OA34 Unravelling the role of B cells and interferon dysregulation in juvenile dermatomyositis
Authors: Syntakas Aris E K , Nguyen Huong D , Restuadi Restuadi , Jebson Bethany R , Alexiou Vicky , Marshall Lucy R , Ralph Elizabeth , Brien Kathryn O’ , Cancemi Dario , Peckham Hannah , Radziszewska Anna , De Gruijter Nina , Hall George T , Castellano Sergi , Ciurtin Coziana , Deakin Claire T , Rosser Elizabeth , Wedderburn Lucy R , Kartawinata Melissa , Wilkinson Meredyth G L ,   and on behalf of the UKJuvenile Dermatomyositis Cohort and Biomarker Study (JDCBS), and the Centre for Adolescent Rheumatology VersusArthritis at UCL, UCLH and GOSH
Published: April 2024

Abstract

Background/Aims
Juvenile dermatomyositis (JDM) is a rare childhood autoimmune disease, characterised by muscle inflammation and skin rash. At present, the exact mechanisms driving JDM pathogenesis remain unclear. Recent investigations have focused on the potential roles of interferon (IFN) dysregulation and B cells. This study aims to explore alterations in B cell populations and their association with disease severity and IFN pathway dysregulation in JDM patients.

Methods
Transcriptomic, flow cytometry, and clinical data were gathered from a cohort of 61 JDM patients recruited from the UK JDCBS. Clinical demographics and disease variables were extracted from the JDCBS database. Flow cytometry was utilised to examine B cell populations in treatment naïve (‘pre-treatment’ n = 48) and JDM patients on steroids and conventional DMARD treatment, including rituximab (on-treatment n = 24), in parallel with age-matched healthy donors (n = 35). Transcriptomic analysis was performed on the total CD19+ B cells to assess their gene expression profiles in JDM patients. Pathway enrichment analysis was applied to identify the involvement of IFN-related pathways in JDM pathogenesis.

Results
Flow cytometry analysis revealed a significant expansion of total B cells, (defined as CD19+, p &lt; 0.0001, ANOVA) and immature B cells (defined as CD19+ CD24hi CD38hi, p = 0.0416, Kruskal-Wallis) in pre-treatment JDM patients compared to healthy controls, which returned to levels similar to those in healthy donors in on-treatment JDM patients. An inverse relationship between total B cells and the Childhood Myositis Assessment Scale (CMAS), a measure of muscle strength, was observed in pre-treatment JDM patients, indicating a connection between the expanded B cell population and worse disease. Transcriptomic analysis of B cells illustrated distinctive clustering between pre-treatment JDM patients and healthy controls, based on their type I IFN gene expression profiles. Pathway enrichment analysis confirmed the significant enrichment of IFN-related pathways in B cells of pre-treatment JDM patients.

Conclusion
This study validates previous observations (Piper et al., 2018) supporting a significant role of B cells in the pathogenesis of JDM and their association with IFN dysregulation. Notably, pre-treatment JDM patients exhibited an expansion of the total B cell population, and of immature B cells, which correlated with disease activity and were restored to normal levels with treatment. Transcriptomic analysis identified distinct IFN-related gene profiles in B cells from pre-treatment JDM patients. These findings offer valuable insights into the complex autoimmune condition of JDM, potentially opening avenues for novel therapeutic strategies.

Disclosure
A.E.K. Syntakas: None. H.D. Nguyen: None. R. Restuadi: None. B.R. Jebson: None. V. Alexiou: None. L.R. Marshall: None. E. Ralph: None. K. O’Brien: None. D. Cancemi: None. H. Peckham: None. A. Radziszewska: None. N. De Gruijter: None. G.T. Hall: None. S. Castellano: None. C. Ciurtin: None. C.T. Deakin: None. E. Rosser: None. L.R. Wedderburn: None. M. Kartawinata: None. M.G.L. Wilkinson: None.