1118: Monocyte Transcriptomic Analysis Uncovers Heterogeneous Gene Expression Profiles in Systemic Lupus Erythematous (SLE) with and Without Subclinical Atherosclerosis

Laurel Woodridge¹, Elvira Chocano Navarro², George Robinson¹, Paul Ashford¹, Kirsty Waddington³, Anisur Rahman⁴, Christine Orengo⁵, Ines Pineda-Torra⁶ and Elizabeth Jury¹, ¹University College London, London, United Kingdom, ²VIHR, Barcelona, Spain, ³University College London (alumni), London, United Kingdom, ⁴Centre for Rheumatology, Department of Medicine, University College London, London, United Kingdom, ⁵ISMB / UCL, London, United Kingdom, ⁶Cabimer, Sevilla, Spain

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.

Disclosures: L. Woodridge, None; E. Chocano Navarro, None; G. Robinson, None; P. Ashford, None; K. Waddington, None; A. Rahman, None; C. Orengo, None; I. Pineda-Torra, None; E. Jury, None.