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Background: Pulmonary alveolar proteinosis (PAP) is a rare syndrome caused by several distinct diseases leading to progressive dyspnoea, hypoxaemia, risk of respiratory failure and early death due to accumulation of proteinaceous material in the lungs. Diagnostic strategies may include computed tomography (CT) of the lungs, bronchoalveolar lavage (BAL), evaluation of antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), genetic testing and, eventually, lung biopsy. The management options are focused on removing the proteinaceous material by whole lung lavage (WLL), augmentation therapy with GM-CSF, rituximab, plasmapheresis and lung transplantation. The presented diagnostic and management guidelines aim to provide guidance to physicians managing patients with PAP., Methods: A European Respiratory Society Task Force composed of clinicians, methodologists and patients with experience in PAP developed recommendations in accordance with the ERS Handbook for Clinical Practice Guidelines and the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. This included a systematic review of the literature and application of the GRADE approach to assess the certainty of evidence and strength of recommendations. The Task Force formulated five PICO (Patients, Intervention, Comparison, Outcomes) questions and two narrative questions to develop specific evidence-based recommendations., Results: The Task Force developed recommendations for the five PICO questions. These included management of PAP with WLL, GM-CSF augmentation therapy, rituximab, plasmapheresis and lung transplantation. Also, the Task Force made recommendations regarding the use of GM-CSF antibody testing, diagnostic BAL and biopsy based on the narrative questions. In addition to the recommendations, the Task Force provided information on the hierarchy of diagnostic interventions and therapy., Conclusions: The diagnosis of PAP is based on CT and BAL cytology or lung histology, whereas the diagnosis of specific PAP-causing diseases requires GM-CSF antibody testing or genetic analysis. There are several therapies including WLL and augmentation therapy with GM-CSF available to treat PAP, but supporting evidence is still limited., Competing Interests: Conflict of interest: C. McCarthy, F. Bonella, B.C. Trapnell and M. Griese report membership of a scientific advisory board of Savara Inc. B.C. Trapnell reports grants from the NHLBI (HL085453) and Savara, consultancy fees from Savara, and support for attending meetings from Savara. T. Wang reports grants from Savara, consultancy fees from Partner Therapeutics and Savara, payment or honoraria for lectures, presentations, manuscript writing or educational events from Partner Therapeutics and Savara, support for attending meetings from the PAP Foundation, participation on a data safety monitoring board or advisory board with Partner Therapeutics and Savara Inc., and a leadership role with the PAP Foundation (Clinical Director and Vice President). C. McCarthy reports grants from Health Research Board, Ireland, Enterprise Ireland and The LAM Foundation, consultancy fees from Theravance Inc., Savara Inc. and AI Therapeutics, support for attending meetings from Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board with Savara Inc. F. Bonella reports consultancy fees from Boehringer Ingelheim, Sanofi, BMS and Savara Inc., payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim and Sanofi, support for attending meetings from Boehringer Ingelheim, AstraZeneca, Atyr and Savara Pharma, and participation on a data safety monitoring board or advisory board with Boehringer Ingelheim, Sanofi and BMS. M. Fally reports leadership roles with the European Respiratory Society (Member of the Clinical Practice Guidelines Methodology Network and Secretary of Assembly 10, Group 1) and Danish Medical Journal (Associate Editor). A. Hadchouel reports patent issued (PCT/EP2022/064179). S. Jouneau reports the following financial (or non-financial) interests: PI for IMPALA and IMPALA-2 studies (Savara Inc.). R. Borie reports honoraria from Boehringer Ingelheim, Sanofi and Ferrer, support for attending meetings from Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board with Savara. I. Campo reports consultancy fees from Partner's Therapeutics, and participation on a data safety monitoring board or advisory board with Savara. E. Manali reports grants from Savara, consulting fees from Boehringer Ingelheim, CLS Behring and Hoffman-La Roche, payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim, CLS Behring and Hoffman-La Roche, support for attending meetings from Boehringer Ingelheim, CLS Behring, Hoffman-La Roche and Elpen, and a leadership role with the European Respiratory Society (Chair in ERS Task Force for Transition of chILD). H. Prosch reports grants from Boehringer Ingelheim, AstraZeneca, Siemens Healthineers, the Christian Doppler Research Association and EU Commission (EU4Health, Horizon Europe Health), consultancy fees from Boehringer Ingelheim and Sanofi, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, BMS, Boehringer Ingelheim, Bracco, Daiichi Sankyo, Janssen, MSD, Novartis, Roche, Sanofi, Siemens Healthineers and Takeda, support for attending meetings from Boehringer Ingelheim, participation on a data safety monitoring board or advisory board with Boehringer Ingelheim, and a leadership role with the European Society of Thoracic Imaging (Vice President). M. Veltkamp reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim and Chiesi, and participation on a data safety monitoring board or advisory board with Boehringer Ingelheim and Xentria. E. Bendstrup reports honoraria from Boehringer Ingelheim, AstraZeneca and Daichii Sankyo, support for attending meetings from Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board with Boehringer Ingelheim and Simbec-Orion. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: The receptor for advanced glycation end product (RAGE) is a transmembrane receptor accelerating a pro-inflammatory signal. RAGE signalling is promoted by decreased soluble isoform of RAGE (sRAGE), which is a decoy receptor for RAGE ligands, and RAGE SNP rs2070600 minor allele. In Caucasian and Japanese cohorts, low circulatory sRAGE levels and presence of the minor allele are associated with poor survival of idiopathic pulmonary fibrosis (IPF) and increased disease susceptibility to interstitial lung disease, respectively. However, whether sRAGE and RAGE SNP rs2070600 are associated with acute exacerbation of IPF (AE-IPF) is unclear., Methods: This retrospective cohort study evaluated the association between the onset of AE-IPF and serum sRAGE levels in 69 German and 102 Japanese patients with IPF. The association of AE-IPF with RAGE SNP rs2070600 in 51 German and 84 Japanese patients, whose DNA samples were stored, was also investigated., Results: In each cohort, the incidence of AE-IPF was significantly and reproducibly higher in the patients with sRAGE < 467.1 pg/mL. In a pooled exploratory analysis, the incidence of AE-IPF was lowest in the patients with higher sRAGE levels and rs2070600 minor allele, although no significant difference in the incidence was observed between the patients with and without the rs2070600 minor allele., Conclusions: Low sRAGE levels were associated with increased incidence of AE-IPF in two independent cohorts of different ethnicities. The combination of rs2070600 and sRAGE levels may stratify patients with IPF for the risk of AE., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Ethics Committees of Ruhrlandklinik (IRB 06-3170) and Hiroshima University Hospital (IRB33 and M326). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

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 utilized a large, international, multi-center "Classification Criteria for Anti-synthetase Syndrome" (CLASS) project database, which includes both ASSD patients 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 ASSD cases and 1077 controls. Joint, muscle, lung, skin, and cardiac involvement were more prevalent in 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/MRI/muscle biopsy findings suggestive of myopathy, inflammatory rashes, myocarditis, and pulmonary arterial hypertension did not differentiate between 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., (This article is protected by copyright. All rights reserved.)

Background: Non-specific interstitial pneumonia (NSIP) is an interstitial lung disease that can result in end-stage fibrosis. We investigated the influence of body composition and pulmonary fat attenuation volume (CTpfav) on overall survival (OS) in NSIP patients., Methods: In this retrospective single-center study, 71 NSIP patients with a median age of 65 years (interquartile range 21.5), 39 females (55%), who had a computed tomography from August 2009 to February 2018, were included, of whom 38 (54%) died during follow-up. Body composition analysis was performed using an open-source nnU-Net-based framework. Features were combined into: Sarcopenia (muscle/bone); Fat (total adipose tissue/bone); Myosteatosis (inter-/intra-muscular adipose tissue/total adipose tissue); Mediastinal (mediastinal adipose tissue/bone); and Pulmonary fat index (CTpfav/lung volume). Kaplan-Meier analysis with a log-rank test and multivariate Cox regression were used for survival analyses., Results: Patients with a higher (> median) Sarcopenia and lower (< median) Mediastinal Fat index had a significantly better survival probability (2-year survival rate: 83% versus 71% for high versus low Sarcopenia index, p = 0.023; 83% versus 72% for low versus high Mediastinal fat index, p = 0.006). In univariate analysis, individuals with a higher Pulmonary fat index exhibited significantly worse survival probability (2-year survival rate: 61% versus 94% for high versus low, p = 0.003). Additionally, it was an independent risk predictor for death (hazard ratio 2.37, 95% confidence interval 1.03-5.48, p = 0.043)., Conclusion: Fully automated body composition analysis offers interesting perspectives in patients with NSIP. Pulmonary fat index was an independent predictor of OS., Relevance Statement: The Pulmonary fat index is an independent predictor of OS in patients with NSIP and demonstrates the potential of fully automated, deep-learning-driven body composition analysis as a biomarker for prognosis estimation., Key Points: This is the first study assessing the potential of CT-based body composition analysis in patients with non-specific interstitial pneumonia (NSIP). A single-center analysis of 71 patients with board-certified diagnosis of NSIP is presented Indices related to muscle, mediastinal fat, and pulmonary fat attenuation volume were significantly associated with survival at univariate analysis. CT pulmonary fat attenuation volume, normalized by lung volume, resulted as an independent predictor for death., (© 2024. The Author(s).)

Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease (ILD) in sensitized individuals caused by a large variety of inhaled antigens. The clinical form of acute HP is often misdiagnosed, while the chronic form, especially the chronic fibrotic HP, is difficult to differentiate from other fibrotic ILDs. The present guideline for the diagnosis and treatment of HP replaces the former German recommendations for the diagnosis of HP from 2007 and is amended explicitly by the issue of the chronic fibrotic form, as well as by treatment recommendations for the first time. The evidence was discussed by a multidisciplinary committee of experts. Then, recommendations were formulated for twelve questions on important issues of diagnosis and treatment strategies. Recently published national and international guidelines for ILDs and HP were considered. Detailed background information on HP is useful for a deeper insight into HP and the handling of the guideline., Competing Interests: Eine Übersicht der Interessenkonflikte findet sich im Internet unter http://awmf.org; AWMF-Registriernummer 020-036., (Thieme. All rights reserved.)

Purpose: Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease, with a median survival time of 2 to 5 years. The focus of this study is to establish a novel imaging biomarker., Materials and Methods: In this study, 79 patients (19% female) with a median age of 70 years were studied retrospectively. Fully automated body composition analysis (BCA) features (bone, muscle, total adipose tissue, intermuscular, and intramuscular adipose tissue) were combined into Sarcopenia, Fat, and Myosteatosis indices and compared between patients with a survival of more or less than 2 years. In addition, we divided the cohort at the median (high=≥ median, low=

Rationale: Idiopathic pulmonary fibrosis is a fatal and progressive disease with limited treatment options. Objectives: We sought to assess the efficacy and safety of CC-90001, an oral inhibitor of c-Jun N-terminal kinase 1, in patients with idiopathic pulmonary fibrosis. Methods: In a Phase 2, randomized (1:1:1), double-blind, placebo-controlled study (ClinicalTrials.gov ID: NCT03142191), patients received CC-90001 (200 or 400 mg) or placebo once daily for 24 weeks. Background antifibrotic treatment (pirfenidone) was allowed. The primary endpoint was change in the percentage of predicted FVC (ppFVC) from baseline to Week 24; secondary endpoints included safety. Measurements and Main Results: In total, 112 patients received at least one dose of study drug. The study was terminated early because of a strategic decision made by the sponsor. Ninety-one patients (81%) completed the study. The least-squares mean changes from baseline in ppFVC at Week 24 were -3.1% (placebo), -2.1% (200 mg), and -1.0% (400 mg); the differences compared with placebo were 1.1% (200 mg; 95% confidence interval: -2.1, 4.3; P  = 0.50) and 2.2% (400 mg; 95% confidence interval: -1.1, 5.4; P  = 0.19). Adverse event frequency was similar in patients in the combined CC-90001 arms versus placebo. The most common adverse events were nausea, diarrhea, and vomiting, which were more frequent in patients in CC-90001 arms versus placebo. Fewer patients in the CC-90001 arms than in the placebo arm experienced cough and dyspnea. Conclusions: Treatment with CC-90001 over 24 weeks led to numerical improvements in ppFVC in patients with idiopathic pulmonary fibrosis compared with placebo. CC-90001 was generally well tolerated, which was consistent with previous studies. Clinical trial registered with www.clinicaltrials.gov (NCT03142191).

Pulmonary alveolar proteinosis (PAP) is a syndrome that results from the accumulation of lipoproteinaceous material in the alveolar space. According to the underlying pathogenetic mechanisms, three different forms have been identified, namely primary, secondary and congenital. Primary PAP is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling due to the presence of neutralising autoantibodies (autoimmune PAP) or GM-CSF receptor genetic defects (hereditary PAP), which results in dysfunctional alveolar macrophages with reduced phagocytic clearance of particles, cholesterol and surfactant. The serum level of GM-CSF autoantibody is the only disease-specific biomarker of autoimmune PAP, although it does not correlate with disease severity. In PAP patients with normal serum GM-CSF autoantibody levels, elevated serum GM-CSF levels is highly suspicious for hereditary PAP. Several biomarkers have been correlated with disease severity, although they are not specific for PAP. These include lactate dehydrogenase, cytokeratin 19 fragment 21.1, carcinoembryonic antigen, neuron-specific enolase, surfactant proteins, Krebs von Lungen 6, chitinase-3-like protein 1 and monocyte chemotactic proteins. Finally, increased awareness of the disease mechanisms has led to the development of pathogenesis-based treatments, such as GM-CSF augmentation and cholesterol-targeting therapies., Competing Interests: Conflict of interest: F. Bonella reports consultancy fees from Boehringer Ingelheim, Sanofi, BMS and CSL-Behring, payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim and Sanofi, support for attending meetings from Boehringer Ingelheim, Astra Zeneca and Atyr, and participation on a data safety monitoring board or advisory board with Boehringer Ingelheim, Sanofi and BMS. I. Campo reports consultancy fees from Partner Therapeutics, and participation on a data safety monitoring board or advisory board with Savara. All other authors have nothing to disclose., (Copyright ©The authors 2024.)

Renal involvement is a clinically relevant organ manifestation of sarcoidosis, leading to increased morbidity and complications. Although the exact incidence remains unknown, renal disease is likely to occur in up to one third of all sarcoidosis patients. Every patient with newly diagnosed sarcoidosis should receive a renal work-up and screening for disrupted calcium metabolism. Amid various forms of glomerulonephritis, granulomatous interstitial nephritis is the most common one, but it rarely leads to renal impairment. Histologically, granulomas can be absent. Nephrocalcinosis and nephrolithiasis are frequent forms when hypercalcaemia or hypercalciuria occur. Drugs used for treatment of systemic sarcoidosis can also cause renal damage. Due to its high heterogeneity, renal sarcoidosis can be difficult to treat. Glucocorticoids and various immunosuppressive treatments have been proven to be effective based on case series, but clinical trials are lacking. A treatment guideline for renal sarcoidosis is urgently needed. In this review article, we present an overview of the different forms of renal sarcoidosis and the diagnostic steps to confirm renal involvement; in addition, we provide insights on the management and available treatments. A better understanding regarding the pathogenesis of sarcoidosis is the key for the development of more specific, targeted therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This work was endorsed by the European Reference Network (ERN)-LUNG, SARCOIDOSIS Core Network. Aknowledgements, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The present recommendations on the therapy of sarcoidosis of the German Respiratory Society (DGP) was written in 2023 as a German-language supplement and update of the international guidelines of the European Respiratory Society (ERS) from 2021. It contains 5 PICO questions (Patients, Intervention, Comparison, Outcomes) agreed in the consensus process, which are explained in the background text of the four articles: Confirmation of diagnosis and monitoring of the disease under therapy, general therapy recommendations, therapy of cutaneous sarcoidosis, therapy of cardiac sarcoidosis., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany.)

Objectives: The CLASS (Classification Criteria of Anti-Synthetase Syndrome) project is a large international multicentre study that aims to create the first data-driven anti-synthetase syndrome (ASSD) classification criteria. Identifying anti-aminoacyl tRNA synthetase antibodies (anti-ARS) is crucial for diagnosis, and several commercial immunoassays are now available for this purpose. However, using these assays risks yielding false-positive or false-negative results, potentially leading to misdiagnosis. The established reference standard for detecting anti-ARS is immunoprecipitation (IP), typically employed in research rather than routine autoantibody testing. We gathered samples from participating centers and results from local anti-ARS testing. As an "ad-interim" study within the CLASS project, we aimed to assess how local immunoassays perform in real-world settings compared to our central definition of anti-ARS positivity., Methods: We collected 787 serum samples from participating centres for the CLASS project and their local anti-ARS test results. These samples underwent initial central testing using RNA-IP. Following this, the specificity of ARS was reconfirmed centrally through ELISA, line-blot assay (LIA), and, in cases of conflicting results, protein-IP. The sensitivity, specificity, positive likelihood ratio and positive and negative predictive values were evaluated. We also calculated the inter-rater agreement between central and local results using a weighted κ co-efficient., Results: Our analysis demonstrates that local, real-world detection of anti-Jo1 is reliable with high sensitivity and specificity with a very good level of agreement with our central definition of anti-Jo1 antibody positivity. However, the agreement between local immunoassay and central determination of anti-non-Jo1 antibodies varied, especially among results obtained using local LIA, ELISA and "other" methods., Conclusions: Our study evaluates the performance of real-world identification of anti-synthetase antibodies in a large cohort of multi-national patients with ASSD and controls. Our analysis reinforces the reliability of real-world anti-Jo1 detection methods. In contrast, challenges persist for anti-non-Jo1 identification, particularly anti-PL7 and rarer antibodies such as anti-OJ/KS. Clinicians should exercise caution when interpreting anti-synthetase antibodies, especially when commercial immunoassays test positive for non-anti-Jo1 antibodies.

Background: Pulmonary involvement is the leading cause of death in systemic sclerosis (SSc) and may manifest as interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), or in combination of both (ILD with pulmonary hypertension [ILD-PH]). The aim of this analysis was to determine prevalence, clinical characteristics, and survival of these different forms within the registry of the German Network for Systemic Sclerosis., Research Question: Does SSc-associated ILD-PH or ILD without PH affect survival differently, and are there any risk factors that have an additional impact?, Study Design and Methods: Clinical data of 5,831 patients with SSc were collected in the German Network for Systemic Sclerosis registry. Kaplan-Meier estimates were used to compare overall survival in patients with SSc-associated ILD-PH and ILD without PH with patients without pulmonary involvement and those with PAH. The Cox proportional hazard model was used to analyze the influence of pulmonary involvement and other potential predictors on patient survival., Results: Clinical data of 3,257 patients with a mean follow-up time of 3.45 ± 1.63 years have been included in our analysis. At baseline, ILD was present in 34.5%, whereas PH without ILD had a lower prevalence with 4.5%. At the end of follow-up, 47.6% of patients with SSc had ILD, 15.2% had ILD-PH, and 6.5% had PAH. ILD was more frequent in the diffuse cutaneous form (57.3%), whereas PAH did not differ significantly between SSc subtypes. Significant differences in baseline characteristics between PAH vs ILD-PH vs ILD without PH were found for age at diagnosis, sex, SSc subsets, antibody status, FVC, diffusing capacity of the lung for carbon monoxide, and therapy. Overall survival at 5 years was 96.4% for patients without pulmonary involvement and differed significantly between patients with ILD without PH, PAH, and being worst in patients with ILD-PH. Female sex (hazard ratio [HR], 0.3), higher BMI (HR, 0.9), and higher diffusing capacity of the lung for carbon monoxide values (HR, 0.98) were associated with a lower mortality risk., Interpretation: ILD is the most prevalent pulmonary involvement in SSc, whereas the combination of ILD and PH is associated with the most detrimental survival., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: M. K. reports grants and personal fees from Boehringer Ingelheim and Roche, and personal fees from Galapagos. P. M. reports lecture fees from Boehringer Ingelheim. F. B. reports grants and personal fees from Boehringer Ingelheim, Roche, Galapagos, and Savara Pharma. N. B. reports personal fees from Actelion, Boehringer Ingelheim, Roche, Pfizer, MSD, and AbbVie; and grants and personal fees from Novartis and SOBI. C. P. reports personal fees from Boehringer Ingelheim, Pfizer, and Takeda; grants and personal fees from Actelion and Novartis; and grants from Corbus and Amgen. M. S. reports grants and personal fees from Roche/Chugai, Hexal/Sandoz, Janssen, and BMS; and personal fees from AbbVie, Novartis, UCB, Boehringer Ingelheim, and Gilead. P. K. reports personal fees and nonfinancial support from AbbVie, Chugai, Novartis, and Pfizer, unrelated to the present manuscript; and personal fees from Bristol-Myers Squibb, Gilead, and GlaxoSmithKline, unrelated to the present manuscript. N. H. reports lecture fees from Boehringer Ingelheim and Janssen. Nothing declared (M. O., J. W., G. R., U. M.-L., J. H., E. S., C. G., I. K., G. Z., L. S., A. J., M. W., I. J., J. E., C. S., G. K., A. R., T. S., A. K., H. M.-L.)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)