BackgroundSystemic Sclerosis (SSc) is characterized by severe fibroproliferative vasculopathy, exaggerated deposition of extracellular matrix molecules (ECM) in skin and multiple internal organs, and alterations of humoral, cellular and innate immunity. Vascular changes are responsible for the earliest and most severe SSc clinical manifestations, however, the mechanisms responsible have not been elucidated.ObjectivesThe goal of this study was to analyze the gene expression differences between normal and SSc lung microvascular endothelial cells (EC) to improve the understanding of SSc vasculopathy pathophysiology.MethodsPulmonary microvascular EC were isolated employing immunomagnetic procedures from lungs from patients with SSc undergoing lung transplantation. Control pulmonary microvascular EC were isolated from autopsies of individuals who died from non-pulmonary causes. Following isolation, microarrays were performed in EC from each group. Expression of genes with the highest differential expression was validated with RT-PCR and Western blots.ResultsInterferon-stimulated genes (ISGs) including IFI44L, IFI44, IFI6, IFIH1, IFIT1 displayed the highest differential expression; being overexpressed in EC obtained from the three SSc donors (Figure 1). Other genes such as those encoding ECM production related proteins, genes associated with post-translational methylation, and genes for numerous chemokines and cytokines were also differentially overexpressed in SSc EC. Increased gene expression and increased protein levels of selected ISGs were confirmed by Western blots.Figure 1.A: Volcano Plot showing differentially expressed transcripts with 2 fold or greater difference (p<0.05) in expression between SSc and normal control microvascular ECs (130 transcripts corresponding to119 genes). Selected ISGs are encircled (IFI-6, IFIT1, IFI-44,IFI44L,IFIT-3, OAS-1) B: Detail of the resulting heat map of a dendrogram (hierarchically clustered) reveals groups of genes with high expression levels (red squares), low expression levels (blue squares) or background expression levels (yellow squares). Interferon related genes are marked with a red star.ConclusionsNumerous ISGs are differentially overexpressed in SSc pulmonary microvascular EC in comparison with normal control EC. These results suggest that events leading to an interferon response in these cells may play a role in the pathogenesis of SSc lung vasculopathy.References Kahaleh B. Vascular Disease in Scleroderma: Mechanisms of Vascular Injury. Rheumatic Disease Clinics of North America 2008; 34(1):57–71.Trojanowska M. Cellular and molecular aspects of vascular dysfunction in systemic sclerosis. Nat Rev Rheumatol 2010; 6(8):453–60.Matucci-Cerinic M, Kahaleh B, Wigley FM. Review: evidence that systemic sclerosis is a vascular disease. Arthritis and rheumatism 2013; 65(8):1953–62.Pattanaik D, Brown M, Postlethwaite BC, Postlethwaite AE. Pathogenesis of Systemic Sclerosis. Frontiers in immunology 2015; 6:272. Disclosure of InterestNone declared

BackgroundRapid progressive skin involvement in diffuse Systemic Sclerosis (rp-dcSSc) is associated with higher mortality and internal organ involvement. Treatment with Mycophenolate Mofetil (MMF) has been shown to halt the progression of the disease. However, the optimal duration of therapy is unknown and has not been studied. We follow up a known cohort of rp-dcSSc patients treated with MMF after discontinuation of therapy.ObjectivesTo describe the progression of skin involvment in rp-dcSSc patients after discontinuation of MMFMethodsTwenty-five previously untreated consecutive patients with recent-onset (<24 mo) rp-dcSSc received MMF as the only disease-modifying therapy. Their Modified Rodnan skin score (mRSS) and Pulmonary function tests were followed after discontinuation of MMF after 2 years of treatment. Patients were followed up every 3–6 months. Therapy was re-initiated if their mRSS increased more than 20% or worsening respiratory symptoms with progression of restrictive lung disease were reported.ResultsSix patients lost follow up after terminating the open label trial with MMF. From the 19 patients followed up after MMF discontinuation, 26.3%5 required to resume MMF. All these patients required to resume MMF within 6 months after discontinuation. All of them presented increase in mRSS. Two of them (10.5%) presented respiratory symptoms associated with restriction pattern at PFTs. Skin score returned to baseline in 80% of the patients after resuming therapy.Abstract AB0755 – Figure 1mRSS after MMF discontinuation.ConclusionsRecurrent skin progression occurs in up to 26.3% of patients with rp-dcSSc after discontinuation of 2 years of MMF, requiring longer term immunosuppression. In this group, all patients presented active skin disease recurrence within 6 months of treatment discontinuation. Ergo, slow decrease of MMF dose over time and very close follow up is recommended in patients with rp-dcSSc discontinuing MMF even after a prolonged period of time. In addition, these findings support the therapeutic effect of MMF in rp-dcSSc.References[1] Mendoza FA, Nagle SJ, Lee JB, Jimenez SA. A prospective observational study of mycophenolate mofetil treatment in progressive diffuse cutaneous systemic sclerosis of recent onset. J Rheumatol. 2012;39:1241–7[2] Steen VD, Medsger TA Jr. Improvement in skin thickening in systemic sclerosis associated with improved survival. Arthritis Rheum. 2001; 44(12):2828–35.Disclosure of InterestNone declared