title: Associations between circulating endostatin levels and vascular organ damage in systemic sclerosis and mixed connective tissue disease: an observational study.
abstract: BACKGROUND
  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.
authors: Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. silje.reiseter@medisin.uio.no.
authors: Silje
authors: S
authors: Reiseter
authors: Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. oyvind.molberg@medisin.uio.no.|Department of Rheumatology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. oyvind.molberg@medisin.uio.no.
authors: Øyvind
authors: Ø
authors: Molberg
authors: Department of Rheumatology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. rgunnars@ous-hf.no.
authors: Ragnar
authors: R
authors: Gunnarsson
authors: Department of Respiratory Medicine, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. mblund@ous-hf.no.
authors: May Brit
authors: MB
authors: Lund
authors: Department of Radiology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. taalokke@ous-hf.no.
authors: Trond Mogens
authors: TM
authors: Aalokken
authors: Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. paukrust@ous-hf.no.|Department of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. paukrust@ous-hf.no.|Research Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. paukrust@ous-hf.no.|K. G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. paukrust@ous-hf.no.|K. G. Jebsen Thrombosis Research and Expertise Centre, The Arctic University of Norway, Langnes, 9037, Tromsø, Norway. paukrust@ous-hf.no.
authors: Pål
authors: P
authors: Aukrust
authors: Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. thor.ueland@medisin.uio.no.|Research Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. thor.ueland@medisin.uio.no.|K. G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. thor.ueland@medisin.uio.no.|K. G. Jebsen Thrombosis Research and Expertise Centre, The Arctic University of Norway, Langnes, 9037, Tromsø, Norway. thor.ueland@medisin.uio.no.
authors: Thor
authors: T
authors: Ueland
authors: Department of Rheumatology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. tgaren@ous-hf.no.
authors: Torhild
authors: T
authors: Garen
authors: Oslo Centre for Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Ullevål, 0424, Oslo, Norway. cathrine.brunborg@ous-hf.no.
authors: Cathrine
authors: C
authors: Brunborg
authors: Research Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. annika.michelsen@medisin.uio.no.|K. G. Jebsen Thrombosis Research and Expertise Centre, The Arctic University of Norway, Langnes, 9037, Tromsø, Norway. annika.michelsen@medisin.uio.no.
authors: Annika
authors: A
authors: Michelsen
authors: Research Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. Aurelija.abraityte@rr-research.no.|K. G. Jebsen Thrombosis Research and Expertise Centre, The Arctic University of Norway, Langnes, 9037, Tromsø, Norway. Aurelija.abraityte@rr-research.no.
authors: Aurelija
authors: A
authors: Abraityte
authors: Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. a.m.hoffmann-vold@medisin.uio.no.|Department of Rheumatology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. a.m.hoffmann-vold@medisin.uio.no.
authors: Anna-Maria
authors: AM
authors: Hoffmann-Vold
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D001808:Blood Vessels / Q000473:pathology; D002423:Cause of Death; D015331:Cohort Studies; D043169:Endostatins / Q000097:blood*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D008947:Mixed Connective Tissue Disease / Q000097:blood* / Q000401:mortality; D015999:Multivariate Analysis; D012595:Scleroderma, Systemic / Q000097:blood*; D015996:Survival Rate; D014456:Ulcer / Q000097:blood; D014652:Vascular Diseases / Q000097:blood*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D055815:Young Adult
chemical_list: D015415:Biomarkers; D043169:Endostatins; D042461:Vascular Endothelial Growth Factor A