What is the treatment for scleroderma-associated interstitial lung disease (ILD)?

Treatment of Scleroderma-Associated Interstitial Lung Disease

For scleroderma-associated ILD (SSc-ILD), first-line treatment should consist of mycophenolate, azathioprine, rituximab, or cyclophosphamide as immunosuppressive options, with tocilizumab or nintedanib as additional first-line choices, while glucocorticoids should be strongly avoided. 1

First-Line Treatment Approach

Preferred Immunosuppressive Therapies

The 2023 ACR/CHEST guidelines provide conditional recommendations for several immunosuppressive agents as first-line options for SSc-ILD 1:

• Mycophenolate mofetil is conditionally recommended and has emerged as a preferred agent with comparable efficacy to cyclophosphamide but better tolerability 1, 2
• Cyclophosphamide remains a conditionally recommended option, particularly for induction therapy in patients at risk for progression 1, 3
• Rituximab is conditionally recommended as a first-line option 1
• Azathioprine is conditionally recommended as a first-line treatment 1

Additional First-Line Options Specific to SSc-ILD

Tocilizumab is conditionally recommended specifically for SSc-ILD (and MCTD-ILD) as a first-line treatment option 1, representing a biologic therapy alternative.

Nintedanib (an antifibrotic agent) is conditionally recommended specifically for SSc-ILD as a first-line option 1, though it should not be combined upfront with mycophenolate 1.

Critical Avoidance: Glucocorticoids

The guidelines strongly recommend AGAINST glucocorticoids as first-line treatment in SSc-ILD 1—this is one of the few strong (not conditional) recommendations in the guideline. This contrasts sharply with other systemic autoimmune rheumatic disease-associated ILDs where glucocorticoids are conditionally recommended 1. Data from the EUSTAR group showed negative trends in forced vital capacity (FVC) with glucocorticoid use, particularly when starting with FVC <50%, and do not support liberal use of glucocorticoids in SSc-ILD 4.

Agents to Avoid

The following should NOT be used as first-line therapy in SSc-ILD 1:

• Leflunomide
• Methotrexate
• TNF inhibitors
• Abatacept
• Pirfenidone (conditionally recommended against)
• JAK inhibitors (reserved for IIM-ILD)
• Calcineurin inhibitors (reserved for IIM-ILD)
• IVIG or plasma exchange

Management of Progressive Disease Despite First-Line Treatment

When Initial Therapy Fails

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

• Continue to strongly avoid long-term glucocorticoids 1
• Switch to or add: mycophenolate, rituximab, cyclophosphamide, or nintedanib as treatment options 1
• Consider tocilizumab as a treatment option for progressive SSc-ILD 1
• Do NOT add pirfenidone (this is only conditionally recommended for RA-ILD progression, not SSc-ILD) 1

Transplantation Considerations

For SSc-ILD progression despite first-line treatment, the guidelines conditionally recommend referral for stem cell transplantation and/or lung transplantation 1. Selected patients may be candidates for lung transplantation, though meticulous assessment for comorbidities is crucial given the systemic nature of scleroderma 2.

Rapidly Progressive ILD

For patients with rapidly progressive SSc-ILD (RP-ILD), characterized by acute deterioration 1:

• Pulse intravenous methylprednisolone is conditionally recommended as first-line RP-ILD treatment 1
• Combination therapy options: rituximab, cyclophosphamide, IVIG, mycophenolate, calcineurin inhibitors, or JAK inhibitors 1
• Avoid: methotrexate, leflunomide, azathioprine, TNF inhibitors, abatacept, tocilizumab, nintedanib, pirfenidone, and plasma exchange 1

Treatment Sequencing Strategy

Based on the evidence, a practical algorithmic approach:

1. Initial diagnosis of SSc-ILD: Start mycophenolate mofetil OR cyclophosphamide (for induction if high risk for progression) 1, 3
2. If cyclophosphamide used for induction: Transition to mycophenolate or azathioprine for maintenance 3
3. Alternative first-line options: Rituximab, tocilizumab, or nintedanib if standard immunosuppressives are not tolerated 1
4. If progression occurs: Switch immunosuppressive agent, add nintedanib, or consider tocilizumab 1
5. If continued progression: Evaluate for stem cell or lung transplantation 1

Important Clinical Caveats

Do not combine antifibrotics with mycophenolate upfront unless there is evidence of ILD progression on mycophenolate alone 1. The guidelines specifically recommend against upfront combination of nintedanib or pirfenidone with mycophenolate over mycophenolate monotherapy 1.

Certainty of evidence is low to very low for all treatment recommendations 1, reflecting the challenges in conducting high-quality trials in this population. This underscores the importance of close monitoring with pulmonary function tests and high-resolution CT imaging 5.

Early intervention is critical: Immunosuppressive therapy should be started as soon as possible in patients at risk for progression, as these agents may slow disease progression but cannot reverse established fibrotic changes 3, 6.