What are the new treatment options for rheumatoid arthritis‑associated interstitial lung disease in adults with progressive fibrosis?

New Treatment Options for Rheumatoid Arthritis-Associated Interstitial Lung Disease

For progressive RA-ILD despite first-line immunosuppression, add nintedanib as the preferred antifibrotic agent, or pirfenidone if nintedanib is not tolerated. 1, 2

First-Line Treatment Approach

The 2023 ACR/CHEST guidelines establish immunosuppression—not antifibrotics—as the foundation for initial RA-ILD management. 1

Preferred first-line immunosuppressive agents include: 1, 2

• Mycophenolate (most preferred)
• Rituximab (especially when active inflammatory arthritis coexists with ILD, as it addresses both joint disease and may reduce ILD mortality) 2
• Azathioprine
• Cyclophosphamide (particularly for severe cases)

Short-term glucocorticoids (≤3 months) can be used as bridging therapy while immunosuppression takes effect, but long-term steroids must be avoided in progressive disease. 1, 2

Avoid these agents in RA-ILD: methotrexate, leflunomide, TNF inhibitors, and abatacept—discontinue if ILD develops while on these medications. 2

Defining Progressive Disease

Progression despite immunosuppression is defined by any of the following: 2

• ≥10% predicted decline in FVC within 24 months
• 5-10% predicted FVC decline plus worsening respiratory symptoms or increased fibrosis on HRCT
• Worsening respiratory symptoms together with increased fibrosis on HRCT

New Antifibrotic Options for Progressive RA-ILD

This represents the major therapeutic advance in RA-ILD management.

For patients meeting progression criteria despite first-line immunosuppression: 1, 2

• Add nintedanib (preferred antifibrotic—reduces FVC decline rate by 60% over 52 weeks in progressive RA-ILD) 3
• Add pirfenidone (alternative when nintedanib not tolerated or contraindicated) 1, 2

Real-world data from 2024 demonstrates that antifibrotic initiation in progressive RA-ILD achieves modest FVC improvement (+4.7% at 1 year, +7.7% at 2 years) and DLCO stabilization, though discontinuation rates reach 37% due to adverse events—primarily gastrointestinal symptoms and hepatitis. 4

Critical caveat: Pirfenidone is specifically recommended for progressive RA-ILD only—the guidelines conditionally recommend against pirfenidone for other systemic autoimmune rheumatic disease-associated ILDs. 1

When NOT to Initiate Antifibrotics

Do not add antifibrotics in patients stable on mycophenolate without evidence of ILD progression—continue immunosuppression and monitor regularly. 2

Do not use upfront combination therapy (antifibrotic plus mycophenolate) before documented disease progression. 2

Additional Second-Line Options for Progressive Disease

Beyond antifibrotics, the following can be considered for RA-ILD progression: 1

• Tocilizumab (conditionally recommended for progressive RA-ILD)
• Switching to or adding rituximab (if not already used)
• Mycophenolate (if switching from another agent)
• Cyclophosphamide (despite toxicity concerns, observational data supports FVC stabilization)

Emerging Therapies

Abatacept is emerging as a potential first-line option for RA-ILD based on retrospective data, though it is not yet included in formal guideline recommendations. 5

Immunosuppression should be considered regardless of imaging pattern—even UIP pattern on HRCT may respond to immunosuppressive therapy, challenging older paradigms. 5

Practical Management Algorithm

1. Initiate first-line immunosuppression (mycophenolate preferred; rituximab if active arthritis present) 1, 2
2. Add short-term glucocorticoids (≤3 months) as bridge therapy 2
3. Monitor for progression using PFTs at 3 months and HRCT at 6 months 2
4. If progression occurs: Add nintedanib (or pirfenidone if nintedanib not tolerated) 1, 2, 4
5. Consider tocilizumab as alternative second-line agent 1
6. Early lung transplant referral when requiring high-flow oxygen or demonstrating rapid progression despite optimal therapy 2

Critical Pitfalls to Avoid

Do not rely on long-term glucocorticoids for progressive ILD—use only as temporary bridge. 1, 2

Do not continue methotrexate, leflunomide, TNF inhibitors, or abatacept if RA-ILD develops. 2

Do not delay antifibrotic initiation once progression is documented—real-world data shows meaningful FVC stabilization when started appropriately. 4

Anticipate antifibrotic adverse events: 81% of patients experience side effects (predominantly gastrointestinal and hepatic), requiring dose reduction in 40% of nintedanib and 14% of pirfenidone patients. 4

Essential Co-Management

Multidisciplinary collaboration with pulmonology is mandatory for treatment initiation, monitoring response, and escalation decisions. 2