What is the best treatment approach for a patient with hyperuricemia (elevated uric acid levels) and a history of gout?

Treatment of Elevated Uric Acid in Patients with Gout

Initiate xanthine oxidase inhibitor therapy with allopurinol as first-line treatment, starting at 100 mg daily (or 50 mg daily if chronic kidney disease stage ≥3), and titrate upward every 2-5 weeks by 100 mg increments until serum uric acid is below 6 mg/dL, while providing mandatory flare prophylaxis with low-dose colchicine or NSAIDs for at least 6 months. 1, 2

When to Initiate Urate-Lowering Therapy

The decision to start treatment depends on disease burden:

• Strongly recommended for patients with subcutaneous tophi, radiographic damage from gout, or frequent flares (≥2 per year) 1
• Conditionally recommended for patients with >1 prior flare but infrequent attacks (<2 per year) 1
• Conditionally recommended against for first gout flare, except when moderate-to-severe CKD (stage ≥3), serum urate >9 mg/dL, or urolithiasis is present 1
• Conditionally recommended against for asymptomatic hyperuricemia, as 24 patients would need treatment for 3 years to prevent a single gout flare 1, 3

Target Serum Uric Acid Levels

• Minimum target: <6 mg/dL for all patients with gout 1, 2, 4
• Lower target: <5 mg/dL for patients with tophi, chronic arthropathy, or frequent attacks to accelerate crystal dissolution 1, 2

First-Line Therapy: Allopurinol Dosing Protocol

Starting Dose

• 100 mg daily for patients with normal renal function 1, 4
• 50 mg daily for patients with CKD stage ≥4 (eGFR <30 mL/min) 1, 5

Dose Titration

• Increase by 100 mg every 2-5 weeks until target serum urate is achieved 1, 2, 4
• Monitor serum urate every 2-5 weeks during titration 1, 2
• Maximum dose: 800 mg daily 4

Critical Dosing Considerations in Renal Impairment

The dose can be raised above 300 mg daily even with renal impairment, provided there is adequate patient education and monitoring for toxicity (rash, pruritus, elevated liver enzymes). 1, 5 This contradicts older, non-evidence-based algorithms that unnecessarily restricted allopurinol dosing based on creatinine clearance. 1

Specific renal dosing limits only apply at severe impairment:

• CrCl 10-20 mL/min: maximum 200 mg daily 5, 4
• CrCl <10 mL/min: maximum 100 mg daily 5, 4

Risk Management: HLA-B*5801 Screening

Consider genetic testing before initiating allopurinol in high-risk populations: 1, 2

• Korean patients with CKD stage ≥3
• All Han Chinese patients (regardless of renal function)
• All Thai patients (regardless of renal function)

This screening reduces risk of allopurinol hypersensitivity syndrome, which carries a 20-25% mortality rate. 1

Mandatory Flare Prophylaxis

All patients starting urate-lowering therapy require prophylaxis for at least 6 months: 2

• First-line options: Low-dose colchicine or low-dose NSAIDs 2
• Continue prophylaxis until serum urate is normalized and patient has been flare-free for several months 4
• Do not discontinue urate-lowering therapy during acute flares—continue treatment while managing the acute attack 3, 2

Second-Line and Combination Therapy

When Allopurinol Fails or Is Not Tolerated

Switch to febuxostat if allopurinol causes intolerance, adverse events, or fails to achieve target despite maximal dose titration: 1, 3, 6, 7

• Febuxostat 40 mg daily initially, increase to 80 mg after 2 weeks if needed 6
• No dose adjustment required in mild-to-moderate renal impairment 5, 6, 7
• More effective than allopurinol 300 mg daily at lowering serum urate 7, 8

Combination Therapy

Add a uricosuric agent to xanthine oxidase inhibitor when monotherapy fails to achieve target: 1

• Probenecid is first-choice uricosuric for combination therapy 1
• Contraindicated if CrCl <50 mL/min or history of urolithiasis 1, 5
• Alternative agents with uricosuric effects: losartan or fenofibrate (off-label use) 1, 5, 3

Refractory Disease

Pegloticase is appropriate for severe gout with tophi and refractoriness to or intolerance of appropriately dosed oral therapy 1

Monitoring Strategy

• During titration: Check serum urate every 2-5 weeks 1, 2
• After achieving target: Monitor every 6 months to assess adherence 1
• Renal function: Check before initiating therapy and periodically thereafter 2

Common Pitfalls to Avoid

• Never start allopurinol at 300 mg in any patient—this increases toxicity risk and early flare rates 1, 5
• Do not unnecessarily restrict allopurinol dosing based solely on mild-moderate renal impairment—doses above 300 mg are safe with monitoring 1, 5
• Never use probenecid as monotherapy in patients with CrCl <50 mL/min or urolithiasis history 1, 5
• Do not stop urate-lowering therapy during acute flares—continue treatment and manage the acute attack separately 3, 2
• Do not treat asymptomatic hyperuricemia without gout symptoms, even with levels >9 mg/dL 1, 3

Acute Flare Management During Urate-Lowering Therapy

Urate-lowering therapy can be started during an acute gout attack if effective anti-inflammatory management is instituted: 1

• First-line acute treatment: NSAIDs, corticosteroids, or low-dose colchicine 2
• Continue anti-inflammatory therapy until serum urate is normalized and patient is flare-free for several months 4

Adjunctive Measures

• Maintain fluid intake sufficient for daily urinary output ≥2 liters 4
• Consider dietary modifications: reduce animal protein, sodium, refined sugars, oxalate-rich foods, and excessive calcium 4
• Patient education on treatment objectives, adherence, and management of comorbidities 1