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

Overview of attention for article published in Arthritis Research & Therapy, December 2015
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  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (89th percentile)
  • High Attention Score compared to outputs of the same age and source (85th percentile)

Mentioned by

news
1 news outlet
twitter
4 tweeters
patent
1 patent

Citations

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15 Dimensions

Readers on

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42 Mendeley
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Title
Simultaneous inhibition of JAK and SYK kinases ameliorates chronic and destructive arthritis in mice
Published in
Arthritis Research & Therapy, December 2015
DOI 10.1186/s13075-015-0866-0
Pubmed ID
Authors

Alba Llop-Guevara, Mónica Porras, Carla Cendón, Irene Di Ceglie, Francesco Siracusa, Federica Madarena, Vagelis Rinotas, Lluís Gómez, Peter L. van Lent, Eleni Douni, Hyun Dong Chang, Thomas Kamradt, Juan Román

Abstract

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. 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. 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. 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.

Twitter Demographics

The data shown below were collected from the profiles of 4 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 42 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 42 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 11 26%
Student > Ph. D. Student 11 26%
Student > Master 4 10%
Student > Bachelor 3 7%
Student > Doctoral Student 2 5%
Other 5 12%
Unknown 6 14%
Readers by discipline Count As %
Medicine and Dentistry 8 19%
Biochemistry, Genetics and Molecular Biology 6 14%
Immunology and Microbiology 6 14%
Agricultural and Biological Sciences 6 14%
Pharmacology, Toxicology and Pharmaceutical Science 4 10%
Other 3 7%
Unknown 9 21%

Attention Score in Context

This research output has an Altmetric Attention Score of 14. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 16 July 2020.
All research outputs
#1,727,846
of 18,240,594 outputs
Outputs from Arthritis Research & Therapy
#359
of 2,656 outputs
Outputs of similar age
#39,997
of 378,193 outputs
Outputs of similar age from Arthritis Research & Therapy
#43
of 292 outputs
Altmetric has tracked 18,240,594 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 90th percentile: it's in the top 10% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 2,656 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 7.5. This one has done well, scoring higher than 86% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 378,193 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 89% of its contemporaries.
We're also able to compare this research output to 292 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 85% of its contemporaries.