What is ANCA?
ANCA (anti-neutrophil cytoplasmic antibodies) are autoantibodies directed against proteins found in the cytoplasmic granules of neutrophils and monocytes, serving as a diagnostic biomarker for a group of systemic small-vessel vasculitides. 1
Definition and Basic Characteristics
ANCA are autoantibodies that target specific neutrophil proteins, primarily proteinase 3 (PR3) and myeloperoxidase (MPO), which are normally contained within neutrophil cytoplasmic granules 2, 3
These antibodies play a pathogenic role in causing systemic vascular inflammation by binding to their target antigens on neutrophils, leading to neutrophil activation, recruitment to vessel walls, and subsequent tissue injury 2, 4
ANCA Patterns and Subtypes
ANCA testing reveals distinct patterns that correlate with specific diseases:
Cytoplasmic ANCA (c-ANCA): Associated with antibodies to proteinase 3 (PR3-ANCA), predominantly found in granulomatosis with polyangiitis (GPA), occurring in 84-85% of GPA patients 1, 5
Perinuclear ANCA (p-ANCA): Associated with antibodies to myeloperoxidase (MPO-ANCA), more commonly seen in microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) 1, 3
Atypical ANCA (a-ANCA): Rarely seen in systemic small-vessel vasculitis but can occur in other inflammatory conditions 3
ANCA-Associated Vasculitides (AAV)
ANCA defines a specific group of systemic vasculitides that share common pathogenic mechanisms:
The three main AAV diseases are: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) 1
These diseases affect small- and medium-sized blood vessels and are characterized by multisystem organ involvement, most commonly affecting the upper and lower respiratory tract and kidneys 1, 2
ANCA is detectable in approximately 90% of patients with active generalized GPA and MPA, but only in about 30-40% of EGPA patients 1, 5
Clinical Significance and Testing
High-quality antigen-specific immunoassays for PR3-ANCA and MPO-ANCA are recommended as the primary testing method, with both antibodies tested simultaneously when AAV is suspected 1
Key Testing Principles:
ANCA testing should not be used in isolation for diagnosis—it must be interpreted within the proper clinical context, as ANCA can occur in other inflammatory diseases, infections, or as drug-induced phenomena 1, 4
A negative ANCA does not exclude AAV, particularly in patients with disease limited to the respiratory tract or renal-limited vasculitis 1
The 2022 ACR/EULAR classification criteria now weight ANCA serotype heavily, with the prefix indicating ANCA reactivity (MPO-ANCA, PR3-ANCA, or ANCA-negative) becoming a key clinical classification criterion 1
Pathogenic Role
There is compelling evidence that ANCA contributes directly to disease pathogenesis in AAV, representing a loss of tolerance to neutrophil proteins that leads to ANCA-mediated neutrophil activation and tissue injury, with effector T cells also involved 2, 6
Beyond AAV
ANCA with different specificities can occur in non-vasculitic conditions including:
- Systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease 4
- Endocarditis and chronic infections 4
- Hematopoietic malignancies 4
- As an adverse event during pharmacological treatment 4
A positive ANCA test therefore requires careful diagnostic work-up to distinguish AAV from these other conditions, as treatment approaches differ dramatically 4