Gout

Gout results from the deposition of monosodium urate (MSU) crystals in joints and tissues, secondary to hyperuricemia. Hyperuricemia occurs when serum urate levels exceed the physiological saturation point (6.8 mg/dL), leading to urate crystal formation. The pathogenesis involves:

1. Urate Overproduction: Due to increased purine metabolism or reduced degradation. Conditions like myeloproliferative disorders, psoriasis, or increased dietary purine intake contribute.
2. Decreased Renal Excretion: The kidneys excrete two-thirds of uric acid, with the rest eliminated via the gastrointestinal tract. Factors impairing excretion include chronic kidney disease, diuretics (thiazides, loop diuretics), cyclosporine, and lead nephropathy.
3. Enzyme Defects: Mutations in PRPP synthetase (overactivity) or HGPRT deficiency (as seen in Lesch-Nyhan syndrome) enhance purine production or reduce recycling, increasing urate levels.

Inflammatory response begins when MSU crystals activate NLRP3 inflammasomes in resident macrophages, leading to caspase-1 activation and IL-1β production. Subsequent cytokine cascade recruits neutrophils, promoting a robust inflammatory response.

Clinical Presentation

1. Acute Gout Attack
   • Typically presents as a sudden onset of severe joint pain, erythema, swelling, and warmth, often at night.
   • Podagra (1st MTP joint) is the classic presentation, but other commonly affected joints include the ankles, knees, wrists, and elbows.
   • Differential diagnoses include septic arthritis, cellulitis, pseudogout, and other forms of crystal arthropathies (e.g., calcium pyrophosphate deposition disease).

1. Intercritical Gout
   • Asymptomatic periods between attacks. Urate deposition continues in tissues even during this phase.
   • Without ULT, attacks become more frequent and involve more joints over time.
2. Chronic Tophaceous Gout
   • Chronic phase with persistent low-grade inflammation and formation of tophi in joints, bursae, tendons, or cartilage.
   • Tophi are palpable deposits of urate that may ulcerate and discharge chalky material.
   • Chronic tophaceous gout may lead to deformity, joint destruction, and reduced mobility.

Diagnosis

• Clinical Examination
  • Red, swollen, and painful joints are typical.
  • Tophi may appear as nodular, subcutaneous lesions.
• Synovial Fluid Analysis
  • Needle-shaped, negatively birefringent MSU crystals are diagnostic.
  • Synovial fluid may appear cloudy with elevated leukocyte count (5,000 to 80,000 cells/μL, predominantly neutrophils).
• Laboratory Tests
  • Serum Uric Acid: Hyperuricemia supports the diagnosis but is not definitive since levels may be normal during an acute attack. Aim for levels <6 mg/dL or <5 mg/dL in tophaceous gout for control.
  • Renal Function Tests: Assess for chronic kidney disease or renal insufficiency.
  • Complete Blood Count and ESR/CRP: Elevated during acute inflammation.
• Imaging
  • X-ray: Advanced gout shows punched-out erosions with sclerotic margins, often overhanging edges (rat-bite appearance).
  • Dual-Energy CT: Allows non-invasive detection of MSU crystals.
  • Ultrasound: Double-contour sign (urate deposition on the cartilage) and tophi detection.

Management

1. Acute Gout Attack Management

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
  • First-line agents. Common choices include:
    • Indomethacin: 50 mg TID for 2-3 days, then tapering to 25 mg BID for another 5-7 days.
    • Naproxen: 750 mg initially, followed by 250 mg every 8 hours.
    • Ibuprofen: 800 mg TID, dose adjustment based on response and patient tolerance.
  • Avoid in patients with peptic ulcer disease or renal insufficiency.
• Colchicine
  • Effective within the first 36 hours of symptom onset.
  • Dosage: 1.2 mg initially, followed by 0.6 mg one hour later. Maintenance dose of 0.6 mg once or twice daily for prophylaxis.
  • Caution in renal or hepatic impairment; dose adjustment required.
• Corticosteroids
  • Systemic corticosteroids for polyarticular gout or when NSAIDs/colchicine are contraindicated.
    • Prednisone: 30-60 mg daily for 5-10 days, then taper.
    • Intra-articular injection: Triamcinolone acetonide 40 mg for larger joints or 10-20 mg for smaller joints.
• Interleukin-1 Inhibitors (Refractory Cases)
  • Anakinra: 100 mg subcutaneously daily for 3 days.
  • Canakinumab: 150 mg subcutaneously (approved in some countries for resistant cases).

2. Chronic Urate-Lowering Therapy (ULT)

Indications: Recurrent gout attacks (≥2/year), tophi, joint erosions, chronic kidney disease (CKD stage ≥2), or urate nephropathy.

• Xanthine Oxidase Inhibitors
  • Allopurinol: Starting dose 100 mg daily, titrated up every 2-4 weeks until serum uric acid <6 mg/dL.
    • Maximum dose can reach 800 mg/day. Monitor for hypersensitivity, especially in patients with HLA-B*5801 (more common in Han Chinese, Thai, and Korean populations).
  • Febuxostat: Alternative to allopurinol, starting at 40 mg daily, increasing to 80 mg if serum urate remains >6 mg/dL.
    • Contraindicated in patients with a history of cardiovascular disease (FDA warning).
• Uricosuric Agents
  • Probenecid: Enhances renal excretion of uric acid. Dose: 250 mg BID, increasing by 500 mg every 4 weeks, up to a maximum of 2 g/day.
    • Avoid in patients with a history of uric acid nephrolithiasis or overproduction of urate.
• Pegloticase
  • Recombinant uricase enzyme for treatment-refractory gout.
  • Dosage: 8 mg IV every 2 weeks. Monitor for anaphylaxis and infusion reactions.

3. Lifestyle and Dietary Management

• Dietary Recommendations
  • Limit purine-rich foods (red meat, seafood), alcohol (especially beer), and fructose-rich beverages.
  • Encourage low-fat dairy products, cherries, and coffee intake, which may lower uric acid levels.
  • Hydration: Maintain adequate fluid intake (2-3 liters/day) to prevent urate nephrolithiasis.
• Weight Management
  • Gradual weight loss can help lower serum uric acid levels and reduce the risk of gout attacks.

4. Monitoring

• Regularly assess serum uric acid levels every 3-6 months, aiming for <6 mg/dL.
• Monitor renal function and signs of ULT-related adverse effects.
• Evaluate for changes in the size and number of tophi with ULT.

Complications

• Chronic Kidney Disease (CKD) and Urolithiasis: Associated with longstanding hyperuricemia.
• Cardiovascular Disease: Hyperuricemia is an independent risk factor for hypertension and other cardiovascular events.
• Joint Deformities: Result from chronic inflammation and tophi deposition.