MS Part 2 Flashcards
IMMUNOMODULATOR/MAINTENANCE
THERAPIES
Β Interferons (βIFN) = decrease peripheral activation of T
cells, block lymphocytes crossing Blood Brain Barrier
Glatiramer Acetate (GA) = decreases peripheral
activation of T cells, modulates the immune system to T2
state, decreases central inflammatory cascade Brain
these are medications that you have to take continuously in order to settle the inflammation. And then as soon as you stop them, the person will go back to their baseline disease activity.
beta interferon works at the blood-brain barrier wall. It
The palace is the central nervous system. So both of them are like gatekeepers that stopped those bad lymphocytes from getting into the CNS and then attacking the myelin
GA actually also works inside the brain, inside the palace. And it works by changing the, the inflammatory cascade that can occur.
INJECTABLE MAINTENANCE
IMMUNOMODULATORY THERAPIES
1990’s
1. Interferon (IFN)β1b (SC) and IFNβ1a (SC & IM)
2. Glatiramer Acetate (SC)
* Multiple generic products, safe, not largely effective
* First-line therapies
pros cons?
Pros
* Safe
* ≈ 33% relapse reduction
* Take up to pregnancy,
through pregnancy &
breastfeeding
* Cheaper
* GA – little drug interactions
Cons
* Injectables
βIFN Side Effects:
* Flu-like symptoms
* Liver effects
* Leukopenia
* GA Side Effects:
* Rash
* Panic Reaction
DIMETHYL FUMARATE
pros and cons
May act on major transcription
factor erythroid 2 related factor
2 – NrF2 upregulates
antioxidant pathways
thought to work in terms of the central antioxidant pathways. So it’s thought to work within the CNS as well as outside the palace. One of the byproducts of its metabolization is nicotinic acid. So one of the most common side effects is that a flushing for patients and that can be really bothersome
Pros
* Moderate Efficacy
* First line therapy
* Reduces relapses ≈ 50%
* Pill
* History with psoriatic arthritis
Cons
* Facial Flushing (1/3)
* GI “Upset”
* Fatigue
* Headache
* Leukopenia***
* Increased LFT
* Minor Infections
* ASA pre-treatment
* Monitoring (LFT/CBC)
* Do not take during pregnancy/breastfeeding
* Monitoring: CBC,LFT, UA
once/month x 6 months, then
once/6 months
Drug Interactions: (D)
category for live vaccines
*categorized as
immunosuppressive in some
papers
four pills a day. S
people feel really unwell when they first start on it. So we have to taper up the dose and then about 20% will develop problems with lymphopenia, where if it drops below 0.5, we have to switch them to another agent.
this is easily absorbed through the gut. And as a small molecule. This is an agent that we don’t take during pregnancy and breastfeeding.
IMMUNOSUPPRESSIVE/MAINTENANCE
THERAPIES
- Teriflunomide
- Natalizumab
- Spingosine-1-Phosphate Inhibitors
- Fingolimod, Siponimod
- B Cell Depleters
- Ocrelizumab, Ofatumumab
TERIFLUNOMIDE
Antimetabolite – interferes with de novo synthesis of
pyrimidines, blocks cell replication in rapidly dividing cells,
inhibits proliferation of activated T & B cells in periphery
- Immunesuppressive & Immune Cell Depleter – maintenance
Tx
TERIFLUNOMIDE
(AUBAGIO®)
Cons
* Hair loss
* Nausea
* increased Liver function enzymes
* TB reactivation
* Diarrhea
* BP increase
* ? Increased risk of cancer
* careful pre-natal counseling women who
may become pregnant (teratogenic)
* Do not take breastfeeding
* Monitoring: LFT, pregnancy, wash-out, TB
Pros
* Pill
* First line therapy
* Easy to start & stop (have to
do a washout)
* Mostly well tolerated
Drug Interactions:
CYP2C8 inhibitors, amiodarone, live vaccines, immunosuppressants
Most of the time people tolerate it pretty well. It’s one pill a day. It’s easy to take. It’s gentle, so prevents about 1 -3 attacks over time.
Preferred for older pt
it can affect the liver enzymes. We monitor that. It’s again a small molecule that’s absorbed through the gut and can cross the placenta. So it has a very long half-life. So if women want to become pregnant on it, it is teratogenic.
we do a wash out with cholestyramine or activated charcoal before we to get it out of the system
NATALIZUMAB
-Humanized, monoclonal antibody, blocks
α4-integrin subunit with VCAM-1 at the blood
brain barrier
-Anti-trafficking agent, maintenance Tx
works through these receptors on the blood-brain barrier, the VCAM, and stops the lymphocytes from getting through the blood-brain barrier and then attacking the myelin so it can’t adhere and then roll through the blood vessel walls. It’s a really, really good agent. It’s highly effective. So it reduces relapses by 70%.
NATALIZUMAB (TYSABRI®)
pros cons
Pros
* Highly Effective
* IV therapy once/month
* Decreases relapses 68%
* Can use during
pregnancy/postpartum with
monitoring
Cons
* Infusion reactions (antinatalizumab antibodies)
* Rare severe brain infection =
PML (anti-JC virus Antibodies)
* Rebound effect
* Increased liver enzymes
* Risk Stratification for PML Risk
and Monitoring
* CBC, LFT once/month x 6 months,
then every 6 months, anti-tysabri
Abs
* JC virus serology/MRI
Drug Interactions: βIFN,immunosuppressives
. But 60% of us have JC virus that we’ve been exposed to growing up at normally lives in our kidneys and our bones. That JC virus can get activated and cross the blood-brain barrier and causes severe brain infection called PML and opportunistic brain infection
now we have a big risk stratification as to whether people are JC virus positive or not, then that determines how long we can use the agent for their JC virus positive. You can only use it up to a couple of years. A
PML RISK
= PROGRESSIVE
MULTIFOCAL
LEUKENCEPHAL
OPATHY
the risk stratification that we use. And the pharma company itself measures the JC virus antibodies at their private infusion centers. We are not able to get this through a public health care system. They will tell us what their JC virus titers are and when they get to a certain amount, we just stop it and switch to something else.
SPHINGOSINE-1-
PHOSPHATE INHIBITORS
-Fingolimod, Siponimod, Ozanimod, Ponesimod
-Inhibits migration of T cells from lymphoid
tissue and target organs including CNS
-Anti-trafficking agent, maintenance
These work like the sheepdogs. What they do is they take the activated T-cells and they tell them to go to the lymph nodes and stay there so they don’t circulate around in the blood and then cross the blood-brain barrier.
Then they work in the periphery.
SPHINGOSINE-1-PHOSPHATE
INHBITORS
pros c
ons
Pros
* Daily Pill
* Moderate efficacy
* Generics available (fingolimod)
* Siponimod – 1st therapy
approved for ‘active’ secondary
progressive MS
* 1st & 2nd line therapies
Cons
* Rebound effect
* Avoid pregnancy (teratogenic) & in
breastfeeding
* liver effects
* low white cell count
* Infections: shingles (zoster)
* eye – macular edema
* Fingolimod:
* Cancer – basal cell carcinoma
* Bradycardia (1st dose monitoring): . So they’ll drop their heart rate by eight beats per minute on the first dose. You can see why we’re not using that as much anymore. H
* hypertension
* Monitoring: CBC, LFT every 3 months, BP, eyes,
lungs, optometrist, EKG, dermatologist, MRI
Drug Interactions:
- anti-arrhythmics, immunosuppressants, betablockers, drugs that increase QT interval (eg: antidepressants)
- Avoid live vaccines
But you are more prone to infections overall with this sphingosine one phosphate inhibitors, we’ll see shingles and a reactivation so we get them vaccinated for shingles before we start on it. We now recognize that you have less response to vaccines, notably COVID vaccine. You’re more prone to COVID on it.
B CELL DEPLETERS
Ocrelizumab
Ofatumumab
Binding to CD20 on the surface of B cells leading to cell lysis
* Immunosuppressant /Immune cell-depleting agent,
maintenance Tx
These work by cell lysis. These are immunosuppressants but very selective with the B-cells
B CELL DEPLETERS (OCRELIZUMAB
& OFATUMUMAB)
Pros
* Highly effective 1st & 2nd lineb therapies
* Ocrelizumab - IV infusion onceb every 6 months
* Ofatumumab – SC injection once/month
* Relapsing Remitting MS
* Ocrelizumab – 1st therapy for “active” primary progressive MS
* Ocrelizumab – can use breastfeeding
Cons
* Infusion reactions
* Infections (zoster)
* Cardiac events?
* ? Cancers (breast)
B CELL DEPLETERS (OCRELIZUMAB & OFATUMUMAB)
Drug Interactions:
Immunosuppressants, live vaccines
Ofatumumab: That is a very small volume and that’s become the easiest for young newly diagnosed patients to take. You can use them up into pregnancy and then you stop them while the person is pregnant and then restart them during breastfeeding.
Ocrelizumab: lowers your immunoglobulins. And so there’s some thoughts that as we use them over decades that we’ll start seeing more opportunistic infections with them like Rituximab, we see with rituximab. But this hasn’t been proven as yet
IMMUNE RECONSTITUTION
THERAPIES
Alemtuzumab
Cladribine
Autologous Stem Cell Transplant
resetting of the immune system.
the immune system regrows and recovers with a different set of T-cells and B-cells. So then it actually shuts down the inflammation in MS just through shifting the immune system through the reset. So what’s nice and attractive about it is that you hit them hard at the beginning. They’re more prone to infections at the beginning. But then as their immune system recovers, then they’re not prone to opportunistic infections anymore
ALEMTUZUMAB
Humanized monoclonal Ab, targets CD52 (lymphocytes
and monocytes)
Immune cell-depleting agent, immune reconstitution Tx
then it works in the periphery. It shuts down the immune system and then rebuilds it over time.
eople can feel really crappy after taking their infusions of alemtuzumab, mainly because of the aggressive cell lysis that can occur. And so we use it more for aggressive people
