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Background: Idiopathic pulmonary fibrosis (IPF) is characterised by worsening dyspnoea and exercise intolerance. Research question: Does a long-term pulmonary rehabilitation improve exercise tolerance in patients with IPF treated with standard antifibrotic drugs, which are expected to reduce disease progression? Methods: This open-label randomised controlled trial was performed at 19 institutions. Stable patients receiving nintedanib were randomised into pulmonary rehabilitation and control groups (1:1). The pulmonary rehabilitation group underwent initial rehabilitation which included twice-weekly sessions of monitored exercise training for 12 weeks, followed by an at-home rehabilitation programme for 40 weeks. The control group received usual care only, without pulmonary rehabilitation. Both groups continued to receive nintedanib. The primary and main secondary outcomes were change in 6 min walking distance (6MWD) and change in endurance time (using cycle ergometry) at week 52. Results: Eighty-eight patients were randomised into pulmonary rehabilitation (n=45) and control (n=43) groups. Changes in 6MWD were -33 m (95% CI -65 to -1) and -53 m (95% CI -86 to -21) in the pulmonary rehabilitation and control groups, respectively, with no statistically significant difference (mean difference, 21 m (95% CI -25 to 66), p=0.38). Changes in endurance time were significantly better in the pulmonary rehabilitation (64 s, 95% CI -42.3 to 171)) than in the control (-123 s (95% CI -232 to -13)) group (mean difference, 187 s (95% CI 34 to 153), p=0.019). Interpretation: Although pulmonary rehabilitation in patients taking nintedanib did not improve 6MWD in the long term, it led to prolonged improvement in endurance time.

Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis (IPF). Weight loss is recognized as an adverse event during nintedanib treatment, and is a common complication exploitable as a prognostic indicator of IPF. Here, we report a single-center, retrospective cohort study to assess body weight changes during nintedanib therapy in patients with IPF. Sixty-one patients treated with nintedanib for >6 months were included (45 males, mean age ± standard deviation 73.1 ± 7.4 years). Baseline body weight and body mass index were 60.1 ± 12.0 kg and 23.2 ± 3.5 kg/m2, respectively. Mean weight loss during the first 6 months of nintedanib treatment was significant (-3.2 ± 3.4 kg, p < 0.0001) with Common Terminology Criteria for Adverse Events (CTCAE) grades 0,1,2 or 3 of 30, 17, 13 and 1, respectively. Pulmonary function test records 6 months before nintedanib administration were available in a subset of patients (n = 40). Significant differences in weight change over the 6 months before-vs-after nintedanib administration were also observed in these patients [mean differences -2.5 ± 3.4 kg, 95% confidence interval (CI) -3.6, -1.4, p < 0.0001]. Multivariate analysis showed that only baseline body weight was significantly associated with weight loss of CTCAE grade ≥2 (odds ratio 0.921, 95% CI 0.854, 0.994). Median follow-up from starting nintedanib was 34.8 months. There was a significant difference in overall survival between patients with CTCAE grade ≥2-vs-grade<2 (median survival of 25.5 months and 55.2 months, p = 0.014). In the model adjusting for age, sex and lung function, weight loss CTCAE grade ≥2 was an independent predictor for all-cause mortality (hazard ratio 2.448, 95% CI 1.080-5.551). In conclusion, weight loss is an important issue for the management of patients with IPF treated with nintedanib.

Background: Many epidemiological studies have shown that idiopathic pulmonary fibrosis (IPF) is a risk factor for lung cancer (LC), but these studies do not provide direct evidence of a causal association between the two diseases. We investigated the causal association between IPF and different pathological types of LC based on the Mendelian randomization (MR) study. Methods: The genome-wide association study (GWAS) data of IPF and LC were obtained from the latest published articles, and instrumental variables (IVs) for analysis were obtained after screening and eliminating the confounders. MR Analysis was carried out with the help of random effects inverse variance weighting (re-IVW), MR-egger, and weighted median method, and a comprehensive sensitivity test was conducted. Results: The results of re-IVW analysis showed that IPF may increase the risk of lung squamous cell carcinoma (LUSC) (OR = 1.045, 95% CI 1.011 to 1.080, P = 0.008). In addition, no causal relationship was found between IPF and overall LC (OR = 0.977, 95% CI 0.933 to 1.023, P = 0.32), lung adenocarcinoma (LUAD) (OR = 0.967, 95% CI 0.903 to 1.036, P = 0.345) and small cell lung carcinoma (SCLC) (OR = 1.081, 95% CI 0.992 to 1.177, P = 0.074). A comprehensive sensitivity analysis ensured the reliability of the study. Conclusion: In conclusion, from the perspective of genetic association, we found that IPF is an independent risk factor for LUSC and may increase the risk of LUSC, but no such causal relationship was found in LUAD and SCLC.

Background: Rheumatoid arthritis associated interstitial lung disease (RA-ILD) is associated with high levels of morbidity and mortality. The primary aim of this systematic review was to determine the duration of survival, from time of diagnosis of RA-ILD. Methods: Medline (Ovid), Embase (OVID), CINAHL (EBSCO), PubMed, and the Cochrane Library were searched for studies that reported duration of survival from time of diagnosis of RA-ILD. Risk of bias of included studies was assessed based upon 4 domains of the Quality In Prognosis Studies tool. Results for median survival were presented by tabulation and discussed qualitatively. Meta-analysis of cumulative mortality at 1 year, >1y to ≤3 years, >3 years to ≤5 years, and >5 years to≤ 10 years was undertaken, for total RA-ILD population, and according to ILD pattern. Results: 78 studies were included. Median survival for the total RA-ILD population ranged from 2 to 14 years. Pooled estimates for cumulative percentage mortality up to 1 year were 9.0% (95% CI 6.1, 12.5, I2 88.9%), >1 to ≤3 years 21.4% (17.3, 25.9, I2 85.7%), >3 to ≤ 5 years 30.2% (24.8, 35.9, I2 87.7%), and > 5 to ≤ 10 years 49.1% (40.6, 57.7 I2 85.0%). Heterogeneity was high. Only 15 studies were rated as low risk of bias in all 4 domains assessed. Conclusion: This review summarises the high mortality of RA-ILD, however the strength of conclusions that can be made is limited by the heterogeneity of the available studies, due to methodological and clinical factors. Further studies are needed to better understand the natural history of this condition.

Objective: For patients with connective tissue disease-associated interstitial lung disease (CTD-ILD), early medical intervention would be desirable. This study analyzed the real-world, single-center use of nintedanib for CTD-ILD patients. Methods: Patients with CTD who received nintedanib from January 2020 to July 2022 were enrolled. Medical records review and stratified analyses of the collected data were conducted. Results: Reduction in the percentage of predicted forced vital capacity (%FVC) was seen in the elderly group (>70 years; P = .210), males (P = .027), the late group who started nintedanib >80 months after confirmation of an ILD disease activity (P = .03), the severe %DLco (diffusing capacity for carbon monoxide as a percentage of predicted) group (<40%; P = .20), the group who had extensive pulmonary fibrosis at the beginning of nintedanib (pulmonary fibrosis score >35%), and the low-dose group (nintedanib 50-100 mg/d; P = .40). %FVC did not decrease by >5% in the young group (<55 years), the early group who started nintedanib within 10 months after confirmation of an ILD disease activity, and the group whose pulmonary fibrosis score at the beginning of nintedanib was <35%. Conclusion: It is important to diagnose ILD early and start antifibrotic drugs with proper timing for cases in need. It is better to start nintedanib early, especially for patients at risk (>70 years old, male, <40% DLco, and >35% areas of pulmonary fibrosis).

Connective Tissue Disease-Interstitial Lung Disease (CTD-ILD) is a severe and fatal manifestation of systemic autoimmune disorders. Therapies rely on immunomodulators but their efficacy in ILD progression remains uncertain. Nintedanib, an antifibrotic agent that slows pulmonary function decline, has been approved for CTD-ILD treatment. The aim of this study was to assess the effectiveness and safety of nintedanib in CTD-ILD patients in a real-world data setting. A single-center, retrospective, and descriptive analysis of CTD-ILD patients treated with nintedanib from June 2019 to November 2022 was performed. The assessment of nintedanib treatment's efficacy was judged solely on the evolution of pulmonary function tests (PFTs), which were evaluated before and after treatment. Twenty-one patients (67% females, median age 64 years (IQR = 9) with CTD-ILD (systemic sclerosis n = 9, rheumatoid arthritis n = 5, dermatomyositis n = 4, juvenile rheumatoid arthritis n = 1, undifferentiated CTD n = 1, interstitial pneumonia with autoimmune features n = 1), 18 of whom were on concomitant immunosuppressives, had a median follow-up period of 10 months (IQR = 5). PFTs before and after treatment did not significantly differ. The mean FVC% difference was +0.9 (sd = 7.6) and the mean DLco% difference was +3.4 (sd = 12.6), suggesting numerical improvement of PFTs. The average percentage change was -0.3% and +7.6% for FVC% and DLco%, respectively, indicating stabilization of lung function. Our real-world data across a broad spectrum of CTD-ILD suggest that nintedanib could be beneficial in combination with immunosuppressives in slowing the rate of lung function decline.

Introduction: Interstitial lung diseases associated with systemic autoimmune diseases (ILD-SAD) can progress to a fibrotic form that can benefit from antifibrotic treatment. The aim of the study is to describe a cohort of patients with ILD-SAD who manifest progressive pulmonary fibrosis treated with antifibrotics. Methods: Single-centre retrospective observational study from a tertiary care hospital on a cohort of patients with ILD-SAD with progressive pulmonary fibrosis evaluated in a joint pulmonology and rheumatology clinic that initiated treatment with antifibrotic drugs between 01/01/2019 and 01/12/2021. Clinical characteristics were analysed. The evolution of pulmonary function test and adverse effects during treatment were described. Results: 18 patients were included. The mean age was 66.7 ± 12.7 years, with a higher frequency of females (66.7%). Systemic sclerosis (SS) was the most frequent systemic autoimmune disease (36.8%). The majority of patients were receiving systemic glucocorticoid treatment (88.9%), 72.2% of patients were receiving treatment with disease-modifying drugs, the most frequent being mycophenolate mofetil (38.9%), and 22.2% with rituximab. Functional stability was observed after the start of antifibrotic treatment. Two patients died during follow-up, one due to progression of ILD. Conclusion: Our study suggests a beneficial effect of antifibrotic treatment added to immunomodulatory treatment in patients with fibrotic ILD-SAD in real life. In our cohort, patients with ILD-SAD with progressive fibrosing involvement show functional stability after starting antifibrotic treatment. Treatment tolerance was relatively good with a side effect profile similar to that described in the medical literature.

Background: Idiopathic pulmonary fibrosis (IPF), a chronic, progressive lung disease characterized by interstitial remodeling and tissue destruction, affects people worldwide and places a great burden on society. Cellular senescence is thought to be involved in the mechanisms and development of IPF. The aim of this study was to predictively investigate subtypes of IPF according to cellular senescence-related genes and their correlation with the outcome of patients with IPF, providing possible treatment and management options for disease control. Methods: Gene expression profiles and follow-up data were obtained from the GEO database. Senescence-related genes were obtained from the CSGene database and analyzed their correlation with the outcome of IPF. A consensus cluster was constructed to classify the samples based on correlated genes. The GSVA and WGCNA packages in R were used to calculate the immune-related enriched fractions and construct gene expression modules, respectively. Metascape and the clusterProfiler package in R were used to enrich gene functions. The ConnectivityMap was used to probe suitable drugs for potential treatment. Results: A total of 99 cellular senescence-related genes were associated with IPF prognosis. Patients with IPF were divided into two subtypes with significant prognostic differences. Subtype S2 was characterized by enhanced fibrotic progression and infection, leading to acute exacerbation of IPF and poor prognosis. Finally, five cellular senescence-related genes, TYMS, HJURP, UBE2C, BIRC5, and KIF2C, were identified as potential biomarkers in poor prognostic patients with IPF. Conclusion: The study findings indicate that cellular senescence-related genes can be used to distinguish the prognosis of patients with IPF. Among them, five genes can be used as candidate biomarkers to predict patients with a poor prognostic subtype for which anti-fibrosis and anti-infection treatments could be suitable.

Introduction: The diagnosis of Idiopathic pulmonary fibrosis (IPF) requires the careful exclusion of secondary causes of interstitial lung disease (ILD), and the collaboration among different specialists is considered paramount to establish a diagnosis with high diagnostic confidence. The multidisciplinary discussion (MDD) has assumed an increasing importance over the years in the different phases of the IPF diagnostic work-up. Areas covered: The role of MDD in the diagnosis and management of IPF will be described. Practical insights will be provided into how and when to perform MDD based on the available scientific evidence. Current limitations and future perspectives will be discussed. Expert opinion: In the absence of high diagnostic confidence, agreement between different specialists during MDD is recognized as a surrogate indicator of diagnostic accuracy. Often, despite a lengthy evaluation, the diagnosis remains unclassifiable in a significant percentage of patients. MDD therefore appears to be pivotal in attaining an accurate diagnosis of ILDs. The discussion among different specialists can also include other specialists, such as rheumatologists and thoracic surgeons, in addition to the core group of pulmonologists, radiologists, and pathologists. Such discussions can allow greater diagnostic accuracy and have important effects on management, pharmacologic therapies, and prognosis.

Introduction: Interstitial lung disease (ILD) is the leading cause of mortality in patients with systemic sclerosis (SSc). Risk of developing progressive ILD is highest among patients with diffuse cutaneous disease, positive anti-topoisomerase I antibody, and elevated acute phase reactants. With the FDA approval of two medications and a pipeline of novel therapeutics in trials, early recognition and intervention is critical. High-resolution computed tomography of the chest is the current gold standard test for diagnosis of ILD. Yet, it is not offered as a screening tool to all patients due to which ILD can be missed in up to a third of patients. There is a need to develop and validate more innovative screening modalities. Areas covered: In this review, we provide an overview of screening and diagnosis of SSc-ILD, highlighting the recent innovations particularly the role of soluble serologic, radiomic (quantitative lung imaging, lung ultrasound), and breathomic (exhaled breath analysis) biomarkers in the early detection of SSc-ILD. Expert opinion: There is remarkable progress in the development of new radiomics and serum biomarkers in diagnosing SSc-ILD. There is an urgent need for conceptualizing and testing composite ILD screening strategies that incorporate these biomarkers.