What is the treatment for hyperuricemia in gout?

Treatment of Hyperuricemia in Gout

All patients with gout and hyperuricemia should be started on xanthine oxidase inhibitor (XOI) therapy—specifically allopurinol as first-line—with a treat-to-target approach aiming for serum urate <6 mg/dL, combined with lifestyle modifications, and this pharmacologic therapy is indicated for any patient with tophi, ≥2 gout attacks per year, CKD stage 2 or worse, or past urolithiasis. 1

Indications for Pharmacologic Urate-Lowering Therapy (ULT)

Initiate pharmacologic ULT in patients with any of the following 1:

• Tophus or tophi detected on clinical exam or imaging
• Frequent gout attacks (≥2 attacks per year)
• CKD stage 2 or worse
• History of urolithiasis

Baseline Assessment Before Treatment

Before initiating therapy, complete the following evaluation 1, 2:

• Screen for secondary causes: Check for medications elevating uric acid (thiazide/loop diuretics, niacin, calcineurin inhibitors, low-dose aspirin) 1
• Evaluate comorbidities: Assess for obesity, hypertension, diabetes, hyperlipidemia, cardiovascular disease 1, 2
• Assess disease burden: Document frequency/severity of acute attacks, examine for tophi, evaluate for chronic synovitis 1, 2
• Screen for uric acid overproduction: Obtain 24-hour urine uric acid in patients with gout onset before age 25 or history of kidney stones 1, 2
• Discontinue non-essential hyperuricemia-inducing medications when feasible (do NOT discontinue low-dose aspirin for cardiovascular prophylaxis) 1

First-Line Pharmacologic Treatment

Xanthine Oxidase Inhibitors (Preferred First-Line)

Allopurinol is the preferred initial agent 1, 2, 3:

• Starting dose: 100 mg daily (lower in moderate-severe CKD) 1, 3
• Titration: Increase by 100 mg weekly until serum urate <6 mg/dL is achieved 3
• Maximum dose: 800 mg daily (can exceed 300 mg even in CKD patients) 1, 3
• Dosing in renal impairment 3:
  • CrCl 10-20 mL/min: 200 mg daily maximum
  • CrCl <10 mL/min: 100 mg daily maximum
  • CrCl <3 mL/min: May need to lengthen dosing interval

Febuxostat is an alternative XOI with similar efficacy when allopurinol is contraindicated or not tolerated 1, 2, 4

Critical caveat: Consider HLA-B*5801 screening before starting allopurinol in high-risk populations (Koreans with CKD stage 3 or worse, all Han Chinese and Thai patients) to prevent severe hypersensitivity reactions 1

Alternative First-Line: Uricosuric Agents

Probenecid is an alternative first-line agent when XOIs are contraindicated or not tolerated, but only if CrCl >50 mL/min 1, 2

Treat-to-Target Strategy

The cornerstone of management is achieving and maintaining specific serum urate targets 1:

• Minimum target: <6 mg/dL for all gout patients 1, 2
• Optimal target: <5 mg/dL for patients with tophi, chronic tophaceous gout, or severe disease burden 1, 2
• Monitoring frequency: Check serum urate every 2-5 weeks during titration, then every 6 months once target achieved 2, 4

If target not achieved with maximum appropriate XOI monotherapy: Add a uricosuric agent (combination therapy with XOI plus uricosuric) 1

Second-Line and Refractory Disease

Pegloticase is reserved for severe, refractory gout 1, 5:

• Indication: Patients who have failed maximum appropriate doses of XOI and uricosuric combination therapy, or have contraindications/intolerance to oral ULT 1, 5
• Dosing: 8 mg IV infusion every 2 weeks over ≥120 minutes 5
• Critical monitoring: Check serum urate before each infusion; consider discontinuing if levels rise above 6 mg/dL, especially with 2 consecutive elevated levels (indicates loss of therapeutic response and increased anaphylaxis risk) 5
• Premedication required: Antihistamines and corticosteroids before each infusion 5
• Setting: Must be administered in healthcare facility equipped to manage anaphylaxis 5

Non-Pharmacologic Measures

Implement the following lifestyle modifications for all gout patients 1, 2:

Dietary modifications 2:

• Limit: Purine-rich meats and seafood
• Avoid: High fructose corn syrup beverages, energy drinks, alcohol (especially beer)
• Encourage: Low-fat or non-fat dairy products
• Complete alcohol abstinence during active gout flares 2

Other measures 2:

• Weight reduction if obese
• Maintain fluid intake sufficient for ≥2 liters daily urinary output 3
• Maintain neutral or slightly alkaline urine 3

Important limitation: Diet and lifestyle measures alone typically provide only 10-18% decrease in serum urate, which is insufficient for most patients with sustained hyperuricemia above 7 mg/dL 2

Long-Term Management

Once serum urate target is achieved 1:

• Continue ULT indefinitely to maintain serum urate <6 mg/dL, even after tophi and symptoms resolve 1
• Continue prophylaxis against acute flares if ongoing symptoms or tophi present 1
• Monitor regularly for ULT side effects and adherence 1
• Do not discontinue oral ULT when starting pegloticase; discontinue before pegloticase initiation 5

Referral to Specialist

Consider rheumatology referral for 1:

• Unclear etiology of hyperuricemia
• Refractory signs or symptoms despite appropriate therapy
• Difficulty reaching target serum urate, particularly with renal impairment after XOI trial
• Multiple or serious adverse events from ULT

Common Pitfalls to Avoid

• Starting allopurinol at high doses: Always start at 100 mg daily (or lower in CKD) and titrate gradually to minimize adverse events 1, 3
• Failing to titrate to adequate doses: Many patients require allopurinol >300 mg daily; doses up to 800 mg are appropriate 1, 3
• Treating asymptomatic hyperuricemia: Do not initiate ULT for elevated uric acid alone without gout manifestations 6, 7
• Poor adherence: Regular monitoring and patient education are essential; non-adherence is a major cause of treatment failure 2, 8
• Neglecting flare prophylaxis: Continue anti-inflammatory prophylaxis when initiating or titrating ULT to prevent acute attacks that lead to medication discontinuation 3
• Relying on diet alone: Dietary measures are insufficient as monotherapy for most patients requiring ULT 2