What is the clinical description of Granulomatosis with Polyangiitis (GPA)?

Clinical Description of Granulomatosis with Polyangiitis (GPA)

Granulomatosis with polyangiitis (GPA) is an idiopathic chronic inflammatory disease characterized by necrotizing granulomatous lesions and systemic vasculitis strongly associated with antineutrophil cytoplasmic antibodies (C-ANCA). 1

Definition and Classification

GPA (previously known as Wegener's Granulomatosis) is classified as an ANCA-associated vasculitis (AAV) that primarily affects small- to medium-sized blood vessels. It belongs to a group of vasculitides that includes microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). 1

The 2012 Chapel Hill Consensus on vasculitis nomenclature classifies GPA as a primary small vessel vasculitis, though it may be difficult to determine the exact size of vessels involved in GPA. 1

Epidemiology

• Prevalence: 23.7-30 per million in Europe and the USA 1
• Incidence: 2.9-12 per million per year depending on geographic region 1
• Age: Peak incidence in fourth to fifth decades (mean 50 years), but can occur at any age (range 9-97 years) 1
• Gender: Men and women are equally affected, though males may have more severe disease 1
• Race: Predominantly affects Caucasians (93%) 1

Pathophysiology

The pathophysiology of GPA is most likely autoimmune in nature:

• ANCA (particularly PR3-ANCA/proteinase-3) is highly specific for GPA and plays a key role in inducing systemic vasculitis 1
• Mechanism of action:
  • ANCA binds to and activates neutrophils, causing release of oxygen radicals, lytic enzymes, and inflammatory cytokines
  • ANCA may induce immune complex formation
  • ANCA may directly adhere to and kill endothelial cells, causing vasculitis 1

Environmental and Genetic Factors:

• Infectious triggers: Staphylococcus aureus nasal colonization is found more frequently in GPA compared to controls (72% vs 25%) and has been implicated in disease relapses 1
• Genetic susceptibility: Associated with HLA-DP and genes encoding alpha1 antitrypsin (SERPINA1) and proteinase 3 (PRTN3) 1
• Other susceptibility genes include CTLA4, PTPN22, COL11A2, and MHC class II gene cluster 1

Clinical Manifestations

GPA can present with a wide spectrum of manifestations, ranging from limited disease to severe multisystem involvement:

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

• Destructive sinonasal lesions
• Chronic rhinosinusitis
• Nasal crusting, epistaxis
• Saddle nose deformity
• Otological manifestations (in approximately 35% of cases)

2. Pulmonary Manifestations

• Pulmonary nodules or masses
• Alveolar hemorrhage
• Infiltrates

3. Renal Manifestations

• Pauci-immune glomerulonephritis
• Rapidly progressive glomerulonephritis

4. Ocular Manifestations

• Conjunctivitis
• Episcleritis
• Scleritis
• Anterior uveitis 2

5. Other Manifestations

• Skin lesions (palpable purpura)
• Neurological involvement (mononeuritis multiplex)
• Cardiac involvement
• Gastrointestinal involvement

Diagnosis

The diagnosis of GPA relies on a combination of:

1. Clinical assessment: Characteristic pattern of multisystem involvement

2. Laboratory tests:

   • ANCA testing (C-ANCA/PR3-ANCA is highly specific for GPA)
   • Elevated inflammatory markers (ESR, CRP)
   • Renal function tests

3. Histopathology: The gold standard for diagnosis showing:

   • Necrotizing granulomatous inflammation
   • Vasculitis of small- to medium-sized vessels
   • Tissue necrosis

4. Imaging studies:

   • CT and MRI are primary imaging modalities
   • Can show characteristic findings in sinuses, lungs, and other affected organs 3

Treatment

Treatment strategies are tailored to disease severity:

For Severe Disease:

• Remission induction: Rituximab (375 mg/m² once weekly for 4 weeks) plus glucocorticoids is recommended 1, 4
• Alternative: Cyclophosphamide plus glucocorticoids

For Maintenance Therapy:

• Rituximab has shown efficacy for maintenance therapy in severe GPA 1
• Alternative maintenance options include azathioprine

For Limited Disease:

• Less aggressive immunosuppression may be appropriate
• Trimethoprim/sulfamethoxazole may help reduce relapses, especially in patients with S. aureus colonization 1

Prognosis

With modern treatment regimens, the prognosis of GPA has significantly improved:

• Prior to effective treatment, median survival was approximately 5 months 1
• Current treatments have dramatically improved outcomes, though they are still associated with toxicity
• 10-year survival rate is estimated at 40% with kidney involvement and 60-70% without kidney involvement 5

Monitoring

Regular monitoring for:

• Disease activity
• Treatment response
• Medication side effects
• Infection (a common complication of immunosuppressive therapy)

Early diagnosis and prompt treatment are essential to prevent organ damage and improve outcomes in patients with GPA.