Unit 2 - RA and Gout

Question 1

what is RA characterized by?

Answer 1

chronic inflammation of synovial membrane and infiltration by blood-derived cells, mainly CD4+T cells that make inflammatory cytokines TNF-a and IL-1
-activate synovial fibroblasts to recruit other inflammatory cells and release metalloproteinases

Question 2

why is the conservative/traditional approach of RA treatment in question?

Answer 2

1. joint damage is most rapid early in disease and cannot be reversed
2. DMARD given early to retard joint damage
3. RA patients have multiple health problems and reduced life expectancy

Question 3

what are the types of RA treatments?

Answer 3

1. NSAIDs
2. DMARDs (disease-modifying anti-rheumatic drugs)
3. biological response modifiers

Question 4

what are examples of NSAIDs used for RA?

Answer 4

1. indomethacin, naproxen (relieve symptoms in long-term treatment of RA and other musculoskeletal disorders)
2. COX-2 inhibitors (decrease incidence of gastric and duodenal ulcers by 50% as compared to traditional NSAIDs)

eliminate pain and some inflammation of RA, but don’t slow progression of disease
-useful as “bridge therapy” until therapeutic DMARD effect is seen

Question 5

what is the basis of DMARDs?

Answer 5

drugs that retard or halt the progression of disease

-effects may take 2 weeks to 6 months to become clinically evident

Question 6

what are the types of DMARDs?

Answer 6

1. glucocorticoids
2. antimalarial drugs
3. sulfasalazine
4. immunosuppressive drugs (methotrexate, leflunomide)

Question 7

explain what glucocorticoids do for RA? mechanism and side effects?

Answer 7

esp. prednisone used to suppress inflammation by decreasing pain and swelling; prompt and dramatic
- inhibit phospholipase A2 activity that inhibits release of AA from cell membranes, thus formation of prostaglandins
- inhibit production of cytokines that prevent induction of COX-2
- prolonged use causes serious, disabling adverse effects, such that benefits are outweighed by complications
- -but still used to induce remission in disease until slower-acting DMARD takes effect

Question 8

what are intra-articular glucocorticoids used for?

Answer 8

often helpful to alleviate painful symptoms of RA

Question 9

explain what antimalarial drugs do for RA; mech and side effects?

Answer 9

chloroquine and hydroxychloroquine act by inhibiting chemotaxis (decrease T cell activation)

• hydroxyC better than C, with fewer adverse effects
• C causes irreversible retinal damage during long-term treatment
• less efficacious than other DMARDs, so therapeutic use has been in patients with RA who don’t respond to NSAIDs and/or can’t tolerate other DMARDs

Question 10

what disease other than RA are antimalarial drugs used to treat?

Answer 10

SLE

Question 11

explain what sulfasalazine drugs do for RA; mech and side effects?

Answer 11

commonly used in Europe for past decade

• acts more quickly than antimalarials, benefiting in 1 month
• retards radiographic progression of RA
• inhibits IL-1 and TNF-alpha release
• 30% discontinue due to extreme adverse side effects (nausea, vomit, headaches, rash, neutropenia)

Question 12

explain what immunosuppressive drugs do for RA; examples?

Answer 12

reduce pain and swelling ina ffected joints, and slow progression of destruction

• take several weeks to start acting, so greatest benefit is if given early in course of disease (with others for short-term effect)
• methotrexate and leflunomide

Question 13

explain what methotrexate does for RA; mech and side effects?

Answer 13

most commonly used DMARD as gold standard (immunosuppressive folate analog)

• inhibits DHF reductase for anticancer
• low doses for RA inhibit aminoimidazolecarboxammide (AICAR) transformylase and thymidylate synthetase with secondary effects on polymorphonuclear chemotaxis
• -AMP accumulates, is converted to adenosine, to inhibit inflammation
• -low dose side effects are nausea and stomatitis, but hepatotoxicity can occur and patients should be monitored closely

Question 14

explain what leflunomide drugs do for RA; mech and side effects?

Answer 14

newest immunosuppressant

• prodrug taken orally
• active metabolite inhibits dihydroorate dehydrogenase (DHODH) rate-limiting enzyme for de novos ynthesis of pyrimidine (UMP)
• T lymphocyte response to stimuli is inhibited
• -decreased T and B populations and cytokine creation
• most significant adverse effects are alopecia, diarrhea, and hepatotoxicity

Question 15

explain what biological response modifiers do for RA; examples

Answer 15

therapeutics that target the cytokines and/or their receptors

1. TNF-alpha antagonists
2. other cytokine antagonists
3. co-stimulation modulators

Question 16

what are TNF-alpha antagonist examples for RA?

Answer 16

1. etanercept
2. infliximab
3. adalimumab
4. golimumab
5. certolizumab

Question 17

explain what etanercept do for RA; mech and side effects?

Answer 17

fusion protein made of 2 recombinant soluble TNF receptors fused with Fc portion of human IgG1 (extending plasma half-life of soluble receptors)

• binds to TNF directly, preventing its binding to receptors
• twice-weekly subcutaneous injections get significant improvement and are well tolerated

Question 18

explain what infliximab do for RA; mech and side effects?

Answer 18

first biological DMARD to be approved for treating RA

• chimeric (mouse/human) hybrid monoclonal IgG1 Ab VS TNF-alpha
• produces clinically significant improvement within a week of injection
• murine monoclonal Ab are antigenic, and induce production of antimouse Ab in recipients

Question 19

explain what adalimumab do for RA; mech and side effects?

Answer 19

fully human monoclonal anti-TNF-alpha Ab (not antigenic, no hypersensitivity)
-as efficacious as etanercept, but more convenient dosing (twice monthly subcutaneous injections, instead of twice weekly)

Question 20

explain what golimumab do for RA; mech and side effects?

Answer 20

human monoclonal Ab that binds to membrane-bound and soluble TNF-alpha

• once montly dosing
• side effects are increased risk of serious infections, including TB, fungal, and other opportunistic pathogens

Question 21

explain what certolizumab do for RA; mech and side effects?

Answer 21

TNF-alpha antagonist

-humanized Ab Fab fragment conjucated to polyethylene glycol to delay metabolism and elimination

Question 22

explain what anakinra do for RA; mech and side effects?

Answer 22

soluble, recombinant, IL-1 receptor antagonist
-clinically effective as monotherapy or with MTX, but short (6 hour) half life in plasma necessitates frequent daily treatment with high doses

Question 23

explain what tocilizumab do for RA; mech and side effects?

Answer 23

IL-6 receptor antagonist approved in 2008

-serious infections including TB, fungal, viral, and other opportunistic infections

Question 24

explain what abatacept do for RA; mech and side effects?

Answer 24

co-stimulation modulator that inhibits T-cell activation and induces T-cell apoptosis

• approved in 2006 for RA refractory to MTX or TNF-alpha inhibitors
• side ffects include headaches and infections

Question 25

explain what rituximab do for RA; mech and side effects?

Answer 25

co-stimulation modulator that is an anti-CD20 mAb that reduces circulating B cells - approved for RA refractory to TNF-alpha inhibitors - side effects are infections, hypersensitivity reactions, and decrease with repeated dosing

Question 26

what is the current approach to therapy for patients with early RA and low disease activity?

Answer 26

nonbiologic DMARD monotherapy

Question 27

what is the current approach to therapy for patients with moderate/high disease activity, but without poor prognostic features?

Answer 27

initial treatment with DMARD monotherapy, or combo MTX and hydroxychloroquine

Question 28

what is the current approach to therapy for patients with moderate/high disease activity, but with poor prognostic features?

Answer 28

1. combo therapy with MTX/hydroxychloroquine, MTX/sulfasalazine, MTX/sulfasalazine/hydroxychloroquine 2. anti-TNF therapy with or without MTX

Question 29

what is uricase?

Answer 29

an enzyme that converts uric acid to excretable allantoin | -in most mammals, but missing in humans

Question 30

what are the 4 therapeutic strategies used to counter attacks of gout?

Answer 30

1. decreasing synthesis of uric acid with allopurinol 2. increasing excretion of uric acid with uricosuric drugs 3. decreasing mobility of leukocytes with colchicine 4. using NSAIDs and corticosteroids for symptomatic relief

Question 31

what are the 2 general causes of hyperuricemia?

Answer 31

1. high rate of urate production | 2. low rate of urate excretion

Question 32

explain what happens in high rates of urate production?

Answer 32

1. disease states - rapid production and destruction of cells (Hodgkins, lymphomas, multiple myeloma, polychthemia, leukemia, psoriasis) 2. metabolism (ketosis, lactic acidosis) 3. drug induced - antineoplastic agents and radiation therapy, alcohol (lactic acidosis) 4. diet - high purine intake - animal muscle, seafood, beer, HFCS

Question 33

what are the two clinical manifestations of hyperuricemia?

Answer 33

1. acute gouty arthritis | 2. chronic tophaceous gout

Question 34

explainw hat acute gouty arthritis is?

Answer 34

deposits of uric acid in joint tissue that causes inflammation, severe pain, and swelling - can be set off by surgery, overeating/drinking, injury - will subside after a few days if untreated, and joint will return to normal in ~3 days - most often affects metatarsophalangeal joint of big toe (podagra), but can occur in any joint

Question 35

explain what chronic tophaceous gout is?

Answer 35

deposites of urate (tophi) in tissues/joints - persistent and tophi are destructive to surrounding tissue (bone) - renal complications are possible due to tubular obstructions and formation of pure uric acid stones or mixed uric acid calcium oxate - attacks of acute gouty arthritis will also occur

Question 36

what are the types of drug therapy for acute gouty arthritis?

Answer 36

1. colchicine 2. NSAIDs 3. corticosteroids 4. lifestyle changes and altering drug intake (usually enough to control both forms of gout)

Question 37

explain what colchicine is? and mechanism?

Answer 37

alkaloid that dramatically relieves pain and inflammation of gouty arthritis in 12-24 hours - doesn't alter metabolism or excretion of urates - binds to tubulin to prevent polymerization and leads to inhibition of leukocyte migration, phagocytosis, metabolic activity, and release of proinflammatory autacoids - has small therapeutic window for effect

Question 38

what are side effects of colchicine?

Answer 38

1. nausea, vomiting, abdominal pain, and troublesome diarrhea due to inhibition of epithelial cell proliferation 2. long term use soemtimes causes peripheral neuropathy or neutropenia 3. low therapeutic index

Question 39

how do NSAIDs treat acute gouty flares?

Answer 39

inhibit eicosanoid-mediated pain and inflammation via urate crystal phagocytosis - used for initial treatment of acute gout - commonly use: indomethacin, naproxen, sulindac, celecoxib - effective when given within 24 hours of pain onset - doses at higher end of therapeutic range often needed

Question 40

how do corticosteroids treat acute gouty flares?

Answer 40

- intraarticular injection of corticosteroids good for those with acute monoarticular gout - good pain relief and increasingly used for those in whom colchicine and NSAIDs are ineffective or contraindicated

Question 41

what are therapies for chronic tophaceous gout?

Answer 41

1. uricosuric agents (increase rate of excretion of uric acid) 2. drugs which reduce synthesis of uric acid 3. pegloticase

Question 42

how does probenecid treat chronic tophaceous gout? side effects?

Answer 42

uricosuric agent; competes with urate at anionic transport sites of renal tubule and inhibit reabsorption - 2/3 patients respond favorably, such that tophaceous deposits of urate will be reabsorbed, with relief of arthritis and remineralization of bone - side effects are GI irritation, nausea - -paradoxically, reduced ruate levels may cause urate crystal mobilization and acute gouty arthritis - -secretion of weak acids (like penicillin) is reduced by this agent

Question 43

how does allpurinol treat chronic tophaceous gout? side effects?

Answer 43

drug that reduces synthesis of uric acid by inhibiting xanthine oxidase (metabolized to alloxanthine) - allopurinol is a competitive inhibitor, while alloxanthine is a non-competitive inhibitor of XO - has largely replaced use of uricosuric agents - used in patients whose urinary uric acid is high, and to prevent massive uricosuria following chemotherapy of leukemias, lymphomas, and other malignancies that otherwise lead to renal calculi - generally well tolerated, but can get maculopapular rash in 2% of patients, with rare hypersensitivity syndrome - -acute attacks of gouty arthritis occur in early treatment b/c urate crystals are mobilized

Question 44

how does febuxostat treat chronic tophaceous gout? side effects?

Answer 44

drug that reduces synthesis of uric acid by non-competitively inhibiting xanthing oxidase - adverse effects are nausea, rash, arthralgia - expensive - still prospective studies to assess cardiovascular safety

Question 45

how does pegloticase treat chronic tophaceous gout? side effects?

Answer 45

treatment for patients with chronic gout refractory to other therapies -recombinant form of uricase bound to polyethylene glycol