Background/Purpose: Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by marked clinical variability, which complicates both diagnosis and treatment. Among its most severe manifestations are cardiovascular (CV) complications and lupus nephritis (LN), both of which are associated with increased morbidity and mortality. Conventional biomarkers often fall short in capturing the molecular intricacies of these conditions, highlighting the need for integrative multi-omic strategies.

Methods: In this study, proteomic and metabolomic analyses were combined to uncover molecular signatures linked to CV risk and LN. Serum samples from 199 SLE patients were examined using proximity extension assays for proteomic profiling and nuclear magnetic resonance (NMR) spectroscopy for metabolomic analysis. In vitro assays were performed by treating HUVECs and HK2 cells with serum from SLE patients to assess endothelial and renal proteomic responses. Ex vivo experiments involved culturing rat kidney slices with the same sera to evaluate inflammatory signalling through p65 immunofluorescence.

Results: Unsupervised clustering based on proteomic data identified two patient subgroups: one with high disease severity (HDS) and another with low disease severity (LDS). The HDS group showed increased levels of inflammatory proteins (e.g., IL6, CD40, CXCL9) and metabolites (e.g., creatinine, citrate), which were associated with CV risk and renal involvement. Using machine learning, patients were accurately classified into HDS and LDS groups (AUC = 0.77), with biomarkers such as citrate and LDL subclasses playing a key role.These results were validated in an independent patient cohort, confirming the robustness of the identified molecular patterns. In vitro assays revealed that serum from HDS patients induced endothelial dysfunction in HUVECs and triggered inflammatory responses in HK2 kidney cells, including the upregulation of proteins involved in tissue damage and immune activation. Furthermore, ex vivo experiments using rat kidney slices demonstrated NF-κB pathway activation in tissues exposed to HDS serum.

Conclusion: Overall, this study provides compelling evidence that CVS risk and LN in SLE are associated with distinct proteomic-metabolomic signatures that reflect underlying disease mechanisms. The integration of omics data with functional assays offers valuable insights into the molecular drivers of organ-specific damage in SLE. These findings might pave the way for biomarker-driven diagnostic tools and personalized therapeutic strategies based on patient stratification, aiming to mitigate disease-related complications.Supported by ISCIII (PI24/00959, CD21/00187 and RICOR-24/0007/0019), co-financed by European Union, and MINECO (RYC2021-033828-I/PID2022-141500OA-I00).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/endotype-discovery-in-systemic-lupus-erythematosus-using-multi-omic-approaches-toward-precision-insights-into-cardiovascular-and-renal-damage/