Background: Erdheim-Chester disease (ECD) is a rare histiocytic disorder with diverse clinical manifestations. Genetic alterations are recognized as pivotal drivers of disease development. However, the underlying pathogenic mechanisms remain largely unknown. Understanding the role of epigenetic modifications and gene expression dysregulation is critical for elucidating the molecular basis of ECD.

Objectives: This study aimed to identify novel molecular mechanisms involved in ECD through the first integrated methylome and transcriptome analysis ever performed in this disease.

Methods: Peripheral blood samples were collected from 137 ECD patients and 410 controls. The diagnosis of ECD wad made in accordance with the 2020 Guideline criteria. Methylome and transcriptome analyses were performed, followed by functional in silico analyses using different online bioinformatics tools, such as EWAS toolkit and Gene Ontology Resource. Subsequently, methylome and transcriptome data were integrated, and a drug repurposing analysis was performed.

Results: Our case-control study identified 2,511 differentially methylated positions (DMPs) and 1,484 differentially expressed genes (DEGs) associated with ECD. Functional enrichment analyses uncovered novel immune cell types, such as B cells, as well as various immune and tumorigenic molecular pathways, that could be implicated in disease development. In addition, our findings reaffirmed the involvement of established mechanisms, such as the mTOR and MAPK/ERK signaling pathways, in disease pathogenesis. Furthermore, the integrative analysis highlighted significant interactions between DMPs and DEGs, identifying key genes implicated in cell division, immune regulation, and tumorigenesis. Notably, DNA methylation changes were correlated with altered expression levels of LRRC14, a negative regulator of Toll-like receptor-mediated NF-kappaB signaling, which is crucial for immune responses, inflammation, and cell survival. Besides, drug repurposing analyses proposed potential therapeutic agents for ECD, including fostamatinib and auranofin, both of which target IKBKB, a key component of the NF-kappaB signaling cascade.

Conclusion: This study provides key insights into ECD pathogenesis through the first integrative epigenomic and transcriptomic analysis in this condition. Our results highlight disruptions in various neoplastic and inflammatory pathways, identifying B cells and NF-kappaB signaling as relevant factors to disease progression, and revealing IKBKB as a therapeutic target with existing drug options.

REFERENCES: NIL.

Acknowledgements: We thank Sofia Vargas for her excellent technical assistance, the PRECISESADS consortium for providing the control data and all the patients and control donors for their essential collaboration. M.C.M. is recipient of a Juan de la Cierva fellowship (JDC2022-048561-I) from Ministry of Science, Innovation, and Universities.

Disclosure of Interests: 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.