Atrial myxoma (AM) is the most common primary cardiac tumor. Its clinical presentation can be highly heterogeneous and can be characterized by many constitutional manifestations and development of rheumatologic symptoms.We report the case of a patient presenting with a seronegative arthritis characterized by articular and enthesis involvement and purpuric cutaneous lesions that was refractory to conventional treatments and that was later diag- nosed with an AM as first cause of the manifestations. AM can present with different symptoms; among them, it is able to cause some rheumatological manifestation as it is able to secrete proinflammatory cytokines, as interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). The present case is of particular interest as it presents an AM as the cause of an inflammatory arthropathy with articular and enthesis involvement. A paraneoplastic screening is always relevant in rheumatology, especially when encountering a refractory disease.

Background:In March this year, most of the routine activities were cancelled during the streaming of the pandemic in Italy. This prompted a pragmatic reorganization of the traditional care model of nursing and medicine, to quickly give an efficient clinical response. During the first phase of the pandemic, outpatient visits dropped by more than 60%, forcefully shifting to telemedicine to assure continuity of care despite the lockdown.Objectives:The aim of the present work was to describe the strategy adopted during and immediately after the lockdown to assure the follow up of patients and the maintenance of their treatment in an outpatient “virtual” telemedicine clinic dedicated to RDs.Methods:the patient flow to a rheumatology division during the lockdown was evaluated retrospectively from March to September 2020 in accordance with local restrictions, and three periods are described.Results:653/913 (71.5%), 542/542 (100%) and 1.048/1.048 (100%) infusion activities scheduled were performed at the centre for daily infusion and pre-infusion assessment, respectively during the 1st, 2nd and 3rd period. In the outpatient clinic during the 1st period, 96.96% of the cases was shifted to Telemedicine, which decreased to 52.45% in the 2nd period; while in the 3rd period, 97.6% of the performances were carried out at the clinic. Diagnostic procedures, such as ultrasound, capillaroscopy, and joint injection were generally postponed during the 1st period, reduced drastically during the 2nd and performed regularly during 3rd period. Ulcer treatment and the Clinical Trial Unit never stopped their activity. The flow of the activity of the outpatient clinic and the day hospital is represented as monthly trends in graph 1 (See Graph 1).Conclusion:Our data show the feasibility of Telemedicine in a lockdown condition. Shifting stable patients to Telemedicine has the potentiality to minimize the risk of contagion and allow continuity of care. In the future, the use of Telemedicine for specific clinical uses might assure patient assistance also in non-pandemic conditions.References:[1]Rawaf S, Allen LN, Stigler FL et al. Lessons on the COVID-19 pandemic, for and by primary care professionals worldwide. Eur J Gen Pract. 2020 Dec;26(1):129-133. doi: 10.1080/13814788.2020.1820479. PMID: 32985278.[2]McDougall JA, Ferucci ED, Glover J, et al. Telerheumatology: A Systematic Review. Arthritis Care Res (Hoboken). 2017 Oct;69(10):1546-1557. doi: 10.1002/acr.23153. Epub 2017 Aug 22. PMID: 27863164; PMCID: PMC5436947.[3]Romão VC, Cordeiro I, Macieira C, Oliveira-Ramos F, Romeu JC, Rosa CM, Saavedra MJ, Saraiva F, Vieira-Sousa E, Fonseca JE. Rheumatology practice amidst the COVID-19 pandemic: a pragmatic view. RMD Open. 2020 Jun;6(2):e001314. doi: 10.1136/rmdopen-2020-001314. PMID: 32584782; PMCID: PMC7425193.Characters from table content including title and footnotes:Graph 1.Monthly trend for telemedicine and visits during the SARS Cov2 emergencyAcknowledgements:The project (Telereuma) has been supported by an unrestricted grant of Biogen, BMS, and Novartis.Disclosure of Interests:None declared

Patients and health workers were at high risk of infection during the Sars-Cov-2 pandemic lockdown. For this reason, other medical and clinical approaches such as Telemedicine were necessary. Despite Telemedicine was born before COVID-19, the pandemic was the opportunity to accelerate a process already underway for at least a decade and to blow all the barriers away. Our aim is to describe the experience of Telemedicine during and immediately after the first lockdown to assure the follow-up in a 'virtual' outpatient clinic dedicated to Rheumatic and Musculoskeletal Diseases (RMDs) and to give an overview of Telemedicine in the rheumatology field. We retrospectively evaluated the patient flow to our rheumatology division from March to September 2020 and, in accordance with local restrictions, three periods were selected. In the 1st period, 96.96% of the outpatient clinic cases were shifted to Telemedicine; these decreased to 52.45% in the 2nd period, while the 3rd period was characterized by the return of the patients at the clinic (97.6%). Diagnostic procedures were postponed during the 1st period, reduced drastically during the 2nd and performed regularly during the third period. Intravenous infusions were maintained as much as possible during the three periods, to assure therapeutic continuity. Shifting stable patients to Telemedicine has the potential to allow continuity of care, while reducing the risk of contagion during a pandemic. In the next future, the integration of Telemedicine as standard of care for specific clinical applications might assure assistance for RMDs patients also in non-pandemic conditions.

Background Osteoporosis is a frequent complication of rheumatic muscle-skeletal diseases (RMD), with high impact from steroid treatment. It is known that bDMARD impact positively on patients’ prognosis and this is also known for Denosumab, a monoclonal antibody for osteoporosis. The combination treatment with two monoclonal antibodies, bDMARD & denosumab, has addressed the problem of safety and efficacy, with incomplete answers from the available literature. Objectives: to evaluate the impact of the combination treatment bDMARD+Denosumab (COMBO group), compared to mono-therapy with bDMARD (MONO group), on clinical efficacy, safety and treatment retention of bDMARD in patients with RMD. Methods RMD patients treated with COMBO therapy where enrolled from a single centre rheumatology unit; for each case, at least one MONO therapy control (matched per age±5 years, sex, bDMARD, RMD, without osteoporosis) was enrolled. Data on clinical efficacy (3-points Likert scale for physician and patient – improved/stable/worse), safety (locl reaction, serious and non-serious adverse events) and bDMARD treatment retention at 12, 18 and 24 months. Results Out of 129 eligible patients, 77 were enrolled in the protocol: 49 in the MONO and 28 in the COMBO group. The two groups were different of age (slightly higher in the COMBO group), for tender joint count, erythrocyte sedimentation rate and c-reactive protein (higher in the MONO group). Efficacy analysis showed higher percentage of clinical improvement at 12 months in the MONO group at 12 months, being not significant at 18 and 24 months (possibly explained by a different disease activity at baseline visit, corresponding to the overlap of denosumab on top of bDMARD in the COMBO and to the initiation of bDMARD in the MONO group). Between the 2 groups, no difference about safety and retention rate was found. Conclusion: the efficacy of COMBO treatment is similar to MONO therapy. Moreover, the data show that also safety and retention rate are similar. Therefore, the COMBO treatment with 2 different monoclonals can be safely employed in the treatment of RMDs and osteoporosis. Disclosure of Interests Cosimo Bruni: None declared, Cosimo Cigolini: None declared, Giulia Tesei: None declared, Francesca Bartoli: None declared, Ginevra Fiori: None declared, Maria Letizia Conforti: None declared, Silvia Bellando Randone: None declared, Serena Guiducci: None declared, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Pfizer, BMS, Chemomab, Sanipedia, Speakers bureau: Actelion, BMS; MSD, Janssen

Iloprost (ILO) is employed intravenously for the treatment of severe Raynaud phenomenon (RP) and digital ulcers (DU) in systemic sclerosis (SSc). The aim of this study was to evaluate the safety and tolerability of the intravenous treatment with ILO in different phases of SSc. Eighty-one consecutive non-selected SSc patients, all on nifedipine, with moderate RP, treated with ILO infusion, were retrospectively evaluated. Patients were sub classified according to the edematous or fibrotic/atrophic cutaneous phase of the disease. ILO was infused with a progressive increase of the dosage up to the achievement of patient's tolerance, 1 day/week. In cases of slower infusion regimen due to adverse events (AE) at the beginning of the administration, patients received a lower dose of the drug (not possible to quantify precisely the final cumulative dosage). 16/81 SSc patients presented digital edema, 5 developed diarrhea, and 9 developed transient hypotension during the infusion at 20 ml/h that ameliorated when the drug was withdrawn. Moreover, 10/16 edematous patients experienced significant and painful digital swelling, unlike patients in the fibrotic group (p < 0.0001); 11/16 patients reported flushing and 7/16 headache, always controlled with dose tapering below 10 ml/h. In the atrophic/fibrotic phase patients (65/81), 10 developed diarrhea and 24 hypotension at infusion rate of 20 ml/h that led to temporary withdrawal of the drug. When ILO was restarted and kept below 10 ml/h, no side effects were experienced. 23/65 patients experienced flushing and 8/65 headache, all controlled with infusion reduction below 10 ml/h. In these patients, adverse events were significantly less frequent than in the edematous group (p = 0.023 and p = 0.008, respectively). Our data suggest that calcium channel blockers should be transitorily stopped while using ILO and that a pre-treatment approach might reduce or control adverse events. In patients with digital edema, ILO infusion should be carefully employed after the evaluation of patient's drug tolerance.

Background PAH is one of the most severe complication and cause of mortality in SSc, with frequent late diagnosis as asymptomatic in its early stages. Right Heart catheterization (RHC) is the gold standard for PAH detection, though its invasive nature with high risk of procedure related complications stress the need for developing new screening methods to investigate it in early and possibly reversible stages. Pressure Recording Analytical Method (PRAM) was recently developed to obtain a minimally invasive haemodynamic monitoring, using an arterial line and proximal pulsossimetry. This analyses arterial blood pressure curve and measure both cardiac [Cardiac Index, Cardiac Contractility and Vascular Stiffness ratio (dP/dT)] and vascular [vascular stiffness, elastance], which can be usually obtained only through RHC. Objectives to evaluate the clinical usefulness of PRAM method in SSc patients and to identify haemodynamic parameters related to increased risk of developing PAH. Methods 40 ssc patients (35 women, mean age 60±9,3 years; mean disease duration 7.5 years) were evaluated with both RHC and PRAM on the same day. Mean pulmonary arterial pressure (mPAP), cardiac index (CI), systemic vascular resistances (SVR), right cardiac power index (RCPI, calculated with mPAPXCIPRAM/451) were measured and concordance of the two methods was assessed through Bland-Altmann analysis. Systolic pulmonary arterial pressure and TAPSE from echocardiography, forced vital capacity, total lung capacity, both absolute and alveolar volume adjusted Carbone oxide lung diffusion (DLCO and DLCO/VA) from pulmonary function tests, blood tests parameters, nailfold videocapillaroscopy scleroderma patterns were recorded. Univariate and multivariate logistic regression analysis identified variables correlating with RHC-diagnosed PAH: a scoring system was then created, giving 1 point for value satisfying cut-off level. Results PRAM showed concordance with RHC estimate of CI and SVR within 95% interval confidence; 14 patients were diagnosed with PAH (mean age 64,4±9,3, mean disease duration 10.5 years, lSSc 61,5%). Multivariate logistic regression analysis showed DLCO (cut off value 47% obtained through ROC curve analysis, p=0.004) and RCPI (cut off value 0.12 Watt obtained through ROC curve analysis, p<0.001) as the most highly PAH-associated variables. When combining these two variables in the scoring system, patient with score=0 (DLCO<47% and RCPI<0,12 Watt), score=1 (DLCO<47% or RCPI≥0,12 Watt) and score=2 (DLCO<47% and RCPI≥0,12) were 0%, 21.4% and 78.6% of the PAH population respectively. Conclusions PRAM is comparable to RHC in detecting haemodynamic parameters such as SVR and CI. The scoring system combining DLCO and RCPI, obtained with non-invasive tools, could offer the possibility of detecting PAH patients with a high specificity. Disclosure of Interest None declared

UNLABELLED:The term overlap syndromes (OS) is used to define a group of disorders characterized by the presence, in the same patient, of clinical features typical for more than one definite connective tissue disease (CTD).OBJECTIVE:To show that patients may not only have an overlap of two or more CTDs but may also change their disease phenotype from that of a definite CTD to another.PATIENTS AND METHODS:Retrospective analysis of medical records of four patients with a disease duration of about thirty years and a transition from a well definite CTD into another.RESULTS:The first patient was diagnosed, at the beginning of the 1980s, as affected by diffuse cutaneous systemic sclerosis (dcSSc) and developed systemic lupus erythematosus (SLE) twenty-five years later. The second and the third patients were diagnosed with SLE at the beginning of their disease: the second patient developed, in the course of her disease, an overlap syndrome (OS) SSc/rheumatoid arthritis (RA) and the third SSc and finally microscopic polyangiitis (MPA). The fourth patient was diagnosed as primary Sjogren's syndrome (SS) then as rheumatoid arthritis (RA) and finally developed SLE.CONCLUSIONS:Patients may not only show an overlap of two or more CTDs but also a transition from a well definite CTD into another. We propose the term "transitional connective tissue diseases" (TCTDs) to define their disease. A higher number of patients may allow us to better identify this new subgroup of CTDs and probably, also, predictors of evolution.

Background A high percentage of patients with systemic sclerosis (SSc) develop interstitial lung disease (ILD) during the course of the disease. Promising data have recently shown that lung ultrasound (LUS) is able to detect ILD by the evaluation of B-lines (previously called ultrasound lung comets), the sonographic marker of pulmonary interstitial syndrome. Objective To evaluate whether LUS is reliable in the screening of ILD in patients with SSc. Methods Fifty-eight consecutive patients with SSc (54 women, mean age 51±14 years) who underwent a high resolution CT (HRCT) scan of the chest were also evaluated by LUS for detection of B-lines. Of these, 32 patients (29 women, mean age 51±15 years) fulfilled the criteria for a diagnosis of very early SSc. Results At HRCT, ILD was detected in 88% of the SSc population and in 41% of the very early SSc population. A significant difference in the number of B-lines was found in patients with and without ILD on HRCT (57±53 vs 9±9; p<0.0001), with a concordance rate of 83%. All discordant cases were false positive at LUS, providing a sensitivity and negative predictive value of 100% in both SSc and very early SSc. Conclusions ILD may be detected in patients with very early SSc. The presence of B-lines at LUS examination correlates with ILD at HRCT. LUS is very sensitive for detecting ILD even in patients with a diagnosis of very early SSc. The use of LUS as a screening tool for ILD may be feasible to guide further investigation with HRCT.

OBJECTIVE:Systemic sclerosis (SSc) is characterized by early perivascular inflammation, microvascular endothelial cell (MVEC) activation/damage, and defective angiogenesis. Junctional adhesion molecules (JAMs) regulate leukocyte recruitment to sites of inflammation and ischemia-reperfusion injury, vascular permeability, and angiogenesis. This study was undertaken to investigate the possible role of JAMs in SSc pathogenesis.METHODS:JAM-A and JAM-C expression levels in skin biopsy samples from 25 SSc patients and 15 healthy subjects were investigated by immunohistochemistry and Western blotting. Subcellular localization of JAMs in cultured healthy dermal MVECs and SSc MVECs was assessed by confocal microscopy. Serum levels of soluble JAM-A (sJAM-A) and sJAM-C in 64 SSc patients and 32 healthy subjects were examined by enzyme-linked immunosorbent assay.RESULTS:In control skin, constitutive JAM-A expression was observed in MVECs and fibroblasts. In early-stage SSc skin, JAM-A expression was strongly increased in MVECs, fibroblasts, and perivascular inflammatory cells. In late-stage SSc, JAM-A expression was decreased compared with controls. JAM-C was weakly expressed in control and late-stage SSc skin, while it was strongly expressed in MVECs, fibroblasts, and inflammatory cells in early-stage SSc. Surface expression of JAM-A was higher in early-stage SSc MVECs and increased in healthy MVECs stimulated with early-stage SSc sera. JAM-C was cytoplasmic in resting healthy MVECs, while it was recruited to the cell surface upon challenge with early-stage SSc sera. Early-stage SSc MVECs exhibited constitutive surface JAM-C expression. In SSc, increased levels of sJAM-A and sJAM-C correlated with early disease and measures of vascular damage.CONCLUSION:Our findings indicate that JAMs may participate in MVEC activation, inflammatory processes, and impaired angiogenesis in different stages of SSc.

In systemic sclerosis (SSc), Raynaud's phenomenon is the earliest clinical manifestation paralleled by nailfold capillaroscopic alterations that may occur months or even years before the onset of fibrosis.1 This evidence suggests a crucial role of microangiopathy characterised by a progressive loss of capillaries with the formation of avascular areas.1 ,2 Consequent chronic tissue hypoxia leads to skin ulcers and gangrene that heavily burden patients’ quality of life.1 ,2 Vascular endothelial growth factor-A (VEGF-A) is overexpressed in SSc skin, and increased circulating levels of VEGF-A correlate with the severity of nailfold capillary loss.2–4 It has been demonstrated that the VEGF-A primary transcript can be alternatively spliced in its terminal exon, producing two distinct mRNA splice variants that are translated to the proangiogenic VEGF165 and antiangiogenic VEGF165b isoforms.5 These two isoforms bind to the tyrosine kinase receptor VEGFR-2 with the same affinity, but binding of VEGF165b results in an insufficient tyrosine phosphorylation/activation of VEGFR-2 and incomplete or transient downstream signalling, which lead to an impaired angiogenic response.5 ,6 Recently, we have provided the first evidence that dermal expression and plasma levels of VEGF165b are raised in SSc patients, and VEGF165b overexpression prevents SSc dermal microvascular endothelial …

Objective To determine serum concentrations and tissue expression of matrix metalloproteinase-12 (MMP-12) and their correlation with clinical features in patients with systemic sclerosis (SSc). Methods Serum MMP-12 levels from 72 patients with SSc and 42 healthy volunteers were examined by ELISA. Immunohistochemical expression of MMP-12 was analysed in skin biopsies from 20 patients with SSc and 13 healthy subjects and lung biopsies from three patients with SSc-related interstitial lung disease (ILD) and five controls. Results Circulating levels of MMP-12 were significantly increased in patients with SSc compared with healthy controls. Serum MMP-12 levels were significantly higher in both patients with limited cutaneous SSc and those with diffuse cutaneous SSc than in healthy controls, and correlated positively with the extent of skin involvement. MMP-12 levels were raised in SSc patients with ILD compared with patients without ILD, and correlated with severity of lung restriction. Increased serum levels of MMP-12 were also associated with the presence of digital ulcers and severity of nailfold capillary abnormalities. In contrast to almost undetectable MMP-12 expression in healthy skin, MMP-12 was strongly expressed in keratinocytes, dermal endothelial cells, fibroblasts/myofibroblasts and inflammatory cells in the skin of patients with SSc. Affected lung tissue from patients with SSc-related ILD showed strong MMP-12 expression in capillary vessels, inflammatory cells, alveolar macrophages and fibroblasts in the thickened alveolar septa, while faint expression was observed in normal lung tissue. Conclusions MMP-12 levels are increased in patients with SSc and are associated with severity of skin and pulmonary fibrosis and peripheral vascular damage.

Referat zur Arbeit von Maddali Bong S, Del Rosso A, Passalacqua M, Miccio S, Matucci Cerinic M. Manual Lymph Drainage Improving Upper Extremity Edema and Hand Function in Patients With Systemic Sclerosis in Edematous. Arthritis Care & Research 2011, 63 ( 8) 1134–1141

Week Hospital is an innovative inpatient health care organization and management, by which hospital stay services are planned in advance and delivered on week-time basis to elective patients. In this context, a strategic decision is the optimal clinical management of patients, and, in particular, devising efficient and effective admission and scheduling procedures, by tackling different requirements such as beds’ availability, diagnostic resources, and treatment capabilities. The main aim is to maximize the patient flow, by ensuring the delivery of all clinical services during the week. In this paper, the optimal management of Week Hospital patients is considered. We have developed and validated an innovative integer programming model, based on clinical resources allocation and beds utilization. In particular, the model aims at scheduling Week Hospital patients’ admission/discharge, possibly reducing the length of stay on the basis of an available timetable of clinical services. The performance of the model has been evaluated, in terms of efficiency and robustness, by considering real data coming from a Week Hospital Rheumatology Division. The experimental results have been satisfactory and demonstrate the effectiveness of the proposed approach.

Objective To characterise bone marrow-derived mesenchymal stem cells (MSCs) from patients with systemic sclerosis (SSc) for the expression of factors implicated in MSC recruitment at sites of injury, angiogenesis and fibrosis. The study also analysed whether the production/release of bioactive mediators by MSCs were affected by stimulation with cytokines found upregulated in SSc serum and tissues, and whether MSCs could modulate dermal microvascular endothelial cell (MVEC) angiogenesis. Methods MSCs obtained from five patients with early severe diffuse SSc (SSc-MSCs) and five healthy donors (H-MSCs) were stimulated with vascular endothelial growth factor (VEGF), transforming growth factor β (TGFβ) or stromal cell-derived factor-1 (SDF-1). Transcript and protein levels of SDF-1 and its receptor CXCR4, VEGF, TGFβ1 and receptors TβRI and TβRII were evaluated by quantitative real-time PCR, western blotting and confocal microscopy. VEGF, SDF-1 and TGFβ1 secretion in culture supernatant was measured by ELISA. MVEC capillary morphogenesis was performed on Matrigel with the addition of MSC-conditioned medium. Results In SSc-MSCs the basal expression of proangiogenic SDF-1/CXCR4 and VEGF was significantly increased compared with H-MSCs. SSc-MSCs constitutively released higher levels of SDF-1 and VEGF. SDF-1/CXCR4 were upregulated after VEGF stimulation and CXCR4 redistributed from the cytoplasm to the cell surface. VEGF was increased by SDF-1 challenge. VEGF, TGFβ and SDF-1 stimulation upregulated TGFβ1, TβRI and TβRII in SSc-MSCs. TβRII redistributed from the cytoplasm to focal adhesion contacts. SSc-MSC-conditioned medium showed a greater proangiogenic effect on MVECs than H-MSCs. Experiments with blocking antibodies showed that MSC-derived cytokines were responsible for this potent proangiogenic effect. Conclusion SSc-MSCs constitutively overexpress and release bioactive mediators/proangiogenic factors and potentiate dermal MVEC angiogenesis.

Copyright information: Taken from Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcersArthritis Research 2002;4(6):R11-R11.Published online 30 Aug 2002PMCID:PMC153841.Copyright © 2002 Distler et al., licensee BioMed Central Ltd The analysis included patients with pre-systemic sclerosis (pre-SSc) (autoantibodies, capillaroscopy changes and Raynaud's phenomenon, but not yet fulfilling American College of Rheumatology criteria), patients with early SSc (diffuse SSc

Objective.Cardiac involvement means a poor prognosis in systemic sclerosis (SSc). Conduction defects and arrhythmias are frequent in patients with SSc, and may result in sudden cardiac death. We tested whether electrophysiologic studies and implantation of cardioverter defibrillators are recommended when ventricular arrhythmias are present.Method.A cardioverter defibrillator was implanted in 10 patients with SSc who had heart involvement.Result.After 36 months, analysis of the device showed several episodes of ventricular tachycardia in 3 patients, which were promptly reverted by electrical shock delivery.Conclusion.In patients with SSc who are affected by ventricular arrhythmias, the implantation of a cardioverter defibrillator may prevent sudden cardiac death.

Rationale: Systemic sclerosis (SSc) is characterized by widespread microangiopathy, fibrosis, and autoimmunity. Despite the lack of angiogenesis, the expression of vascular endothelial growth factor A (VEGF) was shown to be upregulated in SSc skin and circulation; however, previous studies did not distinguish between proangiogenic VEGF(165) and antiangiogenic VEGF(165)b isoforms, which are generated by alternative splicing in the terminal exon of VEGF pre-RNA.Objective: We investigated whether VEGF isoform expression could be altered in skin and circulation of patients with SSc.Methods and Results: Here, we show that the endogenous antiangiogenic VEGF(165)b splice variant is selectively overexpressed at both the mRNA and protein levels in SSc skin. Elevated VEGF(165)b expression correlated with increased expression of profibrotic transforming growth factor-beta 1 and serine/arginine protein 55 splicing factor in keratinocytes, fibroblasts, endothelial cells, and perivascular inflammatory cells. Circulating levels of VEGF(165)b were significantly higher in patients with SSc than in control subjects. Microvascular endothelial cells (MVECs) isolated from SSc skin expressed and released higher levels of VEGF(165)b than healthy MVECs. Transforming growth factor-beta 1 upregulated the expression of VEGF(165)b and serine/arginine protein 55 in both SSc and healthy MVECs. In SSc MVECs, VEGF receptor-2 was overexpressed, but its phosphorylation was impaired. Recombinant VEGF(165)b and SSc-MVEC-conditioned medium inhibited VEGF(165)-mediated VEGF receptor-2 phosphorylation and capillary morphogenesis in healthy MVECs. The addition of anti-VEGF(165)b blocking antibodies abrogated the antiangiogenic effect of SSc-MVEC-conditioned medium. Capillary morphogenesis was severely impaired in SSc MVECs and could be ameliorated by treatment with recombinant VEGF(165) and anti-VEGF(165)b blocking antibodies.Conclusions: In SSc, a switch from proangiogenic to antiangiogenic VEGF isoforms may have a crucial role in the insufficient angiogenic response to chronic ischemia. (Circ Res. 2011; 109: e14-e26.)

Early activation/damage of endothelial cells and multiple profibrotic T helper type 2 (Th2)-associated cytokines play an important role in the pathogenesis of systemic sclerosis (SSc).1 Interleukin 33 (IL-33) was recently identified as a member of the IL-1 family and a ligand for the orphan receptor ST2L, which mediates the action of IL-33 on polarised Th2 lymphocytes and other leucocyte subsets, and tissue-resident cells, such as vascular endothelial cells and fibroblasts/myofibroblasts.2 IL-33 has been shown to induce IL-13-dependent cutaneous fibrosis and stimulate angiogenesis and vascular permeability.3 4 In healthy human tissues IL-33 protein is constitutively highly expressed in the nuclei of resting endothelial cells, but rapidly lost upon angiogenic or proinflammatory activation.2 Indeed, IL-33 is thought to function as an endogenous ‘alarmin’ that is rapidly released after endothelial cell damage to alert the cells of the innate and adaptive immune system.2 Recently, we have shown that microvascular endothelial cells in inflamed skin from patients with early-stage SSc lacked or had decreased nuclear IL-33 protein expression.5 Instead, IL-33 transcript levels were even upregulated suggesting that, …