What is the treatment for interstitial lung disease (ILD)?

Treatment 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 to slow disease progression. 1, 2, 3

Disease-Specific Treatment Algorithms

Systemic Autoimmune Rheumatic Disease-Associated ILD (SARD-ILD)

Preferred first-line agents:

• Mycophenolate is the preferred immunosuppressive agent due to favorable efficacy and tolerability across all SARD-ILD subtypes 1, 2, 4
• Short-term glucocorticoids (oral prednisone or IV pulse methylprednisolone for acute/severe presentations) may be added as adjunctive therapy, though not required in all patients 1, 2
• Alternative immunosuppressive options include rituximab, azathioprine, and cyclophosphamide, selected based on extrapulmonary manifestations 1, 2

Disease-specific modifications:

• For SSc-ILD: Tocilizumab is conditionally recommended as first-line option; nintedanib is also conditionally recommended 1, 2. Glucocorticoids are strongly contraindicated due to association with scleroderma renal crisis 1, 2
• For RA-ILD: Mycophenolate, rituximab, and tocilizumab are preferred; nintedanib remains controversial without panel consensus 1, 4
• For IIM-ILD: JAK inhibitors and calcineurin inhibitors (tacrolimus) are conditionally recommended as first-line options in addition to mycophenolate and rituximab 1, 2, 4
• For MCTD-ILD: Tocilizumab is conditionally recommended 1, 2

Agents to avoid:

• Methotrexate, leflunomide, TNF inhibitors, and abatacept are strongly recommended against for any SARD-ILD as they may worsen lung disease 1, 2, 4
• Pirfenidone is conditionally recommended against for SARD-ILD 1, 2, 4
• Upfront combination of antifibrotics (nintedanib or pirfenidone) with mycophenolate is not recommended without evidence of progression 1, 2

Idiopathic Pulmonary Fibrosis (IPF)

Antifibrotic therapy is the cornerstone:

• Nintedanib or pirfenidone should be prescribed according to ATS/ERS guidelines to slow FVC decline by approximately 44-57% annually 1, 3
• These agents reduce mean FVC decline (pirfenidone showed 193 mL treatment difference vs placebo at 52 weeks) 5
• Antifibrotic therapy should be prescribed based on disease progression criteria, not specifically for cough 1

Corticosteroids have no role in stable IPF:

• No controlled studies support corticosteroid use for IPF-associated symptoms 1
• "Triple therapy" (corticosteroids + azathioprine + N-acetyl-cysteine) is associated with increased mortality compared to placebo 1
• Corticosteroids should be limited to suspected IPF exacerbation or co-existing asthma/eosinophilic bronchitis 1

Rapidly Progressive ILD (RP-ILD)

Upfront combination therapy is mandatory:

• Triple therapy is required for MDA-5 positive or suspected RP-ILD: IV pulse methylprednisolone + cyclophosphamide + tacrolimus demonstrates survival benefit over sequential approaches 2, 4
• Double or triple therapy for non-MDA-5 RP-ILD: Combine 2-3 agents from: rituximab, cyclophosphamide, tacrolimus, IVIG, mycophenolate, or JAK inhibitors 2, 4
• Early lung transplant referral is essential, particularly when high-flow oxygen is required, rather than waiting for further progression 2

Management of Progressive Disease Despite First-Line Treatment

When ILD progresses on initial therapy:

• Switch to an alternative immunosuppressive agent OR add a second agent 4
• For SSc-ILD progression: Consider adding nintedanib to ongoing immunosuppression 1
• For RA-ILD progression: Nintedanib was proven to slow disease progression and is conditionally recommended 1
• Options for progressive disease include: nintedanib, rituximab, cyclophosphamide, and JAK inhibitors 4

Cough Management in ILD

Algorithmic approach to troublesome cough:

• First, determine if ILD is the cause: look for disease progression, temporal association between cough onset and disease progression, and favorable response to ILD therapy 1
• If cough persists despite ILD treatment, evaluate for: asthma, nonasthmatic eosinophilic bronchitis, upper airway cough syndrome, and GERD 1
• Consider esophageal dysmotility/GERD particularly in systemic sclerosis context 1
• If no cause identified and patient significantly troubled, follow unexplained chronic cough guideline approach as some ILD patients have dysfunctional cough sensory nerves (cough hypersensitivity syndrome) 1

Specific cough therapies:

• Thalidomide showed quality of life improvement in small IPF-associated cough trial but had significant side effects; not recommended for routine use but warrants further study 1
• Inhaled cromolyn sodium (PA101) showed promise with >30% reduction in objective cough frequency in pilot study 1

Monitoring Requirements

Pulmonary function testing schedule:

• Every 3-6 months for first 1-2 years in mild CTD-ILD (FVC ≥70%, <20% fibrosis on HRCT) 1
• Every 3-6 months for moderate-to-severe ILD or progressive disease 1, 2
• A 5% decline in FVC over 12 months is associated with approximately 2-fold increase in mortality 3

Imaging surveillance:

• Baseline HRCT (approximately 91% sensitive, 71% specific for ILD subtypes) 3
• Repeat HRCT within 3-6 months to 1 year depending on underlying disease, ILD pattern, and extent 1
• Repeat within first 3 years after diagnosis to identify progressive disease 1

Laboratory monitoring:

• Complete blood count with differential every 2-4 months for patients on mycophenolate 2

Critical Pitfalls to Avoid

Glucocorticoid-related complications:

• Long-term glucocorticoid use should be reserved for short-term bridging only 2
• Never use glucocorticoids as first-line therapy in SSc-ILD due to renal crisis risk 1, 2
• Avoid "triple therapy" in IPF given mortality data 1

Management structure:

• Co-management by rheumatology and pulmonology is essential for optimal SARD-ILD outcomes 2, 4
• Shared decision-making must consider disease severity, risk factors, and potential toxicities 4

Treatment selection errors:

• Never use methotrexate, leflunomide, TNF inhibitors, or abatacept in any SARD-ILD 1, 2
• Do not add antifibrotics to mycophenolate upfront without evidence of progression 1, 2
• Recognize that UIP pattern in CTD-ILD has better survival than idiopathic UIP, but still requires aggressive treatment 6

Supportive Care and Advanced Therapies

Symptomatic management:

• Structured exercise therapy reduces symptoms and improves 6-minute walk test distance in dyspneic patients 3
• Oxygen therapy reduces symptoms and improves quality of life in patients who desaturate below 88% on 6-minute walk test 3
• For pulmonary hypertension (develops in up to 85% of end-stage fibrotic ILD), inhaled treprostinil improves walking distance and respiratory symptoms 3

Lung transplantation:

• Consider for advanced ILD with median survival of 5.2-6.7 years post-transplant compared to <2 years without transplant in advanced disease 3
• Optimal medical management is preferred over transplant referral as first-line approach, but early referral is essential for RP-ILD 1, 2