lecture 36/39

Question 1

what are the three categories of MS treatment?

Answer 1

treatment of acute attacks
disease-modifying therapies (DMTs)
symptomatic therapies

Question 2

what is the main purpose of DMTs?

Answer 2

reduce relapse rate
may slow the progression of disability
generally used to treat relapsing rather than progressive forms of MS

Question 3

what are first line DMTs?

Answer 3

interferon B1a (avonex, rebif)
interferon B1b (betaseron, extavia)
glatiramer acetate (copaxone)
fingolimod (gilenya)

Question 4

what are second line DMTs?

Answer 4

natalizumab (tysabri)
mitoxantrone (novantrone)

Question 5

what are new DMTs?

Answer 5

teriflunomide (aubagio)
dimethyl fumarate (tecfidera)
cladribine (mylinax)

Question 6

what drugs are used to treat acute attacks of MS?

Answer 6

methylprednisolone
prednisone
adrenocorticotropic hormone (ACTH)

Question 7

how are corticosteroids used to treat MS?

Answer 7

likely act by up-regulating anti-inflammatory genes, down regulating pro-inflammatory genes, and alleviating edema in demyelinated areas

Question 8

what is the MOA of interferon B1a and B1b drugs?

Answer 8

act in the periphery (via inhibition of autoreactive lymphocytes like T cells and dendritic cells) and at the BBB (via inhibition of BBB penetration by decreasing matrix metalloproteinase)

Question 9

what are the clinical features of interferon B1a and B1b?

Answer 9

relatively favorable SE
alleviate disease, but only in a subset of patients
delay the conversion of CIS to clinical MS
efficacy reduced by neutralizing antibodies

Question 10

what is the MOA of glatiramer acetate (copaxone)?

Answer 10

synthetic polypeptide, mimics antigenic properties of myelin basic protein
modulation of antigen-presenting cells such as DC –> leading to decreased T cell activation

Question 11

what is the boxed warning of glatiramer acetate (copaxone)?

Answer 11

rare but severe allergic reactions, anaphylaxis (Added in 2025)

Question 12

what is mOA of fingolimod (gilenya)?

Answer 12

sphingosine-1-phosphate (S1P) receptor agonist
stimulation of oligodendrocyte survival, remyelination
interference with lymphocyte movement out of lymphoid organs

Question 13

what is a clinical feature of fingolimod?

Answer 13

SE include cardiotoxicity, fatal viral encephalitis, and progressive multifocal leukoencephalopathy (PML)

Question 14

what is PML?

Answer 14

progressive multifocal leukoencephalopathy
potentially lethal brain infection that may be caused by fingolimod, natalizumab, or the fumarates

Question 15

what is the MOA of natalizumab?

Answer 15

monoclonal antibody specific for a4 integrin
inhibition of VLA-4 binding to its ligand, interfering with movement of B/T cells into CNS

Question 16

what is VLA-4?

Answer 16

very late antigen that is produced when a4-integrin pairs with B1-integrin
inhibited in natalizumab

Question 17

what are the clinical features of natalizumab?

Answer 17

a key side effect is the development of PML
induced the development of neutralizing antibodies leading to an allergic reaction

Question 18

what is the moa of mitoxantrone (novantrone)?

Answer 18

anthracenedione with cytotoxic activity
reduces lymphocyte numbers by causing DNA strand breaks (via intercalation) and delaying DNA repair (via inhibition of topoisomerase II)

Question 19

what drug was the first cytotoxic drug license for SPMS?

Answer 19

mitoxantrone (novantrone)

Question 20

what is induction therapy?

Answer 20

when a person uses mitoxantrone first then replaces with IFN-B or GLAT therapy

Question 21

what is the moa of teriflunomide (aubagio)?

Answer 21

cytotoxic agent that inhibits dihydroorotate dehydrogenase
inhibits proliferation of peripheral lymphocytes (like activated B/T cells)

Question 22

what is the MOA of dimethyl fumarate, diroximel fumarate, and monomethyl fumarate?

Answer 22

metabolized by esterases in the GI tract, blood, tissue
activate Nrf2-mediated cellular antioxidance responses and anti-inflammatory pathways
may promote remyelination
suppress activated T cells, DC in the periphery

Question 23

what are the clincal features of diroximel fumarate and monomethyl fumarate?

Answer 23

new oral, delayed-release drugs approved in 2019 and 2020

Question 24

what is an important SE of the fumarates?

Answer 24

apparently PML

Question 25

what enzymes are part of the phase 2 response?

Answer 25

glutathione-S-transferase or GST

Question 26

beside fingolimod, what drugs are S1P receptor agonists?

Answer 26

siponimod (mayzent) ozanimod (zeposia) ponesimod (ponvory) they are indicated for RRMS and SPMS

Question 27

what is the moa of cladribine (mylinax)?

Answer 27

taken up in the cells by purine nucleoside transports in cells with a high ratio of deoxycytidine kinase to deoxynucleotidase, cladribin is phosphorylated to the triphosphate form, 2-chloro-dATP --> damages DNA and interferes with DNA metabolism --> cell death --> lymphocyte depletion

Question 28

what are examples of new antibody thearpys and what MS are they used in?

Answer 28

rituximab / ocrelizumab effective for some PPMS patients and stops RRMS

Question 29

what is the moa of rituximab/ocrelizumab?

Answer 29

targets CD20 (which is a B cell marker) doesn;t bind CD20 on stems/plasma cells --> key immune functions are unperturbed decreased disease progression in PPMS, decreased relapse rate in RRMS

Question 30

what are experimental MS drugs?

Answer 30

autologous hematopoietic stem cell transplants T-cell therapy antisense oligonucleotides repositioned drugs (simvastatin, clemastine) drugs with MOA different from those of current therapies

Question 31

what are antisense oligonucleotides?

Answer 31

experimental MS drugs ATL1102, an ASO target VLA-4 to supposedly have similar outcome as natalizumab

Question 32

out of the four options, what drug acts in both the periphery and the CNS? dimethyl fumarate natalizumab rituximab teriflunomide

Answer 32

dimethyl fumarate