BAG3 PROTEIN: A PROMISING NOVEL BIOMARKER OF FIBROSIS IN SYSTEMIC SCLEROSIS

M. De Marco, A. Falco, F. Reppucci, L. Marzullo, A. Rosati, G. Armentaro, A. Minniti, C. Iannone, N. Del Papa, R. Caporali, M. C. TurcoUniversity of Salerno, FIBROSYS s.r.l., Baronissi (SA), Italy “Schola Medica Salernitana” University of Salerno, Department of Medicine, Surgery and Dentistry, Baronissi (SA), Italy ASST Gaetano Pini-CTO, Scleroderma Clinic, Rheumatology Dept., Milano, Italy University of Milan, Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Milano, Italy ASST Gaetano Pini-CTO, Rheumatology Dept., Milano, Italy  Background Systemic Sclerosis (SSc) is a rare autoimmune disease characterized by an abnormal remodelling of tissue matrix, leading to fibrosis of skin and internal organs. Despite progresses made in terms of knowledge of pathogenic mechanisms, no study has yet identified specific biomarkers useful for assessing disease evolution and response to therapies. Bcl2-associated athanogene 3 (BAG3) protein is a member of a family of co-chaperones that interact with the ATPase domain of the heat shock protein (Hsp) 70 through their BAG domain. BAG3 is constitutively present in a few normal cell types and some tumours, while its expression is induced by stressful stimuli in a wide variety of cells. BAG3 interacts with several partner proteins regulating different pathways, including apoptosis, autophagy and motility. Recent studies have demonstrated a pivotal role of extracellular BAG3 in pro-tumor cell signaling in the tumor microenvironment, as well as its involvement in the development of fibrosis in tumor tissues [1]. In addition, a strong correlation between bag3 gene expression and patients’ survival was found in several types of fibrotic tumors [1]. Objectives Our aim was to evaluate the presence of BAG3 in the serum of patients with SSc and to investigate whether circulating levels of BAG3 could have any relationship with different SSc subsets and disease features. Methods We enrolled SSc patients, all classified according to the ACR-EULAR criteria. Videocapillaroscopy (NCV) was performed at the time of serum collection. Lung involvement was assessed by spirometry and high-resolution chest CT. Patients were classified into 3 subgroups (no ILD, limited ILD, and extensive ILD) according to the diagram described by Goh et al.[2]. SSc disease activity was assessed according to the activity indices defined by the EUSTAR score [3]. Evaluation of BAG3 protein in serum samples was performed by a sandwich ELISA assay. Results The study cohort included 106 SSc patients (47 were classified with lcSSc and 59 with dcSSc) and 100 sex and age matched healthy controls (HC). Serum levels of BAG3 were significantly higher in SSc patients (mean value 85,3 pg/mL, 95% confidence interval CI 47,2-123,4) when compared with HC (0,68 pg/mL, 95%CI 0,13-1,23) (p=0.001). When analyzed according to disease subset, dcSSc patients showed values (143,3 pg/mL, 95%CI 78-208,5) significantly higher and lcSSc patients (8,7 pg/mL, 95%CI 1,64-15,9,5) (p=0.001). No correlation was found between BAG3 levels and digital ulcers, mRSS and disease activity. Conversely, BAG3 values positively correlated with the extent of lung damage (237,8 pg/mL, 95%CI 131,2-344 in the extensive lung disease vs 16,3 %CI 7,5-25,3 in the limited). Finally, BAG3 values were significantly higher in patients with late NVC pattern in comparison with NVC pattern early/active (p=0.0008). Conclusion Recent studies have highlighted a central role of extracellular BAG3 in maintaining the tumour microenvironment, as well as in the development of fibrosis in neoplastic tissues. To our knowledge, the presence of BAG3 in the serum of patients with SSc has never been described in the literature. Serum levels of BAG3 were found to be significantly higher in the dcSSc, mostly in those with lung involvement. This is not surprising since the diffuse form of disease has more extensive fibrosis, both in the skin and lung, than lcSSc. Accordingly, BAG3 values correlated with the late pattern at NVC, the one most frequently associated with the more advanced and fibrotic stages of the disease. Conversely, serum BAG3 values did not correlate with disease activity, since these scores reflect the evolution and progression of disease rather than the extent of fibrosis. Indeed, the close correlation between BAG3 levels and the more fibrotic features of the disease, suggests that BAG3 might be a new promising marker of fibrosis. References M. De Marco, N. Del Papa et al., J Cell Biochem 2022 Goh et al. Am J Resp Crit Care Dis 2008 Valentini G et al. Ann Rheum Dis. 2017 Acknowledgements: NIL. Disclosure of Interests Margot De Marco Shareholder of: Shareholder of Fibrosys srl, an academic spin-off that provided anti-BAG3 antibodies., Antonia Falco: None declared, Francesca Reppucci: None declared, Liberato Marzullo Shareholder of: Shareholder of Fibrosys srl, an academic spin-off that provided anti-BAG3 antibodies., Alessandra Rosati Shareholder of: Shareholder of Fibrosys srl, an academic spin-off that provided anti-BAG3 antibodies., Giuseppe Armentaro: None declared, Antonina Minniti: None declared, Claudia Iannone: None declared, Nicoletta Del Papa Speakers bureau: Boheringer-Ingelaim; Janssen, Roberto Caporali Speakers bureau: AbbVie, Amgen, BMS, Celltrion, Fresenius, Galapagos, Janssen, Lilly, Novartis, Pfizer, and UCB, Consultant of: Consultant of: AbbVie, Fresenius, Galapagos, Lilly, Novartis, Pfizer, and UCB, Maria Caterina Turco Shareholder of: Shareholder of Fibrosys srl, an academic spin-off that provided anti-BAG3 antibodies. Keywords: Systemic sclerosis, Biomarkers, Lungs DOI: 10.1136/annrheumdis-2023-eular.4071Citation: , volume 82, supplement 1, year 2023, page 585Session: Systemic sclerosis, myositis and related syndromes - aetiology, pathogenesis and animal models (Poster View)