What is the recommended long‑term management of interstitial lung disease, including antifibrotic therapy, dosing, monitoring, and supportive care?

Long-Term Management of Interstitial Lung Disease

For long-term ILD management, mycophenolate is the preferred first-line immunosuppressive agent across all systemic autoimmune rheumatic disease-associated ILD, with antifibrotic therapy (nintedanib or pirfenidone) reserved for idiopathic pulmonary fibrosis or progressive fibrosing disease despite immunosuppression. 1, 2

First-Line Treatment Selection

For Connective Tissue Disease-Associated ILD

• Mycophenolate (target dose 2g daily) is the preferred first-line agent for systemic sclerosis, rheumatoid arthritis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease-associated ILD 1, 2

• Alternative first-line immunosuppressive options include rituximab (particularly with active inflammatory arthritis, myositis, or Sjögren neuropathy), cyclophosphamide, and azathioprine 1

• Tocilizumab is conditionally recommended as first-line therapy specifically for systemic sclerosis-ILD and mixed connective tissue disease-ILD 1

• Glucocorticoids should be avoided in systemic sclerosis-ILD due to strong association with scleroderma renal crisis (this is a strong recommendation against their use) 1

• For other CTD-ILD, if glucocorticoids are used, keep dose ≤15 mg/day prednisone and limit to short-term bridging therapy (≤3 months) when switching agents 1

For Idiopathic Pulmonary Fibrosis

• Initiate antifibrotic therapy with either nintedanib or pirfenidone, as both reduce annual FVC decline by 44-57% 2, 3

Agents to Avoid

• Do not use methotrexate, leflunomide, TNF inhibitors, or abatacept for ILD treatment, as they may exacerbate lung disease (though they may be appropriate for extrapulmonary manifestations) 1, 2

Management of Progressive Disease Despite First-Line Therapy

When to Define Progression

• Progression is defined as: FVC decline ≥10% predicted, OR FVC decline 5-10% predicted plus worsening respiratory symptoms or increased fibrosis on HRCT, OR worsening symptoms plus increased fibrosis—all within 24 months 1

Treatment Adjustments for Progressive Disease

• Switch to an alternative first-line immunosuppressant (e.g., from mycophenolate to rituximab or cyclophosphamide) 1, 2

• Add nintedanib to ongoing immunosuppression for progressive fibrosing disease, particularly when there is substantial fibrotic disease or usual interstitial pneumonia pattern on CT 1, 2

• The decision between switching versus adding therapy depends on the pace of progression and the amount of fibrotic versus inflammatory disease 1

Antifibrotic Therapy Specifics

Nintedanib

• Conditionally recommended for systemic sclerosis-ILD as first-line option 1

• Conditionally recommended for rheumatoid arthritis-ILD (though panel could not reach full consensus on first-line use) 1

• Recommended against as first-line for Sjögren disease-ILD, inflammatory myopathy-ILD, and mixed connective tissue disease-ILD 1

• FDA-approved for progressive fibrosing ILD of any cause, showing significant reduction in annual FVC decline over 52 weeks 4

Pirfenidone

• Conditionally recommended against as first-line for systemic autoimmune rheumatic disease-associated ILD 1

• Appropriate for idiopathic pulmonary fibrosis 2, 3

Important Caveat on Combination Therapy

• Do not use upfront combination of nintedanib or pirfenidone with mycophenolate as first-line therapy 1

• Do not add antifibrotics to mycophenolate in patients without evidence of ILD progression 1

Monitoring Protocol

Pulmonary Function Testing Frequency

• For mild CTD-ILD (FVC ≥70%, <20% fibrosis on HRCT): PFTs every 6 months for the first 1-2 years 1

• For moderate-to-severe ILD or progressive disease: PFTs every 3-6 months 1, 2

• Short-term PFTs within 3 months of initial evaluation to determine rate of progression 1

HRCT Monitoring

• Repeat HRCT within 6 months of initial evaluation to assess progression rate 1

• Repeat HRCT within first 3 years after diagnosis to identify progressive disease 1

• Subsequent HRCT every 3-6 months to 1 year depending on underlying disease, ILD pattern, and extent 1

Laboratory Monitoring

• Complete blood count every 2-4 months for immunosuppression monitoring 5, 6

Rapidly Progressive ILD Management

Definition and Recognition

• Rapidly progressive ILD is characterized by progression from minimal symptoms to respiratory failure (high-flow oxygen or mechanical ventilation) within days to weeks, without alternative cause like infection or heart failure 1

• This differs from progressive pulmonary fibrosis—the terms are not interchangeable 1

Treatment Approach

• Intravenous glucocorticoids plus 1-2 additional immunosuppressive agents: rituximab, cyclophosphamide, IVIG, mycophenolate, calcineurin inhibitor, or JAK inhibitor 1

• For severe disease or anti-MDA-5 positivity: use dual or triple combination therapy 1

• Consider early lung transplant referral for rapidly progressive cases 1

• Rituximab and cyclophosphamide are preferred over IVIG, though IVIG may be selected if high infection concern exists 1

Supportive Care Measures

Oxygen Therapy

• Prescribe supplemental oxygen for patients who desaturate below 88% on 6-minute walk test, as it reduces symptoms and improves quality of life 3

Exercise Training

• Structured exercise therapy reduces dyspnea symptoms and improves 6-minute walk distance 3

Pulmonary Hypertension Screening

• Consider echocardiogram if pulmonary hypertension is suspected, as up to 85% of patients with end-stage fibrotic ILD develop pulmonary hypertension 1, 3

• Inhaled treprostinil improves walking distance and respiratory symptoms in ILD patients with pulmonary hypertension 3

Lung Transplant Evaluation

• Refer for lung transplant evaluation in patients with advanced ILD or refractory/rapidly progressive disease 1, 3

• Post-transplant median survival is 5.2-6.7 years compared to <2 years in advanced ILD without transplant 3

Critical Pitfalls to Avoid

• Do not use long-term glucocorticoids for ILD progression—reserve only for short-term bridging when switching therapy 1

• Monitor for drug-induced ILD when using DMARDs, as medications like TNF inhibitors, sulfasalazine, cyclophosphamide, rituximab, leflunomide, methotrexate, and sulfonamides carry approximately 1% risk 1

• Do not delay antifibrotic therapy in progressive fibrosing disease with substantial fibrosis or UIP pattern, as this pattern is associated with poor prognosis 1

• Ensure multidisciplinary collaboration between rheumatology and pulmonology for co-management, particularly when initiating ILD treatment in asymptomatic patients with stable mild disease 1, 2