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Scleroderma pp 247–253Cite as

Vascular Biomarkers

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Abstract

Vascular disease is present in every patient with scleroderma and is one of the major sources of morbidity and mortality. It seems, however, that only a subset of patients will develop clinically overt and severe vascular outcomes such as pulmonary hypertension (PH). In addition, different vascular events occur across the duration of the disease with some events almost uniformly early (renal crisis) or late (pulmonary hypertension), and some spanning the entire disease duration (digital ulceration). The inciting events in the microvasculature occur early in the disease course, but there is a subset of patients that have an ongoing chronic insult, the end result of which are a net loss of functional vessels and events such as digital ischemia and pulmonary arterial hypertension (PAH). The ability to detect this process and define it via simple and accessible means (i.e., peripheral blood sampling) would be of great value in terms of defining prognosis, guiding new therapies and potentially targeting therapies in high-risk groups with early indicators of progression. We have a significant amount of evidence of vascular perturbation from studies of peripheral blood in scleroderma, but know very little about the role these measured factors play in pathogenesis or their utility to predict vascular morbidity. This chapter summarizes our current knowledge of biomarkers of vascular disease in scleroderma and explores possible directions of future research in this area.

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References

  1. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95.

    Article  Google Scholar 

  2. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum. 2005;35(1):35–42.

    Article  PubMed  CAS  Google Scholar 

  3. Steen V, Denton CP, Pope JE, Matucci-Cerinic M. Digital ulcers: overt vascular disease in systemic sclerosis. Rheumatology (Oxford). 2009;3(48 Suppl):iii19–24.

    Article  Google Scholar 

  4. Bonassi S, Au WW. Biomarkers in molecular epidemiology studies for health risk prediction. Mutat Res. 2002;511(1):73–86.

    Article  PubMed  CAS  Google Scholar 

  5. Steen V, Medsger Jr TA. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum. 2003;48(2):516–22.

    Article  PubMed  Google Scholar 

  6. Allanore Y, Borderie D, Avouac J, et al. High N-terminal pro-brain natriuretic peptide levels and low diffusing capacity for carbon monoxide as independent predictors of the occurrence of precapillary pulmonary arterial hypertension in patients with systemic sclerosis. Arthritis Rheum. 2008;58(1):284–91.

    Article  PubMed  CAS  Google Scholar 

  7. Herrick AL, Illingworth K, Blann A, Hay CR, Hollis S, Jayson MI. Von Willebrand factor, thrombomodulin, thromboxane, beta-thromboglobulin and markers of fibrinolysis in primary Raynaud’s phenomenon and systemic sclerosis. Ann Rheum Dis. 1996;55(2):122–7.

    Article  PubMed  CAS  Google Scholar 

  8. Abraham DJ, Vancheeswaran R, Dashwood MR, et al. Increased levels of endothelin-1 and differential endothelin type A and B receptor expression in scleroderma-associated fibrotic lung disease. Am J Pathol. 1997;151(3):831–41.

    PubMed  CAS  Google Scholar 

  9. Morelli S, Ferri C, Polettini E, et al. Plasma endothelin-1 levels, pulmonary hypertension, and lung fibrosis in patients with systemic sclerosis. Am J Med. 1995;99(3):255–60.

    Article  PubMed  CAS  Google Scholar 

  10. Morelli S, Ferri C, Di Francesco L, et al. Plasma endothelin-1 levels in patients with systemic sclerosis: influence of pulmonary or systemic arterial hypertension. Ann Rheum Dis. 1995;54(9):730–4.

    Article  PubMed  CAS  Google Scholar 

  11. Mukerjee D, Yap LB, Ong V, et al. The myth of pulmonary Raynaud’s phenomenon: the contribution of pulmonary arterial vasospasm in patients with systemic sclerosis related pulmonary arterial hypertension. Ann Rheum Dis. 2004;63(12):1627–31.

    Article  PubMed  CAS  Google Scholar 

  12. Sulli A, Soldano S, Pizzorni C, et al. Raynaud’s phenomenon and plasma endothelin: correlations with capillaroscopic patterns in systemic sclerosis. J Rheumatol. 2009;36(6):1235–9.

    Article  PubMed  CAS  Google Scholar 

  13. Kim HS, Park MK, Kim HY, Park SH. Capillary dimension measured by computer-based digitalized image correlated with plasma endothelin-1 levels in patients with systemic sclerosis. Clin Rheumatol. 2010;29(3):247–54.

    Article  PubMed  Google Scholar 

  14. Stratton RJ, Coghlan JG, Pearson JD, et al. Different patterns of endothelial cell activation in renal and pulmonary vascular disease in scleroderma. QJM. 1998;91(8):561–6.

    Article  PubMed  CAS  Google Scholar 

  15. Pendergrass SA, Hayes E, Farina G, et al. Limited systemic sclerosis patients with pulmonary arterial hypertension show biomarkers of inflammation and vascular injury. PLoS One. 2010;5(8):e12106.

    Article  PubMed  Google Scholar 

  16. Distler O, Del Rosso A, Giacomelli R, et al. 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. 2002;4(6):R11.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  18. Hummers LK, Hall A, Wigley FM, Simons M. Abnormalities in the regulators of angiogenesis in patients with scleroderma. J Rheumatol. 2009;36(3):576–82.

    Article  PubMed  Google Scholar 

  19. Solanilla A, Villeneuve J, Auguste P, et al. The transport of high amounts of vascular endothelial growth factor by blood platelets underlines their potential contribution in systemic sclerosis angiogenesis. Rheumatology (Oxford). 2009;48(9):1036–44.

    Article  CAS  Google Scholar 

  20. Kuryliszyn-Moskal A, Klimiuk PA, Sierakowski S. Soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement. Clin Rheumatol. 2005;24(2):111–6.

    Article  PubMed  Google Scholar 

  21. Papaioannou AI, Zakynthinos E, Kostikas K, et al. Serum VEGF levels are related to the presence of pulmonary arterial hypertension in systemic sclerosis. BMC Pulm Med. 2009;9:18.

    Article  PubMed  Google Scholar 

  22. Dor Y, Djonov V, Abramovitch R, et al. Conditional switching of VEGF provides new insights into adult neovascularization and pro-­angiogenic therapy. EMBO J. 2002;21(8):1939–47.

    Article  PubMed  CAS  Google Scholar 

  23. D’Alessio S, Fibbi G, Cinelli M, et al. Matrix metalloproteinase 12-dependent cleavage of urokinase receptor in systemic sclerosis microvascular endothelial cells results in impaired angiogenesis. Arthritis Rheum. 2004;50(10):3275–85.

    Article  PubMed  Google Scholar 

  24. Avouac J, Wipff J, Goldman O, et al. Angiogenesis in systemic sclerosis: impaired expression of vascular endothelial growth factor receptor 1 in endothelial progenitor-derived cells under hypoxic conditions. Arthritis Rheum. 2008;58(11):3550–61.

    Article  PubMed  CAS  Google Scholar 

  25. Grigoryev DN, Mathai SC, Fisher MR, et al. Identification of candidate genes in scleroderma-related pulmonary arterial hypertension. Transl Res. 2008;151(4):197–207.

    Article  PubMed  CAS  Google Scholar 

  26. Allanore Y, Borderie D, Airo P, et al. Lack of association between three vascular endothelial growth factor gene polymorphisms and systemic sclerosis: results from a multicenter EUSTAR study of European Caucasian patients. Ann Rheum Dis. 2007;66(2):257–9.

    Article  PubMed  CAS  Google Scholar 

  27. Wipff J, Avouac J, Borderie D, et al. Disturbed angiogenesis in systemic sclerosis: high levels of soluble endoglin. Rheumatology (Oxford). 2008;47(7):972–5.

    Article  CAS  Google Scholar 

  28. Hummers LK, Simons M, Wigley FM, Mulligan-Kehoe MJ. Circulating inhibitors of angiogenesis in scleroderma. Paper presented at: American College of Rheumatology Annual Meeting, 2009; Philadelphia, PA.

    Google Scholar 

  29. Fujimoto M, Hasegawa M, Hamaguchi Y, et al. A clue for telangiectasis in systemic sclerosis: elevated serum soluble endoglin levels in patients with the limited cutaneous form of the disease. Dermatology. 2006;213(2):88–92.

    Article  PubMed  CAS  Google Scholar 

  30. Coral-Alvarado PX, Garces MF, Caminos JE, Iglesias-Gamarra A, Restrepo JF, Quintana G. Serum endoglin levels in patients suffering from systemic sclerosis and elevated systolic pulmonary arterial pressure. Int J Rheumatol. 2010. Epub 2010 Aug 24.

    Google Scholar 

  31. Wipff J, Kahan A, Hachulla E, et al. Association between an endoglin gene polymorphism and systemic sclerosis-related pulmonary arterial hypertension. Rheumatology (Oxford). 2007;46(4):622–5.

    Article  CAS  Google Scholar 

  32. Steinberg G, Khankin EV, Karumanchi SA. Angiogenic factors and preeclampsia. Thromb Res. 2009;123(Suppl 2):S93–9.

    Article  PubMed  Google Scholar 

  33. Kovalchik MT, Guggenheim SJ, Silverman MH, Robertson JS, Steigerwald JC. The kidney in progressive systemic sclerosis: a prospective study. Ann Intern Med. 1978;89(6):881–7.

    PubMed  CAS  Google Scholar 

  34. Cannon PJ, Hassar M, Case DB, Casarella WJ, Sommers SC, LeRoy EC. The relationship of hypertension and renal failure in scleroderma (progressive systemic sclerosis) to structural and functional abnormalities of the renal cortical circulation. Medicine (Baltimore). 1974;53(1):1–46.

    Article  CAS  Google Scholar 

  35. Nihtyanova SI, Parker JC, Black CM, Bunn CC, Denton CP. A longitudinal study of anti-RNA polymerase III antibody levels in systemic sclerosis. Rheumatology (Oxford). 2009;48(10):1218–21.

    Article  CAS  Google Scholar 

  36. Nguyen B, Mayes MD, Arnett FC, et al. HLA-DRB1*0407 and *1304 are risk factors for scleroderma renal crisis. Arthritis Rheum 2011; 63(2):S30–4.

    Google Scholar 

  37. Snow JL, Kawut SM. Surrogate end points in pulmonary arterial hypertension: assessing the response to therapy. Clin Chest Med. 2007;28(1):75–89, viii.

    Article  PubMed  Google Scholar 

  38. Williamson DJ, Wallman LL, Jones R, et al. Hemodynamic effects of Bosentan, an endothelin receptor antagonist, in patients with pulmonary hypertension. Circulation. 2000;102(4):411–8.

    PubMed  CAS  Google Scholar 

  39. Sfikakis PP, Papamichael C, Stamatelopoulos KS, et al. Improvement of vascular endothelial function using the oral endothelin receptor antagonist bosentan in patients with systemic sclerosis. Arthritis Rheum. 2007;56(6):1985–93.

    Article  PubMed  CAS  Google Scholar 

  40. Mittag M, Beckheinrich P, Haustein UF. Systemic sclerosis-related Raynaud’s phenomenon: effects of iloprost infusion therapy on serum cytokine, growth factor and soluble adhesion molecule levels. Acta Derm Venereol. 2001;81(4):294–7.

    Article  PubMed  CAS  Google Scholar 

  41. Korn JH, Mayes M, Matucci Cerinic M, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 2004;50(12):3985–93.

    Article  PubMed  CAS  Google Scholar 

  42. Andreassen AK, Wergeland R, Simonsen S, Geiran O, Guevara C, Ueland T. N-terminal pro-B-type natriuretic peptide as an indicator of disease severity in a heterogeneous group of patients with chronic precapillary pulmonary hypertension. Am J Cardiol. 2006;98(4):525–9.

    Article  PubMed  CAS  Google Scholar 

  43. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55(18):1915–22.

    Article  PubMed  CAS  Google Scholar 

  44. Simeoni S, Lippi G, Puccetti A, et al. N-terminal pro-BNP in sclerodermic patients on bosentan therapy for PAH. Rheumatol Int. 2008;28(7):657–60.

    Article  PubMed  CAS  Google Scholar 

  45. Dimitroulas T, Giannakoulas G, Karvounis H, et al. N-terminal probrain natriuretic peptide as a biochemical marker in the evaluation of bosentan treatment in systemic-sclerosis-related pulmonary arterial hypertension. Clin Rheumatol. 2008;27(5):655–8.

    Article  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Medicine, Division of Rheumatology, Johns Hopkins University, Baltimore, MD, USA

    Laura K. Hummers MD, ScM

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  1. Laura K. Hummers MD, ScM
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Correspondence to Laura K. Hummers MD, ScM .

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Editors and Affiliations

  1. Feinberg School of Medicine, Northwestern University, E. Huron Street 240, Chicago, 60611-2909, Illinois, USA

    John Varga

  2. Royal Free and University College, Medical School, University College London, Rowland Street, London, NW3 2PF, United Kingdom

    Christopher P. Denton

  3. School of Medicine, Div. Rheumatology, Johns Hopkins University, Eastern Avenue 5200, Baltimore, 21224, Maryland, USA

    Fredrick M. Wigley

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Hummers, L.K. (2012). Vascular Biomarkers. In: Varga, J., Denton, C., Wigley, F. (eds) Scleroderma. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-5774-0_20

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  • DOI: https://doi.org/10.1007/978-1-4419-5774-0_20

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  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4419-5773-3

  • Online ISBN: 978-1-4419-5774-0

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