What are the typical signs, symptoms, and diagnostic work‑up for granulomatosis with polyangiitis (Wegener’s granulomatosis) in an adult patient?

Signs, Symptoms, and Diagnosis of Granulomatosis with Polyangiitis (Wegener's)

Clinical Presentation

Granulomatosis with polyangiitis (GPA) classically presents with the "ELK" triad: ENT (ear, nose, throat), lung, and kidney involvement, though upper respiratory symptoms are the most common initial manifestation. 1

Upper Respiratory Tract Manifestations (Most Common)

• Persistent nasal crusting, stuffiness, and epistaxis occur in >90% of patients and represent the hallmark presenting symptoms 1, 2
• Chronic sinusitis with purulent or bloody nasal discharge is the most frequent initial upper-respiratory manifestation 2
• Persistent bleeding, crusting, and nasal obstruction are characteristic sinonasal features 3
• Nasal septal perforation develops in advanced cases 3, 1
• Otitis media and hearing loss may occur 3
• Subglottic stenosis develops in 5-23% of treated patients, presenting with persistent cough, wheezing, and dyspnea that may be misdiagnosed as asthma 1

Pulmonary Manifestations

• Cough and hemoptysis occur in >95% of patients with lower respiratory tract disease 1
• Pulmonary infiltrates and nodules are common radiographic findings 1
• Diffuse alveolar hemorrhage can occur in severe cases, manifesting as diffuse alveolar infiltrates on chest imaging 1
• Tracheobronchial stenosis occurs in 15% of patients 1

Renal Manifestations

• Rapidly progressive glomerulonephritis presenting with hematuria, red-cell casts, and proteinuria signals severe systemic disease 2
• Pauci-immune necrotizing crescentic glomerulonephritis is the characteristic histopathologic pattern 1, 2
• Declining glomerular filtration rate (GFR) indicates organ-threatening renal involvement 2

Systemic and Other Manifestations

• Scleritis and other ocular manifestations commonly accompany nasal symptoms 1
• Peripheral neuropathy, skin lesions including palpable purpura, arthralgia, and myalgia are common systemic features 1
• Non-specific systemic symptoms including fever, malaise, and weight loss 1

Diagnostic Evaluation

The diagnosis of GPA requires a combination of clinical features, positive ANCA serology, and histologic confirmation showing necrotizing vasculitis and granulomatous inflammation. 3

Laboratory Testing

• PR3-ANCA (c-ANCA) testing is mandatory and is positive in 80-90% of patients with generalized GPA, making it highly specific for this disease 1, 2, 4
• ANCA testing must be performed with high-quality, antigen-specific assays for both PR3-ANCA and MPO-ANCA 2
• In cases limited to the sinonasal tract, ANCA can be negative, making diagnosis challenging 3
• The more widespread and severe the presentation, the more likely serum ANCA is to be positive 3

Essential Baseline Laboratory Studies

• Urinalysis to detect hematuria, dysmorphic red cells, red-cell casts, and proteinuria is essential for identifying renal disease 2
• Complete blood count with differential, ESR/CRP, and serum creatinine/GFR should be obtained to assess systemic inflammation and renal function 2
• Elevated ESR (approximately 60 mm/hr) reflects active systemic inflammation typical of GPA 1

Tissue Biopsy

• Biopsy confirmation is required whenever feasible because clinical and serologic data alone may be insufficient 2
• The combination of clinical features, positive ANCA serology, necrotizing vasculitis, and granulomatous inflammation on biopsy establishes the diagnosis 3
• Nasal biopsies often lack sufficient specific features to confirm the diagnosis, and biopsies from other involved organs may be required 3
• Skin biopsy should include the subcutis and be taken from the most tender, erythematous, or purpuric lesion 2
• Kidney biopsy typically shows crescentic necrotizing glomerulonephritis, a hallmark feature 1

Additional Diagnostic Studies

• Chest imaging to evaluate for pulmonary infiltrates, nodules, or alveolar hemorrhage 1
• Pulmonary function tests for assessing respiratory involvement 1
• Brain and/or spinal cord MRI for evaluating CNS manifestations when indicated 1
• Electromyography and nerve conduction studies for neurological involvement 1

Diagnostic Criteria

The American College of Rheumatology requires 2 of 4 criteria for diagnosis: 5

• Positive biopsy for granulomatous vasculitis
• Urinary sediment with red blood cells
• Abnormal chest radiograph
• Oral/nasal inflammation

Key Diagnostic Pitfalls and How to Avoid Them

• Do not delay immunosuppressive therapy while awaiting biopsy results in patients with rapidly progressive glomerulonephritis or alveolar hemorrhage; initiate treatment promptly after obtaining necessary samples 2
• ANCA titers alone must not dictate treatment decisions; disease activity should be evaluated with validated clinical tools such as the Birmingham Vasculitis Activity Score (BVAS) 2
• In patients presenting with chronic rhinosinusitis with epistaxis, systemic constitutional symptoms, and renal abnormalities, ANCA testing should be performed immediately to avoid misdiagnosis and treatment delay 1
• Subglottic stenosis symptoms may be misdiagnosed as asthma; investigate abnormal inspiratory and expiratory flow-volume loops to avoid this pitfall 1

Differential Diagnosis

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

• EGPA requires blood eosinophilia >10% and elevated IgE, which are absent in GPA 1
• Only 35-40% of EGPA patients are ANCA-positive, and when present it is usually p-ANCA/MPO rather than c-ANCA 1
• EGPA more frequently involves cardiac disease and gastrointestinal symptoms 1

Other Considerations

• Polyarteritis nodosa (PAN) is ANCA-negative, making it incompatible with the c-ANCA positivity seen in GPA 1
• Microscopic polyangiitis should be considered in the differential diagnosis 1
• Positive rheumatoid factor can occur in approximately 5% of GPA patients with atypical c-ANCA, but RF alone does not cause the necrotizing glomerulonephritis, severe sinusitis, or pulmonary hemorrhage characteristic of GPA 1