Term
increased rate with aging
women have higher prevalence
obesity
occupation: shipyard workers, agriculture, carpenters (repetitive use injuries)
trauma: sports injuries, age in which injury occurs
genetics: genetic link |
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Definition
| etiology of osteoarthritis |
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Term
osteoarthritis = degenerative joint disease
low-grade inflammation results in pain in the joints, caused by abnormal wearing of the cartilage that covers and acts as a cushion inside joints and destruction or decrease of synovial fluid that lubricates the joints
cartilage damage/loss
irregular thickening of bone
thickening and distortion of capsule
osteophytosis - outgrowths of immature bone that form over time
outcomes:
inflammation, pain, swelling
loss of motion/function |
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Definition
| pathology of osteoarthritis |
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Term
can occur at any age (rate does increase with age)
more common in women
RA is a chronic inflammatory multisystem autoimmune disease that leads to erosion and destruction of the joint surface which impairs range of motion and can cause deformities
cause unknown, but may be due to viral infection (epstein-barr, rubella)
RA can affect multiple other organs in the body
RHEUMATOID FACTOR:
autoantibody commonly found in RA
it is an antibody against the Fc portion of IgG, which is itself an antibody
RF and IgG join to form immune complexes which contribute to the disease process
not all people with RA have detectable RF
anticyclic citrullinated peptide (anti-CCP) |
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Definition
| etiology of rheumatoid arthritis |
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Term
pain
joint stiffness
low-grade fever
weakness
anemia
loss of appetite
symptoms that distinguish RA from other arthritis are inflammation and soft-tissue swelling of many joints at the same time
initially asymmetrical then symmetrical as the disease progresses
pain improves with use of the joint; more stiffness in the morning (as opposed to OA where the pain worsens over the day as the joint is used) |
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Definition
| symptoms of rheumatoid arthritis |
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Term
the synovial membrane (soft tissue that lines the non-cartilaginous surfaces of joints) becomes thickened due to hyperplasia of the synovial lining cells
synovial lining is transformed into the pannus, which invades and destroys adjacent cartilage
increased vascularity which helps facilitate entry of immune cells into the synovium
presence of inflammatory cells such as CD4+ T-cells, macrophages, B-cells, and neutrophils in the synovial fluid and membrane
CD4+ T-cells are thought to be the key mediator of inflammation in RA |
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Definition
| pathology of rheumatoid arthritis |
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Term
CD4+ cells are the main mediator
RA is predominantly a TH1 response: stimulation of macrophages to produce pro-inflammatory cytokines such as TNFa, IL-1, and IL-6
TNFa, IL-1, and IL-6 are key cytokines that drive inflammation in RA:
increase recruitment of neutrophils which release enzymes that degrade cartilage
matrix metalloproteases (stromelysin and collagenases) = enzymes that degrade connective tissue and are main mediators of joint damage in RA
activated CD4+ T-cells:
stimulate B-cells to produce antibodies such as rheumatoid factor
stimulate osteoclasts to break down bone
macrophages are stimulated to produce prostaglandins and cytotoxins |
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Definition
| inflammatory activity of rheumatoid arthritis |
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Term
examples: aspirin, naproxen, ibuprofen
reduce pain, fever, and inflammation
suppress prostanoid synthesis in inflammatory cells through inhibition of COX2
anti-inflammatory effect:
modification of the inflammatory reaction
decrease vasodilation and decrease leukocyte migration with decreased edema
analgesic effect:
reduction in certain types of (especially inflammatory) pain
antipyretic effect:
lowering of body temperature when this is raised in disease (fever) |
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Definition
|
|
Term
salicylates: aspirin, diflunisal
acetic acid derivatives: etodolac, indomethacin, sulindac, tomentin
oxicams: piroximan, meloxicam
propionic acids: fenoprofen, ibuprofen, ketoprofen, naproxen, oxiprozin
fenamates: mefenamic acid, meclofenamic acid
COX-2 inhibitors: celecoxib |
|
Definition
|
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Term
interfere with APC to T-cells
inhibit PG and leukotriene synthesis
impair cell migration blunting inflammatory responses
repression of NF-kB, IL-1, IL-6, and TNFa |
|
Definition
|
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Term
products that are produced by means of biological processes involving recombinant DNA technology
1) substances that are (nearly) identical to the body's own key signaling proteins
2) MONOCLONAL ANTIBODIES - similar to antibodies but are custom designed
3) RECEPTOR CONSTRUCTS (fusion proteins) - based on a naturally occuring receptor linked to an antibody frame. the receptor provides the construct with detailed specificity and the antibody imparts stability |
|
Definition
| products that are considered biologics |
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Term
generally exhibit high molecular complexity and may be quite sensitive to manufacturing process changes
lack of access to the originator's molecular clone or original cell bank, nor the exact fermentation and purification process
nearly undetectable differences in impurities and/or breakdown products are known to have serious health implications
THUS, GENERIC VERSIONS OF BIOLOGICS MIGHT PERFORM DIFFERENTLY THAN THE ORIGINAL BRANDED VERSION OF THE DRUG |
|
Definition
| potential problems associated with biosimilars or follow-up biologics (subsequent versions of innovator biologic products made by a different manufacturer) |
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|
Term
pros:
limited degree of toxicity
effective in patients who fail treatment with other DMARDs
cons:
considerably more expensive
increased risk of TB, congestive HF, cancer
slow onset of action
modest remission and retention rates |
|
Definition
| pros and cons of biologic use in rheumatoid arthritis - protein molecules that block proinflammatory cytokines (immunosuppressants) |
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Term
|
Definition
| strategies for inhibition of cytokine action |
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Term
pro-inflammatory cytokine that will cause the cardinal signs of inflammation to occur:
heat
swelling
redness
pain
loss of function
TNFa acting at its receptors can induce:
apoptotic cell death
cellular proliferation* (macrophages, neutrophils)
differentiation
tumorigenesis (potential lymphoma risk with antagonism)
cellular adhesion*
vascular permeability*
inflammation*
*factors in RA
potent stimulator of synovial fibroblasts, osteoclasts, and chondrocytes
enhance release of metalloproteases (matrix destruction) |
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Definition
| TNFa role in rheumatoid arthritis |
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Term
dimeric fusion protein - soluble receptor construct
binds to and inactivates TNFa
ADRs: mild-moderate injection site reaction |
|
Definition
|
|
Term
infliximab
adalimumab
golimumab
certolizumab pegol
pegol flix a gol
MOA:
antibodies directed against TNFa
binds to and inhibits TNFa from interacting with its receptor |
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Definition
| examples of TNFa antibodies and MOA |
|
|
Term
generation of antibodies:
methotrexate co-administration reduces this aspect
infusion reactions
local injection-site reactions |
|
Definition
| ADRs of TNFa antibodies (infliximab, adalimumab, golimumab, certolizumab pegol) |
|
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Term
pro-inflammatory cytokine involved in RA
stimulates the production of mediators such as prostaglandin, nitric oxide, cytokines, chemokines, and adhesion molecules
produced mostly by monocytes and macrophages
interacts synergistically with TNFa
stimulates fibroblast proliferation
increases lymphocyte proliferation (T and B cells)
increases fever
highly associated with joint damage in RA: IL-1 causes release of metalloproteases from fibroblasts and chondrocytes |
|
Definition
|
|
Term
recombinant IL-1 receptor antagonist
IL-1Ra: naturally occuring competitive antagonist
effectiveness in RA is limited:
less robust effect?
lesser role of IL-1?
need 10-100x excess over IL-1?
short half life
ADR: infection |
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Definition
|
|
Term
humanized monoclonal antibody against the IL-6 RECEPTOR
effective in combination therapy with methotrexate for the treatment of RA |
|
Definition
|
|
Term
pro-inflammatory and anti-inflammatory cytokine
secreted by T-cells and macrophages
IL-6 receptor: MEDIATOR OF FEVER AND OF THE ACUTE PHASE RESPONSE INFLAMMATORY RESPONSES |
|
Definition
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Term
a chimeric monoclonal antibody that targets CD20 B-lymphocytes
CD20: regulates early steps in the activation process for cell cycle initiation and differentiation of B-cells
rituximab has antibody activity against CD20 which:
1) produces complement mediated cytotoxicity
2) produces antibody-dependent cell-mediated cytotoxicity
3) induces apoptosis
causes a rapid and sustained depletion of circulating and tissue based B-cells
depletion lasts 6-9 months!
ADRs:
infusion reactions - cytokine release syndrome; may be severe and/or fatal
increased incidence of infections - bacterial; reactivated viral infections |
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Definition
|
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Term
complete T-cell activation requires 2 signals:
T-cell receptor with MHC on an APC
and
interaction of CD28 on T-cells with CD80/86 on APCs
following optimal T-cell activation, CTLA4 is expressed on the cell surface
expression of CTLA4 causes T-cell activation to cease
binding of CTLA4 to both CD80/86 prevents interaction between CD28 and CD80/86 as the affinity for CTLA4 for CD80/86 is greater than CD28
abatacept is a fusion protein that contains a CTLA4 fragment and IgG
abatacept mimics CTLA4 and competes with CD28 for CD80/86 binding
by blocking CD28 interaction, abatacept prevents the delivery of the secondary costimulatory signal that is required for optimal T-cell activation (inhibiting cytokine release - IL2, IL6, TNFa)
ADRs: infection, malignancy |
|
Definition
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Term
disease modifying anti-rheumatic drug (DMARD) = prevents disease progression
prevents folic acid synthesis by inhibiting dihydrofolate reductase
methotrexate is structurally similar to folic acid
folate plays a central role in metabolic reactions:
cell proliferation
synthesis of DNA precursors
methotrexate slows the appearance of new erosions within joints
reduces lymphocyte and cytokine levels
is active at much lower doses than those needed in cancer chemotherapy
ADRs:
nausea
mucosal ulcers
dose related hepatotoxicity
folic acid deficiency: supplementation with folic acid can help with symptoms; TERATOGENIC |
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Definition
|
|
Term
DMARD
exhibits essentially all of its pharmacologic activity via its active metabolite M1
M1 inhibits dihydroorotate: involved in pyrimidine synthesis
inhibits B and T cell proliferation
orphan drug status for the prevention of solid organ rejection after allograft transplantations
ADRs:
paresthesias
peripheral neuropathy
GI effects: vomiting, diarrhea, abdominal pain
hepatotoxicity
hair loss
interactions:
NSAIDs - M1 inhibits CYP2C9 which is responsible for NSAID metabolism |
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Definition
|
|
Term
DMARD
used for mild RA or in combination with other drugs for more severe disease
mild immunosuppressant, via inhibition of antibody factors
changes in antigen presentation or effects on the innate immune system (accumulates in leukocytes):
stabilizing lysosomyl membranes
inhibiting activity of many enzymes associated with cartilage breakdown (collagenases)
advantages: lack of significant myelosuppression, or hepatic/renal toxicities |
|
Definition
|
|
Term
DMARD
theorized to reduce inflammation by blocking the activity of COX and lipoxygenase
antioxidant action that traps free radicals, which are potentially damaging byproducts of metabolism
ADRs:
can result in serious hepatotoxicity
photosensitivity
dermatological sensitivity |
|
Definition
|
|
Term
men > women
incidence increases with age
obesity
kidney issues
drugs (alcohol, diuretics, levodopa)
genetics
uric acid concentration = dietary purines |
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Definition
|
|
Term
gout is an arthritic condition usually characterized by attacks of acute inflammatory arthritis - a red, hot, tender, swollen joint
the metatarsal-phalangeal joint at the base of the big toe is the most commonly affected
high plasma levels of uric acid (hyperuricemia) cause for urate crystals to form in joints
amount of uric acid is determined by the balance between:
amount ingested
amount made de novo
amount excreted (kidneys): decreased pH and low temp decrease solubility and increase deposits
uric acid crystals can initiate the inflammatory response by activating the classic complement pathway to release chemoattractants for neutrophil recruitment into the synovium
crystals also induce kinins which cause vasodilation, pain, and swelling
phagocytosis by synovial macrophages stimulates the release of proinflammatory cytokines (TNFa, IL-2, IL-6) increasing neutrophil adhesion and migration |
|
Definition
|
|
Term
conversion of nucleic acids to purine nucleotides
de novo synthesis
dietary
cross talk between the de novo and salvage pathway regulate plasma uric acid levels
high de novo purine synthesis = high uric acid levels
increased salvage purine synthesis = low uric acid levels
hypoxanthine guanine phosphotranferase (HGPRT): enzyme responsible for purine salavage; too little = increased uric acid
phosphoribosyl pyrophosphate (PRPP): purine precursor; too much = increased uric acid |
|
Definition
|
|
Term
relieve symptoms of acute attack (pain, swelling):
NSAIDs (indomethacin, naproxen, sulindac) - mainstay therapy; NOT aspirin (can impair uric acid excretion)
corticosteroids
decrease serum urate levels:
dietary - reduce weight, reduce purine rich foods (organ meats), reduce alcohol intake
pharmacologic - uricosuric drugs increase renal clearance (probenacid, sulfinpyrazone); colchicine, allopurinol, pegloticase |
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Definition
| goals of treatment of gout |
|
|
Term
NSAIDs
colchicine
glucocorticoids |
|
Definition
| appropriate pharmacologic intervention for acute gout |
|
|
Term
allopurinol
probenacid
sulfinpyrazone
pegloticase |
|
Definition
appropriate pharmacologic intervention for chronic gout:
hyperuricemia
development of tophi (deposition of urate crystals around the synovial joints)
recurrent gout attacks |
|
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Term
purine analog
xanthine oxidase inhibitor
blocks the metabolism of hypoxanthine and xanthine to uric acid
metabolite: oxypurinol acts similarly
interferes with metabolism of 6-mercaptopurine and azathioprine
febuxostat is another xanthine oxidase inhibitor |
|
Definition
|
|
Term
1) binds to tubulin and inhibits the migration/motility of neutrophils into the area of inflammation
2) inhibits synthesis and release of leukotrienes
plant alkaloid
treatment of acute gouty arthritis
NOT an analgesic - need to provide pain relief with another agent!
does not affect uric acid clearance
anti-inflammatory, reduces frequency, relieves gout pain
has significant toxicity:
N/V/D
myelosuppression
alopecia |
|
Definition
|
|
Term
recombinant uricase (urate oxidase) an enzyme that lowers the levels of uric acid by catalyzing the oxidation of uric acid to allantoin
allantoin is more water soluble and more readily excreted via the kidneys
pegilated = increased circulatory time
can replace xanthine oxidase inhibitors for patient who do not respond or cannot tolerate treatment with xanthine oxidase inhibitors
instead of preventing the synthesis of uric acid, pegloticase breaks down existing uric acid |
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Definition
|
|
Term
originally developed to inhibit tubular secretion of penicillin
competitively inhibits the active reabsorption of uric acid via competitively inhibiting URAT1, preventing reabsorption into the blood
NO ANTI-INFLAMMATORY OR ANALGESIC ACTIVITY
important considerations:
increased excretion of urate may result in kidney stones
may precipitate an acute attack of arthritis due to shift in uric acid homeostasis |
|
Definition
|
|
Term
competitively inhibits the active reabsorption of uric acid
NO ANTI-INFLAMMATORY OR ANALGESIC ACTIVITY
sulfinpyrazone and its metabolite have anti-platelet activity mediated through inhibition of COX
important considerations:
similar to probenecid, but associated with greater ADRs
increased excretion of urate may result in kidney stones
may precipitate an acute attack of arthritis due to shifts in uric acid homeostasis
interferes with metabolism of sulfonylureas and warfarin |
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Definition
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