Gout/RA/OA Flashcards
hyaline cartilage on articular surface
functions: elastic shock absorber spreads weight across surface of a joint; friction-free surface
avascular: composed of type 2 collagen (tensile strength), water and proteoglycans (elasticity and decreases friction), and chondrocytes (maintains cartilaginous matrix)
synovial cavity
synovial cells line synovial cavity: cuboidal cells, 1-4 layers thick (produce synovial fluid, remove debris-phagocytic function, regulate movement of solutes, electrolytes, and proteins from capillaries to synovial fluid), not present over articular cartilage
synovial fluid: viscous filtrate of plasma containing hyaluronic acid; lubricant and provides nutrients to articular cartilage
patterns of arthritis
inflammatory vs non-inflammatory
monoarthritis vs polyarthritis
causes of inflammatory monoarthritis
trauma
crystals (monosodium urate=gout, calcium pyrophosphate=pseudogout)
septic joint
other causes too
lab and radiographic tests to test for inflammation
LAB:
inflammatory markers (erythrocyte sedimentation rate-ESR, C reactive protein-CRP)
peripheral blood leukocytosis (septic arthritis)
joint fluid analysis
RADIOGRAPHIC:
x-ray-erosions of bone at joint margins
synovial fluid analysis for inflammation
non-inflammatory=WBCs 2000; PMNs 50-90%
septic=WBCs >50,000; PMNs <90%
gout
metabolic disorder resulting in elevation of uric acid (hyperuricemia) beyond level of saturation
over production of uric acid contributes to 10% of gout cases
under excretion of uric acid contributes to 90% of gout cases
gout epidemiology
4% prevalence; ~12 million
1.3M : 0.5F
increases in females after menopause (estrogen promotes urate renal excretion)
becoming more common because of increasing BMIs
hyperuricemia-causes of overproduction vs underexcretion
overproduction (90%): metabolic syndrome, renal disease, drugs (diuretics, cyclosporine), etoh
onset of gout in men is directly related to what?
uric acid level
monosodium urate crystal appearance
negatively birefringent; yellow, parallel, allopuriol=gout
precipitation of gout attacks
elevation of uric acid
reduction of uric acid excretion
release of crystals from pre-formed deposits
gout inflammatory cascade
recognition of MSU cyrstals–>phagocytosis of MSU crystals–>inflammasome activation–>caspase-1 activation–>IL-1B activation and release–>IL-1B signal transdution to the endothelium–>pro-inflammatory mediator release–> neutrophil recruitment
CPPD deposition disease
prevalence: ~12% of elderly
etiology: unknown but in most cases related to overproduction of PPi
multiple different presentations (CPPD crystals may be found with urate crystals-“mixed crystals”)
CPPD evlauation-pts <60
Fe, TIBC- hemochromatosis
alk phosphate- hypophosphatasia
Mg- hypomagnesemia
Ca- hyperparathyroidism (can present as acute pseudo gout)
pseudogout-symptoms, diagnosis, and imaging
attacks of acute arthritis similar to gout, but usually in larger joints (knee, wrist, shoulder)
diagnosis: rhomboidal shaped, positively birefringent crystals in joint fluid
x-ray: diagnosis may be suggested by “chrondrocalcinosis” but not seen in all cases
presentation possibilities of CPPD arthritis
1-asymptomatic-most common
2-pseudogout
3-osteoarthritis (OA)-may be associated with widespread OA including OA in atypical joints
4-RA-like (MCP joint enlargement)-may produce chronic low grade inflammation
therapeutic goals of drugs used in the treatment of gout
increase excretion of uric acid
inhibit inflammatory cells
inhibit uric acid biosynthesis
provide symptomatic relief (typically with NSAIDS or steroids-short term)
NSAIDs and the treatment of gout
within first 24 hours
indomethacin, naproxen
asprin=NO!!!!!!
contraindications to NSAIDs need to be considered (ex. peptic ulcers)
steroids and the treatment of gout
symptomatic relief in patients that can’t take NSAIDs
short term use
adverse effects with extended use
colchicine mech
no effect on uric acid excretion. antimitotic (arrests in G1), binds mictrotubules in neutrophils to inhibit activation and migration
colchicine pharmacokinetics
oral. CYP450. rapid, variable absorption. deposits in tissue stores/forms complex with tubulin. P-GLYCOPROTEIN substrate
P-glycoprotein pump
active transport to get rid of drugs, inhibitors block the pump
colchicine adverse effects
significant. narrow therapeutic window. GI toxicity: N/V, diarrhea, abd pain. latent period before stx. limits use of drug.
colchicine contraindications
hepatic or renal disease (decrease dose, less frequent). elderly patients, esp if also taking CYP3A4 of P-gp inhibitor (would increase conc of colchicine)
colchicine therapeutic use
ACUTE gout attacks, prophylactically in patients with chronic gout (adverse effects means it’s not the drug of choice)
indications for prophylaxis
frequent or disabling attacks, urate nephrolithiasis, urate nephropathy, tophaceous gout
therapies that can prevent gout flare
allopurinol, febuxostat, probenecid, pegloticase
allopurinol mech
inhibits terminal steps in uric acid biosynth, plasma uric acid conc decreases, uric acid crystals dissolve
allopurinol pharmacokinetics
metabolized to active compound. Allopurinol is analog of hypoxanthine, converted to oxypurinol by aldehyde oxidoreductase.
plasma half life of allopurinol vs oxypurinol
allopurinol: 1-2 hours, oxypurinol: 18-30 hr
allopurinol adverse effects
hypersensitivity, not always immediate but increases if taken w ACE inhibitors, thiazide diuretics, amoxicillin. also acute gout attack: mobilizes stores of uric acid so give drug with colchicine or NSAID first
therapeutic uses of allopurinol
prevents primary hyperuricemia of chronic gout, also severe forms of gouty nephropathy, tophaceous deposits, renal urate stones
febuxostat mech
non-purine xanthine oxidase inhibitor, forms a stable complex with both reduced and oxidized enzyme and inhibits catalytic fxn in both states. binds enzyme directly.
allopurinol vs febuxostat?
F: more potent, more effective in patients with impaired renal function. F & A have similar basic adverse effects, but CV side effects higher with F than A
uricase
normally absent in humans, converts uric acid to allantoin (inactive, water-soluble metabolite of uric acid)
pegloticase mech
converts uric acid to allantoin, PEGylated
pegloticase pharmacokinetics
IV administration every 2 weeks, long half life
pegloticase adverse effects
infusion site rxn, gout flare, immune response to PEG portion
pegloticase therapeutic uses
refractory chronic gout
uricosuric agents
drug that increases rate of excretion of uric acid
probenecid
increase uric acid excretion by competing with renal tubular acid transporter so less urate is reabsorbed
OAT
organic acid transporter, also URAT1
probenecid pharmacokinetics
oral administration, dose-dependent half-life, plasma protein binding
probenecid adverse effects
some GI side effects, ineffective if have renal insufficiency, C/I in patients w uric acid kidney stones
probenecid therapeutic uses
chronic gout, rarely in patients with kidney disease or overproduction of uric acid. b/c more llikely to produce uric acid stones in kidney.
allopurinol drug interactions
anticoagulants, oral. azathioprine. mercaptopurine.
colchicine drug interactions
amprenavir, carbamazepine, clarithromycin, cyclosporine, erythromycin, rifampin, ritonavir
probenecid drug interactions
cloribrate, methotrexate palatrexate, penicillin, salicylates
what causes an inflammasome activation with acute gout attack?
inflammation inhibitors (NSAIDs, steroids, colchicine, IL-1 inhibitors), urate deposition, tophi
what is RA
inflammatory polyarthritis, affects 1% of the population. T cell disease with B cell contribution. HLA-DR is shared epitope. F> M. invasion by immune lineage cells with recruitment of synovial fibroblasts. synovitis.
pathology of RA
chronic papillary synovitis: chronic inflammation of synovium (CD4+ T cells, plasma cells, macrophages, giant cells –> lymphoid follicles), accompanied by synovial cell hyperplasia, neutrophils and fibrin on joint surfaces in acute phase. pannus fills the joint space.
rheumatoid nodules
develop subcutaneously in areas exposed to pressure. 25%, usually w severe disease. non-tender, firm, round. microscopically: fibrinoid necrosis in center, surrounded by a rim of epithelioid histiocytes, then lymphocytes and plasma cells. cause: vascular damage + necrosis
nodule histio
central fibrinoid necrosis surrounded by palisaded chronic inflammatory cells
RA history features
gradual onset of joint pain, swelling + inflammation for > 6 weeks in 3 or more joints. symmetrical. morning stiffness > 1 hr, for > 6 wks
RA risk factors
genetics (HLA genes), ethnic prevalence, gender (F>M b/c estrogen decreases apoptosis of B cells), infections, cigarettes, stress
cytokines in RA pathogenesis
IFNa,b; IL-1, 6, 12, 15, 18; TNF
CCP (anti-cyclic citrullinated peptide)
may be seen in early RA (RF-), can be positive in some RF- cases. same sensitivity as RF but more specific.
physical features of RA
swan neck deformity, boutiniere deformity
classification of RA
AM stiffness > 1 hr, symmetrical arthritis, at least 3 swollen joints; wrist/mcp/pip involvement; rheumatoid nodules; positive RF; x-ray typical of RA (4/7 for > 6 wks)
RA pulmonary involvement
rheumatoid pleuritis w/ effusion: exudate, low glucose; interstitial fibrosis, nodules, caplan’s syndrome, medication related
therapeutic goals for drug treatment of RA
relieve pain, reduce inflammation, slow/stop joint damage, improve a person’s well being/ability to function
NSAIDs for RA treatment
large doses, long duration, no effect on progression of disease (relieve pain stx)
DMARDs
disease modifying anti rheumatic drugs
etanercept mech
inhibits ability of TNF-a to bind receptor; recombinant fusion protein. neutralizes s-TNF but not m-TNF
etanercept pharmacokinetics
IV, sub-q, 1-2 weeks for onset of action; elimination half life >3 days
etanercept adverse effects
injection site rxn, increased risk of infections (usually in patients taking immunosuppressants, screen for latent TB); lymphomas in kids/adolescents
etanercept therapeutic indications
moderate to severe RA, JIA, early stage RA
adalimumab mech
IgG MAB (all human), binds to soluble and transmembrane forms of TNF-a, prevents from binding to its receptor
adalimumab pharmacokinetics
sub-q, every other week
adalimumab adverse effects
injection site rxn, increased risk of infections (usually in patients taking immunosuppressants, screen for latent TB); lymphomas in kids/adolescents
adalimumab therapeutic uses
active RA (moderate to severe), alone or in combo w/ MTX/other DMARDs, active JIA (moderate to severe) also alone or in combo with MTX
mech of anti-TNFa agents
initially expressed as m-TNF. TNFa can be shed into ECM as s-TNF (soluble). antibodies can bind to m- and s-TNF and neutralize. binding to m- can also induce apoptosis of expressing cells.
tocilizumab mech
humanized Ab, binds to soluble and membrane-bound IL-6 receptors, inhibits IL-6-mediated signaling
tocilizumab pharmacokinetics
IV administration every 4 weeks, sub-q every other week
tocilizumab adverse effects
injection site rxn, increased risk of infections, alterations in lipid profile
tocilizumab therapeutic use
ADULT patients with moderate to severely active RA who had inadequate response to 1 or more TNF antagonists
tofacitinib mech
JAK inhibitor, prevents cytokine or growth-factor-mediated gene expression, decreases CD16/56+ NK cells, serum IgG, IgM, IgA, CRP and increases B cells
JAK mech
JAKs become activated, trigger cytokine receptor phosphorylation, STAT protein recruitment. STATs associate with receptor, activated via P, dimerize, translocate into nucleus to regulate gene expression
tofacitinib pharmacokinetics
oral administration, CYP3A4 mediated metabolism, minor contribution from CYP2C19
tofacitinib adverse effects
increase risk of infections, increase in cholesterol
tofacitinib therapeutic use
treatment of patients with moderate to severely active RA who had inadequate response to MTX. monotherapy or in combo w/ MTX or other DMARDs
pathogenesis of RA
- DCs phagocytose Ag, present to T cells
- activated T cells stimulate B and T cell production
- B cells produce plasma cells, form rheumatoid Ab
- helper T cells activate MP and CTLs
- T cells, MP and CTLs together produce cytotoxic cytokines (eg TNF-a, IL-1, IL-6) and prostaglandins that cause joint inflammation, synovial proliferation, bone and cartilage destruction
site of action of abatacept
blocks co-stimulation of T cells
site of action of MTX, leflunomide
inhibit proliferation and activity of T and B cells
site of action of etanercept, infliximab, adalimumab, golimumab, certolizumab
inactivate TNF-a
site of action of anakinra
blocks activation of IL-1
site of action of tocilizumab
inactivates IL-6
site of action of glucocorticoids
inhibit T cell activation and IL-2 production by regulation of gene transcription
site of action of glucorticoids and NSAIDs
inhibit formation of prostaglandins
rituximab
Ab vs CD20 antigen on B-lymphocytes
definition of OA
progressive joint disorder caused by gradual loss of cartilage. results in bony spurs and cysts at joint margins.
common OA history
gelling after inactivity, pain exacerbated by movement and use, crepitus, joint locking. no fevers, redness of joints, warmth, < 30 mins morning stiffness
OA risk factors
female, increasing age, genetics, obesity, trauma, race/ethnicity (variable)
pathology of OA (early changes)
superficial layers of cartilage are destroyed. fibrillation and cracking of cartilage matrix. limited chondrocyte proliferation & new matrix formation
appearance of femoral head in patient with more advanced OA?
absence of articular cartilage, roughened remaining cartilage. remaining bone is polished (eburnation). subchondral sclerosis develops below.
pathology of OA: subchondral cysts?
formed by break in cartilage, below areas where cartilage is gone. allows synovial fluid to be forced into subchondral space, forming fibrous walled cyst
pathology of OA: osteophyte formation
bony outgrowths develop at margins of articular surface in characteristic locations for specific joints; result in increased joint size
osteophyte location at hip joint
all around joint margin, typically large flat osteophyte on medial surface extending into fovea
osteophyte location at distal interphalangeal joints
heberden nodes
osteophyte location at PIP
bouchard nodes
OA pathogenesis
imbalance in cytokine and growth factor activity, results in matrix loss and degradation
secondary causes of OA
post-traumatic, other joint/bone disease, calciup deposition diseases, gout, congenital (hemochromatosis), metabolic, neuropathic arthropathy
joints affected in OA
PIPs, DIPs, wrists, hips, knees, big toes (not MCPs)
OA findings on physical exam
firm swelling around joints, crepitus, weakness/wasting of muscles acting on joint, tenderness, deformities, heberden’s & bouchard’s nodes, squaring of 1st CMC
how to diagnose OA
imaging, synovial fluid aspiration w/ non-inflammatory WBC, not usually blood tests
OA radiography
narrowing of joint space, osteophytes, changes in subchondral bone including cysts, sclerosis, loss of bone volume, shape changes
