Presse Med.

2015; 44: e137–e151

on line on
www.em-consulte.com/revue/lpm
MULTIPLE SCLEROSIS
www.sciencedirect.com

Quarterly Medical Review

Update on treatments in multiple sclerosis

Laure Michel, Catherine Larochelle, Alexandre Prat

Available online: 23 March 2015 Université de Montréal, faculté de médecine, centre de recherche du CHUM,
département de meuroscience, unité de recherche en neuro-immunologie, H2X0A9
Montréal, Canada

Correspondence:
Alexandre Prat, CRCHUM, 900, rue Saint-Denis, 9e étage, H2X0A9 Montréal, Québec,
Canada.
a.prat@umontreal.ca

Summary
In this issue
Multiple sclerosis: from new
While there is no cure for multiple sclerosis (MS), numerous disease-modifying drugs are now
concepts to updates on available to treat MS patients. In fact, the therapeutic strategies are now more and more complex,
management directly impacting the management of patients. Despite the good safety profile of the first-line
David-Axel Laplaud, Nantes,
France
immunomodulatory drugs, the clinical response is often suboptimal. Important questions remain
about the right timing to switch for a second-line agent and whether escalation therapy is an
The autoimmune concept of
multiple sclerosis appropriate therapeutic strategy. In this review, we conducted a systematic search by PubMed
Bryan Nicol et al., Nantes, using the terms: treatment, multiple sclerosis, therapeutic, DMT and treatment response. Ran-
France domized trials and reviews addressing MS, DMTs and management strategies were selected and
Environmental factors in included in this review. Herein, we present the currently approved and emerging drugs used for
multiple sclerosis the treatment of MS with their relative benefit/risk profiles, and their respective positions in the
Vasiliki Pantazou et al.,
Lausanne, Switzerland therapeutic arsenal. We then focused on the different therapeutic strategies and criteria available
Update on clinically isolated
to evaluate the response to disease-modifying therapies (DMTs).
syndrome
Eric Thouvenot, Nimes, France

R
Update on treatments in
multiple sclerosis
Laure Michel et al., ecent decades have seen considerable advances in our understanding of the natural history
Montréal, Canada
of multiple sclerosis (MS). Correlations between different clinical or radiological inflammatory
Treatment of multiple parameters in the early phase of the disease and the long-term cumulative deficits in the chronic
sclerosis in children and its
challenges phase of the disease are now well established. From a radiological point of view, T2 lesion load at
Sona Narula et al., the beginning of MS is predictive of the disability at 5 years [1] and 20 years [2]. From a clinical
Philadelphia, United States point of view, the interval between the first two relapses as well as the number of relapses during
Advanced imaging tools to the first two years are associated with a shorter duration to attain EDSS (Expanded Disability Status
investigate multiple Scale) 3 or 4, and 6 or 7 [3,4]. Active control of the early inflammatory phase of the disease is
sclerosis pathology
Benedetta Bodini et al., therefore considered to prevent or delay the late progression phase. While there is no cure for MS,
Paris, France numerous disease-modifying drugs are now available to treat MS patients, making the appropriate
Update on rehabilitation choice of therapy more and more complex. Despite the good safety profile of the first-line
in multiple sclerosis immunomodulatory drugs, the clinical response is often suboptimal. Important questions remain
Cécile Donzé, Lille, France
about the right timing to switch for a second-line agent and whether escalation therapy is an
e137

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http://dx.doi.org/10.1016/j.lpm.2015.02.008
© 2015 Elsevier Masson SAS. All rights reserved.
 L. Michel, C. Larochelle, A. Prat
appropriate therapeutic strategy. Herein, we present the cur-
rently approved and emerging drugs used for the treatment of
relapsing MS, focusing on the different therapeutic strategies
and criteria available to evaluate the response to disease-
modifying therapies (DMTs).
Methods
We conducted this review using a comprehensive search of
PubMed with the following search terms: treatment, multiple
sclerosis, therapeutic, DMT and treatment response.
Randomized trials and reviews addressing MS, DMTs and ma-
nagement strategies were selected and included in this review.
Medication approved for the treatment of
MS
Approved disease-modifying treatments in multiple sclerosis
are detailed below [5–54] and summarized in electronic sup-
plement (annex 1).
Glatiramer acetate
Glatiramer acetate (GA) is an immunomodulatory agent and a
synthetic copolymer made of four distinct amino acids randomly
assembled: Glutamic acid, Lysine, Alanine and Tyrosine. GA
20 mg sub-cutaneously (SC) every day is approved for the
treatment of both relapsing-remitting MS (RR-MS) and clinically
isolated syndrome (CIS). GA does not affect the number of
circulating lymphocytes but switches lymphocyte polarization
from a pro-inflammatory TH1 to an anti-inflammatory TH2
profile. Recently, generic GA formulation trial GATE concluded
to similar efficacy as compared to Copaxone® [55]. The lower
frequency regimen of GA 40 mg SC 3  weekly (tiw) has dem-
onstrated superiority to placebo at 6 and 12 months both in
terms of annualized relapse rate (ARR) and cumulative number
of active lesions. GA 40 mg SC tiw displayed the same safety
profile as the 20 mg daily formulation, leading to its acceptance
by the FDA [12]. GA is a generally well-tolerated and safe
injectable medication with no known drug interactions. Local
post-injection reaction is the most frequent adverse event. GA is
considered to be a safe DMT even in early pregnancy [56–59],
although most clinicians will stop the use of any DMT, including
GA, during the childbearing period. There is no apparent impact
of paternal exposure to GA on birth outcome or child health
[60,61]. Finally, while anti-GA IgG antibodies form in most
patients, they do not seem to affect drug efficacy [62].
Interferons beta
Interferons b (INFb) are immunomodulatory medications
approved for the treatment of RR-MS, CIS and secondary pro-
gressive (SP)-MS patients. IFNbs have a limited capacity to
reduce the number of circulating lymphocytes. Both IFNb-1a
and IFNb-1b are considered safe injectable therapeutic options
with limited drug interactions. The most frequent adverse
events of IFNb treatment are benign but annoying flu-like
e138
symptoms (30–60% of patients) that can be alleviated by the
use of acetaminophen or ibuprofen [6,63], and liver enzyme
abnormalities. Long-term discontinuation rate of standard for-
mulations of IFNb is over 20% across all marketed agents [6,63].
The new pegylated IFNb-1a formulation, which is administered
at a dose of 125 mg SC every two weeks, has demonstrated
superiority to placebo in terms of relapse rate, EDSS score and
radiological parameters [26] (ATTAIN study extension for long-
term dose frequency ongoing) and will hopefully improve
adherence. As for GA, recent observational studies have shown
that IFNb are relatively safe before or during pregnancy, but
some conflicting data suggests a potentially increased rate of
spontaneous abortion and of preterm birth in women taking
IFNb during pregnancy [57,64–68]. No apparent significant
impact of paternal exposure is reported [60,61]. Patients on
IFNb can develop neutralizing Abs (Nabs) against IFNb. How-
ever, the use of Nabs titer to guide clinical decision in case of
suboptimal response is becoming less relevant in the view of the
many therapeutic options now available [13,69]. However,
recent guidelines suggest that high titers of Nabs 12–24 months
after initiating therapy should guide to a switch from IFNb to
another class of DMT, even in the absence of significant disease
activity [70,71].
Teriflunomide
Teriflunomide is an oral DMT approved for the treatment of RR-
MS [72]. As inhibitor of pyrimidine synthesis, teriflunomide is
known to reduce the number of circulating leukocytes, but
displays a relatively good safety profile [27]. Significant adverse
events include hepatotoxicity and infections, which seem to be
more frequent than with GA or IFNb. Immunization during
teriflunomide therapy is efficient, but live vaccines should be
avoided [62]. Numerous drug interactions are reported, includ-
ing with warfarin, CYP inducers, substrates of CYP2C8 and many
other medications such as some of the oral anti-diabetic agents,
statins and antibiotics (EMA website). In view of the drug
interaction profile and the reported risk of peripheral neuropa-
thies, teriflunomide should be used with caution in diabetic
patients, as is leflunomide [73]. Moreover, teriflunomide is
labeled as a teratogenic medication (class X) [74] in women
and possibly also in men. As elimination of teriflunomide can
take up to two years, accelerated elimination using cholestyr-
amin 8 g tid for 11 days or activated charcoal 50 g bid for 11 days
is therefore warranted before conception for both females and
males. A similar clearance regimen is suggested before switch-
ing from teriflunomide to another DMT with immunosuppressive
properties [60,74].
Dimethylfumarate
Dimethylfumarate (DMF) is an oral immunomodulatory DMT
approved for the treatment of RR-MS and CIS patients (FDA,
Health Canada and EMA website). DMF has the capacity to reduce
the number of circulating lymphocytes, and lymphopenia can
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Update on treatments in multiple sclerosis
be significant in some individuals. Administration of live
attenuated vaccines is not recommended during therapy. DMF
has no known drug interactions and demonstrate an intermediate
risk of adverse events. Although rare, the use of DMF can be
associated with the development of progressive multifocal leu-
koencephalopathy (PML), an opportunistic demyelinating viral
disease of the CNS, in both MS and in psoriasis [34,75]. Gastroin-
testinal symptoms (abdominal discomfort or pain and diarrhea)
as well as flushing are seen in more than 25% of patients during
the first trimester of therapy, leading to discontinuation in 12–16%
of patients as compared to 10–13% for placebo [76]. Animal
studies suggest some adverse impact of DMF on developing
fetuses [60,76]. A washout period of 1 month is recommended
before conception, although DMF is virtually eliminated from
the circulation after 24 h.
Fingolimod
Fingolimod is a Sphingosine-1-Phosphate receptor agonist and a
generally well-tolerated oral DMT. Fingolimod reduces the num-
ber of circulating lymphocytes. In view of potential serious
cardiac, hepatic, infectious and ocular complications, treatment
with fingolimod requires significant work-up and monitoring
and needs to be used with caution in patients with a history
of cardiac or ocular disease, including diabetic patients [75,77].
Numerous drug interactions with other medication and natural
products, mainly antiarrhythmic agents and immunosuppres-
sants are reported and limit the clinical use of fingolimod.
Congenital malformations are reported to be more frequent
in fetuses exposed to fingolimod and a washout period of
2 months before pregnancy is indicated [78,79]. Administration
of live attenuated vaccines is not recommended during therapy
[62]. Noteworthy, rebound activity or MS reactivation after
discontinuation of fingolimod has been observed, albeit this
phenomenon is relatively rare [77].
Natalizumab
Natalizumab (NTZ) is a humanized monoclonal Ab directed at
the adhesion molecule VLA-4. It is a well-tolerated DMT, which
displays no significant drug interactions, but should not be used
in combination with other DMT or immunosuppressors. NTZ is
associated with a non-negligible risk (overall risk of 1/200, as of
September 2014) of serious infections, especially the JC virus-
induced PML. Twenty to 25% of patients developing PML have
died, and survivors remain with mild to severe disability ([80],
Biogen-Idec). PML risk stratification can be achieved by using
two independent predictive factors in patients JCV (+): the
previous exposure to immunosuppressive agents, and the dura-
tion of treatment with natalizumab (see table I) (FDA and EMA
website). The anti-JCV Abs index may also help to differentiate
patients with a higher risk of PML (index above 1.5) but only in
patients without prior use of immunosuppressive drugs [81]. In
case of seropositivity, most experienced MS specialists will
discontinue NTZ therapy after two years of treatment. NTZ is
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MULTIPLE SCLEROSIS
TABLE I
Estimation of the risk of PML in natalizumab (NTZ) treated patients
Duration of NTZ Prior IS exposure
therapy (months)
No Yes
0–24 0.7 (0.5–1) 1.8 (1.1–7.2)
25—48 5.3 (4.4–6.2) 11.2 (8.6–14.3)
49–72 6.1 (4.8–7.8) Insufficient data
Risk estimates are expressed per 1000 treated patients (95% CI) and were updated
September 1, 2013.
For JCV negative patients: risk is estimated at 0.1 per 100.
IS: immunosuppressive drugs; JCV: JC virus; PML: progressive multifocal
leukoencephalopathy.
not recommended during pregnancy, but fetuses exposed to
NTZ during first trimester display no major health issues so far
[82]. Moreover, NTZ has been used for highly active MS during
third trimester, resulting in transient mild to moderate hemato-
logic abnormalities in the newborns and one subclinical bleed-
ing complication [83]. NTZ cessation can be associated with
severe MS reactivation or MS rebound activity and necessitates
a close monitoring [84,85]. Introduction of a new immunomod-
ulatory agent less than 2 months after last infusion is therefore
now recommended (see section on washout).
Alemtuzumab
Alemtuzumab is a monoclonal antibody directed against CD52.
Alemtuzumab is given IV for a total of 8 days over 2 years and is
associated with infusion reactions in virtually all patients. Slow
(over 4 h) infusion and premedication with methylprednisolone
1 g for the initial 3 days of each course of treatment, and with
acetaminophen and diphenhydramine, is recommended to
decrease the severity of these infusion reactions [86]. Alemtu-
zumab is associated with herpes exacerbations; acyclovir
200 mg bid or equivalent for 1 month starting on the first
day of each treatment course is recommended. Autoimmunity
is the major drawback of alemtuzumab, with as much as 48% of
patients developing clinical autoimmune disease in a long-term
follow-up study [87]. Graves' hyperthyroidism, hypothyroidism
and subacute thyroiditis are the most frequent autoimmune
disorders, found in 34–41% of patients [87,88]. Autoimmune
cytopenias and nephropathies are rare but also reported. Fre-
quent infections are nasopharyngitis, urinary tract infections,
upper respiratory tract infection, sinusitis, oral herpes, influenza
and bronchitis as well as oral and vaginal candidiasis. Serious
infections included appendicitis, gastroenteritis, pneumonia,
herpes zoster and dental infection. Most patients will develop
antibodies to alemtuzumab without any observed clinical
impact. Due to the incidence of serious autoimmune and infec-
tious complications, patients who may not be fully committed to
e139
 L. Michel, C. Larochelle, A. Prat
the prolonged and demanding monitoring after alemtuzumab
infusions should not receive the drug. Pregnancy should be
avoided for at least 4 months following infusion of alemtuzu-
mab; outside of this period, fertility and pregnancy do not
seem affected by previous alemtuzumab treatment [87].
Administration of live attenuated vaccines is not recommended
during therapy.
Mitoxantrone
Mitoxantrone is a type 2 topoisomerase inhibitor with proven
efficacy in MS with very active disease [52,89]. Mitoxantrone
conveys a risk of serious irreversible adverse effects including
heart failure and acute leukemia. To limit the morbidity of the
drug, the maximum dose per month is 20 mg, and the maximal
cumulative lifetime dose is 120 mg or 72 mg/m2. Nevertheless,
incidence of cardiotoxicity on echocardiogram is estimated at
4.1% (assessed on left ventricular fraction < 50%) [90] or 14%
[91] (assessed as a 10% reduction of left ventricular ejection
fraction). Incidence of leukemia ranges between 0.25–0.8%
[91–96]. Mitoxantrone is teratogenic and can cause persistent
amenorrhea especially in women older than 25 years old
[94,97]. Moreover, previous exposure to mitoxantrone increases
the risk of PML in individuals on NTZ (see NTZ section) and
probably on other immunosuppressive DMTs. Taken together,
the long-term effects of mitoxantrone warrant caution when
considering mitoxantrone early in the course of the disease.
Administration of live attenuated vaccines is not recommended
during therapy.
Comparison of DMTs
First-line agents
In RR-MS patients, four classes of DMTs are actually available as
first-line therapies: interferons beta and glatiramer acetate,
injectable DMTs available for more than 15 years, and teriflu-
nomide and dimethylfumarate, newcomer oral DMTs (annex 1).
Comparison of the different IFNb formulations, although not
based on reliable double-blinded head-to-head trials, seems to
favor SC preparations regarding efficacy as well as incidence of
flu-like symptoms, while injection site reactions and develop-
ment of Nabs would be less frequent with IM preparation
[6,63,98,99]. The IFNb-1a SC formulation might be associated
with higher although very rare incidence of thrombotic micro-
angiopathy [100,101]. Differences between the IFNb formula-
tions are however generally not considered clinically significant.
While comparison studies were either post-hoc, unblinded or
small, and are therefore arguably reliable, no significant differ-
ence in terms of clinical and radiological efficacy has been
demonstrated between IFNb and GA [63,98,99,102–105]. A
recent phase III study (TENERE) has demonstrated similar impact
of teriflunomide 14 mg and IFNb on MS clinical activity as
defined by the time to first relapse and the annualized relapse
rate in a cohort of 324 patients [31]. For DMF, the phase III trial
e140
(CONFIRM) compared DMF to placebo and GA to placebo [36].
Post-hoc comparisons of DMF versus GA revealed significant
differences concerning the MRI criteria with a superiority of
DMF over GA. However, this study was not designed to test
the superiority or non-inferiority of DMF compared to GA.
The choice of a first-line agent will therefore be guided by the
profile of side effects, the patients' convenience but also by the
desire of pregnancy.
Combination strategies are widely used in other medical fields
such as rheumatology or cancer. In MS however, the CombiRx
study has analyzed the effect of the association of IFNb-1a and GA
and has found no significant advantage of the combination
therapy over the others arms [102]. Moreover, even if the associ-
ation of therapies with different mechanisms of actions would
seem attractive in theory, safety and costs remain major concerns.
Second- and third-line agents
Fingolimod, natalizumab and alemtuzumab are agents that
have proven therapeutic superiority to selected first-line agents.
Mitoxantrone has also proved to be superior to IFNb, but as an
induction therapy [89] (see section on induction therapy).
The TRANSFORMS study has demonstrated the superior efficacy
of oral fingolimod as compared with IFNb-1a in terms of relapse
rates and MRI outcomes in a cohort of 1153 patients [41]. No
clinical trial has compared the efficacy of NTZ over first-line
medication. SENTINEL has demonstrated the higher efficacy of
adding NTZ to IFNb-1a, as compared to IFNb-1a alone in a cohort of
MS patients who presented a treatment failure under IFNb-1a
[45]. Significant adverse events, including 2 cases of PML, how-
ever occurred and combination is therefore contra-indicated. As
compared to IFNb-1a, alemtuzumab significantly reduced the
risk of disability by 42% in CARE MSII and by 75% in CAMMS223,
and also significantly reduced the relapse rate by 49 to 69% in
these different studies. An extended long-term follow-up with a
median of 7 years follow-up revealed an improvement or stability
of the disability in 60% of patients [87].
Comparative analyses of the efficacy of 2nd line agents have not
been performed. In one multicenter observational study of MS
patients treated with either by NTZ or fingolimod, treatment
outcomes were similar, however the baseline characteristics of
the patients were different [106]. Another observational study
comparing NTZ versus fingolimod was recently published [107].
The authors selected only patients for whom JCV serology was
used to decide treatment to ensure similar baseline character-
istics. Adjusted analyses found significant differences favoring
NTZ concerning clinical and MRI criteria. No studies have yet
compared NTZ vs. alemtuzumab.
Therapeutic strategies
Initiating therapy with DMTs: a shared decision
Two contrasting treatment strategies exist when initiating treat-
ment with DMTs in MS: escalation and induction. Decisions
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Update on treatments in multiple sclerosis
MULTIPLE SCLEROSIS

regarding the best therapeutic plan for individual MS patient are
based on past and current disease activity (clinical relapses,
new/enlarging or enhancing lesions on MRI), on burden of
disease (cognitive status, EDSS, total lesion load, brain atrophy)
but also by the profile of adverse events of the different DMTs,
the patient's preference and the neurologist's experience.
In this section, we will review the different general therapeutic
strategies used in MS and their indications.
Therapeutic escalation
Therapeutic escalation (figure 1) is underpinned by a strong
rationale that treatment has to start with drugs considered
safe before moving to more "aggressive'' therapies which are
more efficient but carry a risk of potentially severe or irreversible
adverse events. This strategy is probably most suitable for
patients presenting with early MS, with low to moderate disease
activity and burden of disease, and expressing concerns regard-
ing the safety profile of second- and third-line therapies. In
these patients, it seems reasonable to start with DMTs displaying
a good safety profile, and to be ready to switch to a different
agent in case of lack of tolerance or of efficacy. This strategy
requires to monitor clinically and radiologically the patient to
identify early signs of breakthrough disease that would be
considered as a suboptimal response or a treatment failure.
Indeed, one of the keys of success in the escalation therapy
is most likely to be able to identify not only a failure of treatment
but also a suboptimal response that can predict a less favorable
evolution of the disease.
How to define a suboptimal response of treatment?
As treatment may be especially beneficial early in the course of
MS, rapid identification of non-responders is crucial to deter-
mine the need for a therapeutic switch. The evaluation of the
response to therapy relies on outcome measures that may
directly or indirectly reflect the progression of a disease. A clear
and consensual definition of a lack of response to the immu-
nomodulatory drugs in MS does not exist, but numerous studies
have suggested some criteria [108–117].
In 2006, Rio et al. have evaluated the clinical criteria, which
would allow early identification of non-responders to IFNb, and
then could be used to predict the long-term disability status at
6 years. They analyzed different criteria based on relapses,
disability progression, or both [118]. In this study, after two
years of treatment the proportion of non-responders ranged

Figure 1
Escalation therapy in multiple sclerosis patients
Three approved lines of therapies can be proposed in multiple sclerosis. The first-line agents include safe immunomodulatory drugs (interferons, glatiramer acetate and
teriflunomide). In case of failure, different second-line agents can be proposed depending of the level of concern (LOC): in case of low/medium LOC: a switch for dimethyl
fumarate, fingolimod or another first-line drug can be legitimate, in case of medium/high LOC, an escalation for natalizumab or mitoxantrone is recommended. A third-line
therapy is now available with alemtuzumab and can be proposed in case of suboptimal response with a second-line drug. Some experimental therapies can sometimes be
proposed in some selected patients with highly active and refractory disease.
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 L. Michel, C. Larochelle, A. Prat
from 7 to 49% of patients depending on the stringency of the
criteria used. Criteria based on disability progression (increase of
at least one EDSS step confirmed at 6 months) showed higher
sensitivity, specificity and accuracy for notable disability after
6 years of treatment than relapse-based criteria. Therefore,
disability progression is probably more relevant than relapse
rate to define a failure of IFNb.
As regards radiological criteria, different studies have suggested
that the presence of gadolinium-enhancing lesions or of new T2
lesions while on IFNb therapy predicts poor long-term response
to treatment and future clinical worsening [2,117,119–122]. In
the same way, the analysis of the longitudinal relationship
between MRI lesions and clinical course over a period of 20 years
has revealed that the change in the volume of lesions during
the first years of the disease is correlated with disability after
20 years [2].
Current recommendations of EMA concerning second-line drugs
include some definitions of "non-responders''. MS patients are
considered as non-responders if after one year of treatment with
IFNb they presented at least one relapse in the previous year
while on therapy and at least nine T2 lesions or one gadolinium-
enhancing lesion on brain MRI (EMA website).
Apart from the EMA, several formal monitoring strategies and
algorithms have been proposed. The Canadian Multiple Sclerosis
Working Group (CMSWG) has published in 2004 and 2013 prac-
tical guidelines to categorize patients with MS receiving DMT by
level of concern (LOC) [69]. In these guidelines, relapse occur-
rence, EDSS progression and MRI evolution are monitored and
the LOC is described as none, low, medium or high. A change of
treatment should be considered if there is a high level of concern
in any one domain, a medium level of concern in any two
domains, or a low level of concerns in the three domains. In
the revised recommendations, the CMSWG also suggests to test
TABLE II
Summary of the criteria used to define a suboptimal response to interferon in MS patients
Canadian Multiple Sclerosis
Working Group (CMSWG)
Clinical criteria Relapses (rate, severity, recovery)
Progression (EDSS, time 25 foot walk)
MRI criteria New Gd+ enhancing lesions/year
New T2 lesions/year
Others criteria Cognition with SDMT before and every 2 or 3 years
Neutralizing Abs
Levels of concerns Low/medium/high
EDSS: Expanded Disability Status Scale; MS: multiple sclerosis; SDMT: Symbol Digit Modalities Test.
e142
cognitive functions using the Symbol Digit Modalities Test at
least every two or three years. The International Working Group
for Treatment Optimization in MS has also formulated some
guidelines concerning suboptimal response [123,124]. They
recommend waiting at least 6 to 12 months to assess efficacy.
The monitoring strategy focuses on the usual parameters
(relapse, disability and MRI) to categorize patients in one of
3 levels of concern (table II). The timing of follow-up visit is
usually every six months, or every 3 months in case of important
signs of disease activity. The first MRI following initiation of
treatment can be performed at one year to evaluate disease
activity and also the long-term prognosis.
Management of treatment failure
Suboptimal response to a first-line DMT warrants either a lat-
eral/transversal switch in some cases with low to moderate LOC
(from one first-line immunomodulatory treatment to another
one) or a vertical switch (therapeutic escalation) in more aggres-
sive cases with moderate to high LOC (from a first-line to a
second- or third-line therapy).
Transversal switch
Switching from a first-line DMT to a different first-line DMT can
represent an acceptable strategy after treatment failure or lack
of tolerability [125–128] (figure 1). There are few data avail-
able concerning the benefit of these switches. Recently, a
Spanish observational study has reported the clinical outcome
after switching from a first-line DMT because of a treatment
failure in 180 patients [129]. Half of these patients switched to
another first-line drug, the other half to a second-line therapy.
Concerning the "first-line switch'' (i.e. IFNb/IFNb, IFNb/GA,
GA/IFNb), all the groups presented a significant reduction of
their ARR after the switch and more than 60% of patients
showed an absence of clinical disease activity. Therefore, it
International Working Group for
treatment optimization in MS
Relapses (rate, severity)
Progression (EDSS over 2 years)
New Gd+ lesions
New T2 lesions
New T1 hypointense lesions
Depression, fatigue
Pain, spasticity
Sexual dysfunction
Quality of life, cognition
Noteworthy/worrisome/actionable
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Update on treatments in multiple sclerosis
seems that in MS patients with a low to medium level of
concern, offering a transversal switch from one first-line DMT
to another is an adequate option.
Vertical switch (escalation)
For patients in whom a worrisome breakthrough of disease
activity has occurred while on first-line therapy, escalation to
more aggressive but often less innocuous second-line drugs
such as fingolimod, NTZ or mitoxantrone can be considered
(figure 1). The choice of therapy will be guided by different
determinants: the level of concern (LOC) regarding the risk of
MS worsening, the potential adverse events associated with the
medications and the age and medical history of the patient.
If the LOC is deemed low to medium, escalation to fingolimod is
a legitimate option. Fingolimod has proven its superiority as
compared to IFNb-1a in the TRANSFORMS study (see "compar-
isons of DMTs''). In the extension study [130], patients who had
been treated first with IFNb-1a were reassigned after one year
to fingolimod for one year. The relapse rate, the number of new
T2 lesions and the number of gadolinium-enhancing lesions
decreased significantly after switching, as compared to the year
under IFNb-1a. Moreover, post-hoc subgroup analyses of
FREEDOMS and TRANSFORMS [131,132] have revealed that in
patients who were considered non-responders to previous IFNb
therapy (defined by both relapses and MRI activity), fingolimod
significantly reduced the ARR as compared to IFNb-1a or pla-
cebo. Recently, an interesting retrospective study in MS patients
switching from IFNb to GA or fingolimod in a real-world setting
has reported that patients who switched to fingolimod were
significantly less likely to experience relapses than those who
switched to GA [133]. Whether these results can be generalized
to all first-line DMTs remains unknown. Post-marketing studies
are needed to answer these questions.
In case of medium or high LOC, more aggressive therapies such
as NTZ and mitoxantrone are valuable second-line options. NTZ
has indeed been approved in case of failure of IFNbs or GA,
while the chemotherapeutic agent mitoxantrone is approved for
MS patients (RR and SP-MS) with rapidly worsening disease.
There are currently no randomized prospective controlled stud-
ies comparing NTZ in monotherapy to other DMTs. Several
observational studies have reported the efficacy of NTZ in
patients presenting a suboptimal response to IFNb or GA
[128,134–137]. These studies conclude to a clinical and radio-
logical improvement after switching from IFNb or GA to NTZ.
For mitoxantrone, two published randomized clinical trials
[52,53] have analyzed the benefit of mitoxantrone therapy
versus placebo in rapidly worsening RR and SP-MS. Edan
et al. showed a significant benefit in 42 MS patients after
6 months of treatment, based on analysis of MRI criteria, relap-
ses and EDSS score. A prospective study comparing a 3 years of
treatment with NTZ to 6 months on mitoxantrone followed by a
maintenance therapy with any first-line DMD is currently ongo-
ing in RR-MS patients (IQALY-SEP study).
tome 44 > n84 > avril 2015
MULTIPLE SCLEROSIS
Alemtuzumab has also demonstrated its efficacy in patients
showing breakthrough MS activity on first-line DMTs. In CARE
MS II, non-responders to IFNb or GA were assigned to alemtu-
zumab (12 or 24 mg), IFNb-1a or placebo [48]. A statistically
significant reduction in ARR, sustained disability, and new
enhanced lesions over 24 months was observed in favor of
alemtuzumab versus IFNb-1a. However, in light of the high
incidence of significant secondary autoimmune diseases follow-
ing treatment with alemtuzumab, the authors would rather
consider it as a third-line agent.
Induction therapy
When?
Immunosuppressive or immune ablative medications currently
available for the treatment of MS patients are associated with
serious and irreversible side effects. Induction strategy is there-
fore generally reserved to patients with very active and aggres-
sive disease. Indeed, in this group of patients, the risk of rapidly
progressive and definitive disability outweighs that of adverse
events associated with more intense immunosuppression or
immunoablation. Once disease control has been achieved, a
maintenance therapy with a safer drug is performed.
Early inflammatory activity (clinical and radiological) is
strongly related to the risk of long-term disability and with
future development of SP-MS [2,4,138]. Epidemiological data
suggest that MS present a two stage course: a first phase
where focal inflammation influence disability progression,
and a second phase during which disability progression seems
less dependent on focal inflammation [4]. MS patients who
present frequent relapses and an important accumulation of T2
lesions during the first years of the disease become disabled
more quickly, as compared to patients who do not [2,4,138]. In
this group of active MS patients, an induction therapy needs to
be considered.
Which drug?
In MS, induction has been studied using different drugs: mitox-
antrone, NTZ, alemtuzumab and fingolimod.
Mitoxantrone
A first randomized clinical trial has assessed in 1997 the short-
term benefits of a six-month treatment by mitoxantrone vs.
placebo in a small group of patients with very active RR-MS or
SP-MS [52]. Mitoxantrone significantly decreased the relapse
rate, the number of enhancing lesions, and also provided some
improvement in the EDSS score. A phase III trial published in
2002 has confirmed these results in SP-MS and RR-MS patients
with active and relatively severe disease [53]. Another random-
ized clinical trial published in 2011 has compared a six-month
induction with mitoxantrone followed by a maintenance ther-
apy with IFNb-1b to a treatment by IFNb-1b, in a group of active
RR-MS patients. The 3-year risk of sustained worsening of
disability was reduced by 65% in the mitoxantrone group,
and the ARR and T2 lesions accumulation were also significantly
e143
 L. Michel, C. Larochelle, A. Prat
reduced [89]. Similar data were obtained when using the GA
instead of IFNb [139]. The induction strategy by mitoxantrone
followed by GA was found to be safe and effective with a
sustained decrease of MRI activity.
Natalizumab
AFFIRM and SENTINEL studies have shown that NTZ was effective
both as monotherapy and in combination with IFNb in patients
with relapsing MS. A post-hoc analysis was conducted to
determine the efficacy of NTZ in patients who presented a
highly active disease (i.e.  2 relapses in the year before study
and > 1 Gd+ on MRI) [140]. They found that NTZ significantly
reduced the risk of disability progression by 64% and relapse
rate by 81% in treatment-naïve patients with highly active
disease and by 58% and 76%, respectively, in patients with
highly active disease despite IFNb-1a treatment. These results
pointed to the important efficacy of NTZ in rapidly worsening
RR-MS.
Fingolimod
As for NTZ, fingolimod has two main indications: failure on
first-line DMTs and rapidly worsening RR-MS patients. Indeed,
subgroup analyses of ARR and confirmed disability progression
over 24 months have been performed in the FREEDOMS study.
Subgroups were defined according to demographic and dis-
ease characteristics but also to response to previous therapy.
The authors have shown that in treatment-naïve patients with
rapidly evolving severe disease, ARR was significantly reduced
on fingolimod by 67% versus placebo over 24 months [131].
However, the risk of disability progression was not significan-
tly lower in the fingolimod group as compared to placebo.
Overall, this sub-analysis suggested that rapidly worsening
RR-MS patients could directly benefit from fingolimod as first-
line therapy.
Alemtuzumab
Alemtuzumab is also foreseen as a good candidate for induction
therapy in MS. In a phase II randomized double-blinded trial
published in 2008 comparing alemtuzumab to IFNb-1a [141],
alemtuzumab has significantly reduced the rate of sustained
accumulation of disability by 75% as compared to IFNb-1a as
well as the ARR and the lesion burden. The 5-year extension
phase has demonstrated a 72% lower risk of accumulation of
disability and a reduction of 69% in ARR as compared to IFNb-1a
[48]. The phase III study CARE MS I has found a superiority of
alemtuzumab as compared to IFNb-1a over 2 years with respect
to ARR (decrease of 55%) and to MRI outcomes [49]. However,
even if the risk of disability lasting for at least 6 months was
lower in the alemtuzumab group compared with interferon beta
1a, the difference was not statistically significant.
The incidence of serious and persisting adverse events fol-
lowing use of alemtuzumab limits its use as an induction
agent to a selected population of patients presenting with an
unusually aggressive disease course, and only after careful
e144
consideration of the risks and benefits of alemtuzumab as
compared to other DMTs.
Which drug in relay?
After induction therapy, the question of maintenance therapy
remains an important problem. In two distinct trials, the efficacy
of maintenance therapy with IFNb [89] or GA [139,142] has
been evaluated following induction with mitoxantrone. Both
trials have reported a good and persistent efficacy after 3 years
[89] and 15 months of treatment [139,142].
As for NTZ, the central issue remains the risk of rebound MS
activity immediately following discontinuation of NTZ [143,144].
It remains actually unclear which drug should be used and
within which time period it would need to be initiated to
suppress rebound activity without leading to overwhelming
CNS immunosuppression. Recently, a randomized non-blinded
placebo-controlled study (RESTORE) has evaluated disease activ-
ity in patients undergoing discontinuation of NTZ, as well as the
clinical efficacy of IFNb-1a, GA or methylprednisolone (MP) to
prevent rebound activity. Placebo-treated patients showed a
clinically significant increase in MRI activity (46%) and in relap-
ses (17%) within 4–12 weeks after discontinuation of NTZ. While
IFNb-1a appeared to be efficient to control MRI-based indices
of disease activity (MRI recurrence: 7%), when compared to GA
(MRI recurrence: 53%) or MP (MRI recurrence: 40%) [144], none
of IFNb, GA or MP was beneficial in terms of controlling clinical
relapses. Additional studies have recently confirmed the risk of
important rebound disease activity following NTZ discontinua-
tion [145–147]. Finally, as RESTORE was not designed nor pow-
ered to compare the efficacy of immunomodulatory drugs,
larger controlled studies are needed.
A randomized blinded clinical trial (Kappos L., TOFINGO, oral
presentation ECTRIMS 2013) has investigated the effect of dif-
ferent washout periods (8, 12 or 16 weeks) on clinical and MRI
disease activity in patients switching from NTZ to fingolimod.
The preliminary results have confirmed that a shorter washout
period is associated with a lower risk of clinical and MRI disease
recurrence. In addition, a recent study has demonstrated that
the relay of NTZ with fingolimod resulted in a slight increase of
the ARR (from 0.26 to 0.38) and that the patients with a
washout period of less than 2 months presented a significantly
lower risk of relapse as compared to those with longer washout
periods [147]. Therefore, fingolimod seems to be an interesting
therapy in relay of NTZ, and shorter washout periods protect
against rebound disease activity.
One of the biggest challenges in the therapeutic management
of RR-MS patients is to choose the most effective drug at the
best time for each patient. For clinically and radiologically
aggressive RR-MS, induction strategy with classical second-line
therapies seems to be the most efficient strategy. In the other
groups of patients, escalation can be successfully applied to
minimize the incidence of serious adverse events. However,
tome 44 > n84 > avril 2015
Update on treatments in multiple sclerosis
MULTIPLE SCLEROSIS

there is a relative lack of evidence to determine if the use of Daclizumab

induction strategy could be widen to include other patients at Daclizumab is a humanized monoclonal Ab directed against the
risk of developing significant disability. a chain of the IL-2 receptor, a molecule up-regulated on acti-
vated T cells. This drug has been used for more than 10 years in
the prevention of kidney transplant rejection.
The washout: when and how? Studies showed that CD25 antagonism was responsible for an
With the arrival of new therapies in MS, the timing of relay from expansion of CD56bright NK regulatory cells, resulting in
one DMT to another has become a crucial issue for MS caregivers decreased T cell activation [149]. The CHOICE phase II pla-
when switching is required (table III). cebo-controlled trial has shown that daclizumab in combination
There does not seem to be major issues concerning the switch with IFNb was effective at reducing the number of new gado-
from IFNbs or GA to other therapies. No washout period is linium-enhancing lesions at 6 months [150]. The SELECT trial has
required before starting another treatment, even for second- compared a 52-week treatment by monthly daclizumab 150 mg
line drugs. Concerning teriflunomide, the EMA recommend no or 300 mg to placebo in 600 patients with active RR-MS [151].
washout period when switching from teriflunomide to IFNb or Treatment with daclizumab has resulted in a 50 to 54% reduc-
GA. However, if a switch to other therapies is decided, such as tion of ARR as compared to placebo. In the MRI sub-study
fingolimod, NTZ or others immunosuppressive drugs, a washout performed in 309 patients, there was a 69 to 78% reduction
period of 3.5 months needs to be respected (=5 half-lives of of new or enlarging gadolinium-enhancing lesions in daclizu-
teriflunomide) or an accelerated elimination procedure has to mab-treated patients, when compared to placebo-treated
be performed. For DMF and fingolimod, the recommended patients. The most common adverse events reported were
washout period is the time necessary to recover a normal white nasopharyngitis, upper respiratory tract infection and headache.
blood cells count, usually between one and two months, Four malignancies were reported in the study: one in the
although it can be longer [148]. placebo group and three in the daclizumab-treated groups.
DECIDE, a phase III trial designed to evaluate the safety and
efficacy of once monthly subcutaneous administration of dacli-
What's new in term of treatment?
zumab as compared to IFNb-1a is ongoing.
Emerging therapies are currently under investigation and can, in
some selected cases, be considered as an alternative treatment.
Rituximab/ocrelizumab/ofatumumab
We chose to briefly summarize three of them: daclizumab, anti-
Rituximab is a human/murine monoclonal Ab directed against
CD20 Abs, and hematopoietic stem cell transplantation.
CD20, a B cell marker. It was the first B cell depletion therapy
used for treatment of MS. Despite the good results of different
studies [152–154], the development program has been
TABLE III suspended.
Durations of wash out periods required after a treatment switch in Ocrelizumab is a recombinant monoclonal humanized anti-CD20
MS patients
Ab. This Ab is structurally similar to rituximab, but as a human-
ized molecule it is expected to be less immunogenic and to
Treatment 1 Treatment 2 Washout
present a more favorable benefit-risk profile. In a phase II study,
IFN or GA Any drug No washout required 218 relapsing MS patients were randomized to receive either
Any drug IFN or GA No washout required placebo, low dose (600 mg) IV ocrelizumab, high dose
(2000 mg) IV ocrelizumab, or IFNb-1a [155]. The study has
NTZ FTY < 2 months after
Teriflunomide discontinuation of NTZ demonstrated a significant reduction in the number of new
DMF gadolinium-enhancing lesions in both ocrelizumab groups as
Teriflunomide FTY Accelerated elimination compared to placebo or to IFNb. ARR was respectively 80% and
NTZ procedure or 3.5 months 73% lower in the 600 mg and 2000 mg groups when compared
Alemtuzumab to placebo. Only the 600 mg group presented a significantly
FTY Teriflunomide When lymphocytes lower ARR when compared to IFNb.
NTZ level are returned to Recently, ofatumumab (a second generation humanized mono-
Alemtuzumab normal levels (1 to 2 months) clonal Ab against CD20), has been tested in a randomized double-
DMF Alemtuzumab When lymphocytes blind placebo-controlled study [156]. Thirty-eight patients have
NTZ level are returned received 2 infusions of 100 mg, 300 mg, or 700 mg of ofatumu-
FTY to normal levels mab or placebo at two weeks interval. At week 24, significant
DMF: dimethylfumarate; FTY: fingolimod; GA: glatiramer acetate; IFN: interferons;
reductions of new gadolinium-enhancing lesions and new T2
MS: multiple sclerosis; NTZ: natalizumab. lesions were observed in the treated groups (all doses).
e145

tome 44 > n84 > avril 2015

 L. Michel, C. Larochelle, A. Prat

There are currently three large phase III trials underway, one in
PP-MS patients (ORATORIO) and two in relapsing MS patients
(OPERA I and II).
Autologous hematopoietic stem cell transplantation
(AHSCT)
In recent years, intense immunosuppression followed by infu-
sions of autologous hematopoietic stem cells has been the
subject of several studies in patients with RR-MS. The aim of
this treatment is first to eradicate the autoreactive cells, and
then to restore the hematopoietic system. Only results from
phase I/II trials are currently available, and there is no data
coming from prospective comparative studies [157–173]. How-
ever, AHSCT appears to be very effective in some selected MS
cases with relapsing-remitting form and/or showing inflamma-
tory MRI activity, who are younger than 40 years and who have a
short disease duration [174]. Concerning the safety profile, the
mortality rate has been evaluated to 1.3% during the period
2001–2007 [175], mainly due to systemic infections. About 10%
of the transplanted patients present autoimmune diseases in
the first two years [176]. In the future, AHSCT will probably be
considered as an alternative therapy for RR-MS patients with
highly active and refractory disease on DMTs.
Conclusion
The considerable advances made recently in our understand-
ing of the pathophysiology of MS have allowed the develop-
ment of many therapies with different mechanisms of
actions. The currently approved DMTs present different levels
of efficacy and tolerability. Escalation strategy, based on the
failure a treatment, has classically been used to treat MS
patients. But, it seems more and more legitimate to consider
induction therapy with more aggressive DMTs in selected
patients populations affected with more severe forms of
MS.
One of the remaining issues in MS is the early estimation of
suboptimal response to first-line DMTs. Clinical and radiological
criteria can actually help to detect early suboptimal responders
and, in the future, biomarkers and pharmacogenomics will
probably guide us to select the most appropriate individualized
therapy.
Disclosure of interest: Laure Michel received honoraria from Novartis and
Teva for counseling and conferences.
Catherine Larochelle declares that she has no conflicts of interest concerning
this article.
Alexandre Prat received honorarium from Novartis, EMD Serono, TEVA,
Sanofi-Genzyme and Biogen for scientific advisory boards and conferences.

Supplementary data
Electronic supplement (Annex 1) available on the website La Presse Médicale (http://www.em-consulte.
com/revue/LPM)
Approved disease-modifying treatments in multiple sclerosis: summary of the mechanisms of actions,
adverse events, indications, contraindications and results of pivotal trials

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