Multiple Sclerosis

  • Autoimmune disease, mediated by myelin-specific CD4 T cells
  • Characterized by:
    • Inflammation
    • Demyelination
    • Gliosis (scarring)
    • Neuronal loss
  • Twenty  years after diagnosis:
    • > 80% patients functional limitations.
    • 50-60% require assistance to walk. (EDSS>6)
    • 70% are limited in ability to perform major activities.
  • Cause  unknown, but believed to be multi-factorial.
  • Develops between the 20-40 year
  • Prevalence à 3/100,000 for India
  • Types of MS:
    • RRMS- Relapsing-Remitting MS  – most common 85%
    • PPMS – Primary-Progressive MS
    • SPMS – Secondary-Progressive MS
    • PRMS – Progressive-Relapsing MS


  • initial important event in MS occurs when autoreactive CD4+ T helper cells are activated in the periphery.
  • they secrete cytokines that damage the oligodendroglial cells. Inside the brain, T cells and accompanying macrophages and microglial cells release osteopontin (OPN), interleukin-23 (IL-23), IFN- and tumour-necrosis factor (TNF), all of which damage the myelin sheath.
  • Concomitantly, B cells (plasma cells) produce myelin-specific antibodies
  • Lymphocytes recognize myelin as foreign and attack.
  • Triggers inflammatory processes
  • Remyelination
  • Newly-formed myelin sheaths are thinner and often not as effective as the original ones.
  • Repeated attacks lead to scar-like plaque up around the damaged axons
  • Axons  are damaged by the attacks
  • the brain is unable to compensate, due to neuroplasticity.

Clinical features

  • Spasticity
  • Ataxia / tremors
  • Cognitive decline
  • Sensory loss (tingling, numbness)
  • Fatigue, Pain, Bowel /Bladder dysfunction, Depression

Diagnostic Tools:

  • -McDonald criteria
  • -MRI
  • -CSF – Oligoclonal bands

Goal of Treatment

  • No known definitive cure for multiple sclerosis.
  • Treatment is aimed at-
  •    -Returning function after an attack,
  •    -Preventing new attacks,
  •    -Preventing disability.

Treatment of acute attack


  •      -reduces severity of attack
  •      – reduces duration of attack
  •      – long term benefits?
  • Dose: 500-1000mg/d for 3-5 days methyl prednisolone, taper with 60-80 mg/d oral dose over 2wks
  • ADR: fluid retention, K+ loss, wt gain, acne, emotional liability gastric disturbances

Plasma exchange:

  •    – benefits patients with fulminant attacks
  •    -pts not responding to steroids
  •    – high cost
  • Dose: 7 exchanges

Disease modifying agents


  • Derived from human cytokines
  • Interferon β 1a, Interferon β 1b:
  • First FDA approved for relapsing forms of secondary progressive MS.
Periphery: Prevents upregulation of MHC II on APCInhibits clonal expansion of TH1 Apoptosis of T cellsDown regulation of co-stimulatory (CD40)               molecules Down regulation of adhesion molecules  
BBB: conversion of cell-associated VCAM-1 into soluble VCAM-1Reduced chemokine & CCR5 receptor expressionReduced T cell migration by inhibition of T cell MMPs  


Effects and Efficacy

  • Reduce severity of relapses & their frequency by about 1/3rd.
  • Fewer lesions on MRI.
  • May reduce the chance of disability in people with relapsing-remitting MS.
  • May help slow the progression of cognitive impairment.
  • Long term efficacy unknown
  • Higher doses of INFβ1b have shown good results but chances of neutralising antibodies


  • Injection site reactions
  • Flu-like symptom complex
  • Elevated liver enzymes, alteration in blood count, hypersensitivity reactions, neutralising antibodies

Glatiramer acetate

  • Polypeptides with the amino acids glutamate, lysine, alanine tyrosine


  •  -Affects antigen presentation
  •  -Th1 to Th2 Shift
  •  -Induces neurotropic factors like brain derived neurotropic factor (BDNF)
  •  – Displaces MBP by binding to MHC molecule


  • -Well tolerated
  • -Lipoatrophy permanent and is perhaps most severe S/E
  • s.c. injections of 20 mg OD
  • JAN 2014 Higher dose & lower frequency regimen approved — 40 mg sc 3 times/week GA at 12 months


  • Potent inhibitor of topoisomerase II
  • Approved for SPMS, PRMS, & worsening RRMS à broadest indication in MS but not used as 1st line because of cardiotoxicity.
  • Action
  •   -intercalates into DNA through hydrogen bonding, crosslinks and strand breaks.
  •  –Induces apoptosis of active immune cells
  •  -Inhibits activation of several pro-inflammatory cells and macrophages.
  • S/E
  • -Rare but possibility of treatment related leukemia
  • Dose-dependent cardiotoxicity


  • Approved for RRMS as monotherapy in 2006
  • Action
  • -Selective adhesion molecule inhibitor (SAM)
  • -Binds to and Blocks α4β1 integrin (VLA4)
  • -Prevents transendothelial migration of activated   leukocytes from small venules into CNS
  • Dose – 300 mg infused i.v. over one hour, every four weeks.
  • S/E
  •   progressive multifocal leukoencephalopathy (PML) if
  •     – > 2 years treatment
  •    –  Prior treatment with an immunosuppressant
  •    –  The presence of anti-JCV antibodies
  • withdrawal from the market in 2005; however, it was reapproved in 2006 by the FDA for commercialization under a special restricted distribution program
  • Fingolimod
  • First orally administered, disease-modifying drug approved by the FDA 2010
  • Sphingosine 1-phosphate receptor (S1PR) modulator
  • Dose -0.5 mg OD
  • oral sphingosine 1-phosphate receptor (S1PR) modulator that subsequent to its phosphorylation binds with high affinity to S1PR
  • leads to an internalization and degradation of the receptor in different tissues and cell types, including lymphocytes.
  • As a consequence, fingolimod inhibits the ability of autoreactive lymphocytes to regress from the lymph nodes towards the CNS.
  • Bradycardia-observed for 6 hours after the first dose.
  • all patients started on fingolimod must be monitored for at least 6 hours following the first dose.
  • Increase the risk of infection (Influenza), and macular oedema can occur with or without visual symptoms


  • Active metabolite of Leflunomide, Immunomodulating drug.
  • Approved by FDA 2012
  • Exerts a cytostatic effect on proliferating B and T.
  • reversibly inhibits the de novo synthesis of pyrimidine by blocking the mitochondrial enzyme dihydro-orotate dehydrogenase (DHODH).
  • By inhibiting DHODH and reducing DNA synthesis, teriflunomide exerts a cytostatic effect on proliferating B and T cells.
  • induce Th-2-mediated anti-inflammatory cytokine activation.
  • black box warning for the risks of hepatotoxicity and teratogenicity

Dimethyl Fumarate

  • Orally administered immune modulator
  • Approved in 2013 in US for RRMS
  • Mechanism of action
  •   -Shift of proinflammatory immune reaction to a Th2-like                                                                                   
       -Promote apoptosis of CD4 & CD8 T cells.
  • S/E à flushing, abdominal pain, diarrhea, and nausea.
  • Like Natalizumab, also a/w PML


  • Humanized monoclonal antibody targeting CD52, a broadly expressed cell–surface molecule on immune cells.
  • Rapid, long-lasting removal of lymphocyte populations from the circulation.
  • Conferred neuroprotective effects.
  • Approved in 2014
  • Dose : IV infusion
  •  -1st  course: 12 mg/day on 5 consecutive days.
  •  -2nd  course: 12 mg/day on 3 consecutive days 12 months after first  treatment course
  • Infusion-related reactions (headache, rash, nausea, fever, itching, insomnia, and fatigue).
  • Infections (i.e., upper respiratory and urinary tract infections, sinusitis, and herpes simplex infections).


  • Humanized monoclonal antibody binds to the high-affinity interleukin-2 (IL-2) receptor subunit (CD25).
  • Approved by FDA IN 2016 for RRMS
  • Reserved for inadequate response to two or more drugs indicated for the treatment of MS
  • Dose -150 mg once monthly s.c.
  • S/E    -Hypersensitivity Reactions, Infections
  •     -Depression and Suicide
  • C/I- Pre-existing hepatic disease or hepatic impairment


  • Humanized anti-CD20 monoclonal antibody.
  • Approval march 2017 in US
  • Treatment of relapsing MS or PPMS
  • Mechanism of action
  •    -Kills B cells by causing antibody-dependent cell-mediated cytotoxicity
  • Dose -Given as parental infusion 600 mg every 6 months
  • Infusion reactions including itchy skin, rash, flushing, throat and mouth irritation, fever, fatigue
  • Increased risk of infections including respiratory tract infection and herpes infection


  • First drug approved by FDA- improve walking in patients.
  • Tablets sustained-release formulation of 4-aminopyridine.
  • Mechanism of action
  • -Blocks K+ channels on the surface of nerve fibers.
  • -Improve the conduction of nerve signals in nerve fibers whose insulating  myelin coating damaged by MS.
  • Maximum recommended dosage is one 10-mg tablet twice daily, with or without food.
  • ADEs
  • Higher dose cause seizures
  • Urinary tract infections.
  • Insomnia, dizziness, headache, nausea, weakness
  • Back pain, balance disorders, swelling in the nose or throat.
  • Tingling, or itching of the skin.

Treatment algorithm

Cladribine – approved in March 2019

  • purine antimetabolite.
  • mechanism – not been fully elucidated but is thought to involve cytotoxic effects on B and T lymphocytes through impairment of DNA synthesis, resulting in depletion of lymphocytes.
  • indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults.
  • Because of its safety profile à generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS.

Black Box Warning:

  • may increase the risk of malignancy.
  • contraindicated in patients with current malignancy; evaluate the benefits and risks on an individual basis for patients with prior or increased risk of malignancy.
  • Risk of Teratogenicity: contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception because of the risk of fetal harm.


  • Approved March 2019
  • sphingosine1-phosphate receptor modulator.
  • specifically indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

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