POS0237 TRANSCRIPTOMIC LANDSCAPES IN IDIOPATHIC INFLAMMATORY MYOPATHY: DIVERGENT PATHWAYS AND IMMUNE CELLS POTENTIALLY DRIVING MUSCLE DAMAGE.

Background:

Idiopathic inflammatory myopathy (IIM) includes heterogeneous phenotypes such as polymyositis (PM), dermatomyositis (DM), and antisynthetase syndrome. The underlying mechanisms of muscle damage remain poorly understood.

Objectives:

The aim of this study was to investigate the transcriptome and immunophenotypic features of muscle biopsies from patients with IIM.

Methods:

Bulk RNA-sequencing was performed on muscle biopsy samples from patients with IIM (PM; n=9, DM; n=16, classified according to the Bohan and Peter criteria) (Figure 1). DM patients were further divided into subgroups negative or positive for anti-aminoacyl tRNA synthetase (ARS) antibodies (n=9 and n=7, respectively). Weighted gene coexpression network analysis (WGCNA), differentially expressed gene (DEG) analysis, and gene set variation analysis (GSVA) were conducted to evaluate specific pathways and functions. Cell proportions were estimated through a deconvolution approach. Mann-Whitney U test and Spearman correlation analyses were used to investigate the differences in cell proportions and relationships with clinical features.

Results:

Among the total of 25 patients with IIM, WGCNA revealed serum creatine kinase (CK) and aldolase levels were significantly correlated with specific gene modules that were associated with cellular respiration, mitochondrial translation, phagocytosis, and cytokine production (Figure 2A and 2B). Additionally, significant positive correlations were observed between CK and the proportions of CD16 negative (CD16n Mono) and positive monocytes (CD16p Mono), as well as myeloid dendritic cells (Figure 2C). DM patients demonstrated higher proportions of CD16n Mono (p=0.043), whereas higher proportions of Th2 cells were found in PM patients (p=0.049). GSVA revealed elevated interferon (IFN)-α response and complement signatures in DM (p=0.017, 0.008, respectively). DEGs in DM were also associated with the response to type I IFN pathway and complement system. Among the DM patients, ARS-DM patients exhibited a higher proportion of Th1 cells (p=0.007) and DEGs were associated with oxidative phosphorylation.

Conclusion:

This research elucidates potential mechanisms underlying muscle damage, highlighting the significant involvement of myeloid cells in DM as compared to PM. Furthermore, DM was associated with higher complement signaling. Distinctive gene expression variations in muscle biopsies from patients with IIM suggest that different pathologic mechanisms underlie muscle damage in each phenotype.

REFERENCES:

NIL.

Acknowledgements:

This research was supported by the Japan Agency for Medical Research and Development (AMED) under Grant Number 19ek0410047.

Disclosure of Interests:

Shinji Izuka Eisai Co., Ltd, Natsuka Umezawa Chugai Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim Japan, Astellas Pharma, Kyowa Kirin Co., Ltd, Otsuka Pharmaceutical Factory, Toshihiko Komai Tanabe Mitsubishi, Kissei, Pfizer, Chugai, Daiichi-Sankyo, Eli Lilly, Novartis, Eisai, Aasahi Kasei, GlaxoSmithKline, GlaxoSmithKline, Yusuke Sugimori: None declared, Naoki Kimura GlaxoSmithKline Co., Ltd., Eisai Co., Ltd., AbbVie LLC, Asahi Kasei Pharma Corporation, Novartis Pharma K.K., Astellas Pharma Inc., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Ayumi Pharmaceutical Corporation, Nobelpharma Co., Ltd., Asahi Kasei Pharma Corporation, AbbVie LLC, Chugai Pharmaceutical Co., Ltd., UCB Japan Co. Ltd., CSL Behring Co., Ltd., The Japanese Blood Products Organization, Fumitaka Mizoguchi: None declared, Yuichiro Fujieda: None declared, Keita Ninagawa The Uehara Memorial Foundation, Takeshi Iwasaki: None declared, Katsuya Suzuki: None declared, Tsutomu Takeuchi: None declared, Koichiro Ohmura Asahi Kasei Pharma、Chugai Pharmaceutical、Mitsubishi Tanabe Pharma, Tsuneyo Mimori EUROIMMUN、Nippon Shinyaku Co., Ltd., Tatsuya Atsumi AbbVie Inc., Alexion Inc., Asahi-Kasei Co,. Astellas Pharma Inc., AstraZeneca plc., Bayer Yakuhin, Bristol-Myers Squibb Co., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co. Ltd., Eli Lilly Japan K.K., Gilead Sciences K.K., GlaxoSmithKline K.K., Janssen Pharmaceutical K.K., Novartis Pharma K.K., and Nippon Boehringer Ingelheim Co., Ltd., Mitsubishi Tanabe Pharma Co.,. Pfizer Inc., Taiho Pharmaceutical Co., Ltd. and UCB Japan Co. Ltd., GlaxoSmithKline K.K. AstraZeneca plc. Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd, GlaxoSmithKline K.K., Eiryo Kawakami lundbeck、Astellas Pharma Inc, Akari Suzuki Daiichi Sankyo and Chugai Pharmaceutical, Yuta Kochi Uehara Memorial Foundation, Kobayashi Foundation, Kazuhiko Yamamoto Chugai Pharmaceutical, Chugai Pharmaceutical, Shinsuke Yasuda Asahi-Kasei, Ono pharmaceuticals, Chugai, Asahi-Kasei, Abbvie, Tanabe-Mitsubishi, Ono Pharmaceutical, Lilly, GSK, Astrazeneka, Immunoforge, Chugai, Asahi-Kasei, Abbvie, Ayumi, Behringer, Tomohisa Okamura Chugai Pharmaceutical, Chugai Pharmaceutical, Mineto Ota GlaxoSmithKline, Keishi Fujio Chugai Pharmaceutical, Chugai Pharmaceutical.