MS II Flashcards
2 treatment options
Disease-modifying treatments and symptom treatments
Disease-modifying treatments
Long-term treatments to modify disease course, delay accumulation of disability
No direct impact on symptoms
Symptom treatments
Treatments to settle symptoms
No direct impact on disease
Clinical progression of MS correlates with _____ but not ____
Axonal loss; but not myelin loss
Things that contribute to disease progression
Inflammation Axonal degeneration Microglial activation Mitochondrial injury Oxidation byproducts Glutamate excitotoxicity ALL POSSIBLE TARGETS
A good drug should target
all contributions to disease progression (incl. Axonal degeneration, Microglial activation, Mitochondrial injury, Oxidation byproducts, Glutamate excitotoxicity)
Complement C1q-C3 is associated with
Synaptic changes in the hippocampus in MS
Pathological pruning of synapses
T/F: Synapse loss is dependent on demyelination and axonal loss
FALSE: Synapse loss can happen independently of demyelination and axon loss
Regulation of microglia in MS
Signal: ‘eat me’ vs ‘don’t eat’ to regulate synaptic pruning
Existing treatments primarily target
inflammatory component of MS
Novel agents should
directly target protection and repair of the CNS as well as targeting inflammation (rather than only focusing on inflammation)
Interferon-beta (βIFN) action
Interferon–beta acts through the interferon-beta
receptor and inhibits antigen presentation and
T cell activation
Interferon-beta (βIFN) mechanism
reduces activation of autoreactive T cells –> decreases pro-inflammatory Th1 cytokines
Interferon-beta (βIFN)
One of the first MS drugs (‘traditional immunomodulatory therapy)
GA (Glatiramer Acetate) peptide mechanism
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
GA (Glatiramer Acetate) peptide
One of the first MS drugs (‘traditional immunomodulatory therapy)
Pros of traditional immunomodulatory therapies
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
Traditional immunomodulatory therapies
includes: βIFN1b/1a(sc/im)/ GA
βIFN Side Effects/cons:
Side effects: – Flu-like symptoms – Injection site reactions – Liver effects – Leukopenia Cons: – injectable (not easy to admin)
GA side effects/cons
Side effects: – Injection Site reactions – Rash – Panic Reaction – Lipoatrophy COns – injectable (not easy to admin)
Dimethyl fumarate: known mechanisms of
action
- 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
Dimethyl fumarate: known immunological
effects in RRMS patients
• 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
With Dimethyl fumarate, you have to monitor ____ because of
Monitor lymphocyte count b/c cases of opportunistic infections (ex. PML)
PML
CNS infection induced by JC virus
Opportunistic infection in immunocompromised patients (ex. those on Dimethyl fumarate)
most cases associated with low lymphocyte count
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
Traffickers
Inhibit traffic of immune cells between different organs
incl. FINGOm, NTS
Immunomodulators
Dimethyl fumarate (DMF)
Teriflunomide (TERI)
DAC
Fingolimod is an analogue of…
an analogue of sphingosine, a polyfunctional endogenous mediator
Fingolimod is derived from
Fingolimod is derived from a natural substance (miriocine), isolated from a fungus
Fingolimod has a similar structure to
Similar stucture to sphingosine
Sphingosine after phosphorylation acts as
- Intracellular messenger
* On the surface of the cell through a receptor( S1P)
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)
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
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)
Natalizumab mechanism of action (circulation)
block receptors on lymphocytes that are needed for adhesion to endothelial cells
lack adhesion –> can’t traffic into CNS
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
PML is most frequent in
Natalizumab (esp with >2 years of treatment)
PML is increased in treatments that…
last over 2 years or those previously treated with other immunosuppressants
Immunodepletion
alemtuzumab (ALEM)
Ocrelizumab (OCR)
Cladribine (2-CbA)
Alemtuzumab: what is it
monoclonal antibody (anti-CD52)
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
Alemtuzumab: safety
Infusion reactions, infections, thyroid disorders, immune-mediated thrombocytopenic purpura (kidney), goodpasture syndrome
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
Ocrelizumab: what is it
Ocrelizumab is a second-generation humanized monoclonal antibody, directed against CD20
Ocrelizumab: mechanism of action
Ocrelizumab depletes circulating B lymphocytes predominately through antibody-mediated cytotoxicity
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
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
T/F: Cladribine must enter cells and be activated in order to exert its effect
True
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
How to inactivate cladribine
Activated cladribine is inactivated by a specific phosphatase
Benefits of Ocrelizumab
- more selective than Alemtuzumab
- taken IV every 6 months (convenient)
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)
How is cladribine similar to a prodrug
Only activated in some cells and activated form is the only form that induces lymphocyte reduction
Definition of immunosuppressant
• Hematological changes such as leukocytopenia, granulocytopenia or lymphopenia • Increased incidence of infections • Increased occurrence of tumours • Decreased efficacy of vaccines
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
Different drugs alter different ____
compartments of the immune system
TERI, DMF, ALemtuzumab, Cladiribine, Ocrelizumab–commonalities
all drugs that decrease lymphocytes
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
Duration of immune response (from shortest to longest term)
Immunomodulators (shortest; daily) < Traffickers (medium) < Immunodepleters (longterm)
Immunomodulators
Dimethyl fumarate, GA, interferons, Terifluonimide
Traffickers
fingolimod, natalizumab
Immunodepleters
Alemtuzumab, Cladribine, ocrelizumab
Need to take ___ into account when stopping a drug
Duration of immune effects
esp. if stopping due to complications
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
Response to vaccines
Most have not shown to decrease the efficacy of vaccines (unlike traditional immunosuppressants)
B cells and vaccine response
- B cell depletion attenuates humoral responses to
vaccines - Level of protection from prior immunization may be
affected
Ocrelizumab and vaccines
Ocrelizumab affects B cells and may decrease immunoglobulins
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
Safety vs efficacy
- The more effective the less safe
- inverse relationship between efficacy and safety for al immunotherapies
