What is the recommended first‑line treatment for idiopathic pulmonary fibrosis?

First-Line Treatment for Idiopathic Pulmonary Fibrosis

Clinicians should initiate antifibrotic therapy with either pirfenidone or nintedanib immediately upon diagnosis of IPF, as these are the only two medications proven to slow disease progression and reduce mortality risk. 1, 2

Recommended Antifibrotic Agents

Pirfenidone

• Target dose: 2,403 mg/day (801 mg three times daily with food) 1, 3, 4
• Reduces FVC decline by approximately 44-57% annually compared to placebo 2
• Demonstrated 30% reduction in progression-free survival risk in patients with mild-to-moderate IPF (FVC >50% predicted and DLCO >35% predicted) 1
• The 2015 ATS/ERS/JRS/ALAT guidelines provide a conditional recommendation for pirfenidone use based on moderate confidence in estimates of effect 5
• If full dose not tolerated, reduce dose rather than discontinue therapy 3

Nintedanib

• Standard dose: 150 mg twice daily (with or without food) 3
• Reduced dose of 100 mg twice daily may be used when standard dose not tolerated 3
• Intracellular tyrosine kinase inhibitor targeting VEGF, FGF, and PDGF receptors involved in fibrogenesis 5, 3
• The 2015 ATS/ERS/JRS/ALAT guidelines provide a conditional recommendation for nintedanib use based on moderate confidence in estimates of effect 5
• Demonstrated reduction in FVC decline and fewer acute exacerbations compared to placebo 5

Critical Treatments to AVOID

Strongly Contraindicated

• Triple therapy (prednisone + azathioprine + N-acetylcysteine) is absolutely contraindicated due to increased mortality and hospitalizations demonstrated in the PANTHER-IPF trial 5, 1, 2
• Ambrisentan (selective endothelin receptor antagonist) should never be used due to documented decline in respiratory status and increased disease progression 5, 1
• Warfarin and oral anticoagulants should not be used for treating IPF in patients without other indications 1, 2

Not Recommended

• Interferon gamma-1b received a strong "no" recommendation based on lack of survival benefit in the INSPIRE trial (n=826) 1
• Corticosteroid monotherapy is not recommended for routine IPF treatment, as no prospective randomized controlled trials have demonstrated efficacy 1, 2

Essential Adjunctive Therapies

Antacid Therapy

• All IPF patients should receive regular proton pump inhibitor (PPI) or H2-receptor antagonist therapy 1
• Up to 90% of IPF patients have abnormal gastroesophageal reflux (often clinically silent) 1
• Observational data shows survival benefit (HR 0.47; 95% CI 0.24-0.93) and smaller FVC decline (mean difference 0.07 L; P=0.05) 1

Vaccinations

• Annual influenza vaccination is strongly recommended 1, 3, 2
• Pneumococcal vaccination (polysaccharide vaccine) is recommended 1, 2

Oxygen Therapy

• Supplemental oxygen should be prescribed for patients with desaturation below 88% during 6-minute walk test or resting hypoxemia 1
• Long-term oxygen therapy is recommended for patients with severe hypoxemia at rest 3, 2

Pulmonary Rehabilitation

• Pulmonary rehabilitation programs are conditionally recommended to improve exercise capacity and quality of life 1, 2

Monitoring Requirements

Pulmonary Function Tests

• Perform FVC and DLCO every 3-6 months to assess treatment response 1, 3, 2
• Oxygen saturation should be monitored at rest and with exercise at each visit 1

Laboratory Monitoring

• Liver function tests monthly for first 6 months of pirfenidone, then every 3 months thereafter 1, 3
• Nintedanib requires liver enzyme monitoring due to 3.2-fold increased risk of elevated AST and 3.6-fold increased risk of elevated ALT 3

Managing Adverse Effects

Pirfenidone

• Common adverse effects include photosensitivity, fatigue, stomach discomfort, anorexia, nausea, rash, and elevated liver enzymes 5, 3
• Manage through gradual dose titration, taking with food, and avoiding sun exposure 3
• Approximately 18.3% of patients permanently discontinue pirfenidone due to adverse effects 6

Nintedanib

• Common adverse effects include diarrhea (2.8-fold higher), nausea (3.1-fold higher), abdominal pain (4.2-fold higher), vomiting (3.6-fold higher), anorexia (2.8-fold higher), and weight loss (3.7-fold higher) compared to placebo 3
• Antidiarrheal agents may be used as needed to control nintedanib-related diarrhea 3
• Dose reduction to 100 mg twice daily is recommended for intolerable gastrointestinal side effects 3
• Only 8.3% of patients permanently discontinue nintedanib due to adverse effects, significantly lower than pirfenidone 6
• Adverse effects due to nintedanib are usually easier to manage with behavioral modifications or additional medications (52.5% vs. 40.6% for pirfenidone, p=0.04) 6

Lung Transplantation Referral

• Patients aged <65 years with severe or worsening disease should be referred for lung transplant evaluation at diagnosis if they have high mortality risk factors 1, 2
• Lung transplantation is the only treatment proven to increase life expectancy in IPF 1

Common Pitfalls to Avoid

• Do not delay treatment initiation – IPF demonstrates almost linear FVC decline regardless of baseline severity, and early treatment is critical to preserving lung function 7
• Do not withhold treatment in patients with "stable" disease – IPF is progressive and irreversible, with median survival of only 2-3 years after diagnosis without treatment 7, 8
• Do not use immunosuppression – IPF does not respond to immunosuppressive therapy and triple therapy increases mortality 2
• Do not assume treatment is only for advanced disease – patients with well-preserved FVC at baseline experience the same rate of decline as those with more advanced disease 7

Evidence Quality Considerations

The 2015 ATS/ERS/JRS/ALAT guidelines provide conditional (weak) recommendations for both pirfenidone and nintedanib, reflecting moderate confidence in estimates of effect 5. However, these remain the only two disease-modifying pharmacological agents approved by regulatory agencies worldwide 9. Individual clinical trials have not been powered to show reductions in mortality, but pooled analyses and observational studies suggest both antifibrotic therapies improve life expectancy 7. The conditional nature of recommendations reflects concerns about adverse effects and cost, emphasizing the need for shared decision-making with patients 5.