When should hyperuricemia be treated, such as in symptomatic gout, tophi, uric‑acid kidney stones, urate nephropathy, serum uric acid >9 mg/dL, or >6.8 mg/dL with chronic kidney disease, hypertension, diabetes, or cardiovascular disease?

When to Treat Hyperuricemia

Pharmacologic urate-lowering therapy should be initiated in patients with established gout who have tophi, frequent attacks (≥2 per year), chronic kidney disease stage ≥3, past urolithiasis, or serum uric acid >9 mg/dL after their first flare—but asymptomatic hyperuricemia alone, regardless of level, should not be treated. 1, 2

Clear Indications for Urate-Lowering Therapy

Absolute Indications (Treat Regardless of Uric Acid Level)

• Any patient with subcutaneous tophi detected on physical examination or imaging, even after a single gout flare 1, 3, 2
• Frequent gout attacks defined as ≥2 attacks per year 1, 3, 2
• Radiographic damage attributable to gout 1, 2
• Chronic tophaceous gouty arthropathy with chronic joint symptoms from synovitis or articular tophi 1

Conditional Indications After First Gout Flare

The American College of Rheumatology recommends initiating urate-lowering therapy after the first gout attack when any of these high-risk features are present: 3, 2

• Serum uric acid >9 mg/dL 3, 2
• Chronic kidney disease stage ≥3 (eGFR <60 mL/min) 1, 3, 2
• History of urolithiasis (kidney stones) 1, 3, 2
• Young age (<40 years) with significant comorbidities 2
• Significant cardiovascular comorbidities including hypertension, ischemic heart disease, or heart failure 2

Infrequent Attacks (<2 per year)

For patients who have experienced more than one gout attack but with infrequent flares (<2 per year), the American College of Rheumatology conditionally recommends starting urate-lowering therapy, though this is a weaker recommendation than for frequent attacks. 2

When NOT to Treat: Asymptomatic Hyperuricemia

The American College of Rheumatology and European guidelines explicitly state that pharmacologic treatment of asymptomatic hyperuricemia is NOT recommended to prevent gout, renal disease, or cardiovascular events. 2 This applies even when serum uric acid is >9 mg/dL in a patient who has never had gout symptoms. 2

Evidence Against Treating Asymptomatic Hyperuricemia

• High-certainty evidence shows limited benefit relative to potential risks, with a number needed to treat of 24 patients for 3 years to prevent a single gout flare 2
• Among patients with asymptomatic hyperuricemia >9 mg/dL, only 20% developed gout within 5 years 2
• While hyperuricemia is associated with cardiovascular and renal disease in observational studies, current evidence does not support urate-lowering therapy for purely asymptomatic hyperuricemia 2, 4, 5, 6

Management of Asymptomatic Hyperuricemia

Instead of pharmacologic therapy, focus on: 1, 2

• Patient education about gout symptoms and when to seek care 2
• Lifestyle modifications: reducing excess body weight, regular exercise, avoiding excess alcohol and sugar-sweetened beverages, limiting purine-rich organ meats and shellfish 1, 2
• Screening for secondary causes: medications (thiazide/loop diuretics), chronic kidney disease, metabolic syndrome 1, 2
• Eliminating non-essential medications that induce hyperuricemia when possible 1, 2

Treatment Protocol When Therapy is Indicated

First-Line Agent and Dosing

Allopurinol is the preferred first-line agent for all patients, including those with moderate-to-severe chronic kidney disease. 2

• Starting dose: ≤100 mg/day in normal renal function; 50 mg/day in CKD stage 4 or worse 1, 3, 2
• Titration: Increase by 100 mg every 2-5 weeks based on serum urate monitoring 1, 3, 2
• Maximum dose: 800 mg/day (FDA-approved maximum) 2, 7
• Target serum urate: <6 mg/dL for all patients; <5 mg/dL for severe gout with tophi, chronic arthropathy, or frequent attacks 1, 3, 2

Critical: Flare Prophylaxis

Colchicine 0.5-1 mg/day must be given for at least 6 months when initiating or escalating urate-lowering therapy to prevent acute gout flares triggered by rapid uric acid reduction. 1, 2 This is a major cause of treatment failure and patient non-adherence when omitted. 2

• If colchicine is contraindicated or not tolerated, use low-dose NSAIDs or low-dose glucocorticoids as alternatives 1, 2
• Reduce colchicine dose in renal impairment and avoid with strong P-glycoprotein/CYP3A4 inhibitors 2

Monitoring Strategy

• During titration: Check serum urate every 2-5 weeks until target achieved 1, 2
• After reaching target: Monitor every 6 months 1, 2
• Continue therapy indefinitely once started, as discontinuation leads to recurrence of hyperuricemia and gout flares 3, 2

Common Pitfalls to Avoid

Critical Errors in Practice

• Not treating tophi: Even a single tophus mandates urate-lowering therapy, regardless of attack frequency 1, 2
• Undertreating with allopurinol: Most patients require doses >300 mg/day to achieve target serum urate <6 mg/dL 2
• Omitting flare prophylaxis: Failing to provide colchicine when starting therapy is a major cause of treatment failure 2
• Stopping therapy prematurely: Discontinuing prophylaxis before 6 months significantly increases breakthrough flare risk 2
• Overtreating asymptomatic hyperuricemia: Do not initiate therapy for elevated uric acid alone without gout symptoms or high-risk features 2
• Stopping urate-lowering therapy during acute flares: Continue therapy and add anti-inflammatory treatment instead 2

Special Considerations in Renal Disease

• Allopurinol can be safely titrated above traditional creatinine clearance-based dose limits with appropriate monitoring 2
• Probenecid is not recommended when creatinine clearance <50 mL/min 1, 2
• Febuxostat can be used without dose adjustment in CKD, but carries FDA warnings about increased cardiovascular mortality in patients with established cardiovascular disease 8

Drug Interactions

• Reduce azathioprine or 6-mercaptopurine by 65-75% when used with allopurinol due to xanthine oxidase inhibition 2, 7
• Monitor for interactions with warfarin, thiazide diuretics, cyclosporine, and ampicillin 2
• Low-dose aspirin (≤325 mg daily) can be continued for cardiovascular prophylaxis despite modest urate-elevating effects 2

When to Refer to a Specialist

Consider rheumatology referral for: 1

• Unclear etiology of hyperuricemia 1
• Refractory signs or symptoms of gout 1
• Difficulty reaching target serum urate, particularly with renal impairment after trial of xanthine oxidase inhibitor 1
• Multiple and/or serious adverse events from pharmacologic urate-lowering therapy 1