ORIGINAL ARTICLE

Overview of the management of relapsing remitting multiple

sclerosis and practical recommendations
P. Galloa and B. Van Wijmeerschb,*
Department of Neurosciences, Multiple Sclerosis Centre Veneto Region (CeSMuV), University Hospital of Padova, Padova, Italy; and
b
Rehabilitation and MS-Centre Overpelt and Biomedical Institute, University Hasselt, Hasselt, Belgium

EUROPEAN JOURNAL OF NEUROLOGY

Keywords:

disease-modifying
therapy, escalation,
glatiramer acetate,
interferon-beta, multiple
sclerosis, propensity
score,
relapsing remitting,
switching
Received 21 November 2014
Accepted 5 June 2015
European Journal of
Neurology 2015, 22 (Suppl. 2):
1421
doi:10.1111/ene.12799

The initial phases of the clinical course of relapsing remitting multiple sclerosis (MS) are characterized by a mainly inammatory pathology which gives
way to a largely neurodegenerative process as the disease evolves. As all currently available disease-modifying therapies aim to control inammation, the
window of opportunity for use is early in the disease course, specically at the
time of a clinically isolated syndrome suggestive of MS or in the early stages
of relapsing remitting MS. Approximately 30% of patients treated with rstline immunomodulators (interferon-b or glatiramer acetate) show a suboptimal
response during the rst 12 years and require a switch to an alternative therapy. It is recommended not to wait too long to switch in order to prevent disease progression. Patients with a poor prognosis in particular may require a
timely switch to a second-line agent. Regular monitoring of disease and therapy in patients with MS is essential. In the rst year after diagnosis, clinical
evaluations (neurological status, symptomatic assessment, patient well-being)
should be performed at baseline, 3, 6 and 12 months, and then every 6 months
thereafter. Brain magnetic resonance imaging (MRI) should be performed
every 6 months in the rst year of treatment, and at least once yearly thereafter. A spinal cord MRI should be performed once yearly in patients presenting spinal symptoms.

Early treatment of relapsing remitting

multiple sclerosis
The initial stages of the clinical course of relapsing remitting multiple sclerosis (MS) are characterized by a mainly inammatory pathology which, over
time, gives way to a largely neurodegenerative component. After 1520 years on average, most cases of
relapsing remitting MS have evolved to secondary
progressive MS. The inammation in MS is manifest
by brain and/or spinal cord lesions which can be
observed by magnetic resonance imaging (MRI). The
window of opportunity for use of current diseaseCorrespondence: P. Gallo, Department of Neurosciences, Multiple
Sclerosis Centre Veneto Region (CeSMuV), University Hospital of
Padova, via Giustiniani 5, 35128 Padova, Italy (tel.: +39 049
8213631; fax: +39 049 8751770; e-mail: paolo.gallo@unipd.it).
*
The details of the ParadigMS group are given in the Appendix.

14

modifying therapy is when inammatory inltrates are

still being generated, which is typically from the time
of a clinically isolated syndrome (CIS) suggestive of
MS through to the early-to-mid stages of clinically
denite relapsing remitting MS. Although treatment
in later stages is still possible, the eect is considerably
less pronounced.
Studies of disease-modifying therapy in patients
with CIS support the early initiation of treatment over
a wait and see approach. In the BENEFIT trial, the
risk of conversion to clinically denite MS was
reduced by 37% [hazard ratio (HR) 0.63, 95% condence interval (CI) 0.480.83; P = 0.003] in patients
who received early treatment for 2 years with interferon-b (IFN-b) compared with those who were randomized to delayed treatment [1]. Likewise in the
CHAMPS study, the cumulative probability of developing clinically denite MS during 3 years follow-up

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OVERVIEW OF RRMS MANAGEMENT

in patients with an initial acute demyelinating event

was 44% lower with IFN-b than placebo (rate ratio
0.56; 95% CI 0.380.81; P = 0.002) [2]. In the PreCISe study, glatiramer acetate (GA) was shown to
reduce the risk of conversion to clinically denite MS
by 45% compared with placebo by preventing a second relapse (HR 0.55, 95% CI 0.400.77; P = 0.0005)
[3]. The benets of early intervention have also been
demonstrated with oral disease-modifying treatment.
In the TOPIC trial, teriunomide 7 mg and 14 mg
once daily reduced the risk for conversion of CIS to
clinically denite MS by 37% (P = 0.0271) and 43%
(P = 0.0087), respectively, compared with placebo [4].
The level of benet in patients with CIS exceeds the
30% reduction in the annualized relapse rate achieved
with disease-modifying therapy in patients with relapsing remitting MS, supporting early treatment.
Enigmatically, the 37% reduction in the risk of conversion of CIS to clinically denite MS observed with
early versus delayed IFN-b treatment in the BENEFIT trial was not associated with any benets in disability outcomes at 5-year follow-up [1]. On further
analysis, it was considered that the Expanded Disability Status Scale (EDSS) lacked sensitivity to changes
in disability at such an early stage of MS. Examination of other outcomes indicated that the Paced Auditory Serial Addition Test (PASAT) score, a measure
of cognitive function, and accumulation of active T2
lesions on MRI scans were both in favour of early
IFN-b treatment.
In relapsing remitting MS, timing of treatment
relates to the balance between inammatory and neurodegenerative components. Early in the disease
course, pro-inammatory mediators penetrate the
blood brain barrier (BBB) and originate a process
leading to neuronal damage. Over time, the persistent
presence of inammation within the central nervous
system (CNS) decreases the drive towards development of new inammatory lesions. Sustained B-cell
maturation within the CNS contributes to establishment of a compartmentalized humoral immune
response. Indeed, B cells from lymphoid follicle-like
structures in the cerebral meninges are believed to be
responsible for the MS-specic subpial cortical
demyelination [5]. Given that all current disease-modifying therapies for MS act at the level of the peripheral immune system or BBB, their ecacy depends on
their relative ability to prevent the initial autoimmune
response and penetration by immune mediators across
the BBB.
Several prognostic factors can inform the clinical
decision of whether to treat aggressively from the time
of a rst demyelinating event or to adopt a wait and
see approach (Table 1). Clinical and MRI factors are

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15

well established in determining MS prognosis, whereas

cerebrospinal uid (CSF) markers are not yet available in routine practice. Electrophysiology uses
evoked potentials to assess the function of sensory
and motor pathways and has prognostic and monitoring value. Leocani and colleagues demonstrated that
more severely altered evoked potential scores at baseline were associated with a higher risk of disability
progression at a mean of 30 months follow-up in a
group of patients with clinically denite MS [6]. Optical coherence tomography, which captures thinning of
the retinal nerve bre layer, may also prove useful in
assessing the extent of neurodegeneration in patients
with MS [7].

Switching therapy in relapsing remitting MS

Rationale for switching

As MS involves diverse damage mechanisms not

addressed by a single agent alone, any given diseasemodifying agent might be expected to be more eective in some patients than in others. Approximately
30% of MS patients receiving disease-modifying therapy show a suboptimal therapeutic response during
the initial 12 years of treatment. The diering mechanisms of action amongst the current range of therapeutic options provide a strong rationale to switch
early in the event of a suboptimal response even
though this approach raises some clinical questions:
When to switch? How to switch? Is it best to switch
to another rst-line agent, escalate to second-line therapy, or wait and see?
A general rule in medicine is that a therapy that
produces a suboptimal response must be changed.

Table 1 Factors indicative of poor prognosis in patients with multiple sclerosis

Clinical

Magnetic resonance
imaging

Cerebrospinal uid
markers

Male gender
Higher age at onset
Multifocal presentation
Involvement of pyramidal and cerebellar
systems
Partial recovery from relapses
High relapse rate during the rst 2 years
from onset
High T1 lesion load
Persistence of activity (increased T2 lesion
volume, gadolinium enhancement)
Brain and grey matter atrophy
Spinal cord lesions
Immunoglobulin G oligoclonal bands
Increased lymphocyte count
Markers of neurodegeneration (14-3-3, tau,
NFL h&l)

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P. GALLO AND B. VAN WIJMEERSCH

Switching therapies is ideally performed in accordance

with the rules of evidence-based medicine and good
clinical practice. In the setting of relapsing remitting
MS, however, the current scientic literature on
switching therapy is limited and no study conducted
to date has provided Class 1 evidence. In the absence
of guidelines for switching therapy, decisions must
continue to be based on limited published data and
clinical experience. Herein we examine the clinical literature and oer some practical recommendations
based on our interpretation of the ndings and clinical
experience.

Table 2 Clinical indications for a switch in disease-modifying therapy

Intolerable side
eects

Neutralizing
antibodies
Risk of lifethreatening
infection
Unacceptable disease
activitya

When to switch?

The most frequent precipitating factor prompting a

switch in disease-modifying therapy is an unacceptable
level of disease activity (Table 2), but there is no current consensus about the denition of suboptimal
response or the parameters on which to base a decision.
To guide clinical decision-making, a modied version
of the original Rio scoring system has been proposed as
a method of predicting response to IFN treatment [8].
The Modied Rio Score straties patients into four
groups (03) based on the number of new T2 lesions on
MRI and the number of clinical relapses during the rst
year of treatment (Table 3). Higher scores are associated with an increased risk of disability progression
over the next 4 years. Recently the scoring system was
further simplied by introducing the classication of
non-responder for patients who have new T2 lesions
on MRI during the rst 6 months of therapy. This
modication was supported by a meta-analysis which
showed that the eect of a disease-modifying agent on
MRI lesions over a 69 month period was predictive of
its eects on relapses over longer follow-up periods
(1224 months) in patients with relapsing remitting
MS [9]; in other words, MRI activity can be used as a
surrogate for relapse.
Recommendations for switching

Some suggestions for use of disease-modifying therapies in everyday clinical practice and basic switch
principles are outlined in Box 1.
Evidence for switching

Some but not all studies investigating switching

between rst-line therapies in relapsing remitting MS
have reported positive outcomes [1014], and generalizability is further hampered by small sample sizes and
methodological variation. A retrospective analysis
reported signicant (P < 0.05) decreases in annualized

Adverse reaction: injection site reaction,

infusion reaction, infections
Persistent symptoms: u-like symptoms,
headache, nausea
Laboratory abnormalities: increased liver
enzymes, severe autoimmune
hypothyroidism
Anti-IFN-b (high-titre), anti-natalizumab
John Cunningham virus causing progressive
multifocal leucoencephalopathy (note:
pertinent for natalizumab use)
Clinical activity: relapse rate, cognitive
decline, increased EDSS (transition to
progression)?
MRI activity: appearance of two or more
T2 lesions, persistence of active lesions?
A mix of clinical and MRI parameters?

EDSS, Expanded Disability Status Scale; IFN, interferon; MRI,

magnetic resonance imaging.
a
There is no current consensus on the denition of suboptimal
response or the parameters on which to base a decision to switch.
Table 3 Modied Rio Score. Adapted from [8]
Score

Criteria

0
1

New T2 lesions
New T2 lesions
and relapses =
New T2 lesions
and relapses =
New T2 lesions

2
3

1
>

4 and relapses = 0
4 and relapses = 1, or new T2 lesions > 4
4 and relapses 2, or new T2 lesions > 4
4 and relapses 2

relapse rates for 90 patients treated with IFN-b or GA

who were switched to an alternative rst-line agent
(IFN-b/IFN-b, IFN-b/GA, GA/IFN-b) due to suboptimal response [10]. Likewise, a signicant reduction
from 1.23 to 0.53 (P = 0.0001) in the annualized
relapse rate was reported in a prospective study of 85
patients switched from weekly IFN-b 6 MU intramuscularly to daily GA 20 mg subcutaneously because of
persistent disease activity or unacceptable toxicity [11].
An observational study from the USA tracked outcomes of patients who were switchers for failure,
switchers not for failure or non-switchers after suboptimal response to rst-line disease-modifying therapy
with IFN-b or GA [12]. Disease activity was suppressed
by all treatment switches in the switchers for failure
group, but the decrease in the median annualized
relapse rate was signicant only for IFN-b/IFN-b
(P = 0.02) and GA/IFN-b (P = 0.01) switches and not
for IFN-b/GA switches. Finally, a prospective longitudinal observational study from Argentina reported
reductions in the annualized relapse rate of 57% 78%
according to subgroup in the 3-year period after

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Box 1. Disease-modifying therapy in relapsing remitting MS: basic switch principles and suggestions for use
Minimize adherence issues by providing appropriate communication, education and support for
patients, family and caregivers
Screen for disease activity, especially in the rst
2 years of therapy

Consider use of MRI for monitoring/surveillance

Take prognostic factors into account to guide

switch decisions

Switch suboptimal responses quickly

In the event of poor prognosis, consider a
timely switch to a second-line agent
Document and evaluate accurately:
o Relapse rate
o EDSS increase
o MRI changes/activity

Any switches based on cognitive loss should be

veried with formal testing
Avoid waiting too long to switch. Remember: all
that can be done should be done to halt disease
progression and prevent physical and cognitive
impairment

patients had been switched from low-dose to high-dose

IFN-b (n = 31), from IFN-b to either GA (n = 52) or
mitoxantrone (n = 13) or from GA acetate to IFN-b
(n = 16) [13]. In contrast, an observational study from
Italy documented no benet after 2 years follow-up in
121 patients who were switched from low-dose IFN-b
to high-dose, high-frequency IFN-b because of
breakthrough disease [14].
In a separate study, these same Italian investigators
reported signicant dierences after 24 months in the
proportions of patients who were free from relapse
(P < 0.0001), disability progression (P = 0.0045), MRI
activity
(P = 0.0003)
and
combined
activity
(P < 0.0001) following escalation to second-line natalizumab compared with switching between rst-line
immunomodulators (IFN-b/IFN-b, IFN-b/GA, GA/
IFB-b) after patients had failed rst-line treatment. The
ndings were conrmed in propensity-score-adjusted
models, with HRs ranging from 0.38 to 0.56 in favour
of the escalation approach [15]. Although studies of
escalation to natalizumab have also been mainly small,
single centre and limited by methodological weaknesses
[1618], in contrast to switch studies the results have
been concordant and homogeneous. Escalation to second-line therapy with natalizumab has consistently

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17

been shown to reduce disease activity and improve clinical status in patients with relapsing remitting MS who
show a suboptimal response to IFN-b and GA.
Using propensity scores to compare data sets

To facilitate comparisons between studies of varying

design, propensity scores have been used to match
patients from dierent data sets for demographic and
disease characteristics.
A head-to-head comparison of the ecacy of escalating from a rst-line immunomodulator (IFN/GA)
to natalizumab (TOP study) versus maintaining IFN/
GA therapy (MSCOMET study) was conducted in
two patient cohorts with relapsing remitting MS who
had experienced on-treatment relapse in the
12 months prior to baseline [19]. TOP (Tysabri Observational Program) is an ongoing observational registry
of 4821 patients commencing natalizumab treatment
in 16 countries [20], whereas MSCOMET is a longitudinal MSBase Registry substudy of 1000 IFN- and
GA-treated patients from 14 countries.
As the two cohorts were not comparable for patient
numbers, demographic and clinical characteristics,
propensity matching (1:1) was performed for the baseline characteristics of gender, age, disease duration
and EDSS score and for pre-baseline treatment and
relapse activity [19]. In this manner, investigators were
able to match 759 patients from each cohort
(n = 1518). The results were clearly in favour of
switching to natalizumab. The rate of rst relapse was
2.35-fold greater (95% CI 1.932.85; P < 0.001) in
patients who continued with IFN or GA than in those
who switched to natalizumab. In line, the annualized
relapse rate decreased by 83% (HR 0.11; P < 0.0001)
in the switch-to-natalizumab group compared with the
patient groups continuing with IFN or GA.
Similar methodology was applied in a study from
the USA which used a claims database to compare
relapse rates in MS patients switching from IFN to
ngolimod or GA [21]. In this instance, the matched
sample population on the basis of propensity scores
was 264 patients (132 in each cohort). At 1 year postswitch, patients who had been switched from IFN to
ngolimod had a 59% lower probability of relapse
[odds ratio (OR) 0.41; 95% CI 0.210.80; P = 0.0091]
and 62% fewer relapses per year (rate ratio 0.38; 95%
CI 0.210.68; P = 0.0013) compared with patients
who were switched to GA.
Suggestions for clinical practice

Although current evidence for switching or escalating

disease-modifying therapy is not suciently strong to

18

P. GALLO AND B. VAN WIJMEERSCH

support the establishment of a treatment algorithm, it

is still possible to formulate some practical recommendations for everyday practice.
Consider a switch between rst-line therapies when
adverse eects are intolerable despite optimized
management strategies.
Consider a switch between rst-line therapies or
escalate to second-line therapy when the relapse rate
is unchanged by current therapy or the decrease is
unsatisfactory.
Consider escalation to second-line therapy when the
patient shows rapid physical or mental deterioration.

Consider escalation to second-line therapy when

there is persistent MRI activity, even in the absence
of clinical relapse (MRI activity = relapse).
Bear in mind that early treatment and timely
switching is benecial, especially for patients with
poor prognoses.
Based on the above-mentioned recommendations
and our clinical experience in the care of MS patients,
we have proposed some ow diagrams to guide treatment and switching decisions (Figs 13). The rst step
is to estimate a patients prognosis as accurately as
possible as this, in combination with treatment
response during the rst 12 years on a given therapy,

Figure 1 Proposed ow chart for treatment of patients with good prognostic

features. CIS, clinically isolated syndrome; GA, glatiramer acetate; IFNb,
interferon b; MRI, magnetic resonance
imaging; MS, multiple sclerosis; RRMS,
relapsing remitting MS.

Aggressive (clinical)
onset RRMS

Non-aggressive (clinical) onset RRMS,

but with negave MRI prognosc factors
(black hole, atrophy, corcal lesions, high T2LV)

Second-line therapy

CIS or RRMS
with posive clinical and MRI
prognosc factors

No therapy
MRI monitoring

Risk straficaon
Careful evaluaon of the risk/benefit rao

JCV- or Low JCV index

JCV+ and High JCV index

JCV + or - status

Natalizumab

Fingolimod

Alemtuzumab

Natalizumab
monitoring
protocol

Fingolimod
monitoring
protocol

Alemtuzumab
monitoring
protocol

First-line
therapy

MRI at 6 and 12 months,

then annually
Rescue therapy
(selected cases)
Intense/marked
immunossupression
(612 months)

Risk
straficaon

Switch to first- or
second-line therapies

Figure 2 Proposed ow chart for treatment of patients with poor prognostic

features. CIS, clinically isolated syndrome; IFN, interferon; MS, multiple
sclerosis; MRI, magnetic resonance
imaging; JCV, John Cunningham virus;
RRMS, relapsing remitting MS; T2LV,
T2 lesion volume.

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19

Inducon/rescue
therapy

Risk stracaon
Careful evaluaon of the risk/benet rao
Cyclophosphamide (high dose)

800-1200 mg/m2/month
for up to one year or
50 mg/kg/day for 4 days

Mitoxantrone

10 mg/m2/month
for up to 6 months

Alemtuzumab

12 mg/day
for 5 days 1st year,
for 3 days 2nd year

Autologous HSCT

Non-Myeloablave
Regimen

Strong systemic immunosuppression

Possible long-lasng eect

Figure 3 Proposed ow chart for

treatment of patients requiring
induction/rescue therapy.

is the main guide towards following a specic treatment ow chart.

To minimize the risk of recurring disease activity, a
wash-out period is not generally recommended when
switching between treatments. This recommendation is
supported by Class III evidence of a signicantly lower
relapse risk in patients who continued versus those who
quit (OR 4.40; 95% CI 1.7211.23) or switched (OR
3.28; 95% CI 0.9910.79) natalizumab treatment after
24 doses [22]. An immediate start of a new treatment is
recommended since the risk of developing progressive
multifocal leucoencephalopathy, in the case of John
Cunningham virus antibody positive status, is far lower
than the risk of a severe relapse. Due to its long half-life
an exception is teriunomide; in this instance, an accelerated wash-out procedure using activated charcoal or
cholestyramine is recommended, followed by prompt
administration of subsequent treatment.

Monitoring disease and therapy

Patients receiving disease-modifying therapy for
relapsing remitting MS must be followed carefully.
Our recommendations for monitoring disease and
therapy are provided below.
Monitoring disease activity

Disease activity should be monitored as broadly and

sensitively as possible to identify clinical versus subclinical disease activity as well as relapse versus progression of disability.
A standard approach to clinical follow-up includes
the following.

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Risk stracaon
Switch to rst- or second-line therapies

Neurological status:
EDSS (or other instruments)/neurological examination
Multiple Sclerosis Functional Composite: NineHole Peg Test, 25-foot Timed Walk, PASAT or
Symbol Digit Modalities Test
Cognitive screening battery (BICAMS, MACFIMS, RAO)
Symptomatic assessment and well-being:
Quality of life measurement
Evaluation by a multidisciplinary team (e.g. neurologist, neuropsychologist, physiotherapist, MS
nurse, social worker)
Magnetic resonance imaging of the brain and
spinal cord should be performed regularly to identify
relapses at a subclinical level. Conventional sequences
include T2/uid-attenuated inversion recovery lesion
load, T1 lesions and gadolinium-enhancing lesions.
Advanced techniques for possible future use include,
amongst others, double inversion recovery, grey matter/white matter volume changes and magnetization
transfer ratio.
Cerebrospinal uid markers and laboratory values
to monitor disease activity in relapsing remitting MS
continue to have limited value. There is no evidence
to date to support repeat lumbar punctures. Laboratory monitoring (e.g. liver function tests) can be performed according to treatment status.
Electrophysiology should be considered as motor,
sensory, visual and brainstem evoked potentials provide insight into the brain at a functional level and
may have prognostic utility at baseline as well as for
ongoing detection of subclinical disease activity/deterioration.

20

P. GALLO AND B. VAN WIJMEERSCH

Optical coherence tomography (retinal nerve bre

thickness) as a surrogate marker of neurodegeneration
may be a future tool in the early detection of subclinical disease progression.

Timing of monitoring
Patients should be monitored closely during the rst
year of disease-modifying therapy. Clinical evaluations
should be performed at baseline, 3, 6 and 12 months,
and then every 6 months thereafter. Brain MRIs
should be performed every 6 months in the rst year
of treatment and at least once yearly thereafter. A
spinal cord MRI should be performed at baseline and
at least once yearly in patients presenting spinal cord
symptoms. Electrophysiology should be performed at
the start of treatment to provide prognostic clues and
repeated annually to identify subtle subclinical
changes.

Acknowledgements
The ParadigMS project is sponsored by Genzyme
for logistical and organizational purposes. Writing
assistance was provided by Kerry Dechant (Content
Ed Net, Madrid, Spain), with funding from Genzyme, a Sano company, EMEA HQ, Naarden, the
Netherlands.

Disclosure of conflicts of interest

Dr Gallo has received honoraria from Bayer Schering,
Biogen Idec/Elan, Merck Serono, Novartis, SanoAventis and Teva; has been a consultant for Bayer
Schering, Biogen Idec, Genzyme, Merck Serono and
Novartis; and has received research support from
Bayer, Biogen Idec/Elan, Schering and Teva. Dr Van
Wijmeersch has received advisory honoraria, speaker
fees and research support from Bayer Schering, Biogen Idec, Genzyme/Sano, Merck Serono, Novartis
and Teva.

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Appendix
The authors write on behalf of the ParadigMS group:
a group of European, Asian and Middle East experts

2015 The Author(s)

European Journal of Neurology 2015 EAN

21

in multiple sclerosis comprising, Bernd C. Kieseier

(Germany), Paolo Gallo (Italy), Nikolaos Grigoriadis
(Greece), Eva Havrdova (Czech Republic), Andreas
Lysandropoulos (Belgium), Celia Oreja Guevara
(Spain), Carlo Pozzilli (Italy), Maura Pugliatti (Italy),
Sven Schippling (Switzerland), Vincent van Pesch
(Belgium), Bart Van Wijmeersch (Belgium), Mona
Akhawajah (Saudi Arabia), Alexey Boyko (Russia),
Andrew Chan (Germany), Raymond Hupperts
(Netherlands), Ralf Linker (Germany), Maria Pia Sormani (Italy). The content of this publication is based
upon an in-depth discussion on this topic by all group
members. The views expressed therefore are based on
the group members opinions and do not represent
the views of Genzyme, a Sano Company, the European Academy of Neurology or the European Journal
of Neurology.