Understanding ANCA-Associated Vasculitis (AAV): GPA, MPA, and EGPA

ANCA-associated vasculitides (AAV) are a group of rare, potentially life-threatening autoimmune diseases characterized by inflammation of small- to medium-sized blood vessels. These conditions are associated with anti-neutrophil cytoplasmic antibodies (ANCAs), which target enzymes inside neutrophils, leading to tissue damage in multiple organs.

1. Overview of AAV Subtypes

Granulomatosis with Polyangiitis (GPA)

Formerly: Wegener’s granulomatosis.
Key Features: Granulomatous inflammation; upper and lower respiratory tract involvement; glomerulonephritis.
Common Antibody: PR3-ANCA (c-ANCA).
Organs Affected: Sinuses, lungs, kidneys, eyes, skin.

Microscopic Polyangiitis (MPA)

Key Features: Non-granulomatous necrotizing vasculitis; kidney and lung involvement.
Common Antibody: MPO-ANCA (p-ANCA).
Organs Affected: Kidneys, lungs, nerves, skin.

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Formerly: Churg-Strauss syndrome.
Key Features: Asthma, eosinophilia, granulomatous vasculitis.
Common Antibody: MPO-ANCA (p-ANCA) or ANCA-negative (~40%).
Organs Affected: Lungs, heart, nerves, GI tract, skin.

2. Immunology and ANCA Testing

ANCA (Anti-Neutrophil Cytoplasmic Antibodies)

ANCAs are autoantibodies that target proteins in neutrophil cytoplasm:

Proteinase 3 (PR3): Most associated with GPA.
Myeloperoxidase (MPO): Associated with MPA and some EGPA.

Testing Methods

Method	Description	Utility
IIF (Indirect Immunofluorescence)	Visualizes ANCA pattern on neutrophils.	Screening test. Detects c-ANCA (cytoplasmic) and p-ANCA (perinuclear) patterns.
Immunoassay (ELISA)	Detects antibodies against PR3 or MPO.	Confirms antigen-specific diagnosis. More specific.

ANCA Patterns

Pattern	Target Antigen	Associated Disease
c-ANCA	PR3	GPA
p-ANCA	MPO	MPA, EGPA
Negative ANCA	None detected	EGPA (up to 40% cases)

3. Clinical Presentation

Multisystem Involvement

Each subtype affects different organs. Below is a breakdown by system:

Organ System	GPA	MPA	EGPA
ENT	Chronic sinusitis, nosebleeds, saddle-nose	Rare	Rhinitis, nasal polyps
Lungs	Nodules, cavitations, hemoptysis	Pulmonary hemorrhage, infiltrates	Asthma, eosinophilic pneumonia
Kidneys	RPGN, hematuria, proteinuria	RPGN	Rarely severe
Skin	Purpura, ulcers	Palpable purpura	Nodules, rash
Nerves	Rare	Mononeuritis multiplex	Common (foot drop, tingling)
Heart	Rare	Rare	Myocarditis, heart failure
GI Tract	Ulcers (rare)	Ischemia	Abdominal pain, bleeding

4. Diagnostic Approach

Step-by-Step Evaluation

Step 1: Clinical Suspicion

Constitutional symptoms: fever, fatigue, weight loss.
Multisystem signs: kidney + lung + ENT (GPA); lung + kidney (MPA); asthma + eosinophilia (EGPA).

Step 2: Lab Tests

Test	Finding
CBC	Eosinophilia (EGPA), anemia
ESR/CRP	Elevated (active inflammation)
Urinalysis	RBC casts, hematuria, proteinuria
ANCA	PR3 or MPO positivity
Renal function	Elevated creatinine in glomerulonephritis

Step 3: Imaging

Chest X-ray or CT:
- GPA: Nodules, cavitation
- MPA: Ground-glass infiltrates (hemorrhage)
- EGPA: Transient infiltrates, consolidation

Step 4: Biopsy (Definitive Diagnosis)

Biopsy Site	Findings
Kidney	Pauci-immune crescentic glomerulonephritis
Lung	Granulomas (GPA, EGPA)
Skin	Leukocytoclastic vasculitis
Nerves	Vasculitis in epineural arteries

5. Disease-Specific Features

GPA (PR3-ANCA)

Saddle-nose deformity from cartilage destruction.
Upper airway destruction and cavitary lung lesions.
More aggressive renal disease.
High relapse rate, especially with PR3-positivity.

🔹 MPA (MPO-ANCA)

Pulmonary-renal syndrome.
No granulomas or sinus involvement.
Often rapidly progressive kidney disease.

EGPA (± MPO-ANCA)

Marked eosinophilia (>10% on differential).
Allergic history: asthma, rhinitis.
Cardiac involvement is a major cause of mortality.
ANCA-positive EGPA: more vasculitic (renal, neuro).
ANCA-negative EGPA: more eosinophilic (lungs, heart).

6. Treatment Overview

Induction Therapy (Initial control of disease)

Drug	Use
Glucocorticoids	First-line for all AAV
Cyclophosphamide	Severe or life-threatening cases
Rituximab	Preferred in GPA/MPA; safer long-term
Plasma exchange (PLEX)	Previously used for severe renal/pulmonary hemorrhage (less common now)

Drug	Notes
Azathioprine	Commonly used after induction
Methotrexate	Used in less severe, non-renal cases
Rituximab	Effective for relapse prevention, especially PR3-ANCA GPA
Mepolizumab	For EGPA with eosinophilic predominance; anti-IL-5 monoclonal antibody

7. Clinical Pearls

PR3-ANCA positivity = high relapse risk, particularly in GPA.
Asthma + eosinophilia + neuropathy = EGPA, even if ANCA-negative.
Kidney biopsy is often essential for confirming AAV and guiding therapy.
Heart involvement in EGPA must be screened regularly due to high morbidity.
Avoid delay in treatment—AAV can progress rapidly and irreversibly damage organs.

Summary Table: Comparing AAV Subtypes

Feature	GPA	MPA	EGPA
ANCA Type	PR3 (c-ANCA)	MPO (p-ANCA)	MPO (p-ANCA) or negative
Granulomas	Present	Absent	Present
Eosinophilia	No	No	Yes
Asthma	Rare	Rare	Common
ENT Involvement	Yes	No	Yes
Cavitary Lung Lesions	Yes	No	No
Renal Disease	Common, severe	Common, severe	Less common
Neuropathy	Less common	Common	Very common
Cardiac Involvement	Rare	Rare	Common (↑ mortality)

Conclusion

ANCA-associated vasculitis is a complex group of diseases that require a multidisciplinary approach, involving rheumatologists, nephrologists, pulmonologists, and pathologists. Understanding the differences between GPA, MPA, and EGPA—from immunological markers to clinical features—is essential for accurate diagnosis, effective treatment, and improving patient outcomes.

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