Background: Precision application of targeted therapies is urgently needed to improve long-term clinical outcomes for children affected by inflammatory arthritis, known as Juvenile Idiopathic Arthritis (JIA). Progress in JIA has been hampered by a lack of understanding of the cellular basis of joint inflammation at the disease site itself.

Objectives: To utilise high-resolution, next-generation sequencing technologies to define the inflammatory landscape of the synovium of children with JIA for the first time.

Methods: We obtained synovial tissue samples in early JIA using minimally invasive synovial biopsy techniques, alongside matched peripheral blood and synovial fluid samples. Tissue analysis was performed by single-cell RNA-sequencing, multiplexed immunofluorescence and spatial transcriptomics.

Results: We identify spatial tissue niches of resident and infiltrating cell populations that define the inflamed synovial tissue architecture. We localise gene signatures of arthritis severity and disease risk to effector cell populations, particularly resident SPP1+ macrophages and fibrin-associated myeloid cells. Combined analyses of matched synovial fluid and peripheral blood reveals differences in cellular composition, signalling pathways and transcriptional programs across these anatomical compartments. Furthermore, our analysis reveals several pathogenic cell populations that are shared with adult-onset inflammatory arthritis, as well as age-associated differences that include increased vascularity, prominence of innate immunity and enriched TGFβ-driven stromal subsets that upregulate expression of disease risk-associated genes in the inflamed paediatric joint.

Conclusion: Overall, our findings demonstrate the need for age-specific analysis of synovial tissue pathology to inform future precision-based treatment algorithms in inflammatory arthritis.

REFERENCES: NIL.

Acknowledgements: We are grateful to all the participants and their parents and families who contributed to this study, and the clinical and study teams who supported recruitment and data collection. We thank Michael Brenner, Helena Jonsson, Fan Zhang, Soumya Raychaudhuri and the AMP RA/SLE network, for their provision of access to the data for analysis and additional supporting information.

Disclosure of Interests: Chrissy Bolton*: None declared, Christopher Mahony: None declared, Elizabeth Clay: None declared, Patricia Ines Reis Nisa: None declared, Søren Lomholt: None declared, Annie Hackland: None declared, Paulynn S Chin: None declared, Charlotte Smith: None declared, Vicky Alexiou: None declared, Huong Nguyen: None declared, Manigandan Thyagarajan: None declared, Zishan Sheikh: None declared, Penny Davis: None declared, Samantha Chippington: None declared, Sunit Davda: None declared, Sandrine Compeyrot-Lacassagne: None declared, Charlene Foley: None declared, Inga Tursevich: None declared, Benjamin Ingledow: None declared, Klaudia Kupiec: None declared, Megan Hanlon: None declared, Edward DiCarlo: None declared, Samantha Smith: None declared, Stephen Eyre: None declared, Samuel Kemble: None declared, Georgiana Neag: None declared, Roopa Madhu: None declared, Mukta G Palshikar: None declared, Ilya Korsunsky: None declared, Gao Ce: None declared, Miles Tran: None declared, Calliope Dendrou: None declared, Christopher D Buckley CBD is one of the founders of Mestag Therapeutics. CDB has received consulting fees from GSK, Roche, AbbVie and Takeda, has received research support from Roche, Janssen and Celsius, Mark Coles For Roche, Founder of Mestag Therapeutics, For Roche and Mestag, From Roche, Karim Raza: None declared, Ellen Gravallese: None declared, Andrew Filer: None declared, Eslam Al-Abadi: None declared, Kevin Wei KW is a consultant for Mestag Therapeutics and Gilead Sciences. KW reports grant support from Gilead Sciences, Merck Sharp & Dome, and 10X Genomics, Elizabeth Rosser: None declared, Lucy Wedderburn Consultancies for Pfizer and Cabaletta unrelated to this work. Research grant funding from Pfizer, AbbVie and SOBI, unrelated to this work, Adam P. Croft: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.