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Objective: Anti-synthetase syndrome (ASSD) is a rare systemic autoimmune rheumatic disease (SARD) with significant heterogeneity and no shared classification criteria. We aimed to identify clinical and serological features associated with ASSD that may be suitable for inclusion in the data-driven classification criteria for ASSD., Methods: We used a large, international, multicenter "Classification Criteria for Anti-synthetase Syndrome" (CLASS) project database, which includes both patients with ASSD and controls with mimicking conditions, namely, SARDs and/or interstitial lung disease (ILD). The local diagnoses of ASSD and controls were confirmed by project team members. We employed univariable logistic regression and multivariable Ridge regression to evaluate clinical and serological features associated with an ASSD diagnosis in a randomly selected subset of the cohort., Results: Our analysis included 948 patients with ASSD and 1,077 controls. Joint, muscle, lung, skin, and cardiac involvement were more prevalent in patients with ASSD than in controls. Specific variables associated with ASSD included arthritis, diffuse myalgia, muscle weakness, muscle enzyme elevation, ILD, mechanic's hands, secondary pulmonary hypertension due to ILD, Raynaud phenomenon, and unexplained fever. In terms of serological variables, Jo-1 and non-Jo-1 anti-synthetase autoantibodies, antinuclear antibodies with cytoplasmic pattern, and anti-Ro52 autoantibodies were associated with ASSD. In contrast, isolated arthralgia, dysphagia, electromyography/magnetic resonance imaging/muscle biopsy findings suggestive of myopathy, inflammatory rashes, myocarditis, and pulmonary arterial hypertension did not differentiate between patients with ASSD and controls or were inversely associated with ASSD., Conclusion: We identified key clinical and serological variables associated with ASSD, which will help clinicians and offer insights into the development of data-driven classification criteria for ASSD., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Interstitial lung diseases (ILDs) include a variety of inflammatory and fibrotic pulmonary conditions. This study employs high-resolution metabolomics (HRM) to explore plasma metabolites and pathways across ILD phenotypes, including non-fibrotic ILD, idiopathic pulmonary fibrosis (IPF), and non-IPF fibrotic ILD. The study used 80 plasma samples for HRM, and involved linear trend and group-wise analyses of metabolites altered in ILD phenotypes. We utilized limma one-way ANOVA and mummichog algorithms to identify differences in metabolites and pathways across ILD groups. Then, we focused on metabolites within critical pathways, indicated by high pathway overlap sizes and low p-values, for further analysis. Targeted HRM identified putrescine, hydroxyproline, prolyl-hydroxyproline, aspartate, and glutamate with significant linear increases in more fibrotic ILD phenotypes, suggesting their role in ILD fibrogenesis. Untargeted HRM highlighted pathway alterations in lysine, vitamin D3, tyrosine, and urea cycle metabolism, all associated with pulmonary fibrosis. In addition, methylparaben level had a significantly increasing linear trend and was higher in the IPF than fibrotic and non-ILD groups. This study highlights the importance of specific amino acids, metabolic pathways, and xenobiotics in the progression of pulmonary fibrosis., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Cadmium (Cd) is a toxic environmental metal that interacts with selenium (Se) and contributes to many lung diseases. Humans have widespread exposures to Cd through diet and cigarette smoking, and studies in rodent models show that Se can protect against Cd toxicities. We sought to identify whether an antagonistic relationship existed between Se and Cd burdens and determine whether this relationship may associate with metabolic variation within human lungs. We performed metabolomics of 31 human lungs, including 25 with end-stage lung disease due to idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive lung disease (COPD)/emphysema and other causes, and 6 non-diseased lungs. Results showed pathway associations with Cd including amino acid, lipid and energy-related pathways. Metabolic pathways varying with Se had considerable overlap with these pathways. Hierarchical cluster analysis (HCA) of individuals according to metabolites associated with Cd showed partial separation of disease types, with COPD/emphysema in the cluster with highest Cd, and non-diseased lungs in the cluster with the lowest Cd. When compared to HCA of metabolites associated with Se, the results showed that the cluster containing COPD/emphysema had the lowest Se, and the non-diseased lungs had the highest Se. A greater number of pathway associations occurred for Cd to Se ratio than either Cd or Se alone, indicating that metabolic patterns were more dependent on Cd to Se ratio than on either alone. Network analysis of interactions of Cd and Se showed network centrality was associated with pathways linked to polyunsaturated fatty acids involved in inflammatory signaling. Overall, the data show that metabolic pathway responses in human lung vary with Cd and Se in a pattern suggesting that Se is antagonistic to Cd toxicity in humans., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests.

Both environmental exposure to vanadium pentoxide (V 2 O 5 , V +5 for its ionic counterparts) and fibroblast senescence are associated with pulmonary fibrosis, but whether V +5 causes fibroblast senescence remains unknown. We found in a dose-response study that 2-40 μM V +5 caused human lung fibroblasts (HLF) senescence with increased senescence-associated β-galactosidase activity and p16 expression, while cell death occurred at higher concentration (LC 50 , 82 μM V +5 ). Notably, measures of reactive oxygen species (ROS) production with fluorescence probes showed no association of ROS with V +5 -dependent senescence. Preloading catalase (polyethylene-conjugated), a H 2 O 2 scavenger, did not alleviate the cellular senescence induced by V +5 . Analyses of the cellular glutathione (GSH) system showed that V +5 oxidized GSH, increased GSH biosynthesis, stimulated cellular GSH efflux and increased protein S-glutathionylation, and addition of N-acetyl cysteine inhibited V +5 -elevated p16 expression, suggesting that thiol oxidation mediates V +5 -caused senescence. Moreover, strong correlations between GSSG/GSH redox potential (E h ), protein S-glutathionylation, and cellular senescence (R 2  > 0.99, p < 0.05) were present in V +5 -treated cells. Studies with cell-free and enzyme-free solutions showed that V +5 directly oxidized GSH with formation of V +4 and GSSG in the absence of O 2 . Analyses of V +5 and V +4 in HLF and culture media showed that V +5 was reduced to V +4 in cells and that a stable V +4 /V +5 ratio was rapidly achieved in extracellular media, indicating ongoing release of V +4 and reoxidation to V +5 . Together, the results show that V +5 -dependent fibroblast senescence is associated with a cellular/extracellular redox cycling mechanism involving the GSH system and occurring under conditions that do not cause cell death. These results establish a mechanism by which environmental vanadium from food, dietary supplements or drinking water, can cause or contribute to lung fibrosis in the absence of high-level occupational exposures and cytotoxic cell death., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing lung disease with an estimated median survival of 2-5 years and a significant impact on quality of life (QoL). Current approved medications, pirfenidone and nintedanib, have shown a reduction in annual decline of forced vital capacity but no impact on QoL. The minimal clinically important difference (MCID) is a threshold value for a change in a parameter that is considered meaningful by the patient rather than solely relying on statistically significant change in the parameter. This review provides a brief overview of the MCID methodology along with detailed discussion of reported MCID values for commonly used physiological measures and patient-reported outcome measures in IPF. While there is no gold standard methodology for determining MCID, there are certain limitations in the MCID literature in IPF, mainly the choice of death, hospitalisation and pulmonary function tests as sole anchors, and pervasive use of distribution-based methods which do not take into account the patient's input. There is a critical need to identify accurate thresholds of outcome measures that reflect patient's QoL over time in order to more precisely design and evaluate future clinical trials and to develop algorithms for patient-oriented management of IPF in outpatient clinics., Educational Aims: To understand the concept of MCID and the methods used to determine these values.To understand the indications and limitations of MCID values in IPF., Competing Interests: Conflict of interest: M. Kang reports grants from National Heart, Lung, and Blood Institute (Division T32 grant: 5T32HL116271-07; PI Dr. David Guidot), during the conduct of the study. Conflict of interest: L. Marts reports grants from aTyr Pharma, outside the submitted work. Conflict of interest: J.A. Kempker reports grants from Agency for Healthcare Quality and Research (K08HS025240) and personal fees from Grifols, Inc, outside the submitted work. Conflict of interest: S. Veeraraghavan reports personal fees from Boehringer Ingelheim (Advisory board), and research support grants from Fibrogen, Bellerophon, Biogen, Nitto Denko, Pliant, Galapagos and Galecto, outside the submitted work., (Copyright ©ERS 2021.)