01b: Urate Metabolism and Crystal-Induced Arthritis Flashcards
What is gout?
Intense inflammatory arthritis with destructive potential to joints caused by immuno-reactivity to precipitated uric acid crystals in individuals with hyperuricemia.
Cardinal signs/symptoms of acute gout
- 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
Cardinal signs/symptoms of chronic gout
Features/presentation extremely variable
- Attacks more frequent or continuous sx
- Tophi
- Articular damage, destruction, disability
- Nephropathy/nephrolithiasis
- Cardiovascular risk (?)
What is podagra?
Inflammation of first metatarsophalangeal joint (big toe).
What is olecranon bursitis?
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.
What are tophi?
Deposit of monosodium urate crystals in people with longstanding high levels of uric acid in the blood; pathognomonic for gout.
Gout epidemiology
- Most common inflammatory arthritis
- US prevalence = 6.1 million
- Tophaceaous gout = ~75% of untx chronic gout pts w/ dz > 20yrs
- Increases w/ age
What are risk factors for incident gout?
- 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)
What level of hyperuricemia is associated with gout?
>9.0 mg/dL (nl 3.5 - 7.2 mg/dL)
Describe urate metabolism.
- 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)
Describe urate excretion.
- 80-90% via renal excretion
- 10% via gut
- If system overloaded –> urate supersaturation and crystallization –> gout
What are the two mechanisms behind urate supersaturation?
- Increased uric acid production
- 10% of gout patients
- >1000mg/day
- Decreased uric acid excretion
- 90% of gout patients
- <300mg/day
How do inborn errors of metabolism contribute to increased urate levels?
- 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
Describe nephronal handling of uric acid
- 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
- Urate reabsorbed in exchange for:
- **OAT **and **UAT **bring urate back into blood
Describe the genetics of hyperuricemia
- 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
What are the hallmark crystal findings in acute gout synovial fluid?
- Needle-shaped
- Intracellular (phagocytic cell)
- Negative birefringence w/ polarized LM
How do urate crystals cause inflammation?
- 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
What are the genetics of urate-induced inflammation?
- Chromosomes **1q21 **and 4q25 contain genes involved in inflammation:
- IL-6 receptor
- Fc gamma receptor Ia
- C-reactive protein
- Longevity genes
What are important points in the diagnosis of gout?
- 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
What are the treatment goals with gout?
- Acute attack:
- Reduce inflammation
- Reduce pain
- Chronic gout
- Reduce hyperuricemia
- Reduce frequency/prevent flares
What are the treatment options for acute gout?
- Colchicine
- NSAIDs
- Intra-articular corticosteroids
- Systemic corticosteroids/ACTH
- Analgesics
- Ice
- Investigational: systemic anti-IL-1 therapy and other anti-cytokine biologics
Colchicine
- Efficacy
- MOA
- Toxicity
- Best when used in early gout attack (within first 12-24 hrs)
- Unknown; likely interferes w/ neutrophil chemotaxis (prevents macrophages/inflammosome from releasing IL-1)
- Diarrhea (dose-relationship), myopathy (especially pts w/ renal/hepatic insufficiency, on HMG-coA reductase inhibitors (statins) or cyclosporine), bone marrow suppression
NSAIDs: types used and SFx
- Indomethacin (non-selective): risk of GI toxicity
- **Etoricoxib **(COX-2 inhibitor)
Corticosteroids
- Indications
- Side effects
- Treatment of choice for acue mono/oligoarticular gout; refractory to NSAIDS/colchicine; C/I to NSAIDs/colchicine
- Rebound flares if used w/o NSAIDS/colchicine; multiple problems in pts w/ comorbidities
What role does cytokine inhibition play in acute gout?
- Treatment of acute gout (reduced pain)
- Flare prophylaxi
What are the management strategies for chronic gout?
- 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
Allopurinol
- Indication
- MOA
- Pharma
- Toxicity
- Chronic gout; over-produces, under-excretors and those with urate nephrolithiasis
- Xanthine oxidase inhibitor
- Renal-adjusting necessary
- Allopurinol hypersensitivity (rash, fever, eosinophilia, renal and hepatic dysfunction; 20% mortality rate), C/I w/ azathioprine, mercaptopurine; caution w/ warfarin
Rasburicase
- Indication
- MOA
- Toxicity
- Chronic gout, tumor lysis syndrome prevention
- Uricase replacement
- Immunogenicity w/ repeated infusions
What concomitant management is suggested with chronic gout?
- 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
How is acute gout prophylaxed against during urate lowering therapy?
- 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
What does this image show?
Chondrocalcinosis: accumulation of calcium pyrophosphate dihydrate (CPPD) crystals in joint cartilage
What is calcium pyrophosphate deposition disease?
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
What are the multiple presentations of CPPD?
- Asymptomatic chondrocalcinosis: in isolation or conjunction with osteoarthritis
- Acute CPPD inflammatory arthritis
- Chronic CPPD inflammatory arthritis: mono, oligo or polyarticular; rarely can resemble RA
What is the epidemiology of CPPD?
- F>M
- Primarily seen in elderly
- Primarily seen in knee
What associated conditions are seen in CPPD?
- Prior joint damage/injury
- Hereditary forms
- Associated w/ specific disorders:
- Hemochromatosis
- Hyperparathyroidism
- Hypophosphatasia
- Hypomagnesemia
- Age
What is the pathophysiologic mechanism behind CPPD?
- Gain-of-function mutation in ANKH gene –> ↑extracellular inorganic pyrophosphate (ePPi)
- Higher ePPi –> CPPD deposition in chondrocytes –> immunogenic response
True or false: management strategies for CPPD are the same as those for gout
True; both dz converge on same ending pathophysiology (crystals bind TLRs which activate inflammasome)
What is hydroxyapatite deposition disease?
- Intra-articular and periarticular hydroxyapatite deposition
- Also known as Milwaukee shoulder
- Predisposing factors: age, CPPD, dialysis, trauma
