Recent advances and updates in the management of multiple sclerosis

1. Recent Advances And Updates In The
Management Of Multiple Sclerosis
DR.TEJAL AGARWAL

2.  Multiple sclerosis (MS) is an immune-mediated, inflammatory
demyelinating disease of CNS that leads to irreversible disability.
 Primarily in young adults 20 – 40yr age group.
 Affects more women than men.
 3 main components of disease process – inflammation,
demyelination, axonal loss.

3. Periphery
1. Antigen presentation to CD4+ prompting
activation and proliferation of pro-
inflammatory lymphocytes (Th1 and Th17)
2. Secretion of pro-inflammatory cytokines
3. Up-regulation of adhesion molecules
4. T cell migration across the blood brain barrier
into the CNS
5. B cell activation, proliferation and migration
into the CNS
6. Migration of monocytes and macrophages into the
CNS
7. Inadequate T regulatory function
Blood Brain Barrier
CNS
8. Presentation of CNS antigen to T cell
with reactivation
9. Recruitment of other inflammatory cells:
CD8+
B cells
monocytes
macrophages
microglia
10. Damage to myelin,
oligodendrocytes and axons resulting from:
cytokine damage antibody activity
complement damage oxidative stress
mitochondrial dysfunction
Inflammatory Cascade in Multiple Sclerosis

5. Bacteroides and Firmicutes
 MS is associated with gut microbial
dysbiosis.
 Alterations of the MS gut microbiota may
include reduction of bacteria
species(Bacteroides and Firmicutes) that
generate immune-modulatory molecules,
including short-chain fatty acids which
increase production of regulatory T cells.
 Bacteria can produce cytokines that can
influence both pro and anti-inflammatory
immune cells .
 Multiple studies have demonstrated
differing gut microbiomes in MS vs controls.
 However much needs to be determined
regarding its exact role in pathogenesis of
MS .
Gut Microbiome

6. MS Phenotypes based on clinical course
 Clinically isolated syndrome – First attack of MS
 RRMS – Most common (85-90%)
 SPMS
 PPMS

7. • relapses and/or
• lesion formation on MRI
ACTIVITY
• Advancement of disease driven by
underlying process rather than due
to poor relapse recovery.
DISEASE PROGRESSION

8. Radiologically isolated syndrome

9. 50% of these patients develop MS over a median follow-up of 10 years.
Factors that increase the likelihood of patients with RIS converting to MS based on
retrospective studies include
 male sex;
 age younger than 37 years;
 presence of spinal cord lesions, infratentorial lesions, and
 CSF-specific oligoclonal bands; and
 the development of gadolinium-enhancing lesions on follow-up MRI.

10.  -MS “prodrome”/ presymptomatic MS : 5 to 10 years before the diagnosis of MS, patients
have a higher use of health care services with and constellation of nonspecific symptoms,
including pain, headache, and fatigue, as well as mood symptoms.
 Solitary sclerosis :patients whose imaging findings at the time of clinically isolated
syndrome do not fulfill the minimum MRI requirement for an MS diagnosis but the
existing “multiple” additional CNS lesions are unexplained by other pathology and are
typical of MS in location,orientation,and shape.

12. Diagnostic criteria revisions- 2017

15. PPMS

16. What’s new?
2010 Mc DONALDS CRITERIA 2017 Mc DONALDS CRITERIA
OCB not considered. Recommendation to use the presence of
OCBs in CSF to make the diagnosis of MS
in a patient with typical CIS who has MRI
evidence of DIS .
Symptomatic lesions were excluded. Both symptomatic and asymptomatic MRI
lesions canbe considered in determining
DIT and DIS
MRI lesions in the optic nerve in a patient
presenting with ON remain an exception
(not used for DIS) due to lack of evidence .

17. 2010 Mc DONALDS CRIETERIA 2017 Mc DONALDS CRIETERIA
Cortical lesions could not be used in fulfilling
MRI criteria for dissemination in space in the
2010 McDonald criteria.
Cortical and juxtacortical lesions can be used
in fulfilling MRI criteria for DIS.
The diagnostic criteria for PPMS in the 2017
McDonald criteria remain the same, except
the removal of the distinction between
symptomatic and asymptomatic MRI lesions
and that cortical lesions can be used.

19. What's new in
Investigations..

20. Neurofilament light chain (NfL)
 These are scaffolding proteins of the neuronal cytoskeleton and is released in the extracellular
space following axonal damage.
 NfL levels are increased in the cerebrospinal fluid of MS patients as well as in degenerative and
traumatic neurological diseases.
 CSF NfL levels are further increased during relapses and are positively associated with MRI lesion
load and disability scores in MS.
 CSF NfL levels have also been shown to be a marker of treatment response.
 Treatment effects on CSF NfL levels have already been shown for fingolimod, natalizumab and
rituximab in MS patients.

21. Serum levels closely reflect CSF -NfL
sNfL measurements could be used to indicate recent neuronal damage and this
could be particularly useful in case of ‘clinically silent disease’ or when clinical
changes are difficult to interpret
High sNfL levels were also associated with a higher risk of future clinical relapses
and EDSS worsening.
However,they are not specific for MS ,and their clinical utility is in conjuction with
other diagnostic markers of MS.

22. IMAGING
 THE CENTRAL VEIN SIGN :the presence of a vein at the center of WM lesions, can improve the
differentiation between MS and its mimics.
 In MS, most newly developing T2-hyperintense WM lesions or gadolinium (Gd)-enhancing lesions show
the CVS.
 40%rule,: if more than 40% of white matter lesions demonstrate the central vein sign, the likelihood of a
diagnosis of MS is quite high.
 Best detected in SWI (3D-EPI) imaging sequence.
 Key challenges: the lack of a standardized imaging protocol, lack of validated CVS-based diagnostic
criteria and the need of automated methods to detect the CVS.

24. Chronic active lesions- Paramagnetic rim sign
 Pathologically, 57% of all chronic WM lesions show a peripheral ‘rim’ of iron-
laden activated microglia/macrophages s/o ongoing demyelination and axonal
loss.
 This rim corresponds to a paramagnetic rim seen on SWI.
 useful in diagnosing progressive forms of MS - have a higher proportion of
lesions demonstrating paramagnetic rim lesions.

26. CORTICAL IMAGING
 On 7 T MRI, majority of studies report cortical lesions in at least 90% of patients .
 Cortical lesions are a highly relevant marker of clinical severity, relating to EDSS, cognitive
and motor function.
 PMS patients showed consistently higher cortical lesion load than RRMS patients.(Cortical
lesion load >=7 and its accumulation over time predicts conversion to SPMS.)
 T2*GRE and T2 FLAIR sequences at 7 T provide high-resolution anatomical images of
cortical lesions.

28. Leptomeningeal enhancement and subpial demyelination- 7T FLAIR CONTRAST.

30. Main Targets In Treatment
 RRMS
Treatment of Acute Relapses
Prevention of acute relapses by Disease Modifying agents(DMT)
 PPMS
Prevention of progression – major unmet need.
Symptomatic management
Rehabilitative care

31.  Until late 20th century, MS treatment consisted of mainly
corticosteroids and wide-spectrum immunosuppressants- azathioprine,
cyclophosphamide and methotrexate.
 First DMT approved by FDA was injectable agent IFN beta 1B in 1993.
 Followed by Glatiramer and various other forms of IFN, and recent
highly effective monoclonal antibodies.
 Newer disease-modifying therapies offer greater efficacy and
convenience, but they also have serious side effects

32. Disease Modifying Agents

33. Advent Of Various DMT

35. Monoclonal Antibodies- High Efficacy Drugs
 Monoclonal antibodies for (RRMS) include - natalizumab,
ocrelizumab, rituximab (off-label), ofatumumab, and alemtuzumab.
 Natalizumab and alemtuzumab have similar benefit for reducing
relapse rates.

36. Natalizumab (TYSABRI)
 Recombinant Mab against the alpha-4 subunit of integrin on T cells
preventing adherence to vascular endothelium and transmigration across
BBB.
 Very effective in reducing relapse rates in MS.
 Approved for monotherapy in relapsing forms of MS- Clinically isolated
syndrome, RRMS, active SPMS.
 Data from 2 randomized trials - AFFIRM and SENTINEL showed that
natalizumab significantly reduced the risk for having a relapse during two
years of treatment relative risk and risk for experiencing progression at two
years.

37.  Natalizumab is more effective than many other DMT s – reduction
in ARR of 54-68% more than IFN and Glatiramer (33%).
 Dosing - 300 mg IV infusion over one hour every four weeks
monitoring for hypersensitivity reactions.
- Extended interval dosing (6-8 weekly) in Seropositive patients
reduces risk of PML with no decrease in efficacy(TOUCH program
analysis)

38.  Adverse effects - PML –reactivation of JC virus, infusion reaction,
UTI, respiratory infections, opportunistic infections(herpes
,P.jiroveci,MAC,aspergillosis).
 Contraindications- patients who have or have had PML and those
with previous hypersensitivity reaction to natalizumab, impaired
cell mediated immunity.
 Incidence of Natalizumab associated PML - 3.99 per 1000 patients

39.  Factors determining the risk of PML for an individual patient
- Anti JCV antibody status
- Prior immunosuppressant treatment
- Duration of natalizumab exposure
 Risk of PML is low (<1:10,000) for patients who are seronegative for
anti-JCV antibodies.

40.  Rebound can occur between 3 and 6 months after stopping
natalizumab.
 Other disease-modifying therapies should be started (within 12
weeks )before this time to minimize rebound risk.

41. Alemtuzumab ( LEMTRADA)
 Humanized monoclonal antibody against CD52 expressing cells-
mainly T cells, B cells and minimal effect on natural killer cells, and
monocytes.
 Alemtuzumab, an IgG1 subclass, binds complement and lyses target
cells. It causes a rapid depletion of all types of lymphocytes.
 Different lymphocyte types recover at different rates and degrees,
causing long-term increases in regulatory and memory T cells,
decreased TH1 and TH17 cells.

42. Mechanism of action

43.  Two pivotal studies, the CARE MS-I (Comparison of Alemtuzumab
and Rebif Efficacy in Multiple Sclerosis, Study One) and CARE MS-II
compared efficacy of Alemtuzumab with interferon beta-1a
 Established positive effects in ARR reduction
 Reduction in ARR and disability progression noted in refractory and
highly active MS .

44.  Indications -
 FDA approved in 2014 in RRMS (preferably in highly active) –not
responding to 2 or more DMT
 active SPMS
 Not recommended in CIS

45.  Contraindications – HIV, active infection, hypersensitivity
 Adverse Effects- melanoma ,LPD,Thyroid carcinoma .

46.  Dosing - IV infusion at 12 mg daily for five consecutive days (total
60 mg) followed 12 months later by 12 mg daily for three
consecutive days.
 Premedication with IVMP -1gm for the first three days of therapy
and later prophylactic antiviral therapy .
 Monitoring-
 VZV antibody status – vaccinate if negative and wait for 6 weeks
 CBC, CUE, LFT( monthly), Prot to creat ratio(baseline), TFT ( 3
monthly)
 Dermatology screen for melanoma yearly.
 Marrow suppression, autoimmune disorder monitor till 4 years
after completion.

49. Rituximab
 Against the CD20 on B cells- causing both ADCC and Complement
mediated damage and reducing B cell lineages.
 Off label treatment for RRMS.
 Observational studies showed lower rate of clinical relapses and
MRI measures of disease activity compared with IFN, glatiramer
acetate, and DMF.
 Adverse effects —Infusion reactions, hypogammaglobulinemia,
infection, reactivation of hepatitis B, and neutropenia

50.  HERMES ,OLYMPUS ,RIFUND-MS
trails showed efficacy of rituximab
in MS.
 Rituximab is substantially
cheaper than ocrelizumab.
 The typical dose used in MS is 500
mg or 1000 mg IV every 6
months.

51. Ocrelizumab ( OCREVUS)
 Anti CD 20 Mab but binds at different but overlapping epitope to
Rituximab.
 Antibody dependant cell mediated cytotoxicity and results in B cell
depletion.
 Indications
- RRMS( safe and tolerable even in most aggressive RRMS)
- Active SPMS
- CIS
- PPMS

52.  In two RCT’s OPERA I and OPERA II in patients with RRMS – on comparison
with S/c IFN Beta 1a over 2 years showed
1. - Significant reduction in Annual relapse rate
2. - Decrease in mean gadolinium enhancing lesions per year on MRI(95%)
3. - Disability progression at 24 weeks.

53. ORATORIO trial

55.  Monitoring - Baseline levels of Immunoglobulins IgA,G,M
- Viral markers/TB
- Live vaccines – till 4 weeks prior
-Live vaccines not to be used during and after
Ocrelizumab till B cell replenishment.

56.  Adverse effects - Infusion reactions(34%) , upper and lower
respiratory tract infections, and skin infections.
 Serious HSV and VZV infections are known to occur.
 Increased risk of malignancy ( Breast ) – 0.5%
 Reactivation of Hepatitis B.

57. OFATUMUMAB ( KESIMPTA)
 Ofatumumab is a fully human antibody targeted against CD 20 of
B cells that is used to treat chronic leukemia
 Causes B cell depletion by high binding affinity, result in efficient B-
cell lysis, mainly mediated through complement dependent
cytotoxicity.
 FDA approved (Aug 2020) for subcutaneous injectable use in MS –
advantage being that it can be self administered.

58.  On treatment cessation, B-cell repletion and reconstitution of
humoral immunity have been reported to occur faster with
ofatumumab than with other intravenously administered B-cell–
targeted therapies.
 INDICATIONS - Adults with Relapsing forms of MS – CIS, RRMS,
SPMS.

59. ASCLEPIOS

61.  DOSING - Subcutaneous injection, starting with 20 mg administered
at weeks zero, one, and two ( Loading Dose ). Subsequently, the
dose is 20 mg per month starting at week four.

62.  Lowers B-cell numbers during the 4-week loading regimen, and the
initial B-cell depletion is maintained by monthly injections.
 Screening for Hepatitis B and quantitative Ig levels estimation.
 Should not be used in active infections.
 Live vaccines should be deferred during or after drug use until B cell
repletion occurs.

63. Ublituximab (OCREVUS)
 FDA approved for relapsing forms of MS - RRMS, Active SPMS, CIS.
 Anti CD 20 – ADCC mediated B cell depleting agent.
 Glyco-engineered to elicit strong NK cell mediated response against
B lymphocytes.
 Intravenous infusion - with shorter infusion time 1 hour

65. Oral Therapies
 Approved Oral DMT’s For Relapsing-remitting Multiple Sclerosis
(RRMS) are
 Dimethyl Fumarate, Diroximel Fumarate, Monomethyl Fumarate
 Teriflunomide,
 Fingolimod, Siponimod, Ozanimod,Ponesimod
 Cladribine

66. Fumarates
 Have neuroprotective and immunomodulatory properties through
activation of the nuclear factor like 2 (Nrf2) pathway.
 DMF - prototype drug.
 metabolized to monomethyl fumarate
 Dosing- Oral tablet – 120 mg twice daily f/d 1 week later by 240 mg twice
daily with food [ regular monitor of TLC and differential,LFT]
 Adv Effects – Gastro intestinal, anaphylaxis and angioedema, herpes
zoster and other serious opportunistic infections, hepatotoxicity, and
lymphopenia

67.  Diroximel fumarate
Recently approved fumarate ( 2019 ), has the same dosing frequency
and mechanism of action as DMF, but with improved tolerability, and
less gastrointestinal (GI) side effects.
- Dose – Oral tablet 231 mg twice daily f/d 1 week later by 462 mg
twice daily.
- adv effects – similar to DMF
 Monomethyl Fumarate
- Approved in 2020,
- Dose – 95 mg BD f/d 1 week later by 190 mg BD.

68. S1P receptor modulators
 Naïve and central memory lymphocytes use the S1P receptor to exit
lymph nodes.
 Without this receptor, they get trapped in lymph nodes and
removed from the circulation.
 S1p receptor modulators bind with receptor causing it to be
internalized and removed from the cell surface.
 Naïve lymphocytes comprise about 80% of circulating lymphocytes,
so fingolimod decreases absolute lymphocyte counts by 80%. The
20% remaining are effector cells

70.  Approved for Relapsing MS.

71.  Contraindications –
 Recent (< 6months) MI, unstable angina, stroke, TIA, h/o 2nd or
3rd degree AV block or sinus node dysfunction ,a prolonged QT
interval ≥500 msec & treatment with anti-arrhythmic drugs .
 Patients who have diabetes because they are at increased risk for
macular edema.
 Known to have paradoxical worsening of MS and Rebound effect
after withdrawal.

72.  Siponimod-
 More selective S1P receptor modulator – subtypes 1 and 5.
 Less cardiac side effects- hence first dose monitoring needed only
those with cardiac h/o and HR <55.
 For Relapsing MS/ SPMS in 2019
 Dose - 2mg / day
 Slow metabolisers -CYP2C9*1/*3 or *2/*3 genotype testing before
initiation of therapy ( half the dose ),Contra indicated in CYP2C9
3*/3* Homozygous patients.

73.  Ozanimod- acts on S1P1/S1P5 receptors
 FDA approved in 2020 for relapsing MS based on SUNBEAM and RADIANCE
trials.
 recommended starting dose of ozanimod is 0.23 mg once daily
 Ponesimod
 approved in 2021.
 started at 2 mg daily and slowly titrated over 15 days to a recommended
maintenance dose of 20 mg once daily.

74. Teriflunomide-
 Inhibits dihydroorotate dehydrogenase leading to reduced de novo
pyrimidine synthesis thus limiting the number of activated
lymphocytes
 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
 A/E – hepatotoxic,peripheral neuropathy,HTN,thinning of hair.
 CI – Pregnancy

75. CLADRIBINE
 Oral Immune reconstitution therapy.
 Purine analogue, is metabolized to its active form and concentrated
in DNA of lymphocytes and monocytes selectively but not in other
cells. Single stranded DNA breaks cannot be repaired, thus promote
apoptosis in lymphocytes eventually resulting in cell death.
 Reapproved in 2019 for RRMS and SPMS based on CLARITY trial
data. But not for CIS.

76.  Increased risk of malignancy secondary to effect on
immunosurveillance rather than direct toxicity to a particular organ.
 Teratogenicity risk
 Cytopenias
 Hence reserved for patients who do not tolerate or have
inadequate response to other drugs.

78.  Dosing – Oral with induction regimen – Short course
 Dose of cladribine is 1.75 mg/kg per course, taken as 10mg/d to
20mg/d for 4 to 5 days in week 1 and week 5.
 The dose is repeated 1 year later.
 No treatment is given in years 3 and 4.

79. Hematopoietic Stem Cell Therapy
 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.
 In HALT-MS, the efficacy of AHSCT was evaluated in patients with
MS with disability progression on DMT.
 The trial results demonstrated that AHSCT achieved event-free
survival of 69.2%, MRI activity-free survival of 86.3% at 5 years.

81.  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.
 BEAT MS is an ongoing randomized trial evaluating the safety,
efficacy, and cost-effectiveness of AHSCT compared with best
available therapy.

82. Emerging therapies -Bruton tyrosine kinase
inhibitors
 Tyrosine kinases are enzymes that mediate the phosphorylation of tyrosine residues of
molecules that have crucial roles in cellular proliferation and differentiation, metabolism,
survival, and apoptosis.
 Bruton’s tyrosine kinase (BTK) is expressed by B-cells and myeloid cells, suggesting that its
modulation , provide therapeutic benefits for patients with MS.
 BTK is also expressed in microglia, which are implicated in neuroinflammation of
progressive as well as relapsing phenotypes, making it an attractive target for both
forms of MS.

84.  Emerging oral drugs for MS.
 Irreversible BTK inhibitors (evobrutinib, tolebrutinib, and orelabrutinib),
reversible BTK inhibitors (fenebrutinib and BIIB091), and
a selective tyrosine kinase inhibitor (masitinib)
are currently under investigation in various phases of development.

86.  Evobrutinib was evaluated in a randomized, double-blind, placebo-
controlled phase II trial in patients with RMS.
 The results showed a lower total number of GdE lesions during
weeks 12–24, with baseline-adjusted rate ratio 0.30 for evobrutinib
75 mg once daily (95% CI: 0.14–0.63).
 However, no changes in ARR or disability progression were detected
with any evobrutinib dose

88.  Another phase IIb, randomized, double-blind, placebo-controlled
trial evaluated the efficacy of tolebrutinib in RMS (defined as either
relapsing–remitting or relapsing SPMS) and found a dose-
dependent (85%) reduction in the number of new GdE lesions after
12 weeks of treatment .

91.  There are currently many ongoing phase III clinical trials evaluating
 Fenebrutinib in RMS (fenhance 1/ fenhance 2) and PPMS (fentrepid
trial );
 Tolebrutinib in RMS (GEMINI 1/2), non-relapsing SPMS (HERCULES)
and PPMS (PERSEUS) and
 Evobrutinib in RMS (EVOLUTION 1/2).

93. FREXALIMAB
 Frexalimab (SAR441344) is a novel monoclonal antibody that is
thought to block the costimulatory CD40/CD40L cellular pathway
necessary for adaptive (T and B cells) and innate (macrophages and
dendritic cells) immune cell activation and function, without
lymphocyte-depletion.
 In a phase 2 trial,Frexalimab met primary endpoint with 89%
reduction in new gadolinium-enhancing T1 brain lesions achieved
at Week 12 in the higher-dose treatment arm, compared with
placebo in patients with RRMS

94. Remyelination Therapy
 In MS, demyelination with progressive failure of remyelination is
thought to lead to axonal degeneration and permanent disability.
 While endogenous remyelination occurs, it is often incomplete and
fails progressively over time. Therefore, current research is focused
on developing novel therapies to promote remyelination.

95.  Oligodendrocytes are the cells that produce myelin and are crucial
for axonal health independent of myelination.
 Impaired oligodendrocyte precursor cell (OPC) differentiation is
involved in remyelination failure and promoting that differentiation
can have impact on disability particularly in progressive MS.

98. Potential targets in steps of remyelination
 Block inhibitors of remyelination (e.g., anti-LINGO monoclonal
antibody),
 increase the clearance of myelin debris,
 increase the number of OPC within the brain (e.g., transplantation
of human OPC), and
 stimulate OPC differentiation e.g., clemastine
 Combination of approaches is needed to target successful
remyelination. ( exercise+ clemastine).

99. OPICINUMAB
 Anti LINGO-1 monoclonal antibody .
 LINGO-1 (leucine-rich repeat neuronal protein 1) is a cell-surface
glycoprotein expressed on CNS neurons and oligodendrocytes and inhibits
oligodendrocyte differentiation, myelination.
 RENEW trial – RCT - Opicinumab vs placebo with IVMP in subjects with
first unilateral onset acute optic neuritis within 28 days from symptom
onset showed significant difference in at 24 weeks improvement in VEP
latency at 32 weeks but not at 24 weeks.
 SYNERGY trial – failed to show benefit vs IFN in RRMS and PPMS

100.  CLEMASTINE
 Is an antihistamine, is an antagonist of H1 and reverse antagonist of
M1/M3 receptors.
 Enhances oligodendrocyte differentiation and wrapping of myelin,
even when compared with known pro-remyelinating agents such as
thyroid hormone.
 ReBUILD trial - phase 2 RCT -Clemastine in subjects with early
RRMS with chronic optic neuropathy showed decrease in latency
but with increased incidence of fatigue.

101.  Mesenchymal stem cells (MSCs) are an area of interest in
progressive disease for immunomodulation and potential
remyelination and because of their ability to differentiate into
various types of cells.
 These cells can be isolated from bone marrow, adipose tissue,
umbilical cord.
 A phase 1A trial of intrathecal human umblical cord blood derived
cell therapy in adults(DUOC -01) with PPMS is underway.

103. Neuroprotective Agents
 Goal of therapies aimed at neuroprotection is to prevent irreversible
disability and slow progression.
 SIMVASTATIN –
 Potential neuroprotective agent because of immunomodulator effects.
 MS-STAT was a phase 2, randomized study of 80 mg simvastatin vs placebo
in an SPMS . The Simvastatin group had a decreased rate of whole brain
atrophy compared with placebo.
 No significant difference between groups in the rate of new and enlarging
brain lesions or in the relapse rate.
 MS-OPT ,a randomized high dose simvastatin treatment in SPMS analysing
impact on vascular perfusion and oxidative damage is ongoing.

104. IBUDILAST –
 Ibudilast inhibits cyclic nucleotide phosphodiesterases, toll-like
receptor 4, and is able to cross the blood-brain barrier.
 SPRINTMS was a phase 2 randomized trial of ibudilast vs placebo
and showed significantly reduced rate of brain atrophy compared
with placebo.
 There was no statistically significant effect on disability
progression and patients treated with ibudilast had higher rates of
gastrointestinal symptoms (particularly nausea, diarrhea, and
abdominal pain), depression, and headache.

105.  Phenytoin is a voltage-gated sodium channel inhibitor, which is a
mechanism that has been shown to have neuroprotective
properties in preclinical trials.
 One randomized, placebo-controlled phase 2 trial showed that
patients with acute optic neuritis who were given phenytoin within
2 weeks of onset had 30% less retinal nerve fiber layer thinning
compared with placebo.
 Alpha Lipoic Acid - ALA has potential neuroprotective effects, as it
is a cofactor for the oxidation-reduction portion of mitochondrial
reactions and with anti-inflammatory properties.
 It showed benefit in reducing the rate of brain atrophy

106.  Metformin may exhibit neuroprotective effects
 by protecting against oxidative stress,
 inducing an anti-inflammatory profile,
 also may induce remyelination by improving OPC responsiveness.

107. •BIOTIN :
• Biotin (vitamin B7) is a cofactor for multiple carboxylase enzymes involved in
fatty-acid synthesis and energy production.
• Biotin is proposed for treatment of MS because it may increase
remyelination and overcome the energy inefficiencies in demyelinated
axons.
• In an open-label pilot study of high-dose biotin (100-600 mg/day), 23
patients with progressive MS showed improvements in visual acuity and
visual evoked potentials (reappearance of P100 waveform).
• MD1003 is a high-dose oral formulation of 300 mg daily showed no benefit
in disabilty measures for treatment of progressive MS in recent trials.

108. NAC
 N-acetyl derivative of the naturally occurring amino acid, L-cysteine
 scavenges free radicals and restores neuronal glutathione, a major
endogenous antioxidant.
 A randomized clinical trial as a neuroprotective agent in primary and secondary
PMS is ongoing -NAC 1200 mg TID or matching placebo (1:1) as an add-on
therapy during a 15-month intervention period.

109. Treatment Of Relapsing MS
 2 approaches- Escalation and early high efficacy regimen.
 An escalation approach, the patient is started on a low- to
moderate-efficacy DMT (eg, injectable or oral DMT), and if there is
breakthrough disease, the patient’s therapy is escalated to a highly
effective choice(Mon Ab).
 The benefit of escalation therapy is minimizing the risk, but the
concern is for the potential for undertreatment.

110.  The alternative approach is to start a highly effective therapy as
the first treatment option.
 Observational studies demonstrate starting DMT earlier in the
disease course, preferably after the first clinical attack, leads to
better long-term clinical outcomes.
 Highly effective DMT include natalizumab, rituximab, ocrelizumab,
and alemtuzumab.
 The tradeoffs to higher efficacy are increased risks, such as
infection, autoimmunity, and malignancy, with less long-term
safety data

111.  TREAT-MS (Traditional Versus Early Aggressive Therapy for Multiple
Sclerosis Trial 2025) and DELIVER-MS (Determining the
Effectiveness of earLy Intensive Versus Escalation approaches for
RR-MS 2026) are ongoing trials comparing early aggressive
therapy with traditional therapy
 Consider initial aggressive therapy for patients who appear to be at
high risk for aggressive disease and early disability.
 Consider switching patients to more aggressive therapy in the
presence of breakthrough disease (exacerbations, MRI activity, or
worsening disability)

112.  Newer study observations indicate early onset of treatment
prevents long term disability – particularly in aggressive forms of
MS in which early identification of suboptimal response to DMT is
key.
 Three markers for aggressive disease: clinical attacks, disability, and
MRI activity.
 The most common schemata for identifying aggressive disease -
the
1. Canadian MS Working Group Assessment,
2. The modified Rio score ,
3. NEDA.

113.  Canadian MS Working Group Assessment rates changes in relapses,
disability, and MRI as having low, medium, or high levels of
concern.
 The Working Group recommends switching to more aggressive
therapy if a
 high level of concern is present in any one domain,
 a medium level of concern is present in any two domains,
 or a low level of concern is present in all three domains.

114.  Modified Rio score was developed in patients newly starting
DMT’s to predict outcomes at 4 yrs– based on two criteria: new T2 lesions
and clinical relapses.
Score 0 – 24%
Score 1 – 33%
Score 2 and above – 65%
In the modified Rio score, scores of 0 represented responders, and scores ≥ 2
represented nonresponders.
Initially, a score of 1 was indeterminate. If on a repeat analysis after an
additional 6 months, those patients had > 1 new lesion on a MRI or a relapse,
they were considered nonresponders.
Patients determined to be nonresponders based on the modified Rio score
probably would benefit from changing therapy to a more efficacious agent.

116. NEDA - strong predictor of good outcome in medium term

119. Discontinuation Of Disease-modifying Therapy
 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.
 DISCO-MS study -It prospectively evaluated randomized discontinuation of
DMT in patients with MS who are 55 years old and older and who have had 5
years of stable disease.
 Results- this study could not conclude whether disease-modifying therapy
discontinuation is non-inferior to continuation of therapy.

120. TREATMENT OF PROGRESSIVE MS
Objective Measures Of Progression:
 EDSS- increase of 1 score over 6 months.
 Multiple Sclerosis Functional Composite-
three part ,stadardised ,quantitative assessment –
25 foot walk for leg function and ambulation
9 hole peg test for arm and hand function
Symbol digit modalities test
low contrast assessment of visual acuity.
 Worsening of more than 20% on a timed 25-foot walk32 and 9-hole peg test and changed EDSS
at 24 weeks delineated the separation between SPMS and non progression.

121. All DMTs indicated for RRMS are indicated for
active SPMS .
No DMTs are FDA approved to treat nonactive
SPMS

122. DMT Trials In Progressive MS

123. Non Active Stable Progressive Ms
No formal guidelines .
older age, longer periods of stable disease on DMT with
absent relapses or MRI activity, and an EDSS score less
than 6 are associated with a low risk of disease
recrudescence and worsening when stopping DMT
use.(DISCO-MS).
Cost , toxicity vs risk of rebound (continuous monitoring
recommended).

125. EMBOLD STUDY –Allogenic T cell
immunotherapy
 ATA188 is an experimental therapy that uses immune T-cells to fight
of EBV-infected immune cells in MS patients.
 It contains T-cells obtained from healthy donors who have
previously been infected with EBV
 Data from the trial’s Phase 1 part showed that ATA188 help
patients achieve confirmed disability improvement.
 Phase 2 is currently ongoing.

126. Pregnancy

127. Pediatric MS: <18 yrs, 10%
 Pediatric-onset MS differs from adult-onset MS in that pediatric patients have more than
three times higher relapse rates . Overall, 99% of pediatric patients present with relapsing
forms of MS .
 The efficacy of DMT treatments on MS disability declines with advancing age, arguing in
favor of treating children with MS early with high efficacy DMTs (fingolimod, dimethyl
fumarate, natalizumab, ocrelizumab,rituximab).
 In conjunction with DMT initiation, counselling on modifiable risk factors that may impact
their MS -smoking (passive or active), vitamin D deficiency,diet quality, obesity or sedentary
lifestyle.

128.  The first FDA approved DMT for the treatment of pediatric MS was
fingolimod, which was studied in the PARADIGMS study.
 Safety profiles were similar between the two groups except for
increased seizure frequency in the fingolimod arm.
 Fingolimod is the only oral DMT drug approved in pediatric MS.

129.  The TERIKIDS phase 3 randomized trial comparing
teriflunomide and placebo did not show a significant
difference in time to first relapse.
 The FDA rejected approval of teriflunomide for the treatment
of pediatric MS;however, the European Commission approved
teriflunomide for the treatment of pediatric patients aged 10 to
17 years.

130. Other Trials Under Way
Dimethyl fumarate (CONNECT)
Peginterferon beta-1a (BIIB017)
Alemtuzumab (lemkids)
Ocrelizumab (operetta 2), and
Ofatumumab and siponimod (NEOS)
Efficacy between ocrelizumab and fingolimod
(NCT04075266)

131. AAN 2018 guidelines
 Starting DMT :
 Clinicians should counsel people with newly diagnosed MS about specific
treatment options with DMT at a dedicated treatment visit. Level B
 Clinicians must ascertain preferences in terms of safety, route of
administration, lifestyle, cost, efficacy, AEs and tolerability in the choice of
DMT. Level A
 Counsel patients that DMTs are prescribed to reduce relapses and new
MRI lesion activity and not for symptom improvement in people with MS.
Level B

132.  After discussing the risks and benefits, DMT should be prescribed to
people with a single clinical demyelinating event and ≥2 brain
lesions characteristic of MS who decide they want this therapy.
(Level B)
 Clinicians should offer DMTs to people with relapsing forms of MS
with recent clinical relapses or MRI activity. (Level B)
 Recommend serial imaging at least annually for the first five years
and close follow-up rather than initiating DMT in people with CIS
or RRMS who are not on DMT and no active lesions, No relapse
since 2 years.( Level C)

133.  Clinicians should monitor the family plans of women with MS and
counsel regarding reproductive risks and use of birth control during
DMT use in women of childbearing potential who have MS. (Level
B)
 If women with MS are planning pregnancy soon, DMT use may
need to be deferred until after pregnancy
 Clinicians should counsel men with MS on their reproductive plans
regarding treatment implications before initiating treatment with
teriflunomide or cyclophosphamide. (Level B)

134.  Switching DMT :
 Discuss switching from one DMT to another who have been using a DMT long
enough for the treatment to take full effect and are adherent to their therapy when
they experience
1)one or more relapses
2)two or more unequivocally new MRI-detected lesions
3) increased disability on examination, over a one-year period of using a DMT. (Level B)
 Clinicians should evaluate the degree of disease activity, adherence, AE that may
affect adherence and MOA of DMTs when switching DMTs with breakthrough disease
activity during DMT use. (Level B)
 Discuss a change to noninjectable or less frequently injectable DMTs who report
intolerable discomfort with the injections or in those who report injection fatigue on
injectable DMTs. (Level B)

135.  Switch DMT or reducing dosage or frequency when there are persistent
laboratory abnormalities. (Level B)
 If a patient develops malignancy or opportunistic infection while using a
DMT, discuss switching to an alternate DMT, especially for people using
azathioprine, methotrexate, MMF, cyclophosphamide, fingolimod,
teriflunomide, alemtuzumab, DMF. (Level B)
 Counsel people considering natalizumab discontinuation that there is an
increased risk of MS relapse within six months of discontinuation(Level A)
and should initiate treatment(fingolimod, rituximab) within eight to 12
weeks after natalizumab discontinuation Level B

136.  Counsel women to stop their DMT before conception for planned
pregnancies and should not initiate DMTs during pregnancy unless
the risk of MS activity during pregnancy outweighs the risk
associated with the specific DMT during pregnancy. (Level B)

137.  Stopping DMT :
 People with MS who are stable on DMT should continue their
current DMT unless the patient and physician decide a trial off
therapy is warranted. (Level B)
 Clinicians should review the associated risks of continuing DMTs
versus those of stopping DMTs in people with CIS using DMTs who
have not been diagnosed with MS. Level B

138.  Clinicians may advise discontinuation of DMT in people with SPMS
who do not have ongoing relapses (or gadolinium-enhanced
lesions on MRI activity) and have not been ambulatory (EDSS 7 or
greater) for at least two years. Level C

139. Thank You