What antifibrotic is recommended for rheumatoid arthritis–associated interstitial lung disease?

Antifibrotic Therapy for Rheumatoid Arthritis-Associated Interstitial Lung Disease

For first-line treatment of RA-ILD, antifibrotics are not recommended; instead, use immunosuppression with mycophenolate, azathioprine, rituximab, or cyclophosphamide. 1 For progressive RA-ILD despite first-line immunosuppression, add nintedanib as the preferred antifibrotic, with pirfenidone as an alternative option. 1, 2

First-Line Treatment: Immunosuppression, Not Antifibrotics

The 2023 ACR/CHEST guidelines explicitly state that the expert panel could not reach consensus on recommending nintedanib as first-line therapy for RA-ILD, and they conditionally recommend against pirfenidone as first-line treatment for all systemic autoimmune rheumatic disease-associated ILD (SARD-ILD), including RA-ILD. 1

Preferred first-line agents include:

• Mycophenolate (most preferred immunosuppressant) 2
• Rituximab (particularly beneficial when active inflammatory arthritis coexists with ILD) 2
• Azathioprine 1, 2
• Cyclophosphamide (especially for severe cases) 2

Short-term glucocorticoids (≤3 months) can be used as part of initial therapy, but long-term glucocorticoids should be avoided. 2

When to Add Antifibrotic Therapy

Defining Progressive Disease

Add antifibrotic therapy when RA-ILD progresses despite first-line immunosuppression, defined as: 1

• FVC decline ≥10% predicted within 24 months, OR
• FVC decline 5-10% predicted PLUS worsening respiratory symptoms or increased fibrosis on HRCT, OR
• Worsening respiratory symptoms AND increased fibrosis on HRCT

Critical distinction: Residual fibrotic changes on HRCT alone do not equal progression—comparison to baseline imaging is necessary to document increased fibrosis. 3

Nintedanib for Progressive RA-ILD

Nintedanib is the preferred antifibrotic for progressive RA-ILD. 1, 2

• Dosing: 150 mg twice daily (can reduce to 100 mg twice daily if not tolerated) 3
• Evidence: In the INBUILD trial subgroup analysis, nintedanib reduced FVC decline by 60% in progressive RA-ILD patients over 52 weeks 4
• Mechanism: Slows disease progression but does not reverse existing fibrosis 3

Adverse effects to anticipate: 3

• Diarrhea (most common—occurs in 75.7% vs 31.6% placebo)
• Other GI effects: abdominal pain, nausea, vomiting, anorexia, weight loss
• Liver enzyme elevations (AST, ALT)
• Real-world discontinuation rates are 18.5-30% due to adverse events 5, 6

Pirfenidone as Alternative

Pirfenidone can be added for progressive RA-ILD when nintedanib is not tolerated or contraindicated. 1, 2

• The ACR/CHEST guidelines conditionally recommend adding pirfenidone specifically for RA-ILD progression (but recommend against it for other SARD-ILD types) 1
• Real-world data show similar drug persistence between nintedanib and pirfenidone (median 150.3 weeks) 6
• Dose reduction required in 14% of patients due to adverse effects 5

Important Caveats

Do NOT add antifibrotics to stable patients: For patients on mycophenolate without evidence of ILD progression, the guidelines conditionally recommend against adding nintedanib or pirfenidone. 1, 3 Continue immunosuppression alone and monitor closely with PFTs every 3-6 months and HRCT within 6 months. 3, 7

Do NOT use upfront combination therapy: The guidelines conditionally recommend against combining nintedanib or pirfenidone with mycophenolate as initial therapy (before documented progression). 1

Additional Options for Refractory Progressive Disease

If RA-ILD continues to progress despite immunosuppression plus antifibrotic therapy: 1, 2

• Tocilizumab is conditionally recommended for RA-ILD progression
• Consider early referral for lung transplantation in severe, progressive cases 2, 3

Monitoring Strategy

Initial 3 years after diagnosis are critical for identifying progressive disease: 3

• PFTs every 3-6 months 3, 7
• HRCT within 6 months of diagnosis, then as needed to assess progression 2, 3
• Maintain low threshold for bronchoscopy in patients receiving pulse corticosteroids and immunosuppression due to high infection risk 7

Real-World Effectiveness

Real-world studies demonstrate that antifibrotics stabilize lung function in progressive RA-ILD: 5, 6

• FVC stabilization or modest improvement after antifibrotic initiation (mean improvement +4.7% at 1 year, +7.7% at 2 years) 5
• TLC improvement (600 ± 900 mL improvement vs 800 ± 300 mL decline pre-treatment) 6
• However, DLCO may continue to decline despite treatment 5, 6
• Drug retention at end of follow-up: 63% of patients remain on therapy 5