Article Text

Extended report
Prediction of worsening of skin fibrosis in patients with diffuse cutaneous systemic sclerosis using the EUSTAR database
  1. Britta Maurer1,
  2. Nicole Graf2,
  3. Beat A Michel1,
  4. Ulf Müller-Ladner3,
  5. László Czirják4,
  6. Christopher P Denton5,
  7. Alan Tyndall6,
  8. Carola Metzig7,
  9. Vivian Lanius7,
  10. Dinesh Khanna8,
  11. Oliver Distler1,
  12. EUSTAR co-authors
  1. 1Division of Rheumatology, University Hospital Zurich, Zurich, Switzerland
  2. 2Graf Biostatistics, Winterthur, Switzerland
  3. 3Department of Rheumatology and Clinical Immunology, Justus-Liebig University Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany
  4. 4Department of Rheumatology and Immunology, Faculty of Medicine, University of Pécs, Pécs, Hungary
  5. 5Centre for Rheumatology, Royal Free and University College London Medical School, London, UK
  6. 6Department of Rheumatology, University Hospital Basel, Basel, Switzerland
  7. 7Bayer Pharma AG, Berlin, Germany
  8. 8University of Michigan Scleroderma Program, Ann Arbor, Michigan, USA
  1. Correspondence to Dr Oliver Distler, Division of Rheumatology, University Hospital Zurich, Gloriastrasse 25, Zurich 8091, Switzerland; oliver.distler{at}usz.ch

Abstract

Objectives To identify predictive parameters for the progression of skin fibrosis within 1 year in patients with diffuse cutaneous SSc (dcSSc).

Methods An observational study using the EUSTAR database was performed. Inclusion criteria were dcSSc, American College of Rheumatology (ACR) criteria fulfilled, modified Rodnan skin score (MRSS) ≥7 at baseline visit, valid data for MRSS at 2nd visit, and available follow-up of 12±2 months. Worsening of skin fibrosis was defined as increase in MRSS >5 points and ≥25% from baseline to 2nd visit. In the univariate analysis, patients with progressive fibrosis were compared with non-progressors, and predictive markers with p<0.2 were included in the logistic regression analysis. The prediction models were then validated in a second cohort.

Results A total of 637 dcSSc patients were eligible. Univariate analyses identified joint synovitis, short disease duration (≤15 months), short disease duration in females/patients without creatine kinase (CK) elevation, low baseline MRSS (≤22/51), and absence of oesophageal symptoms as potential predictors for progressive skin fibrosis. In the multivariate analysis, by employing combinations of the predictors, 17 models with varying prediction success were generated, allowing cohort enrichment from 9.7% progressive patients in the whole cohort to 44.4% in the optimised enrichment cohort. Using a second validation cohort of 188 dcSSc patients, short disease duration, low baseline MRSS and joint synovitis were confirmed as independent predictors of progressive skin fibrosis within 1 year resulting in a 4.5-fold increased prediction success rate.

Conclusions Our study provides novel, evidence-based criteria for the enrichment of dcSSc cohorts with patients who experience worsening of skin fibrosis which allows improved clinical trial design.

  • Systemic Sclerosis
  • Outcomes Research
  • Qualitative Research
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Introduction

Skin fibrosis is a hallmark feature of systemic sclerosis (SSc). The extent of skin fibrosis is usually measured by the modified Rodnan skin score (MRSS), which assesses skin thickness in 17 body surface areas with a 0 (normal) to 3 (severe) scale.1 There are numerous studies that demonstrate a correlation of the extent and the progression of skin fibrosis with mortality in patients with diffuse cutaneous SSc (dcSSc).2

The MRSS is regularly used as primary outcome measure in clinical trials since it is routinely performed at SSc centres and has been found to be reliable, valid and responsive to change.3 However, the use of the MRSS as a primary outcome measure in clinical trials is hampered by the spontaneous regression of skin fibrosis and the high variability between patients in time to peak skin score during the disease course.4–7 Attempts to enrich study populations for patients with progressive skin disease have been largely unsuccessful, and identification of patients being at risk for further progression of skin fibrosis remains challenging.8–11 While several risk factors have been identified in single-centre cohorts, there is no unbiased analysis of large multicentre datasets, and no validated algorithm to optimally identify patients at risk for MRSS progression.

The aim of the study was to identify predictive markers for progressive skin fibrosis in dcSSc patients within 1 year since data entry, to enable improved cohort enrichment for progressive patients in clinical trials with skin fibrosis as the primary endpoint.

Methods

Patients and study design

For this observational study, real-life data derived from the multicentre prospective cohort of the European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) group were used. Each EUSTAR centre has been approved by the local ethics committee. The whole EUSTAR registry comprising 10'019 SSc patients from 179 centres at the time of data extraction was included in the study.12 Subjects had to meet the following inclusion criteria: dcSSc, fulfilling American College of Rheumatology (ACR) criteria,13 MRSS at first visit ≥7, valid data for MRSS at 2nd visit, and 12±2 months between baseline and 2nd visit. Baseline visit was defined as the first entry into the EUSTAR database. The criterion of MRSS ≥7 equals the minimal MRSS score that is required to qualify as diffuse cutaneous, and was deliberately chosen not to miss early patients who will become progressive later on. The follow-up time of 12 months has been chosen since it is considered a relevant period to detect significant changes in MRSS, and is therefore used in many clinical studies with skin fibrosis.9 ,11 EUSTAR centres are advised that the same investigator is performing the MRSS on follow-up visits in individual patients, and EUSTAR investigators are trained on a regular basis on how to perform the MRSS (see online data supplement).14

Objectives of the study

The primary endpoint was defined as worsening of skin fibrosis from baseline to 2nd visit in dcSSc patients. Worsening of skin fibrosis was defined as increase in MRSS >5 points and ≥25% from the baseline to 2nd visit, which is considered clinically meaningful.10

A subanalysis was performed to assess whether immunosuppressive treatment had an effect on the primary endpoint. Since data collection changed from paper case report forms (CRF) to electronic CRFs in 2007–2009, information about immunosuppressive drugs was collected systematically only after 2009. Therefore, patients with baseline visit after 2009 were used for this specific subanalysis.

Statistical analysis

The main research question was whether it would be possible to identify a combination of markers to predict worsening of skin fibrosis in dcSSc patients within 1 year since data entry. Variables included for the analysis except medication are shown in table 1.

Table 1

Patients’ characteristics (total n=637) at baseline: for nominal variables, the absolute and relative frequencies are shown

In the univariate analysis, patients with progressive fibrosis were compared to non-progressive patients. For all nominal variables, a two-sided Fisher's exact test was employed. For ordinal variables, the exact Mann–Whitney U test was performed. For continuous, normally distributed variables, a two-sided, independent samples t test was employed. For non-normally distributed variables, a two-sided Mann–Whitney U test was used.

Additionally, descriptive statistics using Receiver Operating Characteristic (ROC) analysis was employed with MRSS progression as state variable to define cut-off points for disease duration and MRSS at baseline visit.

Predictors with p<0.2 in the univariate analysis were included in the logistic regression analysis. Different logistic regression models were compared for prediction success. A ROC curve was run for each model, and sensitivity and specificity was calculated.

Data validation

For validation of the prediction models, a second cohort with 188 new patients was extracted from the EUSTAR database 11 months after the first data extraction fulfilling the same inclusion criteria as for the initial analysis, except for allowing a follow-up time of 12±3 months.

Results

Study population

A total of 637 patients were eligible, of which 9.7% had progressive skin disease at 12 months follow-up. Patients’ characteristics are provided in table 1.

Effects of immunosuppressive treatment

Since treatment with immunosuppressive drugs might affect changes of the MRSS, we performed a subanalysis in 149 patients with available information on immunosuppressive treatment (see online data supplement). In this subanalysis, it could not be shown that immunosuppression prevented the progression of skin disease, which occurred in 5% (n=20) without, and in 8.5% (n=129) with, immunosuppressive therapy (p=1.0). Therefore, immunosuppressive treatment was not included in the subsequent analyses.

Potential prediction markers of progressive skin fibrosis

The univariate analysis suggested that joint synovitis (ie, joint swelling), shorter disease duration and lower MRSS at baseline are predictive of progressive skin disease. There were trends that (1) MRSS progression was less often observed in patients with oesophageal symptoms in past medical history and (2) that patients with MRSS progression had slightly higher left ventricular ejection fraction (LVEF) as measured by echocardiography as non-progressive patients (table 2).

Table 2

Potential prediction markers (univariate analysis)

In patients with short disease duration (≤15 months), a low skin thickness progression rate (STPR)6 ,17 was predictive of MRSS progression (table 2) indicating that low STPR is more likely to progress in the next 12 months than high STPR. This result was supported by an additional analysis demonstrating that patients with progression in the first 12 months of the study showed a significantly greater decrease in the MRSS in the following 12 months (n=26/245, median(Q1,Q3) -6.0(−10,−1)) than patients without progression in the first 12 months (n=219/245; median(Q1,Q3) 0.0(−4,1); p<0.001). Analysis of interaction items showed that in females or in patients without creatine kinase (CK) elevation, a disease duration ≤15 months was predictive of MRSS progression.

Identification of cut-off points for MRSS at baseline and disease duration to distinguish progressors from non-progressors

Because progressive patients had a lower MRSS at baseline (table 2), we next aimed to identify optimal cut-off points to differentiate between both groups. Using ROC curve analysis with progression as state variable, we found that the sensitivity to identify patients with progressive skin disease increased evenly up to an MRSS score of 22/51 (see online data supplement). Thereafter, specificity decreased without further gain in sensitivity (figure 1A). The predictive value of this cut-off point was confirmed by univariate analysis, since 12.3% of patients with a low MRSS at baseline (≤22/51) were progressing compared to only 2.9% with an MRSS>22/51 (p<0.001). The sensitivity for the prediction of MRSS progression was 91.9% (95% CI 82.2 to 97.3), and specificity was 70.4% (95% CI 25.9 to 33.5).

Figure 1

Definition of cut-off points for modified Rodnan skin score (MRSS) at baseline and disease duration. (A) MRSS at baseline visit according to presence or absence of MRSS progression. (B) Cumulative percentage of progressors and non-progressors according to disease duration up to 60 months. The black and grey lines indicate the cumulative percentage of patients with and without MRSS progression (left y-axis). The grey area visualises the difference in the cumulative percentage of patients with and without MRSS progression (right x-axis). At 15 months, the difference is at its maximum. It stays stable thereafter before slightly decreasing again.

Additionally, disease duration (table 2) was predictive of worsening of skin fibrosis confirming previous results.18 By comparing cumulative percentages between patients with and without progression of MRSS, we observed that the difference in the cumulative percentage between progressors and non-progressors increased within 15 months and stayed stable, thereafter, before decreasing again (figure 1B). Using ROC curve analysis, disease duration of ≤15 months was identified to have an optimal combination of specificity (79.5%, 95% CI75.8 to 82.82) and sensitivity (37.9%, 95% CI25.5 to 51.6) for the prediction of MRSS progression.

Prediction models of worsening of skin fibrosis

Next, to predict worsening of skin fibrosis within 1 year since data entry, a logistic regression analysis was performed using the identified potential prediction markers joint synovitis, disease duration (≤15 vs >15 months), gender, MRSS at baseline (≤22/51 vs >22/51), oesophageal symptoms, and the interaction between disease duration and gender/CK elevation (see online data supplement). LVEF% was not included in the multivariate analysis due to the large number of missing values (75.7%). Similarly, the STPR was not kept because the interaction between STPR and disease duration did not prove to be a significant predictor for progression (p=0.982).

For the multivariate analysis, 573 patients with valid data for the above mentioned prediction markers were eligible. A total of 17 models were derived from the multivariate analysis and were compared with respect to prediction success (table 3). Prediction success is interpreted by percentage of patients who will be progressors among the patients who meet a particular variable. For example, 122 patients had joint synovitis and 20 (16.4%) had progressive disease at 12 month follow-up.

Table 3

Prediction models of progressive skin fibrosis (multivariate analysis)

The model with the highest prediction success rate (44.4%) was model 10 (table 3) (area under the ROC curve: 0.73 (95% CI 0.66 to 0.79, p<0.0001)), with an overall accuracy of 89.9% (98.1% for no progression, 14.3% for progression) (see online supplementary table S4). Out of the 18 cases predicted by model 10 to have MRSS progression, 8 (44.4%) actually had progressive skin disease. A test of the full model against a constant-only model was statistically significant (χ2=39.637, p<0.001 with df=5). Of note, the high impact of a low MRSS at baseline (OR 6.027) suggests defining a maximum MRSS at baseline to enrich clinical studies for progressive patients. According to model 10, the identified prediction markers of progressive skin fibrosis enable the enrichment of clinical cohorts of dcSSc patients from 9.7% up to 44.4%. However, to ensure feasibility of a clinical study, the overall number of patients that can be enrolled has to be considered for the final choice of the prediction model. This means that albeit the prediction success rate is lower than that of model 10, a prediction model such as model 8 (table 4) (area under the ROC curve: 0.69 (95% CI 0.62 to 0.76, p<0.0001)) with less restrictive inclusion criteria might be the better choice for clinical trial design (prediction success rate 23.8% (n=20/84)).

Table 4

Prediction model 8 (multivariate analysis)

Validation of the prediction models for progressive skin fibrosis in a second cohort

To validate the prediction models in a second cohort, data of additional 188 patients of the EUSTAR registry, who were not part of the previous dataset because they were entered after the first extraction of the database, were analysed. Of the 188 patients, 6.4% had progressive skin disease.

Univariate analysis of predictors of interest confirmed joint synovitis (p=0.073), low MRSS at baseline (p=0.186), and short disease duration (p=0.032) as potential predictors, since despite the statistically non-significant p value, low MRSS at baseline proved to have an excellent negative predictive value, as only 1 out 55 patients with high MRSS at baseline was a progressor. Moreover, short disease duration was a significant predictor for progressive skin fibrosis in female patients (p=0.018). No impact was seen for absence of oesophageal symptoms or short disease duration in patients without CK elevation.

Therefore, models with joint synovitis, disease duration, gender and MRSS at baseline were considered for the multivariate analysis, for which 167 patients with valid data for these variables were available. A total of 10 models combining those parameters were compared with respect to prediction success (table 5).

Table 5

Prediction models of progressive skin fibrosis (EUSTAR validation cohort)

Thus, the validation cohort confirmed the previously identified prediction markers with low MRSS at baseline again being of particularly high impact in all models (range OR 5.394–10.463). Online supplementary table S5 gives information about whether the validation confirmed the individual models. Model 10 appeared to be affected by overfitting as the calibration slope decreased considerably in the validation dataset, while other models, such as model 8, showed no decrease, indicating that this model might be of better use for clinical studies.19

In conclusion, the identified and validated criteria including joint synovitis, short disease duration, interaction between female gender and short disease duration, and low MRSS at baseline allow the enrichment for dcSSc patients with progressive active skin fibrosis by up to 4.5-fold.

Discussion

Based on real-life data from the large multicentre EUSTAR cohort, this study revealed that only 6.4–9.7% of an unselected cohort (also not limiting disease duration) of dcSSc patients showed clinically relevant worsening of skin fibrosis at 12 months follow-up. Our newly developed and validated evidence-based prediction models allow an improved cohort enrichment for dcSSc patients with progressive skin fibrosis resulting in an increased progression rate of up to 4.5-fold.

Advantages of our study are that the data were derived from a large, multicentre cohort, and that the extensive list of clinical, laboratory and diagnostic parameters used for the analysis represent key features of the disease as defined by EUSTAR expert consensus.16 Furthermore, the majority of patients from this EUSTAR study were well characterised and showed typical features of dcSSc with respect to, for example, auto-antibody profile, disease characteristics and organ involvement. An additional strength is the unbiased selection of parameters, for example, the dataset was on purpose not limited to patients with early disease to be able to evaluate the relative importance of disease duration in interaction with other parameters by multivariate analysis. This strategy also allowed to define cut-offs for predictive markers, such as disease duration or MRSS at baseline for an optimised differentiation between progressors and non-progressors. Furthermore, the EUSTAR-derived dataset also allowed an analysis for 12 months follow-up, which is considered by many experts as the optimal trial duration to detect meaningful changes in skin fibrosis.9 ,11

In the derivation cohort as well as in the validation cohort, short disease duration, low MRSS at baseline, and joint synovitis were confirmed as independent predictors of progressive skin fibrosis (see online data supplement). This is supported by recent studies suggesting that joint synovitis and short disease duration are associated with active disease or with risk for severe organ involvement.18 ,20 Furthermore, by using descriptive statistics, we could define a cut-off point of 15 months to differentiate patients with progressive skin fibrosis from non-progressors, thus providing an example of an evidence-based definition of disease duration as inclusion criterion for clinical study design. So far, in many clinical trials, early disease (<18 months) was used as an enrichment criterion. However, the importance of an evidence-based definition is supported by findings of a recent study.4 The analysis of 3 dcSSc randomised controlled trials (RCT) showed that only in the group with a disease duration of ≤6 months, a brief worsening of MRSS occurred, whereas patients with a disease duration of >24 months showed a greater rate of decline as compared with patients with a disease duration of <24 months (p<0.05). Overall, 8% of patients in this analysis showed MRSS worsening (defined as ≥5.3 units).

Of note, in our study, a low MRSS at baseline had a consistent and high impact on the prediction of progressive skin fibrosis in dcSSc, with a cut-off point of 22/51 distinguishing optimally between both groups. This is of great importance for clinical study design, because it defines an inclusion criterion, and also helps to avoid ceiling effects in therapeutic trials aiming at skin fibrosis. However, so far, most dcSSc RCTs have included a lower limit of 16–20 units and an upper limit of RCTs of 40–45 units to capture patients with variation of skin fibrosis. An analysis of 7 dcSSc trials showed that the average (SD) MRSS was 25.1 (8.2) units, and that the MRSS improved over the period of 1 year.21 The current analysis challenges the criterion to include an MRSS between 16 and 45 units and suggests that patients with early evolving MRSS with an upper limit of 22 should be included to capture progressive disease over time. Thus, an antifibrotic agent has a real chance to interrupt the process and discriminate from the placebo over a period of 1 year.

Our study also has certain limitations. First, we performed a temporal validation in another EUSTAR-derived cohort, but no external validation. While the temporal validation convincingly confirmed the major parameters discussed above, the results still need to be further validated in other datasets. Furthermore, it has to be emphasised that risk prediction modelling strongly depends on the baseline characteristics of the respective cohort. For example, in a cohort focusing on early dcSSc, disease duration is much more unlikely to be identified as an independent parameter. Second, the data for this study were derived from an observational cohort. Although quality measures are installed in EUSTAR,14 these data have the inherited limitations of registry data. This includes, for example, missing values, and although key factors had low numbers of ‘missings’ in this analysis, other parameters such as LVEF%, acute phase reactants, and spirometry data could not be included in the multivariate analysis because of missing values. Therefore, some potential predictors might have been missed. Third, since reliable information on immunosuppressive treatment was only available in a small subgroup of patients, we cannot exclude that it might affect MRSS progression in other cohorts. Fourth, high STPR is often considered a potential risk factor, because it has been shown to predict early organ involvement and decreased survival in dcSSc patients.17 However, our study revealed that a low STPR at baseline identified patients with progression of skin fibrosis in the 12-month follow-up period. These results are not contradictory, because patients with recent rapid skin progression might have already reached their individual high peak skin score, but can still develop progressive involvement of internal organs leading to increased mortality. Taken together, these data support the important concept that patients with recent high activity of skin fibrosis are not necessarily continuing their high skin fibrosis activity in the next 12-month observation period. These findings have direct impact on clinical trial design, because recent trials on skin fibrosis often aimed to include recently active patients.9 ,11 ,22

In summary, our study identified prediction markers of progressive skin fibrosis with short disease duration, low MRSS at baseline and joint synovitis having the highest impact. The derived evidence-based prediction models allow improved cohort enrichment in clinical trials, and lead also to the identification of patients at risk for progressive skin fibrosis in clinical practice.

References

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Supplementary materials

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Footnotes

  • Handling editor Tore K Kvien

  • Collaborators Collaborators of the EUSTAR centres (numerical order of centres): Ingo H Tarner, Department of Rheumatology and Clinical Immunology, Justus-Liebig University Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany; Marco Matucci Cerinic, Department of Medicine, Section of Rheumatology, University of Florence, Italy; Serena Guiducci, Department of Medicine, Section of Rheumatology, University of Florence, Italy; Ulrich Walker, Department of Rheumatology, University Hospital Basel, Basel, Switzerland; Giovanni Lapadula, Rheumatology Unit-DiMIMP, School of Medicine University of Bari, Italy; Florenzo Iannone, Rheumatology Unit-DiMIMP, School of Medicine University of Bari, Italy; Radim Becvar, Institute of Rheumatology, 1st Medical School, Charles University, Prague, Czech Republic; Stanislaw Sierakowsky, Department of Rheumatology and Internal Diseases, Medical University of Bialystok, Poland; Otylia Kowal Bielecka, Department of Rheumatology and Internal Diseases, Medical University of Bialystok, Poland; Maurizio Cutolo, Research Laboratory and Division of Rheumatology Department of Internal Medicine, University of Genova, Italy; Alberto Sulli, Research Laboratory and Division of Rheumatology Department of Internal Medicine, University of Genova, Italy; Gabriele Valentini, Department of Clinical and Experimental Medicine “F-Magrassi” II, Naples, Italy; Giovanna Cuomo, Department of Clinical and Experimental Medicine “F-Magrassi” II, Naples, Italy; Serena Vettori, Department of Clinical and Experimental Medicine “F-Magrassi” II, Naples, Italy; Gabriele Riemekasten, Department of Rheumatology, Charitè University Hospital, Berlin, German Rheumatism Research Centre Berlin (DRFZ), a Leibniz institute, Germany; Simona Rednic, Department of Rheumatology, University of Medicine & Pharmacy “Iuliu Hatieganu” Cluj, Cluj-Napoca, Romania; Ileana Nicoara, Department of Rheumatology, University of Medicine & Pharmacy “Iuliu Hatieganu” Cluj, Cluj-Napoca, Romania; André Kahan, Department of Rheumatology, University Cochin Hospital, Paris, France; Yannick Allanore, Department of Rheumatology, University Cochin Hospital, Paris, France; P Vlachoyiannopoulos, Department of Pathopysiology, Medical School, National University of Athens, Greece; C Montecucco, Unita’ Operativa e Cattedra di Reumatologia, IRCCS Policlinico S Matteo, Pavia, Italy; Roberto Caporali, Unita’ Operativa e Cattedra di Reumatologia, IRCCS Policlinico S Matteo, Pavia, Italy; Patricia E Carreira, Servicio de Reumatología, Hospital 12 de Octubre, Madrid, Spain; Srdan Novak, Department of Rheumatology and Clinical Immunology, Internal Medicine, KBC Rijeka, Croatia; Cecilia Varju, Department of Rheumatology and Immunology, Faculty of Medicine, University of Pécs, Hungary; Carlo Chizzolini, Department of Immunology and Allergy, University Hospital, Geneva, Switzerland; Eugene J Kucharz, Department of Internal Medicine and Rheumatology, Medical University of Silesia, Katowice, Poland; Anna Kotulska, Department of Internal Medicine and Rheumatology, Medical University of Silesia, Katowice, Poland; Magdalena Kopec-Medrek, Department of Internal Medicine and Rheumatology, Medical University of Silesia, Katowice, Poland; Malgorzata Widuchowska, Department of Internal Medicine and Rheumatology, Medical University of Silesia, Katowice, Poland; Franco Cozzi, Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Padova, Italy; Blaz Rozman, University Medical Center Ljublijana, Division of Internal Medicine, Department of Rheumatology, Ljubliana, Slovenia; Carmel Mallia, “Stella Maris”, Balzan, Malta; Bernard Coleiro, “Stella Maris”, Balzan, Malta; Armando Gabrielli, Istituto di Clinica Medica Generale, Ematologia ed Immunologia Clinica, Università Politecnica delle Marche Polo Didattico, University of Ancona, Italy; Dominique Farge, Assistance Publique-Hôpitaux de Paris; Saint-Louis Hospital; Internal Medicine and Vascular Disease Unit; INSERM UMRS 1160; Paris 7 Diderot University, Sorbonne Paris Cité, 1 avenue Claude-Vellefaux, 75010 Paris, France; Adrian Hij, Assistance Publique-Hôpitaux de Paris; Saint-Louis Hospital; Internal Medicine and Vascular Disease Unit; INSERM UMRS 1160; Paris 7 Diderot University, Sorbonne Paris Cité, 1 avenue Claude-Vellefaux, 75010 Paris, France; Paolo Airò, Spedali Civili di Brescia, Servizio di Reumatologia Allergologia e Immunologia Clinica, Brescia, Italy; Roger Hesselstrand, Department of Rheumatology, Lund University Hospital, Sweden; Agneta Scheja, Department of Rheumatology, Lund University Hospital, Sweden; Frank Wollheim, Department of Rheumatology, Lund University Hospital, Sweden; Duska Martinovic, Department of Internal Medicine, Clinical Hospital of Split, Croatia; Alexandra Balbir Gurman, B. Shine Department of Rheumatology, Rambam Health Care Campus, Haifa, Israel; Yolanda Braun-Moscovici, B. Shine Department of Rheumatology, Rambam Health Care Campus, Haifa, Israel; M Govoni, Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Ferrara, Italy; Andrea Lo Monaco, Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Ferrara, Italy; Nicolas Hunzelmann, Department of Dermatoloy, University Hospital Cologne, Germany; Raffaele Pellerito, Ospedale Mauriziano, Centro di Reumatologia, Torino, Italy; Lisa Maria Bambara, Università degli Studi di Verona, Dipartimento di Medicina Clinica e Sperimentale, Reumatologia-Medicina Interna B, Policlinico GB Rossi, Verona, Italy; Paola Caramaschi, Università degli Studi di Verona, Dipartimento di Medicina Clinica e Sperimentale, Reumatologia-Medicina Interna B, Policlinico GB Rossi, Verona, Italy: Carol Black, Centre for Rheumatology, Royal Free and University College London Medical School, London, UK; Nemanja Damjanov, Institute of Rheumatology, Belgrade, Serbia & Montenegro; Jörg Henes, Medizinische Universitätsklinik, Abt. II (Onkologie, Hämatologie, Rheumatologie, Immunologie, Pulmonologie), Tübingen, Germany; Vera Ortiz Santamaria, Rheumatology Granollers General Hospital, Barcelona, Spain; Stefan Heitmann, Department of Rheumatology, Marienhospital Stuttgart, Germany; Dorota Krasowska, Department of Dermatology, Medical University of Lublin, Poland; Matthias Seidel, Medizinische Universitäts-Poliklinik, Department of Rheumatology, Bonn, Germany; Mara Oleszowsky, Medizinische Universitäts-Poliklinik, Department of Rheumatology, Bonn, Germany; Harald Burkhardt, Klinikum der Johann Wolfgang Goethe Universität, Medizinische Klinik III, Rheumatologische Ambulanz, Frankfurt am Main, Germany; Andrea Himsel, Klinikum der Johann Wolfgang Goethe Universität, Medizinische Klinik III, Rheumatologische Ambulanz, Frankfurt am Main, Germany; Maria J Salvador, Rheumatology Department, Hospitais da Universidade, Coimbra, Portugal; Bojana Stamenkovic, Institute for Prevention, Treatment and Rehabilitation of Rheumatic and Cardiovascular Diseases, Niska Banja, Serbia and Montenegro; Aleksandra Stankovic, Institute for Prevention, Treatment and Rehabilitation of Rheumatic and Cardiovascular Diseases, Niska Banja, Serbia and Montenegro; Mohammed Tikly, Rheumatology Unit, Department of Medicine Chris Hani Haragwanath, Hospital and University of the Witwatersrand, Johannesburg, South Africa; Maya N. Starovoytova, Institute of Rheumatology, Russian Academy of Medical Science, Moscow, Russia; Lidia P. Ananieva, Institute of Rheumatology, Russian Academy of Medical Science, Moscow, Russia; Raffaella Scorza, U.O. Immunologia Clinica—Centro di Riferimento per le Malattie Autoimmuni Sistemiche, Milano, Italy; Merete Engelhart, Department of Rheumatology, University Hospital of Gentofte, Hellerup, Denmark; Gitte Strauss, Department of Rheumatology, University Hospital of Gentofte, Hellerup, Denmark; Henrik Nielsen, Department of Rheumatology, University Hospital of Gentofte, Hellerup, Denmark; Kirsten Damgaard, Department of Rheumatology, University Hospital of Gentofte, Hellerup, Denmark; Gabriella Szücs, Third Department of Medicine, Rheumatology Division, University of Debrecen, Medical Center, Debrecen, Hungary; Antonio Zea Mendoza, Servicio de Reumatología, Hospital Ramon Y Cajal, Madrid, Spain; Carlos de la Puente Buijdos, Servicio de Reumatología, Hospital Ramon Y Cajal, Madrid, Spain; Walter A. Sifuentes Giraldo, Servicio de Reumatología, Hospital Ramon Y Cajal, Madrid, Spain; Øyvind Midtvedt, Department of Rheumatology, Rikshospitalet University Hospital, Oslo, Norway; Torhild Garen, Department of Rheumatology, Rikshospitalet University Hospital, Oslo, Norway; Eric Hachulla, Department of Internal Medicine, Hôpital Claude Huriez, Lille cedex, France; David Launay, Department of Internal Medicine, Hôpital Claude Huriez, Lille cedex, France; Guido Valesini, Department of Internal Medicine and Medical Specialities, “Sapienza” University of Rome, Italy; Valeria Riccieri, Department of Internal Medicine and Medical Specialities, “Sapienza” University of Rome, Italy; Ruxandra Maria Ionescu, Department of Rheumatology—St. Maria Hospital, Carol Davila, University of Medicine and Pharmacy, Bucharest, Romania; Daniela Opris, Department of Rheumatology—St. Maria Hospital, Carol Davila, University of Medicine and Pharmacy, Bucharest, Romania; Laura Groseanu, Department of Rheumatology—St. Maria Hospital, Carol Davila, University of Medicine and Pharmacy, Bucharest, Romania; Fredrick M. Wigley, Johns Hopkins University, Division of Rheumatology, Johns Hopkins School of Medicine, Baltimore, USA; Carmen M. Mihai, Department of Internal Medicine and Rheumatology Clinic, Ion Cantacuzino Clinical Hospital, Bucharest, Romania; Roxana Sfrent Cornateanu, Department of Internal Medicine and Rheumatology Clinic, Ion Cantacuzino Clinical Hospital, Bucharest, Romania; Razvan Ionitescu, Department of Internal Medicine and Rheumatology Clinic, Ion Cantacuzino Clinical Hospital, Bucharest, Romania; Ana Maria Gherghe, Department of Internal Medicine and Rheumatology Clinic, Ion Cantacuzino Clinical Hospital, Bucharest, Romania; Marilena Gorga, Department of Internal Medicine and Rheumatology Clinic, Ion Cantacuzino Clinical Hospital, Bucharest, Romania; Rucsandra Dobrota, Department of Internal Medicine and Rheumatology Clinic, Ion Cantacuzino Clinical Hospital, Bucharest, Romania; Mihai Bojinca, Department of Internal Medicine and Rheumatology Clinic, Ion Cantacuzino Clinical Hospital, Bucharest, Romania; Georg Schett, Department of Internal Medicine 3, University Hospital Erlangen, Germany; Jörg HW Distler, Department of Internal Medicine 3, University Hospital Erlangen, Germany; Pierluigi Meroni, Dipartimento e Cattedra di Reumatologia, Università degli Studi di Milano, Istituto Ortopedico "Gaetano Pini", Milano, Italy and IRCCS Istituto Auxologico Italiano, Milan, Italy; Silvana Zeni, Dipartimento e Cattedra di Reumatologia, Università degli Studi di Milano, Istituto Ortopedico "Gaetano Pini", Milano, Italy; Luc Mouthon, Department of Internal Medicine, Hôpital Cochin, Paris, France; Filip De Keyser, rsity of Ghent, Department of Rheumatology, Gent, Belgium; Vanessa Smith, rsity of Ghent, Department of Rheumatology, Gent, Belgium; Francesco P. Cantatore, U.O. Reumatologia-Università degli Studi di Foggia, Ospedale "Col. D'Avanzo", Foggia, Italy; Ada Corrado, U.O. Reumatologia-Università degli Studi di Foggia, Ospedale "Col. D'Avanzo", Foggia, Italy; Susanne Ullman, University Hospital of Copenhagen, Department of Dermatology D-40, S-Bispebjerg Hospital, Copenhagen, Denmark; Line Iversen, University Hospital of Copenhagen, Department of Dermatology D-40, S-Bispebjerg Hospital, Copenhagen, Denmark; Maria R. Pozzi, Dipartimento di Medicina, Ospedale San Gerardo, Monza, Italy; Kilian Eyerich, Department of Dermatology and Allergy of the TU Munich, Germany; Rüdiger Hein, Department of Dermatology and Allergy of the TU Munich, Germany; Elisabeth Knott, Department of Dermatology and Allergy of the TU Munich, Germany; Jacek Szechinski, Department of Rheumatology and Internal Diseases, Wroclaw University of Medicine, Wroclaw, Poland; Piotr Wiland, Department of Rheumatology and Internal Diseases, Wroclaw University of Medicine, Wroclaw, Poland; Magdalena Szmyrka-Kaczmarek, Department of Rheumatology and Internal Diseases, Wroclaw University of Medicine, Wroclaw, Poland; Renata Sokolik, Department of Rheumatology and Internal Diseases, Wroclaw University of Medicine, Wroclaw, Poland; Ewa Morgiel, Department of Rheumatology and Internal Diseases, Wroclaw University of Medicine, Wroclaw, Poland; Brigitte Krummel-Lorenz, Endokrinologikum Frankfurt, Germany; Petra Saar, Endokrinologikum Frankfurt, Germany; Martin Aringer, Division of Rheumatology, Department of Medicine III/Department of Dermatology, University Medical Center Carl Gustav Carus, Technical University of Dresden, Germany; Claudia Günther, Division of Rheumatology, Department of Medicine III/Department of Dermatology, University Medical Center Carl Gustav Carus, Technical University of Dresden, Germany; Branimir Anic, University Hospital Centre Zagreb, Division of Clinical Immunology and Rheumatology, Department of Medicine, Zagreb, Croatia; Marko Baresic, University Hospital Centre Zagreb, Division of Clinical Immunology and Rheumatology, Department of Medicine, Zagreb, Croatia; Miroslav Mayer, University Hospital Centre Zagreb, Division of Clinical Immunology and Rheumatology, Department of Medicine, Zagreb, Croatia; Sebastião C. Radominski, Hospital de Clínicas da Universidade Federal do Paraná, Curitiba—Paraná, Brasil; Carolina de Souza Müller, Hospital de Clínicas da Universidade Federal do Paraná, Curitiba—Paraná, Brasil; Valderílio F. Azevedo, Hospital de Clínicas da Universidade Federal do Paraná, Curitiba—Paraná, Brasil; Svetlana Agachi, Municipal Centres of Research in Scleroderma, Hospital "Sacred Trinity", Department of Rheumatology, Chisinau, Republic of Moldova; Liliana Groppa, Municipal Centres of Research in Scleroderma, Hospital "Sacred Trinity", Department of Rheumatology, Chisinau, Republic of Moldova; Lealea Chiaburu, Municipal Centres of Research in Scleroderma, Hospital "Sacred Trinity", Department of Rheumatology, Chisinau, Republic of Moldova; Eugen Russu, Municipal Centres of Research in Scleroderma, Hospital "Sacred Trinity", Department of Rheumatology, Chisinau, Republic of Moldova; Thierry Zenone, Department of Medicine, Unit of Internal Medicine, Valence cedex 9, France; Simon Stebbings, Dunedin School of Medicine, Dunedin, New Zealand; John Highton, Dunedin School of Medicine, Dunedin, New Zealand; Lisa Stamp, Department of Medicine, University of Otago, Christchurch, New Zealand; Peter Chapman, Department of Medicine, University of Otago, Christchurch, New Zealand; John O'Donnell, Waikato University Hospital, Rheumatology Unit, Hamilton City, New Zealand; Kamal Solanki, Waikato University Hospital, Rheumatology Unit, Hamilton City, New Zealand; Alan Doube, Waikato University Hospital, Rheumatology Unit, Hamilton City, New Zealand; Douglas Veale, Department of Rheumatology, Bone and Joint Unit, St. Vincent's University Hospital, Dublin, Ireland; Marie O’Rourke, Department of Rheumatology, Bone and Joint Unit, St. Vincent's University Hospital, Dublin, Ireland; Esthela Loyo, Reumatologia e Inmunologia Clinica, Hospital Regional Universitario Jose Ma Cabral y Baez, Clinica Corominas, Santiago, Dominican Republic; Mengtao Li, Department of Rheumatology, Peking Union Medical College Hospital (West Campus), Chinese Academy of Medical Sciences, Beijing, China; Edoardo Rosato, Centro per la Sclerosi Sistemica—Dipartimento di Medicina Clinica, Università La Sapienza, Policlinico Umberto I, Roma, Italy; Simonetta Pisarri, Clinical Emergency Hospital St. Pantelimon, Bucharest, Romania; Cristina-Mihaela Tanaseanu, Division of Rheumatology & Rehabilitation GR.T.Popa, Center for Biomedical Research, European Center for Translational Research-“GR.T.Popa” University of Medicine and Pharmacy, Rehabilitation Hospital, Iasi, Romania; Monica Popescu, Division of Rheumatology & Rehabilitation GR.T.Popa, Center for Biomedical Research, European Center for Translational Research-“GR.T.Popa” University of Medicine and Pharmacy, Rehabilitation Hospital, Iasi, Romania; Alina Dumitrascu, Division of Rheumatology & Rehabilitation GR.T.Popa, Center for Biomedical Research, European Center for Translational Research-“GR.T.Popa” University of Medicine and Pharmacy, Rehabilitation Hospital, Iasi, Romania; Isabela Tiglea, Division of Rheumatology & Rehabilitation GR.T.Popa, Center for Biomedical Research, European Center for Translational Research-“GR.T.Popa” University of Medicine and Pharmacy, Rehabilitation Hospital, Iasi, Romania; Rodica Chirieac, Division of Rheumatology & Rehabilitation GR.T.Popa, Center for Biomedical Research, European Center for Translational Research-“GR.T.Popa” University of Medicine and Pharmacy, Rehabilitation Hospital, Iasi, Romania; Codrina Ancuta, Division of Rheumatology & Rehabilitation GR.T.Popa, Center for Biomedical Research, European Center for Translational Research-“GR.T.Popa” University of Medicine and Pharmacy, Rehabilitation Hospital, Iasi, Romania; Daniel E Furst, Division of Rheumatology, Department of Medicine, University of California at Los Angeles, Rehab Center, Los Angeles, USA; Suzanne Kafaja, Division of Rheumatology, Department of Medicine, University of California at Los Angeles, Rehab Center, Los Angeles, USA; Paloma García de la Peña Lefebvre, Hospital Universitario Madrid Norte Sanchinarro, Madrid, Spain; Silvia Rodriguez Rubio, Hospital Universitario Madrid Norte Sanchinarro, Madrid, Spain; Marta Valero Exposito, Hospital Universitario Madrid Norte Sanchinarro, Madrid, Spain; Jean Sibilia, University Hospital of Strasbourg-Department of Rheumatology, Hôpital de Hautepierre, Service de Rhumatologie, Strasbourg Cedex, France; Emmanuel Chatelus, University Hospital of Strasbourg-Department of Rheumatology, Hôpital de Hautepierre, Service de Rhumatologie, Strasbourg Cedex, France; Jacques Eric Gottenberg, University Hospital of Strasbourg-Department of Rheumatology, Hôpital de Hautepierre, Service de Rhumatologie, Strasbourg Cedex, France; Hélène Chifflot, University Hospital of Strasbourg-Department of Rheumatology, Hôpital de Hautepierre, Service de Rhumatologie, Strasbourg Cedex, France; Ira Litinsky, Department of Rheumatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; Algirdas Venalis, State Research Institute for Innovative Medicine, Vilnius University, Vilnius, Lithuania; Irena Butrimiene, State Research Institute for Innovative Medicine, Vilnius University, Vilnius, Lithuania; Paulius Venalis, State Research Institute for Innovative Medicine, Vilnius University, Vilnius, Lithuania; Rita Rugiene, State Research Institute for Innovative Medicine, Vilnius University, Vilnius, Lithuania; Diana Karpec, State Research Institute for Innovative Medicine, Vilnius University, Vilnius, Lithuania; Eduardo Kerzberg, Osteoarticular Diseases and Osteoporosis Centre, Pharmacology and Clinical Pharmacological Research Centre, School of medicine—University of Buenos Aires, Rheumatology and Collagenopathies Department, Ramos Mejía Hospital, Buenos Aires, Argentina; Fabiana Montoya, Osteoarticular Diseases and Osteoporosis Centre, Pharmacology and Clinical Pharmacological Research Centre, School of medicine—University of Buenos Aires, Rheumatology and Collagenopathies Department, Ramos Mejía Hospital, Buenos Aires, Argentina; Vanesa Cosentino, Osteoarticular Diseases and Osteoporosis Centre, Pharmacology and Clinical Pharmacological Research Centre, School of medicine—University of Buenos Aires, Rheumatology and Collagenopathies Department, Ramos Mejía Hospital, Buenos Aires, Argentina.

  • Contributors The authors as listed on the title page of the manuscript have all made substantial contributions which qualfies them as authors. BM: design of the study, acquisition of data, analysis, interpretation of data, drafting the article. OD: design of the study, analysis, interpretation of data, drafting the article. NG: acquisition of data, analysis, interpretation of data, revising the article. VL, CM: analysis, interpretation of data, revising the article. DK, BAM, UM-L, LC, CPD, AT: conception of the study, interpretation of data, revising the article. EUSTAR co-authors: acquisition of data, interpretation, revising the article. All authors have finally approved the submitted version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding The analysis of this investigator-initiated study was partially supported by a grant from Bayer to the University of Zurich. CPD: EULAR ODP Grant ‘Regulatory networks underlying the pathogenesis of systemic sclerosis’; OD: EULAR ODP Grant ‘Identification and validation of novel biomarkers in systemic sclerosis’; DK: NIH/ NIAMS K24 AR063120.

  • Competing interests OD has/had consultancy relationship and/or has received research funding in the area of systemic sclerosis and related conditions from Actelion, Pfizer, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, Roche/Genentech, Medac, Biovitrium, Boehringer Ingelheim Pharma, Novartis, 4 D Science, Active Biotec, Bayer-Schering, Sinoxa, Serodapharm, EpiPharm and Biogen. NG has received fees for participation in review activities such as data monitoring boards, statistical analysis, end point committees, and the like and payment for writing or reviewing the manuscript. DK has consultancy relationship in the area of systemic sclerosis from Actelion, Bayer, Biogen Idec, BMS, DIGNA, Genentech/ Roche, Gilead, InterMune, Merck, Sanofi-Aventis/Genzyme, United Therapeutics. CPD has consulted for and received honoraria from Actelion, Pfizer, GlaxoSmithKline, Digna, Sanofi Aventis, Merck-Serono, Boehringer Ingelheim, Roche, CSL Behring and Biogen. CM and VL are full-time employees of Bayer Pharma AG, Berlin, Germany. All others were supported by their respective institutions. The real or perceived potential conflicts listed above are accurately stated.

  • Ethics approval Ethics approval has been obtained from all respective local ethics committees.

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

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