Very Early Systemic Sclerosis and Pre-systemic Sclerosis: Definition, Recognition, Clinical Relevance and Future Directions

  • Silvia Bellando-RandoneEmail author
  • Marco Matucci-Cerinic
Scleroderma (J Varga, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Scleroderma


Purpose of Review

The approach to systemic sclerosis (SSc) has changed over the years with an increasing focus on the very early diagnosis of the disease. The terminology identifying patients in the early phase of SSc has been significantly confusing in the last three decades. The purpose of this article is to analyze how the concept of “very early SSc” has evolved over the years, which is the role of an early diagnosis and how early treat patients.

Recent Findings

Several attempts have been made over time, to create more sensitive and specific classification criteria to include the largest number of SSc patients, also in the earliest phase. An algorythm for the very early diagnosis of SSc was identified, diagnostic preliminary criteria proposed, and new 2013 ACR/EULAR SSc classification criteria published, including new items and adding emphasis to the vasculopathic manifestations. True biomarkers that could predict the disease evolution are still missing.


Treat or not to treat patients in the earliest phases still remain a dilemma. For the moment, the only feasible clinical strategy in very early SSc remains a tight follow up program to detect in “real time” the early internal organ involvement which may allow an aggressive therapeutic agenda.


Systemic sclerosis Early diagnosis Puffy fingers Raynaud phenomenon Classification criteria 


Compliance with Ethical Standards

Conflict of Interest

The authors 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.


Papers of Particular Interest, Published Recently, Have Been Highlighted as: • Of importance •• Of major importance

  1. 1.
    Gabrielli A, Avvedimento EV, Krieg T. Scleroderma [review]. N Engl J Med. 2009;360:1989–2003.CrossRefPubMedGoogle Scholar
  2. 2.
    Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117:557–67.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Dinkler M. Zur lehre von der sklerodermie. Dtsch Arch Klin Med. 1981;48:514–77.Google Scholar
  4. 4.
    Campbell PM, LeRoy EC. Pathogenesis of systemic sclerosis: a vascular hypothesis. Semin Arthritis Rheum. 1975;4:351–68.CrossRefPubMedGoogle Scholar
  5. 5.
    Sen S, Sinhamahapatra P, Choudhury S, Gangopadhyay A, Bala S, Sircar G, et al. Cutaneous manifestations of mixed connective tissue disease: study from a tertiary care hospital in eastern India. Indian J Dermatol. 2014;59(1):35–40.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Walker UA, Tyndall A, Czirják L, Denton C, Farge-Bancel D, Kowal-Bielecka O, et al. Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database. Ann Rheum Dis. 2007;66:754–63.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    •• Koenig M, Joyal F, Fritzler MJ, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum. 2008;58(3):902–12. This work highlights the progression of patients characterised by RP, ANA positivity and capillaroscopic modifications to definite SSc according to the old ARA criteria (1980). Google Scholar
  8. 8.
    Avouac J, Fransen J, Walker UA, et al. Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research group. Ann Rheum Dis. 2011;70(3):476–81.CrossRefPubMedGoogle Scholar
  9. 9.
    Galluccio F, Matucci CM. Two faces of the same coin: Raynaud phenomenon and digital ulcers in systemic sclerosis. Autoimmun Rev. 2011;10:241–3.CrossRefPubMedGoogle Scholar
  10. 10.
    • Johnson SR. New ACR EULAR guidelines for systemic sclerosis classification. Curr Rheumatol Rep. 2015;17:3. This article describes the innovative, rigorous, New ACR EULAR criteria development strategy that was used. CrossRefGoogle Scholar
  11. 11.
    Steen VD, Medsger TA Jr. Long-term outcomes of scleroderma renal crisis. Ann Intern Med. 2000;133:600–3.CrossRefPubMedGoogle Scholar
  12. 12.
    Stephen C, Mathai MHS, Hassoun PM. Therapy for pulmonary arterial hypertension associated with systemic sclerosis. Curr Opin Rheumatol. 2009;21(6):642–8.CrossRefGoogle Scholar
  13. 13.
    Bruni C, Praino E, Allanore Y, et al. Use of biologics and other novel therapies for the treatment of systemic sclerosis. Expert Rev Clin Immunol. 2017;13(5):469–82.CrossRefPubMedGoogle Scholar
  14. 14.
    Fine LG, Denton CP, Korn J, de Crombrugghe B, Black CM. Systemic sclerosis: current pathogenetic concepts and future prospects for targeted therapies. Lancet. 1996;3(47):1453–8.Google Scholar
  15. 15.
    Cappelli S, Bellando Randone S, Martinović D, et al. “to be or not to be,” ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum. 2012;41(4):589–98.CrossRefPubMedGoogle Scholar
  16. 16.
    Bellando Randone S, Cutolo M, Czirjak L, Matucci Cerinic M. Mixed connective tissue disease, a roundabout to rheumatic diseases? Curr Rheumatol Rev. 2009;5(2):133–140.Google Scholar
  17. 17.
    Mosca M, Tani C, Vagnani S, Carli L, Bombardieri S. The diagnosis and classification of undifferentiated connective tissue diseases. J Autoimmun. 2014;48–49:50–2.CrossRefPubMedGoogle Scholar
  18. 18.
    LeRoy EC, Maricq HR, Kahaleh MB. Undifferentiated connective tissue syndromes. Arthritis Rheum. 1980;23(3):341–3.CrossRefPubMedGoogle Scholar
  19. 19.
    Maricq HR, Harper FE, Khan MM, Tan EM, LeRoy EC. Microvascular abnormalities as possible predictors of disease subsets in Raynaud phenomenon and early connective tissue disease. Clin Exp Rheumatol. 1983;1(3):195–205.PubMedGoogle Scholar
  20. 20.
    Harper FE, Maricq HR, Turner RE, Lidman RW, Leroy EC. A prospective study of Raynaud phenomenon and early connective tissue disease. A five-year report. Am J Med. 1982;72(6):883–8.CrossRefPubMedGoogle Scholar
  21. 21.
    LeRoy EC, Medsger TA Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol. 2001;28:1573–6.PubMedGoogle Scholar
  22. 22.
    Hachulla E, Launay D. Diagnosis and classification of systemic sclerosis. Clin Rev Allergy Immunol. 2011;40(2):78–83.CrossRefPubMedGoogle Scholar
  23. 23.
    Simeón-Aznar CP, Fonollosa-Plá V, Tolosa-Vilella C, et al. Registry of the Spanish network for systemic sclerosis: clinical pattern according to cutaneous subsets and immunological status. Semin Arthritis Rheum. 2012;41(6):789–800.CrossRefPubMedGoogle Scholar
  24. 24.
    Valentini G, Cuomo G, Abignano G, et al. Early systemic sclerosis: assessment of clinical and preclinical organ involvement in patients with different disease features. Rheumatology. 2011;50:317–23.CrossRefPubMedGoogle Scholar
  25. 25.
    • Lepri G, Bellando-Randone S, Guiducci S, et al. Esophageal and anorectal involvement in patients with very early diagnosis of systemic sclerosis (VEDOSS): report from a single EUSTAR centre. Ann Rheum Dis. 2015;74(1):124–814. The study provides demonstrate the presence of GI involvement since the very early phases of SSc. CrossRefPubMedGoogle Scholar
  26. 26.
    Czirjak L, Matucci-Cerinic M. Beyond Raynaud’s phenomenon hides very early systemic sclerosis: the assessment of organ involvement is always mandatory. Rheumatology. 2011;50:250–1.CrossRefPubMedGoogle Scholar
  27. 27.
    Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma)- Arthritis Rheum 1980; 23:581–90.Google Scholar
  28. 28.
    LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15(2):202–5.PubMedGoogle Scholar
  29. 29.
    Guiducci S, Bellando Randone S, Matucci CM. A new way of thinking about systemic sclerosis: the opportunity for a very early diagnosis. Isr Med Assoc J. 2016;18(3–4):141–3.PubMedGoogle Scholar
  30. 30.
    Spencer-Green G. Outcomes in primary Raynaud phenomenon: a meta-analysis of the frequency, rates, and predictors of transition to secondary diseases. Arch Intern Med. 1998;158:595–600.CrossRefPubMedGoogle Scholar
  31. 31.
    LeRoy EC, Maricq HR, Kahaleh BM. Undifferentiated connective tissue syndromes. Arthritis Rheum. 1980;23:341–3.CrossRefPubMedGoogle Scholar
  32. 32.
    Lundberg IE. The prognosis of MCTD. Rheum Dis Clin N Am. 2005;31:535–47.CrossRefGoogle Scholar
  33. 33.
    Matucci-Cerinic M, Allanore Y, Czirják L, Tyndall A, Müller-Ladner U, Denton C, et al. The challenge of early systemic sclerosis for the EULAR Scleroderma Trial and Research group (EUSTAR) community. It is time to cut the Gordian knot and develop a prevention or rescue strategy. Ann Rheum Dis. 2009;68:1377–80.CrossRefPubMedGoogle Scholar
  34. 34.
    •• Minier T, Guiducci S, Bellando-Randone S, Bruni C, Lepri G, The EUSTAR co-workers, et al. Preliminary analysis of the very early diagnosis of systemic sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis. Ann Rheum Dis. 2014;73(12):2087–93. The study provides preliminary data demonstrating that puffy fingers may indicate the presence of an underlying SSc. CrossRefPubMedGoogle Scholar
  35. 35.
    • Bruni C, Guiducci S, Bellando-Randone S, Lepri G, Braschi F, Fiori G, et al. Digital ulcers as a sentinel sign for early internal organ involvement in very early systemic sclerosis. Rheumatology (Oxford). 2015;54:72–6. The study showed that digital ulcers are already present since the earliest phases of disease, correlating with gastrointestinal involvement. and may represent a sentinel sign for early organ involvement in VEDOSS patients. CrossRefGoogle Scholar
  36. 36.
    van den Hoogen F, Khanna D, Fransen J, et al. Classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013;72:1747–550.CrossRefPubMedGoogle Scholar
  37. 37.
    •• Trapiella-Martínez L, Díaz-López JB, Caminal-Montero L, Tolosa-Vilella C, Guillén-Del Castillo A, RESCLE Investigators, on Behalf of the Autoimmune Diseases Study Group (GEAS), Spanish Society of Internal Medicine (SEMI) et al. Very early and early systemic sclerosis in the Spanish scleroderma Registry (RESCLE) cohort. Autoimmun Rev. 2017 Aug;16(8):796–802. The paper classifies retrospetively, the spanish patient of the RESCLE Register. The data confirm that a part of the patients are satisfying the VEDOSS criteria and provides the evidence that this patients need more time to satisfy the ACR EULAR CRITERIA than early patients. Google Scholar
  38. 38.
    Fransen J, Johnson SR, van den Hoogen F, Baron M, Allanore Y, Carreira PE, et al. Items for developing revised classification criteria in systemic sclerosis: results of a consensus exercise. Arthritis Care Res. 2012;64(3):351–7.CrossRefGoogle Scholar
  39. 39.
    •• Hoffmann-Vold AM, Gunnarsson R, Garen T, Midtvedt O, Molberg O. Performance of the 2013 American College of Rheumatology/European league against rheumatism classification criteria for systemic sclerosis (SSc) in large, well defined cohorts of SSc and mixed connective tissue disease. J Rheumatol. 2015;42(1):60–3. The article confirms the higher sensitivity of 2013 ACR/EULAR SSc criteria than ACR 1980 criteria in a large and representative group of consecutive patients with SSc. CrossRefPubMedGoogle Scholar
  40. 40.
    Johnson SR, Naden RP, Fransen J, van den Hoogen F, Pope JE, Baron M, et al. Multicriteria decision analysis methods with 1000Minds for developing systemic sclerosis classification criteria. J Clin Epidemiol. 2014;67(6):706–14.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Bellando-Randone S, Guiducci S, Matucci-Cerinic M. From Raynaud’s phenomenon to very early diagnosis of systemic sclerosis—The VEDOSS approach. Curr Rheumatol Rev. 2013;9(4):245–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Matucci-Cerinic M, Steen V, Nash P, Hachulla E. The complexity of managing systemic sclerosis: screening and diagnosis. Rheumatology. 2009;48:iii8–iii13.CrossRefPubMedGoogle Scholar
  43. 43.
    •• Herrick AL, Pan X, Peytrignet S, Lunt M, Hesselstrand R, Mouthon L, et al. Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS). Ann Rheum Dis. 2017;76(7):1207–18. This paper hihglights, in a real life setting, the utility of immunusuppressants for the tratment pf early SSc (< 3 years). CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Silvia Bellando-Randone
    • 1
    • 2
    Email author
  • Marco Matucci-Cerinic
    • 1
    • 2
  1. 1.Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
  2. 2.Department of Geriatric Medicine, Division of RheumatologyAOUCFlorenceItaly

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