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Genes May 2024Systemic sclerosis (SSc) is a rare autoimmune connective tissue disorder characterized by massive fibrosis, vascular damage, and immune imbalance. Advances in... (Review)
Review
Systemic sclerosis (SSc) is a rare autoimmune connective tissue disorder characterized by massive fibrosis, vascular damage, and immune imbalance. Advances in rheumatology and immunology over the past two decades have led to a redefinition of systemic sclerosis, shifting from its initial perception as primarily a "hyperfibrotic" state towards a recognition of systemic sclerosis as an immune-mediated disease. Consequently, the search for genetic markers has transitioned from focusing on fibrotic mechanisms to exploring immune regulatory pathways. Immunogenetics, an emerging field at the intersection of immunology, molecular biology, and genetics has provided valuable insights into inherited factors that influence immunity. Data from genetic studies conducted thus far indicate that alterations in genetic messages can significantly impact disease risk and progression. While certain genetic variations may confer protective effects, others may exacerbate disease susceptibility. This paper presents a comprehensive review of the most relevant genetic changes that influence both the risk and course of systemic sclerosis. Special emphasis is placed on factors regulating the immune response, recognizing their pivotal role in the pathogenesis of the disease.
Topics: Scleroderma, Systemic; Humans; Immunogenetics; Genetic Predisposition to Disease
PubMed: 38790215
DOI: 10.3390/genes15050586 -
Medical Engineering & Physics Jun 2024Scleroderma is a chronic and progressive autoimmune disorder of connective tissues often causing lesions and deformities of the hands. Individuals affected by this...
Scleroderma is a chronic and progressive autoimmune disorder of connective tissues often causing lesions and deformities of the hands. Individuals affected by this condition experience daily life limitations and are typically unable to take part in sport activities that involve impacts on the hands. In this article we describe the design and manufacturing of custom-made hand orthoses to play sitting volleyball, for an elite paralympic athlete affected by scleroderma. The devices consist of a carbon fibre shell with an internal silicone padding and an external polymeric multilayer cover. The manufacturing of the orthoses involves digital modelling, 3D printing, composite lamination and an innovative method to create a strong and durable chemical bonding between silicone and carbon fibre. The internal silicone padding proved to be effective in hosting and protecting the hands, whereas the external shell with polymeric multilayer cover allowed to dampen the ball shocks while effectively hitting the ball. Indeed, these devices allowed the athlete to take part in the 2020 Tokyo Paralympic games and were used for two years without showing any damage.
Topics: Humans; Equipment Design; Hand; Orthotic Devices; Volleyball; Athletes; Scleroderma, Systemic; Printing, Three-Dimensional
PubMed: 38789218
DOI: 10.1016/j.medengphy.2024.104174 -
Cirugia Y Cirujanos 2024We present the case of a 44 year old woman with systemic sclerosis who presented with intense abdominal pain without signs of peritonitis. An abdominal computed...
We present the case of a 44 year old woman with systemic sclerosis who presented with intense abdominal pain without signs of peritonitis. An abdominal computed tomography showed generalized intestinal dilation, intestinal pneumatosis and an extensive pneumoperitoneum. A diagnostic laparoscopy was performed but no perforation nor gastrointestinal leakage were found. Spontaneous pneumoperitoneum in patients with systemic sclerosis without visceral perforation is an extremely rare complication. Physicians must have a low threshold of suspicion for this entity when a patient with systemic sclerosis presents with spontaneous pneumoperitoneum in the absence of peritoneal signs.
Topics: Humans; Female; Pneumoperitoneum; Adult; Scleroderma, Systemic; Tomography, X-Ray Computed; Laparoscopy; Abdominal Pain
PubMed: 38782392
DOI: 10.24875/CIRU.22000182 -
Environmental Pollution (Barking, Essex... Aug 2024Nowadays, silica products are widely used in daily life, especially in skin applications, which inevitably increases the risk of silica exposure in general population....
Nowadays, silica products are widely used in daily life, especially in skin applications, which inevitably increases the risk of silica exposure in general population. However, inadequate awareness of silica's potential hazards and lack of self-protection are of concern. Systemic sclerosis (SSc) is characterized by progressive tissue fibrosis under environmental and genetic interactions. Silica exposure is considered an important causative factor for SSc, but its pathogenesis remains unclear. Within this study, we showed that lower doses of silica significantly promoted the proliferation, migration, and activation of human skin fibroblasts (HSFs) within 24 h. Silica injected subcutaneously into mice induced and exacerbated skin fibrosis. Notably, silica increased histone deacetylase-4 (HDAC4) expression by inducing its DNA hypomethylation in normal HSFs. The elevated HDAC4 expression was also confirmed in SSc HSFs. Furthermore, HDAC4 was positively correlated with Smad2/3 phosphorylation and COL1, α-SMA, and CTGF expression. The HDAC4 inhibitor LMK235 mitigated silica-induced upregulation of these factors and alleviated skin fibrosis in SSc mice. Taken together, silica induces and exacerbates skin fibrosis in SSc patients by targeting the HDAC4/Smad2/3 pathway. Our findings provide new insights for evaluating the health hazards of silica exposure and identify HDAC4 as a potential interventional target for silica-induced SSc skin fibrosis.
Topics: Scleroderma, Systemic; Histone Deacetylases; Animals; Silicon Dioxide; Mice; Fibrosis; Humans; Smad3 Protein; Skin; Smad2 Protein; Fibroblasts; Repressor Proteins; Signal Transduction
PubMed: 38782158
DOI: 10.1016/j.envpol.2024.124194 -
Journal of Dental Research Jul 2024Scleroderma (systemic sclerosis, SSc) is an autoimmune fibrosing connective tissue disease of unknown etiology. SSc patients show increased levels of autoantibodies,... (Review)
Review
Scleroderma (systemic sclerosis, SSc) is an autoimmune fibrosing connective tissue disease of unknown etiology. SSc patients show increased levels of autoantibodies, profibrotic cytokines, and extracellular matrix remodeling enzymes that collectively cause activated (myo)fibroblasts, the effector cell type of fibrosis. Despite these impacts, no disease-modifying therapy exists; individual symptoms are treated on a patient-to-patient basis. SSc research has been principally focused on symptoms observed in the lung and skin. However, SSc patients display significant oral complications that arise due to fibrosis of the not only skin, causing microstomia, but also the gastrointestinal tract, causing acid reflux, and the oral cavity itself, causing xerostomia and gingival recession. Due to these complications, SSc patients have impaired quality of life, including periodontitis, tooth loss, reduced tongue mobility, and malnutrition. Indeed, due to their characteristic oral presentation, SSc patients are often initially diagnosed by dentists. Despite their clinical importance, the oral complications of SSc are severely understudied; high-quality publications on this topic are scant. However, SSc patients with periodontal complications possess increased levels of matrix metalloproteinase-9 and chemokines, such as interleukin-6 and chemokine (C-X-C motif) ligand-4. Although many unsuccessful clinical trials, mainly exploring the antifibrotic effects of anti-inflammatory agents, have been conducted in SSc, none have used oral symptoms, which may be more amenable to anti-inflammatory drugs, as clinical end points. This review summarizes the current state of knowledge regarding oral complications in SSc with the goal of inspiring future research in this extremely important and underinvestigated area.
Topics: Humans; Scleroderma, Systemic; Mouth Diseases; Microstomia; Periodontal Diseases; Xerostomia; Fibrosis
PubMed: 38779873
DOI: 10.1177/00220345241249408 -
Arthritis Research & Therapy May 2024To perform a detailed morphological analysis of the inorganic portion of two different clinical presentations of calcium-based deposits retrieved from subjects with SSc...
BACKGROUND
To perform a detailed morphological analysis of the inorganic portion of two different clinical presentations of calcium-based deposits retrieved from subjects with SSc and identify a chemical dissolution of these deposits suitable for clinical use.
METHODS
Chemical analysis using Fourier Transform IR spectroscopy ('FTIR'), Raman microscopy, Powder X-Ray Diffraction ('PXRD'), and Transmission Electron Microscopy ('TEM') was undertaken of two distinct types of calcinosis deposits: paste and stone. Calcinosis sample titration with ethylenediaminetetraacetic acid ('EDTA') assessed the concentration at which the EDTA dissolved the calcinosis deposits in vitro.
RESULTS
FTIR spectra of the samples displayed peaks characteristic of hydroxyapatite, where signals attributable to the phosphate and carbonate ions were all identified. Polymorph characterization using Raman spectra were identical to a hydroxyapatite reference while the PXRD and electron diffraction patterns conclusively identified the mineral present as hydroxyapatite. TEM analysis showed differences of morphology between the samples. Rounded particles from stone samples were up to a few micron in size, while needle-like crystals from paste samples reached up to 0.5 µm in length. Calcium phosphate deposits were effectively dissolved with 3% aqueous solutions of EDTA, in vitro. Complete dissolution of both types of deposit was achieved in approximately 30 min using a molar ratio of EDTA/HAp of ≈ 300.
CONCLUSIONS
Stone and paste calcium-based deposits both comprise hydroxyapatite, but the constituent crystals vary in size and morphology. Hydroxyapatite is the only crystalline polymorph present in the SSc-related calcinosis deposits. Hydroxyapatite can be dissolved in vitro using a dosage of EDTA considered safe for clinical application. Further research is required to establish the optimal medium to develop the medical product, determine the protocol for clinical application, and to assess the effectiveness of EDTA for local treatment of dystrophic calcinosis.
Topics: Edetic Acid; Humans; Calcinosis; Spectroscopy, Fourier Transform Infrared; Microscopy, Electron, Transmission; X-Ray Diffraction; Spectrum Analysis, Raman; Female; Durapatite; Middle Aged; Male; Calcium Chelating Agents
PubMed: 38778407
DOI: 10.1186/s13075-024-03324-7 -
Journal of Medical Case Reports May 2024Mucosal melanoma, an aggressive type of malignancy different from the cutaneous melanomas commonly seen in the head and neck region, represents < 1% of all malignant...
BACKGROUND
Mucosal melanoma, an aggressive type of malignancy different from the cutaneous melanomas commonly seen in the head and neck region, represents < 1% of all malignant melanomas. The pathogenesis of mucosal melanoma is unknown. Targetable mutations commonly seen in cutaneous melanoma, such as in the BRAF and NRAS genes, have a lower incidence in mucosal melanoma. Mucosal melanoma carries a distinct mutational pattern from cutaneous melanoma. Surgery with negative margins is the first-line treatment for mucosal melanoma, and systemic therapy is not well defined. Talimogene laherparepvec, an oncolytic viral immunotherapy, is United States Food and Drug Administration approved for the treatment of advanced malignant cutaneous melanoma, with local therapeutic benefits. Mucosal melanoma was initially excluded from talimogene laherparepvec's initial phase III clinical trial.
CASE PRESENTATION
We present the case of a white female patient in her 40s with past medical history of systemic lupus erythematous, scleroderma, and estrogen-receptor-positive invasive ductal breast carcinoma. Following a bilateral mastectomy, the patient was found to have BRAF-negative mucosal melanoma of her hard palate with a soft palate skip lesion. Owing to the presence of a skip mucosal lesion as well as the anticipated defect and need for free-flap reconstructive surgery, nonsurgical management was considered. The patient was referred to medical oncology, where-based on the patient's complicated medical history and the risk of immunotherapy possibly worsening her prior autoimmune diseases-local talimogene laherparepvec injections were chosen as the primary therapy for her mucosal lesions. Though talimogene laherparepvec is approved for the treatment of cutaneous melanoma, there are limited data available on the use of talimogene laherparepvec in mucosal melanomas.
CONCLUSION
The patient had a complete local tumor response at both the primary lesion as well as the skip lesion with the local injections. She had no side effects and maintained a high quality of life during treatment.
Topics: Humans; Melanoma; Female; Biological Products; Adult; Herpesvirus 1, Human; Mouth Mucosa; Injections, Intralesional; Treatment Outcome; Antineoplastic Agents, Immunological; Oncolytic Virotherapy; Palatal Neoplasms
PubMed: 38778387
DOI: 10.1186/s13256-024-04554-8 -
Clinical and Experimental Medicine May 2024Systemic sclerosis (SSc) is characterized by microvascular damage of skin and internal organs with chronic hypoxia and release of cytokines and hormones such as...
INTRODUCTION
Systemic sclerosis (SSc) is characterized by microvascular damage of skin and internal organs with chronic hypoxia and release of cytokines and hormones such as neutrophil gelatinase-associated lipocalin (NGAL), fibroblast growth factor-23 (FGF-23) and Klotho. Aim of the study was to evaluate FGF-23, Klotho and NGAL serum levels in SSc patients and healthy controls (HC) and to evaluate serum levels changes of FGF-23, Klotho and NGAL after Iloprost.
METHODS
Twenty-one SSc patients and 20 HC were enrolled. In SSc patients, peripheral venous blood samples were collected at the first day before the autumn Iloprost infusion (t0), 60 min (t1) and 14 days after Iloprost infusion (t2).
RESULTS
SSc patients had higher serum level of FGF-23 [18.7 ± 6.4 pg/ml versus 3.6 ± 2.2 pg/ml, p < 0.001], Klotho [5.1 ± 0.8 pg/ml versus 2.3 ± 0.6 pg/ml, p < 0.001] and NGAL [20.9 ± 2.6 pg/ml versus 14.5 ± 1.7 pg/ml, p < 0.001] than HC. Iloprost infusion reduces serum level of FGF-23 (18.7 ± 6.4 pg/ml versus 10.4 ± 5.5 pg/ml, p < 0.001), Klotho (5.1 ± 0.8 pg/ml versus 2.5 ± 0.6 pg/ml, p < 0.001) and NGAL (20.9 ± 2.6 pg/ml versus 15.1 ± 2.3 pg/ml, p < 0.001) between t0 and t1. The Iloprost infusion reduces serum level of FGF-23 (18.7 ± 6.4 pg/ml versus 6.6 ± 5.1 pg/ml), Klotho (5.1 ± 0.8 pg/ml versus 2.3 ± 0.4 pg/ml) and NGAL (20.9 ± 2.6 pg/ml versus 15.5 ± 1.9 pg/ml) between t0 and t2.
CONCLUSIONS
SSc patients had higher FGF-23, Klotho and NGAL than HC. Iloprost reduces serum levels of FGF-23, Klotho and NGAL.
Topics: Humans; Iloprost; Female; Middle Aged; Male; Fibroblast Growth Factor-23; Scleroderma, Systemic; Fibroblast Growth Factors; Lipocalin-2; Adult; Glucuronidase; Klotho Proteins; Cytokines; Aged; Hypoxia; Infusions, Intravenous; Inflammation
PubMed: 38777916
DOI: 10.1007/s10238-024-01374-4 -
Archives of Rheumatology Mar 2024This study aimed to translate the Scleroderma Skin Patient-Reported Outcome (SSPRO) questionnaire to the Turkish (SSPRO-T) language and to assess its validity and...
OBJECTIVES
This study aimed to translate the Scleroderma Skin Patient-Reported Outcome (SSPRO) questionnaire to the Turkish (SSPRO-T) language and to assess its validity and reliability.
PATIENTS AND METHODS
Fifty-four systemic sclerosis (SSc) patients (51 females, 3 males; mean age: 49.8±10.4 years; range, 22 to 65 years) participated in the reliability and validity analysis between October 2022 and December 2022. The translation and cross-cultural adaptation of the SSPRO-T was applied in accordance with the procedure described by the Beaton guidelines. The SSPRO-T, the Scleroderma Health Assessment Questionnaire (SHAQ), the Health Assessment Questionnaire Disability Index (HAQ-DI), Skindex-29, and patient global skin severity were conducted in all participants for construct validity. The SSPRO-T was retested to assess its reliability after seven days.
RESULTS
The SSPRO-T had a four-factor structure. The total SSPRO-T score and its subgroups correlated positively with SHAQ, HAQ-DI, Skindex-29, and patient global skin severity. The internal consistency and reliability were excellent in overall SSPRO-T and in the subgroups: physical effect, emotional effect, physical limitation, and social effect (Cronbach's α=0.94, 0.80, 0.95, 0.93, and 0.84, respectively). The SSPRO-T had excellent test-retest reliability (r=0.91, p<0.001). In addition, no floor effect or ceiling effect was observed.
CONCLUSION
The SSPRO-T questionnaire is a reliable and valid tool and can be used in research and clinical practice in Turkish patients with SSc.
PubMed: 38774706
DOI: 10.46497/ArchRheumatol.2023.10183 -
Scientific Reports May 2024As an autoimmune disease, up to 73% of patients with primary biliary cholangitis (PBC) have a combination of extrahepatic autoimmune diseases (EHAIDs); however, the...
As an autoimmune disease, up to 73% of patients with primary biliary cholangitis (PBC) have a combination of extrahepatic autoimmune diseases (EHAIDs); however, the causal relationship between PBC and EHAIDs is unclear. The genome-wide association analyses provided 14 GWAS data for PBC and EHAIDs, and bidirectional, two-sample MR analyses were performed to examine the relationship between PBC and EHAIDs. The analysis using MR provides a strong and meaningful estimation of the bidirectional correlation between PBC and 7 EHAIDs: rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, autoimmune hypothyroidism, inflammatory bowel disease and ulcerative colitis of its types. In addition, PBC increases the risk of autoimmune thyroid diseases such as autoimmune hyperthyroidism and Graves' disease, as well as multiple sclerosis and psoriasis. Additionally, PBC is identified as a risk factor for Crohn's disease and Celiac disease. Based on genetic evidence, there may be connections between PBC and specific EHAIDs: not all coexisting EHAIDs induce PBC, and vice versa. This underscores the significance of prioritizing PBC in clinical practice. Additionally, if any liver function abnormalities are observed during treatment or with EHAIDs, it is crucial to consider the possibility of comorbid PBC.
Topics: Humans; Liver Cirrhosis, Biliary; Autoimmune Diseases; Genome-Wide Association Study; Mendelian Randomization Analysis; Colitis, Ulcerative; Arthritis, Rheumatoid; Inflammatory Bowel Diseases; Sjogren's Syndrome; Lupus Erythematosus, Systemic; Genetic Predisposition to Disease; Celiac Disease; Graves Disease; Risk Factors; Crohn Disease; Scleroderma, Systemic; Multiple Sclerosis; Polymorphism, Single Nucleotide; Psoriasis
PubMed: 38773317
DOI: 10.1038/s41598-024-62509-x