Publications by authors named "Barbara Ruaro"

54 Publications

Interstitial Lung Disease at High Resolution CT after SARS-CoV-2-Related Acute Respiratory Distress Syndrome According to Pulmonary Segmental Anatomy.

J Clin Med 2021 Sep 2;10(17). Epub 2021 Sep 2.

Department of Radiology, Cattinara Hospital, University of Trieste, Strada di Fiume 447, 34128 Trieste, Italy.

Background: The purpose of this study was to evaluate High-Resolution CT (HRCT) findings in SARS-CoV-2-related ARDS survivors treated with prolonged low-dose methylprednisolone after hospital discharge.

Methods: A total of 44 consecutive patients (M: 32, F: 12, average age: 64), hospitalised in our department from April to September 2020 for SARS-CoV-2-related ARDS, who had a postdischarge CT scan, were enrolled into this retrospective study. We reviewed the electronic medical charts to collect laboratory, clinical, and demographic data. The CT findings were evaluated and classified according to lung segmental distribution. The imaging findings were correlated with spirometry results and included ground glass opacities (GGOs), consolidations, reticulations, bronchiectasis/bronchiolectasis, linear bands, and loss of pulmonary volume.

Results: Alterations in the pulmonary parenchyma were observed in 97.7% of patients at HRCT (median time lapse between ARDS diagnosis and HRCT: 2.8 months, range 0.9 to 6.7). The most common findings were linear bands (84%), followed by GGOs (75%), reticulations (34%), bronchiolectasis (32%), consolidations (30%), bronchiectasis (30%) and volume loss (25%). They had a symmetric distribution, and both lower lobes were the most affected areas.

Conclusions: A reticular pattern with a posterior distribution was observed 3 months after discharge from severe COVID-19 pneumonia, and this differs from previously described postCOVID-19 fibrotic-like changes. We hypothesized that the systematic use of prolonged low-dose of corticosteroid could be the main reason of this different CT scan appearance.
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http://dx.doi.org/10.3390/jcm10173985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432464PMC
September 2021

THE ROLE OF CHEST CT IN DECIPHERING INTERSTITIAL LUNG INVOLVEMENT: SYSTEMIC SCLEROSIS VERSUS COVID-19.

Rheumatology (Oxford) 2021 Jul 28. Epub 2021 Jul 28.

Department of Experimental and Clinical Medicine, University of Florence, and Infectious and TropicalDiseases Unit, AOUC, Florence, Italy.

Objective: To identify the main computed tomography (CT) features that may help distinguishing a progression of interstitial lung disease (ILD) secondary to Systemic sclerosis (SSc) from COVID-19 pneumonia.

Methods: This multicentric study included 22 international readers divided in the radiologist group (RAD) and non-radiologist group (nRAD). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study.

Results: Fibrosis inside focal ground glass opacities (GGO) in the upper lobes; fibrosis in the lower lobe GGO; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONS in the lower lobes (p < 0.0001) and signs of fibrosis in GGO in the lower lobes (p < 0.0001) remained independently associated with COVID-19 pneumonia or SSc-ILD, respectively. A predictive score was created which resulted positively associated with the COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity).

Conclusion: The CT differential diagnosis between COVID-19 pneumonia and SSc-ILD is possible through the combination the proposed score and the radiologic expertise. The presence of consolidation in the lower lobes may suggest a COVID-19 pneumonia while the presence of fibrosis inside GGO may indicate a SSc-ILD.
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http://dx.doi.org/10.1093/rheumatology/keab615DOI Listing
July 2021

Correlation between Potential Risk Factors and Pulmonary Embolism in Sarcoidosis Patients Timely Treated.

J Clin Med 2021 Jun 2;10(11). Epub 2021 Jun 2.

Department of Pulmonology, University Hospital of Cattinara, 34127 Trieste, Italy.

Background: Some studies with inconclusive results have reported a link between sarcoidosis and an increased risk of pulmonary embolism (PE). This study aimed at assessing a possible correlation between potential risk factors and PE in sarcoidosis patients.

Methods: A total of 256 sarcoidosis patients (84 males and 172 females; mean age at diagnosis 49 ± 13) were enrolled after giving written informed consent. Clinical evaluations, laboratory and radiology tests were performed to evaluate the presence of pulmonary embolism.

Results: Fifteen sarcoidosis patients with PE (4 males and 11 females; mean age at diagnosis 50 ± 11), diagnosed by lung scintigraphy and 241 sarcoidosis patients without PE (80 males and 161 females; mean age at diagnosis 47 ± 13), were observed. There was a statistically significant increase of the presence of antiphospholipid antibodies in the sarcoidosis group with pulmonary embolism. There was no statistically significant difference between the two groups as to smoking habit, obesity or hereditary thrombophilia frequency ( > 0.05, respectively).

Conclusions: This study demonstrates a significant correlation between the presence of antiphospholipid antibody positivity and the pulmonary embolism events in our sarcoidosis patients. Furthermore, we propose screening for these antibodies and monitoring, aimed at timely treatment.
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http://dx.doi.org/10.3390/jcm10112462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199598PMC
June 2021

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

Evaluation of Correlations between Genetic Variants and High-Resolution Computed Tomography Patterns in Idiopathic Pulmonary Fibrosis.

Diagnostics (Basel) 2021 Apr 23;11(5). Epub 2021 Apr 23.

Department of Pulmonology, University Hospital of Cattinara, 34127 Trieste, Italy.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease (ILD). This prospective observational study aimed at the evaluation of any correlation between genetic variants associated with IPF susceptibility and high-resolution computed tomography (HRCT) patterns. It also aimed at evidencing any differences in the HRTC pattern between the familial and sporadic form at diagnosis and after two years.

Methods: A total of 65 IPF patients (mean age at diagnosis 65 ± 10) were enrolled after having given written informed consent. HRCT and genetic evaluations were performed.

Results: A total of 19 familial (mean age 62 ± 15) and 46 sporadic (mean age 70 ± 9) IPF patients were enrolled. A statistically significant difference was evidenced in the HRTC pattern at diagnosis between the two groups. Sporadic IPF patients had a predominantly usual interstitial pneumonia (UIP) pattern compared with those patients with familial IPF (60.0% vs. 21.1%, respectively). Moreover, familial IPF patients had more alternative diagnoses than those with sporadic IPF (31.6% vs. 2.2%, respectively). Furthermore, there was a slight increase in the typical UIP pattern in the familial IPF group at two years from diagnosis.

Conclusions: Genetic factors play a pivotal role in the risk of developing IPF. However, further studies are required to clarify how these genetic factors may guide clinical treatment decisions.
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http://dx.doi.org/10.3390/diagnostics11050762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146750PMC
April 2021

The Relationship between Pulmonary Damage and Peripheral Vascular Manifestations in Systemic Sclerosis Patients.

Pharmaceuticals (Basel) 2021 Apr 23;14(5). Epub 2021 Apr 23.

Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Firenze, 50121 Florence, Italy.

Systemic sclerosis (SSc) is an autoimmune disease, characterized by the presence of generalized vasculopathy and tissue fibrosis. Collagen vascular disorder in SSc is due to fibroblast and endothelial cell dysfunctions. This leads to collagen overproduction, vascular impairment and immune system abnormalities and, in the last stage, multi-organ damage. Thus, to avoid organ damage, which has a poor prognosis, all patients should be carefully evaluated and followed. This is particularly important in the initial disease phase, so as to facilitate early identification of any organ involvement and to allow for appropriate therapy. Pulmonary disease in SSc mainly involves interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). High-resolution computed tomography (HRCT) and pulmonary function tests (PFT) have been proposed to monitor parenchymal damage. Although transthoracic echocardiography is the most commonly used screening tool for PAH in SSc patients, definitive diagnosis necessitates confirmation by right heart catheterization (RHC). Moreover, some studies have demonstrated that nailfold videocapillaroscopy (NVC) provides an accurate evaluation of the microvascular damage in SSc and is able to predict internal organ involvement, such as lung impairment. This review provides an overview of the correlation between lung damage and microvascular involvement in SSc patients.
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http://dx.doi.org/10.3390/ph14050403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145021PMC
April 2021

The History and Mystery of Alveolar Epithelial Type II Cells: Focus on Their Physiologic and Pathologic Role in Lung.

Int J Mol Sci 2021 Mar 4;22(5). Epub 2021 Mar 4.

Pulmonology Department, University Hospital of Cattinara, 34128 Trieste, Italy.

Alveolar type II (ATII) cells are a key structure of the distal lung epithelium, where they exert their innate immune response and serve as progenitors of alveolar type I (ATI) cells, contributing to alveolar epithelial repair and regeneration. In the healthy lung, ATII cells coordinate the host defense mechanisms, not only generating a restrictive alveolar epithelial barrier, but also orchestrating host defense mechanisms and secreting surfactant proteins, which are important in lung protection against pathogen exposure. Moreover, surfactant proteins help to maintain homeostasis in the distal lung and reduce surface tension at the pulmonary air-liquid interface, thereby preventing atelectasis and reducing the work of breathing. ATII cells may also contribute to the fibroproliferative reaction by secreting growth factors and proinflammatory molecules after damage. Indeed, various acute and chronic diseases are associated with intensive inflammation. These include oedema, acute respiratory distress syndrome, fibrosis and numerous interstitial lung diseases, and are characterized by hyperplastic ATII cells which are considered an essential part of the epithelialization process and, consequently, wound healing. The aim of this review is that of revising the physiologic and pathologic role ATII cells play in pulmonary diseases, as, despite what has been learnt in the last few decades of research, the origin, phenotypic regulation and crosstalk of these cells still remain, in part, a mystery.
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http://dx.doi.org/10.3390/ijms22052566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961977PMC
March 2021

The Treatment of Lung Involvement in Systemic Sclerosis.

Pharmaceuticals (Basel) 2021 Feb 13;14(2). Epub 2021 Feb 13.

Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Firenze, 50121 Firenze FI, Italy.

Systemic sclerosis (SSc) patients are often affected by interstitial lung disease (ILD) and, although there have been recent treatment advances, it remains the leading cause of death among SSc, with a 10-year mortality up to 40%. African Americans and subjects with diffuse cutaneous SSc or anti-topoisomerase 1 antibodies are most commonly affected. Currently, early ILD diagnosis can be made, and it is pivotal to improve the prognosis. The diagnostic mainstay test for SSc-ILD is high-resolution computed tomography for the morphology and pulmonary function tests for the functional aspects. Treatment planning and intensity are guided by the disease severity and risk of progression. Traditionally, therapy has depended on combinations of immunosuppressants, particularly cyclophosphamide and mycophenolate mofetil, which can be supplemented by targeted biological and antifibrotic therapies. Benefits have been observed in trials on hematopoietic autologous stem cell transplantation for patients with progressive SSc, whilst lung transplantation is reserved for refractory SSc-ILD cases. Herein, recent advances in SSc-ILD treatment will be explored.
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http://dx.doi.org/10.3390/ph14020154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918752PMC
February 2021

Digital Ulcers in Systemic Sclerosis.

Presse Med 2021 Feb 3;50(1):104064. Epub 2021 Feb 3.

Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Firenze, & Department of Geriatric Medicine, Division of Rheumatology AOUC, Firenze, Italy. Electronic address:

Digital ulcers (DU) are one of the most common complication of Systemic Sclerosis (SSc)-related vasculopathy and represent an important burden for the patients as well as for the society. Still today there is no agreement on the definition, classification and cathegorization of DU even if they are of pivotal importance in clinical practice, for treatment choice and prognostic outcomes, as well as for clinical trials. DU management requires a dedicated multidisciplinary team, that must remain ever vigilant for the development of infective complications and gangrene throughout their disease course, as well as patient education that is crucial to obtain the best compliance to assure the success of the treatment. Currently several drugs are available for DU treatment but in the future, more investigations will be needed to ameliorate the approach and the systemic and local therapies.
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http://dx.doi.org/10.1016/j.lpm.2021.104064DOI Listing
February 2021

What Role Does Trabecular Bone Score Play in Chronic Inflammatory Rheumatic Diseases?

Front Med (Lausanne) 2020 30;7:600697. Epub 2020 Nov 30.

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

Patients suffering from rheumatic inflammatory diseases, e.g., systemic sclerosis, rheumatoid arthritis, and ankylosing spondylitis, are at risk of low bone mass. Dual-energy X-ray Absorptiometry (DXA) is the traditional radiological measurement technique for bone mineral density (BMD). The recently developed trabecular bone score (TBS) enhances the skeletal information provided by standard BMD. It re-analyzes the spatial dynamics of pixel intensity changes in lumbar spine DXA images, defining a quantitative index, characterizing trabecular bone microarchitecture. It has been demonstrated that low TBS values are associated with an increased incidence of fractures in patients with rheumatic diseases. These methods used together for bone damage evaluation can be of value to identify individuals who will potentially fracture. The main scientific literature on the clinical aspects of osteoporosis, including the use of TBS in evaluating this pathology, are herein reported aimed at shedding light on the role trabecular bone score plays in chronic inflammatory rheumatic diseases.
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http://dx.doi.org/10.3389/fmed.2020.600697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793927PMC
November 2020

Epithelial-Mesenchymal Transition: A Major Pathogenic Driver in Idiopathic Pulmonary Fibrosis?

Medicina (Kaunas) 2020 Nov 13;56(11). Epub 2020 Nov 13.

Pulmonology Department, University Hospital of Cattinara, 34149 Trieste, Italy.

Despite the fact that epithelial-mesenchymal transition (EMT) is a common downstream mechanism of all fibrosing diseases, whether it represents a leading process in the development of idiopathic pulmonary fibrosis has been widely discussed and is still a matter of debate. According to the most recent advances, EMT is thought to be mainly driven by the overexpression of several developmental pathways upstream of dysfunctional epithelial regeneration, which indeed normally occurs after damage and during tissue turnover. Future research should likely be directed at investigating the molecular mechanisms underlying epithelial dysfunction, in order to allow for both the removal of the wording "idiopathic" from idiopathic pulmonary fibrosis ("IPF") and for the identification of earlier and more effective therapeutic targets than the late process of fibrosis.
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http://dx.doi.org/10.3390/medicina56110608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697350PMC
November 2020

Peripheral blood perfusion in patients with systemic lupus erythematosus and in primary Raynaud's phenomenon.

Eur J Rheumatol 2021 Jan 11;8(1):7-11. Epub 2020 Nov 11.

Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, San Martino Polyclinic Hospital, University of Genova, Genoa, Italy.

Objective: This study aims to evaluate blood perfusion (BP) in various cutaneous regions of the hands and face in patients with systemic lupus erythematosus (SLE) and primary Raynaud's phenomenon (PRP) and healthy subjects (HS).

Methods: A total of 20 patients with SLE, 20 patients with PRP, and 20 HS were enrolled. BP was detected by laser speckle contrast analysis in different regions of the hand and at the facial level. The absolute nailfold capillary number (CN) was assessed by nailfold videocapillaroscopy.

Results: Patients with SLE and PRP had significantly lower BP levels than those of HS in 3 hand areas (fingertip, palm, and periungual; p<0.01). However, the SLE, PRP, and HS groups had comparable BP values at the hand dorsum and face. The BP and CN values revealed a positive correlation in the periungual, fingertip, and palm of hands (p<0.01), only in patients with SLE.

Conclusion: Our data demonstrated a correlation between functional and morphological microvascular impairment in patients with SLE.
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http://dx.doi.org/10.5152/eurjrheum.2020.20027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861644PMC
January 2021

Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS.

Intensive Care Med 2020 12 4;46(12):2284-2296. Epub 2020 Nov 4.

Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.

Current literature addressing the pharmacological principles guiding glucocorticoid (GC) administration in ARDS is scant. This paucity of information may have led to the heterogeneity of treatment protocols and misinterpretation of available findings. GCs are agonist compounds that bind to the GC receptor (GR) producing a pharmacological response. Clinical efficacy depends on the magnitude and duration of exposure to GR. We updated the meta-analysis of randomized trials investigating GC treatment in ARDS, focusing on treatment protocols and response. We synthesized the current literature on the role of the GR in GC therapy including genomic and non-genomic effects, and integrated current clinical pharmacology knowledge of various GCs, including hydrocortisone, methylprednisolone and dexamethasone. This review addresses the role dosage, timing of initiation, mode of administration, duration, and tapering play in achieving optimal response to GC therapy in ARDS. Based on RCTs' findings, GC plasma concentration-time profiles, and pharmacodynamic studies, optimal results are most likely achievable with early intervention, an initial bolus dose to achieve close to maximal GRα saturation, followed by a continuous infusion to maintain high levels of response throughout the treatment period. In addition, patients receiving similar GC doses may experience substantial between-patient variability in plasma concentrations affecting clinical response. GC should be dose-adjusted and administered for a duration targeting clinical and laboratory improvement, followed by dose-tapering to achieve gradual recovery of the suppressed hypothalamic-pituitary-adrenal (HPA) axis. These findings have practical clinical relevance. Future RCTs should consider these pharmacological principles in the study design and interpretation of findings.
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http://dx.doi.org/10.1007/s00134-020-06289-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641258PMC
December 2020

Trabecular Bone Score and Bone Quality in Systemic Lupus Erythematosus Patients.

Front Med (Lausanne) 2020 30;7:574842. Epub 2020 Sep 30.

Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine (Di.M.I.), IRCCS San Martino Polyclinic Hospital, University of Genova, Genoa, Italy.

Systemic lupus erythematosus (SLE) patients run a higher risk of having low bone mass due to multifactorial events that include physical inactivity, persistent inflammation, low vitamin D levels, and glucocorticoid treatment. This study aimed at obtaining a comparison between bone involvement in SLE patients and healthy matched subjects (HS). A total of 40 SLE females (average age 54.1 ± 16.3 years) and 40 age-gender matched HS (average age 54.2 ± 15.9 years) were enrolled after having obtained informed written consent. Bone mineral density (BMD, g/cm) of the lumbar spine (L1-L4) was analyzed by a dual-energy X-ray absorptiometry (DXA) scan (GE, Lunar Prodigy). The lumbar spine trabecular bone score (TBS) was derived for each spine DXA examination by the TBS index (TBS iNsight Medimaps). The lumbar spine TBS score was statistically significantly lower in SLE patients than in HS (0.797 ± 0.825 vs. 1.398 ± 0.207, < 0.001, as was BMD ( < 0.001) in all areas examined. SLE is associated with significant low bone mass as evidenced by DXA and TBS. This study emphasizes the importance of using DXA and TBS in the evaluation of the different aspects of bone architecture.
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http://dx.doi.org/10.3389/fmed.2020.574842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554588PMC
September 2020

Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia.

Open Forum Infect Dis 2020 Oct 12;7(10):ofaa421. Epub 2020 Sep 12.

Pulmonology Department, S. Maria della Misericordia University Hospital, Udine, Italy.

Background: In hospitalized patients with coronavirus disease 2019 (COVID-19) pneumonia, progression to acute respiratory failure requiring invasive mechanical ventilation (MV) is associated with significant morbidity and mortality. Severe dysregulated systemic inflammation is the putative mechanism. We hypothesize that early prolonged methylprednisolone (MP) treatment could accelerate disease resolution, decreasing the need for intensive care unit (ICU) admission and mortality.

Methods: We conducted a multicenter observational study to explore the association between exposure to prolonged, low-dose MP treatment and need for ICU referral, intubation, or death within 28 days (composite primary end point) in patients with severe COVID-19 pneumonia admitted to Italian respiratory high-dependency units. Secondary outcomes were invasive MV-free days and changes in C-reactive protein (CRP) levels.

Results: Findings are reported as MP (n = 83) vs control (n = 90). The composite primary end point was met by 19 vs 40 (adjusted hazard ratio [aHR], 0.41; 95% CI, 0.24-0.72). Transfer to ICU and invasive MV were necessary in 15 vs 27 ( = .07) and 14 vs 26 ( = .10), respectively. By day 28, the MP group had fewer deaths (6 vs 21; aHR, 0.29; 95% CI, 0.12-0.73) and more days off invasive MV (24.0 ± 9.0 vs 17.5 ± 12.8;  = .001). Study treatment was associated with rapid improvement in PaO:FiO and CRP levels. The complication rate was similar for the 2 groups ( = .84).

Conclusion: In patients with severe COVID-19 pneumonia, early administration of prolonged MP treatment was associated with a significantly lower hazard of death (71%) and decreased ventilator dependence. Treatment was safe and did not impact viral clearance. A large randomized controlled trial (RECOVERY trial) has been performed that validates these findings. ClinicalTrials.gov NCT04323592.
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http://dx.doi.org/10.1093/ofid/ofaa421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543560PMC
October 2020

Interstitial lung disease in patients with antisynthetase syndrome: a retrospective case series study.

Jpn J Radiol 2021 Jan 2;39(1):40-46. Epub 2020 Sep 2.

Department of Radiology, University of Trieste, Strada di Fiume 447, 34128, Trieste, Italy.

Purpose: Antisynthetase syndrome (ASS) is a rare systemic autoimmune condition associated to the presence of anti-aminoacyl-tRNA synthetase antibodies. Interstitial lung disease (ILD) is the most prevalent manifestation of ASS and is a major determinant of morbidity and mortality. The aim of this study was to describe the radiological characteristics of patients with ASS-associated-ILD in our institution.

Materials And Methods: Medical records from 2014 to 2020 were retrospectively reviewed and patients with a diagnosis of ASS and evidence of ILD on HRCT were included. HRCT images were reviewed by two thoracic radiologists in consensus. Five HRCT patterns were defined: cellular non-specific interstitial pneumonia (NSIP), organizing pneumonia (OP), mixed NSIP/OP pattern, acute interstitial pneumonia (AIP) pattern and fibrotic pattern. Descriptive statistics was calculated for all variables.

Results: Twenty-two patients with ASS who met inclusion criteria were included. The disease presented with the typical triad of ASS in 45% of patients, 55% had ILD only at the onset. Cellular NSIP was present in 27% of patients, OP in 23%, mixed NSIP/OP in 9%, AIP in 18% and a fibrotic pattern in 23%.

Conclusion: HRCT findings in ASS-associated ILD are often non-specific; nevertheless, it is important to consider this diagnosis, especially in patients presenting with acute onset of symptoms.
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http://dx.doi.org/10.1007/s11604-020-01030-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813732PMC
January 2021

Monitoring the microcirculation in the diagnosis and follow-up of systemic sclerosis patients: Focus on pulmonary and peripheral vascular manifestations.

Microcirculation 2020 11 26;27(8):e12647. Epub 2020 Jul 26.

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

Systemic sclerosis (SSc) is a connective tissue disease, characterized by vascular damage and progressive fibrosis, affecting the skin and internal organs. The vascular changes include functional and structural abnormalities in the microcirculation, which play a central role not only in diagnosis but also in the prognosis and follow-up of systemic sclerosis patients. Nailfold videocapillaroscopy (NVC) is a safe, validated, noninvasive, inexpensive, reliable, and reproducible method that allows for the evaluation of structural changes in scleroderma microangiopathy. However, capillary blood flow/perfusion cannot be measured by NVC under standard conditions and, consequently, must rely on various laser techniques and thermography for the assessment and quantification of cutaneous blood perfusion. Other emerging technologies, such as optical Doppler tomography and spectroscopy, may be used to evaluate the skin flow. This review updates current knowledge on the use of microvascular evaluation techniques in SSc, including complications such as digital ulcers and pulmonary arterial hypertension.
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http://dx.doi.org/10.1111/micc.12647DOI Listing
November 2020

Innovations in the Assessment of Primary and Secondary Raynaud's Phenomenon.

Front Pharmacol 2019 16;10:360. Epub 2019 Apr 16.

Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine (Di.M.I.), San Martino Polyclinic Hospital, University of Genova, Genova, Italy.

Raynaud's phenomenon (RP) is characterized by intense vasospasm of the digital arteries that causes characteristic color changes in fingers. There are two main types of RP: Primary RP (PRP) and Secondary RP (SRP). PRP is a benign condition. Whilst SRP is associated with several connective tissue diseases (CTD), in particular systemic sclerosis (SSc). The objectives of this report were: to present a short review on morphological (nailfold videocapillaroscopy, NVC) and functional techniques (laser tools and thermography) that allow for a correct diagnosis and treatment of RP and to investigate blood perfusion (BP) by laser speckle contrast analysis (LASCA) in different skin areas of hands and face in PRP, SRP to SSc, and healthy subjects (CNT). 31 PRP patients (LeRoy criteria), 70 SRP to SSc (ACR/EULAR criteria) and 68 CNT were enrolled. BP was assessed by LASCA at the level different areas of hands and face. NVC was performed to distinguish between PRP and SRP, and to detect the proper pattern of nailfold microangiopathy in SSc patients. Both PRP and SRP showed a statistically significant lower BP than CNT at the level of fingertips ( < 0.0001), periungual ( < 0.0001), palmar aspect of 3rd finger ( < 0.0001), and palm areas ( < 0.0001). Moreover, BP was significantly lower in PRP than in SRP to SSc with the "Early" pattern of microangiopathy in the same areas as above ( < 0.04). By considering a small cohort of patients, BP of hands was found lower in PRP than in SSc patients with the "Early" NVC pattern of microangiopathy.
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http://dx.doi.org/10.3389/fphar.2019.00360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495407PMC
April 2019

Correlation between circulating fibrocytes and dermal thickness in limited cutaneous systemic sclerosis patients: a pilot study.

Rheumatol Int 2019 Aug 6;39(8):1369-1376. Epub 2019 May 6.

Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, IRCCS San Martino Polyclinic Hospital, Viale Benedetto XV, No 6, 16132, Genoa, Italy.

The objective is to detect any possible correlation between the modified Rodnan skin score (mRSS) and dermal thickness (DT) measured by skin high-frequency ultrasound (US) and the percentage of circulating fibrocytes in patients with limited cutaneous systemic sclerosis (lcSSc). Eight lcSSc patients and five healthy subjects (control group, CNT) were enrolled. The skin involvement was evaluated by mRSS and US (18 and 22 MHz probes) in all 13 subjects in the 17 standard skin areas evaluated by mRss. Circulating fibrocytes were isolated from the peripheral blood mononuclear cells (PBMCs) of all lcSSc patients and the CNT group to analyze their percentage at baseline time (T0) when the experiments started with PBMCs' isolation and collection and after 8 days of culture (T8). Non-parametric tests were used for the statistical analysis. A positive correlation between the percentage of circulating fibrocytes at T0, mRSS (p = 0.04 r = 0.96), and DT-US, evaluated by the 22 MHz and the 18 MHz probes (p = 0.03, r = 0.66 and p = 0.05, r = 0.52, respectively), was observed in lcSSc patients. Conversely, at T8, there was no correlation (p > 0.05) between these parameters in lcSSc group. In the CNT group, no correlations between mRSS or DT-US and the percentage of circulating fibrocytes were observed both at T0 and T8. The study shows the presence of a significant relationship between the percentage of circulating fibrocytes and DT, as evidenced by both mRSS and US, in limited cutaneus SSc. This observation may well suggest the reasonable hypothesis of a crucial contribution of circulating fibrocytes to skin fibrosis progression, which might be considered as further biomarkers.
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http://dx.doi.org/10.1007/s00296-019-04315-7DOI Listing
August 2019

Aminaphtone Efficacy in Primary and Secondary Raynaud's Phenomenon: A Feasibility Study.

Front Pharmacol 2019 4;10:293. Epub 2019 Apr 4.

Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, IRCCS San Martino Polyclinic Hospital, Genova, Italy.

Objectives: The aim of this six-month open feasibility study was to evaluate skin blood perfusion and clinical symptom changes during aminaphtone treatment in patients with either primary or secondary Raynaud's phenomenon to systemic sclerosis.

Methods: Ninety-two patients referring for Raynaud's phenomenon have been enrolled in November during routine clinical assessment, after informed consent. Aminaphtone was administered 75 mg twice daily in addition to current treatments to forty-six patients. Skin blood perfusion was measured by Laser Speckle Contrast Analysis (LASCA) at the level of fingertips, periungual areas, dorsum and palm of hands, and face at baseline (W0), after one (W1), four (W4), twelve (W12) and twenty-four (W24) weeks of treatment. Raynaud's condition score (RCS) and both frequency and duration of Raynaud's attacks were assessed at the same time.

Results: Compared with the control group, despite colder period of the year, aminaphtone treated patients showed a progressive statistically significant increase of blood perfusion, as well as a decrease of RCS, frequency of Raynaud's attacks/day and their duration, from W0 to W12 in all skin areas. From W12 to W24 no further increase of blood perfusion was observed. The results were similar in both primary and secondary Raynaud's phenomenon patients. Five weeks after aminaphtone discontinuation blood perfusion values were significantly higher than those at baseline in the majority of skin areas.

Conclusion: This study demonstrates that aminaphtone treatment increases skin blood perfusion and improves Raynaud's phenomenon clinical symptoms, with sustained efficacy up to 6 months, even in patients with systemic sclerosis. A randomized, blind, controlled, clinical trial including a larger number of subjects is advisable to confirm these early results.
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http://dx.doi.org/10.3389/fphar.2019.00293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458253PMC
April 2019

The impact of transducer frequency in ultrasound evaluation of subclinical skin involvement in limited cutaneous systemic sclerosis patients.

Clin Exp Rheumatol 2019 Jul-Aug;37 Suppl 119(4):147-148. Epub 2019 Feb 25.

Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, San Martino Polyclinic Hospital, Genoa, Italy.

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October 2019

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

Dickkopf-1 (Dkk-1) serum levels in systemic sclerosis and rheumatoid arthritis patients: correlation with the Trabecular Bone Score (TBS).

Clin Rheumatol 2018 Nov 6;37(11):3057-3062. Epub 2018 Oct 6.

Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine (Di.M.I.), Polyclinic San Martino Hospital, University of Genova, Viale Benedetto XV, no. 6, 16132, Genoa, Italy.

The aim of this research was to determine any correlations between Dickkopf-1 serum levels (Dkk-1, a natural inhibitor of the Wnt signaling pathway promoting osteoclastogenesis) and the Trabecular Bone Score (TBS), in systemic sclerosis (SSc) and rheumatoid arthritis (RA) patients. It also aimed at determining any difference in Dkk-1 serum levels between SSc and RA patients and a control group (CNT) of healthy subjects. A prospective study was carried out in 60 SSc and 60 RA patients and 60 CNT. Dkk-1 serum levels were evaluated by the ELISA method (Quantikine Human Dkk-1 Immunoassay, R&D System, Minneapolis, USA). The severity of microvascular damage was evaluated by nailfold videocapillaroscopy (NVC patterns: "Early," "Active," "Late"), in the SSc patients. TBS analysis and bone mineral density (BMD, g/cm) were measured in all patients/subjects. The SSc patients showed higher Dkk-1 serum levels than RA (p < 0.004) and CNT (p < 0.0001) patients. SSc patients, showing the "Late" NVC pattern had statistically higher Dkk-1 serum levels than patients with either the "Active" or "Early" (p < 0.004) patterns. Only in the "Late" NVC pattern group of SSc patients was there a significant negative correlation between Dkk-1 and TBS values (p < 0.0001). The increased Dkk-1 serum levels and decreased TBS values observed suggest a diffuse bone damage in SSc patients with advanced disease, as demonstrated by the concomitant presence of the "Late" NVC pattern. Moreover, the bone remodeling in SSc seems even higher than that in RA patients.
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http://dx.doi.org/10.1007/s10067-018-4322-9DOI Listing
November 2018

A circulating cell population showing both M1 and M2 monocyte/macrophage surface markers characterizes systemic sclerosis patients with lung involvement.

Respir Res 2018 Sep 24;19(1):186. Epub 2018 Sep 24.

Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Polyclinic San Martino Hospital, Genoa, Italy.

Background: Systemic sclerosis (SSc) is a disorder characterized by immune system alterations, vasculopathy and fibrosis. SSc-related interstitial lung disease (ILD) represents a common and early complication, being the leading cause of mortality. Monocytes/macrophages seem to have a key role in SSc-related ILD. Interestingly, the classically (M1) and alternatively (M2) activated monocyte/macrophage phenotype categorization is currently under revision. Our aim was to evaluate if circulating monocyte/macrophage phenotype could be used as biomarker for lung involvement in SSc. To this purpose we developed a wide phenotype characterization of circulating monocyte/macrophage subsets in SSc patients and we evaluated possible relations with lung involvement parameter values.

Methods: A single centre cross-sectional study was performed in fifty-five consecutive SSc patients, during the year 2017. All clinical and instrumental tests requested for SSc follow up and in particular, lung computed tomography (CT) scan, pulmonary function tests (PFTs), Doppler echocardiography with systolic pulmonary artery pressure (sPAP) measurement, blood pro-hormone of brain natriuretic peptide (pro-BNP) evaluation, were performed in each patient in a maximum one-month period. Flow cytometry characterization of circulating cells belonging to the monocyte/macrophage lineage was performed using specific M1 (CD80, CD86, TLR2 and TLR4) and M2 surface markers (CD204, CD163 and CD206). Non-parametric tests were used for statistical analysis.

Results: A higher percentage of circulating CD204CD163CD206TLR4CD80CD86 and CD14CD206CD163CD204TLR4CD80CD86 mixed M1/M2 monocyte/macrophage subsets, was identified to characterize patients affected by SSc-related ILD and higher systolic pulmonary artery pressure. Mixed M1/M2 monocyte/macrophage subset showed higher percentages in patients positive for anti-topoisomerase antibody, a known lung involvement predictor.

Conclusions: The present study shows for the first time, through a wide flow cytometry surface marker analysis, that higher circulating mixed M1/M2 monocyte/macrophage cell percentages are associated with ILD, sPAP and anti-topoisomerase antibody positivity in SSc, opening the path for research on their possible role as pathogenic or biomarker elements for SSc lung involvement.
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http://dx.doi.org/10.1186/s12931-018-0891-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154930PMC
September 2018

Effects of CTLA4-Ig treatment on circulating fibrocytes and skin fibroblasts from the same systemic sclerosis patients: an in vitro assay.

Arthritis Res Ther 2018 07 27;20(1):157. Epub 2018 Jul 27.

Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genoa, IRCCS San Martino Polyclinic Hospital, Viale Benedetto XV, 616132, Genoa, Italy.

Background: Systemic sclerosis (SSc) is characterized by vasculopathy and progressive fibrosis. CTLA4-Ig (abatacept) is able to interact with the cell surface costimulatory molecule CD86 and downregulate the target cell. The aim of this study was to evaluate the in-vitro effects of CTLA4-Ig treatment on circulating fibrocytes and skin fibroblasts isolated from the same SSc patient.

Methods: Circulating fibrocytes and skin fibroblasts were obtained from eight SSc patients with "limited" cutaneous involvement and from four healthy subjects (HSs). Samples were analyzed by fluorescence-activated cell sorter analysis (FACS) at baseline (T0) and after 8 days of culture (T8) for CD45, collagen type I (COL I), CXCR4, CD14, CD86, and HLA-DRII expression. Circulating fibrocytes were treated for 3 h and skin fibroblasts for 24/48 h with CTLA4-Ig (10, 50, 100, 500 μg/ml). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed for CD86, COL I, FN, TGFβ, αSMA, S100A4, CXCR2, CXCR4, CD11a, and Western blotting was performed for COL I and FN.

Results: Using qRT-PCR, the T8-cultured SSc circulating fibrocytes which had not been treated with CTLA4-Ig showed higher gene expression for CD86, αSMA, S100A4, TGFβ, and COL I compared with HS circulating fibrocytes. Interestingly, αSMA/COL I gene expression was significantly lower only in the SSc circulating fibrocytes treated with CTLA4-Ig for 3 h (p < 0.01, p < 0.05). On the contrary, no effects were observed for either SSc or HS skin fibroblasts after CTLA4-Ig treatment. COL I and FN protein expression was unchanged in both SSc and HS skin fibroblasts by Western blot.

Conclusions: Circulating fibrocytes seem to be more responsive to CTLA4-Ig treatment than skin fibroblasts from the same SSc patient, likely due to their higher expression of CD86. CTLA4-Ig treatment might downregulate the fibrotic process in SSc patients by downregulating the fibrocytes, circulating progenitor cells.
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http://dx.doi.org/10.1186/s13075-018-1652-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062881PMC
July 2018

Increase in circulating cells coexpressing M1 and M2 macrophage surface markers in patients with systemic sclerosis.

Ann Rheum Dis 2018 12 16;77(12):1842-1845. Epub 2018 Jul 16.

Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Polyclinic San Martino Hospital, Genoa, Italy.

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http://dx.doi.org/10.1136/annrheumdis-2018-213648DOI Listing
December 2018

Reply.

Arthritis Care Res (Hoboken) 2019 05 8;71(5):695-696. Epub 2019 Apr 8.

Centro Hospitalar e Universitário de Coimbra,and University of Coimbra, Coimbra, Portugal.

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http://dx.doi.org/10.1002/acr.23689DOI Listing
May 2019

Is laser speckle contrast analysis (LASCA) the new kid on the block in systemic sclerosis? A systematic literature review and pilot study to evaluate reliability of LASCA to measure peripheral blood perfusion in scleroderma patients.

Autoimmun Rev 2018 Aug 6;17(8):775-780. Epub 2018 Jun 6.

Department of Rheumatology, Ghent University Hospital, Department of Internal Medicine, Ghent University, Corneel Heymanslaan 10, Ghent, Belgium. Electronic address:

Objectives: A reliable tool to evaluate flow is paramount in systemic sclerosis (SSc). We describe herein on the one hand a systematic literature review on the reliability of laser speckle contrast analysis (LASCA) to measure the peripheral blood perfusion (PBP) in SSc and perform an additional pilot study, investigating the intra- and inter-rater reliability of LASCA.

Methods: A systematic search was performed in 3 electronic databases, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In the pilot study, 30 SSc patients and 30 healthy subjects (HS) underwent LASCA assessment. Intra-rater reliability was assessed by having a first anchor rater performing the measurements at 2 time-points and inter-rater reliability by having the anchor rater and a team of second raters performing the measurements in 15 SSc and 30 HS. The measurements were repeated with a second anchor rater in the other 15 SSc patients, as external validation.

Results: Only 1 of the 14 records of interest identified through the systematic search was included in the final analysis. In the additional pilot study: intra-class correlation coefficient (ICC) for intra-rater reliability of the first anchor rater was 0.95 in SSc and 0.93 in HS, the ICC for inter-rater reliability was 0.97 in SSc and 0.93 in HS. Intra- and inter-rater reliability of the second anchor rater was 0.78 and 0.87.

Conclusions: The identified literature regarding the reliability of LASCA measurements reports good to excellent inter-rater agreement. This very pilot study could confirm the reliability of LASCA measurements with good to excellent inter-rater agreement and found additionally good to excellent intra-rater reliability. Furthermore, similar results were found in the external validation.
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http://dx.doi.org/10.1016/j.autrev.2018.01.023DOI Listing
August 2018
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