Associations between circulating endostatin levels and vascular organ damage in systemic sclerosis and mixed connective tissue disease: an observational study

Arthritis Research & Therapy, Aug 2015

Introduction Systemic sclerosis (SSc) and mixed connective tissue disease (MCTD) are chronic immune-mediated disorders complicated by vascular organ damage. The aim of this study was to examine the serum levels of the markers of neoangiogenesis: endostatin and vascular endothelial growth factor (VEGF), in our unselected cohorts of SSc and MCTD. Methods Sera of SSc patients (N = 298) and MCTD patients (N = 162) from two longitudinal Norwegian cohorts were included. Blood donors were included as controls (N = 100). Circulating VEGF and endostatin were analyzed by enzyme immunoassay. Results Mean endostatin levels were increased in SSc patients 93.7 (37) ng/ml (P < .001) and MCTD patients 83.2 (25) ng/ml (P < .001) compared to controls 65.1 (12) ng/ml. Median VEGF levels were elevated in SSc patients 209.0 (202) pg/ml compared to MCTD patients 181.3 (175) pg/ml (P = .017) and controls 150.0 (145) pg/ml (P < .001). Multivariable analysis of SSc subsets showed that pulmonary arterial hypertension (coefficient 15.7, 95 % CI: 2.2–29.2, P = .023) and scleroderma renal crisis (coefficient 77.6, 95 % CI: 59.3–100.0, P < .001) were associated with elevated endostatin levels. Multivariable analyses of MCTD subsets showed that digital ulcers were associated with elevated endostatin levels (coefficient 10.5, 95 % CI: 3.2–17.8, P = .005). The risk of death increased by 1.6 per SD endostatin increase (95 % CI: 1.2–2.1, P = .001) in the SSc cohort and by 1.6 per SD endostatin increase (95 % CI: 1.0–2.4, P = .041) in the MCTD cohort after adjustments to known risk factors. Conclusions Endostatin levels were elevated in patients with SSc and MCTD, particularly SSc patients with pulmonary arterial hypertension and scleroderma renal crisis, and MCTD patients with digital ulcers. Elevated endostatin levels were also associated with increased all-cause mortality during follow-up in both groups of patients. We propose that endostatin might indicate the degree of vascular injury in SSc and MCTD patients.

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Associations between circulating endostatin levels and vascular organ damage in systemic sclerosis and mixed connective tissue disease: an observational study

Reiseter et al. Arthritis Research & Therapy Associations between circulating endostatin levels and vascular organ damage in systemic sclerosis and mixed connective tissue disease: an observational study Silje Reiseter 0 Øyvind Molberg 0 2 Ragnar Gunnarsson 2 May Brit Lund 1 Trond Mogens Aalokken 6 Pål Aukrust 0 3 4 5 8 Thor Ueland 0 3 4 8 Torhild Garen 2 Cathrine Brunborg 7 Annika Michelsen 4 8 Aurelija Abraityte 4 8 Anna-Maria Hoffmann-Vold 0 2 0 Institute of Clinical Medicine, University of Oslo , 0318 Oslo , Norway 1 Department of Respiratory Medicine, Oslo University Hospital Rikshospitalet , 0424 Oslo , Norway 2 Department of Rheumatology, Oslo University Hospital Rikshospitalet , 0424 Oslo , Norway 3 K. G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo , 0318, Oslo , Norway 4 Research Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet , 0424 Oslo , Norway 5 Department of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet , 0424 Oslo , Norway 6 Department of Radiology, Oslo University Hospital Rikshospitalet , 0424 Oslo , Norway 7 Oslo Centre for Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Ullevål , 0424 Oslo , Norway 8 K. G. Jebsen Thrombosis Research and Expertise Centre, The Arctic University of Norway , Langnes, 9037 Tromsø , Norway Introduction: Systemic sclerosis (SSc) and mixed connective tissue disease (MCTD) are chronic immune-mediated disorders complicated by vascular organ damage. The aim of this study was to examine the serum levels of the markers of neoangiogenesis: endostatin and vascular endothelial growth factor (VEGF), in our unselected cohorts of SSc and MCTD. Methods: Sera of SSc patients (N = 298) and MCTD patients (N = 162) from two longitudinal Norwegian cohorts were included. Blood donors were included as controls (N = 100). Circulating VEGF and endostatin were analyzed by enzyme immunoassay. Results: Mean endostatin levels were increased in SSc patients 93.7 (37) ng/ml (P < .001) and MCTD patients 83.2 (25) ng/ml (P < .001) compared to controls 65.1 (12) ng/ml. Median VEGF levels were elevated in SSc patients 209.0 (202) pg/ml compared to MCTD patients 181.3 (175) pg/ml (P = .017) and controls 150.0 (145) pg/ml (P < .001). Multivariable analysis of SSc subsets showed that pulmonary arterial hypertension (coefficient 15.7, 95 % CI: 2.2-29.2, P = .023) and scleroderma renal crisis (coefficient 77.6, 95 % CI: 59.3-100.0, P < .001) were associated with elevated endostatin levels. Multivariable analyses of MCTD subsets showed that digital ulcers were associated with elevated endostatin levels (coefficient 10.5, 95 % CI: 3.2-17.8, P = .005). The risk of death increased by 1.6 per SD endostatin increase (95 % CI: 1.2-2.1, P = .001) in the SSc cohort and by 1.6 per SD endostatin increase (95 % CI: 1.0-2.4, P = .041) in the MCTD cohort after adjustments to known risk factors. Conclusions: Endostatin levels were elevated in patients with SSc and MCTD, particularly SSc patients with pulmonary arterial hypertension and scleroderma renal crisis, and MCTD patients with digital ulcers. Elevated endostatin levels were also associated with increased all-cause mortality during follow-up in both groups of patients. We propose that endostatin might indicate the degree of vascular injury in SSc and MCTD patients. - Introduction Systemic sclerosis (SSc) is a chronic multiorgan disease characterized by vasculopathy, progressive fibrosis of the skin and internal organs and distinct serum autoantibodies [1, 2]. The primary event in SSc is assumed to be vascular injury [3], which leads to clinical manifestations such as Raynaud’s phenomenon and digital ulcers [4]. Mortality is increased and mainly driven by pulmonary arterial hypertension (PAH) and pulmonary fibrosis [5]. Microangiopathy is thought to be responsible for the lifethreatening organ involvement, such as PAH, scleroderma renal crisis (SRC), cardiomyopathy, gastric antrial vascular actasia [3] and possibly also pulmonary fibrosis [6]. Vascular injury has an impact in other connective tissue diseases (CTDs) and is particularly evident in mixed connective tissue disease (MCTD), a chronic immunemediated disease associated with anti-U1-RNP autoantibodies and clinical features from SSc, systemic lupus erythematosus (SLE) and polymyositis (PM). MCTD appears to be genetically distinct from other CTDs [7], but there is an ongoing debate whether it should be categorized as a distinct disease, an overlap syndrome or an undifferentiated CTD [8]. Even though organ involvement in MCTD is more extensive than initially described, organ involvement is less severe than in SSc [9]. The vasculopathy in MCTD has been found to resemble the vasculopathy found in SSc [10] and it has been suggested that there is an association between pulmonary hypertension (PH) and anti-U1-RNP autoantibodies in SSc [11] and SLE [12]. Ide (...truncated)


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Silje Reiseter, Øyvind Molberg, Ragnar Gunnarsson, May Lund, Trond Aalokken, Pål Aukrust, Thor Ueland, Torhild Garen, Cathrine Brunborg, Annika Michelsen, Aurelija Abraityte, Anna-Maria Hoffmann-Vold. Associations between circulating endostatin levels and vascular organ damage in systemic sclerosis and mixed connective tissue disease: an observational study, Arthritis Research & Therapy, 2015, pp. 231, 17, DOI: 10.1186/s13075-015-0756-5