Multiple Sclerosis Flashcards
What are the goals of current therapies for MS?
shorten relapses, reduce severity of relapse, reduce accumulation of disability, prevent disease, reverse disability (promote remyelination), alleviate symptoms
What is the most successful type of current MS therapy?
Immunomodulators
What are the three agents used to tx acute MS?
Methylprednisone (Corticosteroids), ACTH, Plasmapharesis
How does Methylpredinisone act and what other drug is given with it?
Unclear MOA (suppresses both T and B cells and may reduce cytokine release) and it shortens acute attack to hasten recovery. It is given IV with oral prednisone taper
What are the short and long term side effects of taking methylprednisone
short term: insomnia, mood changes, fluid retention, epigastric pain, HTN
long term: osteroporosis, cushingoid, secondary malignancies
Why would you administer Plasmapharesis?
helps w/acute MS attacks nonresponsive to methylprednisone
Why would you give ACTH? What is it’s drawback?
For acute MS attacks if patient allergic to corticosteroids or with poor IV access (can be injected SC or IM). Drawback = expensive!
Name the 4 beta interferons used to treat relapse remitting MS (RRMS)
Avonex, Rebif, Betaseron, Extavia
What are the proposed MOA’s for all of the beta interferons?
inhibit T-cell activation, shift from Th1 to Th2, inhibit lymphocyte migration into CNS, anti-proliferative effect, apoptosis of autoreactive T cells, anti-viral, IFN-gamma antagonism, don’t cross BBB
Which of the IFN-betas is considered low dose? What are it’s effects?
Avonex; shown to decerase relapse rate by 1/3 and reduce MRI lesions and decrease disability/brain atrophy
Which of the IFN-betas are considered high dose and of these, which are considered more efficacious than low dose Avonex?
Rebif (more efficacious), Betaseron (more efficacious), Extavia
Which two IFN betas don’t have effect on disease progression despite decreasing relapse rate and enhancing lesions on MRI?
Betaseron and Extavia
What are the side effects of the IFN-beta-1a Rebif and the IFN-beta-1b Betaseron and Extavia
flu-like symptoms, injection site reactions, anemia, menstrual irregularities, depression, increased LFTs and hypothyroidism (monitor every 3 months)
Which of the IFN-B have the least neutralizing antibodies that form and which have the most?
Least: Avonex
Most: Betaseron
What are the side effects of Avonex?
mild anemia, increased LFT (monitor every 6 months), hypothyroid, flu-like symptoms and minor irritation at injection site <>
What type of drug is Glatiramer acetate and what are its possible mechanisms of action?
it’s a Myelin basic protein analog (mixture of 4 AA’s); it causes T-cell apoptosis since it looks like MBP, induces anti-inflammatory shift from Th1 to Th2, induces Treg with induction of anergy, and possible neuroprotction
What are the effects of Glatiramer acetate on RRMS?
acts in CNS (not peripherally); decreases relapse rate by 1/3 and has modest effect on MRI activity but NO effect on disease progression; decreases brain atrophy
Are the side effects of Glatiramer acetate mild or severe?
MIld: injection site reactions, anxiety like reactions (chest tightness, SOB)
What do the studies say for 1st line treatments in terms of when to tx MS patients and what type of dosage to use?
Treat EARLY! High dose interferons are superior! More frequent dosing!
What would the professor recommend as an overall good 1st line therapy?
Rebif over Avonex (more efficacious), Rebif over Betaseron (less neutralizing antibodies), Rebif over Copaxone (Glatiramer acetate) re: MRI effects. Ultimately depends on patient tolerance of side effects and # of injections
What type of drug is Natalizumab and what’s it’s MOA?
Monoclonal antibody; MOA: binds to VLA4 expressed on surface of all leukocytes to inhibit leukocyte migration across BBB
What are some of the therapeutics and drawbacks of Natalizumab?
Therapeutics: decrease relapse rate by 2/3 and greatly reduces MRI lesions; only have to take 1/month
Drawbacks: drug doesn’t work if patients develop positive antibodies to Natalizumab; these pts also more commonly have side effects
What are the side effects of Natalizumab?
PML (progressive multifocal leukencephalopathy) (JC virus)–>esp if immunosuppressed and + for anti-JC virus antibodies; systemic hypersensitivity reactions, urticaria, headaches, dizziness, fatigue, arthralgia, rigors
THUS this drug is considered 2nd, maybe even 3rd line for use
What type of drug is Fingolimod and what is its MOA?
Sphingosine-1-phosphate analog (1st oral drug approved for MS); MOA: prodrug that sequesters circulating lymphocytes in secondary lymphoid organs via induction of intracellular internalization of receptors on lymphocytes (no effect on lymphocyte induction, proliferation or memory function)
What are some of the important side effects of Fingolimod?
bradycardia and heart block (must do 6hr monitoring for 1st dose); macular edema (must do ophtho exam before and after 3 months); minor: reduced FEV1, inc LFTs, lymphopenia leukopenia, back pain, blurred vision, headache, dizzy, infections
What must patients taking Fingolimod have antibodies to prior to taking the medication?
VZV
What is the MOA for the immunosuppressant Teriflunomide?
selective dihydro-orotate dehydrogenase inhibitor that blocks de novo pyramidine synthesis, reducing T and B cell proliferation and function against auto antigens; preserves replication and function of cells living on salvage pathway (hematopoietic cells, memory cells)
What are the pros and cons to taking Teriflunomide?
Pros: oral admin just as efficacious as 1st line injectables, overall relatively safe
Cons: hepatotoxicity and teratogenicity based on animal data
What is the MOA of Dimethyl Fumarate?
Antiinflammatory effects: inhibits expression of adhesion molecules; induces Th1–>Th2 shift
Neuroprotective effects: activates Nrf2 pathway to induce antioxidant enzyme production and clear free radicals and protect against oxidative stress
What are the side effects of Dimethyl Fumarate?
N/V, diarrhea, stomach pain, flushing, itching, redness
What is observed in secondary progressive MS (SPMS) as compared to RRMS?
greater lesion burden, increased axonal loss w/comparable lesion burden, impaired recovery mechanisms, increased spinal cord/brain atrophy, disability progresses despite decline in MRI activity, new inflammatory activity–>disability progression
What are the potential therapies for SPMS?
Mitoxantrone (only FDA approved therapy), Azathioprine, Methotrexate, Cyclophosphamide (all immunosuppressants)
What class of drug is Mitoxantrone and what is it’s MOA?
Class: Anthracenedione; MOA: broad immunosuppression/modulation of B cells, T cells, and macrophages; decreases frequency of clinical relapse, reduces disease progression and reduces disability
What are some side effects of Mitoxantrone?
cardiac toxicity (decrease in LVEF and irreversible CHF), can induce acute leukemia, N/V, alopecia, menstrual problems, increased susceptibility to infection
How are the immunosuppressants Azathioprine, Methotrexate, and Cyclophosphamide used to treat MS and what are their side effects?
Used in SPMS where other drugs have been ineffective or as combination with other therapies; Side effects include systemic toxicity (requires blood monitoring)
What are the therapies for primary progressive MS?
no FDA approved drugs yet; no trials w/immunosuppressants, pulse steroids perhaps, or IVIg
