Granulomatosis with Polyangiitis (Wegener's Granulomatosis)
Overview and Nomenclature
Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, is an ANCA-associated vasculitis characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tract, necrotizing vasculitis of small vessels, and necrotizing glomerulonephritis. 1
The terminology was changed from the eponymous "Wegener's granulomatosis" to the descriptive term "granulomatosis with polyangiitis" to improve clarity and consistency in diagnosis and classification. 1
Epidemiology
- Prevalence: 23.7-30 per million inhabitants 2
- Incidence: 2.9-12 cases per million per year, varying by geographic region 2
- Age at onset: Typically 40-60 years old 3
- Gender distribution: Affects men and women equally 2
Clinical Features
Upper Respiratory Tract (Most Common Initial Presentation)
- Chronic sinusitis with purulent or bloody nasal discharge 2
- Crusting rhinitis and epistaxis 3
- Saddle nose deformity from cartilage destruction 3
- Otitis media with conductive hearing loss 3
Lower Respiratory Tract
- Excavated lung nodules or masses, often cavitary 3
- Alveolar hemorrhage presenting with hemoptysis and diffuse infiltrates 3
- Pulmonary infiltrates that may be fleeting or persistent 4
Renal Involvement
- Rapidly progressive glomerulonephritis with hematuria, red cell casts, and proteinuria 5
- Declining GFR indicating severe systemic disease requiring aggressive immunosuppression 5
Other Systemic Manifestations
- Mononeuritis multiplex affecting peripheral nerves 3
- Necrotic purpura and cutaneous vasculitis 3
- Ocular involvement including scleritis, episcleritis, and orbital pseudotumor 6
Diagnostic Approach
Laboratory Testing
ANCA testing is mandatory using high-quality antigen-specific assays for both PR3-ANCA and MPO-ANCA. 5
- PR3-ANCA (c-ANCA): Positive in 80-90% of patients with generalized GPA 1, 3
- MPO-ANCA: Less common in GPA, more typical of microscopic polyangiitis 5
Essential Initial Workup
- Urinalysis: To detect hematuria with dysmorphic red blood cells, red cell casts, and proteinuria 5
- Complete blood count with differential 5
- Inflammatory markers: ESR and CRP 5
- Renal function tests: Creatinine and GFR 5
Tissue Biopsy
Biopsy confirmation is necessary whenever feasible, as clinical and serological findings alone may be insufficient. 5
- Skin biopsy: Should extend to the subcutis from the most tender, reddish or purpuric lesion 5
- Renal biopsy: Shows necrotizing crescentic glomerulonephritis 6
- Lung or upper airway biopsy: Demonstrates necrotizing vasculitis, geographic necrosis, and granulomatous inflammation 4, 7
Critical Diagnostic Pitfall
Do not rely solely on ANCA titers for treatment decisions; structured clinical assessment using validated tools like Birmingham Vasculitis Activity Score (BVAS) should guide management. 5
Treatment Algorithm
Severe Disease (Organ-Threatening or Life-Threatening Manifestations)
For severe GPA with glomerulonephritis, alveolar hemorrhage, or other organ-threatening disease, use combination therapy with high-dose glucocorticoids PLUS either rituximab OR cyclophosphamide for remission induction. 5
Induction Therapy Options:
Option 1: Rituximab + Glucocorticoids
- Rituximab is at least as effective as cyclophosphamide and possibly more effective 7
- Rituximab is preferred over cyclophosphamide for relapsing disease 5
- Particularly excellent for patients with prior cyclophosphamide exposure 8
Option 2: Cyclophosphamide + Glucocorticoids
- Given for 3-6 months only (short-course induction) 5, 4
- Remains the agent with greatest experience for alveolar hemorrhage requiring mechanical ventilation or rapidly progressive glomerulonephritis requiring dialysis 8
- After 3-6 months, switch to maintenance therapy 4
Non-Severe Disease (Limited, Non-Life-Threatening)
For limited GPA without organ-threatening manifestations, use methotrexate combined with glucocorticoids for induction. 8, 4
Maintenance Therapy After Remission Induction
Continue treatment for at least 18-24 months with one of the following agents: 5
- Rituximab
- Azathioprine
- Methotrexate
- Mycophenolate mofetil
Low-dose glucocorticoids (5-7.5 mg/day) should be continued for 2 years, then slowly reduced by 1 mg every 2 months. 5
Adjunctive Therapy
- Trimethoprim-sulfamethoxazole may reduce relapses, particularly in patients with Staphylococcus aureus nasal colonization (found in 72% of GPA patients) 2, 4
Prognosis and Follow-Up
- Ten-year survival rate now exceeds 80% with modern immunosuppressive therapy 3
- Relapses are frequent and require ongoing monitoring 3
- Monitor disease activity using structured clinical assessment tools rather than ANCA titers alone 5
Key Clinical Pitfalls to Avoid
Do not delay treatment waiting for biopsy confirmation in patients with rapidly progressive glomerulonephritis or alveolar hemorrhage—begin immunosuppression immediately after obtaining necessary samples 5
Do not use ANCA titers alone to guide treatment decisions—clinical assessment with validated tools is essential 5
Do not continue cyclophosphamide beyond 3-6 months due to cumulative toxicity—switch to maintenance agents 5, 4
Do not assume isolated upper respiratory symptoms are benign—check urinalysis and renal function to exclude systemic disease 5