Multiple Sclerosis

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

Pathophysiology

• 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

Glucocorticoids:

•      -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

Interferons

• 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

ADR

• 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

Action

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

S/E

• -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

Mitoxantrone

• Potent inhibitor of topoisomerase II
• Approved for SPMS, PRMS, & worsening RRMS à broadest indication in MS but not used as 1^st 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

Natalizumab

• 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

Teriflunomide

• 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

Alemtuzumab

• 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
•  -1^st  course: 12 mg/day on 5 consecutive days.
•  -2^nd  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).

Daclizumab

• 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

Ocrelizumab

• 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

Dalfampridine

• 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.

Siponimod

• 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.