G. Cuomo

A genetic variation located in the promoter region of the UPAR (CD87) gene is associated with the vascular complications of systemic sclerosis

OBJECTIVE The UPAR gene encodes a pleiotropic receptor (urokinase-type plasminogen activator receptor [uPAR]) involved in fibrosis, immunity, angiogenesis, and vascular remodeling. Previous studies have implicated uPAR in systemic sclerosis (SSc) vasculopathy and impaired angiogenesis. We undertook this study to investigate whether UPAR gene promoter polymorphisms might be associated with SSc phenotypes in the European Caucasian population. METHODS We studied a total population of 1,339 individuals. The Italian discovery cohort comprised 388 SSc patients and 391 healthy controls. The French replication cohort consisted of 344 SSc patients and 216 healthy controls. The UPAR rs344781 and rs4251805 single-nucleotide polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS In the Italian cohort, the rs344781 G allele was associated with SSc-related digital ulceration (odds ratio [OR] 1.39), pulmonary arterial hypertension (PAH) (OR 1.81), anticentromere antibody (ACA) positivity (OR 1.45), and limited cutaneous SSc (lcSSc) (OR 1.37). The rs344781 GG genotype was associated with SSc-related (OR 3.79), ACA-positive SSc (OR 2.17), and lcSSc (OR 1.96). Allelic and genotypic associations with SSc-related digital ulceration and ACA-positive SSc were replicated in the French sample. Combined analyses showed an association of the rs344781 G allele and GG genotype with SSc-related digital ulceration (allele OR 1.41, genotype OR 2.15), SSc-related PAH (allele OR 1.65, genotype OR 3.16), ACA-positive SSc (allele OR 1.47, genotype OR 2.40), and lcSSc (allele OR 1.34, genotype OR 1.77). In a multivariate logistic regression analysis model including the above associated phenotypes of SSc patients, the rs344781 GG genotype remained an independent risk factor for SSc-related digital ulceration (OR 1.96) and SSc-related PAH (OR 2.68). CONCLUSION The UPAR rs344781 gene variant is associated with the SSc vascular phenotype.

Value of systolic pulmonary arterial pressure as a prognostic factor of death in the systemic sclerosis EUSTAR population.

Objective. The aim of this study was to assess the prognostic value of systolic pulmonary artery pressure (sPAP) estimated by echocardiography in the multinational European League Against Rheumatism Scleroderma Trial and Research (EUSTAR) cohort. Methods. Data for patients with echocardiography documented between 1 January 2005 and 31 December 2011 were extracted from the EUSTAR database. Stepwise forward multivariable statistical Cox pulmonary hypertension analysis was used to examine the independent effect on survival of selected variables. Results. Based on our selection criteria, 1476 patients were included in the analysis; 87% of patients were female, with a mean age of 56.3 years (s.d. 13.5) and 31% had diffuse SSc. The mean duration of follow-up was 2.0 years (s.d. 1.2, median 1.9). Taking index sPAP of <30 mmHg as reference, the hazard ratio (HR) for death was 1.67 (95% CI 0.92, 2.96) if the index sPAP was between 30 and 36 mmHg, 2.37 (95% CI 1.14, 4.93) for sPAP between 36 and 40 mmHg, 3.72 (95% CI 1.61, 8.60) for sPAP between 40 and 50 mmHg and 9.75 (95% CI 4.98, 19.09) if sPAP was >50 mmHg. In a multivariable Cox model, sPAP and the diffusing capacity for carbon monoxide (DLCO) were independently associated with the risk of death [HR 1.833 (95% CI 1.035, 3.247) and HR 0.973 (95% CI 0.955, 0.991), respectively]. sPAP was an independent risk factor for death with a HR of 3.02 (95% CI 1.91, 4.78) for sPAP ≥36 mmHg. Conclusion. An estimated sPAP >36 mmHg at baseline echocardiography was significantly and independently associated with reduced survival, regardless of the presence of pulmonary hypertension based on right heart catheterization.

OP0227 Features and longitudinal analysis of systemic sclerosis patients with inappropriate exercise-induced increase in pulmonary artery pressure estimated by echocardiography

Background Patients with Systemic Sclerosis (SSc) are at risk of developing pulmonary hypertension (PH). The role of exercise testing in predicting this severe complication is still debated. In SSc, a subset of patients show a response to exercise with particularly high (≥48 mmHg) pulmonary artery systolic pressures (PASP)1. Objectives To describe baseline characteristics of SSc patients with an echocardiographic inappropriate response to exercise and determine its predictive value for the development of PH in SSc. Methods Patients with SSc in NYHA class I-II and a peak tricuspid regurgitant jet velocity <3 m/s at rest echocardiography consecutively admitted to 2 Rheumatology Units were enrolled. Clinical characterisation of SSc patients was performed according to EUSTAR recommendations. The risk prediction score (RPS) based on clinical parameters was calculated2. Baseline and stress echocardiography were assessed using similar commercial equipments and a standard protocol1. Right heart catheterisation confirmed PH if suspicion arose during follow-up. Data were analysed with SPSS software. Results A total of 170 patients had complete data at the end of follow-up. According to the previously defined cut-off of exercise PASP (ePASP), SSc patients were divided into those with a value below (group 1, n=149) or above 48 mmHg (group 2, n=21). Patients in both groups had comparable features concerning sex, cutaneous subset and autoantibody profile. There was no statistically significant difference in age, disease duration, mRSS, FVC (% pred), DLCO (%) or DLCO/VA (%). Presence of interstitial lung disease tended to be more frequent in group 2 than in group 1 (62% vs 37%, p=0.053). RPS values also did not discriminate between groups (3.4±0.9 vs 3.2±0.8). After a mean of 32±0.7 months, 165 (96%) were still in follow-up, 5 (3%) patients had died (all SSc-related deaths, but none including PH). Six patients (3.5%) developed PH confirmed at right heart catheterisation. Mean DLCO (p<0.01), DLCO/VA (p<0.05), RPS (<0.05), ePASP (p<0.05) or the difference between ePASP and PASP at rest (DPASP) (p<0.001) measured at the study enrolment were significantly different in patient who subsequently developed PH versus those free of this complication at the end of follow-up. Univariate PH-free survival was significantly lower in patients with an ePASP ≥48 mmHg (p<0.05) or in those in the 5th quintile of RPS (p<0.01), but at the multivariate Cox Regression, adjusting for potential confounders, only the value of DPASP (5 mmHg increase, HR 3.4 (1.4-8), p<0.01) and being in the highest quintile of RPS (HR 9.3 (1.4-63.7), p<0.05) significantly predicted survival. Conclusions The subset of SSc patients with an inappropriate increase in PASP detected by stress echocardiography cannot be distinguished by any of the disease specific features, including a recently described and validated RPS. The difference between PASP values at rest and under stress is predictive of subsequent development of PH independently of other known predictors based on clinical observations. References D’Alto M, et al. Heart 2011;97:112. Meune C, et al. Arthritis Rheum 2011;63:2790. Disclosure of Interest None Declared

Hypocomplementemia in systemic sclerosis- author reply

Hudson et al. argue that the conclusions of our study on hypocomplementemia in systemic sclerosis cannot be extended to other series. First of all, we would like to underline that our study is the 3rd one at least pointing out a definite prevalence of hypocomplementemia in Systemic Sclerosis (Della Rossa et al. (1); Hudson et al. (2); Cuomo et al. (3). Therefore, hypocomplementemia can be considered a defined feature occurring in about 15-20% of SSc patients. Secondly, differences in the autoantibody profile between Italian...