Type I interferon endotypes drive divergent clinical trajectories in childhood-onset SLE uncovered through a novel systems immunology approach

OBJECTIVES: Childhood-onset systemic lupus erythematosus (cSLE) is a severe autoimmune disease with significant morbidity and enhanced type I interferon (IFN-I) signalling, potentially contributing to its aggressive clinical course. This study aimed to deliver the most comprehensive multiomic characterisation of IFN-I signalling in cSLE, defining its heterogeneity at transcriptomic, proteomic, and cellular levels, and linking these profiles to detailed clinical trajectories. METHODS: We profiled 74 young females with cSLE and 20 matched controls using RNA-sequencing of peripheral blood mononuclear cells, single molecule array (SIMOA) for IFNα quantification, IFN-I luciferase reporter cells, spectral flow cytometry, and Olink proteomics (validated by enzyme-linked immunosorbent assay, (ELISA)). Clinical data were assessed in endotype groups based on IFN-I readouts with longitudinal trajectory analysis, and clustering reproducibility was tested in independent validation cohorts. RESULTS: Gene expression analysis revealed significantly upregulated genes in cSLE with strong IFN-I pathway enrichment. Patients clustered into IFN-high (65%) and IFN-low (35%) groups, independent of disease activity. IFN-high patients showed elevated IFNα, reporter cell activity, reduced lymphocyte counts, and greater in vitro response to anifrolumab. LAMP3 emerged as a stable and reproducible biomarker of IFN-high status. T cells and plasmacytoid dendritic cells were most sensitive to IFN-I ex vivo, with distinct functional marker profiles. Integrated transcriptomic, proteomic, and cellular data defined 6 IFN-driven endotypes with unique immune signatures and clinical phenotypes. Endotypes differed in IFN-I activity, organ damage, flare burden, and corticosteroid exposure with divergent longitudinal trajectories. CONCLUSIONS: Multilevel IFN profiling revealed an important biomarker of IFN-high patients for potential use in clinical practice, immune lineage-specific responses, and clinically meaningful endotypes, supporting systems immunology approaches and biomarker-guided personalised treatment strategies.