NOVEL IgG AND IgA AUTOANTIBODIES IN TWO INDEPENDENT COHORTS ASSOCIATE WITH GLOBAL AND ORGAN-SPECIFIC DISEASE ACTIVITY IN SYSTEMIC LUPUS ERYTHEMATOSUS: IMPLICATIONS FOR ANTI-LIN28A AND ANTI-IRF5

O050 / #258 Topic: AS20 - Precision Medicine ABSTRACT CONCURRENT SESSION 08: RECENT ADVANCES IN LUPUS BIOMARKERS 23-05-2025 1:40 PM - 2:40 PM Background/Purpose Autoantibodies are a hallmark of systemic lupus erythematosus (SLE), but among a multitude of autoantigen specificities, few are mapped and used in routine clinical practice. Autoantibodies currently used for surveillance, such as anti-dsDNA, show only modest associations with SLE disease activity. The aim of this study was to identify and validate novel autoantibodies that reflect global and organ-specific disease activity in systemic lupus erythematosus (SLE). Methods Serum samples were screened for IgG and IgA seroreactivity against 1609 protein autoantigens using an immunome microarray (Sengenics). We determined differentially abundant autoantibodies (daAAbs) in SLE patients vs healthy controls within a discovery (n=199 vs n=111) and an independent validation cohort (n=30 vs n=84) from the European PRECISESADS project (NTC02890121). Validated daAAbs were analyzed in relation to global and organ-specific disease activity using linear and logistic regression, along with daAAb target pathway enrichment analysis. Results We validated 89 IgG and 66 IgA daAAbs. IgG anti-LIN28A, IgG anti-HMGN5, and both isotypes for anti-IRF5 and anti-TGIF1 were associated with a SLE Disease Activity Index 2000 (SLEDAI-2K) score ≥10, negatively associated with Lupus Low Disease Activity State (LLDAS), and highly prevalent in patient subgroups with active disease across organ manifestations. IgG anti-LIN28A levels exceeded the cut-off for positivity in 53% of patients with CNS involvement, a prevalence higher than that observed for anti-dsDNA (20%), and 47% of patients with renal activity. A cluster of IgG and IgA daAAbs against RNA-binding proteins, including anti-LIN28A, was predominantly represented in patients with CNS activity. IgA anti-FOSL2 was associated with musculoskeletal activity. Enriched pathways related to DNA binding and repair exhibited considerable overlap across organ systems. Conclusions This study identified and validated novel IgG and IgA autoantibodies. Among those, IgG anti-LIN28A, IgG anti-HMGN5, and both isotypes for anti-IRF5 and anti-TGIF1 were associated with high disease activity and were highly prevalent in subgroups of patients with active disease across organ manifestations. IgG anti-LIN28A levels exceeded the cut-off for positivity in more than half of the patients with CNS involvement, a prevalence higher than that observed for the routine clinical marker anti-dsDNA, and almost half of the patients with renal activity. Additionally, IgG and IgA LIN28A formed autoantibody clusters predominantly represented in patients with CNS activity. The findings of IgA seroreactivity are novel and point to the importance of mucosal immunity in SLE, while the overall findings have direct implications for the early identification of patients with active or evolving disease, and for timely and informed therapeutic intervention.