Frontiers of Targeted Therapy and Predictors of Treatment Response in Systemic Sclerosis

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 37844

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Special Issue Editor

Institute of Rheumatology and Department of Rheumatology of the First Faculty of Medicine, Charles University, Prague, Czech Republic
Interests: systemic sclerosis; inflammatory myopathies; rheumatoid arthritis; spondyloarthritis; biomarkers; potential anti-fibrotic therapy; animal models of dermal fibrosis; atherosclerosis; cardiovascular risk; body composition; rehabilitation; sexual dysfunction

Special Issue Information

Dear Colleagues,

Systemic sclerosis (scleroderma, SSc) is the most enigmatic and challenging of all rheumatic diseases. To date, it is considered incurable and carries the highest cause-specific mortality of all connective tissue diseases. Despite advancements in basic, translational, and clinical research in recent years, the etiology and pathophysiology of this complex and heterogeneous condition remain to be elucidated. The heterogeneity, highly variable clinical presentations, multisystemic manifestations, natural history, response to treatment, and low prevalence, level of public awareness, or government investment represent some of the reasons for the slow progress so far. Despite the large numbers of clinical trials and the progress made in their design over the last decade, no approved disease-modifying therapies exist for SSc to date. Currently available pharmacological therapies predominantly target inflammatory and vascular pathways, have variable and unpredictable clinical efficacy, usually undesirable safety profiles, and only a modest effect on long-term survival. Therefore, there is a substantial unmet need for novel potential therapeutic targets targeting the main pathological features of this disease (alterations in the immune and vascular systems leading to progressive tissue fibrosis). There is also a large unmet need for potential predictors of treatment response of the currently available therapies to optimize the stratification of patients with this heterogeneous disease in order to minimize possible adverse events and maximize the potential benefit of therapy. Hopefully, novel advancements in these aspects of the management of SSc will contribute to a reduction of suffering and disability and improvement in morbidity and mortality of our patients in the near future.

Dr. Michal Tomcik
Guest Editor

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Keywords

  • systemic sclerosis
  • scleroderma
  • skin fibrosis
  • interstitial lung disease
  • pulmonary hypertension
  • digital ulcers
  • targeted therapy
  • predictors of treatment response

Published Papers (14 papers)

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Editorial

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4 pages, 189 KiB  
Editorial
Frontiers of Targeted Therapy and Predictors of Treatment Response in Systemic Sclerosis
by Michal Tomcik
Biomedicines 2022, 10(12), 3053; https://doi.org/10.3390/biomedicines10123053 - 28 Nov 2022
Viewed by 1113
Abstract
Systemic sclerosis (scleroderma, SSc) is one of the most challenging rheumatic diseases, characterized by vasculopathy, dysregulation of the immune response, and progressive tissue fibrosis affecting the skin, lungs, heart, digestive tract, and kidneys [...] Full article

Research

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12 pages, 504 KiB  
Article
Delphi-Based Consensus on Interstitial Lung Disease Screening in Patients with Connective Tissue Diseases (Croatian National-Based Study)
by Mislav Radić, Srđan Novak, Marko Barešić, Ana Hećimović, Dijana Perković, Jasna Tekavec-Trkanjec, Miroslav Mayer, Višnja Prus, Jadranka Morović-Vergles, Daniela Marasović Krstulović, Mislav Cerovec, Ljiljana Bulat Kardum, Miroslav Samaržija and Branimir Anić
Biomedicines 2022, 10(12), 3291; https://doi.org/10.3390/biomedicines10123291 - 19 Dec 2022
Cited by 7 | Viewed by 2529
Abstract
The aim of this study was to develop a Croatian Delphi-based expert consensus for screening interstitial lung disease (ILD) associated with connective tissue disease (CTD). A systematic literature review was conducted on risk factors for the development of ILD, prevalence and incidence of [...] Read more.
The aim of this study was to develop a Croatian Delphi-based expert consensus for screening interstitial lung disease (ILD) associated with connective tissue disease (CTD). A systematic literature review was conducted on risk factors for the development of ILD, prevalence and incidence of ILD, diagnostic and screening methods for ILD, and prognosis of ILD in idiopathic inflammatory myopathy (IIM), mixed connective tissue disease (MCTD), primary Sjögren’s syndrome (pSS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) were performed. Based on the evidence found, experts developed questionnaires for screening and monitoring ILD in each CTD, which were provided via an online survey. Following the electronic survey, two screening algorithms were developed based on the consensus opinions. The detection strategy for ILD included high-resolution computed tomography (HRCT) in addition to pulmonary function testing for IIM, MCTD, and SSc. and pulmonary function testing for newly diagnosed pSS, RA and SLE. However, in patients with identified risk factors for ILD HRCT, these tests should also be performed. A screening strategy for early identification of patients with various CTD-ILD was first developed by a multidisciplinary team of rheumatologists, pulmonologists, and radiologists to identify early CTD patients at risk of ILD, a severe extra-articular manifestation of CTD. Full article
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12 pages, 825 KiB  
Article
Clinical Predictors of Lung-Function Decline in Systemic-Sclerosis-Associated Interstitial Lung Disease Patients with Normal Spirometry
by Tamas Nagy, Nora Melinda Toth, Erik Palmer, Lorinc Polivka, Balazs Csoma, Alexandra Nagy, Noémi Eszes, Krisztina Vincze, Enikő Bárczi, Anikó Bohács, Ádám Domonkos Tárnoki, Dávid László Tárnoki, György Nagy, Emese Kiss, Pál Maurovich-Horvát and Veronika Müller
Biomedicines 2022, 10(9), 2129; https://doi.org/10.3390/biomedicines10092129 - 31 Aug 2022
Cited by 6 | Viewed by 2074
Abstract
Interstitial lung disease (ILD) is the leading cause of mortality in systemic sclerosis (SSc). Progressive pulmonary fibrosis (PPF) is defined as progression in 2 domains including clinical, radiological or lung-function parameters. Our aim was to assess predictors of functional decline in SSc-ILD patients [...] Read more.
Interstitial lung disease (ILD) is the leading cause of mortality in systemic sclerosis (SSc). Progressive pulmonary fibrosis (PPF) is defined as progression in 2 domains including clinical, radiological or lung-function parameters. Our aim was to assess predictors of functional decline in SSc-ILD patients and compare disease behavior to that in idiopathic pulmonary fibrosis (IPF) patients. Patients with normal forced vital capacity (FVC > 80% predicted; SSc-ILD: n = 31; IPF: n = 53) were followed for at least 1 year. Predictors of functional decline including clinical symptoms, comorbidities, lung-function values, high-resolution CT pattern, and treatment data were analyzed. SSc-ILD patents were significantly younger (59.8 ± 13.1) and more often women (93 %) than IPF patients. The median yearly FVC decline was similar in both groups (SSc-ILD = −67.5 and IPF = −65.3 mL/year). A total of 11 SSc-ILD patients met the PPF criteria for functional deterioration, presenting an FVC decline of −153.9 mL/year. Cough and pulmonary hypertension were significant prognostic factors for SSc-ILD functional progression. SSc-ILD patients with normal initial spirometry presenting with cough and PH are at higher risk for showing progressive functional decline. Full article
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18 pages, 865 KiB  
Article
MiRNAs in Systemic Sclerosis Patients with Pulmonary Arterial Hypertension: Markers and Effectors
by Mor Zaaroor Levy, Noa Rabinowicz, Maia Yamila Kohon, Avshalom Shalom, Ariel Berl, Tzipi Hornik-Lurie, Liat Drucker, Shelly Tartakover Matalon and Yair Levy
Biomedicines 2022, 10(3), 629; https://doi.org/10.3390/biomedicines10030629 - 8 Mar 2022
Cited by 5 | Viewed by 2427
Abstract
Background: Pulmonary arterial hypertension (PAH) is a major cause of death in systemic sclerosis (SSc). Early detection may improve patient outcomes. Methods: We searched for circulating miRNAs that would constitute biomarkers in SSc patients with PAH (SSc-PAH). We compared miRNA levels and laboratory [...] Read more.
Background: Pulmonary arterial hypertension (PAH) is a major cause of death in systemic sclerosis (SSc). Early detection may improve patient outcomes. Methods: We searched for circulating miRNAs that would constitute biomarkers in SSc patients with PAH (SSc-PAH). We compared miRNA levels and laboratory parameters while evaluating miRNA levels in white blood cells (WBCs) and myofibroblasts. Results: Our study found: 1) miR-26 and miR-let-7d levels were significantly lower in SSc-PAH (n = 12) versus SSc without PAH (SSc-noPAH) patients (n = 25); 2) a positive correlation between miR-26 and miR-let-7d and complement-C3; 3) GO-annotations of genes that are miR-26/miR-let-7d targets and that are expressed in myofibroblast cells, suggesting that these miRNAs regulate the TGF-β-pathway; 4) reduced levels of both miRNAs accompanied fibroblast differentiation to myofibroblasts, while macitentan (endothelin receptor-antagonist) increased the levels. WBCs of SSc-noPAH and SSc-PAH patients contained equal amounts of miR-26/miR-let-7d. During the study, an echocardiograph that predicted PAH development, showed increased pulmonary artery pressure in three SSc-noPAH patients. At study initiation, those patients and an additional SSc-noPAH patient, who eventually developed PAH, had miR-let-7d/miR-26 levels similar to those of SSc-PAH patients. This implies that reduced miR-let-7d/miR-26 levels might be an early indication of PAH. Conclusions: miR-26 and miR-let-7d may be serological markers for SSc-PAH. The results of our study suggest their involvement in myofibroblast differentiation and complement pathway activation, both of which are active in PAH development. Full article
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15 pages, 2778 KiB  
Article
Plasma Metabolomic Profiling Reveals Four Possibly Disrupted Mechanisms in Systemic Sclerosis
by Thomas Bögl, Franz Mlynek, Markus Himmelsbach, Norbert Sepp, Wolfgang Buchberger and Marija Geroldinger-Simić
Biomedicines 2022, 10(3), 607; https://doi.org/10.3390/biomedicines10030607 - 4 Mar 2022
Cited by 9 | Viewed by 2762
Abstract
Systemic sclerosis (SSc) is a rare systemic autoimmune disorder marked by high morbidity and increased risk of mortality. Our study aimed to analyze metabolomic profiles of plasma from SSc patients by using targeted and untargeted metabolomics approaches. Furthermore, we aimed to detect biochemical [...] Read more.
Systemic sclerosis (SSc) is a rare systemic autoimmune disorder marked by high morbidity and increased risk of mortality. Our study aimed to analyze metabolomic profiles of plasma from SSc patients by using targeted and untargeted metabolomics approaches. Furthermore, we aimed to detect biochemical mechanisms relevant to the pathophysiology of SSc. Experiments were performed using high-performance liquid chromatography coupled to mass spectrometry technology. The investigation of plasma samples from SSc patients (n = 52) compared to a control group (n = 48) allowed us to identify four different dysfunctional metabolic mechanisms, which can be assigned to the kynurenine pathway, the urea cycle, lipid metabolism, and the gut microbiome. These significantly altered metabolic pathways are associated with inflammation, vascular damage, fibrosis, and gut dysbiosis and might be relevant for the pathophysiology of SSc. Further studies are needed to explore the role of these metabolomic networks as possible therapeutic targets of SSc. Full article
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13 pages, 1269 KiB  
Article
Treatment and Systemic Sclerosis Interstitial Lung Disease Outcome: The Overweight Paradox
by Alexandra Nagy, Erik Palmer, Lorinc Polivka, Noemi Eszes, Krisztina Vincze, Eniko Barczi, Aniko Bohacs, Adam Domonkos Tarnoki, David Laszlo Tarnoki, György Nagy, Emese Kiss, Pal Maurovich-Horvat and Veronika Müller
Biomedicines 2022, 10(2), 434; https://doi.org/10.3390/biomedicines10020434 - 13 Feb 2022
Cited by 6 | Viewed by 2510
Abstract
(1) Background: Systemic sclerosis (SSc) is frequently associated with interstitial lung diseases (ILDs). The progressive form of SSc-ILD often limits patient survival. The aim of our study is to evaluate the clinical characteristics and predictors of lung function changes in SSc-ILD patients treated [...] Read more.
(1) Background: Systemic sclerosis (SSc) is frequently associated with interstitial lung diseases (ILDs). The progressive form of SSc-ILD often limits patient survival. The aim of our study is to evaluate the clinical characteristics and predictors of lung function changes in SSc-ILD patients treated in a real-world setting. (2) Methods: All SSc-ILD cases previously confirmed by rheumatologists and a multidisciplinary ILD team between January 2017 and June 2019 were included (n = 54). The detailed medical history, clinical parameters and HRCT were analyzed. The longitudinal follow-up for pulmonary symptoms, functional parameters and treatment were performed for at least 2 years in no treatment, immunosuppression and biological treatment subgroups. (3) Results: In SSc-ILD patients (age 58.7 ± 13.3 years, 87.0% women), the main symptoms included dyspnea, cough, crackles and the Raynaud’s phenomenon. The functional decline was most prominent in untreated patients, and a normal body mass index (BMI < 25 kg/m2) was associated with a significant risk of deterioration. The majority of patients improved or were stable during follow-up. The progressive fibrosing-ILD criteria were met by 15 patients, the highest proportion being in the untreated subgroup. (4) Conclusions: SSc-ILD patients who are overweight are at a lower risk of the functional decline and progressive phenotype especially affecting untreated patients. The close monitoring of lung involvement and a regular BMI measurement are advised and early treatment interventions are encouraged. Full article
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7 pages, 17233 KiB  
Article
Bisphosphonates for the Treatment of Calcinosis Cutis—A Retrospective Single-Center Study
by Lilian Rauch, Rüdiger Hein, Tilo Biedermann, Kilian Eyerich and Felix Lauffer
Biomedicines 2021, 9(11), 1698; https://doi.org/10.3390/biomedicines9111698 - 16 Nov 2021
Cited by 12 | Viewed by 2375
Abstract
(1) Background: Calcinosis cutis is a frequent symptom of autoimmune connective tissue diseases leading to pain, transcutaneous expulsion of calcified material and bacterial superinfection. There is a high need for new therapeutic options as no standardized treatment algorithm is established. While case reports [...] Read more.
(1) Background: Calcinosis cutis is a frequent symptom of autoimmune connective tissue diseases leading to pain, transcutaneous expulsion of calcified material and bacterial superinfection. There is a high need for new therapeutic options as no standardized treatment algorithm is established. While case reports indicate beneficial effects of bisphosphonates, standardized evaluation of treatment effects is missing. (2) Methods: In this retrospective analysis we evaluate the effects of intravenous pamidronate, a second-generation bisphosphonate, in seven patients with calcinosis cutis using consecutive clinical pictures, radiological examinations and patient’s subjective evaluation. (3) Results: 5/6 patients reported a reduction of pain, improvement of general condition and cessation of calcinosis progression. Regression of skin lesions was detectable in clinical pictures of 2/6 patients, while 1/6 patients had stable disease. Radiological examination revealed improvement or stable disease in 3/5 patients. Fever was the most common side effect. One out of seven patients developed osteonecrosis of the jaw. (4) Conclusions: Bisphosphonates appear to have beneficial effects in a subgroup of calcinosis cutis patients. While patient’s subjective evaluation was mainly positive, objective assessments showed improvement in approximately half of the cases. With regard to potential severe side effects, a careful risk-benefit evaluation is necessary before treatment initiation. Full article
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18 pages, 3630 KiB  
Article
Inhibition of Hsp90 Counteracts the Established Experimental Dermal Fibrosis Induced by Bleomycin
by Hana Štorkánová, Lenka Štorkánová, Adéla Navrátilová, Viktor Bečvář, Hana Hulejová, Sabína Oreská, Barbora Heřmánková, Maja Špiritović, Radim Bečvář, Karel Pavelka, Jiří Vencovský, Jörg H. W. Distler, Ladislav Šenolt and Michal Tomčík
Biomedicines 2021, 9(6), 650; https://doi.org/10.3390/biomedicines9060650 - 7 Jun 2021
Cited by 5 | Viewed by 2578 | Correction
Abstract
Our previous study demonstrated that heat shock protein 90 (Hsp90) is overexpressed in the involved skin of patients with systemic sclerosis (SSc) and in experimental dermal fibrosis. Pharmacological inhibition of Hsp90 prevented the stimulatory effects of transforming growth factor-beta on collagen synthesis and [...] Read more.
Our previous study demonstrated that heat shock protein 90 (Hsp90) is overexpressed in the involved skin of patients with systemic sclerosis (SSc) and in experimental dermal fibrosis. Pharmacological inhibition of Hsp90 prevented the stimulatory effects of transforming growth factor-beta on collagen synthesis and the development of dermal fibrosis in three preclinical models of SSc. In the next step of the preclinical analysis, herein, we aimed to evaluate the efficacy of an Hsp90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), in the treatment of established experimental dermal fibrosis induced by bleomycin. Treatment with 17-DMAG demonstrated potent antifibrotic and anti-inflammatory properties: it decreased dermal thickening, collagen content, myofibroblast count, expression of transforming growth factor beta receptors, and pSmad3-positive cell counts, as well as leukocyte infiltration and systemic levels of crucial cytokines/chemokines involved in the pathogenesis of SSc, compared to vehicle-treated mice. 17-DMAG effectively prevented further progression and may induce regression of established bleomycin-induced dermal fibrosis to an extent comparable to nintedanib. These findings provide further evidence of the vital role of Hsp90 in the pathophysiology of SSc and characterize it as a potential target for the treatment of fibrosis with translational implications due to the availability of several Hsp90 inhibitors in clinical trials for other indications. Full article
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Review

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29 pages, 2120 KiB  
Review
Autoantibodies as Biomarker and Therapeutic Target in Systemic Sclerosis
by Hanna Graßhoff, Konstantinos Fourlakis, Sara Comdühr and Gabriela Riemekasten
Biomedicines 2022, 10(9), 2150; https://doi.org/10.3390/biomedicines10092150 - 1 Sep 2022
Cited by 9 | Viewed by 2757
Abstract
Systemic sclerosis (SSc) is a rare connective tissue disorder characterized by immune dysregulation evoking the pathophysiological triad of inflammation, fibrosis and vasculopathy. In SSc, several alterations in the B-cell compartment have been described, leading to polyclonal B-cell hyperreactivity, hypergammaglobulinemia and autoantibody production. Autoreactive [...] Read more.
Systemic sclerosis (SSc) is a rare connective tissue disorder characterized by immune dysregulation evoking the pathophysiological triad of inflammation, fibrosis and vasculopathy. In SSc, several alterations in the B-cell compartment have been described, leading to polyclonal B-cell hyperreactivity, hypergammaglobulinemia and autoantibody production. Autoreactive B cells and autoantibodies promote and maintain pathologic mechanisms. In addition, autoantibodies in SSc are important biomarkers for predicting clinical phenotype and disease progression. Autoreactive B cells and autoantibodies represent potentially promising targets for therapeutic approaches including B-cell-targeting therapies, as well as strategies for unselective and selective removal of autoantibodies. In this review, we present mechanisms of the innate immune system leading to the generation of autoantibodies, alterations of the B-cell compartment in SSc, autoantibodies as biomarkers and autoantibody-mediated pathologies in SSc as well as potential therapeutic approaches to target these. Full article
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17 pages, 742 KiB  
Review
Emerging Evidence and Treatment Perspectives from Randomized Clinical Trials in Systemic Sclerosis: Focus on Interstitial Lung Disease
by Caterina Oriana Aragona, Antonio Giovanni Versace, Carmelo Ioppolo, Daniela La Rosa, Rita Lauro, Maria Concetta Tringali, Simona Tomeo, Guido Ferlazzo, William Neal Roberts, Alessandra Bitto, Natasha Irrera and Gianluca Bagnato
Biomedicines 2022, 10(2), 504; https://doi.org/10.3390/biomedicines10020504 - 21 Feb 2022
Cited by 2 | Viewed by 3276
Abstract
Systemic sclerosis (SSc) is a complex rare autoimmune disease with heterogeneous clinical manifestations. Currently, interstitial lung disease (ILD) and cardiac involvement (including pulmonary arterial hypertension) are recognized as the leading causes of SSc-associated mortality. New molecular targets have been discovered and phase II [...] Read more.
Systemic sclerosis (SSc) is a complex rare autoimmune disease with heterogeneous clinical manifestations. Currently, interstitial lung disease (ILD) and cardiac involvement (including pulmonary arterial hypertension) are recognized as the leading causes of SSc-associated mortality. New molecular targets have been discovered and phase II and phase III clinical trials published in the last 5 years on SSc-ILD will be discussed in this review. Details on the study design; the drug tested and its dose; the inclusion and exclusion criteria of the study; the concomitant immunosuppression; the outcomes and the duration of the study were reviewed. The two most common drugs used for the treatment of SSc-ILD are cyclophosphamide and mycophenolate mofetil, both supported by randomized controlled trials. Additional drugs, such as nintedanib and tocilizumab, have been approved to slow pulmonary function decline in SSc-ILD. In this review, we discuss the therapeutic alternatives for SSc management, offering the option to customize the design of future studies to stratify SSc patients and provide a patient-specific treatment according to the new emerging pathogenic features of SSc-ILD. Full article
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18 pages, 1272 KiB  
Review
Targeting Systemic Sclerosis from Pathogenic Mechanisms to Clinical Manifestations: Why IL-6?
by Anca Cardoneanu, Alexandra Maria Burlui, Luana Andreea Macovei, Ioana Bratoiu, Patricia Richter and Elena Rezus
Biomedicines 2022, 10(2), 318; https://doi.org/10.3390/biomedicines10020318 - 29 Jan 2022
Cited by 14 | Viewed by 3670
Abstract
Systemic sclerosis (SS) is a chronic autoimmune disorder, which has both cutaneous and systemic clinical manifestations. The disease pathogenesis includes a triad of manifestations, such as vasculopathy, autoimmunity, and fibrosis. Interleukin-6 (IL-6) has a special role in SS development, both in vascular damage [...] Read more.
Systemic sclerosis (SS) is a chronic autoimmune disorder, which has both cutaneous and systemic clinical manifestations. The disease pathogenesis includes a triad of manifestations, such as vasculopathy, autoimmunity, and fibrosis. Interleukin-6 (IL-6) has a special role in SS development, both in vascular damage and in the development of fibrosis. In the early stages, IL-6 participates in vascular endothelial activation and apoptosis, leading to the release of damage-associated molecular patterns (DAMPs), which maintain inflammation and autoimmunity. Moreover, IL-6 plays an important role in the development of fibrotic changes by mediating the transformation of fibroblasts into myofibroblasts. All of these are associated with disabling clinical manifestations, such as skin thickening, pulmonary fibrosis, pulmonary arterial hypertension (PAH), heart failure, and dysphagia. Tocilizumab is a humanized monoclonal antibody that inhibits IL-6 by binding to the specific receptor, thus preventing its proinflammatory and fibrotic actions. Anti-IL-6 therapy with Tocilizumab is a new hope for SS patients, with data from clinical trials supporting the favorable effect, especially on skin and lung damage. Full article
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32 pages, 2241 KiB  
Review
Therapeutic Options for Systemic Sclerosis: Current and Future Perspectives in Tackling Immune-Mediated Fibrosis
by Theodoros-Ioannis Papadimitriou, Arjan van Caam, Peter M. van der Kraan and Rogier M. Thurlings
Biomedicines 2022, 10(2), 316; https://doi.org/10.3390/biomedicines10020316 - 29 Jan 2022
Cited by 11 | Viewed by 5332
Abstract
Systemic sclerosis (SSc) is a severe auto-immune, rheumatic disease, characterized by excessive fibrosis of the skin and visceral organs. SSc is accompanied by high morbidity and mortality rates, and unfortunately, few disease-modifying therapies are currently available. Inflammation, vasculopathy, and fibrosis are the key [...] Read more.
Systemic sclerosis (SSc) is a severe auto-immune, rheumatic disease, characterized by excessive fibrosis of the skin and visceral organs. SSc is accompanied by high morbidity and mortality rates, and unfortunately, few disease-modifying therapies are currently available. Inflammation, vasculopathy, and fibrosis are the key hallmarks of SSc pathology. In this narrative review, we examine the relationship between inflammation and fibrosis and provide an overview of the efficacy of current and novel treatment options in diminishing SSc-related fibrosis based on selected clinical trials. To do this, we first discuss inflammatory pathways of both the innate and acquired immune systems that are associated with SSc pathophysiology. Secondly, we review evidence supporting the use of first-line therapies in SSc patients. In addition, T cell-, B cell-, and cytokine-specific treatments that have been utilized in SSc are explored. Finally, the potential effectiveness of tyrosine kinase inhibitors and other novel therapeutic approaches in reducing fibrosis is highlighted. Full article
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18 pages, 1074 KiB  
Review
Novel Concepts in Systemic Sclerosis Pathogenesis: Role for miRNAs
by Iulia Szabo, Laura Muntean, Tania Crisan, Voicu Rednic, Claudia Sirbe and Simona Rednic
Biomedicines 2021, 9(10), 1471; https://doi.org/10.3390/biomedicines9101471 - 14 Oct 2021
Cited by 11 | Viewed by 2128
Abstract
Systemic sclerosis (SSc) is a rare connective tissue disease with heterogeneous clinical phenotypes. It is characterized by the pathogenic triad: microangiopathy, immune dysfunction, and fibrosis. Epigenetic mechanisms modulate gene expression without interfering with the DNA sequence. Epigenetic marks may be reversible and their [...] Read more.
Systemic sclerosis (SSc) is a rare connective tissue disease with heterogeneous clinical phenotypes. It is characterized by the pathogenic triad: microangiopathy, immune dysfunction, and fibrosis. Epigenetic mechanisms modulate gene expression without interfering with the DNA sequence. Epigenetic marks may be reversible and their differential response to external stimuli could explain the protean clinical manifestations of SSc while offering the opportunity of targeted drug development. Small, non-coding RNA sequences (miRNAs) have demonstrated complex interactions between vasculature, immune activation, and extracellular matrices. Distinct miRNA profiles were identified in SSc skin specimens and blood samples containing a wide variety of dysregulated miRNAs. Their target genes are mainly involved in profibrotic pathways, but new lines of evidence also confirm their participation in impaired angiogenesis and aberrant immune responses. Research approaches focusing on earlier stages of the disease and on differential miRNA expression in various tissues could bring novel insights into SSc pathogenesis and validate the clinical utility of miRNAs as biomarkers and therapeutic targets. Full article
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Other

2 pages, 940 KiB  
Correction
Correction: Štorkánová et al. Inhibition of Hsp90 Counteracts the Established Experimental Dermal Fibrosis Induced by Bleomycin. Biomedicines 2021, 9, 650
by Hana Štorkánová, Lenka Štorkánová, Adéla Navrátilová, Viktor Bečvář, Hana Hulejová, Sabína Oreská, Barbora Heřmánková, Maja Špiritović, Radim Bečvář, Karel Pavelka, Jiří Vencovský, Jörg H. W. Distler, Ladislav Šenolt and Michal Tomčík
Biomedicines 2023, 11(10), 2736; https://doi.org/10.3390/biomedicines11102736 - 9 Oct 2023
Viewed by 476
Abstract
In the original publication [...] Full article
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