090514 gout, rheumatold arth, osteoarth Flashcards
synovial membrane is not present over what?
articular cartilage
patterns of arthritis
inflam or non-inflam
monoarthritis or polyarthritis
what are some causes of inflammatory monoarthritis?
trauma
crystals (monosodium urate, calcium pyrophosphate)
septic joint
other
how can you tell if the arthritis is inflammatory (vs non inflammatory)?
morning stiffness of longer than 1 hr
PE: erythema and warmth, synovitis (thickening of synovium around joints, tenderness upon palpation)
lab: ESR and CRP, peripheral blood leukocytosis, joint fluid analysis
radiography: XR (erosions of bone at joint margins)
WBCs would be elevated in synovial fluid for what types of arthritis?
inflammatory (septic would have an extraoridinarily high WBC count)
90% of gout occurs due to?
underexcretion
where does uric acid in gout come from?
1/3 from dietary nucleotides and nucleoproteins
2/3 from cellular nucleotides and nucleoproteins
how is uric acid usually excreted?
1/3 through the gut (bacterial degradation)
2/3 through renal excretion
how much is usually excreted of uric acid of the filtered load?
10%
how would does overproduction-induced hyperuricemia occur?
enzymatic abnormalities
increased cell turnover
diet
ethanol
how would underexcretion-induced hyperuricemia occur?
metabolic syndrome
renal disease
drugs like diuretics, cyclosporine
ethanol
what is the onset of gout in men related to?
uric acid level
what test supports gout?
yellow, parallel crystals of monosodium urate (mneunomic is yellow, parallel, allopurinol–all double L’s)
uric acid level–if higher, higher chance of gout happening
swelling, warmth, tenderness
tophaceous gout
large deposits of uric acid crystals
can get secondary calcification of tophi
what can precipitate a gout attack?
elevation of uric acid
reduction of uric acid (see third point here)
release of crystals from pre-formed deposits
inflammatory cascade of gout
MSU crystals are phagocytosed by monocyte, you get inflammasome activation, then monocyte release IL-1, which then activates the endothelium, get pro-inflammatory mediators and neutrophil recruitment
CPPD deposition disease occurs in whom?
12% of elderly
what is the cause of CPPD deposition disease
unknown but most cases are related to overproduction of PPi
what is CPPD
calcium pyrophosphate dihydrate, formed from pyrophosphate and calcium coming together to make the crystal
in pts less than 60, CPPD can occur how?
secondary to problems like hemochromatosis, hypophosphatasia, hypomagnesemia, hyperparathyroidism
how is psuedogout diff from gout
acute arthritis like gout, but in usually larger joints (knee, wrist, shoulder)
Diagnosed from thromboidal shaped, positively birefringent cyrstals in joint fluid
XR: diagnosis may be supported by chondrocalcinosis but not seen always
CPPD arthritis signs
commonly asymptomatic
or pseudogout - acute inflam of 1 or 2 joints
or osteoarthritis (but may be associated with osteoarthritis in atypical joints)
or like rheumatoid arthritis (MCP involvement)
how should NSAIDs be used to treat gout
within first 24 hrs
indomethacin, naproxen
never use aspirin (aspirin inhibits uric acid secretion)
for the inflammation in gout
how are steroids used to treat gout
symptomatic relief for pts that can’t take NSAIDs
used short term
MOA of colchicine in treating gout
antimitotic
interferes with microtubule formation, inhibits neutrophil activation and migration
route of administration of colchicine for gout
oral
what is notable about colchicine for gout
CYP450 metabolism
substrate for P-glycoprotein
significant adverse effects (narrow therpeutic toxicity window, GI) —therefore use is limited
contraindicated for hepatic or renal disease pts, elderly, CYP3A4 and P glyprotein drug taking pts
for multiple acute gout attacks, drug therapies to prevent gout flare and destruction on joint snad kidneys?
allopurinol
febuxostat
probenecid
pegloticase
allopurinol MOA
blocks xanthine oxidase, inhibiting terminal steps in uric acid biosynthesis
converted to oxypurinol, which is the active compound (hypoxanthine normally is converted to xantine; allonpurinol is a structural analog of hypoxanthine)
adverse effects of allopurinol
hypersensitivity
acute gout attack (give drug w/ colchicine or NSAID)
use of allopurinol
prevention of primary hyperurecemia of chronic gout
prophylactic treatment in secondary forms of hyperurecemia
febuxostat MOA
non-purine xanthine oxidase inhibitor (not a structural analog for binding to xanthine oxidase)
forms stable complex with both reduced and oxidized xanthine oxidase and inhibits catalytic fxn in both states
compare fubuxostat vs allopurinol in treating gout
febuxostat is more potent
incidence of adverse events like dizziness, diarrhea, headache and nausea was similar in both drugs
incidence of CV side effects higher in febuxostat
MOA of pegloticase
PEGylated-polyethylene glycol covalently linked to the molecule
the molecule is a recombinant form of urate oxidase enzyme (uricase, an enzyme usually not in humans)
uricase will convert uric acid to allantoin
side effects of pegloticase
infusion site rxns (must be given IV)
gout flare
immune response (at PEG portion of molecule)
uses of colchicine
acute gout attacks (within hours)
prophylactically in pts with chronic gout
use of pegloticase
refractory chronic gout
probenecid MOA
increases uric acid exretion by competing with renal tubular acid transcrporter (OAT/URAT1) so that less urate is reabsorbed
route of administration of probenecid
oral
what is notable about probenecid
dose-dependent half life (second order kinetics)
plasma protein binding
side effects of probenecid
GI
ineffective in pts with renal insufficiency
contraindicated in pt with uric acid kidney stones
Rheumatoid arthritis involves what cells of immune system
T cell disease with significant B cell contribution
what factors predispose someone to getting rheumatoid arthritis
genetic (HLA-DR) hormonal (females more than males) environmental (smoking) infections stress
what do you see in rheumatoid arthritis with regards to the synovrium
invasion by immune lineage cells with recruitment of local cells (synovial fibroblasts)
get proliferation of synovium (synovitis) with characteristics of a benign locally invasive tumor
pathology of rheumatoid arthritis
chronic papillary synovitis:
chronic inflammation of synovium (frequently formed lymphoid follicles)
accompanied by synovial cell hyperplasia–resulting in papillary like pattern on surface of synovium
hyperplastic inflammed synovium extends over articular surface forming pannus which fills joint space (gradually, articular cartilage is destroyed; increased osteoclast activity in underlying bone; end result may be joint fusion (ankylosis) due to fibrosis and ossification)
diff btwn rheumatoid arthritis and osteoarthritis
ostephytes and new bone formation are not prominent in RA
rheumatoid nodules
occur in 25% (usually in severe disease)
central zone of fibrinoid necrosis surrounded by rim of epithelioid histiocytes and then lymphocytes and plasma cells
caused by necrosis secondary to vascular damage possibly secondary to vasculitis
develop commonly on skin subcutaneously in areas exposed to pressure (extensor surfaces of forearm and elbow)
Hx of RA
gradual onset of joint pain, swelling, inflammation
inflam present for greater than 6 weeks in 3 or more joints
symmetrical in nature
morning stiffness lasting more than 1 hour for >6 wks
difficulty opening jars, etc, pain in the ball of foot upon arising from bed
what is RF?
IgM binding to IgG
however, not positive in all RA pts
anti-cyclic citrullinated peptide (CCP)
may be seen in early RA
positive in some cases of RF negative RA
same sensitivity as RF; more specific than RF
correlates with overall disease activity
clinical presentation of RA
affects usually small joints of hands and feet
usually not DIPs; PIPs and MCPs are common
tends to be in rows
can see swan neck deformity (hyperflexion of DIP, hyperextension of PIP); Boutiniere deformity (PIP flexion, DIP hyperextension)
criteria for classification of RA
4 out of the 7 below for greater than 6 weeks:
AM stiffness greater than 1 hr symmetrical arthritis at least three swollen joints wrist, MCP, PIP involvement rheumatoid nodules positive RF XR change typical of RA in hand
how is RA systemic?
can have: Sjogren's CV disease (similar to diabetes) lung involvement GI (b/c of NSAIDs or other med side effects) neurology (hand numbness, neuropathy)
pulmonary involvement of RA
rheumatoid pleuritis with exudate that is low in glucose
interstitial fibrosis
nodules
Caplan’s syndrome (rheumatoid pneumoconiosis)
medication related (unusual chronic infections)
for RA, etanercept MOA
inhibits the ability of soluble TNF-alpha to bind to its receptor
is a recombinant fusion protein
onset of action of etanercept
1-2 weeks
adverse effects of etanercept
injection site rxns
increased risk of infections
lymphomas in children
etanercept is used for
initially just used for moderate to severe RA, but now used for early stage
adalimumab MOA
IgG monoclonal antibody
binds to soluble and transmembrane forms of TNF-alpha
adverse effects of adalimumab
same as for etanercept
tocilizumab MOA
humanized antibody that binds to soluble and membrane bound IL-6 receptors, inhibiting IL-6 signanling
adverse effects of tocilizumab
injection site rxns
increased risk of infec
alterations in lipid profile
uses of tocilizumab
adults pts with moderately to severely active RA who haven’t had a good response to TNF antagonists
tofacitinib MOA
JAK inhibitor, inhibiting cytokine or growth factor mediated gene expression and intracellular activity of immune cells
what is notable about tofacitinib
it is administered orally (as opposed to tocilizumab and TNF inhibitors)
CYP3A4 metabolism
adverse effects of tofacitinib
increased risk of infec
increase in cholesterol
uses of tofacitinib
moderately to severely active RA in pts who have had inadquate response to methotrexate
biologic DMARDs
proteins designed mostly to target cyokines and cell-surface molecules
osteoarthritis
progressive disorder of the joints caused by gradual loss of cartilage
bony spurs and cysts develop at margins of joints
risk factors for osteoarthritis
female gender (particularly knee and hand) increasing age race or ethnicity genetics obesity trauma
pathology of osteoarthritis
early changes-superficial layers of cartilage are destroyed (limited chondrocyte proliferation and new matrix formation)
eburnation
advanced osteoarthritis-you see eburnation, which means polished, in the exposed bone
advance osteoarthritis-appearance?
EBURNATION
SUBCHONDRAL SCLEROSIS-more dense bone develops underneath the areas where cartilage is gone–in these areas, in addition, you can get micro fractures and then cysts–(called SUBCHONDRAL CYSTS, where you have break in the cartilage and then the bone and then fluid goes in)
OSTEOPHYTE FORMATION
osteophyte formation
bony outgrowths developed at margins of articular surface - cause increase in joint size
pathogenesis of OA?
imbalance in cytokine and growth factor activity resulting in matrix loss and degradation
etiology is likely multiple:
wear and tear theory is not sufficient to explain
risk factors
which joints are affected in OA
for women-small joints in hands (DIPs PIPs NOT MCPs)
hips
knees
bunions in the feet
PE findings for OA
mild to moderate FIRM swelling around joint line (b/c of formation of chondrophytes or osteophytes at margin)
crepitus
restricted ROM limited by pain
weakness and wasting of muscles acting on joint
periarticular tenderness
deformities
Heberden’s and Bouchard’s nodes
hallux valgus (bunion)
genu varus (bow legs)
genu valgus (knock knees0
diagnosis of OA
blood tests usually not helpful
imaging
synovial fluid aspiration typically viscous and translucent-non inflam WBC count <2000
infliximab MOA
chimeric IgG monoclonal antibody that binds to both soluble and transmembrane forms of TNF-alpha
abatacept MOA
costimulation modulator
inhibits T cell activation by binding to CD80 and CD86 on APC and blocking then the required interaction with CD28
adverse effects of abatacept
headache
hypersensitivity
increased risk of infec
should NOT be used in combo with anakinra or TNF-inhibitors
rituximab MOA
monoclonal Ig directed against CD20 antigen on B lymphocytes; this activates complement dependent B-cell cytotoxicity and antibody dependent cellular toxicity
side effects of rituximab
tumor lysis syndrome leading to acute renal failure
anakinra MOA
antagonist of IL-1 receptor
azathioprine MOA
purine antimetabolite that inhibits purine biosynthesis, inhibiting DNA synthesis
hydroxychloroquine MOA
not understood
useful for early, mild disease in RA
side effects of hydroxychloroquine
retinal damage
lefluonomide MOA
immunomodulatory agent in RA; inhibits dihydroorotate dehydrogenase, which is involved in production of uridine monophosphate
side effects of lefluonomide
diarrhea, rash, alopecia, elevated liver fxn tests
