Endothelial Injury in Scleroderma

Scleroderma, which follows rheumatoid arthritis and systemic lupus erythematosus as the third most prevalent rheumatic disorder, is poorly understood. Connective tissue abnormalities have been explored extensively (1); recently, vascular involvement has been emphasized as a unifying pathogenetic concept (2, 3). The vascular features in scleroderma include Raynaud\u27s phenomenon; an early, edematous phase of the disorder; telangiectasia; capillary abnormalities as seen by nailfold and ultrastructural microscopy; and widespread vascular pathology noted in all involved organs. The most striking histological abnormalities occur in small arteries and arterioles and consist of distinctive intimal proliferation of cells arranged concentrically in a matrix of ground substance; the cells are thought to originate from medial smooth muscle and to migrate toward the intima after injury to the endothelium (4). Evidence for endothelial injury includes: (a) the disappearance of endothelium in association with thrombosis or fibrinoid necrosis in ultrastructural studies; (b) the absence of endothelial cells within the thickened intima (4, 3) the duplication of basement membrane, a common observation in scleroderma and known to occur after endothelial perturbation in other settings. The ability to isolate, characterize, and maintain endothelial cells in vitro provides a target-cell population to study endothelial damage in scleroderma. The present report describes the effect of scleroderma serum on endothelial, smooth muscle, and fibroblast cell types. Sera from patients with scleroderma (31/52) and Raynaud\u27s syndrome (11/19) contain cytotoxic activity specific for endothelial cells which is nondialyzable, heat-stable, and elutes with albumin on gel-filtration chromatography

ANCA in systemic sclerosis, when vasculitis overlaps with vasculopathy: a devastating combination of pathologies

In patients with systemic sclerosis (SSc), the coexistence of ANCA-associated vasculitis (SSc-AAV) has been reported to be associated with a severe disease course, including significant pulmonary and renal involvement. The presence of ANCA is not uncommon in patients with SSc and therefore clinicians must maintain a high index of clinical suspicion about SSc-AAV. p-ANCA and anti-MPO antibodies are the most common antibodies observed. Patients typically present with clinical features of microscopic polyangiitis or renal-limited vasculitis There are multiple areas of potential interaction in the pathogenesis of SSc and AAV which can exacerbate/compound vascular disease. In addition, similar patterns of major internal organ involvement (e.g., lung and kidneys) are seen in both conditions. We highlight a diagnostic approach to SSc-AAV and the paucity of data to inform management. As such, SSc-AAV is typically treated as per isolated AAV which can potentially be hazardous in patients with SSc (e.g., the association between high-dose steroid and scleroderma renal crisis). We propose that this rare clinical entity warrants rigorous investigation including definition of a therapeutic strategy to ameliorate the potentially devastating combination of pathologies in SSc-AAV

The role of the dermatologist in Raynaud’s phenomenon: a clinical challenge

Raynaud’s phenomenon (RP) is a functional vascular disorder involving extremities. In his practice, the dermatologist may frequently encounter RP which affects mainly women and is categorized into a primary benign form and a secondary form associated with different diseases (infections, drugs, autoimmune and vascular conditions, haematologic, rheumatologic and endocrinologic disorders). Still today, the differential diagnosis is a clinical challenge. Therefore, a careful history and a physical examination, together with laboratory tests and nailfold capillaroscopy, is mandatory. RP is generally benign, but a scheduled followâ up for primary RP patients should be established, due to risk of evolution to secondary RP. A combination of conservative measures and medications can help in the management of RP. The importance of avoiding all potential physical, chemical and emotional triggers, as well as quitting smoking, should be strongly suggested to the patient. As firstâ line treatment, dihydropyridine calcium channel blockers should be used. If this approach is not sufficient, prostacyclin derivatives, phosphodiesterases inhibitors and endothelin receptor antagonists can be considered as secondâ line treatment. In cases of acute ischaemia, nifedipine and intravenous prostanoids are helpful. In refractory cases, botulinum injections have shown a significant benefit. The approach to the RP patients requires therefore a coordinated care of specialists together with the primary care physician.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144681/1/jdv14914_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144681/2/jdv14914.pd

Endothelial injury in scleroderma.

Scleroderma, which follows rheumatoid arthritis and systemic lupus erythematosus as the third most prevalent rheumatic disorder, is poorly understood. Connective tissue abnormalities have been explored extensively (1); recently, vascular involvement has been emphasized as a unifying pathogenetic concept (2, 3). The vascular features in scleroderma include Raynaud\u27s phenomenon; an early, edematous phase of the disorder; telangiectasia; capillary abnormalities as seen by nailfold and ultrastructural microscopy; and widespread vascular pathology noted in all involved organs. The most striking histological abnormalities occur in small arteries and arterioles and consist of distinctive intimal proliferation of cells arranged concentrically in a matrix of ground substance; the cells are thought to originate from medial smooth muscle and to migrate toward the intima after injury to the endothelium (4). Evidence for endothelial injury includes: (a) the disappearance of endothelium in association with thrombosis or fibrinoid necrosis in ultrastructural studies; (b) the absence of endothelial cells within the thickened intima (4, 3) the duplication of basement membrane, a common observation in scleroderma and known to occur after endothelial perturbation in other settings. The ability to isolate, characterize, and maintain endothelial cells in vitro provides a target-cell population to study endothelial damage in scleroderma. The present report describes the effect of scleroderma serum on endothelial, smooth muscle, and fibroblast cell types. Sera from patients with scleroderma (31/52) and Raynaud\u27s syndrome (11/19) contain cytotoxic activity specific for endothelial cells which is nondialyzable, heat-stable, and elutes with albumin on gel-filtration chromatography

Bosentan and macitentan prevent the endothelial-to-mesenchymal transition (EndoMT) in systemic sclerosis: in vitro study.

Background: Systemic sclerosis (SSc) is characterized by early vascular abnormalities and subsequent fibroblast activation to myofibroblasts, leading to fibrosis. Recently, endothelial-to-mesenchymal transition (EndoMT), a complex biological process in which endothelial cells lose their specific markers and acquire a mesenchymal or myofibroblastic phenotype, has been reported in SSc. In the present study, we evaluated the ability of endothelin-1 (ET-1) dual receptor antagonists bosentan (BOS) and macitentan (MAC) to antagonize EndoMT in vitro. Methods: Ten women with limited SSc were enrolled. They underwent double skin biopsy (affected and nonaffected skin). Fibroblasts and microvascular endothelial cells (MVECs) were isolated from biopsies. We performed mono- or coculture of MVECs (isolated from nonaffected skin) with fibroblasts (isolated from affected skin and stimulated with ET-1 and transforming growth factor beta [TGF-\u3b2]). In cocultures, the MVEC layer was left undisturbed or was preincubated with BOS or MAC. After 48 h of coculture, MVECs were analyzed for their tube formation ability and for messenger RNA and protein expression of different vascular (CD31, vascular endothelial growth factor-A [VEGF-A], VEGF-A165b) and profibrotic (alpha-smooth muscle actin [\u3b1-SMA], collagen type I [Col I], TGF-\u3b2) molecules. Results: After 48 h, MVECs showed a reduced tube formation ability when cocultured with SSc fibroblasts. CD31 and VEGF-A resulted in downregulation, while VEGF-A165b, the antiangiogenic isoform, resulted in upregulation. At the same time, mesenchymal markers \u3b1-SMA, Col I, and TGF-\u3b2 resulted in overexpression in MVECs. Tube formation ability was restored when MVECs were preincubated with BOS or MAC, also reducing the expression of mesenchymal markers and restoring CD31 expression and the imbalance between VEGF-A and VEGF-A165b. Conclusions: With this innovative EndoMT in vitro model realized by coculturing nonaffected MVECs with affected SSc fibroblasts, we show that the presence of a myofibroblast phenotype in the fibroblast layer, coupled with an ET-1-TGF-\u3b2 synergic effect, is responsible for EndoMT. BOS and MAC seem able to antagonize this phenomenon in vitro, confirming previous evidence of endothelium-derived fibrosis in SSc and possible pharmacological interferenc

Fully covered self-expanding metal stents placed temporarily in the bile duct: safety profile and histologic classification in a porcine model

<p>Abstract</p> <p>Background</p> <p>Fully covered Self-Expanding metal stents (FCSEMS) have been shown efficacious in palliating malignant biliary obstructions. There is little data analyzing mucosal response to their temporary placement in the bile duct.</p> <p>Methods</p> <p>Ten mini pigs underwent endoscopic placement of a FCSEMS (Wallflex, Boston Scientific). FCSEMS were kept in place for three months. At the end of the 3 months, FCSEMS were removed endoscopically. Five pigs were euthanized and their bile ducts harvested. The other five were kept alive for another month post removal. A single pathologist, created a scoring system (to determine degree of inflammation, fibrosis, and epithelial injury), examined all specimens in a blinded fashion.</p> <p>Results</p> <p>Four FCSEMS spontaneously migrated in the duodenum. On post mortem examination, mild mucosal thickness was noted in three bile duct specimens while superficial inflammation of the bile duct was noted in five animals. Histologic examination of the bile duct revealed focal acute inflammation in both groups. For the 5 animals euthanized immediately after stent removal, there was a tendency to have superficial mucosal erosion and fibrosis. In contrast, increased chronic inflammation was more commonly seen in the animals 1 month post stent removal, with all animals in this group showing moderate degrees of mononuclear inflammatory cell mucosal infiltrates. No severe inflammatory or fibrotic duct injury was observed in any of the study animals, with degree of injury graded as mild to moderate.</p> <p>Conclusion</p> <p>FCSEMS appear to induce minimal tissue overgrowth or fibrosis post placement. Ease of removability and no significant histologic injury are advantages noted with FCSEMS., however, further studies are needed to evaluate treating benign biliary strictures with FCSEMS in humans.</p

An interim report of the scleroderma clinical trials consortium working groups

© The Author(s) 2018. The Scleroderma Clinical Trials Consortium represents many of the clinical researchers in the world who are interested in improving the efficiency of clinical trials in systemic sclerosis. The Scleroderma Clinical Trials Consortium has established 11 working groups to develop and validate better ways of measuring and recording multiple aspects of this heterogeneous disease. These include groups working on arthritis, disease damage, disease activity, cardiac disease, juvenile systemic sclerosis, the gastrointestinal tract, vascular component, calcinosis, scleroderma renal crisis, interstitial lung disease, and skin measurement. Members of the Scleroderma Clinical Trials Consortium may join any one or more of these groups. Some of the working groups have only recently started their work, some are nearing completion of their mandated tasks, and others are in the midst of their projects. All these projects, which are described in this article, will help improve clinical trials and observational studies by improving or developing better, more sensitive ways of measuring various aspects of the disease. As Lord Kelvin stated, “To measure is to know. If you cannot measure it you cannot improve it.” The Scleroderma Clinical Trials Consortium is dedicated to improving the lives of patients with systemic sclerosis and it is our hope that the contributions of the working groups will be one important step in this process

Volumetric laser endomicroscopy and its application to Barrett's esophagus: results from a 1,000 patient registry.

Volumetric laser endomicroscopy (VLE) uses optical coherence tomography (OCT) for real-time, microscopic cross-sectional imaging. A US-based multi-center registry was constructed to prospectively collect data on patients undergoing upper endoscopy during which a VLE scan was performed. The objective of this registry was to determine usage patterns of VLE in clinical practice and to estimate quantitative and qualitative performance metrics as they are applied to Barrett's esophagus (BE) management. All procedures utilized the NvisionVLE Imaging System (NinePoint Medical, Bedford, MA) which was used by investigators to identify the tissue types present, along with focal areas of concern. Following the VLE procedure, investigators were asked to answer six key questions regarding how VLE impacted each case. Statistical analyses including neoplasia diagnostic yield improvement using VLE was performed. One thousand patients were enrolled across 18 US trial sites from August 2014 through April 2016. In patients with previously diagnosed or suspected BE (894/1000), investigators used VLE and identified areas of concern not seen on white light endoscopy (WLE) in 59% of the procedures. VLE imaging also guided tissue acquisition and treatment in 71% and 54% of procedures, respectively. VLE as an adjunct modality improved the neoplasia diagnostic yield by 55% beyond the standard of care practice. In patients with no prior history of therapy, and without visual findings from other technologies, VLE-guided tissue acquisition increased neoplasia detection over random biopsies by 700%. Registry investigators reported that VLE improved the BE management process when used as an adjunct tissue acquisition and treatment guidance tool. The ability of VLE to image large segments of the esophagus with microscopic cross-sectional detail may provide additional benefits including higher yield biopsies and more efficient tissue acquisition. Clinicaltrials.gov NCT02215291

What should be known prior to performing EUS exams? (Part II)

In "What should be known prior to performing EUS exams, Part I," the authors discussed the need for clinical information and whether other imaging modalities are required before embarking EUS examinations. Herewith, we present part II which addresses some (technical) controversies how EUS is performed and discuss from different points of view providing the relevant evidence as available. (1) Does equipment design influence the complication rate? (2) Should we have a standardized screen orientation? (3) Radial EUS versus longitudinal (linear) EUS. (4) Should we search for incidental findings using EUS