Objectives To determine the causes of death and risk factors in systemic sclerosis (SSc). Methods Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation. Results We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile. Conclusion Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients’ survival.

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)>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<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.

Objective: To assess fetal and maternal outcomes in women with systemic sclerosis (SSc).Methods: Prospectively collected data on 99 women with SSc from 25 Italian centers were analyzed retrospectively. Women with SSc were observed during 109 pregnancies (from 2000 to 2011), and outcomes were compared to those in the general obstetric population (total of 3,939 deliveries). The maternal age at conception was a mean ± SD 31.8 ± 5.3 years, and the median disease duration at conception was 60 months (range 2–193 months).Results: SSc patients, compared to the general obstetric population, had a significantly increased frequency of preterm deliveries (25% versus 12%) and severe preterm deliveries (<34 weeks of gestation) (10% versus 5%), intrauterine growth restriction (6% versus 1%), and babies with very‐low birth weight (5% versus 1%). Results of multivariable analysis showed that corticosteroid use was associated with preterm deliveries (odds ratio [OR] 3.63, 95% confidence interval [95% CI] 1.12–11.78), whereas the use of folic acid (OR 0.30, 95% CI 0.10–0.91) and presence of anti–Scl‐70 antibodies (OR 0.26, 95% CI 0.08–0.85) were protective. The disease remained stable in most SSc patients, but there were 4 cases of progression of disease within 1 year from delivery, all in anti–Scl‐70 antibody–positive women, 3 of whom had a disease duration of <3 years.Conclusion: Women with SSc can have successful pregnancies, but they have a higher‐than‐normal risk of preterm delivery, intrauterine growth restriction, and babies with very‐low birth weight. Progression of the disease during or after pregnancy is rare, but possible. High‐risk multidisciplinary management should be standard for these patients, and pregnancy should be avoided in women with severe organ damage and postponed in women with SSc of recent onset, particularly if the patient is positive for anti–Scl‐70 antibodies.

Background: Our aim was to compare three‐dimensional (3D) and 2D and 3D speckle‐tracking (2D‐ STE , 3D‐ STE ) echocardiographic parameters with conventional right ventricular ( RV ) indexes in patients with chronic pulmonary hypertension ( PH ), and investigate whether these techniques could result in better correlation with hemodynamic variables indicative of heart failure. Methods and Results: Seventy‐three adult patients (mean age, 53±13 years; 44% male) with chronic PH of different etiologies were studied by echocardiography and cardiac catheterization (25 precapillary PH from pulmonary arterial hypertension, 23 obstructive pulmonary heart disease, and 23 postcapillary PH from mitral regurgitation). Thirty healthy subjects (mean age, 54±15 years; 43% male) served as controls. Standard 2D measurements ( RV –fractional area change–tricuspid annular plane systolic excursion) and mitral and tricuspid tissue Doppler annular velocities were obtained. RV 3D volumes and global and regional ejection fraction (3D‐ RVEF ) were determined. RV strains were calculated by 2D‐ STE and 3D‐ STE . RV 3D global‐free‐wall longitudinal strain (3D GFW ‐ RVLS ), 2D global‐free‐wall longitudinal strain ( GFW ‐ RVLS ), apical‐free‐wall longitudinal strain, basal‐free‐wall longitudinal strain, and 3D‐ RVEF were lower in patients with precapillary PH ( P <0.0001) and postcapillary PH ( P <0.01) compared to controls. 3D GFW ‐ RVLS (hazard ratio 4.6, 95% CI 2.79 to 8.38, P =0.004) and 3D‐ RVEF (hazard ratio 5.3, 95% CI 2.85 to 9.89, P =0.002) were independent predictors of mortality. Receiver operating characteristic curves showed that the thresholds offering an adequate compromise between sensitivity and specificity for detecting hemodynamic signs of RV failure were 39% for 3D‐ RVEF ( AUC 0.89), −17% for 3D GFW ‐ RVLS ( AUC 0.88), −18% for GFW ‐ RVLS ( AUC 0.88), −16% for apical‐free‐wall longitudinal strain ( AUC 0.85), 16 mm for tricuspid annular plane systolic excursion ( AUC 0.67), and 38% for RV ‐ FAC ( AUC 0.62). Conclusions: In chronic PH , 3D, 2D‐ STE and 3D‐ STE parameters indicate global and regional RV dysfunction that is associated with RV failure hemodynamics better than conventional echo indices.

Objective.: To estimate the prevalence, determine the subgroups at risk, and the outcomes of patients with systemic sclerosis (SSc) and gastric antral vascular ectasia (GAVE). Methods.: We queried the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) network for the recruitment of patients with SSc-GAVE. Each case was matched for cutaneous subset and disease duration with 2 controls with SSc recruited from the same center, evaluated at the time the index case made the diagnosis of GAVE. SSc characteristics were recorded at the time GAVE occurred and the last observation was collected to define the outcomes. Results.: Forty-nine patients with SSc and GAVE were included (24 with diffuse cutaneous SSc) and compared to 93 controls with SSc. The prevalence of GAVE was estimated at about 1% of patients with SSc. By multivariate analysis, patients with SSc-GAVE more frequently exhibited a diminished (< 75%) DLCO value (OR 12.8; 95% CI 1.9–82.8) despite less frequent pulmonary fibrosis (OR 0.2; 95% CI 0.1–0.6). GAVE was also associated with the presence of anti-RNA-polymerase III antibodies (OR 4.6; 95% CI 1.2–21.1). SSc-GAVE was associated with anemia (82%) requiring blood transfusion (45%). Therapeutic endoscopic procedures were performed in 45% of patients with GAVE. After a median followup of 30 months (range 1–113 months), survival was similar in patients with SSc-GAVE compared to controls, but a higher number of scleroderma renal crisis cases occurred (12% vs 2%; p = 0.01). Conclusion.: GAVE is rare and associated with a vascular phenotype, including anti-RNA-polymerase III antibodies, and a high risk of renal crisis. Anemia, usually requiring blood transfusions, is a common complication.

Monocytes/macrophages are activated in several autoimmune diseases, including systemic sclerosis (scleroderma; SSc), with increased expression of interferon (IFN)-regulatory genes and inflammatory cytokines, suggesting dysregulation of the innate immune response in autoimmunity. In this study, we investigated whether the lytic form of Epstein-Barr virus (EBV) infection (infectious EBV) is present in scleroderma monocytes and contributes to their activation in SSc. Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) depleted of the CD19+ cell fraction, using CD14/CD16 negative-depletion. Circulating monocytes from SSc and healthy donors (HDs) were infected with EBV. Gene expression of innate immune mediators were evaluated in EBV-infected monocytes from SSc and HDs. Involvement of Toll-like receptor (TLR)8 in viral-mediated TLR8 response was investigated by comparing the TLR8 expression induced by infectious EBV to the expression stimulated by CL075/TLR8/agonist-ligand in the presence of TLR8 inhibitor in THP-1 cells. Infectious EBV strongly induced TLR8 expression in infected SSc and HD monocytes in vitro. Markers of activated monocytes, such as IFN-regulated genes and chemokines, were upregulated in SSc- and HD-EBV-infected monocytes. Inhibiting TLR8 expression reduced virally induced TLR8 in THP-1 infected cells, demonstrating that innate immune activation by infectious EBV is partially dependent on TLR8. Viral mRNA and proteins were detected in freshly isolated SSc monocytes. Microarray analysis substantiated the evidence of an increased IFN signature and altered level of TLR8 expression in SSc monocytes carrying infectious EBV compared to HD monocytes. This study provides the first evidence of infectious EBV in monocytes from patients with SSc and links EBV to the activation of TLR8 and IFN innate immune response in freshly isolated SSc monocytes. This study provides the first evidence of EBV replication activating the TLR8 molecular pathway in primary monocytes. Immunogenicity of infectious EBV suggests a novel mechanism mediating monocyte inflammation in SSc, by which EBV triggers the innate immune response in infected cells.