Immunomics analysis of rheumatoid arthritis identified precursor dendritic cells as a key cell subset of treatment resistance.

Objectives Little is known about the immunology underlying variable treatment response in rheumatoid arthritis (RA). We performed large scale transcriptome analyses of peripheral blood immune cell subsets to identify immune cells that predict treatment resistance. Methods We isolated 18 peripheral blood immune cell subsets of 55 pre-treatment RA patients and 39 healthy controls, and performed RNA sequencing. Transcriptome changes in RA and treatment effects were systematically characterized. Association between immune cell gene modules and treatment resistance was evaluated. We validated predictive value of identified parameters for treatment resistance using quantitative polymerase chain reaction (qPCR) and mass cytometric analysis cohorts. We also characterized the identified population by synovial single cell RNA-seq analysis. Results Immune cells of RA patients were characterized by enhanced interferon and IL6-JAK-STAT3 signaling that demonstrate partial normalization after treatment. A gene expression module of plasmacytoid dendritic cells (pDC) reflecting the expansion of pre-dendritic cells (pre-DC) exhibited strongest association with treatment resistance. Type I interferon signaling was negatively correlated to pre-DC gene expression. qPCR and mass cytometric analysis in independent cohorts validated that the pre-DC associated gene expression and the proportion of pre-DC were significantly higher before treatment in treatment-resistant patients. A cluster of synovial DCs showed both features of pre-DC and proinflammatory conventional DC2s. Conclusions An increase in pre-DC in peripheral blood predicted RA treatment resistance. Pre-DC could have pathophysiological relevance to RA treatment response.