Treatment Options for Refractory Gout
For patients with refractory gout, a combination approach using escalated doses of xanthine oxidase inhibitors (XOIs), addition of uricosuric agents, or pegloticase therapy is recommended based on disease severity and prior treatment response.
Definition of Refractory Gout
Refractory gout is characterized by:
- Failure to normalize serum uric acid levels despite maximum appropriate doses of oral urate-lowering therapy (ULT)
- Inadequate control of signs and symptoms with conventional therapy
- Persistent tophi, frequent flares, or chronic gouty arthropathy despite treatment
Treatment Algorithm for Refractory Gout
Step 1: Maximize XOI Therapy
- Titrate allopurinol to maximum appropriate dose, which can exceed 300 mg daily even in patients with chronic kidney disease (CKD) 1
- For patients who cannot tolerate allopurinol, febuxostat can be titrated up to 80 mg daily (FDA-approved maximum in US) 1
- In cases of severe refractory disease, febuxostat may be increased to 120 mg daily in countries where this dose is approved 1
Step 2: Consider XOI Substitution
- If one XOI is not tolerated or ineffective despite dose titration, substitute with another XOI 1
- Febuxostat may be more effective than allopurinol in patients with renal impairment 1, 2
Step 3: Combination Oral Therapy
- Add a uricosuric agent to an XOI when serum urate target has not been achieved with XOI monotherapy 1, 3
- Options include:
- Combination therapy is particularly useful when the serum urate target (<6 mg/dL) has not been met despite maximum XOI dosing 1
Step 4: Pegloticase for Severe Refractory Disease
- Pegloticase is indicated for patients with severe debilitating chronic tophaceous gout and poor quality of life who have failed or cannot tolerate appropriately dosed oral ULT options, including combinations 1, 4
- Administered as 8 mg intravenous infusion every two weeks 4
- Achieves rapid and substantial reduction in serum urate levels 1
- Monitor serum uric acid levels prior to each infusion and consider discontinuing if levels increase above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed 4
- Premedicate with antihistamines and corticosteroids to reduce risk of infusion reactions 4
Important Considerations
Monitoring and Targets
- Target serum urate level should be <6 mg/dL at minimum 1, 3
- For patients with severe gout, a lower target of <5 mg/dL may be appropriate to hasten crystal dissolution 1, 3
- Monitor serum urate levels every 2-4 weeks during dose titration and every 6 months once target is achieved 3
Safety Considerations
- For allopurinol, start at low doses (100 mg daily or 50 mg in CKD stage ≥3) with gradual titration 3
- Consider HLA-B*5801 screening before initiating allopurinol in high-risk populations (Koreans with stage 3 or worse CKD, and all those of Han Chinese and Thai descent) 1, 3
- Pegloticase carries risk of anaphylaxis and infusion reactions, particularly in patients who develop anti-drug antibodies (indicated by rising uric acid levels) 4
Prophylaxis During ULT Initiation
- Provide anti-inflammatory prophylaxis when starting or adjusting ULT to prevent flares 3
- Options include colchicine, NSAIDs, or prednisone/prednisolone 3
- Continue prophylaxis for 3-6 months 3
Pitfalls to Avoid
- Underdosing of allopurinol (limiting to 300 mg daily) is a common reason for treatment failure 1, 3
- Failure to monitor serum urate levels and adjust therapy accordingly 3
- Discontinuing ULT during acute flares can worsen long-term outcomes 5
- Neglecting to provide prophylaxis when initiating or adjusting ULT 3
- Premature discontinuation of pegloticase before resolution of tophi 1
Refractory gout requires aggressive management to prevent long-term joint damage, disability, and decreased quality of life. With appropriate treatment selection and monitoring, even patients with severe refractory disease can achieve significant improvement in symptoms and quality of life.