Skip to main content

Advertisement

Log in

Microvascular damage in systemic sclerosis: Detection and monitoring with biomarkers

  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Vascular disease is universal in patients with systemic sclerosis (SSc), but there is a wide variability in its severity. It is clear that there is an early insult to the microvasculature, followed-up by on-going chronic process. This results in profound vascular damage in a subset of patients who develop severe events such as digital loss and pulmonary arterial hypertension. Although there is abundant evidence of vascular perturbation from studies of peripheral blood in SSc, there are few data about the ability to use these biomarkers to predict vascular outcomes. This paper examines the possibility of using circulating biomarkers to assess vascular disease activity and to predict severe vascular events among patients with SSc.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Ungerer RG, Tashkin DP, Furst D, et al.: Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis. Am J Med 1983, 75:65–74.

    Article  PubMed  CAS  Google Scholar 

  2. ter Borg EJ, Piersma-Wichers G, Smit AJ, et al.: Serial nailfold capillary microscopy in primary Raynaud’s phenomenon and scleroderma. Semin Arthritis Rheum 1994, 24:40–47.

    Article  PubMed  Google Scholar 

  3. Ohtsuka T, Hasegawa A, Nakano A, et al.: Nailfold capillary abnormality and pulmonary hypertension in systemic sclerosis. Int J Dermatol 1997, 36:116–122.

    Article  PubMed  CAS  Google Scholar 

  4. Ong YY, Nikoloutsopoulos T, Bond CP, et al.: Decreased nailfold capillary density in limited scleroderma with pulmonary hypertension. Asian Pac J Allergy Immunol 1998, 16:81–86.

    PubMed  CAS  Google Scholar 

  5. Steen V, Medsger TA, Jr.: Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum 2003, 48:516–522. This case-control study looked retrospectively at clinical predictors of PAH among patients with limited scleroderma. They found that there was a linear decline in diffusing capacity years preceding the diagnosis of PAH.

    Article  PubMed  Google Scholar 

  6. Medsger TA, Jr.: Assessment of damage and activity in systemic sclerosis. Curr Opin Rheumatol 2000, 12:545–548.

    Article  PubMed  Google Scholar 

  7. Medsger TA Jr., Silman AJ, Steen VD, et al.: A disease severity scale for systemic sclerosis: development and testing. J Rheumatol 1999, 26:2159–2167.

    PubMed  Google Scholar 

  8. Clements PJ, Wong WK, Hurwitz EL, et al.: The Disability Index of the Health Assessment Questionnaire is a predictor and correlate of outcome in the high-dose versus low-dose penicillamine in systemic sclerosis trial. Arthritis Rheum 2001, 44:653–661.

    Article  PubMed  CAS  Google Scholar 

  9. Biomarkers Definitions Working Group: Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001, 69:89–95.

    Article  Google Scholar 

  10. Kahaleh MB: Vascular involvement in systemic sclerosis (SSc). Clin Exp Rheumatol 2004, 22(Suppl 33):S19-S23. This is a nice over view of the histor y and recent progress in our understanding of the scleroderma vascular disease.

    PubMed  CAS  Google Scholar 

  11. Sgonc R, Gruschwitz MS, Dietrich H, et al.: Endothelial cell apoptosis is a primar y pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest 1996, 98:785–792.

    PubMed  CAS  Google Scholar 

  12. Kahaleh MB, Fan PS: Mechanism of serum-mediated endothelial injur y in scleroderma: identification of a granular enzyme in scleroderma skin and sera. Clin Immunol Immunopathol 1997, 83:32–40.

    Article  PubMed  CAS  Google Scholar 

  13. Sgonc R, Gruschwitz MS, Boeck G, et al.: Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95. Arthritis Rheum 2000, 43:2550–2562.

    Article  PubMed  CAS  Google Scholar 

  14. Ihn H, Sato S, Fujimoto M, et al.: Characterization of autoantibodies to endothelial cells in systemic sclerosis (SSc): association with pulmonar y fibrosis. Clin Exp Immunol 2000, 119:203–209.

    Article  PubMed  CAS  Google Scholar 

  15. Tamby MC, Chanseaud Y, Humbert M, et al.: Antiendothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonar y arterial hypertension. Thorax 2005, 60:765–772.

    Article  PubMed  CAS  Google Scholar 

  16. Kahaleh MB, LeRoy EC: Autoimmunity and vascular involvement in systemic sclerosis (SSc). Autoimmunity 1999, 31:195–214.

    Article  PubMed  CAS  Google Scholar 

  17. Gordon JL, Pottinger BE, Woo P, et al.: Plasma von Willebrand factor in connective tissue disease. Ann Rheum Dis 1987, 46:491–492.

    PubMed  CAS  Google Scholar 

  18. Marasini B, Cugno M, Bassani C, et al.: Tissue-type plasminogen activator and von Willebrand factor plasma levels as markers of endothelial involvement in patients with Raynaud’s phenomenon. Int J Microcirc Clin Exp 1992, 11:375–382.

    PubMed  CAS  Google Scholar 

  19. Blann AD, Illingworth K, Jayson MI: Mechanisms of endothelial cell damage in systemic sclerosis and Raynaud’s phenomenon. J Rheumatol 1993, 20:1325–1330.

    PubMed  CAS  Google Scholar 

  20. Herrick AL, Illingworth K, Blann A, et al.: Von Willebrand factor, thrombomodulin, thromboxane, beta-thromboglobulin and markers of fibrinolysis in primar y Raynaud’s phenomenon and systemic sclerosis. Ann Rheum Dis 1996, 55:122–127.

    Article  PubMed  CAS  Google Scholar 

  21. Scheja A, Akesson A, Geborek P, et al.: Von Willebrand factor propeptide as a marker of disease activity in systemic sclerosis (scleroderma). Arthritis Res 2001, 3:178–182.

    Article  PubMed  CAS  Google Scholar 

  22. Hesselstrand R, Ekman R, Eskilsson J, et al.: Screening for pulmonar y hypertension in systemic sclerosis: the longitudinal development of tricuspid gradient in 227 consecutive patients, 1992–2001. Rheumatology (Oxford) 2005, 44:366–371.

    Article  CAS  Google Scholar 

  23. Vancheeswaran R, Magoulas T, Efrat G, et al.: Circulating endothelin-1 levels in systemic sclerosis subsets-a marker of fibrosis or vascular dysfunction? J Rheumatol 1994, 21:1838–1844.

    PubMed  CAS  Google Scholar 

  24. Yamane K, Miyauchi T, Suzuki N, et al.: Significance of plasma endothelin-1 levels in patients with systemic sclerosis. J Rheumatol 1992, 19:1566–1571.

    PubMed  CAS  Google Scholar 

  25. Cambrey AD, Harrison NK, Dawes KE, et al.: Increased levels of endothelin-1 in bronchoalveolar lavage.uid from patients with systemic sclerosis contribute to.broblast mitogenic activity in vitro. Am J Respir Cell Mol Biol 1994, 11:439–445.

    PubMed  CAS  Google Scholar 

  26. 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, 24:111–116.

    Article  PubMed  Google Scholar 

  27. Del Papa N, Colombo G, Fracchiolla N, et al.: Circulating endothelial cells as a marker of ongoing vascular disease in systemic sclerosis. Arthritis Rheum 2004, 50:1296–1304. This study examined circulating endothelial cells as a potential marker of vascular damage and circulating endothelial progenitor cells as an indicator of vasculogenesis. Levels of both were noted to be elevated in scleroderma patients.

    Article  Google Scholar 

  28. 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:R11. Cross-sectional study of multiple regulators of angiogenesis, with correlation with clinical features.

    Article  PubMed  Google Scholar 

  29. 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, 81:294–297.

    Article  PubMed  CAS  Google Scholar 

  30. Choi JJ, Min DJ, Cho ML, et al.: Elevated vascular endothelial growth factor in systemic sclerosis. J Rheumatol 2003, 30:1529–1533.

    PubMed  CAS  Google Scholar 

  31. Hummers LK, Wigley FM, Simons M: Evidence for Abnormal Angiogenesis in Scleroderma Patients. Arthritis Rheum 2004, 50(Suppl 9):S630.

    Google Scholar 

  32. Kawaguchi Y, Harigai M, Hara M, et al.: Expression of hepatocyte growth factor and its receptor (c-met) in skin fibroblasts from patients with systemic sclerosis. J Rheumatol 2002, 29:1877–1883.

    PubMed  CAS  Google Scholar 

  33. Wu MH, Yokozeki H, Takagawa S, et al.: Hepatocyte growth factor both prevents and ameliorates the symptoms of dermal sclerosis in a mouse model of scleroderma. Gene Ther 2004, 11:170–180.

    Article  PubMed  CAS  Google Scholar 

  34. Morishita R, Aoki M, Hashiya N, et al.: Therapeutic angiogenesis using hepatocyte growth factor (HGF). Curr Gene Ther 2004, 4:199–206.

    PubMed  CAS  Google Scholar 

  35. Hebbar M, Peyrat JP, Hornez L, et al.: Increased concentrations of the circulating angiogenesis inhibitor endostatin in patients with systemic sclerosis. Arthritis Rheum 2000, 43:889–893.

    Article  PubMed  CAS  Google Scholar 

  36. Dziankowska-Bartkowiak B, Waszczykowska E, Zalewska A, Sysa-Jedrzejowska A: Correlation of endostatin and tissue inhibitor of metalloproteinases 2 (TIMP2) serum levels with cardiovascular involvement in systemic sclerosis patients. Mediators Inflamm 2005, 2005:144–149.

    Article  PubMed  CAS  Google Scholar 

  37. Kuwana M, Okazaki Y, Yasuoka H, et al.: Defective vasculogenesis in systemic sclerosis. Lancet 2004, 364:603–610. This study also examined circulating endothelial progenitor cells and found that these cells were lower among scleroderma patients and that they had less ability to differentiate into endothelial cells. This suggests that defective vascular repair mechanisms may contribute to scleroderma vascular disease.

    Article  PubMed  CAS  Google Scholar 

  38. Macko RF, Gelber AC, Young BA, et al.: Increased circulating concentrations of the counteradhesive proteins SPARC and thrombospondin-1 in systemic sclerosis (scleroderma). Relationship to platelet and endothelial cell activation. J Rheumatol 2002, 29:2565–2570.

    PubMed  CAS  Google Scholar 

  39. Kahaleh MB, Osborn I, Leroy EC: Elevated levels of circulating platelet aggregates and beta-thromboglobulin in scleroderma. Ann Intern Med 1982, 96:610–913.

    PubMed  CAS  Google Scholar 

  40. Kowal-Bielecka O, Kowal K, Lewszuk A, et al.: Beta thromboglobulin and platelet factor 4 in bronchoalveolar lavage fluid of patients with systemic sclerosis. Ann Rheum Dis 2005, 64:484–486.

    Article  PubMed  CAS  Google Scholar 

  41. Lau CS, McLaren M, Saniabadi A, Belch JJ: Increased whole blood platelet aggregation in patients with Raynaud’s phenomenon with or without systemic sclerosis. Scand J Rheumatol 1993, 22:97–101.

    PubMed  CAS  Google Scholar 

  42. Lau CS, Khan F, McLaren M, et al.: The effects of thromboxane receptor blockade on platelet aggregation and digital skin blood flow in patients with secondary Raynaud’s syndrome. Rheumatol Int 1991, 11:163–168.

    Article  PubMed  CAS  Google Scholar 

  43. Goodfield MJ, Orchard MA, Rowell NR: Increased platelet sensitivity to collagen-induced aggregation in whole blood patients with systemic sclerosis. Clin Exp Rheumatol 1988, 6:285–288.

    PubMed  CAS  Google Scholar 

  44. Munkvad S, Gram J, Jespersen J: Depressed plasma fibrinolytic activity in a group of patients with connective tissue diseases. Scand J Rheumatol 1989, 18:277–282.

    PubMed  CAS  Google Scholar 

  45. Cerinic MM, Valentini G, Sorano GG, et al.: Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis. Semin Arthritis Rheum 2003, 32:285–295. Comprehensive look at a cross section of markers of impaired fibrinolysis, endothelial cell activation, and the coagulation cascade.

    Article  PubMed  CAS  Google Scholar 

  46. Ames PR, Lupoli S, Alves J, et al.: The coagulation/fibrinolysis balance in systemic sclerosis: evidence for a haematological stress syndrome. Br J Rheumatol 1997, 36:1045–1550.

    Article  PubMed  CAS  Google Scholar 

  47. Herrick AL, Matucci Cerinic M: The emerging problem of oxidative stress and the role of antioxidants in systemic sclerosis. Clin Exp Rheumatol 2001, 19:4–8.

    PubMed  CAS  Google Scholar 

  48. D’Angelo WA, Fries JF, Masi AT, Shulman LE: Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. Am J Med 1969, 46:428–440.

    Article  PubMed  CAS  Google Scholar 

  49. Su B, Mitra S, Gregg H, et al.: Redox regulation of vascular smooth muscle cell differentiation. Circ Res 2001, 89:39–46.

    PubMed  CAS  Google Scholar 

  50. Solans R, Motta C, Sola R, et al.: Abnormalities of erythrocyte membrane fluidity, lipid composition, and lipid peroxidation in systemic sclerosis: evidence of free radical-mediated injury. Arthritis Rheum 2000, 43:894–900.

    Article  PubMed  CAS  Google Scholar 

  51. Simonini G, Cerinic MM, Generini S, et al.: Oxidative stress in Systemic Sclerosis. Mol Cell Biochem 1999, 196:85–91.

    Article  PubMed  CAS  Google Scholar 

  52. Montuschi P, Ciabattoni G, Paredi P, et al.: 8-Isoprostane as a biomarker of oxidative stress in interstitial lung diseases. Am J Respir Crit Care Med 1998, 158:1524–1527.

    PubMed  CAS  Google Scholar 

  53. Stein CM, Tanner SB, Awad JA, et al.: Evidence of free radical-mediated injury (isoprostane overproduction) in scleroderma. Arthritis Rheum 1996, 39:1146–1150.

    Article  PubMed  CAS  Google Scholar 

  54. Volpe A, Biasi D, Caramaschi P, et al.: Levels of F2-isoprostanes in systemic sclerosis: correlation with clinical features. Rheumatology (Oxford) 2005, In press.

  55. Cope K A, Hummers LK, Wigley FM, et al.: Abnormal exhaled ethane concentrations in scleroderma. Biomarkers 2006, In press.

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Laura K. Hummers MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hummers, L.K. Microvascular damage in systemic sclerosis: Detection and monitoring with biomarkers. Curr Rheumatol Rep 8, 131–137 (2006). https://doi.org/10.1007/s11926-006-0053-z

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-006-0053-z

Keywords

Navigation