0922: The Multi-Omic Landscape of Systemic Lupus Erythematosus Patients Highlights Metabolic and Immune Pathways Associated with Distinctive Clinical Profiles
IMIBIC/Reina Sofia Hospital/University of Cordoba Córdoba, Spain
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Tomás Cerdó1, Carlos Perez-Sanchez2, Laurel Woodridge3, Mª Angeles Aguirre4, Rafaela Ortega Castro5, Ismael Sánchez-Pareja6, Laura Muñoz-Barrera1, Pedro Segui1, Christian Merlo6, Pedro Ortiz Buitrago7, Desiree Ruiz Vilchez8, Maria del Carmen Abalos-Aguilera8, Pilar Font Ugalde1, Nuria Barbarroja9, Alejandro Escudero10, Elizabeth Jury3 and Chary Lopez-Pedrera11, 1IMIBIC/Reina Sofia Hospital/University of Cordoba, Córdoba, Spain, 2IMIBIC, Córdoba, Spain, 3Centre for Rheumatology Research, Division of Medicine, University College London, London, United Kingdom, 4Reina Sofía University Hospital/ Rheumatology Department, Córdoba, Spain, 5Hospital Reina Sofía, Cordoba, Spain, 6IMIBIC/Reina Sofia Hospital/University of Cordoba, Rheumatology, Córdoba, Spain, 7IMIBIC/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain, 8Rheumatology Department, Reina Sofia University Hospital/Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain, 9University of Cordoba, Córdoba, Spain, 10SAS, Córdoba, Spain, 11IMIBIC - Reina Sofia Hospital, Córdoba, Spain
Background/Purpose: Systemic lupus erythematosus (SLE) poses a significant challenge at the diagnostic and treatment levels due to its severe multisystem nature and notable heterogeneity in clinical course and therapeutic response. We investigated the serum proteomic and metabolomic profiles of SLE, to uncover 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 [proximity extension immunoassay (PEA, Olink)] and 168 serum metabolites, [nuclear magnetic resonance (NMR, Nightingale)] in consecutive SLE patients (n = 135) and age-matched healthy donors (HD) (n = 27). In parallel, an extensive clinical and analytical profile was conducted. To evaluate the contribution of molecular profiles to the disease severity, unsupervised hierarchical clustering analyses were developed.
Results: Fifty-three proteins related to inflammation and organ damage, and 32 metabolites, were significantly altered (p = < 0.05, FC= 1.5, FDR) in the serum of SLE patients compared to HD. Unsupervised hierarchical clustering of proteomic data differentiated 2 patient clusters, where patients belonging to one cluster were characterized by elevated disease activity (SLEDAI >5), and increased incidence of atheroma plaques, dyslipidaemia, and hypertension. The top features driving classification were CD40, PGF, PDL1 and CSF1, with area under the curve >0.9, known to be associated with immune activation. At the molecular level, these patients showed 49 overexpressed proteins (p = < 0.05, FC= 1.5, FDR), enriched in biological pathways linked to chemotaxis and lipid metabolism.
Unsupervised hierarchical clustering of metabolomic data also identified 2 patient clusters with patients in one cluster showing a greater preponderance of lupus nephropathy (LN). The top features driving classification included short chain fatty acids, total fatty acids, total lipids and total free cholesterol, with area under the curve >0.9. Molecularly, these patients showed increased levels of 60 proatherogenic VLDL and LDL subsets (p = < 0.05, FC= 1.5, FDR) and metabolite enrichment analysis identified ketone body and butyrate pathways.
Integrating proteomic and metabolomic patient clusters identified two patient subgroups with the most (N=41) and least (N=36) severe molecular and clinical profiles. The group with more severe profiles ( SLEDAI >5, prevalence of LN, and higher incidence of atheroma plaques, hypertension, and dyslipidaemia) exhibited higher levels of 56 proteins associated with chemotaxis, inflammatory response and cytokine signalling, as well as 53 proatherogenic lipoproteins, (p = < 0.05, FC= 1.5, FDR) confirming the original molecular stratification.
Conclusion: The simultaneous application of proteomic and metabolomic approaches for molecular profiling in SLE patients offers valuable complementary information enabling a more accurate definition of their clinical profile, providing novel therapeutic targets and biomarkers of disease.
Acknowledgements: Supported by ISCIII (PI21/0591, CD21/00187 and RICOR-21/0002/0033) co-financed by FEDER
T. Cerdó: None; C. Perez-Sanchez: None; L. Woodridge: None; M. Aguirre: None; R. Ortega Castro: None; I. Sánchez-Pareja: None; L. Muñoz-Barrera: None; P. Segui: None; C. Merlo: None; P. Ortiz Buitrago: None; D. Ruiz Vilchez: None; M. Abalos-Aguilera: None; P. Font Ugalde: None; N. Barbarroja: None; A. Escudero: None; E. Jury: None; C. Lopez-Pedrera: None.
