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Background: Sarcoidosis is granulomatous disease of unknown origin affecting organ function and quality of life. The King's Sarcoidosis Questionnaire (KSQ) serves as a tool to assess quality of life in sarcoidosis patients with general health and organ specific domains. A German translation has been validated in a German cohort. In this study we assessed, whether clinical parameters influence KSQ scores., Methods: Clinical data (e.g. lung function, organ impairment, serological parameters) for the German validation cohort were extracted from clinical charts and investigated by correlation and linear regression analyses., Results: KSQ subdomain scores were generally lower in patients with respective organ manifestation or on current therapy. LUNG subdomain was significantly predicted by lung functional parameters, however for general health status, only FeV1 exerted significant influence. GHS was not influenced by serological parameters, but was significantly negatively correlated with body mass index (BMI). KSQ provides additional information beyond lung function, clinical or serological parameters in sarcoidosis patients. Notably, high BMI is significantly negatively associated with patients' well-being as measured by KSQ-GHS., Conclusion: This observation may direct further studies investigating the effect of obesity on sarcoidosis-related quality of life and strategies to intervene with steroid-sparing therapies and measures of life style modifications. Trial registration This study was registered in the German Clinical Trials Register (reference number DRKS00010072). Registered January 2016., (© 2021. The Author(s).)

Background: Sarcoidosis is a multisystem granulomatous disease of unknown origin with a variable and often unpredictable course and pattern of organ involvement. In this study we sought to identify specific bronchoalveolar lavage (BAL) cell gene expression patterns indicative of distinct disease phenotypic traits., Methods: RNA sequencing by Ion Torrent Proton was performed on BAL cells obtained from 215 well-characterised patients with pulmonary sarcoidosis enrolled in the multicentre Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Weighted gene co-expression network analysis and nonparametric statistics were used to analyse genome-wide BAL transcriptome. Validation of results was performed using a microarray expression dataset of an independent sarcoidosis cohort (Freiburg, Germany; n=50)., Results: Our supervised analysis found associations between distinct transcriptional programmes and major pulmonary phenotypic manifestations of sarcoidosis including T-helper type 1 (Th1) and Th17 pathways associated with hilar lymphadenopathy, transforming growth factor-β1 (TGFB1) and mechanistic target of rapamycin (MTOR) signalling with parenchymal involvement, and interleukin (IL)-7 and IL-2 with airway involvement. Our unsupervised analysis revealed gene modules that uncovered four potential sarcoidosis endotypes including hilar lymphadenopathy with increased acute T-cell immune response; extraocular organ involvement with PI3K activation pathways; chronic and multiorgan disease with increased immune response pathways; and multiorgan involvement, with increased IL-1 and IL-18 immune and inflammatory responses. We validated the occurrence of these endotypes using gene expression, pulmonary function tests and cell differentials from Freiburg., Conclusion: Taken together, our results identify BAL gene expression programmes that characterise major pulmonary sarcoidosis phenotypes and suggest the presence of distinct disease molecular endotypes., Competing Interests: Conflict of interest: M. Vukmirovic has nothing to disclose. Conflict of interest: X. Yan has nothing to disclose. Conflict of interest: K.F. Gibson has nothing to disclose. Conflict of interest: M. Gulati reports grants from NIH, during the conduct of the study; personal fees for advisory board work and other (PI/publication committee) from Boehringer Ingelheim, other (lectures) from France Foundation, other (PI/centre director) from Pulmonary Fibrosis Foundation, grants from NIH and Sarcoidosis Research Foundation, outside the submitted work. Conflict of interest: J.C. Schupp has nothing to disclose. Conflict of interest: G. DeIuliis has nothing to disclose. Conflict of interest: T.S. Adams has nothing to disclose. Conflict of interest: B. Hu has nothing to disclose. Conflict of interest: A. Mihaljinec has nothing to disclose. Conflict of interest: T.N. Woolard has nothing to disclose. Conflict of interest: H. Lynn has nothing to disclose. Conflict of interest: N. Emeagwali has nothing to disclose. Conflict of interest: E.L Herzog reports grants from NIH, Sanofi, Bristol Myers and Promedior, personal fees for consultancy from Boehringer Ingelheim and Pfizer, outside the submitted work. Conflict of interest: E.S. Chen has nothing to disclose. Conflict of interest: A. Morris reports grants from NIH, during the conduct of the study. Conflict of interest: J.K. Leader has nothing to disclose. Conflict of interest: Y. Zhang has nothing to disclose. Conflict of interest: J.G.N. Garcia has nothing to disclose. Conflict of interest: L.A. Maier grants from NIH (1U01 HL112695-01, U01 HL112707-03) and NIH/NCRR (UL1TRR002535), during the conduct of the study; grants from National Institutes of Health (1R01 HL127461-01A1, R01HL136681-01A1, 1R01 HL140357-01A1, R01HL136681-01A1), FSR, University of Cinncinati under a Mallinckrodt foundation, MNK14344100, ATYR1923-C-002, outside the submitted work; and is a member of the FSR scientific advisory board, for which no compensation is received. Conflict of interest: R.G. Collman reports grants from National Institutes of Health, during the conduct of the study. Conflict of interest: W.P. Drake has nothing to disclose. Conflict of interest: M.J. Becich reports grants from NCATS, NCI, PCORI, NHLBI and CDC NIOSH, other (startup) from SpIntellx, during the conduct of the study; other (startup) from SpIntellx, outside the submitted work; and has patents SpIntellx (multiple) pending. Conflict of interest: H. Hochheiser has nothing to disclose. Conflict of interest: S.R. Wisniewski has nothing to disclose. Conflict of interest: P.V. Benos has nothing to disclose. Conflict of interest: D.R. Moller reports grants from NHLBI (1U01HL112708), during the conduct of the study; personal fees for consultancy from Merck, aTYR and Roivant, personal fees for advisory board work from SarcoMed, personal fees for consultancy/witness from Legal Expert, other (royalties) from Hodder Education and Taylor & Francis Group, outside the submitted work; has patents number 9,683,999 B2 issued, and number 9,977,029 B2 issued; is Chairman and Chief Technical Officer of Sarcoidosis Diagnostic Testing, LLC (a company whose goal is to develop a diagnostic blood test for sarcoidosis) and has received funding including past salary support under the NHLBI STTR programme, grant R41 HL129728 more than 3 years ago; and is a former member of the Scientific Advisory Board of the Foundation for Sarcoidosis Research. Conflict of interest: A. Prasse reports personal fees for lectures and consultancy and non-financial support for meeting attendance from Boehringer Ingelheim and Roche, personal fees for lectures from Novartis and AstraZeneca, personal fees for consultancy from Amgen, Pliant and Nitto Denko, outside the submitted work. Conflict of interest: L.L. Koth has nothing to disclose. Conflict of interest: N. Kaminski reports personal fees for consultancy and/or advisory board work from Biogen Idec, Boehringer Ingelheim, Third Rock, Samumed, NuMedii, Indaloo, Theravance, LifeMax, Three Lake Partners, RohBar and Pliant, non-financial support from Miragen, equity with Pliant, a grant from Veracyte; all outside the submitted work; and has a patent New Therapies in Pulmonary Fibrosis and on Peripheral Blood Gene Expression that have been licensed to Biotech., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Sarcoidosis is a rare granulomatous disease mainly affecting lymph nodes and the lungs but joints, bones, muscles and other organs can also be affected. Sarcoidosis therefore represents an important differential diagnosis to various rheumatic diseases. For the diagnosis and differential diagnostic clarification, bronchoscopy including endobronchial ultrasound-guided fine needle aspiration of mediastinal and hilar lymph nodes represent the main procedures. Because of the high spontaneous remission rate initiating a therapy requires a therapeutic goal defined by sarcoidosis-associated functional organ impairment, especially for acute sarcoidosis. Cortisone represents the most commonly administered medication whereas methotrexate and azathioprine are well-established second-line medications. Antibodies which neutralize tumor necrosis factors (TNF) are a potential third-line therapy.

Background: Propionibacterium acnes was found in lungs and lymph nodes of patients with sarcoidosis and may induce hypersensitivity type granuloma formation. Data regarding the immune response to P. acnes of European sarcoid patients are scarce., Methods: We assessed the total IgG and IgA amount and specific antibodies to P. acnes and to Staphylococcus aureus, serving as a control, in BAL fluid of 64 patients with sarcoidosis and of 21 healthy volunteers. In a subcohort of sarcoid patients and controls, TNF-α and GM-CSF production of BAL cells stimulated with heat-killed P. acnes were measured., Results: In sarcoid patients, the total IgG and IgA levels in BAL fluid were significantly elevated compared to healthy volunteers. IgG and IgA titres against P. acnes and S. aureus were increased in sarcoid patients, yet based on the total amount of antibodies, only antibodies directed against P. acnes were relatively and significantly increased. Furthermore, BAL cells of sarcoid patients produced significantly more TNF-α and GM-CSF upon stimulation with heat-killed P. acnes compared to controls., Conclusions: Patients with sarcoidosis had elevated levels of specific antibodies against P. acnes which suggest contact with this bacterium in the past. Furthermore, BAL cells of sarcoid patients produced inflammatory cytokines (TNF-α and GM-CSF) upon stimulation with P. acnes indicating potential involvement of this pathogen in the pathogenesis of sarcoidosis in some patients.