Search Results (300)

Juvenile scleroderma (JS), comprising localized (JLSd) and systemic (JSSc) forms, is a rare autoimmune disorder. This study investigated associations of polymorphisms in extracellular matrix (MMP1, MMP9) and vascular homeostasis (NOS3) genes with JS risk and immunological phenotypes. A case–control study involved 215JS patients (194 JLSd, 21 JSSc) and 72 controls. SNPs (MMP1 rs1799750, MMP9 rs3918242, NOS3 rs1799983) were genotyped using real-time PCR followed by minisequencing and mass spectrometric analysis of reaction products. Associations with disease risk, subtypes, and immunological markers were analyzed statistically. The MMP9 (rs3918242) CT genotype was significantly associated with JLSd (OR = 2.23, 95% CI: 1.14–4.37, p = 0.022), showing a trend in linear facial forms. The NOS3 (rs1799983) GG genotype demonstrated a trend toward association with JSSc (OR = 2.61, 95% CI: 0.92–7.37, p = 0.065). No significant associations were found for rs1799750 MMP1 and risk of disease development. The MMP9 risk genotype did not correlate with scleroderma-specific autoantibodies, while the NOS3 GG genotype was associated with lower serum levels of anti-collagen IV antibodies (p = 0.039). Genetic associations differ for JS subtypes: MMP9 with JLSd and NOS3 with JSSc. Children with CT polymorphism MMP9 (rs3918242) and with NOS3 (rs1799983) GG genotype were found to be genetically predisposed for the development of JS. Full article

Autoantibodies have long been regarded as passive reflections of immune dysregulation in connective tissue diseases (CTDs). Recent advances in systems immunology and molecular pathology have fundamentally redefined them as active molecular fingerprints that delineate distinct disease endophenotypes with predictive power for clinical trajectories and therapeutic responses. Rather than mere epiphenomena, autoantibodies encode precise information about dominant immune pathways, organ tropism, and pathogenic mechanisms. This review synthesizes emerging evidence that autoantibody repertoires—defined by specificity, structural properties, and functional characteristics—stratify patients beyond traditional clinical taxonomy into discrete pathobiological subsets. Specific signatures such as anti-MDA5 in rapidly progressive interstitial lung disease, anti-RNA polymerase III in scleroderma renal crisis, and anti-Ro52/TRIM21 in systemic overlap syndromes illustrate how serological profiles predict outcomes with remarkable precision. Mechanistically, autoantibody pathogenicity is modulated by immunoglobulin isotype distribution, Fc glycosylation patterns, and tissue-specific receptor expression—variables that determine whether an antibody functions as a biomarker or pathogenic effector. The structural heterogeneity of autoantibodies, shaped by cytokine microenvironments and B-cell subset imprinting, creates a dynamic continuum between pro-inflammatory and regulatory states. The integration of serological, transcriptomic, and imaging data establishes a precision medicine framework: autoantibodies function simultaneously as disease classifiers and therapeutic guides. This endophenotype-driven approach is already influencing trial design and patient stratification in systemic lupus erythematosus, systemic sclerosis, and inflammatory myopathies, and is reshaping both clinical practice and scientific taxonomy in CTDs. Recognizing autoantibodies as endophenotypic determinants aligns disease classification with pathogenic mechanism and supports the transition towards immunologically informed therapeutic strategies. Full article

Background/Objective: Pulmonary involvement in systemic sclerosis (SSc) is typically assessed using pulmonary function tests (PFTs), high-resolution CT (HRCT), and composite indices. Patient-reported outcomes (PRO), including ScleroID, provide insight into quality of life, but their relationship with clinical measures and role in overall disease assessment remain unclear. To assess the correlation between ScleroID scores and both lung involvement and disease activity/damage in a cohort of SSc-ILD patients from a large tertiary care center. Methods: Disease activity [European Scleroderma Study Group Activity Index (EScSG-AI), Scleroderma Clinical Trials Consortium Activity Index (SCTC-AI)], disease severity [Medsger severity scale (MSS)], and PRO measure ScleroID were assessed for associations with the extent and severity of SSc-ILD. Results: In 82 patients with SSc-ILD (mean age 56.0 ± 10.8 years; median disease duration 4.2 ± 4.7 years), higher fibrosis extent (>20%) was associated with worse lung function, greater exercise limitation, and higher ScleroID scores, particularly in fatigue, social life, and body mobility domains (all p ≤ 0.03). Patients with >20% fibrosis also had worse NYHA class and Borg scores during 6-MWD (p < 0.001). Cross-sectional correlations showed that ScleroID total and individual domains were negatively associated with FVC% and 6-MWD, and positively with ILD extent on HRCT. Fatigue, social impact, and mobility domains correlated most strongly with disease activity and severity scores, especially in patients with > 20% fibrosis (r = 0.384–0.635, all p ≤ 0.016), whereas breathlessness showed minimal associations (r < 0.2). Conclusions: In SSc-ILD, greater lung fibrosis and functional impairment are associated with worse patient-reported quality of life, particularly in fatigue, mobility, and social domains. ScleroID scores reflect both physiological severity and disease burden highlighting its value as a multidimensional outcome measure in patients with more advanced disease. Full article

Background: Gastrointestinal (GI) involvement is the most frequent visceral complication of systemic sclerosis (SSc), affecting up to 90% of patients, yet it remains poorly understood compared to pulmonary or cutaneous manifestations. The aim of this review is to integrate current knowledge on the cellular mechanisms underlying GI disease in SSc and to identify research priorities. Methods: A narrative literature review was conducted through a systematic PubMed search up to September 2025, complemented by manual reference screening. Results: Histopathological and functional evidence consistently demonstrates that neuromuscular alterations, including degeneration of enteric neurons, loss of interstitial cells of Cajal, and smooth muscle atrophy, can precede fibrosis, challenging the traditional “fibrosis-first” paradigm. Fibroblast and myofibroblast activation are present in gastric and colonic samples, sustained by profibrotic mediators such as TGF-β, CTGF, and endothelin-1, although the cellular origins of these stromal cells remain uncertain. Additional pathogenic contributions include autonomic dysfunction, barrier dysfunction with dysbiosis, impaired vascular reserve of vessels perfusing the gut, and functional autoantibodies targeting interneural and neuromuscular function and communication. Compared with skin and lung, the GI tract displays less fibrosis and fewer inflammatory infiltrates, but immune-derived mediators and autoantibodies suggest distinct immunopathogenic pathways are activated. Conclusions: Collectively, these findings depict GI involvement in SSc as a multi-compartmental process integrating neural, epithelial, endothelial, stromal, and immune alterations. Addressing the lack of validated biomarkers, mechanistic models, and biomarker-stratified trials will be essential to move beyond symptomatic care and toward precision medicine approaches for SSc-related GI disease. Full article

Localized scleroderma (LSc), or morphea, is an autoimmune connective tissue disease causing inflammation and fibrosis of the skin and underlying tissues. While distinct from systemic sclerosis, its clinical presentation is highly diverse. This review summarizes recent advances in the understanding and management of LSc. Pathophysiological insights have evolved significantly; the somatic mosaicism hypothesis is now supported by the observation of all six of Happle’s classic lesion patterns in LSc. Furthermore, recent single-cell RNA sequencing has elucidated key cellular mechanisms, revealing an IFN-γ-driven pro-fibrotic crosstalk between T cells, dendritic cells, and specific inflammatory fibroblast subpopulations. The discovery of a rare monogenic form of LSc caused by a STAT4 gain-of-function mutation provides a powerful human model, solidifying the critical role of the JAK-STAT pathway. Clinically, LSc is classified into subtypes such as circumscribed, linear, and generalized morphea. Extracutaneous manifestations are common, particularly in juvenile LSc, and are associated with higher disease activity and reduced quality of life, necessitating a multidisciplinary approach. Management is becoming standardized, with methotrexate as the first-line systemic therapy for severe disease. For refractory cases, targeted treatments including abatacept, tocilizumab, and JAK inhibitors are emerging as promising options. In addition, reconstructive therapies like autologous fat grafting are crucial for managing atrophic sequelae. These recent advances are paving the way for more effective, targeted therapies to improve outcomes for patients with this complex disease. Full article

Matrix metalloproteinases (MMPs) are endopeptidases that help maintain tissue homeostasis. Dysregulation of MMP secretion or activity, along with issues in their natural regulators, contributes to the development of many disorders, including autoimmune skin diseases. This article provides a comprehensive review of current research on MMP biology, their physiological functions, and disease-specific evidence in dermatology. Based on available English-language studies, we discuss key papers with important findings and the latest systematic reviews from PubMed. Additionally, a comparison, synthesis, and summary of reported results are included to highlight the specific role of MMPs in dermatology and to identify research gaps that need to be addressed for developing and using MMPs as potential biomarkers in skin disease pathophysiology. Full article

Background: Systemic sclerosis (SSc) is a rare autoimmune disease characterized by progressive fibrosis, systemic inflammation and vascular dysfunction, with manifestations that can affect multiple organs, including the heart. Cardiac involvement in SSc is often underdiagnosed, although it can have serious consequences on the prognosis, especially the occurrence of arrhythmias. These rhythm disturbances can result from direct damage to the myocardium, the conduction system, or the coronary microcirculation. Equally, the medication used can have iatrogenic consequences manifested by severe arrhythmias. Methodology: The aim of this study was to provide a synthesis of incidence, pathogenic mechanisms, diagnostic methods, and therapeutic strategies of arrhythmias associated with SSc. The potential effects of immunomodulatory therapies, such as conventional immunosuppressants and biological therapies, on cardiac electrical function were also analyzed. This narrative review could present the state of the art on arrhythmias associated with SSc, which could serve as a practical guide. In clinical practice, it is necessary to establish a team that includes cardiologists and rheumatologists as well as other specialists to contribute to a correct diagnosis followed by an optimal therapy in patients with SSc. Results: Current data suggest that diffuse myocardial fibrosis, silent ischemia, and inflammatory infiltration may alter the propagation of the electrical impulse in the heart, favoring the occurrence of arrhythmias. Atrioventricular blocks, ventricular tachyarrhythmias, and atrial fibrillation are the most commonly reported rhythm abnormalities in SSc. Also, some therapies used in the treatment of the disease may influence the arrhythmic risk. Conclusions: Cardiac arrhythmias in SSc can have a significant impact on the prognosis of patients, which is why a multidisciplinary approach is essential. Collaboration between rheumatologists, cardiologists, and electrophysiologists is crucial for the early identification and appropriate management of arrhythmic risk in this patient group. Full article

The gastrointestinal (GI) tract is seriously affected by systemic sclerosis (SSc), due to fibrosis and persistent inflammation. Patients with GI involvement frequently exhibit poor nutritional status, which affects disease burden and quality of life. The aim of the present review was to discuss all nutritional issues in SSc and serve as a primer for the nutritional assessment of patients with scleroderma. Patients with SSc suffer from GI impairments that affect the oral cavity, esophagus, stomach, and small and large intestines. Symptomatology includes microstomia, xerostomia, dysphagia, reflux, esophageal dysmotility, small intestinal bacterial overgrowth (SIBO), and fecal incontinence, among others, which may contribute to inadequate food intake. As a result, patients often suffer from malnutrition, sarcopenia, and frailty, while presenting with micronutrient deficiencies that impact disease outcomes and worsen their condition. This aggravated nutritional status is related to greater disease severity, organ involvement, reduced physical function, and increased length of hospitalization and mortality. GI involvement is well-documented within the SSc population, yet routine nutritional assessments are lacking in the hospital setting. Currently, there is a lack of specific recommendations from scientific societies regarding the nutritional care of patients with SSc. Given the high risk of nutritional impairments in this population, systematic assessments should be undertaken, and novel tools tailored to their unique needs should be developed and implemented. Full article

Systemic Sclerosis (SSc) is a systemic autoimmune disease of unknown etiology characterized by a severe fibroproliferative vasculopathy and frequently progressive cutaneous and internal organ fibrosis. The small-vessel vasculopathy and the tissue fibrotic alterations are responsible for the most serious clinical and pathological manifestations of the disease and for its high mortality. Despite the high severity and frequent mortality, there are currently no optimal therapeutic approaches for SSc, and its complex pathogenesis has not been fully elucidated. Numerous studies have suggested that growth factors and related regulatory macromolecules released from inflammatory and other cells present in the affected tissues play a crucial role in the frequently progressive cutaneous and visceral fibrosis. Here, we will review some of the recent studies describing the role of various growth factors and related macromolecules in the development and progression of the fibrotic process in SSc. Full article

Forest ecosystems undergo seasonal shifts in bacterial and fungal communities, but little is known about the specific microbiota associated with Quercus robur–Boletus edulis systems. This study represents the first examination of seasonal changes in soil microbiota in pedunculate oak habitats in Galicia (NW Spain) and their relationship with Boletus edulis and Boletus reticulatus mycelium prevalence and concentration. Soil microbiota richness, diversity, and composition, as well as seasonal variation in Boletus mycelium, were assessed using DNA metabarcoding and qPCR, respectively. Sampling was conducted in autumn at two 30–40-year-old Q. robur stands. Bacterial communities were dominated by Acidobacteria (34%) and Proteobacteria (33%), with Acidobacterium (12%), Paludibaculum (9%), and Edaphobacter (7%) identified as most abundant. Fungal communities were primarily Basidiomycota (93%), led by Russula (46%). For both bacteria and fungi, the highest OTU richness was observed in September, followed by a significant decrease in October and a partial recovery in November. Boletus species were found to exhibit positive correlations with specific bacteria (e.g., Massilia, Rhizobium) and fungi (e.g., Amanita, Clavaria, Inocybe, Scleroderma, Suillus and Mortierella), suggesting a potential influence of these microbes on mycelium development. This study provides novel insights into the seasonal dynamics of soil microbiota and their potential role in Boletus ecology, thereby advancing understanding of host–microbe interactions in temperate forests. Full article

Objectives: Cardiac involvement in scleroderma due to myocardial inflammation and fibrosis is associated with poor outcomes, but there is lack of consensus on its investigation and treatment. In this prospective pilot study, we aimed to assess the cardiac uptake of 18F-FDG-PET/CT in suspected scleroderma cardiomyopathy. Methods: The Scleroderma Heart study involved 16 patients with cardiac scleroderma but no coronary artery disease. 18F-FDG-PET/CTs were performed, and the patients with a positive scan were offered a second 18F-FDG-PET/CT scan after 6–9 months. The clinical characteristics and clinical outcomes (all-cause mortality) were compared between the patients with positive and negative 18F-FDG-PET/CT scans. Results: Of the 16 included patients, 8 (50%) had positive myocardial uptake on the 18F-FDG-PET/CT, 2 of whom showed a pattern consistent with cardiac involvement in scleroderma, while 6 patients more likely had physiological uptake. Over a mean follow-up of 603.3 days, all-cause mortality occurred in six patients (37.5%), and the mortality was similar between the two groups. Five patients with repeat 18F-FDG-PET/CTs showed stable or increased FDG uptake despite immunosuppression. Conclusions: To the best of our knowledge, this is the first study to investigate 18F-FDG-PET/CT in scleroderma patients with suspected cardiac involvement. The cardiac PET showed limited clinical utility due to frequent physiological uptake and lack of correlation with the treatment response. Further studies with larger cohorts and standardised interpretation criteria are needed before cardiac PET can be recommended for routine clinical use in scleroderma cardiomyopathy. Full article

Background/Objectives: Juvenile localized scleroderma (jLoS) is a chronic inflammatory disorder with skin and subcutaneous tissue involvement. Microvascular alterations are thought to contribute to its pathogenesis. This study aimed to investigate microvascular alterations in children with jLoS using nailfold capillaroscopy (NFC) and to compare the capillaroscopic findings between patients and healthy controls. Methods: A total of 13 children diagnosed with jLoS and 16 age- and sex-matched healthy controls were enrolled. Capillaroscopic assessment included capillary density, tortuosity, dilatation, disorganization, branching, and neoangiogenesis. Dilated and giant capillaries, hemorrhages, avascular areas, and capillary loss were evaluated. The Microangiopathy Evaluation Score (MES) was used to semi-quantitatively assess capillary loss, disorganization, and ramifications. Disease activity and damage were evaluated using the modified Localized Scleroderma Skin Severity Index (mLoSSI) and the Localized Scleroderma Damage Index (LoSDI), respectively. Functional status was measured via the 6 min walk test (6MWT). Results: Plaque morphea was the most common subtype (61.5%), and antinuclear antibody (ANA) positivity was present in 53.8% of patients. Compared to controls, jLoS patients exhibited significantly more frequent capillaroscopic abnormalities, including increased tortuosity, crossing, dilatation, and neoangiogenesis (p < 0.05). Capillary density, length, arterial limb width, apical loop width, and disorganization scores were significantly higher, while intercapillary distance was lower in jLoS patients (p < 0.05). No avascular areas or giant capillaries were observed. MESs were similar between groups. Conclusions: NFC revealed significant microvascular alterations in jLoS patients, supporting its utility as a non-invasive tool for early vascular assessment in localized scleroderma. Full article

Melanocortin receptors (MCRs) are responsible for various functions ranging from skin pigmentation, regulation of appetite, stress response and cognition, steroid synthesis, and energy balance to cellular regeneration and immunomodulation. The genetic polymorphism with tissue distribution ranging from the brain, limbic system, and adrenal cortex to neutrophils, monocytes, and macrophages is evident in MCRs. The mutations in MC1R, MC2R, MC3R, and MC4R genes are associated with risk of melanoma, familial glucocorticoid deficiency, obesity, and type 2 diabetes mellitus, respectively. Meanwhile, MC1R, MC2R, and MC5R genes are involved in the risk of major depressive disorder. Melanocortin receptors are involved in different inflammatory disorders, i.e., atopic dermatitis, autoimmune uveitis, sarcoidosis, respiratory diseases, multiple sclerosis, scleroderma, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer’s disease, arthritis, and reperfusion injury. Several newer therapeutic agents related to MCRs have numerous advantages over the current anti-inflammatory drugs, demonstrating therapeutic relevance. Among them, α-MSH analogs play a role in atopic dermatitis and scleroderma, and MC1R agonist Dersimelagon has shown effectiveness in systemic sclerosis. The FDA has recently approved the repository corticotropin injection (RCI) to treat sarcoidosis. The FDA has also approved various melanocortin agonists, i.e., Bremelanotide, Afamelanotide, and Setmelanotide, for the treatment of hypoactive sexual desire disorder, Erythropoietic protoporphyria, and obesity, due to pro-opiomelanocortin and leptin receptor deficiency, respectively. Therefore, this review aims to summarize the function and genetic polymorphism of melanocortin receptors, regulatory pathways involving MCRs, and the existing evidence of the prime effect of MCRs on inflammatory responses via different mechanisms and their potential therapeutic use in inflammatory diseases. Full article

Background: Female sexual dysfunction (FSD) is an underrecognized issue in women with systemic sclerosis (SSc), influenced by physical and psychological factors. Data on FSD in reproductive-age SSc patients, especially those with diffuse cutaneous SSc (dcSSc), remain limited. Objectives: This study aimed to determine the prevalence of FSD and identify its associated factors among reproductive-age women with SSc. Methods: A cross-sectional study (May 2019–March 2020) included sexually active women with SSc aged 18–45. Patients with surgical amenorrhea, prior radiation, hormonal contraceptive use within 12 weeks, or pregnancy were excluded. Sexual function was assessed using the Female Sexual Function Index (FSFI). Results: Among 27 women of reproductive age, 66.7% had the dcSSc subset. The mean age was 39.4 ± 5.2 years (range: 22–45 years), with a mean disease duration of 9.9 ± 7.9 years. FSD was identified in 51.9% of patients (95%CI: 31.9–71.3), with a higher prevalence in the dcSSc subset (71.4%) compared to limited cutaneous SSc (28.6%). Patients with FSD were more likely to be older at disease onset, exhibit telangiectasia, and have longer exposure to cyclophosphamide (CYC), although these findings were not statistically significant. Women with FSD showed significantly lower FSFI scores in arousal, lubrication, orgasm, sexual satisfaction, and total sexual function (p < 0.01 for all). Conclusions: FSD is highly prevalent among SSc women of reproductive age, particularly in those with dcSSc. Disease severity, older age at onset, and prolonged CYC treatment may contribute to the risk of FSD. Early recognition and management of sexual health issues are essential in this patient population. Full article

Background: Patients with systemic sclerosis have a significantly increased incidence of developing various solid malignancies within a few years of systemic sclerosis onset, but the mechanism of tumor promotion is not well understood. The tight skin (TSK) mouse has been a valuable model for investigating systemic sclerosis-related pathologies due to increased extracellular matrix deposition, fibrosis in connective tissues, and altered immune cell activation. Despite the role of extracellular matrix and fibrosis in cancer progression, the potential of the TSK mouse as a model for cancer studies is unexplored. Methods: To investigate the impact of the altered microenvironment in TSK mice on cancer progression, we compared the tumor-forming capabilities (by subcutaneous and intraperitoneal injection) in TSK mice and WT mice using syngeneic breast cancer, melanoma, and ovarian cancer cell lines. We used bulk and single-cell RNA sequencing to characterize these tumors and identify the changes in the TSK microenvironment that promote cancer formation. Results: In all three cancer types, TSK mice exhibited more invasive subcutaneous tumors in comparison to WT controls, underscoring the role of the TSK subcutaneous microenvironment in promoting cancer progression. Furthermore, the heightened invasiveness of ovarian tumors implanted intraperitoneally suggests that the peritoneal microenvironment in TSK mice also promotes tumor progression. Single-cell RNA sequencing analyses of subcutaneous tumors from TSK and WT mice revealed tumor-specific changes in the composition and phenotype of various cell populations. The most consistent alteration in TSK mice included a higher neutrophil-to-lymphocyte ratio and an enrichment in profibrotic subpopulations of myofibroblasts and macrophages. Conclusions: Our research unveils the TSK mouse as a valuable model for studying the intricate connections between systemic sclerosis and cancer Full article