POS0292 MECHANISTIC BASIS FOR THE DISEASE MODIFYING EFFECTS OF BELIMUMAB IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) AND MOLECULAR PREDICTORS OF RESPONSE BY BLOOD TRANSCRIPTOME ANALYSIS: EVIDENCE FOR A ROLE OF THE INNATE IMMUNITY (NEUTROPHILS, COMPLEMENT AND INTERFERON-Α) AND THE DNA DAMAGE RESPONSE
Authors: G. S. Moysidou, P. Garantziotis, M. Grigoriou, D. Nikolopoulos, G. Sentis, D. Nikoleri, A. Filia, M. Nikoloudaki, E. Stergioti, N. Malissovas, N. Kapsala, A. Fanouriakis, G. K. Bertsias, D. Boumpas
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Belimumab has demonstrated disease-modifying effects both in clinical trials and observational studies, however the molecular underpinnings of its effects and their ability to predict early response remain unexplored. <h3>Objectives:</h3> To delineate the immunomodulatory effects of belimumab and identify potential biomarkers of response through a longitudinal, in-depth characterization of the whole blood transcriptome. <h3>Methods:</h3> Whole blood RNA-sequencing was performed in 71 active SLE patients at baseline, 1 and 6 months after belimumab treatment. Treatment response was assessed by the SLE-responder index-4 (SRI-4) and the lupus low disease activity state (LLDAS). DESeq2 was used to detect differentially expressed genes (DEGs) and weighted correlation network analysis (WGCNA) to uncover gene module-traits associations. Abundancies of immune cell types were determined by the CIBERSORTx. SLE susceptibility and severity gene signatures were determined at baseline and after therapy. <h3>Results:</h3> At 6 months, SRI-4 and/or LLDAS were experienced by 60.6% of patients. Belimumab induced widespread changes at the blood transcriptome with a total 286 genes upregulated and 4,702 downregulated compared to healthy controls. Gene modules associated with type I interferon and neutrophil degranulation at baseline predicted attainment of LLDAS at 6 months. This was accompanied by downregulation of the type I and II interferon pathways, complement activation, and SLE "susceptibility" and lupus nephritis gene ("severity") signatures [1] (p value= 0.02); downregulation of the type I interferon gene module was apparent as early as one month after treatment. Patients who did not achieve LLDAS had upregulated pathways linked to DNA damage response and cell metabolism at baseline, and downregulated p53 pathway at 6 months combined with a heightened activation of pathways related to type I interferon and complement activation at 6 months. Of note, no statistically significant correlation was observed between the detected gene modules and the SRI-4 response, indicating that LLDAS, represents a more stringent endpoint that accurately depicts transcriptional aberrations induced by the treatment. <h3>Conclusion:</h3> Molecular fingerprints of innate immunity predict robust clinical response to belimumab, which is associated with reversal of susceptibility and severity signatures consistent with the drug effects on reduction of SLE activity and risk of flares. Dysregulation of the DNA damage response mechanisms combined with unabated interferon-related pathway in non-responders suggest a BAFF-independent mechanism for DNA damage response and interferon induction in these patients. <h3>REFERENCES:</h3> [1] Panousis NI, Bertsias GK, Ongen H, Gergianaki I, Tektonidou MG, Trachana M, Romano-Palumbo L, Bielser D, Howald C, Pamfil C, Fanouriakis A, Kosmara D, Repa A, Sidiropoulos P, Dermitzakis ET, Boumpas DT. Combined genetic and transcriptome analysis of patients with SLE: distinct, targetable signatures for susceptibility and severity. Ann Rheum Dis. 2019 Aug;78(8):1079-1089. doi: 10.1136/annrheumdis-2018-214379. Epub 2019 Jun 5. PMID: 31167757; PMCID: PMC6691930. <h3>Acknowledgements:</h3> This work was supported by an investigator initiated grant by GSK (GSK study number:213662). <h3>Disclosure of Interests:</h3> <b>None declared.</b>