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PMCOL 412 > MS II > Flashcards

MS II Flashcards

1
Q

2 treatment options

A

Disease-modifying treatments and symptom treatments

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2
Q

Disease-modifying treatments

A

Long-term treatments to modify disease course, delay accumulation of disability
No direct impact on symptoms

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3
Q

Symptom treatments

A

Treatments to settle symptoms

No direct impact on disease

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4
Q

Clinical progression of MS correlates with _____ but not ____

A

Axonal loss; but not myelin loss

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5
Q

Things that contribute to disease progression

A 
Inflammation
Axonal degeneration
Microglial activation
Mitochondrial injury 
Oxidation byproducts 
Glutamate excitotoxicity 
ALL POSSIBLE TARGETS
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6
Q

A good drug should target

A

all contributions to disease progression (incl. Axonal degeneration, Microglial activation, Mitochondrial injury, Oxidation byproducts, Glutamate excitotoxicity)

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7
Q

Complement C1q-C3 is associated with

A

Synaptic changes in the hippocampus in MS

Pathological pruning of synapses

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8
Q

T/F: Synapse loss is dependent on demyelination and axonal loss

A

FALSE: Synapse loss can happen independently of demyelination and axon loss

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9
Q

Regulation of microglia in MS

A

Signal: ‘eat me’ vs ‘don’t eat’ to regulate synaptic pruning

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10
Q

Existing treatments primarily target

A

inflammatory component of MS

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11
Q

Novel agents should

A

directly target protection and repair of the CNS as well as targeting inflammation (rather than only focusing on inflammation)

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12
Q

Interferon-beta (βIFN) action

A

Interferon–beta acts through the interferon-beta
receptor and inhibits antigen presentation and
T cell activation

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13
Q

Interferon-beta (βIFN) mechanism

A

reduces activation of autoreactive T cells –> decreases pro-inflammatory Th1 cytokines

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14
Q

Interferon-beta (βIFN)

A

One of the first MS drugs (‘traditional immunomodulatory therapy)

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15
Q

GA (Glatiramer Acetate) peptide mechanism

A

GA is presented as an antigen and generates GA-specific T cells of TH2 bias
i.e. change inflammation characteristics from pro- to anti-inflammatory

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16
Q

GA (Glatiramer Acetate) peptide

A

One of the first MS drugs (‘traditional immunomodulatory therapy)

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17
Q

Pros of traditional immunomodulatory therapies

A 
includes: βIFN1b/1a(sc/im)/ GA
Pros: 
- safe
- ~33% relapse reduction
- reduce GAD enhancement/new T2 lesions
- GA may be neuroprotective 
- May dealt disability progression
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18
Q

Traditional immunomodulatory therapies

A

includes: βIFN1b/1a(sc/im)/ GA

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19
Q

βIFN Side Effects/cons:

A 
Side effects: 
– Flu-like symptoms
– Injection site reactions
– Liver effects
– Leukopenia
Cons:
– injectable (not easy to admin)
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20
Q

GA side effects/cons

A 
Side effects: 
– Injection Site reactions
– Rash
– Panic Reaction
– Lipoatrophy
COns
– injectable (not easy to admin)
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21
Q

Dimethyl fumarate: known mechanisms of

action

A
  • Activation of the Nrf2 pathway
  • Inhibition of NF-kB
  • Blocking cysteine residues
  • Activation of HCAR2
  • Glutathione depletion
  • Inhibition of aerobic glycolysis
  • Activates ROS pathway in monocytes
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22
Q

Dimethyl fumarate: known immunological

effects in RRMS patients

A

• Shift of the immune balance to an anti-inflammatory
profile
• Restoration of cytolytic functions of CD56bright NK cells
• Induction of T cell and B cell apoptosis (modulate immune sys)
• Inhibition of pro-inflammatory cytokines
• Inhibition of T cell activation and proliferation
• Inhibition of B cell expression of costimulatory and
antigen presentation molecules

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23
Q

With Dimethyl fumarate, you have to monitor ____ because of

A

Monitor lymphocyte count b/c cases of opportunistic infections (ex. PML)

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24
Q

PML

A

CNS infection induced by JC virus
Opportunistic infection in immunocompromised patients (ex. those on Dimethyl fumarate)
most cases associated with low lymphocyte count

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25
Teriflunomide: mechanisms of action on activated lymphocytes
Inhibit DHODH (enzyme) --> decreased proliferation of lymphocytes --> fewer T and B cells --> decreased inflam DHODH inhibition cytostatic arrest reduced proliferation
26
Traffickers
Inhibit traffic of immune cells between different organs | incl. FINGOm, NTS
27
Immunomodulators
Dimethyl fumarate (DMF) Teriflunomide (TERI) DAC
28
Fingolimod is an analogue of...
an analogue of sphingosine, a polyfunctional endogenous mediator
29
Fingolimod is derived from
Fingolimod is derived from a natural substance (miriocine), isolated from a fungus
30
Fingolimod has a similar structure to
Similar stucture to sphingosine
31
Sphingosine after phosphorylation acts as
* Intracellular messenger | * On the surface of the cell through a receptor( S1P)
32
FInglomod
blocks S1P receptor on the surface of lymphocytes --> can't sense gradient --> lymphocytes can't exit lymph node --> decreased trafficking --> lymphopenia in periphery (fewer lymphocytes in CNS to cause issues)
33
S1P receptor function
The signal mediated through S1P regulates the exit of lymphocytes from lymph nod when blocked => can't sense gradient --> can't exit lymph node
34
Fingolimod risks/side effects
- risk of blocking lymphocytes - increased frequency of opportunistic infections - receptors can also be present on the heart cells --> cause bradycardia (altered heart rhythm) - macular edema (esp. in those with diabetes or over the age of 50)
35
Natalizumab mechanism of action (circulation)
block receptors on lymphocytes that are needed for adhesion to endothelial cells lack adhesion --> can't traffic into CNS
36
Natalizumab mechanism of action (tissue)
Could have effect w/in CNS | block interactions of lymphocytes w/ cells of CNS (ex. astrocytes and microglia) to prevent activation of these cells
37
PML is most frequent in
Natalizumab (esp with >2 years of treatment)
38
PML is increased in treatments that...
last over 2 years or those previously treated with other immunosuppressants
39
Immunodepletion
alemtuzumab (ALEM) Ocrelizumab (OCR) Cladribine (2-CbA)
40
Alemtuzumab: what is it
monoclonal antibody (anti-CD52)
41
Alemtuzumab: mechanism of action
Anti-CD52 --> induce lymphopenia --> almost complete erasure of immune system (except bone marrow) --> 'reset' immune system (bone marrow replenishes the body with new immune system) --> decreased inflam
42
Alemtuzumab: safety
Infusion reactions, infections, thyroid disorders, immune-mediated thrombocytopenic purpura (kidney), goodpasture syndrome
43
Thyroid disorders with alemtuzumab
Autoimmune reaction to thyroid b/c of repopulation of diff areas and cells occurs at different speeds = imbalanced immune system Can be hypo- or hyperthyroidism
44
Ocrelizumab: what is it
Ocrelizumab is a second-generation humanized monoclonal antibody, directed against CD20
45
Ocrelizumab: mechanism of action
Ocrelizumab depletes circulating B lymphocytes predominately through antibody-mediated cytotoxicity
46
B cells' role in MS
B cells may play a central role in the pathogenesis in MS, being involved in: – Activation of pro-inflammatory T cells – Secretion of pro-inflammatory cytokines – Production of autoantibodies directed against myelin – Contributing to the formation and/or maintenance of persisting immune cell aggregates
47
Cladribine tablets: mechanism of action (overview)
selectively reduces both B and T lymphocytes and impacts cytokines profile (a depleter) Cladribine must enter cells and be activated in order to exert its effect
48
T/F: Cladribine must enter cells and be activated in order to exert its effect
True
49
Cladribine 4-step mechanism
1) Cladribine enters cell via nucleoside transporter 2) Accumulates intracellularly due to ADA resistance 3) Cladribine is activated by specific kinases 4) Activated Cladribine induces lymphocyte reduction
50
How to inactivate cladribine
Activated cladribine is inactivated by a specific phosphatase
51
Benefits of Ocrelizumab
- more selective than Alemtuzumab | - taken IV every 6 months (convenient)
52
Ocrelizumab effects on T-cells
Acts directly on B cells, but depleting B cells has indirect effects on T-cells (b/c B cells are antigen-presenting cells)
53
How is cladribine similar to a prodrug
Only activated in some cells and activated form is the only form that induces lymphocyte reduction
54
Definition of immunosuppressant
``` • Hematological changes such as leukocytopenia, granulocytopenia or lymphopenia • Increased incidence of infections • Increased occurrence of tumours • Decreased efficacy of vaccines ```
55
Unlike original immunosuppressants these newer drugs have immunosuppressant actions like ______ but do no _______
Induce lymphopenia, but do not increase malignancies or decrease the efficacy of vaccines
56
Different drugs alter different ____
compartments of the immune system
57
TERI, DMF, ALemtuzumab, Cladiribine, Ocrelizumab--commonalities
all drugs that decrease lymphocytes
58
T/F: DMTs have different durations of immune effects
True Admin: daily to every 6 months Duration of immune effects need to be taken into account when stopping a drug due to complications
59
Duration of immune response (from shortest to longest term)
Immunomodulators (shortest; daily) < Traffickers (medium) < Immunodepleters (longterm)
60
Immunomodulators
Dimethyl fumarate, GA, interferons, Terifluonimide
61
Traffickers
fingolimod, natalizumab
62
Immunodepleters
Alemtuzumab, Cladribine, ocrelizumab
63
Need to take ___ into account when stopping a drug
Duration of immune effects | esp. if stopping due to complications
64
Reconstituition of immune system
Different subpopulations of cells repopulate at different speeds B cells are first, then T-cells then CD4 lymphocytes Explains why we see some autoimmune diseases in some patients--asynchronous repopulation of cells
65
Response to vaccines
Most have not shown to decrease the efficacy of vaccines (unlike traditional immunosuppressants)
66
B cells and vaccine response
- B cell depletion attenuates humoral responses to vaccines - Level of protection from prior immunization may be affected
67
Ocrelizumab and vaccines
Ocrelizumab affects B cells and may decrease immunoglobulins
68
Immunological considerations for forward planning
- Effect of the DMT on the immune cell compartments - Duration of these effects on the immune system - Dynamics of reconstitution of the immune system - Age of the patient (less or more than 50) - Immunisation status
69
Safety vs efficacy
- The more effective the less safe | - inverse relationship between efficacy and safety for al immunotherapies

PMCOL 412 (35 decks)

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