What medications are recommended for a patient with tophi gout, including urate-lowering therapy (ULT) options such as allopurinol or febuxostat, and what are the typical dosing regimens?

Medications for Tophaceous Gout

For patients with tophi, initiate urate-lowering therapy (ULT) immediately with allopurinol as first-line, starting at 100 mg daily and titrating upward every 2-4 weeks until serum urate is maintained below 6 mg/dL (or below 5 mg/dL until tophi resolve), with mandatory anti-inflammatory prophylaxis for at least 6 months. 1, 2

Strong Indication for Treatment

The presence of subcutaneous tophi is a strong indication to initiate ULT according to the American College of Rheumatology, not a conditional one—this means treatment should be started without hesitation. 1 Tophi represent severe gout with tissue crystal deposition that requires aggressive urate lowering to achieve dissolution. 3

First-Line Medication: Allopurinol

Starting Dose and Titration

• Start allopurinol at 100 mg daily (or 50 mg daily if CKD stage ≥4). 1, 2
• Increase by 100 mg increments every 2-4 weeks until target serum urate is achieved. 1
• Most patients require 400-600 mg daily for moderately severe tophaceous gout, though the maximum FDA-approved dose is 800 mg daily. 2
• The commonly prescribed 300 mg dose is often insufficient—this is a critical pitfall to avoid. 2

Target Serum Urate Levels

• Maintain serum urate <6 mg/dL lifelong for all gout patients. 3, 1
• For patients with tophi, target <5 mg/dL until complete crystal dissolution, then relax to <6 mg/dL. 4, 1
• Achieving lower serum urate levels leads to faster tophi reduction. 5
• Monitor serum urate every 2-5 weeks during titration, then every 6 months once target is achieved. 3, 1

Renal Dosing Considerations

• With creatinine clearance 10-20 mL/min: maximum 200 mg daily. 2
• With creatinine clearance <10 mL/min: maximum 100 mg daily. 2
• Recent evidence from the STOP Gout Trial demonstrates that allopurinol is similarly efficacious and well-tolerated in CKD stage 3 when used in a treat-to-target regimen, with actually lower incidence of gout flares compared to febuxostat. 6

Second-Line Medication: Febuxostat

When to Use Febuxostat

• Allopurinol hypersensitivity or contraindication (particularly in patients with HLA-B*5801 haplotype). 4
• Failure to achieve target serum urate despite appropriate allopurinol dose titration. 1
• Moderate-to-severe CKD where febuxostat may be preferred due to no required dose adjustment. 4

Dosing Regimen

• Start at 40 mg daily with titration to 80 mg daily after 2-4 weeks if serum urate remains ≥6 mg/dL. 4, 7
• The 80 mg dose achieves target serum urate <6 mg/dL in 67% of patients versus 42% with allopurinol 300 mg. 4
• Maximum dose is 80 mg daily (FDA-approved), though 120 mg was studied in trials. 4
• No dose adjustment required regardless of CKD stage, making it advantageous in renal impairment. 4

Critical Cardiovascular Warning

• Febuxostat carries an FDA black box warning for cardiovascular risk. 4
• The American College of Rheumatology conditionally recommends switching to alternative ULT for patients with history of cardiovascular disease or new cardiovascular events. 4
• Shared decision-making is essential when considering febuxostat in patients at high cardiovascular risk. 4

Third-Line Medication: Pegloticase

Indication

• Chronic refractory tophaceous gout unresponsive to conventional therapy (allopurinol and febuxostat). 7
• Pegloticase is a PEGylated uric acid-specific enzyme administered as 8 mg IV infusion every 2 weeks. 7

Critical Safety Requirements

• Must be administered in healthcare settings prepared to manage anaphylaxis. 7
• Pre-medicate with antihistamines and corticosteroids before each infusion. 7
• Discontinue all oral ULT before starting pegloticase. 7
• Monitor serum uric acid before each infusion—consider discontinuing if levels rise above 6 mg/dL, particularly with 2 consecutive elevated levels. 7
• Screen for G6PD deficiency before initiation due to hemolysis risk. 7

Mandatory Anti-Inflammatory Prophylaxis

This is non-negotiable when initiating any ULT:

• Colchicine 0.5-1 mg daily (dose-adjusted for renal function), OR 1
• Low-dose NSAIDs (if not contraindicated by renal function or cardiovascular disease), OR 1
• Prednisone/prednisolone if other options contraindicated. 1
• Continue prophylaxis for at least 6 months after ULT initiation. 1, 7
• Prophylaxis prevents the paradoxical increase in gout flares that occurs when urate lowering mobilizes tissue crystal deposits. 1

Critical Management Principles

Never Stop ULT Once Started

• The American College of Rheumatology strongly recommends continuing ULT indefinitely, even after achieving target serum urate levels. 3
• When ULT is discontinued after achieving remission, only 13% of patients remained flare-free during 5-year follow-up. 3
• Do not stop ULT during acute gout flares—continue current dose and treat the flare separately. 1

Timing of ULT Initiation

• The American College of Rheumatology conditionally recommends starting ULT during an acute flare rather than waiting for resolution, as this does not worsen outcomes and prevents treatment delays. 1
• If already on ULT when a flare occurs, continue without interruption. 1

Common Pitfalls to Avoid

• Do not use allopurinol 300 mg as a fixed dose without checking serum urate and titrating upward. 4, 2
• Do not combine allopurinol and febuxostat—they have redundant mechanisms and increase toxicity risk without benefit. 4
• Do not assume dialysis controls uric acid adequately—pharmacologic ULT remains necessary. 3
• Do not use uricosuric agents in patients with renal calculi or moderate-to-severe CKD. 4

HLA-B*5801 Testing

• Conditionally recommended before starting allopurinol in Southeast Asian descent (Han Chinese, Korean, Thai) and African American patients due to higher risk of severe cutaneous adverse reactions with 25-30% mortality. 4, 1

Evidence for Tophi Resolution

• Achieving and maintaining serum urate <6 mg/dL leads to progressive tophi reduction. 5
• Long-term febuxostat maintenance with serum urate <6 mg/dL demonstrates sustained tophi reduction. 5
• Both allopurinol and febuxostat, when used in treat-to-target regimens, achieve similar tophi reduction rates. 8, 5