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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
Q

Teriflunomide: mechanisms of action on activated lymphocytes

A

Inhibit DHODH (enzyme) –> decreased proliferation of lymphocytes –> fewer T and B cells –> decreased inflam

DHODH inhibition cytostatic arrest reduced proliferation

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26
Q

Traffickers

A

Inhibit traffic of immune cells between different organs

incl. FINGOm, NTS

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27
Q

Immunomodulators

A

Dimethyl fumarate (DMF)
Teriflunomide (TERI)
DAC

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28
Q

Fingolimod is an analogue of…

A

an analogue of sphingosine, a polyfunctional endogenous mediator

29
Q

Fingolimod is derived from

A

Fingolimod is derived from a natural substance (miriocine), isolated from a fungus

30
Q

Fingolimod has a similar structure to

A

Similar stucture to sphingosine

31
Q

Sphingosine after phosphorylation acts as

A
  • Intracellular messenger

* On the surface of the cell through a receptor( S1P)

32
Q

FInglomod

A

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
Q

S1P receptor function

A

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
Q

Fingolimod risks/side effects

A
  • 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
Q

Natalizumab mechanism of action (circulation)

A

block receptors on lymphocytes that are needed for adhesion to endothelial cells
lack adhesion –> can’t traffic into CNS

36
Q

Natalizumab mechanism of action (tissue)

A

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
Q

PML is most frequent in

A

Natalizumab (esp with >2 years of treatment)

38
Q

PML is increased in treatments that…

A

last over 2 years or those previously treated with other immunosuppressants

39
Q

Immunodepletion

A

alemtuzumab (ALEM)
Ocrelizumab (OCR)
Cladribine (2-CbA)

40
Q

Alemtuzumab: what is it

A

monoclonal antibody (anti-CD52)

41
Q

Alemtuzumab: mechanism of action

A

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
Q

Alemtuzumab: safety

A

Infusion reactions, infections, thyroid disorders, immune-mediated thrombocytopenic purpura (kidney), goodpasture syndrome

43
Q

Thyroid disorders with alemtuzumab

A

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
Q

Ocrelizumab: what is it

A

Ocrelizumab is a second-generation humanized monoclonal antibody, directed against CD20

45
Q

Ocrelizumab: mechanism of action

A

Ocrelizumab depletes circulating B lymphocytes predominately through antibody-mediated cytotoxicity

46
Q

B cells’ role in MS

A

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
Q

Cladribine tablets: mechanism of action (overview)

A

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
Q

T/F: Cladribine must enter cells and be activated in order to exert its effect

A

True

49
Q

Cladribine 4-step mechanism

A

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
Q

How to inactivate cladribine

A

Activated cladribine is inactivated by a specific phosphatase

51
Q

Benefits of Ocrelizumab

A
  • more selective than Alemtuzumab

- taken IV every 6 months (convenient)

52
Q

Ocrelizumab effects on T-cells

A

Acts directly on B cells, but depleting B cells has indirect effects on T-cells (b/c B cells are antigen-presenting cells)

53
Q

How is cladribine similar to a prodrug

A

Only activated in some cells and activated form is the only form that induces lymphocyte reduction

54
Q

Definition of immunosuppressant

A 
• Hematological changes such as leukocytopenia,
granulocytopenia or lymphopenia
• Increased incidence of infections
• Increased occurrence of tumours
• Decreased efficacy of vaccines
55
Q

Unlike original immunosuppressants these newer drugs have immunosuppressant actions like ______ but do no _______

A

Induce lymphopenia, but do not increase malignancies or decrease the efficacy of vaccines

56
Q

Different drugs alter different ____

A

compartments of the immune system

57
Q

TERI, DMF, ALemtuzumab, Cladiribine, Ocrelizumab–commonalities

A

all drugs that decrease lymphocytes

58
Q

T/F: DMTs have different durations of immune effects

A

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
Q

Duration of immune response (from shortest to longest term)

A

Immunomodulators (shortest; daily) < Traffickers (medium) < Immunodepleters (longterm)

60
Q

Immunomodulators

A

Dimethyl fumarate, GA, interferons, Terifluonimide

61
Q

Traffickers

A

fingolimod, natalizumab

62
Q

Immunodepleters

A

Alemtuzumab, Cladribine, ocrelizumab

63
Q

Need to take ___ into account when stopping a drug

A

Duration of immune effects

esp. if stopping due to complications

64
Q

Reconstituition of immune system

A

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
Q

Response to vaccines

A

Most have not shown to decrease the efficacy of vaccines (unlike traditional immunosuppressants)

66
Q

B cells and vaccine response

A
  • B cell depletion attenuates humoral responses to
    vaccines
  • Level of protection from prior immunization may be
    affected
67
Q

Ocrelizumab and vaccines

A

Ocrelizumab affects B cells and may decrease immunoglobulins

68
Q

Immunological considerations for forward planning

A
  • 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
Q

Safety vs efficacy

A
  • The more effective the less safe

- inverse relationship between efficacy and safety for al immunotherapies

PMCOL 412 (35 decks)

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