Granulomatosis with Polyangiitis
ANCA-associated small-vessel vasculitis (formerly Wegener granulomatosis) characterised by necrotising granulomatous inflammation of the upper and lower respiratory tract and necrotising glomerulonephritis. Strongly associated with c-ANCA/PR3 antibodies.
Key Facts
GPA (formerly Wegener granulomatosis) is characterised by necrotising granulomatous vasculitis affecting upper airway, lungs, and kidneys c-ANCA (anti-PR3): positive in >90% of generalised GPA; highly specific ENT: nasal crusting, epistaxis, sinusitis, saddle-nose deformity (nasal cartilage destruction), otitis media, subglottic stenosis Pulmonary: cavitating lung nodules, pulmonary haemorrhage, cough, dyspnoea Renal: pauci-immune crescentic GN (as with all AAV) Induction: rituximab (RAVE trial) or cyclophosphamide + prednisolone; maintenance: rituximab (MAINRITSAN) or azathioprine for ≥24 months Relapse rate: 50% within 5 years; PR3-ANCA positive patients have higher relapse risk than MPO Co-trimoxazole 960mg BD: may reduce ENT relapse rate (Stegeman trial)
Overview
Key Facts
GPA is the most common ANCA-associated vasculitis with distinctive upper respiratory tract involvement. PR3-ANCA is both diagnostic and prognostic.
Epidemiology
- Incidence: ~10 per million/year in the UK
- Peak age: 55-70 years; M=F
- More common in Northern European populations
Pathophysiology
- Anti-PR3 antibodies activate neutrophils → necrotising vasculitis
- Granuloma formation in respiratory tract (distinctive feature vs MPA)
- Pauci-immune crescentic GN in kidneys
- Triad: upper airway granulomatous inflammation + lung involvement + renal vasculitis
Clinical Presentation
ENT (90%)
- Nasal crusting, bloody discharge, epistaxis
- Sinusitis (recurrent, destructive)
- Saddle-nose deformity: nasal septal perforation and cartilage destruction
- Subglottic stenosis: stridor, hoarseness (~15%)
- Otitis media (serous or chronic)
- Hearing loss (conductive or sensorineural)
Pulmonary (90%)
- Cavitating lung nodules: multiple, bilateral; can mimic malignancy or TB
- Pulmonary haemorrhage: dyspnoea, haemoptysis
- Cough, pleurisy
Renal (80%)
- Crescentic GN: haematuria, proteinuria, rapidly declining GFR
- May present as RPGN
Other
- Constitutional: fever, weight loss, fatigue
- Eyes: scleritis, orbital pseudotumour (proptosis)
- Skin: palpable purpura
- Nervous system: mononeuritis multiplex, cranial nerve palsies
Red Flags
- Haemoptysis + renal failure → pulmonary-renal syndrome
- Subglottic stenosis → airway compromise
- Rapidly rising creatinine → urgent treatment
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| MPA | No granulomata, no upper airway, p-ANCA/MPO | ANCA, biopsy |
| EGPA | Asthma, eosinophilia | FBC (eosinophils), ANCA |
| TB | Cavitating lesions, AFB positive | Sputum AFB, Mantoux |
| Lung cancer | Cavitating mass, smoking history | CT, biopsy |
| Anti-GBM disease | Linear IgG, anti-GBM antibodies | Anti-GBM, biopsy |
| Cocaine-induced midline destructive disease | Cocaine use, ANCA can be positive | Drug history |
Diagnosis / Investigation
Bloods
- c-ANCA (anti-PR3): positive in >90% generalised GPA
- p-ANCA (anti-MPO): positive in ~10% of GPA
- CRP/ESR: elevated
- U&Es: renal function
- FBC: anaemia, leucocytosis
- Urinalysis: haematuria, red cell casts, proteinuria
Imaging
- CT chest: cavitating nodules (bilateral), ground-glass (haemorrhage)
- CT sinuses: mucosal thickening, bony erosion
- CT neck: subglottic stenosis
Biopsy
- Renal biopsy: pauci-immune crescentic GN
- Nasal/sinus biopsy: necrotising granulomatous vasculitis (may be non-diagnostic due to superficial sampling)
- Lung biopsy: geographic necrosis with granulomata
Management
Induction (Generalised/Organ-Threatening)
- Rituximab 375mg/m² weekly × 4 (RAVE trial) OR IV cyclophosphamide (CYCLOPS protocol) + prednisolone 1mg/kg tapering
- Avacopan 30mg BD as steroid-sparing alternative (ADVOCATE trial)
- Plasma exchange: for pulmonary haemorrhage
Maintenance (≥24 months)
- Rituximab 500mg IV every 6 months (MAINRITSAN – superior to azathioprine)
- OR azathioprine 2mg/kg/day
Limited Disease (ENT Only)
- Methotrexate 20-25mg weekly + prednisolone (NORAM trial)
- Co-trimoxazole 960mg BD: may reduce nasal/ENT relapse (Stegeman trial)
Subglottic Stenosis
- Intralesional corticosteroid injection
- Endoscopic dilation
- May persist despite systemic treatment
Supportive
- Co-trimoxazole for PCP prophylaxis
- Bone protection
- Annual influenza/pneumococcal vaccination
Referral
- All GPA → rheumatology/nephrology
- ENT involvement → ENT surgeon
- Subglottic stenosis → airway specialist
Prognosis
- 5-year survival: 75-80% with treatment
- Relapse rate: ~50% within 5 years; PR3 > MPO
- Renal survival: 70-80% at 5 years
- Leading causes of death: infections (immunosuppression), renal failure, cardiovascular disease
- Subglottic stenosis: may cause chronic morbidity; often refractory
- Rituximab maintenance significantly reduces relapse rate vs azathioprine
Other Relevant Information
GPA vs MPA vs EGPA
| Feature | GPA | MPA | EGPA |
|---|---|---|---|
| ANCA | c-ANCA/PR3 (90%) | p-ANCA/MPO (70%) | p-ANCA/MPO (40%) |
| Upper airway | +++ | - | + |
| Granulomata | Yes | No | Yes (eosinophilic) |
| Asthma | No | No | Yes (>95%) |
| Eosinophilia | No | No | Yes |
| Renal | Crescentic GN | Crescentic GN | Less common |
| Relapse rate | High (50%) | Lower | Moderate |