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ObjectivesLittle 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.MethodsWe 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.ResultsImmune 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.ConclusionsAn increase in pre-DC in peripheral blood predicted RA treatment resistance. Pre-DC could have pathophysiological relevance to RA treatment response.Key messagesWhat is already known about this subject?Limited information is available about the immune cells that are associated with RA treatment resistance.What does this study add?RA treatment resistance can be predicted by an increase in pre-DC in peripheral blood prior to treatment.The expression of genes reflecting an increase in pre-DC is negatively correlated to the type I interferon signature, which is associated with good therapeutic response.Synovial pre-DC-like cells are proinflammatory cDC2s.How might this impact on clinical practice or future developments?Stratified treatment of RA is possible using pre-DC as a biomarker, and it might be possible to develop new therapies for treatment-resistant RA by targeting pre-DC.