Granulomatosis with Polyangiitis
Overview
Granulomatosis with polyangiitis (formerly Wegener’s granulomatosis) is a rare, chronic, systemic necrotising vasculitis affecting small-to-medium-sized vessels, characterised by granulomatous inflammation, necrotising vasculitis, and tissue destruction, primarily involving the upper and lower respiratory tracts and kidneys. It falls under the ANCA-associated vasculitides (AAV). Peak incidence is in the 5th–6th decade, with slight male predominance and higher prevalence in Caucasians.
Definition
Vasculitis: Inflammation of blood vessels, causing vessel wall damage and downstream ischemia or haemorrhage.
Granuloma: Organised collection of macrophages in response to persistent inflammation.
ANCA (anti-neutrophil cytoplasmic antibodies): Autoantibodies targeting neutrophil cytoplasmic components; associated with GPA and other AAVs.
Necrotising glomerulonephritis: Rapidly progressive kidney inflammation with crescent formation, common in GPA.
Anatomy and Physiology
Upper airways (sinuses, nasal mucosa): Rich vascular network vulnerable to necrotising inflammation → septal perforation
Lower respiratory tract (lungs): Bronchi and alveoli susceptible to granulomatous inflammation and cavitating nodules
Kidneys: Glomeruli affected by pauci-immune crescentic glomerulonephritis → rapid renal failure
Immune system: Neutrophil activation by ANCAs → release of lytic enzymes and oxygen radicals → endothelial damage
Aetiology and Risk Factors
Aetiology
Unknown, likely multifactorial
- Age 40–60 years
- Caucasian ethnicity
- Male sex
- Genetic: HLA-DPB1 alleles
- Environmental: Silica dust exposure, nasal carriage of Staphylococcus aureus
Chronic nasal carriage of Staph aureus is associated with GPA relapses【1】.
Pathophysiology
- Environmental/genetic trigger activates innate immune system
- Production of ANCAs, particularly PR3-ANCA (c-ANCA pattern)
- ANCAs bind to primed neutrophils → degranulation and reactive oxygen species release
- Results in necrotising vasculitis of small-to-medium vessels
- Localised granulomatous inflammation in respiratory tract
- Pauci-immune glomerulonephritis in kidneys (little to no immune deposits)
GPA uniquely combines vasculitis and granulomatous inflammation, distinguishing it from other AAVs.
Clinical Manifestations
- Constitutional: Fever, malaise, weight loss, fatigue
- ENT (90%):
- Nasal crusting
- Epistaxis
- Sinusitis
- Septal perforation → saddle nose deformity
- Sensorineural hearing loss
- Pulmonary (85%): Cough, haemoptysis, pleuritic chest pain, subglottic stenosis, bronchial stenosis, cavitating nodules on imaging
- Renal (80%): Microscopic haematuria, proteinuria, rising creatinine → rapidly progressive GN
- Ocular: Scleritis, episcleritis, conjunctivitis, orbital pseudotumour
- Neurological: Mononeuritis multiplex (e.g., foot drop)
- Palpable purpura (Leukocytoclasic vasculitis), ulcers
- Polyarthralgia
If a patient with presumed asthma does not respond to treatment and has stridor or biphasic wheeze, think GPA with subglottic stenosis—especially if they have ENT symptoms or PR3-ANCA positivity.
Diagnosis
Classification Criteria for GPA, MPA, and EGPA (2022)
| Entry Requirement: A diagnosis of small- or medium-vessel vasculitis has been made (biopsy), and other mimicking conditions have been excluded. | |||
| Variables | GPA | MPA | EGPA |
| Clinical criteria | |||
| Nasal passage involvement | +3 | −3 | — |
| Cartilaginous involvement | +2 | — | — |
| Conductive or sensorineural hearing loss | +1 | — | — |
| Obstructive airway disease | — | — | +3 |
| Nasal polyp | — | — | +3 |
| Mononeuritis multiplex | — | — | +1 |
| Laboratory criteria | |||
| PR3-ANCA (or C-ANCA) positivity | +5 | −1 | −3 |
| MPO-ANCA (or P-ANCA) positivity | −1 | +6 | — |
| Serum eosinophil ≥1000/µL | −4 | −4 | +5 |
| Hematuria | — | — | −1 |
| Histological criteria | |||
| Granuloma, granulomatous inflammation, or giant cells | +2 | — | — |
| Pauci-immune glomerulonephritis | +1 | +3 | — |
| Extravascular eosinophilic-predominant inflammation | — | — | +2 |
| Radiological criteria | |||
| Pulmonary nodules, mass, or cavitation on chest imaging | +2 | — | — |
| Fibrosis or ILD on chest imaging | — | +3 | — |
| Nasal/paranasal sinusitis or mastoiditis on imaging | +1 | — | +1 |
| Total Score Cut-off for Classification | ≥5 | ≥5 | ≥6 |
PR3‑ANCA positivity raises the likelihood of GPA and is associated with a higher risk of relapse than MPO‑ANCA positivity.
Investigations
ANCA serology:
- PR3-ANCA (c-ANCA): highly specific (90%)
- Normocytic anaemia
- Leukocytosis
- Elevated creatinine in renal involvement
- Urinalysis: Haematuria, RBC casts, proteinuria
- Chest CT: Nodules, cavitation, infiltrates
- Biopsy: Gold standard
- Lung or nasal biopsy: necrotising granulomas
- Renal biopsy: pauci-immune crescentic GN
A positive c-ANCA (PR3) in a patient with upper/lower respiratory tract symptoms and haematuria is highly suggestive of GPA.
Classification
- GPA is classified under ANCA-associated vasculitides (AAV) alongside:
- Microscopic polyangiitis (MPA)
- Eosinophilic granulomatosis with polyangiitis (EGPA)
- AAVs are small-vessel vasculitides often with multisystem involvement.
Treatment
Induction therapy (for active/severe disease):
- Glucocorticoids: Prednisone 1 mg/kg/day ± pulse methylprednisolone
- Immunosuppressants:
- Rituximab (preferred first-line for many)
- Cyclophosphamide (alternative, esp. in life-threatening cases)
- Plasma exchange: For pulmonary haemorrhage or severe RPGN (though now debated post-PEXIVAS trial)
- Avacopan (C5a inhibitor)
Maintenance therapy (after induction):
- Taper corticosteroids over 6 months (or sooner)
- Avacopan
- Rituximab
- Alternatively, azathioprine, methotrexate, or mycophenolate mofetil may be used if biologics are not feasible.
Adjuncts
- Prophylaxis against Pneumocystis jirovecii (e.g., trimethoprim-sulfamethoxazole)
- Osteoporosis prevention, vaccination
Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis or diffuse alveolar hemorrhage.
Complications and Prognosis
- Renal failure
- Diffuse alveolar haemorrhage
- Saddle nose deformity
- Chronic sinus disease
- Secondary infections due to immunosuppression
- Increased malignancy risk (esp. bladder with cyclophosphamide)
- Rituximab associated Hypogammaglobulinaemia
Poor prognostic factors
- Elevated serum creatinine >500 µmol/L
- Pulmonary haemorrhage
- Older age
- Delayed treatment initiation
- Cardiac involvement
- 5-year survival >80% with treatment
- High relapse rate (30–50%) – requires long-term follow-up
References
- Stegeman CA, Tervaert JW, Sluiter WJ, et al. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med. 1994;120(1):12–17.
- Stone JH, Merkel PA, Spiera R, et al. Rituximab vs cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221–232.
- Yates M, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis. 2016;75(9):1583–1594.
- Walsh M, et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med. 2020;382(7):622–631.
Discussion