What is the recommended approach for diagnosing and treating a patient with suspected Granulomatosis with Polyangiitis (GPA)?

Wegener Evaluation (Granulomatosis with Polyangiitis)

For suspected GPA, immediately obtain PR3-ANCA testing and initiate a systematic evaluation of upper respiratory tract, lungs, and kidneys, as PR3-ANCA is positive in 80-90% of cases and highly specific for diagnosis. 1, 2

Diagnostic Approach

Initial Clinical Assessment

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

• Nasal crusting, stuffiness, and epistaxis are the most common presenting symptoms 1, 3
• Chronic rhinosinusitis with possible nasal polyps 1
• Otitis media and hearing loss 1
• Nasal septal perforation in advanced cases 1
• Subglottic stenosis (occurs in 5-23% of treated patients, often misdiagnosed as asthma) 1

Pulmonary Manifestations:

• Pulmonary infiltrates and nodules on imaging 1
• Cough and hemoptysis (>95% of patients with lower respiratory tract disease) 1
• Diffuse alveolar hemorrhage in severe cases (medical emergency) 1

Renal Manifestations:

• Glomerulonephritis presenting as proteinuria, hematuria, and varying degrees of kidney failure 1
• Kidney biopsy typically shows crescentic necrotizing glomerulonephritis 1

Systemic Manifestations:

• Peripheral neuropathy (common and can be severe) 1
• Skin lesions including palpable purpura 1
• Scleritis and other ocular manifestations 1
• Arthralgias and myalgias 1

Essential Laboratory Testing

ANCA Testing (Critical First Step):

• PR3-ANCA is present in 84-85% of patients with GPA and is highly specific 2
• Use enzyme-linked immunosorbent assay for PR3-ANCA and MPO-ANCA (reference test for ANCA-associated vasculitis) 4
• A positive PR3-ANCA strongly supports diagnosis when combined with compatible clinical features 2

Additional Laboratory Studies:

• Complete blood count with differential 1, 2
• Renal function tests (creatinine, BUN) 1, 2
• Urinalysis (evaluate for hematuria and proteinuria) 1, 2
• Inflammatory markers (ESR, CRP) 1, 2

Imaging Studies

Chest CT (more sensitive than conventional radiographs):

• Essential for detecting pulmonary manifestations 2
• Evaluate for infiltrates, nodules, and alveolar hemorrhage 1

Sinus CT:

• Obtain when upper respiratory tract involvement is suspected 2
• Evaluate extent of rhinosinusitis 4

MRI:

• Useful for detecting CNS lesions, pachymeningitis, retro-orbital lesions, or subglottic inflammation 2

Tissue Biopsy

Biopsy of affected organs is recommended when feasible to confirm diagnosis 1, 2

• Kidney biopsy shows pauci-immune necrotizing and crescentic glomerulonephritis 5
• Lung or gastrointestinal tissue biopsies can reveal typical lesions but are seldom performed in clinical practice 4
• Sino-nasal mucosa/polyp biopsies are often non-diagnostic 4

Important caveat: Do not delay treatment while awaiting kidney biopsy results if clinical presentation is compatible with small-vessel vasculitis and ANCA serology (PR3 or MPO) is positive 6

Disease Activity Assessment

Use validated clinical tools:

• Birmingham Vasculitis Activity Score (BVAS) is the primary validated tool for assessing disease activity 1, 2
• BVAS/WG evaluates manifestations across multiple systems: systemic, cutaneous, mucous/ocular, ENT, pulmonary, cardiovascular, gastrointestinal, and renal 1, 2
• Five-Factor Score (FFS) predicts mortality risk 1, 2

Differential Diagnosis

Distinguish GPA from:

• Eosinophilic granulomatosis with polyangiitis (EGPA): Distinguished by asthma, eosinophilia, and predominantly MPO-ANCA positivity (when ANCA-positive); EGPA rarely presents with PR3-ANCA 4, 2
• Microscopic polyangiitis: Typically lacks granulomatous inflammation and upper airway involvement 2
• Giant cell arteritis: Can present with chronic cough in patients >50 years old, but typically involves extracranial arteries of the head and neck 1
• Lung malignancy: Should be considered in differential diagnosis of pulmonary manifestations 1

Treatment Approach

Disease Severity Classification

Severe GPA is defined by:

• Five-Factor Score (FFS) ≥1 6
• Presence of peripheral neuropathy, alveolar hemorrhage, or other organ/life-threatening manifestations 6

Non-severe GPA is defined by:

• FFS = 0 6
• Absence of peripheral neuropathy, alveolar hemorrhage, or other organ/life-threatening manifestations 6

Induction Therapy for Severe GPA

Initial glucocorticoid therapy:

• Pulsed intravenous methylprednisolone 500-1000 mg daily for 3 days (maximum total 3g) 6
• Followed by high-dose oral glucocorticoids (0.75-1 mg/kg/day) 6
• Taper prednisone to 5 mg/day by weeks 19-52, with target dose of 7.5-10 mg by 3 months 6

Add either rituximab or cyclophosphamide:

Rituximab (preferred for relapsing disease and fertility preservation):

• 375 mg/m² intravenous infusion once weekly for 4 weeks 7
• Administer methylprednisolone 100 mg intravenous or equivalent 30 minutes prior to each infusion 7
• Rituximab is superior for relapsing disease, preserves fertility, and is non-inferior to cyclophosphamide 6

Cyclophosphamide:

• 2 mg/kg/day oral or 15 mg/kg IV pulse every 2-3 weeks 6
• Administer until remission is achieved (usually within 6 months) 1

Mandatory prophylaxis:

• Pneumocystis jirovecii prophylaxis with sulfamethoxazole-trimethoprim for patients treated with cyclophosphamide or rituximab 6
• Screen for hepatitis B, HIV, and tuberculosis before initiating therapy 6

Maintenance Therapy

Rituximab maintenance (preferred):

• 500 mg IV every 6 months reduces relapse rates compared to unscheduled treatment 6

Alternative maintenance agents:

• Azathioprine 2 mg/kg/day 6
• Methotrexate 20-25 mg weekly 6
• Mycophenolate mofetil 2000 mg/day 6

Follow-Up Treatment (After Achieving Disease Control)

For adults:

• Two 500 mg intravenous infusions separated by two weeks, followed by 500 mg IV every 6 months 7
• If induction was with rituximab, initiate follow-up within 24 weeks after last induction infusion, but no sooner than 16 weeks 7

For pediatric patients:

• Two 250 mg/m² intravenous infusions separated by two weeks, followed by 250 mg/m² IV every 6 months 7

Management of Refractory Disease

Refractory GPA is defined as:

• Unchanged or increased disease activity after 4 weeks of appropriate remission-induction therapy 6

Before declaring refractoriness, verify:

• Primary diagnosis accuracy 6
• Treatment regimen appropriateness 6
• Patient compliance 6
• Distinguish active manifestations from irreversible damage using Vasculitis Damage Index 6

For refractory systemic GPA:

• Switch to rituximab if initially treated with cyclophosphamide plus glucocorticoids 6
• Re-induce with rituximab for patients relapsing on maintenance therapy 6

Monitoring During Treatment

Induction phase monitoring:

• Complete blood count weekly 6
• Serum creatinine and urinalysis 6
• Infection surveillance 6

Maintenance phase monitoring:

• Disease activity assessment using Birmingham Vasculitis Activity Score 6
• ANCA titers (though decisions should not be based solely on ANCA levels) 1
• Cardiovascular risk factors 6
• Treatment-related complications 1

Long-term monitoring:

• Bladder cancer screening (urine cytology) for cyclophosphamide-treated patients 6
• Bone density assessment for patients on prolonged glucocorticoids 6

Definition of Remission

Remission is defined as:

• Birmingham Vasculitis Activity Score = 0 6
• Maximum prednisone dose ≤7.5 mg/day 6
• Absence of clinical signs or symptoms attributable to active disease 6

Critical Pitfalls to Avoid

Do not misdiagnose subglottic stenosis symptoms as asthma - investigate abnormal inspiratory and expiratory flow-volume loops 1

Do not use classification criteria (ACR 1990 or ACR-EULAR 2022) as diagnostic criteria - they were not developed for this purpose and have established sensitivity/specificity for classification, not diagnosis 2

Do not delay treatment while awaiting biopsy results if clinical presentation and positive PR3-ANCA strongly suggest GPA 6

Do not escalate immunosuppression unnecessarily - distinguish between active disease and irreversible damage using the Vasculitis Damage Index 6

Do not base treatment decisions solely on ANCA titers - use clinical parameters and validated disease activity scores 1