Management of Hyperuricemia in Adults

Non-Pharmacologic Measures

All patients with hyperuricemia should implement lifestyle modifications regardless of whether pharmacologic therapy is initiated. 1

Dietary Modifications

Limit alcohol consumption, particularly beer and spirits, as this represents the most important modifiable risk factor for gout 1
Avoid sugar-sweetened beverages and high-fructose corn syrup to reduce uric acid production 1
Reduce intake of purine-rich foods including organ meats (liver, kidney) and shellfish 1
Encourage consumption of low-fat dairy products and vegetables, which lower gout risk 1

Lifestyle Interventions

Achieve weight reduction in overweight or obese individuals through regular physical activity 1
Discontinue non-essential urate-elevating medications when alternatives exist, particularly thiazide and loop diuretics 2, 1
Screen for secondary causes including chronic kidney disease, metabolic syndrome, and medication-induced hyperuricemia 1

Criteria for Initiating Urate-Lowering Therapy

Absolute Indications (Initiate Regardless of Serum Urate Level)

Pharmacologic urate-lowering therapy should be started immediately in patients with any of the following: 1

Subcutaneous tophi identified on physical examination or imaging 1
Frequent gout attacks (≥2 per year) 1
Radiographic joint damage attributable to gout 1
Chronic tophaceous gouty arthropathy with persistent joint symptoms 1

Conditional Indications (After First Gout Flare)

Consider initiating therapy in patients experiencing their first gout flare who have: 1

Chronic kidney disease stage ≥3 (eGFR <60 mL/min/1.73 m²) 1
Serum urate >9 mg/dL 1
History of urolithiasis (kidney stones) 1

Asymptomatic Hyperuricemia

Do not initiate urate-lowering therapy for asymptomatic hyperuricemia (elevated serum urate without prior gout flares or tophi), even at levels >9 mg/dL. 1 The American College of Rheumatology conditionally recommends against treatment based on high-certainty evidence showing limited benefit relative to potential risks—the number needed to treat is 24 patients for 3 years to prevent a single gout flare. 1 This recommendation is reinforced by FDA labeling for allopurinol, which explicitly contraindicates use in asymptomatic hyperuricemia. 1

Pharmacologic Urate-Lowering Therapy: Dosing Guidelines

First-Line Agent: Allopurinol

Allopurinol is the preferred first-line agent for all patients, including those with moderate-to-severe chronic kidney disease. 1

Starting Dose

≤100 mg daily in patients with normal renal function 2, 1
50 mg daily in patients with CKD stage 4 or worse 2, 1

Dose Titration Protocol

Increase by 100 mg increments every 2–5 weeks based on serum urate monitoring 2, 1
Continue titration until serum urate <6 mg/dL is achieved 1
Maximum FDA-approved dose is 800 mg daily 2
Doses can be raised above 300 mg daily even with renal impairment, provided adequate patient education and monitoring for drug toxicity (pruritus, rash, elevated hepatic transaminases) 2

Special Populations

Consider HLA-B*5801 testing before initiation in high-risk populations: Koreans with stage 3 or worse CKD, and Han Chinese or Thai patients irrespective of renal function 2

Alternative Xanthine Oxidase Inhibitor: Febuxostat

Febuxostat can be substituted for allopurinol in cases of drug intolerance, adverse events, or failure of upward dose titration. 2

Maximum FDA-approved dose is 80 mg daily (120 mg daily approved internationally for refractory disease) 2
No dose adjustment required in chronic kidney disease, unlike allopurinol 3
Important FDA warning: increased cardiovascular mortality compared to allopurinol in patients with established cardiovascular disease 3
Febuxostat and allopurinol should not be used in combination with each other 2

Uricosuric Agents

Probenecid

First choice among uricosurics for monotherapy 2
Not recommended as first-line monotherapy when creatinine clearance <50 mL/min 2
Contraindicated in patients with history of urolithiasis 2
Measure urinary uric acid before initiation and continue monitoring during therapy 2
Elevated urinary uric acid indicative of uric acid overproduction contraindicates uricosuric therapy 2

Risk Management for Uricosuric Therapy

Instruct patients to increase fluid intake 2
Consider urine alkalinization with potassium citrate and monitor urine pH 2

Alternative Uricosuric Agents

Fenofibrate and losartan have clinically significant uricosuric effects and can be therapeutically useful as components of comprehensive urate-lowering strategy 2

Combination Therapy for Refractory Disease

When serum urate target is not achieved with monotherapy: 2

First step: Attempt upward dose titration of xanthine oxidase inhibitor to maximum appropriate dose 2
Second step: Add a uricosuric agent (probenecid, fenofibrate, or losartan) to the xanthine oxidase inhibitor 2
Alternative: Substitute one xanthine oxidase inhibitor for another if intolerance or adverse events occur 2

Pegloticase (Last-Line Therapy)

Pegloticase is appropriate only for patients with severe gout disease burden and refractoriness to, or intolerance of, appropriately dosed oral urate-lowering therapy. 2

Not recommended as first-line therapy for any case scenario 2
Discontinue all oral urate-lowering agents during pegloticase therapy to avoid masking loss of efficacy and increased risk of infusion reactions 2
Standard dosing: 8 mg every 2 weeks achieved serum urate <6 mg/dL in 42% of patients versus 0% with placebo 2

Treatment Targets

Serum Urate Goals

Target <6 mg/dL for all patients with gout 1
Target <5 mg/dL for severe gout with tophi, chronic arthropathy, or frequent attacks 1
Avoid long-term serum urate <3 mg/dL 1

Flare Prophylaxis During Urate-Lowering Therapy Initiation

Anti-inflammatory prophylaxis is mandatory when initiating or escalating urate-lowering therapy because rapid reduction in serum uric acid destabilizes monosodium urate crystals and triggers acute gout flares. 1, 3

Prophylaxis Protocol

Colchicine 0.5–1 mg daily for at least 6 months 2, 1, 3
Reduce colchicine dose in renal impairment 1
Avoid colchicine with strong P-glycoprotein/CYP3A4 inhibitors 1

Alternative Prophylaxis (if colchicine contraindicated or not tolerated)

Low-dose NSAIDs 1
Low-dose glucocorticoids 1

Monitoring Strategy

During Dose Titration

Check serum urate every 2–5 weeks until target <6 mg/dL is achieved 1
Monitor for drug toxicity including pruritus, rash, and elevated hepatic transaminases 2

After Achieving Target

Monitor serum urate every 6 months 1
Continue urate-lowering therapy indefinitely to maintain serum urate <6 mg/dL 2, 3

During Acute Flares

Do not discontinue urate-lowering therapy during an acute gout flare—continue therapy and add anti-inflammatory treatment 1

Referral to Rheumatology

Consider specialist referral for: 2

Unclear etiology of hyperuricemia 2
Refractory signs or symptoms of gout 2
Difficulty reaching target serum urate, particularly with renal impairment after trial of xanthine oxidase inhibitor 2
Multiple or serious adverse events from pharmacologic urate-lowering therapy 2

Common Pitfalls and Caveats

Overtreatment

Treating asymptomatic hyperuricemia exposes patients to unnecessary medication risks (hypersensitivity reactions, hepatotoxicity, drug interactions) without proven cardiovascular or renal benefit 1

Undertreatment

Starting allopurinol at 300 mg daily without titration is a common error—most patients require doses >300 mg daily to achieve target serum urate <6 mg/dL 1
Stopping prophylaxis before 6 months significantly increases breakthrough flare risk 1
Discontinuing urate-lowering therapy during acute flares leads to treatment failure and poor adherence 1

Drug Interactions

Reduce azathioprine or 6-mercaptopurine by 65–75% when used with allopurinol 1
Monitor for interactions with warfarin, thiazide diuretics, cyclosporine, and ampicillin 1

What are the recommended non‑pharmacologic measures and criteria for initiating urate‑lowering therapy, including dosing guidelines, in an adult with hyperuricemia?

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