ANCA-Associated Vasculitis
Group of small-vessel vasculitides characterised by necrotising inflammation and association with anti-neutrophil cytoplasmic antibodies (ANCA). Includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Renal involvement manifests as pauci-immune crescentic glomerulonephritis.
Key Facts
ANCA-associated vasculitis (AAV) comprises GPA (c-ANCA/PR3), MPA (p-ANCA/MPO), and EGPA (p-ANCA/MPO in 40%) Pauci-immune crescentic GN is the hallmark renal lesion – few/no immune deposits on immunofluorescence Incidence: 20 per million/year in the UK; peak age 60-70 years Induction: rituximab 375mg/m² weekly × 4 (RAVE trial) or IV cyclophosphamide (Euro-Vasculitis) + glucocorticoids Avacopan (C5a receptor inhibitor): steroid-sparing alternative approved per ADVOCATE trial Maintenance: rituximab 500mg every 6 months (MAINRITSAN) or azathioprine 2mg/kg/day for ≥18-24 months Relapse rate: 30-50% within 5 years; PR3-ANCA higher relapse risk than MPO-ANCA 5-year survival: 75-80% with modern treatment; renal failure at diagnosis worsens prognosis
Overview
Key Facts
AAV is characterised by necrotising small-vessel vasculitis, predominantly affecting kidneys, lungs, and upper airways. ANCA testing has revolutionised diagnosis, and rituximab has transformed treatment.
Epidemiology
- Combined incidence: ~20 per million/year in the UK
- GPA and MPA are most common; EGPA is rarer (~2 per million/year)
- Peak age: 60-70 years; rare in children
- M:F roughly equal
- More common in Northern European populations
Aetiology
- Autoimmune with environmental triggers
- ANCA directed against neutrophil granule proteins: PR3 (proteinase 3) or MPO (myeloperoxidase)
- Genetic: HLA associations (HLA-DP for GPA, HLA-DQ for MPA)
- Environmental: silica exposure, infections, drugs (hydralazine, propylthiouracil, minocycline)
Pathophysiology
- ANCA activate primed neutrophils → neutrophil adhesion to endothelium → degranulation and reactive oxygen species release
- Necrotising vasculitis with fibrinoid necrosis of vessel walls
- In kidneys: focal necrotising glomerulonephritis with crescent formation
- Pauci-immune: minimal immunoglobulin/complement deposition (unlike immune complex GN)
- Granuloma formation in GPA (necrotising granulomatous inflammation)
- Eosinophilic infiltration in EGPA
Clinical Presentation
General Features
- Constitutional: fever, malaise, weight loss, night sweats, myalgia, arthralgia
- Renal: haematuria, proteinuria, rapidly declining GFR (RPGN)
- Pulmonary: cough, dyspnoea, haemoptysis, pulmonary infiltrates/haemorrhage
GPA-Specific
- ENT: nasal crusting, epistaxis, saddle-nose deformity, sinusitis, otitis media, subglottic stenosis
- Pulmonary: cavitating lung nodules, pulmonary haemorrhage
- Renal: crescentic GN
- Eyes: scleritis, orbital pseudotumour (proptosis)
MPA-Specific
- Renal: most commonly affected organ; RPGN
- Pulmonary: haemorrhage (no granulomata)
- Skin: purpura, livedo reticularis
- Neuropathy: mononeuritis multiplex
Red Flags
- Pulmonary haemorrhage: life-threatening, requires ICU admission
- Rapidly rising creatinine with active sediment: urgent biopsy and treatment
- Subglottic stenosis: airway compromise in GPA
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Anti-GBM disease | Linear IgG, anti-GBM positive | Anti-GBM antibodies |
| SLE | ANA/dsDNA positive, low complement | Immunology |
| Polyarteritis nodosa | Medium-vessel, microaneurysms, HBV | Angiography, HBsAg |
| IgA vasculitis | Purpura, IgA deposits, normal ANCA | Biopsy |
| Infective endocarditis | Fever, murmur, splinter haemorrhages | Blood cultures, echo |
| Drug-induced ANCA vasculitis | Drug history (PTU, hydralazine) | Drug history, ANCA |
Diagnosis / Investigation
Bloods
- ANCA: c-ANCA/PR3 (GPA), p-ANCA/MPO (MPA, EGPA)
- U&Es: creatinine, eGFR
- FBC: anaemia, eosinophilia (EGPA), thrombocytosis
- CRP/ESR: elevated
- Urine PCR: proteinuria
- Urinalysis: haematuria with red cell casts
- Anti-GBM: exclude dual positivity (30% overlap)
- C3/C4: normal (unlike lupus)
- LFTs, hepatitis serology: baseline before treatment
Imaging
- CT chest: cavitating nodules (GPA), ground-glass opacification (haemorrhage)
- CT sinuses: mucosal thickening, bony destruction (GPA)
- Renal USS: normal-sized kidneys
Special Tests
- Renal biopsy: pauci-immune crescentic GN; focal segmental necrotising lesions
- Lung biopsy: necrotising granulomatous vasculitis (GPA)
- Nerve biopsy: vasculitic neuropathy
Management
Induction (Severe/Organ-Threatening)
- Rituximab 375mg/m² IV weekly × 4 doses (RAVE trial: non-inferior to CYC; superior for relapsing disease)
- OR IV cyclophosphamide: 15mg/kg every 2 weeks × 3, then every 3 weeks × 3 (Euro-Vasculitis/CYCLOPS)
- Prednisolone 1mg/kg/day (max 60mg) tapering to 5mg by 5 months
- IV methylprednisolone 500mg-1g × 3 days for severe presentations
- Avacopan 30mg BD: C5a receptor inhibitor; steroid-sparing (ADVOCATE trial – non-inferior to steroids with fewer side effects)
- Plasma exchange: consider for severe pulmonary haemorrhage or creatinine >500 µmol/L (PEXIVAS showed no benefit for renal outcome but may help pulmonary haemorrhage)
Maintenance (≥18-24 months minimum)
- Rituximab 500mg IV every 6 months (MAINRITSAN: superior to azathioprine for preventing relapse)
- OR Azathioprine 2mg/kg/day (check TPMT before starting)
- Continue low-dose prednisolone (aim to wean off)
Supportive
- PCP prophylaxis: co-trimoxazole 480mg OD during immunosuppression (also reduces ENT relapse in GPA)
- Bone protection: calcium/vitamin D, consider bisphosphonate
- BP control: ACEi/ARB for renal protection
Referral Criteria
- All suspected AAV → urgent nephrology/rheumatology
- Pulmonary haemorrhage → ICU
- Subglottic stenosis → ENT
Prognosis
- 5-year survival: 75-80% (improved dramatically with rituximab)
- Renal survival at 5 years: 70-80%
- Relapse rate: 30-50% within 5 years; PR3 > MPO
- Mortality: infections (from immunosuppression) and cardiovascular disease are leading causes
- ANCA negativity during remission associated with lower relapse risk
- Dialysis-dependent at presentation: ~30% recover enough to discontinue dialysis
- MPA has lower relapse rate but higher mortality than GPA
Other Relevant Information
ANCA-Associated Vasculitis Comparison
| Feature | GPA | MPA | EGPA |
|---|---|---|---|
| ANCA | c-ANCA/PR3 (90%) | p-ANCA/MPO (70%) | p-ANCA/MPO (40%) |
| Upper airway | +++ | - | + |
| Lower airway | Cavitating nodules | Haemorrhage | Asthma, eosinophilic infiltrates |
| Renal | Crescentic GN | Crescentic GN (most common) | Crescentic GN (less common) |
| Granulomata | Yes | No | Yes (eosinophilic) |
| Eosinophilia | No | No | Yes |
Landmark Trials
| Trial | Key Finding |
|---|---|
| RAVE (2010) | Rituximab non-inferior to CYC for induction |
| CYCLOPS (2009) | IV CYC non-inferior to oral CYC with less toxicity |
| MAINRITSAN (2014) | Rituximab superior to AZA for maintenance |
| ADVOCATE (2021) | Avacopan non-inferior steroid-sparing agent |
| PEXIVAS (2020) | Plasma exchange no benefit for renal outcomes |