ANCA Vasculitis is Indeed Pauci-Immune
Yes, ANCA-associated vasculitis is definitively characterized as pauci-immune, meaning there is minimal to absent deposition of immunoglobulins or complement components in affected vessel walls, despite the presence of circulating antineutrophil cytoplasmic antibodies. 1
Pathophysiologic Basis of Pauci-Immune Classification
The term "pauci-immune" (Latin: pauci = few/little) specifically defines the characteristic histopathologic finding in ANCA vasculitis where immune complex deposition is notably absent in tissue specimens. 2, 3
Key Histologic Features
Necrotizing inflammation without immune deposits: The kidney lesion demonstrates pauci-immune focal and segmental necrotizing and crescentic glomerulonephritis (NCGN), with minimal immunofluorescence staining for immunoglobulins or complement. 4
Contrast with immune-complex vasculitis: Unlike other forms of small vessel vasculitis (such as IgA vasculitis or cryoglobulinemic vasculitis), ANCA vasculitis shows little to no immunoglobulin or complement deposition on immunofluorescence microscopy despite active inflammation. 2, 5
Clinical Manifestations Across AAV Subtypes
Granulomatosis with Polyangiitis (GPA)
- Characterized by necrotizing granulomatous inflammation plus vasculitis with pauci-immune glomerulonephritis as a common manifestation. 1
- Predominantly associated with cytoplasmic ANCA (c-ANCA) and anti-proteinase 3 (PR3) antibodies. 1
- Classic triad: destructive sinonasal lesions, pulmonary nodules, and rapidly progressive glomerulonephritis. 1
Microscopic Polyangiitis (MPA)
- Demonstrates vasculitis without granulomatous inflammation, but maintains the pauci-immune pattern on biopsy. 1
- Predominantly associated with perinuclear ANCA (p-ANCA) and anti-myeloperoxidase (MPO) antibodies. 1
- Rapidly progressive pauci-immune glomerulonephritis and alveolar hemorrhage are hallmark features. 1, 4
Eosinophilic Granulomatosis with Polyangiitis (EGPA)
- Shows eosinophilic tissue infiltration plus vasculitis, though only 40% of patients produce detectable ANCA. 1
- Despite lower ANCA positivity, when vasculitis is present, it maintains the pauci-immune pattern. 4
Diagnostic Approach
Laboratory Evaluation
- ANCA testing: High-quality antigen-specific immunoassays for MPO-ANCA and PR3-ANCA are the preferred screening method. 4
- Approximately 90% of patients with small-vessel vasculitis affecting the kidneys have detectable ANCA. 4
Tissue Confirmation
- Kidney biopsy remains the gold standard with diagnostic yield as high as 91.5% in GPA, demonstrating the characteristic pauci-immune pattern with necrotizing inflammation but minimal immune deposits. 4
- Skin biopsy in cutaneous involvement shows dermal small-vessel vasculitis without significant immune complex deposition. 6, 7
Treatment Implications of Pauci-Immune Pathophysiology
Remission Induction for Severe Disease
- Rituximab 375 mg/m² once weekly for 4 weeks is conditionally recommended over cyclophosphamide for remission induction in severe GPA and MPA, achieving 64% complete remission at 6 months. 1, 8
- Alternatively, cyclophosphamide 2 mg/kg daily for 3-6 months can be used, achieving 53% complete remission at 6 months. 8
- High-dose glucocorticoids (1 mg/kg/day prednisone, not exceeding 80 mg/day) with pre-specified tapering are essential adjunctive therapy. 8
Maintenance Therapy
- Rituximab 500 mg IV every 6 months is conditionally recommended for maintenance in severe GPA/MPA. 1
- Mycophenolate mofetil 2000 mg/day in divided doses is recommended for AAV maintenance therapy—subtherapeutic dosing substantially increases relapse risk. 6, 7
- Azathioprine 1.5-2 mg/kg/day for 18-24 months, then decreased to 1 mg/kg/day until 4 years after diagnosis, is an alternative maintenance option. 4
- Glucocorticoids should be continued at 5-7.5 mg/day for 2 years, then slowly reduced by 1 mg every 2 months. 4, 7
Treatment for Non-Severe EGPA
- Mepolizumab is conditionally recommended for non-severe EGPA. 1
Critical Clinical Pitfalls
Do not delay treatment waiting for biopsy confirmation if clinical presentation strongly suggests vasculitis with systemic features—the pauci-immune nature means immunofluorescence may be negative, but clinical urgency demands immediate therapy. 6, 7
Recognize that ANCA negativity does not exclude AAV: Particularly in EGPA, 60% of patients are ANCA-negative, yet still demonstrate pauci-immune vasculitis on biopsy. 1
Monitor for relapse vigilantly: The pauci-immune pattern persists in relapsing disease, and subtherapeutic immunosuppression is a major relapse risk factor requiring aggressive evaluation for systemic involvement. 6, 7