Background/Purpose: Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are autoimmune diseases with overlapping yet distinct immunopathologies. Proteomic profiling of soluble plasma factors can reveal disease- and ancestry-specific immune dysregulation. Using RA as a disease control, we investigated ancestry-specific plasma proteomic signatures in SLE to elucidate unique pathways contributing to disease pathogenesis.

Methods: Serum samples from 90 female participants (SLE=30, RA=30, healthy controls=30) stratified by ancestry-Black, First American, and White were analyzed using the Olink Explore HT assay, quantifying over 5,000 proteins. Differential expression and pathway enrichment analyses were performed with false discovery rate correction (FDR < 0.05) to identify ancestry- and disease-specific proteomic alterations.

Results: Proteomic profiles distinctly separated SLE, RA, and healthy controls, with notable ancestry-associated differences (Figure). In SLE, all ancestries demonstrated increased lipid and vesicle-mediated transport pathways; however, First American patients uniquely exhibited lipid metabolic dysfunction. Black patients showed increased myeloid activity, including neutrophil degranulation and migration pathways. White patients displayed dysregulated protein degradation and nucleotide modification pathways, particularly involving nuclear proteins and SUMOylation. Notably, First American SLE patients had significantly elevated B-cell activation pathways, consistent with heightened interferon hypersensitivity and cellular frequency data. Using RA as a disease control, we observed that Black RA patients had pronounced upregulation of vesicle-mediated transport pathways compared to SLE. Additionally, White RA patients showed downregulation of connective tissue-related pathways and First American RA patients exhibited neuronal and vascular system pathway alterations. Across diseases, Black patients demonstrated predominant dysregulation of innate immune pathways, whereas White and First American patients showed more adaptive immune system involvement.

Conclusion: Ancestry shapes plasma proteomic landscapes in SLE and RA, with distinct immune and metabolic pathways differences. The use of RA as a disease control underscores unique SLE-specific proteomic signatures, particularly in lipid metabolism and B-cell activation among First American patients and myeloid-driven inflammation in Black patients. These results emphasize the importance of integrating ancestry and disease context in proteomic analyses to inform personalized therapeutic strategies in autoimmune diseases.

. A, Heatmap of top predictors revealing distinct soluble proteomic profiles among different ancestries between rheumatic disease and healthy controls. B, UMAPs based on Olink Explore HT Assay highlighting distinct soluble proteomics between two rheumatic diseases (RA and SLE) and healthy controls. C, Volcano plots showing the differentially detected proteins (DEP) between RA and SLE and healthy controls in different ancestries. D, Heatmaps of gene set enrichment analyses based on DEPs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/first-american-sle-patients-demonstrate-enhanced-lipid-metabolism-and-b-cell-activation-by-high-content-proteomic-analyses/