Drug of Choice for RA with ILD
Mycophenolate is the preferred first-line treatment for rheumatoid arthritis-associated interstitial lung disease (RA-ILD), with rituximab as the primary alternative option. 1, 2
First-Line Treatment Hierarchy
The 2023 ACR/CHEST guideline establishes a clear treatment framework for RA-ILD:
Preferred First-Line Options (Conditional Recommendations)
- Mycophenolate ranks as the top choice across all systemic autoimmune rheumatic disease-associated ILD, including RA-ILD 1, 2
- Rituximab serves as the primary alternative, particularly valuable when active inflammatory arthritis coexists with ILD 1, 2
- Azathioprine is conditionally recommended as another first-line option 1, 3
- Cyclophosphamide can be considered, though typically not used in combination with other immunosuppressants 1
- Short-term glucocorticoids (≤3 months) may serve as a bridge when initiating therapy 1, 2
Critical Decision Points
When to choose rituximab over mycophenolate: Select rituximab if the patient has active inflammatory arthritis requiring aggressive joint disease control, as rituximab addresses both manifestations simultaneously 1, 2
Glucocorticoid use: Keep doses ≤15 mg/day prednisone equivalent if used at all; avoid long-term use due to infection risk and lack of clear efficacy data 1
Treatment for Progressive Disease
If ILD progresses despite first-line therapy, the guideline conditionally recommends: 1
- Switching to or adding rituximab if mycophenolate fails
- Adding nintedanib (antifibrotic), especially for UIP pattern on imaging 1, 3
- Adding pirfenidone (antifibrotic) - this recommendation is specific to RA-ILD progression 1
- Adding tocilizumab for RA-ILD progression 1
- Mycophenolate or cyclophosphamide as alternatives 1
Evidence Quality and Important Caveats
Critical limitation: Only 3 randomized controlled trials have enrolled patients with RA-ILD (total n=217), making all recommendations conditional and based on very low-certainty evidence 3
UIP pattern considerations: Antifibrotics (nintedanib, pirfenidone) may be particularly effective for RA-ILD with usual interstitial pneumonia (UIP) pattern on imaging 3, 4. However, azathioprine and glucocorticoids showed worse outcomes than placebo in idiopathic pulmonary fibrosis trials, raising concerns about their use in RA-UIP specifically 3
Emerging data on abatacept: A 2025 emulated target trial found abatacept associated with lower mortality risk compared to rituximab (HR 0.689,95% CI 0.581-0.818), though residual confounding by indication cannot be excluded 5. This suggests abatacept may emerge as a first-line option, though it requires prospective validation 4
Medications to Avoid
The guideline conditionally recommends against the following for RA-ILD treatment: 1
- Methotrexate - may worsen ILD
- Leflunomide - pulmonary toxicity risk
- TNF inhibitors - potential ILD exacerbation
- Abatacept - though recent data challenges this (see above)
- Long-term glucocorticoids for progressive disease 1
Monitoring Requirements
- Pulmonary function tests (FVC and DLCO) every 3-6 months to detect progression 2
- High-resolution CT at baseline, annually, or with significant PFT changes 2
- Complete blood count every 2-4 months for immunosuppression monitoring 2
Rapidly Progressive RA-ILD
For rapidly progressive disease (respiratory failure developing over days to weeks): 1
- IV pulse methylprednisolone conditionally recommended
- Dual or triple combination therapy with rituximab, cyclophosphamide, IVIG, mycophenolate, calcineurin inhibitors, or JAK inhibitors 1
- Avoid nintedanib and pirfenidone as first-line in this setting 1
Co-Management Approach
Rheumatology-pulmonology co-management is essential for initiating ILD treatment, particularly to determine treatment necessity in asymptomatic patients with stable, mild ILD 1