J Neurol (2017) 264:2351–2374

DOI 10.1007/s00415-017-8594-9

REVIEW

The sequence of disease‑modifying therapies in relapsing multiple

sclerosis: safety and immunologic considerations
Gabriel Pardo1 · David E. Jones2

Received: 24 May 2017 / Revised: 11 August 2017 / Accepted: 12 August 2017 / Published online: 6 September 2017
© The Author(s) 2017. This article is an open access publication

Abstract The treatment landscape for relapsing forms of involved in treating people with RMS throughout the entire
multiple sclerosis (RMS) has expanded considerably over course of their disease.
the last 10 years with the approval of multiple new disease-
modifying therapies (DMTs), and others in late-stage clini- Keywords Multiple sclerosis · Therapeutic drug
cal development. All DMTs for RMS are believed to reduce monitoring · Selection for treatment · Re-treatment ·
central nervous system immune-mediated inflammatory pro- Treatment effectiveness
cesses, which translate into demonstrable improvement in
clinical and radiologic outcomes. However, some DMTs are
associated with long-lasting effects on the immune system Introduction
and/or serious adverse events, both of which may compli-
cate the use of subsequent therapies. When customizing a The unpredictable nature of multiple sclerosis (MS) clinical
treatment program, a benefit–risk assessment must consider manifestations within and between patients with apparently
multiple factors, including the efficacy of the DMT to reduce similar characteristics is brought about by a complex and
disease activity, the short- and long-term safety and immu- dynamic pathophysiology involving inflammatory-based
nologic profiles of each DMT, the criteria used to define mechanisms of demyelination and axon loss [1–3]. A range
switching treatment, and the risk tolerance of each patient. of genetic [4, 5], immunopathologic [6–8], and environmen-
A comprehensive benefit–risk assessment can only be tal/epigenetic [9] factors drive the tremendous variability in
achieved by evaluating the immunologic, safety, and efficacy the type, frequency, and severity of signs and symptoms that
data for DMTs in the controlled clinical trial environment may present during the course of MS [10, 11].
and the postmarketing clinical practice setting. This review Despite the heterogeneity in MS disease course, select-
is intended to help neurologists make informed decisions ing an appropriate therapy for relapsing forms of MS
when treating RMS by summarizing the known data for each (RMS) before the approval of fingolimod in 2010 [12, 13]
DMT and raising awareness of the multiple considerations was relatively simple because neurologists had two main
treatment options: interferon beta/glatiramer acetate or
natalizumab. The beta interferons and glatiramer acetate
* Gabriel Pardo have comparable long-term safety profiles and efficacy,
gabriel‑[email protected] reducing the frequency of relapses by ~30% over a 2- to
David E. Jones 3-year treatment period, as evaluated in clinical trials [1,
[email protected] 2, 14]. However, a high proportion of patients experi-
1
ence breakthrough disease or have persistent clinical or
OMRF Multiple Sclerosis Center of Excellence, Oklahoma
radiologic disease activity within 2 years of treatment ini-
Medical Research Foundation, 820 NE 15th Street,
Oklahoma City, OK 73104, USA tiation of these agents [14, 15]. Conversely, the safety of
2 interferon beta and glatiramer acetate over two decades
Department of Neurology, University of Virginia School
of Medicine, PO Box 800394, Charlottesville, VA 22908, is highly favorable and the relative risk for immunologic
USA complications is low [14, 16–18]. Natalizumab [19, 20] is

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2352 J Neurol (2017) 264:2351–2374

more efficacious than interferon beta and glatiramer acetate General principles of treatment sequencing
[21, 22], but has a complex safety profile due to the risk in RMS
of progressive multifocal leukoencephalopathy (PML) [19,
20]. For this reason, historically, natalizumab was gener- The primary aim of treatment is to reduce disease activity to
ally reserved for patients requiring higher efficacy than optimize neurologic reserve, cognition, and physical func-
interferon beta and glatiramer acetate, and, more recently tion [27]. Meeting this goal requires a concordant relation-
in the US, only when the expected benefit is sufficient to ship between the health care professional and patient so that
offset PML risk [19, 20, 23]. the personal preferences of the patient are considered when
Since 2010, new disease-modifying therapies (DMTs) developing or revising the treatment plan (shared decision
have emerged [18]; 13 approved DMTs are currently avail- making). Patients should be informed that different DMTs
able to treat RMS worldwide (Table 1), which target dif- may be required at different times because of suboptimal
ferent pathways of the immune system (Table 2). Several response, safety concerns, intolerable side effects to the
of the new DMTs have demonstrated superior efficacy over DMT, or a change in the risk tolerance of the patient. Within
either interferon beta or glatiramer acetate in Phase III stud- this context, patients could be made aware of commonly
ies of patients with RMS (Table 3). While there may be used criteria necessitating a treatment switch due to subop-
differences in their relative efficacy, additional head-to-head timal response. For interferon beta recipients specifically,
clinical trials, particularly comparator studies between oral the Rio score estimated after 1 year of treatment is prog-
DMTs, are required to confirm and quantify this assertion nostic for ongoing disease activity in the ensuing 3 years
[24]. Oral DMTs such as teriflunomide, dimethyl fumarate, [28, 29]. For DMTs more generally, the Canadian Multiple
and fingolimod offer a convenient route of administration, Sclerosis Working Group recommends changing treatment
while peginterferon beta, daclizumab beta, ocrelizumab, and when there is a low level of concern in all three domains of
alemtuzumab provide a lower dosing frequency, being dosed the MS disease status triad [relapses, disability progression,
once every 2 weeks, monthly, every 6 months, and annually, and magnetic resonance imaging (MRI)], a medium level of
respectively. concern in any two domains, or a high level of concern in
Although the expansion in treatment options for RMS any one domain [30]. Another example is the multifactorial
is welcome, health care professionals are now faced with MS decision model that, by grading the four domains of
complicated decisions on how to individualize initial ther- relapse, disability progression, MRI, and neuropsychology,
apy for patients (see Table 4 for prognostic features in MS) aims to support early treatment decisions and detect treat-
and then select subsequent therapies, based on incomplete ment failure in a timely manner [31].
benefit–risk assessments of the current and potentially Regardless of the clinical criteria used to identify sub-
unknown long-term immunologic and safety risks. The optimally controlled RMS [30, 32], treatment sequencing
most important knowledge deficit is the long-term safety is often necessary to maintain disease control, which may
of newly approved DMTs for RMS, which may not have introduce an additional safety risk [30]. Neurologists have
been fully elucidated during their Phase III clinical trial two major decisions regarding the prescription of DMTs: (1)
programs, and thus may place some patients at risk for choosing the initial DMT expected to reduce disease activity
complications yet to be defined. For instance, some DMTs while recognizing the potential need for alternative later-line
for RMS have been associated with adverse events (AEs) DMTs if the response is suboptimal; and (2) selection of
that only came to light during postmarketing surveillance subsequent treatment choices based on previous DMT use.
[16, 25], culminating in the development of intensive The appropriate course of action selected depends on a thor-
risk reduction strategies to optimize patient safety such ough benefit–risk evaluation for each candidate DMT after
as classifications of PML risk [26]. Other generic factors accounting for specific disease- and patient-related factors
preventing the extrapolation of data to a real-world set- at a specific point in time, as well as the patient’s access to
ting include strict patient selection and high motivation DMTs through their health insurance plans.
in clinical trials. Treatment algorithms for RMS that rank DMTs as first
The purpose of this review is to raise awareness of the and second line have been proposed [33, 34], as have the
issues involved in sequencing RMS therapies by discuss- pros and cons of induction (starting highly effective therapy
ing the immunologic effects and known safety profiles of earlier in the course of the disease) versus escalation treat-
available DMTs. In doing so, the treating neurologist may ment paradigms [35, 36]. However, the initial DMT should
be better able to inform patients on the likely benefits and provide the most favorable benefit–risk profile given the
risks of treatment. level of disease activity over the last 6–12 months, taking

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J Neurol (2017) 264:2351–2374 2353

Table 1  Approved DMTs for MS

DMT (trade name) Administration route Dosing frequency Dose level US Approval year Indication

IFN beta-1b ­(Betaseron®; Subcutaneous injection Every other day 250 mcg 1993a RMS [134]
­Extavia®)
IFN beta-1a (­ Avonex®) Intramuscular injection Once a week 30 mcg 1996 RMS [135]
IFN beta-1a (­ Rebif®) Subcutaneous injection Three times per week 22 and 44 mcg 2002 RMS [136]
Peginterferon beta-1a Subcutaneous injection Once every 2 weeks 125 mcg 2014 RMS [137]
­(Plegridy®)
Glatiramer acetate Subcutaneous injection Daily 20 mg 1996b RMS [138]
­(Copaxone®; ­Glatopa®) Three times per week 40 mg 2014
Dimethyl fumarate Oral capsule Twice a day 240 mg 2013 US: RMS [67]
­(Tecfidera®) Europe: RRMS [139]
Teriflunomide Oral tablets Daily 14 and 7 mg 2012 US: RMS [72]
­(Aubagio®) Europe: RRMS [73]
Fingolimod ­(Gilenya®) Oral capsule Daily 0.5 mg 2010 US: RMS [13]
Europe: second-line treat-
ment or rapidly evolving
severe RRMS [12]
Daclizumab beta Subcutaneous injection Once monthly 150 mg 2016 US: RMS, generally after
­(Zinbryta®)d an inadequate response
to ≥2 D ­ MTsc [82]
Europe: RMS and failure
to respond/unsuitable
for other treatments [81,
140]
Alemtuzumab Intravenous infusion First course: daily for 12 mg 2014 US: generally reserved for
­(Lemtrada®) 5 days; second course: patients who have had
daily for 3 days, 1 year an inadequate response
after the first course to ≥2 drugs for ­RMSc
[100]
Europe: active RRMS
defined by clinical or
imaging features [141]
Natalizumab ­(Tysabri®) Intravenous infusion Every 4 weeks 300 mg Approved 2004; US: RMS when the
reintroduced expected benefit is
2006 sufficient to offset PML
­riskc [20]
Europe: high disease
activity despite IFN beta
or glatiramer acetate;
rapidly evolving severe
RRMS [19]
Ocrelizumab ­(Ocrevus®) Intravenous infusion Twice a year 600 mg 2017 US: RMS or PPMS [118]
Mitoxantrone Intravenous infusion Every 3 months 12 mg/m2 2000 US: secondary (chronic)
­(Novantrone®; Every 3 months 5 mg/m2 progressive, progressive-
­Onkotrone®) relapsing, or worsening
RMS (but not PPMS) as
an early, transient, high-
efficacy strategy [142]

DMT disease-modifying therapy, IFN interferon, MS multiple sclerosis, PML progressive multifocal leukoencephalopathy, PPMS primary pro-
gressive MS, RMS relapsing forms of multiple sclerosis, RRMS relapsing–remitting multiple sclerosis
a
Extavia available in the US since 2009
b
Glatopa available in the US since 2015
c
Only available through a restricted distribution program
d
­ INBRYTA®), which has a different form and structure than an earlier form of dacli-
Formerly daclizumab high-yield process (approved as Z
zumab

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2354 J Neurol (2017) 264:2351–2374

into account the MS type, long-term prognostic factors 2–5 years and short first interattack interval) [33, 35, 38],
(Table 4), patient-related factors, and the fact that the risk and people of African descent [39]. Before an induction
of AEs associated with some DMTs can change over time. strategy is initiated, physicians must consider the appropri-
Importantly, due to the heterogeneity of RMS, the choice of ate maintenance DMT postinduction but, in practice, this is
starting DMT should take into consideration potential future not always possible and data to guide postinduction choices
treatment needs by keeping subsequent treatment options are very limited.
open (e.g., reserving the need for DMTs with a long-lasting The range of available induction therapies is fairly nar-
immunoablative impact on the immune system until a later row, and includes mitoxantrone, alemtuzumab, and to a lim-
time if appropriate). Like a good chess player who thinks ited extent, hematopoietic stem cell transplantation (within
several moves ahead, performing multiple benefit–risk a clinical trial setting). Off-label cyclophosphamide also
assessments across several DMTs for RMS is required when has been investigated in patients with highly active dis-
reviewing medication at any point in time. ease [40]. There are positive neuroradiologic data for the
brief use of immunosuppressive induction therapy with
mitoxantrone before maintenance therapy with glatiramer
Escalation versus induction acetate in patients with highly active RMS [41, 42]. How-
ever, the safety profile of the induction agent may preclude
Clinicians may deliberate on the relative value of an escala- many patients from receiving this treatment strategy. Use of
tion or induction treatment approach. A treatment escala- either immunoablative chemotherapy or immune-depleting
tion approach is based on starting with a relatively safer antibodies followed by autologous hematopoietic stem cell
agent and reactive treatment switches due to breakthrough transplantation has been successful in treating patients with
disease. At every stage in the patient’s disease course, there MS [43–45]. The immune-depleting antibody alemtuzumab
can be lasting effects of previous DMTs on the patient’s may be considered as an induction therapy because its effects
immune system, especially with medications that have pro- on the immune system persist long after treatment cessation,
longed immunologic sequelae. When switching from the enabling dosing on a one-off or annual basis [37]. In con-
initial DMT, it is imperative to consider the mechanism of trast, the high-efficacy DMTs fingolimod and natalizumab
action and duration of pharmacodynamic and immune sys- should not be considered as induction therapies because
tem effects because these can impact the efficacy and safety their rapidly reversible mechanisms of action predispose
of the next agent. Patients with moderate disease activity patients to a quick return of disease activity following treat-
[one disabling relapse in the last year and/or two new gad- ment cessation [46–53]. For a similar reason, it is likely
olinium-enhancing ­(Gd+) lesions, or accumulation of two that daclizumab beta should be used as a maintenance high-
new T2 lesions per year, indicating multifocal attacks] or efficacy DMT rather than as an induction therapy [54, 55].
high disease activity (at least one disabling relapse in 1 year
plus at least three new ­Gd+ lesions, or accumulation of three
new T2 lesions per year) may be placed on a high-efficacy Clinical pharmacology, safety, and monitoring
treatment early in the disease course and continue with that of DMTs
DMT [24, 30]. Some therapies with reversible mechanisms
of action facilitate escalation of therapy towards other agents Most DMTs have a clear pharmacodynamic drug–drug inter-
within a relatively short time frame of discontinuation if action by virtue of their temporal effects on immune cell
safety considerations allow, whereas other DMTs with long- counts and functions (Table 2). Because different DMTs
term effects on the immune system after treatment cessation exert distinct immunologic effects that persist for variable
can limit the scope of subsequent pharmacotherapy. The lat- periods of time after discontinuation, the immune system
ter DMTs also have been used as induction therapies. may not have fully recovered to its pretreatment baseline
Induction involves short-term use of a high-efficacy treat- physiologic composition during transition from one DMT
ment to obtain rapid control of highly active disease and to another. The type and duration of effect of the previous
to increase the likelihood of beneficial long-term outcomes DMT not only influences the selection of the subsequent
[35, 37], justifying an increased risk of serious AEs. The DMT, but also the known and unknown risk of an AE with
induction strategy is generally intended for younger patients the later-line DMT. As currently understood, the armamen-
(<40 years of age) with aggressive RMS who may have tarium of approved and investigational agents for MS can
already received immunomodulatory drugs, with frequent be grouped into DMTs that exert near-term effects on the
(at least two) and severe relapses within the last 12 months, immune system [day-to-week timescale: interferon beta-1a
neuroradiologic activity (at least two additional ­Gd+ lesions and 1b, peginterferon beta-1a, glatiramer acetate, dimethyl
on recent T2 MRI), and who are at increased risk of rapid fumarate, teriflunomide (if an accelerated elimination pro-
accumulation of disability (e.g., high relapse rate in the first cedure with activated charcoal or cholestyramine is used)],

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 Table 2  Mechanism of action and effects on the immune system of DMTs for RMS
DMT Molecular mode of action Effect on immune cells and mediators Time taken for immune system reconstitution after
DMT cessation

SC IFN beta-1b (Betaseron; Extavia) Exert autocrine and paracrine actions via activa- Reduces inflammatory cell migration across the Effects on the immune system endure for five
IM IFN beta-1a (Avonex) tion of the IFN receptor on leucocytes blood–brain barrier, reduces the production of times the serum elimination half-life (i.e., 40 min
SC IFN beta-1a (Rebif) proinflammatory cytokines, and induces anti- to 21.5 h for SC IFN beta-1b [134], 95 h for IM
IM peginterferon beta-1a (Plegridy) inflammatory cytokines [18] IFN beta-1a [135], 345 h for SC IFN beta-1a
[136], and 390 h for SC peginterferon beta-1a)
[137]
J Neurol (2017) 264:2351–2374

Glatiramer acetate (Copaxone) MBP mimetic; thus competes with MBP antigens Protects neurons by diverting T cell responses Effects on the immune system endure for five
to bind with MHC II [58] away from myelin in a dose-dependent manner. times the elimination half-life [138]
Increases production of anti-inflammatory
cytokines and reduces the production of proin-
flammatory cytokines [18]
Dimethyl fumarate (Tecfidera) Activates the nuclear factor (erythroid-derived Mean absolute lymphocyte count decreased >4 weeks for lymphocyte counts to increase, but
2)-like 2 pathway to protect against oxida- by 30% during the first year then remained did not return to baseline values [67]
tive stress–induced cellular injury and loss in stable above the lower limit of normal (i.e.,
neurons and astrocytes [61] 0.91 × 109/L) [63]
6% of patients had lymphocyte counts
<0.5 × 109/L [67]
Effective immune response to recall antigens,
neoantigens, and T cell-independent antigens
similarly to nonpegylated IFN therapy [143]
Teriflunomide (Aubagio) Inhibits proliferation of activated T and B Reduces neutrophils and lymphocytes by 15%, Unknown; reduced white blood cell counts of 15%
lymphocytes via mitochondrial dihydroorotate with mean counts remaining in the normal may be related to bone marrow suppression [72]
dehydrogenase inhibition [144] range [71]
16% and 12% of patients had neutrophil and lym-
phocyte counts <1.5 × 109 and <0.8 × 109/L
with 14 mg dose, respectively [72]
Effective immune response to H1N1, H3N2, and
B influenza strains [145]
Fingolimod (Gilenya) Binds the sphingosine-1-phospate receptor, Dose-dependent reduction in peripheral lympho- ≤2 months to return to normal range [13]; average
blocking lymphocyte egress from lymph nodes cyte count to 20–30% of baseline values [13] lymphocyte counts were 80% of baseline values
[146, 147] Lymphopenia incidence was 7% in placebo- after 3 months [149]
controlled trials [13]
Attenuated response to influenza vaccine in some
patients [148]
Daclizumab beta (Zinbryta)a Humanized monoclonal antibody that selectively Fivefold expansion in ­CD56bright NK cells at Pharmacodynamics are related to the half-life of
blocks high-affinity IL-2 receptor formation on 1 year. Total lymphocyte, ­CD4+ and ­CD8+ daclizumab beta (21 days) and are reversible [55,
activated T cells. Modulation of the IL-2 signal T cell, and B cell counts decrease ≤10% from 81, 82]
leads to selective antagonism of activated T cell baseline during the first year of treatment [81, Total lymphocyte counts return to baseline levels
responses and expansion of immunoregulatory 82, 92] ~8–12 weeks after the last dose [81, 82]
­CD56bright NK cells [81, 87] Effective immune responses to influenza vaccine Treg and ­CD56bright NK cell numbers return to
[150] baseline levels within 24 weeks [81, 93, 95]

13
2355
 Table 2  (continued)
2356

DMT Molecular mode of action Effect on immune cells and mediators Time taken for immune system reconstitution after
DMT cessation

13
Alemtuzumab (Lemtrada) Targets CD52 on lymphocytes and monocytes. Decrease in the level of circulating T and Lymphocytes repopulate within 8 months, but
It readily depletes B cells, T cells, monocytes, B lymphocytes very rapidly, with the lowest T cell populations take >1 year to fully
macrophages, and dendritic cells, leading to values observed within days posttreatment [99] repopulate [100, 101]
long-lasting changes in adaptive immunity, T cell populations do not recover to baseline levels
and reduces the pathogenesis of inflammatory [101]
response in MS [99]
Natalizumab (Tysabri) Monoclonal antibody that selectively inhibits Increases the number of circulating leukocytes ≤16 weeks to return to baseline levels [20]
VLA-4 (α4β1) integrins, preventing leukocyte (including lymphocytes, monocytes, basophils,
migration across the BBB [58] and eosinophils) [20]. Natalizumab does not
affect the absolute count of circulating neutro-
phils [20]
Effective immune responses to recall antigen
(tetanus toxoid) and neoantigen (keyhole limpet
hemocyanin) [151]
Ocrelizumab (Ocrevus) Targets CD20 on B cells through mechanisms CD20+ targeted by ocrelizumab include Median (range) time to B cell repletion to either
that include antibody-dependent cell-mediated pre-B cells, mature B cells, and memory baseline or lower limit of normal was 72 weeks
cytotoxicity, complement-dependent cytotoxic- B cells; lymphoid stem cells and plasma cells (range 27–175 weeks); within 2.5 years after last
ity, and/or the induction of apoptosis [118, 152] are unaffected [119, 152] infusion, B cell counts rose to either baseline
or the lower limit of normal in 90% of patients
[118]
Mitoxantrone (Novantrone) Intercalates with DNA, causing strand breaks, Reduction of leukocytes primarily affecting neu- Unknown
and inhibits DNA repair via inhibition of topoi- trophils and most lymphocyte subsets except
somerase II, leading to cytotoxicity [153] for naive and activated T lymphocytes [154]

BBB blood–brain barrier, DMT disease-modifying therapy, IFN interferon, IL-2 interleukin 2, IM, intramuscular, MBP myelin basic protein, MHC II class II major histocompatibility complex,
MS multiple sclerosis, NK natural killer, RMS relapsing forms of multiple sclerosis, SC, subcutaneous, Treg regulatory T cell, VLA-4 very late activation antigen 4
a
Formerly daclizumab high-yield process (approved as Z
­ INBRYTA®), which has a different form and structure than an earlier form of daclizumab
J Neurol (2017) 264:2351–2374
 Table 3  Efficacy of DMTs for MS
DMT (trade name) ARR reduction Disability ­progressiona Neuroradiologic outcomes

IFN beta-1b (Betaseron; Extavia) 0.25 mg 34% No effect 0.9% reduction in lesion area from baseline
dose [155] versus a 21.4% increase with placebo [134]
IFN beta-1a (Avonex) [156] 18% for ITT population; 32% for completer 37% relative reduction in 24-week CDP by Reduction in number of G ­ d+ lesions (0.80 vs.
population end of year 2 [135] 1.65) and volume of G ­ d+ lesions per patient
(74.1 vs. 122.4 mm3)
IFN beta-1a (Rebif) [157] 29% (22 mcg); 32% (44 mcg) 23% (22 mcg) and 31% (44 mcg) relative Median 1.2% (22 mcg) and 3.8% (44 mcg)
J Neurol (2017) 264:2351–2374

reduction in ≥12-week CDP [158] decrease in T2 lesion burden versus a 10.9%

increase with placebo. Reduced the number of
T2 active lesions by 67% (22 mcg) and 78%
(44 mcg)
Peginterferon beta-1a (Plegridy) [159] 36% at 1 year 38% relative reduction in 12-week CDP and 67% reduction in new or newly enlarging T2
54% reduction in 24-week CDP at 1 year lesions; 86% reduction in ­Gd+ lesions; 53%
reduction in new T1 hypointense lesions at
1 year
Glatiramer acetate (Copaxone; Glatopa) [160] 29% No effect 54% reduction in new or newly enlarging T2
lesions; 41% reduction in new T1 hypointense
lesions; 61% reduction in mean ­Gd+ lesions
[161]
Dimethyl fumarate (Tecfidera) [162] 49% 29% reduction in 24-week CDP 83% reduction in G ­ d+ lesion activity; 78%
reduction in new or newly enlarging T2
hyperintense lesions; 65% reduction in new
nonenhancing T1 lesions
Teriflunomide (Aubagio) [163, 164] 32–36% 30–32% reduction in 12-week CDP 80% reduced risk of G ­ d+ lesions; 67% reduc-
tion in total lesion volume; 31% reduction in
T1 lesion volume; 77% reduction in T2 lesion
volume [163]
Fingolimod (Gilenya) [165–167] 48–54% [165, 166] Data equivocal: FREEDOMS: 30% reduc- FREEDOMS: fewer ­Gd+ lesions (0.2 vs. 1.1)
38–52% versus IFN beta-1a 30 mcg/week IM tion in 12-week CDP [165]; no statistically and new or newly enlarging T2 hyperintense
over 1 year [167] significant effect in FREEDOMS II [166] lesions (2.5 vs. 9.8) [165]
No statistically significant effect in 12-week Data confirmed in FREEDOMS II [166]
CDP versus IFN beta-1a 30 mcg/week IM Fewer ­Gd+ lesions (0.2 vs. 0.5) and new or
over 1 year [167] newly enlarging T2 hyperintense lesions (1.7
vs. 2.6) versus IFN beta-1a 30 mcg/week IM
over 1 year [167]
Daclizumab beta (Zinbryta) [92, 168]b SELECT: 54% over 1 year [92] SELECT: 57% risk reduction in 12- and 76% SELECT: over 1 year: 85% reduction in odds
DECIDE: 45% versus IFN beta-1a 30 mcg/ reduction in 24-week CDP over 1 year [81, of new ­Gd+ lesions; 70% reduction in number
week IM over 144 weeks [168] 92] of new or newly enlarging T2 hyperintense
DECIDE: 27% risk reduction in 24-week CDP lesions [92]
versus IFN beta-1a 30 mcg/week IM over DECIDE: 75% reduction in odds of G ­ d+ lesion
144 weeks [168] activity and 54% reduction in number of new
or newly enlarging T2 hyperintense lesions
over 96 weeks versus IFN beta-1a 30 mcg/
week IM [168]

13
2357
 Table 3  (continued)
2358

DMT (trade name) ARR reduction Disability ­progressiona Neuroradiologic outcomes

13
Alemtuzumab (Lemtrada) Treatment-naive patients
CAMMS223: 69 and 66% in relapse risk CAMMS223: 75 and 69% risk reduction Improvement in lesion load on T2-weighted
over 3 and 5 years, respectively, versus IFN over 3 and 5 years, respectively, versus IFN MRI, and cerebral volume on T1-weighted
beta-1a 44 mcg SC three times per week beta-1a 44 mcg SC three times per week MRI in CAMMS223 [169]
[37, 169] [37, 169]
CARE-MS I: 55% in relapse risk over 2 years CARE-MS I: No statistically significant effect CARE-MS I: reduced the proportions of
versus IFN beta-1a 44 mcg SC three times over 2 years versus IFN beta-1a 44 mcg SC patients with G
­ d+ lesions (7% alemtuzumab
per week [170] three times per week [170] vs. 19% IFN beta-1a 44 mcg SC three times
per week) and new or newly enlarging T2
hyperintense lesions (48 vs. 58%)
Treatment-experienced patients
CARE-MS II: 49% in relapse risk versus IFN CARE-MS II: 42% reduction in 6-month risk No between-group difference on T2 lesion
beta-1a 44 mcg SC three times per week versus IFN beta-1a 44 mcg SC three times volume; reduced the proportions of patients
[105] per week with ­Gd+ lesions (9% alemtuzumab vs. 23%
IFN beta-1a 44 mcg SC three times per week)
and new or newly enlarging T2 hyperintense
lesions (46 vs. 68%)
Natalizumab (Tysabri) [171] AFFIRM: 68% AFFIRM: 42% risk reduction in 12-week AFFIRM: 92% fewer ­Gd+ lesions and 83%
CDP; 54% risk reduction in 24-week CDP reduction in new or newly enlarging T2
hyperintense lesions
Ocrelizumab (Ocrevus) [120] OPERA I: 46% versus IFN beta-1a OPERA I and II: 40% risk reduction in 12- OPERA I: 94% reduction in G ­ d+ lesions; 77%
OPERA II: 47% versus IFN beta-1a and 24-week CDP versus IFN beta-1a reduction in new or newly enlarging T2
hyperintense lesions versus IFN beta-1a
OPERA II: 95% reduction in G ­ d+ lesions;
83% reduction in new or newly enlarging T2
hyperintense lesions versus IFN beta-1a
Mitoxantrone (Novantrone) [172, 173] 63% of relapse risk [172] 70% reduction in 24-week CDP [173] Gd+ lesions (0 vs. 16% on placebo); mean
increase in T2 lesions: 0.29 in the mitox-
antrone group and 1.94 in the placebo group
[172]

Efficacy data are over 2 years and relative to placebo unless otherwise stated
ARR annualized relapse rate, CDP confirmed disability progression, DMT disease-modifying therapy, Gd+ gadolinium-enhancing, IFN interferon, IM intramuscular, ITT intention-to-treat, MRI
magnetic resonance imaging, MS multiple sclerosis, SC subcutaneous
a
Disability progression data are significant unless stated otherwise
b
Formerly daclizumab high-yield process (approved as Z
­ INBRYTA®), which has a different form and structure than an earlier form of daclizumab
J Neurol (2017) 264:2351–2374
J Neurol (2017) 264:2351–2374 2359

Table 4  Prognostic features in MS [2, 30, 39, 174–186]

Better prognosis Poorer prognosis

White African American or nonwhite

Female Male
Younger age Older age
Monofocal onset Multifocal onset
Minimal cortical pathology Early cortical involvement
Onset with optic neuritis or isolated sensory symptoms Onset with motor, cerebellar, or bladder/bowel symptoms
Low relapse rate first 2–5 years High relapse rate first 2–5 years
High degree of remission after first relapse Short interattack latency
Long interval to second relapse Short interval to second relapse
Mild relapse Severe relapse
≥1 moderate or severe attack
Steroids/hospitalization required
Severe effect on activities of daily living
>1 functional system affected
Severe motor/cerebellar brainstem involvement
No or low disability at 5 years Disability at 2 or 5 years
Low lesion load on MRI Abnormal MRI
≥2 ­Gd+/new or newly enlarging T2 hyperintense lesions
or ≥ 2 T1 hypointense lesions
≥2 spinal cord lesions
Baseline brain atrophy
NEDA at 2 years Disease activity at 2 years
Early treatment Late treatment
Low (≤386 ng/L) neurofilament light levels Elevated (>386 ng/L) neurofilament light levels
Absence of oligoclonal IgG bands Presence of oligoclonal IgG bands and ≥10 brain T2 lesions
Absence of IgM bands Presence of IgM bands

Gd+ gadolinium-enhancing, Ig immunoglobulin, MRI magnetic resonance imaging, MS multiple sclerosis, NEDA no evidence of disease activity

mid-term immunologic effects (week-to-month timescale: suggesting that better outcomes may be seen with shorter
fingolimod, natalizumab, and daclizumab beta), and long- washout. Another point for consideration is whether a pre-
term immunologic effects [month-to-year timescale: mitox- vious drug could potentially nullify or attenuate the mode
antrone, teriflunomide (if the rapid elimination procedure of action of later-line therapies: would the B and T cell-
is not implemented), alemtuzumab, and ocrelizumab]. A depleting action of alemtuzumab occur immediately after
more precise classification of the immunologic half-lives use of fingolimod if lymphocytes have not yet exited from
of DMTs will be possible once their effects on lymphocyte secondary lymphoid tissue? Hence, the diverse interactions
subpopulations are better understood. The safety profile and of DMTs with the immune system underscore their efficacy
immunologic effects of interferon beta and glatiramer ace- and safety profile, which, in turn, guides patient monitoring.
tate are such that an immediate transition to another DMT The increased efficacy and/or patient convenience asso-
is possible, providing there are no obvious abnormalities on ciated with newer DMTs relative to interferon beta and
clinical biochemistry. glatiramer acetate must be balanced against known and
Arguably, a transition period between stopping the exist- unknown safety issues. DMTs have the potential to produce
ing DMT and initiating a new DMT may be unnecessary on- and/or off-target-based toxicities that manifest as unex-
with some of the newer DMTs, but there is a fine balance pected serious AEs. Safety concerns for some therapies only
between the duration of washout (if any) and risk of dis- became evident during extension studies and postmarketing
ease. For instance, the immunologic effect of alemtuzumab surveillance studies, requiring ongoing changes to several
persists long after cessation of therapy and is unrelated to DMT product labels [16]. It follows that a more accurate
its biologic half-life, which may expose patients to immune- benefit–risk assessment is possible for a DMT scrutinized
mediated risks when they are switched to subsequent DMTs. by postmarketing surveillance than for a DMT that has com-
However, aggressive rebound disease activity can resume pleted Phase III clinical development, but has yet to undergo
shortly after stopping one agent and initiating another, as has safety evaluation in a large patient population over a pro-
been observed with natalizumab and fingolimod [46–48, 51], tracted period of drug exposure. For instance, a prospective

13
2360 J Neurol (2017) 264:2351–2374

descriptive study of patients with MS between 1995 and antioxidant responses (Table 2) [60]. It is likely that dime-
2006 found an increased malignancy risk with the sequenc- thyl fumarate has several additional immunomodulatory
ing of multiple immunomodulatory and immunosuppressant effects underpinning its efficacy in MS, including directing
therapies, and also with the number of immunosuppressant the immune response away from Th1 [62].
courses [56]. Integrated analyses of patient-level data (N = 2470)
from Phase IIb, Phase III, and long-term extension studies
Beta interferons, peginterferon beta‑1a, and glatiramer of dimethyl fumarate showed that mean absolute lympho-
acetate cyte count decreased by 30%, but generally remained above
the lower limit of normal during the first year of treatment,
The mechanism(s) of action of the beta interferons are not before stabilizing [63]. Separate observational data indicated
yet fully established, although these therapies have been that the dynamics of the absolute lymphocyte count gener-
available since the 1990s. All beta interferons are known ally correlate with ­CD4+ and ­CD8+ counts [64], with the
to exert autocrine and paracrine actions via activation of reduction of ­CD8+ T cells greater than that of ­CD4+ T cells
the interferon receptor on leukocytes (Table 2). Production (−55 vs. −39%) reflected in a 36% increase in the CD4/
of proinflammatory cytokines is reduced, and production CD8 ratio [65]. In patients without severe lymphopenia (i.e.,
of anti-inflammatory cytokines is induced [18]. Attachment <0.5 × 109 cells/L), there is evidence of improvement in
of a polyethylene glycol side chain to the parent interferon lymphocyte counts following discontinuation of dimethyl
beta-1a molecule yields peginterferon beta-1a, which, when fumarate, but full restoration takes >4 weeks [63, 66, 67].
administered subcutaneously, has a longer half-life, higher For patients who become severely lymphopenic on dimethyl
systemic exposure, and lower immunogenicity potential than fumarate, lymphocyte counts may take a long time to recover
intramuscular interferon beta-1a [57]. Glatiramer acetate, a [66]; this delay in lymphocyte recovery may complicate the
synthetic polymer of four amino acids (l-glutamate, l-lysine, switch to a subsequent DMT with myelosuppressive effects.
l-alanine, and l-tyrosine), is a mimetic for the MS autoan- Six percent of patients experienced lymphocyte counts
tigen myelin basic protein (MBP), and thus competes with <0.5 × 109/L (grade ≥3 lymphopenia) in placebo-controlled
MBP antigens for binding to class II major histocompat- trials [67]. The risk of developing moderate to severe lym-
ibility complex (MHC II) [58]. With formation of the MBP phopenia while on dimethyl fumarate may be increased by
antigen/MHC II complex impeded by glatiramer, helper T the following: increasing age, lower baseline absolute lym-
cells have less opportunity for activation and potential to phocyte count, and recent natalizumab exposure (there is a
destroy myelin [58]. In addition, glatiramer binding to MHC greater percentage reduction in absolute lymphocyte count
II inhibits the interaction of MHC II with C ­ D4+ molecules due to the lymphocytosis induced by prior natalizumab) [64,
located on the surface of helper T cells (Th1 and Th2). Con- 66]. Although the risk may be slightly different in patients of
sequently, there is reduced production of proinflammatory older age or with lower baseline absolute lymphocyte count,
cytokines (interferon gamma) by Th1 cells, increased pro- all patients remain at a small risk of lymphopenia. Based
duction of anti-inflammatory cytokines (interleukin 10) by on 7250 cumulative patient-years of exposure, the overall
Th2 cells (promoting a less inflammatory state), and induc- incidence of serious infections was low, and there was no
tion of antigen-specific expansion of F ­ OXP3+ regulatory T apparent correlation between the incidence of infection and
cells [58, 59]. grade of lymphopenia [63].
The effects of beta interferons and glatiramer acetate on Of >230,000 patients treated with dimethyl fumarate
the immune system likely only endure for as long as a patient globally in the 3 years following commercial availability
is exposed to therapeutic drug concentrations (i.e., less than (representing >330,000 patient-years), there have been five
five times the elimination half-life; Table 2). The safety pro- cases of PML in the setting of moderate to severe prolonged
files of the beta interferons and glatiramer acetate are well lymphopenia (absolute lymphocyte count <0.8 × 10 9/L),
established (Table 5). a rare opportunistic brain infection caused by John Cun-
ningham (JC) virus that is normally harmless in immuno-
Dimethyl fumarate competent hosts [25, 68]. There are established risk strati-
fication and mitigation strategies for patients on dimethyl
Following oral administration, dimethyl fumarate is rapidly fumarate in light of its safety profile. In the US, complete
metabolized to its active metabolite monomethyl fumarate, blood counts at baseline and every 6 months thereafter are
which is primarily responsible for its efficacy in MS [60, mandatory to identify patients who may have developed
61]. Similar to other fumarate derivatives, administration severe prolonged lymphopenia [67]. In Europe, a baseline
of dimethyl fumarate activates nuclear factor-erythroid MRI also should be performed within 3 months of initiating
2-related factor 2, resulting in differential effects involving therapy [69].

13
 Table 5  Tolerability, safety, and monitoring issues of DMTs for MS
DMT Common AEs Safety issues Contraindications

IFN beta-1b (Betaseron/Extavia) [134] Injection site reaction, lymphopenia, flu-like Hepatic injury, anaphylaxis, depression (and Pregnancy (increased risk of spontaneous abor-
IFN beta-1a (Avonex) [135] symptoms, myalgia, leukopenia (asymp- suicidal ideation), injection site necrosis, tion) and breastfeeding
tomatic), neutropenia, increased liver congestive heart failure, leukopenia throm- Hypersensitivity reactions to active ingredient
IFN beta-1a (Rebif) [136]
enzymes, headache, hypertonia, pain, rash, botic microangiopathy, flu-like symptom or formulation excipients
Peginterferon beta-1a (Plegridy) [137] insomnia, abdominal pain, asthenia, depres- complex, seizures, autoimmune disorders,
sion, hematologic abnormalities, arthralgia decreased peripheral blood counts
Glatiramer acetate (Copaxone) [138] Injection site reactions, postinjection reaction Cutaneous necrosis Use during pregnancy only if clearly needed
J Neurol (2017) 264:2351–2374

(vasodilatation, rash, dyspnea, chest pain Hypersensitivity reactions to active ingredient

within minutes) or formulation excipients
Dimethyl fumarate (Tecfidera) [67, 68] Flushing, abdominal pain, diarrhea, nausea Anaphylaxis and angioedema, PML, lympho- Hypersensitivity reactions to active ingredient
(usually subsides within 3 months) [187] penia or formulation excipients
Teriflunomide (Aubagio) [72–74] Headache, diarrhea, nausea, alopecia, Hepatic injury, teratogenicity (requires Severe hepatic impairment
increased alanine aminotransferase accelerated elimination procedure), bone Pregnancy and breast feeding
marrow effects, potential immunosuppres- Severe immunodeficiency
sion, infection, peripheral neuropathy, skin Significantly impaired bone marrow function
AEs [including Stevens–Johnson syndrome Severe active infection
or toxic epidermal necrolysis (Lyell’s Severe renal impairment undergoing dialysis
syndrome)], increased blood pressure, Hypoproteinemia (due to high plasma protein
respiratory effects (interstitial lung disease), binding)
pancreatitis, thrombocytopenia Current leflunomide treatment
Hypersensitivity reactions to active ingredient,
leflunomide, or formulation excipients
Fingolimod (Gilenya) [12, 13] Headache, liver transaminase elevation, diar- Asystole and sudden death, infections (includ- Recent myocardial infarction, unstable angina,
rhea, cough, influenza, sinusitis, infection, ing herpes simplex virus and cryptococcal stroke, transient ischemic attack, decompen-
back pain, abdominal pain, pain in extremity infections), PML, macular edema, poste- sated heart failure with hospitalization, or
rior reversible encephalopathy syndrome, class III/IV heart failure
respiratory effects, hepatic injury, terato- History of Mobitz type II second- or third-
genicity, increased blood pressure, basal cell degree AV block or sick sinus syndrome,
carcinoma unless patient has a pacemaker
Baseline QTc interval ≥500 ms
Known immunodeficiency syndrome
Active infection
Treatment with Class IA or Class III anti-
arrhythmic treatment
Active malignancy
Severe liver impairment
Hypersensitivity reactions to active ingredient
or formulation excipients

13
2361
 Table 5  (continued)
2362

DMT Common AEs Safety issues Contraindications

13
Daclizumab-beta (Zinbryta) [81, 82]a Nasopharyngitis, upper respiratory tract infec- Hepatic injury (including autoimmune hepati- Hypersensitivity reactions to active ingredient
tion, rash, influenza, dermatitis, oropharyn- tis), other immune-mediated disorders (skin or formulation excipients
geal pain, bronchitis, eczema and lymphad- reactions, lymphadenopathy, noninfectious Preexisting hepatic disease or hepatic impair-
enopathy, depression, pharyngitis, increased colitis), infections, and depression ment, including ALT or AST ≥2 times the
alanine aminotransferase ULN
History of autoimmune hepatitis or other auto-
immune condition involving the liver
Alemtuzumab (Lemtrada) [100, 141, Rash, headache, pyrexia, nasopharyngitis, Infusion-associated reactions and anaphylaxis HIV infection
188–192] nausea, vomiting, infection (urinary tract, (including bradycardia), thyroid disor- Hypersensitivity reactions to active ingredient
upper respiratory tract, viral including ders and other autoimmune cytopenias, or formulation excipients
herpes, fungal), fatigue, insomnia, urticaria, glomerulonephritis (Goodpasture’s disease),
pruritus, thyroid gland disorders, arthralgia, malignancy (thyroid cancer, melanoma, and
pain in extremity, back pain, oropharyngeal lymphoproliferative disorders), infections
pain, abdominal pain, diarrhea, sinusitis, (including opportunistic such as herpes
paresthesia, dizziness, flushing virus, human papilloma virus, fungal infec-
tions, listeria, and nocardiosis)
Natalizumab (Tysabri) [19, 20, 193, 194] Headache, fatigue, arthralgia, urinary tract PML, hypersensitivity reactions (including Patients who have or have had PML
infection, lower respiratory tract infection, anaphylaxis), immunosuppression/infections Patients at risk of opportunistic infections
gastroenteritis, vaginitis, depression, pain in (including herpes simplex virus, meningitis, Concomitant beta IFN or glatiramer acetate
extremity, abdominal discomfort, diarrhea, and hepatitis B virus infection with acute therapy
rash fatal liver injury), hepatic injury Known active malignancies (except cutaneous
basal cell carcinoma)
Hypersensitivity reactions to active ingredient
or formulation excipients
Ocrelizumab (Ocrevus) [118] Infusion-related reactions and upper respira- Infusion-related reactions, infections, neo- Active hepatitis B virus infection and a his-
tory tract infections plasms tory of life-threatening infusion reaction to
ocrelizumab
Mitoxantrone (Novantrone) [142] Nausea, alopecia, urinary tract infection, Congestive heart failure (can result in death) Baseline LVEF below the lower limit of normal
menstrual disorders (including amenorrhea), may occur either during or months to years Pregnancy and breastfeeding
asthenia after termination of therapy. Secondary Hypersensitivity reactions to active ingredient
acute myeloid leukemia, infection, leuko- or formulation excipients
penia, depression, bone pain, emesis, renal
failure

AE adverse event, AV atrioventricular, DMT disease-modifying therapy, HIV human immunodeficiency virus, IFN interferon, LEVF left ventricular ejection fraction, MS multiple sclerosis, PML
progressive multifocal leukoencephalopathy, ULN upper limit of normal
a
Formerly daclizumab high-yield process (approved as Z
­ INBRYTA®), which has a different form and structure than an earlier form of daclizumab
J Neurol (2017) 264:2351–2374
J Neurol (2017) 264:2351–2374 2363

Teriflunomide occurring extracellular lipid sphingosine-1-phosphate (S1P)

[76]. S1P is an extracellular signaling molecule that regu-
Teriflunomide is the active metabolite of leflunomide, which lates trafficking of many types of T and B cells from the
has anti-inflammatory, antiproliferative, and immunosup- lymph nodes to the blood (Table 2) [58]. Blood T cell levels
pressive properties [70]. Teriflunomide selectively and decrease when S1P receptors are activated, as naive T cells
reversibly inhibits dihydroorotate dehydrogenase, a key mito- are sequestered within secondary lymphoid organs after
chondrial enzyme in the de novo pyrimidine synthesis path- their egress from peripheral blood [58]. Lymphopenia is an
way, resulting in lymphocyte cell cycle impairment, without expected pharmacodynamic effect of fingolimod due to the
causing cell death [58]. Teriflunomide reduces neutrophils increased movement of ­CCR7+ lymphocytes into second-
(during the first 6 weeks) and lymphocytes (during the first ary lymphoid organs [77]. Fingolimod induces a rapid and
3 months) by ~15%, although mean counts remain in the reversible dose-dependent reduction in peripheral lympho-
normal range [71]. Teriflunomide also inhibits protein tyros- cyte count to 20–30% of baseline values [13]. Peripheral
ine kinases, leading to decreased T cell proliferation, and lymphocyte reconstitution following fingolimod discontinu-
a shift in the cytokine profile to a more anti-inflammatory ation occurs over 1–2 months [13], but this period may be
cytokine milieu [58]. extended with fingolimod use exceeding 1 year [78]. Rarely,
The long elimination half-life (18–19 days) of terifluno- an abrupt rise in lymphocyte count occurs during the fingoli-
mide [72], due in part to its extensive enterohepatic recir- mod postwithdrawal period (immune reconstitution inflam-
culation, means that it can take approximately 8 months for matory syndrome), putting patients at risk for MS disease
the body to eliminate the drug, although plasma drug con- reactivation [79].
centrations can still be detected up to 2 years after admin- Cases of PML have occurred in patients with MS receiv-
istration of the last dose [72]. If a rapid switch to another ing fingolimod in the postmarketing setting who had not
DMT is required, then an accelerated elimination procedure been previously treated with natalizumab nor who were
with either administration of cholestyramine or activated taking immunosuppressive or immunomodulatory medica-
charcoal for 11 days should be considered [72], including in tions concomitantly [13]. In addition, affected patients had
patients with cytopenia. Both elimination regimens result no other ongoing identified systemic medical conditions
in a 98% decrease in plasma teriflunomide concentrations resulting in compromised immune system function [13]. For
(i.e., <0.02 mg/L) [72, 73]. this reason, fingolimod should be withheld at the first sign
No new safety signals beyond those detected in individual or symptom suggestive of PML [13]. In addition, patients
trials (and summarized in Table 5) were identified with treat- with signs and symptoms consistent with other opportunistic
ment duration exceeding 12 years and a cumulative exposure pathogens, including herpes simplex viruses 1 and 2, vari-
to teriflunomide exceeding 6800 patient-years [71]. Nonfebrile cella zoster virus, cryptococci, and atypical mycobacteria,
neutropenia and lymphopenia were reported in 5.9% and should undergo prompt diagnostic evaluation and appropri-
0.5% of patients receiving teriflunomide over 1500 patient- ate treatment [13, 80].
years of cumulative treatment exposure, respectively [71]; Fingolimod phosphate acts on four of the five known
no association between neutrophil count decrease and infec- S1P receptor subtypes expressed on a variety of cell types,
tion occurrence was detected [71]. Cases of thrombocyto- including endothelial cells, lymphocytes, smooth muscle
penia, including rare cases with platelet counts <50,000/mm3, and cardiac myocytes, and neural cells [76]. Consequently,
have been reported in the postmarketing setting [74]. Serious fingolimod administration elicits significant off-target phar-
skin reactions, including severe generalized major skin AEs macology, resulting in rare but serious AEs (Table 5) [16].
[Stevens–Johnson syndrome or toxic epidermal necrolysis For these reasons, in Europe, fingolimod is considered a
(Lyell’s syndrome)] have been reported [74]. Teriflunomide second-line DMT following failure of interferon beta or
is causally linked to one fatal case of toxic epidermal necroly- glatiramer acetate, or a first-line agent for patients with
sis [75], but has not been linked with PML. Complete blood highly active disease [12]. No such restrictions are placed
count, tuberculin skin tests (to identify latent tuberculosis on its use in the US, although numerous changes have been
infection), liver function tests, and blood pressure measure- made to the warnings and precautions listed in the fingoli-
ments are required at baseline; liver function and blood pres- mod product label to guide proper use (Table 5) [80]. Hence,
sure also should be monitored monthly for the first 6 months patient selection and monitoring is of paramount impor-
and then regularly thereafter with continued treatment [72]. tance to increase the likelihood that the benefits of fingoli-
mod outweigh its risks. Baseline laboratory tests include
Fingolimod complete blood count, liver enzymes, pregnancy test, and
varicella zoster virus status [12, 13]. Tests that are required
Fingolimod is phosphorylated following oral administra- before dosing, during, and/or posttreatment with fingolimod
tion to fingolimod phosphate, a mimetic for the naturally include cardiac and blood pressure monitoring, complete

13
2364 J Neurol (2017) 264:2351–2374

blood counts, and examination of the fundus for macular from real-world use, although the product label provides
edema [13]. Monitoring for signs of infection and suspicious specific warnings regarding hepatic injury—elevations of
skin lesions in case of basal cell carcinoma also should be serum transaminases and serious events, including fatal
conducted, as per the fingolimod product label [13]. Case cases of autoimmune hepatitis and liver failure—and other
reports of severe disease reactivation following fingolimod immune-mediated disorders (including skin reactions, lym-
withdrawal [46–48] also must be considered when treat- phadenopathy, and noninfectious colitis) as well as depres-
ing patients with highly active disease and in women who sion, infections, autoimmune hemolytic anemia, gastroin-
wish to become pregnant (in whom it is advised to continue testinal AEs, and lymphopenia [81, 82]. These warnings are
therapy only if the potential benefit justifies the potential based on safety and tolerability information from an inte-
risk to the fetus) [12]. grated analysis of six clinical studies (primarily randomized
controlled trials and their extensions) encompassing 2236
Daclizumab beta patients with 5214 patient-years of daclizumab beta expo-
sure [98]. Although this database was not large enough to
Daclizumab beta is a humanized monoclonal antibody detect rare events, the analysis did show that daclizumab
approved for the treatment of RMS as a monthly subcuta- beta had an acceptable safety profile without evidence of
neous self-injectable [81–83]. Daclizumab beta works in cumulative toxicity [98]. Daclizumab beta should be dis-
the periphery by binding CD25 (alpha subunit of the high- continued in cases of significant transaminase elevation [i.e.,
affinity interleukin 2 receptor mostly expressed on activated alanine transaminase (ALT) or aspartate transaminase (AST)
T cells) to modulate interleukin 2 signaling (Table 2) >5 × the upper limit of normal (ULN) only; or total biliru-
[84–87]. Blockade of CD25 by daclizumab beta limits inter- bin greater >2 × ULN; or ALT or AST ≥3 but <5 × ULN
leukin 2 consumption by activated T cells and facilitates cells and total bilirubin >1.5 and <2 × ULN] [82]. Discontinu-
that express the intermediate-affinity interleukin 2 receptor ing daclizumab beta should be considered if severe depres-
[i.e., natural killer (NK) cells and precursors of innate lymphoid sion or suicidal ideation occurs [81, 82]. If serious infection
cells] to receive more interleukin 2 signal, as this receptor develops, daclizumab beta should be withheld until the epi-
does not feature CD25 [88, 89]. Consequently, there is a sub- sode resolves [81, 82].
stantial expansion of immunoregulatory ­CD56bright NK cells
that penetrate the blood–brain barrier and eliminate impor- Alemtuzumab
tant mediators of MS immunopathology, activated T cells,
leaving resting T cells intact (Table 2) [84, 86, 90, 91]. The humanized monoclonal antibody alemtuzumab targets
The pharmacodynamic effects of daclizumab beta are sus- the extracellular glycoprotein CD52, resulting in antibody-
tained in patients with relapsing–remitting MS, as evidenced dependent cytolysis and complement-mediated lysis of T and
by a fivefold expansion of ­CD56bright NK cell levels that pla- B lymphocytes, monocytes, NK cells, macrophages, and den-
teau by the end of the first year of treatment [92, 93]. Modest dritic cells (Table 2) [99, 100]. Alemtuzumab elicits rapid,
10% reductions in circulating total lymphocytes, ­CD4+ and profound, and prolonged B and T cell lymphopenia followed
­CD8+ T cells, and B cells were observed in patients with MS by a reconstituted immune system different in composition
after 1 year of daclizumab beta 150 mg treatment, and regu- from that before treatment, which may rationalize its long-
latory T cell levels were reduced by approximately 50% after term efficacy, given patients only receive two medication
8 weeks [92–94]. The remaining regulatory T cells are func- cycles that are 1 year apart (Table 3) [99, 100]. It can take
tionally active, as evidenced by stable cytokine production, ~8 months for B cells and up to 3 years for T cell subsets to
maintained active cell cycling, and retention of a regulatory recover to the lower limits of the normal range after a single
T cell-specific demethylated region in the FOXP3 promoter, course of alemtuzumab, and T cells may not recover fully to
albeit with a significant decrease in CD25 expression [94]. baseline values [101]. It is worth noting that B cell recovery
The effects of daclizumab beta are reversible; after treatment was rapid in one study; levels of ‘mature naive’ B cells (CD19
cessation, total lymphocyte counts return to baseline levels and CD23 positive but CD27 negative) returned to baseline by
within 12 weeks, and ­CD56bright NK cell and regulatory T 3 months and rose to 165% of baseline values by 12 months
cell counts return to baseline levels within 24 weeks [93, after the first course of alemtuzumab treatment [102]. Con-
95]. There was no apparent impact of antidrug antibodies or versely, CD27-positive memory B cell recovery was slow,
neutralizing antibodies on the pharmacodynamics, efficacy, reaching only 25% of baseline levels by month 12 [102]. The
or safety of daclizumab beta [82, 96]. immunosuppressive effects of alemtuzumab on C ­ D4+ T cell
The safety profile of daclizumab beta was determined subsets lasted for up to 4 years in 29 patients who participated
over a 5-year period and was consistent with that from in CARE-MS I and CARE-MS II [103]. Differential lympho-
the pivotal Phase III trial (Table 5) [97]. Given the recent cyte reconstitution after alemtuzumab treatment may be a bio-
approvals for daclizumab beta, there are only limited data marker for MS relapse, as patients with active disease showed

13
J Neurol (2017) 264:2351–2374 2365

an accelerated recovery of ­CD4+ cells (p = 0.001), with a transmigration out of the vascular space), but does not affect
difference in absolute ­CD4+ counts at 24 months (p = 0.009), the absolute count of circulating neutrophils [20].
while ­CD4+ counts <388 × 106 cells/mL predicted MRI sta- Natalizumab has an elimination half-life of 11 days
bility [104]. Anti-alemtuzumab antibodies reduce plasma [20], although plasma natalizumab concentrations can be
alemtuzumab concentrations during course 2 but not course reduced by 92% within 1 week of plasma exchange sessions
1, although they do not appear to affect clinical outcomes, to treat PML if required [106]. The reversibility of natali-
total lymphocyte count, or AEs [100]. Alemtuzumab induces zumab’s pharmacologic effects on peripheral immune cells
long-term immunodepleting effects, which must be consid- is evident starting at weeks 8–12, with levels returning to
ered when planning subsequent therapies for maintenance those observed or expected in non-natalizumab patients by
treatment or if a patient does not respond adequately. There 16–20 weeks after the last natalizumab dose [107]. This is
are no data on sequencing therapies after alemtuzumab use consistent with the reduction in plasma natalizumab con-
to guide the clinician, who must, therefore, rely on intensive centrations to below the limit of detection by 16 weeks post-
patient monitoring to individualize care. dose [107]. Lymphocyte counts remain within the normal
Although the advantages of long-lasting efficacy and range at all times both for patients receiving natalizumab and
extremely high patient adherence are positive attributes of for those who have stopped natalizumab treatment [107].
alemtuzumab, Table 5 shows that this DMT is associated Patients who develop anti-natalizumab antibodies are more
with several serious AEs that may arise years after starting likely to have hypersensitivity reactions during drug admin-
treatment and are, therefore, not reflective of alemtuzum- istration [20].
ab’s pharmacokinetic profile (elimination half-life, 2 weeks) An intensive risk stratification program is in place to help
[100]. Alemtuzumab is usually reserved for patients with prescribers weigh the clear efficacy benefits of natalizumab
unfavorable prognostic indicators because it is difficult to against the development of PML [19, 20]. Three main fac-
reconcile its superior efficacy over interferon beta with tors drive the risk of developing PML in patients undergo-
exposure to serious AEs in patients with less severe disease. ing natalizumab therapy: (1) therapy ≥24 months; (2) previ-
Even in patients with highly active disease, diligent patient ous use of immunosuppressant treatment; and (3) JC virus
selection and strict adherence to risk monitoring programs antibody positivity [108]. The anti-JC virus antibody index
is required. The alemtuzumab product label recommends value and duration of natalizumab treatment are two key fac-
regular laboratory monitoring up to 4 years after the last tors that enable clinicians and JC virus-positive immunosup-
alemtuzumab dose (and beyond if warranted) for the detec- pressant-naive patients with MS to make informed treatment
tion of secondary autoimmune conditions (e.g., immune and monitoring decisions [109–111].
thrombocytopenia, antiglomerular basement membrane Natalizumab withdrawal often leads to an MS relapse and
disease, and thyroid disorders) [100]. Laboratory testing return of inflammatory disease activity on MRI [49–53].
includes differential blood count, serum creatinine, and urine Younger patients (<40 years of age) were 3.8-fold more
analysis before administration and monthly thereafter [100]. likely to have increased MRI activity during 24 weeks of
Pretreatment thyroid-stimulating hormone level is manda- natalizumab treatment interruption, as were those with one
tory and requires rechecking every 3 months until 4 years ­ d+ lesions (2.7-fold increase) and >five G
to five G ­ d+ lesions
after the last infusion [100]. Patients with active or uncon- (6.2-fold) before natalizumab initiation (vs. no lesions) [52].
trolled infections are not candidates for therapy [100]. Pro- Initiating interferon beta within 30 days postnatalizumab
phylactic oral acyclovir should be taken until C ­ D4+ count dosing in patients who had been free of disease activity
3
is >200 cell/mm to reduce the risk for herpes infections [112], or initiating fingolimod ~4 months postnatalizumab
[100, 105]. dosing in patients with stable Expanded Disability Status
Scale scores [113], was associated with clinical and radio-
Natalizumab logic disease recurrence. A therapeutic gap of no more than
3 months between discontinuing natalizumab and initiating
Natalizumab is a humanized monoclonal antibody that fingolimod appears to minimize the risk of relapse [113].
binds to the integrin molecule very late activation antigen 4 Switching from natalizumab to alemtuzumab (n = 16) [114]
(α4β1), a glycoprotein surface molecule found on all leuko- or off-label rituximab (n = 114 [115] and n = 118 [116])
cytes except neutrophils (Table 2) [58]. Blockade of α4β1 may be a feasible option to maintain disease control, includ-
prevents adhesion of leukocytes to vascular cell adhesion ing in those at high risk of PML. It is currently unknown if
molecule 1, a protein expressed on the surface of vascu- the switch-to therapy selection impacts the risk of PML in
lar endothelial cells in the brain and spinal cord, and thus this context. Data on treatment selection after a PML event
blocks entry of leukocytes into the central nervous system on natalizumab are limited, but there are reports of success-
across the blood–brain barrier [58]. Natalizumab increases ful use of both dimethyl fumarate and fingolimod in this
the number of circulating leukocytes (due to inhibition of situation [117].

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2366 J Neurol (2017) 264:2351–2374

Ocrelizumab Balancing benefits versus risks: information

for patients and physicians
Ocrelizumab is a B cell-directed cytolytic monoclonal anti-
body with a humanized immunoglobulin G1 tail indicated Patient-related factors are key multifactorial inputs that
for the treatment of patients with relapsing or primary pro- influence response to DMTs, and how much a DMT is used
gressive forms of MS as a twice-yearly intravenous infu- in clinical practice. Selecting the treatment best suited for
sion [118]. This recombinant monoclonal antibody binds an individual at each phase of the disease is challenging, but
to a different but overlapping CD20 epitope expressed on can be facilitated by establishing a concordant relationship
B cells to rituximab [119]. By binding to the cell surface with the patient and their significant other (support partner).
antigen CD20 present on pre-B and mature B lymphocytes, A key concept that may be disagreed upon in patients who
it is believed that ocrelizumab induces antibody-dependent feel relatively healthy is the value placed on future health
cellular cytolysis, complement-mediated lysis, and/or apop- benefits versus the present-day inconvenience of administer-
tosis via crosslinking membrane CD20 on the target cell ing DMTs (e.g., tolerability, acquisition cost) and the safety
surface [118, 119]. profile of the DMT. Patient discussions provide an oppor-
Assays for ­CD19+ B cells are used as a surrogate for tunity for the neurologist to relate the goals of the DMT to
B cell counts because ocrelizumab interferes with the CD20 the patient, namely to safely reduce relapses and incidence
assay. As such, ocrelizumab reduces circulating C ­ D19+ and severity of new MRI lesions, thereby reducing the risk
B cell counts 14 days postinfusion to negligible levels [118]. for permanent disability. Educating the patient about both
In clinical studies, B cell counts rose to above the lower the immediate symptomatic and long-term pathophysi-
limit of normal or above baseline counts between infusions ological aspects of MS can facilitate the progression to a
of ocrelizumab at least once in 0.3–4.1% of patients [118]. shared agreement about therapeutic goals and the level of
Median (range) time for B cell counts to return to either risk patients and their partners are willing to assume. The
baseline or the lower limit of normal was 72 (27–175) neurologist can then help guide the patient regarding the
weeks after the last ocrelizumab infusion (Table 2) [118]. long-term goals, general principles of sequencing DMTs,
Within 2.5 years after the last infusion, B cell counts rose and the appropriate DMT treatment, rather than assessing
to either baseline or the lower limit of normal in 90% of their views and discussing details such as relative efficacy
patients [118]. rates and disability rating scales.
Treatment-emergent ocrelizumab AEs observed in a There is some evidence of an effect on delaying disabil-
pooled analysis of the two identical 96-week Phase III ity progression with fingolimod, daclizumab beta, alemtu-
OPERA trials included infections, infusion-related reac- zumab, and natalizumab versus interferon beta or glatiramer
tions, and an incidence rate of first neoplasm of 0.40 per acetate (Table 3). An appreciation of the treatment regimens
100 patient-years of exposure, based on data from 6467 from the patient’s perspective often reveals that their agen-
patient-years of exposure (Table 5) [120]. The ocrelizumab das and priorities may not match those of their neurologist,
prescribing information states that breast cancer occurred who should be guided by evidence-based medicine. The
in 6 of 781 females treated with ocrelizumab versus none risk of the disease, which may be hard to precisely define,
of 668 females treated with subcutaneous interferon beta- is another important part of the benefit–risk discussion in
1a or placebo [118]. Hence, patients receiving ocrelizumab shared decision making. Hence, it is important to convey the
should be encouraged to follow standard breast cancer advantages and disadvantages of each DMT to the patients
screening guidelines. The long-term effects and risks of based on their RMS history and likelihood/unpredictability
B cell depletion on malignancy risk will remain uncertain of future disease-related events.
until long-term real-world follow-up data are available, and PML has been associated with several DMTs for MS,
may currently be underrecognized. As with alemtuzumab, and one of the greatest needs in understanding the ben-
long-term B cell depletion with ocrelizumab may limit efit–risk of a DMT is to quantify the likelihood of PML
subsequent treatment options. For instance, initiation of a after the first DMT and also after two or more DMTs have
later-line therapy while B cell levels remain depleted may been added in sequence. It is important to note that PML
result in cumulative, and presently undocumented, effects risk differs by therapy. A logical classification for stratify-
on immune system function. The appropriate timing for ini- ing DMT PML risk has been proposed, with natalizumab
tiating other DMTs after a patient has received ocrelizumab having the highest PML risk (incidence 1/100–1/1000),
should be considered by the physician. The immunogenicity followed by far lesser degrees of risk for fingolimod
of ocrelizumab appears low, based on the incidence of for- (incidence 1/18,000) and dimethyl fumarate (incidence
mation of treatment-emergent antidrug antibodies (~0.4%) ~1/50,000) [26]. PML risk for other DMTs is very low or
[120]. uncertain [26]. It is currently unknown whether or how

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J Neurol (2017) 264:2351–2374 2367

the sequencing of these therapies might impact the overall European Academy of Neurology, European Committee for
PML risk of each patient. Treatment and Research in Multiple Sclerosis, and American
The immunization status of the patient also is important Academy of Neurology [132, 133]. Because both documents
because of interactions between some DMTs and vaccine are highly data driven, there is no recommendation provided
response. The National Multiple Sclerosis Society does for selecting one DMT over another. Instead, the appropri-
not recommend use of live vaccinations in people with MS ate choice of DMT is the one that the practicing neurologist
[121], and respective product labels for teriflunomide, fin- rationalizes will provide the level of efficacy warranted by
golimod, daclizumab beta, or alemtuzumab advise avoiding the recent disease activity, balanced by patient safety and
use of live attenuated vaccines during and for prespecified preferences.
time periods after stopping therapy [13, 72, 82, 100]. No The long-term immunologic and safety risks of sequenc-
product-specific information is available on the effects of ing multiple therapies are still unknown. Prescribing DMTs
vaccination in patients receiving peginterferon beta-1a, glati- in RMS depends on a thorough benefit–risk analysis, which
ramer acetate, dimethyl fumarate, and natalizumab. There- is inconclusive if the patient’s characteristics are not reflec-
fore, complete or partial prevention of infection by influenza, tive of clinical trial populations, and if the long-term effects
tuberculosis, varicella zoster virus, and hepatitis A and B of DMT in the clinical practice setting are unknown. Pro-
may be considered by vaccination before starting immu- spective industry-sponsored switching studies, patient reg-
nomodulatory therapy. Availability of non-live vaccines, istries, and robust analysis of real-world data are needed
such as the herpes zoster subunit vaccine (HZ/su) contain- to collect data tailored to the therapeutic agent and vari-
ing recombinant varicella zoster virus glycoprotein E and ous patient scenarios. Until such evidence-based medical
the ­AS01B adjuvant system [122], may represent a welcome information is available, decisions on sequencing DMTs for
and more flexible addition to efforts to prevent infection in RMS will depend heavily on the clinical acumen of the neu-
patients with MS receiving DMTs. rologist. In the meantime, sequencing the most appropriate
For elderly patients, a potential benefit–risk consideration therapies for patients with RMS is usually determined by
for the DMTs dimethyl fumarate, teriflunomide, fingolimod, a combination of factors such as disease activity, patient-
alemtuzumab, and ocrelizumab is their variable effect on related factors, and drug-related factors (e.g., pharmacody-
lymphocyte counts, which occur as a consequence of their namic profile).
on- or off-target pharmacology (Table 2). In elderly patients, Treatment should be selected to address the immediate
age-related immunosenescence, characterized by diminished clinical issue, and to keep alternative therapeutic options
levels and functionalities of B and T lymphocytes, may lead available for later-line therapies. This consideration is
to a theoretically greater likelihood of lymphopenia with particularly important early on in the disease course and
these DMTs [123]. One also could hypothesize that elderly even more relevant in today’s therapeutic landscape, which
patients would be less likely to experience breakthrough MS includes DMT options with potentially long-lasting effects
activity for the same reason. Hence, older age affects the on the immune system that can persist for months or even
benefit–risk ratio of DMTs and acts as a prompt for neu- years following discontinuation of therapy. Patients should
rologists to consider hematologic monitoring when making be made aware of these issues so that a shared care decision
prescribing decisions. can be reached, which is driven by matching the level of risk
Progress toward development of pharmacogenetics- and a patient is willing to accept with their prognostic factors.
biomarker-based approaches to individualize treatments
according to patient and DMT characteristics is in its infancy Acknowledgements Biogen provided funding for medical writing
support in the development of this paper; Malcolm Darkes, Ph.D.,
[124, 125]. In the meantime, other factors on which to base and Juliet Bell, Ph.D., from Excel Scientific Solutions wrote and
these decisions include patient preferences, lifestyle and updated the manuscript drafts based on input from the authors, and
beliefs, comorbidities and concomitant medications, immu- Kristen DeYoung from Excel Scientific Solutions copyedited and
nization status, family planning, and age. The first three styled the manuscript per journal requirements. Biogen reviewed
and provided feedback on the paper to the authors. The authors had
factors have a profound influence on adherence to medica- full editorial control of the paper and provided their final approval
tion; poor adherence predisposes the patient to suboptimal of all content.
clinical, neuroradiologic, health-related quality of life, and
pharmacoeconomic outcomes [126–131]. Compliance with ethical standards

Ethical standards The manuscript does not contain clinical studies

or patient data.
Conclusions
Conflicts of interest G. Pardo is an advisor and on the speaker bu-
The topics raised in our review also are emphasized in initial reau for Biogen, EMD Serono, Genentech, Novartis, Sanofi Genzyme,
draft guidelines for the treatment of MS drawn up by the and Teva. D. E. Jones has consulted for Biogen, Novartis, and Sanofi

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2368 J Neurol (2017) 264:2351–2374

Genzyme, and received research or salary support from Biogen, the of subcutaneous interferon beta-1a with glatiramer acetate in
Consortium of Multiple Sclerosis Centers, and the National Multiple patients with relapsing multiple sclerosis (the REbif vs Glati-
Sclerosis Society over the past 2 years. ramer Acetate in Relapsing MS Disease [REGARD] study): a
multicentre, randomised, parallel, open-label trial. Lancet Neurol
Open Access This article is distributed under the terms of the 7:903–914. doi:10.1016/S1474-4422(08)70200-X
Creative Commons Attribution 4.0 International License (http://crea- 15. Limmroth V, Malessa R, Zettl UK, Koehler J, Japp G, Haller P,
tivecommons.org/licenses/by/4.0/), which permits unrestricted use, QUASIMS Study Group et al (2007) Quality Assessment in Mul-
distribution, and reproduction in any medium, provided you give appro- tiple Sclerosis Therapy (QUASIMS): a comparison of interferon
priate credit to the original author(s) and the source, provide a link to beta therapies for relapsing-remitting multiple sclerosis. J Neurol
the Creative Commons license, and indicate if changes were made. 254:67–77. doi:10.1007/s00415-006-0281-1
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