Initial Treatment Approach for Interstitial Lung Disease
For systemic autoimmune rheumatic disease-associated ILD (SARD-ILD), mycophenolate is the preferred first-line immunosuppressive therapy, while for idiopathic pulmonary fibrosis (IPF), antifibrotic therapy with nintedanib or pirfenidone should be initiated promptly to slow disease progression. 1
Disease-Specific First-Line Treatment Selection
For Connective Tissue Disease-Associated ILD (CTD-ILD)
Mycophenolate is the preferred first-line agent due to favorable efficacy and tolerability, with evidence showing it may slow decline or improve forced vital capacity (FVC) at 12 months. 2, 1, 3
Alternative immunosuppressive options include:
- Rituximab - particularly useful when inflammatory arthritis, myositis, or Sjögren neuropathy coexist, as it addresses both pulmonary and extrapulmonary manifestations. 4, 1
- Azathioprine - supported as first-line across most CTD-ILD subtypes, though considered an "additional option" rather than "preferred" in systemic sclerosis-ILD due to limited comparative effectiveness data. 4, 1
- Cyclophosphamide - particularly for patients with systemic sclerosis features or mixed connective tissue disease (MCTD), with trials demonstrating FVC improvement. 4, 1
Short-term glucocorticoids are conditionally recommended as adjunctive therapy but are not required in all patients. 1 However, glucocorticoids are strongly contraindicated as first-line therapy in systemic sclerosis-ILD due to association with scleroderma renal crisis, particularly at doses >15 mg/day prednisone equivalent. 2, 1
For Systemic Sclerosis-ILD (SSc-ILD) Specifically
- Tocilizumab is conditionally recommended as a first-line option for SSc-ILD and MCTD-ILD. 4, 1
- Nintedanib is conditionally recommended specifically for SSc-ILD. 4, 1
For Inflammatory Myopathy-Associated ILD (IIM-ILD)
- JAK inhibitors (such as tofacitinib) are conditionally recommended as first-line options, with emerging evidence showing lower death rates compared to tacrolimus in anti-MDA-5 associated ILD. 4, 1
- Calcineurin inhibitors (particularly tacrolimus over cyclosporine) are conditionally recommended, especially for MDA-5-ILD or more severe presentations requiring rapid onset of action. 4, 1
For Idiopathic Pulmonary Fibrosis (IPF)
Antifibrotic therapy with nintedanib or pirfenidone should be initiated promptly, as these agents slow annual FVC decline by approximately 44% to 57% and reduce the risk of acute respiratory deteriorations. 3, 5 Decline in FVC in IPF is almost linear, with patients having well-preserved FVC at baseline experiencing the same rate of decline as those with advanced disease, making early treatment critical. 5
For Rheumatoid Arthritis-Associated ILD (RA-ILD)
The 2023 ACR guidelines conditionally recommend adding nintedanib or pirfenidone as therapeutic options for progressive RA-ILD despite first-line treatment, with the expert panel suggesting evaluation of the balance between inflammatory and fibrotic processes to adapt therapy over time. 4 Usual interstitial pneumonia (UIP) pattern in RA-ILD is associated with poor prognosis and requires careful evaluation. 4
Agents to Strongly Avoid as First-Line Therapy
The following agents are conditionally recommended against for any SARD-ILD as they may worsen lung disease: 4, 1
- Methotrexate
- Leflunomide
- TNF inhibitors
- Abatacept
Pirfenidone is conditionally recommended against for SARD-ILD (except in progressive disease scenarios). 4, 1
Upfront combination of antifibrotics with mycophenolate is not recommended without evidence of progression, as there is no added benefit. 4, 1
Initial Evaluation and Monitoring Strategy
Baseline Assessment
During initial evaluation, perform:
- Pulmonary function tests (PFTs) within 3 months to determine rate of progression. 4
- High-resolution CT (HRCT) within 6 months to assess disease extent and pattern. 4
Ongoing Monitoring Schedule
For mild CTD-ILD (FVC ≥70% and <20% fibrosis extent on HRCT):
- PFTs every 6 months for the first 1-2 years. 4
For moderate-to-severe ILD or progressive disease:
- PFTs every 3-6 months. 4
- HRCT repeated within 3-6 months to 1 year depending on underlying disease, ILD pattern, and extent. 4
A 5% decline in FVC over 12 months is associated with approximately 2-fold increased mortality compared with no change in FVC. 2, 3
For patients on mycophenolate:
- Complete blood count with differential every 2-4 months. 1
Special Consideration: Rapidly Progressive ILD (RP-ILD)
Upfront combination therapy is mandatory for RP-ILD, including pulse IV methylprednisolone plus 2-3 additional agents such as rituximab, cyclophosphamide, or tacrolimus. 1
For MDA-5 positive RP-ILD, triple therapy with cyclophosphamide, tacrolimus, and glucocorticoids demonstrates survival benefit over sequential approaches. 1
Early lung transplant referral is recommended rather than waiting for progression, particularly when high-flow oxygen is required. 1
Multidisciplinary Collaboration Requirement
A consensus-based multidisciplinary approach improves diagnostic accuracy and patient outcomes. 4 Patients should be evaluated concurrently by pulmonology and rheumatology (or immunology for relevant conditions), with input from thoracic radiologists and pathologists for complex cases. 4
Critical Pitfalls to Avoid
Do not delay immunosuppression while waiting for complete diagnostic workup, as early treatment prevents irreversible organ damage. 2
Avoid long-term high-dose glucocorticoids as monotherapy, as this increases mortality risk without addressing underlying pathophysiology; reserve for short-term bridging only. 2, 1
Do not attribute all dyspnea to ILD without excluding cardiac disease, asthma, and other causes. 2
Be vigilant for disease-modifying anti-rheumatic drug (DMARD) lung toxicity in RA-ILD patients, though the benefit/risk ratio largely favors their use. 4
For patients not tolerating first-line antifibrotic treatment or showing disease progression, switching antifibrotics is a feasible management strategy, with significantly fewer severe adverse effects observed after switching (12.1% vs 43.9%). 6