Erfolgreich durch internationale Zusammenarbeit

Internal Medicine

Cite as: Archiv EuroMedica. 2026. 16; 3. DOI 10.35630/2026/16/Iss.3.03

Received 5 May 2026;
Accepted 9 June 2026;
Published 12 June 2026

PREDICTIVE FACTORS OF PROGRESSION TO DEFINITE SYSTEMIC SCLEROSIS IN PATIENTS WITH RAYNAUD'S PHENOMENON AND VERY EARLY SSc: A NARRATIVE REVIEW

Aleksandra Kamińska1 email orcid id logo, Maria Miller2 orcid id logo,
Kornelia Fimiarz3 orcid id logo, Aleksandra Kłosowicz2 orcid id logo,
Aleksandra Pakulska2 orcid id logo, Aleksandra Błoch2 orcid id logo,
Natalia Rządzińska2 orcid id logo

1 Medical Center HCP in Poznan, Poland
2 Jan Biziel University Hospital No. 2 in Bydgoszcz, Poland
3 Nicolaus Copernicus Hospital in Gdansk, Poland

download article (pdf)

  olakaminska2111@gmail.com

ABSTRACT

Background

Systemic sclerosis (SSc) is an autoimmune disease characterised by microcirculatory disorders, immune activation and fibrosis. Patients with Raynaud's phenomenon (RP) and features of very early SSc require particular attention, as progression to definite SSc may occur early in a subset of patients, while risk assessment remains a significant clinical challenge.

Aims

To analyse clinical, serological, capillaroscopic and molecular factors associated with progression to definite SSc in patients with RP and very early SSc.

Methods

A literature review was conducted using the PubMed and Scopus databases. Original studies assessing predictors of progression to definite SSc or clinically significant disease progression in patients with RP or very early SSc were qualitatively analysed.

Results

The highest reported risk of progression to definite SSc was observed in patients presenting a combination of puffy fingers, antinuclear antibodies, SSc-specific autoantibodies and abnormal nailfold capillaroscopy findings. Molecular biomarkers associated with extracellular matrix remodelling and immune system activation showed potential prognostic value but remain insufficiently validated for routine clinical use. Progression to definite SSc most often occurred during the first few years of follow-up.

Conclusions

Risk assessment for progression to definite SSc should be based on the combined interpretation of clinical features, antinuclear antibodies, SSc-specific autoantibodies and nailfold capillaroscopy findings. Molecular biomarkers may contribute to future prognostic assessment but currently require further validation.

Keywords: systemic sclerosis; VEDOSS; very early systemic sclerosis; Raynaud's phenomenon; disease progression; predictors; autoantibodies; nailfold capillaroscopy.

INTRODUCTION

Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterised by microvascular dysfunction, immune activation and progressive fibrosis of the skin and internal organs [1,2]. The main causes of increased mortality are severe internal organ complications, particularly involving the lungs and the heart [3–5]. Early identification of patients at high risk of developing definite SSc is therefore of considerable clinical importance [6].

The most common clinical manifestation preceding the development of definite SSc, sometimes by many years, is Raynaud's phenomenon (RP) [7]. However, its diagnostic specificity is limited, as it also occurs in individuals who never develop definite SSc [8]. To improve early recognition of SSc, the VEDOSS (Very Early Diagnosis of Systemic Sclerosis) criteria were developed, comprising so-called 'red flags' (RP, puffy fingers and ANA antibodies) and additional parameters: SSc-specific autoantibodies and capillaroscopy abnormalities [1,9]. The co-occurrence of these features may facilitate the identification of patients at an early stage of SSc and improve risk stratification [9,10].

Nevertheless, the progression to definite SSc remains heterogeneous and difficult to predict. In some patients with RP and additional features suggesting the development of SSc, progression to definite SSc occurs within the first few years of the onset of RP, whereas in others progression does not occur or remains very slow [7,10–13]. Moreover, assessment of progression risk remains difficult, because both the rate and clinical expression of disease progression may vary significantly between patients [12,14,15].

SSc-specific autoantibodies and early microangiopathic changes observed in nailfold capillaroscopy have significant prognostic value and are currently regarded as among the major predictive factors of progression to definite SSc [14,16–22]. Capillaroscopic abnormalities were also included in the 2013 ACR/EULAR classification criteria [21,22].

However, organ involvement may occur at a very early stage of the disease, even before the SSc classification criteria are met [23–26]. Furthermore, research suggests that the disease process may begin at the molecular level even before clinical symptoms appear, and involves the activation of the immune system and disruption of the extracellular matrix metabolism. Emerging molecular biomarkers may improve future risk assessment, although their practical clinical value remains uncertain [27,28].

Despite the progress made in understanding the pathogenesis and early manifestations of SSc, there is still no definitive model that would allow for a reliable assessment of the risk of developing SSc in patients with RP or other early signs of the disease [12,29]. Therefore, integrating clinical, serological, microangiopathic and molecular data remains an important challenge.

AIMS

The aim of this narrative review was to analyse predictive factors associated with progression to definite systemic sclerosis in patients with Raynaud's phenomenon and very early systemic sclerosis. The study also sought to determine which clinical, serological, capillaroscopic and molecular factors are most strongly associated with progression to definite SSc and may be useful for risk assessment in clinical practice.

The objectives of the study were:

MATERIALS AND METHODS

Although this article is a narrative review rather than a systematic review, a PRISMA style flow diagram was used to transparently present the process of literature identification, screening and inclusion. A literature review was conducted to identify predictors of progression to definite SSc in various patient groups, ranging from those with isolated RP to patients meeting the VEDOSS criteria or presenting with the early stage of SSc. The literature search was conducted in March 2026 using the PubMed and Scopus databases, with no restrictions on the year of publication. The analysis included studies published in English.

The literature was selected using a combination of the following keywords: systemic sclerosis; VEDOSS; very early systemic sclerosis; Raynaud's phenomenon; disease progression; predictors; autoantibodies; nailfold capillaroscopy. The search strategy used combinations of keywords connected with Boolean operators (AND/OR), including: (systemic sclerosis OR very early systemic sclerosis OR VEDOSS) AND (Raynaud's phenomenon) AND (progression OR predictors), as well as terms related to autoantibodies, nailfold capillaroscopy and molecular biomarkers.

The analysis included original clinical studies, comprising mainly prospective cohort studies, observational studies and cross-sectional analyses, which assessed predictors of progression to definite SSc or focused on clinically significant disease progression in patients with RP, very early SSc and early-stage SSc. Studies were included if they: (1) involved patients with isolated RP or meeting the VEDOSS criteria, or with early-stage SSc; (2) analysed predictive factors for progression to definite SSc or clinically relevant disease progression; (3) had a clearly defined endpoint; (4) described original data; and (5) presented results in quantitative form.

The following were excluded: (1) review papers, case reports and case studies; (2) publications without a clearly defined endpoint; (3) studies with insufficient data on risk factors for progression; and (4) studies in which progression was not analysed as an endpoint.

Ultimately, 9 studies were selected for the final analysis. The studies differed in terms of the characteristics of the study group and the duration of follow-up (ranging from 2 to 20 years). Due to differences between the studies, including the heterogeneity of the study populations and varying definitions of disease progression, no meta-analysis was conducted. The results are presented in the form of a qualitative analysis.

RESULTS

A search of the databases identified 342 articles. After removing duplicates, 241 of them were analysed on the basis of their titles and abstracts. The subsequent assessment focused on 45 full-text articles, of which 9 met the inclusion criteria and were subjected to a qualitative analysis. The detailed study selection process is illustrated in the PRISMA diagram (Figure 1).

Figure 1. PRISMA 2020 flow diagram

Figure 1. PRISMA 2020 diagram

The analysis focused primarily on prospective cohort studies, as well as observational studies and cross-sectional analyses. The studies assessed heterogeneous patient populations, including patients with RP who did not meet the classification criteria for definite SSc but often exhibited additional features of VEDOSS [7,10,24,29], and patients with very early or early SSc without skin or internal organ involvement [27,30–32]. The individual cohorts varied in size, ranging from several dozen to as many as several hundred patients, and in duration of follow-up (from around a dozen months to 20 years). The characteristics of the included studies are shown in Table 1.

Table 1. Characteristics of the studies included in the analysis.

Author Year Type of study Total number Patients with progression, n (%) Population Predictors Follow-up duration Endpoint Key findings
Bellando-Randone et al. 2021 Prospective multicentre cohort study 553 133/254 (52.4%) Patients with Raynaud's phenomenon, not fulfilling the classification criteria for SSc and other connective tissue diseases. VEDOSS criteria ≤5 years Fulfilment of the 2013 ACR/EULAR classification criteria for definite SSc. Puffy fingers, ANA positivity, SSc-specific autoantibodies and abnormal nailfold capillaroscopy were identified as independent predictors of progression to definite SSc.
Siqueira et al. 2022 Single-centre cross-sectional study 217 88/217 (40.5%) Patients with Raynaud's phenomenon and ≥1 symptom suggestive of SSc, without skin thickening and not meeting the classification criteria for another connective tissue disease. VEDOSS criteria ~4 years Fulfilment of the 2013 ACR/EULAR classification criteria for definite SSc. VEDOSS level 1 and level 2 combinations were strongly associated with progression to definite SSc.
Amaral et al. 2024 Prospective observational cohort study 875 174/656 (26.5%); 64/219 (29.2%) Patients with isolated Raynaud's phenomenon. Nailfold capillaroscopic abnormalities 10–11 years Development of SSc or SSc-spectrum disorder among patients who developed secondary RP. Capillaroscopic changes, when assessed in isolation, had limited predictive value for progression to SSc or SSc-spectrum disorders.
Ross et al. 2025 Prospective observational cohort study 114 16/114 (14.0%) Patients meeting the VEDOSS criteria, not meeting the classification criteria for SSc. CXCL10, ELF, histological changes, fibroblast activation ~2.5 years Fulfilment of the 2013 ACR/EULAR classification criteria for definite SSc. Higher baseline CXCL10 levels were associated with progression to definite SSc.
Valentini et al. 2012 Prospective cohort study 76 30/39 (76.9%) Patients with Raynaud's phenomenon classified as early SSc (Koenig criteria) or UCTD. Avascular areas, sIL-2Ra, PIIINP ≤5 years Development of new manifestations consistent with definite SSc. Independent predictors of progression were avascular areas, elevated sIL-2Ra and elevated PIIINP.
Koenig et al. 2008 Prospective cohort study 586 74/586 (12.6%) Patients with Raynaud's phenomenon, not meeting the classification criteria for SSc. SSc-specific autoantibodies (ACA, anti-Scl-70, anti-RNAP III), capillaroscopic abnormalities ≤20 years Development of definite SSc. Independent predictors of progression were capillary enlargement, capillary loss and SSc-specific autoantibodies.
Haverkort et al. 2026 Prospective cohort study 30 13/30 (43.3%) Patients with Raynaud's phenomenon, SSc autoantibodies, abnormal NVC, puffy fingers; no organ involvement. Autoantibodies, capillaroscopic and clinical parameters 3 years Clinically significant disease progression (skin, vascular or internal organ involvement). Anti-RNP antibodies were strongly associated with clinically significant disease progression.
Vasile et al. 2018 Prospective cohort study 66 21/66 (31.8%) Patients meeting the VEDOSS criteria, not meeting the classification criteria for SSc. Capillaroscopic parameters ~2.5 years Fulfilment of the 2013 ACR/EULAR classification criteria for definite SSc. Increased apex width was the strongest independent predictor of progression to definite SSc.
van Leeuwen et al. 2021 Multicentre cohort study 115 48/115 (41.7%) IgG ACA-positive patients with very early SSc at baseline. Levels of IgG, IgM, IgA ACA; puffy fingers ≤5 years Fulfilment of the 2013 ACR/EULAR classification criteria for definite SSc. Higher baseline IgG ACA levels were independently associated with progression to definite SSc.

VEDOSS criteria include Raynaud's phenomenon, puffy fingers, ANA positivity and either SSc-specific autoantibodies or nailfold capillaroscopy abnormalities.

Reported rates of progression to definite SSc varied across the different study groups. In cohorts of patients with isolated RP, progression was reported in approximately 12–13% of patients [7], whereas in studies involving patients meeting the VEDOSS criteria, reported progression rates ranged from approximately 40% to 50% [10,14,29]. The highest reported rates were observed in studies involving patients presenting both SSc-specific autoantibodies and capillaroscopic abnormalities, approaching 80% [7]. In most of the studies analysed, progression to definite SSc was observed within the first few years following the onset of RP, most commonly within 3–5 years [7,10,14,29].

SSc-specific autoantibodies are considered significant predictors of the development of the definite form of the disease. The presence of anti-topoisomerase I antibodies (ATA), anticentromere antibodies (ACA) and other SSc-associated autoantibodies is associated with an increased risk of progression, particularly when they coexist with other features [14,29]. Anti-RNP antibodies were also identified as a potential factor associated with faster clinically significant disease progression, including skin and organ involvement [31]. Higher concentrations of IgG ACA were associated with a significantly higher likelihood of developing definite SSc [14].

Early clinical symptoms also demonstrated significant predictive value. The combination of RP, puffy fingers and positive ANA antibodies was consistently associated with an increased risk of progression to definite SSc [29].

Microvascular abnormalities detected on capillaroscopy represent another important predictive factor. Microcirculatory disorders are sequential in nature, initially involving capillary dilation, followed by capillary loss and the development of telangiectasia [7]. In studies involving patients with VEDOSS, larger capillary loop diameter, greater capillary apex width, and the presence of microhaemorrhages were associated with an increased likelihood of progression [32]. At the same time, some studies suggest that capillaroscopic abnormalities alone may have limited predictive value when other factors are not taken into account [24].

Recent studies reported associations between molecular biomarkers related to immune activation and extracellular matrix remodelling and progression to definite SSc. In patients progressing from VEDOSS to definite SSc, there is increased activation of the immune system, including elevated levels of inflammatory mediators and activation of type I interferon [27].

DISCUSSION

The available data suggest that progression to definite SSc in patients with RP or other risk factors for the development of the disease is multifactorial, depending on clinical symptoms, serological markers and abnormalities detected on capillaroscopy [7,9,10]. These observations point to the limited predictive value of individual predictors when assessed in isolation and suggest that their joint analysis improves the ability to identify high-risk patients.

Patients who meet the criteria for very early SSc require particular attention, since the literature indicates that this group is at increased risk of progression to definite SSc [10,29,33,34]. The VEDOSS concept is of significant clinical importance, as it enables the identification of patients at high risk even before they meet the classic classification criteria [10,35–37]. Cohort studies suggest that the highest likelihood of progression is observed when multiple VEDOSS features coexist, particularly RP, puffy fingers and ANA positivity together with SSc-specific autoantibodies and capillaroscopic abnormalities [10,29,33,34]. However, different combinations of the above features have varying prognostic value and not all patients meeting the VEDOSS criteria ultimately develop the definite form of SSc [29,38]. Moreover, some studies indicate that clinically significant disease progression, including skin and organ involvement, may occur relatively early in a subset of patients with very early SSc [31].

SSc-specific autoantibodies appear to have some of the strongest support in the literature as predictors of progression to definite SSc. However, their predictive value appears to be highest when interpreted in the clinical context and together with other coexisting factors. Both their profile and level may help predict the clinical course of SSc and the risk of internal organ involvement [12,14,16,41]. Different autoantibody profiles are associated with distinct risks of disease progression and organ involvement [16].

Microangiopathic changes detected on capillaroscopy appear to have strong support in the literature as predictors of progression to definite SSc, particularly when interpreted in conjunction with other clinical and serological findings [7,9,24]. The co-occurrence of capillaroscopic abnormalities with SSc-specific autoantibodies in patients meeting criteria for very early SSc is associated with a particularly high likelihood of progression [7,9]. At the same time, capillaroscopic changes alone have limited predictive value [24]. Certain capillaroscopic features, including microhaemorrhages and other signs of advanced microvascular damage, have been associated with an increased risk of progression [32], while the dynamics of microcirculatory changes may also have prognostic significance [42].

Molecular biomarkers are increasingly being investigated as potential prognostic tools, although their clinical utility remains less established than that of clinical features, autoantibodies and capillaroscopy [43,44]. Current evidence suggests that the biological activity of the disease process begins even before overt clinical symptoms appear, as abnormalities associated with immune system activation and extracellular matrix remodelling have already been observed in patients meeting the VEDOSS criteria [27,28]. The potential prognostic value of biomarkers such as PIIINP and sIL-2Ra has also been suggested [30]. Despite promising results, molecular biomarkers remain experimental tools, and the lack of validation in large populations prevents their routine use in clinical practice.

Despite the growing volume of available data, it has not yet been possible to establish clear, validated predictive models that can reliably determine the risk of progression to definite SSc in individual patients [45], which may be due to the multifactorial nature of SSc. The integration of clinical symptoms with serological and capillaroscopy data, supplemented by emerging molecular biomarkers, currently seems to represent the most rational clinical approach [6,45].

5.1. Study limitations

When interpreting the findings of this review, several limitations should be considered. The number of studies included in the main analysis was limited due to the strict inclusion criteria. The included studies were heterogeneous in terms of patient populations, follow-up duration and endpoint definitions, which limited the possibility of quantitative synthesis. In addition, disease progression was not defined uniformly across studies. Most available data were derived from observational studies, which limits the certainty with which the independent prognostic value of individual predictors can be assessed.

CONCLUSIONS

Based on the reviewed data, the most informative combination of predictors of progression to definite SSc includes early clinical features, particularly puffy fingers, together with antinuclear antibodies, SSc-specific autoantibodies and abnormal nailfold capillaroscopy findings. The predictive value of individual factors is limited when assessed in isolation. Therefore, assessment of the risk of progression to definite SSc should rely on an integrated approach combining clinical, serological and capillaroscopic findings. Molecular biomarkers related to immune activation and extracellular matrix remodelling may contribute to future prognostic assessment, but they cannot yet be regarded as equivalent to established clinical, serological and capillaroscopic tools and require further validation. Early identification of high-risk patient groups and their close monitoring remain of key clinical importance and represent a major challenge for modern rheumatology.

DISCLOSURE

Author Contributions

Conceptualization: Aleksandra Kamińska, Maria Miller.

Methodology: Maria Miller, Kornelia Fimiarz.

Formal analysis: Aleksandra Kłosowicz, Aleksandra Pakulska, Kornelia Fimiarz.

Data collection: Aleksandra Kamińska, Aleksandra Błoch, Natalia Rządzińska.

Writing – original draft preparation: Aleksandra Pakulska, Aleksandra Kamińska.

Writing – review and editing: Natalia Rządzińska, Aleksandra Kłosowicz, Maria Miller.

Supervision: Aleksandra Błoch, Kornelia Fimiarz.

All authors have read and agreed to the published version of the manuscript.

Funding

This research did not receive any funding.

Conflict of Interest

Authors declare no conflict of interest.

Use of Artificial Intelligence

Artificial Intelligence was used for language editing and stylistic correction.

REFERENCES

  1. Guiducci S, Bellando-Randone S, Matucci-Cerinic M. A New Way of Thinking about Systemic Sclerosis: The Opportunity for a Very Early Diagnosis. Isr Med Assoc J IMAJ. 2016;18(3–4):141–3. https://pubmed.ncbi.nlm.nih.gov/27228628/
  2. Sobolewski P, Maślińska M, Wieczorek M, Łagun Z, Malewska A, Roszkiewicz M, et al. Systemic sclerosis – multidisciplinary disease: clinical features and treatment. Reumatologia. 2019;57(4):221–33. https://doi.org/10.5114/reum.2019.87619
  3. Tyndall AJ, Bannert B, Vonk M, Airò P, Cozzi F, Carreira PE, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 2010 Oct;69(10):1809–15. https://doi.org/10.1136/ard.2009.114264
  4. Jaafar S, Lescoat A, Huang S, Gordon J, Hinchcliff M, Shah AA, et al. Clinical characteristics, visceral involvement, and mortality in at-risk or early diffuse systemic sclerosis: a longitudinal analysis of an observational prospective multicenter US cohort. Arthritis Res Ther. 2021 Jun 14;23(1):170. https://doi.org/10.1186/s13075-021-02548-1
  5. Steen VD, Medsger TA. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum. 2000 Nov;43(11):2437–44. https://doi.org/10.1002/1529-0131(200011)43:11<2437::AID-ANR10>3.0.CO;2-U
  6. Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017 Oct 7;390(10103):1685–99. https://doi.org/10.1016/S0140-6736(17)30933-9
  7. Koenig M, Joyal F, Fritzler MJ, Roussin A, Abrahamowicz M, Boire G, 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 Dec;58(12):3902–12. https://doi.org/10.1002/art.24038
  8. LeRoy EC, Medsger TA. Criteria for the classification of early systemic sclerosis. J Rheumatol. 2001 Jul;28(7):1573–6. https://pubmed.ncbi.nlm.nih.gov/11469464/
  9. Minier T, Guiducci S, Bellando-Randone S, Bruni C, Lepri G, Czirják L, 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 Dec;73(12):2087–93. https://doi.org/10.1136/annrheumdis-2013-203716
  10. Bellando-Randone S, Del Galdo F, Lepri G, Minier T, Huscher D, Furst DE, et al. Progression of patients with Raynaud's phenomenon to systemic sclerosis: a five-year analysis of the European Scleroderma Trial and Research group multicentre, longitudinal registry study for Very Early Diagnosis of Systemic Sclerosis (VEDOSS). Lancet Rheumatol. 2021 Dec;3(12):e834–43. https://doi.org/10.1016/S2665-9913(21)00244-7
  11. Ferri C, Giuggioli D, Guiducci S, Lumetti F, Bajocchi G, Magnani L, et al. Systemic sclerosis Progression INvestiGation (SPRING) Italian registry: demographic and clinico-serological features of the scleroderma spectrum. Clin Exp Rheumatol. 2020;38 Suppl 125(3):40–7. https://pubmed.ncbi.nlm.nih.gov/32301427/
  12. Liem SIE, Neppelenbroek S, Fehres CM, Wevers BA, Toes REM, Allaart CF, et al. Progression from suspected to definite systemic sclerosis and the role of anti-topoisomerase I antibodies. RMD Open. 2023 Feb;9(1):e002827. https://doi.org/10.1136/rmdopen-2022-002827
  13. Jaeger VK, Wirz EG, Allanore Y, Rossbach P, Riemekasten G, Hachulla E, et al. Incidences and Risk Factors of Organ Manifestations in the Early Course of Systemic Sclerosis: A Longitudinal EUSTAR Study. PloS One. 2016;11(10):e0163894. https://doi.org/10.1371/journal.pone.0163894
  14. van Leeuwen NM, Boonstra M, Bakker JA, Grummels A, Jordan S, Liem S, et al. Anticentromere Antibody Levels and Isotypes and the Development of Systemic Sclerosis. Arthritis Rheumatol. 2021 Dec;73(12):2338–47. https://doi.org/10.1002/art.41814
  15. Volkmann ER, Andréasson K, Smith V. Systemic sclerosis. Lancet. 2023 Jan 28;401(10373):304–18. https://doi.org/10.1016/S0140-6736(22)01692-0
  16. Hamaguchi Y. Autoantibody profiles in systemic sclerosis: predictive value for clinical evaluation and prognosis. J Dermatol. 2010 Jan;37(1):42–53. https://doi.org/10.1111/j.1346-8138.2009.00762.x
  17. Wielosz E, Dryglewska M, Majdan M. Serological profile of patients with systemic sclerosis. Postepy Hig Med Dosw. 2014 Aug 18;68:987–91. https://doi.org/10.5604/17322693.1117543
  18. Smith V, Herrick AL, Ingegnoli F, Damjanov N, De Angelis R, Denton CP, et al. Standardisation of nailfold capillaroscopy for the assessment of patients with Raynaud's phenomenon and systemic sclerosis. Autoimmun Rev. 2020 Mar;19(3):102458. https://doi.org/10.1016/j.autrev.2020.102458
  19. Maricq HR, LeRoy EC. Patterns of finger capillary abnormalities in connective tissue disease by 'wide-field' microscopy. Arthritis Rheum. 1973;16(5):619–28. https://doi.org/10.1002/art.1780160506
  20. Maricq HR. Wide-field capillary microscopy. Arthritis Rheum. 1981 Sep;24(9):1159–65. https://doi.org/10.1002/art.1780240907
  21. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 2013 Nov;65(11):2737–47. https://doi.org/10.1002/art.38098
  22. Lonzetti LS, Joyal F, Raynauld JP, Roussin A, Goulet JR, Rich E, et al. Updating the American College of Rheumatology preliminary classification criteria for systemic sclerosis: addition of severe nailfold capillaroscopy abnormalities markedly increases the sensitivity for limited scleroderma. Arthritis Rheum. 2001 Mar;44(3):735–6. https://doi.org/10.1002/1529-0131(200103)44:3<735::AID-ANR125>3.0.CO;2-F
  23. Lepri G, Guiducci S, Bellando-Randone S, Giani I, Bruni C, Blagojevic J, et al. Evidence for oesophageal and anorectal involvement in very early systemic sclerosis (VEDOSS): report from a single VEDOSS/EUSTAR centre. Ann Rheum Dis. 2015 Jan;74(1):124–8. https://doi.org/10.1136/annrheumdis-2013-203889
  24. Amaral MC, Paula FS, Caetano J, Ames PR, Alves JD. Re-evaluation of nailfold capillaroscopy in discriminating primary from secondary Raynaud's phenomenon and in predicting systemic sclerosis: a randomised observational prospective cohort study. Expert Rev Clin Immunol. 2024 Jun;20(6):665–72. https://doi.org/10.1080/1744666X.2024.2313642
  25. Bonomi F, Bruni C, Peretti S, De Angelis R, Bajocchi G, Giuggioli D, et al. Gastrointestinal involvement in very early and established systemic sclerosis: insights from the SPRING-SIR national Italian registry. Rheumatology. 2026 Jan 8;65(1):keaf457. https://doi.org/10.1093/rheumatology/keaf457
  26. Kucharz EJ, Kopeć-Mędrek M. Systemic sclerosis sine scleroderma. Adv Clin Exp Med Off Organ Wroclaw Med Univ. 2017 Aug;26(5):875–80. https://doi.org/10.17219/acem/64334
  27. Ross RL, Caballero-Ruiz B, Clarke EL, Kakkar V, Wasson CW, Mulipa P, et al. Biological hallmarks of systemic sclerosis are present in the skin and serum of patients with Very Early Diagnosis of Systemic Sclerosis (VEDOSS). Rheumatology. 2025 Jun 1;64(6):3606–17. https://doi.org/10.1093/rheumatology/keae698
  28. Dobrota R, Jordan S, Juhl P, Del Papa N, Maurer B, Becker M, et al. Dysregulation of circulating collagen turnover markers in very early systemic sclerosis. RMD Open. 2024 May 28;10(2):e003306. https://doi.org/10.1136/rmdopen-2023-003306
  29. Siqueira V, Helbingen M, Medeiros-Ribeiro A, da Silva H, Miossi R, Luppino-Assad A, et al. Predictors of progression to systemic sclerosis: analysis of very early diagnosis of systemic sclerosis in a large single-centre cohort. Rheumatol Oxf Engl. 2022 Aug 30;61(9). https://doi.org/10.1093/rheumatology/keac006
  30. Valentini G, Vettori S, Cuomo G, Iudici M, D'Abrosca V, Capocotta D, et al. Early systemic sclerosis: short-term disease evolution and factors predicting the development of new manifestations of organ involvement. Arthritis Res Ther. 2012 Aug 17;14(4):R188. https://doi.org/10.1186/ar4019
  31. Haverkort DA, Den Broeder AA, Kersten BE, Smith V, Vonk MC. Early progression of systemic sclerosis: a longitudinal cohort study on disease evolution and microvascular changes. EULAR Rheumatol Open. 2026 Mar;2(1):326–31. https://doi.org/10.1016/j.ero.2026.02.006
  32. Vasile M, Avouac J, Sciarra I, Stefanantoni K, Iannace N, Cravotto E, et al. From VEDOSS to established systemic sclerosis diagnosis according to ACR/EULAR 2013 classification criteria: a French-Italian capillaroscopic survey. Clin Exp Rheumatol. 2018;36 Suppl 113(4):82–7. https://europepmc.org/article/med/30183599
  33. Herrick AL, Wigley FM. Raynaud's phenomenon. Best Pract Res Clin Rheumatol. 2020 Feb;34(1):101474. https://doi.org/10.1016/j.berh.2019.101474
  34. Ingegnoli F, Boracchi P, Gualtierotti R, Biganzoli EM, Zeni S, Lubatti C, et al. Improving outcome prediction of systemic sclerosis from isolated Raynaud's phenomenon: role of autoantibodies and nail-fold capillaroscopy. Rheumatology. 2010 Apr;49(4):797–805. https://doi.org/10.1093/rheumatology/kep447
  35. Avouac J, Fransen J, Walker UA, Riccieri V, Smith V, Muller C, 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 Mar;70(3):476–81. https://doi.org/10.1136/ard.2010.136929
  36. Barsotti S, Bellando Randone S, Guiducci S, Della Rossa A. Systemic sclerosis: a critical digest of the recent literature. Clin Exp Rheumatol. 2014;32(6 Suppl 86):S194-205. https://pubmed.ncbi.nlm.nih.gov/25372802/
  37. Bellando-Randone S, Matucci-Cerinic M. Very early systemic sclerosis. Best Pract Res Clin Rheumatol. 2019 Aug;33(4):101428. https://doi.org/10.1016/j.berh.2019.101428
  38. Jordan S, Maurer B, Toniolo M, Michel B, Distler O. Performance of the new ACR/EULAR classification criteria for systemic sclerosis in clinical practice. Rheumatology. 2015 Aug;54(8):1454–8. https://doi.org/10.1093/rheumatology/keu530
  39. Johnson SR, Soowamber ML, Fransen J, Khanna D, Van Den Hoogen F, Baron M, et al. There is a need for new systemic sclerosis subset criteria. A content analytic approach. Scand J Rheumatol. 2018 Jan;47(1):62–70. https://doi.org/10.1080/03009742.2017.1299793
  40. Bissell LA, Abignano G, Emery P, Del Galdo F, Buch MH. Absence of Scleroderma pattern at nail fold capillaroscopy valuable in the exclusion of Scleroderma in unselected patients with Raynaud's Phenomenon. BMC Musculoskelet Disord. 2016 Aug 15;17(1):342. https://doi.org/10.1186/s12891-016-1206-5
  41. Nihtyanova SI, Sari A, Harvey JC, Leslie A, Derrett-Smith EC, Fonseca C, et al. Using Autoantibodies and Cutaneous Subset to Develop Outcome-Based Disease Classification in Systemic Sclerosis. Arthritis Rheumatol. 2020 Mar;72(3):465–76. https://doi.org/10.1002/art.41153
  42. Sulli A, Paolino S, Pizzorni C, Ferrari G, Pacini G, Pesce G, et al. Progression of nailfold capillaroscopic patterns and correlation with organ involvement in systemic sclerosis: a 12 year study. Rheumatology. 2020 May 1;59(5):1051–8. https://doi.org/10.1093/rheumatology/kez374
  43. Hasegawa M. Biomarkers in systemic sclerosis: Their potential to predict clinical courses. J Dermatol. 2016 Jan;43(1):29–38. https://doi.org/10.1111/1346-8138.13156
  44. Bruni C, Frech T, Manetti M, Rossi FW, Furst DE, De Paulis A, et al. Vascular Leaking, a Pivotal and Early Pathogenetic Event in Systemic Sclerosis: Should the Door Be Closed? Front Immunol. 2018;9:2045. https://doi.org/10.3389/fimmu.2018.02045
  45. Bellocchi C, Chung A, Volkmann ER. Predicting the Progression of Very Early Systemic Sclerosis: Current Insights. Open Access Rheumatol Res Rev. 2022;14:171–86. https://doi.org/10.2147/OARRR.S285409


back