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Objectives The metabolic state of immune cells is emerging as a critical checkpoint of their effector functions. Previously described transcriptomic data in SLE patients and murine lupus models suggested significant alterations in the metabolic profile of lupus immune cells, but there is lack of single-cell data confirming the changes at the protein level. The aim of this study was to create a detailed immunometabolic profiling at the single-cell level in different stages of lupus disease activity and in ANA+ individuals at risk of developing SLE.Methods Blood samples were obtained from patients from high disease activity SLE (n = 20), low disease activity SLE (n = 23), Sjogren’s Disease (n = 9), Rheumatoid Arthritis (n = 7), age- and sex-matched healthy donors (n = 17), at-risk individuals before (n = 23) and after (n = 23) developing SLE, and at-risk individuals (n =23) who never progressed to SLE. Cryopreserved human peripheral blood mononuclear cells (PBMCs) were thawed and subsequently stained with 50 distinct heavy metal-conjugated antibodies before they were processed by mass cytometry (CyTOF). Raw data were normalised and debarcoded following computational analysis.Results Principal analysis identified 36 distinct cellular components and 6 key metabolic pathways (glycolysis, OxPHOS, PPP, TCA & ETC, fatty acid metabolism, amino acid metabolism). Cellular composition was significantly different among the patient groups with plasmablast expansion being a key element within the high disease activity SLE and the at-risk individuals who progressed to SLE. There were significant differences in the expression of the metabolic enzymes among different cellular components within the same individual. Patients with SLE were characterised by upregulation of glycolysis and OxPHOS pathways, distinct from RA. Cellular and metabolic changes were observed in at-risk individuals highlighting an early immunometabolic reprogramming prior to the development of clinically overt autoimmune disease.Conclusions We identified immunometabolic changes at the single-cell level, which can influence immune function, associated with disease activity in SLE and related diseases. Further, this immunometabolic reprogramming preceded clinically overt SLE or therapy suggesting a fundamental role in pathogenesis. Future analysis will explore the effect of these changes on longitudinal immune function and clinical status.