Overview

Systemic sclerosis–associated interstitial lung disease (SSc-ILD) is one of the most common and severe internal organ manifestations of systemic sclerosis (SSc), occurring in up to 50–60% of patients on HRCT, with clinically significant disease in ~25–30%. It is a major cause of SSc-related mortality. The most frequent histopathological pattern is nonspecific interstitial pneumonia (NSIP), followed by usual interstitial pneumonia (UIP). Risk factors include diffuse cutaneous SSc, anti-topoisomerase I (Scl-70) antibody positivity, male sex, African-American ethnicity, and early disease onset. The most important complication is progressive pulmonary fibrosis leading to respiratory failure and death.

Anatomy and Physiology

• Alveolar-capillary unit: Site of gas exchange; consists of alveolar epithelium, interstitial space, and capillary endothelium.
• Type I pneumocytes: Thin cells covering most alveolar surface, specialized for gas exchange.
• Type II pneumocytes: Produce surfactant, repair alveolar epithelium after injury.
• Interstitial space: Contains fibroblasts, extracellular matrix; normally thin to allow efficient diffusion.
• Pulmonary microvasculature: Maintains low-resistance blood flow for oxygen uptake.

Aetiology and Risk Factors

Aetiology

• Autoimmune-mediated endothelial injury and fibroblast activation
• Genetic predisposition (e.g., HLA alleles, IRF5, STAT4 variants)
• Environmental exposures (silica, organic solvents)
• Microchimerism (fetal cell persistence in maternal circulation)

Risk Factors

• Diffuse cutaneous SSc subtype
• Anti-Scl-70 antibody positivity
• Male sex
• African-American ethnicity
• Early disease onset (<5 years from SSc diagnosis)
• High baseline CRP or ESR
• Smoking

Pathophysiology 

• Endothelial injury → microvascular dysfunction, increased permeability
• Immune activation → infiltration by T cells, B cells, macrophages
• Cytokine release (TGF-β, IL-6, PDGF) → fibroblast activation
• Fibroblast-to-myofibroblast transition → excessive collagen and ECM deposition
• Interstitial thickening → impaired gas exchange, restrictive lung physiology
• Progressive fibrosis → irreversible architectural distortion, honeycombing (UIP)

Clinical Manifestations

• Progressive exertional dyspnea
• Nonproductive cough
• Bibasilar “Velcro” crackles
• Fatigue, reduced exercise tolerance
• Digital ulcers, Raynaud’s phenomenon (coexistent SSc features)
• Signs of pulmonary hypertension in advanced disease

Diagnosis

Diagnostic criteria

• Systemic Sclerosis diagnosis
• HRCT showing ILD pattern
• Exclusion of other ILD causes

Investigations

• High resolution CT (HRCT)
  • NSIP (ground-glass opacities, subpleural sparing) 
  • UIP (honeycombing, reticulation)
• Pulmonary Function Tests: restrictive pattern, ↓ FVC, ↓ DLCO
• Serology: ANA, anti-Scl-70, anti-centromere, anti-RNA polymerase III
• Echocardiography: screen for pulmonary hypertension
• 6-minute walk test: functional assessment

Differential Diagnoses

Classification

• By HRCT/histopathology:
  • Nonspecific Interstitial Pneumonia (NSIP) – most common
  • Usual Interstitial Pneumonia (UIP)
  • Organizing Pneumonia (OP)
  • Lymphoid Interstitial Pneumonia (LIP)
• By extent:
  • Limited (<20% lung involvement)
  • Extensive (>20% lung involvement)

Treatment

• Immunosuppressants:
  • Glucocorticoids – not recommended given risk of renal crisis
  • Mycophenolate mofetil (first-line)
  • Cyclophosphamide OR Rituximab OR Tocilizumab
• Anti-fibrotics:
  • Nintedanib (approved for SSc-ILD)
• Supportive:
  • Oxygen therapy
  • Pulmonary rehabilitation
  • Vaccinations (influenza, pneumococcal)
• Monitoring:
  • Serial PFTs every 3–6 months
  • HRCT as indicated
• Refractory/severe disease
  • Autologous stem cell transplant (skin and lung)
  • CAR T-cell therapy

Complications and Prognosis

Complications

• Progressive pulmonary fibrosis
• Pulmonary hypertension
• Respiratory failure
• Increased infection risk (immunosuppression-related)

Prognosis

• NSIP: better prognosis than UIP
• Poor prognostic factors:
  • Male sex
  • African-American ethnicity
  • Extensive lung involvement (>20%)
  • Rapid FVC decline (>10% in 12 months)
  • UIP pattern

References

1. Hoffmann-Vold AM et al. The identification and management of interstitial lung disease in systemic sclerosis: evidence-based European consensus statements. Lancet Rheumatol. 2020;2(2):e71–e83.
2. Distler O et al. Nintedanib for systemic sclerosis–associated interstitial lung disease. N Engl J Med. 2019;380:2518–2528.
3. Volkmann ER. Natural history of systemic sclerosis–related interstitial lung disease: how to identify a progressive fibrosing phenotype. J Scleroderma Relat Disord. 2020;5(2_suppl):31–40.
4. Goh NS et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med. 2008;177:1248–1254.
5. Bruni C et al. Predicting ILD in systemic sclerosis: the ILD-RISC model. BMC Pulm Med. 2025;25:3722.
6. Khanna D et al. 2013 ACR/EULAR classification criteria for systemic sclerosis. Arthritis Rheum. 2013;65:2737–2747.