What is the diagnostic workup and treatment for a patient suspected of having Granulomatosis with Polyangiitis (GPA) with positive Proteinase 3 antibodies (PR3-ANCA)?

Diagnostic Workup and Treatment for Granulomatosis with Polyangiitis (GPA) with Positive PR3-ANCA

For patients with suspected Granulomatosis with Polyangiitis (GPA) who have positive PR3-ANCA antibodies, a comprehensive diagnostic workup followed by prompt initiation of immunosuppressive therapy with rituximab or cyclophosphamide plus glucocorticoids is recommended to reduce mortality and preserve organ function.

Diagnostic Workup

Initial Testing

• Testing for both PR3-ANCA and MPO-ANCA using high-quality antigen-specific assays is essential for all patients with suspected GPA 1
• PR3-ANCA is detected in 84-85% of patients with GPA, while MPO-ANCA is more common in microscopic polyangiitis 1
• A positive PR3-ANCA result strongly supports the diagnosis of GPA when combined with compatible clinical features 1

Tissue Biopsy

• Biopsy of affected tissue is recommended to confirm the diagnosis whenever possible 1
• However, treatment should not be delayed while awaiting biopsy results if clinical presentation and positive PR3-ANCA strongly suggest GPA 1
• Biopsy sites should be chosen based on clinical involvement and may include kidney, lung, skin, or nasal mucosa 1

Imaging Studies

• CT of the chest is more sensitive than conventional radiographs for detecting pulmonary manifestations 1
• MRI is useful for detecting central nervous system lesions, pachymeningitis, retro-orbital lesions, or subglottic inflammation 1
• Sinus CT scan should be performed when upper respiratory tract involvement is suspected 1

Additional Testing

• Complete blood count with differential (to assess for eosinophilia which may suggest EGPA rather than GPA) 1
• Renal function tests and urinalysis (to detect glomerulonephritis) 1
• Pulmonary function tests (to assess lung involvement) 1
• Echocardiography (to evaluate cardiac involvement) 1

Treatment Approach

Remission Induction for Organ-Threatening or Life-Threatening Disease

• Combination therapy with glucocorticoids plus either rituximab or cyclophosphamide is recommended for induction of remission in patients with new-onset or relapsing GPA with organ-threatening or life-threatening disease 1, 2
• Rituximab is preferred over cyclophosphamide for relapsing disease 1, 2
• Rituximab dosing: 375 mg/m² once weekly for 4 weeks 2
• Glucocorticoids: Initially high-dose (typically IV methylprednisolone 1000 mg/day for 1-3 days), followed by oral prednisone (1 mg/kg/day, not exceeding 80 mg/day) with a pre-specified tapering schedule 2

Remission Maintenance

• After achieving remission, maintenance therapy is crucial to prevent relapse 1, 2
• Options include rituximab, azathioprine, or methotrexate 1, 2
• Maintenance therapy should typically be continued for at least 18-24 months 1

Monitoring

• Regular assessment of disease activity using validated tools such as Birmingham Vasculitis Activity Score (BVAS) 1
• Monitoring of PR3-ANCA levels, although the correlation with disease activity is not consistent in all patients 3, 4
• Regular screening for treatment-related complications and cardiovascular comorbidities 1

Special Considerations

PR3-ANCA Monitoring

• PR3-ANCA levels do not consistently correlate with disease activity in all patients 3, 5, 4
• Some PR3-ANCA antibodies may be non-pathogenic, explaining why some patients in remission maintain high PR3-ANCA levels 4
• The epitope of PR3 recognized by PR3-ANCA may influence pathogenicity 5, 4

Relapse Management

• Relapses are more common in PR3-ANCA positive patients compared to MPO-ANCA positive patients 1
• For relapsing disease, rituximab is preferred over cyclophosphamide 1, 2
• Retreatment with rituximab has been effective for disease flares occurring 8-17 months after initial treatment 2

Treatment Complications

• Monitor for infusion-related reactions with rituximab (12% of patients experience at least one reaction, most commonly with the first infusion) 2
• Infections are common (62% of patients on rituximab experienced an infection within 6 months) 2
• Cardiovascular events, hypophosphatemia, and hyperuricemia may occur with rituximab treatment 2

Pitfalls and Caveats

• Do not delay treatment in rapidly deteriorating patients with compatible clinical presentation and positive PR3-ANCA while awaiting biopsy results 1
• A negative ANCA does not exclude a diagnosis of GPA, as a small proportion of patients with disease limited to the respiratory tract may be ANCA negative 1
• Consider testing for anti-GBM antibodies in the context of pulmonary-renal syndrome 1
• Be aware that some inflammatory conditions and infections can cause false-positive ANCA results 1
• Differentiate GPA from eosinophilic granulomatosis with polyangiitis (EGPA), which rarely presents with PR3-ANCA positivity and has a different clinical phenotype 1