Progressive Pulmonary Fibrosis in Connective Tissue Disease

Abstract

Interstitial lung disease (ILD) is a relatively common complication observed in autoimmune connective tissue disease (CTD). Diagnosis, risk stratification and management are challenging because of the heterogeneous clinical presentation and the unclear underlying pathogenetic mechanisms. This thesis aimed to identify risk factors and biomarkers associated with progressive pulmonary fibrosis (PPF) and mortality in CTD-ILD patients. Factors such as older age, smoking, extent of fibrosis on imaging, and poor lung function were linked to higher mortality. In our cohort primarily consisting of systemic sclerosis (SSc) patients with extensive fibrosis, steroid use, elevated C-reactive protein, and PPF were also associated with mortality. Moreover, we identified risk factors for development of PPF in patients with CTD. Furthermore, three criteria for defining PPF were compared in this thesis. Although different definitions and criteria for PPF are used in literature, we found they have similar prognostic performance. However, the performance of these criteria in predicting mortality was better in certain patient groups. Mortality risk increased in the first 3 years after PPF occurred and plateaued thereafter. So, when establishing PPF in a patient, treatment will be intensified most likely. The use of different PPF criteria may therefore impact treatment decisions. Furthermore, it limits comparison of studies that have used different criteria. The thesis also explored serum biomarkers in CTD-ILD patients, revealing associations between decreased biomarker concentrations (CXCL11, CTGF and KL-6) and improved pulmonary outcomes. Biomarkers were influenced more by the underlying CTD than the lung progression. In primary Sjögren syndrome, we identified KL-6 as a valuable biomarker for preclinical ILD. Lastly, this thesis delved into the treatment landscape for systemic sclerosis associated ILD, considering intensive immunomodulation such as hematopoietic stem cell transplantation (HSCT) for patients with rapid progression. The potential benefits and risks of early HSCT in diffuse cutaneous SSc with ILD are being investigated in the ongoing randomized UPSIDE trial. In the context of SSc, profibrotic mechanisms in skin biopsies were explored. Cellular senescence is a biological process, which can be seen in aging and stress condition, with stopping cell cycle and producing fibro-inflammatory molecules. Endothelial-to-mesenchymal transition (EndMT) ia another profibrotic biological process that endothelial cells transform into active myofibroblast-like condition. The abundance of fibroblast senescence was correlated with EndMT, dermal fibrosis, and inflammation, highlighting potential targets for intervention. Overall, this thesis contributes valuable insights into the complexity of CTD-ILD, identifying risk factors, biomarkers, and potential treatment strategies for better patient outcomes.