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Very early versus early disease: the evolving definition of the ‘many faces’ of systemic sclerosis
  1. Marco Matucci-Cerinic,
  2. Silvia Bellando-Randone,
  3. Gemma Lepri,
  4. Cosimo Bruni,
  5. Serena Guiducci
  1. Department of Rheumatology AVC, Department of Biomedicine & Division of Rheumatology AOUC, Department of Medicine & Denothe Centre, University Florence, Florence, Italy
  1. Correspondence to Professor Marco Matucci-Cerinic, University of Florence, Department of Internal Medicine, Division of Rheumatology, Villa Monna Tessa, Florence 50139, Italy; cerinic{at}

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Systemic sclerosis (SSc) is a challenge for the rheumatologist as it is easy to diagnose when it is evolved to skin fibrosis with obliterative vasculopathy and organ involvement but its diagnosis remains very difficult in the very early/early phase of the disease because the American College of Rheumatology (ACR) and LeRoy criteria, which are currently those largely used to classify SSc, were shown to be not sensitive enough to reach a very early or an early diagnosis of SSc.1–4 Therefore, the SSc diagnosis may be delayed for several years following the onset of Raynaud's phenomenon (RP) and even after the onset of the first non-RP symptom. This reality implies that the diagnosis, and consequently the therapy, are delayed until skin involvement and/or internal organ involvement are evident5–8 and, in too many cases, already irreversible.6

The fact that organ involvement may be present from the earliest stages of SSc corroborates the necessity of a very early or at least an early diagnosis of SSc to try to identify therapy which might achieve disease remission. Moreover, the rheumatologist is also facing today the problem to position the patient in the SSc evolution from its very early to the early and to the established phase. Previously, several attempts have been made to define the early phase of SSc7 and recently even the concept of very early SSc has been widely accepted and investigated.8 RP, despite its lack of specificity, has been proposed as a pivotal sign in a previous attempt to define criteria for the diagnosis of ‘early’ SSc9 and has been also considered as the main ‘sentinel’ sign10 for the identification of ‘very early SSc’.8 Evidence from the EULAR Scleroderma Trial and Research group (EUSTAR) database indicates that the time between the onset of RP and the first non-RP symptom or sign in SSc is a mean of 4.8 years in limited cutaneous SSc and a mean of 1.9 years in diffuse cutaneous SSc.4 This time gap between the onset of signs and the diagnosis, mainly based on dermal or internal organ fibrosis, should now be considered as the ‘window of opportunity’ for SSc patients. Therefore, the best approach to obtain a significant control of the disease progression may be ‘opening this window’ to reach a very early diagnosis of SSc. The results obtained so far in rheumatoid arthritis (RA) have clearly shown that the strategy based on the window of opportunity has achieved a significant control of disease progression using an early aggressive therapy. Therefore, the aim for a very early or early diagnosis becomes definitively the goal of the rheumatologist, thus providing the opportunity for the potential prevention of disease evolution and organ damage. For this reason, EUSTAR has proposed the new preliminary criteria for the diagnosis of very early SSc that are actually under validation (VEDOSS project; RP, antinuclear antibodies positivity and puffy swollen digits turning into sclerodactyly are the ‘red flags’ to suspect SSc and thus to send the patient to a referral centre. The diagnosis of very early SSc is confirmed when specific autoantibodies (anticentromere and antitopoisomerase I antibodies) and/or a capillaroscopic SSc pattern (early, active, late) are found.8

In practice, when an RP is identified, a complete history and a general examination are mandatory with an accurate differential diagnosis and the identification of comorbidities like primary biliary cirrhosis and complications like pulmonary hypertension. Together with RP and puffy fingers turning into sclerodactily, other pathognomonic signs, like teleangectasias, digital ulcers and pitting scars, may strongly suggest that the disease is already evolving to an early SSc with internal organ involvement (dysfunctional lower oesophageal sphincter, ground glass on HRCT, diffusing capacity of carbon monoxide (DLCO) reduction on pulmonary function tests and diastolic dysfunction).11–13 Any suspicion of SSc evolution to organ involvement may be easily confirmed or refuted by further specific investigations.

Recent data have shown that internal organ involvement in SSc is early and subclinical:12 115 patients with secondary RP were divided into three groups and investigated by lung functional study and B-mode echo-Doppler-cardiography and oesophageal manometry. The first group was constituted by patients without clinical manifestations other than RP, but with specific autoantibodies and/or typical capillaroscopic abnormalities. The second group contained patients with the same autoantibody and/or capillaroscopic SSc pattern, but with any of the following manifestations: digital ulcers/scars, puffy fingers, arthritis, telangiectasia, dysphagia/heartburn or shortness of breath; the third group was constituted by patients with specific (ie, disease antibody marker) antinuclear antibodies and capillaroscopic findings plus any disease manifestation. In a high proportion of patients, the presence of SSc-related internal organ involvement including diastolic dysfunction (ie, early cardiac involvement) and/or a diffusing lung capacity for CO <80% of the predictive value (ie, early lung interstitial/vascular involvement) and/or basal low oesophageal sphincter pressure <15 mm Hg (ie, early oesophageal involvement) was found.12 These data clearly identify a SSc subset characterised by very early signs of SSc but who are already evolved to organ involvement and therefore they are patients clearly further evolved and may be classified as early SSc (see figure 1).

Figure 1

The evolution of SSc is presented from very early through early to established SSc in the fibrotic and atrophic phases. The very onset of the disease is identified as a window of opportunity. Anal involvement is defined as an abnormal resting pressure of anal sphincter.11 ACA, anticentromere antibodies; ANA, antinuclear antibodies; ATA, antitopoisomerase I antibodies; NVC, nailfoldvideocapillaroscopy; SSc, systemic sclerosis. This figure is only reproduced in colour in the online version.

It is very well known that RP is a common initial sign in some connective tissue diseases and, moreover, in SSc it may precede the onset of cutaneous or visceral sclerosis even by decades (in particular in limited cutaneous SSc). Today, despite the usefulness of criteria to define very early SSc, the management of these patients remains a major challenge. In fact, the choice of an aggressive treatment, though logical and reasonable, before the patient fulfils the ACR or LeRoy's validated criteria, still remains an option which may expose some patients to overtreatment and risks connected to side effects. The reality is therefore marking the fact that the present criteria for very early SSc are not yet validated while the predictors of severity in this cohort of very early SSc patients are not yet identified. These weaknesses are obviously impairing the capacity of the rheumatologist to act in due time. In practice, this evidence dictates the need for a stringent follow-up of the patients to identify promptly the ‘many changing faces’ of SSc characterised by a heterogeneous mix of vascular, skin and internal organ involvement.

Clearly, the ability to decipher the riddle of very early/early SSc and the capacity to provide a new classification of the disease, now in preparation by a shared effort ACR/EULAR,14 as well as new predictors of activity/severity are crucial issues today. Thus, the identification of genetic, clinical and circulating tests is the next mandatory step to be achieved to lift the curtain on the prognosis of a very early SSc patient without skin involvement burdened by the risk of developing severe organ involvement. The negative predictive value of testing in the very early phase might identify SSc which will not progress to major complications, thus sparing the patients from the use of an aggressive overtreatment. If these issues will be soon clarified we may hopefully look ahead to the window of opportunity as a unique chance to design an aggressive treatment for SSc before damage is done.15 For the moment, the only feasible clinical strategy in very early SSc remains a tight follow-up programme to foster the ‘real time’ detection of the early internal organ involvement followed by an aggressive therapeutic agenda. The EUSTAR effort to validate the criteria with the VEDOSS project will definitively open a new avenue in SSc shedding light on a grey zone today represented by the very early/early phase of the disease.



  • Contributors MMC conceived the study and participated in the drafting of the manuscript. SBR, GL and CB participated in the drafting of the manuscript. SG coordinated the study and participated in the drafting of the manuscript.

  • Funding This work was funded by a grant provided by the Regione Toscana, Italy (Regional Health Research Programme).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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