TY - JOUR
T1 - Biomarker profiles of endothelial activation and dysfunction in rare systemic autoimmune diseases
T2 - Implications for cardiovascular risk
AU - Wienke, Judith
AU - Mertens, Jorre S.
AU - Garcia, Samuel
AU - Lim, Johan
AU - Wijngaarde, Camiel A.
AU - Yeo, Joo Guan
AU - Meyer, Alain
AU - Van Den Hoogen, Lucas L.
AU - Tekstra, Janneke
AU - Hoogendijk, Jessica E.
AU - Otten, Henny G.
AU - Fritsch-Stork, Ruth D.E.
AU - De Jager, Wilco
AU - Seyger, Marieke M.B.
AU - Thurlings, Rogier M.
AU - De Jong, Elke M.G.J.
AU - Van Der Kooi, Anneke J.
AU - Van Der Pol, W. Ludo
AU - Arkachaisri, Thaschawee
AU - Radstake, Timothy R.D.J.
AU - Van Royen-Kerkhof, Annet
AU - Van Wijk, Femke
N1 - Publisher Copyright:
© 2020 Published by Oxford University Press on behalf of the British Society for Rheumatology.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - Objectives: Vasculopathy is an important hallmark of systemic chronic inflammatory connective tissue diseases (CICTD) and is associated with increased cardiovascular risk. We investigated disease-specific biomarker profiles associated with endothelial dysfunction, angiogenic homeostasis and (tissue) inflammation, and their relation to disease activity in rare CICTD. Methods: A total of 38 serum proteins associated with endothelial (dys)function and inflammation were measured by multiplex-immunoassay in treatment-naive patients with localized scleroderma (LoS, 30), eosinophilic fasciitis (EF, 8) or (juvenile) dermatomyositis (34), 119 (follow-up) samples during treatment, and 65 controls. Data were analysed by unsupervised clustering, Spearman correlations, non-parametric t test and ANOVA. Results: The systemic CICTD, EF and dermatomyositis, had distinct biomarker profiles, with 'signature' markers galectin-9 (dermatomyositis) and CCL4, CCL18, CXCL9, fetuin, fibronectin, galectin-1 and TSP-1 (EF). In LoS, CCL18, CXCL9 and CXCL10 were subtly increased. Furthermore, dermatomyositis and EF shared upregulation of markers related to interferon (CCL2, CXCL10), endothelial activation (VCAM-1), inhibition of angiogenesis (angiopoietin-2, sVEGFR-1) and inflammation/leucocyte chemo-attraction (CCL19, CXCL13, IL-18, YKL-40), as well as disturbance of the Angiopoietin-Tie receptor system and VEGF-VEGFR system. These profiles were related to disease activity, and largely normalized during treatment. However, a subgroup of CICTD patients showed continued elevation of CXCL10, CXCL13, galectin-9, IL-18, TNFR2, VCAM-1, and/or YKL-40 during clinically inactive disease, possibly indicating subclinical interferon-driven inflammation and/or endothelial dysfunction. Conclusion: CICTD-specific biomarker profiles revealed an anti-angiogenic, interferon-driven environment during active disease, with incomplete normalization under treatment. This warrants further investigation into monitoring of vascular biomarkers during clinical follow-up, or targeted interventions to minimize cardiovascular risk in the long term.
AB - Objectives: Vasculopathy is an important hallmark of systemic chronic inflammatory connective tissue diseases (CICTD) and is associated with increased cardiovascular risk. We investigated disease-specific biomarker profiles associated with endothelial dysfunction, angiogenic homeostasis and (tissue) inflammation, and their relation to disease activity in rare CICTD. Methods: A total of 38 serum proteins associated with endothelial (dys)function and inflammation were measured by multiplex-immunoassay in treatment-naive patients with localized scleroderma (LoS, 30), eosinophilic fasciitis (EF, 8) or (juvenile) dermatomyositis (34), 119 (follow-up) samples during treatment, and 65 controls. Data were analysed by unsupervised clustering, Spearman correlations, non-parametric t test and ANOVA. Results: The systemic CICTD, EF and dermatomyositis, had distinct biomarker profiles, with 'signature' markers galectin-9 (dermatomyositis) and CCL4, CCL18, CXCL9, fetuin, fibronectin, galectin-1 and TSP-1 (EF). In LoS, CCL18, CXCL9 and CXCL10 were subtly increased. Furthermore, dermatomyositis and EF shared upregulation of markers related to interferon (CCL2, CXCL10), endothelial activation (VCAM-1), inhibition of angiogenesis (angiopoietin-2, sVEGFR-1) and inflammation/leucocyte chemo-attraction (CCL19, CXCL13, IL-18, YKL-40), as well as disturbance of the Angiopoietin-Tie receptor system and VEGF-VEGFR system. These profiles were related to disease activity, and largely normalized during treatment. However, a subgroup of CICTD patients showed continued elevation of CXCL10, CXCL13, galectin-9, IL-18, TNFR2, VCAM-1, and/or YKL-40 during clinically inactive disease, possibly indicating subclinical interferon-driven inflammation and/or endothelial dysfunction. Conclusion: CICTD-specific biomarker profiles revealed an anti-angiogenic, interferon-driven environment during active disease, with incomplete normalization under treatment. This warrants further investigation into monitoring of vascular biomarkers during clinical follow-up, or targeted interventions to minimize cardiovascular risk in the long term.
KW - autoimmune diseases
KW - biomarkers
KW - cardiovascular disease
KW - dermatomyositis
KW - disease activity
KW - endothelial dysfunction
KW - eosinophilic fasciitis
KW - localized scleroderma
UR - http://www.scopus.com/inward/record.url?scp=85102212509&partnerID=8YFLogxK
U2 - 10.1093/rheumatology/keaa270
DO - 10.1093/rheumatology/keaa270
M3 - Article
C2 - 32810267
AN - SCOPUS:85102212509
SN - 1462-0324
VL - 60
SP - 785
EP - 801
JO - Rheumatology
JF - Rheumatology
IS - 2
ER -