How should I evaluate a patient for granulomatosis with polyangiitis (Wegener's granulomatosis)?

Evaluation of Granulomatosis with Polyangiitis (Wegener's Granulomatosis)

Begin with immediate PR3-ANCA (c-ANCA) testing and systematic assessment of the upper respiratory tract, lungs, and kidneys, as PR3-ANCA is positive in 80-90% of GPA cases and is highly specific for diagnosis. 1, 2

Initial Clinical Assessment

Upper Respiratory Tract Manifestations

• Look specifically for nasal crusting, persistent stuffiness, and epistaxis (nosebleeds), which occur in 70-100% of GPA patients and are often the presenting symptoms 1, 2
• Examine for chronic rhinosinusitis with possible nasal polyps, otitis media, and hearing loss 1
• Advanced cases may show nasal septal perforation or saddle-nose deformity from cartilaginous destruction 1
• Arrange ENT consultation with nasal endoscopy to identify friable erythematous mucosa with granulation tissue 1

Pulmonary Evaluation

• Assess for cough and hemoptysis, which occur in >95% of patients with lower respiratory tract disease 1
• Order chest CT (more sensitive than plain radiographs) to detect pulmonary infiltrates, nodules, or cavitation 2
• Evaluate for diffuse alveolar hemorrhage in severe presentations, manifesting as diffuse alveolar infiltrates 1
• Perform pulmonary function testing to detect restrictive or obstructive patterns and assess for subglottic stenosis 1
• Be alert for subglottic stenosis (occurs in 5-23% of treated patients), which presents insidiously with persistent cough, wheezing, and dyspnea often misdiagnosed as asthma 1

Renal Assessment

• Obtain urinalysis looking specifically for hematuria, proteinuria, and red blood cell casts, which indicate pauci-immune necrotizing crescentic glomerulonephritis 1, 2
• Measure 24-hour protein excretion or urine protein-to-creatinine ratio when urinalysis is abnormal 1
• Check serum creatinine and BUN to assess renal function 1
• Obtain kidney biopsy in patients with significant proteinuria (>1 g/day), glomerular hematuria, or unexplained decline in renal function to confirm pauci-immune necrotizing crescentic glomerulonephritis 1

Systemic Manifestations

• Examine for peripheral neuropathy (occurs in 44-63% of patients), particularly mononeuritis multiplex 1
• Look for skin lesions including palpable purpura 1
• Assess for scleritis and other ocular manifestations 1
• Evaluate for arthralgia and myalgia 1

Laboratory Evaluation

Serologic Testing

• PR3-ANCA (c-ANCA) is the critical first diagnostic test, with 80-90% sensitivity and high specificity for GPA 1, 2
• The likelihood of positive ANCA increases with more widespread and severe clinical involvement 1
• Important caveat: In disease limited to the sinonasal tract, ANCA may be negative, complicating diagnosis 1
• Elevated ESR (typically ≈60 mm/hr) reflects active systemic inflammation 1

Additional Laboratory Studies

• Complete blood count with differential 1
• Renal function tests (creatinine, BUN) 1
• Inflammatory markers (ESR, CRP) 1
• Screen for hepatitis B, HIV, and tuberculosis before initiating immunosuppression 3

Histopathologic Confirmation

Biopsy of affected organs is strongly recommended when feasible to confirm diagnosis, as a positive biopsy is strongly supportive of vasculitis. 4

Tissue Sampling Strategy

• Definitive diagnosis requires the combination of clinical features, positive ANCA serology, and biopsy evidence of necrotizing vasculitis with granulomatous inflammation 1
• Critical pitfall: Nasal biopsies frequently lack sufficient diagnostic features; therefore, tissue sampling from other affected organs (lung or kidney) is often necessary for definitive histologic confirmation 1
• Kidney biopsy typically shows crescentic necrotizing glomerulonephritis, a hallmark feature 1
• Histopathology should demonstrate necrotizing vasculitis involving small vessels, extensive "geographic" necrosis, and granulomatous inflammation 5, 6

Additional Diagnostic Studies

Imaging

• High-resolution chest CT for pulmonary assessment 2
• Sinus CT when upper respiratory tract involvement is suspected 2
• Brain and/or spinal cord MRI for evaluating CNS manifestations 1

Specialized Testing

• Audiometry when hearing loss or middle-ear disease is suspected 1
• Electromyography and nerve conduction studies when peripheral neuropathy is clinically suspected 1

Disease Activity Assessment

Use the Birmingham Vasculitis Activity Score (BVAS) as the primary validated tool for assessing disease activity, and the Five-Factor Score (FFS) to predict mortality risk. 1

• BVAS evaluates manifestations across multiple systems including systemic, cutaneous, mucous/ocular, ENT, pulmonary, cardiovascular, gastrointestinal, and renal domains 1

Differential Diagnosis Considerations

Distinguish from Other Vasculitides

• Eosinophilic granulomatosis with polyangiitis (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
• IgA vasculitis and cryoglobulinemic vasculitis show immune-complex deposition on biopsy, whereas GPA demonstrates a pauci-immune (minimal immune-deposit) pattern 1
• Polyarteritis nodosa (PAN) is ANCA-negative and involves medium vessels 1

Other Mimics to Exclude

• Giant cell arteritis (in patients >50 years with chronic cough, but typically involves extracranial arteries with temporal artery abnormalities) 1
• Lung malignancy (consider in differential of pulmonary manifestations) 1

Classification Criteria (For Research, Not Clinical Diagnosis)

The American College of Rheumatology classification requires any two of four features: (1) biopsy-proven necrotizing granulomatous vasculitis, (2) urinary sediment with red blood cells or red cell casts, (3) abnormal chest imaging, and (4) oral or nasal inflammation. These criteria are intended solely for research classification and are not recommended as diagnostic criteria in routine clinical practice. 1, 7

Critical Management Principle

Treatment should not be delayed while awaiting kidney biopsy results if clinical presentation is compatible with small-vessel vasculitis and ANCA serology (PR3) is positive. 3