Characterization of Genetic Landscape and Novel Inflammatory Biomarkers in Patients With Adult-Onset Still's Disease.
No Thumbnail Available
All Authors
Topping, J.
Chang, L.
Nadat, F.
Poulter, JA.
Ibbotson, A.
Lara-Reyna, S.
Watson, CM.
Carter, C.
Pournara, LP.
Zernicke, J.
LTHT Author
Nadat, Fatima
Watson, Christopher
Carter, Clive
Ross, Rebecca
Cargo, Catherine
Del Galdo, Francesco
Savic, Sinisa
Watson, Christopher
Carter, Clive
Ross, Rebecca
Cargo, Catherine
Del Galdo, Francesco
Savic, Sinisa
LTHT Department
Haematology
Pathology
NIHR Leeds Biomedical Research Centre
Rheumatology
Pathology
NIHR Leeds Biomedical Research Centre
Rheumatology
Non Medic
Clinical Scientist
Clinical Scientist
Clinical Scientist
Clinical Scientist
Clinical Scientist
Publication Date
2025
Item Type
Journal Article
Language
Subject
Subject Headings
Abstract
OBJECTIVE: Adult-onset Still disease (AOSD) is a systemic autoinflammatory disorder (AID) of unknown etiology. Genetic studies have been limited. Here, we conducted detailed genetic and inflammatory biomarker analysis of a large cohort with AOSD to investigate the underlying pathology and identify novel targets for potential treatment.
METHODS: We investigated AOSD cases (n = 60) for rare germline and somatic variants using whole exome sequencing with virtual gene panels. Transcriptome profiles were investigated by bulk RNA sequencing whole blood. Cytokine profiling was performed on an extended patient cohort (n = 106) alongside measurements of NLRP3 inflammasome activation using a custom assay and type I interferon (IFN) score using a novel method.
RESULTS: We observed higher than expected frequencies of rare germline variants associated with monogenic AIDs in AOSD cases (AOSD 38.4% vs healthy controls [HCs] 20.4%) and earlier onset of putative somatic variants associated with clonal hematopoiesis of indeterminate potential. Transcriptome profiling revealed a positive correlation between Still Activity Score and gene expression associated with the innate immune system. ASC/NLRP3 specks levels and type I IFN scores were significantly elevated in AOSD cases compared with HCs (P = 0.0001 and 0.0015, respectively), in addition to several cytokines: interleukin (IL)-6 (P < 0.0001), IL-10 (P < 0.0075), IL-12p70 (P = 0.0005), IL-18 (P < 0.0001), IL-23 (P < 0.0001), IFN-alpha2 (P = 0.0009), and IFNgamma (P = 0.0002).
CONCLUSION: Our study shows considerable genetic complexity within AOSD and demonstrates the potential utility of the ASC/NLRP3 specks assay for disease stratification and targeted treatment. The enriched genetic variants identified may not by themselves be sufficient to cause disease, but may contribute to a polygenic model for AOSD.
Journal
Arthritis & Rheumatology