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

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 38039

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Dr. Barbara Ruaro

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Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of Trieste, 34149 Trieste, Italy
Interests: interstitial lung disease; idiopathic pulmonary fibrosis; rheumatic diseases; pulmonary arterial hypertension (PAH)
Special Issues, Collections and Topics in MDPI journals

Dr. Francesco Salton

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Department of Pulmonology, University Hospital of Cattinara, Trieste, Italy
Interests: non-invasive ventilation (NIV); COVID-19 disease; lung cancer; acute respiratory distress syndrome (ARDS); idiopathic pulmonary fibrosis
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Dr. Paola Confalonieri

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SC Pneumologia, ASUGI, Trieste, Italy
Interests: pulmonary medicine; connective tissue diseases; rheumatic diseases; interstitial lung disease; nonspecific interstitial pneumonia; cell culture
Special Issues, Collections and Topics in MDPI journals

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 and gaps in knowledge to effectively manage them. Despite their significant morbidity and mortality, we have limited understanding of their pathogenesis. We would like 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 working using the skills of clinicians, radiologists, and pathologists will be highlighted.

Dr. Barbara Ruaro
Dr. Francesco Salton
Dr. Paola Confalonieri
Guest Editors

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Keywords

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

Published Papers (11 papers)

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Research

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9 pages, 601 KiB

Open AccessArticle

The Effect of Transcutaneous Vagus Nerve Stimulation in Patients with Polymyalgia Rheumatica

by Jacob Venborg, Anne-Marie Wegeberg, Salome Kristensen, Birgitte Brock, Christina Brock and Mogens Pfeiffer-Jensen

Pharmaceuticals 2021, 14(11), 1166; https://doi.org/10.3390/ph14111166 - 16 Nov 2021

Cited by 3 | Viewed by 2155

Abstract

(1) Polymyalgia rheumatica (PMR) is an inflammatory disease characterised by pain, morning stiffness, and reduced quality of life. Recently, vagus nerve stimulation (VNS) was shown to have anti-inflammatory effects. We aimed to examine the effect of transcutaneous VNS (t-VNS) on PMR. (2) Fifteen treatment-naïve PMR patients completed the study. Patients underwent a 5-day protocol, receiving 2 min of t-VNS stimulation bilaterally on the neck, three times daily. Cardiac vagal tone (CVT) measured on a linear vagal scale (LVS), blood pressure, heart rate, patient-reported outcome, and biochemical changes were assessed. (3) t-VNS induced a 22% increase in CVT at 20 min after initial stimulations compared with baseline (3.4 ± 2.2 LVS vs. 4.1 ± 2.9 LVS, p = 0.02) and was accompanied by a 4 BPM reduction in heart rate (73 ± 11 BPM vs. 69 ± 9, p < 0.01). No long-term effects were observed. Furthermore, t-VNS induced a 14% reduction in the VAS score for the hips at day 5 compared with the baseline (5.1 ± 2.8 vs. 4.4 ± 2.8, p = 0.04). No changes in CRP or proinflammatory analytes were observed. (4) t-VNS modulates the autonomic nervous system in patients with PMR, but further investigation of t-VNS in PMR patients is warranted. Full article

(This article belongs to the Special Issue Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations)

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15 pages, 1275 KiB

Open AccessArticle

The Probiotic VSL#3^® Does Not Seem to Be Efficacious for the Treatment of Gastrointestinal Symptomatology of Patients with Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

by Elena P. Calandre, Javier Hidalgo-Tallon, Rocio Molina-Barea, Fernando Rico-Villademoros, Cristina Molina-Hidalgo, Juan M. Garcia-Leiva, Maria Dolores Carrillo-Izquierdo and Mahmoud Slim

Pharmaceuticals 2021, 14(10), 1063; https://doi.org/10.3390/ph14101063 - 19 Oct 2021

Cited by 5 | Viewed by 3467

Abstract

Gastrointestinal symptomatology is frequent among patients with fibromyalgia, which increases disease burden and lacks specific treatment, either pharmacological or non-pharmacological. We aimed to evaluate the efficacy and tolerability of a multi-strain probiotic, VSL#3^®, for the treatment of fibromyalgia-associated gastrointestinal manifestations. This randomized, placebo-controlled trial included 12 weeks of probiotic or placebo treatment followed by 12 weeks of follow up. The primary outcome variable was the mean change from the baseline to the endpoint in the composite severity score of the three main gastrointestinal symptoms reported by patients with fibromyalgia (abdominal pain, abdominal bloating and meteorism). Secondary outcome variables were the severity of additional gastrointestinal symptoms, fibromyalgia severity, depression, sleep disturbance, health-related quality of life and patients’ overall impression of improvement. No differences were found between VSL#3^® (n = 54) and the placebo (n = 56) in the primary outcome (estimated treatment difference: 1.1; 95% confidence interval [CI]: −2.1, 4.2; p = 0.501), or in any of the secondary outcomes. However, responders to VSL#3 were more likely to maintain any improvement during the follow-up period compared to responders in the placebo arm. Overall, VSL#3 tolerability was good. Our data could not demonstrate any beneficial effects of VSL#3^® either on the composite score of severity of abdominal pain, bloating and meteorism or in any of the secondary outcome variables. More research is needed to elucidate specific factors that may predict a favourable response to treatment in patients with fibromyalgia. Full article

(This article belongs to the Special Issue Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations)

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19 pages, 1849 KiB

Open AccessArticle

Higher Ventricular-Arterial Coupling Derived from Three-Dimensional Echocardiography Is Associated with a Worse Clinical Outcome in Systemic Sclerosis

by Francesco Tona, Elisabetta Zanatta, Roberta Montisci, Denisa Muraru, Elena Beccegato, Elena De Zorzi, Francesco Benvenuti, Giovanni Civieri, Franco Cozzi, Sabino Iliceto and Andrea Doria

Pharmaceuticals 2021, 14(7), 646; https://doi.org/10.3390/ph14070646 - 05 Jul 2021

Cited by 6 | Viewed by 2645

Abstract

Primary myocardial involvement is common in systemic sclerosis (SSc). Ventricular-arterial coupling (VAC) reflecting the interplay between ventricular performance and arterial load, is a key determinant of cardiovascular (CV) performance. We aimed to investigate VAC, VAC-derived indices, and the potential association between altered VAC and survival free from death/hospitalization for major adverse CV events (MACE) in scleroderma. Only SSc patients without any anamnestic and echocardiographic evidence of primary myocardial involvement who underwent three-dimensional echocardiography (3DE) were included in this cross-sectional study and compared with healthy matched controls. 3DE was used for noninvasive measurements of end-systolic elastance (Ees), arterial elastance (Ea), VAC (Ea/Ees) and end-diastolic elastance (Eed); the occurrence of death/hospitalization for MACE was recorded during follow-up. Sixty-five SSc patients (54 female; aged 56 ± 14 years) were included. Ees (p = 0.04), Ea (p = 0.04) and Eed (p = 0.01) were higher in patients vs. controls. Thus, VAC was similar in both groups. Ees was lower and VAC was higher in patients with diffuse cutaneous form (dcSSc) vs. patients with limited form (lcSSc) (p = 0.001 and p = 0.02, respectively). Over a median follow-up of 4 years, four patients died for heart failure and 34 were hospitalized for CV events. In patients with VAC > 0.63 the risk of MACE was higher (HR 2.5; 95% CI 1.13–5.7; p = 0.01) and survival free from death/hospitalization was lower (p = 0.005) than in those with VAC < 0.63. Our study suggests that VAC may be impaired in SSc patients without signs and symptoms of primary myocardial involvement. Moreover, VAC appears to have a prognostic role in SSc. Full article

(This article belongs to the Special Issue Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations)

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13 pages, 2946 KiB

Open AccessArticle

Treatment with an Anti-CX3CL1 Antibody Suppresses M1 Macrophage Infiltration in Interstitial Lung Disease in SKG Mice

by Satoshi Mizutani, Junko Nishio, Kanoh Kondo, Kaori Motomura, Zento Yamada, Shotaro Masuoka, Soichi Yamada, Sei Muraoka, Naoto Ishii, Yoshikazu Kuboi, Sho Sendo, Tetuo Mikami, Toshio Imai and Toshihiro Nanki

Pharmaceuticals 2021, 14(5), 474; https://doi.org/10.3390/ph14050474 - 17 May 2021

Cited by 5 | Viewed by 3212

Abstract

CX3C Motif Chemokine Ligand 1 (CX3CL1; fractalkine) has been implicated in the pathogenesis of rheumatoid arthritis (RA) and its inhibition was found to attenuate arthritis in mice as well as in a clinical trial. Therefore, we investigated the effects of an anti-CX3CL1 monoclonal antibody (mAb) on immune-mediated interstitial lung disease (ILD) in SKG mice, which exhibit similar pathological and clinical features to human RA-ILD. CX3CL1 and CX3C chemokine receptor 1 (CX3CR1), the receptor for CX3CL1, were both expressed in the fibroblastic foci of lung tissue and the number of bronchoalveolar fluid (BALF) cells was elevated in ILD in SKG mice. No significant changes were observed in lung fibrosis or the number of BALF cells by the treatment with anti-CX3CL1 mAb. However, significantly greater reductions were observed in the number of M1 macrophages than in M2 macrophages in the BALF of treated mice. Furthermore, CX3CR1 expression levels were significantly higher in M1 macrophages than in M2 macrophages. These results suggest the stronger inhibitory effects of the anti-CX3CL1 mAb treatment against the alveolar infiltration of M1 macrophages than M2 macrophages in ILD in SKG mice. Thus, the CX3CL1-CX3CR1 axis may be involved in the infiltration of inflammatory M1 macrophages in RA-ILD. Full article

(This article belongs to the Special Issue Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations)

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9 pages, 707 KiB

Open AccessArticle

Role of Osteopontin as a Potential Biomarker of Pulmonary Arterial Hypertension in Patients with Systemic Sclerosis and Other Connective Tissue Diseases (CTDs)

by Mattia Bellan, Cristina Piccinino, Stelvio Tonello, Rosalba Minisini, Ailia Giubertoni, Daniele Sola, Roberta Pedrazzoli, Ileana Gagliardi, Erika Zecca, Elisa Calzaducca, Federica Mazzoleni, Roberto Piffero, Giuseppe Patti, Mario Pirisi and Pier Paolo Sainaghi

Pharmaceuticals 2021, 14(5), 394; https://doi.org/10.3390/ph14050394 - 21 Apr 2021

Cited by 10 | Viewed by 1737

Abstract

Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue diseases (CTD). Its early diagnosis is essential to start effective treatment. In the present paper, we aimed to evaluate the role of plasma osteopontin (OPN) as a candidate biomarker of PAH in a cohort of CTD patients. OPN is a pleiotropic protein involved in inflammation and fibrogenesis and, therefore, potentially promising in this specific clinical context. We performed a cross-sectional observational study on a cohort of 113 CTD patients (females N = 101, 89.4%) affected by systemic sclerosis N = 88 (77.9%), mixed connective tissue disease N = 10 (8.8%), overlap syndrome N = 10 (8.8%) or undifferentiated connective tissue disease N = 5 (4.4%). CTD-PAH patients showed significantly higher OPN plasma values than patients with CTD alone (241.0 (188.8–387.2) vs. 200.7 (133.5–281.6) ng/mL; p = 0.03). Although OPN levels were directly correlated with age and inversely with glomerular filtration rate, they remained associated with PAH at multivariate analysis. In conclusion, OPN was significantly associated with PAH among patients with CTD, suggesting it may have a role as a non-invasive disease biomarker of PAH. Full article

(This article belongs to the Special Issue Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations)

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10 pages, 1361 KiB

Open AccessArticle

Cardiopulmonary Exercise Testing Is an Accurate Tool for the Diagnosis of Pulmonary Arterial Hypertension in Scleroderma Related Diseases

by Mattia Bellan, Ailia Giubertoni, Cristina Piccinino, Mariachiara Buffa, Debora Cromi, Daniele Sola, Roberta Pedrazzoli, Ileana Gagliardi, Elisa Calzaducca, Erika Zecca, Filippo Patrucco, Giuseppe Patti, Pier Paolo Sainaghi and Mario Pirisi

Pharmaceuticals 2021, 14(4), 342; https://doi.org/10.3390/ph14040342 - 08 Apr 2021

Cited by 4 | Viewed by 1956

Abstract

The early diagnosis of pulmonary arterial hypertension (PAH) is a major determinant of prognosis in patients affected by connective tissue diseases (CTDs) complicated by PAH. In the present paper we investigated the diagnostic accuracy of cardiopulmonary exercise testing (CPET) in this specific setting. We recorded clinical and laboratory data of 131 patients who underwent a CPET at a pulmonary hypertension clinic. Out of them, 112 (85.5%) had a diagnosis of CTDs; 8 (6.1%) received a diagnosis of CTDs-PAH and 11 (8.4%) were affected PH of different etiology. Among CPET parameters the following parameters showed the best diagnostic performance for PAH: peak volume of oxygen uptake (VO₂; AUC: 0.845, CI95% 0.767–0.904), ratio between ventilation and volume of exhaled carbon dioxide (VE/VCO₂ slope; AUC: 0.888, CI95%: 0.817–0.938) and end-tidal partial pressures (PetCO₂; AUC: 0.792, CI95%: 0.709–0.861). These parameters were comparable among CTDs-PAH and PH of different etiology. The diagnostic performance was even improved by creating a composite score which included all the three parameters identified. In conclusion, CPET is a very promising tool for the stratification of risk of PAH among CTDs patients; the use of composite measures may improve diagnostic performance. Full article

(This article belongs to the Special Issue Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations)

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Review

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16 pages, 331 KiB

Open AccessReview

Pharmacological Interactions of Nintedanib and Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis in Times of COVID-19 Pandemic

by José M. Serra López-Matencio, Manuel Gómez, Esther F. Vicente-Rabaneda, Miguel A. González-Gay, Julio Ancochea and Santos Castañeda

Pharmaceuticals 2021, 14(8), 819; https://doi.org/10.3390/ph14080819 - 20 Aug 2021

Cited by 13 | Viewed by 5646

Abstract

The discovery of antifibrotic agents have resulted in advances in the therapeutic management of idiopathic pulmonary fibrosis (IPF). Currently, nintedanib and pirfenidone have become the basis of IPF therapy based on the results of large randomized clinical trials showing their safety and efficacy in reducing disease advancement. However, the goal of completely halting disease progress has not been reached yet. Administering nintedanib with add-on pirfenidone is supposed to enhance the therapeutic benefit by simultaneously acting on two different pathogenic pathways. All this becomes more important in the context of the ongoing global pandemic of coronavirus disease 2019 (COVID-19) because of the fibrotic consequences following SARS-CoV-2 infection in some patients. However, little information is available about their drug–drug interaction, which is important mainly in polymedicated patients. The aim of this review is to describe the current management of progressive fibrosing interstitial lung diseases (PF-ILDs) in general and of IPF in particular, focusing on the pharmacokinetic drug-drug interactions between these two drugs and their relationship with other medications in patients with IPF. Full article

(This article belongs to the Special Issue Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations)

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16 pages, 2100 KiB

Open AccessReview

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

by Barbara Ruaro, Marco Confalonieri, Francesco Salton, Barbara Wade, Elisa Baratella, Pietro Geri, Paola Confalonieri, Metka Kodric, Marco Biolo and Cosimo Bruni

Pharmaceuticals 2021, 14(5), 403; https://doi.org/10.3390/ph14050403 - 23 Apr 2021

Cited by 17 | Viewed by 3040

Abstract

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. Full article

(This article belongs to the Special Issue Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations)

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18 pages, 984 KiB

Open AccessFeature PaperReview

Respiratory Manifestations in Systemic Lupus Erythematosus

by Salvatore Di Bartolomeo, Alessia Alunno and Francesco Carubbi

Pharmaceuticals 2021, 14(3), 276; https://doi.org/10.3390/ph14030276 - 18 Mar 2021

Cited by 19 | Viewed by 7295

Abstract

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by a wide spectrum of clinical manifestations. The respiratory system can be involved in up to 50–70% of patients and be the presenting manifestation of the disease in 4–5% of cases. Every part of the respiratory part can be involved, and the severity can vary from mild self-limiting to life threatening forms. Respiratory involvement can be primary (caused by SLE itself) or secondary (e.g., infections or drug toxicity), acute or chronic. The course, treatment and prognosis vary greatly depending on the specific pattern of the disease. This review article aims at providing an overview of respiratory manifestations in SLE along with an update about therapeutic approaches including novel biologic therapies. Full article

(This article belongs to the Special Issue Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations)

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21 pages, 700 KiB

Open AccessReview

Pharmacological Interventions for Pulmonary Involvement in Rheumatic Diseases

by Eun Ha Kang and Yeong Wook Song

Pharmaceuticals 2021, 14(3), 251; https://doi.org/10.3390/ph14030251 - 10 Mar 2021

Cited by 2 | Viewed by 2610

Abstract

Among the diverse forms of lung involvement, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are two important conditions in patients with rheumatic diseases that are associated with significant morbidity and mortality. The management of ILD and PAH is challenging because the current treatment often provides only limited patient survival benefits. Such challenges derive from their common pathogenic mechanisms, where not only the inflammatory processes of immune cells but also the fibrotic and proliferative processes of nonimmune cells play critical roles in disease progression, making immunosuppressive therapy less effective. Recently, updated treatment strategies adopting targeted agents have been introduced with promising results in clinical trials for ILD ad PAH. This review discusses the epidemiologic features of ILD and PAH among patients with rheumatic diseases (rheumatoid arthritis, myositis, and systemic sclerosis) and the state-of-the-art treatment options, focusing on targeted agents including biologics, antifibrotic agents, and vasodilatory drugs. Full article

(This article belongs to the Special Issue Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations)

12 pages, 304 KiB

Open AccessReview

The Treatment of Lung Involvement in Systemic Sclerosis

by Barbara Ruaro, Marco Confalonieri, Marco Matucci-Cerinic, Francesco Salton, Paola Confalonieri, Mario Santagiuliana, Gloria Maria Citton, Elisa Baratella and Cosimo Bruni

Pharmaceuticals 2021, 14(2), 154; https://doi.org/10.3390/ph14020154 - 13 Feb 2021

Cited by 14 | Viewed by 2998

Abstract

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. Full article

(This article belongs to the Special Issue Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations)

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