What is the recommended treatment for patients with interstitial lung disease (ILD), particularly those with idiopathic pulmonary fibrosis (IPF)?

Treatment of Interstitial Lung Disease (ILD) and Idiopathic Pulmonary Fibrosis (IPF)

For patients with idiopathic pulmonary fibrosis (IPF), antifibrotic therapy with either nintedanib or pirfenidone is strongly recommended as first-line treatment to slow disease progression, while for non-IPF ILD with progressive pulmonary fibrosis, nintedanib is the preferred antifibrotic agent. 1, 2

Diagnosis and Classification

ILD encompasses over 200 disorders that can be categorized into several groups:

• Idiopathic Pulmonary Fibrosis (IPF): Characterized by usual interstitial pneumonia (UIP) pattern on HRCT
• Non-IPF Progressive Pulmonary Fibrosis (PPF): Includes:
  • Connective tissue disease-associated ILD (CTD-ILD)
  • Hypersensitivity pneumonitis (HP)
  • Fibrotic nonspecific interstitial pneumonia (NSIP)
  • Unclassifiable ILD
  • Occupational ILDs (asbestosis, silicosis)
  • Sarcoidosis with fibrosis

Treatment Algorithm for ILD

1. Idiopathic Pulmonary Fibrosis (IPF)

First-line therapy:

• Antifibrotic agents:
  • Pirfenidone: 801 mg three times daily (2,403 mg/day) with food, titrated over 14 days 3
  • Nintedanib: 150 mg twice daily 2

Key evidence: Pirfenidone demonstrated significant reduction in FVC decline in IPF patients (mean treatment difference 193 mL at 52 weeks compared to placebo) 3

Monitoring:

• Pulmonary function tests (PFTs) every 3-6 months
• Liver function tests monthly for first 6 months, then every 3 months
• HRCT if unexplained clinical deterioration

2. Non-IPF Progressive Pulmonary Fibrosis

First-line therapy based on specific ILD type:

A. Systemic Sclerosis-ILD (SSc-ILD):

• Nintedanib is conditionally recommended as first-line treatment 1
• Avoid glucocorticoids as first-line treatment (strong recommendation) 1
• Mycophenolate is conditionally recommended as an alternative 1

B. Other CTD-ILD (RA-ILD, MCTD-ILD, SjD-ILD, IIM-ILD):

• Mycophenolate, azathioprine, rituximab, or cyclophosphamide are conditionally recommended as first-line options 1
• For IIM-ILD specifically, JAK inhibitors and calcineurin inhibitors are conditionally recommended 1
• Glucocorticoids are conditionally recommended for non-SSc CTD-ILD 1
• For MCTD-ILD, tocilizumab is conditionally recommended as a first-line option 1

C. Progressive Fibrotic ILD (regardless of etiology):

• Nintedanib is conditionally recommended for patients with progressive fibrosis despite standard therapy 1, 2
• Pirfenidone requires further research but may be considered in specific cases based on limited evidence 1, 4

Definition of Progressive Pulmonary Fibrosis

PPF is defined as at least two of the following three criteria occurring within the past year with no alternative explanation 1:

1. Worsening symptoms (increasing dyspnea, cough)
2. Radiological progression (increased reticular abnormality, traction bronchiectasis, honeycombing)
3. Physiological progression (decline in FVC ≥10% predicted, or decline in FVC 5-10% with worsening symptoms or increased fibrosis on HRCT)

Management of Adverse Effects

Pirfenidone:

• GI effects: Nausea, vomiting, diarrhea, dyspepsia - take with food, consider dose reduction
• Photosensitivity: Avoid sun exposure, use sunscreen
• Liver toxicity: Monitor liver enzymes regularly 3

Nintedanib:

• GI effects: Diarrhea, nausea, vomiting - most common side effects
• Hepatic effects: Monitor liver enzymes regularly 2

Supportive Care

• Oxygen therapy: For patients with resting hypoxemia or exercise desaturation below 88% 2, 5
• Pulmonary rehabilitation: Improves exercise capacity and quality of life 2, 5
• Vaccinations: Annual influenza and pneumococcal vaccines 2
• Early palliative care integration: For symptom management 2

Special Considerations

• Lung transplantation: Should be considered for advanced ILD, with median survival improving from <2 years to 5.2-6.7 years post-transplant 5
• Pulmonary hypertension: Occurs in up to 85% of patients with end-stage fibrotic ILD; consider inhaled treprostinil 5

Monitoring Disease Progression

• Pulmonary function tests: A 5% decline in FVC over 12 months is associated with approximately 2-fold increase in mortality 5
• HRCT: For assessment of progression and complications
• Quantitative CT (QCT): May provide more objective measure of progression but requires further validation 1

Common Pitfalls to Avoid

1. Delaying treatment: IPF and progressive ILD are irreversible and fatal diseases; prompt initiation of antifibrotic therapy is critical
2. Overreliance on stability: Even seemingly stable disease can progress rapidly; early intervention is key
3. Discontinuing therapy due to mild side effects: Dose adjustments can often manage side effects without compromising efficacy
4. Misdiagnosis: Ensure accurate diagnosis through multidisciplinary discussion before initiating specific therapy
5. Overlooking comorbidities: Pulmonary hypertension, gastroesophageal reflux disease, and sleep apnea are common and require management

The evidence strongly supports early intervention with antifibrotic therapy in IPF and progressive fibrotic ILD to preserve lung function and improve outcomes, with treatment selection guided by the specific ILD subtype and individual patient factors.