How do you treat a patient with hyperuricemia?

Treatment of Hyperuricemia

Do Not Treat Asymptomatic Hyperuricemia

For patients with asymptomatic hyperuricemia (serum uric acid >6.8 mg/dL without gout symptoms, tophi, or urolithiasis), do not initiate urate-lowering therapy. 1

• The American College of Rheumatology conditionally recommends against pharmacologic urate-lowering therapy in asymptomatic hyperuricemia, even in patients with comorbid chronic kidney disease, cardiovascular disease, or hypertension 1
• The number needed to treat is 24 patients for 3 years to prevent a single incident gout flare, and only 20% of patients with serum urate >9 mg/dL develop gout within 5 years 1
• This recommendation applies even when monosodium urate crystal deposition is detected on imaging (ultrasound or dual-energy CT) 1

When to Initiate Urate-Lowering Therapy

Strong Indications (Initiate Treatment)

Start urate-lowering therapy immediately for patients with:

• One or more subcutaneous tophi 1
• Radiographic damage attributable to gout 1
• Frequent gout flares (≥2 per year) 1

Conditional Indications (Consider Treatment)

Consider initiating therapy for:

• Patients with >1 prior gout flare but infrequent attacks (<2 per year) 1
• First gout flare patients with chronic kidney disease stage ≥3, serum urate >9 mg/dL, or urolithiasis 1

Do Not Treat (First Flare Without Risk Factors)

Do not initiate therapy for patients experiencing their first gout flare without the above risk factors 1

First-Line Treatment: Allopurinol Protocol

Initial Dosing Strategy

Start allopurinol at low doses and titrate gradually:

• Normal renal function: Start 100 mg daily 1, 2, 3
• CKD stage 3 (eGFR 30-59 mL/min): Start 50-100 mg daily 2
• CKD stage 4 (eGFR 15-29 mL/min): Start 50 mg daily 2, 3
• CKD stage 5 (eGFR <15 mL/min): Start 50 mg daily or less 4

Dose Titration

Increase allopurinol by 100 mg every 2-5 weeks until target serum uric acid is achieved 1, 2, 3

• Maximum FDA-approved dose is 800 mg/day 1
• Despite traditional concerns, doses above 300 mg/day can be used safely in renal impairment with proper monitoring 2
• For creatinine clearance 10-20 mL/min: maximum 200 mg daily 4
• For creatinine clearance <10 mL/min: maximum 100 mg daily 4

Target Serum Uric Acid Levels

Achieve and maintain serum uric acid <6 mg/dL for all patients with gout 2, 3, 4

• For severe tophaceous gout, chronic arthropathy, or frequent attacks: Target <5 mg/dL to accelerate crystal dissolution 3
• Monitor serum uric acid every 2-5 weeks during titration 3
• After achieving target, monitor every 6 months 3

Mandatory Flare Prophylaxis

Provide flare prophylaxis with low-dose colchicine or NSAIDs for at least 6 months when initiating urate-lowering therapy 3

• Continue anti-inflammatory therapy until serum uric acid is normalized and patient has been free from acute attacks for several months 4
• Colchicine dose should be reduced in patients with renal impairment 5

Risk Mitigation: HLA-B*5801 Screening

Consider genetic testing for HLA-B*5801 before starting allopurinol in high-risk populations:

• Korean patients with CKD stage ≥3 1, 2
• All Han Chinese patients regardless of renal function 1, 2
• All Thai patients regardless of renal function 1, 2

This screening reduces risk of allopurinol hypersensitivity syndrome 2

Second-Line and Alternative Therapies

Febuxostat

Switch to febuxostat if allopurinol causes intolerance, adverse events, or fails to achieve target despite maximal dose titration 1, 2, 3

• Starting dose: ≤40 mg daily 1
• Can be used without dose adjustment in mild-to-moderate renal impairment 2
• The American College of Rheumatology strongly recommends against pegloticase as first-line therapy 1

Uricosuric Agents

Do not use probenecid or other uricosuric agents as first-line therapy in patients with:

• Creatinine clearance <50 mL/min 2, 5
• History of urolithiasis 2
• Elevated urinary uric acid 2

Consider adding a uricosuric agent (probenecid, fenofibrate, or losartan) to xanthine oxidase inhibitor if monotherapy fails to achieve target 2, 5, 3

Special Populations

Tumor Lysis Syndrome

For patients with preexisting hyperuricemia (≥7.5 mg/dL) at risk for tumor lysis syndrome, rasburicase is preferred over allopurinol 1

• Allopurinol dosing for tumor lysis prevention: 100 mg/m² every 8 hours orally (maximum 800 mg/day) or 200-400 mg/m²/day IV (maximum 600 mg/day) 1
• Start 1-2 days before chemotherapy and continue 3-7 days after 1
• Reduce dose by 50% or more in renal failure 1

Hypertensive Patients

For patients with hypertension and hyperuricemia, consider losartan as the preferred antihypertensive agent due to its uricosuric effects 5

• Loop diuretics can worsen hyperuricemia and should be avoided when possible 5

Drug Interactions

Reduce 6-mercaptopurine and azathioprine doses by 65-75% when used concomitantly with allopurinol 1, 4

• Avoid simvastatin >20 mg daily or pravastatin >40 mg daily with bempedoic acid 1

Common Pitfalls to Avoid

Never Start at Standard Doses

Never start allopurinol at 300 mg in any patient—this increases toxicity risk and early flare rates 2, 3

Continue During Acute Flares

Do not discontinue urate-lowering therapy during acute gout flares 5, 3

• Urate-lowering therapy can be started during an acute attack if effective anti-inflammatory management is instituted 3

Do Not Unnecessarily Restrict Dosing

Do not unnecessarily restrict allopurinol dosing based solely on mild-moderate renal impairment 3

• Doses can be titrated above traditional limits with proper monitoring 2

Ensure Adequate Hydration

Maintain fluid intake sufficient to yield daily urinary output of at least 2 liters 4

• Maintain neutral or slightly alkaline urine 4
• This reduces risk of xanthine crystalluria, though this complication is rare 4