RA and Gout

Question 1

What two NSAIDs are used to relieve symptoms in long-term treatment of RA?

Answer 1

indomethacine and naproxen; don’t halt disease progression!!

Question 2

How are glucocorticoids useful in the Tx of RA?

Answer 2

initially before a DMARD has taken effect; intro-articularly to help alleviate symptoms

Question 3

What are the actions of glucocorticoids?

Answer 3

inhibit PLA2 (inhibiting release of arachidonic acid and prostaglandin formation)
inhibition of cytokine production (preventing induction of COX-2)

Question 4

What was the mechanism of gold salts in the Tx of RA? Are these still used?

Answer 4

antipruritic; repress immune responsiveness, especially by inhibiting proper macrophage function
no longer used - produced serious side effects in 30% of patients

Question 5

The prolonged use of what drugs can cause serious effects such as hyperglycemia, osteoporosis, and poor wound healing?

Answer 5

glucocorticoids

Question 6

What antimalarial drugs have been used in the treatment of RA and SLE? Which was better tolerated?

Answer 6

chloroquine and hydroxychloroquine;
hydroxychloroquine better tolerated and fewer adverse effects (long term chloroquine can cause irreversible retinal damage)

Question 7

Sulfasalazine use for treating RA is increasing. It acts more quickly than antimalarials. What is the proposed mechanism? And what side effects cause a third of patients to discontinue use?

Answer 7

possibly inhibits IL-1 and TNF-alpha release;

side effects: N/V, HA, skin rashes, neutropenia

Question 8

What immunosuppressive drug is the most commonly used DMARD in RA treatment and is still considered the ‘gold standard’?

Answer 8

methotrexate (MTX)

Question 9

What’s the MOA of MTX as learned in cancer? What is likely it’s principal MOA in the low doses used in RA Tx?

Answer 9

typically, inhibits DHFR (folate analog!)
in low dose - inhibition of AICAR transformylase and thymidylate synthetase with secondary effects on PMN chemotaxis
AMP accumulates, converted to adenosine, a potent inhibitor of inflammation

Question 10

What side effects of MTX are seen with the low doses used in RA Tx?

Answer 10

nausea, stomatitis

hepatotoxicity can occur and pts should be monitored for it

Question 11

What’s the new immunosuppressive drug being used in RA? How does it work?

Answer 11

leflunomide; prodrug
inhibits DHODH, required for de novo pyrimidine synthesis
T-cell response to stimuli inhibited

Question 12

Significant side effects of leflunomide?

Answer 12

diarrhea, hepatotoxicity

Question 13

Name the five TNF-alpha antagonists (biologics).

Answer 13

etanercept, infliximab, adalimumab, golimumab, certolizumab

Question 14

Etanercept is the only TNF-alpha antagonist that isn’t a mAb. What is it?

Answer 14

fusion protein of two TNF receptors fused with Fc portion of IgG; binds TNF and prevents it from binding to receptors

Question 15

What’s the problem with infliximab?

Answer 15

it’s a chimeric Ab, so it’s antigenic and can cause production of anti-mouse Abs

Question 16

Adalimumab has more convenient dosing than etanercept. What’s the difference?

Answer 16

etanercept - twice weekly subcu injection

adalimumab - twice monthly subcu

Question 17

Golimumab is only dose once per month which is great! But what are those pesky side effects?

Answer 17

increased risk of serious infections - TB, fungal, other opportunistic

Question 18

The metabolism and elimination of certolizumab is delayed by conjugating it to what molecule?

Answer 18

polyethylene glycol

Question 19

What’s the IL-1 antagonist used for RA treatment? What’s the downside to its use?

Answer 19

anakinra; short half-life necessitates daily high dose treatments

Question 20

Another RA med that can cause serious infections but works by antagonizing IL-6 receptor is..

Answer 20

tocilizumab

Question 21

What two drugs that can be used in RA refractory to TNF inhibitors act by inhibiting lymphocytes?

Answer 21

abatacept and rituximab

Question 22

How does abatacept work? Side effects?

Answer 22

inhibits T-cell activation and induces apoptosis;

HA, infections

Question 23

We know rituximab is anti-CD20 and reduces B-cells. What side effects do you have to watch out for in RA though?

Answer 23

infections; hypersensitivity reactions (decrease with repeat dosing)

Question 24

What are the two general causes of hyperuricemia?

Answer 24

high rate of production and low rate of excretion

Question 25

High rate of urate production might be caused by …

Answer 25

disease states (rapid production and destruction of cells); metabolism (ketosis, acidosis); drug induced (anti-neoplastics, alcohol); diet (high purine intake - animal muscle, seafood, beer)

Question 26

Low rate of irate excretion might be the result of …

Answer 26

renal problems (might just be because you’re getting old); suboptimal urine volumes; drugs (thiazides inhibit urate secretion!)

Question 27

What caused your acute gouty arthritis and what should you do about?

Answer 27

can be set off by surgery, overeating, overdrinking, injury

even untreated it will subside in a few days and the joint will return to normal

Question 28

Can gout be controlled without drugs?

Answer 28

Yes! lifestyle changes (weight loss, diet control, reduced EtOH intake) and altering drug intake will usually be sufficient

Question 29

Colchicine can dramatically relieve the pain and inflammation of gouty arthritis but doesn’t actually affect urate metabolism or excretion. How does it do it?!

Answer 29

binds tubulin, preventing polymerization (it’s an alkaloid from a plant, after all); this inhibits leukocyte migration, phagocytosis, metabolic activity, and release of pro inflammatory autacoids

Question 30

What adverse effects are associated with colchicine?

Answer 30

N/V, abd pain, diarrhea
long term use - peripheral neuropathy or neutropenia
low therapeutic index!!

Question 31

What other things can be helpful in acute gouty arthritis?

Answer 31

NSAIDs (especially indomethacin, naproxen, sulindac, celecoxib)
corticosteroids (intra-articular injection good for monoarticular gout!)

Question 32

What drugs increase the rate of uric acid excretion? How do they do it?

Answer 32

probenecid and sulfinpyrazone;
they’re organic acids that compete with urate at the anionic transporter in renal tubule and inhibit reabsorption; tophaceous deposits will be reabsorbed in most pts

Question 33

What side effects might result from probenecid treatment?

Answer 33

GI irritation, nausea
ironically, reducing urate levels might cause urate crystal mobilization and acute gouty arthritis
secretion of some weak acids reduced (penicillin)

Question 34

What can be used to reduce synthesis of urate?

Answer 34

allopurinol and febuxostat

Question 35

Mechanism of allopurinol?

Answer 35

inhibits xanthine oxidase competitively (its metabolic product, alloxanthine is a non-competitive inhibitor of XO)

Question 36

What pts would you use allopurinol in?

Answer 36

those who produce a lot of urate and have a lot of it in their urine;
to prevent a problem in people following chemotherapy

Question 37

Adverse effects of allopurinol?

Answer 37

maculopapular rash in a couple, rarely hypersensitivity;

actue gouty arthritis as tissue urate is being mobilized

Question 38

How is febuxostat different from allopurinol?

Answer 38

it’s a non-purine, non-competitive antagonist of XO

Question 39

Adverse effects of febuxostat?

Answer 39

nausea, rash, arthralgias, expensive!

cardiovascular safety is currently being assessed

Question 40

If a patient has chronic gout and none of the other drugs are working, what could you use?

Answer 40

pegloticase, a recombinant form of uricase (which metabolizes urate in other species) bound to polyethylene glycol