Op-brhe150265 1757..1758

SSc is a heterogeneous autoimmune CTD characterized by widespread vasculopathy, formation of autoantibodies and varying degrees of skin and major organ fibrosis [1, 2]. The life-threatening nature of this disease is well depicted by a 5-year mortality of 30 50% in a subset of patients with dcSSc and internal organ involvement. Despite the substantial research over the past decade, the aetiology of SSc remains poorly understood; hence treatment is often organ based and does not result in a cure. Nonetheless, the emerging role of epigenetics and the identification of new potentially disease-modifying therapies along with stem cell based approaches to treating certain aspects of the disease are opening new windows towards personalized medicine, raising hope among researchers and clinicians. In this issue and subsequent issues of this Journal, three SSc expert panels present a comprehensive update on epigenetics as a key pathogenic machinery worth targeting, old medications and new targeted therapies, and haematopoietic stem cell transplantation (HSCT) in the management of this condition [3 5]. In recent years, genome-wide association studies have revealed several genes that may predispose a person to develop SSc. However, the low concordance rate in monozygotic twins and the presence, only in some patients, of a strong genetic association may support the involvement of non-genetic mechanisms as well [6]. The comprehensive review by Altorok et al. [3] focuses on the pivotal role of epigenetic modifications in SSc, but leaves many questions unanswered about heterogeneous pathogenetic aspects of the disease. In particular, epigenetic modifications could represent the missing link between genetic and environmental factors influencing disease onset and evolution, hence helping to better define individual susceptibility. Such mechanisms represent stable and heritable modifications in gene expression. These mechanisms do not involve changes in DNA sequence, but include modifications in chromatin structure that modulate the access of transcription factors (i.e. DNA methylation and histone code modifications) and changes in the expression levels of miRNAs, which are small non-coding RNAs acting through negative regulation of post-transcriptional events, transcript degradation or translational suppression [6]. In SSc, specific alterations of different epigenetic mechanisms in key cellular players, such as immune cells, endothelial cells and fibroblasts, may represent the trigger for loss of self-tolerance, vascular injury and fibrosis, respectively [3]. Although the causal nature of epigenetic alterations in SSc remains elusive, oxidative stress and hypoxia are among the best candidates. Notably, epigenetic variation appears to target landmark pathways involved in SSc pathogenesis, such as TGF-b and downstream signalling cascades [3]. Furthermore, it is very important to underline that epigenetic alterations are potentially reversible. Thus, inherited epigenetic modifications can vanish after a variable number of cell divisions, and epigenetic risk factors could be counteracted by treatment with currently available epigenetic modifier molecules, such as histone deacetylase inhibitors and DNA methyltransferase inhibitors, and even synthetic miRNAs [3, 6]. However, the use of these non-specific compounds is likely limited by unwanted side effects. Whether epigenetic modifications are the cause of abnormal immune response, endothelial cell injury and fibroblast activation, or the result of disease progression, or both, still remains unknown. However, an in-depth characterization of the specific epigenome in various cell types involved in SSc pathogenesis may lead to more efficient and tailored therapeutic or even preventive strategies, or both. In the meantime, a better understanding of other key SSc pathogenic pathways and the development of novel therapeutic agents are paving the way for new treatments of a range of disease manifestations, including skin and pulmonary fibrosis, pulmonary arterial hypertension and digital ulcers [4, 7]. As thoroughly reviewed by Nagaraja et al. [4], current treatment of SSc is mainly organ based and employs compounds that are used in clinical practice for a variety of autoimmune, cardiovascular and fibrotic conditions, independent of pathogenic mechanisms. Currently, there is no efficient regulatory body approved treatment for skin fibrosis. Data from treatment trials in SSc support the use of immunosuppressive therapy (i.e. CYC), with the treatment benefit largely relating to the prevention of progression of interstitial lung disease. Recently, the use of targeted therapies and the intensity of the treatment have been considered as pivotal issues for SSc management. Today, the only targeted therapies in SSc are the oral endothelin receptor antagonists and PDE-5 inhibitors that have been associated with