Prognostic Role of Ventricular Ectopic Beats in Systemic Sclerosis: A Prospective Cohort Study Shows ECG Indexes Predicting the Worse Outcome.

BACKGROUND: Arrhythmias are frequent in Systemic Sclerosis (SSc) and portend a bad prognosis, accounting alone for 6% of total deaths. Many of these patients die suddenly, thus prevention and intensified risk-stratification represent unmet medical needs. The major goal of this study was the definition of ECG indexes of poor prognosis. METHODS: We performed a prospective cohort study to define the role of 24h-ECG-Holter as an additional risk-stratification technique in the identification of SSc-patients at high risk of life-threatening arrhythmias and sudden cardiac death (SCD). One-hundred SSc-patients with symptoms and/or signs suggestive of cardiac involvement underwent 24h-ECG-Holter. The primary end-point was a composite of SCD or need for implantable cardioverter defibrillator (ICD). RESULTS: Fifty-six patients (56%) had 24h-ECG-Holter abnormalities and 24(24%) presented frequent ventricular ectopic beats (VEBs). The number of VEBs correlated with high-sensitive cardiac troponin T (hs-cTnT) levels and inversely correlated with left-ventricular ejection fraction (LV-EF) on echocardiography. During a mean follow-up of 23.1±16.0 months, 5 patients died suddenly and two required ICD-implantation. The 7 patients who met the composite end-point had a higher number of VEBs, higher levels of hs-cTnT and NT-proBNP and lower LV-EF (p = 0.001 for all correlations). All these 7 patients had frequent VEBs, while LV-EF was not reduced in all and its range was wide. At ROC curve, VEBs>1190/24h showed 100% of sensitivity and 83% of specificity to predict the primary end-point (AUROC = 0.92,p<0.0001). Patients with VEBS>1190/24h had lower LV-EF and higher hs-cTnT levels and, at multivariate analysis, the presence of increased hs-cTnT and of right bundle branch block on ECG emerged as independent predictors of VEBs>1190/24h. None of demographic or disease-related characteristics emerged as predictors of poor outcome. CONCLUSIONS: VEBS>1190/24h identify patients at high risk of life-threatening arrhythmic complications. Thus, 24h-ECG-Holter should be considered a useful additional risk-stratification test to select SSc-patients at high-risk of SCD, in whom an ICD-implantation could represent a potential life-saving intervention.

Tumour-associated antigens in systemic sclerosis patients with interstitial lung disease: association with lung involvement and cancer risk.

OBJECTIVE: To evaluate the serum levels of tumour-associated antigens (TAAs) in patients with SSc and interstitial lung disease (ILD) and to define whether their levels mirror the severity and the progression of lung damage. METHODS: Data from 80 SSc patients with ILD were collected at baseline and after 2 years as well as from 40 SSc controls without ILD. The occurrence of any malignancy was recorded. RESULTS: At baseline, an increase of at least one TAA was present in 35 SSc patients with ILD compared with 6 SSc patients without ILD (P < 0.0001); this was associated with lower forced vital capacity (FVC) and higher interstitial and alveolar scores. Levels of carbohydrate antigen 15-3 and carcinoembryonic antigen inversely correlated with FVC and directly correlated with alveolar and interstitial scores and their levels were higher in patients who presented a progression of lung damage after 2 years. During 4 years of follow-up, a malignancy was detected in seven patients who already had an increase of at least one TAA. Values of TAAs increased over time in patients who developed cancer, while their trend remained stable in the others. At multivariate analysis, to have three or more TAAs emerged as a strong independent predictor of the development of malignancies [relative risk 24.1 (95% CI 1.8, 315.0), P = 0.02]. CONCLUSION: TAAs can be elevated in the sera of SSc patients and correlate with the degree of lung damage, suggesting a role as severity biomarkers. Close follow-up is necessary in SSc patients because of the increased cancer risk overall in patients with increased TAAs.

Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis.

OBJECTIVES: To assess the long-term efficacy and safety of single and multiple courses of rituximab therapy in systemic sclerosis (SSc) patients with and without lung disease. METHODS: A total of 20 SSc patients with a diffuse disease were treated with rituximab. At baseline and during follow-up the lung involvement was evaluated with pulmonary function tests (FVC and DLCO) and with lung high-resolution computed tomography (HRCT). RESULTS: The skin score, activity, and severity indices improved significantly after 12 months and at final follow-up compared to baseline. After 12 months, there was a significant increase of FVC and TLC compared to baseline (p = 0.024 and p = 0.005, respectively), while the mean DLCO value remained stable. Considering the last available follow-up in six patients with restrictive lung disease at baseline, two patients (33.3%) experienced an increase of more than 10% of FVC, one patient had a decrease of FVC >10%, while in three patients FVC remained stable (50%). After the mean follow-up of 48.5 ± 20.4 months, among the patients with normal lung parameters at baseline, FVC remained stable in 12 (85.7%) and in one patient (14.3%) it increased by more than 10%. At the final follow-up, the alveolar and interstitial HRCT scores remained stable in more than 80% of patients, both in patients with and without restrictive lung disease at baseline. CONCLUSIONS: Anti-CD20 B cell depletion therapy is effective on skin involvement but seems also to preserve the pulmonary function, as supported by a stable or improved FVC and stable interstitial score, suggesting a possible role of rituximab as a modifying therapy overall in early diffuse SSc.