Can we start nintedanib (generic name: nintedanib) upfront in patients with fibrotic interstitial lung disease (ILD) at risk of progressing to progressive pulmonary fibrosis (PPF) without waiting for disease progression?

Upfront Nintedanib in Fibrotic ILD Without Waiting for PPF Progression

The answer depends critically on the underlying ILD type: for SSc-ILD, start nintedanib upfront as first-line therapy; for most other fibrotic ILDs (SjD-ILD, IIM-ILD, MCTD-ILD), do NOT use nintedanib upfront; for RA-ILD, the evidence is insufficient to make a firm recommendation; and for non-autoimmune progressive fibrosing ILDs, nintedanib should be reserved for documented progression meeting PPF criteria. 1

Disease-Specific Recommendations

Systemic Sclerosis-Associated ILD (SSc-ILD)

• Start nintedanib upfront without waiting for progression as a first-line treatment option (conditional recommendation). 1
• Nintedanib 150 mg twice daily reduced annual FVC decline to -52.4 mL/year compared to -93.3 mL/year with placebo in the SENSCIS trial. 2
• The treatment effect was consistent regardless of concomitant mycophenolate use (40% reduction in FVC decline with MMF, 46% without). 2
• This is the only autoimmune ILD where upfront nintedanib has conditional guideline support. 1

Other Autoimmune ILDs - Do NOT Use Upfront

• For SjD-ILD, IIM-ILD, and MCTD-ILD, conditionally recommend AGAINST nintedanib as first-line treatment. 1
• For these conditions, prefer immunosuppressive agents (mycophenolate, azathioprine, rituximab, cyclophosphamide) as first-line therapy. 1
• Nintedanib becomes an option only after documented progression despite first-line immunosuppressive therapy. 1

Rheumatoid Arthritis-Associated ILD (RA-ILD)

• No consensus exists on whether to use nintedanib as first-line therapy in RA-ILD. 1
• The guideline panel could not reach agreement, reflecting genuine clinical equipoise. 1
• Consider immunosuppressive therapy first, reserving nintedanib for documented progression. 1

Progressive Pulmonary Fibrosis (PPF) - When Progression is Documented

Definition of Progression

• PPF is defined by decline in FVC ≥10% predicted within 24 months, OR decline in FVC 5-10% predicted PLUS worsening respiratory symptoms or increased fibrosis on HRCT within 24 months. 1, 3
• This definition comes from the INBUILD trial criteria and represents the evidence base for nintedanib use. 1

Nintedanib for Documented PPF

• For patients with documented PPF who have failed standard management, nintedanib is conditionally recommended (conditional recommendation, low-quality evidence). 1, 3
• Nintedanib reduced annual FVC decline by approximately 107 mL compared to placebo in the INBUILD trial. 1, 3, 4
• Over the entire INBUILD trial (mean exposure 15.6 months), nintedanib reduced the risk of ILD progression or death by 34% (HR 0.66,95% CI 0.53-0.83; p=0.0003). 5
• The benefit was particularly pronounced in patients with UIP-like pattern on HRCT (HR 0.69,95% CI 0.53-0.91; p=0.009). 5

Critical Algorithmic Approach

Step 1: Identify the Underlying ILD Type

• SSc-ILD: Proceed to upfront nintedanib consideration 1
• RA-ILD: Clinical judgment required; no consensus 1
• SjD-ILD, IIM-ILD, MCTD-ILD: Use immunosuppression first 1
• Other fibrotic ILDs: Document progression before nintedanib 1

Step 2: For SSc-ILD - Upfront Treatment Decision

• Confirm SSc-ILD diagnosis with HRCT showing fibrosis 2
• Start nintedanib 150 mg twice daily (can reduce to 100 mg twice daily if not tolerated) 2
• Can combine with mycophenolate mofetil for potentially additive benefit 2
• Strongly avoid daily glucocorticoids as first-line treatment in SSc-ILD 1

Step 3: For Non-SSc ILDs - Document Progression First

• Initiate appropriate immunosuppressive therapy based on ILD type 1
• Monitor FVC every 3-6 months 1
• Document progression using PPF criteria (FVC decline ≥10% or FVC decline 5-10% plus symptoms/imaging worsening over 24 months) 1, 3
• Only after documented progression, consider adding nintedanib 1

Step 4: When Adding Nintedanib After Progression

• Do NOT add nintedanib to stable mycophenolate (conditionally recommend against). 1
• Do NOT use upfront combination of nintedanib with mycophenolate over mycophenolate alone (conditionally recommend against). 1
• Add nintedanib only when progression is documented despite immunosuppression. 1

Important Caveats and Pitfalls

Common Mistake: Treating All Fibrotic ILDs the Same

• The evidence base for upfront nintedanib exists primarily for SSc-ILD and documented PPF. 1
• Using nintedanib upfront in autoimmune ILDs other than SSc-ILD contradicts guideline recommendations. 1
• The INBUILD trial specifically enrolled patients with documented progression, not all fibrotic ILD patients. 1, 5

Quality of Evidence Limitations

• All recommendations carry very low to low certainty of evidence. 1
• The INBUILD trial included only 663 patients with heterogeneous ILD types. 1
• Real-world data suggest familial pulmonary fibrosis may be less responsive to nintedanib. 6

Adverse Effect Management

• Diarrhea occurs in 62-76% of patients (versus 18-32% with placebo). 3, 2
• Reduce dose to 100 mg twice daily for persistent diarrhea before discontinuing. 3, 2
• Monitor liver enzymes monthly for 3 months, then every 3 months. 3
• Weight loss occurs 3.7 times more frequently with nintedanib. 3

Standard Management Must Be Attempted First

• For non-SSc ILDs, "standard management" typically means immunosuppressive therapy. 1
• The PPF indication assumes failure of standard management, not treatment-naive patients. 1
• This paradigm shift from "wait for progression" applies only to SSc-ILD based on current guidelines. 1