Mapping the plasma proteomic architecture of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterised by autoantibodies to nuclear antigens. SLE is highly heterogeneous, both clinically and immunologically, yet the molecular basis underlying this remains incompletely understood. To address this, we profiled the plasma proteome in 260 SLE patients and 86 healthy volunteers (HVs) using the SomaScan v4.1 platform, quantifying 7,288 analytes corresponding to 6,595 unique proteins. We identified 215 proteins that were robustly differentially abundant between SLE patients and HVs in both discovery (n=207 SLE, n=45 HVs) and validation sets (n=53 SLE, n=41 HVs). Within-cases analyses identified 421 proteins associated with disease activity. Network-based clustering delineated correlated protein modules, including an interferon-associated module and a renal-associated module, each linked to distinct clinical features. Autoantibody-stratified analyses further uncovered distinct proteomic endotypes: anti-Sm positivity was associated with increased interferon-stimulated protein levels (e.g., MX1, ISG15, CXCL10) and reduced circulating small ribonuclear proteins, independent of disease activity. Anti-dsDNA antibodies were associated with elevated levels of CD40 ligand (CD40LG) and the neutrophil protease proteinase-3. Moreover, we identified an association between CD40LG and disease activity specific to the anti-dsDNA positive subgroup. Together, these data define plasma protein signatures of SLE and disease activity, highlight autoantibody-specific molecular phenotypes, and provide a basis for precision medicine.