What is the treatment for chronic interstitial lung disease (CILD) or small airway disease?

Treatment of Chronic Interstitial Lung Disease and Small Airway Disease

The treatment approach for chronic interstitial lung disease depends critically on the underlying etiology: for systemic autoimmune rheumatic disease-associated ILD (SARD-ILD), mycophenolate is the preferred first-line immunosuppressive therapy across all subtypes, while for idiopathic pulmonary fibrosis (IPF), antifibrotic therapy with nintedanib or pirfenidone is recommended, as immunosuppression is ineffective and potentially harmful. 1, 2, 3

Initial Diagnostic Classification

Before initiating treatment, establish whether the ILD is:

• SARD-associated: Screen for rheumatoid factor, anti-CCP antibodies, ANA, anti-Scl-70, anti-Jo-1, and other myositis-specific antibodies 2
• Idiopathic (IPF): Exclude connective tissue disease and environmental/occupational exposures including organic antigens, silica, asbestos, and drug toxicity 2
• Progressive fibrosing phenotype: Defined by ≥10% decline in FVC, worsening respiratory symptoms, and/or radiographic progression within the past year despite treatment 2

First-Line Treatment for SARD-ILD

Preferred Immunosuppressive Therapy

• Mycophenolate mofetil is conditionally recommended as the preferred first-line agent across all SARD-ILD subtypes 1, 4, 5, 2
• Alternative first-line options include azathioprine, rituximab, and cyclophosphamide 1, 5

Disease-Specific Considerations

For Systemic Sclerosis-ILD (SSc-ILD):

• Strongly recommend AGAINST glucocorticoids as first-line treatment due to high risk of scleroderma renal crisis, particularly at prednisone doses >15 mg daily 1, 4
• Nintedanib is conditionally recommended as a first-line option 1, 2
• Tocilizumab is conditionally recommended as a first-line option 1, 5

For Inflammatory Myopathy-ILD (IIM-ILD):

• JAK inhibitors are conditionally recommended as first-line options 1
• Calcineurin inhibitors (CNIs) are conditionally recommended as first-line options 1
• Short-term glucocorticoids may be used as part of initial therapy 4

For Rheumatoid Arthritis-ILD (RA-ILD):

• Short-term glucocorticoids may be used as part of initial therapy 4
• Avoid methotrexate, leflunomide, TNF inhibitors, and abatacept as first-line options 1

For Mixed Connective Tissue Disease-ILD (MCTD-ILD):

• Tocilizumab is conditionally recommended as a first-line option 1
• Short-term glucocorticoids may be used as part of initial therapy 4

Rapidly Progressive or Acute SARD-ILD

For patients with rapidly progressive disease or acute respiratory failure:

• Pulse IV methylprednisolone (1000 mg daily for 3 days) followed by moderate-to-high dose oral prednisone (up to 60 mg daily) with slow taper over weeks to months 4
• Must exclude infections or lymphoproliferative disorders before initiating high-dose steroids 4
• Consider upfront combination therapy (triple therapy for MDA-5 positive, double or triple therapy for MDA-5 negative) over monotherapy 1

First-Line Treatment for Idiopathic Pulmonary Fibrosis (IPF)

Antifibrotic therapy with either pirfenidone or nintedanib is recommended for IPF with definite UIP pattern 2, 3

• These agents slow annual FVC decline by approximately 44% to 57% 3
• Do NOT use immunosuppressive therapy for IPF, as it is ineffective and may be harmful 2
• Pirfenidone and nintedanib have similar efficacy in slowing disease progression 2

Management of Progressive Disease Despite First-Line Treatment

For SARD-ILD Progression

Strongly recommend AGAINST long-term glucocorticoids for SSc-ILD progression; conditionally recommend against for other SARD-ILD 1, 4

Second-line options include:

• Mycophenolate, rituximab, cyclophosphamide, and nintedanib 1
• For RA-ILD specifically: Adding pirfenidone is conditionally recommended 1
• For SSc-ILD, MCTD-ILD, or RA-ILD: Tocilizumab is conditionally recommended 1
• For IIM-ILD: CNIs or JAK inhibitors are conditionally recommended 1
• For IIM-ILD and MCTD-ILD: Adding IVIG is conditionally recommended 1

Progressive Pulmonary Fibrosis (PPF) Phenotype

If PPF develops in SARD-ILD despite immunosuppressive therapy:

• Consider adding nintedanib to ongoing immunosuppressive therapy 2
• Early recognition is critical, as progression to irreversible fibrosis significantly worsens prognosis 2

Management of Small Airway Disease Component

While small airway involvement is common in ILD, treatment focuses on the underlying parenchymal disease rather than isolated airway obstruction 6, 7:

• Airflow limitation may be the predominant defect in Wegener's granulomatosis, lymphangioleiomyomatosis, and chronic eosinophilic pneumonia 7
• Bronchodilators may be used as adjunctive therapy 6
• Do NOT routinely prescribe inhaled corticosteroids for chronic cough in pulmonary sarcoidosis 1

Monitoring Strategy

Short-term monitoring:

• PFTs every 3-6 months for mild ILD; more frequent for moderate-to-severe or progressive disease 5
• A 5% decline in FVC over 12 months is associated with approximately 2-fold increase in mortality 3
• Daily assessment of respiratory status and oxygen requirements during inpatient treatment 4

Monitor for complications:

• Steroid-related complications (hyperglycemia, hypertension) 4
• Drug-induced lung disease from TNF-alpha inhibitors, sulfasalazine, cyclophosphamide, rituximab, leflunomide, methotrexate, and sulfonamides 4
• Provide Pneumocystis jirovecii prophylaxis when cyclophosphamide is used 4

Symptomatic Management

For refractory chronic cough:

• First assess for ILD progression, complications from immunosuppressive treatment, or comorbidities (GERD, upper airway disease) 1
• For IPF with chronic cough and negative GERD workup: Do NOT prescribe proton pump inhibitors 1
• Consider trials of gabapentin or multimodality speech pathology therapy 1
• For cough adversely affecting quality of life when alternative treatments fail: Opiates in a palliative care setting with reassessment at 1 week and monthly 1

For dyspnea and exercise limitation:

• Structured exercise therapy reduces symptoms and improves 6-minute walk test distance 3
• Oxygen therapy for 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

Advanced Disease Management

Lung transplant should be considered for patients with end-stage ILD:

• Median survival of 5.2 to 6.7 years post-transplant versus less than 2 years without transplant in advanced ILD 3
• For SSc-ILD progression despite first treatment: Conditionally recommend referral for stem cell transplantation and/or lung transplantation 1
• For rapidly progressive ILD: Conditionally recommend early referral for lung transplantation over later referral after progression 1

Critical Pitfalls to Avoid

• Never use glucocorticoids in SSc-ILD due to scleroderma renal crisis risk 1, 4
• Never use immunosuppression for IPF as it is ineffective and potentially harmful 2
• Never combine nintedanib or pirfenidone upfront with mycophenolate in SARD-ILD without evidence of progression 1
• Always exclude infections before initiating high-dose steroids for rapidly progressive disease 4
• Do not use methotrexate, leflunomide, TNFi, or abatacept as first-line therapy for SARD-ILD 1