Treatment Strategies for MS

Question 1

General ways of managing MS?

Answer 1

• education and counselling
• management of acute attacks-> high dose IV methylprednisolone
• prevention of disease activity (disease modifying treatments)
• symptomatic therapy (spasticity, paroxysmal pain, chronic dysaesthetic pain, fatigue, depression, immobility)
• physical therapy
• treating complications

Question 2

Types of pharmacological treatments for MS?

Answer 2

Acute attacks: high dose steroids

Preventing relapses/disability: immunomodulatory/immunosuppressive

Symptomatic

Question 3

Standard MS treatment to accelerate recovery?

Answer 3

High dose IV methylprednisolone (500-1000 mg/day x 3-5 days); (can also be orally given)

[standard dose oral steroids e.g. prednisolone 60mg is NOT recommended]

Question 4

Treating spasticity in MS

Answer 4

• stretching/physical therapy
• baclofen: oral/intrathecal
• Tizanidine
• benzodiazepines
• botulinum toxin (more selective effect)

Question 5

Baclofen side effects?

Answer 5

[if given orally]

• drowsiness
• hypotonia

Question 6

Treating pain in MS

Answer 6

Paroxysmal pain:

• Gabapentin 900mg/day to max 1.8g/day
• Carbamazepine 100-800mg/day

Chronic dysaesthetic pain:

• Amytripyline 20-100 mg/day
• (other antiepileptic/antidepressants)

[narcotics and NSAIDS are ineffective for neuropathic pain]

Question 7

Treating fatigue in MS

Answer 7

[limited options]

• “energy savings” (day planning, devices)

Pharmacological

• amantadine (unconfirmed)
• antidepressants
• modaffinil

Question 8

Examples of mobility treatment in MS?

Answer 8

• encourage activity
• physiotherapy
• orthotics/aids (e.g. a brace)
• functional stimulation
• managing spasticity

Question 9

“First-line” MS treatment?

Answer 9

• Interferon-β (subcut/IM every other day)
• Glatiramer acetate (GA) (subcut, daily)
• Dimethyl Fumarate (Tecfidera®)

Question 10

Interferon-β mechanism of action?

Answer 10

• Immunomodulatory effects
  Reducing T cell activation
• Reducing IFN-g, IL-12, TNF secretion (controversial)
• Modulating BBB via inhibition of MMP-9 and VLA-4/VCAM-1 interactions

Question 11

Common side effects for Interferon-β

Answer 11

• Injection site reaction
• Flu-like symptoms
• Depression
• Raised LFTs

(overall good long term safety)

Question 12

Glatiramer Acetate (GA) mechanism of action

Answer 12

• Binds to HLA-DR2
• Inhibtion/anergy of MBP reactive cells
• Cytokine shift Th1 -> Th2
• neuroprotective

Question 13

Oral drugs for MS?

Answer 13

• Fingolimod
• Dimethyl Fumarate (Tecfidera®)
• Teriflunomide (Aubagio®)

Question 14

Fingolimod mechanism of action?

Answer 14

Agonist at the S1P1 receptors on T cells

Interferes w/ T-cells trafficking- reduced response to chemotactic cues and reduced exit from lymphoid organs

Question 15

Fingolimod licensing and efficacy?

Answer 15

Licensed for use in highly active MS

Good efficacy on active inflammation and relapses
reduces relapse-related disability

Question 16

Fingolimod side effects?

Answer 16

• MAINLY: Cardiac: (S1P1 and S1P3 in atrial myocytes) -> bradycardia
• herpes infections, skin cancers, raised LFTs, lymphopenia

Question 17

Dimethyl Fumarate (Tecfidera®) mechanism of action

Answer 17

Methyl ester of fumaric acid, blocking pro-inflammatory cytokines production

Question 18

Dimethyl Fumarate (Tecfidera®) licensing and efficacy?

Answer 18

Licensed for use in active MS

Good efficacy on active inflammation and relapses
(reduces relapse-related disability

Question 19

Dimethyl Fumarate (Tecfidera®) side effects?

Answer 19

Flushing and GI symptoms

Question 20

Teriflunomide (Aubagio®) mechanism of action

Answer 20

Decreases proliferation of T and B autoreactive lymphocytes

Question 21

Teriflunomide (Aubagio®) licensing and efficacy

Answer 21

Licensed for use in active MS (if pt can’t tolerate injectibles)

Moderately effective in reducing relapse rate

Question 22

Monoclonal antibodies in MS?

Answer 22

• Natalizumab (Tysabri®)
• Alemtuzumab (Lemtrada®)
• Ocrelizumab (Ocrevus®)
• Cladribine (Mavenclad®)

Question 23

MoA of monoclonal Abs in MS

Answer 23

Natalizumab: reduced transmigration (against α4 integrin subunit)

Alemtuzuab: depletes T and B cells

Cladribine: T and B cell depletion

Ocrelizumab: targets CD20+ B-cells

Question 24

Monoclonal Abs licensing and efficacy?

Answer 24

Natalizumab used for highly active MS

All licensed for highly active MS

Question 25

Natalizumab (Tysabri®) side effects?

Answer 25

Progressive Multifocal Leukoencephalopathy PML- (seen in immunosuppressed pts)

Caused by JC virus -> active replication in glial cells -> oligodendrocyte death -> fatal

Question 26

PML risk factors?

Answer 26

• no. of infusions
• JCV titre (>1.5 high risk)
• prior immunosuppressant use

Question 27

PML management?

Answer 27

• stop natalizumab
• plasma exchange to remove natalizumab
• Possible strategy??: combination of filgrastim (restore lymphocyte adhesion), oral maraviroc (modulates T cell recruitment) and mefloquin/mirtazapine (possible anti-JCV effects)

Question 28

Alemtuzumab (Lemtrada®) side effects?

Answer 28

• autoimmunity: (hyperthyroidism/Graves’, ITP, Goodpastures)
• infusion reactions
• infections (herpetic)

Question 29

Role of Haematopoietic Stem Cell Transplantation (HSCT) in MS?

Answer 29

Resets immune system completely from pt’s own naive cells -> new immune profile

Question 30

Haematopoietic Stem Cell Transplantation (HSCT) efficacy?

Answer 30

Great results, very cheap

BUT transplant related mortality of HSCT ~2% (compared to MS not being life-threatening)