Elevated Serum Levels of Endostatin in Mixed Connective Tissue Disease – Association with Pulmonary Fibrosis and Digital Ulcers

Silje Reiseter¹, Ragnar Gunnarsson², Torhild Garen², May Brit Lund³, T. Mogens Aalokken⁴, Anna-Maria Hoffmann-Vold⁵, Øyvind Molberg^2,6 and Thor Ueland⁷, ¹Department of Rheumatology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, ²Department of Rheumatology, Oslo University Hospital Rikshospitalet, Oslo, Norway, ³Department of Respiratory Medicine, Oslo University Hospital Rikshopitalet, Oslo, Norway, ⁴Department of Radiology, Oslo University Hospital Rikshospitalet, Oslo, Norway, ⁵Department of Rheumatology, Department of Rheumatology, Oslo University Hospital Rikshospitalet, Oslo, Norway, ⁶Institute of Clinical Medicine, University of Oslo, Oslo, Norway, ⁷Research Institute for Internal Medicine, University of Oslo, Oslo, Norway

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Angiogenesis, Mixed connective tissue disease (MCTD), pathogenesis and systemic sclerosis

Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Clinical Aspects and Therapeutics: Determinants of Disease, Classification and Response

Session Type: Abstract Submissions (ACR)

Background/Purpose

Mixed Connective Tissue Disease (MCTD) is a chronic, immune-mediated disorder defined by the combined presence of serum anti-RNP antibodies and selected clinical features of Systemic Sclerosis (SSc), Systemic Lupus Erythematosus and Polymyositis. Previous studies have revealed increased values of endostatin and Vascular Endothelial Growth Factor (VEGF) in MCTD (1) and SSc (2), suggesting that an altered angiogenic balance might play a pathogenic role in both diseases. The aim of this study was to examine the serum levels of endostatin and VEGF in MCTD, compared to SSc and Healthy Controls (HC).

Methods

Sera of MCTD patients (N=169) from the cross-sectional nationwide Norwegian MCTD cohort (n=136) and the Norwegian Systemic Tissue Disease and Vasculitides Registry (NOSVAR) (n=33) were assessed. SSc patients (N=310) were included from NOSVAR. Age- and sex-matched healthy blood donors were included as HC (N=100). Clinical parameters examined in MCTD patients were; digital ulcers (N=136), pulmonary fibrosis (N=158) and Forced Vital Capacity (FVC) % of predicted value (N=142). Pulmonary fibrosis was defined according to the Fleischner Society classification system for high-resolution CT Abnormalities. Serum levels of endostatin and VEGF were assessed by ELISA and compared by Means (M) and Standard Deviation (SD) in all groups. Statistical differences were analyzed by the independent sample t-test with significance level P≤.05.

Results

The levels of endostatin were higher in the MCTD group M(SD) 83.0(24) ng/ml compared to HC 65.1(12) ng/ml (P<.001), but lower compared to SSc 93.0(37) ng/ml, (P<.001). The levels of VEGF in MCTD were not different compared to HC and SSc. However, levels of VEGF were elevated in SSc vs. HC (251.8(185) vs. 186.1(130) pg/ml, P<.001). MCTD patients with digital ulcers had higher endostatin levels (90.4(26) ng/ml) than MCTD patients without digital ulcers (79.6(21) ng/ml, P<.05). Mean endostatin levels were increased in MCTD patients with pulmonary fibrosis 90.5(33) ng/ml compared to MCTD without pulmonary fibrosis 79.9(20) ng/ml (P<.05). Correspondingly, MCTD patients with FVC< 80% had higher endostatin levels 94.5(33) ng/ml than MCTD patients with FVC ≥80% 81.8(21) ng/ml (P<.05).

Conclusion

MCTD patients have significantly elevated serum levels of endostatin, but not elevated serum levels of VEGF. Increased circulating levels of endostatin can indicate dysregulation of angiogenesis in MCTD, particularly in patient subgroups with digital ulcers and pulmonary fibrosis.

References:

1. Distler JH, Strapatsas T, Huscher D, Dees C, Akhmetshina A, Kiener HP, et al. Dysbalance of angiogenic and angiostatic mediators in patients with mixed connective tissue disease. Ann Rheum Dis 2011;70(7):1197-202.

2. Liakouli V, Cipriani P, Marrelli A, Alvaro S, Ruscitti P, Giacomelli R. Angiogenic cytokines and growth factors in systemic sclerosis. Autoimmun Rev 2011;10(10):590-4.

Disclosure:

S. Reiseter,
None;

R. Gunnarsson,
None;

T. Garen,
None;

M. B. Lund,
None;

T. M. Aalokken,
None;

A. M. Hoffmann-Vold,
None;

Molberg,
None;

T. Ueland,
None.

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