What is the primary treatment approach for a patient with rheumatoid arthritis (RA)-related interstitial lung disease (ILD)?

Treatment of Rheumatoid Arthritis-Associated Interstitial Lung Disease

For RA-ILD, mycophenolate is the preferred first-line treatment, with rituximab and azathioprine as additional first-line options, particularly when active inflammatory arthritis coexists. 1, 2

First-Line Treatment Approach

Preferred Immunosuppressive Therapy

• Mycophenolate is the preferred first-line agent across all systemic autoimmune rheumatic disease-associated ILD, including RA-ILD, based on the 2023 ACR/CHEST guidelines 1, 2
• Rituximab is particularly beneficial when active inflammatory arthritis accompanies ILD, as it addresses both joint and lung manifestations simultaneously 1, 2
• Azathioprine represents another conditionally recommended first-line option 1, 2
• Cyclophosphamide can be considered in severe cases, though it is typically not combined with other immunosuppressive agents 1, 2

Role of Glucocorticoids

• Short-term glucocorticoids (≤3 months) are conditionally recommended as part of initial therapy for RA-ILD 1, 2
• Oral prednisone is commonly used, while intravenous pulse methylprednisolone is reserved for acute onset or severe presentations 1
• Glucocorticoids are generally used in combination with other immunosuppressive agents rather than as monotherapy 1

Medications to Avoid

• Methotrexate, leflunomide, TNF inhibitors, and abatacept are conditionally recommended against for RA-ILD treatment 1, 3
• These agents may be appropriate for extrapulmonary manifestations, but some experts would discontinue them if ILD develops during their use 1

Management of Progressive RA-ILD

When First-Line Therapy Fails

• Nintedanib is conditionally recommended for RA-ILD progression despite first-line treatment 1, 2
• Pirfenidone can be added as a treatment option specifically for progressive RA-ILD (this recommendation is unique to RA-ILD and does not apply to other SARD-ILD subtypes) 1, 2
• Mycophenolate, rituximab, and cyclophosphamide remain options if switching or escalating therapy 1, 2
• Tocilizumab is conditionally recommended for progressive RA-ILD 2
• Long-term glucocorticoids should be avoided in progressive disease 1, 2

Antifibrotic Therapy Considerations

The ACR/CHEST panel could not reach consensus on whether to recommend nintedanib as first-line therapy for RA-ILD, reflecting equipoise in the evidence 1. However, for progressive disease, nintedanib has clearer support 1, 2. This contrasts with idiopathic pulmonary fibrosis, where antifibrotics are first-line 4.

Rapidly Progressive RA-ILD

Aggressive Initial Management

• Intravenous pulse methylprednisolone is recommended as first-line therapy for rapidly progressive disease 1, 3
• Upfront combination therapy is conditionally recommended over monotherapy (double or triple therapy for non-MDA-5 associated cases) 1
• Rituximab, cyclophosphamide, IVIG, mycophenolate, calcineurin inhibitors, and JAK inhibitors are all conditionally recommended options 1
• Early referral for lung transplantation is conditionally recommended over later referral after progression on optimal medical management 1

Critical Management Principles

Multidisciplinary Co-Management

• Co-management with pulmonologists is essential for initiation of ILD treatment, particularly to determine treatment necessity in asymptomatic patients with stable, mild ILD 1, 3
• Initial evaluation should include high-resolution CT to determine ILD pattern and pulmonary function tests to establish baseline 2

Monitoring Strategy

• Short-term pulmonary function tests within 3 months and HRCT within 6 months of diagnosis help determine rate of progression 2
• Monitor for progressive pulmonary fibrosis phenotype: ≥10% decline in FVC, worsening respiratory symptoms, and/or radiographic progression within the past year despite treatment 4

Treatment Selection Factors

The choice among recommended first-line options depends on:

• ILD severity and risk factors for progression 1
• Presence of active inflammatory arthritis (favors rituximab) 1, 2
• Other disease manifestations requiring treatment 1
• Cost and potential toxicity profile 1
• Patient preferences regarding treatment burden and side effects 1

Common Pitfalls to Avoid

• Do not use the hierarchy of preferred versus additional options as a mandate for insurance-driven prescribing sequences; clinicians must retain latitude to prescribe based on individual patient factors 1
• Do not continue methotrexate, leflunomide, TNF inhibitors, or abatacept if ILD develops during their use 1, 3
• Do not delay switching therapy if intolerance leads to suboptimal dosing of first-line therapy 1
• Do not use long-term glucocorticoids for progressive disease, as they are associated with increased morbidity 1, 2