Hinze, Alicia M.

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 Rationale Interstitial lung disease (ILD) affects ∼50% of patients with systemic sclerosis (SSc) and is a leading cause of mortality. Visual assessment of ILD extent and morphologies, including ground-glass opacities (GGO) and reticular densities (RD), suffers from poor interobserver agreement, limiting prognostic consistency. CALIPER Quantitative CT (QCT) provides reproducible volumetric measures of parenchymal and vascular features. This study evaluated baseline QCT-derived lung features for association with transplant/mortality risk in SSc-ILD. Methods A retrospective cohort of SSc patients (≥18 years) seen at an academic center from 2007-2018 was identified using ICD codes, with ACR/EULAR 2013 SSc criteria confirmed by chart review. Inclusion required ILD on high-resolution CT (HRCT) ±2 years of SSc diagnosis, and PFTs ±6 months of HRCT. CALIPER quantified volumes of normal lung, GGO, RD, hyperlucency, honeycombing (HC), and pulmonary vascular-related structures (PVRS), which are expressed as percentages of total lung volume. Right heart catheterization confirmed pulmonary hypertension (PH) defined by 2022 ESC/ERS criteria (Eur Heart J, 2022). Cox hazards models assessed associations with combined mortality/transplant outcome, a priori adjusted for age, sex, diffuse SSc subtype, ILD duration, and PH (Column B), and further adjusted for baseline percent predicted FVC (ppFVC) and ppDLCO (Column C)(Table 1). Results Of 132 SSc-ILD patients, median SSc and ILD disease durations at HRCT were 1.4 (0.6, 2.4) and 0.0 (0.0, 0.5) years. Median feature percentages: total ILD 13.0% (IQR: 6.4, 21.0), GGO 10.2% (4.6, 16.9), RD 1.9% (0.8, 3.7), HC 0.03% (0.00, 0.09), PVRS 3.2% (2.3, 4.1). Median ppFVC was 81.1% (69.4, 92.6), and ppDLCO 60.0% (46.0, 75.7); 21 patients had PH. There were 2 transplants and 45 deaths. Every 5% increase in baseline total ILD and GGO associated with 22% (HR 1.22; 95% CI 1.12-1.33) and 24% (1.24; 1.12-1.36) higher risk of transplant/mortality on unadjusted models (Column A), respectively, remaining significant after a priori (CB) and full adjustment (CC)(Table 1). Every 1% increase in RD and PVRS conferred 19% (1.19; 1.08-1.31) and 33% (1.33; 1.08-1.63) higher risk of transplant/mortality in unadjusted models (CA); RD retained significance after a priori adjustment (1.17; 1.03-1.33), while PVRS trended non-significant in adjusted models. Conclusions In early SSc-ILD, QCT-derived GGO, RD, and PVRS provide robust prognostic value for mortality/transplant risk assessment, with small increases in baseline severity—at or below visual detection thresholds—associating with clinically meaningful risk increases. These findings support integrating baseline QCT biomarkers into risk stratification beyond clinical and PFT measures. This abstract is funded by: Rheumatology Research Foundation

Objective We provide evidence‐based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs). Methods We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations. Results Thirty‐five recommendations were generated (including two strong recommendations) for first‐line SARD‐ILD treatment, treatment of SARD‐ILD progression despite first‐line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis–ILD as a first‐line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first‐line ILD treatment in all other SARDs. Conclusion This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs.

Objective We provide evidence‐based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs). Methods We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations. Results Thirty‐five recommendations were generated (including two strong recommendations) for first‐line SARD‐ILD treatment, treatment of SARD‐ILD progression despite first‐line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis–ILD as a first‐line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first‐line ILD treatment in all other SARDs. Conclusion This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs.

ObjectiveWe provide evidence‐based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease.MethodsWe developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation.ResultsFifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high‐resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6‐minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs.ConclusionThis clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.

Objective We provide evidence‐based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease. Methods We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation. Results Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high‐resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6‐minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs. Conclusion This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.

ObjectiveTo determine the independent risk factors for diastolic dysfunction (DD) in patients with systemic sclerosis (SSc) and to evaluate the impact of DD on mortality.MethodsSSc patients enrolled in the Johns Hopkins Scleroderma Center Cohort between November 1, 2006 and November 1, 2017 with ≥1 analyzable 2‐dimensional (2‐D) echocardiogram in our system were included (n = 806). DD risk factors and SSc disease characteristics were prospectively obtained, and the presence or absence of DD was determined using the most recent 2‐D echocardiogram. Logistic regression models examined associations between clinical risk factors and DD, and Cox proportional hazards models were used to assess survival.ResultsDD was present in 18.6% of participants. The majority of participants were female (84%) with a median age of 58.4 years (interquartile range 48.8–68.1). Older age (odds ratio [OR] 1.12 [95% confidence interval (95% CI) 1.09–1.15], P < 0.001), coronary artery disease (OR 3.69 [95% CI 1.52–8.97], P = 0.004), obesity (OR 4.74 [95% CI 2.57–8.74], P < 0.001), longer SSc disease duration (OR 1.04 [95% CI 1.01–1.06], P = 0.004), diffusing capacity for carbon monoxide ≤60% of predicted (OR 2.41 [95% CI 1.40–4.16], P = 0.002), and history of scleroderma renal crisis (OR 3.18 [95% CI 1.12–9.07], P = 0.031) were all independently associated with an increased risk of DD. Anti–Scl‐70 positivity (OR 0.49 [95% CI 0.26–0.93], P = 0.03) and severe gastrointestinal disease (OR 0.48 [95% CI 0.30–0.79], P = 0.004) were associated with a reduced risk of DD. The presence of DD was independently associated with an increase in the risk of mortality (hazard ratio 1.69 [95% CI 1.07–2.68], P = 0.027).ConclusionDD is independently associated with an increased risk of mortality in patients with SSc. Potentially modifiable risk factors, including coronary artery disease and obesity, should be addressed in patients with SSc to reduce mortality risk.

Abstract Objective To investigate the natural history of fibrotic lung disease in recipients of a single lung transplant for scleroderma-associated interstitial lung disease (ILD). Methods Global ILD (including ground glass, nodular opacities and fibrosis) was categorized into severity quintiles on first and last post-transplant CT scans, and percent fibrosis by manual contouring was also determined, in nine single lung transplant recipients. Quantitative mean lung densities and volumes for the native and allograft lungs were also acquired. Results In the native lung, global ILD severity quintile worsened in two cases and percent fibrosis worsened in four cases (range 5–28%). In the lung allograft, one case each developed mild, moderate and severe ILD; of these, new fibrotic ILD (involving &lt;10% of lung) occurred in two cases and acute cellular rejection occurred in one. The average change in native lung density over time was +2.2 Hounsfield Units per year and lung volume +1.4 ml per year, whereas the allograft lung density changed by –5.5 Hounsfield Units per year and total volume +27 ml per year (P = 0.011 and P = 0.039 for native vs allograft density and volume comparisons, respectively). Conclusions While the course of ILD in the native and transplanted lungs varied in this series, these cases illustrate that disease progression is common in the native lung, suggesting that either the immune process continues to target autoantigens or ongoing fibrotic pathways are active in the native lung. Mild lung disease may occur in the allograft after several years due to either allograft rejection or recurrent mild ILD.