REVI E W Open Access

Navigating choice in multiple sclerosis

management

Ralf A. Linker

and Andrew Chan

Abstract

Background: With the advent of modern immunotherapies for relapsing-remitting multiple sclerosis (RRMS) and

the increasing amount of treatment options on the market, MS has evolved as a treatable disease. Yet, at the same

time, new challenges for the treating neurologists arise.

Main body: This review article covers some of these challenges, including when and how to start treatment,

treatment monitoring, and finally considerations on what the increasing choice in treatment options brings to

disease management and longer-term planning. Among others, these important issues comprise pregnancy,

treatment sequencing, switching or even stopping treatment.

Conclusion: The ultimate goal for navigating choices in RRMS management is to choose the right drug for the

right patient at the right time Throughout the article, there is a strong focus on practical aspects and individual

decision making in MS to meet the concept of personalized medicine.

Keywords: MS therapy, Immunomodulation, Personalized medicine, Treatment monitoring, Disease management

Background

In the past 5 years, more than five new treatment options

entered the stage for immunotherapy of relapsing-remitting

multiple sclerosis (RRMS), expanding the treatment arma-

mentarium to more than a dozen substances in total [9].

Some of these compounds represent reformulations of

already existing treatment options while others make use

of bona fide new treatment concepts [11, 33]. While there

is still no cure for MS yet and many unmet needs like op-

timal treatment of chronic progressive disease stages

abound, RRMS has evolved as a treatable condition. In

fact, considerable evidence points at long-term effects of

modern immunotherapies on disability and also quality of

life in cohorts of mostly younger RRMS patients (e.g. for

beta interferons, [22]).

Yet, with the advent of modern RRMS immunotherapy,

new challenges for the treating neurologists arise. In this

review, we will cover some of these new aspects including

when and how to start treatment, treatment monitoring,

and finally considerations on what the increasing choice

in treatment options brings to disease management and

longer-term planning including important issues like preg-

nancy, treatment sequencing, switching or even stopping

treatment. Throughout the article, there will be a strong

focus on practical aspects and individual decision making

to meet the concept of personalized medicine [19].

How to deal with increasing numbers of dise ase

modifying therapies?

When thinking about treatment choices for RRMS, it is

appropriate to discuss if the ever-expanding range of

new disease modifying therapies (DMT) is really useful

or if it is just making treatment regimen too complex

while bringing only marginal benefits to patients. In fact,

accommodating the range of new treatments may be

challenging to the general neurologist managing MS

patients, and in many instances a few substances may

suffice to cover uncomplicated MS phenotypes. To date,

MS is still a chronic disease with a significant risk of

permanent disability impacting on the social roles in

everyday life for the mostly young patients [46]. In

addition, there is considerable heterogeneity regarding

disease mechanisms as well as regarding individual

patient profiles and needs [34]. Thus, at first glance,

an appropriate range of treatment choices seems

clearly beneficial.

* Correspondence: [email protected]

Department of Neurology, Un iversity of Regensburg, Universitätsstr. 84,

93053 Regensburg, Germany

Full list of author information is available at the end of the article

Neurological Researc

act

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Linker and Chan Neurological Research and Practice (2019) 1:5

https://doi.org/10.1186/s42466-019-0005-5

Yet, it may be worthwhile to take a look at the evolu-

tion of immunomodulatory MS therapy over the past 20

years. With only interferon beta preparations and later

also glatiramer acetate as injectable immunomodulators

on the one hand and some limited data for

time-honoured immunosuppressant s like azathioprine,

cyclophosphamide or mitoxantrone on the other, treat-

ment choices were limited, but also easier to choose

from. With more options at hand over the last years,

there certainly is greater complexity and responsibility

for patients as well as treating physicians alike, especially

with respect to treatment adherence and monitoring.

Since the advent of natalizumab as the first monoclo-

nal antibody for MS treatment in 2007, there is an on-

going process of learning about the benefits and risk s of

more than a dozen therapies. In particular, important

points are what to screen for at baseline and what to tell

patients before starting them on a new therapy. Different

monitoring protocols have been instituted to manage

the distinct risk profiles of single compounds with the

rare but imminent risk for progressive multifocal en-

cephalopathy (PML) on treatment with natalizumab as a

very prominent example [17].

However, there has been much inspiration and hope

that the newer compounds may harbour the potential to

yield a higher efficacy for the individual MS patient. The

pivotal AFFIRM trial on natalizumab started enrolling

patients more than 15 years ago thus marking the start

of an era of new therapeutic options [41]. In this trial,

natalizumab reduced the rate of clinical relapse at 1 year

by 68%, the risk of sustained progression of disa bility

over 2 years by 42%, and led to an 83% reduction in the

accumulation of new or enlarging hyperintense T2 le-

sions, as detected by cranial magnetic resonance imaging

(MRI). These results paved the way for the concept of

freedom of disease activity [15] and later no evidence of

disease activity (NEDA, [2]) as new compound trial

read-out which may also impact on our treatment goals

in everyday practice [13]. Over the last 10 years, we now

additionally gained clinical experience with the newer

DMTs and new concepts arose, like selective or pulsed

immune reconstitution therapy (PIRT) with alemtuzu-

mab [60 ] and cladribine [59] as new players in the arma-

mentarium of immunotherapy and bone marrow

transplantation as an ultimate therapy concept. PIRT

may offer lasting effects without continuous treatment

for a significant proportion of patients. However, at this

time point, it is not entirely clear if the proposed im-

mune reconstitution is an immunologically valid scaffold

for the observed sustained clinical effects.

Furthermore, data from the phase II and III random-

ized clinical trials were increasingly supplemented by

data from extension studies and real-world evidence

from registries which are of help to obtain some view on

comparative efficacy of compounds as well as on more

rare side effects [57]. A good example is the MS Base

registry with large patient numbers allowing for propen-

sity matched scoring analyses. In a recently published

study on RR-MS patients from this registry, Kalincik and

co-workers compa red 189 patients given alemtuzumab,

2155 patients given interferon beta, 828 patients given

fingolimod, and 1160 patients given natalizumab [20].

They found similar effects of alemtuzumab and natalizu-

mab on annualized relapse rates. While alem tuzumab

seemed superior to fingolimod and interferon beta in

mitigating relapse activity, natalizumab seemed superior

to alemtuzumab in enabling recovery from disability.

While such studies may be helpful in informing on some

efficacy measures between distinct compounds , treat-

ment decisions between e.g. alemtuzumab and natalizu-

mab may be primarily governed by further factors like

treatment concept (see above) or side effects profile.

Despite all positive data with new compounds, there is

still an ongoing debate on the magnitude of effect s

which can be achieved with our treatment armamentar-

ium. Here, data from a large Italian MS cohort may be

of interest, in which approximately 70% of patients have

been on treatment since 1995 [5]. For the first three

epochs of diagnosis, 1980–1990, 1991–1995 and 1996–

2000, there was a similar rate of patients reaching a

milestone EDSS of 6.0 (i.e. walking with a cane). For pa-

tients diagnosed during the epoch from 2001 to 2005,

this rate was reduced by 37%, and for those diagnosed in

2006–2010, this rate was reduced by 46%. While it may

be too early to draw conclusions for the cohort diag-

nosed since 2011, these data suggest that the course of

MS is significantly influenced by the epoch of diagnosis

with new treatment options probably being an important

variable. Thus, new treatment options may bring signifi-

cant value to the clinical outcomes for patients, and

therefore their quality of life.

Yet, with a large array of options, the responsibility to

make the right choice for the individual patient is also in-

creasing. At this point, it may be worthwhile to turn to

guidelines and how they can inform about decision making.

A good example may be the German guidelines for immuno-

therapy of RRMS (www.kompetenznetz-multiplesklerose.de)

which evolved from the escalation concept of the German

MS Consensus Group [38]. In this guideline, treatments

are grouped, or rather lumped together, for treatment of

mild and moderate versus active and highly active disease

courses. In some cases, the position of a single compound

is rather based on perceived risk profiles and recommen-

dations of the summary of product characteristics than

pure efficacy. Furthermore, it is important to note that this

guideline deliberately did not specify concrete criteria to

define “active” or “highly active” and only sets a scope to

leave room for individual treatment decisions. Finally, the

Linker and Chan Neurological Research and Practice (2019) 1:5 Page 2 of 8

guideline dates from 2014. An update is currently under

revision and European guidelines with even more general

recommendations were recently published [36, 37]. The

limitation of such guidelines can also be witnessed in the

case of the recent newcomer daclizumab, which has been

available in Germany since 2016 and has not been men-

tioned in the guidelines. While the initial European label

allowed its use in all relapsing MS patients, fatal cases of

liver failure first led to restrictions in its use. After fatal

cases of drug reaction with eosinophilia and systemic

symptoms and severe inflammatory brain disorders, e.g.

anti-NMDA-encephalitis and anti-GFAP-IgG associated

encephalitis, daclizumab was finally withdrawn from the

market [8, 32, 43, 47].

Thus, guidelines may only set a fram ework but are of

limited help to inform individual decision making for

single patients.

In a practical approach, three main domains for guid-

ing treatment decisions may be considered: disease ac-

tivity and prognosis, potential drug issu es and the

individual patient profile. Regarding disease activity and

prognosis, the distinction between active and inactive

disease is worthwhile to consider as put forward in the

Lublin classification of the clinical course of MS in 2013

[31]. In addition, patients with rapidly evolving, highly

active disease may be viewed separately. While there is

no consensus on a definition of this group, the EMA re-

cently propose d two relapses in the last year regardless

of therapy or one relapse under therapy with MRI

evidence of active disease (contrast enhancement and

at least 9 T2 lesions) as criteria relevant for the label

of cladribine (http://www.ema.europa.eu/docs/en_GB/

document_library/EPAR_-_Product_Information/human/

004230/WC500234561.pdf). Regarding drug related is-

sues, one may consider tolerability, the individual safety

profile, monitoring frequency, and drug effects. Tolerability

issues may classically comprise flu-like symptoms or also

gastrointestinal side-effects. When discussing drug safety,

autoimmunity, risks for neoplasms and the risk for infec-

tions, particularly opportunistic infections (e.g. PML), are

of paramount interest. Individual pharmacodynamics and

pharmacokinetic properties of single compounds play an

important role for drug-drug interactions, carry-over infec-

tions, rebound effects and sequencing of drugs. Regarding

patient profiles, there is an important role of adherence,

co-morbidities (skin, heart, liver, renal function, other auto-

immune diseases, hematopoietic abnormalities, [26]) and,

finally, personal factors. These factors are nowadays of

particular importance and comprise personal views on

pregnancy and family planning, work, travel, spare-time

activities, daily structure and others, which in turn may

influence quality of life and treatment choices [30].

In summary, it is important to be aware of all available

treatment options for MS. With the unique characteristics

of every patient and the increasing number of individual

factors on disease activity, drug properties and patient

profiles to be considered, a great range of therapeutic op-

tions is highly welcome [19]. Hypothetically, heterogeneity

of pathomechanisms can be met by different modes of ac-

tion of the broad range of immunotherapies like recently

proposed for plasma exchange which may be more effect-

ive in histopathological patterns I and II [54].

Monitoring MS disease activity

Disease monitoring under immunotherapy is in the

focus of an at times controversial debate within the MS

community. Prevailing questions are: What should we

measure? How should we measure? Is there a threshold

of acceptable disease activity, or should we be switching

therapy at the first sign of any uncontrolled activity? To

further set the scene for this discussion, it may be

worthwhile to take a look at disease monitoring in the

setting of phase III clinical MS trials, and then compare

it to the approach in clinical practice. In a clinical phase

III trial, patients are routinely seen every 4 weeks to 3

months. Typical outcomes include assessment of relapse

rates , disability as measured by multiple sclerosis func-

tional composite and EDSS every 3 months by a certified

rater, and additionally cranial MRI, as evidenced in the

NEDA concept (see above). Yet, in the future, patients

reported outcomes (PRO, e.g. MSIS-29), brain atrophy,

or cognitive measures like the symbol digit modalities

test (SDMT) every 6 months may add to this concept

[12]. Alon g this line, visua l quality of life is a potentially

under-recognized parameter, which can be quantified

using the NEI-VFQ 25 [16 ]. In addition, efficacy moni-

toring in clinical trials is more frequent than expected in

clinical practice, and nowadays engages a range of tech-

niques aiming at ma ximising objectivity (e.g. low con-

trast visual acuity charts, optical coherence tomography;

OCT etc.). For OCT, feasibility of automatic segmenta-

tion with man ual correction in specific macular areas

was shown even in a multi-center setting [39]. In

real-life outpatient practice, there is considerably less

time (sometimes only a few minutes), and far fewer re-

sources to assess the patient for ongoing disease activity.

While access to MRI may be good in many health care

settings nowadays, the quality of the radiologist and the

report may vary. In addition, clinical studies require a

quantitative MRI report. Yet, real world MRI reports are

often very descriptive without stating clear quantitative

results relative to the previous scan.

When discussing what to measure, it is impo rtant to

understand current concepts of MS disease evolution.

MS is often des cribed by the iceberg analogy with the

clinical manifestations above the water representing a

small fraction of the full disease pathology [14 ]. In fact,

MS is a microscopic disease and clinical endpoints only

Linker and Chan Neurological Research and Practice (2019) 1:5 Page 3 of 8

represent the literal tip of this iceberg. In accordance,

focal MRI only represents the tip of sub-clinical disease

processes which include grey matter or changes of the

normal appearing white matter (NAWM). It has been

well described that MRI may pick up damage before

clinically relevant changes are observed. There is very

convincing data that new T2-lesions detected by MRI

are a good predictor of later relapses. A range of brain

volumetric changes may very well indicate the level of

end organ (CNS) damage and predict later disability.

However, lack of standardization, among others owing

to high technical variability, may complicate implemen-

tation in clinical routine [3]. Beyo nd MRI techniques,

modern concepts are trying to validate more sensitive,

simpler measures of CNS damage and focus on cogni-

tion (see below), optical coherence tomography [40]or

also serum levels of the neurofilament light chain with

the very sensitive single molecule array (SIMOA) tech-

nique [23, 28].

Yet, nowadays, cranial MRI is most widely employed to

sensitively assess adequate disease control under immuno-

therapy. In addition to many scoring systems for disease

activity, the Rio Score and the modified Rio Score repre-

sent two widely discussed approaches that may define ad-

equate versus inadequate disease control under beta

interferon therapy. While the “classical” Rio Score com-

bines MRI measures, relapses and EDSS [44], the modified

Rio score removes the requirement to measure the EDSS

objectively at every visit [49]. Sormani and co-workers ap-

plied the modified Rio score to phase 3 study data with

interferon beta 1a three times weekly. They further refined

its use by adding a 6-month follow up MRI for those pa-

tients with a score of 1 at year one [50].

Thus, they were able to classify patients as either

“interferon responders” or “non-responders” with the

“non-responder” group being just as likely to progress as

an untreated group. In addition, the modified Rio score

may also identify responders to oral therapies like fingo-

limod or teriflunomide [52] pointing at a general and

not an interferon beta therapy specific principle. While

it is not entirely clear if the same criteria could be used

to stratify responders and non-responders to any other

treatment, such scoring systems provide some guidance

what thresholds of MRI activity may not be tolerated if

the EDSS is not included as part of a scoring system. In

addition, volumetric measures may also be helpful as

shown in a meta-analysis of 13 placebo-controlled

RRMS trials involving more than 18.000 MS patients.

This study revealed that the effects of a given therapy on

T2 lesion volume and the rate of whole brain volume

change combined may explain 75% of its impact on dis-

ability progression [51].

For a practical approach, one may refer to the

MAGNIMS guidelines for MR imaging in MS [58]. It is

recommended to perform the first monitoring scan some

6–12 months after treatment initiation (“rebaselining”)

and then yearly thereafter. In order to co-register images,

patients need to be scanned in the same scanner with the

same protocol including field strength of ≥1.5 T with a

maximum slice thickness of 3 mm (or, better, 3D scans)

and identical sequence parameters, orientation and slice

positioning. For detecting new or enlarging lesions proton

density and/or T2-FLAIR and T2 weighted fast or turbo

spin-echo sequences are recommended. For detecting le-

sions with high inflammatory activity, it is still suggested

to employ gadolinium (Gd) enhanced T1w scans ≥5min

after Gd administration. The use of linear gadolinium con-

trast agents has become somehow scrutinized with reports

on persistent Gd deposition in the dentate nucleus and

the basal ganglia [21

] after repeated application and re-

cently EMA has restricted use of these contrast agents.

Whereas clinical relevance is uncertain and also modern

macrocyclic Gd agents appear to be more stable, indica-

tion for the application of Gd should follow a clear ration-

ale (e.g. clinical symptomatology, new T2-lesions) [7].

Ideally, this imaging approach will yield a quantitative

output for the same measures across repeat scans (i.e.

lesion counts), and if possible, also volumetric measure-

ments (of T2 lesions as well a s brain structures, and

whole brain). Here, it may be advised to look for a

user-friendly system that automatically generates the re-

quested outputs. One example for for reliable detection

and quantification of T2-weighted hyperintense MS le-

sions is the FLAIRfusion image processing approach.

FLAIRfusion provides reliable detection of newly developing

MS lesions along with strong inter- reader agreement across

all levels of expertise in 35 s of reading time with a com-

bined sensitivity of 100%, and a specificity of 88.2% [48]. In

contrast to such automated protocols to quantify inflamma-

tory activity, the assessment of brain atrophy in real-world

settings is much more complicated and respective auto-

matic analysis pipelines are under development [45].

Beyond MRI, measures of cognitive information pro-

cessing (as previously measured by the PASAT-3 test)

and quality of life (QoL) measures seemed to be strong

prognostic factors as baseline prognostic marker; even

stronger than about 20 other baseline variables investi-

gated, including many MRI parameters [42]. This may

be due to the fact that cognitive dysfunction rather rep-

resents a marker of neurodegeneration than inflamma-

tory activity. According to the concept of brain reserve,

neurodegenerative processes in MS may lead to a de-

crease in intracranial volume with time. Ind ividuals with

a larger cognitive reserve may be able to withstand a

more severe disease burden without suffering cognitive

impairment or dementia [55].

Thus, a cognitive decline on treatment may indicate

inadequate disease control. Yet, the absence of cognitive

Linker and Chan Neurological Research and Practice (2019) 1:5 Page 4 of 8

decline may not necessarily mean the reverse (that the

disease is adequately controlled) - it may simply indicate

that some cognitive reserve is still available and the de-

generative processes are hence masked. Unfortunately,

this brain reserve may be depleted even durin g periods

of apparent remission if disease activity is not kept

under control. In fact, cognitive deterioration is strongly

associated with other measures of disease activity, in-

cluding brain volume change. Recent stud ies have shown

cognition to be a strong and sensitive marker of disease

progression over time [35]. It thus is advised to perform

cognitive testing on an annual basis [29]. Ideally, all cog-

nitive domains should be assessed with a battery of test.

Yet, in clinical practice, this is rarely feasible. If testing

only one domain, it is suggested to focus on processing

speed. Here, the SDMT is the most commonly recom-

mended test which is increasingly available as a digital

tool [1].

In summary, it is important to set a treatment goal

and have an agreed threshold for assessing the treatment

response together with the individual patient. It is im-

portant not to miss activity and to have reliable mea-

sures of disease activity as well as neurodegeneration at

hand, and to employ them in an optimal way. To date,

the best available tool is a standardised quantified MRI

which may depict both, inflammatory activity and

neurodegeneration. In addition, one may consider the

assessment of cognition or QoL to monitor for early de-

terioration in functional reserve with the ultimate goal

not to miss the window of opportunity to optimise

immunotherapy before disability accumulates. The

combination of different measures as applied in the “ no

evidence of disease ac tivity” (NEDA) concept or the

“multiple sclerosis de cision model” that incorporates

additional neuropsychological aspects may assist in clin-

ical practice, although not all of those models have been

completely validated yet [53].

Switching, sequencing, and stopping of therapy

Since 2011, three new oral treatment options and three

new monoclonal antibodies for the treatment of relaps-

ing remitting MS have been licensed in the EU. This

plethora of new therapeutic concepts leads to new ques-

tions including issues like sequencing of therapies, how

to switch between different compounds, and when to

stop a given therapy. Kobelt and co-wor kers conducted

a cross-sectional study in 16 countries which included

more than 16.000 participants [27]. Patients reported on

their disease, health-related QoL and resource consump-

tion. Adjusted for purchasing power parity, costs were

22.800€ in mild, 37.100€ in moderate and 57.500€ in se-

vere disease. Healthcare accounted for 68, 47%, or 26%

of these amounts, respectively. Thus, costs and utility

were highly correlated with disease severity, but resource

consumption was heavily influenced by healthcare sys-

tems organization and availability of services. A single

center epoch analysis from Italy revealed that the time

from diagnosis to start of treatment was reduced from

over 10 years in the 1980s to less than 1 year in the re-

cent years. At the same time, the odds of reaching an

EDSS ≥6.0 over the age epoch from 25 to 65 were re-

duced from over 80% to about 20% - a fact which nicely

correlates with the increasing number of available treat-

ment options over time [5].

For sequencing options, different strategies may be

envisioned ranking from “slow escalation” with switching

between compounds with low or moderate efficacy to

“rapid escalation” with immediate switching from a com-

pound with lower or moderate efficacy to a compound

with high efficacy. In some cases, a “hit hard an early”

strategy with immediate start on a high efficacy com-

pound may be the strategy of choice. In short, there are

a large number of possible options, which may crucially

depend on disease activity, drug properties and the indi-

vidual patient profile. When thinking about sequencing

or switching strategies, it is important to remember that

there are few randomized studies addr essing these is-

sues. Many recommendations rely on personal or expert

experience only. In fact, the only randomized phase III

trial directly addressing a rapid escalation setting was

the CARE MS II trial with alemtuzumab treatment in

case of interferon beta failure [6]. Yet, due to severe in-

fections and autoimmunity as possible side effects, this

very switch may not be the most common choice in

every day practice. The mechanism of action of a given

compound, information on pharmacokinetics and

half-life as well as the potential timeline of reversibility

of effects on the immune system are important issues

when considering a switch between compounds. Opti-

mally, such strategies are already considered when start-

ing an individual patient on the very first therapy. To get

a rough idea, compounds for immune therapy of RRMS

may be divided into drugs with anti-proliferative mech-

anism of action, cell depleting antibodies, therapies

interfering with migration or immune cell trafficking

and compounds with multiple perceived mechanisms

(often grossly called “immunomodulators”). Yet, it is im-

portant to remember that even compounds with a per-

ceived “immunomodulatory” mechanism of action may

lead to cell depletion as side effect thus bearing the risk

of opportunistic infections. Accordingly, some author-

ities like e.g. the FDA do not follow such classifications.

In any case, switching to a new therapy will require an

appropriate wash-out with at least normalization of

leukocyte or lymphocyte numbers. Yet, a longer

wash-out period may bear the inherent risk of returning

disease activity especially in higher active patients thus

pointing at the importance of pragmatic timelines in

Linker and Chan Neurological Research and Practice (2019) 1:5 Page 5 of 8

individual cases which require thorough information and

consenting of patients on risks of their disease versus

risks of individual compounds. Finally, it is also import-

ant to note that, to date, there are no good routine blood

markers to monitor qualitative changes of immune com-

petence. Thus, treating neurologists may have to rely on

quantitative numbers of leukocytes or lymphocytes in

many situations [25].

Another important issue to consider is the planning of

a family and the wish to have children, particularly in

higher active patients. This topic comprises conception,

pregnancy and lactation [18]. For some compounds like

teriflunomide or also fingolimod, some evidence from

animal studies point at teratogenic effects. Hence, the

summaries of product characteristics recommend strict

contraception and advise not to use them during con-

ception or pregnancy. For teriflunomide, an accelerated

elimination procedure with an 11 day protocol of chole-

styramine or charcoal intake may be applied to yield

plasma concentrations below 0.02 mg/L. In case of

fingolimod, the wash-put period should comprise at least

2 months. For other compounds including dimethyl fu-

marate, monoclonal antibodies and injectables, a careful

approach weighing the individual risks vs. benefits dur-

ing preg nancy is recommended. Regarding pregnancy

outcomes, prospective data sets for more than 300 preg-

nancies are only available for the injectables and natali-

zumab. However, it is worthwhile noting that larger

numbers of inde x cases are ne cessary to also exclude

rarer events. Data on conception under interferon treat-

ment point at a mildly lower birth weight, but no other

signs of malformation or miscarriage [56]. In contrast,

the experience with natalizumab is more ambiguous and

registry data point at an increased overall rate of birth

defects, yet with no specific pattern of malformations

and no increase in spontaneous abortion rate as com-

pared to the general population [10]. In the case of com-

pounds with a short half-life, like dimethyl fumarate,

controlling time periods between stopping treatment

and conception seem easier, but still require careful

planning. Finally, compounds with pulsed or intermit-

tent application like alemtuzumab or cladribine may

offer the chance of pregnancy during drug free intervals

after an appropriate safety margin. However, experience

on pregnancies after exposure to these compounds is

still limited.

During lactation, there are no comprehensive safety

data for any compound on the market and patients are

mostly advised to rely on immunomodulatory effect

of brea st feeding or t o re-start immunotherapy after

ablacation.

After a longer period without relapses, the discontinu-

ation of disease mod ifying therapy (DMT) is a frequently

considered topic in RR-MS. Yet, data on the disease

course after stopping treatment are scarce. In a mono-

centric approach, several factors that could be associated

with remaining relapse free after cessation of DMT were

analyzed [4]. However, these data warrant further cor-

roboration. In an analysis of the MS B ase registry in-

cluding patients with no rela pses for at least 5 years on

DMT, 485 patients stopping DMT were compared to

854 patients staying on therapy in a propensity-score

matched approach. In this study, the time to first relapse

was similar between both groups while the time to con-

firmed disability progression was significantly shorter

among patients stopping DMT than those continuing

(adjusted hazard ratio = 1.47, [24]). These data argue for

careful evaluation of individual patients and their risk for

progression when discussing the discontinuation of DMT.

Moreover, the results are well in line with many data from

registries pointing at longer term effects of modern im-

munotherapy on disability progression, particularly in the

setting of early treatment initiation in RRMS.

Conclusion

Patient and disease heterogeneity at the initial presentation

and during the disease course renders the increasing treat-

ment choices for RRMS very valuable thus allowing for

personalisation of treatment. First, long-term experience

on drug safety and efficacy of a compound may inform de-

cision making. Here, real-world data and well-structured

registries are of particular importance. Second, optimal

monitoring for treatment response is a key issue. Here, it

is strongly advised to employ standardized MRI protocols

with automated and quantifiable algorithms. In addition,

monitoring for cognition, e.g. with the SDMT as screening

tool should be considered.

For strategic long-term planning, the timing of revers-

ibility of immune cell effects is of particular interest. In

short, the ultimate goal for navigating choices in RRMS

management is to choose the right drug for the right pa-

tient at the right time.

Abbreviations

CNS: Central nervous system; DMT: Disease modifying therapy;

Gd: Gadolinium; MRI: Magnetic resonance imaging; NAMW: Normal

appearing white matter; PIRT: Pulsed immune reconstitution therapy;

PML: Progressive multifocal leukoencephalopathy; PPP: Purchasing power parity;

PRO: Patient reported outcome; QoL: Quality of life; RRMS: Relapsing-remitting

MS; SDMT: Symbol digit modalities test; SIMOA: Single molecule array

Acknowledgements

Not applicable.

Funding

There is no funding.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated

or analysed during the curr ent study.

Linker and Chan Neurological Research and Practice (2019) 1:5 Page 6 of 8

Authors’ contributions

Both authors equally contributed to the conception, literature search and

writing as well as editing of the article. Both authors read and approved the

final manuscript.

Ethics approval and consent to participate

This manuscript does not report or involve the use of any animal or human

data or tissues.

Consent for publication

Not applicable.

Competing interests

RAL received compensation for activities with Almirall, Bayer, Biogen,

Genzyme, Merck, Novartis, Roche and Teva as well as research support from

Biogen and Novartis. AC received research support from Genzyme and

Novartis well as personal compensation for activities with Almirall, Bayer,

Biogen, Genzyme, Merck, Novartis, Sanofi, and Teva.

Publisher’sNote

Springer Nature remains neutral with regard to jurisdictional claims in

published maps and institutional affiliations.

Author details

Department of Neurology, Un iversity of Regensburg, Universitätsstr. 84,

93053 Regensburg, Germany.

Ambulantes Neurozentrum, Inselspital, Bern

University Hospital, Freiburgstr. 4, 3010 Bern, Switzerland.

Received: 18 September 2018 Accepted: 21 November 2018

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