Background: The profound molecular heterogeneity of SLE remains a fundamental barrier to therapeutic progress. Methods: We integrated clinical and multi-omic profiling, including transcriptomics, autoantigen microarrays, proteomics, and flow cytometry, across three randomised trials (BEAT-Lupus, CALIBRATE, ACCESS) and two observational cohorts to identify distinct lupus endotypes. Findings: Using multivariate distance-based matching of autoantibody profiles to integrate molecular heterogeneity, we identified anti-RNP/anti-Sm co-positivity (RNP+Sm+) as a distinct myeloid-dominant inflammatory endotype. Enriched in patients of Black ancestry (approx. 50%), RNP+Sm+ SLE is characterised by expanded intermediate monocytes showing enhanced TLR4-driven inflammation during flares, elevated pro-inflammatory cytokines (TNF-alpha, IL-6, IL-12, IFN-gamma, CCL2), IFNA10-biased interferon signalling, and systemic metabolic activation. IgG autoantibody profiling confirmed epitope spreading to spliceosomes and novel autoreactivity against circadian-metabolic regulators (SIRT1, NCOA1, SREBF1). Clinically, this endotype manifests as high-grade disease activity (2.5-fold flare risk), nephritis, vasculitis, and enteritis. Hyperferritinaemia correlates with flares exclusively in RNP+Sm+ SLE (r=0.81), reflecting underlying macrophage activation. RNP+Sm+ patients exhibit profound therapeutic resistance: 44% failed first-line immunosuppression (rising to 61% in Black patients), while also showing substantially reduced efficacy (60% lower response) with second-line B-cell-depleting therapies (rituximab, obinutuzumab). Resistance to rituximab therapy was driven by rapid B-cell repopulation, rising BAFF levels, and sustained cytokines despite peripheral depletion. Consequently, they remain heavil