What are autoimmune lung diseases and their treatment options?

Autoimmune Lung Diseases: Overview and Management

Definition and Epidemiology

Autoimmune lung diseases, specifically connective tissue disease-associated interstitial lung disease (CTD-ILD), represent approximately 20% of all interstitial lung diseases and are a leading cause of death in patients with systemic autoimmune rheumatic diseases (SARDs). 1

Key Disease Associations

• Systemic sclerosis (SSc): Affects >50% of patients, leading cause of death and hospitalization 1
• Rheumatoid arthritis (RA): ILD prevalence 7-15%, accounts for 39% of CTD-ILDs 1, 2
• Idiopathic inflammatory myopathies (IIM): Prevalence 33-50%, includes dermatomyositis, polymyositis, antisynthetase syndrome 1, 2
• Mixed connective tissue disease (MCTD) and Sjögren disease (SjD): Less common but significant associations 1

Clinical Significance

• Progressive pulmonary fibrosis (PPF) develops in 16-40% of CTD-ILD cases, causing irreversible lung damage 1, 3
• ILD is associated with elevated mortality and represents the primary cause of death in SSc patients alongside cardiovascular disease 1, 2

Risk Factors for ILD Development

Systemic Sclerosis

• Anti-Scl-70 (topoisomerase) antibody positivity 1
• Antinuclear antibody with nucleolar pattern 1
• Diffuse cutaneous subtype, male sex, African American race 1
• Early disease (first 5-7 years after onset) 1
• Elevated acute phase reactants 1

Rheumatoid Arthritis

• High-titer rheumatoid factor and anti-CCP antibodies 1
• Cigarette smoking, older age at RA onset 1
• Male sex, higher body mass index, high disease activity 1

Idiopathic Inflammatory Myopathies

• Specific myositis-associated antibodies (particularly anti-MDA5, anti-synthetase antibodies) 1, 4

Screening and Monitoring Recommendations

Initial Screening

The American College of Rheumatology/American College of Chest Physicians (2024) conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) of the chest for screening patients with SARDs at risk for ILD. 1

• Conditionally recommend against: 6-minute walk test distance, chest radiography, ambulatory desaturation testing, or bronchoscopy for screening 1
• Strongly recommend against: Surgical lung biopsy for screening 1

Monitoring for Progression

For patients with established ILD, conditionally recommend monitoring with PFTs, HRCT chest, and ambulatory desaturation testing. 1

• Conditionally recommend against monitoring with 6-minute walk test distance, chest radiography, or bronchoscopy 1

Clinical Presentation

Early ILD can occur asymptomatically with irreversible lung function loss, while symptomatic patients present with: 1

• Nonproductive cough
• Dyspnea on exertion
• Fatigue (often masked by other organ involvement or comorbidities)

Treatment Approach

First-Line Therapy by Disease

Systemic Sclerosis-ILD

The ACR/CHEST guidelines (2024) provide two strong recommendations specifically for SSc-ILD: strongly recommend AGAINST using glucocorticoids as first-line therapy and after ILD progression due to risk of scleroderma renal crisis. 1, 4

Preferred first-line options: 1

• Mycophenolate
• Cyclophosphamide
• Nintedanib (antifibrotic agent)

Other SARDs (RA, IIM, MCTD, SjD)

Glucocorticoids are conditionally recommended for first-line ILD treatment in all SARDs except systemic sclerosis. 1

Additional preferred options include: 1

• Mycophenolate (better tolerated long-term than cyclophosphamide)
• Cyclophosphamide (intravenous preferred over oral to reduce bladder cancer risk)
• Rituximab
• Calcineurin inhibitors (tacrolimus, cyclosporine) - particularly beneficial for IIM-ILD

Rapidly Progressive ILD (RP-ILD)

For RP-ILD, the ACR recommends upfront combination therapy with intravenous pulse methylprednisolone as first-line due to rapid onset of action. 4

Triple Therapy (Preferred for MDA-5 Associated ILD)

Corticosteroids plus two immunosuppressive agents: 4

• Rituximab (preferred for RP-ILD with underlying CTD)
• Plus cyclophosphamide, calcineurin inhibitor, or mycophenolate

Double Therapy (For Other RP-ILD Causes)

Corticosteroids plus one immunosuppressive agent 4

Additional Salvage Options

• Intravenous immunoglobulin (IVIG) may reduce all-cause death rates 4
• Plasma exchange for refractory cases, particularly with MDA-5 antibody positivity 4

Progressive Fibrosing ILD

Antifibrotic agents (nintedanib, pirfenidone) should be added in cases of progressive pulmonary fibrosis despite immunosuppressive therapy. 1, 2, 3

• Nintedanib has proven efficacy in slowing ILD progression in SSc-ILD (SENSCIS trial) 3
• These agents target common fibrotic pathways across different ILD etiologies 3

Critical Management Considerations

Drug-Induced ILD

• Consider TNF-alpha inhibitors, rituximab, and methotrexate as potential causes 4
• Withdrawal of offending medication is essential 4
• Patients with preexisting ILD have higher risk of drug-related pneumonitis 4

SSc-Specific Cautions

• High-dose glucocorticoids should be avoided except in life-threatening RP-ILD due to scleroderma renal crisis risk 4

Monitoring Treatment Response

• Assess improvement in oxygenation and respiratory status 4
• Monitor infection risk with combination immunosuppression 4
• If no improvement after 48 hours on corticosteroids, add additional agents (infliximab, mycophenolate, or IVIG) 4

Transplant Considerations

Early referral for lung transplantation should be considered in appropriate candidates with progressive disease despite medical therapy. 1, 4

Multidisciplinary Management

Management of CTD-ILD should ideally be decided by an interdisciplinary ILD board integrating rheumatology and pulmonology perspectives. 1, 2

This approach ensures: 1

• Optimal coordination of care
• Simultaneous consideration of pulmonary and rheumatological manifestations
• Early recognition to stabilize or slow irreversible lung function loss