OP0006 CHARACTERISATION OF GENETIC LANDSCAPE AND NOVEL INFLAMMATORY BIOMARKERS IDENTIFIES NOVEL TREATMENT TARGETS IN ADULT-ONSET STILL’S DISEASE
Authors: L. Chang, J. Topping, F. Nadat, J. Poulter, C. Watson, C. Carter, L. Pournara, J. Zernicke, R. Ross, C. Cargo, F. Del Galdo, J. Rech, B. Fautrel, E. Feist, M. Mcdermott, S. Savic
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Adult-onset Still's disease (AOSD) is a systemic autoinflammatory condition of unknown aetiology. AOSD is presumed to have a polygenic basis but there is genetic and clinical overlap with monogenic autoinflammatory disorders[1]. Genetic studies thus far have been limited and although a role for NLRP3 inflammasome in disease pathogenesis has been postulated, further research is needed to elucidate the precise aetiology. <h3>Objectives:</h3> Here, we conducted detailed genetic and inflammatory biomarker analysis of a large AOSD patient cohort to investigate the underlying pathology and identify novel targets for potential treatment. <h3>Methods:</h3> In this study we included 103 AOSD patients. We performed whole exome sequencing on 60 AOSD cases (at a mean combined read depth of approximately 100×), to identify rare germline variants and somatic mutations from virtual gene panels. Differential gene expression profiles between AOSD cases (n=27) and healthy controls (n=10) were investigated using Bulk RNAseq performed on whole blood. We also conducted cytokine profiling on the full cohort, and measured NLRP3 inflammasome activation using a custom assay and Type I Interferon (IFN) score using a novel method. The genetic landscape and biomarker datasets were compared to test whether there was a cumulative effect of rare genetic variants on the inflammatory disease signature. <h3>Results:</h3> We found a strong genetic association between AOSD (Figure 1), and the presence of rare germline variants (n=106, CADD&gt;15, MAF&lt;1%) and somatic mutations (n=26) within genes associated with monogenic autoinflammatory disorders and clonal haematopoiesis of indeterminate potential. Transcriptome analysis revealed 2834 differentially expressed genes, with significant enrichment in pathways associated with neutrophil degranulation and the innate immune system. Profiling of inflammatory markers (Figure 2) showed significantly elevated ASC/NLRP3 speck levels in AOSD compared to healthy controls (p=0.0001), and AOSD patients with resistant, arthritis predominant disease (p&lt;0.0001). AOSD patients also showed significant elevation in several cytokines: IL-18 (p&lt;0.0001), IL-6 (p&lt;0.0001), IL-23 (p&lt;0.0001), IL-12p70 (p=0.0005), IFNγ (p=0.0002) and IFN-α2 (p=0.0009). Likewise, the Type I IFN score was also significantly higher in AOSD compared to healthy controls (p=0.0015) and other autoinflammatory diseases. <h3>Conclusion:</h3> Our study demonstrated considerable genetic complexity within AOSD and the potential utility of the ASC/NLRP3 speck assay for disease stratification and a potential treatment target. Many enriched variants may not, by themselves, be sufficient to cause disease but could contribute to a polygenic model for AOSD. <h3>REFERENCES:</h3> [1] Giacomelli, R., Ruscitti, P. &amp; Shoenfeld, Y. A comprehensive review on adult onset Still's disease. J Autoimmun 93, 24-36, doi:10.1016/j.jaut.2018.07.018 (2018). <h3>Acknowledgements:</h3> Funding from European Union's Horizon 2020 research and innovation programme (ImmunAID). Prof Sinisa Savic is supported by a senior fellowship from Kennedy Trust. <h3>Disclosure of Interests:</h3> Leon Chang: None declared, Joanne Topping: None declared, Fatima Nadat: None declared, James Poulter: None declared, Christopher Watson: None declared, Clive Carter: None declared, Linda Pournara: None declared, Jan Zernicke: None declared, Rebecca Ross: None declared, Catherine Cargo: None declared, Francesco Del Galdo: None declared, Jürgen Rech Speaker honoraria from BMS, Novartis and SOBI, Consulting fees from BMS, Novartis and SOBI, Research grant form Novartis, and Sobi, Bruno Fautrel Honoraria from AbbVie, Amgen, Biogen, BMS, Celltrion, Fresenius Kabi, Galapagos, Lilly, Medac, MSD, NORDIC Pharma, Novartis, Pfizer, Roche, Sandoz, SOBI, UCB, Viatris, Research grants from AbbVie, Lilly, MSD, Novartis, Pfizer, Eugen Feist Received speaker's honorarium from Pfizer, Abbvie, Lilly, Galapagos, BMS, Sandoz, Novartis, Sobi, Roche, Janssen, Sanofi, UCB, Consultant of: Abbvie, Lilly, Galapagos, Sanofi, Novartis, Grant/research support from: Pfizer, BMS, Roche, Lilly; Novartis, Galapagos, Michael McDermott: None declared, Sinisa Savic Speaker's honorarium Takeda, Novartis, SOBI, BioCryst; Research grants: SOBI, Novartis, CSL Behring, Received honorarium for participating on advisory boards from Novartis, Takeda, BioCryst, KalVista, Celldex Therapeutics, CSL Behring, SOBI, Pharming.