Unveiling Endotypes in Systemic Lupus Erythematosus Through Multi‐Omic Analysis: Insights into Cardiovascular and Renal Complications
Arthritis & Rheumatology, 2026
Cerdó T., Woodridge L., Corrales S., Muñoz‐Castañeda J., Torralbo A., Rahman A., Farinha F., Castro R., Segui P., Sanchez‐Pareja I., Muñoz‐Barrera L., Merlo C., Ruiz‐Vilchez D., Ábalos‐Aguilera M., Font P., Puerto N., Alarcón‐Riquelme M., Escudero‐Contreras A., Aguirre‐Zamorano M., Perez‐Sanchez C., Jury E., Lopez‐Pedrera C.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Immunological & Inflammatory Diseases CVD Nephrology | Pathophysiology Patient Stratification | Cell Culture Supernatant Serum Rat Cell Culture Supernatant |  Olink Target 96 Olink Target 96 Mouse R Reveal |
Abstract
Background
Systemic lupus erythematosus (SLE) shows clinical and molecular heterogeneity, and cardiovascular (CV) complications and lupus nephritis (LN) remain leading causes of morbidity and mortality. This study investigated whether omic profiling can reveal molecular endotypes linked to these outcomes.
Methods
Serum from 199 SLE patients underwent proximity extension assay–based proteomics and targeted NMR metabolomics. Unsupervised clustering was performed on proteomic data, followed by integrative multi‐omics factor analysis, logistic regression, and machine learning models. SLE cohorts from University College London, a subset with expanded Olink‐Reveal panel and untargeted metabolomics, and in vitro (HUVEC, HK2) and ex vivo (rat kidneys) models exposed to patient sera were used for validation and mechanistic exploration.
Results
Proteomic clustering identified two molecular subgroups (Cluster 1 [C1] and Cluster 2 [C2]). Compared with C2, C1 showed damage burden and increased rates of lupus nephritis (1.8‐fold), hypertension (3‐fold), dyslipidemia (2‐fold), obesity (8‐fold), and abnormal CRP/ESR (4‐fold), consistent with CV risk. Forty‐seven inflammatory and organ damage proteins and multiple metabolites were increased in C1. Neural network models based on metabolites and clinical variables discriminated clusters (AUC=0.77), highlighting citrate, and lipoproteins as key features. Multi‐omics analyses and external cohorts confirmed reproducibility and enrichment in pathways related to leukocyte trafficking, endothelial stress, and nephritis. In vitro, serum from SLE patients induced NF‐κB activation in rat kidneys compared with controls, supporting a pro‐inflammatory effect.
Conclusions
Multi‐omic profiling delineates molecular endotypes in SLE integrating immune, vascular, and metabolic pathways associated with CV risk and LN, supporting their potential for precision risk stratification.
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