Systemic Sclerosis Or Scleroderma Research Articles

Vitamin D in Systemic Sclerosis: A Review.

(1) Background: In the present paper we aimed to review the evidence about the potential implication of vitamin D in the pathogenesis and management of systemic sclerosis (SSc); (2) Methods: we performed a review of the literature looking for studies evaluating the potential role of vitamin D and its analogs in SSc. We searched the PubMed, Medline, Embase, and Cochrane libraries using the following strings: (vitamin D OR cholecalciferol) AND (systemic sclerosis OR scleroderma). We included cohort studies, case-control studies, randomized controlled trials, and observational studies. (3) Results: we identified nine pre-clinical and 21 clinical studies. Pre-clinical data suggest that vitamin D and its analogs may suppress fibrogenesis. Clinical data are concordant in reporting a high prevalence of hypovitaminosis D and osteoporosis in SSc patients; data about the association with clinical manifestations and phenotypes of SSc are, conversely, far less consistent; (4) Conclusions: in vitro data suggest that vitamin D may play an antifibrotic role in SSc, but clinical data confirming this finding are currently lacking. Hypovitaminosis D is common among SSc patients and should be treated to reduce the risk of osteoporosis.

Serotonin and systemic sclerosis. An emerging player in pathogenesis.

Systemic sclerosis (SSc) is a complex, autoimmune disease characterized by multiple organ fibrosis and vasculopathy. Experimental and clinical evidence indicates that serotonin is crucially involved in the fibrotic process and mediates vascular manifestations such as Raynaud's phenomenon (RP) or pulmonary arterial hypertension (PAH), all key features of SSc. In this review, we summarize the current knowledge on the potential contribution of serotonin in SSc pathogenesis and provide a rationale for further investigation of this molecule as a therapeutic target. Medline and Cochrane databases were searched from inception to April 2021 using the search terms (systemic sclerosis OR scleroderma OR Raynaud OR Pulmonary arterial hypertension) AND serotonin. Serotonin, a key molecule in an array of central and peripheral functions, has a multifaceted role in regulating fibrosis and vasculopathy. Experimental data suggest that serotonin drives fibrosis in the skin and visceral organs, promotes platelet aggregation, induces vasoconstriction and increases pulmonary vascular resistance. Earlier human trials regarding drugs that inhibit serotonin signaling produced mixed results. However, recent advances in the understanding of the underlying molecular mechanisms could help identify novel therapeutics targeting the serotonin pathway and inform future clinical trials. Serotonin may be a mediator in both fibrosis and vasculopathy. Further exploration of the potential role of serotonin in SSc is justified.

Open questions on the management of targeted therapies for the treatment of systemic sclerosis-interstitial lung disease: results of a EUSTAR survey based on a systemic literature review.

Background:The results of randomized controlled (RCT) and retrospective studies have expanded the armamentarium of drugs for systemic sclerosis (SSc) – interstitial lung disease (ILD) treatment. The correct positioning of these drugs is not yet clarified.Objectives:Systemic literature review (SLR) on rituximab (RTX), tocilizumab (TCZ), nintedanib and abatacept (ABT) for the treatment of SSc-ILD. The results of the SLR were used to create a dedicated survey.Design:The study was performed as a systematic review.Data sources and methods:the SLR was performed using the following terms: “(systemic sclerosis OR scleroderma) AND (interstitial lung disease OR lung fibrosis OR pulmonary fibrosis) AND (rituximab OR tocilizumab OR abatacept OR nintedanib)”. The results of the SLR were integrated in a survey including 8 domains. These were sent to all EUSTAR members and to the participants of the 2020 Scleroderma World Congress.Results:41 studies (34 on RTX, 5 on TCZ, 2 on ABT, and 1 on nintedanib) were identified. RCTs supported the use of TCZ and nintedanib, while retrospective studies supported the use of RTX for SSc-ILD. No clear data were obtained about ABT. The survey showed that RTX is the most available option (96%) whereas the most frequent reason for targeted therapy introduction is lung progression while on csDMARDs (86% RTX, 59% TCZ and 63% nintedanib). Combination therapy was the most frequently mentioned therapeutic scheme for nintedanib (75%) and RTX (63%). Physicians’ perception of safety was similar for all drugs, while drug efficacy was the same for RTX and nintedanib, followed by TCZ (4.8 ± 2). The most frequently raised concerns pertained to efficacy, safety and combination regimens.Conclusion:Our SLR supports the use of RTX, TCZ and nintedanib for SSc-ILD patients and underlines the need for more data about upfront combination versus monotherapy. It also highlighted the need to identify predictors supporting drug choice according to both pulmonary and extra-pulmonary manifestations.

Prevalence of Barrett's Esophagus in Female Patients With Scleroderma.

Systemic sclerosis or scleroderma (SSc) is a chronic autoimmune disease that renders the esophagus prone to significant gastroesophageal reflux due to impaired esophageal clearance and reduced lower esophageal sphincter pressure. The reported prevalence of Barrett's esophagus (BE) in women with SSc varies from 2% to 37% and is derived from older studies with small sample sizes. We aimed to assess the prevalence of BE in a large cohort of women with SSc. Women with SSc referred from the Mayo Clinic Arizona Rheumatology Clinic who completed esophagogastroduodenoscopy between 2002 and 2020 were included. Demographic and high-resolution manometry data were evaluated. The diagnosis of scleroderma was confirmed by an expert rheumatologist. The BE diagnosis was confirmed by an expert gastrointestinal pathologist. There were 235 women with SSc who underwent EGD. High-resolution manometry (HRM) was completed in 172 patients. Women with SSc with BE were significantly more likely to have scleroderma esophagus (absent contractility with hypotensive lower esophageal sphincter) on HRM than women with SSc without BE (P = 0.018). There were 30 patients with SSc (12.8%) with histologically proven BE. Dysplasia was found in 13 (43.3%): 4 with indefinite, 7 with low grade, and 2 with adenocarcinoma. The incidence of any dysplasia was 5.3% per year (0.9% per year for adenocarcinoma). This the largest study on prevalence of BE in women with SSc, yielding a prevalence of 12.8%. Women with SSc with BE were significantly more likely to have absent contractility with hypotensive lower esophageal sphincter findings on HRM. The high prevalence and incidence of dysplasia found suggest that women with SSc should be included in the screening recommendations for BE.

An Update on Systemic Sclerosis and its Perioperative Management.

Purpose of ReviewSystemic sclerosis or scleroderma (SSc) is a systemic, immune-mediated disease characterized by abnormal cutaneous and organ-based fibrosis that results in progressive end-organ dysfunction and decreased survival. SSc results in significant challenges for the practicing anesthesiologist due to its rarity, multi-system involvement, and limited evidence-based guidance for optimal perioperative care. In this update, we briefly discuss the recent evidence on the pathophysiology and current management of SSc, review the anesthesia-related literature, and extrapolate these observations into an optimal perioperative strategy for the care of SSc patients.Recent FindingsEvidence shows that patients with SSc demonstrate an increased risk for perioperative myocardial infarction, high rates of interstitial lung disease, pulmonary arterial hypertension, neurological disease, gastric dysmotility disorders, and challenging airway management, all findings that may result in suboptimal perioperative outcomes.SummaryAdvances in SSc medical management have resulted in improved survival, likely increasing the number of patients who will be exposed to perioperative care. Optimal perioperative management and risk stratification should expand beyond the well-described airway challenges and consider numerous systemic manifestations of systemic sclerosis such as pulmonary arterial hypertension, interstitial lung disease, and cardiac sequelae.

Ultrasonography for the Assessment of Skin in Systemic Sclerosis: A Systematic Review.

To identify and synthesize the best available evidence on the use of ultrasound to assess skin involvement in systemic sclerosis (SSc). We conducted a systemic review of the literature on PubMed Medline and Embase, using the vocabulary terms ("systemic sclerosis OR scleroderma") AND ("ultrasonography" OR "elasticity imaging techniques") AND ("skin" OR "dermis"). Two independent reviewers selected articles, collected data from studies, and carried out a manual search of the references from the studies included. This search was further enhanced by a review of bibliographic references extrapolated from these studies. The quality of the evidence was assessed by the Effective Public Health Practice Project system. A total of 30 studies were identified, enrolling 1,171 SSc patients, predominantly middle-aged (mean age 55.5 years) females (88.8%). The ultrasound skin measurements that were reported included thickness in 28 studies and/or echogenicity (7 studies), and/or stiffness (6 studies), and/or vascularity (1 study). The main comparator was the global and site-specific modified Rodnan skin thickness score. Reported interrater and intrarater reproducibility appeared to be excellent, but this reproducibility was assessed by a small number of studies. Moreover, there were no published evaluations of construct or criterion validity of skin ultrasound assessment. The responsiveness to change of ultrasound elastography has not been assessed. Published reports have strong limitations and are highly heterogeneous, hindering the evidence to support the use of skin ultrasound assessment in clinical practice. Further studies, with modern devices and appropriate methodology, are needed to establish the real value of skin ultrasound assessment in the early diagnosis and monitoring of SSc patients.

The role of endothelial cells in the vasculopathy of systemic sclerosis: A systematic review.

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by fibroproliferative vasculopathy, immunological abnormalities and progressive fibrosis of multiple organs including the skin. In this study, all English speaking articles concerning the role of endothelial cells (ECs) in SSc vasculopathy and representing biomarkers are systematically reviewed and categorized according to endothelial cell (EC) (dys)function in SSc. A sensitive search on behalf of the EULAR study group on microcirculation in Rheumatic Diseases was developed in Pubmed, The Cochrane Library and Web of Science to identify articles on SSc vasculopathy and the role of ECs using the following Mesh terms: (systemic sclerosis OR scleroderma) AND pathogenesis AND (endothelial cells OR marker). All selected papers were read and discussed by two independent reviewers. The selection process was based on title, abstract and full text level. Additionally, both reviewers further searched the reference lists of the articles selected for reading on full text level for supplementary papers. These additional articles went through the same selection process. In total 193 resulting articles were selected and the identified biomarkers were categorized according to description of EC (dys)function in SSc. The most representing and reliable biomarkers described by the selected articles were adhesion molecules for EC activation, anti-endothelial cell antibodies for EC apoptosis, vascular endothelial growth factor (VEGF), its receptor VEGFR-2 and endostatin for disturbed angiogenesis, endothelial progenitors cells for defective vasculogenesis, endothelin-1 for disturbed vascular tone control, Von Willebrand factor for coagulopathy and interleukin (IL)-33 for EC-immune system communication. Emerging, relatively new discovered biomarkers described in the selected articles, are VEGF165b, IL-17A and the adipocytokines. Finally, myofibroblasts involved in tissue fibrosis in SSc can derive from ECs or epithelial cells through a process known as endothelial-to-mesenchymal transition. This systematic review emphasizes the growing evidence that SSc is primarily a vascular disease where EC dysfunction is present and prominent in different aspects of cell survival (activation and apoptosis), angiogenesis and vasculogenesis and where disturbed interactions between ECs and various other cells contribute to SSc vasculopathy.

A New Era in the Treatment of Scleroderma-associated Interstitial Lung Disease?

Pulmonary involvement in systemic sclerosis or scleroderma (SSc) is mainly represented by SSc-associated interstitial lung disease (SSc-ILD) and pulmonary hypertension1,2. SSc-ILD is a major challenge: It is both a very frequent and a very severe complication of SSc. According to the literature, SSc-ILD is or will be present in around one-half of patients with diffuse SSc, and one-third of patients with limited cutaneous SSc3. SSc-ILD is now one of the leading causes of death in SSc4. This explains why much effort has been expended to understand and better know the characteristics of patients with SSc-ILD as well as to manage them properly. However, despite decades of observational studies and a few randomized ones, the optimal management of patients with SSc-ILD is still a matter of debate. From an historic point of view, the cornerstone of SSc-ILD treatment has mainly been immunosuppressants. This can be explained by the fact that SSc is a connective tissue disease in which inflammation and immune abnormalities play a central role5. The immune system, especially in regards to B and T lymphocytes, is fully involved in fibroblast activation and fibrogenesis by secreting proinflammatory and profibrotic cytokines and growth factors6. The most common immunosuppressant, cyclophosphamide (CYC), has been tested in many open-label studies and a few randomized control trials (RCT), as well as being recommended in the European League Against Rheumatism Scleroderma Trials and Research group guidelines7. However, the results of those RCT are still dividing the medical community. In the FAST study, there was no significant … Address correspondence to Prof. D. Launay, Service de Medecine Interne, Hopital Claude-Huriez, CHRU Lille, rue Michel Polonovski, F-59037 LILLE Cedex, France. E-mail: david.launay{at}univ-lille2.fr

Genética de la esclerodermia

Systemic sclerosis or scleroderma (SSc) is an autoimmune pathology with a variable clinical expression grouped within genetically complex diseases, in which environmental and genetical factors combine. Genes of the HLA regions were those first associated with susceptibility to present SSc, mainly the HLA-DRB1⁎11/⁎06/⁎16 allelles. However, through association studies, different candidate genes that belong to the triad of autoimmunity, endothelial disfunction and fibrosis have been proposed as genes implicated in the predisposition to disease. In spite of these initial advances, up until recently most studies have had little statistical power, due to the small number of patients included and the lack of reproduction in independent populations. Recently, the development of genotyping platforms and data analysis has allowed for the application of a new type of strategy known as «genome wide association studies» the analysis of the genetics to complex diseases, which are potent tools in the study of these multifactorial diseases. This paper pretends to perform a review of the recent advances in the study of the genetics of scleroderma, presenting results obtained in the analysis of the main candidate genes outside the HLA regions and the contribution of GWAS to the understanding of the molecular mechanisms of this disease.

Endothelial Fli1 Deficiency Impairs Vascular Homeostasis: A Role in Scleroderma Vasculopathy

Systemic sclerosis or scleroderma (SSc) is a complex autoimmune connective tissue disease characterized by obliterative vasculopathy and tissue fibrosis. The molecular mechanisms underlying SSc vasculopathy are largely unknown. Friend leukemia integration factor 1 (Fli1), an important regulator of immune function and collagen fibrillogenesis, is expressed at reduced levels in endothelial cells in affected skin of patients with SSc. To develop a disease model and to investigate the function of Fli1 in the vasculature, we generated mice with a conditional deletion of Fli1 in endothelial cells (Fli1 CKO). Fli1 CKO mice showed a disorganized dermal vascular network with greatly compromised vessel integrity and markedly increased vessel permeability. We show that Fli1 regulates expression of genes involved in maintaining vascular homeostasis including VE-cadherin, platelet endothelial cell adhesion molecule 1, type IV collagen, matrix metalloproteinase 9, platelet-derived growth factor B, and S1P(1) receptor. Accordingly, Fli1 CKO mice are characterized by down-regulation of VE-cadherin and platelet endothelial cell adhesion molecule 1, impaired development of basement membrane, and a decreased presence of alpha-smooth muscle actin-positive cells in dermal microvessels. This phenotype is consistent with a role of Fli1 as a regulator of vessel maturation and stabilization. Importantly, vascular characteristics of Fli1 CKO mice are recapitulated by SSc microvasculature. Thus, persistently reduced levels of Fli1 in endothelial cells may play a critical role in the development of SSc vasculopathy.

Systemic sclerosis or scleroderma

This article provides a definition of systemic sclerosis orscleroderma and its epidemiology

Lipid peroxidation and trace elements in systemic sclerosis

Oxidative stress appears to be important in the causation and perpetuation of tissue injury and fibrosis in systemic sclerosis or scleroderma (SSc). We conducted a case-control study to assess lipid peroxidation levels as determined by measuring fasting plasma malondialdehyde (MDA) and serum levels of the trace elements selenium, iron, zinc and copper in SSc. Plasma MDA levels were almost tenfold higher in patients than in controls (p=0.00007), and an inverse relationship between MDA levels and disease duration (r=-0.52, p=0.044) was observed. Selenium levels were lower in patients than in controls (p=0.012). Within the patient cohort, copper correlated inversely with the total skin score (r=-0.52, p=0.03). Our findings provide further evidence that lipid peroxidation is increased and antioxidant capacity is reduced in SSc. The gradual decline in MDA levels with time suggests that antioxidant therapy, if to be useful in SSc, is most likely to be effective early in the course of the disease.