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MSS > Gout/RA/OA > Flashcards

Gout/RA/OA Flashcards

1
Q

hyaline cartilage on articular surface

A

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)

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2
Q

synovial cavity

A

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

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3
Q

patterns of arthritis

A

inflammatory vs non-inflammatory

monoarthritis vs polyarthritis

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4
Q

causes of inflammatory monoarthritis

A

trauma
crystals (monosodium urate=gout, calcium pyrophosphate=pseudogout)
septic joint
other causes too

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5
Q

lab and radiographic tests to test for inflammation

A

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

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6
Q

synovial fluid analysis for inflammation

A

non-inflammatory=WBCs 2000; PMNs 50-90%

septic=WBCs >50,000; PMNs <90%

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7
Q

gout

A

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

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8
Q

gout epidemiology

A

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

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9
Q

hyperuricemia-causes of overproduction vs underexcretion

A

overproduction (90%): metabolic syndrome, renal disease, drugs (diuretics, cyclosporine), etoh

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10
Q

onset of gout in men is directly related to what?

A

uric acid level

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11
Q

monosodium urate crystal appearance

A

negatively birefringent; yellow, parallel, allopuriol=gout

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12
Q

precipitation of gout attacks

A

elevation of uric acid
reduction of uric acid excretion
release of crystals from pre-formed deposits

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13
Q

gout inflammatory cascade

A

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

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14
Q

CPPD deposition disease

A

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”)

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15
Q

CPPD evlauation-pts <60

A

Fe, TIBC- hemochromatosis
alk phosphate- hypophosphatasia
Mg- hypomagnesemia
Ca- hyperparathyroidism (can present as acute pseudo gout)

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16
Q

pseudogout-symptoms, diagnosis, and imaging

A

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

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17
Q

presentation possibilities of CPPD arthritis

A

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

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18
Q

therapeutic goals of drugs used in the treatment of gout

A

increase excretion of uric acid
inhibit inflammatory cells
inhibit uric acid biosynthesis
provide symptomatic relief (typically with NSAIDS or steroids-short term)

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19
Q

NSAIDs and the treatment of gout

A

within first 24 hours
indomethacin, naproxen
asprin=NO!!!!!!
contraindications to NSAIDs need to be considered (ex. peptic ulcers)

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20
Q

steroids and the treatment of gout

A

symptomatic relief in patients that can’t take NSAIDs
short term use
adverse effects with extended use

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21
Q

colchicine mech

A

no effect on uric acid excretion. antimitotic (arrests in G1), binds mictrotubules in neutrophils to inhibit activation and migration

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22
Q

colchicine pharmacokinetics

A

oral. CYP450. rapid, variable absorption. deposits in tissue stores/forms complex with tubulin. P-GLYCOPROTEIN substrate

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23
Q

P-glycoprotein pump

A

active transport to get rid of drugs, inhibitors block the pump

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24
Q

colchicine adverse effects

A

significant. narrow therapeutic window. GI toxicity: N/V, diarrhea, abd pain. latent period before stx. limits use of drug.

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25
Q

colchicine contraindications

A

hepatic or renal disease (decrease dose, less frequent). elderly patients, esp if also taking CYP3A4 of P-gp inhibitor (would increase conc of colchicine)

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26
Q

colchicine therapeutic use

A

ACUTE gout attacks, prophylactically in patients with chronic gout (adverse effects means it’s not the drug of choice)

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27
Q

indications for prophylaxis

A

frequent or disabling attacks, urate nephrolithiasis, urate nephropathy, tophaceous gout

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28
Q

therapies that can prevent gout flare

A

allopurinol, febuxostat, probenecid, pegloticase

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29
Q

allopurinol mech

A

inhibits terminal steps in uric acid biosynth, plasma uric acid conc decreases, uric acid crystals dissolve

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30
Q

allopurinol pharmacokinetics

A

metabolized to active compound. Allopurinol is analog of hypoxanthine, converted to oxypurinol by aldehyde oxidoreductase.

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31
Q

plasma half life of allopurinol vs oxypurinol

A

allopurinol: 1-2 hours, oxypurinol: 18-30 hr

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32
Q

allopurinol adverse effects

A

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

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33
Q

therapeutic uses of allopurinol

A

prevents primary hyperuricemia of chronic gout, also severe forms of gouty nephropathy, tophaceous deposits, renal urate stones

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34
Q

febuxostat mech

A

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.

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35
Q

allopurinol vs febuxostat?

A

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

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36
Q

uricase

A

normally absent in humans, converts uric acid to allantoin (inactive, water-soluble metabolite of uric acid)

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37
Q

pegloticase mech

A

converts uric acid to allantoin, PEGylated

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38
Q

pegloticase pharmacokinetics

A

IV administration every 2 weeks, long half life

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39
Q

pegloticase adverse effects

A

infusion site rxn, gout flare, immune response to PEG portion

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40
Q

pegloticase therapeutic uses

A

refractory chronic gout

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41
Q

uricosuric agents

A

drug that increases rate of excretion of uric acid

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42
Q

probenecid

A

increase uric acid excretion by competing with renal tubular acid transporter so less urate is reabsorbed

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43
Q

OAT

A

organic acid transporter, also URAT1

44
Q

probenecid pharmacokinetics

A

oral administration, dose-dependent half-life, plasma protein binding

45
Q

probenecid adverse effects

A

some GI side effects, ineffective if have renal insufficiency, C/I in patients w uric acid kidney stones

46
Q

probenecid therapeutic uses

A

chronic gout, rarely in patients with kidney disease or overproduction of uric acid. b/c more llikely to produce uric acid stones in kidney.

47
Q

allopurinol drug interactions

A

anticoagulants, oral. azathioprine. mercaptopurine.

48
Q

colchicine drug interactions

A

amprenavir, carbamazepine, clarithromycin, cyclosporine, erythromycin, rifampin, ritonavir

49
Q

probenecid drug interactions

A

cloribrate, methotrexate palatrexate, penicillin, salicylates

50
Q

what causes an inflammasome activation with acute gout attack?

A

inflammation inhibitors (NSAIDs, steroids, colchicine, IL-1 inhibitors), urate deposition, tophi

51
Q

what is RA

A

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.

52
Q

pathology of RA

A

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.

53
Q

rheumatoid nodules

A

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

54
Q

nodule histio

A

central fibrinoid necrosis surrounded by palisaded chronic inflammatory cells

55
Q

RA history features

A

gradual onset of joint pain, swelling + inflammation for > 6 weeks in 3 or more joints. symmetrical. morning stiffness > 1 hr, for > 6 wks

56
Q

RA risk factors

A

genetics (HLA genes), ethnic prevalence, gender (F>M b/c estrogen decreases apoptosis of B cells), infections, cigarettes, stress

57
Q

cytokines in RA pathogenesis

A

IFNa,b; IL-1, 6, 12, 15, 18; TNF

58
Q

CCP (anti-cyclic citrullinated peptide)

A

may be seen in early RA (RF-), can be positive in some RF- cases. same sensitivity as RF but more specific.

59
Q

physical features of RA

A

swan neck deformity, boutiniere deformity

60
Q

classification of RA

A

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)

61
Q

RA pulmonary involvement

A

rheumatoid pleuritis w/ effusion: exudate, low glucose; interstitial fibrosis, nodules, caplan’s syndrome, medication related

62
Q

therapeutic goals for drug treatment of RA

A

relieve pain, reduce inflammation, slow/stop joint damage, improve a person’s well being/ability to function

63
Q

NSAIDs for RA treatment

A

large doses, long duration, no effect on progression of disease (relieve pain stx)

64
Q

DMARDs

A

disease modifying anti rheumatic drugs

65
Q

etanercept mech

A

inhibits ability of TNF-a to bind receptor; recombinant fusion protein. neutralizes s-TNF but not m-TNF

66
Q

etanercept pharmacokinetics

A

IV, sub-q, 1-2 weeks for onset of action; elimination half life >3 days

67
Q

etanercept adverse effects

A

injection site rxn, increased risk of infections (usually in patients taking immunosuppressants, screen for latent TB); lymphomas in kids/adolescents

68
Q

etanercept therapeutic indications

A

moderate to severe RA, JIA, early stage RA

69
Q

adalimumab mech

A

IgG MAB (all human), binds to soluble and transmembrane forms of TNF-a, prevents from binding to its receptor

70
Q

adalimumab pharmacokinetics

A

sub-q, every other week

71
Q

adalimumab adverse effects

A

injection site rxn, increased risk of infections (usually in patients taking immunosuppressants, screen for latent TB); lymphomas in kids/adolescents

72
Q

adalimumab therapeutic uses

A

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

73
Q

mech of anti-TNFa agents

A

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.

74
Q

tocilizumab mech

A

humanized Ab, binds to soluble and membrane-bound IL-6 receptors, inhibits IL-6-mediated signaling

75
Q

tocilizumab pharmacokinetics

A

IV administration every 4 weeks, sub-q every other week

76
Q

tocilizumab adverse effects

A

injection site rxn, increased risk of infections, alterations in lipid profile

77
Q

tocilizumab therapeutic use

A

ADULT patients with moderate to severely active RA who had inadequate response to 1 or more TNF antagonists

78
Q

tofacitinib mech

A

JAK inhibitor, prevents cytokine or growth-factor-mediated gene expression, decreases CD16/56+ NK cells, serum IgG, IgM, IgA, CRP and increases B cells

79
Q

JAK mech

A

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

80
Q

tofacitinib pharmacokinetics

A

oral administration, CYP3A4 mediated metabolism, minor contribution from CYP2C19

81
Q

tofacitinib adverse effects

A

increase risk of infections, increase in cholesterol

82
Q

tofacitinib therapeutic use

A

treatment of patients with moderate to severely active RA who had inadequate response to MTX. monotherapy or in combo w/ MTX or other DMARDs

83
Q

pathogenesis of RA

A
  1. DCs phagocytose Ag, present to T cells
  2. activated T cells stimulate B and T cell production
  3. B cells produce plasma cells, form rheumatoid Ab
  4. helper T cells activate MP and CTLs
  5. 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
84
Q

site of action of abatacept

A

blocks co-stimulation of T cells

85
Q

site of action of MTX, leflunomide

A

inhibit proliferation and activity of T and B cells

86
Q

site of action of etanercept, infliximab, adalimumab, golimumab, certolizumab

A

inactivate TNF-a

87
Q

site of action of anakinra

A

blocks activation of IL-1

88
Q

site of action of tocilizumab

A

inactivates IL-6

89
Q

site of action of glucocorticoids

A

inhibit T cell activation and IL-2 production by regulation of gene transcription

90
Q

site of action of glucorticoids and NSAIDs

A

inhibit formation of prostaglandins

91
Q

rituximab

A

Ab vs CD20 antigen on B-lymphocytes

92
Q

definition of OA

A

progressive joint disorder caused by gradual loss of cartilage. results in bony spurs and cysts at joint margins.

93
Q

common OA history

A

gelling after inactivity, pain exacerbated by movement and use, crepitus, joint locking. no fevers, redness of joints, warmth, < 30 mins morning stiffness

94
Q

OA risk factors

A

female, increasing age, genetics, obesity, trauma, race/ethnicity (variable)

95
Q

pathology of OA (early changes)

A

superficial layers of cartilage are destroyed. fibrillation and cracking of cartilage matrix. limited chondrocyte proliferation & new matrix formation

96
Q

appearance of femoral head in patient with more advanced OA?

A

absence of articular cartilage, roughened remaining cartilage. remaining bone is polished (eburnation). subchondral sclerosis develops below.

97
Q

pathology of OA: subchondral cysts?

A

formed by break in cartilage, below areas where cartilage is gone. allows synovial fluid to be forced into subchondral space, forming fibrous walled cyst

98
Q

pathology of OA: osteophyte formation

A

bony outgrowths develop at margins of articular surface in characteristic locations for specific joints; result in increased joint size

99
Q

osteophyte location at hip joint

A

all around joint margin, typically large flat osteophyte on medial surface extending into fovea

100
Q

osteophyte location at distal interphalangeal joints

A

heberden nodes

101
Q

osteophyte location at PIP

A

bouchard nodes

102
Q

OA pathogenesis

A

imbalance in cytokine and growth factor activity, results in matrix loss and degradation

103
Q

secondary causes of OA

A

post-traumatic, other joint/bone disease, calciup deposition diseases, gout, congenital (hemochromatosis), metabolic, neuropathic arthropathy

104
Q

joints affected in OA

A

PIPs, DIPs, wrists, hips, knees, big toes (not MCPs)

105
Q

OA findings on physical exam

A

firm swelling around joints, crepitus, weakness/wasting of muscles acting on joint, tenderness, deformities, heberden’s & bouchard’s nodes, squaring of 1st CMC

106
Q

how to diagnose OA

A

imaging, synovial fluid aspiration w/ non-inflammatory WBC, not usually blood tests

107
Q

OA radiography

A

narrowing of joint space, osteophytes, changes in subchondral bone including cysts, sclerosis, loss of bone volume, shape changes

MSS (28 decks)

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