Is Ofev (nintedanib) or Esbriet (pirfenidone) recommended in the treatment of Interstitial Lung Disease (ILD) secondary to scleroderma?

Ofev (Nintedanib) is Conditionally Recommended for Scleroderma-ILD as First-Line Treatment

For people with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib (Ofev) is conditionally recommended as a first-line treatment option, while pirfenidone (Esbriet) is conditionally recommended against for all systemic autoimmune rheumatic disease-associated ILD (SARD-ILD), including scleroderma. 1

First-Line Treatment Recommendations

Nintedanib (Ofev) - Conditionally Recommended

• Nintedanib is specifically conditionally recommended for SSc-ILD as a first-line treatment option based on the 2023 ACR/CHEST guidelines 1
• The SENSCIS trial demonstrated that nintedanib reduced the annual rate of FVC decline to -52.4 ml/year compared to -93.3 ml/year with placebo (difference of 41.0 ml/year, P=0.04) 2
• This represents a 44-57% reduction in annual FVC decline, which is clinically meaningful given that a 5% FVC decline over 12 months is associated with approximately 2-fold increased mortality 3

Pirfenidone (Esbriet) - Conditionally Recommended Against

• For all SARD-ILD patients, including scleroderma, pirfenidone is conditionally recommended against as a first-line treatment option 1
• This recommendation applies uniformly across all systemic autoimmune rheumatic diseases, with no exception made for scleroderma 1
• The LOTUSS trial only evaluated tolerability of pirfenidone in SSc-ILD but did not demonstrate efficacy, with exploratory disease outcomes remaining largely unchanged 4

Preferred First-Line Options for SSc-ILD

The guideline stratifies treatment options into "preferred" therapies and "additional options" 1:

Preferred Immunosuppressive Agents

• Mycophenolate, azathioprine, rituximab, and cyclophosphamide are conditionally recommended as first-line treatment options for SARD-ILD, including scleroderma 1
• Tocilizumab is conditionally recommended specifically for SSc-ILD and MCTD-ILD as a first-line option 1

Glucocorticoids - Strongly Recommended Against

• For SSc-ILD specifically, glucocorticoids are strongly recommended against as first-line treatment (this is a strong recommendation, not conditional) 1
• This contrasts with other SARD-ILD where glucocorticoids receive a conditional recommendation for use 1

Combination Therapy Considerations

Avoid Upfront Antifibrotic Combinations

• Adding nintedanib or pirfenidone to mycophenolate is conditionally recommended against for patients already on mycophenolate without ILD progression 1
• Upfront combination of nintedanib or pirfenidone with mycophenolate over mycophenolate alone is conditionally recommended against 1

Treatment for Progressive SSc-ILD Despite First-Line Therapy

If SSc-ILD progresses despite initial treatment:

• Nintedanib is conditionally recommended as a treatment option for SARD-ILD progression, including scleroderma 1
• Mycophenolate, rituximab, and cyclophosphamide are also conditionally recommended options 1
• Pirfenidone remains conditionally recommended against for SSc-ILD progression (it is only conditionally recommended for RA-ILD progression) 1
• Tocilizumab is conditionally recommended for SSc-ILD progression 1
• Long-term glucocorticoids are strongly recommended against for SSc-ILD progression 1

Safety Profile Considerations

Nintedanib Adverse Events

• Diarrhea is the most common adverse event, occurring in 75.7% of patients versus 31.6% with placebo 2
• Gastrointestinal adverse events (diarrhea, nausea, vomiting) are the primary tolerability concern and may require dose reduction or discontinuation 2, 5
• The safety profile in SSc-ILD is consistent with that observed in IPF patients 2, 5
• Serious adverse events were infrequent and mostly related to worsening cardiopulmonary involvement of SSc itself 5

Pirfenidone Adverse Events

• Gastrointestinal symptoms (diarrhea, dyspepsia, vomiting), photosensitivity, and skin rashes are common 6, 4
• In the LOTUSS trial, 96.8% of SSc-ILD patients experienced treatment-emergent adverse events 4
• The gastrointestinal and skin adverse events are particularly concerning in scleroderma given the frequent involvement of these organs in the disease itself 4

Rapidly Progressive ILD Exception

• For patients with rapidly progressive ILD (RP-ILD) associated with scleroderma, both nintedanib and pirfenidone are conditionally recommended against as first-line treatment 1
• In RP-ILD, pulse intravenous methylprednisolone, rituximab, cyclophosphamide, IVIG, mycophenolate, CNI, and JAK inhibitors are conditionally recommended instead 1

Clinical Decision Algorithm

For newly diagnosed SSc-ILD:

1. Consider nintedanib as a first-line option alongside immunosuppressive agents (mycophenolate, rituximab, cyclophosphamide, azathioprine) 1
2. Tocilizumab is an additional first-line option for SSc-ILD 1
3. Avoid glucocorticoids (strong recommendation against) 1
4. Do not use pirfenidone 1

For SSc-ILD progression despite first-line therapy:

1. Add or switch to nintedanib if not already used 1
2. Consider tocilizumab, mycophenolate, rituximab, or cyclophosphamide 1
3. Avoid adding pirfenidone 1
4. Strongly avoid long-term glucocorticoids 1
5. Consider referral for stem cell transplantation and/or lung transplantation 1

For rapidly progressive SSc-ILD:

1. Use pulse IV methylprednisolone with combination immunosuppression 1
2. Avoid both nintedanib and pirfenidone 1