Low-dose pulse cyclophosphamide in interstitial lung disease associated with systemic sclerosis (SSc-ILD): efficacy of maintenance immunosuppression in responders and non-responders

To investigate the long-term disease course of patients with recently deteriorated systemic sclerosis (SSC)-interstitial lung disease (ILD) undergoing continuous immunosuppressive treatment with cyclophosphamide (CYC) as induction therapy

CXCL4 in undifferentiated connective tissue disease at risk for systemic sclerosis (SSc) (previously referred to as very early SSc)

The aim of the study was to evaluate CXCL4 levels in undifferentiated connective tissue disease at risk for SSc (UCTD-SSc-risk) and confirm its increase and investigate its prognostic value. Serum CXCL4 levels were measured in 45 patients and 24 controls. CXCL4 was significantly higher in UCTD-SSc-risk patients than in controls. It resulted higher in patients with a shorter disease duration and in those lacking capillaroscopic alterations. We confirm that CXCL4 levels are increased in UCTD-risk-SSc patients. Further studies are needed to investigate the role of CXCL4 assessment in UCTD-risk-SSc

Effect of Nintedanib on Progression of Systemic Sclerosis-Associated Interstitial Lung Disease Over 100 Weeks: Data From a Randomized Controlled Trial

OBJECTIVE In the SENSCIS trial, participants with systemic sclerosis-associated interstitial lung disease (SSc-ILD) were randomized to receive nintedanib or placebo until the last participant reached week 52 but for 100 weeks or less. Nintedanib reduced the rate of decline in forced vital capacity (FVC) (ml/year) over 52 weeks by 44% (41 ml [95% confidence interval (95% CI): 2.9-79.0]) versus placebo. We investigated the effect of nintedanib over the whole SENSCIS trial. METHODS The annual rate of decline in FVC (ml/year) over the whole trial was assessed descriptively using 1) on-treatment data plus off-treatment data from participants who prematurely discontinued treatment (intent-to-treat analysis) and 2) only on-treatment data to assess the effect of nintedanib in participants who remained on treatment. RESULTS In the intent-to-treat analysis, the adjusted mean (SE) annual rate of decline in FVC over 100 weeks was -54.9 (11.1) and -88.8 (10.9) ml/year in the nintedanib (n = 287) and placebo (n = 288) groups, respectively (difference 34.0 ml/year [95% CI: 3.4-64.5]). In the on-treatment analysis, the adjusted mean (SE) annual rate of decline in FVC over 100 weeks was -55.1 (12.3) and -94.0 (11.7) ml/year in the nintedanib (n = 286) and placebo (n = 288) groups, respectively (difference 38.9 ml/year [95% CI: 5.6-72.1]). The adverse event profile of nintedanib over 100 weeks was consistent with that observed over 52 weeks. CONCLUSION Nintedanib provides a sustained benefit on slowing the progression of SSc-ILD over 100 weeks, with adverse events that are manageable for most patients

Effectiveness and safety of tocilizumab in patients with systemic sclerosis : a propensity score matched controlled observational study of the EUSTAR cohort

Objectives Tocilizumab showed trends for improving skin fibrosis and prevented progression of lung fibrosis in systemic sclerosis (SSc) in randomised controlled clinical trials. We aimed to assess safety and effectiveness of tocilizumab in a real-life setting using the European Scleroderma Trial and Research (EUSTAR) database. Methods Patients with SSc fulfilling the American College of Rheumatology (ACR)/EULAR 2013 classification criteria, with baseline and follow-up visits at 12±3 months, receiving tocilizumab or standard of care as the control group, were selected. Propensity score matching was applied. Primary endpoints were the modified Rodnan skin score (mRSS) and FVC at 12±3 months compared between the groups. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months. Results Ninety-three patients with SSc treated with tocilizumab and 3180 patients with SSc with standard of care fulfilled the inclusion criteria. Comparison between groups did not show significant differences, but favoured tocilizumab across all predefined primary and secondary endpoints: mRSS was lower in the tocilizumab group (difference -1.0, 95% CI -3.7 to 1.8, p=0.48). Similarly, FVC % predicted was higher in the tocilizumab group (difference 1.5 (-6.1 to 9.1), p=0.70). The percentage of progressive/regressive patients favoured tocilizumab over controls. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles. Conclusion Although this large, observational, controlled, real-life EUSTAR study did not show significant effectiveness of tocilizumab on skin and lung fibrosis, the consistency of direction of all predefined endpoints generates hypothesis for potential effectiveness in a broader SSc population

miR-145 is a key regulator of the TGF-β signaling pathway in systemic sclerosis and counteracts experimental fibrosis

microRNAs (miRNAs) are key regulators of different basic cellular processes. A number of miRNAs have been found to be dysregulated in many disease settings, most notably cancers. The role of miRNAs in systemic sclerosis (SSc), as well as in other fibrotic disorders has been scarcely investigated. Here we analyzed miRNA expression profile in SSc and identified miR-145 as a deeply down-regulated miRNA in SSc dermal fibroblasts and skin, which plays a crucial role in the regulation of the TGF-beta pathway in vitro and in vivo

Role of MicroRNAs in Fibrosis

Fibrosis is the leading cause of organ dysfunction in diseases such as systemic sclerosis, liver cirrhosis, cardiac fibrosis, progressive kidney disease, and idiopathic pulmonary fibrosis. The hallmark of fibrosis is tissue remodeling with excess deposition of extracellular matrix components, predominantly collagens. Different cell types, cytokines, growth factors, and enzymes interact in complex pathogenic networks with myofibroblasts playing a pivotal role. MicroRNAs are small non-coding RNAs acting as negative regulators of gene expression at the post-transcriptional level. MicroRNAs have been associated with many basic cellular processes as well as with a wide spectrum of diseases, most notably cancer. This review provides a comprehensive overview of microRNAs regulating profibrotic pathways and extracellular matrix synthesis. The potential of miRNA for targeted therapeutic approaches in fibrotic disorders is also discussed

[Survival and death causes in 251 systemic sclerosis patients from a single Italian center].

OBJECTIVE: To investigate survival in Italian systemic sclerosis (SSc) patients from a tertiary center, reporting death causes. MATERIALS AND METHODS: We analyzed the charts of 251 SSc patients prospectively enrolled in our Rheumatology Unit from 2000 to 2008. Baseline characteristics were recorded. In 2008 the vital status and the causes of death were assessed. Overall and subgroup survival were analyzed by the Kaplan-Meier method and the log-rank test. RESULTS: In 2008, 82% of patients were alive, 8% were known to have died and 10% were lost to follow-up. Overall 5- and 8-year survival were 94.8% and 77.1%, respectively. Patients with an age greater than the median value of the cohort (χ²=4.4; p=0.036), diffuse cutaneous SSc (χ²=3.9; p=0.048), digital ulcers (χ²=6; p=0.015), articular (χ²=5.3; p=0.021), lung (χ²=5.6; p=0.018) and heart involvement (χ²=9.3; p=0.002) had a poorer survival than patients without these features. The majority of SSc-related deaths (60%) were secondary to interstitial lung disease and heart involvement (both 33.3%); 50% of non-SSc-related deaths were due to cancer. CONCLUSIONS: Our study reports an improvement in survival of Italian SSc patients during the last decade with respect to the previous ones. Moreover, a reduction in deaths from renal involvement and an increase in deaths from interstitial lung disease were recorded in Italian SSc patients. Our data are consistent with those from recent survival studies carried out on SSc patients from other geographic area