PT  - JOURNAL ARTICLE
AU  - Saeko Yamada
AU  - Yasuo Nagafuchi
AU  - Min Wang
AU  - Mineto Ota
AU  - Hiroaki Hatano
AU  - Yusuke Takeshima
AU  - Mai Okubo
AU  - Satomi Kobayashi
AU  - Yusuke Sugimori
AU  - Nakano Masahiro
AU  - Ryochi Yoshida
AU  - Norio Hanata
AU  - Yuichi Suwa
AU  - Yumi Tsuchida
AU  - Yukiko Iwasaki
AU  - Shuji Sumitomo
AU  - Kanae Kubo
AU  - Kenichi Shimane
AU  - Keigo Setoguchi
AU  - Takanori Azuma
AU  - Hiroko Kanda
AU  - Hirofumi Shoda
AU  - Xuan Zhang
AU  - Kazuhiko Yamamoto
AU  - Kazuyoshi Ishigaki
AU  - Tomohisa Okamura
AU  - Keishi Fujio
TI  - Immunomics analysis of rheumatoid arthritis identified precursor dendritic cells as a key cell subset of treatment resistance
AID  - 10.1136/ard-2022-223645
DP  - 2023 Mar 08
TA  - Annals of the Rheumatic Diseases
PG  - ard-2022-223645
4099  - http://ard.bmj.com/content/early/2023/03/07/ard-2022-223645.short
4100  - http://ard.bmj.com/content/early/2023/03/07/ard-2022-223645.full
AB  - 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 patients with RA requiring addition of new treatment and 39 healthy controls, and performed RNA sequencing. Transcriptome changes in RA and treatment effects were systematically characterised. Association between immune cell gene modules and treatment resistance was evaluated. We validated predictive value of identified parameters for treatment resistance using quantitative PCR (qPCR) and mass cytometric analysis cohorts. We also characterised the identified population by synovial single cell RNA-sequencing analysis.Results Immune cells of patients with RA were characterised by enhanced interferon and IL6-JAK-STAT3 signalling that demonstrate partial normalisation after treatment. A gene expression module of plasmacytoid dendritic cells (pDC) reflecting the expansion of dendritic cell precursors (pre-DC) exhibited strongest association with treatment resistance. Type I interferon signalling 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 pro-inflammatory 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.Data are available in a public, open access repository. The datasets generated during this study are available at the National Bioscience Database Center (NBDC) with the study accession code of hum0214 and hum0383. We used publicly available software for the analyses.