What is the management of exfoliative erythroderma (EE) induced by Febuxostat (febuxostat) in an adult patient with a history of gout, potential renal impairment, and cardiovascular disease?

Management of Febuxostat-Induced Exfoliative Erythroderma

Immediately discontinue febuxostat and do not rechallenge, as this is a potentially life-threatening drug reaction requiring urgent intervention. 1, 2, 3

Immediate Management Steps

Discontinuation and Hospitalization

• Stop febuxostat immediately upon recognition of exfoliative erythroderma (erythroderma). 1, 3
• Hospitalize the patient for initial evaluation and treatment, as erythroderma is a medical emergency requiring intensive monitoring and supportive care. 3, 4
• Monitor for progression to DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms), which has been documented with febuxostat and can include fever, elevated liver enzymes, acute kidney injury, and eosinophilia. 2

Supportive Care Requirements

• Maintain strict temperature control, as patients lose thermoregulatory capacity through widespread skin inflammation. 3
• Replace fluids and electrolytes aggressively due to transepidermal water loss. 3
• Implement infection prevention protocols and treat any secondary infections promptly, as the skin barrier is compromised. 3
• Apply emollients and topical corticosteroids to affected skin areas. 3

Systemic Treatment

• Administer systemic corticosteroids (typically prednisone 0.5-1 mg/kg/day) for severe cases with systemic involvement. 3, 4
• Monitor liver function, renal function, and complete blood count with differential to assess for DRESS syndrome features. 2

Alternative Urate-Lowering Therapy

Transition to Allopurinol (if appropriate)

• Switch to allopurinol as first-line urate-lowering therapy once the skin reaction has completely resolved, starting at ≤100 mg daily and titrating by 100 mg every 2-5 weeks to achieve target serum uric acid <6 mg/dL. 1, 5
• Obtain HLA-B*5801 testing before starting allopurinol if the patient is of Southeast Asian descent (Han Chinese, Korean, Thai) or African American, as these populations have 3-fold increased risk of severe hypersensitivity reactions. 5, 1
• Do not start allopurinol if HLA-B*5801 is positive, as this significantly increases risk of allopurinol hypersensitivity syndrome with mortality rates of 25-30%. 6

Cross-Reactivity Considerations

• The risk of skin reaction with febuxostat in patients with prior allopurinol cutaneous reactions is moderately increased (OR 3.85), suggesting limited but present cross-reactivity. 7
• However, given that this patient has already developed erythroderma to febuxostat, do not attempt allopurinol if there is any history of severe cutaneous reactions to allopurinol, as the consequences of severe cutaneous adverse reactions are potentially fatal. 6, 2

Alternative Options for Refractory Cases

• Consider uricosuric agents (probenecid, lesinurad) if allopurinol is contraindicated, provided the patient does not have moderate-to-severe CKD (stage >3) or history of renal calculi. 5
• For patients who cannot tolerate any oral urate-lowering therapy and have severe tophaceous gout, consider pegloticase (biologic uricase), though this requires specialist referral. 5

Mandatory Prophylaxis When Restarting Urate-Lowering Therapy

• Provide anti-inflammatory prophylaxis with colchicine 0.5-0.6 mg once or twice daily (dose-adjusted for renal function) for at least 3-6 months when initiating any new urate-lowering therapy. 1, 8
• Alternative prophylaxis includes low-dose NSAIDs or prednisone/prednisolone if colchicine is contraindicated. 5, 1
• Continue prophylaxis for at least 6 months after initiating therapy, or for 3 months after achieving target serum uric acid <6 mg/dL. 1

Long-Term Monitoring and Goals

• Target serum uric acid <6 mg/dL for all gout patients; consider <5 mg/dL if tophi are present until complete crystal dissolution occurs. 1, 8
• Monitor serum uric acid every 2-5 weeks during dose titration of the new urate-lowering agent, then every 6 months once target is achieved. 1
• Assess medication adherence before making dose adjustments. 6

Critical Pitfalls to Avoid

• Never rechallenge with febuxostat after exfoliative erythroderma, as this can result in more severe and potentially fatal reactions. 2, 3
• Do not delay hospitalization when erythroderma is suspected, as early intervention significantly reduces mortality and morbidity. 3, 4
• Do not start allopurinol during the acute phase of the skin reaction; wait for complete resolution. 1
• Do not initiate any new urate-lowering therapy without concurrent anti-inflammatory prophylaxis, as this dramatically increases the risk of acute gout flares. 1, 8
• In patients with cardiovascular disease and renal impairment, carefully weigh the risks and benefits of all available urate-lowering options through shared decision-making. 5