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`Multiple Sclerosis Journal 22(11)
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`Visit SAGE journals online
`http://msj.sagepub.com
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`Multiple Sclerosis Journal
`2016, Vol. 22(11) 1402-1404
`DOK: 10.1177/
`1352458516649039
`© The Author(s), 2016.
`Reprints and permissions:
`http://www.sagepub.co.uk/
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`Correspondenceto:
`AE Miller
`Icahn School of Medicine
`at Mount Sinai, 5 East 98th
`Street, Box 1138, New York,
`NY10029, USA.
`Aaron.miller@ mssm.edu
`Aaron E Miller
`Icahn School of Medicine
`at Mount Sinai, NewYork,
`NY, USA
`
`1402
`
`5.
`
`6.
`
`Bermel RA and Naismith RT. Using MRI to make
`informedclinical decisions in multiple sclerosis care.
`Curr Opin Neurol 2015; 28: 244-249,
`
`Lublin FD, Cofield SS, Cutter GR,et al. Randomized
`study combining interferon and glatirameracetate in
`multiple sclerosis. Ann Neurol 2013; 73: 327-340.
`
`7.
`
`8.
`
`Tintore M, Rovira A,RioJ, et al. Defining high,medium
`and low impact prognostic factors for developing
`multiple sclerosis. Brain 2015; 138: 1863-1874.
`
`Brex PA, Ciccarelli O, O’ RiordanJI, et al. A longitudinal
`study of abnormalities on MRI and disability from
`multiple sclerosis. V Engl J Med 2002; 346: 158-164.
`
`Multiple sclerosis should be treated using
`a step-downstrategy rather than a step-up
`strategy—Commentary
`
`Aaron E Miller
`
`In this issue ofMultiple Sclerosis Journal, Prof. Gavin
`Giovannoni and Dr Robert Naismith have argued,
`respectively, that initiation of disease-modifying ther-
`apy (DMT) for multiple sclerosis (MS) should utilize
`a step-down approach(i.e. beginning with a high-effi-
`cacy induction strategy)! versus a step-up or escala-
`tion approach.This is a critically important issue as
`we all would like to be able to provide people with
`multiple sclerosis (PwWMS) the most effective, safe,
`and well-tolerated DMT possible. Both authors have
`provided cogent, but flawed, arguments in support of
`their positions.
`
`Prof. Giovannoni has eloquently emphasized the
`importance of “hidden”disabilities in MS,particularly
`the high prevalence of cognitive impairment, which
`occurs even very early in the disease process.>+
`Cognitive abnormality has been demonstrated for peo-
`ple with clinically isolated syndrome (CIS) and even
`for asymptomatic patients with the so-called radiolog-
`ically isolated syndrome. Giovannoninotes, for exam-
`ple,
`the very high rates of unemployment among
`PwMS,evenat times whentheir physical disability is
`modest as indicated by Expanded Disability Status
`Scale (EDSS) in the range of 3.0—-3.5 (or even less).
`He also points out the evidence for axonal loss early in
`the course of the illness. Indeed, this destruction of
`axons, often regarded as part of a neurodegenerative
`process, may be even greater in the early stages of
`MS.
`In making his argument
`for a step-down
`approach, Giovannoni focuses on an induction therapy
`with whathe regards as high-efficacy DMT,including
`treatments such as alemtuzumab,cladribine (an agent
`which has heretofore been denied approval by both
`American and European regulatory agencies), or
`hematopoietic stem cell therapy (a treatment that as
`
`yet has not been subjected to any definitive rand-
`omized controlled trial).
`Induction therapy in his
`descriptionis “given as a short course andhasthe abil-
`ity to induce long-term remission andthe possibility of
`a cure.” In his discussion, he neglects the possibility of
`high-efficacy therapies that do require continued
`administration, such as natalizumab or ocrelizumab.
`Thelatter is a humanized anti-CD20 monoclonal anti-
`body, which has recently had two highly successful
`phase III trials against interferon beta-la (IFNB-1la)
`thrice weekly as an active comparator® and will likely
`achieve approval
`from regulatory agencies in late
`2016 or early 2017.
`
`In advocating for his step-down approach, Giovannoni
`has essentially borrowed the “time is brain” concept
`from the stroke field, albeit on a longer time spec-
`trum. His argument that this strategy might preserve
`cognitive function may well be true, but, unfortu-
`nately, currently very little evidence exists to support
`its validity. This is certainly a hypothesis that is ame-
`nable to testing with the use of an adequate neuropsy-
`chological evaluation, rather than a single modality
`such as the Paced Auditory Serial Addition Test
`(PASAT)or the SymbolDigit Modality Test (SDMT).
`
`Most importantly, Giovannoni has neglected to con-
`sider safety issues in the choice ofthe initial DMT.
`While efficacy is very important, it must be balanced
`by acceptable risk. The high-efficacy strategies he
`advocates carry the risk of potentially very serious or
`even fatal adverse events. Alemtuzumab is associ-
`ated with serious autoimmunedisorders;”* cladribine
`raised safety concerns, particularly related to malig-
`nancies,’ for regulators; and hematopoietic stem cell
`transplantation (HSCT) continues to be associated
`
`IPR2023-00480
`
`hitp://msj.sagepub.com
`Merck 2078
`Hopewell v Merck
`
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`

`AE Miller
`
`to a
`with serious morbidity and mortality (albeit
`lesser extent in more recent studies) because of the
`profound immunosuppression or
`immunoablation
`involved,!®!2
`
`Declaration of Conflicting Interests
`The author(s} declared no potential conflicts of inter-
`est with respect to the research, authorship, and/or
`publication ofthis article.
`
`In stark contrast, Naismith emphasizes the safety
`and long experience with the injectable drugs. Both
`glatiramer acetate (GA) and IFNB preparations have
`been used extensively for more than 20years.
`Serious adverse events have been extremely unusual
`and, as Naismith points out, they “do not cause can-
`cers, opportunistic infections, or secondary autoim-
`munediseases, nor ... teratogenicity.”
`
`Doesthis edgein safety, justify the use of these less
`effective agents asinitial therapy for relapsing multi-
`ple sclerosis (RMS)? Naismith emphasizesthe effi-
`cacy of interferon and GA whenusedvery early in the
`course of MS,specifically in patients with CIS and in
`those with favorable clinical and magnetic resonance
`imaging (MRI) prognostic features. Yet, these prog-
`nostic features are fallible and many patients initiate
`DMTwhenthey already have a diagnosis of definite
`MS.Ina recenttrial comparing alemtuzumabto thrice
`weekly IFNB-1a, the annualized relapse rate with the
`former (0.18) was less than half that of the latter
`(0.39).? In the CombiRx trial'3 cited by Naismith,
`23%-25% ofpatients treated with IFNB, GA,or the
`combination experienced confirmed disability pro-
`gression overthe 3-year periodofthe trial. And thisis
`a measure only of physical neurological disability
`without consideration of cognitive change.
`
`At this time, then, the controversy posed about the
`correct strategy for initiation of DMT in RMSpatients
`cannot be resolved.A clinicaltrial could be designed
`to address this question by assigning one group of
`patients initially to high-efficacy therapy and another
`to other drugs, allowing for step escalation. However,
`the answer would requirea longtrial that should prop-
`erly include a multi-dimensional cognitive battery.
`
`In the meantime, how should clinicians advise PWMS
`about the wisest course of action when initiating a
`DMT? Thephysician should havea very frank discus-
`sion abouttherisks of the respective agents, as well as
`abouttheefficacy data. Consideration should be given
`to the prognostic factors in the individual’s situation
`and this information should be utilized to help the
`patient select the initial therapy in a process of shared
`decision making, In all cases, the importance of close
`follow-up and regular monitoring, both clinically and
`by MRI, should be emphasized in order to determine
`the need foralternate therapy in a timely manner.
`
`Funding
`The author(s) received no financial support for the
`research,authorship, and/or publication ofthis article.
`
`References
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`using a step-down strategy rather than a step-up
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`
`2. Naismith RT. Multiple sclerosis should be treated
`using a step-down strategy rather than a step-up
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`
`3. Feiullet L, Reuter F, Audoin B,et al. Early cognitive
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`9. Giovannoni G, Comi G, Cook§,et al. A placebo-
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`Multiple Sclerosis Journal 22(11)
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`hematopoietic cell transplantation for relapsing-
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`
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