Systemic sclerosis approach, some other relevant biomarkers may not have reached statistical significance and thus been missed. Fourth, due to the small sample size and missing data, we could not assess the added value of chemerin serum levels when integrated in PAH diagnostic algorithm and/or risk assessment. This should be addressed in future studies by performing multilevel analysis on larger cohorts. Fifth, due to sample availability considerations, lung experiments included different patient populations, such as iPAH, SSc-ILD and patients with participation of group 3 PH. Finally, as our work had a cross-sectional design, we could not assess the capacity of chemerin level variations to reflect changes in PVR during follow-up. Longitudinal studies are warranted to test its value as a surrogate for treatment efficacy and failure. CONCLUSIONS Using a wide-scale proteomic approach, we identified chemerin as a potential surrogate for PVR in SSc-PAH patients, which could be interesting as a non-invasive assessment of haemo- dynamic severity. Chemerin and its receptor CMKLR1 could contribute to the pathogenesis of the disease through PA-SMC proliferation, but could also be involved in inflammatory and fibrotic processes occurring during SSc. Further studies should investigate the potential of this pathway as a marker of disease progression and as a therapeutic target. Author affiliations 1 Boston University School of Medicine, E5 Arthritis Center, Boston, Massachusetts, USA 2 Univ. Lille, U1286 – INFINITE – Institute for Translational Research in Inflammation, Lille, France 3 INSERM, Lille, France 4 CHU Lille, Département de Médecine Interne et Immunologie Clinique, Lille, France 5 Centre National de Référence Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), Lille, France 6 Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNET), Lille, France 7 Université Paris Saclay, School of Medicine, Le Kremlin-Bicêtre, France 8 INSERM UMR_S 999, Hôpital Marie-Lannelongue, Le Plessis-Robinson, France 9 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA 10 Univ. Grenoble Alpes, INSERM, HP2, Grenoble, France 11 AP-HP, Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Kremlin-Bicêtre, France 12 Univ. Lille, CHU Lille, ULR 2694 - METRICS: Évaluation des technologies de santé et des pratiques médicales, Lille, France 13 Inria, MODAL: MOdels for Data Analysis and Learning, Lille, France 14 Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UAR 2014 - US 41 - PLBS, bilille, Lille, France 15 Division of Rheumatology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA Twitter David Montani @Montanidavid Acknowledgements The authors wish to acknowledge the contributions of Giuseppina Stifano (Boston University), Eric A. Stratton (Boston University), Barbara Girerd (Le Kremlin-Bicêtre), Nicolas Gonnet (Grenoble), Alain Duhamel (Lille) and Sylvain Dubucquoi (Lille). Contributors All individuals listed as authors met the ICMJE guidelines for determining authorship. SS and RL conceived, designed and supervised the overall study. LR, JCM and RL screened and included patients in the discovery cohort, and contributed samples for the serum experiments. SS, DM and J-LC screened and included patients in the validation cohort, and contributed samples for the serum experiments. SS, LR and JCM performed experiments on serum samples. AMB contributed additional clinical data. SS and LR created and managed the database. CT and GM performed statistical analyses and created Figure 1. SS created figures 2 and 3. EV and RL provided lung samples for the single-cell RNA sequencing. EV performed sequencing experiments, analysed the generated dataset and created Figure 4. LT, DM, MH and CG provided lung samples for the confocal and PASMCs for the proliferation experiments. EH and DL contributed serum samples for the proliferation experiments. LT performed the confocal stainings and PASMC proliferation experiments, and created figure 5 and supplemental figure S1. CT and GM performed statistical analyses. SS created figure 6 and supplemental figure S2. SS wrote the first draft of the manuscript and created the Tables. LT, CG and RL
made major revisions to the manuscript. MH provided his PAH expertise. EH and DL provided their SSc expertise. All authors read and approved the submitted version. SS acts as the guarantor of this study. Funding This work was supported by NIH National Institute of Arthritis Musculoskeletal and Skin Disease grants to RL: Scleroderma Core Centers (5P30AR061271), Scleroderma Center of Research Translation (1P50AR060780) and 2R01AR051089. Competing interests SS reports travel grants from Shire, Sanofi-Genzyme, SOBI and Novartis; consulting fees from Novartis; outside the submitted work. J-LC reports grants from United Therapeutic, Bioprojet and Topadur, outside the submitted work. DM reports grants and personal fees from Actelion, grants and personal fees from Bayer, personal fees from GSK, personal fees from Pfizer, personal fees from MSD, personal fees from Chiesi, outside the submitted work. EH reports consulting fees from Actelion, Boehringer Ingelheim, GSK, Roche-Chugai, Sanofi-Genzyme; speaking fees from Actelion, GSK, Roche-Chugai; and research funding from CSL Behring, GSK, Roche-Chugai, outside the submitted work. DL reports personal fees from Actelion, grants and personal fees from Takeda, grants and personal fees from CSL Behring, outside the submitted work. MH reports personal fees from Actelion, grants and personal fees from Bayer, grants and personal fees from GSK, personal fees from Merck, personal fees from United Therapeutics, personal fees from Acceleron, outside the submitted work. RL reports research grants from Formation, Elpidera and Kiniksa, outside the submitted work. RL has served as a consultant for Bristol Myers Squibb, Boehringer-Mannheim, Merck, Magenta and Genentech/Roche, outside the submitted work. Over the last three years, CG, reports grants from Acceleron, ShouTi, and Janssen and grants and personal fees from Merck, outside the submitted work. Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. Patient consent for publication Not applicable. Ethics approval This study involves human participants and was approved by institutional review boards from Boston University (IRB# H-31479), Lille University (Comité de Protection des Personnes CPP# 2019-87), Grenoble University (IRB# 6705), Le Kremlin-Bicetre centre (Comité de Protection des Personnes CPP# 8.06.06) and University of Pittsburgh (IRB# PRO14010265, CORID #415 and 718). Written informed consent was obtained from all patients before sample collection. Participants gave informed consent to participate in the study before taking part. Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Data are available on reasonable request. Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. ORCID iDs REFERENCES 1 Lefèvre G, Dauchet L, Hachulla E, et al . Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis. Arthritis Rheum 2013;65:2412–23. 2 Humbert M, Guignabert C, Bonnet S, et al . Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J 2019;53:1801887. 3 Sobanski V, Launay D, Hachulla E, et al . Current approaches to the treatment of Systemic-Sclerosis-Associated pulmonary arterial hypertension (SSc-PAH). Curr Rheumatol Rep 2016;18:10. 4 Galiè N, Humbert M, Vachiery J-L, et al . 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint Task force for the diagnosis and treatment of pulmonary hypertension of the European Society of cardiology (ESC) and the European respiratory Society (ERS): endorsed by: association for European paediatric and congenital cardiology (AEPC), International Society for heart and lung transplantation (ISHLT). Eur Heart J 2016;37:67–119. 5 Pokeerbux MR, Giovannelli J, Dauchet L, et al . Survival and prognosis factors in systemic sclerosis: data of a French multicenter cohort, systematic review, and meta- analysis of the literature. Arthritis Res Ther 2019;21:86. Sébastien Sanges http://orcid.org/0000-0003-0280-411X Eleanor Valenzi http://orcid.org/0000-0003-0656-6542 David Montani http://orcid.org/0000-0002-9358-6922 Eric Hachulla http://orcid.org/0000-0001-7432-847X
Sanges S, et al . Ann Rheum Dis 2023; 82 :365–373. doi:10.1136/ard-2022-223237
372
Powered by FlippingBook