`
`DEFINING SUCCESS IN MULTIPLE SCLEROSIS:
`TREATMENT FAILURES AND NONRESPONDERS’
`
`Benjamin Greenberg, MD, MHS.t and Elliot M. Frohman, MD, PhD, FAAIN?
`
`ABSTRACT
`
`Despite significant therapeutic advances in the
`treatment of multiple sclerosis (MS), the challenges
`facing neurologists are considerable. Because reli-
`able predictors of sustained and progressive dis-
`ability are lacking,
`there is a critical need for
`guidance regarding the definition and identifica-
`tion of treatment success andfailure, breakthrough
`disease, and inadequate treatment
`response.
`Likewise, clinicians need practical treatment algo-
`rithms that focus on strategies for nonresponders,
`including the relative merits of drug dosage adjust-
`ment, switching therapies, and the use of combina-
`tion therapies. This article identifies characteristics
`of patients with MS whoare inadequate responders
`and discusses issues regarding treatment modifica-
`tion in these individuals.
`(Adv Stud Med. 2008;8(8):274-283)
`
`Ithough there have been. significant
`advances in the management ofpatients
`with multiple sclerosis (MS) over the
`past decade, neurologists continue to
`face substantial challenges in the diag-
`nosis, monitoring, and treatment ofthis disorder.
`
`4
`edinas trom co Multisite Think Tank heic
`
`
`
`CoVirecio
`of Neurology,
`Assistant
`Pr
`o
`Hopkins Tronsverse Myelitis Center, Director
`Johns Hopkins
`
`Encephalitis Center,
`D
`nent
`of Neurology,
`“he
`Johns
`D
`‘
`Floptr
`kins University Schoo)
`of Medicine Baltimore, Maryland
`*FIO
`e
`t Neurology and Opnthaimology,
`Irene VVad
`
`& Rober Atha Dist nauished Chair
`in Neuroloay, Kenney:Mar
`
`Dixon Pickens Distinguished Professor in MAS Research, Director
`Multiple Sclerosis Prog om and Clinical Center,
`University
`Texas Southwestern Medical Center at Dallas, Dallas,
`Texas
`Address correspondence to’ Benjamin Greenberg,
`VV
`
`
`of Medicir
`MHS, The Johns Hopkins
`ty School
`
`nore
`600 North Wolfe Street
`627
`2 287 E-ma
`
`bgreent 7@ hm
`
`isease onset and progression in MS is
`highly variable; this makes it challeng-
`ing to predict its course for individual
`patients. The underlying mechanisms
`that
`lead to MS progression remain
`uncertain, which makes the timing of treatment initi-
`ation a significant challenge.
`Initially, an unidentified factor triggers immunesys-
`tem inflammatory“attacks” on myelin sheaths, causing
`interference in the conduction of nerve impulses. These
`episodes of inflammation are sometimes clinically appar-
`ent, manifesting as a “relapse.” The transition from relaps-
`ing to progressive disease typically represents a crossroads
`for treatment response;yetit is clear that axonal damage
`maybe presentat the earliest stage of disease or mayoccur
`at any time over the course of MS. The extent of axonal
`damage amongpatients with MSis highly variable, butit
`does appear that the accumulation of axonal destruction
`underlies clinical progression.'? The benefits of early
`treatment are becoming increasingly apparent as evidence
`mounts to showthat episodes of inflammation contribute
`to permanent axonal damage.
`To date, no single drug has provenfully effective in
`halting disease progression or disability. Furthermore,
`there are limited comparative data among currently
`approved MS agentsto assist clinicians in choosing an
`initial therapy. After therapyis initiated, it
`is equally
`hard to define what constitutes success and failure for
`an individual patient. Markers that are frequently used
`in assessing treatment efficacy in patients with MS,
`suchas relapse frequency, acquired neurologic deficits,
`or new findings from magnetic resonance imaging
`(MRI) studies, are not absolute predictors of long-term
`prognosis.’ Adverse effects of treatment, as well as treat-
`ment noncompliance, further confound clinical assess-
`ment and therapeutic modification. Nonetheless,
`it
`is
`recognized that currently approved agents are likely to
`reduce disease activiry and improve quality oflife for
`
`TWi v Merck
`
`IPR2023-00050
`
`lol. 8, No. 8 @ August 2008
`
`Merck 2007
`
`

`

`PROCEEDINGS
`________=[="H"Hn"noDaDnDn={2[==an=—_—=—="""{""[{a{"["X["XxX*xK[K"[_[—[RaR[{R{{[=[{={[{[_[=====ana=—~=—_—_=—eoeoe——
`
`DEFINING MS NONRESPONDERS
`
`Defining nonresponders is a challenge within the cur-
`rent environment of partially effective therapeutic
`options, in tandem with a disease that is highly variable
`both in its presentation and course. Typical presentations
`and the characteristics ofdisease progression in MS have
`been well described in several studies worldwide; howev-
`er, grouped data providelittle to help prognosticate in
`individual cases.* In its natural history, MS prognosis is
`determined by the frequency and features of relapses in
`the early years of disease, as well as by distinguishing
`between relapsing-remitting disease and progressive dis-
`ease, which may overlap with relapses (Table 1).
`Approximately 85% of patients present with a relaps-
`ing-remitting (RRMS) pattern of disease that is char-
`acterized by an initial episode of acute disease-related
`symptomsfollowed, in most, by some residual deficits
`or a full recovery over a few weeks to months. Up to
`20% of these patients may remain clinically stable for
`
`
`
`Disease Pattern
`
`Desenption of Disease Course
`
`Comments
`
`patients with relapsing MS. To achieve these benefits,
`treatment must be continued for years; stopping therapy
`can result in a return to pretreatment disease levels.*
`In this article, we explore several key concepts that
`clinicians must grapple with in order to accurately identi-
`fy nonresponders, including those exhibiting disease pro-
`gression, breakthrough disease,
`treatment success, and
`treatmentfailure. When faced with a patient whofits the
`portrait of a nonresponder, the clinician has the latitude
`to choose among divergentstrategies, including continu-
`ing current therapy, changing the dose of a current med-
`ication, switching therapies, or introducing combination
`therapy. To explore current views on these topics, we also
`present responses to survey questions posed to communi-
`ty neurologists during 2 recent conferences held in Dallas,
`TX, and Philadelphia, PA, on the topic of MS disease-
`modifying therapy nonresponders. In addition, we pro-
`pose algorithms for treating this group of patients and
`provide guidance forclinical decision making.
`
`
`
`Clinically isolated syndrome
`
`4. clinically discrete demyelinating event involving
`the optic nerve.
`spinal cord. or brain stem/
`cerebellum
`
`Subclinical demyelination seen on brain MRI
`
`Mut
`e differential diagnoses must be
`considered,
`
`Relapsing-remitting MS
`
`Episodic onset followed by residual deficits ar
`full recovery
`
`Pnmary progressive MS
`
`Ageressive progression is present from the outset
`WHAGUT reiapsing events
`
`Secondary progressive MS
`
`Chronic, steady increases ir
`
`SyMPIOMS and disability
`
`Progressive relapsing MS
`
`Benign MS
`
`Clinically definite MIS
`
`along with acute
`Progressive disease fram oriset
`relapses, with or without recovery
`Patient
`fi
`remains fully functiona’
`i5 years after disease onset
`
`in all neurologic systems
`
`Evidence of lesion in the CNS dissennated ©
`ver
`and space (>!
`episode involving >
`
`
`time
`CNS
`
`Presentation in approximately 85% of cases
`Presents most frequently Mh WOMEN aged 20-40
`4pproximately 20% remain clinically stable for
`20 years after ar
`initial episode
`about
`|5%-20% of cases
`t
`Occurs ir
`Affects men and women equaliy occurs :n gider
`ndwiduals. and is unresponsive to
`mmunomodulatory agents
`
`Occurs aimost universally in definite MS. Time
`framework vanes greatl
`Rare
`
`Many will go 0n to develop progression
`after
`|S years
`
`Diagnosis according to 2005 McDonald cntena
`inciudes definne MRI lesions and may include
`other supportive evidence such as CSF and
`visual evoked potentials
`
`CNS = central nervous system; CSF = cerebrospinal fuic: MR!
`
`= mapnetic
`
`resonance mag
`
`ng,
`
`"1S
`
`= multiple sclerosis
`
`Johns Hopkins Advanced Studies i: Medicine @
`
`

`

`
`
`PROCEEDINGS
`
`up to 20years without therapy, giving rise to the concept
`of “benign MS,” which raises the clinical question of
`whether or not early treatment will alter the course of
`disease in this subset ofpatients. Benign disease is statis-
`tically more frequent in younger female patients with
`fewer functional symptoms and lowerdisabilityscores at
`onset.” However, recent data from longitudinal surveys
`of patients with benign MS showthat many(if not
`most) of these patients will ultimately acquire significant
`disability. With or without treatment, a large number of
`patients with MS progress to a secondary-progressive
`(SPMS)pattern over time. Evidence indicates that, once
`progressive disease develops,
`the rate of progression is
`influenced little by the pattern ofdisease onset.’
`To further confound decision making for patients
`with MS, up to 15% follow a primaryprogressive pat-
`tern, in which progressionpersists with or without treat-
`ment; however, such patients may eventually develop
`relapses (designated as progressive relapsing MS), and
`therefore may benefit from therapy. Patients whopresent
`
`with a clinicallyisolated syndrome that cannot be defin-
`itively diagnosed at onset as MS are considered in a sep-
`arate article in this monograph (see article by Bruce
`Cree, MD, PhD, MCR,and TimothyL. Vollmer, MD).
`
`CLINICAL DEFINITION OF DISEASE PROGRESSION
`In the clinical setting, measures of ongoing disease
`activity are determined by a composite of relapse rate,
`periodic MRI findings, the clinical neurologic examina-
`tion, disability scores, neuropsychological
`functioning
`assessments, as well as the patient's assessmentof his or
`her level of functioning (eg, activities of daily living
`[ADLs]) and quality oflife. Disability has classically been
`quantified by sequential use of the Expanded Disability
`Status Scale (EDSS; Table 2)."The EDSS quantifies dis-
`ability in the areas of pyramidal, cerebellar, brain stem,
`sensory, bowel and bladder, visual, and cognitive func-
`uioning. However, this assessmentis highly limited in its
`characterization ofvitally important aspects of function,
`such as cognitive and intellectual capability, mood, and
`
`
`
`Score
`
`Descnption
`
`0
`t
`
`15
`2
`
`No disability
`Minimal signs in |
`
`function
`
`>) funcuon
`Minimal signs in
`Minimal disability in |
`function
`
`Ambulation
`
`Fully ambulatory
`
`Mild disability in | function or minima! disability in 2 functions
`25
`
`3 Moderate disability in|function or mild disability in 3-4 functions
`35
`Moderate disability in >) function
`4
`Severe disability but able to work, walks without aid 500 meters without rest
`
`45
`5
`aS
`
`co
`65
`7
`
`5
`
`8
`8.5
`9
`
`95
`10
`
`bevere disability but able to work, walks without aid 300 meters without rest
`Severe disability. unabie to work, walks without aid 200 meters without rest
`Severe disability, limited actyrties, walks without
`aid 100 meters without rest
`
`(cane, crutch, or brace)
`Above plus intennittent or unilateral walking ard
`crutches, or braces)
`Above plus constant bilateral walking aid (canes,
`Wheelchair bound, wheels self and transfers alone
`Wheelchair bound, may need aid for transfers and mobility in wheelchair
`Bed or chair bound: retains many sel-care functions
`Bed bound; retains some self-care functions
`Bed bound: needs assistance with self-care. can communicate and eat
`
`Totally dependent. unable to communicate effectively or eat/swallaw
`Death due to MS
`
`Assisted arnbulation
`
`Non-ambulatory
`
`MS=multiple sclerosis
`Data from Kurtzke
`
`276
`
`Vol. 8, No. 8 @ August 2008
`
`

`

`PROCEEDINGS
`
`
`
`quality oflife. Instead, the EDSSis principally weighted
`on ambulation, which severely limits its ability to fully
`represent all aspects of disability that are important to
`patients with MS and their families. Individuals with
`EDSSscores from 1 to 4.5 are fully ambulatory, whereas
`those with scores from 5 to 9.5 have increasing degrees of
`ambulatory dysfunction and dependency in ADLs. Both
`MRIchanges over time and increasing MRI lesion vol-
`ume are associated with worsening of EDSSscores’; how-
`ever, clinical use of the EDSSis limited due to time and
`staffing constraints, particularly due to the 500-meter
`walk requirement. A modified functional assessment is
`provided by the MS Functional Composite (MSFC),
`which combines a 25-foot timed walk, the 9-hole peg test
`to assess upper extremity function, and the paced serial
`auditory addition test
`to assess information processing
`speed."* In spite of the importanceofthese tools in assess-
`ing disease progression, 92% of neurologists working in
`the community (48 out of 52) surveyed indicated that
`they did nor perform an EDSS or MSFCatevery clinic
`visit. Thus,
`it
`is probably unreasonable to assume that
`these tools could be used to determine whether patients
`are “nonresponders” in typical neurology practices.
`Numerous clinical
`risk factors have traditionally
`been used to predict more rapid disease progression,
`including older age at onset, male gender, MRI] status,
`shorter interval between first and second attack, high
`relapse rate during the first 2 years, and incomplete
`recovery following an attack. Patient risk is assessed
`according to the number of risk factors identified;
`individuals with 0or |
`risk factor are classified as low
`risk, whereas those with 2 or3 risk factors are classified
`as medium risk, and patients with 4 or more risk fac-
`tors are classified as high risk. Yet, prospective studies
`stratifying patients into these arms and assessing its
`impact on therapeutic decision making are lacking.
`
`ROLE OF IMAGING STUDIES IN
`PREDICTING DISEASE PROGRESSION
`Althoughthe diagnosis of MS remainsa clinical one,
`evidence from MRI studies has proven increasingly valu-
`able in diagnosing and managing the disease and in pre-
`dicting progression. Although MRI is currently the most
`sensitive tool for investigating MS,
`it
`is important to
`note that the appearance of multiple lesions on any sin-
`gle MRIstudy is nor diagnostic or predictive of disease
`progression; conversely, serial studies have shown that
`clinical evidence of disease stability is not reflective of
`current disease activity as defined by MRI findings."
`
`Newlesions on MRI in a patient whois clinically stable
`are indicative ofactive disease, and are particularly useful
`in defining breakthrough disease in individual patients.
`Indeed, the 2005 revision of the McDonald criteria for
`diagnosis of MS accepts the appearance of new lesions
`on MRIas fulfilling the separation in ime component
`of the diagnostic criteria (Table 3).'*”
`
`DEFINING TREATMENT SUCCESS
`It is importantto be able to recognize when a current
`therapy should be maintained and when a therapeutic
`change is warranted. Ideally, a successful therapy would
`prevent all new symptomsand disabilities; however, no
`current therapies are fully successful in this fashion. At
`present, assessing treatment efficacy requires the use of
`all available markers and predictors of the future course
`of the disease. Signs of progression may include an
`increase in the rate of relapse, new MRIevidenceofdis-
`ease activity, progressive disability as measured on the
`EDSS, or the appearance of new brain stem/cerebellar or
`cognitive deficits. Signs of disease progression in a treat-
`ment-naive patient signal the need to initiate therapy. In
`somecases, disease progression may be an indication of
`treatment failure. If a patient does not experience a
`reduction in progression or rate of relapses after initiat-
`ing a therapy, then it could be argued that the patient is
`not deriving a significant benefit from the medication.
`When asked to assess the relationship berween relapse
`rate as one measure of disease progression and the recog-
`nition oftreatment failure, 44% and 56% ofneurolo-
`gists (7 = 27) judged that treatment failure had occurred
`when the numberofrelapses taking place during a 12-
`month period was | or 2, respectively.
`
`DEFINING BREAKTHROUGH DISEASE
`Althoughdisease progression can be considered treat-
`ment failure, in an individual patient it might beclassi-
`fied as breakthroughdisease. Because ofthe variability of
`MS,it is necessary to define breakthrough disease on a
`case-by-case basis. Breakthrough is generally character-
`ized as unacceptableclinical or radiographic evidence of
`disease activity that is not sufficiently controlled by cur-
`rent treatment intervention, assuming treatment compli-
`ance.
`In breakthrough disease, treatment efficacy that
`had been established over a period of time disappears,
`and there is further progression ofdisability,
`increased
`relapse frequency,
`increased MRI evidence of disease
`activity, and new cognitive or brain stem/cerebellar
`deficits. Breakthrough ditters from treatment failure pri-
`
`Johns Hopkins Advanieel Studies m Medicine s
`
`
`
`

`

`PROCEEDINGS
`
`
`MRI Criteria for Lesion Dissemination in Time
`
`MRI Crtena for Lesion Dissemination in Space
`
`3 months after the onset
`least
`Detection of Gd enhancement at
`of the initial clinical event,
`if not at the site corresponding to the
`intial event
`
`OR
`
`Detection of anew T2 lesion if t appears al any time compared
`with a reference scan done at
`least 30 days after the onset of
`the intial clinical event
`
`Three of the following
`¢ At least
`| Gd-enhancing lesion or 9 T2 hypenntenselesions
`if there is no Gd-enhancing lesion
`At least
`|
`infratentonai
`lesion
`At
`least
`|
`juxtacortical lesron
`A
`PAL least
`3 penventncular lesions
`
`Badolinjum
`Gd
`MRI = magnetic resonance imaging: MS = multiple
`Data from Nielsen et al
`
`marilyin the timing of worsening ofdisease activity and
`manifestations. Breakthrough activityis not necessarilya
`reason for discontinuation of current therapy, although
`modification should be considered. Hopefully, the use of
`newer imaging techniques,
`including magnetic reso-
`nafice spectroscopy, magnetization transfer, and diffu-
`sion tensor imaging, will
`lead to improvements in the
`ability to assess disease burden.'
`Distinguishing treatmentfailure trom breakthrough
`disease depends a great deal on a collaborative interpreta-
`tion of objective and subjective findings bythe clinician
`and patient. Treatment failure in one patient may be
`viewed as breakthrough disease in another. In order to
`help patients with MS differentiate berween treatment
`failure and breakthrough disease.
`they should be made
`aware early in the course oftreatment that disease activity
`is expected even with therapy. Thus, before initiation of
`therapy, patients should be educated regarding available
`treatment options, the time course for evaluating a treat-
`ment, and realistic expectations while on therapy. The
`patient's tolerance for ongoing disease activity should be
`explored, and the patient should undergo regular evalua-
`tion ofdisease activity with ongoing discussion ofthe ben-
`efits and risks of therapy modification. Regular evaluations
`should include sequential neurologic examination and
`patient assessment of his or her qualityoflife and ability
`to perform ADLs, For patients receiving interferon (IFN)
`B therapies, some argue thatit is also prudent to evaluate
`levels of neutralizing antibodies (NAbs) to IFN (to differ-
`
`sgarding spinal cord lesions
`
`A soundb
`cord lesion can be considered equivalent to a bram
`infratentonal lesion
`
`An enhancing spinal cord lesion is considered equivalent to. an
`prnh ncn brain lewon
`Individual spinal cord lesions can contnbute together with individual
`brain lesions to reach the required number of T2 lesions
`
`entiate between breakthrough disease and treatmentfail-
`ure). NAbs have been shown to decrease the biologic
`response to treatment with IFN§ after 18 to 24 months of
`therapy, and MRIlesions are increased in NAb-positive
`patients,'*"*" It is important to note thatclinical stability
`does not preclude the need to investigate for development
`of NAbs, as occult disease is more common in NAb-posi-
`uve patients. The development of NAbs is more likely
`seen with high doses of IFN, versus low-dose IFN, but can
`be seen with either, Alchough the European community
`recommends regular screening for NAbs, the recommen-
`dation has not been recreated in America. Indeed,a single
`positive NAb test in a patient who is doing well is not jus-
`tification to withdrawtherapy. It has also been noted that
`5% to 10% of patients undergoing therapy with natal-
`izumab can develop NAbs that diminish or negate treat-
`ment effects, Of the US Food and Drug Administration
`(FDA)-approved medications currently available, only
`glatiramer acetate (GA) has not been associated with clin-
`ically significant antibody formation,
`
`TREATMENT ALGORITHMS
`
`treatment strategies are employed over the
`Several
`course of MS to achieve the best possible patient out-
`comes, Current therapies for MS are summarized in Table
`4." Optimal therapies should demonstrate long-term
`benetit to patients with regard to physical, MRI, and cog-
`nitive Outcome measures and a favorable side-effect pro-
`
`N~! -’
`
`Vol 8, No os August 2008
`
`

`

`
`
`PROCEEDINGS
`
`file. Although current therapies do not cure MS,several
`medications are currently approved by the US FDAas
`disease-modifying agents (DMAs) that demonstrate at
`least some of the above capabilities, Primary approved
`therapies, including IFNB (intramuscular IFNB-1a, sub-
`cutaneous IFNB-1b, and subcutaneous IFNB-la) and
`GA, have been shown to alter the natural history of MS
`
`by preventing or delaying disease progression. At 18 to 24
`months, IFNB agents appear to be more effective than
`GA in controlling the formation ofnew MRI lesions, but
`relapse rate reductions are verysimilar. Among the IFNB
`agents, intramuscular IFNB-1a and subcutaneous IFNB-
`la are the only agents approved by the US FDA to reduce
`disability progression in RRMS, Naralizumab is recom-
`
`
`
`Treatrnent
`
`Status
`
`Suggested Mechanismof Action
`
`Efficacy
`
`IFNB by SC injection
`
`3 US FDA-approved agents
`+ IFNB-la (IM and SC)
`* IFNB-Ib (SC)
`
`* Inhibits adhesior
`§ and transport
`« Inhibits synthe
`of MMPs
`
`° All 3 reduced relapses and disability, but
`only modestly
`* All 3 significantly reduced Gd+ and T2
`lesions on MRI
`
`* Blocks antigen presentation
`« May showlass of efficacy after 2 years» IM IFNB-Ia and SC IFNB-1b improved
`f neutralizing antibodies are present
`cognitive dysfunction
`
`GA bydaily SC
`injection
`
`| US FDA-approved agent
`
`Natalizumab
`
`| US FDA-approved agent
`
`« Increases regulatory T cells
`« Suppresses cytokines
`* Block: anuigen presentavon
`
`« Selective adhesion molecule
`nhibrtor
`
`* Reduced relapses and disability
`* Reduced Gd+ and T2 lesions on MRI
`
`* Dramatic reduction in relapse rate,
`MRI
`lesion formation, and disability over
`2-year Study
`* Safety, with respect to development of
`PML, needs to be verified im post-market
`Ing surveillance
`
`Mitoxantrone
`
`| US FDA-approved agent
`
`« Antineoplastic agent
`* Reduces
`cytolones
`
`¢ Used pnmanty in secondary progressive MS
`* Reduced lesions seen on MRI
`
`Corticosteroids
`{usually IV methyl-
`prednisolone}
`
`Azathioprine
`
`Adjuvant therapy used ove
`the past 2 decades
`
`© Eliminates lymphocytes
`* Potential carcdiotoxic effects
`Increased risk of leukemia
`synthesis an
`
`* Inhibits
`MMPs
`cytokine
`© Alters
`* Reduces CINS
`
`profile
`
`* Slows progression
`¢ Platform for combination therapy
`
`of
`
`© Hastens recovery from relapses
` ces tissue damage
`9
`* Re
`lesion recovery
`* Promote
`
`Adjuvant therapy first proposed
`for MS therapy 30 years ago
`
`=» Inhibits punne
`
`stherst
`
`* Slows secondary progression
`* Potential for bone marrow toxicity
`
`Methotrexate
`
`Adjuvant therapy
`
`« Folate antagonis
`
`Plasma exchange
`
`Adjuvarrt therapy
`
`« Rem
`
`ves
`
`deletenous antibodies
`
`Intravenous immuno-
`globulin
`
`Adjuvant therapy
`
`¢ Antridiotyp!
`« Blocks Fe
`re
`«Alt
`
`tc
`
`
`
`* Slows secondary progression
`« Currently being studied in combination
`with IM IFINB-
`1a and corticosteroids
`* Short-term treatment for acute inflamma-
`tory demyelinating polyneuropathy
`
`¢ Treatment and prevention of
`relapses in patients with treatment failures
`
`nite,
`©
`= gadolimun:,
`[PM =
`interferon,
`IM
`ntramuscuiar IV = ontravencus
`CNS = central nervous system FDA=Food and Drug Adminntration G4 glatirame
`
`tt
`progressive myuitiioca leukoencenhalopathy: SC = subcutaneous
`MMP = matrix metalloprotease: MR)
`= magnenc
`resonance imaging.
`/1S
`mpit
`z
`
`Johns Hopkins Advanced Studies in Medicine @
`
`279
`
`

`

`
`
`PROCEEDINGS
`
`mended for patients who have had an inadequate
`response to, or are unable ro tolerate, other primary MS
`therapies. In addition, mitoxantrone may be considered
`for worsening disease in selected relapsing patients or
`patients with SPMSwith or withoutrelapse. With any of
`these therapies (with the exception of mitoxantrone),
`treatment must be sustained for years.
`When asked to choose between IFN, natalizumab,
`combination glatiramer and IFN, cyclophosphamide,
`and monthly steroids as a therapy change for a patient
`currently receiving glatiramer, 46%of surveyed neurolo-
`gists selected IFN, 42% selected natalizumab, and 12%
`indicated combination glatiramer and IFN (= 26).
`Discussions indicated thatas safety data for natalizumab
`becomeclearer, it may become the preferred second-line
`drug for most patients. Although DMAs reduce the
`number of RRMS relapses, they appear to be less effec-
`tive (or ineffective)
`in purely progressive disease, and
`seem to have limited effect once the disease enters a sec-
`ondary-progressive phase.'' Current data indicate that
`mitoxantrone is the most
`favorable SPMS treatment
`option; however, GA has not yet been studied in SPMS.
`There are 3 strategies to consider when break-
`through disease is encountered on a current therapy:
`(1) change the dose; (2) switch therapies; or (3) add a
`therapyto the current regimen (combination therapy).
`A review of open-label, prospective studies ranging in
`duration from 63 weeks to 6 years, and involving near-
`ly $000patients, revealed no advantage toincreasing the
`dose of an ongoing primarytherapy."’'! For example, an
`evaluation of extended intramuscular IFNB-la treat-
`ment conducted by Clanet et al found equal efficacy
`over 4 years among patients with MStreated with either
`30 or 60 pg intramuscular IFNB- 1a.”
`
`SWITCHING THERAPIES
`There are no current data from controlled, prospec-
`tive, direct-comparisonclinical trials to support switching
`therapies in the event of treatmentfailure with a primary
`DMA in MS. Furthermore,
`there is little evidence to
`direct when we should discontinue a therapyin the event
`of breakthrough disease.“ Recent data from the retro-
`spective QUASIMS (Quality Assessment
`in MS
`Therapy) study compared IFNB therapies in RRMS and
`found noclinical benefit as a result of switching berween
`IFNs.” In QUASIMS, 4754 patients with RRMS who
`were enrolled in open-label studies of intramuscular
`IFNB-la, subcutaneous IFNB-1b, and subcutaneous
`IFNB-la (at 2 doses) were analyzed retrospectively.
`
`Evaluated outcomes included disability progression, per-
`cent of progression-free patients, percent ofrelapse-free
`patients, annualized relapse rate, and reasons for changing
`therapies. Investigators concluded that switching between
`different IFNB agents provided no clinical benefits; how-
`ever, findings based on aggregate data do not preclude a
`benefit for individual patients. Furthermore, the study
`found that NAbs had no observable impact on clinical
`efficacy until 2 years after the initiation of IFN therapy.
`In summary, unless side effects are significant, toxicity is
`unacceptable, or NAbs are present after 2 years of thera-
`py.
`there is currently no tried and true algorithm for
`changing therapies between IFNB agents or between an
`IFNB agent and GA.Yet, these data did not track the out-
`comes for patients switching from an injectable medica-
`tion to natalizumab.
`
`COMBINATION THERAPY
`Compared with the limited benefits of dose
`changeswith a current agent or switching agents when
`breakthrough disease is encountered in patients with
`RRMS, combination therapy has some potential dis-
`tinct advantages." The current strategy for designing
`a combination regimen has been developed in antici-
`pation of encountering 3 disease stages, During the
`first stage, a patient is stabilized on a platform DMA,
`such as an IFNB or GA.
`Therapyis escalated to stage 2 when breakthrough
`disease occurs.
`In general, this would involve main-
`taining platform therapyat the same dose and adding
`pulsed corticosteroids intermittently as needed to con-
`trol relapses and symptoms, If breakthrough disease
`persists, stage 3 is implemented by continuing the
`platform agent along with pulsed corticosteroids
`and/or the addition of another agent or changing the
`platform agent. There are no large-scale trials that
`identify the efficacy oflong-term combination thera-
`pies in MS,
`thus first-line consideration should be
`given to switching therapies altogether, Potential stage
`3 agents include oral immunosuppressantdrugs (stage
`3A) and intravenous immunosuppressant agents (stage
`3B).
`In addition to disease-modifying combination
`therapies, several adjunctive medicationsare also used
`in MS co alleviate symptoms such as spasticity, neuro-
`pathic pain, fatigue, and bladder dysfunction.
`As noted, pulsed corticosteroids are frequently used
`in combination with platform therapies during relapses.
`Corticosteroids have both anti-inflammatory and
`immunosuppressive effects, and are not toxic to bone
`
`280
`
`Vol. 8, No. 8 August 2008
`
`

`

`PROCEEDINGS
`
`
`
`marrow. They have been shown to provide rapid
`response and symptom improvement, as well as an
`increase in the time to sustained worsening on the
`EDSS.''** Using steroids as a DMA has also been stud-
`ied with varying schedules, including | g of methylpred-
`nisilone once every 4 monthswith oral taper, or | g daily
`for 1 to 3 days at 1- to 3-month intervals. Frequent use
`of corticosteroids must be monitored carefully, and pre-
`cautions appropriate to long-term steroid use should be
`observed, including blood glucose monitoring and bone
`density measurements.
`In addition to immunomodulatory agents, cyto-
`toxic agents have potential uses in combination with
`platform therapies. Agents that have been used in
`treating MS include azathioprine, cyclophosphamide,
`mitoxantrone, methotrexate,
`cladribine,
`and
`mycophenolate mofetil.“ Other potential candi-
`dates include anti-infectious agents, antioxidants, T-
`cell activation inhibitors, matrix metalloproteinase
`inhibitors, statins, and neuroprotective agents.
`Some combination therapies are currently being eval-
`uated in clinical
`trials involving patients with RRMS,
`including studies of intramuscular IFNB-la plus GA
`compared with either agent plus placebo,’
`investigations
`of intramuscular IFNB-1a in combination with azathio-
`prine and/or prednisone,“ and comparisons ofintramus-
`cular
`IFNB-la combined with methotrexate plus
`placebo, intramuscular IFNB-la combined with intra-
`venous steroids plus placebo, and all 3 active agents.”
`Additional ongoing research includes a small study of
`cyclophosphamide plus intravenous steroids in RRMS
`not responsive to IFNB agents or GA, and a safety and
`mechanistic study of intramuscular
`IFNB-la_ plus
`mycophenolate mofetil compared with intramuscular
`[FNB-1a plus placebo in patients with early RRMS.”
`
`CumNIcaL DECISION MAKING
`
`Asa general rule, most compliant and noncompliant
`patients with MShave a positive opinion ofthe effective-
`ness of their MS therapy. Nonetheless,
`it
`is critical
`to
`assess medication compliancein all patients with MS as a
`precondition for assessing treatment success orfailure, or
`for confirming disease breakthrough. Medication-taking
`behavior must be assessed for long- and short-term com-
`pliance andforpersistence of adherence. Noncompliance
`is a term used to describe failure to take medication as
`prescribed in a general sense, whereas nonadherence gen-
`erally refers to short-term discontinuation of a medica-
`
`tion. A lack ofpersistence signifies loss of adherence or
`compliance after a significant period of compliance.
`Noncompliant patients may forget to take medications or
`lack an understanding of how to take them, or may have
`unrealistic expectations and beliefs about their medica-
`tions. Nonadherent patients may have a temporary
`inability to access their medications, complex life events
`that interfere in self-care, depression or cognitive lapses,
`or a temporary perception of adverse effects, Lack of per-
`sistence may occur for many reasons, buttypically occurs
`in patients who are feeling well and do not understand
`the long-term benefits of maintaining their medical regi-
`men.
`In all cases, a therapeutic alliance between the
`patient and provider underlies successful medication
`compliance. The provider must set the stage for realistic
`expectations regarding disease progression and benefits of
`therapy, and stay in close contact with patients, particu-
`larly during therapeutic initiation or adjustment.In addi-
`tion, providers must inquire about, monitor, and manage
`adverse effects, and employ a multidisciplinary approach
`to patient care, ensuring that patients have access to ther-