Various connective tissue diseases tend to affect specific organs, lungs being the organ with the most serious repercussions and consequences. The diagnosis of interstitial lung disease makes the treatment more difficult and worsens long-term prognosis and overall survival. Positive results from the registration studies of nintedanib led to approval of the drug for the treatment of idiopathic pulmonary fibrosis and chronic fibrosing interstitial lung diseases in connective tissue diseases. After registration, real-world data on the use of nintedanib are being collected in everyday clinical practise. The objective of the study was to collect and analyse real world experience gathered after the registration of nintedanib for the treatment of CTD-ILD and to show if the positive results collected from a homogeneous and "representative" study population can be applied to everyday clinical practice. We are presenting a retrospective observational case-series study of patients treated with nintedanib from the three largest Croatian centers specialised in the treatment of connective tissue diseases with interstitial lung diseases. Stabilisation or improved of lung function tests was reported in 68% of patients when changes in predicted FVC were observed and in 72% of patients when changes in DLco were analysed. Almost all of the reported patients (98%) were treated with nintedanib as an add-on drug to immunosuppressants. The most common side-effects were gastrointestinal symptoms and abnormal liver function tests in less extent. Our real-world data confirm the tolerability, efficacy and similar side-effects of nintedanib as reported in pivotal trials. Key Points • Interstitial lung disease is a common manifestation of several connective tissue diseases and its progressive fibrosing phenotype contributes to high mortality rate and many unmet needs regarding the treatment remain. • Registration studies of nintedanib obtained sufficient data and positive results to support approval of the drug. • Real-world evidence from our CTD-ILD centres confirm the clinical trial data regarding efficacy, tolerability and safety of nintedanib.

Lung ultrasound (LUS) is a promising tool for detecting systemic sclerosis-associated interstitial lung disease (SSc-ILD). Currently, consensus on the best LUS findings and execution technique is lacking. Objectives: To compare qualitative and quantitative assessment of B-lines and pleural line (PL) alterations in SSc-ILD with chest computed tomography (CT) analysis. Methods: During 2021-2022, consecutive SSc patients according to 2013 ACR/EULAR classification criteria underwent pulmonary functional tests (PFTs). On the same day, if a CT was performed over a ± 6 months period, LUS was performed by two certified blinded operators using a 14-scans method. The ≥10 B-lines cut-off proposed by Tardella and the Fairchild's PL criteria fulfilment were selected as qualitative findings. As quantitative assessment, total B-lines number and the quantitative PL score adapted from the semi-quantitative Pinal-Fernandez score were collected. CT scans were evaluated by two thoracic radiologists for ILD presence, with further processing by automated texture analysis software (qCT). Results: 29 SSc patients were enrolled. Both qualitative LUS scores were significantly associated to ILD presence on CT, with Fairchild's PL criteria resulting in slightly more accuracy. Results were confirmed on multivariate analysis. All qualitative and quantitative LUS findings were found to be significantly associated with qCT ILD extension and radiological abnormalities. Mid and basal PL quantitative score correlated with mid and basal qCT ILD extents. Both B-lines and PL alterations differently correlated with PFTs and clinical variables. Conclusion: This preliminary study suggests the utility of a comprehensive LUS assessment for SSc-ILD detection compared with CT and qCT.

Objective: Interstitial lung diseases (ILDs) are a group of diffuse parenchymal lung disorders that can be idiopathic [idiopathic pulmonary fibrosis (IPF)] or associated with other diseases and are characterized by varying degrees of inflammation and fibrosis with poor prognosis. Several indicators are essential in diagnosing these individuals and differentiating between IPF and ILD. Patients and methods: The study involved 44 IPF patients, 22 ILD (non-IPF) patients, and 24 healthy people. We aimed to compare ILD (non-IPF) and IPF patient groups with each other and with healthy people in terms of interleukin (IL)-1, tumor necrosis factor-alpha (TNF-α), matrix metalloproteinase (MMP)-1, MMP-7, galectin (Gal)-3, IL-6, Krebs von den Lungen-6 (KL-6), total antioxidant status (TAS), total oxidant status (TOS), pyruvate kinase (PK), complete blood count (CBC), ferritin, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) features. Furthermore, it was intended to assess the patient groups in terms of visual semi-quantitative score (VSQS) (IPF alone), respiratory function tests (RFT), and 6-minute walk test (6MWT), also potential correlations between these tests and the previously indicated parameters. Results: MMP-1, MMP-7, Gal-3, IL-6, KL-6, forced vital capacity (FVC), % FVC, forced expiratory volume in 1 second (FEV1), % FEV1, TAS, TOS, and PK values significantly elevated in IPF and ILD. Weight, IL-1, MMP-1, MMP-7, Gal-3, IL-6, KL-6, % FVC, FEV1, % FEV1, eosinophil count, and % red blood cell distribution width (RDW) values differed between IPF and ILD. VSQS, 6MWT, and PK were substantially linked with MMP-1, MMP-7, Gal-3, IL-6, and KL-6 in IPF. Conclusions: The factors investigated can be helpful in the diagnosis and distinction of IPF and ILD. In addition to focusing on the inflammatory environment in IPF and ILD patients, oxidant and antioxidant interactions must be studied.

Background: Idiopathic pulmonary fibrosis (IPF), a type of interstitial lung disease (ILD), is a chronic disease with an unknown etiology. The occurrence of lung cancer (LC) is one of the main causes of death in patients with IPF. However, the pathogenesis driving these malignant transformations remains unclear; therefore, this study aimed to identify the shared genes and functional pathways associated with both disease conditions. Methods: Data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. To identify overlapping genes in both diseases, the "limma" package in R software and weighted gene coexpression network analysis (WGCNA) were used. Venn diagrams were used to obtain the shared genes. The diagnostic value of the shared genes was assessed using receiver operating characteristic (ROC) curve analysis. Gene Ontology (GO) term enrichment was performed on the shared genes between lung adenocarcinoma (LUAD) and IPF, and the genes were also functionally enriched using Metascape. A protein-protein interaction (PPI) network was created using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. Finally, the link between shared genes and common antineoplastic medicines was investigated using the CellMiner database. Results: The coexpression modules associated with LUAD and IPF were discovered using WGCNA, and 148 genes were found to overlap. In addition, 74 upregulated and 130 downregulated overlapping genes were obtained via differential gene analysis. Functional analysis of the genes revealed that these genes are primarily engaged in extracellular matrix (ECM) pathways. Furthermore, COL1A2, POSTN, COL5A1, CXCL13, CYP24A1, CXCL14, and BMP2 were identified as potential biomarkers in patients with LUAD secondary to IPF showing good diagnostic values. Conclusions: ECM-related mechanisms may be the underlying link between LC and IPF. A total of 7 shared genes were identified as potential diagnostic markers and therapeutic targets for LUAD and IPF.

Background: A genomic classifier for usual interstitial pneumonia (gUIP) has been shown to predict histological UIP with high specificity, increasing diagnostic confidence for idiopathic pulmonary fibrosis (IPF). Whether those with positive gUIP classification exhibit a progressive, IPF-like phenotype remains unknown. Methods: A pooled, retrospective analysis of patients who underwent clinically indicated diagnostic bronchoscopy with gUIP testing at seven academic medical centres across the USA was performed. We assessed the association between gUIP classification and 18-month progression-free survival (PFS) using Cox proportional hazards regression. PFS was defined as the time from gUIP testing to death from any cause, lung transplant, ≥10% relative decline in forced vital capacity (FVC) or censoring at the time of last available FVC measure. Longitudinal change in FVC was then compared between gUIP classification groups using a joint regression model. Results: Of 238 consecutive patients who underwent gUIP testing, 192 had available follow-up data and were included in the analysis, including 104 with positive gUIP classification and 88 with negative classification. In multivariable analysis, positive gUIP classification was associated with reduced PFS (hazard ratio 1.58, 95% CI 0.86-2.92; p=0.14), but this did not reach statistical significance. Mean annual change in FVC was -101.8 mL (95% CI -142.7- -60.9 mL; p<0.001) for those with positive gUIP classification and -73.2 mL (95% CI -115.2- -31.1 mL; p<0.001) for those with negative classification (difference 28.7 mL, 95% CI -83.2-25.9 mL; p=0.30). Conclusions: gUIP classification was not associated with differential rates of PFS or longitudinal FVC decline in a multicentre interstitial lung disease cohort undergoing bronchoscopy as part of the diagnostic evaluation.

Cell senescence has recently emerged as a potentially relevant pathogenic mechanism in fibrosing interstitial lung diseases (f-ILDs), particularly in idiopathic pulmonary fibrosis. We hypothesized that senescent human fibroblasts may suffice to trigger a progressive fibrogenic reaction in the lung. To address this, senescent human lung fibroblasts, or their secretome (SASP), were instilled into the lungs of immunodeficient mice. We found that: (1) human senescent fibroblasts engraft in the lungs of immunodeficient mice and trigger progressive lung fibrosis associated to increasing levels of mouse senescent cells, whereas non-senescent fibroblasts do not trigger fibrosis; (2) the SASP of human senescent fibroblasts is pro-senescence and pro-fibrotic both in vitro when added to mouse recipient cells and in vivo when delivered into the lungs of mice, whereas the conditioned medium (CM) from non-senescent fibroblasts lacks these activities; and, (3) navitoclax, nintedanib and pirfenidone ameliorate lung fibrosis induced by senescent human fibroblasts in mice, albeit only navitoclax displayed senolytic activity. We conclude that human senescent fibroblasts, through their bioactive secretome, trigger a progressive fibrogenic reaction in the lungs of immunodeficient mice that includes the induction of paracrine senescence in the cells of the host, supporting the concept that senescent cells actively contribute to disease progression in patients with f-ILDs.

Objective: Interstitial lung disease (ILD) is the leading cause of mortality in systemic sclerosis (SSc). Novel biomarkers are crucial to improve outcomes in SSc-ILD. We aimed to compare the performance of potential serum biomarkers of SSc-ILD that reflect different pathogenic processes: KL-6 and SP-D (epithelial injury), CCL18 (type 2 immune response), YKL-40 (endothelial injury and matrix remodelling) and MMP-7 (ECM remodelling). Methods: Baseline and follow-up serum samples from 225 SSc patients were analysed by ELISA. Progressive ILD was defined according to the 2022-ATS/ERS/JRS/ALAT guidelines. Linear mixed models and random forest models were used for statistical analyses. Results: Serum levels of KL-6 (MD 35.67 [95% CI 22.44-48.89, p< 0.01]), SP-D (81.13 [28.46-133.79, p< 0.01]), CCL18 (17.07 [6.36-27.77, p< 0.01]), YKL-40 (22.81 [7.19-38.44, p< 0.01]) and MMP-7 (2.84 [0.88-4.80, p< 0.01]) were independently associated with the presence of SSc-ILD. A machine-learning model including all candidates classified patients with or without ILD with an accuracy of 85%. The combination of KL-6 and SP-D was associated with the presence (0.77 [0.53-1.00, p'<0.01]) and previous progression of SSc-ILD (OR 1.28 [1.01-1.61, p'=0.047]). Higher baseline levels of KL-6 (OR 3.70 [1.52-9.03, p< 0.01]) or SP-D (OR 2.00 [1.06-3.78, p= 0.03]) increased the odds of future SSc-ILD progression, independent of other conventional risk factors, and the combination of KL-6 and SP-D (1.109 [0.665-1.554, p< 0.01] showed improved performance compared with KL-6 and SP-D alone. Conclusion: All candidates performed well as diagnostic biomarkers for SSc-ILD. The combination of KL-6 and SP-D might serve as biomarker for the identification of SSc patients at risk of ILD progression.

Interstitial lung diseases (ILDs) are a large group of pulmonary disorders characterized histologically by the cardinal involvement of the pulmonary interstitium. The prototype of ILDs is idiopathic pulmonary fibrosis (IPF), an incurable disease characterized by progressive distortion and loss of normal lung architecture through unchecked collagen deposition. Acute exacerbations are dramatic events during the clinical course of ILDs, associated with high morbidity and mortality. Infections, microaspiration, and advanced lung disease might be involved in the pathogenesis of acute exacerbations. Despite clinical scores, the prediction of the onset and outcome of acute exacerbations is still inaccurate. Biomarkers are necessary to characterize acute exacerbations better. We review the evidence for alveolar epithelial cell, fibropoliferation, and immunity molecules as potential biomarkers for acute exacerbations of interstitial lung disease.

Purpose of review: To characterize patterns of disease progression in the designation of progressive pulmonary fibrosis (PPF), including their relative prevalence and subsequent prognostic significance, in patients with fibrotic interstitial lung disease (ILD), including key patient sub-groups. Recent findings: In recent large clinical cohorts, PPF criteria suited to early PPF identification, based on their prevalence and short time to progression, include a relative forced vital capacity (FVC) decline exceeding 10% and various combinations of lower thresholds for FVC decline, symptomatic worsening and serial progression of fibrosis on imaging. Amongst numerous candidate PPF criteria, these progression patterns may have the greatest prognostic significance based on subsequent mortality, although there are conflicting data based on subsequent FVC progression. The prevalence of patterns of progression is similar across major diagnostic sub-groups with the striking exception of patients with underlying inflammatory myopathy. Summary: Based on prevalence and the prognostic significance of PPF criteria, and the need for early identification of disease progression, recent published data in large clinical cohorts provide support for the use of the INBUILD PPF criteria. The patterns of disease progression used to designate PPF in a recent multinational guideline are mostly not based on data in previous and subsequent real-world cohorts.

Interstitial lung disease (ILD) is a frequent complication of rheumatoid arthritis (RA) that is associated with a significant increase in mortality. Several risk factors for the development of ILD in patients with RA have been identified, but ILD can still develop in the absence of these risk factors. Screening tools for RA-ILD are required to facilitate early detection of RA-ILD. Close monitoring of patients with RA-ILD for progression is crucial to enable timely implementation of treatment strategies to improve outcomes. Patients with RA are commonly treated with immunomodulatory therapies, although their efficacy in slowing the progression of RA-ILD remains the subject of debate. Clinical trials have shown that antifibrotic therapies slow decline in lung function in patients with progressive fibrosing ILDs, including patients with RA-ILD. The management of patients with RA-ILD should be based on multidisciplinary evaluation of the severity and progression of their ILD and the activity of their articular disease. Close collaboration between rheumatologists and pulmonologists is essential to optimize patient care.