OP0148 METABOLOMICS IN JUVENILE-ONSET SLE: IDENTIFYING NEW BIOMARKERS TO PREDICT CARDIOVASCULAR RISK
Authors: George Robinson, Anna Radziszewska, Chris Wincup, Coziana Ciurtin, Yiannis Ioannou, Ines Pineda Torra, Elizabeth Jury
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Juvenile-onset systemic lupus erythematosus (JSLE) is an autoimmune disorder characterised by immune dysregulation, chronic inflammation and increased cardiovascular risk (CVR). Cardiovascular disease is the leading cause of mortality in JSLE not attributable to lupus flare. Our findings in adult-onset SLE link immune cell dysregulation with dyslipidaemia but little is known about the immune profile or whether abnormal lipid metabolism contributes to disease pathogenesis in JSLE. <h3>Objectives</h3> The objective of this study was to investigate dyslipidaemia and CVR in a cohort of JSLE patients using in depth metabolomics and relate this to clinical and immune cell profiles and to identify novel biomarkers to predict CVR in these patients. <h3>Methods</h3> Metabolic biomarker analysis (NMR) and in-depth immune cell phenotyping (30 subsets by flow cytometry) was performed on serum and PBMCs respectively from a discovery cohort of 35 JSLE patients (median age 19 (14-25), 12 males, 23 females) compared with 39 age/sex matched healthy donors (HCs) (median age 18 (16-25), 17 males, 22 females). Data was analysed using cluster and correlation-correlation and receiver operating characteristic (ROC) analysis. Results were validated in a second cohort of 31 JSLE patients. <h3>Results</h3> Patient stratification by metabolomic profile using unbiased hierarchical clustering revealed 3 groups that each had a unique lipoprotein profile, immune cell phenotype and clinical presentation. Group-1 had decreased atheroprotective high density lipoproteins (HDL) and increased atherogenic very low and low density lipoproteins (VLDL/LDL) and Group-2 had elevated HDL but reduced VLDL/LDL indicating that these groups could be at high and low CVR respectively. This hypothesis was validated by previously recognised markers of CVR including the atherogenic index of plasma, ApoB:A1 ratios and lipid biomarkers we previously identified to be associated with pre-clinical atherosclerotic plaque in adult SLE patients. Patients in Group-1 had a significant increase in plasmablasts and activated T-cells compared to HCs and had clinical features associated with increased disease activity. These immunopathogenic properties were not seen in low CVR Group-2. Patients in Group-3 displayed an intermediate CVR but a pro-inflammatory immune cell profile. This metabolomic patient stratification was validated in a separate JSLE cohort. Importantly ApoB:A1 ratio was identified as a highly predictive biomarker (ROC area under the curve&gt;0.99) distinguishing between JSLE patients in Group-1 and 2, indicating high and low CVR respectively. Finally, longitudinal analysis revealed that the ApoB:A1 ratio biomarker remained stable over time. <h3>Conclusion</h3> ApoB:A1 ratio and metabolomic lipoprotein signatures could be new biomarkers to predict CVR in JSLE patients. Patient stratification using these biomarkers could provide an opportunity for tailored disease treatments using lipid modification therapy and/or diet/lifestyle interventions. <h3>References</h3> [1] Kone-Paut, I., et al., Lupus in adolescence. Lupus, 2007. 16(8): p. 606-12. [2] Ambrose, N., et al., Differences in disease phenotype and severity in SLE across age groups. Lupus, 2016. [3] McDonald, G., et al., Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients. J Clin Invest, 2014. 124(2): p. 712-24. [4] McMahon, M., et al., Dysfunctional proinflammatory high-density lipoproteins confer increased risk of atherosclerosis in women with systemic lupus erythematosus. Arthritis &amp; Rheumatism, 2009. 60(8): p. 2428-2437. <h3>Acknowledgement</h3> Rosetrees Trust, Lupus UK, Versus Arthritis <h3>Disclosure of Interests</h3> None declared