Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis.

Objectives Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database. Methods Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12\ub13 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression. Results Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model. Conclusions The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trial

Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry

OBJECTIVES: The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc). METHODS: The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers. RESULTS: Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group. CONCLUSIONS: This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies

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

Mapping and predicting mortality from systemic sclerosis.

reserved71simixedElhai, M; Meune, C; Boubaya, M; Avouac, J; Hachulla, E; Balbir-Gurman, A; Riemekasten, G; Airò, P; Joven, B; Vettori, S; Cozzi, F; Ullman, S; Czirják, L; Tikly, M; Müller-Ladner, U; Caramaschi, P; Distler, O; Iannone, F; Ananieva, Lp; Hesselstrand, R; Becvar, R; Gabrielli, A; Damjanov, N; Salvador, Mj; Riccieri, V; Mihai, C; Szücs, G; Walker, Ua; Hunzelmann, N; Martinovic, D; Smith, V; Müller, Cs; Montecucco, Cm; Opris, D; Ingegnoli, F; Vlachoyiannopoulos, Pg; Stamenkovic, B; Rosato, E; Heitmann, S; Distler, Jhw; Zenone, T; Seidel, M; Vacca, A; Langhe, E; Novak, S; Cutolo, M; Mouthon, L; Henes, J; Chizzolini, C; Mühlen, Cav; Solanki, K; Rednic, S; Stamp, L; Anic, B; Santamaria, Vo; De Santis, M; Yavuz, S; Sifuentes-Giraldo, Wa; Chatelus, E; Stork, J; Laar, Jv; Loyo, E; García de la Peña Lefebvre, P; Eyerich, K; Cosentino, V; Alegre-Sancho, Jj; Kowal-Bielecka, O; Rey, G; Matucci-Cerinic, M; Allanore, Y; Eustar, Group.Elhai, M; Meune, C; Boubaya, M; Avouac, J; Hachulla, E; Balbir-Gurman, A; Riemekasten, G; Airò, P; Joven, B; Vettori, S; Cozzi, F; Ullman, S; Czirják, L; Tikly, M; Müller-Ladner, U; Caramaschi, P; Distler, O; Iannone, F; Ananieva, Lp; Hesselstrand, R; Becvar, R; Gabrielli, A; Damjanov, N; Salvador, Mj; Riccieri, V; Mihai, C; Szücs, G; Walker, Ua; Hunzelmann, N; Martinovic, D; Smith, V; Müller, Cs; Montecucco, Cm; Opris, D; Ingegnoli, F; Vlachoyiannopoulos, Pg; Stamenkovic, B; Rosato, E; Heitmann, S; Distler, Jhw; Zenone, T; Seidel, M; Vacca, A; Langhe, E; Novak, S; Cutolo, M; Mouthon, L; Henes, J; Chizzolini, C; Mühlen, Cav; Solanki, K; Rednic, S; Stamp, L; Anic, B; Santamaria, Vo; De Santis, M; Yavuz, S; Sifuentes-Giraldo, Wa; Chatelus, E; Stork, J; Laar, Jv; Loyo, E; García de la Peña Lefebvre, P; Eyerich, K; Cosentino, V; Alegre-Sancho, Jj; Kowal-Bielecka, O; Rey, G; Matucci-Cerinic, M; Allanore, Y; Eustar, Group

Brief Report: Smoking in Systemic Sclerosis: A Longitudinal European Scleroderma Trials and Research Group Study

Objective: Data on the role of tobacco exposure in systemic sclerosis (SSc; scleroderma) severity and progression are scarce. We aimed to assess the effects of smoking on the evolution of pulmonary and skin manifestations, based on the European Scleroderma Trials and Research group database. Methods: Adult SSc patients with data on smoking history and a 12–24-month follow-up visit were included. Associations of severity and progression of organ involvement with smoking history and the Comprehensive Smoking Index were assessed using multivariable regression analyses. Results: A total of 3,319 patients were included (mean age 57 years, 85% female); 66% were never smokers, 23% were ex-smokers, and 11% were current smokers. Current smokers had a lower percentage of antitopoisomerase autoantibodies than previous or never smokers (31% versus 40% and 45%, respectively). Never smokers had a higher baseline forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio than previous and current smokers (P < 0.001). The FEV1/FVC ratio declined faster in current smokers than in never smokers (P = 0.05) or ex-smokers (P = 0.01). The baseline modified Rodnan skin thickness score (MRSS) and the MRSS decline were comparable across smoking groups. Although heavy smoking (>25 pack-years) increased the odds of digital ulcers by almost 50%, there was no robust adverse association of smoking with digital ulcer development. Conclusion: The known adverse effect of smoking on bronchial airways and alveoli is also observed in SSc patients; however, robust adverse effects of smoking on the progression of SSc-specific pulmonary or cutaneous manifestations were not observed