What is the treatment for interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF) and ILD associated with connective tissue diseases?

Treatment for Interstitial Lung Disease

For systemic autoimmune rheumatic disease-associated ILD, start with mycophenolate as first-line therapy; for idiopathic pulmonary fibrosis and progressive pulmonary fibrosis, initiate antifibrotic therapy with nintedanib or pirfenidone. 1, 2

First-Line Treatment by ILD Subtype

Connective Tissue Disease-Associated ILD

Mycophenolate is the preferred first-line immunosuppressive agent for all forms of SARD-ILD, including systemic sclerosis, rheumatoid arthritis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease. 1, 2, 3

Alternative first-line options include:

• Rituximab (conditionally recommended as alternative for SSc-ILD and other SARD-ILD) 1, 2, 3
• Cyclophosphamide (conditionally recommended alternative) 1, 2
• Azathioprine (conditionally recommended for RA-ILD) 3

Critical caveat for systemic sclerosis-ILD: Glucocorticoids are strongly contraindicated as first-line therapy due to association with scleroderma renal crisis, particularly at doses >15 mg/day prednisone equivalent. 1, 2 This is one of only two strong recommendations in the 2023 ACR/CHEST guideline. 1

For other SARD-ILD subtypes, short-term glucocorticoids may be considered conditionally, but avoid long-term use. 1

Idiopathic Pulmonary Fibrosis

Initiate antifibrotic therapy with either nintedanib or pirfenidone, both of which reduce annual FVC decline by 44-57%. 1, 2, 4, 5

• Pirfenidone 2,403 mg/day (administered three times daily with food) demonstrated statistically significant reduction in FVC decline at 52 weeks in clinical trials (mean treatment difference 193 mL compared to placebo). 4
• Nintedanib shows similar efficacy in slowing lung function decline. 1, 2, 5

Do not use long-term glucocorticoids in IPF as they are associated with increased mortality. 3

Progressive Pulmonary Fibrosis (Non-IPF)

For patients with progressive fibrotic ILD from causes other than IPF (including fibrotic hypersensitivity pneumonitis, CTD-ILD, fibrotic NSIP, sarcoidosis):

Consider antifibrotic therapy with nintedanib, which has demonstrated efficacy in slowing FVC decline across multiple progressive fibrotic ILD subtypes. 1, 2, 5

Evidence for pirfenidone in non-IPF progressive fibrotic ILD remains insufficient, though further research is recommended. 1

Treatment of Progressive Disease Despite First-Line Therapy

When ILD progresses despite initial immunosuppressive treatment, the algorithmic approach includes:

1. Switch to an alternative immunosuppressant (e.g., from mycophenolate to rituximab or cyclophosphamide) 1, 2
2. Add nintedanib to ongoing immunosuppression 1, 2, 3
3. Add pirfenidone to ongoing immunosuppression 1, 2

Avoid long-term glucocorticoids even in progressive disease; reserve only for short-term bridging to another therapy. 1, 2 This is particularly critical in SSc-ILD where glucocorticoids remain strongly contraindicated even with progression. 1

Rapidly Progressive ILD

For rapidly progressive ILD (progression from wellness to respiratory failure within days to weeks, primarily seen in MDA-5 positive inflammatory myopathy):

Initiate high-dose methylprednisolone pulse therapy combined with upfront combination immunosuppression. 3 This represents a distinct clinical scenario requiring aggressive intervention, different from the chronic progressive phenotype.

Consider early referral for lung transplantation in patients with rapidly progressive disease, as transplant improves symptoms with median survival of 5.2-6.7 years compared to <2 years without transplant in advanced ILD. 2, 5

Specific Agents to Avoid

Do not use the following agents for ILD treatment, though they may be appropriate for extrapulmonary manifestations:

• Methotrexate 1, 3
• Leflunomide 1, 3
• TNF inhibitors 1, 3
• Abatacept 1, 3

Some clinicians discontinue these medications if ILD develops during their use. 1

Emerging Therapies

Tocilizumab is FDA-approved for SSc-ILD, particularly effective in patients with early disease and elevated inflammatory markers. 2, 6 This represents a unique intervention targeting the inflammatory component in early SSc-ILD.

Co-Management and Monitoring

Initiate ILD treatment in co-management with pulmonology, particularly for determining treatment necessity in asymptomatic patients with stable, mild ILD. 2, 3

Monitoring frequency based on disease severity:

• Mild disease: PFTs every 6 months for 1-2 years 2
• Moderate-to-severe or progressive disease: PFTs every 3-6 months 2

Critical Pitfalls to Avoid

1. Never delay immunosuppression in SARD-ILD, as irreversible fibrosis can progress asymptomatically. 2
2. Never use long-term glucocorticoids in SSc-ILD at any disease stage due to scleroderma renal crisis risk. 1, 2
3. Do not prescribe proton pump inhibitors for cough in IPF patients with negative acid reflux workup, as evidence does not support this practice. 1
4. Do not routinely prescribe inhaled corticosteroids for chronic cough in pulmonary sarcoidosis. 1

Management of ILD-Associated Cough

When troublesome cough occurs:

1. Assess for ILD progression or immunosuppressive treatment complications (drug side effects, pulmonary infection) 1
2. Follow unexplained chronic cough guidelines if cough persists after addressing ILD-specific causes 1
3. Consider neuromodulators (gabapentin) or speech pathology management for refractory cough 1
4. Reserve opiates for cough refractory to alternative therapies 1