What are the typical presentations and differential diagnoses of Granulomatosis with Polyangiitis (GPA), formerly known as Wegener granulomatosis?

Granulomatosis with Polyangiitis (Wegener Granulomatosis): Clinical Presentations and Differential Diagnoses

Typical Clinical Presentations

GPA characteristically presents with the "ELK triad" of ear-nose-throat (ENT), lung, and kidney involvement, with upper respiratory tract symptoms being the initial manifestation in 70-100% of cases. 1, 2

Upper Respiratory Tract Manifestations (Most Common Initial Presentation)

• Nasal symptoms including crusting, stuffiness, and epistaxis are the most frequent presenting complaints 1
• Chronic rhinosinusitis with possible nasal polyps occurs commonly 1
• Nasal septal perforation develops in advanced cases 1
• Otitis media and hearing loss may occur 1
• Subglottic stenosis develops in 5-23% of treated patients, presenting insidiously with persistent cough, wheezing, and dyspnea that may initially be misdiagnosed as asthma 3

Lower Respiratory Tract Involvement (>90% of Patients)

• Cough and hemoptysis occur in >95% of patients with lower respiratory tract disease 3
• 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 3, 1
• Tracheobronchial stenosis occurs in 15% of patients 3
• Clinical presentation ranges from subacute nonspecific respiratory illness to rapidly progressive respiratory insufficiency 3

Renal Involvement (Hallmark Feature)

• Glomerulonephritis is a defining feature of GPA, though not always present at initial presentation 1
• Manifests as proteinuria, hematuria, and varying degrees of kidney failure 1
• Kidney biopsy shows crescentic necrotizing glomerulonephritis, the pathologic hallmark 1
• Elevated serum creatinine indicates pauci-immune necrotizing crescentic glomerulonephritis 4
• Without treatment, renal involvement carries a 10-year survival rate of only 40% 2

Systemic and Other Manifestations

• Peripheral neuropathy is a common systemic manifestation 1
• Skin lesions including palpable purpura 1
• Arthralgia and myalgia 1
• Scleritis and other ocular manifestations 1
• Non-specific systemic symptoms including fever, malaise, and weight loss 3

Diagnostic Evaluation

Laboratory Findings

• PR3-ANCA (c-ANCA) is positive in 80-90% of GPA cases and is highly specific for this diagnosis 1, 4
• Urinalysis shows hematuria and proteinuria in cases with renal involvement 1
• Complete blood count with differential, inflammatory markers (ESR, CRP), and renal function tests (creatinine, BUN) are essential 1
• Negative ANA helps exclude systemic lupus erythematosus 4

Histopathologic Confirmation

• Biopsy of affected organs demonstrates necrotizing vasculitis of small arteries, granulomatous inflammation, and geographic necrosis 4, 5
• Biopsy should be performed when feasible to confirm diagnosis 1

Differential Diagnoses

Primary Differential: Other ANCA-Associated Vasculitides

• Microscopic polyangiitis (MPA) is the most important differential, sharing many features with GPA including ANCA positivity and renal involvement, but lacking granulomatous inflammation and upper respiratory tract involvement 1, 6
• Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome) should be considered, particularly when eosinophilia is present; overlap syndromes can occur with features of both GPA and EGPA 1, 7

Other Vasculitides and Systemic Conditions

• Giant cell arteritis can present with chronic cough in patients >50 years old, but typically involves extracranial arteries of the head and neck with temporal artery abnormalities 3
• Systemic lupus erythematosus (excluded by negative ANA) 4
• Other small-vessel vasculitides 1

Organ-Specific Differential Diagnoses

For pulmonary manifestations:

• Lung malignancy (when nodules or masses are present)
• Tuberculosis or fungal infections (when cavitary lesions present)
• Goodpasture syndrome (when alveolar hemorrhage is prominent)

For upper respiratory tract manifestations:

• Chronic rhinosinusitis from other causes
• Nasal malignancy
• Cocaine-induced midline destructive lesions

For renal manifestations:

• Other causes of rapidly progressive glomerulonephritis
• Anti-GBM disease (Goodpasture syndrome)

Clinical Pitfalls and Caveats

• Subglottic stenosis symptoms are insidious and may be misdiagnosed as asthma; abnormal inspiratory and expiratory flow-volume loops should prompt further investigation 3
• ANCA can be negative in 10-20% of cases, so diagnosis should not be excluded based solely on negative serology 1, 4
• Upper respiratory tract involvement may precede systemic manifestations by months to years 2
• Staphylococcus aureus colonization occurs in 72% of GPA patients and is strongly implicated in disease relapses, warranting prophylactic trimethoprim/sulfamethoxazole 4
• Relapse risk is up to 50% even with appropriate treatment 4