Feasibility study of stem-cell enriched autologous lipotransfer to treat oro-facial fibrosis in systemic sclerosis (Sys-Stem): Protocol for open-label randomised controlled trial.

INTRODUCTION: Oro-facial fibrosis is a common and disabling manifestation of systemic sclerosis (SSc), causing a plethora of functional, aesthetic and social compromise, yet is without effective treatment. Autologous lipotransfer is an established minimally invasive surgical procedure that is postulated to exert anti-fibrotic effects by adipose-derived stem cells, and presents a novel method in the treatment of fibrotic conditions. This study aims to assess the safety and efficacy of autologous lipotransfer for facial involvement in SSc. METHODS AND ANALYSIS: This is the first randomised controlled study with an open label design to assess autologous lipotransfer for oro-facial involvement in systemic sclerosis. The goals of this study are to assess the feasibility of using a range of quantitative and qualitative outcome measures to effectively measure disease severity and treatment outcome, and to assess patient acceptability for future multi-centre trials. A total of 50 participants will be randomised to a treatment or control group. The treatment group will receive autologous fat transfer to the peri-oral region by a single surgeon. Dermal fibroblasts and adipose-derived stem cells will be isolated from tissue samples. All outcome measures will be taken at baseline, then at 6 weeks, 3 months and 6 months from the time of intervention in the treatment arm, or from baseline in the control arm. ETHICS AND DISSEMINATION: The study has ethical approval (REC reference 19/LO/0718). Results will be available to patients, patient user groups, clinicians and the public through presentations at national and international rheumatology conferences and published in peer reviewed journals. TRIAL REGISTRATION: Registered on ISRCTN registry (ISRCTN17793055).

N-terminal pro Brain Natriuretic Peptide as predictor of outcome in scleroderma renal crisis.

OBJECTIVES: Although in scleroderma renal crisis (SRC) outcome has improved to a great extent with the introduction of ACE inhibitors, there remains significant mortality and morbidity with frequent requirement for renal replacement therapy. Therefore, novel biomarkers to identify patients at high risk of poor outcome would be valuable. The aim of this study was to assess the role of the N terminal fragment of pro Brain Natriuretic Peptide (N-TproBNP) as predictor of outcome in SRC. METHODS: 20 subjects with confirmed SRC were retrospectively enrolled. Clinical data, full blood count, creatinine, eGFR and N-TproBNP at presentation were collected. RESULTS: Patients requiring renal replacement therapy presented significantly higher levels of N-TproBNP and creatinine (p>0.01), lower eGFR (p<0.01) and haemoglobin levels (p=0.01) and shorter disease duration (p<0.01) compared to those who did not require dialysis. Whereas all the candidate variables significantly predicted renal outcome in univariate models, N-TproBNP was the only variable to hold significance in predicting renal outcome in a Firth's multivariate logistic regression model (p=0.05, OR 7.6). ROC curve of N-TproBNP to identify patients requiring renal replacement therapy provided a sensitivity of 88.9%, with a specificity of 81.8% at a cut-off value of 360 pmol/L (95% CI 0.84-1.00, area under the curve 0.94). In our cohort, this provided a positive predictive value of 80% and a negative predictive value of 90%. CONCLUSIONS: N-TproBNP peptide may be a useful biomarker in risk-stratification of renal outcome in SRC, selectively identifying patients likely to require renal replacement therapy.

Cytokines in the immunopathology of systemic sclerosis.

Cytokines and growth factors are key regulators of immune activation, vascular alteration and excessive production of extracellular matrix which are hallmark events in the pathogenesis of systemic sclerosis (SSc). They modulate cell-cell and cell-matrix interactions. In particular, cytokines play a central role in the immunopathogenesis of SSc on the basis of molecular pathways which are complex and not completely understood. The majority of cytokines that may be involved in SSc pathogenesis have effect upon or are derived from cells of the immune system, including both the innate and adaptive compartments. Novel therapies that block key mediators that drive the fibrotic response are being developed and appear as potential therapeutic tools in the treatment of SSc, highlighting the importance for an effective therapy targeted towards the molecular and cellular pathways. This article reviews cytokine biology in that context, with particular emphasis on immunopathology of the disease, therapeutic targeting and the way that current or emerging treatments for SSc might impact on cytokine biology.

Management of digital vasculopathy in systemic sclerosis: benefits of multiple courses of endothelin-1 receptor antagonists.

Two patients with scleroderma and recurrent digital ulcers (DUs) were treated with bosentan for 6 months. Treatment was associated with a reduction in the number of new DUs; however, DUs recurred on treatment discontinuation. This case report illustrates the positive response of digital vasculopathy to bosentan and describes the benefits of multiple bosentan treatment courses in these patients.

Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts: evidence for autocrine regulation of myofibroblast differentiation.

OBJECTIVE: To investigate expression of the chemokine receptor CCR2 on key cell types involved in the pathogenesis of systemic sclerosis (SSc) and to assess the potential for autocrine activation of SSc dermal fibroblasts via CCL2/CCR2. METHODS: Chemokine receptor expression in skin biopsy tissues and explanted dermal fibroblasts from a well-characterized cohort of SSc patients was examined using immunohistochemistry and flow cytometry techniques. Autocrine regulation of the expression of fibrotic markers in CCR2+ SSc fibroblast cell lines was assessed using specific ligand or receptor antagonists. RESULTS: We identified strong CCR2 expression in skin biopsy samples of early-stage diffuse cutaneous SSc (dcSSc), but not late-stage dcSSc or limited cutaneous SSc. Double labeling confirmed up-regulation of CCL2/CCR2 on myofibroblasts, pericytes, lymphocytes, macrophages, and endothelial cells. Explanted dermal fibroblasts from early dcSSc tissues expressed CCR2 and CXCR2 in 55% and 66% of cell strains, respectively. There was no expression in control fibroblasts. CCR2+ fibroblasts demonstrated a profibrotic phenotype, with overexpression of alpha-smooth muscle actin (alpha-SMA), connective tissue growth factor (CTGF), and CCL2. Flow cytometric analysis identified a subset of CCR2+ SSc fibroblasts expressing the myofibroblast marker alpha-SMA. In these cultures, specific inhibition of CCL2 or CCR2 attenuated the overexpression of alpha-SMA, but not CTGF or plasminogen activator inhibitor 1. CONCLUSION: Our results show that CCR2 is up-regulated in early dcSSc on cell types known to be activated in the disease, which is consistent with a key role in SSc pathogenesis. CCR2 expression on SSc fibroblasts appears to regulate the expression of CCL2 and alpha-SMA. Our findings suggest potential autocrine regulation of key profibrotic properties via a CCL2/CCR2 loop in early-stage dcSSc.