What medications are used to treat Idiopathic Interstitial Lung Disease (ILD)?

Treatment of Interstitial Lung Disease (ILD)

For systemic autoimmune rheumatic disease-associated ILD (SARD-ILD), mycophenolate is the preferred first-line immunosuppressive therapy, while nintedanib is the antifibrotic of choice specifically for systemic sclerosis-associated ILD (SSc-ILD). 1

First-Line Treatment by ILD Subtype

SARD-ILD (General Approach)

Preferred immunosuppressive options (conditionally recommended as first-line):

• Mycophenolate 2-3 g/day orally - most preferred due to similar efficacy to cyclophosphamide with superior adverse effect profile 1
• Rituximab - two IV infusions 2 weeks apart, then one infusion every 6 months; particularly preferred when inflammatory arthritis, myositis, or Sjögren neuropathy coexist 1
• Cyclophosphamide - 600 mg/m² IV or 100-150 mg/day orally; demonstrates FVC improvement in SSc-ILD and MCTD-ILD 1
• Azathioprine 150 mg/day - supported across diseases but considered "additional option" rather than "preferred" in SSc-ILD due to limited effectiveness evidence 1

Glucocorticoid use:

• Conditionally recommended for SARD-ILD other than SSc-ILD as first-line treatment (typically combined with immunosuppressives) 1
• Strongly recommended AGAINST for SSc-ILD as first-line daily therapy 1

Disease-Specific Antifibrotic Therapy

SSc-ILD:

• Nintedanib 150 mg twice daily is conditionally recommended as first-line option 1
• Reduce to 100 mg twice daily if not tolerated 1
• SENSCIS trial demonstrated slowed FVC decline; INBUILD trial showed superiority across progressive ILDs 1

SSc-ILD and MCTD-ILD:

• Tocilizumab 162 mg subcutaneously weekly or 4-8 mg/kg IV monthly is conditionally recommended 1

IIM-ILD (Inflammatory Myopathy-associated ILD):

• JAK inhibitors conditionally recommended as first-line option 1
• Calcineurin inhibitors (CNIs) conditionally recommended as first-line option 1
• Conditionally recommend AGAINST nintedanib for IIM-ILD 1

RA-ILD:

• No consensus reached on nintedanib use 1

SjD-ILD and MCTD-ILD:

• Conditionally recommend AGAINST nintedanib 1

Medications to AVOID as First-Line

Strongly discouraged across all SARD-ILD:

• Leflunomide 1
• Methotrexate 1
• TNF inhibitors 1
• Abatacept 1
• Pirfenidone (conditionally recommended against for SARD-ILD) 1
• IVIG or plasma exchange 1

Do NOT add antifibrotics to stable mycophenolate:

• Conditionally recommend against adding nintedanib or pirfenidone to mycophenolate without evidence of progression 1
• Conditionally recommend against upfront combination of antifibrotics with mycophenolate over mycophenolate alone 1

Treatment for Progressive ILD Despite First-Line Therapy

For SARD-ILD progression:

• Mycophenolate, rituximab, cyclophosphamide, and nintedanib are conditionally recommended 1
• Strongly recommend AGAINST long-term glucocorticoids in SSc-ILD progression; conditionally recommend against in other SARD-ILD 1

For RA-ILD progression:

• Conditionally recommend adding pirfenidone 1

For SSc-ILD, MCTD-ILD, or RA-ILD progression:

• Tocilizumab conditionally recommended 1

For IIM-ILD progression:

• CNIs conditionally recommended 1
• JAK inhibitors conditionally recommended 1

For IIM-ILD and MCTD-ILD progression:

• Adding IVIG conditionally recommended 1

Rapidly Progressive ILD (RP-ILD)

First-line treatment for SARD with RP-ILD:

• Pulse IV methylprednisolone conditionally recommended 1
• Rituximab, cyclophosphamide, IVIG, mycophenolate, CNIs, and JAK inhibitors conditionally recommended 1
• Conditionally recommend AGAINST: methotrexate, leflunomide, azathioprine, TNF inhibitors, abatacept, tocilizumab, nintedanib, pirfenidone, and plasma exchange 1

Idiopathic Pulmonary Fibrosis (IPF)

For IPF specifically:

• Nintedanib or pirfenidone are first-line antifibrotic therapies that slow annual FVC decline by 44-57% 2
• Pirfenidone dosing: increase to 801 mg three times daily as tolerated 3
• Both medications reduce FVC decline and are FDA-approved for IPF 3, 2, 4

Common Pitfalls and Monitoring

Antifibrotic side effects:

• Nintedanib: predominantly diarrhea, dyspepsia, vomiting 4
• Pirfenidone: gastrointestinal symptoms, photosensitivity, skin rashes 4
• Discontinue if side effects are more threatening than disease itself 4

Supportive interventions for SSc-ILD:

• Aggressive GERD treatment with proton pump inhibitors (often exceeding maximum approved dose) to prevent aspiration-related worsening 1
• Smoking cessation, vaccinations (influenza, COVID-19, pneumococcal), oxygen therapy if hypoxic 1
• Consider lung transplantation referral for SSc-ILD progression despite treatment 1

Prognostic monitoring:

• 5% decline in FVC over 12 months associates with approximately 2-fold mortality increase 2
• Regular laboratory monitoring for kidney/liver function on immunosuppressives 5