POS1408 INTEGRATED METABOLOMICS AND PROTEOMICS NETWORK ANALYSIS IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS HIGHLIGHTS METABOLIC AND IMMUNITY PATHWAYS ASSOCIATED WITH DISTINCTIVE CLINICAL PROFILES

Background Systemic lupus erythematosus (SLE) is a severe multisystem disease, notably heterogeneous in terms of clinical course and therapeutic response, which converts it into a significant challenge at the diagnostic and treatment levels. Objectives This study investigated the serum proteomic and metabolomic profiles of SLE, in order to identify new mechanisms underlying relevant clinical patterns. Methods Proteomic and metabolomic approaches were used to assess the serum levels of 184 inflammation and organ damage-related proteins [by proximity extension immunoassay (PEA, Olink)] and 250 metabolic markers [by nuclear magnetic resonance (NMR) covering glycolysis metabolites, amino acids and 130 lipid measures (NMR, Nightingale)] in consecutive SLE patients (n = 133) and age-matched healthy donors (HD) (n = 27). In parallel, an extensive clinical and analytical profile of recruited subjects was performed. To evaluate the contribution of molecular profiles to the disease severity, unsupervised clustering analyses were developed. Results Thirty-six proteins related to inflammation and organ damage, and 17 metabolites were coordinately altered in the serum of SLE patients in relation to HD. Unsupervised clustering analyses differentiated 2 patient clusters (C1 and C2) presenting different proteomic profiles. Clinically, although no differences were found in terms of age or disease duration, patients belonging to C1 were characterized by a significantly higher status of disease activity (SLEDAI > 6) and prevalence of positivity for anti-ENA and anti-dsDNA antibodies than patients belonging to C2, along with a preponderance of patients with biopsy diagnosed lupus nephritis (LN), abnormal creatinine and proteinuria. Besides, this cluster comprised SLE patients with higher CV risk, revealed by an elevated incidence of atheroma plaques, dyslipidemia, and hypertension. Statistical analysis between clusters revealed 67 serum proteins deregulated, among which C1 displayed elevated well-recognized inflammatory cytokines and regulatory proteins of leukocyte activity [(IFN, IL, CSF-1, LIF-R, MCP-1, MCP-4, CCL, CXCL, MMP, PDL, 4E-BP1), accompanied by proteins involved in renal damage (KIM1, LAT2, NPPC, ERBB2IP). Regarding metabolomic profile, comparative analysis between proteome clusters characterized increased levels of proatherogenic VLDL and LDL lipoprotein subsets in C1, and reduced levels of anti-atherogenic HDL lipoproteins subsets, total cholesterol, ketone bodies (acetate) and glycolysis related metabolites (lactate). Interestingly, statistical analyses showed that proteins and metabolites markers correlated significantly, suggesting potential interconnections related to different aspects of lupus pathology. Conclusion The present study showed a multi-omics landscape identifying molecular patterns that distinguished patients with high disease activity and lupus nephropathy, including several novel candidate proteins and metabolites markers. The study of the specific role and suitability of these mediators as SLE biomarkers would provide insights for the management of this complex autoimmune disorder. Acknowledgements Supported by ISCIII (PI21/0591, CD21/00187 and RICOR-RD21/0002/0033) co-financed by FEDER. Disclosure of Interests None Declared.