`
`DEFINING SUCCESS IN MULTIPLE SCLEROSIS:
`TREATMENT FAILURES AND NONRESPONDERS’
`
`Benjamin Greenberg, MD, MHS.t and Elliot M. Frohman, MD, PhD, FAAN?
`
`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-
`rithmsthat 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
`ofpatients with MS whoare inadequate responders
`and discusses issues regarding treatment modifica-
`tion in these individuals.
`(Adv Stud Med. 2008;8(8):274-283)
`
`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 immune sys-
`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 thar axonal damage
`maybe presentat theearliest stage ofdisease or mayoccur
`at any time over the course of MS. The extent of axonal
`damage among patients with MSis highly variable, butit
`does appear that the accumulation of axonal destruction
`underlies clinical progression.'? The benefits of early
`treatment are becomingincreasingly apparent as evidence
`mounts to showthat episodes of inflammation contribute
`to permanent axonal damage.
`To date, no single drug has proven fully 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 therapy is 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,
`i
`;
`;
`—_
`suchas relapse frequency, acquired neurologic deficits,
`or new findings from magnetic resonance imaging
`5
`:
`(MRI) studies, are not absolute predictors of long-term
`aa
`prognosis.‘ Adverse effects of treatment, as well as treat-
`ment noncompliance, further confound clinical assess-
`ment and therapeutic modification. Nonetheless,
`it
`is
`.
`7
`recognized that currently approved agents are likely to
`reduce disease activity and improve quality oflife for
`Merck 2007
`Merck 2007
`TWi v Merck
`TWiv Merck
`IPR2023-00049
`IPR2023-00049
`fol. 8, No. 8 @ August 2008
`
`
`
`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.
`
`*Basad'ion oroceedinas from a AMulilsite Think Tonk herd
`in September 2007
`:
`jJohris
`CorVirecio,
`Neurology,
`T Assistant
`Professoy
`£
`lohns Ficipkiris
`Hopkins Transverse Myelitis Center, Director
`of Neu ology
`he
`Encephai tis Center Depariment
`
`
`Hopkins University School
`of Medicine, Baltimore, Maryl
`
`of Neurology and Ophthalmology,
`Irene VVade
`*Prolessor
`
` +
`in Neurol
`y Kenney Mare
`Listinguishe:
`seurowogy,,
`Kenney
`Dixon Pickens Distinguished Professor in MS Research, Director
`Multiple Sclerosis Progrom and Clinical Centers,
`University
`Texas Southwestern Medical Center af Dallas, Dallas, Texos _
`
`cutee Sey ro: Benjamin
`Vino
`e jonns Moprns
`690 North Wolf
`
`=
`;
`-
`21287 E-mail
`boreenb
`
`SI
`
`
`
`cne
`
`

`

`PROCEEDINGS
`
`DEFINING MS NONRESPONDERS
`
`Defining nonresponders is a challenge within the cur-
`rent environment of partially effective therapeutic
`options, in tandem with a disease thar 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 provide little 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
`betweenrelapsing-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 ofdisease 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
`
`Descnption 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 pretreatmentdisease 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
`
`
`Relapsing-rem ing MS
`
`A clinically discrete demyelinating event involving
`cord. or brain stem/
`the opbc nerve. spinal
`cerebellum
`
`Episodic onset followed
`full
`recovery
`
`by residual deficits Gr
`
`Pnmary progressive MS
`
`Appressive progression!s
`without relapsing events
`
`4 aresent
`
`from the out
`
`Secondary progresswe MS
`
`Chronic, steady increase
`
`SiN symptoms and disability
`
`Progressive relapsing MS
`
`Benign MS
`
`Clinically definite MS
`
`set along with acute
`Progressivedisease from oc
`relapses, with or watho
`ut recovery
`remains.
`fully
`unctiona’
`if
`Patient
`(5 years after disease onset
`Evidence of lesion in the CNS disseminated over time
`>
`area of the CIS
`ano space
`episode involving >
`
`in all neurologic systems
`
`Subclinical demyelination seen on brain MRI
`
`Multiple differential diagnoses must be
`considered.
`
`Presentationin approximately 85% of cases
`Presents most frequently in women aged 20-40
`Approximately 2O% remain clinically stable for
`20 years after an initial epsode
`about
`
`
`Affects men and women
`equally o¢curs :n cider
`ndividuals. and is unresponsive to
`mmunomodulatory agents
`
`Occurs almost universally in definite MS. Time
`framework vanes preatl
`Rare
`
`Many will goon to develop progression
`after
`15 years
`
`et
`2005 McDer
`ald cntena
`Diagnosis according to 2005
`includes definite MRI lesions and may include
`other supportive evidence such as CSF and
`visual evoked potentials
`
`CNS = central nervous system; CSF = cerebrospinal|
`
`ic MR = mapnetc
`
`resonance maging,
`
`'1S =n
`
`2 sclerosis
`
`Johns Hopkins Advanced Studies:Medicine ©
`
`

`

`
`
`PROCEEDINGS
`
`up to 20 years 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 show that many(if not
`most) of these patients will ultimately acquire significant
`disability. With or without treatment, a large numberof
`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 primary progressive 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 Timothy L. Vollmer, MD).
`
`CLINICAL DEFINITION OF DISEASE PROGRESSION
`In the clinical setting, measures of ongoing disease
`activity are determined by a composite ofrelapse rate,
`periodic MRI findings, the clinical neurologic examina-
`tion, disability scores, neuropsychological
`functioning
`assessments, as well as the patient's assessment ofhis 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-
`uoning. However, this assessmentis highly limited in its
`characterization ofvitally important aspects of function,
`such as cognitive and intellectual capability, mood, and
`
`
`
`Ambulation
`
`Score
`
`Descnption
`
`0
`I
`
`Mio disability
`Mirrnal signs in) funtion
`
`Minimal signs in >) funcuen
`(5
`Minimal disability in |
`function
`?
`Mild disability in | function of minimal disability in 2 functions
`25
`
`3 Moderate disability in|function or mild disability in 3-4 functions
`55
`Moderate disability in >! function
`4
`Severe disability but able to:.work walks without aid 500 meters wit
`
`Fully ambulatory
`
`rout rest
`
`45
`5
`55
`
`6
`6.5
`7
`
`5
`
`8
`85
`9
`95
`10
`
`Severe disability but able to work, walks without aid 300 meters without rest
`thout rest
`Severe disability. unable to work, walks without aid 200 meters w
`Severe disability, limited actwrties. walks without ait 100 meters without rest
`
`(cane, crutch, or brace)
`Above plus intennittent or unilateral walking aid
`Above plus constant bilateral walking aid (canes, crutches, or braces)
`Wheelchair bound, wheels self and transfers alone
`Wheelchair bound, may need aid for transfers and mobility in wheelchair
`Bed or chair bound: retains many self-care functrons
`Bed bound: retains some self-care functrons
`can conmvnunicate and eat
`Bed bound needs assistance with self-care.
`Totally dependent, unable to communicate effectively or eat/swallaw
`Death due to MS
`
`Assisted arnbulation
`
`Non-ambulatory
`
`Ms = multiple scerose
`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-
`umeare 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 ts
`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 MSFC atevery 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 0 or |
`risk factor are classified as low
`risk, whereas those with 2 or 3 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 STUDIESIN
`PREDICTING DISEASE PROGRESSION
`Although the 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 MRIis currently the most
`sensitive tool for investigating MS,
`it
`is important
`ro
`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 retlective of
`current disease activity as defined by MRI
`findings."'
`
`Newlesions on MRI in a patient whois clinically stable
`are indicative of active 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 ume component
`of the diagnostic criteria (Table 3).'*"
`
`DEFINING TREATMENT SUCCESS
`It is important to 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 symptoms and 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 MRI evidence of dis-
`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
`some cases, 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
`nor 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 of treatment failure, 44% and 56% ofneurolo-
`gists (= 27) judged that treatmentfailure had occurred
`when the number ofrelapses taking place during a 12-
`month period was | or 2, respectively.
`
`DEFINING BREAKTHROUGH DISEASE
`Although disease progression can be considered treat-
`ment failure, in an individual patient it might be classi-
`fied as breakthrough disease. Because of the variability of
`MS, it is necessary to define breakthrough disease on a
`case-by-case basis. Breakthrough is generally character-
`ized as unacceptable clinical 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 differs from treatment failure pri-
`
`Johns Hopkins Advanced Studies iy Medicine
`
`
`
`

`

`PROCEEDINGS
`
`
`MRI Crtena for Lesion Dissemination in Time
`
`MRI Critena for Lesion Dissemination in Space
`
`3 months after the onset
`* Detection of Gd enhancement ai least
`of the initial clinical event,
`if not at the site comesponding to the
`initial event
`
`OR
`
`* Detection of anew T2 lesion if 1 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-enhancinglesion or 9 T2 hypenntense lesions
`if there is no Gd-enhancing lesion
`e At least
`|
`infratentonal lesion
`© Atleast
`|
`juctacortical lesion
`* At
`least
`3 penventncular lesions
`
`Regarding spinal cord lesions
`* A sonal cord lesion can be considered equivalent to a bram
`infratentonal lesion
`
`* Anvenhancing spinal cord lesion is considered equivalent to. ar
`enhancing brain leuion
`individual spinal cord lesions can contribute together with individual
`brain lesions to reach the required number of T2 lesions
`
`*
`
`Gd = gadolinium. MRI =
`Data from Nielsen et al
`
`MapnetiC MeSOMance
`
`maging MS = multiple
`
`sclere
`
`marilyin the timing of worsening ofdisease activity and
`manifestations. Breakthrough activity is not necessarily a
`reason for discontinuation ofcurrent therapy, although
`modification should be considered. Hopefully, the use of
`newer imaging techniques,
`including magnetic reso-
`nance 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 by the 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 of treatment 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. Forpatients receiving interferon (IFN)
`B therapies, some argue thatit is also prudent to evaluate
`levels of neutralizing antibodies (NAbs) to IFN (to differ-
`
`entiate between breakthrough disease and treatment fail-
`ure). NAbs have been shown to decrease the biologic
`response to treatment with I[FN§ after 18 to 24 months of
`therapy, and MRI lesions 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, Although 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-
`izmab 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
`benefit to patients with regard to physical, MRI, and cog-
`nitive Outcome measures and a favorable side-effect pro-
`
`Ny=~! nx
`
`Vol. & No 8 August 2008
`
`

`

`
`
`PROCEEDINGS
`
`file. Although current therapies do not cure MS,several
`medications are currently approved by the US FDA as
`disease-modifying agents (DMAs) that demonstrate at
`least some of the above capabilities. Primary approved
`therapies, including IFNB (intramuscular IFNB-1a, sub-
`cutaneous IFNB-ib, and subcutaneous IFNB-1a) 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 very similar. 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-
`
`
`
`Treatment
`
`Status
`
`Suggested Mechanism of Action
`
`Efficacy
`
`IFNB by SC injection
`
`3 US FDA-approved agents
`* IFNB-la (IM and SC)
`* IFNB-Ib (SC)
`
`GA bydaily SC
`injection
`
`| US FDA-approved agent
`
`Natalizurnab
`
`| US FDA-approved agent
`
`* Inhibrts adhesion
`syn
`©
`Inmpits
`ith esis and transport
`of MMPs
`&
`Blocks antigen presentation
`May show
`loss of efficacy after
`2 years
`‘ neutralzing antibodies are present
`Increases t
`Suppresses
`Blocks antigen presentation
`adhe
`
`Selective
`mnmhibrtor
`
`on molecule
`
`egulatory T cells
`cytokines
`
`Mitoxantrone
`
`1 US F DA-approved agent
`
`Antineop!
`Reduce:
`Eliminates
`
`Potent
`Increased
`
`Stic agent
`ytolones
`
`yYMPNOCyies
`cardiotomc effects
`risk of leukemia
`
`* All 3 reduced relapses and disability, but
`only modestly
`* All 3 significantly reduced Gd+ and T2
`lessons on MRI
`
`» IM IFNB- la and SC IFNB- Ib improved
`cognitive dysfunction
`
`* Reduced relapses and disability
`* Reduced Gd+ and T2 lesions on MR!
`
`Dramatic reduction in relapse rate.
`MRI lesson formation, and Grabiltty over
`2-year Study
`
`* Safety, with respect to development of
`PML, needs to be verified in post-market
`Ing surveillance
`
`* Used pamanty in secondary progressive MS
`* Reduced lesions seen on MRI
`* Slows progression
`Platform fe combination therapy
`
`Corhoosterods
`(usually IV methyl-
`prednisolone)
`
`Adjuvant therapy used ove
`the past 2 decades
`
`* Inhibits synthesis and transport of
`MMPs
`cytolone profile
`« Alters
`* Reduces CNS edetna
`
`* Hastens recovery from relapses
`
`* Reduces tissue damage
`* Promotes lesion recovery
`
`Azathioprine Adjuvant therapy first proposed=* Inhibits punne ESI * Slows secondary progression
`
`
`
`
`
`
`for MS therapy 30 years ago
`*« Potential for bone marrow toxicity
`
`Methotrexate
`
`Adjuvant therapy
`
`* Folate
`
`antagonist
`
`Plasma exchange
`
`Adjuvant therapy
`
`« Ren
`
`feletenous antibodies
`
`Intravenous immuno-
`globulin
`
`Adjuvant therapy
`
`
`. affects
`* Anti-idioty
`
`
`« Blocks Fe
`« Alte
`
`+
`
`* Slows secondary progression
`Currently being studied in combination
`with IM IFINB-|a and corticosteroids
`* Short-term treatment for acute inflamma-
`tory dem yelnating polyneur Dopat ny
`e Ty tment and prevention of
`relapses in patients with treatment failures
`
`5 IrAVeNncas,
`
`ry Ft 4 = interferon:
`IM
`ntvramuscutar [Vv
`CNS = central nervous systery FDA=Food and Drug Adminstration GA=piatirar
`des
`rt
`sve myitioca leukoencephalopathy: SC = subcutaneous.
`MMP = main metalloprotease: MR)
`= magnene
`resonance imaging MS
`mpk
`
`Johns Hopkins Advanced Studies m Medicine
`
`279
`
`

`

`
`
`PROCEEDINGS
`
`mended for patients who have had an inadequate
`response to, or are unable to colerate, other primary MS
`therapies. In addition, mitoxantrone may be considered
`for worsening disease in selected relapsing patients or
`patients with SPMSwith or withoutrelapse. With anyof
`these therapies (with the exception of mitoxantrone),
`treatment must be sustained for years.
`When asked to choose between IFN, natalizumab,
`combination glatramer and IFN, cyclophosphamide,
`and monthly steroids as a therapy change for a patient
`currently receiving glatiramer, 46% ofsurveyed neurolo-
`gists selected IFN, 42% selected natalizumab, and 12%
`indicated combination glatiramer and IFN (#7 = 26).
`Discussions indicated that as safety data for natalizamab
`becomeclearer, it may become the preferred second-line
`drug for most patients. Although DMAs reduce the
`number of RRMSrelapses, 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
`therapy to 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 5000 patients, revealed no advantage to increasing 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 amongpatients with MS treated with either
`30 or 60 pg intramuscular IFNB-1a.”
`
`SWITCHING THERAPIES
`There are no current data from controlled, prospec-
`tive, direct-comparison clinical 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 no clinical benefit as a result of switching berween
`IFNs.” In QUASIMS, 4754 patients with RRMS who
`were enrolled in open-label studies of intramuscular
`IFNB-1a, 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 of relapse-free
`patients, annualized relapse rate, and reasons for changing
`therapies. Investigators concluded that switching between
`different IFNB agents provided noclinical 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 berween IFNB agents or between an
`IFNBagent and GA. Yer, 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
`changes with 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 immunosuppressant drugs (stage
`3A) and intravenous immunosuppressant agents (stage
`3B).
`In addition to disease-modifying combination
`therapies, several adjunctive medicationsare also used
`in MS to alleviate symptomssuch as spasticity, neuro-
`pathic pain, fatigue, and bladder dysfunction.
`As noted, pulsed corticosteroids are frequently used
`in combination with plattorm 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 potendal uses in combination with
`platform therapies. Agents that have been used in
`treating MSinclude 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 crials involving patients with RRMS,
`including studies of intramuscular IFNB-la plus GA
`compared with either agent plus placebo,” investigations
`of intramuscular IFNB-la 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 ro 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.“""
`
`CLINICAL DecISION MAKING
`
`Asa general rule, most compliant and noncompliant
`patients with MShave a positive opinion of the 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 or failure, 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, bur typically 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-
`apies, social workers, nurses, and other providers who
`have a good