Joint and tendon involvement predict disease progression in systemic sclerosis: A EUSTAR prospective study

OBJECTIVE: To determine whether joint synovitis and tendon friction rubs (TFRs) can predict the progression of systemic sclerosis (SSc) over time. PATIENTS AND METHODS: We performed a prospective cohort study that included 1301 patients with SSc from the EUSTAR database with disease duration 643 years at inclusion and with a follow-up of at least 2 years. Presence or absence at clinical examination of synovitis and TFRs was extracted at baseline. Outcomes were skin, cardiovascular, renal and lung progression. Overall disease progression was defined according to the occurrence of at least one organ progression. RESULTS: Joint synovitis (HR: 1.26, 95% CI 1.01 to 1.59) and TFRs (HR: 1.32, 95% CI 1.03 to 1.70) were independently predictive of overall disease progression, as were also the diffuse cutaneous subset (HR: 1.30, 95% CI 1.05 to 1.61) and positive antitopoisomerase-I antibodies (HR: 1.25, 95% CI 1.02 to 1.53). Regarding skin progression, joint synovitis (HR: 1.67, 95% CI 1.06 to 2.64) and TFRs (HR: 1.69, 95% CI 1.02 to 2.77) were also independently predictive of worsening of the modified Rodnan skin score. For cardiovascular progression, joint synovitis was predictive of the occurrence of new digital ulcer(s) (HR: 1.45, 95% CI 1.08 to 1.96) and decreased left ventricular ejection fraction (HR: 2.20, 95% CI 1.06 to 4.57); TFRs were confirmed to be an independent predictor of scleroderma renal crisis (HR: 2.33, 95% CI 1.03 to 6.19). CONCLUSIONS: Joint synovitis and TFRs are independent predictive factors for disease progression in patients with early SSc. These easily detected clinical markers may be useful for the risk stratification of patients with SSc

A gender gap in primary and secondary heart dysfunctions in systemic sclerosis: A EUSTAR prospective study

Objectives. In agreement with other autoimmune diseases, systemic sclerosis (SSc) is associated with a strong sex bias. However, unlike lupus, the effects of sex on disease phenotype and prognosis are poorly known. Therefore, we aimed to determine sex effects on outcomes. Method. We performed a prospective observational study using the latest 2013 data extract from the EULAR scleroderma trials and research (EUSTAR) cohort. We looked at (i) sex influence on disease characteristics at baseline and (ii) then focused on patients with at least 2 years of follow-up to estimate the effects of sex on disease progression and survival. Results. 9182 patients with SSc were available (1321 men) for the baseline analyses. In multivariate analysis, male sex was independently associated with a higher risk of diffuse cutaneous subtype (OR: 1.68, (1.45 to 1.94); p<0.001), a higher frequency of digital ulcers (OR: 1.28 (1.11 to 1.47); p<0.001) and pulmonary hypertension (OR: 3.01 (1.47 to 6.20); p<0.003). In the longitudinal analysis (n=4499), after a mean follow-up of 4.9 (±2.7) years, male sex was predictive of new onset of pulmonary hypertension (HR: 2.66 (1.32 to 5.36); p=0.006) and heart failure (HR: 2.22 (1.06 to 4.63); p=0.035). 908 deaths were recorded, male sex predicted deaths of all origins (HR: 1.48 (1.19 to 1.84); p<0.001), but did not significantly account for SSc-related deaths. Conclusions. Although more common in women, SSc appears as strikingly more severe in men. Our results obtained through the largest worldwide database demonstrate a higher risk of severe cardiovascular involvement in men. These results raise the point of including sex in the management and the decisionmaking process

Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: A EUSTAR analysis

none194Dobrota, Rucsandra; Maurer, Britta; Graf, Nicole; Jordan, Suzana; Mihai, Carina; Kowal-Bielecka, Otylia; Allanore, Yannick; Distler, Oliver; Cerinic, Marco Matucci; Guiducci, Serena; Walker, Ulrich; Lapadula, Giovanni; Iannone, Florenzo; Becvar, Radim; Sierakowsky, Stanislaw; Cutolo, Maurizio; Sulli, Alberto; Valentini, Gabriele; Cuomo, Giovanna; Vettori, Serena; Riemekasten, Gabriela; Siegert, Elise; Rednic, Simona; Nicoara, Ileana; Kahan, André; Vlachoyiannopoulos, P.; Montecucco, C.; Caporali, Roberto; Carreira, Patricia E.; Novak, Srdan; Czirják, László; Varju, Cecilia; Chizzolini, Carlo; Kucharz, Eugene J.; Kotulska, Anna; Kopec-Medrek, Magdalena; Widuchowska, Malgorzata; Cozzi, Franco; Rozman, Blaz; Mallia, Carmel; Coleiro, Bernard; Gabrielli, Armando; Farge, Dominique; Wu, Chen; Marjanovic, Zora; Faivre, Helene; Hij, Darin; Dhamadi, Roza; Airò, Paolo; Hesselstrand, Roger; Wollheim, Frank; Wuttge, Dirk M.; Andréasson, Kristofer; Martinovic, Duska; Balbir-Gurman, Alexandra; Braun-Moscovici, Yolanda; Trotta, F.; Monaco, Andrea Lo; Hunzelmann, Nicolas; Pellerito, Raffaele; Mauriziano, Ospedale; Bambara, Lisa Maria; Caramaschi, Paola; Black, Carol; Denton, Christopher; Damjanov, Nemanja; Henes, Jörg; Santamaria, Vera Ortiz; Heitmann, Stefan; Krasowska, Dorota; Seidel, Matthias; Burkhardt, Harald; Himsel, Andrea; Salvador, Maria J.; Da Silva, José Antonio Pereira; Stamenkovic, Bojana; Stankovic, Aleksandra; Tikly, Mohammed; Ananieva, Lidia P.; Denisov, Lev N.; Müller-Ladner, Ulf; Frerix, Marc; Tarner, Ingo; Scorza, Raffaella; Engelhart, Merete; Strauss, Gitte; Nielsen, Henrik; Damgaard, Kirsten; Mendoza, Antonio Zea; de la Puente, Carlos; Giraldo, Walter A. Sifuentes; Midtvedt, Øyvind; Reiseter, Silje; Hachulla, Eric; Launay, David; Valesini, Guido; Riccieri, Valeria; Ionescu, Ruxandra Maria; Opris, Daniela; Groseanu, Laura; Cornateanu, Roxana Sfrent; Ionitescu, Razvan; Gherghe, Ana Maria; Soare, Alina; Gorga, Marilena; Bojinca, Mihai; Schett, Georg; Distler, Jörg H.W.; Beyer, Christian; Meroni, Pierluigi; Ingegnoli, Francesca; Mouthon, Luc; Keyser, Filip De; Smith, Vanessa; Cantatore, Francesco P.; Corrado, Ada; Pozzi, Maria R.; Eyerich, Kilian; Hein, Rüdiger; Knott, Elisabeth; Wiland, Piotr; Szmyrka-Kaczmarek, Magdalena; Sokolik, Renata; Morgiel, Ewa; Madej, Marta; Krummel-Lorenz, Brigitte; Saar, Petra; Aringer, Martin; Günther, Claudia; Westhovens, Rene; de Langhe, Ellen; Lenaerts, Jan; Anic, Branimir; Baresic, Marko; Mayer, Miroslav; Radominski, Sebastião C.; de Souza Müller, Carolina; Azevedo, Valderílio F.; Agachi, Svetlana; Groppa, Liliana; Chiaburu, Lealea; Russu, Eugen; Popa, Sergei; Zenone, Thierry; Stebbings, Simon; Highton, John; Stamp, Lisa; Chapman, Peter; O'Donnell, John; Solanki, Kamal; Doube, Alan; Veale, Douglas; O'Rourke, Marie; Loyo, Esthela; Li, Mengtao; Rosato, Edoardo; Amoroso, Antonio; Gigante, Antonietta; Tanaseanu, Cristina-Mihaela; Popescu, Monica; Dumitrascu, Alina; Tiglea, Isabela; Foti, Rosario; Chirieac, Rodica; Ancuta, Codrina; Villiger, Peter; Adler, Sabine; de la Peña Lefebvre, Paloma García; Rubio, Silvia Rodriguez; Exposito, Marta Valero; Sibilia, Jean; Chatelus, Emmanuel; Gottenberg, Jacques Eric; Chifflot, Hélène; Litinsky, Ira; Venalis, Algirdas; Butrimiene, Irena; Venalis, Paulius; Rugiene, Rita; Karpec, Diana; Saketkoo, Lesley Ann; Lasky, Joseph A.; Kerzberg, Eduardo; Montoya, Fabiana; Cosentino, Vanesa; Limonta, Massimiliano; Brucato, Antonio Luca; Lupi, Elide; Spertini, François; Ribi, Camillo; Buss, Guillaume; Pasquali, Jean Louis; Martin, Thierry; Gorse, AudreyDobrota, Rucsandra; Maurer, Britta; Graf, Nicole; Jordan, Suzana; Mihai, Carina; Kowal Bielecka, Otylia; Allanore, Yannick; Distler, Oliver; Cerinic, Marco Matucci; Guiducci, Serena; Walker, Ulrich; Lapadula, Giovanni; Iannone, Florenzo; Becvar, Radim; Sierakowsky, Stanislaw; Cutolo, Maurizio; Sulli, Alberto; Valentini, Gabriele; Cuomo, Giovanna; Vettori, Serena; Riemekasten, Gabriela; Siegert, Elise; Rednic, Simona; Nicoara, Ileana; Kahan, André; Vlachoyiannopoulos, P.; Montecucco, Carlomaurizio; Caporali, Roberto; Carreira, Patricia E.; Novak, Srdan; Czirják, László; Varju, Cecilia; Chizzolini, Carlo; Kucharz, Eugene J.; Kotulska, Anna; Kopec Medrek, Magdalena; Widuchowska, Malgorzata; Cozzi, Franco; Rozman, Blaz; Mallia, Carmel; Coleiro, Bernard; Gabrielli, Armando; Farge, Dominique; Wu, Chen; Marjanovic, Zora; Faivre, Helene; Hij, Darin; Dhamadi, Roza; Airò, Paolo; Hesselstrand, Roger; Wollheim, Frank; Wuttge, Dirk M.; Andréasson, Kristofer; Martinovic, Duska; Balbir Gurman, Alexandra; Braun Moscovici, Yolanda; Trotta, F.; Monaco, Andrea Lo; Hunzelmann, Nicolas; Pellerito, Raffaele; Mauriziano, Ospedale; Bambara, Lisa Maria; Caramaschi, Paola; Black, Carol; Denton, Christopher; Damjanov, Nemanja; Henes, Jörg; Santamaria, Vera Ortiz; Heitmann, Stefan; Krasowska, Dorota; Seidel, Matthias; Burkhardt, Harald; Himsel, Andrea; Salvador, Maria J.; Da Silva, José Antonio Pereira; Stamenkovic, Bojana; Stankovic, Aleksandra; Tikly, Mohammed; Ananieva, Lidia P.; Denisov, Lev N.; Müller Ladner, Ulf; Frerix, Marc; Tarner, Ingo; Scorza, Raffaella; Engelhart, Merete; Strauss, Gitte; Nielsen, Henrik; Damgaard, Kirsten; Mendoza, Antonio Zea; de la Puente, Carlos; Giraldo, Walter A. Sifuentes; Midtvedt, Øyvind; Reiseter, Silje; Hachulla, Eric; Launay, David; Valesini, Guido; Riccieri, Valeria; Ionescu, Ruxandra Maria; Opris, Daniela; Groseanu, Laura; Cornateanu, Roxana Sfrent; Ionitescu, Razvan; Gherghe, Ana Maria; Soare, Alina; Gorga, Marilena; Bojinca, Mihai; Schett, Georg; Distler, Jörg H. W.; Beyer, Christian; Meroni, Pierluigi; Ingegnoli, Francesca; Mouthon, Luc; Keyser, Filip De; Smith, Vanessa; Cantatore, Francesco P.; Corrado, Ada; Pozzi, Maria R.; Eyerich, Kilian; Hein, Rüdiger; Knott, Elisabeth; Wiland, Piotr; Szmyrka Kaczmarek, Magdalena; Sokolik, Renata; Morgiel, Ewa; Madej, Marta; Krummel Lorenz, Brigitte; Saar, Petra; Aringer, Martin; Günther, Claudia; Westhovens, Rene; de Langhe, Ellen; Lenaerts, Jan; Anic, Branimir; Baresic, Marko; Mayer, Miroslav; Radominski, Sebastião C.; de Souza Müller, Carolina; Azevedo, Valderílio F.; Agachi, Svetlana; Groppa, Liliana; Chiaburu, Lealea; Russu, Eugen; Popa, Sergei; Zenone, Thierry; Stebbings, Simon; Highton, John; Stamp, Lisa; Chapman, Peter; O'Donnell, John; Solanki, Kamal; Doube, Alan; Veale, Douglas; O'Rourke, Marie; Loyo, Esthela; Li, Mengtao; Rosato, Edoardo; Amoroso, Antonio; Gigante, Antonietta; Tanaseanu, Cristina Mihaela; Popescu, Monica; Dumitrascu, Alina; Tiglea, Isabela; Foti, Rosario; Chirieac, Rodica; Ancuta, Codrina; Villiger, Peter; Adler, Sabine; de la Peña Lefebvre, Paloma García; Rubio, Silvia Rodriguez; Exposito, Marta Valero; Sibilia, Jean; Chatelus, Emmanuel; Gottenberg, Jacques Eric; Chifflot, Hélène; Litinsky, Ira; Venalis, Algirdas; Butrimiene, Irena; Venalis, Paulius; Rugiene, Rita; Karpec, Diana; Saketkoo, Lesley Ann; Lasky, Joseph A.; Kerzberg, Eduardo; Montoya, Fabiana; Cosentino, Vanesa; Limonta, Massimiliano; Brucato, Antonio Luca; Lupi, Elide; Spertini, François; Ribi, Camillo; Buss, Guillaume; Pasquali, Jean Louis; Martin, Thierry; Gorse, Audre

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

Objective 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. Methods 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. Results 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. Conclusion 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

Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study.

Objective To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice. Methods We performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab. Results 254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47-5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)&gt;10% (OR: 1.03 [0.55-1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56-3.53], p&lt;0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83-9.62]; p=0.019 as compared with controls vs 3 [0.66-5.35]; p=0.012). Conclusion Rituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial

Update on the profile of the EUSTAR cohort: an analysis of the EULAR Scleroderma Trials and Research group database

Objectives Systemic sclerosis (SSc) is a rare disease requiring multicentre collaboration to reveal comprehensive details of disease-related causes for morbidity and mortality.Methods The European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) group initiated a database to prospectively gather key data of patients with SSc using a minimal essential dataset that was reorganised in 2008 introducing new items. Baseline visit data of patients who were registered between 2004 and 2011 were analysed using descriptive statistics.Results In June 2011, 7655 patients (2838 with diffuse cutaneous (dc) and 4481 with limited cutaneous (lc) SSc who fulfilled the American College of Rheumatology diagnostic criteria had been registered in 174 centres, mainly European. The most prominent hallmarks of disease were Raynaud's phenomenon (96.3%), antinuclear antibodies (93.4%) and a typical capillaroscopic pattern (90.9%). Scleroderma was more common on fingers and hands than on any other part of the skin. Proton pump inhibitors (65.2%), calcium channel blockers (52.7%), and corticosteroids (45.3%) were most often prescribed. Among the immunosuppressant agents, cyclophosphamide was used more often in dcSSc than in lcSSc.Conclusions The EUSTAR database provides an abundance of information on the true clinical face of SSc that will be helpful in improving the classification of SSc and its subsets and for developing more specific therapeutic recommendations

Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study

To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice

Phenotypes determined by cluster analysis and their survival in the prospective european scleroderma trials and research cohort of patients with systemic sclerosis

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