Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations 2022

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (26 January 2023) | Viewed by 21730

Special Issue Editors


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Guest Editor
Division of Rheumatology, Jewish General Hospital, Director of the Canadian Scleroderma Research Group, Professor of Medicine, McGill University, Montreal, Canada
Interests: systemic sclerosis; connective tissue diseases; interstitial lung disease

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Guest Editor
Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185 Rome, Italy
Interests: connective tissue diseases; systemic sclerosis; microvascular damage; laser techniques

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Guest Editor
Unit of Angiology, AULSS 1 Dolomiti, Ospedale San Martino, Belluno, Italy
Interests: vascular damage; capillaroscopy; laser techniques; rheumatic diseases

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Guest Editor
Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of Trieste, 34149 Trieste, Italy
Interests: non-invasive ventilation (NIV); acute respiratory distress syndrome (ARDS); idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; lung cancer; COVID-19 disease
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Special Issue Information

Dear Colleagues,

Rheumatic diseases represent a heterogeneous group of severe autoimmune disorders. Patients with rheumatic diseases may present with a number of different vascular and pulmonary manifestations. The present Special Issue intends to provide an overview of the diversity and complexity of vascular and pulmonary manifestations of rheumatologic diseases in addition to gaps in knowledge to effectively manage them. Despite their significant morbidity and mortality we have only a limited understanding of their pathogenesis. We wish to provide an overview of the pathophysiology and current management approach of these disorders, highlighting tools which assist with diagnosis, risk stratification, and therapy. Finally, the importance of a multidisciplinary team using the skills of clinicians, radiologists, and pathologists will be highlighted.

Dr. Barbara Ruaro
Prof. Dr. Murray Baron
Prof. Dr. Edoardo Rosato
Prof. Dr. Romeo Martini
Prof. Dr. Marco Confalonieri
Guest Editors

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Keywords

  • rheumatic diseases
  • pathophysiology
  • therapy
  • pulmonary fibrosis
  • pulmonary arterial hypertension (PAH)
  • imaging techniques

Published Papers (9 papers)

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Editorial

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3 pages, 181 KiB  
Editorial
Special Issue “Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations 2022”
by Barbara Ruaro, Murray Baron, Edoardo Rosato, Romeo Martini and Marco Confalonieri
Pharmaceuticals 2023, 16(5), 652; https://doi.org/10.3390/ph16050652 - 27 Apr 2023
Viewed by 1241
Abstract
This Special Issue, titled “Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations”, aims to demonstrate recent and new advances and future trends in the field of rheumatic diseases [...] Full article

Research

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10 pages, 1239 KiB  
Article
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
by Barbara Ruaro, Ilaria Gandin, Riccardo Pozzan, Stefano Tavano, Chiara Bozzi, Michael Hughes, Metka Kodric, Rossella Cifaldi, Selene Lerda, Marco Confalonieri, Elisa Baratella, Paola Confalonieri and Francesco Salton
Pharmaceuticals 2023, 16(2), 307; https://doi.org/10.3390/ph16020307 - 16 Feb 2023
Cited by 9 | Viewed by 2850
Abstract
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 [...] Read more.
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. Full article
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19 pages, 3513 KiB  
Article
Nano Methotrexate versus Methotrexate in Targeting Rheumatoid Arthritis
by Heba F. Salem, Marwa Mohamed Abd El-Maboud, Amira S. A. Said, Mohamed Nabil Salem, Dina Sabry, Nadia Hussain, Omnia A. M. Abd El-Ghafar and Raghda R. S. Hussein
Pharmaceuticals 2023, 16(1), 60; https://doi.org/10.3390/ph16010060 - 31 Dec 2022
Cited by 4 | Viewed by 2187
Abstract
Nanomedicine has emerged as an important approach for targeting RA medication. Rheumatoid arthritis (RA) is a widespread autoimmune disorder marked by multiple inflamed joints. Gold nanoparticles (GNPs) have been demonstrated as efficacious nanocarriers due to their unique characteristics and the relative simplicity of [...] Read more.
Nanomedicine has emerged as an important approach for targeting RA medication. Rheumatoid arthritis (RA) is a widespread autoimmune disorder marked by multiple inflamed joints. Gold nanoparticles (GNPs) have been demonstrated as efficacious nanocarriers due to their unique characteristics and the relative simplicity of their synthesis in varied sizes; moreover, they have the capability to alleviate several inflammatory markers. The current objective was to combine methotrexate (MTX) with GNPs to overcome MTX restrictions. GNPs were fabricated by a chemical reduction technique, utilizing sodium citrate and tween 20. The MTX-GNPs formulations were characterized in vitro by % entrapment efficiency (%EE), particle size, polydispersity index (PDI) zeta potential, and % release. The MTX-GNPs formulation was administrated as an intra-articular solution, and additionally, incorporated into a Carbopol gel to investigate its anti-arthritic effectiveness and bioavailability in vivo. The results indicated that a %EE of 87.53 ± 1.10%, and a particle size of 60.62 ± 2.41 nm with a PDI of 0.31 ± 0.03, and a zeta potential of −27.80 ± 0.36 mV were optimal. The in vitro release of MTX from the MTX-GNPs formulation demonstrated that the MTX-GNPs formulation’s release was 34.91 ± 1.96% and considerably (p < 0.05) lower than that of free MTX, showing a significant difference in dissolution patterns (p < 0.05). In vivo, MTX-GNPs formulations inhibited IL-6 by 36.52%, ACCP (63.25 %), COMP (28.16%), and RANKL (63.67%), as well as elevated IL-10 by 190.18%. Transdermal MTX-GNPs decreased IL-6 by 22.52%, ACCP (56.63%), COMP (52.64%), and RANKL (79.5%), as well as increased IL-10 by 168.37%. Histological investigation supported these recent findings. Conclusions: Marked improvements in MTX anti-arthritic effects are seen when it is conjugated to GNPs. Full article
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13 pages, 774 KiB  
Article
SIGLEC-1 in Systemic Sclerosis: A Useful Biomarker for Differential Diagnosis
by Jakob Höppner, Vincent Casteleyn, Robert Biesen, Thomas Rose, Wolfram Windisch, Gerd Rüdiger Burmester and Elise Siegert
Pharmaceuticals 2022, 15(10), 1198; https://doi.org/10.3390/ph15101198 - 28 Sep 2022
Cited by 11 | Viewed by 1895
Abstract
Systemic Sclerosis (SSc) is a clinically heterogeneous disease that includes an upregulation of type I interferons (IFNs). The aim of this observational study was to investigate the IFN-regulated protein Sialic Acid–Binding Ig-like Lectin 1 (SIGLEC-1) as a biomarker for disease phenotype, therapeutic response, [...] Read more.
Systemic Sclerosis (SSc) is a clinically heterogeneous disease that includes an upregulation of type I interferons (IFNs). The aim of this observational study was to investigate the IFN-regulated protein Sialic Acid–Binding Ig-like Lectin 1 (SIGLEC-1) as a biomarker for disease phenotype, therapeutic response, and differential diagnosis in SSc. Levels of SIGLEC-1 expression on monocytes of 203 SSc patients were determined in a cross-sectional and longitudinal analysis using multicolor flow cytometry, then compared to 119 patients with other rheumatic diseases and 13 healthy controls. SSc patients higher SIGLEC-1 expression on monocytes (2097.94 ± 2134.39) than HCs (1167.45 ± 380.93; p = 0.49), but significantly lower levels than SLE (8761.66 ± 8325.74; p < 0.001) and MCTD (6414.50 ± 1846.55; p < 0.001) patients. A positive SIGELC-1 signature was associated with reduced forced expiratory volume (p = 0.007); however, we were unable to find an association with fibrotic or vascular disease manifestations. SIGLEC-1 remained stable over time and was independent of changes in immunosuppressive therapy. However, SIGLEC-1 is suitable for differentiating SSc from other connective tissue diseases. SIGLEC-1 expression on monocytes can be useful in the differential diagnosis of connective tissue disease but not as a biomarker for SSc disease manifestations or activity. Full article
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Review

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12 pages, 499 KiB  
Review
The Role of Bronchoalveolar Lavage in Systemic Sclerosis Interstitial Lung Disease: A Systematic Literature Review
by Martina Orlandi, Laura Antonia Meliante, Arianna Damiani, Lorenzo Tofani, Cosimo Bruni, Serena Guiducci, Marco Matucci-Cerinic, Silvia Bellando-Randone and Sara Tomassetti
Pharmaceuticals 2022, 15(12), 1584; https://doi.org/10.3390/ph15121584 - 19 Dec 2022
Cited by 4 | Viewed by 2386
Abstract
The role of Bronchoalveolar Lavage (BAL) in the evaluation of systemic sclerosis (SSc) interstitial lung disease (ILD) is still controversial. The aim of this systematic literature review was to investigate the use of BAL in SSc-ILD, and to focus on the pros and [...] Read more.
The role of Bronchoalveolar Lavage (BAL) in the evaluation of systemic sclerosis (SSc) interstitial lung disease (ILD) is still controversial. The aim of this systematic literature review was to investigate the use of BAL in SSc-ILD, and to focus on the pros and cons of its real-life application. Methods: PubMed, Cochrane, and Embase were questioned from inception until 31 December 2021. Results: Eighteen papers were finally analyzed. A positive correlation was observed between lung function and BAL cytology; in particular, BAL neutrophilia/granulocytosis was related to lower diffusing capacity for carbon monoxide (DLCO) values and lower forced vital capacity (FVC). Moreover, a positive correlation between BAL cellularity and high-resolution computed tomography (HRCT) findings has been reported by several authors. Cytokines, chemokines, growth factors, coagulation factors, and eicosanoids have all been shown to be present, more often and in higher quantities in SSc-ILD patients than in the health control and, in some cases, they were related to more severe pulmonary disease. There was no consensus regarding the role of BAL cellularity as a predictor of mortality. Full article
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15 pages, 564 KiB  
Review
Gastroesophageal Reflux Disease in Idiopathic Pulmonary Fibrosis: Viewer or Actor? To Treat or Not to Treat?
by Barbara Ruaro, Riccardo Pozzan, Paola Confalonieri, Stefano Tavano, Michael Hughes, Marco Matucci Cerinic, Elisa Baratella, Elisabetta Zanatta, Selene Lerda, Pietro Geri, Marco Confalonieri and Francesco Salton
Pharmaceuticals 2022, 15(8), 1033; https://doi.org/10.3390/ph15081033 - 22 Aug 2022
Cited by 20 | Viewed by 3253
Abstract
Background: Idiopathic pulmonary fibrosis (IPF) is a rare and severe disease with a median survival of ∼3 years. Several risk factors have been identified, such as age, genetic predisposition, tobacco exposure, and gastro-oesophageal reflux disease (GERD). Prevalence of GERD in IPF is high [...] Read more.
Background: Idiopathic pulmonary fibrosis (IPF) is a rare and severe disease with a median survival of ∼3 years. Several risk factors have been identified, such as age, genetic predisposition, tobacco exposure, and gastro-oesophageal reflux disease (GERD). Prevalence of GERD in IPF is high and may affect 87% of patients, of whom only half (47%) report symptoms. Objective: The aim of this study is to review current evidence regarding the correlation between GERD and IPF and to evaluate the current studies regarding treatments for GERD-IPF. Methods: A review to identify research papers documenting an association between GERD and IPF was performed. Results: We identified several studies that have confirmed the association between GERD and IPF, with an increased acid exposure, risk of gastric aspiration and bile acids levels in these patients. Few studies focused their attention on GERD treatment, showing how antiacid therapy was not able to change IPF evolution. Conclusions: This review investigating the correlation between GERD and IPF has confirmed the hypothesized association. However, further large prospective studies are needed to corroborate and elucidate these findings with a focus on preventative and treatment strategies. Full article
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Other

8 pages, 2447 KiB  
Case Report
Rituximab in Idiopathic Pulmonary Hemosiderosis in Children: A Novel and Less Toxic Treatment Option
by Suzanne W. J. Terheggen-Lagro, Eric G. Haarman, Niels W. Rutjes, J. Merlijn van den Berg and Dieneke Schonenberg-Meinema
Pharmaceuticals 2022, 15(12), 1549; https://doi.org/10.3390/ph15121549 - 13 Dec 2022
Cited by 2 | Viewed by 2337
Abstract
Idiopathic pulmonary hemosiderosis (IPH) is a rare, potentially life-threatening chronic disease. Steroids are the cornerstone of treatment, even though toxicity and side-effects are very common. Recently, rituximab (RTX) has been suggested as a treatment option, although evidence for its efficacy and long-term safety [...] Read more.
Idiopathic pulmonary hemosiderosis (IPH) is a rare, potentially life-threatening chronic disease. Steroids are the cornerstone of treatment, even though toxicity and side-effects are very common. Recently, rituximab (RTX) has been suggested as a treatment option, although evidence for its efficacy and long-term safety is lacking. We describe the disease course of two pediatric patients with IPH that were treated with RTX for over 4 years. Demographics, treatments, and clinical variables such as growth, infections, imaging follow-up by CT, and data from pulmonary function tests were retrospectively described. These are the first two cases described with a long-term follow-up of pediatric IPH patients treated with RTX. RTX was well-tolerated and prevented outbreaks of bleeding. In addition, RTX had a robust steroid-sparing effect resulting in the improvement of growth, pulmonary function, and CT abnormalities. Full article
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5 pages, 1845 KiB  
Case Report
The Challenge of Diagnosing and Managing Pulmonary Arterial Hypertension in Systemic Sclerosis with Interstitial Lung Disease
by Elisabetta Zanatta, Martina Perazzolo Marra, Giulia Famoso, Elisabetta Balestro, Chiara Giraudo, Fiorella Calabrese, Federico Rea and Andrea Doria
Pharmaceuticals 2022, 15(9), 1042; https://doi.org/10.3390/ph15091042 - 24 Aug 2022
Cited by 3 | Viewed by 1774
Abstract
Pulmonary hypertension (PH) in patients with Systemic Sclerosis (SSc) may stem from a variety of underlying causes, thus making a correct diagnosis and management difficult. The main challenges lie in the distinction between pulmonary arterial hypertension (PAH, group 1) and PH due to [...] Read more.
Pulmonary hypertension (PH) in patients with Systemic Sclerosis (SSc) may stem from a variety of underlying causes, thus making a correct diagnosis and management difficult. The main challenges lie in the distinction between pulmonary arterial hypertension (PAH, group 1) and PH due to interstitial lung disease (PH-ILD, group 3) in patients with concomitant lung fibrosis — a very common occurrence in SSc. A consensus among experts remains elusive. Some studies have suggested that among SSc patients with PH, those with an ILD extension > 20% at high-resolution computed tomography (HRCT) should be considered as affected by PH-ILD, whereas other Authors have found that a wide proportion of these patients exhibit features of both PAH and group 3 PH-ILD. We report the case of a 46-year-old male SSc patient with a stable and extensive ILD (>20%) who developed a histologically documented pulmonary vasculopathy typical of PAH and received PAH-specific treatment as bridge to transplant. Moreover, we documented PH disease course by right heart catheterization (RHC), with and without specific vasodilator therapies, which are essential in PAH but not indicated and/or harmful in PH-ILD. Full article
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11 pages, 1502 KiB  
Brief Report
Tofacitinib May Inhibit Myofibroblast Differentiation from Rheumatoid-Fibroblast-like Synoviocytes Induced by TGF-β and IL-6
by Piero Ruscitti, Vasiliki Liakouli, Noemi Panzera, Adriano Angelucci, Onorina Berardicurti, Elena Di Nino, Luca Navarini, Marta Vomero, Francesco Ursini, Daniele Mauro, Vincenza Dolo, Francesco Ciccia, Roberto Giacomelli and Paola Cipriani
Pharmaceuticals 2022, 15(5), 622; https://doi.org/10.3390/ph15050622 - 18 May 2022
Cited by 10 | Viewed by 2585
Abstract
During rheumatoid arthritis (RA), the pathogenic role of resident cells within the synovial membrane is suggested, especially for a population frequently referred to as fibroblast-like synoviocytes (FLSs). In this study, we assess the markers of myofibroblast differentiation of RA-FLSs by ex vivo observations [...] Read more.
During rheumatoid arthritis (RA), the pathogenic role of resident cells within the synovial membrane is suggested, especially for a population frequently referred to as fibroblast-like synoviocytes (FLSs). In this study, we assess the markers of myofibroblast differentiation of RA-FLSs by ex vivo observations and in vitro evaluations following the stimulation with both TGF-β and IL-6. Furthermore, we investigated the possible inhibiting role of tofacitinib, a JAK inhibitor, in this context. Myofibroblast differentiation markers were evaluated on RA synovial tissues by immune-fluorescence or immune-histochemistry. RA-FLSs, stimulated with transforming growth factor (TGF-β) and interleukin-6 (IL-6) with/without tofacitinib, were assessed for myofibroblast differentiation markers expression by qRT-PCR and Western blot. The same markers were evaluated following JAK-1 silencing by siRNA assay. The presence of myofibroblast differentiation markers in RA synovial tissue was significantly higher than healthy controls. Ex vivo, α-SMA was increased, whereas E-Cadherin decreased. In vitro, TGF-β and IL-6 stimulation of RA-FLSs promoted a significant increased mRNA expression of collagen I and α-SMA, whereas E-Cadherin mRNA expression was decreased. In the same conditions, the stimulation with tofacitinib significantly reduced the mRNA expression of collagen I and α-SMA, even if the Western blot did not confirm this finding. JAK-1 gene silencing did not fully prevent the effects of stimulation with TGF-β and IL-6 on these features. TGF-β and IL-6 stimulation may play a role in mediating myofibroblast differentiation from RA-FLSs, promoting collagen I and α-SMA while decreasing E-Cadherin. Following the same stimulation, tofacitinib reduced the increases of both collagen I and α-SMA on RA-FLSs, although further studies are needed to fully evaluate this issue and confirm our results. Full article
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