What is the treatment for Eosinophilic Granulomatosis with Polyangiitis (EGPA)?

Treatment for Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Treatment for EGPA must be stratified based on disease severity: severe disease (Five-Factor Score ≥1, peripheral neuropathy, alveolar hemorrhage, or organ-threatening manifestations) requires glucocorticoids plus cyclophosphamide or rituximab, while non-severe disease can be treated with glucocorticoids alone or combined with mepolizumab. 1

Disease Severity Classification

Before initiating treatment, determine disease severity using the Five-Factor Score (FFS):

• Severe EGPA: FFS ≥1 OR presence of renal insufficiency, proteinuria, cardiomyopathy, gastrointestinal involvement, central nervous system involvement, peripheral neuropathy, or alveolar hemorrhage 1
• Non-severe EGPA: FFS = 0 and absence of the above organ-threatening manifestations 1

Remission Induction Therapy

Severe EGPA

Initiate high-dose glucocorticoids (0.75-1 mg/kg/day oral prednisone or methylprednisolone 500-1000 mg IV daily for 3 days) PLUS either cyclophosphamide or rituximab. 1

Cyclophosphamide regimen:

• Administer 0.6 g/m² IV pulses every 2 weeks for 1 month, then every 4 weeks thereafter 1
• Continue until remission is achieved, typically within 6 months; may extend to 9-12 months for slow responders 1

Rituximab regimen (preferred alternative):

• Administer 1-gram IV infusions separated by 2 weeks 1
• The REOVAS trial demonstrated comparable efficacy to cyclophosphamide for patients with FFS ≥1, with similar adverse event profiles 1
• Critical advantage: Rituximab showed no difference in response between ANCA-positive and ANCA-negative patients, unlike earlier observational data 1

Non-Severe EGPA

For non-severe disease, glucocorticoids combined with mepolizumab is the preferred first-line approach over traditional immunosuppressants. 1

• Glucocorticoids alone achieve 93% remission rates but result in 35% early relapse within the first year 1
• Mepolizumab 300 mg subcutaneously every 4 weeks plus glucocorticoids is conditionally recommended over methotrexate, azathioprine, or mycophenolate mofetil based on the MIRRA trial 1
• The MIRRA trial demonstrated superior remission rates (defined as BVAS = 0 and prednisolone ≤4 mg/day) in relapsing/refractory patients without organ-threatening manifestations 1

Important caveat: Mepolizumab has NOT been studied in severe EGPA with organ-threatening manifestations and should NOT be used as first-line therapy in this setting 1

Remission Maintenance Therapy

Severe EGPA Maintenance

Use rituximab, mepolizumab, or traditional DMARDs (azathioprine, methotrexate, leflunomide) in combination with low-dose glucocorticoids. 1

Rituximab maintenance (preferred):

• Administer 500 mg IV every 6 months 1, 2
• Scheduled rituximab maintenance reduces relapse rates compared to unscheduled treatment 1
• Particularly effective in patients who achieved remission with rituximab induction 1

Mepolizumab maintenance:

• Continue 300 mg subcutaneously every 4 weeks 1
• Effective for controlling asthma and reducing glucocorticoid exposure 1
• Observational data suggest efficacy for major organ manifestations including neuropathy and cardiomyopathy 1

Non-Severe EGPA Maintenance

Glucocorticoids alone or combined with mepolizumab are recommended. 1

• Taper glucocorticoids to the minimum effective dose (ideally ≤7.5 mg/day prednisone) to reduce toxicity 1
• Mepolizumab is particularly valuable for patients requiring prednisone ≥7.5 mg/day for respiratory manifestations 1

Management of Relapses

Distinguish between systemic relapses (vasculitis recurrence) and respiratory relapses (isolated asthma/ENT exacerbations) as they require different treatment approaches. 1

Severe Systemic Relapses

Use rituximab or cyclophosphamide with glucocorticoids. 1

• Rituximab 375 mg/m² IV once weekly for 4 weeks plus glucocorticoids 2
• If relapse occurs while on rituximab maintenance, switch to cyclophosphamide 3

Non-Severe Systemic and Respiratory Relapses

Increase glucocorticoid dose and/or add mepolizumab. 1

• Optimize inhaled therapies (high-dose inhaled glucocorticoids plus long-acting β2-agonists) 1, 4
• Mepolizumab 300 mg subcutaneously every 4 weeks is recommended for relapsing-refractory disease without organ-threatening manifestations 1

Refractory Disease

Refractory EGPA is defined as unchanged or increased disease activity after 4 weeks of appropriate remission-induction therapy. 1

• For refractory disease without organ-threatening manifestations: add mepolizumab to glucocorticoids 1
• For severe refractory disease: switch from cyclophosphamide to rituximab or vice versa 3
• Do NOT combine rituximab and cyclophosphamide 3

Essential Adjunctive Respiratory Management

All patients with asthma or ENT involvement require optimization of topical/inhaled therapies in collaboration with pulmonologists and otolaryngologists. 1

• High-dose inhaled glucocorticoids plus long-acting β2-agonists for asthma control 1, 4
• Nasal rinses and topical therapies for ENT manifestations 1
• Critical pitfall: Failure to optimize inhaled therapies leads to unnecessary systemic immunosuppression escalation 1

Special Populations

Treatment modifications are required for specific patient groups: 1

• Young patients: Prefer rituximab over cyclophosphamide to preserve fertility 1
• Elderly (>65 years): Reduce cyclophosphamide dose to fixed 500 mg (not 500 mg/m²) and shorten glucocorticoid duration to 9 months 1
• Pregnancy: Use only glucocorticoids, IV immunoglobulins, or azathioprine; discontinue cyclophosphamide, mycophenolate, methotrexate 3-6 months before conception 1
• Mepolizumab is approved for patients ≥6 years old 1

ANCA status should NOT influence treatment decisions despite earlier observational data suggesting differential responses 1

Monitoring Requirements

Disease activity must be assessed using validated clinical tools, not laboratory parameters alone. 1

• Eosinophil count and ANCA titers are unreliable biomarkers for disease activity 1
• Routine monitoring of lung function, cardiovascular status, and neurological complications is essential 1
• Long-term surveillance for treatment-related complications: infections, malignancy, osteoporosis 1

Glucocorticoid Tapering Strategy

Taper glucocorticoids to ≤7.5 mg/day prednisone as the definition of remission. 1

• Glucocorticoid-related toxicity is particularly problematic in EGPA due to high cumulative exposure 1
• Most patients cannot discontinue glucocorticoids entirely due to glucocorticoid-dependent asthma 5
• Mepolizumab is the most effective glucocorticoid-sparing agent, demonstrated in the MIRRA trial 1

Alternative Dosing Consideration

Emerging evidence suggests mepolizumab 100 mg every 4 weeks may be sufficient for some patients with predominantly respiratory manifestations, though 300 mg remains the FDA-approved dose 4, 6. This lower dose achieved comparable clinical efficacy in case series but requires further validation 6.

Rescue Therapy for Refractory Cardiac Involvement

High-dose IV immunoglobulin (2 g/kg every 4 weeks) can be considered for cardiac involvement not responsive to standard immunosuppression, though evidence is limited to case reports 7. This is particularly relevant when conventional therapy fails to improve left ventricular function 7.