Multiple Sclerosis

Question 1

Interferons (1/7)

Answer 1

Interferon‐Beta (1A and 1B) has several effects
in the immune system:
– Reduces activation of T‐cells
– Reduce entry of T‐cells into the CNS

Reduces inflammation
– Inhibits pro‐inflammatory cytokines

Adverse Effects: Flu like illness, depression, fatigue, injection site reactions

Question 2

Glatiramer (2/7)

Answer 2

Accidental discovery, when looking to create MS in an animal model

Mechanism not well understood
– Inhibits activation of T‐cells (likely by binding with major histocompatibility complex (MHC), and interfering with antigen presentation)
– May promote anti‐inflammatory cytokines

Side Effects:
- local injection site reactions, chest pain, post injection reaction, infection (more tolerable than interferon)

Question 3

Integrin inhibitors - Natalizumab (3/7)

Answer 3

Integrins such as Alpha4 Beta1 (α4β1)
facilitate the passage of lymphocytes across
the blood brain barrier. Bind to vascular cell adhesion molecule (VCAM). Natalizumab binds to α4β1 integrin, thus interfering with the interaction between it and VCAM, preventing transmigration of activated lymphocytes into tissue

Adverse effects

• Major safety issue: PML
• Progressive multifocal leukoencephalopathy
• PML is caused by an opportunistic infection (JC virus) of the CNS
• Severely disabling, can be fatal

Now a surveillance program
– Attempts to identify patients at higher risk
- Risk factors: (JC virus, Concomitant use of immunosuppressants, Use of natalizumab beyond 2 years)

Question 4

Sphingosine receptor modulators
Prototype: Fingolimod
(4/7)

Answer 4

• First oral disease‐modifying therapy for MS
• S1P receptors (they promote T-cell release from lymph nodes) are also found in the CNS
• Therefore may also directly mitigate immune mediated
  damage to myelin
• But mechanism currently unknown

Adverse effects:

• Cardiovascular
• S1P receptors also found in the heart
• Bradycardia, heart block
• Serious infections
• Malignancy
• PML (?)

Question 5

Fumaric acid esters
Prototype: dimethyl fumarate
(5/7)

Answer 5

• Also orally administered
• Mechanism also not well understood
• Activates the nuclear erythroid 2‐related factor 2 (nrf‐2) transcriptional pathway
• Nrf‐2 mediates the cells antioxidant response to
  oxidative stress
• Also may have an anti‐inflammatory effect in CNS
• DMF was first developed for treatment of psoriasis (improved MS)

AE

• Common adverse effects:
• Gastrointestinal
• Flushing
• Rare/serious: PML

Question 6

Immunomodulators
Prototype: teriflunomide
(6/7)

Answer 6

Mechanism:
- Inhibits activity of dihydroorotate dehydrogenase (DHODH)
- This reduces de novo pyrimidine synthesis
- Therefore effects specific to rapidly
dividing lymphocytes

Adverse effects:
– Gastrointestinal
– Alopecia
– Increased risk of infection

Question 7

CD52 inhibitors
• Prototype: alemtuzumab
(7/7)

Answer 7

Mechanism:

• CD52 likely plays a role in T‐cell activation and migration
• Alemtuzumab depletes both T‐cells and B‐cells “resets” the balance of lymphocytes? (CD-52 is thought to be an effective method for reducing T-cell activation)

Adverse effects:
– Autoimmune disorders
– Serious infections
– PML (? risk)