Multi-omic profiling reveals immune and proteolytic remodeling beyond B cells during belimumab therapy in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex, multisystem autoimmune disease driven by dysregulated immune responses, with B cells and plasma cell-derived autoantibodies against nuclear antigens playing central pathogenic roles. Belimumab, a monoclonal antibody targeting B cell-activating factor (BAFF or TNFSF13B), is clinically approved for SLE. However, its broader mechanism of action beyond B cell depletion remains incompletely understood. Here, we present the first longitudinal multi-omics characterization of peripheral blood mononuclear cells (PBMCs) from SLE patients treated with belimumab, with samples collected at baseline and over a 16-month follow-up period. Integrating proteomics, activity-based protease profiling, and single-cell RNA sequencing (scRNA-seq), we identified treatment-associated proteomic changes not only in B cells but also in T cells, NK cells, and monocytes, revealing previously unrecognized immune compartments affected by belimumab therapy. Among the most significantly downregulated proteins was S100A12, a monocyte-derived alarmin previously reported to be elevated in SLE. Downregulation of S100A12 following belimumab treatment was independently validated by ELISA, suggesting a potential indirect immunomodulatory effect on monocyte biology. These findings expand our mechanistic understanding of belimumab beyond B cell-intrinsic effects and nominate S100A12 as a candidate pharmacodynamic biomarker warranting further investigation in future in vitro and clinical studies.