No, Cytoplasmic Anti-Neutrophil Antibodies (c-ANCA) Are Not the Same as Anti-Neutrophil Antibodies in Severe Congenital Neutropenia
These are fundamentally different entities: c-ANCA (cytoplasmic anti-neutrophil cytoplasmic antibodies) are autoantibodies associated with ANCA-associated vasculitis, while anti-neutrophil antibodies in severe congenital neutropenia (SCN) refer to surface anti-neutrophil autoantibodies that may occasionally be detected in autoimmune neutropenia, which is a distinct condition from SCN. 1, 2
Understanding the Key Distinctions
c-ANCA in ANCA-Associated Vasculitis
- c-ANCA represents antibodies directed against intracellular neutrophil antigens, specifically proteinase 3 (PR3) or myeloperoxidase (MPO), and are diagnostic markers for small-vessel vasculitis including granulomatosis with polyangiitis and microscopic polyangiitis 1, 2
- These antibodies cause systemic vasculitis with rapidly progressive glomerulonephritis, pulmonary hemorrhage, and multi-organ involvement—not isolated neutropenia 1, 3
- MPO-ANCA positivity predicts rapidly progressive glomerulonephritis with microscopic hematuria, dysmorphic red blood cells, red cell casts, and moderate proteinuria 2
Severe Congenital Neutropenia (SCN)
- SCN is a genetic disorder characterized by maturation arrest of myelopoiesis at the promyelocyte/myelocyte stage, resulting in absolute neutrophil counts <0.5 × 10⁹/L from early infancy 1, 4
- The most common genetic defects are autosomal dominant ELANE mutations (encoding neutrophil elastase) and autosomal recessive HAX1 mutations 4
- Anti-neutrophil antibodies are not part of the pathophysiology of SCN 4
Anti-Neutrophil Antibodies in Autoimmune Neutropenia
- Surface anti-neutrophil autoantibodies (directed against HNA1a, HNA1c, HNA1b, HNA2a, or MHC antigens) are found in autoimmune neutropenia (AIN), which is a completely separate condition from SCN 5
- Patients with detectable anti-neutrophil surface antibodies typically have autoimmune neutropenia with average duration of 27 months and eventual resolution, not congenital neutropenia 5
- Patients with true SCN (ELANE mutations) have undetectable anti-neutrophil antibodies, more severe younger-onset infections, and decreased serum neutrophil elastase activity 5
Critical Diagnostic Pitfall to Avoid
The presence of anti-neutrophil antibodies should prompt evaluation for autoimmune neutropenia rather than SCN. 5 In a study of 38 patients with persistent neutropenia, 30 had detectable anti-neutrophil surface antibodies consistent with autoimmune neutropenia, while only 3 patients without detectable antibodies had ELANE mutations confirming true SCN 5.
Clinical Implications
For SCN Management
- Treatment is daily subcutaneous G-CSF (3-10 mcg/kg/day for congenital neutropenia vs. 1-3 mcg/kg/day for cyclic/idiopathic forms) to maintain neutrophil counts in the normal or low-normal range 1
- Over 90% of SCN patients respond to G-CSF with absolute neutrophil counts >1.0 × 10⁹/L 6
- Major concern is 11% risk of progression to MDS/AML at median age 16.2 years, often associated with acquired CSF3R and RUNX1 mutations 1, 4
- Hematopoietic stem cell transplantation is the only alternative for G-CSF-refractory patients 1, 4
For ANCA-Associated Vasculitis
- Treatment requires aggressive immunosuppression with rituximab or cyclophosphamide plus glucocorticoids, not G-CSF 1
- Plasma exchange is indicated for patients with moderate-high or high risk of end-stage kidney disease 1
The distinction is critical because misdiagnosis leads to inappropriate treatment: SCN requires G-CSF support, while ANCA-associated vasculitis requires immunosuppression, and autoimmune neutropenia may resolve spontaneously or respond to immunomodulation 1, 5.