Approach to Hyperuricemia
Asymptomatic hyperuricemia (elevated serum urate without gout symptoms or tophi) should NOT be treated with pharmacologic urate-lowering therapy, regardless of the serum urate level. 1, 2
Distinguishing Asymptomatic from Symptomatic Hyperuricemia
The critical first step is determining whether hyperuricemia is truly asymptomatic or represents undiagnosed gout:
- Asymptomatic hyperuricemia = serum urate >6.8 mg/dL with no history of gout flares, no subcutaneous tophi on physical exam or imaging, and no radiographic joint damage from urate deposition 1
- Symptomatic hyperuricemia (gout) = any history of acute gouty arthritis, presence of tophi, or radiographic evidence of urate-related joint damage 1
Key Evaluation Points
- Perform a thorough joint examination for subcutaneous tophi, particularly at the first metatarsophalangeal joints, fingers, elbows, and ears 1
- Consider musculoskeletal ultrasound if there is diagnostic uncertainty, as it can detect subclinical urate deposits 3
- Assess for secondary causes: diuretic use, chronic kidney disease, medications (thiazides, loop diuretics, low-dose aspirin >325 mg/day, cyclosporine), alcohol consumption, and dietary factors 1
- Measure serum creatinine and calculate eGFR to identify chronic kidney disease 1
Management of Asymptomatic Hyperuricemia
Pharmacologic urate-lowering therapy is NOT recommended for asymptomatic hyperuricemia, even when serum urate exceeds 9 mg/dL. 1, 2 The evidence shows:
- Number needed to treat is 24 patients over 3 years to prevent one gout flare 2
- Only 20% of patients with serum urate >9 mg/dL develop gout within 5 years 2
- Potential harms (including severe allopurinol hypersensitivity reactions) outweigh uncertain benefits 2, 4
Non-Pharmacologic Interventions (Strongly Recommended)
Lifestyle modifications are the cornerstone of management for asymptomatic hyperuricemia: 1, 2
- Weight reduction if BMI >25 kg/m² through caloric restriction and regular exercise 1
- Alcohol limitation, especially beer and spirits; limit to ≤1 drink/day for women, ≤2 drinks/day for men 1, 2
- Dietary modifications: 1, 2
- Avoid high-fructose corn syrup and sugar-sweetened beverages
- Limit purine-rich organ meats (liver, kidney, sweetbreads) and shellfish
- Reduce red meat consumption
- Encourage low-fat dairy products and vegetables
- Maintain adequate hydration (≥2 liters daily urine output) 5
Medication Review
- Discontinue non-essential urate-elevating medications when safe alternatives exist: 1, 2
- Thiazide and loop diuretics (if hypertension can be controlled with alternative agents)
- High-dose aspirin (>325 mg/day); low-dose aspirin (≤325 mg/day) for cardiovascular prophylaxis may be continued 2
Comorbidity Management
- Aggressively treat associated conditions that contribute to hyperuricemia and cardiovascular risk: 1
- Hypertension (target <130/80 mmHg; consider losartan which has mild uricosuric effects)
- Hyperlipidemia (consider fenofibrate which lowers urate)
- Hyperglycemia/diabetes
- Obesity
- Smoking cessation
Monitoring Strategy
- Patient education about gout symptoms (sudden-onset severe joint pain, typically affecting the first metatarsophalangeal joint) and when to seek care 2
- No routine serum urate monitoring is required in truly asymptomatic patients 2
- Annual assessment of renal function, blood pressure, and metabolic parameters 2
Management of Symptomatic Hyperuricemia (Gout)
Absolute Indications for Urate-Lowering Therapy
Initiate pharmacologic ULT immediately in patients with: 1, 6
- Any subcutaneous tophi detected on physical exam or imaging (even after a single flare)
- Frequent gout attacks (≥2 flares per year)
- Radiographic joint damage attributable to gout
- Chronic tophaceous gouty arthropathy (persistent joint symptoms from synovitis or articular tophi)
Conditional Indications After First Gout Flare
Consider initiating ULT after the first gout flare if any of the following are present: 1, 6
- Chronic kidney disease stage ≥3 (eGFR <60 mL/min/1.73 m²)
- Serum urate >9 mg/dL
- History of urolithiasis (kidney stones)
- Young age (<40 years)
- Significant comorbidities (hypertension, ischemic heart disease, heart failure)
Pharmacologic Urate-Lowering Therapy Protocol
First-Line Agent: Allopurinol
Allopurinol is the preferred first-line xanthine oxidase inhibitor for all patients, including those with moderate-to-severe CKD. 1, 6
Starting Dose
- Normal renal function (eGFR ≥60 mL/min): 100 mg/day 1, 5
- CKD stage 3 (eGFR 30-59 mL/min): 50-100 mg/day 1, 5
- CKD stage 4 (eGFR 15-29 mL/min): 50 mg/day 1, 5
- CKD stage 5 (eGFR <15 mL/min): 50 mg every other day or 100 mg twice weekly 5
Dose Titration Strategy
- Increase by 100 mg every 2-5 weeks based on serum urate monitoring 1, 6, 5
- Target serum urate <6 mg/dL for all patients (minimum goal) 1, 6
- Target serum urate <5 mg/dL for severe disease (tophi, chronic arthropathy, or frequent attacks) 1, 6
- Maximum FDA-approved dose is 800 mg/day, which can be used even in patients with CKD stages 3-4 with appropriate monitoring 1, 5
- Most patients require >300 mg/day to achieve target serum urate 1
Monitoring During Titration
- Check serum urate every 2-5 weeks during dose escalation until target is achieved 1, 6
- After reaching target, monitor serum urate every 6 months 1, 6
- Monitor for adverse effects: rash, hepatotoxicity, gastrointestinal symptoms 5
Mandatory Flare Prophylaxis
All patients starting or escalating ULT must receive anti-inflammatory prophylaxis for at least 6 months to prevent acute gout flares triggered by rapid urate lowering. 1, 6
First-Line Prophylaxis: Colchicine
- Dose: 0.5-1 mg/day (typically 0.6 mg once or twice daily) 1, 6
- Duration: minimum 6 months, continue longer if tophi persist or flares occur 1, 6
- Dose adjustment in renal impairment: 1
- CKD stage 3: 0.3-0.6 mg/day
- CKD stage 4-5: 0.3 mg/day or every other day
- Avoid concomitant use with strong CYP3A4 inhibitors (clarithromycin, ketoconazole, ritonavir) or P-glycoprotein inhibitors (cyclosporine) due to risk of colchicine toxicity 1
Alternative Prophylaxis Options
If colchicine is contraindicated or not tolerated: 1, 6
- Low-dose NSAIDs (e.g., naproxen 250 mg twice daily, ibuprofen 400 mg twice daily) with gastroprotection
- Low-dose glucocorticoids (e.g., prednisone 5-10 mg/day)
Critical Management Pitfalls
- Never discontinue ULT during an acute gout flare; continue therapy and add anti-inflammatory treatment 6, 2
- Starting allopurinol at high doses precipitates acute flares; always start low and titrate gradually 1, 6
- Stopping prophylaxis before 6 months markedly increases breakthrough flare risk 1, 6
- Failing to titrate allopurinol to target serum urate is the most common cause of treatment failure; most patients need >300 mg/day 1
Alternative Urate-Lowering Agents
When to Consider Alternatives
- Allopurinol failure: inability to achieve target serum urate <6 mg/dL despite 800 mg/day 1
- Allopurinol intolerance: rash, hypersensitivity reaction, or other adverse effects 1
- Allopurinol hypersensitivity syndrome risk: consider HLA-B*5801 screening in high-risk populations (Korean descent with CKD stage ≥3, Han Chinese, Thai descent) 1
Febuxostat
- Starting dose: 40 mg/day, titrate to 80 mg/day if needed 1
- More potent than allopurinol at achieving target serum urate 2
- No dose adjustment required for mild-to-moderate CKD 1
- Cardiovascular safety concern: FDA black box warning regarding increased cardiovascular mortality compared to allopurinol in patients with established cardiovascular disease 4
Combination Therapy: Allopurinol + Uricosuric Agent
Add probenecid to allopurinol if target serum urate not achieved with allopurinol 800 mg/day: 1
- Probenecid dose: 500 mg twice daily, may increase to 1000 mg twice daily 1
- Contraindications: creatinine clearance <50 mL/min, history of urolithiasis, urine uric acid excretion >800 mg/24 hours 1
- Ensure adequate hydration (≥2 liters/day urine output) and consider urine alkalinization with potassium citrate 5
Pegloticase (Last Resort)
Reserved for severe refractory tophaceous gout after failure of appropriately dosed oral ULT: 1, 6
- Indication: extensive tophi, chronic arthropathy, and inability to achieve target serum urate with oral agents 1
- Dose: 8 mg IV every 2 weeks 1
- Requires rheumatology referral for administration and monitoring 1
Acute Gout Flare Management
First-Line Pharmacologic Options
Oral NSAIDs or colchicine are first-line agents for acute gout attacks; NSAIDs are preferred when not contraindicated. 1, 6
NSAIDs (Preferred)
- Indomethacin 50 mg three times daily until flare resolves (typically 5-7 days) 1
- Naproxen 500 mg twice daily 1
- Ibuprofen 800 mg three times daily 1
- Add proton pump inhibitor for gastroprotection 1
- Contraindications: CKD stage ≥4, active peptic ulcer disease, heart failure, anticoagulation 1
Colchicine
- Acute flare dosing: 1.2 mg at onset, followed by 0.6 mg one hour later (FDA-approved regimen) 1, 6
- Low-dose regimen (0.5 mg three times daily) provides adequate efficacy with fewer adverse effects than traditional high-dose regimens 1, 6
- Most effective when started within 24 hours of symptom onset 1
- Dose adjustment in renal impairment as described above 1
Alternative Options
- Intra-articular corticosteroid injection (e.g., triamcinolone 40 mg) after joint aspiration is highly effective for monoarticular flares in accessible joints 1, 6
- Systemic corticosteroids (prednisone 30-40 mg/day for 5-7 days, then taper) when NSAIDs and colchicine are contraindicated 1, 6
Management During Acute Flare
- Continue ULT at current dose; do not stop or adjust during acute flare 6, 2
- Add anti-inflammatory therapy to ongoing ULT 6
- Do not initiate ULT during acute flare unless patient is already on prophylaxis 1
Long-Term Management Strategy
Treatment Duration
ULT should be continued indefinitely to maintain serum urate <6 mg/dL. 1, 6, 2
- After complete resolution of tophi and absence of flares for ≥2-3 years, highly selected patients with consistently low serum urate (<6 mg/dL for ≥5 years) may consider discontinuation under close monitoring 2
- Most patients require lifelong therapy to prevent recurrence 2
Monitoring Schedule
- During titration: serum urate every 2-5 weeks 1, 6
- After achieving target: serum urate every 6 months 1, 6
- Annual assessment: renal function, liver enzymes, complete blood count 5
When to Refer to Rheumatology
Consider specialist referral for: 1
- Unclear etiology of hyperuricemia
- Refractory gout despite appropriate oral ULT
- Difficulty achieving target serum urate, particularly with renal impairment after xanthine oxidase inhibitor trial
- Multiple or serious adverse events from pharmacologic ULT
- Consideration of pegloticase therapy
Special Populations
Chronic Kidney Disease
- Allopurinol remains first-line agent even in CKD stages 3-5 1, 6
- Start at lower doses (50 mg/day for CKD stage ≥4) and titrate gradually 1, 5
- Doses >300 mg/day can be safely used in CKD with appropriate monitoring 1
- Avoid uricosuric agents when creatinine clearance <50 mL/min 1
Cardiovascular Disease
- Continue low-dose aspirin (≤325 mg/day) for cardiovascular prophylaxis despite modest urate-elevating effects 2
- Exercise caution with febuxostat in patients with established cardiovascular disease due to increased mortality signal 4
- Optimize blood pressure control with losartan (mild uricosuric effect) when appropriate 1