Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations

This book aims to summarize the latest advances in the rheumatic diseases, particularly regarding their pathophysiology and targeted therapy, with a focus on the recent efforts of vascular and pulmonary manifestations in order to anticipate new and future directions of these research topics. Rheumatic diseases represent a heterogeneous group of severe autoimmune disorders. The present Special Issue aims to provide an overview of the diversity and complexity of vascular and pulmonary manifestations of rheumatic diseases and to highlight gaps in our knowledge of how to effectively manage them. Despite their significant morbidity, we have a limited understanding of their pathogenesis. The eleven published articles reported here underline the complexity of rheumatic diseases and the difficulty of managing them. The manuscripts provide an overview of the pathophysiology and current management approach of these disorders, highlighting tools that assist with diagnosis, risk stratification, and therapy. A significant number of articles have reported innovative and effective treatments for the most frequent and debilitating complications of rheumatic diseases. The book emphasizes the importance of multidisciplinary teams using the skills of laboratory researchers, clinicians, radiologists, and pathologists. Furthermore, recent findings are presented and discussed, highlighting strategies to combat worsening symptoms of rheumatic diseases. The research described in this book provide an extremely useful example of the results achieved in the field of anti-rheumatic drug development. Detailed information on new breakthroughs can be found in this book. We strongly encourage a wide group of readers to explore the book that we are presenting for inspiration to develop new approaches to the diagnosis and treatment of rheumatic diseases

Clinical Evaluation of the ButterfLife Device for Simultaneous Multiparameter Telemonitoring in Hospital and Home Settings

We conducted a two-phase study to test the reliability and usability of an all-in-one artificial intelligence-based device (ButterfLife), which allows simultaneous monitoring of five vital signs. The first phase of the study aimed to test the agreement between measurements performed with ButterfLife vs. standard of care (SoC) in 42 hospitalized patients affected by acute respiratory failure. In this setting, the greatest discordance between ButterfLife and SoC was in respiratory rate (mean difference -4.69 bpm). Significantly close correlations were observed for all parameters except diastolic blood pressure and oxygen saturation (Spearman's Rho -0.18 mmHg; p = 0.33 and 0.20%; p = 0.24, respectively). The second phase of the study was conducted on eight poly-comorbid patients using ButterfLife at home, to evaluate the number of clinical conditions detected, as well as the patients' compliance and satisfaction. The average proportion of performed tests compared with the scheduled number was 67.4%, and no patients reported difficulties with use. Seven conditions requiring medical attention were identified, with a sensitivity of 100% and specificity of 88.9%. The median patient satisfaction was 9.5/10. In conclusion, ButterfLife proved to be a reliable and easy-to-use device, capable of simultaneously assessing five vital signs in both hospital and home settings

Correlation between Microvascular Damage and Internal Organ Involvement in Scleroderma: Focus on Lung Damage and Endothelial Dysfunction

Background. Systemic sclerosis (SSc) is an incurable connective tissue disease characterized by decreased peripheral blood perfusion due to microvascular damage and skin thickening/hardening. The microcirculation deficit is typically secondary to structural vessel damage, which can be assessed morphologically and functionally in a variety of ways, exploiting different technologies. Objective. This paper focuses on reviewing new studies regarding the correlation between microvascular damage, endothelial dysfunction, and internal organ involvement, particularly pulmonary changes in SSc. Methods. We critically reviewed the most recent literature on the correlation between blood perfusion and organ involvement. Results. Many papers have demonstrated the link between structural microcirculatory damage and pulmonary involvement; however, studies that have investigated correlations between microvascular functional impairment and internal organ damage are scarce. Overall, the literature supports the correlation between organ involvement and functional microcirculatory impairment in SSc patients. Conclusions. Morphological and functional techniques appear to be emerging biomarkers in SSc, but obviously need further investigation

Different Methods to Improve the Monitoring of Noninvasive Respiratory Support of Patients with Severe Pneumonia / ARDS Due to COVID-19: An Update.

The last guidelines for the hospital care of patients affected by coronavirus disease-2019 (COVID-19)-related acute respiratory failure have moved towards a widely accepted use of noninvasive respiratory support (NIRS) as opposed to early intubation at the pandemic onset. The establishment of severe COVID-19 pneumonia goes through different pathophysiological phases that partially resemble typical acute respiratory distress syndrome (ARDS) and have been categorized into different clinicalradiological phenotypes. These can variably benefit on the application of external positive end-expiratory pressure (PEEP) during noninvasive mechanical ventilation, mainly due to variable levels of lung recruit ability and lung compliance during different phases of the disease. A growing body of evidence suggests that intense respiratory effort producing excessive negative pleural pressure swings (Ppl) plays a critical role in the onset and progression of lung and diaphragm damage in patients treated with noninvasive respiratory support. Routine respiratory monitoring is mandatory to avoid the nasty continuation of NIRS in patients who are at higher risk for respiratory deterioration and could benefit from early initiation of invasive mechanical ventilation instead. Here we propose different monitoring methods both in the clinical and experimental settings adapted for this purpose, despite further research is required to allow their extensive application in clinical practice. We reviewed the needs and available tools for a clinical-physiological monitoring that aims at optimizing the ventilatory management of patients affected by acute respiratory distress syndrome due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection

Nintedanib in Idiopathic Pulmonary Fibrosis: Tolerability and Safety in a Real Life Experience in a Single Centre in Patients also Treated with Oral Anticoagulant Therapy

Idiopathic pulmonary fibrosis (IPF) is a rare and severe disease with a median survival of ~3 years. Nintedanib (NTD) has been shown to be useful in controlling interstitial lung disease (ILD) in IPF. Here we describe the experience of NTD use in IPF in a real-life setting. Objective. Our objective was to examine the safety profile and efficacy of nintedanib even in subjects treated with anticoagulants. Clinical data of patients with IPF treated with NTD at our center were retrospectively evaluated at baseline and at 6 and 12 months after the introduction of NTD. The following parameters were recorded: IPF clinical features, NTD tolerability, and pulmonary function tests (PFT) (i.e., Forced Vital Capacity (FVC) and carbon monoxide diffusing capacity (DLCO)). In total, 56 IPF patients (34% female and 66% male, mean onset age: 71 ± 11 years, mean age at baseline: 74 ± 9 years) treated with NTD were identified. At enrollment, HRCT showed an UIP pattern in 45 (80%) and a NSIP in 11 (20%) patients. For FVC and FEV1 we found no significant change between baseline and 6 months, but for DLCO we observed a decrease (p = 0.012). We identified a significant variation between baseline and 12 months for FEV1 (p = 0.039) and for DLCO (p = 0.018). No significant variation was observed for FVC. In the cohort, 18 (32%) individuals suspended NTD and 10 (18%) reduced the dosage. Among individuals that suspended the dosage, 14 (78%) had gastrointestinal (GI) collateral effects (i.e., diarrhea being the most common complaint (67%), followed by nausea/vomiting (17%) and weight loss (6%). Bleeding episodes have also not been reported in patients taking anticoagulant therapy. (61%). One patient died within the first 6 months and two subjects died within the first 12 months. In a real-life clinical scenario, NTD may stabilize the FVC values in IPF patients. However, GI side effects are frequent and NTD dose adjustment may be necessary to retain the drug in IPF patients. This study confirms the safety of NTD, even in patients treated with anticoagulant drugs

Chronic Thromboembolic Pulmonary Hypertension: An Observational Study

Background and Objectives: Chronic thromboembolic pulmonary hypertension (CTEPH) has a high mortality. The treatment of CTEPH could be balloon pulmonary angioplasty (BPA), medical (MT) or pulmonary endarterectomy (PEA). This study aims to assess the clinical characteristics of CTEPH patients, surgically or medically treated, in a pulmonology referral center. Materials and Methods: A total of 124 patients with PH with suspected CTEPH (53 male subjects and 71 female subjects; mean age at diagnosis 67 ± 6) were asked to give informed consent and then were evaluated. The presence of CTEPH was ascertained by medical evaluations, radiology and laboratory tests. Results: After the evaluation of all clinical data, 65 patients met the inclusion criteria for CTEPH and they were therefore enrolled (22 males and 43 females; mean age at diagnosis was 69 ± 8). 26 CTEPH patients were treated with PEA, 32 with MT and 7 with BPA. There was a statistically significant age difference between the PEA and MT groups, at the time of diagnosis, the PEA patients were younger than the MT patients, whereas there was no statistically significant difference in other clinical characteristics (e.g., smoking habit, thrombophilia predisposition), as well as functional and hemodynamic parameters (e.g., 6-min walk test, right heart catheterization). During three years of follow-up, no patients in the PEA groups died; conversely, eleven patients in the MT group died during the same period (p < 0.05). Furthermore, a significant decrease in plasma BNP values and an increase in a meter at the six-minute walk test, 1 and 3 years after surgery, were observed in the PEA group (p < 0.05). Conclusions: This study seems to confirm that pulmonary endarterectomy (PEA) can provide an improvement in functional tests in CTEP

Prolonged higher dose methylprednisolone vs. conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS)

Background: Dysregulated systemic inflammation is the primary driver of mortality in severe coronavirus disease 2019 (COVID-19) pneumonia. Current guidelines favour a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg daily. A comparative randomised controlled trial (RCT) with a higher dose and a longer duration of intervention was lacking. Methods: We conducted a multicentre, open-label RCT to investigate methylprednisolone 80 mg as a continuous daily infusion for 8 days followed by slow tapering versus dexamethasone 6 mg once daily for up to 10 days in adult patients with COVID-19 pneumonia requiring oxygen or noninvasive respiratory support. The primary outcome was reduction in 28-day mortality. Secondary outcomes were mechanical ventilation-free days at 28 days, need for intensive care unit (ICU) referral, length of hospitalisation, need for tracheostomy, and changes in C-reactive protein (CRP) levels, arterial oxygen tension/inspiratory oxygen fraction (P aO2 /F IO2 ) ratio and World Health Organization Clinical Progression Scale at days 3, 7 and 14. Results: 677 randomised patients were included. Findings are reported as methylprednisolone (n=337) versus dexamethasone (n=340). By day 28, there were no significant differences in mortality (35 (10.4%) versus 41 (12.1%); p=0.49) nor in median mechanical ventilation-free days (median (interquartile range (IQR)) 23 (14) versus 24 (16) days; p=0.49). ICU referral was necessary in 41 (12.2%) versus 45 (13.2%) (p=0.68) and tracheostomy in 8 (2.4%) versus 9 (2.6%) (p=0.82). Survivors in the methylprednisolone group required a longer median (IQR) hospitalisation (15 (11) versus 14 (11) days; p=0.005) and experienced an improvement in CRP levels, but not in P aO2 /F IO2 ratio, at days 7 and 14. There were no differences in disease progression at the prespecified time-points. Conclusion: Prolonged, higher dose methylprednisolone did not reduce mortality at 28 days compared with conventional dexamethasone in COVID-19 pneumonia

Complement protein C1q stimulates hyaluronic acid degradation via gC1qR/HABP1/p32 in malignant pleural mesothelioma

Complement component C1q can act as a pro-tumorigenic factor in the tumor microenvironment (TME). The TME in malignant pleural mesothelioma (MPM) is rich in C1q and hyaluronic acid (HA), whose interaction enhances adhesion, migration and proliferation of malignant cells. HA-bound C1q is also capable of modulating HA synthesis. Thus, we investigated whether HA-C1q interaction would affect HA degradation, analyzing the main degradation enzymes, hyaluronidase (HYAL)1 and HYAL2, and a C1q receptor candidate. We first proceeded with the characterization of HYALs in MPM cells, especially HYAL2, since bioinformatics survival analysis revealed that higher HYAL2 mRNA levels have an unfavorable prognostic index in MPM patients. Interestingly, Real-Time quantitative PCR, flow cytometry and Western blot highlighted an upregulation of HYAL2 after seeding of primary MPM cells onto HA-bound C1q. In an attempt to unveil the receptors potentially involved in HA-C1q signaling, a striking co-localization between HYAL2 and globular C1q receptor/HABP1/p32 (gC1qR) was found by immunofluorescence, surface biotinylation and proximity ligation assays. RNA interference experiments revealed a potentially regulatory function exerted by gC1qR on HYAL2 expression, since C1QBP (gene for gC1qR) silencing unexpectedly caused HYAL2 downregulation. In addition, the functional blockage of gC1qR by a specific antibody hindered HA-C1q signaling and prevented HYAL2 upregulation. Thus, C1q-HA interplay is responsible for enhanced HYAL2 expression, suggesting an increased rate of HA catabolism and the release of pro-inflammatory and pro-tumorigenic HA fragments in the MPM TME. Our data support the notion of an overall tumor-promoting property of C1q. Moreover, the overlapping localization and physical interaction between HYAL2 and gC1qR suggests a potential regulatory effect of gC1qR within a putative HA-C1q macromolecular complex

A New Thiopurine S-Methyltransferase Haplotype Associated With Intolerance to Azathioprine

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The CDC42-Interacting Protein 4 Controls Epithelial Cell Cohesion and Tumor Dissemination

SummaryThe role of endocytic proteins and the molecular mechanisms underlying epithelial cell cohesion and tumor dissemination are not well understood. Here, we report that the endocytic F-BAR-containing CDC42-interacting protein 4 (CIP4) is required for ERBB2- and TGF-β1-induced cell scattering, breast cancer (BC) cell motility and invasion into 3D matrices, and conversion from ductal breast carcinoma in situ to invasive carcinoma in mouse xenograft models. CIP4 promotes the formation of an E-cadherin-CIP4-SRC complex that controls SRC activation, E-cadherin endocytosis, and localized phosphorylation of the myosin light chain kinase, thereby impinging on the actomyosin contractility required to generate tangential forces to break cell-cell junctions. CIP4 is upregulated in ERBB2-positive human BC, correlates with increased distant metastasis, and is an independent predictor of poor disease outcome in subsets of BC patients. Thus, it critically controls cell-cell cohesion and is required for the acquisition of an invasive phenotype in breast tumors