Type I interferon pathway activation in connective tissue disease associated interstitial lung disease

Interstitial lung disease (ILD) underlies morbidity and mortality in connective tissue diseases (CTDs) such as systemic sclerosis. ILD encompasses a range of inflammatory and fibrotic pneumopathies, some of which manifest progressive characteristics. Up to 40% of ILDs are progressive, marked by radiologic progression, lung function decline, and increased symptoms. Immunosuppression is standard therapy for ILD, whereas antifibrotics like nintedanib are used in progressive fibrotic cases. Many patients deteriorate despite treatment, underscoring the need for biomarkers and targeted interventions. Type I interferon (IFN-I) signaling is implicated in CTD-ILD: interferon stimulated gene expression correlates with accelerated pulmonary decline and sustained IFN-I can precipitate ILD. In addition, IFN-I blocking agents like anifrolumab are under clinical investigation for CTD-ILD. This review examines IFN-I's role and therapeutic targeting in ILD.