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The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis

OBJECTIVES: Cardiovascular (CV) mortality in RA patients is 50% higher than in the general population. There is increasing recognition that systemic inflammation is a major driver of this. IL-6 is implicated in cardiovascular disease (CVD) in the general population but its role in CVD in RA is undef...

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Autores principales: Davies, Ruth, Williams, Jessica, Sime, Katie, Jin, Hyun-Sun, Thompson, Charlotte, Jordan, Lauren, Lang, Derek, Halcox, Julian P, Ellins, Elizabeth, Jones, Gareth W, Jones, Simon A, Rose-John, Stefan, Williams, Anwen, Choy, Ernest
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213430/
https://www.ncbi.nlm.nih.gov/pubmed/33313793
http://dx.doi.org/10.1093/rheumatology/keaa725
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author Davies, Ruth
Williams, Jessica
Sime, Katie
Jin, Hyun-Sun
Thompson, Charlotte
Jordan, Lauren
Lang, Derek
Halcox, Julian P
Ellins, Elizabeth
Jones, Gareth W
Jones, Simon A
Rose-John, Stefan
Williams, Anwen
Choy, Ernest
author_facet Davies, Ruth
Williams, Jessica
Sime, Katie
Jin, Hyun-Sun
Thompson, Charlotte
Jordan, Lauren
Lang, Derek
Halcox, Julian P
Ellins, Elizabeth
Jones, Gareth W
Jones, Simon A
Rose-John, Stefan
Williams, Anwen
Choy, Ernest
author_sort Davies, Ruth
collection PubMed
description OBJECTIVES: Cardiovascular (CV) mortality in RA patients is 50% higher than in the general population. There is increasing recognition that systemic inflammation is a major driver of this. IL-6 is implicated in cardiovascular disease (CVD) in the general population but its role in CVD in RA is undefined. Of the two modes of IL-6 signalling, trans-signalling is pro-inflammatory whereas classical signalling is linked with inflammation resolution. This study examines the role of IL-6 trans-signalling in CVD in a mouse model and patients with RA. METHODS: Myography determined the effect of IL-6 trans-signalling blockade, using sgp130Fc, on aortic constriction in murine collagen-induced arthritis. Serum CCL2 and sVCAM-1 as soluble biomarkers of sIL-6R trans-signalling were investigated in a human cross-sectional study. An observational longitudinal study investigated the association between these biomarkers and progression of subclinical atherosclerosis in early RA by measuring carotid intima-media thickness (CIMT). RESULTS: sgp130Fc reduced arthritis severity, serum CCL2 and sVCAM-1 and restored vascular function in collagen-induced arthritis (CIA). In established RA, sVCAM-1 correlated with the 28-joint DAS (DAS28) and CV risk. In early RA, baseline DAS28 was associated with CIMT change at 6 months. CIMT ‘rapid progressors’ at 12 months had higher baseline sVCAM-1, haemoglobin A1c, cholesterol:high-density lipoprotein cholesterol ratio and LDL cholesterol. CONCLUSIONS: IL-6 trans-signalling plays a pivotal role in vascular dysfunction in CIA. In early RA, sVCAM-1 was associated with progression of subclinical atherosclerosis. Inflammation from RA onset in CVD-susceptible individuals may accelerate atherosclerosis. IL-6 trans-signalling blockade may be beneficial to RA patients and perhaps for atherosclerosis in the general population.
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spelling pubmed-82134302021-06-21 The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis Davies, Ruth Williams, Jessica Sime, Katie Jin, Hyun-Sun Thompson, Charlotte Jordan, Lauren Lang, Derek Halcox, Julian P Ellins, Elizabeth Jones, Gareth W Jones, Simon A Rose-John, Stefan Williams, Anwen Choy, Ernest Rheumatology (Oxford) Clinical Science OBJECTIVES: Cardiovascular (CV) mortality in RA patients is 50% higher than in the general population. There is increasing recognition that systemic inflammation is a major driver of this. IL-6 is implicated in cardiovascular disease (CVD) in the general population but its role in CVD in RA is undefined. Of the two modes of IL-6 signalling, trans-signalling is pro-inflammatory whereas classical signalling is linked with inflammation resolution. This study examines the role of IL-6 trans-signalling in CVD in a mouse model and patients with RA. METHODS: Myography determined the effect of IL-6 trans-signalling blockade, using sgp130Fc, on aortic constriction in murine collagen-induced arthritis. Serum CCL2 and sVCAM-1 as soluble biomarkers of sIL-6R trans-signalling were investigated in a human cross-sectional study. An observational longitudinal study investigated the association between these biomarkers and progression of subclinical atherosclerosis in early RA by measuring carotid intima-media thickness (CIMT). RESULTS: sgp130Fc reduced arthritis severity, serum CCL2 and sVCAM-1 and restored vascular function in collagen-induced arthritis (CIA). In established RA, sVCAM-1 correlated with the 28-joint DAS (DAS28) and CV risk. In early RA, baseline DAS28 was associated with CIMT change at 6 months. CIMT ‘rapid progressors’ at 12 months had higher baseline sVCAM-1, haemoglobin A1c, cholesterol:high-density lipoprotein cholesterol ratio and LDL cholesterol. CONCLUSIONS: IL-6 trans-signalling plays a pivotal role in vascular dysfunction in CIA. In early RA, sVCAM-1 was associated with progression of subclinical atherosclerosis. Inflammation from RA onset in CVD-susceptible individuals may accelerate atherosclerosis. IL-6 trans-signalling blockade may be beneficial to RA patients and perhaps for atherosclerosis in the general population. Oxford University Press 2020-12-11 /pmc/articles/PMC8213430/ /pubmed/33313793 http://dx.doi.org/10.1093/rheumatology/keaa725 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Clinical Science
Davies, Ruth
Williams, Jessica
Sime, Katie
Jin, Hyun-Sun
Thompson, Charlotte
Jordan, Lauren
Lang, Derek
Halcox, Julian P
Ellins, Elizabeth
Jones, Gareth W
Jones, Simon A
Rose-John, Stefan
Williams, Anwen
Choy, Ernest
The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis
title The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis
title_full The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis
title_fullStr The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis
title_full_unstemmed The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis
title_short The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis
title_sort role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis
topic Clinical Science
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213430/
https://www.ncbi.nlm.nih.gov/pubmed/33313793
http://dx.doi.org/10.1093/rheumatology/keaa725
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