Background: Juvenile dermatomyositis (JDM) is a rare pediatric autoimmune disease characterized by chronic inflammation of muscle and skin. A hallmark of JDM is an elevated interferon (IFN) signature, accompanied by mitochondrial dysfunction, which contribute to disease severity. Despite these insights, the spatial and cell-specific mechanisms underlying JDM pathogenesis remain poorly understood.

Objectives: This study leverages spatial transcriptomics to dissect the in-situ molecular landscape of muscle tissue in JDM, focusing on defects in the IFN and mitochondrial pathways.

Methods: Muscle biopsies from three JDM patients and three healthy controls were analyzed using the GeoMx Digital Spatial Profiler. The regions of interest (ROIs) selected encompassed muscle regions, immune-infiltrated muscle areas, and CD68+ macrophage-enriched regions. Differential gene expression (DGE) analysis, pathway enrichment analysis and pathway clustering were performed to uncover molecular patterns associated with JDM.

Results: Muscle tissue from JDM patients exhibited 448 differentially expressed genes, with significant enrichment in IFN and mitochondrial pathways. IFN expression was consistently elevated across all JDM ROIs, suggesting pervasive inflammation. In contrast, mitochondrial markers displayed region-specific expression patterns. DGE analysis revealed distinct transcriptomic based on clinical muscle strength, as weaker patients exhibited heightened IFN expression. Notably, mitochondrial dysfunction was evident in all patients, regardless of muscle strength, suggesting a fundamental role in JDM pathology.

Conclusion: Spatial transcriptomics provides novel insights into the molecular mechanisms of JDM, emphasizing the critical roles of IFN and mitochondrial pathways. These findings offer potential biomarkers and therapeutic targets. Future studies utilizing single-cell spatial approaches could further elucidate cell-specific contributions to JDM pathology.

REFERENCES: NIL.

Acknowledgements: The Juvenile Dermatomyositis Cohort Biomarker Study and Repository (JDCBS).

Disclosure of Interests: Aris Eleftherios Syntakas: None declared, Melissa Kartawinata: None declared, Huong Nguyen: None declared, Charalampia Papadopoulou: None declared, Muthana Al-Obaidi: None declared, Clarissa Pilkington: None declared, Yvonne Glackin: None declared, Ashirwad Merve: None declared, Olumide Ogunbiyi: None declared, Lucy Wedderburn Pfizer Inc, Pfizer Inc, Cabaletta Bio Inc, AbbVie, Sobi, Lilly, Meredyth Wilkinson: 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.