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Arthritis Rheumatol. 2019 Sep;71(9):1553-1570. doi: 10.1002/art.40906. Epub 2019 Aug 12.

Phenotypes Determined by Cluster Analysis and Their Survival in the Prospective European Scleroderma Trials and Research Cohort of Patients With Systemic Sclerosis.

Collaborators (248)

Guiducci S, Walker U, Kyburz D, Lapadula G, Iannone F, Maurer B, Jordan S, Becvar R, Sierakowsky S, Kowal Bielecka O, Cutolo M, Sulli A, Valentini G, Cuomo G, Siegert E, Rednic S, Nicoara I, Kahan A, Vlachoyiannopoulos P, Montecucco C, Caporali R, Stork J, Inanc M, Carreira PE, Novak S, Czirják L, Varju C, Chizzolini C, Kucharz EJ, Kotulska A, Kopec-Medrek M, Widuchowska M, Rozman B, Mallia C, Coleiro B, Gabrielli A, Farge D, Wu C, Marjanovic Z, Faivre H, Hij D, Dhamadi R, Airò P, Hesselstrand R, Wollheim F, Wuttge DM, Andréasson K, Martinovic D, Balbir-Gurman A, Braun-Moscovici Y, Trotta F, Lo Monaco A, Hunzelmann N, Pellerito R, Mauriziano O, Maria Bambara L, Caramaschi P, Morovic-Vergles J, Black C, Damjanov N, Henes J, Ortiz Santamaria V, Heitmann S, Krasowska D, Seidel M, Hasler P, Burkhardt H, Himsel A, Bajocchi G, Maria Nuova AS, João Salvador M, Pereira Da Silva JA, Stamenkovic B, Stankovic A, Francesco Selmi C, De Santis M, Marasini B, Tikly M, Ananieva LP, Denisov LN, Müller-Ladner U, Frerix M, Tarner I, Scorza R, Puppo F, Engelhart M, Strauss G, Nielsen H, Damgaard K, Szücs G, Szamosi S, Zea Mendoza A, de la Puente C, Sifuentes Giraldo WA, Midtvedt Ø, Reiseter S, Garen T, Valesini G, Riccieri V, Maria Ionescu R, Opris D, Groseanu L, Wigley FM, Sfrent Cornateanu R, Ionitescu R, Maria Gherghe A, Soare A, Gorga M, Bojinca M, Mihai C, Milicescu M, Sunderkötter C, Kuhn A, Sandorfi N, Schett G, Distler JH, Beyer C, Meroni P, Ingegnoli F, Mouthon L, De Keyser F, Smith V, Paolo Cantatore F, Corrado A, Ullman S, Iversen L, Alberto von Mühlen C, Marilu Bohn J, Scussel Lonzetti L, Rosa Pozzi M, Eyerich K, Hein R, Knott E, Wiland P, Szmyrka-Kaczmarek M, Sokolik R, Morgiel E, Madej M, Houssiau FA, Jose Alegre-Sancho J, Krummel-Lorenz B, Saar P, Aringer M, Günther C, Westhovens R, de Langhe E, Lenaerts J, Anic B, Baresic M, Mayer M, Üprus M, Otsa K, Yavuz S, Granel B, Cezar Radominski S, de Souza Müller C, Azevedo VF, Jimenez S, Busquets J, Agachi S, Groppa L, Chiaburu L, Russu E, Popa S, Zenone T, Pileckyte M, Stebbings S, Highton J, Mathieu A, Vacca A, Sampaio-Barros PD, Yoshinari NH, Marangoni RG, Martin P, Fuocco L, Stamp L, Chapman P, O'Donnell J, Solanki K, Doube A, Veale D, O'Rourke M, Loyo E, Li M, Abdel Atty Mohamed WA, Rosato E, Amoroso A, Gigante A, Oksel F, Yargucu F, Tanaseanu CM, Popescu M, Dumitrascu A, Tiglea I, Foti R, Chirieac R, Ancuta C, Furst DE, Villiger P, Adler S, van Laar J, Kayser C, Eduardo C AL, Fathi N, Hassanien M, de la Peña Lefebvre PG, Rodriguez Rubio S, Valero Exposito M, Sibilia J, Chatelus E, Gottenberg JE, Chifflot H, Litinsky I, Emery P, Buch M, Del Galdo F, Venalis A, Butrimiene I, Venalis P, Rugiene R, Karpec D, Ann Saketkoo L, Lasky JA, Kerzberg E, Montoya F, Cosentino V, Limonta M, Luca Brucato A, Lupi E, Rosner I, Rozenbaum M, Slobodin G, Boulman N, Rimar D, Couto M, Spertini F, Ribi C, Buss G, Kahl S, Hsu VM, Chen F, McCloskey D, Malveaux H, Louis Pasquali J, Martin T, Gorse A, Guffroy A, Poindron V.

Author information

Université Lille, INSERM U995 LIRIC, CHU Lille, and Referral Center for Rare Systemic Autoimmune Diseases North and North-West of France, Lille, France.
Université Lille, INSERM U995 LIRIC, and CHU Lille, Lille, France.
Hôpital Cochin, APHP, and Université Paris Descartes, Paris, France.
University Clinic Schleswig-Holstein, University of Lübeck, Lübeck, Germany.
Spedali Civili di Brescia, Brescia, Italy.
Second University of Naples, Naples, Italy.
University of Padua, Padua, Italy.
University Hospital Zurich, Zurich, Switzerland.
Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy.
Royal Free Hospital, University College London, London, UK.



Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is typically subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) depending on the extent of skin involvement. This subclassification may not capture the entire variability of clinical phenotypes. The European Scleroderma Trials and Research (EUSTAR) database includes data on a prospective cohort of SSc patients from 122 European referral centers. This study was undertaken to perform a cluster analysis of EUSTAR data to distinguish and characterize homogeneous phenotypes without any a priori assumptions, and to examine survival among the clusters obtained.


A total of 11,318 patients were registered in the EUSTAR database, and 6,927 were included in the study. Twenty-four clinical and serologic variables were used for clustering.


Clustering analyses provided a first delineation of 2 clusters showing moderate stability. In an exploratory attempt, we further characterized 6 homogeneous groups that differed with regard to their clinical features, autoantibody profile, and mortality. Some groups resembled usual dcSSc or lcSSc prototypes, but others exhibited unique features, such as a majority of lcSSc patients with a high rate of visceral damage and antitopoisomerase antibodies. Prognosis varied among groups and the presence of organ damage markedly impacted survival regardless of cutaneous involvement.


Our findings suggest that restricting subsets of SSc patients to only those based on cutaneous involvement may not capture the complete heterogeneity of the disease. Organ damage and antibody profile should be taken into consideration when individuating homogeneous groups of patients with a distinct prognosis.

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