19.2 ANCA-Associated and Immune Complex Small Vessel Vasculitis

4. Small Vessel Vasculitides: ANCA-Associated Vasculitides (AAV)

ANCA-associated vasculitides are systemic necrotizing vasculitides targeting small vessels (arterioles, capillaries, venules) characterized by pauci-immune necrotizing crescentic glomerulonephritis and circulating antineutrophil cytoplasmic antibodies (ANCA):

                      ANCA Patterns & Antigenic Specificities
                                         |
     +-----------------------------------+-----------------------------------+
     |                                                                       |
1. Cytoplasmic ANCA (c-ANCA)                                        2. Perinuclear ANCA (p-ANCA)
   - Antigen: Proteinase 3 (PR3)                                       - Antigen: Myeloperoxidase (MPO)
   - Granulomatosis with Polyangiitis (GPA / Wegener's)                - Microscopic Polyangiitis (MPA) (80%)
     (> 90% sensitivity & specificity)                                 - Eosinophilic GPA (EGPA / Churg-Strauss) (40-50%)
   - Cavitating pulmonary nodules; saddle-nose                         - Pulmonary-renal syndrome; severe asthma/eosinophilia

Granulomatosis with Polyangiitis (GPA, formerly Wegener's Granulomatosis)

Systemic necrotizing granulomatous vasculitis with a classic clinical triad:

1. Upper Respiratory Tract (Ear, Nose & Throat - 90%): Severe, chronic, bloody, purulent rhinosinusitis, recurrent epistaxis, nasal mucosal crusting, chondritis with nasal septal perforation and destruction of the nasal bridge producing the pathognomonic saddle-nose deformity. Chronic otitis media, conductive/sensorineural hearing loss, and subglottic stenosis presenting with progressive dyspnoea and inspiratory stridor.
2. Lower Respiratory Tract (Pulmonary - 80%): Cough, haemoptysis, pleuritic chest pain. Chest radiography and CT reveal multiple bilateral cavitating pulmonary nodules, thick-walled cavitary lesions, and patchy ground-glass infiltrates representing diffuse alveolar haemorrhage.
3. Renal (Glomerulonephritis - 75–80%): Rapidly progressive crescentic glomerulonephritis; active nephritic sediment with dysmorphic RBCs and red cell casts, leading to acute renal failure.

• Other Manifestations: Proptosis / retro-orbital pseudotumour, scleritis, mononeuritis multiplex, and pyoderma gangrenosum-like cutaneous ulcers.
• Diagnostic Serology: c-ANCA (cytoplasmic staining pattern on indirect immunofluorescence) directed specifically against Proteinase 3 (PR3-ANCA); positive in > 90% of active systemic GPA.
• Histopathology: Triad of: (1) Necrotizing vasculitis of small arteries/veins; (2) Geographic necrosis surrounded by palisading histiocytes; and (3) Poorly formed granulomas with multinucleated giant cells.

Microscopic Polyangiitis (MPA)

Systemic necrotizing small-vessel vasculitis manifesting as a severe pulmonary-renal syndrome:

• Clinical Presentation: Rapidly progressive necrotizing crescentic glomerulonephritis accompanied by pulmonary capillaritis presenting as life-threatening diffuse alveolar haemorrhage (haemoptysis, acute drop in haemoglobin, bilateral alveolar consolidation, and elevated carbon monoxide transfer coefficient [KCO] due to intra-alveolar RBC uptake of CO).
• Vital Contrasts with GPA:
  1. NO granulomatous inflammation on biopsy;
  2. NO upper respiratory tract (ENT) destruction (no saddle-nose, no sinus crusting, no subglottic stenosis); and
  3. NO cavitating lung nodules on imaging.
• Diagnostic Serology: p-ANCA (perinuclear staining pattern) directed specifically against Myeloperoxidase (MPO-ANCA); positive in > 75–85% of MPA patients.

Eosinophilic Granulomatosis with Polyangiitis (EGPA, formerly Churg-Strauss)

Eosinophil-rich necrotizing granulomatous vasculitis characterized by three distinct clinical phases:

1. Prodromal / Allergic Phase: Severe, late-onset, adult-onset refractory asthma, allergic rhinitis, and nasal polyposis, typically persisting for years.
2. Eosinophilic Infiltrative Phase: Marked peripheral blood eosinophilia (> 10% of total white cells, or absolute eosinophil count > 1.5 × 10⁹/L) and tissue eosinophilic infiltration (eosinophilic gastroenteritis, eosinophilic pneumonia with migratory, non-cavitating pulmonary infiltrates).
3. Systemic Vasculitic Phase: Systemic small-vessel vasculitis manifesting as:
   • Mononeuritis Multiplex: Present in > 70% of patients; the most frequent vasculitic feature.
   • Cardiovascular Disease: Eosinophilic myocarditis, endomyocardial fibrosis, pericarditis, and coronary arteritis; cardiac involvement represents the primary cause of mortality in EGPA.
   • Renal: Pauci-immune necrotizing crescentic GN (typically milder and less frequent than in GPA or MPA).

• Diagnostic Serology: p-ANCA / MPO-ANCA is positive in only 40–50% of EGPA patients. Clinical dichotomy: ANCA-positive patients predominantly suffer from glomerulonephritis, mononeuritis multiplex, and purpura; ANCA-negative patients predominantly suffer from cardiomyopathy, pericarditis, and severe lung infiltration.

Management of ANCA-Associated Vasculitides

• Remission Induction (Organ- or Life-Threatening Disease):
  • High-dose intravenous pulsed methylprednisolone (500–1,000 mg IV daily for 3 days) followed by tapering oral prednisolone;
  • PLUS either Rituximab (375 mg/m² weekly for 4 doses or 1,000 mg IV every 2 weeks for 2 doses) OR intravenous Cyclophosphamide (15 mg/kg IV every 2–3 weeks for 3–6 months).
  • Rituximab is now the preferred first-line agent, especially in patients with relapsing disease, childbearing potential (preserves ovarian/testicular reserve), and PR3-ANCA positive GPA.
  • Avacopan: Oral selective complement C5a receptor (C5aR1) antagonist, approved as an adjunctive therapy to reduce or eliminate high-dose glucocorticoid exposure during induction.
  • Mandatory Prophylaxis: All patients receiving induction immunosuppression for AAV must receive co-trimoxazole (e.g. 480 mg daily or 960 mg three times weekly) as mandatory antimicrobial chemoprophylaxis against Pneumocystis jirovecii pneumonia (PJP).
• Remission Maintenance: Transition to maintenance therapy after achieving remission at 3–6 months: maintenance rituximab infusions every 6 months, or oral azathioprine (2 mg/kg/day) or oral methotrexate, continued for at least 24–48 months.

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5. Immune Complex Small Vessel Vasculitides

IgA Vasculitis (Henoch-Schönlein Purpura - HSP)

Systemic small-vessel leukocytoclastic vasculitis characterized by tissue deposition of IgA1-dominant immune complexes.

• Epidemiology: Most common vasculitis of childhood (peak age 4–7 years), but can occur in adults where it carries a much higher risk of progressive, chronic renal disease.
• Classic Clinical Tetrad:
  1. Palpable Purpura: Non-thrombocytopenic, symmetrical, raised purpuric lesions and petechiae distributed gravitationally over dependent areas—predominantly the buttocks and lower extremities (spares trunk and face).
  2. Arthralgia / Non-Deforming Arthritis: Transient oligoarthritis affecting knees and ankles without permanent erosion.
  3. Gastrointestinal Symptoms: Colicky, cramping abdominal pain, nausea, vomiting, gastrointestinal bleeding, and bowel ischemia. In young children, bowel wall edema can trigger ileo-ileal or ileocolic intussusception.
  4. Renal Disease (IgA Glomerulonephritis): Microscopic haematuria, sub-nephrotic proteinuria, and nephritic syndrome. Renal histology is indistinguishable from primary IgA nephropathy (Berger's disease).
• Diagnostic Investigation: Coagulation profile and platelet count are COMPLETELY NORMAL (distinguishing it from ITP, TTP, or DIC). Skin punch biopsy demonstrates leukocytoclastic vasculitis with diagnostic, pathognomonic perivascular IgA and C3 deposition on direct immunofluorescence.
• Management: Primarily supportive (analgesia, hydration). Systemic corticosteroids are indicated for severe disabling abdominal pain or progressive glomerulonephritis, but do not prevent renal progression.

Cryoglobulinaemic Vasculitis

Systemic vasculitis driven by cryoglobulins—immunoglobulins that reversibly precipitate at cold temperatures (< 37 °C) and redissolve upon warming.

• Classification (Brouet Criteria):
  • Type I (Monoclonal): Monoclonal IgM or IgG. Associated with lymphoproliferative disorders (multiple myeloma, Waldenström's macroglobulinaemia); causes hyperviscosity and digital necrosis.
  • Type II (Mixed): Monoclonal IgM with rheumatoid factor activity directed against polyclonal IgG.
  • Type III (Polyclonal): Polyclonal IgM with rheumatoid factor activity directed against polyclonal IgG.
• Strong Association with Hepatitis C Virus (HCV): > 80–90% of mixed cryoglobulinaemia (Types II and III) is secondary to chronic Hepatitis C virus infection.
• Clinical Features: Meltzer's Triad—palpable purpura, severe arthralgias, and profound fatigue/asthenia. Also causes mononeuritis multiplex, digital ischemia, and type I membranoproliferative glomerulonephritis (MPGN).
• Serology: Detectable serum cryoglobulins, positive Rheumatoid Factor (RF > 90%), detectable HCV RNA, and characteristically profound depression of serum C4 (C4 is typically undetectable or near-zero, while C3 is normal or mildly depressed).
• Management: Direct-acting antiviral (DAA) therapy to eliminate HCV; rituximab and plasma exchange for severe vasculitic flares.

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6. Comparative Synthesis: ANCA-Associated Vasculitides

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