Rho-GTPase pathways may differentiate treatment response to TNF-alpha and IL-17A inhibitors in psoriatic arthritis

Abstract Biological therapies have dramatically improved the therapeutic landscape of psoriatic arthritis (PsA); however, 40–50% of patients are primary non-responders with response rates declining significantly with each successive biological therapy. Therefore, there is a pressing need to develop...

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Autores principales:	Sara Rahmati, Darren D. O’Rielly, Quan Li, Dianne Codner, Amanda Dohey, Kari Jenkins, Igor Jurisica, Dafna D. Gladman, Vinod Chandran, Proton Rahman
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/89afa7b431d842f397da1b39a9b64a04
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spelling	oai:doaj.org-article:89afa7b431d842f397da1b39a9b64a042021-12-02T16:18:02ZRho-GTPase pathways may differentiate treatment response to TNF-alpha and IL-17A inhibitors in psoriatic arthritis10.1038/s41598-020-78866-22045-2322https://doaj.org/article/89afa7b431d842f397da1b39a9b64a042020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78866-2https://doaj.org/toc/2045-2322Abstract Biological therapies have dramatically improved the therapeutic landscape of psoriatic arthritis (PsA); however, 40–50% of patients are primary non-responders with response rates declining significantly with each successive biological therapy. Therefore, there is a pressing need to develop a coherent strategy for effective initial and subsequent selection of biologic agents. We interrogated 40 PsA patients initiating either tumour necrosis factor inhibitors (TNFi) or interleukin-17A inhibitors (17Ai) for active PsA. Patients achieving low disease activity according to the Disease Activity Index for PsA (DAPSA) at 3 months were classified as responders. Baseline and 3-month CD4+ transcript profiling were performed, and novel signaling pathways were identified using a multi-omics profiling and integrative computational analysis approach. Using transcriptomic data at initiation of therapy, we identified over 100 differentially expressed genes (DEGs) that differentiated IL-17Ai response from non-response and TNFi response from non-response. Integration of cell-type-specific DEGs with protein–protein interactions and further comprehensive pathway enrichment analysis revealed several pathways. Rho GTPase signaling pathway exhibited a strong signal specific to IL-17Ai response and the genes, RAC1 and ROCKs, are supported by results from prior research. Our detailed network and pathway analyses have identified the rewiring of Rho GTPase pathways as potential markers of response to IL17Ai but not TNFi. These results need further verification.Sara RahmatiDarren D. O’RiellyQuan LiDianne CodnerAmanda DoheyKari JenkinsIgor JurisicaDafna D. GladmanVinod ChandranProton RahmanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sara Rahmati Darren D. O’Rielly Quan Li Dianne Codner Amanda Dohey Kari Jenkins Igor Jurisica Dafna D. Gladman Vinod Chandran Proton Rahman Rho-GTPase pathways may differentiate treatment response to TNF-alpha and IL-17A inhibitors in psoriatic arthritis
description	Abstract Biological therapies have dramatically improved the therapeutic landscape of psoriatic arthritis (PsA); however, 40–50% of patients are primary non-responders with response rates declining significantly with each successive biological therapy. Therefore, there is a pressing need to develop a coherent strategy for effective initial and subsequent selection of biologic agents. We interrogated 40 PsA patients initiating either tumour necrosis factor inhibitors (TNFi) or interleukin-17A inhibitors (17Ai) for active PsA. Patients achieving low disease activity according to the Disease Activity Index for PsA (DAPSA) at 3 months were classified as responders. Baseline and 3-month CD4+ transcript profiling were performed, and novel signaling pathways were identified using a multi-omics profiling and integrative computational analysis approach. Using transcriptomic data at initiation of therapy, we identified over 100 differentially expressed genes (DEGs) that differentiated IL-17Ai response from non-response and TNFi response from non-response. Integration of cell-type-specific DEGs with protein–protein interactions and further comprehensive pathway enrichment analysis revealed several pathways. Rho GTPase signaling pathway exhibited a strong signal specific to IL-17Ai response and the genes, RAC1 and ROCKs, are supported by results from prior research. Our detailed network and pathway analyses have identified the rewiring of Rho GTPase pathways as potential markers of response to IL17Ai but not TNFi. These results need further verification.
format	article
author	Sara Rahmati Darren D. O’Rielly Quan Li Dianne Codner Amanda Dohey Kari Jenkins Igor Jurisica Dafna D. Gladman Vinod Chandran Proton Rahman
author_facet	Sara Rahmati Darren D. O’Rielly Quan Li Dianne Codner Amanda Dohey Kari Jenkins Igor Jurisica Dafna D. Gladman Vinod Chandran Proton Rahman
author_sort	Sara Rahmati
title	Rho-GTPase pathways may differentiate treatment response to TNF-alpha and IL-17A inhibitors in psoriatic arthritis
title_short	Rho-GTPase pathways may differentiate treatment response to TNF-alpha and IL-17A inhibitors in psoriatic arthritis
title_full	Rho-GTPase pathways may differentiate treatment response to TNF-alpha and IL-17A inhibitors in psoriatic arthritis
title_fullStr	Rho-GTPase pathways may differentiate treatment response to TNF-alpha and IL-17A inhibitors in psoriatic arthritis
title_full_unstemmed	Rho-GTPase pathways may differentiate treatment response to TNF-alpha and IL-17A inhibitors in psoriatic arthritis
title_sort	rho-gtpase pathways may differentiate treatment response to tnf-alpha and il-17a inhibitors in psoriatic arthritis
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/89afa7b431d842f397da1b39a9b64a04
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Rho-GTPase pathways may differentiate treatment response to TNF-alpha and IL-17A inhibitors in psoriatic arthritis

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