Can Granulomatosis with Polyangiitis (GPA) cause pulmonary fibrosis and Interstitial Lung Disease (ILD), and what is the best treatment approach?

Granulomatosis with Polyangiitis (GPA) and Interstitial Lung Disease: Diagnosis and Treatment

Can GPA Cause Pulmonary Fibrosis and ILD?

Yes, Granulomatosis with Polyangiitis (GPA) can cause interstitial lung disease (ILD) and pulmonary fibrosis, with rituximab being the preferred first-line treatment for remission induction in active, severe GPA with lung involvement. 1

Epidemiology and Presentation

GPA-associated ILD is less common than in microscopic polyangiitis (MPA), but still significant:

• Prevalence of ILD in GPA: approximately 23% of patients 2
• More common in patients with anti-MPO antibodies (46-71%) than anti-PR3 antibodies (0-29%) 2
• ILD can be the first manifestation of GPA, preceding vasculitis diagnosis in some cases 3

Radiographic Patterns in GPA-ILD

Several patterns may be observed on high-resolution CT (HRCT):

• Usual interstitial pneumonia (UIP) pattern: seen in approximately 45.8% of AAV-ILD cases 4
• Nonspecific interstitial pneumonia (NSIP): more common in c-ANCA positive patients (60.9%) 3
• Other patterns: chronic hypersensitivity pneumonitis-like pattern, cryptogenic organizing pneumonia-like pattern 4
• Ground glass opacities (often representing diffuse alveolar hemorrhage) 2
• Reticulations, interlobular septal thickening, and honeycombing may also be present 2

Diagnosis

A multidisciplinary approach is essential for accurate diagnosis:

1. High-Resolution CT (HRCT): Gold standard for confirming ILD diagnosis with ~91% sensitivity and 71% specificity 5

2. Pulmonary Function Tests (PFTs):

   • Typically show restrictive pattern (reduced FVC, normal FEV1/FVC ratio)
   • Reduced DLCO
   • Baseline and follow-up measurements essential to assess progression 5

3. Bronchoalveolar Lavage (BAL):

   • Useful for specific ILD patterns
   • May reveal neutrophilia (suggesting fibrosing process)
   • Can help exclude alternative diagnoses 1

4. Lung Biopsy:

   • Surgical lung biopsy (preferably via video-assisted thoracoscopy) provides best tissue samples
   • Transbronchial biopsies are not helpful in confirming UIP pattern 1
   • In treated GPA, classic necrotic nodules and vasculitis may not be present, but other features like bronchiolitis fibrosa, interstitial fibrosis, and micronodular scars may be seen 6

Treatment

First-Line Treatment for Active, Severe GPA with ILD

Rituximab is conditionally recommended over cyclophosphamide for remission induction in active, severe GPA. 1

Rationale:

• Rituximab has similar efficacy to cyclophosphamide but better toxicity profile
• Rituximab dosing: 375 mg/m² IV weekly for 4 doses or 1,000 mg on days 1 and 15 1
• Always combined with glucocorticoids for remission induction

Glucocorticoid Therapy

• Initial high-dose: Prednisone 1 mg/kg/day (generally up to 80 mg/day) or equivalent 1
• IV pulse methylprednisolone (500-1,000 mg/day for 3-5 days) may be used in severe cases 1
• Taper gradually based on clinical response

Alternative First-Line Options

If rituximab is not available or contraindicated:

• Cyclophosphamide: Up to 2 mg/kg/day oral or intermittent IV (15 mg/kg IV every 2 weeks for 3 doses, then every 3 weeks) 1

Maintenance Therapy

After achieving remission:

• Rituximab: 500 mg IV every 6 months or 1 g IV every 4 months 1
• Alternative options: Methotrexate, azathioprine, or mycophenolate mofetil 1

Pneumocystis Prophylaxis

• For patients with GPA receiving rituximab or cyclophosphamide, prophylaxis against Pneumocystis jirovecii pneumonia is conditionally recommended 1

Monitoring and Follow-up

Regular monitoring is crucial:

• PFTs every 3-6 months in the first year, then every 3-12 months 5
• HRCT when clinically indicated, typically within first 3 years after diagnosis 5
• Ambulatory oxygen desaturation testing every 3-12 months 5
• A 5% decline in FVC over 12 months is associated with doubled mortality 5

Treatment of Refractory Disease

For patients with progressive disease despite first-line therapy:

• Consider adding or switching to cyclophosphamide (if rituximab was first-line) or rituximab (if cyclophosphamide was first-line) 5
• Consider adding nintedanib or pirfenidone for progressive fibrotic disease 5
• For patients unable to receive other immunomodulatory therapy, IV immunoglobulin (IVIG) is conditionally recommended 1

Prognosis

• ILD significantly affects quality of life and survival in AAV patients
• Mortality is increased 2-4 times in patients with AAV-ILD 2
• AAV-ILD has intermediate survival compared to idiopathic pulmonary fibrosis (3-year survival in AAV-ILD: 94% vs. 69% in IPF) 4

Cautions and Pitfalls

1. Diagnostic challenges:

   • Classic GPA features may be absent in treated disease 6
   • ILD can precede other vasculitis manifestations, leading to delayed diagnosis 3

2. Treatment considerations:

   • Avoid dosing immunosuppressive therapy based on ANCA titer results alone 1
   • Plasma exchange is not routinely recommended for GPA with glomerulonephritis 1
   • Inhaled corticosteroids are not recommended for chronic cough in ILD 1

3. Monitoring pitfalls:

   • Inadequate monitoring can result in undetected disease progression
   • Delayed treatment initiation can lead to irreversible fibrosis 5