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Introduction Early and accurate SLE diagnosis is critical to identify and treat inflammatory organ manifestations before irreversible organ damage occurs. Conventional serological tests (anti-double-stranded DNA (anti-dsDNA), anti-Smith) and complement biomarkers (C3/C4) lack sensitivity in early disease, contributing to diagnostic delays. We conducted systematic analysis of a Multianalyte Assay Panel (MAP) index which integrates cell-bound complement activation products (CB-CAPs) with conventional markers to evaluate its diagnostic performance across diverse US clinical cohorts.Methods Biomarker data from studies conducted between 2011 and 2025 were analysed for 3132 individuals: 1210 who met the 1997 American College of Rheumatology (ACR) classification criteria for SLE, 687 healthy controls and 1235 disease controls. CB-CAPs were measured by semiquantitative flow cytometry; autoantibodies by ELISA; complement C3/C4 by immunoturbidimetry. Diagnostic ORs (DORs), likelihood ratios (LRs) and sensitivity/specificity were calculated. Sensitivity between the algorithm and conventional serological and complement tests was compared within the SLE cohort.Results Against healthy controls, the MAP index demonstrated the strongest diagnostic accuracy (DOR=105.0) compared with CB-CAPs alone (56.8), anti-dsDNA/Smith (31.8) and complement C3/C4 (8.2). Against disease controls, performance of CB-CAPs alone, anti-dsDNA/Smith and C3/C4 remained superior (DOR=22.3 vs 20.3, 13.7 and 8.8). The MAP index yielded the highest LR+ (33.7) and lowest LR– (0.3). Within the SLE cohort, the MAP index showed higher sensitivity than anti-dsDNA (OR=27.5), B lymphocyte-bound C4d (20.8) and erythrocyte-bound C4d (14.6) (all adjusted p<0.001). Integration of the algorithm identified 24.5% more SLE cases than conventional markers (serologies and complement), reducing the proportion of patients with negative serologies and normal complement from 52.0% to 27.5%.Conclusions The MAP index integrating CB-CAPs demonstrated markedly superior diagnostic accuracy and generalisability compared with conventional serological tests alone. Its enhanced sensitivity and specificity address key diagnostic gaps, supporting an earlier more definitive SLE diagnosis with potential for earlier intervention, prevention of organ damage and improved long-term outcomes.