O13 Innate immunity transcriptional profiles as potential predictive biomarkers for treatment response in systemic lupus erythematosus: Insights from a longitudinal study

Background Systemic Lupus Erythematosus (SLE) is a prototypic, systemic autoimmune disease that can affect many organs. Current treatment of SLE is largely empirical, while the existing immunosuppressive treatments fail to induce remission in over 40% of patients. Methods Whole blood transcriptome samples were obtained from 95 patients with moderate to severe SLE at baseline, 1 month and 6 months after initiation of treatment with cytotoxic agents (cyclophosphamide, mycophenolate mofetil), mycophenolate mofetil/anti-CD40 antibody, rituximab or belimumab. Disease activity was assessed using the SLEDAI-2K. Response to treatment was defined as achievement of Low Disease Activity State (LLDAS) or remission at 6 months. Differentially expressed genes (DEGs) were identified using the DEseq2. Weighted correlation network analysis (WGCNA) was applied to detect modules of co-expressed transcripts. Abundances of cell types were assessed by CIBERSORTx. Results 95 patients were enrolled in our study. Most of the patients were women (93.7%) with a mean SD age at SLE diagnosis of 42.9 13.6 years and a mean disease duration SD at sampling of 5.1 7.2 years. Cyclophosphamide was the most frequently used immunosuppressive agent (n=46), followed by belimumab (n=24) and rituximab (n=21). 43 patients responded to treatment. Transcriptional disturbances related to type I interferon signaling (p=0.04, r= 0.15) and leukocyte chemotaxis (p=0.005, r=0.21) positively correlated with response to treatment at 6 months. Enrichment of processes linked to complement activation and PI3KK/Akt pathway distinguishes active Lupus Nephritis (LN) responders from LN non-responders at baseline. Gene expression signatures indicative of cell cycle checkpoint regulation and humoral immunity emerged as potential determinants of resistant disease 6 months after treatment initiation. Marked reduction in the naïve B cell compartment uniquely characterized successful response induction, while the neutrophilic fraction exhibited a statistically significant reduction upon treatment, irrespective of the 6-month outcome. Conclusions Baseline transcriptional signatures related to innate immunity correlated with 6-month response to treatment in SLE. Disturbances linked to cell cycle regulation decisively shaped the transcriptional landscape of 'resistant' disease. Acknowledgements This work was supported by grants from EU (SYSCID grant agreement number 733100), ERC (LUPUSCARE grant agreement number 742390), FOREUM all to DTB.