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RMD Open May 2024To untangle the association between smoking and systemic sclerosis (SSc).
OBJECTIVES
To untangle the association between smoking and systemic sclerosis (SSc).
METHODS
In the European Scleroderma Trials and Research cohort, the autoantibody status was compared between ever-smokers and never-smokers. Time until disease progression was assessed using Kaplan-Meier curves. Cox models were built to investigate the influence of smoking over 15 years of follow-up. All analyses were performed for the total cohort and stratified for sex and for positivity of anti-centromere (ACA) and anti-topoisomerase antibodies (ATA).
RESULTS
Overall, 12 314 patients were included in the study. Of these, 10 393 were women (84%), 4637 were ACA-positive (38%), 3919 were ATA-positive (32%) and 4271 (35%) were ever-smokers. In men, but not in women, smoking was associated with mortality (HR 1.63, 95% CI 1.23 to 2.16, p=0.001). Ever-smoking women were at higher risk for skin progression (HR 1.10, 95% CI 1.00 to 1.22, p=0.046) and for 'any organ progression' (HR 1.07, 95% CI 1.00 to 1.13, p=0.036). In women, 34% of never-smokers were ATA-positive compared with 21% of ever-smokers (p<0.001). In the group of ever-smokers, higher exposure rates, reflected by the number of pack-years (OR 0.98, 95% CI 0.97 to 0.99, p<0.001) and by smoking duration (OR 0.96, 95% CI 0.95 to 0.97, p<0.001), were associated with lower frequency of ATA. In ACA-positive patients, the risk of mortality (HR 1.29, 95% CI 1.02 to 1.63, p=0.033), cardiac involvement (HR 1.25, 95% CI 1.03 to 1.43, p=0.001), skin progression (HR 1.21, 95% CI 1.03 to 1.42, p=0.018) and 'any organ progression' (HR 1.14, 95% CI 1.05 to 1.24, p=0.002) was increased among smokers. In ATA-positive smoking patients, mortality (HR 1.40, 95% CI 1.10 to 1.78, p=0.006), skin progression (HR 1.19, 95% CI 1.03 to 1.37, p=0.020) digital ulcers (HR 1.17, 95% CI 1.02 to 1.34, p=0.029) and 'any organ progression' (HR 1.11, 95% CI 1.00 to 1.22, p=0.048) occurred more frequently.
CONCLUSIONS
Our stratified analysis demonstrates that smoking is associated with an increased risk for mortality in male SSc patients but not in women. Strikingly, smoking is associated with lower prevalence of ATA positivity, in particular in women. In both ATA-positive and ACA-positive patients, smoking is a risk factor for mortality, skin progression and 'any organ progression'.
Topics: Humans; Scleroderma, Systemic; Female; Male; Middle Aged; Smoking; Disease Progression; Adult; Proportional Hazards Models; Risk Factors; Autoantibodies; Aged; Kaplan-Meier Estimate; Cohort Studies
PubMed: 38772679
DOI: 10.1136/rmdopen-2024-004101 -
Journal of Ayurveda and Integrative... May 2024Diffuse systemic sclerosis or scleroderma is a chronic connective tissue disorder involving many systems and visceral organs. The association of interstitial lung...
Diffuse systemic sclerosis or scleroderma is a chronic connective tissue disorder involving many systems and visceral organs. The association of interstitial lung disease carries high mortality risk. This is a case report of a patient aged 25-years, who was diagnosed as diffuse systemic sclerosis, a disease complex along with Interstitial Lung Disease (ILD), sclerodactyly. She also presented with digital ulcers and calcium deposits in the ulcers. The symptomatology was understood by analysing the dosha predominance and the composition of the different qualities of each dosha in the patient. This complicated case with a bad prognosis was managed with Ayurvedic treatment procedures and medicines. Matrabasti (medicated enema) with mahamasha taila and dhanvantara taila was given. yogabasti with dashamoola ksheera paka, dhanvantara taila and madhu (decoctive enema), along with other palliative medicines like rasna yoga raja, Yogendra rasa, vasakasava, drakshadi paka, kaishora guggulu, raktapachakaghana vati and Mahatiktaka ghrita were given to the patient. After 1-1.2 years of continuous treatments, patient started showing gradual changes in her health condition. Relief from joint pains, intake of normal food, weight gain, re-establishment of menstruation, healing of ulcers was some of the changes seen in the patient. This case report summaries the effective management of diffuse systemic sclerosis after deducing the complex disease structure to dosa and guna involved and treated by adopting ayurvedic medicine and treatment procedures.
PubMed: 38760244
DOI: 10.1016/j.jaim.2023.100883 -
Biochemical and Biophysical Research... Aug 2024The contributions of anti-Topoisomerase 1 (Top1) autoantibodies to the pathophysiology of diffuse cutaneous systemic sclerosis (dcSSc), the most aggressive scleroderma...
The contributions of anti-Topoisomerase 1 (Top1) autoantibodies to the pathophysiology of diffuse cutaneous systemic sclerosis (dcSSc), the most aggressive scleroderma subtype, are unknown. Top1 catalyzes DNA relaxation and unwinding in cell nuclei, a site previously considered inaccessible to antibodies. The discovery of autoantibodies in systemic lupus erythematosus that penetrate nuclei and inhibit DNA repair raised the possibility that nuclear-penetrating autoantibodies contribute to mechanisms of autoimmunity. Here we show that an anti-Top1 autoantibody produced by a single B cell clone from a patient with dcSSc penetrates live cells and localizes into nuclei. Functionally, the autoantibody inhibits formation of the Top1 cleavage complex necessary for DNA nicking, which distinguishes it from cytotoxic camptothecin Top1 inhibitors used in cancer therapy that trap the cleavage complex rather than preventing its formation. Discovery of a patient-derived cell-penetrating scleroderma anti-Top1 autoantibody that inhibits Top1 cleavage complex formation supports the hypothesis that anti-Top1 autoantibodies contribute to cellular dysfunction in dcSSc and offers a valuable antibody reagent resource for future studies on anti-Top1 autoantibody contributions to scleroderma pathophysiology.
Topics: DNA Topoisomerases, Type I; Humans; Autoantibodies; Cell Nucleus; Scleroderma, Diffuse
PubMed: 38759301
DOI: 10.1016/j.bbrc.2024.150123 -
Scientific Reports May 2024We aimed to develop a systemic sclerosis (SSc) subtypes classifier tool to be used at the patient's bedside. We compared the heart rate variability (HRV) at rest (5-min)...
We aimed to develop a systemic sclerosis (SSc) subtypes classifier tool to be used at the patient's bedside. We compared the heart rate variability (HRV) at rest (5-min) and in response to orthostatism (5-min) of patients (n = 58) having diffuse (n = 16, dcSSc) and limited (n = 38, lcSSc) cutaneous forms. The HRV was evaluated from the beat-to-beat RR intervals in time-, frequency-, and nonlinear-domains. The dcSSc group differed from the lcSSc group mainly by a higher heart rate (HR) and a lower HRV, in decubitus and orthostatism conditions. Stand-up maneuver lowered HR standard deviation (sd_HR), the major axis length of the fitted ellipse of Poincaré plot of RR intervals (SD2), and the correlation dimension (CorDim) in the dcSSc group while increased these HRV indexes in the lcSSc group (p = 0.004, p = 0.002, and p = 0.004, respectively). We identified the 5 most informative and discriminant HRV variables. We then compared 341 classifying models (1 to 5 variables combinations × 11 classifier algorithms) according to mean squared error, logloss, sensitivity, specificity, precision, accuracy, area under curve of the ROC-curves and F1-score. F1-score ranged from 0.823 for the best 1-variable model to a maximum of 0.947 for the 4-variables best model. Most specific and precise models included sd_HR, SD2, and CorDim. In conclusion, we provided high performance classifying models able to distinguish diffuse from limited cutaneous SSc subtypes easy to perform at the bedside from ECG recording. Models were based on 1 to 5 HRV indexes used as nonlinear markers of autonomic integrated influences on cardiac activity.
Topics: Humans; Heart Rate; Female; Male; Middle Aged; Scleroderma, Systemic; Phenotype; Adult; Aged; Algorithms; Electrocardiography
PubMed: 38750078
DOI: 10.1038/s41598-024-60553-1 -
The Journal of Clinical Investigation Mar 2024Transforming growth factor β (TGF-β) signaling is a core pathway of fibrosis, but the molecular regulation of the activation of latent TGF-β remains incompletely...
Transforming growth factor β (TGF-β) signaling is a core pathway of fibrosis, but the molecular regulation of the activation of latent TGF-β remains incompletely understood. Here, we demonstrate a crucial role of WNT5A/JNK/ROCK signaling that rapidly coordinates the activation of latent TGF-β in fibrotic diseases. WNT5A was identified as a predominant noncanonical WNT ligand in fibrotic diseases such as systemic sclerosis, sclerodermatous chronic graft-versus-host disease, and idiopathic pulmonary fibrosis, stimulating fibroblast-to-myofibroblast transition and tissue fibrosis by activation of latent TGF-β. The activation of latent TGF-β requires rapid JNK- and ROCK-dependent cytoskeletal rearrangements and integrin αV (ITGAV). Conditional ablation of WNT5A or its downstream targets prevented activation of latent TGF-β, rebalanced TGF-β signaling, and ameliorated experimental fibrosis. We thus uncovered what we believe to be a novel mechanism for the aberrant activation of latent TGF-β in fibrotic diseases and provided evidence for targeting WNT5A/JNK/ROCK signaling in fibrotic diseases as a new therapeutic approach.
Topics: Wnt-5a Protein; Animals; Transforming Growth Factor beta; Mice; Humans; Fibrosis; Fibroblasts; rho-Associated Kinases; Scleroderma, Systemic; Mice, Knockout; Wnt Proteins; MAP Kinase Signaling System; Myofibroblasts; Signal Transduction; Idiopathic Pulmonary Fibrosis
PubMed: 38747285
DOI: 10.1172/JCI159884 -
Clinical, Cosmetic and Investigational... 2024Systemic sclerosis represents a persistent autoimmune disorder marked with fibrosis affecting both skin and other organs, which leads to a diminished quality of life and...
BACKGROUND
Systemic sclerosis represents a persistent autoimmune disorder marked with fibrosis affecting both skin and other organs, which leads to a diminished quality of life and increased mortality. The affected skin provides a valuable opportunity to explore the pathogenesis of systemic sclerosis. Nevertheless, the roles of various cell populations within scleroderma remain intricate.
METHODS
We conducted a comprehensive reanalysis of recently published single-cell RNA-sequencing data from skin tissue cells in scleroderma. Through the utilization of Seurat, irGSEA, AUCell packages, and WGCNA analysis, we aimed to unveil crucial genes associated with the disease's etiological factors. Our investigation involved the characterization of heterogeneous pathway activities in both healthy and SSc-affected skin. Furthermore, we employed immunofluorescence techniques to validate the expression patterns of hub genes and differentially expressed genes.
RESULTS
The Endothelial-to-Mesenchymal Transition (EndMT) pathway was upregulated in SSc skin. Notably, the M4 module within Endothelial cell subpopulation 1 exhibited a strong association with EndMT. Furthermore, we identified three overexpressed genes (, I) that demonstrated a significant correlation with EndMT. Importantly, their expression levels were markedly higher in skin of individuals with SSc when compared to healthy controls.
CONCLUSION
and serve as potential key players in the pathogenesis of SSc skin through EndMT-dependent mechanisms.
PubMed: 38742168
DOI: 10.2147/CCID.S456593 -
Current Treatment Options in... Dec 2023Systemic sclerosis (SSc) and myositis are two different entities that may coexist as an overlap syndrome. Immunological biomarkers such as anti-PM/Scl or anti-Ku...
PURPOSE OF REVIEW
Systemic sclerosis (SSc) and myositis are two different entities that may coexist as an overlap syndrome. Immunological biomarkers such as anti-PM/Scl or anti-Ku reinforce the syndrome. This review is focused on the treatment of different and characteristic manifestations of this syndrome.
RECENT FINDINGS
Among the different phenotypes of muscle involvement in patients with SSc, the fibrotic pattern and the sporadic inclusion body myositis must be identified early to avoid a futile immunosuppressive treatment. Other forms such as dermatomyositis, non-specific myositis and immune-mediated necrotizing myopathy need to receive conventional immunosuppressive therapy considering that high dose of glucocorticoids may induce a scleroderma renal crisis in patients with SSc. Physicians must be aware of the existence of a "double trouble" association of hereditary myopathy with an autoimmune phenomenon. Several autoantibodies, mainly anti-PM/Scl and anti-Ku may help to define specific phenotypes with characteristic clinical manifestations that need a more specific therapy. Vasculopathy is one of the underlying mechanisms that link SSc and myositis. Recent advances in this topic are reviewed.
SUMMARY
Current treatment of SSc associated myopathy must be tailored to specific organs involved. Identifying the specific clinical, pathological, and immunological phenotypes may help to take the correct therapeutic decisions.
PubMed: 38737329
DOI: 10.1007/s40674-023-00206-y -
Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: From Bedside to Bench and Back Again.International Journal of Molecular... Apr 2024Systemic sclerosis (SSc) is a heterogeneous disease characterized by autoimmunity, vasculopathy, and fibrosis which affects the skin and internal organs. One key aspect... (Review)
Review
Systemic sclerosis (SSc) is a heterogeneous disease characterized by autoimmunity, vasculopathy, and fibrosis which affects the skin and internal organs. One key aspect of SSc vasculopathy is pulmonary arterial hypertension (SSc-PAH) which represents a leading cause of morbidity and mortality in patients with SSc. The pathogenesis of pulmonary hypertension is complex, with multiple vascular cell types, inflammation, and intracellular signaling pathways contributing to vascular pathology and remodeling. In this review, we focus on shared molecular features of pulmonary hypertension and those which make SSc-PAH a unique entity. We highlight advances in the understanding of the clinical and translational science pertinent to this disease. We first review clinical presentations and phenotypes, pathology, and novel biomarkers, and then highlight relevant animal models, key cellular and molecular pathways in pathogenesis, and explore emerging treatment strategies in SSc-PAH.
Topics: Humans; Scleroderma, Systemic; Animals; Pulmonary Arterial Hypertension; Biomarkers; Hypertension, Pulmonary; Disease Models, Animal; Translational Research, Biomedical; Signal Transduction
PubMed: 38731946
DOI: 10.3390/ijms25094728 -
Journal of Clinical Medicine May 2024Nodular or keloidal scleroderma is a rare condition with unclear cause and sporadic mentions in the medical literature. It was first recognized in the 19th century, yet... (Review)
Review
Nodular or keloidal scleroderma is a rare condition with unclear cause and sporadic mentions in the medical literature. It was first recognized in the 19th century, yet its classification is still debated due to the limited number of reported cases. This rare variant of scleroderma is associated with either progressive systemic sclerosis or localized morphea. Clinically, it presents with asymptomatic nodules or plaques, resembling spontaneous keloid formation, often found on the trunk and proximal extremities. Recent literature reviews show a predominance of women with a mean age of 44 years. Diagnosis relies on clinical and histopathological findings, which usually show overlapping features of both scleroderma and true keloids, secondarily to an excessive fibrosing reaction attributed to collagen formation. We present an unusual case of a 70-year-old female patient who displayed the coexistence of two distinct subtypes of morphea (nodular/keloidal and linear), and exclusive skin involvement, which contrasts with the typical presentation of nodular/keloidal scleroderma, often associated with organ-specific disease. However, recent publications have diverged from previous ones regarding systemic sclerosis, with no systemic involvement reported between 2018 and 2024, which we evaluated in our descriptive literature review. With less than 50 cases reported in total, our case underlines the importance of recognizing this rare disease, ensuring appropriate evaluation, treatment, and follow-up.
PubMed: 38731191
DOI: 10.3390/jcm13092662 -
Frontiers in Immunology 2024Systemic autoimmune diseases (SADs) are a significant burden on the healthcare system. Understanding the complexity of the peripheral immunophenotype in SADs may... (Comparative Study)
Comparative Study
Comparative single-cell multiplex immunophenotyping of therapy-naive patients with rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus shed light on disease-specific composition of the peripheral immune system.
INTRODUCTION
Systemic autoimmune diseases (SADs) are a significant burden on the healthcare system. Understanding the complexity of the peripheral immunophenotype in SADs may facilitate the differential diagnosis and identification of potential therapeutic targets.
METHODS
Single-cell mass cytometric immunophenotyping was performed on peripheral blood mononuclear cells (PBMCs) from healthy controls (HCs) and therapy-naive patients with rheumatoid arthritis (RA), progressive systemic sclerosis (SSc), and systemic lupus erythematosus (SLE). Immunophenotyping was performed on 15,387,165 CD45 live single cells from 52 participants (13 cases/group), using an antibody panel to detect 34 markers.
RESULTS
Using the t-SNE (t-distributed stochastic neighbor embedding) algorithm, the following 17 main immune cell types were determined: CD4/CD57 T cells, CD4/CD57 T cells, CD8/CD161 T cells, CD8/CD161/CD28 T cells, CD8 T cells, CD3/CD4/CD8 T cells, TCRγ/δ T cells, CD4 NKT cells, CD8 NKT cells, classic NK cells, CD56/CD98 cells, B cells, plasmablasts, monocytes, CD11cdim/CD172dim cells, myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs). Seven of the 17 main cell types exhibited statistically significant frequencies in the investigated groups. The expression levels of the 34 markers in the main populations were compared between HCs and SADs. In summary, 59 scatter plots showed significant differences in the expression intensities between at least two groups. Next, each immune cell population was divided into subpopulations (metaclusters) using the FlowSOM (self-organizing map) algorithm. Finally, 121 metaclusters (MCs) of the 10 main immune cell populations were found to have significant differences to classify diseases. The single-cell T-cell heterogeneity represented 64MCs based on the expression of 34 markers, and the frequency of 23 MCs differed significantly between at least twoconditions. The CD3 non-T-cell compartment contained 57 MCs with 17 MCs differentiating at least two investigated groups. In summary, we are the first to demonstrate the complexity of the immunophenotype of 34 markers over 15 million single cells in HCs vs. therapy-naive patients with RA, SSc, and SLE. Disease specific population frequencies or expression patterns of peripheral immune cells provide a single-cell data resource to the scientific community.
Topics: Humans; Immunophenotyping; Lupus Erythematosus, Systemic; Female; Single-Cell Analysis; Arthritis, Rheumatoid; Middle Aged; Adult; Male; Scleroderma, Systemic; Aged; Leukocytes, Mononuclear; Biomarkers
PubMed: 38726007
DOI: 10.3389/fimmu.2024.1376933