Treatment of Multiple REVIEW ARTICLE

Sclerosis

C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
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ONLINE
By Anne Cross, MD, FAAN; Claire Riley, MD
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ABSTRACT
PURPOSE OF REVIEW: Given the expansion of options for the treatment of
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relapsing multiple sclerosis, this review outlines the framework for

developing a treatment strategy, with consideration of when to switch or
discontinue therapies, and a comprehensive elaboration of the
mechanisms of action, efficacy, and safety considerations for each of the CITE AS:
therapeutic classes. CONTINUUM (MINNEAP MINN)
2022;28(4, MULTIPLE SCLEROSIS
AND RELATED DISORDERS):
RECENT FINDINGS: The armamentarium of immunotherapies has grown rapidly, 1025–1051.
to encompass 19 US Food and Drug Administration (FDA)-approved
immunotherapies available in 2021, which are addressed in the review. The Address correspondence to
coronavirus pandemic that began in 2020 underscored existing concerns Dr Claire Riley, 710 W 168th St,
Ste 246, New York, NY 10032,
regarding vaccine efficacy in those treated with immune-suppressing
[email protected].
immunotherapies, which are also addressed here.
RELATIONSHIP DISCLOSURE:
Dr Cross has received personal
SUMMARY: By choosing a treatment strategy before exploring the individual compensation in the range of
medications, patients and providers can focus their efforts on a subset of $500 to $4999 for serving as a
the therapeutic options. Although the mechanisms of action, routes of consultant for Biogen, EMD
Serono, Janssen Global
administration, efficacy, safety, and tolerability of the described agents Services, LLC, and TG
and classes differ, all are effective in reducing relapse frequency in Therapeutics, Inc and in the
multiple sclerosis (MS), with most also showing a reduction in the range of $5000 to $9999 for
serving as a consultant for
accumulation of neurologic disability. These powerful effects are Genentech, Inc, Horizon
improving the lives of people with MS. Pharmacovigilance is critical for the Therapeutics plc, Jazz
Pharmaceuticals, Inc, and
safe use of these immune-modulating and -suppressing agents, and vaccine Novartis AG; for serving on the
efficacy may be reduced by those with immune-suppressing effects. scientific advisory board for
EMD Serono, Novartis AG, and
Race to Erase MS; and for
serving as the Secretary of
Board of Governors for The
INTRODUCTION Consortium of Multiple

O
nce a diagnosis of multiple sclerosis (MS) is made, deciding on a Sclerosis Centers. Dr Cross has
treatment strategy is critical. The process of shared decision received intellectual property
interests from a discovery or
making, wherein the provider solicits patient values and care technology relating to health
preferences and then leads an evidence-based discussion of care, and the institution of
Continued on page 1051
treatment options based on those values and preferences to
culminate in a joint treatment decision, is associated with better adherence to
treatment in MS care.1 Compared with paternalism, in which the provider UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
assumes the decision-making role independently, the process of shared decision USE DISCLOSURE:
making is time-consuming, which is challenging in the current medical Drs Cross and Riley report no
environment. However, benefits in treatment adherence and consequently disclosures.

outcomes resulting from improved adherence make this the preferable approach. © 2022 American Academy
Typically, patients and providers are relatively, but not completely, aligned in of Neurology.

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 TREATMENT OF MULTIPLE SCLEROSIS

terms of goals and priorities when choosing a treatment strategy for MS. Survey
studies have highlighted some important differences between the goals of
patients and providers at this critical juncture. In the NARCOMS (North
American Research Committee on Multiple Sclerosis) database, for example,
patients prioritize reduction of disability progression, risk of adverse events, and
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effect on relapse rate, relatively like providers when they are developing
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treatment guidelines. However, patients also prioritize bothersome side effects

and deprioritized MRI outcomes compared with providers participating on a
guideline panel. Providers were more likely to prioritize relapse rate reduction
compared with potential for serious adverse events.2 Identifying those shared
goals and strategies and conducting the evidenced-based discussion may be too
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ambitious for a single provider visit; in fact, MS practice guidelines published in

2018 recommend a dedicated treatment visit because a patient may be
overwhelmed by new information during the visit when diagnosis is rendered.3

TREATMENT STRATEGIES
The two prevailing strategies in practice for the treatment of relapsing MS are an
escalation approach and an early high-efficacy or intensive approach.4,5 An
escalation approach involves initiating immunotherapy following diagnosis
(relapsing-remitting [RRMS] or clinically isolated syndrome [CIS] with a high
risk for subsequent RRMS) with an initial treatment selection among the modest
to moderate efficacy categories. This initial treatment is then followed by careful
monitoring for breakthrough disease activity and escalation to a higher-efficacy
therapy if breakthrough is identified. Escalation prioritizes safety while using
MRI to assess radiographic efficacy in addition to the usual clinical metrics of
relapse activity and disability measurements. In contrast, an early high-efficacy
approach aims to rapidly gain control of inflammatory activity by using agents
with robust radiographic and clinical efficacy at the time of diagnosis. A 2017
meta-analysis of 38 clinical trials of disease-modifying therapies (DMTs) suggests
that earlier age at the time of treatment initiation may predict better treatment
response, which might be interpreted as favoring an early high-efficacy approach.6
Retrospective cohort studies have shown a reduction in disability progression
and conversion to secondary progressive MS in patients who were treated with
an early high-efficacy/intensive approach versus the escalation approach,4,7 but
by design, these studies are susceptible to bias including confounding by
indication.8 Another study, analyzing the age at which a patient reached a
disability outcome based on the year of diagnosis as a proxy for medication
efficacy, demonstrated that those patients diagnosed in the era of high-efficacy
medication were more likely to reach disability milestones later in life.9
Interestingly, an inflection point was seen in the 2001 to 2005 epoch, with a
further reduction in the hazard ratio from 2006 to 2010. Various other
improvements in diagnosis and treatment approach were continually underway
after 2000, with earlier and more accurate diagnosis and more aggressive
imaging surveillance as well, which may confound the conclusion that the advent
of more high-efficacy therapies alone could be credited for these results.9 A
similar approach using the Swedish MS Registry also suggests a risk reduction in
reaching significant disability milestones in patients diagnosed more recently.
This study examined patients diagnosed with relapsing MS between 1995 and
2010 and found, for example, a 7% decrease per year in the risk of reaching an
Expanded Disability Status Scale (EDSS) score of 6.0.10 Although both studies

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 support that the availability of higher-efficacy agents has improved outcomes KEY POINTS
overall for patients with MS, these available data do not allow the conclusion that
● Shared decision making is
a higher-efficacy agent should be used first rather than upon careful escalation. associated with better
Similarly, the MSBase database, an international online registry of MS and other adherence to multiple
neuroimmunologic conditions, was explored for lessons on timing high-efficacy sclerosis (MS) treatment.
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therapy and disability outcomes, yielding a conclusion that those patients who
● Patients and providers
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were exposed to high-efficacy therapy within 2 years of diagnosis had a better

may have different goals
disability outcome than those who were exposed to high-efficacy agents later. when choosing a treatment
Importantly, this result favors either early high-efficacy or rapid escalation for strategy. Establishing shared
incomplete efficacy and does not distinguish between the two.11 Arguably, the goals for treatment is critical
power of a randomized controlled trial is needed to disentangle these complex to the therapeutic alliance.
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relationships, and indeed, two pragmatic trials funded by the Patient-Centered ● A dedicated treatment
Outcomes Research Institute (PCORI) are ongoing to examine the approaches, visit is useful to have an
TREAT-MS (TRaditional versus Early Aggressive Therapy for Multiple Sclerosis in-depth discussion of the
trial) and DELIVER-MS (Determining the Effectiveness of earLy Intensive risks, benefits, and
treatment options available
Versus Escalation approaches for RR-MS).5 to the patient to facilitate
shared decision making.
SWITCHING DISEASE-MODIFYING THERAPY
In large observational cohort studies, switching DMT in MS is most commonly ● Prevailing treatment
strategies for relapsing MS
done because of a lack of efficacy, followed by tolerability concerns.12 Studies of
include an escalation
switch patterns and disease outcomes performed with propensity matching, approach, prioritizing safety
although with remaining potential confounders, generally support that switching with a planned switch to
to high-efficacy medication rather than lateral transitions (ie, a change between higher-efficacy agents for
agents of similar efficacy but different mechanisms of action) is more likely to be breakthrough disease
activity, and an early
associated with better MS-disease control as measured by the annualized relapse high-efficacy approach,
rate.13,14 The decision of when to switch medication for lack of efficacy is where highest-efficacy
informed by the treatment target. As immunotherapies have demonstrated agents are initiated at the
higher efficacy, the features of a successful treatment have commensurately time of diagnosis for
expedited control of
evolved. Initially, scores such as the Rio and Modified Rio were used to predict disease activity.
and define treatment failure.15,16 The concept of disease activity–free status,
modeled from rheumatology, was introduced during the expansion of MS ● MRI provides a
therapeutic options17 and has evolved into “no evidence of disease activity” high-sensitivity assessment
of disease-modifying
(NEDA), a composite end point defined as absence of MRI disease activity (new/
therapy (DMT) efficacy and
enlarging T2 lesions, gadolinium-enhancing T1 lesions), relapse, and disability should be used to set a new
progression. These three pillars define NEDA-3, and the addition of the absence baseline. It has been
of accelerated brain volume loss defines NEDA-4.18 Indeed, only a small fraction suggested that MRI be done
approximately 6 months
of treatment courses is consistent with NEDA; for example, in the CLIMB
after treatment initiation
(Comprehensive Longitudinal Investigation of Multiple Sclerosis and Brigham and to monitor response to
and Women’s Hospital) cohort, 46% of patients met NEDA-3 criteria at 1 year, the DMT at least yearly.
but only 7.9% retained NEDA-3 status at 7 years.19 This analysis included patients
who enrolled in the prospective study between 2000 and 2005; thus, they did not
have access to the full complement of modest-, moderate-, and high-efficacy
immunotherapies now available. NEDA-3 status at 2 years was predictive of a
lack of disability at 7 years in this cohort. Interestingly, although achieving NEDA
was a strong predictor of good outcome in the medium term, lack of persistence
of NEDA was not always a poor prognostic sign and did not have a strong
negative predictive value.19
CASE 3-1 addresses the selection of an initial treatment strategy, as well as an
individual DMT, and the decision-making process regarding switching because
of incomplete efficacy.

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 TREATMENT OF MULTIPLE SCLEROSIS

CASE 3-1 An 18-year-old man presented with 1 week of left-sided weakness and
incoordination. He had no notable medical history and had a family
history of psoriasis in a parent. He had no remote history of neurologic
symptoms and had a normal birth history.
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His neurologic examination was significant for bilateral end-gaze

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nystagmus and 4/5 left-sided weakness in his face, arm, and leg in an upper
motor neuron pattern. He had bilateral dysmetria on finger-nose-finger
testing, and his gait was wide based and unsteady. Brain MRI showed highly
active classic-appearing multiple sclerosis (MS) lesions (FIGURE 3-1). CSF
showed nine CSF-restricted oligoclonal bands and a modest lymphocytic
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pleocytosis with no serum or CSF red flags for alternative diagnoses. His
CSF values at diagnosis are below.

Parameter Value
White blood cells 10 cells/mm3

Lymphocytes 92% of nucleated cells

Monocytes 8% of nucleated cells

Red blood cells 0 cells/mm3

Protein 48 mg/dL

Oligoclonal bands unique to the CSF 9

The patient was diagnosed with relapsing MS and treated with high-dose
corticosteroids (1 g IV methylprednisolone for 3 days) with significant
improvement in his neurologic examination. His preference for treatment
strategy was an escalation approach, prioritizing safety over efficacy.
Despite extensive discussion of the potential risks of permanent neurologic
disability from MS, he and his parents preferred this approach.
He started treatment with an interferon beta. He had frequent
relapses every 2 to 3 months, including worsening of ataxia, but
responded repeatedly to steroids. After 6 months on interferon beta, his
brain MRI showed 4 enhancing lesions and 10 new nonenhancing T2
lesions. A transition to natalizumab was advised, but he declined for
safety concerns, preferring a trial of glatiramer acetate. Relapses
continued every 2 to 3 months including development of an internuclear
ophthalmoplegia and bladder and bowel dysfunction. Two courses of
steroids were administered during this time. Six months after starting
glatiramer acetate, MRI showed 3 new enhancing lesions and 10 new
nonenhancing T2 lesions. JC virus antibody testing became available, and
he was found to be JC virus antibody negative. He transitioned to
natalizumab with complete control of new T2 lesions and enhancing
lesions within 6 months and no clinical relapses since starting
natalizumab. His neurologic examination improved markedly on
natalizumab, with only minimal dysmetria on examination, constipation,
and an Expanded Disability Status Scale score of 2.0.

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FIGURE 3-1
Imaging from the patient in CASE 3-1.
Initial sagittal fluid-attenuated
inversion recovery (FLAIR) brain MRI
revealed multiple lesions in the
periventricular, juxtacortical, and
subcortical regions, including the
bilateral cerebellar peduncles and
brainstem, as well as cervical spine (A).
Some but not all demonstrated
gadolinium contrast enhancement on
sagittal postcontrast T1-weighted MRI (B).

This patient, diagnosed at the time of limited disease-modifying therapy COMMENT

(DMT) options, demonstrates a case with multiple prognostic indicators of
aggressive disease that escalated to a high-efficacy treatment over the
course of 1 year. Treatment with a modest-efficacy agent was agreed on
following an evidenced-based discussion and shared decision making. The
first two DMT choices did not stop new disease activity. However, the strong
therapeutic alliance that had developed between the patient and provider
resulted in acceptance of an initially feared treatment. Here, repeated MRI
surveillance provided necessary information to guide this patient with a low
risk tolerance to transition to a high-efficacy treatment early in his disease
course, improving his long-term prognosis. MRI provides a high-sensitivity
assessment of DMT effectiveness and should be done at a minimum yearly
basis to monitor response to DMT in a patient with relapsing MS.20

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 TREATMENT OF MULTIPLE SCLEROSIS

DISCONTINUATION OF DISEASE-MODIFYING THERAPY

Immunosenescence, which refers to age-associated decline of the immune
system function, may simultaneously increase the risk of immunotherapies and
reduce the inflammatory activity of MS disease in older individuals. In
recognition of this, with concerns regarding the safety of DMTs in the aging MS
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population, coupled with the potential waning efficacy of currently available

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DMTs in older adults6 and the massive cost of decades of immunotherapy,

evaluations of treatment discontinuation are underway. Retrospective cohort
studies have examined the question of discontinuation, but these studies suffer
from methodologic challenges as do prospective studies comparing escalation
and early high-efficacy treatment strategies. One MSBase study found that
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discontinuation of injectable DMTs after an extended relapse-free period

was associated with disease progression in all adults, although relapse risk was
not different between those who remained on treatment.21 Evidence suggests
that patients 45 years old and older who discontinue DMT after a period of
stability are more likely to have a stable disease course versus those younger than
45 at discontinuation, who are more likely to have a new attack or radiographic
disease activity.22 A pragmatic, PCORI-funded study, DISCOMS
(Discontinuation of DMT in MS), is fully enrolled with results expected in 2022.
It prospectively evaluates randomized discontinuation of DMT in patients with
MS who are 55 years old and older and who have had 5 years of stable disease.

DISEASE-MODIFYING THERAPY
The MS field is arguably the first subspecialty within neurology to have effective
DMTs. Since 1993, when interferon beta-1b was approved by the FDA, those
with relapsing MS have benefitted from the possibility of reducing future relapses
and subsequent disability. In 1996, glatiramer acetate and interferon beta-1a
were also FDA approved for the treatment of patients with relapsing forms of MS.
In general, the interferons beta (five different ones are now available) and
glatiramer acetate reduce annualized relapse rates by about 20% to 30%. Moreover,
these DMTs delay developing definite MS in those with CIS who are at high risk.
Now, more than 28 years after the first DMT was approved, those with MS benefit
from 19 FDA-approved DMTs, several with generic versions available.
The DMTs for relapsing MS can be categorized by their mechanism of action.
Thus far, the DMTs for relapsing MS comprise 10 different mechanisms of
action. The approved agents have distinct risk profiles, and, in general, the more
effective the DMT, the greater the associated risks. The interferons beta and
glatiramer acetate are considered immunomodulatory, but the remaining DMTs
are all considered to be immunosuppressive in varying degrees. Patients taking
any of the immunosuppressive DMTs should be monitored for infection and
need to keep up to date on all appropriate cancer screening. Patients with active
infections should not start treatment with any of the immunosuppressive DMTs
until the infection is treated. Vaccination with live or live-attenuated vaccines is
generally not recommended for people taking an immunosuppressive DMT.
Studies of immunologic responses to inactivated vaccines have been done for
many of the available DMTs. Several studies have also now examined responses
to mRNA COVID-19 vaccines, finding intact humoral responses for most DMTs,
with the exception of sphingosine-1-phosphate receptor modulators and
B cell–depleting monoclonal antibodies where lowered responses have been
observed in several studies.23-25

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 Currently, the MS field lacks any proven way to choose the best DMT for an KEY POINTS
individual patient. Clinicians choose agents based on the balance of efficacy
● Immunosenescence, the
versus risks in balance with the aggressiveness of disease, comorbid conditions in decline of immune system
an individual patient, and patient preference. In the United States, insurance function with advancing age,
coverage often plays a role in DMT selection. may render an older patient
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In the following sections, DMTs for MS are discussed, categorized based on more susceptible to the
infectious or neoplastic risks
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the mechanism of action. In each section, the type of patient with MS for which
of DMTs.
the medication is approved, data on clinical efficacy, MRI effects, safety,
comments related to pregnancy risks and response to vaccinations, and ● DMTs for relapsing MS
mechanism of action are discussed, and they are summarized in TABLE 3-1.26-49 have proliferated and
TABLE 3-2 provides guidance on vaccinations and responses to vaccinations for diversified, with improved
efficacy, variable routes of
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each DMT.23,50-59 administration, and

generally an acceptable
Interferons Beta safety and tolerability
In 1993, interferon beta-1b was the first DMT approved for MS.27 Five distinct profile since the first
approval of DMT in 1993.
versions of the type I interferon beta are now approved for CIS, RRMS, and One agent is approved for
active secondary progressive MS (SPMS) in adults. The interferons beta are all primary progressive MS, and
given by subcutaneous or IM injections. The efficacy versus placebo in one for pediatric MS.
annualized relapse rate for patients with relapsing MS ranges from 18% reduction
● The first approved class
by interferon beta-1a at 30 μg/wk IM to 32% for interferon beta-1a at 44 μg 3 times
for relapsing MS in 1993,
a week subcutaneously and 31% reduction for standard-dose interferon beta-1b interferons beta ushered in
subcutaneously every other day. To gauge the relative efficacies among the treatment era of
interferons beta, at least one study found a dose effect, with a higher interferon relapsing MS and have a
long-standing safety track
beta-1a dose providing more benefit as measured by the annualized relapse
record.
rate.60 In studies of higher-dosed interferon beta-1a and -1b, MRI activity was
reduced by around 80% versus placebo.27 In various studies, disability worsening
was reduced by 30% to 40% versus placebo by the interferons beta. A large
MSBase observational study of more than 14,000 patients with RRMS, in which
the vast majority were taking one of the interferons beta or glatiramer acetate,
showed that treatment reduced disability accrual by 19% to 44% (and risk of
requiring a walking aid by 67%) over a median follow-up of 6 years.61
The interferons beta have been associated with increased rates of depression,
hepatotoxicity, allergic reactions, leukopenia, thrombocytopenia, thrombotic
microangiopathy, seizures, necrosis, and infections at injection sites, but these
are all uncommon. Hepatic transaminases and complete blood cell counts
(CBCs) should be monitored at least annually. These drugs are considered
immunomodulatory, not immunosuppressive, and are not associated with
opportunistic infections or increased cancer rates. Common side effects include a
flulike feeling lasting for several hours after a dose, which can be lessened by
nonsteroidal anti-inflammatory medications or acetaminophen. Depression and
suicide have been reported to occur with increased frequency in patients
receiving interferons beta. Neutralizing antibodies against interferon beta can
develop, reducing or obviating effectiveness.
As of 2020, interferons beta are considered nonteratogenic based on
cumulative real-world pregnancy data. It is considered safe to breastfeed while
using interferon beta. Numerous studies have reported adequate immune
responses to a variety of vaccine types in patients with MS treated with
interferons beta.51
Despite more than 30 years of study, the mechanism of action of interferons
beta in MS is not fully established. Although the available interferons beta have

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 TREATMENT OF MULTIPLE SCLEROSIS

TABLE 3-1 Approved Disease-Modifying Therapies for Multiple Sclerosis

Efficacy (versus placebo, unless otherwise noted)

Disease-
modifying Subtype of multiple Annualized relapse
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treatment sclerosis rate reduction Disability reduction MRI

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Interferon Clinically isolated 18% for 30 μg/wk; 32% for Interferon beta-1a New/persisting
beta-1a syndrome (CIS), 44 μg 3 times a week versus 30 μg/wk and 44 μg 3 times gadolinium-enhancing
relapsing-remitting placebo a week reduced by 37% and lesion or new/
multiple sclerosis 30%, respectively, versus enlarging T2 lesion
(RRMS), active placebo reduced 81% by 44 μg
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secondary 3 times a week

progressive MS subcutaneously
(SPMS) versus placebo

Interferon CIS, RRMS, active 31% for 250 μg every other No effect in phase 3 RRMS 83% reduction in rate
beta-1b SPMS day versus placebo trial; analysis of two SPMS of active lesions over
trials found risk of 6-month 3 years versus
confirmed disability placebo
progression reduced by
20%, and by 30-40% in
active SPMS

Glatiramer CIS, RRMS, active 29% versus placebo 28% lower disability versus T1-weighted
acetate SPMS placebo over 2-year trial, gadolinium-enhancing
disability defined by 1.0 lesions at months 6
Expanded Disability Status and 12 reduced by 45%
Scale score increase versus placebo

Teriflunomide CIS, RRMS, active 31-36% reduction versus 30% and 31% reduction in 80% reduction in
SPMS placebo at 14 mg/d 12-week confirmed gadolinium-enhancing
disability progression lesions versus placebo
versus placebo at 14-mg dose

Fumarates

Dimethyl CIS, RRMS, active 44-53% reduction versus Confirmed disability Gadolinium-
fumarate SPMS placebo progression proportion enhancing lesions
reduced by 38% (significant) reduced by 90% and
and 21% (nonsignificant) 74%

Diroximel CIS, RRMS, active Diroximel fumarate and Not studied Not studied
fumarate and SPMS monomethyl fumarate
monomethyl have the same active
fumarate metabolite as dimethyl
fumarate; diroximel
fumarate and monomethyl
fumarate were approved
at doses yielding an
equivalent amount of the
active metabolite to
dimethyl fumarate

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 CONTINUED FROM PAGE 1032
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Mechanisms of action Monitoring References

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Inhibits proinflammatory cytokines, such as Complete blood cell De Stefano N et al, 201426
interferon gamma, tumor necrosis factor-α, and count (CBC), liver
lymphotoxin; increases interleukin 10; reduced function tests (LFTs),
adhesion molecule and class II MHC expression thyroid-stimulating
hormone (TSH)
mcYM3Np3kcfSeh/dT6Z8hFUcZWtoLaDNpWA+ps2y++u0X on 06/18/2024

Inhibits proinflammatory cytokines, such as CBC, LFTs, TSH IFNB Multiple Sclerosis
interferon gamma, tumor necrosis factor-α, and Study Group, 199327
lymphotoxin; increases interleukin 10; reduced
adhesion molecule and class II MHC expression

Alters T cell cytokine profile toward that of Th2 No laboratory monitoring Johnson KP et al, 199528
immunomodulatory cells; induces regulatory T cells

Inhibits dihydroorotate dehydrogenase, thereby LFTs, blood pressure Confavreux C et al,

inhibiting lymphocyte proliferation clinical monitoring for 201429
peripheral neuropathy

Activates nuclear factor erythroid 2-related factor 2 CBC with differential, Gold R et al, 201230;
(Nrf2) pathway, which enhances response to LFTs Fox RJ et al, 201231
oxidative stress

Activates nuclear factor erythroid 2-related factor 2 CBC with differential, Package inserts32,33
(Nrf2) pathway, which enhances response to LFTs
oxidative stress

CONTINUED ON PAGE 1034

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 TREATMENT OF MULTIPLE SCLEROSIS

CONTINUED
CONTINUED FROM FROM PAGE 1033
PAGE 1033

Efficacy (versus placebo, unless otherwise noted)

Disease-
modifying Subtype of multiple Annualized relapse
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treatment sclerosis rate reduction Disability reduction MRI

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Sphingosine-1-phosphate receptor modulators

Fingolimod CIS, RRMS, active 50% versus placebo;52% 30% confirmed disability 30% reduction in rate
SPMS in adults and versus interferon beta-1a progression reduction of brain volume
children aged 30 μg/ week versus placebo in adults; reduction versus
10 years and older no difference versus placebo or interferon
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82% versus interferon

interferon beta-1a beta-1a 30 μg/wk in
beta-1a 30 μg/wk in
30 μg/wk in children older adults and 66%
children 10-17 years old
than 12 months reduction versus
interferon beta-1a
30 μg/wk in
gadolinium-enhancing
lesions in children
10-17 years old

Siponimod CIS, RRMS, active 55% versus placebo in 21% 3-month confirmed 79% reduction in T2
SPMS SPMS disability progression lesion volume
reduction versus placebo in
SPMS

Ozanimod CIS, RRMS, active 38% and 48% reduction No statistical difference 53% and 63% reduction
SPMS versus interferon beta-1a for confirmed disability in gadolinium-
30 μg/wk progression versus enhancing lesions
interferon beta-1a 30 μg/wk versus interferon
beta-1a 30 μg/wk

Ponesimod CIS, RRMS, active 30.5% versus teriflunomide No statistical difference New T1-weighted
SPMS 14 mg/d for confirmed disability gadolinium-enhancing
progression versus lesions reduced by
teriflunomide 58.5% versus
teriflunomide

Oral cladribine RRMS and active 58% versus placebo Nonsignificant reduction in Median T1-weighted
SPMS, after 3-month confirmed gadolinium-enhancing
suboptimal response disability progression lesions and active
to one or more T2-weighted lesions
disease-modifying reduced
therapy

Natalizumab CIS, RRMS, and 67% versus placebo 42% reduction in 12-week 92% reduction in
active SPMS confirmed disability T1-weighted
progression gadolinium-enhancing
lesions

Anti–CD20- CIS, RRMS, active In relapsing MS: 46% and In relapsing MS: 40% 94% and 95% reduction
ocrelizumab SPMS, primary 47% compared with reduction in 12-week in T1-weighted
progressive MS interferon beta-1a 44 μg confirmed disability gadolinium-enhancing
3 times a week progression versus lesions versus
subcutaneously interferon beta-1a; in interferon beta-1a
primary progressive MS: 44 μg 3 times per
24% reduction in 12-week week
confirmed disability
progression versus placebo

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 CONTINUED FROM PAGE 1034
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Mechanisms of action Monitoring References

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Modulates sphingosine-1-phosphate receptors 1, 3, CBC with differential, Cohen JA et al, 201034;

4, and 5; must be phosphorylated before being LFTs, ophthalmology, Kappos L et al, 201035;
active in vivo; lymphocytes unable to migrate out of dermatology, blood Chitnis T et al, 201836
lymphoid tissue; may have direct effects in central pressure
mcYM3Np3kcfSeh/dT6Z8hFUcZWtoLaDNpWA+ps2y++u0X on 06/18/2024

nervous system (CNS)

Modulates sphingosine-1-phosphate receptors 1 CBC with differential, Kappos L et al, 201837

and 5; lymphocytes are unable to migrate out of LFTs, ophthalmology,
lymphoid tissue; may have direct effects in CNS dermatology, blood
pressure

Modulates sphingosine-1-phosphate receptors 1 CBC with differential, Cohen JA et al, 201938;

and 5; lymphocytes are unable to migrate out of LFTs, ophthalmology, Comi G et al, 201939
lymphoid tissue; may have direct effects in CNS dermatology, blood
pressure

Modulates sphingosine-1-phosphate receptor 1; CBC with differential, Kappos L et al, 202140

lymphocytes are unable to migrate out of lymphoid LFTs, ophthalmology,
tissue; may have direct effects in CNS dermatology, blood
pressure

Cytotoxic to T and B lymphocytes by impairing DNA CBC with differential, Giovanni G et al, 201041
synthesis LFTs

Monoclonal antibody targeting the alpha 4 LFTs and JC virus Polman CH et al, 200642
integrins, part of the VLA-4 adhesion molecule antibody

Lytic monoclonal antibody targeting CBC with differential, Hauser SL et al, 201743;
CD20 molecule on surface of B cells lymphocyte subsets, Montalban X et al,
quantitative 201744
immunoglobulins, LFTs

CONTINUED ON PAGE 1036

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 TREATMENT OF MULTIPLE SCLEROSIS

CONTINUED FROM PAGE 1035

CONTINUED FROM PAGE 1035

Efficacy (versus placebo, unless otherwise noted)

Disease-
modifying Subtype of multiple Annualized relapse
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treatment sclerosis rate reduction Disability reduction MRI

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Anti–CD20- CIS, RRMS, active 51% and 59% compared with 34.4% reduction in 12-week 98% and 94% reduction
ofatumumab SPMS teriflunomide 14 mg/d confirmed disability in T1-weighted
progression versus gadolinium-enhancing
teriflunomide lesions versus
teriflunomide 14 mg
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daily

Anti–CD52- RRMS and active 49-55% reduction versus 42% reduction in confirmed Nonsignificant
alemtuzumab SPMS, after interferon beta-1a disability progression in reduction in
suboptimal 44 μg 3 times a week study 1, no significant T2-weighted lesion
response to two or reduction in study 2 versus volume versus
more other agents interferon beta-1a 44 μg interferon beta-1a
3 times per week 44 μg 3 times per week

Mitoxantrone SPMS, worsening 66% reduction versus 64% reduction in 3-month 59% reduction in new
RRMS; note: 3 placebo in RRMS confirmed disability lesions over 2 years in
randomized progression in worsening RRMS
controlled trials had RRMS and SPMS
only 287 subjects
with MS in total

different dosages and administration regimens, they all are thought to have the
same mechanism of action. Interferon beta-1a is identical to endogenous human
interferon beta-1a. Interferon beta-1b differs from interferon beta-1a by a single
amino acid and is not fully glycosylated. Interferons beta bind to specific
receptors on the membranes of human cells, inducing gene expression. Increased
expression of the immunoregulatory cytokine interleukin 10 and increased
circulating soluble VCAM-1 were shown in patients with MS treated with
interferons beta compared with placebo.62,63 Additional interferon beta effects
include increased suppressor T-cell activity, reduced proinflammatory cytokine
production, and decreased antigen presentation to T cells.

Glatiramer Acetate
Glatiramer acetate was initially FDA approved for RRMS by the FDA in 1996.
Subsequently, approval was expanded to include CIS and active SPMS in adults.
Like the interferons beta, glatiramer acetate is delivered parenterally by a
subcutaneous injection at 20 mg daily or 40 mg 3 times a week. The drug has an
interesting history. It was originally produced to mimic myelin basic protein, a
major protein component of myelin, and is a random polymer of the four most
abundant amino acids in myelin basic protein. In a multicenter trial of about 250
total patients with RRMS, the annualized relapse rate was reduced by 29% with
borderline statistical significance.28 In a similarly sized study enrolling similar
patients, the cumulative number of gadolinium-enhancing lesions was reduced
by 35% versus placebo.64 In a randomized controlled trial in patients with CIS,
the time to development of a second attack was significantly delayed in those on

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 CONTINUED FROM PAGE 1036
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Mechanisms of action Monitoring References

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Lytic monoclonal antibody targeting CD20 molecule CBC with differential, Hauser SL et al, 202045
on surface of B cells lymphocyte subsets,
quantitative
immunoglobulins, LFTs
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Monoclonal antibody that lyses cells expressing CBC with differential, Cohen JA et al, 201246;
CD52 lymphocyte subsets, Coles AJ et al, 201247
LFTs, TSH, creatinine,
urinalysis

Anthracenedione chemotherapeutic agent causing CBC with differential, Millefiorini E et al, 199748;
myelosuppression LFTs, cardiac ejection Hartung HP, et al, 200249
fraction

glatiramer acetate compared with placebo; 24.7% of patients taking glatiramer

acetate versus 42.9% in the placebo group developed a relapse within
36 months.65 In a 12-month study of 40-mg subcutaneous injections 3 times a
week, the cumulative number of T1-weighted gadolinium-enhancing lesions at
months 6 and 12 was reduced by 45%, and a 34% reduction in confirmed relapses
versus placebo was seen.66
Glatiramer acetate has no known drug interactions, no recommended
laboratory monitoring, and no associations with opportunistic infections or
cancer. Side effects include the immediate postinjection reaction, which includes
at least two of the following: flushing, chest pain, palpitations, tachycardia,
anxiety, dyspnea, constriction of the throat, and urticaria. The reaction is self-
limited, requires no treatment, typically occurs infrequently in an individual, and
poses no health risk. Lipoatrophy at injection sites may develop with prolonged
use. Glatiramer acetate is considered safe for women to take at the time of
conception and throughout pregnancy with no increased risk of teratogenicity or
fetal loss, and it is safe to use while breastfeeding. A large database of exposures
to branded glatiramer acetate during pregnancy showed no increase in risk of
congenital anomalies versus the general population.67
Several studies have addressed the responses to vaccinations in patients with
MS who are taking glatiramer acetate in comparison with those on other DMTs
and with healthy controls. Most have examined responses to seasonal influenza
vaccines. The majority reported reduced responses compared with controls and
with patients treated with interferons beta but still at levels considered to
be protective.51

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 TREATMENT OF MULTIPLE SCLEROSIS

TABLE 3-2 Vaccine Considerations When Using Disease-Modifying Treatments

Disease-modifying Effect of disease-modifying therapy on

treatment Guidance on vaccinations50 vaccination responsesa and level of evidence References
yrcUFRwFKruqWNgh290rRP7iLxJJDfJ9S+eCEqoqElVEq80qB8qUDU79Tip6hCYLjYDhpK+DMyagl7K2pMc6w8whxSzj8VfBbApX

Interferon beta-1a No need to delay starting one or Mostly observational studies of effects on Ciotti JR et al,
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and interferon alter dosing of interferons beta seasonal influenza, tetanus/diphtheria, and 202051
beta-1b for any vaccination; no pneumococcal polysaccharide vaccine (PPSV23)
contraindication for live or vaccines; no adverse effect on vaccine
live-attenuated vaccines effectiveness has been shown; level 3 evidence

Glatiramer acetate No need to delay starting or alter Mostly observational studies examined effects Ciotti JR et al,
202051
mcYM3Np3kcfSeh/dT6Z8hFUcZWtoLaDNpWA+ps2y++u0X on 06/18/2024

dosing for any vaccination; no on seasonal influenza and PPSV23 vaccines;

contraindication for live or reduced rates of seroprotection were observed
live-attenuated vaccines in some but not all studies but still achieving
seroprotection for most; level 3 evidence

Teriflunomide No need to delay starting or alter Randomized controlled trial in healthy people Bar-Or A et al,
dosing for vaccination found lower humoral responses to neoantigen 201552
(rabies) than with placebo; all subjects on
teriflunomide achieved seroprotective
responses; no impact on cellular memory
response to recall antigens; level 2 evidence

Fumarates

Dimethyl No need to delay starting or alter Dimethyl fumarate treatment does not reduce Ciotti JR et al,
fumarate, dosing for vaccinations T cell–dependent and humoral immune 202051
diroximel responses; level 3 evidence
fumarate, and
No data on diroximel fumarate and monomethyl
monomethyl
fumarate
fumarate

Sphingosine-1-phosphate receptor modulators

Fingolimod Delay starting for 4 weeks after Blinded randomized controlled trial of response Achiron A
any necessary vaccinations; to seasonal influenza vaccine and tetanus et al, 202123;
pediatric patients, if possible, booster showed 35-45% reduced proportion Kappos L et al,
should be up to date with all achieving seroprotective titers versus placebo; 201553
immunizations before initiating level 2 evidence
fingolimod; avoid live and
Observational study of humoral response to
live-attenuated vaccines during
BNT162b2 COVID-19 mRNA vaccine found only 3.
and for 2 months after treatment
8% (versus 100% of patients with untreated
because of the risk of infection
multiple sclerosis [MS]) mounted a protective
humoral antibody response; level 3 evidence
Vaccinations may be less effective during and for
up to 2 months after discontinuation of
fingolimod

Siponimod Delay starting siponimod for Randomized controlled trial showed reduced Ufer M et al,
4 weeks after necessary response in healthy people taking siponimod to 201754;
vaccinations; if the patient is influenza A and B vaccinations; interruption of siponimod
already taking it, pause dosing improved response; vaccinations may be package
siponimod for 1 week before and less effective during and for up to 4 weeks after insert55
until 4 weeks after a planned discontinuation of siponimod; level 2 evidence
vaccination; avoid live and
live-attenuated vaccines during
and for 4 weeks after treatment

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1038 AUGUST 2022

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 CONTINUED FROM PAGE 1038

Disease-modifying Effect of disease-modifying therapy on

treatment Guidance on vaccinations50 vaccination responsesa and level of evidence References
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Ozanimod Delay starting for 4 weeks after No data available; vaccine responses are None
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necessary vaccinations; avoid expected to be similar to those of fingolimod; available

live and live-attenuated vaccines vaccinations may be less effective during and for
during and for 3 months after up to 3 months after discontinuation of ozanimod
treatment

Ponesimod Delay starting for 4 weeks after No data available; vaccine responses are None
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necessary vaccinations; avoid expected to be similar to those of fingolimod; available

live and live-attenuated vaccines vaccinations may be less effective during and for
during and up to 1-2 weeks after up to 2 weeks after discontinuation of
treatment ponesimod

Oral cladribine Delay starting or redosing by Oral cladribine did not reduce humoral antibody Achiron A
2-4 weeks after vaccination; if responses in patients with MS who were et al, 202123;
the patient is already taking it, receiving the BNT162b2 COVID-19 mRNA vaccine; Wu GF et al,
limited data suggest that altered one ongoing prospective study found protective 202156
timing of vaccination in relation responses to an influenza vaccine (Flucelvax) in 3
to drug dosing is not needed of 3 patients—two with low absolute lymphocyte
counts of 381 cells/mL and ~600 cells/mL; level 3
evidence

Natalizumab No need to delay starting or alter Small randomized controlled trial found a Kaufman M
dosing of natalizumab for nonstatistically significant trend for lower et al, 201457;
vaccination response to recall and neoantigen vaccines; Ciotti JR et al,
several observational studies found reduced 202051
responses to seasonal influenza vaccines;
studies suggest inadequate response to some
immunizations; level 3 evidence

Anti-CD20: Delay starting anti-CD20 Ocrelizumab: reduced humoral response to Achiron A

ocrelizumab and treatment by 2-4 weeks or more BNT162b2 COVID-19 mRNA vaccine (22.7% versus et al, 202123;
ofatumumab after vaccination 100% response of patients with untreated MS); Bar-Or A,
led to poorer humoral response to vaccinations 202058
to both recall and new antigens
Ofatumumab: treatment is expected to lead to
similar reductions in responses to vaccinations;
level 2 evidence

Anti–CD52: Delay starting drug by 2-4 weeks T cell–dependent antigen recall humoral McCarthy CL
alemtuzumab for necessary vaccinations; if the responses, IgG levels tested before and after et al, 201359
patient is already taking tetanus, diphtheria, polio, Haemophilus
alemtuzumab, vaccination is influenzae type b, meningococcal group C
most effective 24 weeks or more (neoantigen), and PPSV23 were all maintained,
after the last dose induced, or enhanced after vaccination;
vaccination within 6 months of treatment
resulted in a smaller proportion of responders;
T-cell responses to vaccination were not
analyzed; level 3 evidence

IgG = immunoglobulin; mRNA = messenger ribonucleic acid.

a
Note that most studies of responses to vaccination were observational, likely underpowered “convenience” studies of evidence level 3 or 4.
When level 2 evidence was available, it is specifically mentioned. Most studies examined only serologic responses and not cell-mediated
immunity.

CONTINUUMJOURNAL.COM 1039

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 TREATMENT OF MULTIPLE SCLEROSIS

Like the interferons beta, glatiramer acetate is considered immunomodulatory

and not immunosuppressive. The mechanism of action of glatiramer acetate
is not fully understood. Glatiramer acetate may alter T cells toward a less
inflammatory Th2 subtype. Other studies have found enhancement of regulatory
T cells.
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Teriflunomide
Teriflunomide is a once-daily oral medication that was FDA approved in 2012 for
adults with CIS, RRMS, and active SPMS. It is available in two tablet sizes, 7 mg
and 14 mg. Efficacy was better in the pivotal clinical trials for the higher dose of
14 mg/d, with a 31% to 36% reduction in the annualized relapse rate versus
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placebo and a 30% to 31% reduction in 12-week confirmed disability progression

versus placebo.68 An 80% reduction in gadolinium-enhancing lesions was seen at
the higher dose. Thus, most practitioners use the 14-mg/d dose. Notably, in a
head-to-head comparison trial versus interferon beta-1a 44 μg 3 times a week,
relapses were statistically more common with teriflunomide 7 mg/d and trended
toward being more common with teriflunomide 14 mg/d than with interferon
beta-1a.69
Patients should screen negative for latent tuberculosis before initiation.
Teriflunomide can be hepatotoxic, and thus, monthly hepatic function testing is
needed for at least 6 months after initiation. Peripheral neuropathy has been
associated with teriflunomide use, as has elevation of blood pressure. Commonly
reported side effects include nausea, headache, and transient hair thinning.
Teriflunomide has several potential drug interactions listed in its package
insert.70 Teriflunomide was teratogenic in animal studies and is contraindicated
in pregnant women and in males and females of reproductive potential who are
not using effective contraception. In the event of pregnancy or serious adverse
effects, accelerated removal of the drug can be achieved with cholestyramine or
activated charcoal given for 11 days.
Studies have revealed modest reductions in responses to vaccinations in those
on 14-mg/d teriflunomide. However, responses were seen, including in a study of
rabies vaccination in healthy individuals, where geometric mean titers for
antibodies were lower than with placebo, but all healthy subjects taking
teriflunomide achieved protective antibody levels.52
Teriflunomide inhibits dihydroorotate dehydrogenase leading to reduced de
novo pyrimidine synthesis. This prevents lymphocytes from actively
proliferating, thus limiting the number of lymphocytes that are activated and
able to access the central nervous system (CNS). This is the presumed
mechanism of action of teriflunomide in relapsing MS.

Fumarates
Dimethyl fumarate was FDA approved in 2013 for CIS, RRMS, and active
SPMS in adults. In two large studies, dimethyl fumarate reduced the annualized
relapse rate versus placebo by 53% and 44%.30 The proportion of people with
confirmed disability progression was reduced by 38% (significant) and 21%
(nonsignificant) in the two studies. The mean number of gadolinium-enhancing
lesions at the 2-year study end was reduced by 90% and 74%. Diroximel fumarate
and monomethyl fumarate have the same active metabolite as does dimethyl
fumarate. Diroximel fumarate and monomethyl fumarate were approved at
doses yielding an equivalent amount of this active metabolite.

1040 AUGUST 2022

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 Side effects of all the fumarates include flushing, which can be improved with KEY POINTS
a nonenteric-coated aspirin (81 mg or 325 mg) taken 30 minutes before, and
● A modest-efficacy
gastrointestinal disturbance (pain, diarrhea, nausea), which improves with time. self-injectable with no
For dimethyl fumarate, flushing is improved by taking the medication with food, monitoring requirements,
but diroximel fumarate should not be taken with a high-calorie, fatty meal or glatiramer acetate may be
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alcohol. In a 5-week double-blind randomized controlled trial, diroximel particularly appealing to

those who are prioritizing
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fumarate–treated patients had significantly fewer gastrointestinal symptoms

safety, are planning a
than dimethyl fumarate–treated patients.71 pregnancy, or are risk
Risks include hepatotoxicity, lymphopenia, and infections, including herpes averse.
infections and rare cases of progressive multifocal leukoencephalopathy (PML).
PML was associated with prolonged lymphopenia. Opportunistic infections have ● Teriflunomide
demonstrates a modest
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been reported with dimethyl fumarate, including infections with Nocardia, reduction in relapse paired
Listeria monocytogenes, Mycobacterium tuberculosis, and Aspergillus. Periodic with a reduction in
monitoring of CBCs with differential and liver function tests is recommended. confirmed disability
Women should not become pregnant while on one of the fumarates. It is not progression more commonly
seen with higher-efficacy
known how much of these DMTs is secreted in breastmilk; breastfeeding while DMTs.
taking them is not recommended. A small study of vaccine responses in patients
taking dimethyl fumarate did not find any reductions in T cell–dependent and ● Fumarates require
humoral immune responses.72 minimal screening for
initiation and safety
The fumarates activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)
surveillance. Twice daily
pathway in humans, which is a key factor in the cellular response to oxidative dosing must be achieved to
stress. This is speculated to be the main mechanism of action of dimethyl maintain efficacy.
fumarate in MS. However, the full mechanism of action of the fumarates in MS is
still being elucidated.

Sphingosine-1-phosphate Receptor Modulators

Fingolimod was approved in 2010 as both the first oral MS DMT and the first
sphingosine-1-phosphate (S1P) receptor modulator for human use. It is indicated
for CIS, RRMS, and active SPMS in patients 10 years of age and older. Its efficacy
was shown in two studies in adults, a 24-month study in comparison with
placebo and a 12-month study in comparison with interferon beta-1a.34,35 In these
studies, the annualized relapse rate was reduced by 50% versus placebo and 52%
versus interferon beta-1a at 30 μg/wk IM. The risk of confirmed disability
progression was reduced by 30% versus placebo in the 24-month study, but no
significant reduction in confirmed disability progression was noted in the shorter
12-month study versus active comparator. A 30% reduction in the rate of brain
volume reduction versus placebo was seen in both studies. In the 24-month
randomized controlled trial, 37.8% more patients on fingolimod than placebo
were free of gadolinium-enhancing lesions.35
The PARADIGMS randomized controlled trial studied 215 children aged 10 to
17 years old randomly assigned 1:1 to fingolimod or interferon beta-1a 30 μg/wk
IM, with the annualized relapse rate as the primary end point.36 The pediatric
patients with MS who were treated with fingolimod had an 82% lower annualized
relapse rate and 66% fewer gadolinium-enhancing lesions compared with those
taking interferon beta-1a.36 Fingolimod is currently the only FDA-approved oral
DMT for pediatric patients with RRMS.
Siponimod was approved in 2019 for adults with CIS, RRMS, and active SPMS.
This oral agent selectively modulates S1P receptors 1 and 5. It was studied in more
than 1500 patients with SPMS in a placebo-controlled randomized controlled trial
with the primary end point of reduction of confirmed disability progression.

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 TREATMENT OF MULTIPLE SCLEROSIS

Patients in that study were older (median age, 49 years) with longer disease
duration and more disability (median baseline EDSS score, 6.0) than is typical for
most trials done with other drugs for MS,37 but they were consistent with a
progressive MS cohort. Siponimod reduced confirmed disability progression by
21% versus placebo but did not significantly delay the time to 20% deterioration
yrcUFRwFKruqWNgh290rRP7iLxJJDfJ9S+eCEqoqElVEq80qB8qUDU79Tip6hCYLjYDhpK+DMyagl7K2pMc6w8whxSzj8VfBbApX

in the timed 25-foot walk. Although siponimod had a significant effect on disability
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progression compared with placebo in patients with active SPMS (with MS relapse
in the 2 years before the study), siponimod did not statistically improve disability
progression in those with inactive SPMS. Reduction in T2 lesion volume was
statistically improved by siponimod compared with placebo. The typical dose for
siponimod is 2 mg/d, but the dose depends on patient CYP2C9 genotype. If the
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patient has the CYP2C9*1/*3 or *2/*3 genotype, the dose is reduced to 1 mg/d.
Siponimod is contraindicated for CYP2C9 3*/3* homozygous patients.
Ozanimod is another selective S1P receptor 1 and 5 modulator, approved in
2020 for use in adults with CIS, RRMS, and active SPMS. The dose is 0.92 mg
once daily taken orally after an initial 7-day up-titration. Ozanimod is converted
to an active metabolite with a long biological half-life; the median time for
peripheral blood lymphocytes to normalize after discontinuation of the drug is
30 days. The active metabolite was approximately 50% lower in people who
smoked cigarettes. Ozanimod is contraindicated in patients taking a monoamine
oxidase inhibitor or with severe untreated sleep apnea.
Ozanimod was studied in two randomized controlled trials of approximately
850 patients each in which subjects were randomly assigned 1:1 to ozanimod or
interferon beta-1a 30 μg/wk IM. The annualized relapse rate was statistically
significantly lower in the ozanimod arm versus the comparator arm with mean
reductions of 38% and 48% in the two trials, and the number of gadolinium-
enhancing lesions was lower by 53% and 63%. New/enlarging T2 lesions were
significantly lower in the ozanimod groups, but a statistically significant
difference in 3- or 6-month confirmed disability progression was not observed
over 2 years.38,39
Ponesimod, an oral selective S1P receptor 1 modulator, was approved in 2021
for adults with CIS, RRMS, or active SPMS. Like siponimod and ozanimod, an
up-titration is required at initiation. Because of its short half-life, if 4 or more
consecutive doses are missed, titration should be reinitiated. Ponesimod was
studied in a randomized controlled trial of more than 1100 people with relapsing
MS in a 1:1 comparison to teriflunomide 14 mg/d. The primary end point,
annualized relapse rate, was reduced by 30.5%, and the number of new
gadolinium-enhancing lesions from baseline to week 108 was reduced by 58.5%.
No statistical difference was found for confirmed disability progression between
treatment groups.40
Fingolimod requires monitoring of the first dose because of the risk of
bradycardia or cardiac arrhythmia. All of the S1P receptor modulators are
contraindicated in any patient who within the prior 6 months had myocardial
infarction, unstable angina, stroke, transient ischemic attack, or decompensated
heart failure requiring hospitalization and in those with class III/IV heart failure,
Mobitz type II second-degree or third-degree atrioventricular block, or sick sinus
syndrome without a functioning pacemaker. An ECG should be done before
prescribing any of the S1P receptor modulators. Pulmonary evaluation may be
needed for people with a history of asthma or chronic obstructive pulmonary
disease. Infections are increased with all DMTs of the S1P receptor modulator

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 class. Patients should be monitored for infections, including PML and KEY POINT
cryptococcal disease. All patients should have evidence of prior varicella-zoster
● Sphingosine-1-phosphate
virus (VZV) infection or be vaccinated against VZV before initiation of an S1P modulators offer moderate
receptor modulator. Monitoring for macular edema is needed, especially in the efficacy with some safety
initial year of treatment. Patients with diabetes mellitus or uveitis are at increased risks including cardiac
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risk for macular edema, which is typically reversible on prompt discontinuation effects, macular edema, and
rebound of relapses but
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of the S1P receptor modulator.

excellent tolerability.
Additional risks and side effects (discussed in the package inserts55,73-75) for Fingolimod is US Food and
this class of drug include risk of rebound of MS activity after discontinuation, Drug Administration (FDA)
posterior reversible encephalopathy syndrome (PRES), and the potential for approved for use in
pediatric MS.
increased malignancies including several types of lymphoma.
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Pregnancy must be avoided in women taking any of the S1P receptor

modulators because these drugs can cause fetal harm.
Live-attenuated vaccines are contraindicated during treatment with any of the
S1P receptor modulators. Data from studies of fingolimod and siponimod suggest
that vaccinations are less effective during treatment with S1P receptor
modulators. Responses to vaccinations in people taking fingolimod were studied
in a randomized, multicenter, placebo-controlled study with seasonal influenza
vaccine and tetanus toxoid booster. The proportion achieving seroprotection was
reduced by 22% to 50% in those on fingolimod.53 In a study of humoral responses
in patients with MS receiving the BNT162b2 COVID-19 mRNA vaccine, only
3.8% (versus 100% of patients with untreated MS) mounted a protective
humoral antibody response.23
Siponimod has a short biological half-life, with lymphocytes returning to the
circulation 7 to 10 days after drug discontinuation. Responses to influenza and
pneumococcal vaccinations were assessed in healthy people treated with
uninterrupted siponimod versus a scenario of treatment interruption from
10 days before until 14 days after vaccination. The interrupted siponimod group
responded better to influenza A and B vaccinations than those who took
siponimod without interruption.54 Stopping siponimod 7 to 10 days before
vaccination and resuming siponimod (with up-titration) 2 or more weeks later is
a potential strategy to improve vaccine response. A strategy of drug interruption
around vaccinations might also be useful for ponesimod, which has a similarly
short biological half-life. When stopping S1P receptor modulators, the possibility
of MS disease activity rebound should be weighed against the benefits of
improved vaccination response.
Clinical vaccination studies have not been reported yet for ozanimod and
ponesimod. A phase 3b, multicenter, open-label study of the immune responses
to several vaccines is ongoing for patients receiving ozanimod.76
The mechanisms of action of S1P receptor modulators are not fully known.
These drugs down-modulate the S1P1 receptor on lymphocytes, resulting in
functional antagonism that inhibits lymphocyte exit from secondary lymphoid
tissues. The presumed main mechanism of action of all of the S1P receptor
modulators is reduction in lymphocyte trafficking into the CNS due to
sequestration of otherwise intact lymphocytes in lymphoid tissues. Additionally,
S1P receptor modulators all cross the blood-CNS barrier, where they can interact
with S1P receptors found on oligodendrocytes, neurons, and astrocytes and
affect neurogenesis and cellular function and migration. Fingolimod was shown
to modulate human oligodendroglial cells in vitro and to possibly enhance
remyelination capacity.77

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 TREATMENT OF MULTIPLE SCLEROSIS

Cladribine
This oral cytotoxic drug was FDA approved in 2019 for adults with RRMS or
active SPMS. Use is recommended only after suboptimal response to another
DMT. It is given at 3.5 mg/kg administered orally and divided into two treatment
courses (1.75 mg/kg per course) at least 43 weeks apart. Each treatment course is
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divided into two treatment cycles, which occur 23 to 27 days apart.

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Oral cladribine reduced the annualized relapse rate by 58% versus placebo in
one study of more than 850 patients with active relapsing MS. Three-month
confirmed disability progression was not statistically reduced. The median
number of gadolinium-enhancing lesions and the median number of active T2
lesions were each zero versus 0.33 and 0.67, respectively, in the patients given
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a placebo.41
Patients should be monitored for infections. Antiherpes prophylaxis is given
to those with lymphocyte counts less than 200 cells/mL. Before use, testing to
exclude those with active or latent human immunodeficiency virus (HIV),
tuberculosis, hepatitis B, hepatitis C, and other acute infection should be done.
Patients who are antibody negative to VZV should be vaccinated before
treatment. Treatment may increase the risk of malignancy; oral cladribine is
contraindicated for those with an active malignancy. Oral cladribine is
contraindicated for use in pregnancy and lactation. Effective contraception
should be used while taking cladribine. Because oral cladribine may reduce the
effectiveness of oral contraceptives, a barrier contraceptive should be added
during and for at least 4 weeks after each treatment course. Men of reproductive
potential should use effective contraception when taking oral cladribine.
Vaccination with live or live-attenuated vaccines should be 4 weeks before
therapy initiation, and these vaccines are contraindicated during oral cladribine
treatment. Oral cladribine did not reduce humoral antibody responses in Israeli
patients with MS who were receiving the BNT162b2 COVID-19 mRNA vaccine.23
One ongoing prospective study found protective responses to an influenza
vaccine (Flucelvax) in 3 of 3 oral cladribine–treated patients tested, one who had
low absolute lymphocyte counts of 381 cells/mL.56
Oral cladribine impairs DNA synthesis and probably works in relapsing MS
through its cytotoxic effects on both B and T lymphocytes. Typically, the nadir of
lymphocyte counts occurs 2 to 3 months after the start of each treatment cycle.
Oral cladribine can penetrate the blood-CNS barrier.

Natalizumab
Natalizumab is a monoclonal antibody delivered at 300 mg by IV infusion every
4 weeks that is indicated for CIS, RRMS, and active SPMS in adults. Initially
approved in 2004, it was temporarily removed from the market in 2005 by the
manufacturer when PML developed in some patients receiving it. The drug was
subsequently made available as part of a Risk Evaluation and Mitigation
Strategies (REMS) program in 2006. Natalizumab was studied in patients with
active RRMS in two randomized controlled trials, in one study as a monotherapy
versus placebo and in the other study in combination with interferon beta-1a
30 μg/wk versus interferon beta-1a alone. The annualized relapse rate was
reduced by 67% versus placebo and by 56% when in combination with interferon
beta-1a versus interferon beta-1a plus placebo.42,78 As a monotherapy,
natalizumab reduced the mean number of gadolinium-enhancing lesions by 92%
versus placebo.

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 Natalizumab has been associated with excess infections, including herpetic KEY POINTS
infections. Natalizumab increases the risk of developing encephalitis and
● The short courses of oral
meningitis caused by herpes simplex virus and VZV. In addition to PML, an cladribine therapy may
infection of cerebellar granule cells by JC virus has been seen, which is associated present a unique
with ataxia and managed similarly to PML. Although rare, other opportunistic opportunity for those with
yrcUFRwFKruqWNgh290rRP7iLxJJDfJ9S+eCEqoqElVEq80qB8qUDU79Tip6hCYLjYDhpK+DMyagl7K2pMc6w8whxSzj8VfBbApX

infections (including Pneumocystis jirovecii pneumonia, pulmonary adherence challenges or

plans for pregnancy after a
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Mycobacterium avium-intracellulare, bronchopulmonary aspergillosis, and

full two-cycle course.
Burkholderia cepacia) have been observed. Natalizumab has been uncommonly
associated with severe hepatoxicity. Regarding PML, the risk is almost 100% ● Rapid control of relapsing
confined to people with antibodies to the JC virus. Extended interval dosing MS can be achieved with
(every 6 weeks) may reduce risk of PML without increased MS activity.79 natalizumab, but careful
pharmacovigilance is
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Neutralizing antibodies against natalizumab can develop, negating effectiveness needed to surveil for
of the drug. Abrupt discontinuation of natalizumab can result in renewed or progressive multifocal
rebound MS activity, and it is advisable to commence another DMT within leukoencephalopathy.
12 weeks after stopping natalizumab.80 In practice, minimizing the washout Extended interval dosing
provides a rational
period to 4 to 6 weeks to diminish rebound relapse risk is balanced with potential approach to mitigating
risk of PML.81 progressive multifocal
Pregnancy is not generally recommended for women taking natalizumab. leukoencephalopathy risk.
Fetal malformation and pregnancy loss are not specific concerns, but exposure in Natalizumab is considered
safe for patients who are JC
the third trimester may cause reversible hematologic alterations.82,83 In pregnant virus antibody negative.
patients with highly active disease, administration of natalizumab has been
studied, and small studies suggest that treatment through the first trimester may ● Anti-CD20 treatments
reduce risk of MS disease activation compared with discontinuation at the time of provide high efficacy with a
rapid onset of benefits.
conception.84 Natalizumab is detectable in breast milk.
Ocrelizumab is the only
Responses to vaccinations have been assessed in people taking natalizumab in agent approved for primary
several small studies, primarily examining humoral responses to seasonal progressive MS.
influenza vaccines. An inadequate response to immunization occurred in a
significant proportion of patients with MS who were being treated with
natalizumab.85,86 Vaccination with live or live-attenuated vaccines during
natalizumab treatment is not recommended.
Natalizumab binds to alpha 4 integrins expressed on the surface of
mononuclear leukocytes, including B and T lymphocytes, thereby blocking
interaction with their receptors. This prevents these cells from binding to
activated CNS endothelium, preventing trafficking of leukocytes across the
blood-CNS barrier. Natalizumab may also function by blocking movement
of cells through tissues, by blocking alpha 4 integrin interactions with
fibronectin.

Ocrelizumab and Ofatumumab

Ocrelizumab and ofatumumab are anti-CD20 cytolytic monoclonal antibodies
approved in 2017 and 2020, respectively, for CIS, RRMS, and active SPMS in
adults. Ocrelizumab is also approved for primary progressive MS in adults. The
dose for ocrelizumab is 600 mg IV every 6 months, and for ofatumumab it is
20 mg delivered subcutaneously monthly. Ocrelizumab was studied in patients
with relapsing MS in two large randomized controlled trials in which the drug
was compared with interferon beta-1a 44 μg subcutaneously 3 times a week.43
Ocrelizumab reduced the annualized relapse rate by 46% and 47% ( P < 0.0001 in
both) and 12-week confirmed disability progression by 40% ( P = 0.0006, two
studies combined). In the two relapsing MS studies, gadolinium-enhancing
lesions were reduced 94% and 95% ( P < 0.0001 for each). Ocrelizumab was also

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 TREATMENT OF MULTIPLE SCLEROSIS

studied versus placebo in patients with primary progressive MS and reduced

EDSS progression by 24% ( P = 0.03) and reduced worsening of the timed 25-foot
walk by 25%.44
Ofatumumab was studied in patients with relapsing MS in two large
randomized controlled trials in comparison to oral teriflunomide 14 mg/d.45
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Ofatumumab reduced annualized relapse rate by 51% and 59% (both P < 0.001).
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Three-month confirmed disability progression was reduced 34.4% ( P = 0.002,

two studies combined). Ofatumumab reduced gadolinium-enhancing lesions by
98% and 94% (both P < 0.001) versus teriflunomide.45
Hepatitis B virus screening and quantitative serum immunoglobulins are
required before starting either drug. Upper and lower respiratory infections and
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infections with herpes viruses are increased by anti-CD20 treatments. PML has
occurred, albeit rarely, in people taking anti-CD20 monoclonal antibodies. An
increased risk of malignancy with anti-CD20 treatments may exist. Breast cancer
occurred more frequently in ocrelizumab-treated patients in clinical trials.
Pregnancy is not recommended for women taking ocrelizumab or
ofatumumab. The risks of these drugs for the pregnant woman and for the baby
are not fully known. Ocrelizumab and ofatumumab are both IgG1 subtype
immunoglobulins that can cross the placental barrier. Transient peripheral B-cell
depletion has been seen in infants exposed to anti-CD20 antibodies
during pregnancy.
Any required immunizations with live or live-attenuated vaccines should be
completed at least 4 weeks before initiation of either drug. As B cell–depleting
drugs, both ocrelizumab and ofatumumab are expected to interfere with the
effectiveness of vaccines. This has been shown for ocrelizumab in a study of
patients with MS receiving the BNT162b2 COVID-19 mRNA vaccine, where only
22.7% (versus 100% of patients with untreated MS) mounted a protective
humoral antibody response.23 An earlier study investigated effects of
ocrelizumab on responses to other vaccine types. Patients taking ocrelizumab
had a poorer humoral response to vaccinations including vaccinations to both
recall and new antigens.58 Treatment with ofatumumab is expected to lead to
similar reductions in responses to vaccinations.
The mechanisms of action of these two anti-CD20 lytic monoclonal antibodies
are not entirely understood but likely relate to the important roles B lymphocytes
play in T-cell activation and in the production of proinflammatory cytokines and
chemokines. B lymphocytes are also important for the development of ectopic
lymphoid structures, which have been noted in the meninges of some patients
with MS and are associated with a worse MS course. Although B cells produce
antibodies and are the precursors of plasma cells, antibody levels in blood and
CSF are not affected early on when these drugs already reduce disease activity.
Thus, reduction in antibody production is not likely to play a major role in early
benefits of anti-CD20 agents.

Alemtuzumab
This anti-CD52 cytolytic monoclonal antibody that is approved in adults with
RRMS and active SPMS is delivered via IV infusion in a 5-day course, with a
second 3-day course 1 year later. FDA approval in 2001 was controversial because
of the single-blind nature of the clinical trials and the potential toxicities.46,47
Prescribers and pharmacies must be certified with a Risk Evaluation and
Mitigation Strategies program before using it.

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 Alemtuzumab is recommended only for patients with relapsing MS who have KEY POINT
had an inadequate response to two or more DMTs. Alemtuzumab was compared
● Close therapeutic alliance
with interferon beta-1a 44 μg subcutaneously 3 times a week in two single-blind is critical for prudent use of
studies. The annualized relapse rate was reduced 49% to 55% by alemtuzumab, high-efficacy alemtuzumab,
compared with interferon beta-1a, with a 42% reduction in 6-month confirmed requiring extensive
yrcUFRwFKruqWNgh290rRP7iLxJJDfJ9S+eCEqoqElVEq80qB8qUDU79Tip6hCYLjYDhpK+DMyagl7K2pMc6w8whxSzj8VfBbApX

disability progression in one study, but no significant reduction in confirmed laboratory monitoring for
4 years after a final infusion.
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disability progression in the other study.46,47

Serious side effects of alemtuzumab include a potentially life-threatening
infusion reaction. Anti–herpes virus prophylaxis must be given from the first day
of the initial 5-day dosing period until either 2 months after completion of the
5-day treatment or until the CD4+ lymphocyte count is more than 200 cells/mL,
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whichever occurs last. Other rare risks include stroke, which has been reported
within a few days of infusion. A variety of secondary autoimmune conditions
have been reported, including immune thrombocytopenia and anti–glomerular
basement membrane disease. Because of these and other risks, it is advised to
monitor CBCs with differential, serum creatinine levels, and urinalysis with urine
cell counts monthly and a thyroid test every 3 months until 48 months after the
last dose. This agent may also increase the risk of cancer, including melanoma,
thyroid cancer, and lymphoproliferative cancers, and it may cause fetal harm.
Vaccine responses in people who have had a course of alemtuzumab within
the prior 6 months may not be adequate, and thus, it is advised that vaccination
take place 2 to 4 weeks before treatment or at least 6 months afterward. Live viral
vaccines should not be given while the patient is immunosuppressed after a
course of alemtuzumab.59 The mechanism of action is believed to be immune
suppression related to the death of circulating T lymphocytes (CD4 and CD8), B
lymphocytes, natural killer cells, and monocytes/macrophages. These cells return
in differential fashion, with CD4 T cells taking the longest time to return to
normal levels (years in some cases). As a monoclonal antibody, little
alemtuzumab is thought to cross the blood-CNS barrier.

Mitoxantrone
Mitoxantrone is an antineoplastic anthracenedione that intercalates into DNA,
causing damage, and it inhibits topoisomerase II. Given as an IV infusion every
3 months, mitoxantrone is approved for use in SPMS, relapsing progressive MS,
and worsening RRMS. Although the data from three randomized controlled trials
showed benefit in reducing the annualized relapse rate, MRI activity, and clinical
progression in patients with very active MS,48,49,87 mitoxantrone has serious and
sometimes life-threatening risks including dose-limiting cardiotoxicity; the
lifetime dose is limited to 140 mg/m2. Potentially fatal secondary leukemia has
been reported several times in patients with MS. With other highly effective and
less risky DMTs available, mitoxantrone is now rarely used for MS.

CONCLUSION
Treatment of MS requires the command of a vast portfolio of DMT classes and
agents, diverse in their routes of administration, efficacy, tolerability, and safety
profiles. Until more established evidence-based approaches to selecting a
treatment strategy or agent are established, the model of shared decision making
is most advantageous for securing adherence and building therapeutic alliance.
Careful surveillance of clinical and radiographic efficacy should be used for

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 TREATMENT OF MULTIPLE SCLEROSIS

escalation or early high-efficacy approaches, with a switch in class of DMT for

incomplete efficacy, unacceptable tolerability, or safety concerns following an
adequate trial. The efficacy of vaccines is diminished by some DMT classes,
further complicating the treatment sequencing paradigm in the face of novel
antigens and a global pandemic. Future therapeutic classes are likely to expand
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these options further, in the hopes of moving toward more complete control of
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MS, the most common disabling neurologic disease of young and middle life.

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DISCLOSURE
Continued from page 1025 of $5000 to $9999 for serving as a consultant for
Dr Cross has received research support from and Novartis AG and for serving on an advisory board for
F. Hoffman-La Roche Ltd, and Genentech, Inc. Biogen, EMD Serono, Genentech, Inc, and Novartis
Dr Riley has received personal compensation in the AG; and in the range of $10,000 to $49,999 for
range of $500 to $4999 for serving on an advisory serving on a relapse adjudication panel for TG
board for Janssen Global Services, LLS; in the range Therapeutics, Inc.

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