RA

Question 1

Initial therapy

Answer 1

DMARD (i.e. Methotrexate) w/ NSAID and corticosteroid

Question 2

Initial therapy if mild

Answer 2

Hydroxychloroquine instead of methotrexate b/c less toxic

Question 3

If initial treatment failure…

Answer 3

Biological agents (TNF-alpha inhibitors) used as monotherapy or with methotrexate

Question 4

If not good response to TNF-a inhibitor…

Answer 4

non-TNF-a drugs (anakinra, rituximab, toclizumab)

Question 5

What kind of treatment can lead to longer disease-free remission, less joint destruction, and better quality of life?

Answer 5

Early, aggressive treatment w/ MTX and/or biological agent

Question 6

AMPLE trial

Answer 6

Triple therapy (i.e. MTX + Sulfasalazine + Hydroxychloroquine) is just as good and much cheaper than using a biological agent (i.e. MTX + etanercept)

Question 7

TEAR trial

Answer 7

trial was done in pts w/ early, poor-prognosis RA
First study to demonstrate that initial MTX monotherapy w/ option to step-up combination therapy results in similar outcomes to immediate combo therapy (and not all pts ended up needing any combo therapy)

Question 8

DMARDs–non-biological agents

Answer 8

Methotrexate
Hydroxychloroquine
Leflunomide
Sulfasalazine

Question 9

Common property of all DMARDs

Answer 9

ability to improve inflammatory symptoms and slow progression of joint erosions

Question 10

What usually limits use of non-biological DMARDs

Answer 10

toxicity and inadequate response

Question 11

MTX–MOA

Answer 11

immunosuppression

inhibition of AICAR transformylase–> AICA riboside accumulation–> inhibition of adenosine deaminase–> increased circulating adenosine concentrations–> inhibition of lymphocyte proliferation; suppression of IL-1, IFN-y, and TNF secretion; increased secretion of IL-4; impaired release of histamine from basophils; decreased chemotaxis of neutrophils

Question 12

MTX–>adenosine

Answer 12

increases

Question 13

adenosine–>lymphocytes

Answer 13

inhibits proliferation

decreases

Question 14

adenosine–>IL-1

Answer 14

decreases

Question 15

adenosine–>IFN-y

Answer 15

decreases

Question 16

adenosine–>TNF

Answer 16

decreases

Question 17

adenosine–>IL-4

Answer 17

increases

Question 18

adenosine–>release of histamine from basophils

Answer 18

decreases

Question 19

adenosine–>chemotaxis of neutrophils

Answer 19

decreases

Question 20

MTX metabolism

Answer 20

undergoes polyglutamation when enters cell (so retained intracellularly)

Hepatic
(contraindicated in alcoholism, hepatic disease,etc.)

Enterohepatic recirculation (increases terminal half-life)

Question 21

MTX elimination

Answer 21

renal (caution in renal failure; alkalinization and hydration reduce renal damage and aid elimination)

involves tubular secretion
(competition w/ weak acids and probenecid)

Question 22

MTX adverse effects

Answer 22

Myelosuppresion

Pulmonary toxicity
–can be fatal, acute/chronic interstitial pneumonitis, pulmonary fibrosis

Cat. X teratogen
contraindicated in breast feeding

Vaccination

Malignant lymphomas in low dose MTX

Severe and sometimes fatal derm rxns

GI toxicity in pts w/ PUD/ulcerative colitis (esp. when given w/ NSAIDs)

Question 23

Sulfasalazine indications

Answer 23

pt responded inadequately to salicylates or other NSAIDs

Question 24

Sulfasalazine MOA

Answer 24

anti-inflammatory properties of mesalamine (metabolic product)… an inhibitor of PG and LT production

Question 25

Sulfasalazine metabolism

Answer 25

metabolized to active components (sulfapyridine and mesalamine) by bacteria in colon further metabolyzed via acetylation and hydroxylation in liver

Question 26

Sulfasalazine elimination

Answer 26

Renal | Caution in pts w/ renal dysfunction

Question 27

Sulfasalazine Contraindications

Answer 27

hypersensitivity to 5-aminosalicylate, salicylate, sulfonamide drugs

Question 28

Sulfasalazine Toxicities

Answer 28

Hematotoxicity | potentially fatal blood dyscrasias...infrequent

Question 29

Leflunomide MOA

Answer 29

active primary metabolite (A77 1726) inhibits dihydroorotate dehydrogenase (DHODH), an enzyme in cell mitochondria that catalyzes key step in de novo pyrimidine synthesis--> in T and B cells, cell cyle progression is arrested and collaborative interaction interrupted--> immunoglobulin production suppressed Cytostatic (not toxic) at normal doses

Question 30

Leflunomide Elimination

Answer 30

Major metabolite (A77 1726) has uricosuric effect and is eliminated in feces primarily other metabolites and conjugates also eliminated Hepatic metabolism and thus toxicity w/ chronic use

Question 31

Leflunomide contraindications

Answer 31

pts w/ severe immunosuppression Cat. X teratogen

Question 32

Hydroxychloroquine

Answer 32

usually associated w/ treatment of malaria also can be for RA and SLE Different MOA and is pretty slow acting (since very different MOA, compliments combo therapy)

Question 33

Hydroxychloroquine MOA

Answer 33

increases intracellular vacuole pH and alters protein degredation by acidic hydrolases in lysosome, assembly of macromolecules in endosomes, and post-translation modification of proteins in golgi. acidic cytoplasmic compartments required for antigenic protein to be digested and for peptides to assemble w/ alpha and beta chains of MHC class II proteins. So... drug diminishes formation of MHC protein complexes required to stimulate CD4+ T cells and results in down regulation of immune response

Question 34

Hydroxychloroquine Elimination

Answer 34

Renal | Extensive and slow

Question 35

Hydroxychloroquine metabolism

Answer 35

partial Hepatic

Question 36

Hydroxychloroquine cautions and contraindications

Answer 36

Ocular disease (b/c drug--> corneal opacities, keratopathy, retinopathy) Hepatic disease or alcoholism Blood dyscrasias CNS toxicity (polyneuritis, ototoxicity, seizures, neuromyopathy)

Question 37

Which drugs must be monitored w/ CBCs?

Answer 37

all non-biological DMARDs

Question 38

Which drugs must be monitored w/ LFTs?

Answer 38

MTX Sulfasalazine Leflunomide

Question 39

Which drugs must be monitored w/ serum creatinine/BUN?

Answer 39

MTX | Sulfasalazine

Question 40

Which drugs must be monitored w/ serum uric acid?

Answer 40

MTX

Question 41

Which drugs must be monitored w/ urinalysis?

Answer 41

Sulfasalazine

Question 42

Which drugs must be monitored w/ pregnancy testing?

Answer 42

Leflunomide

Question 43

Which drugs must be monitored w/ serum electrolytes

Answer 43

Leflunomide

Question 44

Which drugs must be monitored w/ opthalmalogic exam?

Answer 44

Hydroxychloroquine