Skip to main content

Advertisement

SpringerLink
Log in

The Current State of Biomarkers in Systemic Sclerosis

  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Scleroderma is a complex, multisystem autoimmune rheumatic disease with wide heterogeneity in phenotype and outcome. There are often coexisting ongoing pathologic processes including immune system activation, progressive fibrosis, and vascular disease in subsets of patients. Currently, it is challenging to identify patients at risk for developing adverse outcomes and to determine which patients are responding to current therapies. For these reasons, it is highly valuable to find easily measurable biomarkers that may represent ongoing disease activity or treatment response. This review examines the current state of biomarker development in systemic sclerosis and identifies areas in which further work should be directed.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance

  1. Penn H, Howie AJ, Kingdon EJ, et al.: Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM 2007, 100:485–494.

    Article  CAS  PubMed  Google Scholar 

  2. Valentini G, Bencivelli W, Bombardieri S, et al.: European Scleroderma Study Group to define disease activity criteria for systemic sclerosis. III. Assessment of the construct validity of the preliminary activity criteria. Ann Rheum Dis 2003, 62:901–903.

    Article  CAS  PubMed  Google Scholar 

  3. Dziadzio M, Usinger W, Leask A, et al.: N-terminal connective tissue growth factor is a marker of the fibrotic phenotype in scleroderma. QJM 2005, 98:485–492.

    Article  CAS  PubMed  Google Scholar 

  4. Sato S, Nagaoka T, Hasegawa M, et al.: Serum levels of connective tissue growth factor are elevated in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. J Rheumatol 2000, 27:149–154.

    CAS  PubMed  Google Scholar 

  5. Dziadzio M, Smith RE, Abraham DJ, et al.: Circulating levels of active transforming growth factor beta1 are reduced in diffuse cutaneous systemic sclerosis and correlate inversely with the modified Rodnan skin score. Rheumatology (Oxford) 2005, 44:1518–1524.

    Article  CAS  Google Scholar 

  6. •• Sargent JL, Milano A, Bhattacharyya S, et al.: A TGFbeta-responsive gene signature is associated with a subset of diffuse scleroderma with increased disease severity. J Invest Dermatol 2009 Oct 8 (Epub ahead of print). This study used data from in vitro studies of scleroderma fibroblasts to develop a mechanistically derived gene expression profile. This TGF-β responsive gene signature from skin biopsies correlated with the diffuse subset of scleroderma and with more significant skin and lung disease.

  7. Chung L, Fiorentino DF, Benbarak MJ, et al.: Molecular framework for response to imatinib mesylate in systemic sclerosis. Arthritis Rheum 2009, 60:584–591.

    Article  CAS  PubMed  Google Scholar 

  8. Denton CP, Merkel PA, Furst DE, et al.: Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum 2007, 56:323–333.

    Article  CAS  PubMed  Google Scholar 

  9. Krieg T, Perlish JS, Fleischmajer R, Braun-Falco O: Collagen synthesis in scleroderma: selection of fibroblast populations during subcultures. Arch Dermatol Res 1985, 277:373–376.

    Article  CAS  PubMed  Google Scholar 

  10. Black CM, McWhirter A, Harrison NK, et al.: Serum type III procollagen peptide concentrations in systemic sclerosis and Raynaud’s phenomenon: relationship to disease activity and duration. Br J Rheumatol 1989, 28:98–103.

    Article  CAS  PubMed  Google Scholar 

  11. Diot E, Diot P, Valat C, et al.: Predictive value of serum III procollagen for diagnosis of pulmonary involvement in patients with scleroderma. Eur Respir J 1995, 8:1559–1565.

    Article  CAS  PubMed  Google Scholar 

  12. Scheja A, Wildt M, Wollheim FA, et al.: Circulating collagen metabolites in systemic sclerosis. Differences between limited and diffuse form and relationship with pulmonary involvement. Rheumatology (Oxford) 2000, 39:1110–1113.

    Article  CAS  Google Scholar 

  13. Heickendorff L, Zachariae H, Bjerring P, et al.: The use of serologic markers for collagen synthesis and degradation in systemic sclerosis. J Am Acad Dermatol 1995, 32:584–588.

    Article  CAS  PubMed  Google Scholar 

  14. Dziadzio M, Smith RE, Abraham DJ, et al.: Serological assessment of type I collagen burden in scleroderma spectrum disorders: a systematic review. Clin Exp Rheumatol 2004, 22:356–367.

    CAS  PubMed  Google Scholar 

  15. White B, Moore WC, Wigley FM, et al.: Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis. Ann Intern Med 2000, 132:947–954.

    CAS  PubMed  Google Scholar 

  16. Strange C, Bolster MB, Roth MD, et al.: Bronchoalveolar lavage and response to cyclophosphamide in scleroderma interstitial lung disease. Am J Respir Crit Care Med 2008, 177:91–98.

    Article  CAS  PubMed  Google Scholar 

  17. Yanaba K, Hasegawa M, Takehara K, Sato S: Comparative study of serum surfactant protein-D and KL-6 concentrations in patients with systemic sclerosis as markers for monitoring the activity of pulmonary fibrosis. J Rheumatol 2004, 31:1112–1120.

    CAS  PubMed  Google Scholar 

  18. • Hant FN, Ludwicka-Bradley A, Wang HJ, et al.: Surfactant protein D and KL-6 as serum biomarkers of interstitial lung disease in patients with scleroderma. J Rheumatol 2009, 36:773–780. In this study, serum collected from patients in the Scleroderma Lung Study was examined for these two glycoproteins that are secreted by pneumocytes. Researchers showed clear correlations of these markers with clinical measures of active lung disease in scleroderma including CT evidence of ground glass, BAL fluid cytology, and pulmonary function.

    Article  CAS  PubMed  Google Scholar 

  19. Luzina IG, Atamas SP, Wise R, et al.: Gene expression in bronchoalveolar lavage cells from scleroderma patients. Am J Respir Cell Mol Biol 2002, 26:549–557.

    CAS  PubMed  Google Scholar 

  20. Kodera M, Hasegawa M, Komura K, et al.: Serum pulmonary and activation-regulated chemokine/CCL18 levels in patients with systemic sclerosis: a sensitive indicator of active pulmonary fibrosis. Arthritis Rheum 2005, 52:2889–2896.

    Article  CAS  PubMed  Google Scholar 

  21. Prasse A, Pechkovsky DV, Toews GB, et al.: CCL18 as an indicator of pulmonary fibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis. Arthritis Rheum 2007, 56:1685–1693.

    Article  CAS  PubMed  Google Scholar 

  22. • Carulli MT, Handler C, Coghlan JG, et al.: Can CCL2 serum levels be used in risk stratification or to monitor treatment response in systemic sclerosis? Ann Rheum Dis 2008, 67:105–109. In this large cross-sectional study, the chemokine CCL2 was noted to be elevated in scleroderma and levels correlated with fibrotic disease features. This marker is notable for having clear variability with phenotype being higher in those with earlier, active disease.

    Article  CAS  PubMed  Google Scholar 

  23. Steen VD: Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 2005, 35:35–42.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  PubMed  Google Scholar 

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

    Article  Google Scholar 

  26. Peters-Golden M, Wise RA, Hochberg MC, et al.: Carbon monoxide diffusing capacity as predictor of outcome in systemic sclerosis. Am J Med 1984, 77:1027–1034.

    Article  CAS  PubMed  Google Scholar 

  27. Morgan C, Knight C, Lunt M, et al.: Predictors of end stage lung disease in a cohort of patients with scleroderma. Ann Rheum Dis 2003, 62:146–150.

    Article  CAS  PubMed  Google Scholar 

  28. Hachulla E, de Groote P, Gressin V, et al.: The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France. Arthritis Rheum 2009, 60:1831–1839.

    Article  PubMed  Google Scholar 

  29. • 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, 58:284–291. This is the first study to examine biomarkers to predict the development of pulmonary vascular disease in a prospective cohort study. Elevated levels of NT-proBNP predicted development of pulmonary vascular disease in this cohort.

    Article  CAS  PubMed  Google Scholar 

  30. Dimitroulas T, Giannakoulas G, Karvounis H, et al.: Natriuretic peptides in systemic sclerosis-related pulmonary arterial hypertension. Semin Arthritis Rheum 2009 Jun 16 (Epub ahead of print).

  31. Mathai SC, Hassoun PM: N-terminal brain natriuretic peptide in scleroderma-associated pulmonary arterial hypertension. Eur Heart J 2007, 28:140–141; author reply 141.

    Google Scholar 

  32. Williams MH, Handler CE, Akram R, et al.: Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension. Eur Heart J 2006, 27:1485–1494.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Hesselstrand R, Ekman R, Eskilsson J, et al.: Screening for pulmonary hypertension in systemic sclerosis: the longitudinal development of tricuspid gradient in 227 consecutive patients, 1992–2001. Rheumatology (Oxford) 2005, 44:366–371. (Published erratum appears in Rheumatology [Oxford] 2005, 44:569.)

  36. Iannone F, Riccardi MT, Guiducci S, et al.: Bosentan regulates the expression of adhesion molecules on circulating T cells and serum soluble adhesion molecules in systemic sclerosis-associated pulmonary arterial hypertension. Ann Rheum Dis 2008, 67:1121–1126.

    Article  CAS  PubMed  Google Scholar 

  37. 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, 151:831–841.

    CAS  PubMed  Google Scholar 

  38. 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, 54:730–734.

    Article  CAS  PubMed  Google Scholar 

  39. Shi-Wen X, Renzoni EA, Kennedy L, et al.: Endogenous endothelin-1 signaling contributes to type I collagen and CCN2 overexpression in fibrotic fibroblasts. Matrix Biol 2007, 26:625–632.

    Article  PubMed  Google Scholar 

  40. Stratton RJ, Coghlan JG, Pearson JD, et al.: Different patterns of endothelial cell activation in renal and pulmonary vascular disease in scleroderma. QJM 1998, 91:561–566.

    Article  CAS  PubMed  Google Scholar 

  41. • Mulligan-Kehoe MJ, Drinane MC, Mollmark J, et al.: Antiangiogenic plasma activity in patients with systemic sclerosis. Arthritis Rheum 2007, 56:3448–3458. In this article, the authors demonstrate that plasma from scleroderma patients is angiostatic in in vitro models of angiogenesis. Angiostatin appears to be at least partially responsible for this abnormality and levels of this molecule are noted to be elevated in scleroderma plasma.

    Article  CAS  PubMed  Google Scholar 

  42. 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.

    Article  PubMed  Google Scholar 

  43. Hummers LK, Hall A, Wigley FM, Simons M: Abnormalities in the regulators of angiogenesis in patients with scleroderma. J Rheumatol 2009, 36:576–582.

    Article  PubMed  Google Scholar 

  44. 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, 95:109–116.

    Article  CAS  PubMed  Google Scholar 

  45. 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  CAS  PubMed  Google Scholar 

  46. •• Wipff J, Avouac J, Borderie D, et al.: Disturbed angiogenesis in systemic sclerosis: high levels of soluble endoglin. Rheumatology (Oxford) 2008, 47:972–975. Soluble endoglin is notable for having predictive capability in other disease states. In this study, the authors show that soluble endoglin strikingly correates with a particular phenotype in scleroderma that associates with vascular disease (centromere antibody, digital ulcers, low DLCO), making this a very exciting biomarker candidate.

    Article  CAS  Google Scholar 

  47. Hummers LK, Simons M, Wigley FM, Mulligan-Kehoe MJ: Circulating inhibitors of angiogenesis in scleroderma. Presented at the 73rd Annual Scientific Meeting of the American College of Rheumatology. Philadelphia, PA; October 16–21, 2009.

  48. Wang A, Rana S, Karumanchi SA: Preeclampsia: the role of angiogenic factors in its pathogenesis. Physiology (Bethesda) 2009, 24:147–158.

    Google Scholar 

Download references

Acknowledgment

This work is supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health grant K23 AR052742.

Disclosure

No potential conflict of interest relevant to this article was reported.

Author information

Authors and Affiliations

  1. Division of Rheumatology, Johns Hopkins Scleroderma Center, Johns Hopkins University, 5501 Hopkins Bayview Circle, Room 1B.7, Baltimore, MD, 21224, USA

    Laura K. Hummers

Authors
  1. Laura K. Hummers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Laura K. Hummers.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hummers, L.K. The Current State of Biomarkers in Systemic Sclerosis. Curr Rheumatol Rep 12, 34–39 (2010). https://doi.org/10.1007/s11926-009-0081-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-009-0081-6

Keywords

Search

Navigation