What is granulomatosis with polyangitis?

Granulomatosis with Polyangiitis: Definition and Overview

Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, is a rare autoimmune small-vessel vasculitis characterized by necrotizing granulomatous inflammation of the respiratory tract, necrotizing vasculitis of small to medium-sized vessels, and necrotizing glomerulonephritis affecting primarily the upper airways, lungs, and kidneys. 1, 2

Core Pathological Features

The disease is defined by three cardinal histopathological hallmarks that distinguish it from other vasculitides:

• Necrotizing vasculitis involving small arteries and arterioles 2, 3
• Necrotizing granulomatous inflammation with geographic necrosis patterns 2, 4
• Tissue eosinophilia and inflammatory infiltrates in affected organs 3

Epidemiology and Demographics

GPA demonstrates specific population characteristics that inform clinical suspicion:

• Prevalence ranges from 23.7 to 30 per million population in Europe and the United States 1
• Incidence varies from 2.9 to 12 cases per million per year depending on geographic region 1
• Peak age at diagnosis is middle-aged to elderly adults (mean ~50 years), with equal gender distribution 5
• Racial predilection strongly favors Caucasians, though all racial groups can be affected 5

Clinical Presentation Pattern

GPA typically evolves through a characteristic sequence, though phases often overlap:

Upper Respiratory Tract Manifestations (70-100% of cases)

• Nasal symptoms: Chronic rhinosinusitis, nasal crusting, stuffiness, and epistaxis are often the first presenting features 6, 5
• ENT involvement: Otitis media, hearing loss, and potential nasal septal perforation in advanced cases 6
• Sinus disease: Paranasal sinus abnormalities occur in 85-100% of head and neck involvement 5

Lower Respiratory Tract Disease

• Pulmonary manifestations: Infiltrates, nodules, and potentially life-threatening alveolar hemorrhage in severe cases 6, 4
• Bronchial involvement: Necrotizing inflammation affecting the airways 4

Renal Involvement

• Glomerulonephritis: Pauci-immune necrotizing crescentic glomerulonephritis is the hallmark renal manifestation 2
• Clinical presentation: Hematuria, proteinuria, and progressive renal dysfunction with elevated creatinine 2, 6

Systemic Manifestations

• Neurological: Peripheral neuropathy and potential CNS involvement 6
• Cutaneous: Palpable purpura and other skin lesions 6
• Musculoskeletal: Arthralgia and myalgia 6
• Ocular: Scleritis and other eye manifestations 6

Serological Hallmark

PR3-ANCA (proteinase-3 anti-neutrophil cytoplasmic antibodies) positivity occurs in 80-90% of GPA cases and is highly specific for this diagnosis, distinguishing it from other vasculitides 2, 6. However, ANCA negativity does not exclude the diagnosis when clinical and histological features are consistent 3.

Pathophysiology

The disease mechanism involves a complex autoimmune process:

• ANCA-mediated pathogenesis: Autoantibodies bind to and activate neutrophils, causing release of oxygen radicals, lytic enzymes, and inflammatory cytokines that damage vessel walls 1
• Genetic susceptibility: Strong associations with HLA-DP, SERPINA1 (alpha-1 antitrypsin), and PRTN3 (proteinase 3) genes 1
• Environmental triggers: Staphylococcus aureus colonization found in 72% of GPA patients and strongly implicated in disease relapses 2

Prognosis Without Treatment

Untreated GPA has a mean survival of only 5 months, making early diagnosis and treatment critical 2. With modern immunosuppressive therapy, mean survival has improved dramatically to 21.7 years from diagnosis, though 10-year survival remains approximately 40% when kidneys are involved 2.

Clinical Importance for ENT Physicians

ENT physicians have a determining role in recognizing early disease onset, as upper respiratory tract symptoms are often the first manifestation in 70-100% of cases, occurring before systemic vasculitis develops 5. Early recognition and referral for appropriate immunosuppressive therapy is essential to prevent progression to life-threatening systemic disease and renal failure 5.