Citations

Abstract Rationale The diagnosis of interstitial lung disease (ILD) requires a multidisciplinary discussion (MDD), in which high-resolution computed tomography (HRCT) and histopathology play key roles. Genomic classifiers have recently been introduced for clinical use, in which lung tissue obtained via transbronchial forceps biopsy undergoes whole-transcriptome RNA sequencing followed by gene expression analysis. These molecular tools are particularly valuable in establishing a diagnosis of idiopathic pulmonary fibrosis (IPF) in patients without a definite usual interstitial pneumonia (UIP) pattern on imaging. Although genomic classifiers are increasingly utilized in clinical practice, data on their diagnostic performance continue to evolve, warranting an updated analysis of the current evidence. Methods A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. Comprehensive search of PubMed, MEDLINE, Embase, Scopus and the Cochrane Library were performed through October 2025 using predefined terms including “genomic classifier,” “Envisia,” “UIP,” and “interstitial lung disease.” Eligible studies were which enrolled adult patients with ILD of uncertain etiology in whom genomic classifiers were compared with histopathologic or MDD based reference standards. True positive, false positive, false negative, and true negative data were extracted to calculate pooled estimates of sensitivity, specificity and the area under the receiver-operating characteristic curve (AUROC) using a random-effects bivariate model. Results Six studies comprising 347 patients met inclusion criteria, with sample sizes ranging from 24 to 98 participants. Across studies, sensitivity ranged from 59% to 85% and specificity from 75% to 100%. The pooled sensitivity was 68% (95% CI, 60-76%; P < 0.001) and specificity 77% (95% CI, 70-85%; P < 0.001), with an estimated AUROC of 0.73 (95% CI, 0.65-0.81) indicating discriminative performance. In two studies evaluating clinical impact, incorporation of genomic classifier data into MDD increased diagnostic confidence in ILD subtyping by 30-50%. No major adverse events related to transbronchial tissue acquisition were reported. Conclusions Genomic classifiers represent a promising, less invasive adjunct for identifying UIP patterns in ILD, demonstrating good overall diagnostic accuracy. Incorporating classifier results within MDD frameworks enhances diagnostic confidence and may reduce the need for surgical lung biopsy in appropriately selected patients. However, small study sizes, potential funding bias and limited accessibility highlight the need for larger, independently conducted prospective studies to further define their role in future IPF diagnostic algorithms. This abstract is funded by: None

Abstract Background Telomere maintenance and surfactant-related genetic mutations are increasingly recognized as contributing factors in familial pulmonary fibrosis (PF). Pathogenic variants in the SFTPA2 gene have been associated with early-onset pulmonary fibrosis and an elevated risk of developing lung cancer. Currently, PF lacks a definitive cure beyond lung transplantation, and treatment options remain limited. Understanding the prevalence and clinical implications of pathogenic SFTPA2 variants is critical. This study aims to assess the prevalence of PF, lung cancer, and other co-morbidities among individuals carrying pathogenic SFTPA2 variants. Ultimately, this study seeks a comprehensive understanding of the natural history and potential screening needs for SFTPA2 variants. Methods Individuals with pathogenic SFTPA2 variants were identified in the Tapestry genomic database at our academic medical center. Electronic medical records (EMR) were reviewed for personal or family histories of PF, lung cancer, and other significant comorbidities. Imaging reports were evaluated for radiographic evidence of PF or lung cancer. Studies were approved by the local IRB. Results Out of 98,109 participants in the Tapestry database, 18 individuals were identified as carriers of SFTPA2 variants. The variants (NM_001098668.4) included c.460G>C - p.(Ala154Pro) in 13 individuals, c.557A>G - p.(Tyr186Cys) in 1 individual, and c.532G>A - p.(Val178Met) in 4 individuals. The mean age was 60.5 years, and 67% were female. No participants had a formal diagnosis of PF; however, five (28%) had prior chest CTs showing ground-glass opacities, fibrosis, or irregular nodularity. EMR review did not confirm clinically significant PF. Notably, 44% reported a family history of primary lung cancer, though no familial PF was documented. Comorbidities included inflammatory bowel disease (22%, with a tapestry cohort prevalence of 9%) and a personal history of cancer in 44%, encompassing nine distinct malignancies such as metastatic colon adenocarcinoma (1), prostate cancer (1), basal cell carcinoma of the skin (1), endometrial cancer (1), breast cancer (2), melanoma (1), and squamous cell carcinoma of the skin (1). Conclusions In this cohort of individuals with SFTPA2 variants, no cases of clinically confirmed PF or lung cancer were identified. However, there was a notable prevalence of abnormal parenchymal chest CT findings, inflammatory bowel disease, personal cancer history, and family history of lung cancer. These findings underscore the variable penetrance of SFTPA2 variants and highlight the need for longitudinal studies to elucidate the genetic, environmental, and immunologic factors that modulate disease expression. Improved understanding may inform screening strategies and therapeutic interventions for at-risk individuals. This abstract is funded by: None

Abstract Rationale Patients with interstitial lung disease related to systemic autoimmune rheumatic diseases (SARD-ILD) may develop progressive pulmonary fibrosis (PPF), characterized by irreversible loss of lung function and high mortality risk. The risk of PPF by SARD subtype is not well characterized in large, representative real-world data sources. We characterized patients with SARD-ILD and compared the risk of PPF by SARD subtype in a multicenter cohort derived from the national Patient-Centered Clinical Research Network (PCORnet). Methods Harmonized electronic health record (EHR) data was collected from seven PCORnet centers. Included patients had at least two ICD-9/ICD-10 codes for ILD between 2015-2021, an ILD diagnosis that persisted following chest CT and/or lung biopsy, at least one year of potential follow-up, and sufficient lung function data to assess PPF. The presence of SARD, subtypes of which were classified by ICD codes, was also required. PPF was defined by ≥ 5% absolute decline in FVC, lung transplantation or death. The incidence of PPF was compared across SARD subtypes using Kaplan Meier estimates and Cox proportional hazards models adjusted for age, sex, enrolling center and baseline FVC. Results The cohort included 6,288 patients with SARD-ILD, of whom 68.4% were female, with a mean (SD) age of 61.2 (13.9) years. The most common underlying SARD was rheumatoid arthritis (RA, 42.8%), followed by systemic sclerosis (SSc, 22.3%), mixed connective tissue disease (MCTD, 21.5%), Sjögren’s syndrome (16.9%), systemic lupus erythematosus (SLE, 14.5%) and polymyositis/dermatomyositis (PM/DM, 12.0%). Mean FVC and DLCO at baseline were 78.7 (22.9) % and 51.9 (21.3) % of predicted, respectively. Patients with PM/DM had the lowest mean FVC (70.4 [SD 21.3]) % of predicted) and DLCO (45.1 [SD 18.5] % of predicted). During the follow-up period, antifibrotic, corticosteroid, and non-steroidal immunosuppressive drugs were used by 7.6%, 89.3% and 77.5% of the overall cohort, respectively. The cumulative incidence of PPF, transplant or death at one year ranged from 20.6% to 29.0%, depending on SARD-ILD subtype, with higher risk among those with RA, SSc or MCTD as compared with PM/DM (figure). Conclusions In a large, harmonized EHR dataset, the risk of PPF at one year among patients with SARD-ILD was high. Variability of PPF risk by SARD-ILD subtype was similar to that observed in traditional cohort studies, with lower risk among patients with myositis despite poorer lung function at baseline. These findings establish the feasibility of PCORnet as a tool to understand PPF among patients with SARD-ILD. This abstract is funded by: Genentech

Abstract Introduction The lung is the most commonly affected organ in sarcoidosis, present in over 90% of cases. However, cardiac involvement may also occur and can significantly complicate patient outcomes. We propose to explore further. Methods Adults with isolated pulmonary sarcoidosis and combined pulmonary-cardiac sarcoidosis were identified using ICD-10 codes from the National Inpatient Sample (2016-2022). Patients with any additional organ involvement beyond lung or heart were excluded to ensure distinct comparison groups. We compared age, sex, race, insurance type, hospital characteristics, comorbidities, and healthcare burden between groups. Results Over the seven-year study period, we identified 154,125 hospitalizations of patients with either isolated pulmonary or combined pulmonary-cardiac sarcoidosis. Of these, 2.41% (n = 3,715) were combined pulmonary-cardiac cases, while the remainder were isolated pulmonary sarcoidosis. Patients with combined pulmonary-cardiac sarcoidosis were significantly younger(mean age: 58.2 vs. 62.0 years, p < 0.001), but had a higher mean Charlson Comorbidity Index (CCI) score (3.49 vs. 2.77, p < 0.001) compared to those with isolated pulmonary disease. Multiple demographic differences were found: isolated pulmonary cases were predominantly female(59.5%), with a higher proportion of White patients(46.7%), whereas combined cases were predominantly male(60.4%), with a higher proportion of Black patients(53.0%). Both groups were primarily covered by Medicare(58.1% of isolated vs. 48.1% of combined), with a higher proportion of combined pulmonary-cardiac sarcoidosis cases treated at urban teaching centers(92.3% vs. 78.9%, p < 0.001). Patients with combined pulmonary-cardiac sarcoidosis demonstrated a higher prevalence of multiple comorbidities, including chronic kidney disease, prior myocardial infarction, complete atrioventricular block, obstructive sleep apnea, congestive heart failure, peripheral vascular disease, and valvular disease. Conversely, the prevalence of chronic obstructive pulmonary disease was lower in this group. Hospitalization burden was substantially greater among patients with combined pulmonary-cardiac sarcoidosis (Charlson Comorbidity Index 2.77±0.01 vs. 3.49±0.07), evidenced by longer mean length of stay (6.1±0.05 vs. 7.6±0.32 days) and significantly higher total hospital charges ($82,987±1,121 vs. $122,460±6,991) (Table 1). Conclusions Combined pulmonary-cardiac sarcoidosis affected younger patients with greater comorbidity and hospitalization burden, with notable racial disparities. As cardiac sarcoidosis is frequently underdiagnosed, systematic cardiac screening protocols in high-risk sarcoidosis patients are essential for earlier detection and improved management. This abstract is funded by: None

Abstract Introduction/Rationale Hepatic sarcoidosis (HS) is a rare manifestation of sarcoidosis occurring in 6 to 11% of patients with sarcoidosis. Little is known about the clinical characteristics and overall outcome of patients who present with HS. Two recent single center studies from Europe and the U.S. outlined the clinical characteristics, outcomes, and therapeutic interventions in these patients. Our study aims to add to this body of knowledge; in particular, highlighting the clinical presentation, therapeutic interventions, comorbid disease burden, and overall outcomes in patients with HS presenting to a large tertiary care sarcoidosis center of excellence in the U.S. Methods We performed a retrospective review of all patients with hepatic sarcoidosis (HS) seen at the Sarcoidosis Center of Excellence at East Carolina University (ECU) between 2000 and 2025. Data including demographics, clinical manifestations, diagnostic tests, treatments and outcomes, were extracted. Results A total of 794 patients with sarcoidosis were identified. Twenty-one (21) patients had over 50% of missing data and were excluded. Of the 773 patients included in the study, 62 patients (8%) had hepatic sarcoidosis. Of these, 73% were female and 79% were African American. The mean age at diagnosis was 40 years. Thirty-nine percent (39%) of patients underwent a liver biopsy and majority (64%) had a Scadding CXR I or II at diagnosis. There was no significant difference in the age (at diagnosis), race, gender, BMI, smoking status, or pulmonary function when patients with HS were compared to the rest of the cohort (n = 711) (Table 1). CXR Scadding stage at presentation was also similar except that 5% of non-HS patients had a stage IV CXR at presentation compared to 0 patients with HS (Table 1). Evaluation for other organ involvement revealed that patients with HS were more likely to have splenic, Calcium-Vit D dysregulation, extra-thoracic lymphadenopathy, and bone/bone marrow involvement than non-HS patients (Table 2/Figure 1). Treatment patterns including use of methotrexate and infliximab were identical except that only 5% of patients were treated with ursodiol. This was unexpectedly low (Table 3). Outcomes including fatigue at any point during the follow-up and mortality are presented in Table 4. 10.4% of non-HS patients died versus 4.9% of HS patients. No patients in our cohort underwent a liver transplant. Conclusion Hepatic sarcoidosis was found in 8% of patients and was associated with multi-organ disease. Patients received similar medications, including methotrexate, as patients without hepatic sarcoidosis. This abstract is funded by: None

Abstract Rationale Systemic sclerosis (SSc) is a rare, chronic autoimmune disease characterized by vasculopathy and fibrosis of the skin and internal organs. Among its manifestations, interstitial lung disease (ILD) is the leading cause of mortality, yet its clinical course is variable, ranging from stable to progressive pulmonary fibrosis (PPF). The 2022 ATS/ERS/JRS/ALAT guidelines defined progressive PPF as a phenotype of non- Idiopathic Pulmonary Fibrosis (IPF) - ILDs that behave similarly to IPF. Although a subset of SSc-ILD patients develop PPF, biomarkers predicting progression remain lacking. We and others have shown that endothelial dysfunction contributes to the progression of fibrotic lung disease, and that the pulmonary vasculature, continuously exposed to the bloodstream, is influenced by soluble circulating factors, including circulating extracellular vesicles (cEVs), which carry bioactive cargo capable of modulating endothelial behavior. Here, we investigated whether cEVs from SSc patients with distinct fibrotic phenotypes differentially influence human lung endothelial cells (ECs), promoting a pro-fibrotic endothelial phenotype. Methods plasma samples were collected from five groups: 1) Healthy controls (n = 4); 2) SSc-noILD (no high-resolution-CT (HCRT( or functional evidence of ILD at time of enrollment, n = 4); 3) SSc-ILD (HCRT and functional evidence of ILD without meeting the PPF criteria at time of sampling, n = 3); 4) SSc-PPF (meeting the PPF criteria, plasma collected prior to anti-fibrotic therapy, n = 4); 5) IPF (plasma collected prior to anti-fibrotic therapy, n = 3). cEVs were isolated using size-exclusion-chromatography and characterized using Nanoparticle Tracking Analysis (NTA). Human lung ECs were treated with cEVs from the five groups (2x109 particles/ml, 48 hours), followed by qPCR for markers selected for their established involvement in endothelial dysfunction during lung fibrotic progression. Results NTA showed no significant differences in plasma cEV concentrations across the five groups. Human lung ECs exposed to cEVs from SSc or SSc-ILD patients exhibited no significant gene expression changes compared to healthy controls. In contrast, cEVs from SSc-PPF patients markedly downregulated endothelial identity (PECAM1, ERG, TEK), barrier integrity (CDH13, S1PR1), and basement membrane (COL4A1, HSPG2) genes, similarly to changes induced by cEVs from IPF patients. Conclusion cEVs from SSc-PPF patients induce pro-fibrotic transcriptional changes in lung ECs resembling those induced by IPF cEVs and distinct from SSc-ILD cEVs, suggesting that EVs carry cargo that both reflect and influence fibrosis progression. These findings highlight the potential of cEVs as biomarkers for identifying SSC-ILD patients at risk of progression and highlight the clinical relevance of future studies aimed at characterizing their cargo. This abstract is funded by: James Depauw Grant for Pilot Projects

Abstract A population of pathologic fibroblasts has been identified in several human fibrotic lung diseases, including IPF. These cells, marked by high expression of collagen triple-helix repeat containing 1 (CTHRC1), display an invasive phenotype and aggressively deposit extracellular matrix. The goal of this study was to identify transcriptional regulators of the CTHRC1+ pathologic fibroblast state. We analyzed published single-cell RNA sequencing data of IPF and control lungs to predict transcription factor activity in CTHRC1+ fibroblasts, which led us to hypothesize that transcription factors in the nuclear factor of activated T-cells (NFAT) family may contribute to the pathologic fibroblast state. To test whether NFAT family members promote and/or maintain pathologic fibroblasts, we silenced each cytosol-localized NFAT (NFATc1-4) in lung fibroblasts from IPF donors (passage 3-6, N = 5 donors) and measured expression of key NFAT target genes related to fibrosis using qPCR. NFATC1 silencing significantly reduced expression of CTHRC1, SERPINE1, FN1, HAS2, and TNC, whereas other computationally predicted regulators showed little effect. Our computational analysis also predicted high activator protein 1 (AP-1) activity in pathologic fibroblasts, which interestingly has been found to act in concert with NFATs to promote an effector response in T-cells. Thus, we hypothesized that NFAT:AP-1 signaling may be involved in lung fibroblast activation. To test this hypothesis, we employed a small molecule inhibitor of NFAT:AP-1 complex formation on DNA (“Compound 10”, 25-50 µM). NFAT:AP-1 inhibition significantly reduced expression of fibrillar collagens COL1A1 and COL3A1, as well as CTHRC1 in primary IPF lung fibroblasts. Additionally, NFAT:AP-1 inhibition prevented TGF-β-mediated increase of several fibrosis-related NFATc1 targets. Aside from CTHRC1, NFAT:AP-1 inhibition led to decrease in a different set of NFATc1 targets than NFATc1 silencing, suggesting a potentially complex relationship between NFATc1 and AP-1 in fibroblast gene regulation. Finally, in mouse precision cut lung slices (PCLS) stimulated with a fibrosis-inducing cocktail ex vivo, NFAT:AP-1 inhibition prevented increased expression of Col1a1 and Cthrc1. Taken together, these studies suggest that NFATc1, together with AP-1, is involved in fibrogenic activation of pathological fibroblasts. Ongoing and future experiments will determine the roles of these signaling mechanisms in matrix deposition and contraction, as well as fibroblast invasion using human fibroblasts and PCLS models. Furthermore, we aim to determine how mechanical forces and soluble factors encountered in IPF lungs promote NFAT signaling in fibroblasts. This abstract is funded by: NHLBI, Pulmonary Fibrosis Foundation

Abstract Pulmonary hyalinizing granuloma (PHG) is a rare lung disease that usually presents as nodules or masses and can be mistaken for malignancy or infection on imaging. Its etiology remains unclear, but it is frequently associated with autoimmune diseases, chronic inflammation, or prior infection. Given its nonspecific radiographic features PHG presents a diagnostic challenge, especially in patients with connective tissue disorders. A 64-year-old woman with long-standing Sjögren’s syndrome and interstitial lung disease, presented with a 20-year history of progressive dyspnea, morning joint stiffness, xerostomia, and xerophthalmia. Serologic testing revealed elevated ANA (1:320, speckled), positive anti-SS-A/Ro antibodies, rheumatoid factor (90 IU/mL), and anti-NXP-2 antibody, with normal IgG4 levels. Pulmonary function testing confirmed severe restrictive impairment and markedly reduced diffusion capacity. CT dating back at least 4 years demonstrated a usual interstitial pneumonia (UIP) pattern with a straight edge sign, the four corners sign and anterior predominance, consistent with connective tissue disease-associated ILD (CTD-ILD). Four years prior, lung biopsy showed pattern consistent with Nonspecific Interstitial Pneumonia. In the year leading up to her death, she was found to have Pseudomonas pneumonia within the cystic lung at the left base. We suspect chronic infection-related inflammation caused bilateral disease progression, with imaging now revealing thick consolidative opacities in both the lung apices and bases. PET-CT showed diffuse hypermetabolic activity in consolidative areas. Due to severe functional impairment, she received a bilateral lung transplant but died from surgery-related complications. Gross examination of explanted lungs revealed multiple firm, coalescent nodules within areas of fibrosis. Histopathologic analysis showed dense, lamellar, keloid-like hyaline collagen arranged concentrically around vessels with perivascular lymphoplasmacytic infiltrates, these findings were consistent with PHG. Special stains were negative for amyloid, iron, and infectious organisms. This case demonstrates the potential consequences of uncontrolled inflammation in patients with ILD and emphasizes the importance of considering empirical treatment due to the elevated risk of significant complications in advanced lung disease. In patients with Sjögren’s syndrome and progressive ILD, the coexistence of fibrotic and nodular lesions can obscure the distinction between progressive fibrosis, neoplasia, and rare entities such as PHG. Although corticosteroids and immunosuppressive agents may stabilize disease in select cases, no standardized therapy exists. Lung transplantation remains the only curative option in end-stage disease. Pulmonary hyalinizing granuloma should be considered in patients with autoimmune disorders and atypical pleural thickening or nodular consolidations. This abstract is funded by: None

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrosing interstitial lung disease that continues to have high morbidity and mortality. There are only 3 approved medications, (nintedanib, pirfenidone and nerandomilast) which marginally slow FVC decline and only nerandomilast having some mortality benefit. All three have no effect on quality of life (exacerbations and hospitalizations). There is an urgent need to find more effective treatment options. Since IPF is predominantly a disease of the elderly with a peak prevalence in those 65 and older, it is common for these individuals to have other comorbidities such as Hyperlipidemia (HLD). Interestingly, in a prior small study of IPF patients, there is evidence to suggest clinical benefit from ezetimibe, a medication used to treat HLD. This study aims to further evaluate the clinical benefits of ezetimibe in patients with IPF in a large national cohort. Methods We conducted this study using the Optum Labs Data Warehouse (OLDW). The OLDW contains de-identified administrative claims data, including medical and pharmacy claims and enrollment records. This study used claims data from commercial, Medicare Advantage (MA), and Medicare Fee-for-service (FFS) enrollees between October 1st, 2014, and December 31st, 2021. Diagnosis of IPF was defined using ICD-9 and ICD-10 codes. Patients without a diagnosis of IPF were excluded. P < 0.05 was set to determine statistical significance. Two matched patient cohorts depending on ezetimibe use were defined. Primary outcome was all-cause mortality, and secondary outcome was hospitalizations. Results We identified 7724 patients with IPF. After adjusting for age, age group, gender, race, health plan, year of IPF diagnosis, smoking, diabetes, statin treatment, and antifibrotic treatment, two cohorts were identified and matched, patients treated with ezetimibe (n = 3862) and patients not treated with ezetimibe (n = 3862). Among the patients with IPF treated with ezetimibe, ezetimibe use was associated with a reduction in all-cause mortality (hazard ratio [95% CI]: 0.704 [0.660 - 0.752], p-value: <0.001) and hospitalizations(hazard ratio [95% CI]: 0.907 [0.857 - 0.959], p-value: 0.001) compared to patients not treated with ezetimibe. Conclusion In patients with IPF, treatment with ezetimibe may be associated with improved clinical outcomes. Further studies are necessary to confirm benefits, assess anti-fibrotic effects, and inform implementation in management of IPF. As IPF remains a disease with limited treatment options, repurposing drugs continues to offer an avenue to find affordable, safe and already approved medications for use. This abstract is funded by: None