What is the treatment for scleroderma-associated Interstitial Lung Disease (ILD)?

Treatment for Scleroderma-Associated Interstitial Lung Disease

For scleroderma-ILD, mycophenolate mofetil is the preferred first-line treatment based on the most recent high-quality guidelines, with comparable efficacy to cyclophosphamide but superior tolerability. 1, 2

First-Line Immunosuppressive Therapy

The 2024 American College of Rheumatology/American College of Chest Physicians guidelines and 2024 American Thoracic Society guidelines establish a clear treatment hierarchy:

Preferred First-Line Agent

• Mycophenolate mofetil is conditionally recommended as the preferred first-line agent, with demonstrated efficacy comparable to cyclophosphamide but better tolerability 1, 2
• Typical dosing: Start at 500-1000 mg twice daily, titrating to 1500 mg twice daily as tolerated 3
• Monitoring: CBC with differential and LFTs at baseline, 2-3 weeks after starting, and every 3 months on stable dosing 3

Alternative First-Line Options

The following agents are conditionally recommended as first-line alternatives 1, 2:

• Cyclophosphamide: Particularly for induction therapy in patients at high risk for progression 3, 1

  • IV dosing: 500-750 mg/m² every 4 weeks for 6 months 3
  • Oral dosing: 1-2 mg/kg/day (maximum 100-200 mg/day) for 6 months 3
  • Two high-quality RCTs demonstrated improvements in FVC (2.5% placebo-corrected), total lung capacity (4.1%), dyspnea scores, and quality of life 3

• Rituximab: Emerging as a first-line option with growing evidence base 1, 2

• Azathioprine: Can be used as first-line therapy, particularly as maintenance after cyclophosphamide induction 1

  • Dosing: 2-3 mg/kg/day 3

• Tocilizumab: Conditionally recommended as first-line for SSc-ILD 1

• Nintedanib: Antifibrotic agent recommended as first-line option, but should NOT be combined upfront with mycophenolate unless there is evidence of ILD progression on mycophenolate alone 1

Critical Glucocorticoid Guidance

The ACR/CHEST guidelines strongly recommend AGAINST using glucocorticoids as first-line treatment for SSc-ILD due to the risk of triggering scleroderma renal crisis, particularly at prednisone doses >15 mg daily. 4, 1

• This is a strong recommendation with high-quality evidence for SSc-ILD specifically 4, 1
• For SSc-ILD progression despite first-line treatment, the guidelines strongly recommend against long-term glucocorticoids 3

Exception for Rapidly Progressive ILD

• In the rare case of rapidly progressive SSc-ILD (RP-ILD), pulse IV methylprednisolone (1000 mg daily for 3 days) may be considered, but this requires individualized risk-benefit assessment given SRC risk 4, 1
• This should be combined with other immunosuppressive agents (rituximab, cyclophosphamide, IVIG, mycophenolate, or calcineurin inhibitors) 3, 1

Agents to Avoid as First-Line Therapy

The following should NOT be used as first-line treatment for SSc-ILD 1:

• Leflunomide
• TNF inhibitors
• Abatacept
• Pirfenidone (requires further research per ATS guidelines) 2
• JAK inhibitors
• IVIG or plasma exchange
• Calcineurin inhibitors (CNIs)

Management of Progressive Disease

For patients with SSc-ILD progression despite first-line treatment 1:

1. Continue to strongly avoid long-term glucocorticoids 3

2. Switch to or add alternative immunosuppressive agents:

   • Mycophenolate (if not already used)
   • Rituximab
   • Cyclophosphamide
   • Nintedanib (can be added to mycophenolate if progression occurs) 1

3. Consider referral for:

   • Stem cell transplantation (at centers with strong SSc-ILD experience) 3, 1
   • Lung transplantation (before patient deteriorates to ineligibility) 3, 1

Practical Treatment Algorithm

Initial approach:

1. Start mycophenolate mofetil as preferred first-line agent 1, 2
2. If high risk for rapid progression, consider cyclophosphamide for induction (6 months) followed by maintenance with mycophenolate or azathioprine 3, 1

If progression on first-line therapy:

1. Switch to alternative immunosuppressive (rituximab, cyclophosphamide if not used initially) 1
2. Consider adding nintedanib to mycophenolate 1
3. Evaluate for transplantation referral 1

Key Monitoring Parameters

• Pulmonary function tests: Every 3-6 months to assess treatment response 4
• High-resolution CT: For baseline assessment and monitoring disease progression 5
• Medication-specific monitoring: As outlined above for each agent 3

Critical Pitfalls to Avoid

• Never use high-dose glucocorticoids in SSc-ILD due to scleroderma renal crisis risk 4, 1
• Do not combine nintedanib with mycophenolate upfront—only add nintedanib if progression occurs on mycophenolate alone 1
• Provide Pneumocystis jirovecii prophylaxis when using cyclophosphamide 4
• Screen for alternative etiologies (infections, lymphoproliferative disorders) before initiating immunosuppression 4
• Monitor for drug-induced lung disease from immunosuppressive agents themselves 4