first-line treatment for acute exacer-
`bations. Currently, no consensus exists
`on the optimal dosing regimen/route of
`administration for corticosteroid treat-
`ment. The dosing can range from 500
`mg daily for 3 days up to 2000 mg daily
`for 7 days. However, most RRMS trials
`today use 1000 mg daily for 3 days as a
`standardtreatment protocol. At the molec-
`ular level, corticosteroids are potent anti-
`inflammatorydrugs that reduce edema
`andaidin the stabilization of the blood-
`brain barrier. They also appear to re-
`pair
`regulatory T-cell
`(Tyg)
`function
`during acute exacerbations.*” Although
`corticosteroids have been used for de-
`cades for acute exacerbations, newevi-
`dence suggests pulse corticosteroid ther-
`apycan significantly reduce the rate of
`brain atrophy” andalso can reduce the
`relapse rate when used as an add-on
`
`
`
`
`32 33
`
`1445933525
`Change in EDSSbefore to after exacerbation
`
`a2 4 3
`
`FIGURE 3-2
`
`in Expanded Disability
`The net change
`Status Scale (EDSS) score from before an
`exacerbation to after. Forty-two percent of
`patients demonstrate measureable residual.
`Reprinted from Lublin F, Baier M, Cutter G. Effect of relapses on development
`of residual deficit in multiple sclerosis, Neurology 2003;61(1 1):1528-1532.
`Copyright © 2002, with permission from AAN Enterprises, Inc. All nights
`reserved.
`
`Continuum Lifelong Learning Neuro! 2010; 16(5)
`
`Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
`
`

`

`therapyfor patients on interferon ther-
`apy who developbreakthroughdisease.””
`Froma practical standpoint, the use
`of IV corticosteroids has several advan-
`tages over oral administration. Patients
`can be monitoredin a hospital or out-
`patient IV clinic setting to assess daily
`functional gains and monitor potential
`side effects, and IV administration en-
`sures patient complianceparticularlyif
`they are receiving pulse steroids on
`a regular basis. Patients would have to
`take large numbers of prednisone tab-
`lets to equal what
`is given intrave-
`nously, but, on the other hand, use of
`oral corticosteroids in comparable doses
`to IV administration has the advantage
`of substantially reducing the cost of
`treatment andreducing inconvenience
`to the patient because treatment can
`be administeredat the patient’s home
`and obviously does not
`require IV
`placement. As of this time, equivalent
`efficacy of large-dose oral steroids to
`comparable doses administered intra-
`
`venously has not been demonstrated,
`althoughthe practice appears to be gen-
`erallysafe.
`There is a renewed interest in PLEX
`for patients whoare poor responders to
`corticosteroids after an acute relapse.
`A retrospective analysis of 41 patients
`who underwent PLEX for treatment of
`severe attacks of CNS demyelination
`despite corticosteroid therapyinterven-
`tion showedthat 63% of patients had
`improved EDSSscoresafter 6 months.””
`Thirty-nine percent of the patients had
`clinically important improvementover a
`short period of time (median 12 days).
`The median EDSSscore at time of PLEX
`initiation was 7.0. These data are consis-
`tent with results from a double-blindran-
`domized control trial performed at the
`Mayo Clinic, which showeda significant
`improvement in 42%of patients treated
`with PLEX versus 5.9% improvement in
`the “sham” PLEX group.*! As Case 3-3
`illustrates, PLEX appears to work best in
`patients who have failed conventional
`
`Case 3-3
`A 35-year-old woman diagnosed with MS 5 years earlier presented to the
`emergency department with a chief concern of being unable to walk
`for the past 24 hours. She had been incontinent of urine over the past
`weekand at times had difficulty emptying her bladder. She also reported
`numbness from her waist to her toes bilaterally. She denied dysuria,
`hematuria, fever, cough, chills, or other symptoms of infection. Her
`workupin the emergency department was negative for infection, and she
`was admitted to the neurology unit. She had been compliant with her
`DMT but was frustrated as she had been admitted only 6 months earlier for
`a similar exacerbation that responded well to corticosteroids.
`MRI scans ofthe brain, cervical, and thoracic cord were ordered and showed
`multiple enhancing/nonenhancing lesions in the brain. Four newcord lesions at
`C4, C7, T8, and T12, all of which enhanced after gadolinium administration,
`were also present. High-dose corticosteroid therapy was started, but after
`5 days of treatment and aggressive physical therapy, she remained bedridden.
`The patient subsequently started a regimen of PLEX every other day for
`five sessions with noticeable improvement. She was able to ambulate with
`assistance after 2 weeks. She remained stable off PLEX and continued
`to take her DMT.
`Comment. This case is an example of a patient whois a good candidate
`for PLEX therapy as she failed to respond to high-dose corticosteroid
`therapy after a severe relapse.
`
`Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
`
`Continuum Lifelong Learning Neuro! 2010; 16(5)
`
`

`

`CONTINUUM »® CURRENT AND EMERGING THERAPEUTICS
`
`relapse treatments. Some evidence sug-
`gests that patients whorespondwell to
`PLEX havea specific immunopathologic
`pattern within biopsied brain tissue
`(pattern IVD), characterized by immu-
`noglobulin deposition and antibody,
`complement-mediated demyelination.**
`At this time, no reliable noninvasive bio-
`markers are available to identifythis sub-
`set of patients.
`
`CYTOTOXIC THERAPIES
`
`The ISD class of medications has been
`used for decades to treat patients with
`MS. In particular, patients with aggres-
`sive disease maybenefit from parenteral
`cytotoxic agents, such as cyclophospha-
`mide, mitoxantrone,andcladribine. The
`approval of mitoxantrone (Novantrone)
`in 2002 in the United States allowed
`physicians to prescribe an FDA-approved
`chemotherapeutic drug with indica-
`tions for usage in patients with rapidly
`worsening RRMS or secondary pro-
`gressive MS. Although data from two
`clinical
`trials showits efficacy in re-
`ducing disability and relapse rates,*?
`the use of mitoxantrone has declined
`over time because of concerns over the
`increased incidence of secondary lym-
`phoid cancers, andin particular promye-
`locytic leukemia, in the MS population
`comparedto the cancer population™
`and impaired left ventricular ejection
`fraction,
`leading to congestive heart
`failure in some patients. In 2008, the
`FDA recommendedthatall patients who
`received mitoxantronein the past should
`have yearly quantitative left ventricular
`ejection fraction evaluations performed
`indefinitely to detect late-occurring car-
`diac toxicity.**
`including azathioprine,
`Oral
`ISDs,
`mycophenolate mofetil, and metho-
`trexate, have also been used in MS
`treatment. A recent Cochrane review”
`of five randomizedclinical trials utiliz-
`ing azathioprine in MS showed a re-
`duction in the numbero