What is Granulomatosis with Polyangiitis (GPA) vasculitis?

Granulomatosis with Polyangiitis (GPA) Vasculitis

Granulomatosis with polyangiitis (GPA) is an idiopathic chronic inflammatory disease characterized by necrotizing granulomatous lesions and systemic small to medium-sized vessel vasculitis that is strongly associated with anti-neutrophil cytoplasmic antibodies (ANCA), particularly PR3-ANCA. 1

Epidemiology and Classification

• Prevalence: 23.7-30 per million in Europe and USA
• Incidence: 2.9-12 per million per year
• Peak age: 40-50 years (range 9-97 years)
• Gender: Equal distribution, though males may have more severe disease
• Demographics: Predominantly affects Caucasians (93%)
• Classification: One of the ANCA-associated vasculitides (AAV), alongside microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) 1

Pathophysiology

• ANCA (particularly PR3-ANCA/proteinase-3) is highly specific for GPA and plays a central role in disease pathogenesis
• Mechanism involves:
  • ANCA binding to and activating neutrophils
  • Release of oxygen radicals, lytic enzymes, and inflammatory cytokines
  • Formation of immune complexes
  • Direct endothelial cell damage causing vasculitis 1

Risk Factors and Triggers

• Staphylococcus aureus nasal colonization (found in 72% of GPA patients vs 25% of controls)
• Genetic susceptibility factors:
  • HLA-DP genes
  • Alpha1 antitrypsin (SERPINA1)
  • Proteinase 3 (PRTN3)
  • CTLA4, PTPN22, COL11A2, and MHC class II gene cluster 1

Clinical Manifestations

GPA typically affects multiple organ systems with varying severity:

1. Upper Respiratory Tract (70-100% of cases):

   • Chronic rhinosinusitis, nasal crusting, epistaxis
   • Saddle nose deformity from cartilage destruction
   • Otological manifestations
   • Septal perforation 2, 1

2. Pulmonary (common):

   • Nodules or masses (often cavitating)
   • Alveolar hemorrhage
   • Infiltrates 1, 3

3. Renal:

   • Pauci-immune glomerulonephritis
   • Rapidly progressive glomerulonephritis 1

4. Ocular:

   • Conjunctivitis, episcleritis, scleritis
   • Anterior uveitis 1

5. Other systems:

   • Skin lesions
   • Neurological involvement (including mononeuritis multiplex)
   • Cardiac involvement
   • Gastrointestinal involvement 2, 1

Diagnostic Approach

Diagnosis relies on a combination of:

1. Clinical assessment:

   • Characteristic pattern of multi-system involvement
   • Persistent bleeding, crusting and obstruction of sinonasal cavity
   • Development of septal perforation 2

2. Laboratory testing:

   • ANCA testing: PR3-ANCA (c-ANCA) is present in 80-90% of GPA cases
   • Elevated inflammatory markers
   • In cases limited to sinonasal tract, ANCA may be negative 2, 1

3. Histopathology:

   • Necrotizing granulomatous inflammation
   • Vasculitis of small to medium-sized vessels
   • Tissue necrosis
   • Note: Nasal biopsies often lack specific features to confirm diagnosis 2, 1

4. Imaging studies:

   • CT and MRI to assess extent of disease 1

Differential Diagnosis

Important to distinguish from other ANCA-associated vasculitides:

• Eosinophilic granulomatosis with polyangiitis (EGPA):

  • Characterized by asthma, eosinophilia
  • More common in patients with adult-onset asthma
  • Often presents with chronic rhinosinusitis with eosinophilic nasal polyps
  • p-ANCA (MPO) positive in approximately 35% of cases 2

• Microscopic polyangiitis (MPA):

  • Lacks granulomatous inflammation
  • Different pattern of organ involvement 1

Treatment

Treatment approach depends on disease severity:

1. Remission Induction:

   • First-line therapy: Rituximab (375 mg/m² once weekly for 4 weeks) plus glucocorticoids
   • Alternative: Cyclophosphamide plus glucocorticoids 1, 4

2. Maintenance Therapy:

   • Rituximab has shown efficacy for maintenance in severe GPA
   • Alternatives: Azathioprine or less aggressive immunosuppression
   • In young patients, cyclophosphamide should be switched to azathioprine in the maintenance phase 1, 5

3. Adjunctive Therapy:

   • Trimethoprim/sulfamethoxazole may help reduce relapses, especially in patients with S. aureus colonization 1

Prognosis

• Without treatment: 50% mortality within 6 months 6
• With modern treatment: 10-year survival rate of 40% with kidney involvement and 60-70% without kidney involvement 1, 5
• Regular monitoring is essential for:
  • Disease activity
  • Treatment response
  • Medication side effects
  • Infection prevention 1

Special Considerations

• Overlapping with other autoimmune conditions like rheumatoid arthritis is extremely rare 7
• Superinfections can complicate management and delay immunosuppressive treatment 8
• Multidisciplinary approach involving rheumatologists, ENT specialists, nephrologists, pulmonologists, and ophthalmologists is crucial for optimal management 5