Observational Study

. 2015 Aug 28;17(1):231.

doi: 10.1186/s13075-015-0756-5.

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

Silje Reiseter¹, Øyvind Molberg^{2

3}, Ragnar Gunnarsson⁴, May Brit Lund⁵, Trond Mogens Aalokken⁶, Pål Aukrust^{7

8

9

10

11}, Thor Ueland^{12

13

14

15}, Torhild Garen¹⁶, Cathrine Brunborg¹⁷, Annika Michelsen^{18

19}, Aurelija Abraityte^{20

21}, Anna-Maria Hoffmann-Vold^{22

23}

Affiliations

¹ Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. silje.reiseter@medisin.uio.no.
² Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. oyvind.molberg@medisin.uio.no.
³ Department of Rheumatology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. oyvind.molberg@medisin.uio.no.
⁴ Department of Rheumatology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. rgunnars@ous-hf.no.
⁵ Department of Respiratory Medicine, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. mblund@ous-hf.no.
⁶ Department of Radiology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. taalokke@ous-hf.no.
⁷ Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. paukrust@ous-hf.no.
⁸ Department of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. paukrust@ous-hf.no.
⁹ Research Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. paukrust@ous-hf.no.
¹⁰ K. G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. paukrust@ous-hf.no.
¹¹ K. G. Jebsen Thrombosis Research and Expertise Centre, The Arctic University of Norway, Langnes, 9037, Tromsø, Norway. paukrust@ous-hf.no.
¹² Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. thor.ueland@medisin.uio.no.
¹³ Research Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. thor.ueland@medisin.uio.no.
¹⁴ K. G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. thor.ueland@medisin.uio.no.
¹⁵ K. G. Jebsen Thrombosis Research and Expertise Centre, The Arctic University of Norway, Langnes, 9037, Tromsø, Norway. thor.ueland@medisin.uio.no.
¹⁶ Department of Rheumatology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. tgaren@ous-hf.no.
¹⁷ Oslo Centre for Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Ullevål, 0424, Oslo, Norway. cathrine.brunborg@ous-hf.no.
¹⁸ Research Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. annika.michelsen@medisin.uio.no.
¹⁹ K. G. Jebsen Thrombosis Research and Expertise Centre, The Arctic University of Norway, Langnes, 9037, Tromsø, Norway. annika.michelsen@medisin.uio.no.
²⁰ Research Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. Aurelija.abraityte@rr-research.no.
²¹ K. G. Jebsen Thrombosis Research and Expertise Centre, The Arctic University of Norway, Langnes, 9037, Tromsø, Norway. Aurelija.abraityte@rr-research.no.
²² Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. a.m.hoffmann-vold@medisin.uio.no.
²³ Department of Rheumatology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. a.m.hoffmann-vold@medisin.uio.no.

PMID: 26315510
PMCID: PMC4551562
DOI: 10.1186/s13075-015-0756-5

Observational Study

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

Silje Reiseter et al. Arthritis Res Ther. 2015.

. 2015 Aug 28;17(1):231.

doi: 10.1186/s13075-015-0756-5.

Authors

Affiliations

¹ Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. silje.reiseter@medisin.uio.no.
² Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. oyvind.molberg@medisin.uio.no.
³ Department of Rheumatology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. oyvind.molberg@medisin.uio.no.
⁴ Department of Rheumatology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. rgunnars@ous-hf.no.
⁵ Department of Respiratory Medicine, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. mblund@ous-hf.no.
⁶ Department of Radiology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. taalokke@ous-hf.no.
⁷ Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. paukrust@ous-hf.no.
⁸ Department of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. paukrust@ous-hf.no.
⁹ Research Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. paukrust@ous-hf.no.
¹⁰ K. G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. paukrust@ous-hf.no.
¹¹ K. G. Jebsen Thrombosis Research and Expertise Centre, The Arctic University of Norway, Langnes, 9037, Tromsø, Norway. paukrust@ous-hf.no.
¹² Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. thor.ueland@medisin.uio.no.
¹³ Research Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. thor.ueland@medisin.uio.no.
¹⁴ K. G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. thor.ueland@medisin.uio.no.
¹⁵ K. G. Jebsen Thrombosis Research and Expertise Centre, The Arctic University of Norway, Langnes, 9037, Tromsø, Norway. thor.ueland@medisin.uio.no.
¹⁶ Department of Rheumatology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. tgaren@ous-hf.no.
¹⁷ Oslo Centre for Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Ullevål, 0424, Oslo, Norway. cathrine.brunborg@ous-hf.no.
¹⁸ Research Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. annika.michelsen@medisin.uio.no.
¹⁹ K. G. Jebsen Thrombosis Research and Expertise Centre, The Arctic University of Norway, Langnes, 9037, Tromsø, Norway. annika.michelsen@medisin.uio.no.
²⁰ Research Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. Aurelija.abraityte@rr-research.no.
²¹ K. G. Jebsen Thrombosis Research and Expertise Centre, The Arctic University of Norway, Langnes, 9037, Tromsø, Norway. Aurelija.abraityte@rr-research.no.
²² Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. a.m.hoffmann-vold@medisin.uio.no.
²³ Department of Rheumatology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway. a.m.hoffmann-vold@medisin.uio.no.

PMID: 26315510
PMCID: PMC4551562
DOI: 10.1186/s13075-015-0756-5

Abstract

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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Figures

**Fig. 1**
a-b Endostatin and vascular endothelial growth factor (VEGF) serum levels in systemic sclerosis (SSc), mixed connective tissue disease (MCTD) and controls

**Fig. 2**
a, b and c Mean endostatin levels in different systemic sclerosis (SSc) subsets

**Fig. 3**
a and b Mean endostatin levels and clinical parameters in mixed connective tissue disease (MCTD)

**Fig. 4**
Kaplan-Meier curve for tertiles of endostatin

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

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LinkOut - more resources

Full Text Sources

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