Review
Interstitial lung disease as the initial manifestation of systemic autoimmune disease: a narrative review of autoantibodies, biomarkers, prognosis, and management
H.M. Moutsopoulos1
- Science section, National Academy of Athens, Greece. hmoutsop@med.uoa.gr
CER20351
Review
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PMID: 42873695 [PubMed]
Received: 19/07/2026
Accepted : 28/09/2026
In Press: 13/10/2026
Abstract
Interstitial lung disease (ILD) may be the first or only clinically apparent manifestation of systemic autoimmune rheumatic disease (SARD), preceding extrapulmonary features by months or years. The European Respiratory Society/American Thoracic Society research classification of interstitial pneumonia with autoimmune features (IPAF) provides a framework for patients with interstitial pneumonia and autoimmune features who do not meet criteria for a defined SARD. Importantly, IPAF requires features from at least two of three domains – clinical, serologic, and morphologic – and cannot be assigned on autoantibody positivity alone. Extended, phenotype-directed autoantibody testing can reveal lung-dominant anti-synthetase syndrome, clinically amyopathic dermatomyositis, early systemic sclerosis, rheumatoid arthritis, or Sjögren’s syndrome (Autoimmune epithelitis). Prognosis is heterogeneous and is driven more consistently by the fibrotic burden, usual interstitial pneumonia pattern, baseline and longitudinal pulmonary physiology, and comorbidities than by the IPAF label itself. KL-6, surfactant protein D, CCL18, MMP-7, and multiplex proteomic signatures are promising biomarkers, but none is sufficiently validated to replace serial high-resolution computed tomography and pulmonary function testing. Management should be individualised through multidisciplinary discussion. Immunomodulation is most defensible for inflammatory or SARD-like phenotypes, whereas antifibrotic therapy should be considered when progressive pulmonary fibrosis is established despite appropriate management. IPAF should therefore be viewed as a dynamic research phenotype within a continuum of lung-dominant autoimmunity, requiring longitudinal reassessment for evolution to a defined SARD.
