treatments in multiple sclerosis.pptx

Treatment of multiple sclerosis:
Today and Future
Dr . Ahmed Kohail
Assistant Lecturer of Neurology
Faculty of Medicine - Al-Azhar University
Fellow of the European Board of Neurology ( FEBN )

Multiple sclerosis (MS) is an immune-mediated, inflammatory
demyelinating disease of the central nervous system (CNS) that leads to
irreversible disability and currently is estimated to affect 1 million
people in the United States and more than 2million people globally.
The most common disease type is relapsing remitting (85%–90%), and
most treatments target this disease subtype. Some of these relapsing
remitting MS (RRMS) patients will transition to a secondary progressive
course. A small proportion of patients (10%) has primary progressive
MS (PPMS), which is characterized by progression from onset.

Since the introduction of the ﬁrst injectable therapies more than 15
years ago, numerous compounds targeting different pathophysiological
pathways have been developed. While this increases the therapeutic
options for MS patients . it also poses new challenges concerning the
identiﬁcation of the most appropriate therapeutic strategy to use in
individual cases. For this reason there has recently been an increasing
effort in developing decisional algorithms to stratify patients based on
their clinical and radiological characteristics.

An overview of currently approved oral disease modifying therapies (as of April 2020)

Infusion therapies
Natalizumabwas the first approved infusion DMT for RRMS in 2004.
 It is a monoclonal antibody against a-4 integrin and is a selective adhesion
molecule inhibitor, given by a monthly infusion.
 This therapy dramatically changed the landscape of treatment not only because of
its route and frequency of administration but also because of its high efficacy on
relapses and MRI activity.
 Its use has been limited because of the serious risk of developing progressive
multifocal leukoencephalopathy (PML).

Infusion therapies
Rituximabis a CD20 monoclonal antibody that historically has been
used off label for treatment of MS supported by phase 2 placebo-controlled
trial evidence demonstrating efficacy in RRMS.
This DMT was often used in patients with highly active disease that were JCV
seropositive, thus limiting the use of natalizumab.

Infusion therapies
In 2017, ocrelizumab, also a CD20 monoclonal antibody, was FDA-
approved for the treatment of RRMS and PPMS based on the results of the
OPERA I/II and ORATORIO studies,respectively.
Ocrelizumab is different from rituximab because it is humanized, which has the
potential to decrease infusion reactions.

Infusion therapies
Alemtuzumabis a humanized monoclonal antibody that targets the
CD52 antigen expressed on T cells, B cells, monocytes, and eosinophils that
produces rapid, profound, and prolonged lymphocyte depletion with gradual
reconstitution.
It is administered for 5 consecutive days during the first cycle followed by a 3-
day course 1 year later, with the potential for re-treatment.

STEM CELL TRANSPLANT
Stem cell therapy is of increasing interest in several neurologic conditions,
including MS. Particularly, the role of immunoablation and autologous hematopoietic stem cell
transplantation (AHSCT) in treatment-resistant relapsing disease is currently under investigation.
Despite the variety of DMTs , there is kind of patients who have continued inflammatory disease
activity or are limited by adverse events who may be candidates for AHSCT.
Recently, the American Society for Blood and Bone Marrow Transplantation created a task force to
review the evidence and provide recommendations regarding treatment-refractory MS as an
indication for AHSCT.
Many retrospective studies found an overall incidence of relapse-free survival at 5 years after
transplant of 80% to 87%, with many studies showing Expanded Disability Status Scale (EDSS)
stability or improvement .

STEM CELL TRANSPLANT
Overall, it appears that AHSCT is most effective and of most
benefit in patients with active, relapsing disease despite DMT,
and in patients who are younger with a relatively short disease
duration, but still ambulatory although accruing disability.
There is an ongoing randomized trial evaluating the safety,
efficacy, and cost-effectiveness of AHSCT compared with best
available therapy (natalizumab, CD20 monoclonal antibodies,
and alemtuzumab) in treatment-refractory relapsing patients

TREATMENT STRATEGIES FOR RRMS
( Escalation vs early initiation of highly
effective treatment)

With the increasing number of approved therapies, there
are a variety of treatment approaches that can be used.
Treatment decisions should be tailored to each individual
patient with regards to disease phenotype, risk profile,
and patient preference .
There are 2 general approaches: escalation and
early highly effective treatment.

Escalation Strategy
The escalation strategy consists in the first-line use of low-risk,
low-efficacy therapies and subsequent treatment monitoring.
When there is break-through disease , the treatment is switched to a more
efficacious DMT.
This approach is more conservative and applies best to patients with a
reduced risk for developing aggressive forms of MS.
Glatiramer acetate, interferons and teriflunomide can be indicated in low-
risk patients, in patients with a high need for safety, and in patients with
no access to specialized MS centres

Escalation Strategy
With the advent of the newer DMTs, the threshold for escalation
has lowered, but is still dependent on comfort of the practitioner
and patients using the medications, access to the support needed
for the therapies (ie, infusion centers), and cost.
The benefit of escalation therapy is minimizing the risk, but the
concern is for the potential for undertreatment of disease activity
that may lead to accumulation of disability and disease
progression.

Early highly effective treatment
strategy
Consists of 2 categories :
 High-efﬁcacy therapy continuous
 High-efﬁcacy therapy pulsed

strategy
High-efficacy therapy continuous :
MS patients who are treatment naı ¨ve can now be offered an early intensive therapeutic
approach. Mounting evidence indicates that an early aggressive treatment could prevent
chronic immune activation and better preserve long-term neural integrity, specifically in
younger patients (31–40 years old) with lower EDSS (EDSS < 2) .
Natalizumab, fumarate derivates, S1PR antagonists, and
B-cell depleting agents are used for this purpose.
Although some of these drugs lack direct evidence of a superior efficacy compared to
baseline therapies, the high-effective drugs are indicated in patients with highly active MS
and early development of disability. Upon disease activity or drug intolerance, the therapy
should be switched to another drug within the same efficacy class but different mechanism
of action .

strategy
High-efﬁcacy therapy pulsed :
Induction therapy using immune-depleting reagents for a short period, followed by a
treatment free period, is a relatively new approach.
It is based on the concept that the early depletion of autoreactive immune cells will have a
long-term effect because chronic phenomena such as antigen-spreading and
compartmentalization of the immune response within the CNS are not established yet. Drugs
such as cladribine and alemtuzumab exert a strong immune suppression
through short therapeutic cycles.

Factors that may suggest a more severe course of the disease include :
 Male gender
 Older age at presentation
 Increased severity and frequency of relapses
 Higher burden of spinal cord and infratentorial lesions
 Increased T2 lesions burden
 Increased contrast-enhancing lesion burden
 Increased brain atrophy

Although observational studies suggest that early high-efficacy treatment
may have long-term benefits, there is currently no randomized trials that have
evaluated the 2 treatment strategies.
There are 2 ongoing large, randomized multicenter trials in treatment-naı ¨ve
RRMS patients who will evaluate the 2 treatment approaches: Determining
the Effectiveness of Early Intensive versus Escalation approaches for the
Treatment of Relapsing-RemittingMultiple Sclerosis (DELIVER-MS,
NCT03535298) and Traditional versus Early Aggressive Therapy for Multiple
Sclerosis Trial (TREAT-MS, NCT03500328

Decision-making algorithm for MS therapeutic
choice

European Committee for Treatment and
Research in Multiple Sclerosis (ECTRIMS)
Recommendations, 2021

 Offer interferon or glatiramer acetate to patients with clinically isolated syndrome
(CIS) highly suggestive of MS and an abnormal MRI with lesions suggestive of
MS who do not fulfil criteria for MS.
 For patients with relapsing-remitting MS, the choice between a wide range of available
drugs (interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine,
fingolimod, ozanimod, ponesimod, natalizumab, alemtuzumab, ocrelizumab, rituximab, or
ofatumumab), from modestly to highly effective, will depend on factors including:
underlying disability progression, disease severity/clinical or radiological activity, patient
characteristics and morbidity, drug safety profile, family planning, and patient preferences.

Progressive MS
 For patients with secondary progressive MS with evidence of inflammatory activity (relapses and/or MRI activity)
offer treatment with siponimod. Treatment with other therapies use for relapsing remitting MS may also be
considered.
 For secondary progressive MS without evidence of inflammatory activity, particularly in young patients and those
in whom progression has started recently, consider treatment with siponimod or anti-CD20 monoclonal antibodies,
taking into account that there is scarce evidence to support their use in this setting.
 For patients with active secondary progressive MS when there is no other therapy available, consider treatment with
mitoxantrone, taking into account the safety concerns and tolerability issues of this agent.

Consider ocrelizumabfor patients with primary progressive MS, particularly early and active (clinically
and/or radiologically) disease.

Emphasis Toward Higher-Efficacy Drugs
 Consider choosing a higher-efficacy disease-modifying drug early on, according to disease activity
(either clinically or on MRI).
 Offer a more efficacious drug to patients who show evidence of disease activity with their current
treatment.
 When treatment with a high-efficacy drug is stopped, whether because of inefficacy or risk of adverse
effects, consider starting another high-efficacy drug, taking into account clinical and MRI disease
activity before and during treatment, pharmacokinetics and biological activity of the previous drug,
and the potential for resumed disease activity or even rebound syndrome (particularly with
natalizumab and S1P modulators).
 In the stable patient (clinically and on MRI) who shows no safety or tolerability issues, consider
continuing treatment with disease-modifying therapy taking into account patient characteristics and
comorbidities, drug safety profile, family planning, and patient preferences.

Recommendations for pregnant women and mothers who choose to breastfeed
include:
Advise women who wish to become pregnant to plan their pregnancy beforehand.
Advise women of childbearing potential that MS disease-modifying therapies are not
licensed during pregnancy, with the exception of interferons and glatiramer acetate.
For women planning a pregnancy, offer interferons and glatiramer acetate and
consider continuing these agents during pregnancy after assessment of risk and
benefits. Consider using dimethyl fumarate until pregnancy is confirmed and
stopping during pregnancy after assessment of the risks and benefits.

For women with highly active disease who wish to become pregnant, there are a number of therapeutic
options:
1) treatment with long lasting effects such as alemtuzumab or cladribine provided that at least 4 or 6
months respectively have elapsed between the last dose and conception
2) treatment with anti-CD20 drugs before pregnancy with advice to wait for 2-6 months after the last
infusion before becoming pregnant and to avoid further infusions during pregnancy, or
3) for patients treated with natalizumab, consider continuing treatment during pregnancy using a 6-week
extended dosage regimen until the end of the second trimester or up until week 34, and resuming after
delivery (in newborns exposed to natalizumab check for hematological abnormalities and liver function)

Only interferons and ofatumumabare currently approved during breastfeeding.

Long-Lasting Treatments
When using long-lasting treatments (alemtuzumab or cladribine) in patients who experience
disease activity before the treatment is completed (between the first and second cycles), consider
waiting until completion of the therapeutic regimen before switching to other drugs.
Consider offering additional courses of alemtuzumab after the first two cycles at least 1 year
apart from each other when disease activity has not remitted completely or reappears after a
period of stability, taking into account the balance between the potential benefits and side effects.

When should disease-modifying
treatment be stopped?

In RMS patients with an anticipated mild disease course at onset (based on
clinical and radiological features,i.e. severity of and recovery from first relapse,
relapse frequency, MRI lesion load and activity, and CSF parameters and stable
disease during the preceding 5 years on category 1 DMD treatment (no further
clinical orradiological MS activity or progression),

The guideline :
 (a)gives a weak recommendation to pause category 1 DMD treatment;
 (b) strongly emphasises that patients should be informed that the advocated period of 5 years is
not evidence-based and that no data from controlled trials
 assessing the impact of treatment discontinuation on future relapses and disability progression
are available;
 (c) highlights that the decision on whether to pause or not to pause DMD treatment has to be
taken on a strictly individual basis and in consideration of the individual patient’s wishes; and
 (d) demands regular clinical and MRI assessments to monitor upcoming disease activity (at 6
and 12 months and subsequently every 12months following discontinuation of treatment
This recommendation only seemingly contradicts the ECTRIMS/EAN guidelines which
recommend “to consider continuing a DMD if a patient is stable (clinically and on MRI) and shows
no safety or tolerability issues

Regarding category 2 and 3 DMDs, breakthrough or rebound MS activity after
cessation of natalizumab, S1P modulators and - problably - CD20 antibodies is, of
course, an issue. Thus, the DGN guideline states that complete cessation of these
drugs (without substitution) is not recommended, even if patients have been free of
any disease activity for 5 years

Hopefully, three ongoing prospective randomised trials, two including patients with RRMS
(DISCOMS [10], estimated completion date February 2022; DOT-MS [11], estimated
completion date January 2024) and one including an SPMS population older than 50 years
(Stop-I-SEP [12], estimated completion date January 2026), will clarify the impact of
treatment discontinuation on focal disease activity and disability progression in the
foreseeable future.

treatments in multiple sclerosis.pptx

treatments in multiple sclerosis.pptx

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