Abrogation of transforming growth factor-β-induced tissue fibrosis in mice with a global genetic deletion of Nox4.

Excessive connective tissue deposition in skin and various internal organs is characteristic of systemic sclerosis (SSc). The profibrotic growth factor TGF-β plays a crucial role in SSc pathogenesis. The expression of NADPH oxidase 4 (NOX4), a critical mediator of oxidative stress, is potently stimulated by TGF-β.

Prediction of disease relapse in a cohort of paediatric patients with localized scleroderma.

Background: Localized scleroderma (LS) is an autoimmune condition of the skin and underlying tissue. Active or recurring disease can lead to cumulative tissue damage, especially in paediatric-onset disease.

Objectives: To highlight the rate of relapse of LS activity in a cohort of paediatric patients and to evaluate for potential clinical and laboratory predictors of disease relapse.

Simultaneous inhibition of c-Abl and Src kinases abrogates the exaggerated expression of profibrotic genes in cultured systemic sclerosis dermal fibroblasts.

Objectives: To examine the effects of simultaneous inhibition of c-Abl and Src kinases on the gene expression and in vitro production of profibrotic molecules by dermal fibroblasts from patients with diffuse systemic sclerosis (SSc) of recent onset.

Methods: Dermal fibroblasts from normal individuals or from patients with diffuse cutaneous SSc fulfilling the American College of Rheumatology/EULAR SSc classification criteria were cultured in media containing increasing concentrations of the dual c-Abl and Src kinase inhibitor Bosutinib for 24 h. Total soluble collagen in cell culture supernatants was quantified.

Gender differences in early systemic sclerosis patients: a report from the EULAR scleroderma trials and research group (EUSTAR) database.

Objectives: To describe differences in clinical presentation between men and women in a large group of patients with early (<3 years' duration) systemic sclerosis (SSc) according to disease subsets.

Methods: A cross-sectional analysis of the prospective EULAR Scleroderma Trial and Research database (EUSTAR) was performed. Patients fulfilling preliminary ACR 1980 classification criteria for SSc, with less than 3 years from the first non-Raynaud's symptom at first entry, were selected.

Photoacoustic Oxygenation Quantification in Patients with Raynaud's: First-in-Human Results.

The purpose of this study was to investigate the use of photoacoustic imaging for quantifying fingertip oxygenation as an approach to diagnosing and monitoring Raynaud's phenomenon. After 30 min of acclimation to room temperature, 22 patients (7 patients with secondary Raynaud's associated to Scleroderma and 15 healthy controls) provided informed consent to undergo fingertip Doppler imaging and high-frequency photoacoustic imaging before and 5, 15 and 30 min after cold stimulus (submerged hand in a 15 °C water bath for 1 min). High-frequency ultrasound and photoacoustic imaging was performed on the nail bed of each patient's second through fifth finger on their dominant hand, using a Vevo 2100 LAZR system with an LZ-250 probe (Fujifilm VisualSonics, Toronto, ON, Canada) in oxy-hemoglobin quantification mode.

Existing and novel biomarkers for precision medicine in systemic sclerosis.

The discovery and validation of biomarkers resulting from technological advances in the analysis of genomic, transcriptomic, lipidomic and metabolomic pathways involved in the pathogenesis of complex human diseases have led to the development of personalized and rationally designed approaches for the clinical management of such disorders. Although some of these approaches have been applied to systemic sclerosis (SSc), an unmet need remains for validated, non-invasive biomarkers to aid in the diagnosis of SSc, as well as in the assessment of disease progression and response to therapeutic interventions. Advances in global transcriptomic technology over the past 15 years have enabled the assessment of microRNAs that circulate in the blood of patients and the analysis of the macromolecular content of a diverse group of lipid bilayer membrane-enclosed extracellular vesicles, such as exosomes and other microvesicles, which are released by all cells into the extracellular space and circulation.

Abrogation of transforming growth factor-β-induced tissue fibrosis in TBRIcaCol1a2Cre transgenic mice by the second generation tyrosine kinase inhibitor SKI-606 (Bosutinib).

Transforming growth factor-β (TGF-β) plays a crucial role in the pathogenesis of Systemic Sclerosis (SSc) and other fibrotic disorders. TGF-β-mediated c-Abl and Src kinase activation induces strong profibrotic cascade signaling. The purpose of this study was to test in vivo the antifibrotic activity of Bosutinib (SKI-606), a second generation c-Abl and Src kinase inhibitor, on TGF-β induced cutaneous and pulmonary fibrosis.

Occupational Therapy Treatment to Improve Upper Extremity Function in Individuals with Early Systemic Sclerosis: A Pilot Study.

Objective: To determine the feasibility and preliminary effects of occupational therapy to improve upper extremity function in patients with early systemic sclerosis (SSc; scleroderma) who have upper extremity contractures.

Methods: A single-group pilot clinical rehabilitation trial was conducted at the University of Michigan Scleroderma Center. Patients with SSc and ≥1 upper extremity contracture (n = 21) participated in a total of 8 weekly in-person occupational therapy sessions.

Identification of novel systemic sclerosis biomarkers employing aptamer proteomic analysis.

There is an important unmet need for clinically validated non-invasive biomarkers for SSc diagnosis, assessment of disease activity, extent of internal organ involvement, therapeutic response and prognosis. There is also an unmet need for biomarkers to accurately differentiate primary RP from recent onset RP evolving into SSc. The lack of sensitive and specific biomarkers for SSc and SSc-associated RP is a limitation for the optimal clinical management of these patients.

PTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and internal organs. Protein tyrosine phosphatases have received little attention in the study of SSc or fibrosis. Here, we show that the tyrosine phosphatase PTP4A1 is highly expressed in fibroblasts from patients with SSc.

Multiplex assessment of serum cytokine and chemokine levels in idiopathic morphea and vitamin K-induced morphea.

The levels of 63 cytokines, chemokines, and growth factors were measured in the serum of four patients with idiopathic morphea and of one patient with vitamin K-induced morphea employing a multiplex assay to identify the role of inflammatory/immunologic events in their pathogenesis. Full-thickness skin biopsies of affected skin were analyzed by histopathology. Luminex assays for 63 cytokines, chemokines, and growth factors were performed in the sera from four patients with idiopathic morphea and in two different samples of serum obtained in two separate occasions from one patient with vitamin K-induced morphea.

Review article: pathogenesis and clinical manifestations of gastrointestinal involvement in systemic sclerosis.

Background: Gastrointestinal tract (GIT) involvement is a common cause of debilitating symptoms in patients with systemic sclerosis (SSc). There are no disease modifying therapies for this condition and the treatment remains symptomatic, largely owing to the lack of a clear understanding of its pathogenesis.

Aims: To investigate novel aspects of the pathogenesis of gastrointestinal involvement in SSc.

Exosomes isolated from serum of systemic sclerosis patients display alterations in their content of profibrotic and antifibrotic microRNA and induce a profibrotic phenotype in cultured normal dermal fibroblasts.

Objectives: Exosomes are lipid bilayer-bound microvesicles containing various macromolecules including numerous microRNA (miRNA). Exosomes mediate intercellular communication by fusing and releasing their macromolecular content into target cells. Here, we analysed the content of profibrotic and antifibrotic miRNAs in exosomes isolated from the serum of systemic sclerosis (SSc) patients and tested their ability to induce a profibrotic phenotype in normal human dermal fibroblasts in vitro.

In systemic sclerosis skin perfusion of hands is reduced and may predict the occurrence of new digital ulcers.

Systemic sclerosis (SSc) patients are at high risk for the development of ischemic digital ulcers (DUs). The aim of this study was to assess in SSc patients a correlation between skin perfusion evaluated by LDPI and DUs and to evaluate the prognostic value of skin perfusion to predict the new DUs occurrence. Fifty eight (47 female, 11 male) SSc patients were enrolled.

Treatment of Rapidly Progressive Systemic Sclerosis: Current and Futures Perspectives.

Introduction: Systemic Sclerosis (SSc) is a systemic autoimmune disease characterized by severe and often progressive cutaneous, pulmonary, cardiac and gastrointestinal tract fibrosis, cellular and humoral immunologic alterations, and pronounced fibroproliferative vasculopathy. There is no effective SSc disease modifying therapy. Patients with rapidly progressive SSc have poor prognosis with frequent disability and very high mortality.

Cancer and autoimmunity: Harnessing longitudinal cohorts to probe the link.

In many autoimmune rheumatic diseases, there is an increased risk of cancer compared to the general population. While reasons for this increased risk have not been elucidated, it has been hypothesized that the link between cancer and autoimmunity may be bidirectional. For instance, chronic inflammation and damage from the rheumatic disease or its therapies may trigger malignant transformation; conversely, antitumor immune responses targeting cancers may become cross-reactive resulting in autoimmunity.

The Recurrence of Digital Ulcers in Patients with Systemic Sclerosis after Discontinuation of Oral Treprostinil.

Objective: Prior studies investigating the efficacy of oral treprostinil to treat digital ulcers (DU) in systemic sclerosis (SSc)-associated Raynaud phenomenon have yielded conflicting results. In this investigation, we examined whether DU burden increased after patients withdrew from oral treprostinil that was administered during an open-label extension study.

Methods: A multicenter, retrospective study was conducted to determine DU burden in the year after withdrawal from oral treprostinil.

Role of muscarinic-3 receptor antibody in systemic sclerosis: correlation with disease duration and effects of IVIG.

Gastrointestinal dysmotility in systemic sclerosis (SSc) is associated with autoantibodies against muscarinic-3 receptor (M3-R). We investigated the temporal course of the site of action of these autoantibodies at the myenteric neurons (MN) vs. the smooth muscle (SM) M3-R in relation to disease duration, and determined the role of intravenous immunoglobulin (IVIG) in reversing these changes.

Current and future direction in the management of scleroderma.

Scleroderma is a heterogeneous disease with a complex etiology. As more information is gained about the underlying mechanisms and the improved classifications of scleroderma subtypes, treatments can be better personalized. Improving scleroderma patients' early diagnosis before end organ manifestations occur should improve clinical trial design and outcomes.

Left Ventricular Mass and Intrarenal Arterial Stiffness as Early Diagnostic Markers in Cardiorenal Syndrome Type 5 due to Systemic Sclerosis.

Background: Cardiorenal syndrome type 5 (CRS-5) includes a group of conditions characterized by a simultaneous involvement of the heart and kidney in the course of a systemic disease. Systemic sclerosis (SSc) is frequently involved in the etiology of acute and chronic CRS-5 among connective tissue diseases. In SSc patients, left ventricular mass (LVM) can be used as a marker of nutritional status and fibrosis, while altered intrarenal hemodynamic parameters are suggestive of early kidney involvement.