Corticosteroids and DMARDs Flashcards
RA is a progressive, systemic, inflammatory disorder characterized by (Blank) synovitis, joint erosions and multisystem (Blank) articular manifestations.
symmetrical
extra-articular
(blank) is at the root of all problems in RA, including joint pain, swelling and stiffness.
Inflammation
-> therefore controlling inflammation is key
What are the 2 categories that mdications fall into for treatment of RA?
- drugs that treat pain and inflammation but do not limit joint damage
- drugs that help control disease and limit joint damage
What drugs are used to treat pain and inflammation but do not limit joint damage?
corticosteroids (glucorticosteroids), NSAIDS and other analgesics
What drugs hep control disease and limit joint damage?
DMARDS (disease modifying anti-rheumatic drugs) and
Biologics
Rheumatologists tend to use (blank) and (Blank) as the first tratment in RA therapy, with (blank X 2) playing supportive roles and controlling acute inflammation
DMARDS
Biologics
Steroids, NSAIDs
(blank) and their biologically active synthetic derivatives (prednisone, dexamethasone, prednisolone) potently suppress inflammation and their usefulness in a variety of inflammatory and autoimmune disease making them among the most frequently prescribed drugs.
Corticosteroids (glucocorticoids)
Why are corticosteroids (glucocorticoids) dangerous?
because they exert effects on almost every organ system, the clincal use and withdrawal from corticosteroids are complicated by many serious or life-threatening side effects
Disease-modifying anti-rheumatic drugs (DMARDs) are a category of unrelated drugs defined by their use in (blank)
RA
DMARDs are either (blank) or (Blank)
antimetabolites
TNF alpha blockers
Steroids blunt the immune system but are insufficient to do what?
slow the progression of the disease
NSAIDs treat inflammation but not the (blank)
underlying disease
DMARDs can do what to the progression of the disease (RA)?
slow down or stop progression of joint damage
Are the side effects of all DMARDs the same?
no
(blank) for RA are drugs targeting specific parts of the immune system to inhibit inflammation.
Biologics
What do Biologics do?
reduce joint pain and swelling and control symptoms and disease activity of moderate to severe RA when DMARDs fail.
Whats pretty cool about using biologics long term?
they can slow down joint damage and improve joint use and movement
What are these signs of:
- recurrent hyperuricemia
- arthritis
- severe pain
Gout
What is gout caused by?
by deposition of uric acid crystals in the joint space as a result of long-standing hyperuricemia (increased production or decreased excretion of uric acid), causing an inflammatory reaction
What does an acute attack of gout present as?
severe joint pain most often in distal phalangeal joints
What is the inflammatory response to gout like?
local infiltration of granulocytes-> which phagocytize the urate crystals
(blank) production is high in synovial tissues and in the leukocytes associated with the inflammatory process.
lactate
Since lactate production is high in synovial fluid and in the leukocytes associated with the inflammatory process, what does this mean for the pathology of gout?
that the pH will drop which facilitates the deposition of uric acid
Urate is also deposited in interstitial tissues of the (blank) and accumulates as (Blank)
kidney
kidney stones
What is the solubility in serum of uric acid?
7 mg/dl
Levels of urate are (blank) in children and are elevated in (blank) after puberty
3-4
boys
Levels of urate are (lower/higher) in women but (Fall/Rise) after menopause
lower
rise
Gout is more prevalent in (Blank) 95% of cases with peak incidence in the (blank) decade
male
5th
Gout is prositively correlated with …..?
short, fat, diabetic alcoholicl males who live in warm places and are poor and stupid
How do we get urate from AMP?
AMP-> IMP-> hypoxanthine-> xanthine-> uric acid (keto) -> uric acid (enol)-> urate
Adenosine deaminase deficiency is associated with (blank)
SCID
What causes primary gout?
loss of hypoxanthine-guanine phosphoribosyl transferase deficiency (x-linked, Lesch-Nyhan)
What are the normal uric acid levels in females?
Males?
- 4-6.0 mg/dL
3. 4-7 mg/dL
What causes secondary gout?
- Overproduction of urate secondary to increased breakdown of blood cells as in leukemia
- Chemotherapy
- decreased excretion of urate due to use of alcohol, thiazide diuretics or low doses of aspirin
You can get asymptomatic hyperuricemia, patients with serum urate above (blank) are at risk of devloping out.
7 mg/dl
What is this:
exquisitely painful monoarticular arthritis which presents most commonly in 1st metatarsal joint with 90% of untreated patients having involvement of the great toe.
acute gout
What is this:
following the initial attack of gout, a remission of indeterminate length
Intercritical period
What is this:
frank gouty arthrtis with xtals in the synovium and some degree of erosion of bone.
Chronic tophaceous gout
What is this:
Uric acid kidney stones occur in 20% of patients with gout
Nephrolithiasis
Chronic gout leads to deposition of urates into a chalky mass known as a (blank)
tophus.
Where are you most likely to find tophi?
in soft tissues, including tendons and ligaments, around joints
Tophaceous gout results from continued precipitation of (blank) during attacks of acute gout
sodium urate crystals
How do you know you have gout
befringement shows urate crystals-> needle like
If you see rhomboid shape crystal what is it ?
calcium pyrophosphate-> pseudo gout
Who do you typically see pseudogout in and what is the disease progression?
over age of 50-> can lead to acute, subacute, chronic arthritis of knees, wrists, elbows, shoulders, and ankles. THe articular damage is progressive, though in most persons not severe
What drug is used ONLY for gouty arthritis?
Colchicine-> it is an antiinflammatory agent, and a prophylactic agent
What is the drug of choice for acute atacks of gouty arthritis?
How long does it take to work?
Colchicine
12-24 hours after oral admin
T or F
Cochicine does NOT influence the renal excretion of uric acid or its concentration in blood
T
How does colchicine work?
binds to tubulin and interferes with the function of mitotic spindles/,microtubules of granulocytes-> granulocytes cant get into the inflamed area
Since Colchicine prevents granulocytes from entering inflamed area then you reduce the amount of (Blank) and thus reduce inflammation
lactic acid
Neutrophils exposed to urate crystals, do what with them?
ingest them and produce a glycoprotein which may be causative agent of acute gouty arthritis
This glycoprotein substance that neutrophils produce when ingesting urate crystals is thought to be the causative agent of acute gouty arthritis , what drug is thought to prevent the metabolizm of granulocytes and thus decrease this glycoprotein and relieve arthritic gouty symptoms?
colchicine
(blank) inhibits the release of histamine-containing granules from mast cells
Colchicine
Large amounts of colchicine enter the (blank) tract… how?
intestinal
bile and intestinal secretions
Since colchicine is predominantly in the intestine, where does poisioning show its manifestations?
GI tract :)
The kidney, liver, and spleen also contain high concentrations of colchicine, but it is apparently largely excluded from (blank, blank and blank)
heart, skeletal muscle, brain
Colchicine is metabolized to a mixture of compounds by (blank). THe majority of the drug is excreted in (Blank) but 10-20% is excreted in the (blank)
CYP3A
Feces
Urine
IF you have a patient with liver disease, what will happen to the excretion of colchicine?
that hepatic uptake and elimination are reduced and a greater fraction will now be excreted in urine
What are the adverse effects of colchicine?
Orally-> nausea, vomiting, abdominal pain, and diarrhea
IV-> sloughing skin and subcutaneous tissue
What are the benefits of giving colchicine via IV?
reduces risk of GI distubrances and provides faster relief (6-12 hrs)
If you give very high doses of colchicine what may this result in?
liver damage and blood dyscrasias
How do uricosuric agents work?
they treat gout by increase the excretion of uric acid by blockings its reabsorption for the urine
What are three uricosuric agents?
probenecid
sulfinpyrazone
benzbromarone
What is this:
anti-inflammatory NSAID and uricosuric
sulfinpyrazone
What is this:
a uricosuric that is potent, effective and dosed once daily
Benzbromarone
What is this:
organic acids
-reduce urate levels by acting on the anionic transport site in the rental tubule to prevent reabsorption of uric acid
Probenecid (benemid) and sulfinpyrazone (anturane)
(blank) and (Blank) undergo rapid oral absorption and should be used with (blank)
Probenecid (benemid) and sulfinpyrazone (anturane)
Colchicine
Probenecid and sulfinpyrazone inhibit the excretion of other drugs that are actively secreted by renal tubules, including (blank X 4)
penicillin, NSAIDs, cephalosporins, and methotrexate
Increased urinary concentration of uric acid may result in the formation of (blank).
Urate stones (urolithiasis)
How can you decrease the risk of urate stones?
ingestion of large volumes of liquid and potassium citate (alkalize urine)
What are common adverse effects of probenecid and sulfinpyrazone?
GI disturbances and dermatitis
-rarely blood dyscrasias
(blank) inhibit the synthesis of uric acid by inhibiting the xanthine oxidase, an enzyme that converts hypoxanthine to xanthine and xanthine to uric acid, the terminal steps in uric acid biosynthesis
Allopurinol
Allopurinol is metabolized by xanthine oxidase to (blank), which also inhibits xanthine oxidase.
alloxanthine
Allopurinal also inhibits de novo (blank) synthesis
purine
Allopurinol represents a (blank) approach to therapy
rational
Allopurinal commonly produces (blank) disturbances and (blank)
GI
dermatitis
Allopurinal rarely produces these side effects:?
hypersensitivity, including fever, hepatic dysfunction and blood dyscrasias
Allopurinol should be used with caution in patients with (blank) or (blank)
liver disease or bone marrow depression
Allopurinol blocks the action of xanthine oxidase by (blank) and is also metaobilized by it to form alloxanthine which also inhibits xanthine oxidase
substrate competition
What are the three FDA approved NSAIDs used in gout?
indomethacin, naproxen, sulindac
What are the benefits of using NSAIDs in gout?
faster onset of relief (compared with colchicine)
- w.in 2-4 hous for indomethacin
- less toxic; better tolerated
- widespread use and familiarity
- cost
(blank) such as prednisone, prednisolone, and triamcinolone have been used to relieve gout.
corticosteroids
T or F
steroids may have less utility in acute gout because they do not work as well as NSAIDs or colchicine
T
T or F
corticosteroids are the “last resort” therapy, used in patients that cannot take or do not benefit from NSAIDs or colchicine
T
What is febuxostat (Uloric)?
used to treat gout by lowering uric acid levels
How does febuxostate (uloric) lower uric acid levels and is it effective?
non-purine inhibitor- forms a complex with the enzyme resulting in inhibition
-lowers it even better allopurinol
How do you metabolize and eliminate febuxostate (uloric)?
CYP2C9
-renal and hepatic elimination
In whom do you use febuxostate (uloric)?
used for patients with attacks, not asymptomatic patients. Can and is combined wiht NSAIDs or Colchicine
What are the SEs of febuxostat (uloric)?
LIver toxicity and potential CV SE are of concern and being evaluated in phase IV
(blank) is indicated for use in the pediatric population for management of elevated uric acid in patients receiving chemotherapy for leukemia, lymphoma, or solid tumors and are anticipated to develop tumor lysis syndrome.
Rasburicase (Elitek)
(blank) occurs in malignancies that are highly proliferative and have high tumor burdens, such as lymphomas and leukemias.
Tumor lysis syndrome
What metabolic abnormalities usually accompany tumor lysis syndrome?
hyperphosphatemia, hyperkalemia, hyperuricemia, hypocalcemia and renal dysfunction
(blank) is a hallmark finding of tumor lysis syndrome
Hyperuricemia (uric acid level greater or equal to 8 mg/dL)
Which has more SEs, rasburicase (for children with cancer) or allopurinol?
rasburicase
Which is more expensive, Rasburicase or Allopurinol?
RASBURICASE By a lot!!!
Acute gout is treated with (blank) .
Nonsalicylate NSAIDs (indomethacin, naproxen, and sulindac)
Acute gout is treated with Nonsalicylate NSAIDs (indomethacin, naproxen, and sulindac). These NSAIDs are preferred to colchicine because of the (blank) associated with the use of colchicine.
diarrhea
Chronic gout is treated with (blank) to increase the elimination of uric acid and (blank) to inhibit uric acid production
uricosuric agents (probenecid, sulfinpyrazone) Allopurinol
What are maitenance drugs for gout?
allopurinol (zyloprim), probenecid (benemid) and sulfinpyrazone (anturane)
(blank) is needed for several weeks to prevent acute attacks while serum uric acid levels are being lowered
Colchicine
What besides meds to you need to give to prevent renal calculi in gout?
High fluid intake and alkaline urine
What are the corticosteroids used in RA?
predinisone, predinisolone, dexamethasone
What are the DMARDS; anti-TNF alpha drugs?
adalimumab, infliximab, etanercept, anakinra
What are the DMARDs: antimetabolites?
Azathioprine, Methotrexate, cyclophosphamide, cyclosporine
(blank) is a chronic, progressive, systemic, autoimmune disease
Rheumatoid arthritis (RA)
What besides joint problems will you get with RA?
pulmonary and vascular involvement, peripheral neuropathy, keratoconjunctivitis
What is the most common systemic inflammatory disease and what age is it most common in?
RA-> 30-60 in women (later in life for men) 3X times more likely in women.
40 to 60% of patients with advanced RA will survive (blank) years or less following diagnosis and die (blank) years earlier than expecte.
5 years or less
10-15 years
What are the goals of RA therapy?
control inflammation
- alleviate pain
- slow progression/rate of joint damage
- reduce disease activity and induce remission
- maintain function for essential daily activities
- max quality of life
What are the ways you can do combo therapy for RA therapy?
several DMARDs
DMARDS oral and biological
DMARDs and corticosteroids
What do corticosteroids target?
phospholipase A2
What do NSAIDs target?
COX
What do 5 LOX inhibitos Sulfasalazine, leukotriene receptor antagonist (Zafirulukast, zileuton) inhibit?
LOX
What do you want to inhibit LOX?
cuz it creates HETEs, leukotrienes, lipoxins which will mobilize phagocytes, change vascular permeability and cause inflammation
What does COX do?
creates prostanoids (prostaglandins, prostacyclin, thromboxane)-> creates inflammation
What does COX-1 do?
prostaglandins associated with:
GI mucosal integrity
Platelet function
Renal function
What does COX-2 do?
Prostaglandins associated with:
Inflammation
Pain
Fever
What are the pros of NSAID therapy?
Effective (±) control of inflammation and pain
Effective reduction in swelling
Improves mobility, flexibility, range of motion
Improve quality of life
Low-cost
What are the cons of NSAID therapy?
Does not affect disease progression
GI toxicity common
Renal complications (eg, irreversible renal insufficiency, papillary necrosis may occur)
Hepatic dysfunction
CNS toxicity with high dose (salicylates)
What is this:
involved in a wide range of physiological processes, includingstress response, immune response, and regulation of inflammation, carbohydrate metabolism, proteincatabolism, bloodelectrolytelevels, and behavior. There are 2 types, glucocorticoids and mineralcorticoids
Corticosteroids
What is this:
control carbs, fat and protein metabolism, and are anti-inflammatory by preventing phospholipid release, decreasing eosinophil action and a number of other mechanisms.
Glucocorticoids
(Blank) control electrolyte and water levels, mainly by promoting sodium retention in the kidney.
Mineralcorticoids
(blank) are physiological modulators of the immune system and protect the organism against life-threatening consequences of a full-blown inflammatory response.
Glucocorticoids
(blank) profoundly inhibit the immune system at multiple sites.
Corticosteroids
Corticosteroids regulate gene transcription, inhibit expression of (blank), (blank), (blank), and (blank)
IFN-gamma
Interleukins
TNF-alpha
GM-CSF (granulocyte-macrophage colony-stimulating factor)
Corticosteroids will increase circulating levels of (blank) by interfering with adhesion and decrease (Blank X 3)
neutrophils
Eosinophils, lymphocytes, and monocytes
The (blank and blank) are capable of bidirectional interactions in response to stress, and these interactions appear to be important for homeostasis
HPA axis and the immune system
Corticosteroids enter target cells by (blank) and bind to cytosoic receptors which are transcription factors, The steroid receptor complex translocates into the (blank),
simple diffusion
nucleus
Corticosteroids inhibit (blank) production
Eicosanoid production
Corticosteroids (glucocorticoids) inhibit (blank) which inhibits phospholipase A2 which inhibits COX-2 expression
Lipocortin
What are the 2 glucocorticoids of note?
prednisone
dexamethasone
The corticosteroids prednisone and dexamethasone prevent (Blank) and (blank) activation
leukocyte and endothelial cell activation
Corticosteroids block the synthesis of cytokines, how so?
binds to response element of cytokine gene and inhibits transcription
- binds to other stimulatory factors
- accelerates degredation of mRNA coding for cytokine
Corticosteroids block the action of cytokines, how so?
- inhibits transcription of “transcription factors” induced by cytokines
- blocks the action of cytokine-induced transcription factors
- blocks the synthesis of cytokine receptors
Corticosteroids block the effects on inflammatory mediators, how so?
- increases lipocortin (inhibits PLA2)
- decreases prodction of enzymes inolved in creating inflammatory mediators
- decreased expression of adhesion molecules
- increased expression of genes coding for enzymes that degrade inflammatory mediators
How do you give prednisone?
orally
How do you give dexamethasone?
oral, injectable, topical
Compared to the endogenous corticosteroids, the synthetic ones have stronger (blank), lower (blank), Longer (blank)
potency
dose
duration
Corticosteroids are well absorbed (blank)
orally
Corticosteroids are highly bound to (blank)
plasma proteins-CSBG
How are corticosteroids metabolized and excreted?
metabolized by liver an excreted by kidney
Is there a lag time before onset of action for steroids?
yes!
THe plasma half life of corticosteroids is (longer/shorter) than biological halflife
shorter
T or F
there is a persistence of effect after disappearnce from plasma
T
What are the adverse effects of Chronic use of glucocorticoids?
- adrenocortical insufficiency: suppression of HPA
- Cushings syndome (buffalo hump, moon face)
- DM
- CNS effects
- impaired wound healing
- MSK effects (osteoporosis, muscle weakness, atrophy)
- CV effects (fluid retention, edema, HTN)
- gastric ulcer
- increased suscpetibility to infection
- growth inhibition in children
What are the pros of corticosteroid therapy in RA?
Anti-inflammatory and immunosuppressive effects
Can be used to bridge gap between initiation of DMARD therapy and onset of action
Intra-articluar injections can be used for individual joint flares and this is the major benefit in rheumatic arthritis
What are the cons of corticosteroid therpay in RA?
Does not conclusively affect disease progression
Tapering and discontinuation of use often unsuccessful
Low doses result in skin thinning, ecchymoses, and Cushingoid appearance
Significant cause of steroid-induced osteopenia
(blank) blunt the immune response but are insufficient to slow down the progression of the disease
Steroids,
(blank) treat the inflammation symptoms but no the underlying cause
NSAIDs
(blank) retard or halt the underlying progression, limiting the amount of joint damage that occurs in RA while lacking the anti-inflammatory and analgesic effects observed with NSAIDs; having an effect on RA with more delayed onset than either NSAIDs or corticosteroids.
DMARDs
Do DMARDs have a delayed onset?
yes D for Delayed
DMARDs come in 2 categories?
oral or biologic drugs
(blank) DMARDs are small-molecule chemical drugs. The mechanism of action of each of these drugs is not well defined or unknown in some cases.
Oral
(blank) DMARDs are genetically engineered antibodies and proteins.
Biologic DMARDs
What are the most typical members of the biologic DMARDs drug class?
Tumor necrosis factor-alpha (TNFalpha) blockers
-other targets are IL-1 and IL-6 AND CD20 and CD28
Biologic DMARDs block the activity of (blank) and other cell-signaling molecules
immunostimulatory cytokines
WHen do use DMARDs?
Established persistent disease (chronic synovitis), development of erosions or joint space narrowing on radiographs
Should you wait for radiographic changes to give DMARDs?
No
Are DMARDs fast or slow acting? How long does it take to work?
slow acting, taking greater than 3 months for measurable clinical benefits to be observe
What DMARD is a purine synthesis inhibitor?
Azathioprine
What DMARD is a calcineurin inhibitor?
Ciclosporin (cyclosporin A)
What DMARD is a pyrimidine synthesis inhibitor?
Leflunomide
What DMARD is a purine metabolism inhibitor?
Methotrexate (MTX)
What DMARD is a T-cell costimulatory signal inhibitor?
Abatacept
What DMARDs are a TNF alpha inhibitor?
Adalimumab
Etanercept
Golimumab
Infliximab
What DMARD suppress IL-1 and TNF-alpha, induces apoptosis of inflammatory cells and decreases chemotaxis
Chloroquine and hydroxychloroquine
What DMARD reduces numer of T lymphocytes?
D-penicillamine
What DMARD inhibits macrophage activation?
gold salts (sodium, aurothiomalate)
What DMARD inhibits 5-LO?
minocycline
What DMARD is a chimeric monoclonal antibody against CD20 on B cell surface
Rituximab
What DMARD suppresses IL-1 and TNF alpha, induces apoptosis of inflammatory cells and increase chemotactic factors?
Sulfasalazine (SSZ)
What does Anakinra do?
inhibits IL-1
WHat does Tocilizumab do?
inhibist IL-6
What is the recommended dose of methotrexate?
7.5-20 mg/wk
What are the advantages of DMARDs?
Slow disease progression Improve functional disability Decrease pain Interfere with inflammatory processes Retard development of joint erosions
How long does it take for methotrexate to work? what is its potential toxicity? what are the toxicities to monitor?
1-3 months
moderate
hepatoxicity, pulmonary, myelosuppression
Methotrexate blocks (blank) thus inhibiting may carbon transfer reactions and blocks (blank)
dihydrofolate reductase
thymidylate synthase
What are the pros of using methotrexate (MTX, Rheumatrex)?
Long-term clinical experience
Favorable rate of continuation of therapy (50% - 3 yrs)
Proven efficacy in moderate to severe RA
What are the cons of methotrexate?
Laboratory monitoring every 4-8 weeks
Toxicities: hepatotoxicity, myelosuppression, pulmonary (pneumonitis)
How does sulfasalazine (asulfidine) work and what are its pros?
COX and lipoxygenase inhibitor
-Clinical effectiveness demonstrated in short-term use, mild level of toxicity
What are the cons of sulfasalazine (asulfidine)?
Effective for mild-to-moderate RA
Contraindicated in patients with sulfa intolerance or G6PD deficiency
Toxicities: myelosuppression, gastrointestinal, decreased digoxin absorption
Rate of AEs dose-dependent
CBC every 2-4 weeks for 3 months, then every 12 weeks
What DMARD is this:
Immunosuppressant; purine synthesis inhibitor. Prevents leukocyte proliferation
Azathioprine (Imuran)
What are the pros of Azathioprine (Imuran)?
Effective in refractory RA
Metabolized to 6-mercaptopurine
What are the cons of Azathioprine (Imuran)?
High risk for severe leukopenia and/or thrombocytopenia
Other toxicities: hepatotoxicity, may increase cancer risk, high risk for opportunistic infections, macrocytic anemia, severe bone marrow depression, GI
Requires monitoring every 1-2 weeks with dosage change, every 1-3 months thereafter; myelosupression increased with ACE-I or Allopurinol
What DMARD blocks phagocytosis?
Gold Auranofin (ridaura)
What are the pros of Gold Auranofin?
Effective in refractory RA
Only gold preparation for oral use
Accumulates in synovium
What are the cons of Gold Auranofin?
Requires long course to determine effectiveness (6 mo.)
Toxicities: skin lesions, stomatitis, oral ulcerations, glomerulonephritis, nephrosis, thrombocytopenia, agranulocytosis
Requires close monitoring for side effects, contraindicated in hepatic or renal disease, should not be combined with other immunosuppressants; caution with X-rays.
What is this:
Inhibits de novo pyrimidine biosynthesis through the inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase.
Laboratory studies have demonstrated that it has effects on stimulated T cells.
leflunomide (arava)
What are the pros of leflunomide?
- early onset of action (~4 weeks)
- stabilized benefit for long term use
- rpevents the expansion of activated lymphocytes
- selectively targets autoimmune lymphocytes to reduce untoward AEs
What are the cons of leflunomide?
-less clinical experience
-toxicities: hepatotoxicity, GI
-expensive
long T 1/2 requires loading
-Css takes 6 months
What are biological DMARDs?
Genetically engineered antibodies and proteins
How do biological DMARDs work?
block the activity of immunostimulatory cytokines and other cell-signaling molecules
What are the three categories of DMARDs?
- tumor necrosis factor (TNF alpha) blockers
- IL-1 blockers
- anti-B cell (CD20) antibody
What are the three drugs that are TNF alpha blockers?
- etanercept (enbrel)
- infliximab (remicade)
- adalimumab (humira)
What drug is an IL-1 blocker?
anakinra (kineret)
What drug is an anti-B cell (CD20) antibody?
rituximab (rituxan)
What is this
A dimeric fusion protein consisting of the extracellular ligand-binding portion of the human tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1
Binds to TNF and prevents its interaction with the TNF receptor
Etanercept (Enbrel)
What is etanercept (enbrel) indicate for?
- reducing signs and symptoms, including major clinical response, in RA
- inhibiting the progression of structural damage, improving physical function in patients w/ moderately to severely active rheumatoid arthritis
- can be initiated in combo w methotrexate (MTX) or used alone
How do you administer Etanercept (enbrel)?
via injection
What are the concerns of Etanercept (enbrel) ?
-fatal injections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens
What are the common pathogens associated with fatal injections with Etanercept (enbrel)?
TB, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listerosis, and pneumocystosis
Who should you avoid giving Etanercept (enbrel) to?
avoid in diabetics and anyone prone to infection
What are adverse reactions of etanercept (enbrel)?
- Injection site reactions (37%)
a. mild to moderate erythemia and/or itching, pain or swelling but can continue drug admin - infection (pneumonia 7%)
- may increase risk of malignancies
What is this:
chimeric. mouse/human IgG1 monoclonal antibody that binds to TNFalpha with high affinity and specificity
Infliximab (Remicade)
What does Infliximab (Remicade) do?
Binds to TNF apha which Inhibits TNF alpha binding with TNF alpha receptor
So what is an adverse reaction to Infliximab (remicade) and how do:
you remedy it?
can induce allergic reactions and reduce long-term efficacy
-methotrexate could potentiate the antirheumatoid activity and reduce its immunogenicity
What is this:
Recombinant human IgG1 monoclonal antibody specific for human TNF, and the first product consisting entirely of human peptide sequences.
Adalimumab (humira)
How does adalimumab (humira) work>
binds to TNF alpha and blocks interaction with p55 and p75 cell surface receptors
What is this:
Considered as a class, for patients with longstanding active RA requiring a change in therapy,
Biologica DMARD therapy
Biologic DMARDs provide a (lessened/greater) symptom response and remission rate than do the oral DMARDs.
greater
Should you combing biologic DMARDs with other Biologic DMARDs?
no, it increases risk of serious adverse effects
What are the positives to Combo DMARD therapy (biologics with orals or orals and orals)?
- does not increase toxicity levels
- long-term outcome more favorable
- superior efficacy to single-DMARD regimen
What are the possible DMARD combo therapies?
- methotrexate + sulfasalazine + hydroxychloroquine
- methotrexate + cyclosporine
- Methotrexate + leflunomide
- methotrexate + biologic DMARD
In patients with longstanding active RA, Combining up to (blank) oral DMARDS (MTX, sulfasalazine, hydroxychloroquine) produces greater improvements in disease activity than one or two oral DMARDs
3
For patients with early RA who have not previously been treated with oral DMARDs, (blank) (sulfasalazine and MTX) does not improve symptom response, radiographic progression, or functional capacity more than monotherapy.
combining oral DMARDs
In patients with inadequate disease control, biologic DMARDs used in combination with (blank) offer greater relief than monotherapy with either MTX or a biologic DMARD without increasing treatment discontinuation due to adverse effects.
methotrexate (MTX)
When should DMARDs be initiated in RA?
early!
DMARDs may be limited by their (blank) profiles
toxicity
DMAR combo treatment is inidacted as a DMARD plus (blank)
methotrexate
(blank) DMARDs are indicated when oral DMARDs are not successful
Biologic
(blank) appears to be superior to oral DMARD alone in advanced disease
Biologic DMARDs plus Methotrexate
The oral DMARDs, particuarly (blank), remain effective first-line treatments for RA
Methotrexate (MTX)
(blank) and (blank) are similarly effective for patients with early RA, and (Blank) may provide comparable results
Methotrexate (MTX)
Sulfasalazine
leflunomide
For patients with early RA who have not been treated with methotrexate (MTX-naive), treatment with either (blank) or (blank) provides similar benefits for symptoms and function. However, (blank) are more effective at limiting radiographic evidence of progression
MTX, biologic DMARD
Biologic DMARDs
Adding (blank) to treatment with oral DMARDs improves function and may limit radiographic progression, although there is evidence that the combo increases the risks of adverse effects.
prednisone
For patients with longstanding active disease (RA), (Blank) therapy can provide more improvement than monotherapy
two or three oral DMARDs in combination
Evidence is accumulating that (blank) as a class offer greater likelihood of remission in patients with longstanding active disease than do oral ones.
biologic DMARDs
COmbing (blank) provides no additional benefits and increases the risk of serious adverse effects.
biologic DMARDs
In patients with inadequate disease control, (blank combined with blank) offer greater relief than monotherapy with either.
biologic DMARDs with methotrexate
Which has less bad SEs, oral or biologic DMARDs?
neither, Oral-> toxicity
Biologics-> serious infections
Tolerability is similar b/w DMARDs of both classes
