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Simultaneous inhibition of JAK and SYK kinases ameliorates chronic and destructive arthritis in mice

INTRODUCTION: Despite the broad spectrum of antirheumatic drugs, RA is still not well controlled in up to 30-50 % of patients. Inhibition of JAK kinases by means of the pan-JAK inhibitor tofacitinib has demonstrated to be effective even in difficult-to-treat patients. Here, we discuss whether the ef...

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Autores principales: Llop-Guevara, Alba, Porras, Mónica, Cendón, Carla, Di Ceglie, Irene, Siracusa, Francesco, Madarena, Federica, Rinotas, Vagelis, Gómez, Lluís, van Lent, Peter L., Douni, Eleni, Chang, Hyun Dong, Kamradt, Thomas, Román, Juan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675041/
https://www.ncbi.nlm.nih.gov/pubmed/26653844
http://dx.doi.org/10.1186/s13075-015-0866-0
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author Llop-Guevara, Alba
Porras, Mónica
Cendón, Carla
Di Ceglie, Irene
Siracusa, Francesco
Madarena, Federica
Rinotas, Vagelis
Gómez, Lluís
van Lent, Peter L.
Douni, Eleni
Chang, Hyun Dong
Kamradt, Thomas
Román, Juan
author_facet Llop-Guevara, Alba
Porras, Mónica
Cendón, Carla
Di Ceglie, Irene
Siracusa, Francesco
Madarena, Federica
Rinotas, Vagelis
Gómez, Lluís
van Lent, Peter L.
Douni, Eleni
Chang, Hyun Dong
Kamradt, Thomas
Román, Juan
author_sort Llop-Guevara, Alba
collection PubMed
description INTRODUCTION: Despite the broad spectrum of antirheumatic drugs, RA is still not well controlled in up to 30-50 % of patients. Inhibition of JAK kinases by means of the pan-JAK inhibitor tofacitinib has demonstrated to be effective even in difficult-to-treat patients. Here, we discuss whether the efficacy of JAK inhibition can be improved by simultaneously inhibiting SYK kinase, since both kinases mediate complementary and non-redundant pathways in RA. METHODS: Efficacy of dual JAK + SYK inhibition with selective small molecule inhibitors was evaluated in chronic G6PI-induced arthritis, a non-self-remitting and destructive arthritis model in mice. Clinical and histopathological scores, as well as cytokine and anti-G6PI antibody production were assessed in both preventive and curative protocols. Potential immunotoxicity was also evaluated in G6PI-induced arthritis and in a 28-day TDAR model, by analysing the effects of JAK + SYK inhibition on hematological parameters, lymphoid organs, leukocyte subsets and cell function. RESULTS: Simultaneous JAK + SYK inhibition completely prevented mice from developing arthritis. This therapeutic strategy was also very effective in ameliorating already established arthritis. Dual kinase inhibition immediately resulted in greatly decreased clinical and histopathological scores and led to disease remission in over 70 % of the animals. In contrast, single JAK inhibition and anti-TNF therapy (etanercept) were able to stop disease progression but not to revert it. Dual kinase inhibition decreased Treg and NK cell counts to the same extent as single JAK inhibition but overall cytotoxicity remained intact. Interestingly, treatment discontinuation rapidly reversed such immune cell reduction without compromising clinical efficacy, suggesting long-lasting curative effects. Dual kinase inhibition reduced the Th1/Th17 cytokine cascade and the differentiation and function of joint cells, in particular osteoclasts and fibroblast-like synoviocytes. CONCLUSIONS: Concurrent JAK + SYK inhibition resulted in higher efficacy than single kinase inhibition and TNF blockade in a chronic and severe arthritis model. Thus, blockade of multiple immune signals with dual JAK + SYK inhibition represents a reasonable therapeutic strategy for RA, in particular in patients with inadequate responses to current treatments. Our data supports the multiplicity of events underlying this heterogeneous and complex disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13075-015-0866-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-46750412015-12-11 Simultaneous inhibition of JAK and SYK kinases ameliorates chronic and destructive arthritis in mice Llop-Guevara, Alba Porras, Mónica Cendón, Carla Di Ceglie, Irene Siracusa, Francesco Madarena, Federica Rinotas, Vagelis Gómez, Lluís van Lent, Peter L. Douni, Eleni Chang, Hyun Dong Kamradt, Thomas Román, Juan Arthritis Res Ther Research Article INTRODUCTION: Despite the broad spectrum of antirheumatic drugs, RA is still not well controlled in up to 30-50 % of patients. Inhibition of JAK kinases by means of the pan-JAK inhibitor tofacitinib has demonstrated to be effective even in difficult-to-treat patients. Here, we discuss whether the efficacy of JAK inhibition can be improved by simultaneously inhibiting SYK kinase, since both kinases mediate complementary and non-redundant pathways in RA. METHODS: Efficacy of dual JAK + SYK inhibition with selective small molecule inhibitors was evaluated in chronic G6PI-induced arthritis, a non-self-remitting and destructive arthritis model in mice. Clinical and histopathological scores, as well as cytokine and anti-G6PI antibody production were assessed in both preventive and curative protocols. Potential immunotoxicity was also evaluated in G6PI-induced arthritis and in a 28-day TDAR model, by analysing the effects of JAK + SYK inhibition on hematological parameters, lymphoid organs, leukocyte subsets and cell function. RESULTS: Simultaneous JAK + SYK inhibition completely prevented mice from developing arthritis. This therapeutic strategy was also very effective in ameliorating already established arthritis. Dual kinase inhibition immediately resulted in greatly decreased clinical and histopathological scores and led to disease remission in over 70 % of the animals. In contrast, single JAK inhibition and anti-TNF therapy (etanercept) were able to stop disease progression but not to revert it. Dual kinase inhibition decreased Treg and NK cell counts to the same extent as single JAK inhibition but overall cytotoxicity remained intact. Interestingly, treatment discontinuation rapidly reversed such immune cell reduction without compromising clinical efficacy, suggesting long-lasting curative effects. Dual kinase inhibition reduced the Th1/Th17 cytokine cascade and the differentiation and function of joint cells, in particular osteoclasts and fibroblast-like synoviocytes. CONCLUSIONS: Concurrent JAK + SYK inhibition resulted in higher efficacy than single kinase inhibition and TNF blockade in a chronic and severe arthritis model. Thus, blockade of multiple immune signals with dual JAK + SYK inhibition represents a reasonable therapeutic strategy for RA, in particular in patients with inadequate responses to current treatments. Our data supports the multiplicity of events underlying this heterogeneous and complex disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13075-015-0866-0) contains supplementary material, which is available to authorized users. BioMed Central 2015-12-10 2015 /pmc/articles/PMC4675041/ /pubmed/26653844 http://dx.doi.org/10.1186/s13075-015-0866-0 Text en © Llop-Guevara et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Llop-Guevara, Alba
Porras, Mónica
Cendón, Carla
Di Ceglie, Irene
Siracusa, Francesco
Madarena, Federica
Rinotas, Vagelis
Gómez, Lluís
van Lent, Peter L.
Douni, Eleni
Chang, Hyun Dong
Kamradt, Thomas
Román, Juan
Simultaneous inhibition of JAK and SYK kinases ameliorates chronic and destructive arthritis in mice
title Simultaneous inhibition of JAK and SYK kinases ameliorates chronic and destructive arthritis in mice
title_full Simultaneous inhibition of JAK and SYK kinases ameliorates chronic and destructive arthritis in mice
title_fullStr Simultaneous inhibition of JAK and SYK kinases ameliorates chronic and destructive arthritis in mice
title_full_unstemmed Simultaneous inhibition of JAK and SYK kinases ameliorates chronic and destructive arthritis in mice
title_short Simultaneous inhibition of JAK and SYK kinases ameliorates chronic and destructive arthritis in mice
title_sort simultaneous inhibition of jak and syk kinases ameliorates chronic and destructive arthritis in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675041/
https://www.ncbi.nlm.nih.gov/pubmed/26653844
http://dx.doi.org/10.1186/s13075-015-0866-0
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