Skip to main content

Advertisement

SpringerLink
Log in

Quantitating Skin Fibrosis: Innovative Strategies and Their Clinical Implications

  • SCLERODERMA (J VARGA, SECTION EDITOR)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Skin fibrosis is the final outcome of a variety of pathologic processes ranging from aberrant wound healing (keloids) to environmentally induced conditions (nephrogenic systemic fibrosis) to idiopathic or autoimmune conditions (morphea and systemic sclerosis). The quantitative assessment of skin fibrosis has been a major burden of clinical and biomarker research in the field for the past three decades. Here, we review the efforts that reached some sort of validation and the ones we envisage have the potential for further development focusing on systemic sclerosis as prototype of fibrotic disease.

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

Fig. 1

Similar content being viewed by others

References

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

  1. Wick G, Grundtman C, Mayerl C, et al. The immunology of fibrosis. Annu Rev Immunol. 2013;31:107–35.

    Article  CAS  PubMed  Google Scholar 

  2. Steen VD, Medsger Jr TA. Improvement in skin thickening in systemic sclerosis associated with improved survival. Arthritis Rheum. 2001;44:2828–35.

    Article  CAS  PubMed  Google Scholar 

  3. Clements PJ, Hurwitz EL, Wong WK, et al. Skin thickness score as a predictor and correlate of outcome in systemic sclerosis: high-dose versus low-dose penicillamine trial. Arthritis Rheum. 2000;43:2445–54.

    Article  CAS  PubMed  Google Scholar 

  4. LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15:202–5.

    CAS  PubMed  Google Scholar 

  5. Rodnan GP, Lipinski E, Luksick J. Skin thickness and collagen content in progressive systemic sclerosis and localized scleroderma. Arthritis Rheum. 1979;22:130–40.

    Article  CAS  PubMed  Google Scholar 

  6. Czirjak L, Foeldvari I, Muller-Ladner U. Skin involvement in systemic sclerosis. Rheumatology (Oxford). 2008;47:v44–5.

    Article  Google Scholar 

  7. Clements PJ, Furst DE, Wong WK, et al. High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, double-blind, randomized, controlled clinical trial. Arthritis Rheum. 1999;42:1194–203.

    Article  CAS  PubMed  Google Scholar 

  8. Khanna D, Clements PJ, Furst DE, et al. Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2009;60:1102–11.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Merkel PA, Clements PJ, Reveille JD, et al. Current status of outcome measure development for clinical trials in systemic sclerosis: report from OMERACT 6. J Rheumatol. 2003;30:1630–47.

    PubMed  Google Scholar 

  10. Pope JE, Baron M, Bellamy N, et al. Variability of skin scores and clinical measurements in scleroderma. J Rheumatol. 1995;22:1271–6.

    CAS  PubMed  Google Scholar 

  11. Clements PJ, Lachenbruch PA, Seibold JR, et al. Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol. 1993;20:1892–6.

    CAS  PubMed  Google Scholar 

  12. Clements PJ. Measuring disease activity and severity in scleroderma. Curr Opin Rheumatol. 1995;7:517–21.

    Article  CAS  PubMed  Google Scholar 

  13. Falanga V, Bucalo B. Use of a durometer to assess skin hardness. J Am Acad Dermatol. 1993;29:47–51.

    Article  CAS  PubMed  Google Scholar 

  14. Kissin EY, Schiller AM, Gelbard RB, et al. Durometry for the assessment of skin disease in systemic sclerosis. Arthritis Rheum. 2006;55:603–9.

    Article  PubMed  Google Scholar 

  15. Kissin EY, Merkel PA, Lafyatis R. Myofibroblasts and hyalinized collagen as markers of skin disease in systemic sclerosis. Arthritis Rheum. 2006;54:3655–60.

    Article  PubMed  Google Scholar 

  16. Merkel PA, Silliman NP, Denton CP, for the CAT-192 Research Group and the Scleroderma Clinical Trials Consortium, et al. Validity, reliability, and feasibility of durometer measurements of scleroderma skin disease in a multicenter treatment trial. Arthritis Rheum. 2008;59:699–705.

    Article  PubMed  Google Scholar 

  17. Nives Parodi M, Castagneto C, Filaci G, et al. Plicometer skin test: a new technique for the evaluation of cutaneous involvement in systemic sclerosis. Br J Rheumatol. 1997;36:244–50.

    Article  CAS  PubMed  Google Scholar 

  18. Kuwahara Y, Shima Y, Shirayama D, et al. Quantification of hardness, elasticity and viscosity of the skin of patients with systemic sclerosis using a novel sensing device (Vesmeter): a proposal for a new outcome measurement procedure. Rheumatology (Oxford). 2008;47:1018–24.

    Article  CAS  Google Scholar 

  19. Enomoto DN, Mekkes JR, Bossuyt PM, et al. Quantification of cutaneous sclerosis with a skin elasticity meter in patients with generalized scleroderma. J Am Acad Dermatol. 1996;35:381–7.

    Article  CAS  PubMed  Google Scholar 

  20. Black MM, Bottoms E, Shuster S. Skin collagen content and thickness in systemic sclerosis. Br J Dermatol. 1970;83:552–5.

    Article  CAS  PubMed  Google Scholar 

  21. Castro S, Jimenez SA. Biomarkers in systemic sclerosis. Biomark Med. 2010;4:133–47.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Abignano G, Buch M, Emery P, et al. Biomarkers in the management of scleroderma: an update. Curr Rheumatol Rep. 2011;13:4–12.

    Article  PubMed  Google Scholar 

  23. Moinzadeh P, Denton CP, Abraham D, et al. Biomarkers for skin involvement and fibrotic activity in scleroderma. J Eur Acad Dermatol Venereol. 2012;26:267–76. This review, analyzing the biomarkers for skin involvement in systemic sclerosis developed to date, gives a wide view of the advances in this field highlighting the weaknesses and strengths of each.

    Article  CAS  PubMed  Google Scholar 

  24. Castelino FV, Varga J. Current status of systemic sclerosis biomarkers: applications for diagnosis, management and drug development. Expert Rev Clin Immunol. 2013;9:1077–90.

    Google Scholar 

  25. Hesselstrand R, Kassner A, Heinegård D, et al. COMP: a candidate molecule in the pathogenesis of systemic sclerosis with a potential as a disease marker. Ann Rheum Dis. 2008;67:1242–8.

    Article  CAS  PubMed  Google Scholar 

  26. Hesselstrand R, Andréasson K, Wuttge DM, et al. Increased serum COMP predicts mortality in SSc: results from a longitudinal study of interstitial lung disease. Rheumatology (Oxford). 2012;51:915–20. This study recently showed that serum COMP is a predictor of mortality in systemic sclerosis, and is a stronger marker of skin rather than lung fibrosis.

    Article  CAS  Google Scholar 

  27. Farina G, Lemaire R, Korn JH, et al. Cartilage oligomeric matrix protein is overexpressed by scleroderma dermal fibroblasts. Matrix Biol. 2006;25:213–22.

    Article  CAS  PubMed  Google Scholar 

  28. Farina G, Lemaire R, Pancari P, et al. Cartilage oligomeric matrix protein expression in systemic sclerosis reveals heterogeneity of dermal fibroblast responses to transforming growth factor beta. Ann Rheum Dis. 2009;68:435–41.

    Article  CAS  PubMed  Google Scholar 

  29. Farina G, Lafyatis D, Lemaire R, et al. A four-gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2010;62:580–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Abignano G, Cuomo G, Buch MH, et al. ELF TEST: a clinical grade, validated serum test, biomarker of overall fibrosis in systemic sclerosis. Ann Rheum Dis. 2013;0:1–8. doi:10.1136/annrheumdis-2012-202843. This study shows the potential use of three CE-marked serum tests as surrogate outcome measures of overall fibrosis in scleroderma.

    Google Scholar 

  31. Chapin R, Hant FN. Imaging of scleroderma. Rheum Dis Clin N Am. 2013;39:515–46.

    Article  Google Scholar 

  32. Akesson A, Hesselstrand R, Scheja A, et al. Longitudinal development of skin involvement and reliability of high frequency ultrasound in systemic sclerosis. Ann Rheum Dis. 2004;63:791–6.

    Article  CAS  PubMed  Google Scholar 

  33. Kaloudi O, Bandinelli F, Filippucci E, et al. High frequency ultrasound measurement of digital dermal thickness in systemic sclerosis. Ann Rheum Dis. 2010;69:1140–3.

    Article  PubMed  Google Scholar 

  34. Ch'ng SS, Roddy J, Keen HI. A systematic review of ultrasonography as an outcome measure of skin involvement in systemic sclerosis. Int J Rheum Dis. 2013;16:264–72. This is a comprehensive review of the most important studies published between 1995 and 2010 regarding the use of ultrasonography as an outcome measure of skin involvement in systemic sclerosis. It also highlights the current unmet need and the major aspects to be developed in further studies.

    Article  PubMed  Google Scholar 

  35. Ihn H, Shimozuma M, Fujimoto M, et al. Ultrasound measurement of skin thickness in systemic sclerosis. Br J Rheumatol. 1995;34:535–8.

    Article  CAS  PubMed  Google Scholar 

  36. Hesselstrand R, Scheja A, Wildt M, et al. High-frequency ultrasound of skin involvement in systemic sclerosis reflects oedema, extension and severity in early disease. Rheumatology. 2008;47:84–7.

    Article  CAS  PubMed  Google Scholar 

  37. Iagnocco A, Kaloudi O, Perella C, et al. Ultrasound elastography assessment of skin involvement in systemic sclerosis: lights and shadows. J Rheumatol. 2010;37:1688–91.

    Article  PubMed  Google Scholar 

  38. Di Geso L, Filippucci E, Girolimetti R, et al. Reliability of ultrasound measurements of dermal thickness at digits in systemic sclerosis: role of elastosonography. Clin Exp Rheumatol. 2011;29:926–32.

    PubMed  Google Scholar 

  39. Santiago T, Alcacer-Pitarch B, Del Galdo F, et al. Assessment of skin involvement by acoustic radiation force impulse (ARFI) imaging in patients with systemic sclerosis. Ann Rheum Dis. 2013;72(Suppl3):157. Although preliminary, this study reveals the potential of shear wave ultrasound in quantifying skin fibrosis in scleroderma.

    Google Scholar 

  40. Schmitt AM. Principles and application of optical coherent tomography in dermatology. Dermatology. 2008;217:12–3.

    Article  PubMed  Google Scholar 

  41. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science. 1991;254:1178–81.

    Article  CAS  PubMed  Google Scholar 

  42. Gambichler T, Jaedicke V, Terras S. Optical coherence tomography in dermatology: technical and clinical aspects. Arch Dermatol Res. 2011;303:457–73.

    Article  PubMed  Google Scholar 

  43. Marschall S, Sander B, Mogensen M, Jørgensen TM, Andersen PE. Optical coherence tomography-current technology and applications in clinical and biomedical research. Anal Bioanal Chem. 2011;400:2699–720.

    Article  CAS  PubMed  Google Scholar 

  44. Welzel J, Lankenau E, Birngruber R, et al. Optical coherence tomography of the human skin. J Am Acad Dermatol. 1997;37:958–63.

    Article  CAS  PubMed  Google Scholar 

  45. Chu CR, Williams A, Tolliver D, et al. Clinical optical coherence tomography of early articular cartilage degeneration in patients with degenerative meniscal tears. Arthritis Rheum. 2010;62:1412–20.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Aydin SZ, Ash Z, Del Galdo F, et al. Optical coherence tomography: a new tool to assess nail disease in psoriasis? Dermatology. 2011;222:311–3.

    Article  PubMed  Google Scholar 

  47. Aydin SZ, Castillo-Gallego C, Ash ZR, et al. Potential use of optical coherence tomography and high-frequency ultrasound for the assessment of nail disease in psoriasis and psoriatic arthritis. Dermatology. 2013. doi:10.1159/000351702.

    PubMed  Google Scholar 

  48. Babalola O, Mamalis A, Lev-Tov H, et al. Optical coherence tomography (OCT) of collagen in normal skin and skin fibrosis. Arch Dermatol Res. 2013. doi:10.1007/s00403-013-1417-7. The authors review the most important studies involving optical coherence tomography and sketch the potential development of the technique in skin imaging.

    Google Scholar 

  49. Mogensen M, Morsy HA, Thrane L, et al. Morphology and epidermal thickness of normal skin imaged by optical coherence tomography. Dermatology. 2008;217:14–20.

    Article  PubMed  Google Scholar 

  50. Abignano G, Aydin SZ, Castillo-Gallego C, et al. Virtual skin biopsy by optical coherence tomography: the first quantitative imaging biomarker for scleroderma. Ann Rheum Dis. 2013;72:1845–51. This is the first study validating optical coherence tomography as a quantitative and reliable biomarker of severity of skin involvement in systemic sclerosis.

    Article  PubMed  Google Scholar 

  51. Alex A, Povazay B, Hofer B, et al. Multispectral in vivo three-dimensional optical coherence tomography of human skin. J Biomed Opt. 2010;15:026025.

    Article  PubMed  Google Scholar 

  52. Gladkova ND, Petrova GA, Nikulin NK, et al. In vivo optical coherence tomography imaging of human skin: norm and pathology. Skin Res Technol. 2000;6:6–16.

    Article  PubMed  Google Scholar 

  53. Gambichler T, Matip R, Moussa G, Altmeyer P, Hoffmann K. In vivo data of epidermal thickness evaluated by optical coherence tomography: effects of age, gender, skin type, and anatomic site. J Dermatol Sci. 2006;44:145–52.

    Article  PubMed  Google Scholar 

  54. Gambichler T, Boms S, Stücker M, Kreuter A, Sand M, Moussa G, et al. Comparison of histometric data obtained by optical coherence tomography and routine histology. J Biomed Opt. 2005;10:44008.

    Article  PubMed  Google Scholar 

  55. Gambichler T, Moussa G, Regeniter P, Kasseck C, Hofmann MR, Bechara FG, et al. Validation of optical coherence tomography in vivo using cryostat histology. Phys Med Biol. 2007;52:N75–85.

    Article  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Giuseppina Abignano and Francesco Del Galdo declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Wellcome Trust Brenner Building, Level 5, Beckett Street, St James’s University Hospital, LS9 7TF, Leeds, UK

    Giuseppina Abignano & Francesco Del Galdo

Authors
  1. Giuseppina Abignano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesco Del Galdo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giuseppina Abignano.

Additional information

This article is part of the Topical Collection on Scleroderma

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abignano, G., Del Galdo, F. Quantitating Skin Fibrosis: Innovative Strategies and Their Clinical Implications. Curr Rheumatol Rep 16, 404 (2014). https://doi.org/10.1007/s11926-013-0404-5

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11926-013-0404-5

Keywords

Search

Navigation