What is Granulomatosis with Polyangiitis (GPA)?

What is Granulomatosis with Polyangiitis (GPA)?

Granulomatosis with polyangiitis (GPA), formerly known as Wegener's Granulomatosis, is an idiopathic chronic inflammatory disease characterized by necrotizing granulomatous lesions and systemic vasculitis of small and medium vessels, strongly associated with anti-neutrophil cytoplasmic antibodies (ANCA), particularly PR3-ANCA. 1

Disease Definition and Classification

GPA is classified as an ANCA-associated vasculitis (AAV) that affects small and medium-sized blood vessels. 1 The disease is defined by three pathological hallmarks:

• Necrotizing granulomatous inflammation of the respiratory tract 1, 2
• Systemic necrotizing vasculitis of small and medium vessels 2, 3
• Pauci-immune necrotizing glomerulonephritis when kidneys are involved 4, 3

The Chapel Hill Consensus classification system categorizes GPA as a small-vessel vasculitis, though determining exact vessel size involvement can be challenging in clinical practice. 1

Epidemiology

GPA predominantly affects Caucasians with equal distribution between men and women, with peak incidence in the fourth to fifth decades (mean age 50 years). 1

Prevalence and incidence data:

• European prevalence: 23.7 per million population 1
• United States prevalence: 30 per million 1
• Overall incidence: 2.9-12 per million per year depending on geographic region 1
• Age range: 8-99 years, though pediatric cases are rare 5

Pathophysiology

The pathophysiology is most likely autoimmune, with PR3-ANCA playing a central pathogenic role by binding to and activating neutrophils. 1

Key pathogenic mechanisms include:

• ANCA-induced neutrophil activation releases oxygen radicals, lytic enzymes, and inflammatory cytokines 1
• Immune complex formation and direct endothelial cell damage causing vasculitis 1
• Staphylococcus aureus colonization found in 72% of GPA patients (versus 28% in chronic rhinosinusitis and 25% in controls), strongly implicated in disease relapses 1, 4

Genetic susceptibility involves:

• HLA-DP association 1
• SERPINA1 (alpha-1 antitrypsin) and PRTN3 (proteinase 3) genes 1
• Additional susceptibility genes: CTLA4, PTPN22, COL11A2, and MHC class II gene cluster 1

Clinical Manifestations

GPA classically affects the upper respiratory tract (70-100% of cases), lungs, and kidneys—remembered by the acronym "ELK" (ENT, Lungs, Kidneys). 5

Upper Respiratory Tract (Most Common Initial Presentation)

• Nasal crusting, stuffiness, and epistaxis are common presenting symptoms 6
• Chronic rhinosinusitis with or without nasal polyps (85-100% of cases) 1, 5
• Nasal septal perforation in advanced cases 6
• Otological disease including otitis media and hearing loss (19-61% of cases) 1, 5

Lower Respiratory Tract

• Pulmonary nodules or masses (granulomatous manifestation) 3
• Pulmonary infiltrates 6
• Alveolar hemorrhage in severe cases (vasculitic manifestation) 3

Renal Involvement

• Pauci-immune necrotizing crescentic glomerulonephritis is the hallmark renal manifestation 4, 6
• Presents with hematuria, proteinuria, and elevated creatinine 6
• Renal involvement indicates "generalized" or "severe" GPA with high risk of progressive dysfunction 4

Other Systemic Manifestations

• Peripheral neuropathy including mononeuritis multiplex 6, 3
• Ocular involvement including scleritis and retro-orbital tumors 6, 3
• Skin lesions including palpable purpura 6
• Arthralgia and myalgia 6
• Pachymeningitis (central nervous system involvement) 3

Serological Markers

PR3-ANCA (c-ANCA) is highly specific for GPA and present in 80-90% of cases. 4, 6

Important serological considerations:

• ANCA testing should be performed in all suspected cases 6
• 10-20% of GPA patients are ANCA-negative, making diagnosis more challenging 1
• Negative ANA helps exclude systemic lupus erythematosus and other autoimmune conditions 4

Diagnosis

Diagnosis is based on the combination of clinical features, positive PR3-ANCA serology, and histopathological confirmation when feasible. 4, 2

Diagnostic Approach

• Clinical assessment of characteristic organ involvement (upper respiratory tract, lungs, kidneys) 4
• ANCA testing (PR3-ANCA highly specific) 4, 6
• Histopathological confirmation showing necrotizing vasculitis, granulomatous inflammation, and geographic necrosis 4
• Biopsy is strongly recommended but not always essential if clinical and serological features are highly suggestive 2, 7

Essential Laboratory Tests

• Complete blood count with differential 6
• Urinalysis for hematuria and proteinuria 6
• Inflammatory markers (ESR, CRP) 6
• Renal function tests (creatinine, BUN) 6

Imaging Studies

• CT and MRI are primary modalities for evaluating GPA manifestations 3
• Chest imaging for pulmonary involvement 6
• Sinus imaging for upper respiratory tract disease 6

Important Caveat

Classification criteria (1990 ACR criteria and 2022 ACR-EULAR criteria) should NOT be used as diagnostic criteria, as they were developed for research classification, not clinical diagnosis. 1 These criteria have established sensitivity and specificity for distinguishing GPA from other vasculitides but are not designed to diagnose GPA in individual patients.

Disease Assessment Tools

The Birmingham Vasculitis Activity Score (BVAS) is the primary validated tool for assessing disease activity. 6

• Five-Factor Score (FFS) predicts mortality risk based on prognostic factors 6
• BVAS evaluates manifestations across multiple organ systems 6

Prognosis

Without treatment, GPA has a mean survival of only 5 months, but with modern immunosuppressive therapy, mean survival has improved to 21.7 years from diagnosis. 4

Survival statistics:

• 10-year survival rate: 40% when kidneys are involved 4, 5
• 10-year survival rate: 60-70% without kidney involvement 5
• Complete remission achieved in approximately 64% of patients by 6 months 4
• Relapse risk: up to 50% of patients 4
• Mortality rates: 5% or higher even with treatment 4

Treatment Principles

Standard remission-induction therapy for generalized GPA is glucocorticoids combined with either cyclophosphamide or rituximab. 1, 6

Remission Induction

• Severe disease (organ-threatening manifestations): glucocorticoids plus cyclophosphamide or rituximab 1, 6
• Plasma exchange may be considered for pulmonary hemorrhage or severe renal involvement 6

Maintenance Therapy

• Options include azathioprine, methotrexate, rituximab, or co-trimoxazole 6
• In young patients, cyclophosphamide should be switched to azathioprine in the maintenance phase 5

Adjunctive Therapy

Prophylactic trimethoprim/sulfamethoxazole reduces relapse rates by targeting Staphylococcus aureus colonization 4

Multidisciplinary Management

A multidisciplinary approach is necessary for diagnosis and treatment, involving otorhinolaryngologists, rheumatologists, nephrologists, pulmonologists, and ophthalmologists. 5

ENT physicians have a determining role in recognizing early disease onset since upper respiratory tract involvement is the most common initial presentation. 5