In-depth Analysis of ANCA-Associated Vasculitis P-ANCA (Perinuclear ANCA) and C-ANCA (Cytoplasmic ANCA): Histology, Immunology, Clinical Presentation, and Diagnostic Criteria

Introduction: ANCA-associated vasculitis (AAV) refers to a group of autoimmune diseases characterized by inflammation of small to medium-sized blood vessels, leading to multi-organ damage. This group includes Granulomatosis with Polyangiitis (GPA, formerly Wegener's Granulomatosis), Microscopic Polyangiitis (MPA), and Eosinophilic Granulomatosis with Polyangiitis (EGPA, formerly Churg-Strauss Syndrome). This article provides a detailed exploration of the histological features, immunological mechanisms, clinical presentation, and diagnostic criteria of AAV, emphasizing specific numerical values where applicable.

P-ANCA (Perinuclear ANCA)

1. Histology:

   • Microscopic Polyangiitis (MPA):

     • Necrotizing Vasculitis: Characterized by necrotizing inflammation of small vessels without granuloma formation.

     • Pauci-Immune Crescentic Glomerulonephritis: Found in approximately 80% of MPA cases, this kidney involvement typically shows crescents in more than 50% of glomeruli on biopsy.

   • Eosinophilic Granulomatosis with Polyangiitis (EGPA):

     • Eosinophilic Infiltration: Eosinophils infiltrate tissues at a level typically exceeding 1,500 eosinophils/μL, which is considered diagnostic.

     • Granulomas: Granulomas are present but often smaller and less organized compared to GPA.

2. Immunology:

   • P-ANCA: Detected in approximately 70% of MPA patients and 40-60% of EGPA patients. P-ANCA primarily targets Myeloperoxidase (MPO), with anti-MPO antibodies found in more than 80% of P-ANCA positive cases.

3. Clinical Presentation:

   • Microscopic Polyangiitis (MPA):

     • Renal Involvement: Present in 90% of cases, with manifestations such as hematuria, proteinuria, and rapidly progressive glomerulonephritis (RPGN).

     • Pulmonary Capillaritis: Occurs in 30-50% of patients, often presenting with hemoptysis.

   • Eosinophilic Granulomatosis with Polyangiitis (EGPA):

     • Asthma: A history of asthma is found in over 95% of patients.

     • Eosinophilia: Peripheral blood eosinophilia is typically greater than 10% of total leukocyte count.

4. Diagnostic Criteria:

   • P-ANCA Testing: The presence of P-ANCA with anti-MPO specificity is a key diagnostic marker. In MPA, the sensitivity is approximately 70-80%, and in EGPA, it ranges from 40-60%.

   • ANCA Titer Levels: A titer greater than 1:160 is considered clinically significant for P-ANCA.
     

C-ANCA (Cytoplasmic ANCA)

1. Histology:

   • Granulomatosis with Polyangiitis (GPA):

     • Granulomas: Necrotizing granulomas are found in 80-90% of patients with GPA, particularly in the respiratory tract.

     • Pauci-Immune Crescentic Glomerulonephritis: Present in 60-80% of cases, characterized by crescents in more than 50% of glomeruli on biopsy.

2. Immunology:

   • C-ANCA: Detected in approximately 90% of patients with active GPA. C-ANCA primarily targets Proteinase 3 (PR3), with anti-PR3 antibodies present in more than 90% of C-ANCA positive cases.

3. Clinical Presentation:

   • Upper Respiratory Tract Involvement: Occurs in about 90% of GPA patients, with symptoms such as chronic sinusitis, nasal crusting, and epistaxis.

   • Pulmonary Involvement: Found in 60-80% of cases, often presenting with nodules, cavitations, or hemoptysis.

   • Renal Involvement: Seen in approximately 80% of cases, often presenting as rapidly progressive glomerulonephritis (RPGN).

4. Diagnostic Criteria:

   • C-ANCA Testing: The presence of C-ANCA with anti-PR3 specificity is highly sensitive and specific for GPA, with a sensitivity of approximately 90% and specificity of over 95%.

   • ANCA Titer Levels: A titer greater than 1:160 is considered clinically significant for C-ANCA.
     

Diagnostic Approach and Management:

1. Initial Diagnostic Workup:

   • ANCA Testing: Both C-ANCA and P-ANCA titers should be evaluated. Specificity for anti-PR3 and anti-MPO should be confirmed using ELISA.

   • Renal Biopsy: Indicated in cases with suspected glomerulonephritis to confirm pauci-immune crescentic glomerulonephritis.

   • Imaging: Chest CT scans should be performed to assess for pulmonary nodules, cavitations, or diffuse alveolar hemorrhage, particularly in patients with respiratory symptoms.

2. Induction Therapy:

   • High-Dose Glucocorticoids: Initiated at 1 mg/kg/day, typically up to 60-80 mg/day of prednisone, with a gradual taper.

   • Cyclophosphamide: Administered at 2 mg/kg/day orally or intravenously in severe cases, particularly with renal involvement.

   • Rituximab: An alternative to cyclophosphamide, given as 375 mg/m² weekly for 4 weeks.

3. Maintenance Therapy:

   • Azathioprine: Administered at 1-2 mg/kg/day orally to maintain remission.

   • Methotrexate: An alternative at 15-25 mg weekly, particularly in patients with less severe disease.

   • Long-term Monitoring: Regular follow-up every 3-6 months, with ANCA titers, renal function tests, and chest imaging as indicated.

4. Supportive Care:

   • Hypertension Management: ACE inhibitors or ARBs are recommended, particularly in patients with renal involvement.

   • Infection Prophylaxis: Trimethoprim-sulfamethoxazole is often used to prevent Pneumocystis jirovecii pneumonia in patients on long-term immunosuppressants.
     

Conclusion:

ANCA-associated vasculitis represents a challenging group of diseases requiring precise diagnostic and therapeutic strategies. Understanding the histological features, immunological markers, and clinical presentations is essential for early diagnosis and effective management. With a focus on specific numerical values and criteria, clinicians can better navigate the complexities of AAV and provide targeted care to improve patient outcomes.