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RMSK > 01b: Urate Metabolism and Crystal-Induced Arthritis > Flashcards

01b: Urate Metabolism and Crystal-Induced Arthritis Flashcards

1
Q

What is gout?

A

Intense inflammatory arthritis with destructive potential to joints caused by immuno-reactivity to precipitated uric acid crystals in individuals with hyperuricemia.

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2
Q

Cardinal signs/symptoms of acute gout

A
  • Intense articular inflammtion (calor, dolor, rubor, tumor)
  • “Touch-me-not” tenderness
  • Rapid onset of sx
  • Joint predilection: 1st metatarsophalangeal, midfoot, ankle, knee, wrist, elbow, distal interphalangeal
  • Inter-critical resolution of sx
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3
Q

Cardinal signs/symptoms of chronic gout

A

Features/presentation extremely variable

  • Attacks more frequent or continuous sx
  • Tophi
  • Articular damage, destruction, disability
  • Nephropathy/nephrolithiasis
  • Cardiovascular risk (?)
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4
Q

What is podagra?

A

Inflammation of first metatarsophalangeal joint (big toe).

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5
Q

What is olecranon bursitis?

A

Inflammation of the subcutaneous synovial-lined sac of the bursa overlying the olecranon process at the proximal aspect of the ulna; may be 2/2 gout.

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6
Q

What are tophi?

A

Deposit of monosodium urate crystals in people with longstanding high levels of uric acid in the blood; pathognomonic for gout.

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7
Q

Gout epidemiology

A
  • Most common inflammatory arthritis
  • US prevalence = 6.1 million
  • Tophaceaous gout = ~75% of untx chronic gout pts w/ dz > 20yrs
  • Increases w/ age
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8
Q

What are risk factors for incident gout?

A
  • Hyperuricemia (necessary but not sufficient)
  • Obesity
  • HTN
  • Rx: diuretics, cyclosporine (for dry eye dz), tacrolimus (post-xp immunosuppressant), low-dose aspirin
  • Dietary: red meat, shellfish, certain types of fish, beer, liquor (not wine)
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9
Q

What level of hyperuricemia is associated with gout?

A

>9.0 mg/dL (nl 3.5 - 7.2 mg/dL)

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10
Q

Describe urate metabolism.

A
  • Diet and cell breakdown produce purines
  • Purines are converted via xanthine oxidase (2x) to uric acid
  • In other animals, urate oxidase breaks down uric acid to allantoin (soluble and easy to excrete vs. uric acid, which is less soluble and crystalizes in solution when supersaturated)
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11
Q

Describe urate excretion.

A
  • 80-90% via renal excretion
  • 10% via gut
  • If system overloaded –> urate supersaturation and crystallization –> gout
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12
Q

What are the two mechanisms behind urate supersaturation?

A
  • Increased uric acid production
    • 10% of gout patients
    • >1000mg/day
  • Decreased uric acid excretion
    • 90% of gout patients
    • <300mg/day
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13
Q

How do inborn errors of metabolism contribute to increased urate levels?

A
  • Lead to gain of function in de novo synthesis: more IMP being produced (substrate in urate production)
  • Cause loss of function in salvage pathway: Less urate substrates being rerouted
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14
Q

Describe nephronal handling of uric acid

A
  • Uric acid is filtered by the glomerulus
  • Through reabsorption and secretion, 7-12% of uric acid is ultimately excreted from the body
  • **URAT1 **is the transporter responsible for reabsorption and secretion of uric acid
    • Urate reabsorbed in exchange for:
      • lactate
      • nicotinate
      • pyrazinamide
    • Drugs exist which inhibit urate reabsorption
    • Loss of function of URAT1 –> hypouricemia
  • **OAT **and **UAT **bring urate back into blood
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15
Q

Describe the genetics of hyperuricemia

A
  • Mutations in:
    • Hypoxanthine guanine phosphoribosyl transferase (HPRT): role in the generation of purine nucleotides through the purine salvage pathway
    • Phosphirobosyl pyrophosphatase synthetase (PRPSI): involved in the synthesis of nucleotides
      • Early onset gout
      • Lesch-Nyhan syndrome: disorder passed down through families that affects how the body builds and breaks down purines
  • Idiopathic hyperuricemia:
    • Polygenic
    • Polymorphisms in URAT1 and other urate transport proteins
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16
Q

What are the hallmark crystal findings in acute gout synovial fluid?

A
  • Needle-shaped
  • Intracellular (phagocytic cell)
  • Negative birefringence w/ polarized LM
17
Q

How do urate crystals cause inflammation?

A
  • Bind TLRs on macrophages
    • Innate immune recognition of molecular motifs common to pathogens
  • TLRs signal activation of NALP3 inflammasome, which produces cytokines:
    • IL-1
    • TNF
    • IL-18
  • ​Cytokine cascade promotes endothelial priming, neutrophil influx, leukotriene production and bradykinin generation
18
Q

What are the genetics of urate-induced inflammation?

A
  • Chromosomes **1q21 **and 4q25 contain genes involved in inflammation:
    • IL-6 receptor
    • Fc gamma receptor Ia
    • C-reactive protein
    • Longevity genes
19
Q

What are important points in the diagnosis of gout?

A
  • Demonstration of uric acid crystals should be attempted in all patients
  • Asx joints often demonstrate crystals
  • Serum uric acid levels can be low/nl during acute attack
  • Acute gout and septic arthritis can coexist
  • Gout and RA are rarely seen together
20
Q

What are the treatment goals with gout?

A
  • Acute attack:
    • Reduce inflammation
    • Reduce pain
  • Chronic gout
    • Reduce hyperuricemia
    • Reduce frequency/prevent flares
21
Q

What are the treatment options for acute gout?

A
  • Colchicine
  • NSAIDs
  • Intra-articular corticosteroids
  • Systemic corticosteroids/ACTH
  • Analgesics
  • Ice
  • Investigational: systemic anti-IL-1 therapy and other anti-cytokine biologics
22
Q

Colchicine

  1. Efficacy
  2. MOA
  3. Toxicity
A
  1. Best when used in early gout attack (within first 12-24 hrs)
  2. Unknown; likely interferes w/ neutrophil chemotaxis (prevents macrophages/inflammosome from releasing IL-1)
  3. Diarrhea (dose-relationship), myopathy (especially pts w/ renal/hepatic insufficiency, on HMG-coA reductase inhibitors (statins) or cyclosporine), bone marrow suppression
23
Q

NSAIDs: types used and SFx

A
  • Indomethacin (non-selective): risk of GI toxicity
  • **Etoricoxib **(COX-2 inhibitor)
24
Q

Corticosteroids

  1. Indications
  2. Side effects
A
  1. Treatment of choice for acue mono/oligoarticular gout; refractory to NSAIDS/colchicine; C/I to NSAIDs/colchicine
  2. Rebound flares if used w/o NSAIDS/colchicine; multiple problems in pts w/ comorbidities
25
Q

What role does cytokine inhibition play in acute gout?

A
  • Treatment of acute gout (reduced pain)
  • Flare prophylaxi
26
Q

What are the management strategies for chronic gout?

A
  • Reduce/eliminate flares through urate lowering:
    • ↓exogenous purines (via diet)
    • ↓endogenous purines (difficult b/c cannot modify cell breakdown)
    • Facilitate urate handling
  • Prophylax against flares
  • Urate therapy recommended if:
    • 2+ significant attacks/year
    • Tophi
    • Radiographic damage
27
Q

Allopurinol

  1. ​Indication
  2. MOA
  3. Pharma
  4. Toxicity
A
  1. Chronic gout; over-produces, under-excretors and those with urate nephrolithiasis
  2. Xanthine oxidase inhibitor
  3. Renal-adjusting necessary
  4. Allopurinol hypersensitivity (rash, fever, eosinophilia, renal and hepatic dysfunction; 20% mortality rate), C/I w/ azathioprine, mercaptopurine; caution w/ warfarin
28
Q

Rasburicase

  1. Indication
  2. MOA
  3. Toxicity
A
  1. Chronic gout, tumor lysis syndrome prevention
  2. Uricase replacement
  3. Immunogenicity w/ repeated infusions
29
Q

What concomitant management is suggested with chronic gout?

A
  • Diet: ↓red meat, shellfish, fatty fish, alcohol, sugar, sweetened soda; ↑water, low-fat dairy
  • Weight loss
  • Treat other RFs: HTN, psoriasis, chronic dehydration
  • Consider alternates to diuretics
30
Q

How is acute gout prophylaxed against during urate lowering therapy?

A
  • Prophylax: **colchicine **> NSAID for first several mos of urate therapy
  • Do not start therapy during acute attack
  • Do not discontinue therapy if attack occurs (more likely when rapid uric acid shifts)
  • If prone to attack, start low and slowly titrate up therapy
  • Typical timeframes:
    • 4-12mos to normalize serum urate levels
    • 12-24mos for noticeable tophi reduction
31
Q

What does this image show?

A

Chondrocalcinosis: accumulation of calcium pyrophosphate dihydrate (CPPD) crystals in joint cartilage

32
Q

What is calcium pyrophosphate deposition disease?

A

Type of arthritis that causes sudden attacks of joint pain and swelling, caused by a build-up of calcium pyrophosphate crystals in the joints.

NB: Also called chondrocalcinosis or pseudogout

33
Q

What are the multiple presentations of CPPD?

A
  • Asymptomatic chondrocalcinosis: in isolation or conjunction with osteoarthritis
  • Acute CPPD inflammatory arthritis
  • Chronic CPPD inflammatory arthritis: mono, oligo or polyarticular; rarely can resemble RA
34
Q

What is the epidemiology of CPPD?

A
  • F>M
  • Primarily seen in elderly
  • Primarily seen in knee
35
Q

What associated conditions are seen in CPPD?

A
  • Prior joint damage/injury
  • Hereditary forms
  • Associated w/ specific disorders:
    • Hemochromatosis
    • Hyperparathyroidism
    • Hypophosphatasia
    • Hypomagnesemia
  • Age
36
Q

What is the pathophysiologic mechanism behind CPPD?

A
  • Gain-of-function mutation in ANKH gene –> ↑extracellular inorganic pyrophosphate (ePPi)
  • Higher ePPi –> CPPD deposition in chondrocytes –> immunogenic response
37
Q

True or false: management strategies for CPPD are the same as those for gout

A

True; both dz converge on same ending pathophysiology (crystals bind TLRs which activate inflammasome)

38
Q

What is hydroxyapatite deposition disease?

A
  • Intra-articular and periarticular hydroxyapatite deposition
  • Also known as Milwaukee shoulder
  • Predisposing factors: age, CPPD, dialysis, trauma

RMSK (16 decks)

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