Background: The FIBRONET study was an observational study of patients with idiopathic pulmonary fibrosis (IPF) in Italy.

Objectives: In this post hoc descriptive analysis, we describe changes in lung function, anxiety/depression, coughing, exacerbations, and adverse events (AEs) in patients receiving nintedanib treatment.

Methods: Patients with IPF from 20 centers in Italy, aged ≥40 years who received nintedanib for ≥7 months, were followed up for 12 months from study enrollment, attending clinic visits every 3 months. Outcomes included change in forced vital capacity (FVC)% predicted from baseline to 12 months, anxiety/depression measured by the Hospital Anxiety and Depression Scale (HADS), and the proportion of patients with cough, AEs, and exacerbations.

Results: In total, 52 patients received nintedanib (mean duration of 11.6 months). Ten patients had dose reductions from 150 mg to 100 mg twice daily, due to AEs. FVC% predicted was unchanged in the overall nintedanib population (78.7% at baseline; 79.8% at 12 months) and those with a reduced dose (77.7% at baseline; 81.0% at 12 months). HADS score was low at baseline and throughout the study. The proportion of patients with cough decreased from 50.0% to 21.2% over 12 months. Two patients experienced exacerbations, 2 patients discontinued treatment, and 27 (51.9%) reported AEs. The most common AE was diarrhea (34.6%).

Conclusions: In patients with IPF who received nintedanib in the FIBRONET study, FVC% predicted was stable over 12 months, and the proportion of patients with cough decreased. The safety profile was consistent with the known safety profile for nintedanib in IPF.

Abstract: Patients with idiopathic pulmonary fibrosis (IPF) are at a high risk of lung cancer (LC). Antifibrotic therapy slows disease progression and possibly prolongs survival. However, whether antifibrotic therapy affects LC development in patients with IPF remains unknown. This multicentre retrospective study evaluated 345 patients with IPF. The incidence and prevalence of LC were significantly lower in patients with IPF receiving antifibrotic therapy than those not receiving. Subsequently, LC-related mortality was significantly lower in patients with IPF receiving antifibrotic therapy. These results suggest that antifibrotic therapy was possibly associated with a reduced risk of LC development in patients with IPF, which may be partly associated with its survival benefit.

Background: Idiopathic pulmonary fibrosis (IPF) can combine with emphysema, a condition termed as IPF with emphysema (IPFE). We compared the clinical, radiologic, and physiologic features of IPF and IPFE.

Research design and methods: Newly diagnosed IPF and IPFE patients were recruited between January 2018 and September 2020. Symptoms, high resolution computed tomography (HRCT), pulmonary function test (PFT) data, composite physiologic index (CPI), gender-age-physiology (GAP) scores, and follow-up data were obtained.

Results: The IPFE group had greater proportion of male smokers, and of lung cancer cases. The IPFE group had higher VC, FVC FEV1, and lower FEV1/FVC and DLCO and lower percent fibrosis on HRCT. Both groups had similar symptoms and mortality. Mortality rate was associated with inability to perform PFT, CPI, GAP scores, percent fibrosis, VC, FVC, FEV1, and DLCO, serum SCC-Ag and CA125, and anti-fibrotic therapy (≥12 months) in IPF, while it was associated with inability to perform PFT, CPI, percent fibrosis, DLCO, serum CEA, CYFRA21-1 and CA125, and anti-fibrotic therapy (≥12 months) in IPFE.

Conclusion: IPF and IPFE patients are different in smoking history, physiologic indices, HRCT patterns and prognostic factors, however, they have similar mortality. Anti-fibrotic therapy could improve the survival rate in both IPF and IPFE.

Aim: To explore the experience of people with idiopathic pulmonary fibrosis living through the COVID-19 pandemic.

Design: A qualitative descriptive design using semi-structured interviews.

Method: Purposive sampling was employed to recruit 13 participants with idiopathic pulmonary fibrosis attending the respiratory department of a large urban teaching hospital in Limerick, Ireland. Data were collected between January 2021 and February 2021 through semi-structured interviews, using an online platform. Reflective thematic analysis was used for data analysis.

Results: Four key themes were identified from participant's experience of living through the COVID-19 pandemic: (1) fear of contracting COVID-19 disease, (2) living with reduced social interaction, (3) the adjustment in the relationship with healthcare professionals (HCP) and (4) navigating an altered landscape.

Conclusion: Healthcare professionals have a key role in protecting the physical and psychological health of the person with idiopathic pulmonary fibrosis during this time and into the future. Through being cognisant of the additional supportive care needs of people with idiopathic pulmonary fibrosis, HCP can focus on developing targeted interventions aimed to enhance care provision.

Impact: This study considers people with idiopathic pulmonary fibrosis as a particularly vulnerable group whose experiences of living through the COVID-19 pandemic warrant specific attention. Participants felt compelled to self-isolate due to fear and anxiety of contracting COVID-19 disease. Participants reported increased social isolation with some experiencing anger and resentment at loss of precious time with loved ones. Participants felt an increased responsibility for self-monitoring their condition and had concerns about differentiating symptoms of COVID-19 disease from an exacerbation. A variety of strategies that helped them cope through the pandemic were identified and also the important role these played. The results from this study can be used to inform HCP' understanding of challenges experienced by people with idiopathic pulmonary fibrosis during enforced restrictions related to the COVID-19 pandemic.

Abstract: Recent clinical practice guidelines have addressed the diagnosis of idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (fHP). These disease-specific guidelines were developed independently, without clear direction on how to apply their respective recommendations concurrently within a single patient, where discrimination between these two fibrotic interstitial lung diseases represents a frequent diagnostic challenge. The objective of this review, created by an international group of experts, was to suggest a pragmatic approach on how to apply existing guidelines to distinguish IPF and fHP. Key clinical, radiologic, and pathologic features described in previous guidelines are integrated in a set of diagnostic algorithms, which then are placed in the broader context of multidisciplinary discussion to guide the generation of a consensus diagnosis. Although these algorithms necessarily reflect some uncertainty wherever strong evidence is lacking, they provide insight into the current approach favored by experts in the field based on currently available knowledge. The authors further identify priorities for future research to clarify ongoing uncertainties in the diagnosis of fibrotic interstitial lung diseases.

Background and importance Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease. Its treatment with antifibrotic drugs (pirfenidone and nintedanib) is characterised by a high incidence of adverse effects (AE) that together with the progression of the disease make therapeutic persistence difficult.

Aim and objectives The objective was to compare pirfenidone and nintedanib in terms of effectiveness, safety, and durability of treatment in a tertiary hospital.

Material and methods Retrospective observational study of patients treated with pirfenidone and/or nintedanib between November 2012 nd May 2021.

Variables collected: age, sex, forced vital capacity (FVC), dose, duration of treatment, reason for suspension, AE and adherence. Effectiveness was measured as a <10% reduction in FVC at 12 and 24 months. Data sources: outpatient dispensing program and clinical history. Analysis with SPSS Statistics 21.

Results 83 patients received pirfenidone and 58 nintedanib (76% and 69% men, respectively). Mean age 73 years with pirfenidone and 72 years with nintedanib. Dose reductions were greater with nintedanib (38% vs 18% pirfenidone, p=0.008), and more patients switched drugs with nintedanib (26%) than with pirfenidone (17%) without statistically significant differences (p=0.194).

The percentage of patients who progressed was higher with pirfenidone (38% vs 23%) without statistically significant differences (p=0.132). The speed of progression was also higher with pirfenidone (within the first 12 months: 73% vs 38%, p=0.028).

The median durability by Kaplan–Meier was greater with nintedanib: 23 months (95% CI 12 to 33) versus 22 months (95% CI 11 to 33), although without statistical significance (p=0.689).

Reasons for suspension: with pirfenidone 23/45 death, 19/45 AE, 2/45 change of hospital and 1/45 lung transplantation; with nintedanib 9/23 death, 8/23 AE, 3/23 anticoagulant treatment and 3/23 change of hospital.

The percentage of patients with AE was practically the same: 45% (37/83) pirfenidone and 43% (25/58) nintedanib.

Adherence was similar in both groups (92% for pirfenidone and 87% for nintedanib).

Conclusion and relevance Pirfenidone and nintedanib have very similar safety and durability profiles, and it seems that with pirfenidone a greater number of patients progress and do so faster; however, larger sample size studies would be necessary to achieve statistical significance.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare lung disease that is ultimately fatal. A Phase I study (NCT03230487) has investigated the safety, tolerability and pharmacokinetics of BI 1015550, a potent and selective inhibitor of phosphodiesterase 4B, in healthy male subjects. In this present Phase Ic study (NCT03422068), the safety, tolerability and pharmacokinetics of BI 1015550 was investigated in patients with IPF. Methods: Patients with IPF aged ≥40 years who had not been treated with nintedanib or pirfenidone within 30 days of visit 1 or did not plan to initiate these treatments, were enrolled. Patients were randomized to placebo or 18 mg twice daily (BID) BI 1015550 for a maximum duration of 12 weeks. The primary endpoint was the number of drug‐related adverse events (AEs) on treatment. Secondary endpoints were pharmacokinetic parameters and additional safety parameters. Results: A total of 15 patients were randomized and treated. Ten patients were treated with BI 1015550 and 5 patients with placebo for a median duration of 53.5 and 84 days, respectively. Thirteen patients were male, all patients were white, and the mean (standard deviation) age was 69.7 (8.3) years. Of the 15 patients, 9 (60%) were never smokers and 6 (40%) were former smokers. Overall baseline forced vital capacity (FVC) was 3574.0 (1108.0) mL and mean FVC% predicted was 91.7% (15.3). Demographic characteristics were generally comparable between groups. A summary of AEs is show in the table. Most AEs were mild or moderate in intensity and there were no reported deaths. There was one severe AE of insomnia in a patient treated with BI 1015550 which was considered drug‐related, and this was the only AE leading to discontinuation in the study. The most frequently reported AEs by organ class were gastrointestinal disorders and these were more common in patients treated with BI 1015550 than in patients receiving placebo. There were no clinically relevant findings with respect to 12‐lead electrocardiogram or vital signs. Conclusions: In this Phase Ic study, BI 1015550 at 18 mg BID was well tolerated in patients with IPF who had not received background antifibrotic treatment. A Phase II study (NCT04419506) investigating the efficacy, safety and tolerability of BI 1015550 is underway in patients with IPF.

Introduction: Short telomeres are recognized as risk factor for idiopathic pulmonary fibrosis (IPF). We aimed to assess the role of telomere length (TL) in fibrotic-Interstitial Lung Diseases (f-ILDs) associated with a usual interstitial pneumonia (UIP) pattern as well as in IPF acute exacerbation (IPF-AE).

Aim and methods: TL was measured from peripheral white blood cells using a multiplex quantitative polymerase chain reaction in consecutive patients with f-ILDs, all presenting UIP pattern in the high-resolution chest-computed-tomography and compared to age-matched healthy controls.

Results: Seventy-nine individuals were included (mean age 69.77 ± 0.72 years); 24 stable IPF, 18 IPF-AE, 10 combined pulmonary fibrosis and emphysema, 7 Rheumatoid arthritis-UIP-ILDs and 20 controls. TL in all patients was significantly shorter compared to controls [mean T/S ratio (SE) 0.77 (±0.05) vs 2.26 (±0.36), p < 0.001] as well as separately in each one of f-ILD subgroups. IPF-AE patients presented significantly shorter TL compared to stable IPF (p = 0.029). Patients with IPF and shorter than the median TL (0-0.72) showed reduced overall survival (p = 0.004). T/S < 0.72 was associated with increased risk for IPF-AE (OR = 30.787, 95% CI: 2.153, 440.183, p = 0.012) independent of age, gender, smoking and lung function impairment. A protective effect of TL was observed, as it was inversely associated with risk of death both in UIP-f-ILDs (HR = 0.174, 95%CI: 0.036, 0.846, p = 0.030) and IPF patients (HR = 0.096, 95%CI: 0.011, 0.849, p = 0.035).

Conclusions: Shorter TL characterizes different UIP f-ILDs. Although no difference was observed in TL among diverse UIP subgroups, IPF-AE presented shorter TL compared to stable IPF. Reduced overall survival and higher hazard ratio of death are associated with shorter TL in IPF.

Background: Proposed criteria for progressive fibrosing interstitial lung disease (PF-ILD) have been linked to increased mortality risk, but lung function trajectory after satisfying individual criteria remains unknown. Because survival is rarely employed as the primary end-point in therapeutic trials, identifying PF-ILD criteria that best predict subsequent change in forced vital capacity (FVC) could improve clinical trial design.

Methods: A retrospective, multicentre longitudinal cohort analysis was performed in consecutive patients with fibrotic connective tissue disease-associated ILD (CTD-ILD), chronic hypersensitivity pneumonitis and idiopathic interstitial pneumonia at three US centres (test cohort) and one UK centre (validation cohort). 1-year change in FVC after satisfying proposed PF-ILD criteria was estimated using joint modelling. Subgroup analyses were performed to determine whether results varied across key subgroups.

Results: 1227 patients were included, with CTD-ILD predominating. Six out of nine PF-ILD criteria were associated with differential 1-year change in FVC, with radiological progression of fibrosis, alone and in combination with other features, associated with the largest subsequent decline in FVC. Findings varied significantly by ILD subtype, with CTD-ILD demonstrating little change in FVC after satisfying most PF-ILD criteria, while other ILDs showed significantly larger changes. Findings did not vary after stratification by radiological pattern or exposure to immunosuppressant therapy. Near-term change in FVC after satisfying proposed PF-ILD criteria was heterogeneous depending on the criterion assessed and was strongly influenced by ILD subtype.

Conclusions: These findings may inform future clinical trial design and suggest ILD subtype should be taken into consideration when applying PF-ILD criteria.

RATIONALE Reliable outcome prediction in patients with fibrotic lung disease using baseline high-resolution computed tomography (HRCT) data remains challenging. OBJECTIVES To evaluate the prognostic accuracy of a deep learning algorithm (SOFIA), trained and validated in the identification of UIP-like features on HRCT (UIP probability), in a large cohort of well characterised patients with progressive fibrotic lung disease, drawn from a national registry. METHODS SOFIA and radiologist-UIP probabilities were converted to PIOPED-based UIP probability categories (UIP not included in the differential: 0-4%, low probability of UIP: 5-29%, intermediate probability of UIP: 30-69%, high probability of UIP: 70-94%, and pathognomonic for UIP:95-100%) and their prognostic utility assessed using Cox proportional hazards modelling. MEASUREMENTS AND MAIN RESULTS On multivariable analysis adjusting for age, gender, guideline based radiologic diagnosis and disease severity (using total ILD extent on HRCT, %predicted FVC, DLco or the CPI), only SOFIA-UIP probability PIOPED categories predicted survival. SOFIA-PIOPED UIP probability categories remained prognostically significant in patients considered indeterminate (n=83) by expert radiologist consensus (HR1.73, p<0.0001, 95%CI 1.40-2.14). In patients undergoing surgical lung biopsy (SLB) (n=86), after adjusting for guideline-based histologic pattern and total ILD extent on HRCT, only SOFIA-PIOPED probabilities were predictive of mortality (HR1.75, p<0.0001, 95%CI 1.37-2.25). CONCLUSIONS Deep learning-based UIP probability on HRCT provides enhanced outcome prediction in patients with progressive fibrotic lung disease when compared to expert radiologist evaluation or guideline-based histologic pattern. In principle this tool may be useful in multidisciplinary characterisation of fibrotic lung disease. The utility of this technology as a decision support system when ILD expertise is unavailable requires further investigation.

Rationale: Progressive fibrotic interstitial lung disease (PF-ILD) is a heterogeneous group of chronic fibrotic lung diseases, characterized by progressive destruction of the lung parenchyma. The INBUILD trial demonstrated that nintedanib was associated with a reduction in the rate of forced vital capacity (FVC) decline in PF-ILD. In the wake of this new treatment approach, identifying risk factors that may predict an increased likelihood of PF-ILD development has become increasingly pressing. Methods: We identified adult patients with at least two documented ICD 9 or 10 codes for interstitial lung disease (ILD) between the year of 2009 and 2019 using Cleveland Clinic’s electronic medical record (EMR). For inclusion, patients were required to have a documented FVC value between 12 months prior and 6 months following the initial documentation of ILD, and at least one FVC measurement within the 3-28 months period following the initial FVC documentation. Index date was defined as the FVC date closest to first documented ILD diagnosis. Patients were excluded if, within 3 months of diagnosis, they were evaluated by a lung transplant provider or underwent lung transplant. Progression was defined as a greater than 10% relative decline in predicted FVC over the 28-month period from the index date. Lung transplant and all-cause death were considered competing risks if they occurred in the absence of progression. Results: We identified 5934 patients meeting inclusion criteria. Mean age (SD) at time of first diagnosis was 62±14 years; 83% of the cohort self-identified as Caucasian, with 12% self-identifying as Black. Fifty-two percent of patients had undifferentiated ILD at the time of first diagnosis (Table 1). Median FVC at the time of diagnosis was 81% predicted (IQR 66-94%), Median DLCO was 41% predicted (IQR 20-67%). Within the first year of initial ILD diagnosis, prednisone was prescribed to 43% of patients; 39% received a prescription for an alternate immunosuppressive agent. 998 (16.8%) patients experienced ≥10% relative decline in FVC during 28 months post-index among all ILD patients, and progression was differential by ILD sub-categories (Table-1). Conclusions: 16.8% of ILD patients experienced a ≥10% decline in FVC within 24 months of first documented diagnosis. Incidence of progression was observed to be higher in IPF patients, and lower in sarcoidosis patients. Identifying factors associated with an increased risk of PF-ILD prior to the onset of progression may help to guide early therapy initiation and improve our understanding of the prognosis in this patient population.

Background: The forced vital capacity (FVC) of healthy individuals depends on their age, sex, ethnicity and height. Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterised by loss of FVC. We compared FVC values in the subjects with SSc-ILD in the SENSCIS trial of nintedanib versus placebo with values from hypothetical matched healthy references.

Methods: The SENSCIS trial enrolled subjects with SSc with first non-Raynaud symptom in the prior ≤ 7 years, extent of fibrotic ILD on HRCT ≥ 10%, and FVC ≥ 40% predicted. FVC at baseline and decline in FVC over 52 weeks were compared with FVC values in hypothetical healthy reference subjects matched 1:1 to the subjects in the trial for age, sex, ethnicity and height, determined using equations published by the European Respiratory Society Global Lung Function Initiative.

Results: At baseline, mean (SD) FVC was 2460 (737) mL in the nintedanib group (n = 287) compared with 3403 (787) mL in the hypothetical matched healthy references. Mean (SD) FVC was 2544 (817) mL in the placebo group (n = 286) compared with 3516 (887) mL in the hypothetical matched healthy references. Mean (SE) changes in FVC at week 52, i.e., age-related loss of lung function, in the hypothetical healthy references matched to the nintedanib and placebo groups, respectively, were - 26.3 (0.5) mL and - 25.8 (0.5) mL. The difference in the change in FVC at week 52 between the nintedanib group and the hypothetical healthy references was 26.6 mL (95% CI: 1.2, 52.0; p = 0.04). The difference in the change in FVC at week 52 between the placebo group and the hypothetical healthy references was 77.5 mL (95% CI: 51.4, 103.7; p < 0.0001).

Conclusions: Subjects with SSc-ILD in the SENSCIS trial had impaired lung function at baseline and experienced further deterioration over 52 weeks. The decline in FVC in the placebo group was four-fold greater than in a hypothetical group of matched healthy references, whereas the decline in FVC in patients who received nintedanib was two-fold greater than in hypothetical healthy references. These data highlight the clinical relevance of the slowing of FVC decline provided by nintedanib.

Introduction and Aim of the study: Interstitial lung disease (ILD) is one of leading cause of morbidity and mortality among systemic sclerosis (SSc) patients. Assessment of respiratory symptoms, full pulmonary function tests (PFTs) and a chest HRCT are fundamental to ensure early identification of ILD. Recently, lung ultrasound and diaphragmatic ultrasound (DUS) were proposed as interesting novel tools. The objective of this study is to perform DUS among SSc-ILD patients compared to patients without pulmonary involvement.

Patients and Methods: 36 patients from Genoa Scleroderma Unit were enrolled between June 2020 and October 2020. All patients fulfilled ACR-EULAR SSc criteria and had to be clinically stable and without change of therapeutic regimen during the last 3 months. Patients were divided into two arms: 17 were affected by SSc-ILD, while 19 didn’t suffer from respiratory disease and represented the control group.

Results: Diaphragmatic mobility during quite breath (QB) was similar between patients and control groups (p=0.43). During deep breath (DB), DM was lower among patients with a median value of5,64 (4,57-6,78) compared to controls (p<0.001). During QB, at FRC, the DT of SSc-ILD cases was significantly thicker than controls(p=0.02). Among SSc-ILD group, during DB, DM positively correlated with lung function; DT negatively correlated with lung volumes.

Conclusions: SSc-ILD is a serious complication among SSc patients and diaphragmatic ultrasound could be a promising non-invasive tool.

Objectives: Amyopathic dermatomyositis (ADM) is a heterogeneous and life-threatening autoimmune disease with high mortality. In particular, anti-MDA5 antibody-positive patients are at high risk of developing rapidly progressive interstitial lung disease (ILD). This study aimed to identify immunological signatures among ADM-ILD patients and discover the biomarkers predicting prognosis.

Methods: The landscape of 42 immune-cell phenotypes in the peripheral blood of 82 ADM-ILD patients and 82 age- and sex-matched healthy donors was measured by multi-color flow cytometry. Patients were stratified using an unsupervised machine learning method (hierarchical clustering analysis) by immune-cell subsets. Multiple Wilcoxon sign-rank tests and supervised machine learning methods were performed to identify important immune cell subsets. Kaplan-Meier survival analysis with log-rank tests was used to create survival curves.

Results: We identified two distinct clusters correlated with different disease activities and clinical outcomes in ADM-ILD. Cluster 1 was enriched in the activated CD45RA+ HLA-DR+ CD8+ T cells with decreased CD56dim NK propotions and showed a higher prevalence of rapidly progressive ILD and higher mortality. In contrast, the other subgroup Cluster 2, the non-activated-T cell-dominant cluster, displayed favorable clinical outcomes with high survival. Our data also revealed that immunophenotype was an independent risk factor associated with 1-year survival.

Conclusions: Peripheral immunological features may have the potential to stratify patients with ADM-ILD with different disease severity and clinical outcomes, which may have implications for outcome prediction, pathogenesis study and therapy selection.

Objectives: Lung vascular and parenchymal changes can be recently assessed quantitatively in thoracic computed tomography (CT) images using automated software tools. We investigated the vessel parameters of patients with Systemic Sclerosis (SSc), quantified by CT imaging, and correlated them with the interstitial lung disease (ILD) features.

Methods: SSc patients undergoing standard of care pulmonary function testing and CT evaluation were retrospectively evaluated. CT images were analyzed for ILD patterns and total pulmonary vascular volume (PVV) extents with Imbio LTA. Vascular analysis (volumes, numbers, and densities of vessels, separating arteries and veins) was performed with an in-house developed software. A threshold of 5% ILD extent was chosen to define the presence of ILD, and commonly used cut-offs of lung function were adopted.

Results: 79 patients (52 women, 40 ILD, age 56.2 ± 14.2 years, total ILD extent 9.5 ± 10.7%, PVV/LV% 2.8%) were enrolled. Vascular parameters for total and separated PVV significantly correlated with functional parameters and ILD pattern extents. SSc-ILD patients presented with an increased number and volume of arterial vessels, in particular those between 2-4 mm of diameter, and with a higher density of arteries and veins of < 8 mm in diameter. Considering radiological and functional criteria concomitantly, as well as the descriptive trends from the longitudinal evaluations, the normalized PVVs, vessel numbers and densities increased progressively with the increase/worsening of ILD extent and functional impairment.

Conclusion: In SSc patients CT vessel parameters increase in parallel with ILD extent and functional impairment and may represent a biomarker of SSc-ILD severity.

Rationale: In the INBUILD trial in subjects with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF), nintedanib reduced the rate of decline in FVC over 52 weeks compared with placebo. We used data from this trial to investigate the effects of nintedanib on circulating biomarkers of epithelial injury, inflammation and extracellular matrix (ECM) turnover. Methods: Subjects had diffuse fibrosing ILD (other than IPF) of >10% extent on HRCT, FVC ≥45% predicted, DLco ≥30%-<80% predicted, and met criteria for progression of ILD within the prior 24 months, despite management deemed appropriate in clinical practice. Blood samples were taken at baseline and at weeks 12, 24, 36 and 52. Fold changes in adjusted mean levels of circulating biomarkers were analyzed using a linear mixed model for repeated measures. Data were log10 transformed before analysis and estimates of change from baseline were back-transformed. Results: A total of 663 subjects received trial medication (332 nintedanib, 331 placebo). Over 52 weeks, there were treatment-related decreases in fold change from baseline in levels of Krebs von den Lungen-6 (KL-6), surfactant protein D (SP-D), CA-125 and CA19-9 (markers of epithelial injury) in subjects who received nintedanib versus placebo (Figure). The most pronounced difference between nintedanib and placebo was observed for CA-125. Small decreases in the fold change from baseline in N-terminal propeptide of type VI collagen (pro-C6) (a marker of ECM turnover) and soluble intercellular adhesion molecule s-ICAM (a marker of inflammation) were observed in subjects who received nintedanib compared with placebo (Figure). Increases in the fold change from baseline in c-reactive protein (CRP) and interleukin-8 (IL-8) (markers of inflammation) were observed in subjects who received nintedanib versus placebo at week 12 but not at week 52 (Figure). Conclusions: Data from the INBUILD trial suggest that nintedanib reduced circulating levels of markers of epithelial injury in subjects with progressive fibrosing ILDs. Changes in these biomarkers were observed as early as week 12 of treatment.