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Clinical and epidemiological research
Extended report
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
  1. Tünde Minier1,
  2. Serena Guiducci2,
  3. Silvia Bellando-Randone2,
  4. Cosimo Bruni2,
  5. Gemma Lepri2,
  6. László Czirják1,
  7. Oliver Distler3,
  8. Ulrich A Walker4,
  9. Jaap Fransen5,
  10. Yannick Allanore6,
  11. Christopher Denton7,
  12. Maurizio Cutolo8,
  13. Alan Tyndall4,
  14. Ulf Müller-Ladner9,
  15. Marco Matucci-Cerinic2,
  16. and the EUSTAR co-workers
  1. 1Department of Rheumatology and Immunology, University of Pécs, Pécs, Hungary
  2. 2Department of Biomedicine, Division of Rheumatology AOUC and Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy
  3. 3Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
  4. 4Department of Rheumatology, University Hospital Basel, Basel, Switzerland
  5. 5Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  6. 6Department of Rheumatology, Université Paris Descartes, Paris, France
  7. 7Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School, Royal Free Campus, London, UK
  8. 8Department of Internal Medicine, University of Genova, Research Laboratory and Academic Clinical Unit of Rheumatology, Viale Benedetto, Italy
  9. 9Department of Internal Medicine and Rheumatology, Justus-Liebig-University Giessen, Giessen, Germany
  1. Correspondence to Professor Marco Matucci-Cerinic, Division of Rheumatology AOUC, Denothe Centre, Department of Biomedicine, University of Florence, Villa Monna Tessa, Viale Pieraccini 18, Florence 50139, Italy; cerinic{at}unifi.it

Abstract

Objectives The EULAR (European League Against Rheumatism) Scleroderma Trials and Research Group (EUSTAR) has identified preliminary criteria for very early diagnosis of systemic sclerosis (SSc). Our aim was to assess the prevalence of each proposed diagnostic item in a large observational patient cohort with Raynaud's phenomenon (RP).

Methods Baseline data of 469 RP patients enrolled into the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) cohort are presented.

Results 68% of all RP patients were antinuclear antibody (ANA) positive. ANA+ RP patients more frequently had previous or current puffy fingers (PuFi) (38.5% and 23.3%, p<0.01) and an SSc pattern on nailfold capillaroscopy (NC) (53.6% and 13.4%, p<0.001) than ANA− patients. Telangiectasia, current digital ulcers and digital pitting scars were also commoner in ANA+ RP patients. 38% of ANA+ patients presented with all three features, which should raise suspicion of very early SSc (ANA+RP+PuFi constitutes a ‘red flag’). These patients more frequently exhibited an NC SSc pattern, sclerodactyly and telangiectases compared to ANA+ patients without PuFi. Almost 90% of patients with ‘red flags’ had anti-centromere or anti-topoisomerase I antibodies and/or an NC SSc pattern, and fulfilled the EUSTAR criteria for very early SSc. Previous or current PuFi were present in 23.3% of ANA− RP patients, eight of whom also had an NC SSc pattern.

Conclusions In addition to well-characterised predictive factors, PuFi is an important sign raising suspicion for underlying very early SSc in patients with RP. The relevance of PuFi in ANA− RP patients should be clarified.

  • Systemic Sclerosis
  • Outcomes research
  • Autoantibodies
  • Disease Activity
  • Pulmonary Fibrosis

https://doi.org/10.1136/annrheumdis-2013-203716

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    Introduction

    Systemic sclerosis (SSc) is characterised by generalised microangiopathy, immune dysregulation and fibrosis of the skin and internal organs. The disease is associated with significant disability and increased mortality, and represents a heavy socio-economic burden for society. A study using the data of almost 1000 diffuse cutaneous SSc (dcSSc) patients enrolled into the Pittsburgh Scleroderma Databank has demonstrated that severe organ involvement affecting the skin, kidneys, heart, lungs and gastrointestinal tract most often occurs early in the course of the disease less than 3 years after disease onset.1 Survival for these patients with early severe internal organ involvement was markedly reduced (50% at 5 years). Furthermore, another study from a single centre showed that internal organ involvement may appear even before SSc patients fulfil the classification criteria of the American College of Rheumatology (ACR), formerly the American Rheumatism Association (ARA).2–4 In this latter study, screening with sensitive tools for internal organ involvement in early SSc patients (defined as patients having Raynaud’s phenomenon (RP) with SSc marker autoantibodies and/or typical nailfold capillaroscopic (NC) findings and no manifestations other than puffy fingers (PuFi) or arthritis) identified at least one preclinical functional alteration in 42–48% of cases.3 ,4

    Although recent meta-analyses have shown some improvement in the overall survival of SSc patients, this improvement was similar to that observed in the general population and therefore SSc-related mortality remains high and unchanged.5–9

    The lack of early diagnostic criteria and valid predictors of disease evolution are significant limiting factors for identification and treatment in the earliest phase of the disease.10 In order to overcome this limitation, the EULAR (European League Against Rheumatism) Scleroderma Trials and Research Group (EUSTAR) has performed a multicentre web-based Delphi exercise with the involvement of a large number of scleroderma experts.11 As result, the presence of RP, PuFi and antinuclear antibody (ANA) positivity were identified as the three key features (‘red flags’) that should raise suspicion of very early SSc. The SSc pattern on NC and the presence of some specific SSc antibodies (anti-centromere antibody (ACA) or anti-topoisomerase I (TOPO-I)) were considered to be necessary for the diagnosis of very early SSc.

    Compared to the classification criteria of early SSc proposed by LeRoy and Medsger in 2001,12 the experts proposed a further new item, namely the presence of PuFi as an additional warning sign for very early SSc.

    PuFi or puffy hands are considered reliable early signs of connective tissue disease and have even been found to be independent predictors of the evolution of RP into SSc.13 PuFi were also included in the recently revised classification criteria of SSc.14 Nevertheless, only a few studies have assessed their significance in the transition from RP into early SSc.15–18

    For validation of the very early diagnostic criteria, a multicentre prospective observational study called VEDOSS (Very Early Diagnosis Of SSc) was started in March 2010 with the participation of the EUSTAR centres. The present work reports cross-sectional results from the VEDOSS study up to 15 February 2012.

    In this study we have assessed the prevalence of early signs of SSc (ANA positivity and PuFi) in patients with RP enrolled into the VEDOSS database and examined how many patients fulfil the criteria for very early SSc (SSc-specific nailfold capillary changes and/or the presence of SSc-related autoantibodies) at the time of enrolment. We also tested the relevance of PuFi for detecting SSc in our RP patient cohort, a feature surprisingly rarely studied although considered to be an early sign of SSc.

    Methods

    Design and patients

    The data of 516 RP patients enrolled into the VEDOSS online database from 1 March 2010 until 15 February 2012 were included in the current analysis. However, 47 patients who had missing data on ANA were excluded, leaving data from 469 patients with RP for statistical analyses. Inclusion criteria for the VEDOSS database were: patients with RP, willing and able to be followed up for 3 years. Patients fulfilling the ACR criteria for SSc were excluded.2

    The study was performed in 33 EUSTAR centres throughout and outside Europe.

    Clinical assessments

    Physical examination included assessment for the presence of PuFi, digital ulcers (DUs), digital pitting scars, telangiectases, calcinosis, tendon friction rubs, symptoms corresponding to median nerve compression syndrome, and oesophageal symptoms. Any history of previous PuFi and digital pitting scars was also recorded. As there are no clear guidelines for assessing PuFi, the presence of PuFi was determined by expert opinion in the participating tertiary centres.

    Skin involvement was evaluated by assessing the modified Rodnan skin score (MRSS).19 Sclerodactyly was recorded when skin thickening was found only on the fingers and not proximal to the metacarpophalangeal joints.2

    To determine NC pattern, each EUSTAR centre performed capillaroscopy independently with their own instruments. The extent of giant capillaries, haemorrhages, capillary loss and ramified/bushy capillaries (no, rare, moderate, extensive) on NC examination was recorded, and based on these findings, an early, active or late SSc pattern was assigned by one investigator (TM).20

    Laboratory tests were performed according to local laboratory standards and included ANA (determined in 100% of patients), ACA (95.5%), TOPO-I (95.3%), U1RNP antibody (71%), RNA polymerase III antibody (29.4%), anti-fibrillarin antibody (16.4%), anti-synthetase antibodies (22.6%), PM-Scl antibody (57.5%) and anti th/To antibody (11.0%). Not all tests were available in all centres, for example, anti-Th/To antibody was tested in 13/33 centres and anti-RNA-polymerase III autoantibody in 15/33 centres (for prevalence see table 1).

    View this table:
    Table 1

    Demographic and clinical data of 469 patients with RP enrolled into the VEDOSS online database

    The diagnosis of primary RP was made if ANA was negative, no scleroderma pattern was seen on NC and patients presented with neither sclerodactyly, DUs, digital pitting scars, PuFi, elevated erythrocyte sedimentation rate (ESR<25 mm/h) or any further obvious signs or symptoms of a connective tissue or other disease.

    Data collection

    Data were prospectively collected using standard case record forms entered in an online database.

    Statistical methods

    For statistical analyses, Pearson χ2 test or Fisher's exact test, the independent samples t test, or the independent sample Wilcoxon test were used, as appropriate.

    SPSS V.19.0 for Windows was used for all statistical analyses (SPSS, Chicago, Illinois, USA).

    Results

    The demographic and clinical data of the enrolled RP patients are presented in table 1. Of 469 RP patients, 67.8% were ANA positive and 32.2% were ANA negative. Slightly more than half of the ANA− patients (80/151, 52.9%) were diagnosed with primary RP, as they did not present with an SSc pattern on NC, SSc-related specific clinical symptoms or an elevated ESR. However, an NC SSc pattern was detected in 13.4% of ANA− RP patients.

    ANA+ versus ANA− patients with RP

    There were more females in the ANA+ group, while ANA− patients were approximately 4 years younger. There were no differences regarding duration of RP (table 1).

    Previous or current PuFi and oesophageal symptoms were the most common clinical features in ANA+ patients. These two features were significantly more frequent in the ANA+ group compared to the ANA− group (38.5% vs 23.3%, p=0.001, and 35.2% vs 18.4%, p<0.001, respectively).

    Current PuFi (9.8% vs 3.4%, p=0.015), digital pitting scars (4.7% vs 0.7%, p=0.027), telangiectasia (12.3% vs 1.4%, p<0.001) and an SSc pattern on NC (53.6% vs 13.4%, p<0.001) were also seen significantly more frequently in ANA+ patients compared to ANA− patients. In the ANA+ group, the NC pattern showed a different distribution (early (15.4% vs 5.6%), active (30.7% vs 7.7%) and late (7.5% vs 0%)) compared to the ANA− group (table 1).

    ACA or TOPO-I antibody and NC SSc patterns were present in more than half of the ANA+ patients (table 1). Sclerodactyly was uncommon but more frequently present in ANA+ patients.

    ANA− patients with RP and PuFi

    In the ANA− group, previous or current PuFi were found in 35 cases (23.3%). Five of these particular patients also presented with PuFi at the time of physical examination. ANA− patients with previous or current PuFi more frequently presented with NC SSc patterns compared to ANA− patients without PuFi (25.8% vs 10%, p=0.023). Seven ANA− patients with previous or current PuFi had sclerodactyly at the time of enrolment, with two patients also having an SSc pattern on NC. None of the ANA− patients with sclerodactyly presented with DUs, digital pitting scars or telangiectases. No one in the ANA− patient subgroup without PuFi presented with sclerodactyly.

    Patients with RP, ANA positivity and PuFi

    More than one-third (38.5%) of ANA+ patients with RP had current or previous PuFi, and thus presented with all three ‘red flags’ suggested by EUSTAR for suspicion of very early SSc (figure 1). When compared with ANA+ RP patients without PuFi, patients with ‘red flags’ more frequently had sclerodactyly (17.8% and 6.2%, p=0.002), telangiectases (17.3% vs 9.2%, p=0.033) and oesophageal symptoms (42.1% vs 30.9%, p=0.043) (table 2). Seventy-three percent of ANA+ RP patients with previous or current PuFi had an NC SSc pattern compared to only 41.2% of patients without PuFi (p<0.001). In both groups, the active pattern was seen most frequently (in 42% of patients with previous or current PuFi, and in 22.2% of patients without), the late pattern was more frequent in ANA+ RP patients with previous or current PuFi (12.0% vs 4.7%), and the frequency of the early pattern was approximately equal (17.2% vs 14.2%) (table 2).

    View this table:
    Table 2

    Clinical characteristics of antinuclear antibody (ANA) positive and ANA negative patients with Raynaud's phenomenon (RP) and puffy fingers

    Figure 1
    Figure 1

    Flowchart of Very Early Disease Onset of Systemic Sclerosis (VEDOSS) cohort data. Ab, antibody; ACA, anti-centromere antibody; ACR criteria, American College of Rheumatology classification criteria (1980); ANA, antinuclear antibody; anti-TOPO I, anti-topoisomerase I antibody; NC, nailfold capillaroscopy; RP, Raynaud's phenomenon; SSc, systemic sclerosis.

    There was no difference in the frequency of SSc-related autoantibodies between ANA+ RP patients with PuFi compared to those without PuFi.

    More than half of patients with previous or current PuFi (n=72, 59.5%) had SSc-specific autoantibodies: ACA in 55 patients and TOPO-I in 17 patients (figure 1).

    There were no significant differences in age at RP onset, duration of RP or any other clinical features between ANA+ RP patients with current PuFi (n=31) and those with previous PuFi but not at the time of enrolment (n=91) (data not shown).

    Very early SSc patients

    A total of 108 patients (88.5% of ANA+ RP patients with previous or current PuFi) fulfilled the criteria for very early SSc: 23 patients had only specific autoantibody positivity, 35 patients had only an NC SSc pattern, 49 patients had both specific antibody positivity (ACA or TOPO-I) and a specific NC pattern, and one patient had an SSc pattern on NC but no available ACA or TOPO-I antibody results (figure 1).

    Sclerodactyly (19.3% vs 6.7%, p<0.001) and telangiectases (19.4% vs 8.6%, p=0.007) were more common in patients fulfilling the VEDOSS criteria compared to other ANA+ RP patients.

    The positive predictive value (PPV) of ANA positivity for developing SSc in RP patients enrolled into the VEDOSS cohort was 33.9%. The PPV increased to 88.5% in ANA+ patients with PuFi. The negative predictive value could not be assessed in the absence of longitudinal data.

    Forty-eight ANA+ RP patients with previous or current PuFi (39% of patients with ‘red flags’ and 44% of patients fulfilling the VEDOSS criteria) fulfilled the new ACR-EULAR classification criteria for SSc, compared to only 13% of ANA+ RP patients with no PuFi (figure 2). Patients fulfilling the ACR-EULAR classification criteria more commonly presented with current PuFi, sclerodactyly and telangiectasia compared to patients fulfilling only the VEDOSS diagnostic criteria (data not shown). There was no difference in duration of RP (median 4.5 years, IQR 1–14.7) in patients fulfilling the new classification criteria compared to those fulfilling the very early diagnostic criteria (median 3.5 years, IQR 1–9, p=0.356), age at RP onset or any other clinical signs or laboratory parameters between these two patient groups (data not shown).

    Figure 2
    Figure 2

    The new ACR-EULAR classification criteria for systemic sclerosis in patients with Raynaud's phenomenon enrolled into the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) database. ACR, American College of Rheumatology; ANA, antinuclear antibodies; EULAR, European League Against Rheumatism; PuFi, puffy fingers; RP, Raynaud's phenomenon.

    All three ANA− RP patients who also fulfilled these criteria for SSc presented with previous or current PuFi (figure 2).

    ANA+ RP patients with SSc-specific autoantibodies (ACA or TOPO-I positivity)

    A total of 170 ANA+ patients (53.4%) had specific autoantibodies. The presence of ACA or TOPO-I antibodies was associated with an increased frequency of oesophageal symptoms (70/169 (41.4%) vs 40/141 (28.4%), p=0.017), an NC SSc pattern (99/163 (60.7%) vs 61/138 (44.2%), p=0.004) and current PuFi (22/170 (12.9%) vs 8/141 (5.7%), p=0.031).

    RP onset was 8 years later in ANA+ patients with specific antibodies compared to ANA+ patients with no ACA or TOPO-I antibodies (mean 44.1 years (SD 16.4) vs mean 35.8 years (SD 14.6), p<0.001).

    Discussion

    Our study on the baseline data of this large prospective multicentre patient cohort with RP highlights: (i) the relevance of the ‘red flags’ identified by EUSTAR; and (ii) the importance of PuFi in the identification of patients with very early SSc. Almost 90% of ANA+ RP patients with previous or current finger oedematous skin changes (PuFi) already had an NC SSc pattern and/or SSc-specific autoantibodies. Our results also suggest that ANA− patients with PuFi should be followed up and carefully investigated as 20% of these patients presented with sclerodactyly and other SSc signs (eg, an SSc pattern on NC, oesophageal symptoms, elevated ESR), another 17% (6/35 ANA− patients with previous or current PuFi) presented with an NC SSc pattern, and three patients (8%) fulfilled the new ACR-EULAR classification criteria for SSc.

    The aim of the VEDOSS criteria is to facilitate SSc diagnosis at the earliest possible stage so that early screening for pre-clinical internal organ involvement can be implemented.21

    The ACR classification criteria are frequently used but do not identify early SSc cases.2 ,22 In an attempt to overcome this problem, LeRoy and Medsger proposed new classification criteria for early SSc, which included RP and also the presence of SSc-specific autoantibodies and changes characteristic for SSc on NC.12 A single centre large prospective study on RP patients supported this proposal,18 showing that approximately 80% of RP patients who had both SSc-specific autoantibodies and an SSc pattern on NC developed overt SSc (study specific definition) at 15 years.

    A joint international collaborative initiative supported by the ACR and EULAR developed revised classification criteria for SSc. Twenty-three items were identified and then reduced to seven and weighted, while a provisional threshold of nine points is proposed.14 ,23 ,24

    Attempts were also made to establish diagnostic criteria in SSc. In 2010, Hudson et al developed diagnostic criteria for SSc by analysing a large Canadian multicentre patient cohort (n=1048). In addition to RP and skin involvement, they identified mat-like telangiectases and SSc-related antibodies (ACA and TOPO-I) as important diagnostic clues, which improved the sensitivity of the ACR criteria from 57% to 97%.25 However, this study was performed on a patient cohort with an established diagnosis of SSc (87.8% of patients fulfilled the ACR criteria) and relatively long disease duration (mean 11 years (SD 9.5)). Therefore, these criteria may fail to identify very early or mild SSc cases.

    In our analysis we show that ANA+ RP patients presented with PuFi and specific NC alterations more often than ANA− patients, and also more frequently had other SSc-related specific signs such as telangiectasia, oesophageal symptoms, current DUs and digital pitting scars. More than one third of ANA+ patients presented with all three ‘red flags’ (ANA, RP and PuFi), which should raise suspicion of very early SSc. As expected, these patients more frequently had SSc-specific NC changes compared to other ANA+ patients without PuFi, constituting a distinct subgroup within the RP cohort. Previous or current PuFi were associated with specific NC changes independently of the presence of SSc-specific autoantibodies. Almost 90% of patients with ‘red flags’ additionally presented with ACA or TOPO-I and/or an SSc NC pattern and fulfilled the diagnostic criteria for very early SSc suggested by EUSTAR.11 The validity of these criteria seems to be supported by the finding that 44% (48/108) of these patients fulfilled the new ACR-EULAR classification criteria for SSc compared to only 13% (26/195) of ANA+ RP patients without PuFi. We have further demonstrated that both current and previous PuFi help to identify SSc patients, as 25% of these patients also fulfilled the ACR-EULAR classification criteria (figure 2).

    Our results suggest that PuFi may also be an important sign in ANA− RP patients, as previous or current PuFi in ANA− RP patients was also more frequently associated with an NC SSc pattern compared to patients without PuFi. All ANA− patients with sclerodactyly (n=7, 4.9%) in our patient cohort presented with previous or current PuFi. Furthermore, all three ANA− RP patients who fulfilled the ACR-EULAR criteria had current (one patient) or previous PuFi (two patients).

    Thus, PuFi may be a valuable clinical sign in patients with RP and should be further evaluated in ANA− patients. This is also supported by a recent single centre study which demonstrated that PuFi predicts progression from RP to SSc (HR 1.89, 95% CI 1.12 to 3.26).18

    We are aware that our study has some limitations. For feasibility reasons, ANA positivity was determined according to the local laboratory standards of the participating EUSTAR centres and not in a central laboratory, and therefore false positive and false negative cases might be present in the database. However, the large patient sample size intended to be enrolled could prevent statistically significant associations with no eventual clinical importance. The results of tests for gastrointestinal involvement were not included in the case record form and investigations were only mandatory in enrolled patients when clinically indicated. Therefore, our study is not able to identify all pre-clinical organ involvement. In both ANA+ and ANA− patients, the duration of RP was already relatively long at the time of enrolment into the study (medians of 4 and 5 years, respectively). This might influence the possibility of identifying incident VEDOSS cases among the enrolled patients. We are also aware that patients identified with the very early diagnostic criteria may also have scleroderma with limited cutaneous involvement or even undifferentiated connective tissue disease. This can be clarified by examining the follow-up data of these patients after a longer period of time and evaluating how many patients fulfil both the ACR 1980 classification criteria and the ACR-EULAR revised classification criteria. Another limitation may be that although this is an international multicentre patient cohort, a few centres made large contributions to RP patient enrolment. Our results cannot be generalised to the entire RP population as patients were enrolled in tertiary centres with a specific focus on SSc. These patients may differ in clinical characteristics and disease course from RP patients seen in general practice or in other medical departments (eg, angiology). Also, the proportion of patients fulfilling very early SSc classification criteria is not representative of patients with RP seen by general physicians. For the same reason the PPV calculated is also not generalisable.

    The strength of our study is that we present the data of a fairly large patient cohort with RP.

    In summary, to our knowledge this is the first work examining the significance of PuFi in a large international multicentre patient cohort with RP, showing that PuFi is an important sign that raises suspicion of very early SSc in RP patients. In addition, the presence of ANA, SSc-related autoantibodies (ACA and TOPO-I antibodies) and an SSc NC pattern strengthens the role of RP and PuFi as important signs for the final diagnosis of very early SSc. PuFi were also present in ANA− RP patients and were associated with sclerodactyly and NC changes. Therefore, follow-up should be conducted both in ANA+ RP PuFi patients as well as in ANA− RP PuFi patients to ascertain the real causes behind these signs.

    Our preliminary results confirm in a multicentre prospective study carried out on a large patient cohort, that the EUSTAR VEDOSS criteria (RP, ANA positivity and PuFi) can identify a patient subset with a predisposition to develop early SSc. The forthcoming follow-up data of the VEDOSS study will be fundamental to demonstrate the true importance of the signs to identify those VEDOSS patients who will develop internal organ involvement.

    References

    1. ↵
      1. Steen VD,
      2. Medsger TA Jr.
      . Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 2000;43:2437–44.
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      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.
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      1. Valentini G,
      2. Cuomo G,
      3. Abignano G,
      4. et al
      . Early systemic sclerosis: assessment of clinical and pre-clinical organ involvement in patients with different disease features. Rheumatology (Oxford) 2011;50:317–23.
      OpenUrlAbstract/FREE Full Text
    4. ↵
      1. Valentini G,
      2. Vettori S,
      3. Cuomo G,
      4. et al
      . Early systemic sclerosis: short-term disease evolution and factors predicting the development of new manifestations of organ involvement. Arthritis Res Ther 2012;14:R188.
      OpenUrlCrossRefPubMed
    5. ↵
      1. Ioannidis JP,
      2. Vlachoyiannopoulos PG,
      3. Haidich AB,
      4. et al
      . Mortality in systemic sclerosis: an international meta-analysis of individual patient data. Am J Med 2005;118:2–10.
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      1. Steen VD,
      2. Medsger TA
      . Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis 2007;66:940–4.
      OpenUrlAbstract/FREE Full Text
    7. ↵
      1. Tyndall AJ,
      2. Bannert B,
      3. Vonk M,
      4. 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;69:1809–15.
      OpenUrlAbstract/FREE Full Text
    8. ↵
      1. Komocsi A,
      2. Vorobcsuk A,
      3. Faludi R,
      4. et al
      . The impact of cardiopulmonary manifestations on the mortality of SSc: a systematic review and meta-analysis of observational studies. Rheumatology (Oxford) 2012;51:1027–36.
      OpenUrlAbstract/FREE Full Text
    9. ↵
      1. Elhai M,
      2. Meune C,
      3. Avouac J,
      4. et al
      . Trends in mortality in patients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford) 2012;51:1017–26.
      OpenUrlAbstract/FREE Full Text
    10. ↵
      1. Matucci-Cerinic M,
      2. Allanore Y,
      3. Czirjak L,
      4. 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.
      OpenUrlAbstract/FREE Full Text
    11. ↵
      1. Avouac J,
      2. Fransen J,
      3. Walker UA,
      4. 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;70:476–81.
      OpenUrlAbstract/FREE Full Text
    12. ↵
      1. LeRoy EC,
      2. Medsger TA Jr.
      . Criteria for the classification of early systemic sclerosis. J Rheumatol 2001;28:1573–6.
      OpenUrlAbstract/FREE Full Text
    13. ↵
      1. Luggen M,
      2. Belhorn L,
      3. Evans T,
      4. et al
      . The evolution of Raynaud's phenomenon: a longterm prospective study. J Rheumatol 1995;22:2226–32.
      OpenUrlPubMedWeb of Science
    14. ↵
      1. van den Hoogen F,
      2. Khanna D,
      3. Fransen J,
      4. et al
      . Classification Criteria for Systemic Sclerosis: An ACR-EULAR Collaborative Initiative. Arthritis Rheum 2013; in press.
    15. ↵
      1. Gerbracht DD,
      2. Steen VD,
      3. Ziegler GL,
      4. et al
      . Evolution of primary Raynaud's phenomenon (Raynaud's disease) to connective tissue disease. Arthritis Rheum 1985;28:87–92.
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      1. Kallenberg CG
      . Early detection of connective tissue disease in patients with Raynaud's phenomenon. Rheum Dis Clin North Am 1990;16:11–30.
      OpenUrlPubMedWeb of Science
    17. ↵
      1. Vayssairat M,
      2. Baudot N,
      3. Gaitz JP
      . Raynaud's phenomenon together with antinuclear antibodies: a common subset of incomplete connective tissue disease. J Am Acad Dermatol 1995;32:747–9.
      OpenUrlCrossRefPubMed
    18. ↵
      1. Koenig M,
      2. Joyal F,
      3. Fritzler MJ,
      4. 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;58:3902–12.
      OpenUrlCrossRefPubMedWeb of Science
    19. ↵
      1. Clements P,
      2. Lachenbruch P,
      3. Siebold J,
      4. et al
      . Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J Rheumatol 1995;22:1281–5.
      OpenUrlPubMedWeb of Science
    20. ↵
      1. Cutolo M,
      2. Sulli A,
      3. Pizzorni C,
      4. et al
      . Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis. J Rheumatol 2000;27:155–60.
      OpenUrlPubMedWeb of Science
    21. ↵
      1. Matucci-Cerinic M,
      2. Bellando-Randone S,
      3. Lepri G,
      4. et al
      . Very early versus early disease: the evolving definition of the 'many faces' of systemic sclerosis. Ann Rheum Dis 2012;72:31921.
      OpenUrlPubMedWeb of Science
    22. ↵
      1. Lonzetti LS,
      2. Joyal F,
      3. Raynauld JP,
      4. 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;44:735–6.
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      1. Fransen J,
      2. Johnson SR,
      3. van den Hoogen F,
      4. et al
      . Items for developing revised classification criteria in systemic sclerosis: results of a consensus exercise. Arthritis Care Res (Hoboken) 2012;64:351–7.
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      1. Johnson SR,
      2. Fransen J,
      3. Khanna D,
      4. et al
      . Validation of potential classification criteria for systemic sclerosis. Arthritis Care Res (Hoboken) 2012;64:358–67.
      OpenUrlCrossRefPubMedWeb of Science
    25. ↵
      1. Hudson M,
      2. Fritzler MJ,
      3. Baron M
      . Systemic sclerosis: establishing diagnostic criteria. Medicine (Baltimore) 2010;89:159–65.
      OpenUrlCrossRefPubMedWeb of Science

    Footnotes

    • Handling editor Tore K Kvien

    • http://group.bmj.com/products/journals/instructions-forauthors/co_owned_licence.pdf

    • Collaborators Paolo Airò, Stefania Zingarelli (Brescia); Lidia Ananieva, Oxana Desinova (Moscow); Codrina Mihaela Ancuta, Codruta Iulia Belibou (Iasi); Jerome Avouac (Paris); Radim Becvar, Simona Skacelova (Prague); Lorenzo Beretta, Barbara Vigone (Milan); Paola Caramaschi, Dania Sabbagh (Verona); Patrick Carpentier (Grenoble); Nemanja Damjanov, Katarina Simic-Pasalic (Belgrade); Jorg HW Distler (Nuremberg); Dominique Farge-Bancel, Sondess Hadj-Khelifa (Paris); Rosario Foti, Marcella Di Gangi (Catania); Paloma Garcia de la Pena Lefebvre (Madrid); Eric Hachulla (Lille); Maria Joao Salvador (Coimbra); Cristiane Kayser, Cintia Zumstein Camargo (Sao Paulo); Gábor Kumánovics (Pécs); Mengtao Li, Dong Xu (Beijing); Bianca Marasini, Laura Belloli (Milan); Britta Maurer (Zurich); Miroslav Mayer (Zagreb); Carina Mihai, Ana Maria Gherghe (Bucharest); Valeria Riccieri, Katia Stefanantoni (Rome); Felice Salsano, Edoardo Rosato (Rome); Jean-Luc Senecal, Martial Koenig (Montreal); Patricia Senet, Camille Frances (Paris); Alenka Sipek (Ljubljana); Aleksandra Stankovic, Bojana Stamenkovic (Nis); Vanessa Smith (Ghent); Ingo H Tarner (Giessen); Piotr Wiland (Wroclaw).

    • Contributors All authors contributed to the concept, and writing and revision of the manuscript.

    • Competing interests None.

    • Ethics approval . Ethics committee approval for the study was obtained at each participating EUSTAR centre (based on Ethics Committee Approval, Basel, No. 323/09).

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