Pos0623 integrated serum proteomic and metabolomic profiles in systemic sclerosis patients characterize new biomarkers associated to relevant pathological features

Background Systemic sclerosis (SSc) is a heterogeneous multisystemic autoimmune disease, characterized by extensive skin fibrosis, vascular abnormalities, and autoantibodies against various cellular antigens. The integrated analysis of proteomic and metabolomic in SSc might shed light in the pathogenesis of the disease and reveal novel biomarkers. Objectives The aim of this study was to characterize the circulating proteomic and metabolomic profiles in SSc and their association with key clinical features. Methods Serum NMR metabolomics (Nightingale; 250 metabolites covering glycolysis metabolites, amino acids and lipid measures), and proteomics, involving the analysis of 92 organ damage-related proteins [by proximity extension immunoassay (PEA, Olink)] were performed on serum from 72 SSc patients and 43 age-matched healthy donors (HD). Main disease complications in the SSC cohort, including lung fibrosis, skin fibrosis, renal, vascular, and esophageal involvement were assessed, and prevalence of circulating autoantibodies, along with standard demographic and inflammatory parameters were analyzed by multiple t-test. Unsupervised hierarchical clustering methodologies were applied using Metaboanalyst software to identify subgroups of patients based on their proteomic profiles. Gene ontology enrichment was used to interrogate the biological meaning of the distinctive molecular signatures identified. Results Sixteen circulating proteins related to organ damage (9 increased and 7 reduced) as well as 143 metabolites (37 increased and 101 reduced) were found altered in SSc patients in relation to HD. Unsupervised clustering analyses differentiated 3 patients clusters presenting different proteomic profiles. Clinically, patients belonging to cluster 1 (C1) were characterized by a significant prevalence of multiple organ involvement (84%) in relation to C2 (52%) and C3 (43%), mostly encompassing lung and skin fibrosis and esophageal dysmotility. Immunologically, C1 further displayed the highest percentage of positivity for anti-scl70 antibodies. Nineteen proteins were identified as significantly altered in cluster 1 (C1) in relation to C2 and C3, mostly involved in biological processes such as cell proliferation, apoptosis, cell adhesion, migration, and immune response. Among them, two were functionally linked with cutaneous diseases (CALR and BANK1), two with digestive disorders (FGR and STXBP3) and three with lung disfunction (FOSB, SMAD1 and FOXO1). Levels of some overexpressed proteins in C1 (BID, INPPL1, BANK1 and FOSB) were further related to the positivity for anti-scl70, the specific SSC-autoantibody mostly associated to a bad prognosis and multiple organ involvement in SSC. Interestingly, thirty-five metabolic markers were found deregulated when comparing those proteomic clusters of SSC, comprising lipoprotein subsets, sphingomyelins, cholesterol, lactate, and albumin. Moreover, significant correlations were identified among the levels of proteins and metabolites found deregulated, pointing at a concordance on their involvement in mechanisms underlying the disease process. Conclusion: 1) Serum proteomic and metabolomic signatures are significantly altered in SSC patients and associated to relevant clinical profiles. 2) Clinical classification of SSc patients could be improved based on serum proteomic and metabolomic profile, adding new insights to the underlying pathophysiological mechanisms. Acknowledgements Supported by ISCIII (PI21/0591, CD21/00187 and RICOR-RD21/0002/0033) co-financed by FEDER; Fundación Andaluza de Reumatología. Disclosure of Interests None Declared.