What is the best course of action for a middle-aged to elderly patient with hypertension, type 2 diabetes, and gout who develops vasculitis secondary to treatment with enalapril, dapagliflozin, and febuxostat?

Management of Vasculitis Secondary to Enalapril, Dapagliflozin, and Febuxostat

Immediately discontinue all three suspected medications—enalapril, dapagliflozin, and febuxostat—as withdrawal of the offending drug alone is often sufficient to induce prompt resolution of drug-induced vasculitis without requiring immunosuppressive therapy. 1, 2

Immediate Actions

Discontinue all suspected medications immediately. Drug-induced vasculitis resolves after discontinuing the offending agent in the majority of cases, making withdrawal the cornerstone of management. 1, 2, 3

• Stop enalapril (ACE inhibitor associated with drug-induced vasculitis). 3
• Stop dapagliflozin (SGLT2 inhibitor).
• Stop febuxostat (xanthine oxidase inhibitor associated with drug-induced vasculitis). 3

The interval between drug exposure and vasculitis symptoms is extremely variable (hours to years), and vasculitis can occur after dose increases or rechallenge. 3

Assess Disease Severity

Determine if the vasculitis is life-threatening or organ-threatening versus limited cutaneous involvement, as this dictates whether immunosuppressive therapy is needed beyond drug withdrawal. 4, 2

For Severe/Systemic Vasculitis (Life- or Organ-Threatening):

• Initiate cyclophosphamide plus corticosteroids if there is renal involvement (rapidly rising creatinine, active urine sediment), pulmonary involvement (hemoptysis, infiltrates), or other organ-threatening manifestations. 4
• Consider rituximab plus corticosteroids as an alternative if cyclophosphamide is contraindicated or in patients without the most severe disease. 4
• Add plasmapheresis if the patient requires dialysis or has rapidly increasing serum creatinine. 4
• Add plasmapheresis for diffuse pulmonary hemorrhage. 4

For Limited Cutaneous Vasculitis:

• Drug withdrawal alone is usually sufficient for complete remission in cutaneous drug-induced vasculitis, with excellent prognosis. 2
• Corticosteroids may be considered for symptomatic relief but are often unnecessary. 2

Monitor for Resolution

Observe for clinical improvement within days to weeks after drug discontinuation. 1, 2

• Most drug-induced vasculitis cases resolve promptly after withdrawal of the offending agent. 1, 2
• If symptoms persist or worsen despite drug withdrawal, consider that this may represent idiopathic vasculitis rather than drug-induced, requiring more aggressive immunosuppression. 1

Alternative Medication Management

For Hypertension (Replacing Enalapril):

Switch to a calcium channel blocker (amlodipine 2.5-10 mg daily) or thiazide diuretic (chlorthalidone 12.5-25 mg daily) as these are not associated with vasculitis and are effective first-line antihypertensive agents. 4

• Avoid restarting ACE inhibitors or ARBs given the association with drug-induced vasculitis in this patient. 4, 3
• Target blood pressure <130/80 mmHg for patients with diabetes. 4

For Type 2 Diabetes (Replacing Dapagliflozin):

Restart or optimize metformin as first-line therapy if not contraindicated by renal function (eGFR >30 mL/min). 4

• Consider adding a GLP-1 receptor agonist for additional glycemic control and cardiovascular benefit if needed.
• Avoid restarting SGLT2 inhibitors until vasculitis has completely resolved and causality is clarified.

For Gout/Hyperuricemia (Replacing Febuxostat):

Switch to allopurinol once vasculitis has resolved, starting at low dose (≤100 mg daily, lower if CKD present) and titrating to target serum uric acid <6 mg/dL. 4

• Test for HLA-B*5801 allele before starting allopurinol if the patient is of Southeast Asian descent (Han Chinese, Korean, Thai) or African American, as this allele is associated with severe cutaneous adverse reactions. 4
• Provide mandatory gout flare prophylaxis with colchicine (0.5-1 mg daily, dose-adjusted for renal function) or low-dose NSAIDs (if not contraindicated) for at least 6 months when initiating allopurinol. 4, 5
• Do not restart febuxostat given its association with drug-induced vasculitis in this patient and the FDA black box warning for cardiovascular risk. 4, 3

Critical Pitfalls to Avoid

• Never delay drug withdrawal while awaiting confirmatory testing—clinical suspicion alone warrants immediate discontinuation. 1, 2
• Do not rechallenge with the suspected offending drugs, as vasculitis can recur and may be more severe. 3
• Avoid combining ACE inhibitors with ARBs or renin inhibitors, as this is potentially harmful. 4
• Never combine allopurinol with febuxostat, as they have redundant mechanisms and increase toxicity without therapeutic benefit. 5, 6
• Death occurs in 10% of published drug-induced vasculitis cases, predominantly when multiple organ systems are involved, emphasizing the importance of prompt recognition and treatment. 3

Follow-Up Monitoring

• Monitor renal function, urinalysis, and inflammatory markers (CRP, ESR) weekly initially, then monthly until complete resolution. 4
• Assess for recurrence of vasculitis symptoms with each clinical visit.
• If vasculitis does not resolve within 4-6 weeks of drug withdrawal, reconsider the diagnosis and evaluate for idiopathic vasculitis requiring long-term immunosuppression. 1