What is the recommended treatment approach for patients with rheumatoid arthritis (RA) and interstitial lung disease (ILD)?

Treatment of Rheumatoid Arthritis-Associated Interstitial Lung Disease

For RA-ILD, initiate mycophenolate 1000-1500 mg twice daily as first-line therapy, with azathioprine or rituximab as alternatives, and reserve short-term glucocorticoids (≤3 months) only for initial combination therapy. 1, 2

First-Line Treatment Algorithm

Mycophenolate is the preferred first-line agent across all systemic autoimmune rheumatic disease-associated ILDs, including RA-ILD, based on the 2023 ACR/CHEST guideline hierarchy. 1

• Dose mycophenolate at 1000-1500 mg twice daily with complete blood count monitoring every 2-4 months. 2
• Azathioprine serves as the first alternative when mycophenolate is not tolerated or contraindicated. 1, 2
• Rituximab is conditionally recommended as another first-line option, particularly valuable given its dual benefit for both articular and pulmonary manifestations. 1, 2
• Cyclophosphamide represents an additional first-line option, especially for more severe presentations. 1, 2

Glucocorticoid Use: Critical Limitations

Short-term glucocorticoids (≤3 months) are conditionally recommended only as part of initial combination therapy, but long-term use is conditionally recommended against. 1, 2

• The guideline strongly emphasizes avoiding overreliance on glucocorticoids given substantial adverse effects without proven long-term efficacy. 2, 3
• This is particularly important in RA-UIP pattern disease, where azathioprine and glucocorticoids showed worse outcomes compared to placebo in idiopathic pulmonary fibrosis trials. 4

Progressive RA-ILD Despite First-Line Therapy

When RA-ILD progresses on initial treatment, the approach depends on what was used first-line:

Switch to or add agents not previously used from this hierarchy: 1, 2

• Mycophenolate, rituximab, or cyclophosphamide (if not already used as first-line). 1, 2
• Pirfenidone is conditionally recommended as add-on therapy specifically for progressive RA-ILD. 1, 2
• Nintedanib is conditionally recommended for progressive RA-ILD. 1, 2
• Tocilizumab is conditionally recommended for progressive RA-ILD despite first-line treatment. 1, 2

Antifibrotic Considerations

Antifibrotics (pirfenidone and nintedanib) may be particularly effective for RA-ILD with usual interstitial pneumonia (UIP) pattern, given their proven efficacy in idiopathic pulmonary fibrosis. 4

• These agents target fibrotic pathways to regulate fibrogenic cellular activity and extracellular matrix homeostasis. 5
• The decision to add versus switch therapy depends on current medication and disease severity. 1

Rapidly Progressive RA-ILD

For rapidly progressive RA-ILD, initiate upfront combination therapy (double or triple therapy) over monotherapy. 1, 2

• Pulse intravenous methylprednisolone is conditionally recommended as first-line treatment. 1, 2
• Combine with agents from this list: rituximab, cyclophosphamide, IVIG, mycophenolate, calcineurin inhibitors, or JAK inhibitors. 1, 2
• Avoid methotrexate, leflunomide, azathioprine, TNF inhibitors, abatacept, tocilizumab, nintedanib, and pirfenidone as first-line options in rapidly progressive disease. 1
• Consider early referral for lung transplantation over waiting for progression on optimal medical management. 1

Monitoring Strategy

Perform pulmonary function tests (FVC and DLCO) every 3-6 months to assess disease progression. 2, 3

• High-resolution CT scanning at baseline and annually (or with significant PFT changes) is recommended. 2, 3
• HRCT is the primary diagnostic method for evaluating ILD in RA patients, while pulmonary function tests are better suited for assessing progression. 6

Critical Pitfalls to Avoid

Do not use methotrexate or leflunomide as primary RA-ILD treatment, despite their role in managing articular disease. 1

• While some observational data suggest these DMARDs may have beneficial roles, the 2023 guideline conditionally recommends against them for rapidly progressive disease. 1, 6
• Avoid delaying second-line therapy in progressive disease, as this is discouraged by the ACR. 3
• Treatment decisions must balance articular activity, ILD activity, comorbidities, and infection risk. 4

Evidence Quality Considerations

The recommendations for RA-ILD are based predominantly on conditional evidence, as only three randomized controlled trials have enrolled patients with RA-ILD (total n=217). 4

• Most guideline recommendations extrapolate from trials in other systemic autoimmune rheumatic diseases or rely on observational data. 4
• Management decisions should involve collaboration between rheumatologists and pulmonologists given the complexity of balancing joint and lung disease. 2