What is the treatment approach for a patient with the eosinophilic variant of Granulomatosis with Polyangiitis (GPA)?

Treatment of Eosinophilic Variant of GPA

Critical Clarification

The term "eosinophilic variant of GPA" is a misnomer—this describes Eosinophilic Granulomatosis with Polyangiitis (EGPA), which is a distinct disease entity from classic GPA, despite both being ANCA-associated vasculitides. EGPA has unique pathophysiology centered on eosinophilic inflammation and requires different treatment strategies than GPA 1.

Disease Severity Stratification

Treatment must be stratified based on the Five-Factor Score (FFS) and presence of organ-threatening manifestations 1:

Severe EGPA is defined by:

• FFS ≥1 (renal insufficiency with creatinine >1.58 mg/dL, proteinuria >1 g/day, cardiomyopathy, gastrointestinal involvement, or CNS involvement) 1
• Peripheral neuropathy (multiple mononeuropathies) 1
• Alveolar hemorrhage 1
• Mesenteric ischemia, limb digital ischemia, or severe eye disease (central retinal artery/vein occlusion, ischemic optic neuropathy) 1

Non-severe EGPA is defined by FFS=0 and absence of the above organ-threatening manifestations 1.

Remission Induction for Severe EGPA

For severe EGPA, initiate pulsed intravenous methylprednisolone (500-1,000 mg daily for 3 days, maximum 3g total) followed by high-dose oral glucocorticoids (0.75-1 mg/kg/day) plus either cyclophosphamide or rituximab 1.

Cyclophosphamide Regimen

• Administer intravenous cyclophosphamide pulses (0.6 g/m² per pulse) every 2 weeks for 1 month, then every 4 weeks 1
• Continue until remission is achieved, typically within 6 months; extend up to 9-12 months for slow responders 1
• The REOVAS trial demonstrated 12 cyclophosphamide pulses over 5 months achieved superior relapse-free survival compared to 6 pulses 1

Rituximab as Alternative

• Administer rituximab 1-gram pulses 2 weeks apart 1, 2
• The REOVAS trial showed rituximab is non-inferior to cyclophosphamide for inducing remission (BVAS=0 on prednisone ≤7.5 mg/day) in patients with FFS ≥1 1
• Rituximab 375 mg/m² once weekly for 4 weeks is also effective based on FDA-approved dosing for ANCA-associated vasculitis 2

Glucocorticoid Tapering

• After pulse therapy, taper oral prednisone to 7.5-10 mg/day by 3 months and to 5 mg/day by weeks 19-52 3

Remission Induction for Non-Severe EGPA

For non-severe EGPA, glucocorticoids combined with mepolizumab is the preferred approach 1, 4.

• Initiate oral glucocorticoids (0.75-1 mg/kg/day) 1
• Add mepolizumab 300 mg subcutaneously every 4 weeks 1
• Alternative options include glucocorticoids with methotrexate, azathioprine, or mycophenolate mofetil 4
• Glucocorticoids alone can be used if biologics/immunosuppressants are contraindicated 1

Maintenance Therapy

For severe EGPA in remission, use glucocorticoids combined with rituximab, methotrexate, azathioprine, or mepolizumab 4.

• Rituximab 500 mg IV every 6 months reduces relapse rates compared to unscheduled treatment 3
• Taper glucocorticoids to the minimum effective dose (ideally ≤7.5 mg/day prednisone) 1

For non-severe EGPA in remission, continue the original targeted therapy or immunosuppressant while tapering glucocorticoids 4.

• Mepolizumab is particularly effective for maintaining remission in patients requiring prednisone ≥7.5 mg/day for respiratory manifestations 1

Management of Refractory Disease

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

Before declaring refractoriness, exclude:

• Alternative diagnoses (infections, malignancies) 1
• Inadequate treatment dosing or patient non-compliance 1
• Irreversible damage versus active disease 1

Refractory Systemic Manifestations

• Switch to rituximab if cyclophosphamide fails 1
• Switch to cyclophosphamide if rituximab fails 1
• Consider plasma exchange or intravenous immunoglobulin for severe cases 1

Refractory Respiratory Manifestations

• Add mepolizumab 300 mg every 4 weeks to optimized glucocorticoids and inhaled therapy 1
• Lower dose mepolizumab (100 mg every 4 weeks) shows comparable efficacy in cohort studies, particularly for respiratory control 1
• Consider functional endoscopic sinus surgery for refractory ENT disease 1

Management of Relapsing Disease

For severe systemic relapses, use glucocorticoids combined with rituximab or cyclophosphamide 4.

For non-severe relapses, distinguish between systemic and respiratory relapses 1, 4:

Respiratory Relapses

• Optimize topical therapies (bronchodilators, inhaled corticosteroids) 1
• Increase oral glucocorticoids with short courses of high-dose therapy (0.5-1 mg/kg/day for 5-7 days without tapering) 1
• Add mepolizumab if inadequate response 1

Minor Systemic Relapses

• Optimize glucocorticoid dosing 1
• Add mepolizumab in addition to glucocorticoids 1

Definition of Remission

Remission is defined as BVAS=0 with prednisone ≤7.5 mg/day, including control of asthma and ENT manifestations 1.

• A more stringent definition using prednisone ≤4 mg/day may be adopted with availability of IL-5 biologics 1
• Steroid-free remission should be the ultimate goal to minimize glucocorticoid toxicity 1

Critical Monitoring

Monitor for:

• Cardiac involvement (most common cause of death in EGPA): obtain troponin, BNP, and echocardiography 1, 5
• Peripheral neuropathy: perform EMG-ENG; consider sural nerve biopsy if diagnosis uncertain 1
• Renal involvement: monitor urinalysis, 24-hour proteinuria, serum creatinine 1
• Treatment-related toxicity: complete blood count weekly during induction, infection surveillance 3

Common Pitfalls

• Do not rely solely on ANCA status for treatment decisions—less than 50% of EGPA patients are ANCA-positive, and ANCA status does not guide therapy choice 1, 5
• Do not undertreat peripheral neuropathy—this manifestation requires aggressive immunosuppression despite not being in the original FFS 1
• Do not ignore asthma/ENT manifestations in remission definition—these reflect disease activity and should be controlled, not dismissed as non-vasculitic 1
• Do not use mepolizumab monotherapy for organ-threatening disease—the MIRRA trial specifically excluded life- or organ-threatening manifestations 1