B3.024 Rheumatoid Arthritis Therapy

Question 1

DMARDs

Answer 1

disease modifying anti-rhuematic drug
immunosuppressive agents with goal of inducing/maintaining remission
older, oral

Question 2

methotrexate mechanism

Answer 2

inhibition of dihydrofolate reductase-decreases synthesis of purines and pyrimidines thus interfering with DNA synthesis, repair, and cellular replication
increases adenosine release from cells which can dampen inflammation

Question 3

what is given along with methotrexate

Answer 3

folic acid

prevent side effects

Question 4

methotrexate administration

Answer 4

oral or subQ
weekly dose
low: 15-25 mg per week

Question 5

methotrexate side effects

Answer 5

oral ulcers
GI
nausea
cytopenias
liver tox
teratogen

Question 6

leflunomide (Arava) mechanism

Answer 6

inhibits dihydroorotate dehydrogenase inhibiting pyrimidine synthesis leading to reduction of lymphocytes

Question 7

leflunomide half life

Answer 7

prodrug; enterohepatocyte circulation leads to long half life

Question 8

luflunomide administration

Answer 8

oral

Question 9

leflunomide side effects

Answer 9

diarrhea
cytopenias
liver tox
teratogen

Question 10

hydroxychloroquine mechanism

Answer 10

multiple
inhibits activity of TLRs
inhibits acidification of lysosomes ultimately interfering with antigen processing

Question 11

hydroxychloroquine administration

Answer 11

oral

Question 12

hydroxychloroquine side effects

Answer 12

rare retinal tox

Question 13

sulfasalazine mechanism

Answer 13

sulfapyridine is active moiety but mechanism not identified

Question 14

sulfasalazine administration

Answer 14

oral

Question 15

sulfasalazine side effects

Answer 15

rash
GI
hepatotoxicity
cytopenias

Question 16

azathioprine mechanism

Answer 16

protein synthesis inhibitor

Question 17

azathioprine administration

Answer 17

oral

Question 18

azathioprine side effects

Answer 18

cytopenias
rash
GI
pancreatitis

Question 19

list all conventional DMARDs

Answer 19

methotrexate
leflunomide
hydroxychloroquine
sulfasalazine
azathioprine

Question 20

what are biologics

Answer 20

newer medications that are made by molecular biologic techniques

Question 21

what do biologics target

Answer 21

cytokines
T cell activation
deplete B cells

Question 22

what is the main goal of TNF inhibitors

Answer 22

reduce joint inflammation and damage to joints

Question 23

what are the different TNH inhibitors?

Answer 23

etanercept
adalimumab
certolizumab
golimumuab
infliximab

Question 24

etanercept mechanism (subq)

Answer 24

fusion protein of TNF receptor linked to Fc portion of IgG

etanercept binds TNF and blocks its interaction with cell surface receptors

Question 25

adalimumab &golimumab mechanism (subq)

Answer 25

human monoclonal antibodies directed against TNF

Question 26

certolizumab mechanism (subq)

Answer 26

Fab fragment of a humanized monoclonal antibody directed against TNF

Question 27

infliximab mechanism (infusion)

Answer 27

chimeric monoclonal antibody directed against TNF

Question 28

tocilizumab mechanism

Answer 28

human monoclonal antibody targeting IL-6 receptor | reduces inflammation and joint damage

Question 29

tocilizumab administration

Answer 29

subq or IV

Question 30

ankinra mechanism

Answer 30

antagonist of IL-1 receptor | FDA approved for RA but not very effective

Question 31

abatacept mechanism

Answer 31

binds CD80/86 on APCs, blocking the interaction of CD28 between APCs and T cells results in T cells than cannot be activated fully

Question 32

abatacept administration

Answer 32

subq or IV

Question 33

rituximab mechanism

Answer 33

monoclonal antibody directed against CD20 antigen on B lymphocytes result is depletion of B cells (but not existing plasma cells without CD20)

Question 34

rituximab administration

Answer 34

IV

Question 35

why is rituximab's success surprising?

Answer 35

current understanding does not place B cells as most prominent player (T cells more prominent)

Question 36

tofacitinib mechanism

Answer 36

inhibits JAK enzymes | prevents cytokine/growth factor mediated gene expression and intracellular activity of immune cells

Question 37

what type of drug is tofacitinib?

Answer 37

targeting synthetic DMARD | one of the most effective

Question 38

tofacitinib administration

Answer 38

oral

Question 39

1st line approach to RA therapy

Answer 39

methotrexate

Question 40

2nd line approach to RA therapy

Answer 40

either: sulfasalazide + hydroxychloroquine + methotrexate (triple therapy) OR TNF inhibitors + methotrexate

Question 41

3rd line approach to RA therapy

Answer 41

``` abatacept rituximab tocilizumab anakinra tofacitinib ```

Question 42

what are the combining factors that create "pre-arthritis"

Answer 42

susceptibility genes (MHC shared epitope, PAD, PTPN) environmental factors epigenetic modifications post translational modifications (acetylation, carbanylation, citrullination...etc.)

Question 43

what happens after pre-arthritis?

Answer 43

``` production of autoantibodies and loss of tolerance asymptomatic synovitis (cellular infiltrate) symptomatic arthritis ```

Question 44

which RA drugs are teratogenic?

Answer 44

``` methotrexate leflunomide tocilizumab abatacept rituximab tofacitinib ```