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Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic...
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Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Medical Research".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 27148

Special Issue Editors

Dr. Eloisa Romano

E-Mail Website
Guest Editor
Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
Interests: angiogenesis; cellular and molecular mechanisms of tissue fibrosis; pathogenesis of autoimmune diseases; chronic inflammatory and connective tissue diseases; systemic sclerosis; scleroderma; endothelial cell biology
Special Issues, Collections and Topics in MDPI journals
Dr. Irene Rosa

E-Mail Website
Guest Editor
Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
Interests: anatomy; histology; morphological and functional aspects of stromal cells and endothelial cells; angiogenesis; tissue fibrosis; systemic sclerosis; scleroderma
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Mirko Manetti

E-Mail Website
Guest Editor
Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
Interests: anatomy; histology; morphological and functional aspects of stromal cells; endothelial cell biology; angiogenesis; cellular and molecular mechanisms of tissue fibrosis; pathogenesis of autoimmune, chronic inflammatory and connective tissue diseases; animal models of human disorders; systemic sclerosis; scleroderma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are very glad to announce a Special Issue entitled "Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets" that is being prepared for Life.

Systemic sclerosis (SSc, or scleroderma) is a complex multifaceted connective tissue disease identified by early microvascular involvement, perivascular tissue inflammation and autoimmune reactions evolving into progressive fibrosis of the skin and internal organs. Microangiopathy clinically presents as Raynaud’s phenomenon, abnormal nailfold capillaries, digital ulcers, pulmonary arterial hypertension and scleroderma renal crisis, and together with myofibroblast-orchestrated untreatable fibrosis, often leading to organ failure, accounting for the high disease morbidity and mortality.

In recent years, there have been substantial advances in our understanding of SSc pathogenesis, especially in deciphering the cellular and molecular mechanisms underlying endothelial cell damage, uncontrolled fibroblast activation and dysfunctional immune response. Compelling evidence also suggests the existence of common pathways bridging SSc-related vasculopathy, tissue fibrosis and immune system abnormalities. Hence, expanding our knowledge on the molecular signatures underlying the development and progression of SSc is crucial to gain insights into their potential clinical relevance as novel biomarkers and/or therapeutic targets.

Outstanding experts interested in this Special Issue are invited to submit original manuscripts and reviews dealing with any of the abovementioned aspects of SSc.

Dr. Eloisa Romano
Dr. Irene Rosa
Dr. Mirko Manetti
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Life is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • systemic sclerosis
  • scleroderma
  • pathogenetic mechanisms
  • fibrosis
  • fibroblasts
  • myofibroblasts
  • vasculopathy
  • angiogenesis
  • endothelial cells
  • immune cells
  • autoantibodies
  • biomarkers
  • molecular pathways
  • therapeutic targets

Published Papers (13 papers)

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Editorial

Jump to: Research, Review, Other

5 pages, 208 KiB  
Editorial
Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets
by Eloisa Romano, Irene Rosa and Mirko Manetti
Life 2023, 13(2), 513; https://0-doi-org.brum.beds.ac.uk/10.3390/life13020513 - 13 Feb 2023
Cited by 1 | Viewed by 1198
Abstract
Systemic sclerosis (SSc, or scleroderma) is a multifaceted rare connective tissue disease [...] Full article
(This article belongs to the Special Issue Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets)

Research

Jump to: Editorial, Review, Other

10 pages, 1179 KiB  
Article
Sympatho-Vagal Dysfunction in Systemic Sclerosis: A Follow-Up Study
by Gabriel Dias Rodrigues, Angelica Carandina, Costanza Scatà, Chiara Bellocchi, Lorenzo Beretta, Pedro Paulo da Silva Soares, Eleonora Tobaldini and Nicola Montano
Life 2023, 13(1), 34; https://0-doi-org.brum.beds.ac.uk/10.3390/life13010034 - 23 Dec 2022
Cited by 5 | Viewed by 1249
Abstract
Systemic sclerosis (SSc) patients often present cardiovascular autonomic dysfunction, which is associated with the risk of arrhythmic complications and mortality. However, little is known regarding the progression of cardiac autonomic impairment over time. We aimed to evaluate the cardiac autonomic modulation among SSc [...] Read more.
Systemic sclerosis (SSc) patients often present cardiovascular autonomic dysfunction, which is associated with the risk of arrhythmic complications and mortality. However, little is known regarding the progression of cardiac autonomic impairment over time. We aimed to evaluate the cardiac autonomic modulation among SSc with limited cutaneous (lcSSc), diffuse cutaneous (dcSSc) subset, and age-matched healthy control (HC) at baseline (t0) and five-year follow-up (t1). In this follow-up study, ECG was recorded at t0 and t1 in twenty-four SSc patients (dcSSc; n = 11 and lcSSc; n = 13) and 11 HC. The heart rate variability (HRV) analysis was conducted. The spectral analysis identified two oscillatory components, low frequency (LF) and high frequency (HF), and the sympatho-vagal balance was assessed by the LF/HF ratio. The LF/HF increased (p = 0.03), and HF reduced at t1 compared to t0 in dcSSc (p = 0.03), which did not occur in the lcSSc and HC groups. Otherwise, both lcSSc and dcSSc groups presented augmented LF/HF at t0 and t1 compared to HC (p < 0.01). In conclusion, a worsening of cardiac autonomic dysfunction is related to the dcSSc subset, in which a more extent of skin fibrosis and internal organs fibrosis is present. Full article
(This article belongs to the Special Issue Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets)
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11 pages, 570 KiB  
Article
Total Facial Autologous Fat Grafting for Treating Skin Manifestations in Scleroderma
by Ariel Berl, Ofir Shir-az, Noa Perk, Abraham Levy, Yair Levy and Avshalom Shalom
Life 2022, 12(12), 1997; https://0-doi-org.brum.beds.ac.uk/10.3390/life12121997 - 30 Nov 2022
Cited by 4 | Viewed by 4011
Abstract
Systemic sclerosis (SSc) or scleroderma, is a rare, systemic autoimmune connective tissue disease that can cause fibrosis of cutaneous tissue and visceral organs. Facial involvement can have a deleterious effect on patients’ function, cosmetic appearance and quality of life. This study describes our [...] Read more.
Systemic sclerosis (SSc) or scleroderma, is a rare, systemic autoimmune connective tissue disease that can cause fibrosis of cutaneous tissue and visceral organs. Facial involvement can have a deleterious effect on patients’ function, cosmetic appearance and quality of life. This study describes our experience and results with total facial autologous fat grafting for treating scleroderma. It includes 14 women and 3 men with SSc, at an average age of 51.3 years who underwent 32 autologous fat grafting surgeries between 2017–2022. The surgical technique is further described and demographic and surgical data, including preoperative and postoperative measurements were analyzed. Patients who had multiple surgeries ultimately received grafts with twice the volume of fat than in the first procedure. The oral opening increased an average of 33%. All patients reported improvement in quality of life and were very satisfied with the aesthetic outcomes. The use of autologous fat grafting to treat SSc patients successfully increased oral openings and improved facial manifestations. The procedure is reproducible, safe and leads to improvement in facial manifestations and patients’ quality of life. It can be repeated over time to preserve or enhance the results. Full article
(This article belongs to the Special Issue Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets)
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13 pages, 1484 KiB  
Article
Increased Circulating Soluble Junctional Adhesion Molecules in Systemic Sclerosis: Association with Peripheral Microvascular Impairment
by Eloisa Romano, Irene Rosa, Bianca Saveria Fioretto, Marco Matucci-Cerinic and Mirko Manetti
Life 2022, 12(11), 1790; https://0-doi-org.brum.beds.ac.uk/10.3390/life12111790 - 04 Nov 2022
Cited by 6 | Viewed by 1102
Abstract
Systemic sclerosis (SSc, scleroderma) is a severe disease characterized by peripheral microcirculation abnormalities manifesting with Raynaud’s phenomenon, nailfold videocapillaroscopic (NVC) changes, and even ischemic digital ulcers (DUs) that are often refractory to treatments. In the wake of previously described associations between the circulating [...] Read more.
Systemic sclerosis (SSc, scleroderma) is a severe disease characterized by peripheral microcirculation abnormalities manifesting with Raynaud’s phenomenon, nailfold videocapillaroscopic (NVC) changes, and even ischemic digital ulcers (DUs) that are often refractory to treatments. In the wake of previously described associations between the circulating levels of soluble junctional adhesion molecules (sJAMs) and SSc clinical features, here, we measured sJAM-A and sJAM-C levels by enzyme-linked immunosorbent assay in serum samples from a large case series of 110 SSc patients and 85 healthy controls, focusing on their possible association with peripheral vascular clinical features and their potential as biomarkers that are either diagnostic or mirror SSc-related microvasculopathy severity. Our data demonstrated that serum sJAM-A and sJAM-C are significantly increased in patients with SSc vs. healthy controls, especially in those featuring early/active NVC patterns and the presence of ischemic DUs. Moreover, circulating sJAM-C levels showed good diagnostic accuracy in discriminating between patients and controls, as assessed by receiver operator characteristics curve analysis. Finally, logistic regression revealed that, when comparing sJAM-A to sJAM-C, the latter might be better suited as a biomarker for SSc-related DUs. Our promising findings provide the necessary groundwork for longitudinal follow-up analyses of SSc patients aiming to assess whether circulating sJAM-C levels might be predictive for the development of new DUs, as well as DU recurrence and/or refractoriness to targeted therapies. Full article
(This article belongs to the Special Issue Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets)
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12 pages, 808 KiB  
Article
Circulating Neurovascular Guidance Molecules and Their Relationship with Peripheral Microvascular Impairment in Systemic Sclerosis
by Eloisa Romano, Irene Rosa, Bianca Saveria Fioretto, Marco Matucci-Cerinic and Mirko Manetti
Life 2022, 12(7), 1056; https://0-doi-org.brum.beds.ac.uk/10.3390/life12071056 - 14 Jul 2022
Cited by 4 | Viewed by 1408
Abstract
Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease whose earliest clinical manifestations are microvascular tone dysregulation and peripheral microcirculatory abnormalities. Following previous evidence of an association between circulating neurovascular guidance molecules and SSc disturbed angiogenesis, here, we measured the levels of [...] Read more.
Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease whose earliest clinical manifestations are microvascular tone dysregulation and peripheral microcirculatory abnormalities. Following previous evidence of an association between circulating neurovascular guidance molecules and SSc disturbed angiogenesis, here, we measured the levels of soluble neuropilin 1 (sNRP1), semaphorin 3E (Sema3E), and Slit2 by enzyme-linked immunosorbent assay in serum samples from a large case series of 166 SSc patients vs. 110 healthy controls. We focused on their possible correlation with vascular disease clinical features and applied logistic regression analysis to determine which of them could better reflect disease activity and severity. Our results demonstrate that, in SSc: (i) sNRP1 is significantly decreased, with lower sNRP1 serum levels correlating with the severity of nailfold videocapillaroscopy (NVC) abnormalities and the presence of ischemic digital ulcers (DUs); (ii) both Sema3E and Slit2 are increased, with Sema3E better reflecting early NVC abnormalities; and (iii) higher Sema3E correlates with the absence of DUs, while augmented Slit2 associates with the presence of DUs. Receiver operator characteristics curve analysis revealed that both circulating sNRP1 and Sema3E show a moderate diagnostic accuracy. Moreover, logistic regression analysis allowed to identify sNRP1 and Sema3E as more suitable independent biomarkers reflecting the activity and severity of SSc-related peripheral microvasculopathy. Full article
(This article belongs to the Special Issue Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets)
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10 pages, 284 KiB  
Article
Genetic Association between TNFA Polymorphisms (rs1799964 and rs361525) and Susceptibility to Cancer in Systemic Sclerosis
by Joanna Kosałka-Węgiel, Sabina Lichołai, Sylwia Dziedzina, Mamert Milewski, Piotr Kuszmiersz, Anna Rams, Jolanta Gąsior, Aleksandra Matyja-Bednarczyk, Helena Kwiatkowska, Mariusz Korkosz, Andżelika Siwiec, Paweł Koźlik, Agnieszka Padjas, Wojciech Sydor, Jerzy Dropiński, Marek Sanak, Jacek Musiał and Stanisława Bazan-Socha
Life 2022, 12(5), 698; https://0-doi-org.brum.beds.ac.uk/10.3390/life12050698 - 07 May 2022
Cited by 3 | Viewed by 1762
Abstract
Tumor necrosis factor (TNF)-α is a proinflammatory cytokine that plays an important role in the pathogenesis of autoimmune diseases. The aim of the study was to establish an association between TNF-α promoter variability and systemic sclerosis (SSc). The study included 43 SSc patients [...] Read more.
Tumor necrosis factor (TNF)-α is a proinflammatory cytokine that plays an important role in the pathogenesis of autoimmune diseases. The aim of the study was to establish an association between TNF-α promoter variability and systemic sclerosis (SSc). The study included 43 SSc patients and 74 controls. Four single nucleotide polymorphisms (rs361525, rs1800629, rs1799724, and rs1799964) located at the promoter of the TNFA gene were genotyped using commercially available TaqMan allelic discrimination assays with real-time PCR. The rs1799724 allele was associated with an increased SSc susceptibility (p = 0.028). In turn, none of the polymorphisms studied were related to the clinical and laboratory parameters of SSc patients, except for a higher prevalence of anti-Ro52 antibodies in the AG rs1800629 genotype in comparison to GG carriers (p = 0.04). Three of four cancer patients had both CT rs1799964 and AG rs361525 genotypes; thus, both of them were related to the increased risk of cancer, as compared to the TT (p = 0.03) and GG carriers (p = 0.0003), respectively. The TNFA C rs1799724 variant is associated with an increased risk of SSc, while the CT rs1799964 and AG rs361525 genotypes might enhance cancer susceptibility in SSc patients, although large observational and experimental studies are needed to verify the above hypothesis. Full article
(This article belongs to the Special Issue Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets)
11 pages, 903 KiB  
Article
Serum C-X-C Chemokine Ligand 1 Levels in Patients with Systemic Sclerosis: Relationship of Clinical and Laboratory Observations to Anti-CD20 Monoclonal Antibody Administration
by Ruriko Kawanabe, Ayumi Yoshizaki, Kazuki M. Matsuda, Hirohito Kotani, Teruyoshi Hisamoto, Yuta Norimatsu, Ai Kuzumi, Takemichi Fukasawa, Satoshi Ebata, Asako Yoshizaki-Ogawa and Shinichi Sato
Life 2022, 12(5), 646; https://0-doi-org.brum.beds.ac.uk/10.3390/life12050646 - 27 Apr 2022
Cited by 1 | Viewed by 2000
Abstract
Objectives: To determine whether C-X-C chemokine ligand 1 (CXCL1), which is a potent neutrophil chemoattractant and activator that plays important role in inflammation, is elevated in patients with systemic sclerosis (SSc) and whether it is associated with the clinical features and disease activity [...] Read more.
Objectives: To determine whether C-X-C chemokine ligand 1 (CXCL1), which is a potent neutrophil chemoattractant and activator that plays important role in inflammation, is elevated in patients with systemic sclerosis (SSc) and whether it is associated with the clinical features and disease activity of patients with SSc. In addition, to determine whether the changes in serum CXCL1 levels before and after treatment correlate with changes in disease activity in SSc patients who received an anti-CD20 monoclonal antibody drug. Patients and method: We examined patient serum collected in the DesiReS trial, which was a double-blind, parallel-group, randomized, placebo-controlled, multicenter, phase II clinical trial. In the trial, patients were randomly allocated to the drug or placebo group and received 375 mg/m2 of an anti-CD20 antibody, rituximab, or placebo once a week for four weeks. We obtained serum samples from 47 patients administered at our hospital, including 3 males and 44 females, the median age of 48 years, range 27–71 years, with 42 diffuse cutaneous SSc and 5 with limited cutaneous SSc. Serum CXCL1 levels were measured using multiplex immunoassay in patient serum before and 24 weeks after administration and also in serum from 33 healthy controls. Results: Serum CXCL1 levels were significantly higher in SSc patients (mean 25.70 ng/mL; 95% confidence interval (CI) 18.35–33.05 ng/mL) than in the healthy controls (15.61 ng/mL; 95% CI 9.73–21.51 ng/mL). In addition, SSc patients with elevated CXCL1 levels had a significantly higher percentage of area occupied with interstitial shadows (p < 0.05), increased serum levels of surfactant protein (SP)-A (p < 0.05), SP-D (p < 0.05), Krebs von den Lungen-6 (p < 0.01), and C-reactive protein (p < 0.05) compared to those with normal levels. Furthermore, defining Δ as the value after rituximab administration minus the value before rituximab administration, baseline serum CXCL1 levels correlated with Δ percent predicted diffusing capacity for carbon monoxide (p < 0.01). In addition, ΔCXCL1 correlated with ΔSP-A (p < 0.05). Similarly, serum CXCL1 levels after rituximab administration correlated with percent predicted forced vital capacity (p < 0.05) and serum SP-D levels (p < 0.05) after rituximab. Conclusions: Our results suggest that serum CXCL1 is associated with the disease activity of SSc-ILD, and high serum CXCL1 levels are one of the predictors of improvement in SSc-ILD with rituximab. Full article
(This article belongs to the Special Issue Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets)
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12 pages, 2071 KiB  
Communication
Microvasculopathy-Related Hemorrhagic Tissue Deposition of Iron May Contribute to Fibrosis in Systemic Sclerosis: Hypothesis-Generating Insights from the Literature and Preliminary Findings
by Petros P. Sfikakis, Nikolaos I. Vlachogiannis, Panagiotis A. Ntouros, Sophie Mavrogeni, Thomas G. Maris, Apostolos H. Karantanas and Vassilis L. Souliotis
Life 2022, 12(3), 430; https://0-doi-org.brum.beds.ac.uk/10.3390/life12030430 - 16 Mar 2022
Cited by 4 | Viewed by 2249
Abstract
Microvascular wall abnormalities demonstrated by nailfold capillaroscopy in systemic sclerosis (SSc) may result in microhemorrhagic deposition of erythrocyte-derived iron. Such abnormalities precede fibrosis, which is orchestrated by myofibroblasts. Iron induces endothelial-to-mesenchymal transition in vitro, which is reversed by reactive oxygen species (ROS) scavengers. [...] Read more.
Microvascular wall abnormalities demonstrated by nailfold capillaroscopy in systemic sclerosis (SSc) may result in microhemorrhagic deposition of erythrocyte-derived iron. Such abnormalities precede fibrosis, which is orchestrated by myofibroblasts. Iron induces endothelial-to-mesenchymal transition in vitro, which is reversed by reactive oxygen species (ROS) scavengers. The conversion of quiescent fibroblasts into profibrotic myofibroblasts has also been associated with ROS-mediated activation of TGF-β1. Given that iron overload predisposes to ROS formation, we hypothesized that the uptake of erythrocyte-derived iron by resident cells promotes fibrosis. Firstly, we show that iron induces oxidative stress in skin-derived and synovial fibroblasts in vitro, as well as in blood mononuclear cells ex vivo. The biological relevance of increased oxidative stress was confirmed by showing the concomitant induction of DNA damage in these cell types. Similar results were obtained in vivo, following intravenous iron administration. Secondly, using magnetic resonance imaging we show an increased iron deposition in the fingers of a patient with early SSc and nailfold microhemorrhages. While a systematic magnetic resonance study to examine tissue iron levels in SSc, including internal organs, is underway, herein we propose that iron may be a pathogenetic link between microvasculopathy and fibrosis and an additional mechanism responsible for increased oxidative stress in SSc. Full article
(This article belongs to the Special Issue Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets)
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14 pages, 1273 KiB  
Article
Investigation of the Expression of Inflammatory Markers in Oral Biofilm Samples in Patients with Systemic Scleroderma and the Association with Clinical Periodontal Parameters—A Preliminary Study
by Mayte Buchbender, Amelie Lugenbühl, Jakob Fehlhofer, Christian Kirschneck, Jutta Ries, Rainer Lutz, Michael Sticherling and Marco Rainer Kesting
Life 2021, 11(11), 1145; https://0-doi-org.brum.beds.ac.uk/10.3390/life11111145 - 27 Oct 2021
Cited by 5 | Viewed by 1643
Abstract
Background: Systemic scleroderma (SSc) has multiple orofacial effects. The aim of this study was to analyze the expression of inflammatory mediators in biofilm samples. It was hypothesized that different expression levels and clinical associations might be drawn. Methods: A total of 39 biofilm [...] Read more.
Background: Systemic scleroderma (SSc) has multiple orofacial effects. The aim of this study was to analyze the expression of inflammatory mediators in biofilm samples. It was hypothesized that different expression levels and clinical associations might be drawn. Methods: A total of 39 biofilm samples from group 1 = SSc and group 2 = healthy control were examined for the expression levels of interleukin (IL)-2,-6, and -10; matrix metalloprotease (MMP)-9; and surface antigens CD90 and CD34 by quantitative real-time PCR and clinical parameters. Relative quantitative (RQ) gene expression was determined using the ∆∆CT method. Results: The mean bleeding on probing values (p = 0.006), clinical attachment loss (CAL) (p = 0.009), gingival recession (p = 0.020), limited mouth opening (p = 0.001) and cervical tooth defects (p = 0.011) were significantly higher in group 1. RQ expressions of IL-2 and CD34 were significantly lower, IL-6, MMP-9, and CD90 were significantly higher. There was a significant positive correlation of IL-6/MMP-9 and negative correlation of mouth opening/CAL and IL-6/CAL. Conclusion: Different expression levels of IL-2, IL-6, MMP-9, CD34 and CD90 were detected in biofilm samples from patients with SSc compared to control. An immunological correlation to the clinical parameters of mouth opening and CAL was shown; thus, we conclude that SSc might have an impact on periodontal tissues. Full article
(This article belongs to the Special Issue Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets)
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Review

Jump to: Editorial, Research, Other

11 pages, 703 KiB  
Review
Potential Role of JAK Inhibitors in the Treatment of Systemic Sclerosis-Associated Interstitial Lung Disease: A Narrative Review from Pathogenesis to Real-Life Data
by Elisa Fiorentini, Francesco Bonomi, Silvia Peretti, Martina Orlandi, Gemma Lepri, Marco Matucci Cerinic, Silvia Bellando Randone and Serena Guiducci
Life 2022, 12(12), 2101; https://0-doi-org.brum.beds.ac.uk/10.3390/life12122101 - 14 Dec 2022
Cited by 7 | Viewed by 2809
Abstract
Background: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is one of the most relevant complications of SSc and the major cause of death. The pathogenesis of SSc-ILD involves a complex interplay of multiple cell types and different molecular pathways, with both inflammation and fibrosis [...] Read more.
Background: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is one of the most relevant complications of SSc and the major cause of death. The pathogenesis of SSc-ILD involves a complex interplay of multiple cell types and different molecular pathways, with both inflammation and fibrosis as pathological hallmarks. To date, there are no treatments able to target both components of the disease. Janus kinase inhibitors (JAKinibs) represent an interesting therapeutic option because they exert both anti-inflammatory and anti-fibrotic properties. Methods: Here, we performed a narrative review concerning the potential role of JAKinibs in SSc-ILD to define the state of art and to evaluate the pathogenetic rationale behind this type of treatment. Results: Currently, few studies investigated SSc-ILD response to JAKinibs treatment. Data were analyzed from three clinical studies and four case reports and progression of SSc-ILD was not evident in 93.5% of patients treated with JAKinibs. Conclusions: Available evidence of efficacy of JAKinibs in SSc-ILD is sparse but promising. JAKinibs could be an interesting treatment in SSc-ILD because of their potential inhibition of the fibrotic processes combined with their anti-inflammatory action. Moreover, JAKinibs were also shown in some studies to have a potential effect on pulmonary arterial hypertension (PAH), another threatening complication in SSc. More data are necessary to define JAKinibs role in SSc-ILD treatment. Full article
(This article belongs to the Special Issue Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets)
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19 pages, 851 KiB  
Review
Animal Models of Systemic Sclerosis: Using Nailfold Capillaroscopy as a Potential Tool to Evaluate Microcirculation and Microangiopathy: A Narrative Review
by Angélica Mandujano and Melissa Golubov
Life 2022, 12(5), 703; https://0-doi-org.brum.beds.ac.uk/10.3390/life12050703 - 08 May 2022
Cited by 4 | Viewed by 2139
Abstract
Systemic sclerosis (SSc) is an autoimmune disease with three pathogenic hallmarks, i.e., inflammation, vasculopathy, and fibrosis. A wide plethora of animal models have been developed to address the complex pathophysiology and for the development of possible anti-fibrotic treatments. However, no current model comprises [...] Read more.
Systemic sclerosis (SSc) is an autoimmune disease with three pathogenic hallmarks, i.e., inflammation, vasculopathy, and fibrosis. A wide plethora of animal models have been developed to address the complex pathophysiology and for the development of possible anti-fibrotic treatments. However, no current model comprises all three pathological mechanisms of the disease. To highlight the lack of a complete model, a review of some of the most widely used animal models for SSc was performed. In addition, to date, no model has accomplished the recreation of primary or secondary Raynaud’s phenomenon, a key feature in SSc. In humans, nailfold capillaroscopy (NFC) has been used to evaluate secondary Raynaud’s phenomenon and microvasculature changes in SSc. Being a non-invasive technique, it is widely used both in clinical studies and as a tool for clinical evaluation. Because of this, its potential use in animal models has been neglected. We evaluated NFC in guinea pigs to investigate the possibility of applying this technique to study microcirculation in the nailfold of animal models and in the future, development of an animal model for Raynaud’s phenomenon. The applications are not only to elucidate the pathophysiological mechanisms of vasculopathy but can also be used in the development of novel treatment options. Full article
(This article belongs to the Special Issue Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets)
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16 pages, 2028 KiB  
Review
α2-Antiplasmin as a Potential Therapeutic Target for Systemic Sclerosis
by Yosuke Kanno and En Shu
Life 2022, 12(3), 396; https://0-doi-org.brum.beds.ac.uk/10.3390/life12030396 - 09 Mar 2022
Cited by 4 | Viewed by 2632
Abstract
Systemic sclerosis is a connective tissue disease of unknown origin that is characterized by immune system abnormalities, vascular damage, and extensive fibrosis of the skin and visceral organs. α2-antiplasmin is known to be the main plasmin inhibitor and has various functions such as [...] Read more.
Systemic sclerosis is a connective tissue disease of unknown origin that is characterized by immune system abnormalities, vascular damage, and extensive fibrosis of the skin and visceral organs. α2-antiplasmin is known to be the main plasmin inhibitor and has various functions such as cell differentiation and cytokine production, as well as the regulation of the maintenance of the immune system, endothelial homeostasis, and extracellular matrix metabolism. The expression of α2-antiplasmin is elevated in dermal fibroblasts from systemic sclerosis patients, and the blockade of α2-antiplasmin suppresses fibrosis progression and vascular dysfunction in systemic sclerosis model mice. α2-antiplasmin may have promise as a potential therapeutic target for systemic sclerosis. This review considers the role of α2-antiplasmin in the progression of systemic sclerosis. Full article
(This article belongs to the Special Issue Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets)
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Other

8 pages, 248 KiB  
Case Report
Systemic Sclerosis and Idiopathic Portal Hypertension: Report of a Case and Review of the Literature
by Michele Colaci, Maria Letizia Aprile, Domenico Sambataro, Gianluca Sambataro and Lorenzo Malatino
Life 2022, 12(11), 1781; https://0-doi-org.brum.beds.ac.uk/10.3390/life12111781 - 04 Nov 2022
Cited by 2 | Viewed by 1235
Abstract
The presence of liver involvement in systemic sclerosis (SSc) is considered atypical, besides the possible coexistence of other autoimmune hepatic disorders. However, the occurrence of portal hypertension and, more specifically, of the syndromes called idiopathic portal hypertension (IPH) and regenerative nodular hyperplasia (RNH) [...] Read more.
The presence of liver involvement in systemic sclerosis (SSc) is considered atypical, besides the possible coexistence of other autoimmune hepatic disorders. However, the occurrence of portal hypertension and, more specifically, of the syndromes called idiopathic portal hypertension (IPH) and regenerative nodular hyperplasia (RNH) have been anecdotally reported in the literature for SSc patients. We described a case of SSc woman complicated by IPH; moreover, we reviewed the literature on the topic. A 61-year-old female SSc patient was admitted to our hospital because of the onset of ascites. SSc, as a limited skin subset of disease with anticentromere antibodies, was diagnosed 11 years previously, with no significant visceral involvement. We excluded possible causes of portal hypertension, namely chronic infections, autoimmune hepatic diseases, neoplasia, thrombosis of portal vein, and Budd–Chiari syndrome. Finally, IPH was diagnosed. A review of the literature identified a number of case reports or case series that described IPH in the course of SSc. No specific SSc pattern linked to IPH emerged, even though reports from the literature often described the limited skin subset. Coexistence of prothrombotic states and overlap with other hepatic diseases could facilitate IPH onset. Besides being a rare condition, the onset of IPH in SSc patients is an occurrence that should be taken into account. Full article
(This article belongs to the Special Issue Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets)
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