What are the alternative management options for chronic gout when allopurinol (Zyloprim) fails?

Management of Chronic Gout When Allopurinol Fails

When allopurinol fails to adequately control chronic gout, febuxostat should be used as the next-line therapy, followed by uricosuric agents or pegloticase for refractory cases, with appropriate prophylaxis during therapy transitions to prevent acute flares.

Alternative Urate-Lowering Therapies

Febuxostat

• First alternative after allopurinol failure
  • Start with 40 mg daily, can be increased to 80 mg daily if target serum urate levels (<6 mg/dL) are not achieved after 2 weeks 1
  • More effective than allopurinol in lowering serum urate levels, with 53-62% of patients achieving target levels compared to 21% with allopurinol 2
  • Particularly advantageous in patients with renal impairment as no dose adjustment is required in moderate to severe renal insufficiency 1, 3
  • Can be used up to 120 mg daily (approved outside the USA) for refractory cases 4

Uricosuric Agents

• Consider as second-line alternatives or in combination therapy
  • Probenecid: Effective in patients with normal renal function but contraindicated in patients with urolithiasis 4
  • Benzbromarone: Can be used in patients with mild to moderate renal impairment 4
  • Combination therapy: Adding a uricosuric agent (probenecid, fenofibrate, or losartan) to a xanthine oxidase inhibitor is recommended when monotherapy fails to achieve target serum urate levels 4

Pegloticase

• Reserved for severe, refractory cases
  • Indicated only for patients with severe gout disease burden who have failed or cannot tolerate appropriately dosed oral urate-lowering therapies 4, 1
  • Highly effective with 42% of patients achieving serum urate <6 mg/dL at 6 months 4
  • Associated with higher risk of infusion reactions and flares during initiation 4, 1
  • Should not be combined with other urate-lowering therapies 1

Flare Prophylaxis During Therapy Transition

• Essential when initiating or changing urate-lowering therapy
  • Colchicine: 0.6-1.5 mg daily for 3-6 months after starting new therapy 4, 1
  • Alternative: Low-dose prednisone/prednisolone if colchicine is contraindicated 1
  • Prophylaxis significantly reduces the number and severity of acute gout flares during therapy transitions 4

Target Serum Urate Levels

• Standard target: <6 mg/dL for most patients
• Lower target: <5 mg/dL for patients with tophaceous gout 1
• Achieving and maintaining target levels is associated with:
  • Reduced frequency of acute attacks
  • Resolution of tophi (83% median reduction in tophus area with febuxostat 80 mg) 2
  • Improved quality of life

Monitoring and Follow-up

• Monitor serum urate levels 2-4 weeks after initiating or changing therapy
• Assess for adverse effects:
  • Febuxostat: Liver function abnormalities, rash, nausea, and arthralgias 3, 5
  • Uricosuric agents: Urolithiasis, gastrointestinal effects
  • Pegloticase: Infusion reactions, anaphylaxis

Common Pitfalls and Caveats

1. Inadequate dosing: Many patients fail allopurinol therapy due to suboptimal dosing (≤300 mg/day) 6

   • Consider dose optimization of allopurinol (up to 800 mg/day) before switching therapies if no hypersensitivity exists

2. Renal impairment considerations:

   • Febuxostat is preferred over allopurinol in patients with renal impairment 1, 3
   • Probenecid is ineffective in patients with significant renal impairment 4

3. Cardiovascular risk:

   • Monitor for cardiovascular events with febuxostat as some studies showed increased thromboembolic events 5

4. Compliance issues:

   • Educate patients about the importance of continuous therapy even during symptom-free periods
   • Emphasize that urate-lowering therapy is typically lifelong

5. Acute flares during therapy initiation:

   • Always use prophylaxis when starting or changing urate-lowering therapy
   • Do not discontinue urate-lowering therapy during acute flares 1

By following this algorithmic approach to managing chronic gout when allopurinol fails, clinicians can effectively control hyperuricemia, reduce the frequency of acute attacks, resolve tophi, and improve patients' quality of life.