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Impaired angiogenesis as a feature of digital ulcers in systemic sclerosis

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Abstract

Impaired angiogenesis in systemic sclerosis has a major role in tissue injury pathogenesis. Our objective was to determine whether angiogenic biomarkers (vascular endothelial growth factor (VEGF), endoglin, and endostatin) are related to microvascular damage and to determine their predictive value for new digital ulcers (DU). The main outcome of the study was the occurrence of a new digital ulcer during 3-year follow-up. This prospective longitudinal study was performed between October 2011 and December 2014. Seventy-seven patients definitely diagnosed with systemic sclerosis where divided into two groups: those with active DU at baseline and those with no DU until enrollment. Patients were matched by sex and age with healthy controls. Serum levels of VEGF, endoglin, and endostatin were measured at enrollment, and several nailfold videocapillaroscopies were performed during the 3-year follow-up. Serum levels of VEGF were lower (245.06, 158.68–347.33; p < 0.001) and those of endoglin were higher (3.013, 1.463–7.023; p < 0.001) in patients with active DU than those with no DU history (339.49, 202.00–730.93/1.879, 0.840–3.280), and they were higher than those found in controls (178.030, 101.267–222.102)/0.277, 0.154–0.713), respectively. No differences in endostatin levels were found between groups (p = 0.450). Endoglin was the only biomarker significantly different (p = 0.031) between patients with diffuse versus limited systemic sclerosis and between early, active, and late patterns (p = 0.020). VEGF was identified as an independent predictor for the development of new DU. Our study confirmed the relationship between angiogenic vascular biomarkers and the occurrence of DU. Endoglin and VEGF serum levels are potential risk factors, and VEGF has a predictive value for the occurrence of new DU.

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References

  1. Avouac J, Vallucci M, Smith V, Senet P, Ruiz B, Sulli A et al (2013) Correlations between angiogenic factors and capillaroscopic patterns in systemic sclerosis. Arthritis Res Ther 15(2):R55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Silva I, Almeida J, Vasconcelos C (2015) A PRISMA-driven systematic review for predictive risk factors of digital ulcers in systemic sclerosis patients. Autoimmun Rev 14(2):140–52

    Article  CAS  PubMed  Google Scholar 

  3. Herrick AL (2013) Management of Raynaud’s phenomenon and digital ischemia. Curr Rheumatol Rep 15(1):303

    Article  PubMed  Google Scholar 

  4. Ferri C, Valentini G, Cozzi F, Sebastiani M, Michelassi C, La Montagna G et al (2002) Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine 81(2):139–53

    Article  PubMed  Google Scholar 

  5. Amanzi L, Braschi F, Fiori G, Galluccio F, Miniati I, Guiducci S et al (2010) Digital ulcers in scleroderma: staging, characteristics and sub-setting through observation of 1614 digital lesions. Rheumatol (Oxford, England) 49(7):1374–82

    Article  Google Scholar 

  6. Rabquer BJ, Koch AE (2012) Angiogenesis and vasculopathy in systemic sclerosis: evolving concepts. Curr Rheumatol Rep 14(1):56–63

    Article  PubMed  Google Scholar 

  7. Lambova SN, Muller-Ladner U (2010) Capillaroscopic pattern in systemic sclerosis—an association with dynamics of processes of angio- and vasculogenesis. Microvasc Res 80(3):534–9

    Article  PubMed  Google Scholar 

  8. Distler O, Del Rosso A, Giacomelli R, Cipriani P, Conforti ML, Guiducci S et al (2002) Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers. Arthritis Res 4(6):R11

    Article  PubMed  PubMed Central  Google Scholar 

  9. Guiducci S, Distler O, Distler JH, Matucci-Cerinic M (2008) Mechanisms of vascular damage in SSc—implications for vascular treatment strategies. Rheumatol (Oxford, England) 47(Suppl 5):v18–20

    Article  CAS  Google Scholar 

  10. Serrati S, Chilla A, Laurenzana A, Margheri F, Giannoni E, Magnelli L et al (2013) Systemic sclerosis endothelial cells recruit and activate dermal fibroblasts by induction of a connective tissue growth factor (CCN2)/transforming growth factor beta-dependent mesenchymal-to-mesenchymal transition. Arthritis Rheum 65(1):258–69

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Farouk HM, Hamza SH, El Bakry SA, Youssef SS, Aly IM, Moustafa AA et al (2013) Dysregulation of angiogenic homeostasis in systemic sclerosis. Int J Rheum Dis 16(4):448–54

    Article  CAS  PubMed  Google Scholar 

  13. Wipff J, Avouac J, Borderie D, Zerkak D, Lemarechal H, Kahan A et al (2008) Disturbed angiogenesis in systemic sclerosis: high levels of soluble endoglin. Rheumatol (Oxford, England) 47(7):972–5

    Article  CAS  Google Scholar 

  14. O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS et al (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88(2):277–85

    Article  PubMed  Google Scholar 

  15. Hebbar M, Peyrat JP, Hornez L, Hatron PY, Hachulla E, Devulder B (2000) Increased concentrations of the circulating angiogenesis inhibitor endostatin in patients with systemic sclerosis. Arthritis Rheum 43(4):889–93

    Article  CAS  PubMed  Google Scholar 

  16. Committee SfSCotARADaTC. Preliminary criteria for the classification of systemic sclerosis (scleroderma). 1980;23:581–90.

  17. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr et al (1988) Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. The Journal of rheumatology 15(2):202–5

    CAS  PubMed  Google Scholar 

  18. Cutolo M, Pizzorni C, Secchi ME, Sulli A (2008) Capillaroscopy. Best Prac Res Clin Rheumatol 22(6):1093–108

    Article  Google Scholar 

  19. Medsger TA Jr, Silman AJ, Steen VD, Black CM, Akesson A, Bacon PA et al (1999) A disease severity scale for systemic sclerosis: development and testing. J Rheumatol 26(10):2159–67

    PubMed  Google Scholar 

  20. Distler O, Distler JH, Scheid A, Acker T, Hirth A, Rethage J et al (2004) Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis. Circ Res 95(1):109–16

    Article  CAS  PubMed  Google Scholar 

  21. Coral-Alvarado PX, Garces MF, Caminos JE, Iglesias-Gamarra A, Restrepo JF, Quintana G (2010) Serum endoglin levels in patients suffering from systemic sclerosis and elevated systolic pulmonary arterial pressure. Int J Rheumatol 2010

  22. Morris E, Chrobak I, Bujor A, Hant F, Mummery C, Ten Dijke P et al (2011) Endoglin promotes TGF-beta/Smad1 signaling in scleroderma fibroblasts. J Cell Physiol 226(12):3340–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Michalska-Jakubus M, Kowal-Bielecka O, Chodorowska G, Bielecki M, Krasowska D (2011) Angiopoietins-1 and -2 are differentially expressed in the sera of patients with systemic sclerosis: high angiopoietin-2 levels are associated with greater severity and higher activity of the disease. Rheumatol (Oxford, England) 50(4):746–55

    Article  CAS  Google Scholar 

  24. Ichimura Y, Asano Y, Akamata K, Aozasa N, Noda S, Taniguchi T et al (2013) Serum angiopoietin-like protein 3 levels: possible correlation with progressive skin sclerosis, digital ulcers and pulmonary vascular involvement in patients with systemic sclerosis. Acta Derm Venereol

  25. Manetti M, Guiducci S, Ibba-Manneschi L, Matucci-Cerinic M (2011) Impaired angiogenesis in systemic sclerosis: the emerging role of the antiangiogenic VEGF(165)b splice variant. Trends Cardiovasc Med 21(7):204–10

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was partially supported by an investigational grant from Centro Hospitalar do Porto. The authors thank the Clinical Pathology Department for their valuable technical assistance.

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Authors and Affiliations

  1. Angiology and Vascular Surgery Service and Clinical Immunology Unit, Centro Hospitalar do Porto, Porto, Portugal

    Ivone Silva

  2. Internal Medicine, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal

    Cristiana Almeida

  3. Health Information and Decision Sciences Department, CINTESIS— Center for Research in Health Technologies and Information Systems, Universidade do Porto, Porto, Portugal

    Andreia Teixeira

  4. Clinical Pathology Department, Clinical Chemistry, Centro Hospitalar do Porto, Porto, Portugal

    José Oliveira

  5. Clinical Immunology Unit, Centro Hospitalar do Porto; Instituto de Ciências Biomédicas Abel Salazar, Multidisciplinar Unit of biomedical investigation, University of Porto, Porto, Portugal

    Carlos Vasconcelos

Authors
  1. Ivone Silva
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  2. Cristiana Almeida
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  3. Andreia Teixeira
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  4. José Oliveira
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  5. Carlos Vasconcelos
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Corresponding author

Correspondence to Ivone Silva.

Ethics declarations

This study was approved by the institutional review board (including the Ethical for Health Committee of Centro Hospitalar do Porto). All patients or parents, in the cases of the two children, signed informed consents before inclusion in the study. Data were collected by analysis of clinical file data and by clinical interview.

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Silva, I., Almeida, C., Teixeira, A. et al. Impaired angiogenesis as a feature of digital ulcers in systemic sclerosis. Clin Rheumatol 35, 1743–1751 (2016). https://doi.org/10.1007/s10067-016-3219-8

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  • DOI: https://doi.org/10.1007/s10067-016-3219-8

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