Unit 2 - RA and Gout Flashcards
(45 cards)
what is RA characterized by?
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
why is the conservative/traditional approach of RA treatment in question?
- joint damage is most rapid early in disease and cannot be reversed
- DMARD given early to retard joint damage
- RA patients have multiple health problems and reduced life expectancy
what are the types of RA treatments?
- NSAIDs
- DMARDs (disease-modifying anti-rheumatic drugs)
- biological response modifiers
what are examples of NSAIDs used for RA?
- indomethacin, naproxen (relieve symptoms in long-term treatment of RA and other musculoskeletal disorders)
- 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
what is the basis of DMARDs?
drugs that retard or halt the progression of disease
-effects may take 2 weeks to 6 months to become clinically evident
what are the types of DMARDs?
- glucocorticoids
- antimalarial drugs
- sulfasalazine
- immunosuppressive drugs (methotrexate, leflunomide)
explain what glucocorticoids do for RA? mechanism and side effects?
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
what are intra-articular glucocorticoids used for?
often helpful to alleviate painful symptoms of RA
explain what antimalarial drugs do for RA; mech and side effects?
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
what disease other than RA are antimalarial drugs used to treat?
SLE
explain what sulfasalazine drugs do for RA; mech and side effects?
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)
explain what immunosuppressive drugs do for RA; examples?
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
explain what methotrexate does for RA; mech and side effects?
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
explain what leflunomide drugs do for RA; mech and side effects?
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
explain what biological response modifiers do for RA; examples
therapeutics that target the cytokines and/or their receptors
- TNF-alpha antagonists
- other cytokine antagonists
- co-stimulation modulators
what are TNF-alpha antagonist examples for RA?
- etanercept
- infliximab
- adalimumab
- golimumab
- certolizumab
explain what etanercept do for RA; mech and side effects?
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
explain what infliximab do for RA; mech and side effects?
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
explain what adalimumab do for RA; mech and side effects?
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)
explain what golimumab do for RA; mech and side effects?
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
explain what certolizumab do for RA; mech and side effects?
TNF-alpha antagonist
-humanized Ab Fab fragment conjucated to polyethylene glycol to delay metabolism and elimination
explain what anakinra do for RA; mech and side effects?
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
explain what tocilizumab do for RA; mech and side effects?
IL-6 receptor antagonist approved in 2008
-serious infections including TB, fungal, viral, and other opportunistic infections
explain what abatacept do for RA; mech and side effects?
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