Background/Purpose: A leading cause of mortality in SLE is cardiovascular disease (CVD) through accelerated atherosclerosis: the build-up of cells and lipids in the vascular wall.

Methods: Subclinical atherosclerotic plaques were detected by vascular ultrasound scanning in women with SLE. Molecular profiles of patients with (SLE-P, N=13) and without (SLE-NP, N=7) plaques were investigated using monocyte RNA-sequencing and bioinformatics analysis.

Results: Monocyte gene expression profiles of SLE-NP women were defined by pathways implicated in inflammation and immune-response, including cytokine signalling, that have known involvement in SLE pathology. The elevated inflammatory signal in SLE-NP patients overlapped with gene expression in monocytes and inflammatory and interferon-inducible aortic macrophages, supporting the involvement of chronic inflammation in both SLE and CVD. However, SLE-P women had a comparatively dampened inflammatory signature compared to SLE-NP, including genes involved in cell proliferation and cytokine production/signalling. Interferon response was heterogeneous across SLE-P and SLE-NP groups and applying an interferon-targeting clinical trial (Anifrolumab) 4-gene signature (IFI44, IFI44L, RSAD2 and IFI27) uncovered two distinct endotypes (p= 1.06^-4) that could not be explained by differences in routine disease measures or known clinical predictors. However, this did not predict atherosclerosis, and 86% of patients with low interferon response had subclinical atherosclerosis. Notably atherosclerotic burden was positively correlated with interferon score in SLE-P patients (plaque thickness p=0.027, r=0.709; length, p=0.003, r=0.855; and number of plaques, p=0.008, r=0.794) suggesting the anti-inflammatory gene signature in SLE-P may be lost as atherosclerosis progresses. Strikingly, lipid metabolism – a key driver of atherosclerosis pathology – was upregulated in SLE-P patients including pathways such as fatty acid biosynthesis and apoptosis. Transcription factor analysis uncovered genes downregulated by Liver-X nuclear receptor, a nuclear receptor regulating lipoprotein metabolism and cholesterol transport. Finally, lipid-associated genes responsive to Fluvastatin (lipid-modulating) treatment were oppositely regulated in SLE-P.

Conclusion: Heterogeneous gene expression profiles in SLE with atherosclerosis revealed dampened inflammation and lipid dysregulation. This presents an exciting opportunity for improved patient stratification using a personalised medicine approach to identify patients that could benefit from anti-inflammatory and lipid-targeting treatments that have shown mixed efficacy in SLE to date.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/monocyte-transcriptomic-analysis-uncovers-heterogeneous-gene-expression-profiles-in-systemic-lupus-erythematous-sle-with-and-without-subclinical-atherosclerosis/