Publications by authors named "Gemma Lepri"

41 Publications

The Updated Role of Ultrasound in Assessing Dermatological Manifestations in Systemic Sclerosis.

Open Access Rheumatol 2021 28;13:79-91. Epub 2021 Apr 28.

Unit of Pulmonology, University Hospital of Trieste, Trieste, Italy.

Systemic sclerosis (SSc), an autoimmune connective tissue disease, characterized by skin fibrosis, increased dermal thickness and microvascular involvement. Fibroblasts and myofibroblasts deposit excessive amounts of collagenous and non-collagenous extracellular matrix components in the skin. This leads to microvascular abnormalities and Raynaud's phenomenon, with painful digital ulcers (DU) at the fingertips adding to patient discomfort. The skin involvement and severity in SSc was evaluated by the Modified Rodnan skin score (mRSS). Although high-frequency ultrasound (HUS) has been widely researched in the study of skin thickness and DU in SSc, its adoption into clinical practice is not yet common. However, novel insights into the still relatively unknown disease pathogenesis in SSc and its evaluation may be provided by HUS, including early (pre-clinical) skin involvement. It may also be useful in both the evaluation and follow-up of DU. Indeed, it is a non-invasive, safe, inexpensive and reproducible method able to assess not only SSc patients' cutaneous structural changes, but also their vascular system changes. Moreover, several recent studies have reported that elastosonography (ES) is of use when investigating skin involvement in systemic sclerosis. This review aims at providing information as to role HUS and ES play in research advancements and the clinical perspectives in the evaluation of skin thickness and DU in SSc patients.
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http://dx.doi.org/10.2147/OARRR.S282612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092351PMC
April 2021

One year in review 2020: systemic sclerosis.

Clin Exp Rheumatol 2020 May-Jun;38 Suppl 125(3):3-17. Epub 2020 Jul 6.

Service de Rhumatologie, Hôpital Cochin, Université de Paris, INSERM U1016, Paris, France.

Systemic sclerosis (SSc) is a connective tissue disease characterised by diffuse microangiopathy and immune dysregulation which ultimately results in widespread fibrosis of the skin and internal organs. This complex autoimmune disease is characterised by heterogeneous clinical manifestations and variable disease course in which the severity of pathology dictates the disease prognosis and course. Every year novel insights into the pathogenesis, organ involvement and treatment of this severe disease are published. Herewith, we provide an overview of the most significant literature contributions published last year, with the aim of helping the clinician in the understanding and management of SSc patients.
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September 2020

Screening for pulmonary arterial hypertension in systemic sclerosis: A systematic literature review.

Eur J Intern Med 2020 08 12;78:17-25. Epub 2020 Jun 12.

Dept. Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Viale Pieraccini 18, Florence, 50139, Italy.

Pulmonary arterial hypertension (PAH) carries a high morbidity and mortality burden in Systemic Sclerosis (SSc). Therefore, PAH screening and early detection are pivotal. A systematic literature review (SLR) to search for all screening tools and modalities for SSc-PAH was performed in reference to right heart catheterization as diagnostic gold standard. Papers from 2 previously published SLRs and derived from a systematic search on Pubmed, EMBASE, Web of Science for papers published from 03/10/2017 to 31/12/2018 were manually included. A total of 199 papers were reviewed and 32 were extracted, with a low bias risk according to QUADAS2. Echocardiography, pulmonary function tests, clinical features and serum biomarkers were the most frequently tools used for screening, with different parameters combined in a variable fashion, as single item or as part of composite algorithms. Among the composite algorithms, the DETECT score, ESC/ERS 2009 or 2015 guidelines, ASIG and ITINER-air algorithms were the most commonly used in a wide range of patients. In different cohorts, DETECT and ASIG showed higher sensitivity and negative predictive value than ESC/ERS 2009. In conclusion, the literature shows echocardiography as the leading screening tool for SSc-PAH. In particular, systolic pulmonary arterial pressure (sPAP) and tricuspid regurgitation velocity (TRV), both as single items or part of composite algorithms, including also serum biomarkers, clinical and functional items, are the most frequent parameters evaluated.
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http://dx.doi.org/10.1016/j.ejim.2020.05.042DOI Listing
August 2020

The systemic sclerosis patient in the COVID-19 era: the challenging crossroad between immunosuppression, differential diagnosis and long-term psychological distress.

Clin Rheumatol 2020 Jul 8;39(7):2043-2047. Epub 2020 Jun 8.

Department of Experimental and Clinical Medicine, Department of Geriatric Medicine, Division of Rheumatology AOUC & Scleroderma Unit, University of Florence, Florence, Italy.

COVID-19 is a world health emergency which may inevitably affect the management of a complex autoimmune disease such as systemic sclerosis (SSc). Several SSc patients are frail and, in this pandemic, need a careful protection. The COVID-19 infection might complicate the clinical scenario of interstitial lung disease (ILD) in SSc because it determines a severe pneumonia characterized by radiological features similar to SSc-ILD. The striking CT similarities between the 2 diseases make it difficult to distinguish a worsening of SSc-ILD from COVID-19-ILD superinfection. Moreover, other aspects, like isolation during lock down, may cause a significant psychological stress which will pile up on the already difficult contact with the patients for a routine check-up. Moreover, the drug shortage is a real problem in these times. For these reasons, the rheumatologist in daily clinical practice should carefully differentiate the possible COVID-19 infection in order to optimize the patient management. Therefore, the challenge in everyday life will be to achieve in due time the differential diagnosis as well as the long-term psychological impact.Key Points• SSc patients should be encouraged to continue their chronic therapy; in case of immunosuppressive therapy it must be discontinued for safety in case of COVID-19 infection.• Psychological support must be guaranteed to every SSc patients.• COVID-19 pneuminia is hard to distinguish from an interstitial lung disease due to SSc lung involvment.• Data sharing is fundamental for an optimal managment of SSc patients during COVID-19 pandemia.
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http://dx.doi.org/10.1007/s10067-020-05193-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276334PMC
July 2020

The emerging role of lung ultrasound in COVID-19 pneumonia.

Eur J Rheumatol 2020 Aug 7;7(Suppl 2):S129-S133. Epub 2020 May 7.

Division of Rheumatology, Department of Experimental and Clinical Medicine, Università degli Studi di Firenze, Firenze, Toscana, Italy.

In the last decades lung ultrasound (LUS) has become of crucial importance in the evaluation and monitoring of a widely range of pulmonary diseases. One of the major benefits which favours this examination, is that this is a non-invasive, low-cost and radiation-free imaging modality which allows repeated imaging. LUS plays an important role in a wide range of pathologies, including cardiogenic oedema, acute respiratory distress syndrome and fibrosis. Specific LUS findings have proved useful and predictive of acute respiratory distress syndrome which is of particular relevance in the suspicion and monitoring of patients with lung disease. Furthermore, several studies have confirmed the role of LUS in the screening of interstitial lung diseases in connective tissue diseases. Given these data, LUS will likely play an important role in the management of COVID-19 patients from identification of specific abnormalities corresponding to definite pneumonia phases and CT scans findings. In addition, LUS could allow reduction in the exposure of health-care workers to potential infection. Herein, we provide a summary on emerging role of lung ultrasound in COVID-19 pneumonia.
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http://dx.doi.org/10.5152/eurjrheum.2020.2063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431334PMC
August 2020

Prognostic Value of Lung Ultrasound B-Lines in Systemic Sclerosis.

Chest 2020 10 29;158(4):1515-1525. Epub 2020 Apr 29.

Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy.

Background: A high percentage of systemic sclerosis (SSc) patients experience interstitial lung disease (ILD) during the disease course. Recent data have shown that lung ultrasound (LUS) can assess ILD by the evaluation of B-lines, the sonographic sign of pulmonary interstitial involvement.

Research Question: To establish the prognostic value of B-lines in a large number of patients with SSc.

Study Design And Methods: A total of 396 consecutive patients with SSc, who were enrolled at three Rheumatology Departments, underwent a comprehensive LUS examination on the anterolateral and posterior chest for a total of 58 scanning sites. All available clinical, imaging, and functional data were recorded. Patients were followed after enrolment to establish the prognostic role of LUS.

Results: The median number of B-lines was higher in patients with the diffuse cutaneous subset (44 vs 17 B-lines; P < .0001), topoisomerase I autoantibodies (39 vs 16 B-lines; P < .0001), and the presence of ILD at chest high-resolution CT (45 vs 9 B-lines; P < .0001). At multivariable analysis, the number of posterior B-lines ≥5 was associated with new development or worsening ILD (hazard ratio, 3.378; 95% CI, 1.137-9.994; P = .028), with additional value over topoisomerase I positivity. The prognostic value was further confirmed in the subgroup of patients with known ILD at baseline (hazard ratio, 1.010; 95% CI, 1.003-1.018; P = .008).

Interpretation: Lung ultrasound B-lines are associated with worsening or development of pulmonary deterioration. In the near future, LUS might become part of the diagnostic and prognostic armamentarium in patients with SSc, which would allow a more sustainable and user-friendly approach to this very fragile population.
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http://dx.doi.org/10.1016/j.chest.2020.03.075DOI Listing
October 2020

The Renal Resistive Index: A New Biomarker for the Follow-up of Vascular Modifications in Systemic Sclerosis.

J Rheumatol 2021 02 1;48(2):241-246. Epub 2020 Apr 1.

C. Bruni, MD, G. Lepri, MD, G. Tesei, MD, S. Guiducci, MD, D. Melchiorre, MD, S. Bellando-Randone, MD, M. Matucci-Cerinic, MD, Department of Experimental and Clinical Medicine, University of Florence, and Division of Rheumatology AOUC & Scleroderma Unit, Florence.

Objective: The aim of the present retrospective observational study was to evaluate the change of Renal Resistive Index (RRI) over time (ΔRRI) and under treatment in patients with systemic sclerosis (SSc) as well as to correlate these changes with disease complications.

Methods: Two hundred thirty patients [29 male, median age 57 (IQR 48-67) yrs] were enrolled. At baseline and follow-up (3.43, IQR 2.81-4.45 yrs), we collected the following data: disease variables, nailfold videocapillaroscopy (NVC) pattern, forced vital capacity (FVC), diffusing lung capacity for carbon monoxide (DLCO), systolic pulmonary arterial pressure (sPAP), presence of interstitial lung disease, RRI, evaluation of glomerular filtration rate, and new onset of pulmonary arterial hypertension (PAH).

Results: RRI value is high in SSc patients with digital ulcers and anticentromere antibodies, active and late NVC patterns, and limited cutaneous SSc. A significant correlation was observed between ΔRRI and ΔsPAP (R = 0.17, = 0.02), with statistically higher ΔRRI (0.08 ± 0.02 vs 0.03 ± 0.05, = 0.04) in patients complicated by PAH onset. No other new-onset complication was associated with ΔRRI. The receiver-operating characteristic curve analysis confirmed the predictive role of ΔRRI in development of new PAH (area under the curve 0.84, 95% CI 0.75-0.93, = 0.02). In patients with SSc never exposed to sildenafil, ΔRRI was higher (0.04 ± 0.05) compared to both patients exposed to sildenafil during the study period (0.01 ± 0.05, = 0.03) or in those exposed at the time of baseline evaluation (0.00 ± 0.05, = 0.01).

Conclusion: RRI and its variation in time are a reliable marker of SSc-related vasculopathy, both in renal and extrarenal compartments.
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http://dx.doi.org/10.3899/jrheum.191101DOI Listing
February 2021

Recent advances steer the future of systemic sclerosis toward precision medicine.

Clin Rheumatol 2020 Jan 23;39(1):1-4. Epub 2019 Nov 23.

Department of Experimental and Clinical Medicine, University of Florence, and Department of Geriatric Medicine, Division of Rheumatology AOUC, Florence, Italy.

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http://dx.doi.org/10.1007/s10067-019-04834-5DOI Listing
January 2020

Performance of ultra-high-frequency ultrasound in the evaluation of skin involvement in systemic sclerosis: a preliminary report.

Rheumatology (Oxford) 2020 07;59(7):1671-1678

Department of Experimental and Clinical Medicine, University of Florence and Department of Geriatric Medicine, Division of Rheumatology AOUC, Florence, Italy.

Objective: High frequency ultrasound allows visualization of epidermis, dermis and hypodermis, precise measurement of skin thickness, as well as assessment of skin oedema, fibrosis and atrophy. The aim of this pilot cross-sectional observational study was to assess the performance and multiobserver variability of ultra-high-frequency (UHF) (50 MHz) ultrasound (US) in measuring skin thickness as well as the capacity of UHF-derived skin features to differentiate SSc patients from healthy controls.

Methods: Twenty-one SSc patients (16 limited and five diffuse SSc) and six healthy controls were enrolled. All subjects underwent US evaluation by three experts at three anatomical sites (forearm, hand and finger). Dermal thickness was measured and two rectangular regions of interest, one in dermis and one in hypodermis, were established for texture feature analysis.

Results: UHF-US allowed a precise identification and measurement of the thickness of the dermis. The dermal thickness in the finger was significantly higher in patients than in controls (P < 0.05), while in the forearm it was significantly lower in patients than in controls (P < 0.001). Interobserver variability for dermal thickness was good to excellent [forearm intraclass correlation coefficient (ICC) = 0.754; finger ICC = 0.699; hand ICC = 0.602]. Texture computed analysis of dermis and hypodermis was able to discriminate between SSc and healthy subjects (area under the curve >0.7).

Conclusion: These preliminary data show that skin UHF-US allows a very detailed imaging of skin layers, a reliable measurement of dermal thickness, and a discriminative capacity between dermis and hypodermis texture features in SSc and healthy subjects.
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http://dx.doi.org/10.1093/rheumatology/kez439DOI Listing
July 2020

One year in review 2019: systemic sclerosis.

Clin Exp Rheumatol 2019 Jul-Aug;37 Suppl 119(4):3-14. Epub 2019 Oct 3.

Rheumatology Unit, University of Florence, Italy.

Systemic sclerosis (SSc) is a complex disorder characterised by the involvement of small arteries, microvessels and connective tissue, with deposition of fibrotic tissue and microvascular obliteration in the skin and internal organs. Due to the multifaceted nature of the disease, several articles are published in the medical literature every year, aimed at exploring different aspects of the pathogenesis, internal organ involvement and clinical aspects, and possible therapeutic approaches. In this article we have reviewed the literature on SSc of the past year, with the aim of identifying novel approaches that may help the treating physician in the clinical management of patients.
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October 2019

Pregnancy in Systemic Sclerosis: Results of a Systematic Review and Metaanalysis.

J Rheumatol 2020 06 1;47(6):881-887. Epub 2019 Sep 1.

From the Department of Experimental and Clinical Medicine, University of Florence, and the Department of Geriatric Medicine, Division of Rheumatology and Scleroderma Unit, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence, Italy; Department of Family Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; Faculty of Medicine, Alexandria University, Alexandria, Egypt; Department of Emergency Medicine, Division of Medicine IV AOUC; Department of Maternal-Neonatal Caref, Careggi University Hospital, Florence, Italy; University of California at Los Angeles, Los Angeles, California; University of Washington, Seattle, Washington, USA; University of Florence, Florence, Italy.

Objective: Through a systematic literature search (SLR) and metaanalysis, to determine maternal and fetal outcomes in pregnancies involving systemic sclerosis (SSc), to analyze the effect of pregnancy on disease activity, and to examine predictors of fetal and maternal outcomes.

Methods: An SLR was performed for articles on SSc and pregnancy published between 1950 and February 1, 2018. Reviewers double-extracted articles to obtain agreement on > 95% of predefined critical outcomes.

Results: Out of 461 publications identified, 16 were included in the metaanalysis. The metaanalysis showed that pregnancies involving SSc were at higher risk of miscarriage (OR 1.6, 95% CI 1.22-2.22), fetuses with intrauterine growth retardation (IUGR; OR 3.2, 95% CI 2.21-4.53), preterm births (OR 2.4, 95% CI 1.14-4.86), and newborns with low birth weight (OR 3.8, 95% CI 2.16-6.56). Patients with SSc had a 2.8 times higher chance of developing gestational hypertension (HTN; OR 2.8, 95% CI 2.28-3.39) and a 2.3 times higher chance of cesarean delivery compared to controls (OR 2.3, 95% CI 1.37-3.8). The definitions of disease worsening/new visceral organ involvement were too inexact to have any confidence in the results, although worsening or new disease manifestations during pregnancy in 44/307 cases (14.3%) and 6 months postpartum in 32/306 cases (10.5%) were reported. The data did not permit definition of predictors of disease progression and of maternal and fetal outcomes.

Conclusion: Pregnancies involving SSc have increased frequency of miscarriages, IUGR, preterm deliveries, and newborns with low birth weight compared to healthy controls. Women with SSc were more prone to develop gestational HTN and to undergo cesarean delivery. Disease manifestations seem to remain stable or improve in most patients.
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http://dx.doi.org/10.3899/jrheum.181460DOI Listing
June 2020

Enthesopathy and involvement of synovio-entheseal complex in systemic sclerosis: an ultrasound pilot study.

Rheumatology (Oxford) 2020 03;59(3):580-585

Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, and Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi (AOUC), Florence, Italy.

Objectives: SSc is a chronic autoimmune disease characterized by inflammation of the skin and multiple internal organs. Articular involvement is one of the main features of SSc, and typical hallmarks of SpA have been found in SSc patients. The aim of the present study was to estimate the prevalence of entheseal and synovio-entheseal complex (SEC) alterations in a cohort of SSc patients.

Methods: One hundred SSc patients and 25 healthy subjects were included in this cross-sectional study. The enthesis sites of lateral epicondylar common extensor tendons (CET) and the enthesis of the Glasgow Ultrasound Enthesis Scoring System were evaluated. SEC involvement was evaluated only at CET enthesis.

Results: In SSc, the Glasgow Ultrasound Enthesis Scoring System score was significantly higher (median 4.0, interquartile range 2.0-7.0) than in controls (median 1.0, interquartile range 0.0-3.0) (P < 0.0001). CET enthesis of SSc patients showed more frequent US B-mode alterations than that of controls (χ2 = 11.47, P = 0.0007 for size; χ2 = 13.79, P = 0.0002 for cortical irregularity, χ2 = 5.24, P = 0.022 for calcification/enthesophytes). Power Doppler US signal at CET enthesis was significantly more frequent in SSc patients than in healthy controls (χ2 = 9.11, P = 0.0025), as was the concomitant SEC involvement (χ2 = 8.52, P = 0.0035).

Conclusion: These data show that SSc patients frequently present US features of enthesopathy. Moreover, CET enthesopathy was correlated with SEC inflammation, suggesting that entheseal inflammation in SSc may share the same micro-anatomical targets as found in SpA.
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http://dx.doi.org/10.1093/rheumatology/kez322DOI Listing
March 2020

Clinical-Serological Characterization and Treatment Outcome of a Large Cohort of Italian Children with Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection and Pediatric Acute Neuropsychiatric Syndrome.

J Child Adolesc Psychopharmacol 2019 10 29;29(8):608-614. Epub 2019 May 29.

Department of Experimental and Clinical Medicine and Department of Biomedicine, Division of Rheumatology AOUC & Transition Clinic, University of Florence, Florence, Italy.

Pediatric autoimmune neuropsychiatric disorder associated with infection (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS) are emerging immune-mediated encephalopathies characterized by sudden onset of seemingly inexplicable complex neuropsychiatric symptoms, including obsessions, compulsions, and heterogeneous tics, which occur in children. Main goal of this study was to report our experience in a large cohort of Italian children affected by either PANDAS or PANS and treated long term with an antibiotic regimen similar to that used for acute rheumatic fever. The clinical charts of a cohort of 371 consecutive Italian children, 345 with PANDAS (93.0%) and 26 with PANS (7.0%), were retrospectively evaluated. Antistreptococcal, antinuclear antibodies, and serologic evaluation for a group of common autoantibodies and microbial agents were also assessed. A strict differential diagnosis with other autoimmune diseases displaying neuropsychiatric manifestations was performed. Antistreptolysin O and anti-DNase B antibody titers were tested and were positive in all PANDAS subjects, but negative in PANS. Anti- antibodies and anti-Epstein-Barr virus Nuclear Antigen antibodies were found positive in 11 (42.3%) and 5 (19.2%) patients with PANS, respectively. Among PANDAS cases, a clear streptococcal infection was clinically evident at the onset of neurological symptoms in only 74 patients (21.4%), whereas the relationship with was confirmed by serologic tests in the other 271 (78.6%). All patients fulfilling the diagnostic criteria for PANDAS ( = 345) received amoxicillin/clavulanic acid for 10-21 days at diagnosis, while those who were diagnosed with PANS ( = 26) received treatment according to the causative agent. Thereafter, all PANDAS/PANS patients received prophylaxis with benzathine benzylpenicillin for an overall period of at least 5 years to prevent subsequent potential streptococcal infections. To date, 75.0% of PANDAS patients ( = 258) have shown an improvement of neurologic symptoms, mainly observed within 3-5 months of treatment for PANDAS cases, while 88.4% of PANS patients ( = 23) have improved after 6-12 months. Infection-related relapses of neurologic manifestations were observed in both PANDAS and PANS patients ( = 167 out of 371; 45% of the total cohort) in the long term. Our study has confirmed the usefulness of the preliminary diagnostic criteria for PANDAS and PANS, revealing also the importance of early diagnosis to reduce the risk of evolution toward disabling chronic neurologic sequelae. Long-term antibiotic prophylaxis has resulted in a substantial benefit to reduce neurological symptoms for the majority of PANDAS and PANS patients over a 7-year period.
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http://dx.doi.org/10.1089/cap.2018.0151DOI Listing
October 2019

Undifferentiated connective tissue disease: state of the art on clinical practice guidelines.

RMD Open 2018 26;4(Suppl 1):e000786. Epub 2019 Feb 26.

Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.

The term 'undifferentiated connective tissue disease' (UCTD) is generally used to describe clinical entities characterised by clinical and serological manifestations of systemic autoimmune diseases but not fulfilling the criteria for defined connective tissue diseases (CTDs). In this narrative review, we summarise the results of a systematic literature research, which was performed as part of the ERN ReCONNET project, aimed at evaluating existing clinical practice guidelines (CPGs) or recommendations. No specific CPG on UCTD were found, potential areas of intervention are absence of a consensus definition of UCTD, need for specific monitoring and therapeutic protocols, stratification of UCTD based on the risk of developing a defined CTD and preventive measure for the future development of a more severe condition. Patients feel uncertainty regarding the name of the disease and feel the need of a better education and understanding of these conditions and its possible changes over time.
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http://dx.doi.org/10.1136/rmdopen-2018-000786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397427PMC
February 2019

Mixed connective tissue disease: state of the art on clinical practice guidelines.

RMD Open 2018 18;4(Suppl 1):e000783. Epub 2018 Oct 18.

Department of Rheumatology, Universitätsklinikum Düsseldorf, Düsseldorf, Germany.

Mixed connective tissue disease (MCTD) is a complex overlap disease with features of different autoimmune connective tissue diseases (CTDs) namely systemic sclerosis, poly/dermatomyositis and systemic lupus erythematous in patients with antibodies targeting the U1 small nuclear ribonucleoprotein particle. In this narrative review, we summarise the results of a systematic literature research which was performed as part of the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases project, aimed at evaluating existing clinical practice guidelines (CPGs) or recommendations. Since no specific CPGs on MCTD were found, other CPGs developed for other CTDs were taken into consideration in order to discuss what can be applied to MCTD even if designed for other diseases. Three major objectives were proposed for the future development of CPGs: MCTD diagnosis (diagnostic criteria), MCTD initial and follow-up evaluations, MCTD treatment. Early diagnosis, epidemiological data, assessment of burden of disease and QOL aspects are among the unmet needs identified by patients.
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http://dx.doi.org/10.1136/rmdopen-2018-000783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203102PMC
October 2018

Systemic sclerosis: state of the art on clinical practice guidelines.

RMD Open 2018 18;4(Suppl 1):e000782. Epub 2018 Oct 18.

Department of Rheumatology, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal.

Systemic sclerosis (SSc) is an orphan disease characterised by autoimmunity, fibrosis of the skin and internal organs, and vasculopathy. SSc may be associated with high morbidity and mortality. In this narrative review we summarise the results of a systematic literature research, which was performed as part of the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases project, aimed at evaluating existing clinical practice guidelines or recommendations. Only in the domains 'Vascular & Ulcers' (ie, non-pharmacological approach to digital ulcer), 'PAH' (ie, screening and treatment), 'Treatment' and 'Juveniles' (ie, evaluation of juveniles with Raynaud's phenomenon) evidence-based and consensus-based guidelines could be included. Hence there is a preponderance of unmet needs in SSc referring to the diagnosis and (non-)pharmacological treatment of several SSc-specific complications. Patients with SSc experience significant uncertainty concerning SSc-related taxonomy, management (both pharmacological and non-pharmacological) and education. Day-to-day impact of the disease (loss of self-esteem, fatigue, sexual dysfunction, and occupational, nutritional and relational problems) is underestimated and needs evaluation.
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http://dx.doi.org/10.1136/rmdopen-2018-000782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203100PMC
October 2018

One year in review 2018: systemic sclerosis.

Clin Exp Rheumatol 2018 Jul-Aug;36 Suppl 113(4):3-23. Epub 2018 Sep 28.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy.

Systemic sclerosis is a rare acquired systemic disease characterised by a complex pathogenesis and multi organ involvement. Every year the scientific world contributes to enrich the knowledge on the pathogenesis, clinical manifestations, diagnosis and treatment of this complex and severe disease. Herewith, we provide an overview of the most significant literature contributions published over the last year.
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January 2019

One year in review 2018: systemic vasculitis.

Clin Exp Rheumatol 2018 Mar-Apr;36 Suppl 111(2):12-32. Epub 2018 May 18.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy.

Systemic vasculitis are heterogeneous, complex and disabling disorders. Following the previous annual reviews of this series, this paper gives a brief overview on current knowledge about recent literature on small- and large-vessel systemic vasculitis, with a specific focus on pathogenetic and clinical aspects, novel possible disease-related biomarkers and current and future therapies that are in the pipeline.
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July 2018

Cross-Sectional Evaluation of Plasma Vitamin D Levels in a Large Cohort of Italian Patients with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections.

J Child Adolesc Psychopharmacol 2018 03 7;28(2):124-129. Epub 2017 Nov 7.

2 Rheumatology Section, Department of Internal Medicine, Transition Clinic, University of Florence , Florence, Italy .

Background: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are immune-mediated diseases characterized by obsessive-compulsive symptoms and/or tics triggered by group A Streptococcus infections. Despite the well-known action of 25-hydroxyvitamin D [25(OH)D] on different conditions driven by systemic inflammation, there are no data about the 25(OH)D status in patients with PANDAS.

Aims: To evaluate plasma 25(OH)D levels in a large cohort of children and adolescents with PANDAS and comparing the results with healthy controls.

Methods: We have evaluated plasma 25(OH)D levels in 179 Italian patients with PANDAS (49 females, 130 males, mean age at diagnosis: 101.4 ± 30.1 months) and in an age-, gender-, and body mass index-matched control group of 224 healthy subjects.

Results: Patients with PANDAS have shown more frequently reduced 25(OH)D levels (<30 ng/mL) in comparison with controls (94.6% vs. 82.5%, p = 0.0007). Patients with PANDAS had also lower levels of 25(OH)D than controls (20.4 ± 6.9 ng/mL vs. 24.8 ± 7.3 ng/mL, p < 0.0001). This difference was observed during both winter (13.7 ± 3.25 ng/mL vs. 21.4 ± 5.9 ng/mL, p < 0.0001) and summer (21.8 ± 6.5 ng/mL vs. 32.5 ± 8.7 ng/mL, p < 0.0001). Notably, serum 25(OH)D levels correlated with both number of streptococcal (strep) infections before diagnosis of PANDAS (p < 0.005) and with infection recurrence (p < 0.005).

Conclusions: PANDAS patients have reduced 25(OH)D levels, which appear related to streptococcal infections and the probability of recurrence. Further long-term studies with higher number of patients are needed to investigate and confirm this relationship.
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http://dx.doi.org/10.1089/cap.2016.0159DOI Listing
March 2018

One year in review 2017: systemic lupus erythematosus.

Clin Exp Rheumatol 2017 Jul-Aug;35(4):551-561. Epub 2017 Jul 11.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that predominately affects women. It is characterised by a broad spectrum of clinical manifestations, however, its course and organ involvement are unpredictable. Although over the last few decades an improvement in survival for SLE patients has been observed, pathogenic mechanisms underlying this disease are still unclear. Comorbidities, due to both disease and treatment, as well as multiple aspects of SLE, are under intensive investigation. Following the previous annual reviews of this series, we hereby provide a critical digest of the recent papers on SLE focusing on pathogenesis, clinical and laboratory features, as well as current and new therapeutic strategies published over the last year.
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August 2017

The "myth" of loss of angiogenesis in systemic sclerosis: a pivotal early pathogenetic process or just a late unavoidable event?

Arthritis Res Ther 2017 07 6;19(1):162. Epub 2017 Jul 6.

Department of Experimental and Clinical Medicine, Division of Rheumatology and Scleroderma Unit, Azienda Ospedaliera Universitaria Careggi, University of Florence, Viale Pieraccini 18, 50139, Florence, Italy.

Systemic sclerosis is considered a disease dominated by a "loss of angiogenesis", although in its early phases evidence indicates a disturbed angiogenic response only. In fact, microvascular changes are primarily due to endothelial cell injury, triggering downstream significant enlargement of the capillary in an inflammatory environment, followed by capillary rupture (microhemorrhages). Subsequent pro-angiogenic efforts lead to an aberrant angiogenesis and, eventually, to a total loss of vessel repair and regeneration (loss of angiogenesis). This clearly suggests that the pathogenetic process has a steady progression: from an early excessive pro-angiogenesis, to an aberrant microvascular regeneration, then ending with a late loss of angiogenesis. Herein, we suggest the loss of angiogenesis should not be considered as an overall "myth" characterizing systemic sclerosis but as a very late event of the vascular pathogenesis. Future research should be oriented essentially on the earlier phases dominated by excessive pro-angiogenesis and microvascular aberration.
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http://dx.doi.org/10.1186/s13075-017-1370-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501068PMC
July 2017

Evidence for a Derangement of the Microvascular System in Patients with a Very Early Diagnosis of Systemic Sclerosis.

J Rheumatol 2017 08 15;44(8):1190-1197. Epub 2017 May 15.

From the Department of Internal Medicine, São João Hospital Center, Al Prof Hernâni Monteiro; I3S, Instituto de Investigação e Inovação em Saúde, University of Porto; Departamento de Biomedicina, Unidade de Bioquímica, Faculty of Medicine, University of Porto; Nobre Laboratory, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Experimental and Clinical Medicine, Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi (AOUC), University of Florence; Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence; Department of Translational Medical Sciences, Centre for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.

Objective: To investigate whether patients with a very early diagnosis of systemic sclerosis (VEDOSS) may already present circulating markers and signs of microvascular dysfunction.

Methods: Serum samples were obtained from 55 patients with systemic sclerosis (SSc), 25 patients with VEDOSS, and 55 matched healthy controls (HC). Serum levels of pan-vascular endothelial growth factor (VEGF) and soluble neuropilin-1 (sNRP-1) were measured by ELISA. Human dermal microvascular endothelial cells (H-MVEC) were cultured and stimulated with SSc, VEDOSS, and HC sera. Protein expression of NRP-1 was analyzed by Western blotting, cell proliferation by 5'-bromodeoxyuridine assay, migration capacity by wound-healing assay, and capillary-like tube formation by Matrigel assay.

Results: Serum levels of pan-VEGF were increased in patients with VEDOSS and SSc versus HC (p = 0.05 and p = 0.003, respectively). Serum levels of sNRP-1 were significantly reduced in patients with VEDOSS and SSc compared with controls (p = 0.012 and p = 0.027, respectively). NRP-1 expression was decreased in H-MVEC stimulated with VEDOSS sera (p < 0.001 vs HC). Proliferation was reduced in H-MVEC stimulated either with VEDOSS or SSc sera in comparison with HC sera (p = 0.015 and p = 0.043, respectively). Wound healing was compromised in H-MVEC stimulated with VEDOSS and SSc sera versus HC sera (p < 0.01 for both). Capillarogenesis was decreased in H-MVEC stimulated with VEDOSS sera (p < 0.01) and SSc sera (p < 0.001) compared with cells stimulated with HC sera.

Conclusion: Similar to patients with SSc, patients with VEDOSS already present biological signs of endothelial dysfunction. Our data demonstrate that VEDOSS sera significantly modify endothelial cell behavior and impair the angiogenic potential of the microvascular system.
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http://dx.doi.org/10.3899/jrheum.160791DOI Listing
August 2017

One year in review 2017: systemic vasculitis.

Clin Exp Rheumatol 2017 Mar-Apr;35 Suppl 103(1):5-26. Epub 2017 Mar 29.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy.

Systemic vasculitis is a group of heterogeneous, disabling disorders. Great interest has recently arisen in pathophysiology, clinical phenotypes and therapy of large- and small-vessel vasculitis. The general work hypothesis has been to promote research focused on disease-related pathogenetic pathways, with the ultimate goal of identifying novel diagnostic and prognostic biomarkers, thus leading towards more effective targeted treatments. Following the previous annual reviews of this series, we will hereby provide a critical digest of the recent literature on small- and large-vessel systemic vasculitis, with a specific focus on novel possible disease-related biomarkers and their impact on current and future therapies.
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July 2017

Sequential nailfold videocapillaroscopy examinations have responsiveness to detect organ progression in systemic sclerosis.

Semin Arthritis Rheum 2017 08 10;47(1):86-94. Epub 2017 Feb 10.

Rheumatology A department, Cochin Hospital, Paris Descartes University, Sorbonne Paris Cité, 27 rue du faubourg Saint Jacques, 75014 Paris, France.

Objective: To determine the merit of nailfold videocapillaroscopy (NVC) to detect meaningful microvascular changes over time in patients with systemic sclerosis (SSc) and whether these changes are associated with overall disease progression and organ involvements.

Methods: A prospective cohort of 140 SSc patients was recruited over a 12-month period and was followed up on an annual basis for 3 years. Detailed NVC analysis was performed at inclusion and repeated annually. Disease progression and organ damage were defined according to validated definitions.

Results: Significant NVC changes were detected in 72 SSc patients (51%) during the follow-up period. Patients with incident or increased number of giant capillaries were less at risk to develop new digital ulcers (DU) [hazard ratio (HR) = 0.53, 95% confidence interval (CI): 0.07-0.93]. Loss of capillaries over time was confirmed as a robust and independent marker of organ progression. The reduction of the number of capillaries was associated with overall disease progression (HR = 4.35, 95% CI: 1.87-10.12), occurrence of new DU (HR = 5.33, 95% CI: 1.69-16.71), lung vascular progression (HR = 18.53, 95% CI: 1.28-78.33), progression of skin fibrosis (HR = 4.22, 95% CI: 1.24-14.36), and worsening of the Medsger severity score (HR = 5.26, 95% CI: 1.78-15.52).

Conclusion: Significant NVC changes are observed in almost half of the patients with SSc during a follow-up of 3 years. Sequential NVC examinations have responsiveness to detect disease progression. Sequential NVC is confirmed of value to monitor SSc, as well as progressive loss of capillaries over time as a potential surrogate marker for disease progression.
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http://dx.doi.org/10.1016/j.semarthrit.2017.02.006DOI Listing
August 2017

Proangiogenic effects of soluble α-Klotho on systemic sclerosis dermal microvascular endothelial cells.

Arthritis Res Ther 2017 Feb 10;19(1):27. Epub 2017 Feb 10.

Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, AOUC, Largo Brambilla 3, 50134, Florence, Italy.

Background: Systemic sclerosis (SSc) is characterized by endothelial cell (EC) apoptosis, impaired angiogenesis and peripheral microvasculopathy. Soluble α-Klotho (sKl) is a pleiotropic molecule with multiple effects on ECs, including antioxidant and vasculoprotective activities. On the EC surface, sKl interacts with vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) and transient receptor potential canonical-1 (TRPC-1) cation channel to control EC homeostasis. Here, we investigated whether sKl might act as a protective factor to improve angiogenesis in dermal microvascular endothelial cells (MVECs) from SSc patients (SSc-MVECs).

Methods: Wound healing assay was performed on healthy dermal MVECs (H-MVECs) challenged with sera from healthy controls or SSc patients with or without the addition of sKl. Capillary morphogenesis on Matrigel was assessed in H-MVECs and SSc-MVECs at basal conditions and treated with sKl, as well as in H-MVECs challenged with healthy or SSc sera in presence or absence of sKl. The expression of α-Klotho, VEGFb, VEGFR-2, TRPC-1, Ki67 and active caspase-3 in H-MVECs and SSc-MVECs was investigated by western blotting. Immunostaining for α-Klotho was performed in H-MVECs and SSc-MVECs, and in healthy and SSc skin sections.

Results: Treatment with sKl effectively counteracted the inihibitory effects of SSc sera on wound healing ability and angiogenic performance of H-MVECs. The addition of sKl significantly improved angiogenesis and maintained over time capillary-like tube formation in vitro by SSc-MVECs. Stimulation of SSc-MVECs with sKl resulted in the upregulation of the proliferation marker Ki67 in parallel with the downregulation of proapoptotic active caspase-3. The expression of α-Klotho was significantly lower in SSc-MVECs than in H-MVECs. The expression of TRPC-1 was also significantly decreased, while that of VEGFR-2 and VEGFb was significantly increased, in SSc-MVECs compared with H-MVECs. Challenge with sKl either significantly increased TRPC-1 or decreased VEGFb in SSc-MVECs. Ex vivo analyses revealed that α-Klotho immunostaining was almost absent in the dermal microvascular network of SSc skin compared with control skin.

Conclusions: Our findings provide the first evidence that α-Klotho is significantly decreased in the microvasculature in SSc skin and that sKl administration may effectively improve SSc-MVEC functions in vitro by acting as a powerful proangiogenic factor.
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http://dx.doi.org/10.1186/s13075-017-1233-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5301388PMC
February 2017

One year in review 2016: spondyloarthritis.

Clin Exp Rheumatol 2017 Jan-Feb;35(1):3-17. Epub 2017 Jan 26.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Florence, Italy.

Spondyloarthritis represents a heterogeneous group of articular inflammatory diseases that share common genetic, clinical and radiological features. Recently, novel insights into the epidemiology, pathogenesis and treatment of these diseases have been provided. Herewith, we present an overview ofthe most significant literature contributions published over the past year.
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June 2017

Effects of rituximab in connective tissue disorders related interstitial lung disease.

Clin Exp Rheumatol 2016 Sep-Oct;34 Suppl 100(5):181-185. Epub 2016 Oct 14.

Paris Descartes University, Rheumatology A Department, APHP, Cochin Hospital, Paris, France.

Objectives: Interstitial lung disease (ILD) is a key prognostic factor in connective tissue disorders (CTDs). The aim of our study was to assess the changes in pulmonary functional tests (PFTs) in various CTDs, including anti-synthetase syndrome (SYN), systemic sclerosis (SSc) and mixed connective tissue disorder (MCTD), following the use of rituximab therapy.

Methods: A multicentre retrospective analysis of patients with ILD secondary to SYN (n=15), MCTD (n=6) and SSc (n=23). PFTs were performed at baseline and at 1 and 2 years of follow-up. The primary outcome was the change in forced vital capacity (FVC) at 1 year.

Results: In the SYN population, median FVC changed from 53.0% (42.0-90.0) at baseline to 51.4% (45.6-85.0) at 1 year and 63.0 (50-88) (p=0.6) at 2 years (p=0.14). In SSc, FVC changed from 81.0% (66.0-104.0) at baseline to 89.0% (65.0-113.0) at 1 year (p=0.1) and 74.5 (50-91) at 2 years (p=0.07). In the MCTD population, FVC changed from 64.5% (63.0-68.0) at baseline to 63.0% (59.0-71.0) at 1 year (p=0.6) and 61 (59-71) after 2 years (p=0.8). DLCO showed a trend for improvement in the SYN population (p=0.06 at 1 year and 0.2 at years) while changes remain non-significant in the SSc and MCTD patients. In SYN patients, the percentage of responders at 1 year for FVC (33.3%) was greater than in SSc (9.5%) (p=0.07) and MCTD (17%) (p=0.45). RTX showed a satisfactory safety profile.

Conclusions: A trend of improvement of PFTs was observed in SYN patients although not reaching significance, while SSc and MCTD patients were stabilised.
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January 2017

Skin Telangiectasia and the Identification of a Subset of Systemic Sclerosis Patients With Severe Vascular Disease.

Arthritis Care Res (Hoboken) 2016 07;68(7):1021-7

Paris Descartes University, Sorbonne Paris Cité, Hôpital Cochin, Paris, France.

Objective: Cutaneous telangiectasia (CT) are common in systemic sclerosis (SSc) patients, but their ability to stratify patients by risk is poorly known. We aimed to determine whether the number and size of CT were associated with the pattern of microvascular lesions assessed by nailfold videocapillaroscopy (NVC) and markers reflecting the severity of SSc-related vasculopathy.

Methods: We performed a cross-sectional study, including consecutive SSc patients over a 6-month period. We also considered 3 predefined subsets of patients according to the number of hand or face CT: absence, ≤10, or >10 hand or face CT (profuse CT). Pseudotumoral CT were defined as CT with >5 mm diameter.

Results: A total of 87 patients were included, of whom 75 (86%) had CT (27 with profuse and 19 with pseudotumoral CT). Profuse and pseudotumoral CT were both associated with capillary loss (P < 0.001 and P = 0.002, respectively) and severe neoangiogenesis (P = 0.015 and P = 0.041, respectively), 2 hallmarks of the late NVC pattern. In multivariate analysis, profuse CT were independently associated with past or current digital ulcers (odds ratio [OR] 2.95 [95% confidence interval (95% CI) 1.09-19.63]), and pseudotumoral CT were independently associated with the late NVC pattern (OR 4.84 [95% CI 1.32-26.19]) and with precapillary pulmonary hypertension (OR 12.60 [95% CI 1.68-94.53]).

Conclusion: We demonstrate that the number and size of CT are associated with the most severe NVC pattern. In addition, profuse and pseudotumoral CT identify a subset of patients with a more severe vascular phenotype. Further prospective studies should determine whether CT number and size could serve as an early clinical biomarker for the development of severe vascular disease.
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http://dx.doi.org/10.1002/acr.22766DOI Listing
July 2016

Plexin-D1/Semaphorin 3E pathway may contribute to dysregulation of vascular tone control and defective angiogenesis in systemic sclerosis.

Arthritis Res Ther 2015 Aug 21;17:221. Epub 2015 Aug 21.

Department of Experimental and Clinical Medicine, Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi (AOUC), University of Florence, Viale Pieraccini 18, I-50139, Florence, Italy.

Introduction: The vascular and nervous systems have several anatomic and molecular mechanism similarities. Emerging evidence suggests that proteins involved in transmitting axonal guidance cues, including members of class III semaphorin (Sema3) family, play a critical role in blood vessel guidance during physiological and pathological vascular development. Sema3E is a natural antiangiogenic molecule that causes filopodial retraction in endothelial cells, inhibiting cell adhesion by disrupting integrin-mediated adhesive structures. The aim of the present study was to investigate whether in systemic sclerosis (SSc) Plexin-D1/Sema3E axis could be involved in the dysregulation of vascular tone control and angiogenesis.

Methods: Sema3E levels were measured by quantitative colorimetric sandwich ELISA in serum samples from 48 SSc patients, 45 subjects with primary Raynaud's phenomenon (pRP) and 48 age-matched and sex-matched healthy controls. Immunofluorescence staining on skin sections from 14 SSc patients and 12 healthy subjects was performed to evaluate Sema3E and Plexin-D1 expression. Western blotting was used to assess Plexin-D1/Sema3E axis in human SSc and healthy dermal microvascular endothelial cells (SSc-MVECs and H-MVECs, respectively) at basal condition and after stimulation with recombinant human vascular endothelial growth factor (VEGF), SSc and healthy sera. Capillary morphogenesis on Matrigel was performed on H-MVECs treated with healthy, pRP or SSc sera in the presence of Sema3E and Plexin-D1 soluble peptides.

Results: Serum Sema3E levels were significantly higher both in pRP subjects and SSc patients than in controls. In SSc, Sema3E levels were significantly increased in patients with early nailfold videocapillaroscopy (NVC) pattern compared to active/late patterns and pRP, and in patients without digital ulcers versus those with ulcers. In SSc skin, Sema3E expression was strongly increased in the microvascular endothelium. Cultured SSc-MVECs showed higher levels of phosphorylated Plexin-D1 and Sema3E expression than H-MVECs, and stimulation with SSc sera increased phosphorylated Plexin-D1 and Sema3E in H-MVECs. The addition of Sema3E-binding Plexin-D1 soluble peptide significantly attenuated the antiangiogenic effect of SSc sera on H-MVECs.

Conclusions: Our findings suggest that Plexin-D1/Sema3E axis is triggered in SSc endothelium and may have a role in the dysregulation of angiogenesis and vascular tone control by inducing neuro-vascular mechanism alterations clinically evident in particular in the early disease phases.
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http://dx.doi.org/10.1186/s13075-015-0749-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546224PMC
August 2015