&
`
`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[SC IM 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 higherrisk for the developmentof secondary cancers. Plasma
`exchange for severe relapses mot responsive to corticosteroid therapy has regained
`interest in the past few years. Furthermore,six new agents that will dramatically impact
`our ability to preventdisability in patients with MSarein 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 optionsforclinically isolated syndrome,
`relapsing-remitting MS (RRMS), and exacerbations of RRMS.It also addresses the
`managementof 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 throughout this article.
`
`multiple sclerosis (RRMS). Interferon
`DISEASE-MODIFYING
`beta-lb (Betaseron) was approvedin
`THERAPIES
`1993, glatiramer acetate (Copaxone) in
`Thedecade 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-1a (Rebif) in 2002 (Table 3-1).
`
`Relationship Discloaine Dr Greenberg has received personal compensition for activities with Biogen Idec:
`DieGenix, inc. EMD Serone, Ing; and Teva Neuroscience. Dr Khatri has received personal compensationfor
`k
`consulting, speaking, and advisory board activities fromBayer: Biogen Idec; EMD Serono, Ine.; Pfizer Inc: and
`Teva Neuroscience Dr Khatn has received research support from Bayer: Biogen Idec; Covidian; Medtronic Merck 2008
`Inc, Novartis: Pfizer Inc; and Teva Neuroscience. Mr Kramer has received personal compensition for TWi V Merck
`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 TPR2023-00050
`of muluple agents.
`including alemtuzumiih, BGOOO12. daclizumab. FIVYT20. laquinimed. and teriflunomide
`Dr Khatri and Mr Krimer have nothing to disclose
`
`
`
`
`
`Copyright
`
`«
`
`2010, American Academy of Neurology All nghts reserved
`
`Copyright © Amencan Academyof Neurology. Unauthorized reproductionof this article is prohibited 2
`
`
`
`

`

`KEY POINT
`
`Moresimilarities than differences exist
`termine whether there is a long-term
`@=More similarities
`therapeutic benefit, With the known
`among these agents, andall four re-
`than differences
`duce the numberof relapses by ap-
`biases of retrospective analyses in mind,
`exist among
`;
`-
`,
`:
`the injectable
`proximately 30% (somewhat lower in
`the long-term data showthat certain
`disease-modifying
`the intent-to-treat analysis of the piv-
`subsets of patients in each of the pivotal
`
`otal IM interferon beta-la trial). Two_trials do well on continuous therapy. therapies for
`drugs, SC and IMinterferon beta-1a,
`In general, the injectable DMTs are
`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 eo
`
`Current US Food and Drug Administration-Approved Disease-Modifying
`Therapies for Relapsing-Remitting Multiple Sclerosis
`
`Drug
`
`Dosing
`
`Modeof Action
`
`Adverse Effects
`
`Precautions
`
`Interferon beta-1a
`
`(Avonex)
`
`30 jig IM
`once a
`week
`
`Promotes
`Ty1—Ty2 shift
`
`Leukopenia
`LFT abnormalities
`
`Obtain baseline
`and periodic LFTs
`and complete
`blood cell count
`
`Pregnancy
`Category
`
`Cc
`
`
`
`(Rebif) 44 19 SC=Promotes LFT abnormalities|Obtain baseline
`
`3timesa
` Ty1—Ty2 shift
`and periodic LFTs
`week
`and complete
`blood cell count
`
`Interferon beta-1b
`
`(Betaseron/
`Extavia)
`
`Has antiviral/
`8miIUSC
`every other anti-inflammatory
`day
`properties
`
`LFT abnormalities
`
`Glatiramer
`acetate
`(Copaxone)
`
`20mg SC
`every day
`
`Promotessuppressor
`cells of Ty2
`Bystander suppression
`
`Injection site
`reactions
`
`Obtain baseline
`and periodic LFTs
`and complete
`blood cell count
`
`B
`
`Possibly promotes
`brain-derived
`neurotrophic factor
`production
`
`Mitoxantrone 12 mg/m?—_—Antineoplastic- Leukemia Preexisting x
`
`maximum anthracenedione
`(0.44%-0.67%)
`heart failure or
`
`
`
`
`
`os
`mean
`
`>
`
`class
`
`Congestive heart
`failure
`
`immunodeficiency
`
`
`
`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; T,1 = helper T cell type 1; T.2 = helper T cell type 2
`
`Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
`
`Continuum Lifelong Learning Neurol 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 and liver 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-
`amer acetate 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
`episodesofa 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, and usu-
`ally develops within 15 minutes of the
`injection andusually occurs after several
`months of 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 andthe prolonged use
`of interferon therapy. A population-
`basedstudyofIsraeli patients with MS
`on glatiramer acetate showeda slightly
`increased risk of breast cancer.** Al-
`though notstatisticallysignificant, this
`concern warrants further investigation.
`The exact mechanisms ofthe interfer-
`on therapies and glatiramer acetate are
`not known. In general,
`the injectable
`DMTs have an anti-inflammatoryeffect
`on the immunesystem, shifting from a
`proinflammatorystate (helperT cell type
`
`Continuum Lifelong Learning Neurol 2010; 16(5)
`
`1 [T1}) to a more anti-inflammatory
`(helper T cell type 2 [Ty2]) cytokine
`profile. Earlier clinical trials showeda su-
`perioreffect ofhigh-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” showednosignifi-
`cantclinical differences between glatir-
`ameracetate and the high-dose/high-
`frequencyinterferons.
`
`SECOND-GENERATION DISEASE-
`MODIFYING THERAPIES
`
`Natalizumab represents the first 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 very late antigen-4, which
`is expressed on all white bloodcells 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’sefficacy 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 reproductionof 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 womanwas diagnosed with RRMS. Her presenting symptoms
`wereleft 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 abnormal signal 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 MRIof the brain and cervical cord 1 year later to assess
`drug efficacy showed a single new lesion of increased signal intensity 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 was stable 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 dampened by the
`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 onIMinterferon
`beta-la and one on azathioprine in a
`separate trial for Crohn disease). Natali-
`zumab was voluntarily withdrawn from
`the market in 2005 and reintroduced in
`2006, as no cases of PML were detectedin
`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, but it is
`
`well knownfrom otherdisease 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-
`mabfromthe 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 drugeli-
`mination. Steroids are sometimes added
`to the regimen to prevent immunerecon-
`stitution inflammatory syndrome (IRIS).
`Natalizumabwasonlystudied 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 Neurol 2010; 16/5)
`
`

`

`CONTINUUM ® CURRENT AND EMERGING THERAPEUTICS
`
`KEY POINT
`
`At this time, strict
`guidelines do not
`exist forclinicians
`
`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 ofa 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 immunogenicity of the in-
`terferons in descending orderis: SC in-
`terferon beta-1b, SC interferon beta-1a,
`andIMinterferon beta-1a.
`
`In contrast, the implication of the
`presence of NAbs during treatment with
`natalizumab is more straightforward.If
`a patient develops persistent NAbs (de-
`finedas twopositive titers separated by
`42 days),'° then theclinical 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
`comparedtothe high-dose interferons.
`
`CLINICALLY ISOLATED
`SYNDROME
`
`Clinically isolated syndrome (CIS) is de-
`finedas an initial 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
`and an 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 rememberhaving any of the above symptoms in
`the past. Heinitially had seen an orthopedic surgeon, who gave him
`hydrocodonefor the pain and ordered an MRIof the cervical spine.
`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 enhancementafter the administration of gadolinium. Further diagnostic
`workup, including MRIof the brain and CSF studies, was ordered. MRI of
`the brain showed three periventricular lesions that were Sey His
`CSF analysis was unremarkable.
`Comment. Thiscase providesa good exampleofa cutieatidimciile meet
`the criteria for recent clinical trials in patients with CIS. Placebo-controlled
`trials of patients with CIS show a significant delay in thetime between the first
`and secondclinical episodes in patients initiated on DMT.
`
`Continuum Lifelong Learning Neurol 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.
`Thefact that demyelination, axonalloss,
`and brain atrophyoccurearlyin thedis-
`li
`:
`Se
`ease process” supports therationale for
`initiating preventive treatment sooner
`rather than later in appropriate patients
`with CIS, suchas the patient 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-
`19
`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,etal. Adaptive functional changes in the cerebral cortex of patients with nondisabling
`MS correlate with the extent of brain structure damage. Ann Neuro! 2002;51(3):330-339. Reprinted with permission
`
`KEY POINT
`
`The fact that
`
`demyelination,
`axonal loss, and
`
`brain atrophy
`occur early in
`the disease
`process
`
`supports the
`rationale for
`
`initiating
`preventive
`treatment
`sooner rather
`than later in
`appropriate
`patients with
`clinicallyisolated
`syndrome
`
`
`
`Copyright
`
`© American Academyof Net
`
`IroOloOgy
`
`Unauthorized reproductionof this article is prohibited
`
`Continuum Lifelong Learning Neuro! 2010; 16(5
`
`

`

`CONTINUUM
`
`» CURRENT AND EMERGING THERAPEUTICS
`
`longer and not
`secondary to
`another medical
`condition
`(ie, infection,
`fever, heat
`exhaustion)
`
`KEY POINT
`placebo-controlled trials with_interfe- of theinitial relapse,it is consideredpart
`
`An exacerbationis
`of the same relapse. Exacerbations are
`ron beta-lb, IM interferon beta-la, and
`defined as a new
`importantfor several reasons: (1) exacer-
`glatiramer acetate showeda significant
`or worsening
`bations are a markerforclinical disease
`delay in the time to the next relapse, sig-
`symptom of MS,
`nifying conversion toclinically 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-
`groupthatinitially received placebo?”
`ing disease outcome andtherefore can
`help with treatment selection; but (3)all
`These CIS trials have included open-label
`extensions that suggest treating patients
`exacerbations are not equal. A study of
`with DMTsafter the diagnosis ofCIS alters
`224 patients showedthat 42% ofsubjects
`the course ofofMS. 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
`is the recently termed radiologicallyiso-
`change on EDSSat an average of 42 days
`after an exacerbation (Figure 3-2).7**°
`lated syndrome,” which aptly describes
`patients who have a brain MRI performed
`This implies that relapses pose a sig-
`for reasons other than a demyelinating
`nificant
`risk for
`the development of
`event andhave lesions highly suggestive
`sustaineddisability. In addition, the eco-
`nomic impact of exacerbationsis signifi-
`of demyelination. No controlledtrials ex-
`amining the value of treating patients
`cant. The average cost per relapse is
`estimated to be $4682.”° Treatments for
`with radiologically isolated syndrome
`have been done.
`acute exacerbations vary depending on
`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-
`inflammatory drugs that reduce edema
`and aid in the stabilization of the blood-
`brain barrier. They also appear to re-
`pair
`regulatory T-cell
`(Ty,)
`function
`during acute exacerbations.~” Although
`corticosteroids have been used for de-
`cades for acute exacerbations, newevi-
`dence suggests pulse corticosteroid ther-
`apy can significantly reduce the rate of
`brain atrophy’ andalso can reduce the
`relapse rate when used as an add-on
`
`TREATMENT OF
`EXACERBATIONS
`
`An exacerbation is defined as a new
`or worsening symptomof MS, usually
`lasting 24 hours or longer, and not
`secondaryto another medical condition
`(ie, infection, fever, heat exhaustion). If
`the same symptomrecurs within 30 days
`
`
`
`i aa a3
`499332938
`Change in EDSS before to after exacerbation
`
`-_
`
`esS8SSS23S888
`
`Numberofsubjects
`
`FIGURE 3-2
`
`The net change in Expanded Disability
`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(11):1528-1532.
`Copyright © 2002, with permission from AAN Enterprises, Inc. All rights
`reserved.
`
`Continuum Lifelong Learning Neurol 2010; 16(5)
`
`Copyright © American Academyof Neurology. Unauthorized reproduction ofthis 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 compliance particularlyif
`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 administered at 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 renewedinterest in PLEX
`for patients who are 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 showed that 63% of patients had
`improved EDSS scores after 6 months.”
`Thirty-nine percent of the patients had
`clinically important improvementover a
`short period of time (median 12 days).
`The median EDSSscoreat time of PLEX
`initiation was 7.0. These data are consis-
`tent with results from a double-blind ran-
`domized control trial performed at the
`Mayo Clinic, which showedasignificant
`improvement in 42%of patients treated
`with PLEX versus 5.9%improvementin
`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 departmentwith a chief concern of being unable to walk
`for the past 24 hours. She had been incontinent of urine over the past
`weekandat 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
`DMTbut was frustrated as she had been admitted only 6 months earlier for
`a similar exacerbation that responded well to corticosteroids.
`MRI scansofthe brain,cervical, and thoracic cord were ordered and showed
`multiple enhancing/nonenhancinglesions in the brain. Four new cord 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 who is 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 Neurol 2010; 16(5)
`
`

`

`CONTINUUM » CURRENT AND EMERGING THERAPEUTICS
`
`relapse treatments. Some evidence sug-
`gests that patients who respondwell to
`PLEX havea specific immunopathologic
`pattern within biopsied brain tissue
`(pattern IMM), characterized by immu-
`noglobulin deposition and antibody/
`complement-mediated demyelination.7
`At this time, no reliable noninvasive bio-
`markers are available to identify this sub-
`set ofpatients.
`
`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, and cladribine. 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 secondarypro-
`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-
`phoidcancers, andin particular promye-
`locytic leukemia,
`in the MS population
`compared to the cancer population®™*
`and impairedleft 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-
`diactoxicity.**
`including azathioprine,
`Oral
`ISDs,
`mycophenolate mofetil, and metho-
`trexate, have also been used in MS
`treatment. A recent Cochrane review”
`of five randomized clinical trials utiliz-
`ing azathioprine in MS showed a re-
`duction in the numberofrelapses from
`
`Continuum Lifelong Learning Neuro! 2010; 16(5)
`
`years 1 to 3. Data fromthree smalltrials
`with a total of 87 patients showed a
`statistically significant benefit in reduc-
`ing the rate ofdisability. However, the
`utility of these agents is unproven in
`large clinical trials, and current data do
`not adequately support their use.
`Combining oral ISDs with standard
`DMTtherapies makes sense from a path-
`ologic standpointin that different mech-
`anisms of action may impart a comple-
`mentary or synergistic benefit. Newly
`published data regarding the combi-
`nation of these drugs is nowavailable.
`Unfortunately, an oral ISD/DMT com-
`bination has thus far not shown addi-
`tional benefit in recent clinical trials. A
`randomizedstudyfailed to showa treat-
`ment benefit for relapse reduction or
`disability after 2 years with the addition
`of either azathioprine or azathioprine
`plus low-dose corticosteroids to IMin-
`terferon beta-la.*” A second randomized
`trial failed to showbenefit of adding low-
`dose oral methotrexate or methotrexate
`and every other month IV methylpred-
`nisoloneto interferon beta-la.
`
`TREATING SUBOPTIMAL
`RESPONDERSTO DISEASE-
`MODIFYING THERAPIES
`
`Noneofthe preventive medications uti-
`lized for MS patients works well enough
`to allowall patients to maintain their
`current clinical status over long periods
`oftime. Isa suboptimal response defined
`by changes on MRI, numberofrelapses
`per vear, EDSS, or isolated cognitive
`changes?Or,is it a combination of these
`or other variables? The problemis that
`the termsuboptimal responder is poorly
`defined, even among physicians at ter-
`tiary MS centers. A variety offactors are
`responsible for the suboptimal response
`to DMTs. These include, but are not
`limited to,
`the neurodegenerative as-
`pects of the disease process (presumably
`particularly important in patients who
`transition into secondary progression),
`
`Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
`
`

`

`KEY POINT
`
`M@ No consensus
`exists on how
`much clinical/
`
`paraclinical
`worsening is
`necessary before
`deciding to
`change or add to
`an MS patient's
`treatment
`
`regimen.
`
`patient noncompliance with DMTs, treat-
`ment refractory disease,
`the presence
`of neutralizing antibodies in interferon
`beta-treated patients, and individually
`variable responses to treatment. There-
`fore, when patients with relapsing-
`remitting MS experience changes in their
`disease course, strategies must be em-
`ployed to mitigate further disease pro-
`gression. No consensus exists on how
`much clinical/paraclinical worsening is
`necessary before deciding to change or
`add to an MS patient's treatment regi-
`men. However, in general, the following
`may suggest a suboptimal response in
`the patient with RRMS:(1) Increase in
`relapses versus baseline after 6 to 12
`months on a DMT; no decrease in re-
`lapses once on therapy, or relapse rate
`of greater than one per year; (2) EDSS
`progression (eg,
`| or more points con-
`firmed over 6 months); or (3) increase
`in MRI measuresof disease activity (eg,
`newenhancing lesions, two or more T2
`lesions annually, or new T1 hypointense
`lesions)?"
`With these ideas in mind, clinicians
`have utilized a number of different
`treatment modalities for patients with
`
`MS who continue to have relapses de-
`spite appropriate first-line DMT ther-
`apy (Table 3-2).’* As described above,
`aclinician couldcertainlyconsider switch-
`ing to natalizumab in the setting of a
`patient on DMTwith frequent relapses
`andinflammatory changes on MRI. The
`addition of other drugs to a “platform
`agent’ makes logical sense froma treat-
`ment perspective as different mecha-
`nisms of action could theoretically have
`a therapeutically additive effect on th