Multiple Sclerosis (MS) is a chronic neuroinflammatory disease that results from neuroinflammation and autoimmune changes causing demyelination. Relapsing-Remitting MS is the most common form and may progress to Secondary Progressive MS. Genetic and environmental factors like Vitamin D deficiency and Epstein-Barr virus infection influence susceptibility. MS pathology involves blood-brain barrier breakdown, oligodendrocyte damage, and inflammation resulting in demyelinating lesions. Treatment involves immunomodulatory, immunosuppressive, or immune reconstitution agents to reduce inflammation and neurodegeneration.

1. Multiple Sclerosis
Presented by: Aditya Ajit Singh
Department of Pharmacology and
Toxicology
Reg. no. : PC/2019/212
PC-620
Subject teacher: Dr. Dharmendra Kumar Khatri

2. General Introduction
• Multiple Sclerosis (MS) is a chronic neuroinflammatory
disease.
• Although the pathophysiology remains unclear it is
postulated that MS is a result of neuroinflammation and
autoimmune changes.
• Progressive disease.
• A microenvironment is created wherein, free radical
damage occurs and immune cells are altered.
• Follicular structures of demyelinated nerves and B cells are
present.
1.Correale, Jorge et al. “Progressive multiple sclerosis: from pathogenic mechanisms to treatment.” Brain : a journal of neurology vol. 140,3 (2017): 527-546.
2.Doshi, Anisha, and Jeremy Chataway. “Multiple sclerosis, a treatable disease.” Clinical medicine (London, England) vol. 16,Suppl 6 (2016): s53-s59.

3. Types of MS
Multiple Sclerosis
Relapsing-Remitting MS (RRMS) Primary Progressive MS (PPMS) Secondary Progressive MS (SPPMS)
Profund Lymphocytic Inflammation Narrow rim of activated microglia and macrophages Develops after 10-15 years of onset of RRMS
The severity waxes and wanes Deterioration continues Rapid Neurodegeneration
Relative Incidence
RRMS PPMS SPMS
78%
10
12
Garg, Neeta, and Thomas W Smith. “An update on immunopathogenesis, diagnosis, and treatment of multiple sclerosis.” Brain and
behavior vol. 5,9 (2015)

4. Howard, Jonathan et al. “Epidemiology of Multiple Sclerosis.” Neurologic clinics vol. 34,4 (2016): 919-939.
Clinical Course of MS
Asymptomatic RRMS PPMS
Normal CIS RRMS
Clinical
disability
Time
X
SPMS
SPMS

5. Aetiology
Multiple factors contribute to the progression of MS, to name a few
are:
1. It is observed that people with Vit.D deficiency suffer from
symptoms of MS.
2. Infection with EBV doubles the chances of MS.
3. Smoking increases the risk of MS by 30%.
4. Genetic single nucleotide polymorphism in HLA-DRB1,
TNFR1 gene
Vitamin D
Smoking
Genetic
factors
Infection with
EBV
MS
Owens, Brian. “Multiple sclerosis.” Nature vol. 540,7631 (2016)

6. Pathophysiology
• The characteristic pathological hallmark of MS is
perivenular inflammatory lesions which leads to
breakdown of the blood–brain barrier (BBB)
• The inflammatory infiltrates contain T-lymphocytes,
dominated by MHC class I restricted CD8+ T-cells; MHC
class 2 restricted CD4+ T-cells; B-cells and plasma cells
are also present, although in much lower numbers
• Oligodendrocyte damage and demyelination occur as a
result of inflammation
• An imbalance in effector and regulator T-cells also
contributes to the pathological mechanism of Multiple
Sclerosis
1.Dobson, R, and G Giovannoni. “Multiple sclerosis - a review.” European journal of neurology vol. 26,1 (2019): 27-40.
2.Oh, Jiwon et al. “Multiple sclerosis: clinical aspects.” Current opinion in neurology vol. 31,6 (2018): 752-759.

7. Maintenance/Escalation Therapy (MET)
Chronic therapy that is maintained over time resulting in changes in
immune function only during active treatment
Immunomodulation Immuno-suppression
MET that results in continuous
immunomodulation
Interferonβ
Glatiramer acetate
Teriflunomide
MET that results in continuous
immunosuppression
Fingolimod
Ocrelizumab
Dimethyl fumarate
Immuno-Reconstitution Therapy (IRT)
Short course therapy resulting in long term qualitative changes in
immune function
Partial IRT Complete IRT
Selectively affects adaptive
immune system
Cladribine
Affects both innate and
adaptive immune system
Mitoxantrone
Alemtuzumab
HSCT
TREATMENT MS
Hart, Felecia M, and Jacquelyn Bainbridge. “Current and emerging treatment of multiple sclerosis.” The American journal of managed care vol.
22,6 Suppl (2016)

8. IMMUNOMODULATORY AGENTS MECHANISM (MOA) ROUTE ADVERSE EVENTS
Interferon β IFN β balances the expression of pro
and anti inflammatory cytokines in the
brain and reduces the number of
inflammatory cell that crosses BBB
SC 20-50mcg abnormal LFTs, leukopenia
Glatiramer Acetate Shifts the population of T cells from
proinflammatory Th1 T-cells to
regulatory Th2 T-cells that suppress
the inflammatory response.
Prefilled syringe 20 mg
SC daily or 40 mg SC
three times weekly
Injection site reactions,
lipoatrophy, flushing
reactions
Teriflunomide Dihydro-orotate
dehydrogenase inhibitor
(reduced de novo
pyrimidine synthesis),
anti-proliferative
7 or 14 mg daily PO Hair thinning, gastrointestinal
symptoms (nausea,
diarrhoea), abnormal LFTs,
leukopenia
IMMUNOMODULATING AGENTS

9. IMMUNOSUPRESSIVE
AGENTS
MECHANISM (MOA) ROUTE ADVERSE EVENTS
Fingolimod Selective sphingosine 1-
phosphate modulator,
prevents egress of
lymphocytes from
lymph node
0.5 mg daily PO Bradycardia (first dose),
hypertension, bronchospasm,
lymphopenia, abnormal
LFTs, infections, basal cell
carcinoma, macular oedema,
opportunistic infections
Natalizumab Anti-VLA4, selective
adhesion molecule
Inhibitor prevents immune cells
from crossing blood vessel walls
to reach affected organs
300 mg IV Progressive multifocal
leukoencephalopathy
Ocrelizumab Anti-CD20, B-cell
depleter
Initially 300 mg IV,
followed 2 weeks later
by second dose of
300 mg IV
Hypogammaglobulinemia with
prolonged use
Dimethyl fumarate NRF2
activation,
downregulation of
NFκB
240 mg twice daily PO Flushing, gastrointestinal
symptoms (dyspepsia, cramps
and diarrhoea)
IMMUNOSUPRESSIVE AGENTS

10. IMMUNE RECONSTITUTION
AGENTS
MECHANISM (MOA) ROUTE ADVERSE EVENTS
Alemtuzumab Anti-CD52, non-selective
immune depleter
12 mg IVI 5 days year1,
12 mg IVI 3 days
year 2
Opportunistic infections,
leukopenia
Cladribine Deoxyadenosine (purine)
analogue, adenosine
deaminase inhibitor,
selective T- and B-cell
depletion
10 mg tablets: cumulative
dose of 3.5 mg/kg over
2 years. Tablets given
for 4–5 days in months
1 and 2 in year 1
Lymphopenia, infections (in
particular herpes zoster)
Mitoxantrone Immune depleter
(topoisomerase
inhibitor)
12 mg/m2 IVI 3 monthly
for 2 years; maximum
dose of 140 mg/m2
Leukopenia, hair loss,
nausea, vomiting, infections,
cardiomyopathy,
amenorrhoea
IMMUNE RECONSTITUTION AGENTS

11. Summary
• Multiple sclerosis is a type of chronic neuroinflammatory and autoimmune disease.
• Relapsing-Remitting is the most common form of MS which further progresses to SPMS
• Genetic factors, Vit D and EBV infection determines susceptibility to MS
• BBB breakdown , Oligodendrocyte damage along with inflammation results in the characteristic demyelinating
lesions in MS
• MRI alongside with CSF analysis is the best diagnostic technique for MS
• Immunomodulatory, immunosuppressive and immune reconstitutions agents are indicated in the treatment of MS

12. References
1. Correale, Jorge et al. “Progressive multiple sclerosis: from pathogenic mechanisms to
treatment.” Brain : a journal of neurology vol. 140,3 (2017): 527-546.
2. Doshi, Anisha, and Jeremy Chataway. “Multiple sclerosis, a treatable disease.” Clinical medicine
(London, England) vol. 16,Suppl 6 (2016): s53-s59.
3. Garg, Neeta, and Thomas W Smith. “An update on immunopathogenesis, diagnosis, and treatment of
multiple sclerosis.” Brain and behavior vol. 5,9 (2015)
4. Owens, Brian. “Multiple sclerosis.” Nature vol. 540,7631 (2016).
5. Howard, Jonathan et al. “Epidemiology of Multiple Sclerosis.” Neurologic clinics vol. 34,4 (2016): 919-
939.
6. Dobson, R, and G Giovannoni. “Multiple sclerosis - a review.” European journal of neurology vol. 26,1
(2019): 27-40.
7. Oh, Jiwon et al. “Multiple sclerosis: clinical aspects.” Current opinion in neurology vol. 31,6 (2018):
752-759.
8. Hart, Felecia M, and Jacquelyn Bainbridge. “Current and emerging treatment of multiple