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Monocyte-derived transcriptomes explain the ineffectiveness of abatacept in rheumatoid arthritis

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Title: Monocyte-derived transcriptomes explain the ineffectiveness of abatacept in rheumatoid arthritis
Authors: Takeshi Iwasaki, Ryu Watanabe, Hiromu Ito, Takayuki Fujii, Koichiro Ohmura, Hiroyuki Yoshitomi, Koichi Murata, Kosaku Murakami, Akira Onishi, Masao Tanaka, Shuichi Matsuda, Fumihiko Matsuda, Akio Morinobu, Motomu Hashimoto
Source: Arthritis Research & Therapy, Vol 26, Iss 1, Pp 1-11 (2024)
Publisher Information: BMC, 2024.
Publication Year: 2024
Collection: LCC:Diseases of the musculoskeletal system
Subject Terms: Rheumatoid arthritis, Abatacept, Multi-omics, Monocyte, TLR5, MYD88, Diseases of the musculoskeletal system, RC925-935
More Details: Abstract Background The biological mechanisms underlying the differential response to abatacept in patients with rheumatoid arthritis (RA) are unknown. Here, we aimed to identify cellular, transcriptomic, and proteomic features that predict resistance to abatacept in patients with RA. Methods Blood samples were collected from 22 RA patients treated with abatacept at baseline and after 3 months of treatment. Response to treatment was defined by the European League Against Rheumatism (EULAR) response criteria at 3 months, and seven patients were classified as responders and the others as non-responders. We quantified gene expression levels by RNA sequencing, 67 plasma protein levels, and the expression of surface molecules (CD3, 19, and 56) by flow cytometry. In addition, three gene expression data sets, comprising a total of 27 responders and 50 non-responders, were used to replicate the results. Results Among the clinical characteristics, the number of monocytes was significantly higher in the non-responders before treatment. Cell type enrichment analysis showed that differentially expressed genes (DEGs) between responders and non-responders were enriched in monocytes. Gene set enrichment analysis, together with single-cell analysis and deconvolution analysis, identified that Toll-like receptor 5 (TLR5) and interleukin-17 receptor A (IL17RA) pathway in monocytes was upregulated in non-responders. Hepatocyte growth factor (HGF) correlated with this signature showed higher concentrations in non-responders before treatment. The DEGs in the replication set were also enriched for the genes expressed in monocytes, not for the TLR5 and IL17RA pathway but for the oxidative phosphorylation (OXPHOS) pathway. Conclusions Monocyte-derived transcriptomic features before treatment underlie the differences in abatacept efficacy in patients with RA. The pathway activated in monocytes was the TLR5 and IL17RA-HGF signature in the current study, while it was the OXPHOS pathway in the replication set. Elevated levels of HGF before treatment may serve as a potential biomarker for predicting poor responses to abatacept. These findings provide insights into the biological mechanisms of abatacept resistance, contributing valuable evidence for stratifying patients with RA.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 1478-6362
73040428
Relation: https://doaj.org/toc/1478-6362
DOI: 10.1186/s13075-023-03236-y
Access URL: https://doaj.org/article/349a98cfe73040428b6ad347d65b135d
Accession Number: edsdoj.349a98cfe73040428b6ad347d65b135d
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  Data: <searchLink fieldCode="AR" term="%22Takeshi+Iwasaki%22">Takeshi Iwasaki</searchLink><br /><searchLink fieldCode="AR" term="%22Ryu+Watanabe%22">Ryu Watanabe</searchLink><br /><searchLink fieldCode="AR" term="%22Hiromu+Ito%22">Hiromu Ito</searchLink><br /><searchLink fieldCode="AR" term="%22Takayuki+Fujii%22">Takayuki Fujii</searchLink><br /><searchLink fieldCode="AR" term="%22Koichiro+Ohmura%22">Koichiro Ohmura</searchLink><br /><searchLink fieldCode="AR" term="%22Hiroyuki+Yoshitomi%22">Hiroyuki Yoshitomi</searchLink><br /><searchLink fieldCode="AR" term="%22Koichi+Murata%22">Koichi Murata</searchLink><br /><searchLink fieldCode="AR" term="%22Kosaku+Murakami%22">Kosaku Murakami</searchLink><br /><searchLink fieldCode="AR" term="%22Akira+Onishi%22">Akira Onishi</searchLink><br /><searchLink fieldCode="AR" term="%22Masao+Tanaka%22">Masao Tanaka</searchLink><br /><searchLink fieldCode="AR" term="%22Shuichi+Matsuda%22">Shuichi Matsuda</searchLink><br /><searchLink fieldCode="AR" term="%22Fumihiko+Matsuda%22">Fumihiko Matsuda</searchLink><br /><searchLink fieldCode="AR" term="%22Akio+Morinobu%22">Akio Morinobu</searchLink><br /><searchLink fieldCode="AR" term="%22Motomu+Hashimoto%22">Motomu Hashimoto</searchLink>
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  Data: Abstract Background The biological mechanisms underlying the differential response to abatacept in patients with rheumatoid arthritis (RA) are unknown. Here, we aimed to identify cellular, transcriptomic, and proteomic features that predict resistance to abatacept in patients with RA. Methods Blood samples were collected from 22 RA patients treated with abatacept at baseline and after 3 months of treatment. Response to treatment was defined by the European League Against Rheumatism (EULAR) response criteria at 3 months, and seven patients were classified as responders and the others as non-responders. We quantified gene expression levels by RNA sequencing, 67 plasma protein levels, and the expression of surface molecules (CD3, 19, and 56) by flow cytometry. In addition, three gene expression data sets, comprising a total of 27 responders and 50 non-responders, were used to replicate the results. Results Among the clinical characteristics, the number of monocytes was significantly higher in the non-responders before treatment. Cell type enrichment analysis showed that differentially expressed genes (DEGs) between responders and non-responders were enriched in monocytes. Gene set enrichment analysis, together with single-cell analysis and deconvolution analysis, identified that Toll-like receptor 5 (TLR5) and interleukin-17 receptor A (IL17RA) pathway in monocytes was upregulated in non-responders. Hepatocyte growth factor (HGF) correlated with this signature showed higher concentrations in non-responders before treatment. The DEGs in the replication set were also enriched for the genes expressed in monocytes, not for the TLR5 and IL17RA pathway but for the oxidative phosphorylation (OXPHOS) pathway. Conclusions Monocyte-derived transcriptomic features before treatment underlie the differences in abatacept efficacy in patients with RA. The pathway activated in monocytes was the TLR5 and IL17RA-HGF signature in the current study, while it was the OXPHOS pathway in the replication set. Elevated levels of HGF before treatment may serve as a potential biomarker for predicting poor responses to abatacept. These findings provide insights into the biological mechanisms of abatacept resistance, contributing valuable evidence for stratifying patients with RA.
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