What are the causes of Granulomatosis with Polyangiitis (GPA)?

Causes of Granulomatosis with Polyangiitis (GPA)

Granulomatosis with polyangiitis (GPA) is primarily an autoimmune disease with a complex etiology involving genetic predisposition, environmental factors, and potential infectious triggers that interact to cause small vessel vasculitis and granulomatous inflammation.

Pathophysiology

GPA is characterized by three main pathological features:

• Necrotizing granulomatous inflammation
• Systemic small vessel vasculitis
• Necrotizing glomerulonephritis

Autoimmune Mechanisms

• The disease is strongly associated with anti-neutrophil cytoplasmic antibodies (ANCA), particularly those directed against proteinase-3 (PR3-ANCA) 1
• ANCA induces systemic vasculitis by:
  • Binding to and activating neutrophils
  • Causing release of oxygen radicals, lytic enzymes, and inflammatory cytokines
  • Inducing immune complex formation
  • Directly adhering to and killing endothelial cells 1
• PR3-ANCA is highly specific for GPA and is present in approximately 90% of systemic forms and 50% of localized forms 2

Genetic Factors

Several genetic associations have been identified:

• Strong association with HLA-DP and genes encoding:
  • Alpha1 antitrypsin (SERPINA1)
  • Proteinase 3 (PRTN3) 1
• Other susceptibility genes include:
  • CTLA4
  • PTPN22
  • COL11A2
  • MHC class II gene cluster 3
• Familial cases of GPA have been reported, with shared HLA haplotypes, particularly HLA-DPB1*04:01 allele 4
• Genetic predisposition appears to be stronger in Caucasians, who represent 93% of GPA cases 1, 5

Environmental and Infectious Triggers

• Staphylococcus aureus: Nasal colonization is found more frequently in GPA patients compared to controls (72% vs 25%) 1

  • S. aureus has been strongly implicated as a causative agent, especially in disease relapses
  • Relapses can be reduced by using trimethoprim/sulfamethoxazole 1, 5

• Other environmental exposures associated with increased risk:

  • Silica
  • Organic solvents
  • Farming 1

Demographic and Clinical Patterns

• Predominantly affects Caucasians (93%)
• Peak incidence in fourth to fifth decades (mean age 50 years)
• Age range: 9-97 years
• Equal gender distribution, though males may have more severe disease 1, 5
• Prevalence: 23.7-30 per million in Europe and USA
• Incidence: 2.9-12 per million per year depending on geographic region 1, 5

Disease Presentation and Classification

GPA typically presents with:

• Upper respiratory tract involvement (70-100% of cases)
• Pulmonary manifestations
• Renal involvement (glomerulonephritis)

The European Vasculitis Study Group classifies GPA as:

• Localized (restricted to respiratory tract)
• Early systemic (non-imminent without renal involvement)
• Generalized 1

Clinical Implications

Understanding the causes of GPA has important implications for management:

• Genetic testing may be considered in familial cases
• Nasal swabs to detect S. aureus colonization can guide prophylactic antibiotic therapy
• Trimethoprim/sulfamethoxazole may reduce relapses in patients with S. aureus colonization 1, 5

Pitfalls and Caveats

• The diagnosis of GPA should not rely solely on ANCA testing, as some patients may be ANCA-negative
• Environmental triggers may vary between populations and geographic regions
• The genetic associations identified so far explain only a portion of disease susceptibility
• Early diagnosis and treatment are crucial, as untreated GPA has a high mortality rate (estimated 10-year survival rate of 40% with kidney involvement) 6
• A multidisciplinary approach involving rheumatologists, nephrologists, pulmonologists, and ENT specialists is essential for comprehensive management

In summary, GPA results from a complex interplay between genetic predisposition, environmental exposures, and infectious triggers (particularly S. aureus) that lead to autoimmune small vessel vasculitis and granulomatous inflammation.