What is chronic granulomatous polyangitis?

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 of the respiratory tract, systemic vasculitis of small-to-medium vessels, and pauci-immune glomerulonephritis, strongly associated with antineutrophil cytoplasmic antibodies (ANCA). 1

Disease Classification and Nomenclature

• GPA is classified as an ANCA-associated vasculitis (AAV), which also includes microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). 1
• The 2012 Chapel Hill Consensus classification categorizes GPA based on affected blood vessel size (small-to-medium vessels), though this has limited clinical applicability since vessel involvement can be heterogeneous. 1
• The American College of Rheumatology and European League Against Rheumatism recommend using the descriptive term "Granulomatosis with Polyangiitis" rather than the eponymous "Wegener's granulomatosis" to improve diagnostic clarity. 2

Epidemiology

• The prevalence in Europe is approximately 23.7 per million, and in the USA 30 per million, with an overall incidence ranging from 2.9-12 per million per year depending on geographic region. 1
• GPA predominantly affects Caucasians, with equal sex distribution, and can occur across a wide age range (8-99 years), though peak incidence is in the fourth decade. 1, 3

Pathophysiology

• The pathophysiology is most likely autoimmune, with PR3-ANCA (proteinase-3 antibodies) being highly specific for GPA and present in 80-90% of cases. 4, 2
• ANCA induces systemic vasculitis by binding to and activating neutrophils, causing release of oxygen radicals, lytic enzymes, and inflammatory cytokines, which leads to endothelial cell damage and vasculitis. 1
• Staphylococcus aureus colonization is found in 72% of GPA patients (compared to 28% in chronic rhinosinusitis and 25% in controls) and is strongly implicated in disease relapses. 1, 4
• Genetic susceptibility involves HLA-DP, genes encoding alpha-1 antitrypsin (SERPINA1), and proteinase 3 (PRTN3). 1

Clinical Manifestations

The classic triad involves the upper respiratory tract (ENT), lungs, and kidneys—remembered by the acronym "ELK." 3

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

• Nasal crusting, stuffiness, epistaxis, and destructive sinonasal lesions are the most common initial manifestations (85-100% involvement). 1, 3
• Otological disease occurs in approximately 35% of cases. 3

Lower Respiratory Tract:

• Pulmonary nodules, cavitary lesions, and alveolar hemorrhage (pulmonary capillaritis). 1, 5

Renal Involvement:

• Rapidly progressive pauci-immune necrotizing crescentic glomerulonephritis with elevated creatinine, carrying high risk for end-stage kidney disease. 4
• The 10-year survival rate is approximately 40% when kidneys are involved versus 60-70% without renal involvement. 4, 3

Other Manifestations:

• Scleritis and other ocular involvement. 1
• The disease evolves stage-wise, typically starting as respiratory tract inflammation followed by systemic vasculitis manifestations. 5

Diagnosis

Diagnosis requires the combination of clinical features, positive PR3-ANCA serology (80-90% sensitivity), and ideally histopathological confirmation showing necrotizing vasculitis, granulomatous inflammation, and geographic necrosis. 4

• A negative ANA test helps exclude systemic lupus erythematosus and other autoimmune conditions. 4
• Disease severity is classified according to EUVAS criteria, with "generalized" or "severe" GPA defined by estimated glomerular filtration rate <50 mL/min/1.73 m² or diffuse pulmonary hemorrhage. 1, 4

Prognosis

• Without treatment, mean survival is only 5 months, but with modern immunosuppressive therapy, mean survival has improved to 21.7 years from diagnosis. 4
• Approximately 64% of patients achieve complete remission by 6 months, but relapse risk remains up to 50%, and mortality rates remain at 5% or higher even with treatment. 4
• Early mortality during the first year is primarily due to infections under immunosuppressive treatment. 5

Treatment Principles

Standard therapy combines glucocorticoids with immunosuppressive agents (rituximab or cyclophosphamide for remission induction), followed by maintenance therapy for at least 18 months. 1, 3

Remission Induction:

• Rituximab is recommended for remission induction in severe GPA. 1
• Reduced-dose glucocorticoid regimens (40% of standard dose at 6 months) reduce serious infections compared to standard dosing. 1

Maintenance Therapy:

• Rituximab, azathioprine, or methotrexate for maintenance, with duration recommended for at least 18 months, though optimal duration remains undetermined. 1, 6

Adjunctive Measures:

• Prophylactic trimethoprim-sulfamethoxazole reduces relapse rates by targeting Staphylococcus aureus colonization. 1, 4
• Nasal irrigation, topical intranasal corticosteroids, and regular debridement of crusts for upper respiratory tract involvement. 1

Plasma Exchange:

• Plasma exchange probably reduces one-year risk of end-stage kidney disease in severe AAV (particularly those requiring dialysis) but increases risk of serious infections and has little effect on mortality. 1

Important Caveats

• Endoscopic surgery has a very limited role in GPA and is associated with poor outcomes, increased scarring, and adhesions—it should be a last resort. 1
• Treatment of refractory disease activity, often represented by granulomatous manifestations, remains challenging and may result in significant organ damage if not treated successfully. 5
• A multidisciplinary approach involving otorhinolaryngologists, rheumatologists, nephrologists, pulmonologists, and ophthalmologists is essential for optimal diagnosis and management. 3
• Chronic granulomatous disease (CGD) can mimic GPA with ANCA positivity and should be considered in the differential diagnosis, particularly in patients with recurrent opportunistic infections since childhood. 7