Progression from at-risk state to clinical and severe systemic lupus erythematosus involves molecular dysregulations potentially reversible by biologics: implications for early diagnosis and treatment

OBJECTIVES: Understanding the molecular events underlying systemic lupus erythematosus (SLE) onset and progression can facilitate early intervention strategies. We explored transcriptomic changes during progression from preclinical to clinical and advanced SLE, and assessed their potential reversibility by targeted agents. METHODS: This includes multicentre prospective study of individuals with nondiagnostic features suggestive of SLE. Baseline blood RNA-sequencing was performed in groups who progressed to classifiable SLE or not (n = 36 each), and compared with healthy (n = 42) and early SLE (n = 43). Transcriptome analysis included supervised methods, gene module-based clustering, and drug reversibility/repurposing pipelines with publicly available data. An independent at-risk cohort (n = 15 progressors, n = 20 nonprogressors) was used to validate molecular classifiers. RESULTS: At-risk individuals exhibited deregulated metabolic, cytokine signalling, haematologic, and stress-response pathways. Progressors vs nonprogressors showed heightened interferon (IFN)-alpha (α)/gamma (γ) and inflammatory cytokine activity, corroborated by Gene Set Enrichment Analysis and coexpression analysis, and intensified during SLE classification. Unsupervised modelling of gene module-eigengene patterns revealed molecular heterogeneity among progressors, differing in p53/insulin activity and Toll-like receptor (TLR) signalling. Importantly, we characterised a 17-gene susceptibility signature that predicted transition with an area under the curve 0.80 of the receiver operating characteris (95% CI: 0.65-0.94) in the external cohort. Analysis across the continuum-from healthy and at-risk states to early SLE and lupus nephritis-revealed stepwise upregulation of IFN-α/γ, haem metabolism, and oxidative phosphorylation pathways, with additional IFN-related genes activated in established disease. SLE susceptibility and progression signatures demonstrated in silico reversibility by anifrolumab and belimumab. CONCLUSIONS: IFN-α/γ and inflammatory cytokine signatures characterise evolving/early SLE, whereas amplification of IFN signalling and oxidative phosphorylation denotes severity. Blood molecular profiling may aid risk stratification and rationalise early biologic approaches.