Pathogenesis Of Systemic Sclerosis Research Articles

Single-cell transcriptomes and chromatin accessibility of endothelial cells unravel transcription factors associated with dysregulated angiogenesis in systemic sclerosis

ObjectivesVasculopathy emerges early in systemic sclerosis (SSc) and links to endothelial cell (EC) injury and angiogenesis. Understanding EC transcriptomes and epigenomes is crucial for unravelling the mechanisms involved.MethodsTranscriptomes and chromatin...

Upregulation of GPX4 drives ferroptosis resistance in scleroderma skin fibroblasts

The pathogenesis of systemic sclerosis (SSC) fibrosis involves the rapid proliferation of skin fibroblasts, and current anti-fibrotic treatments are limited. This study investigated the relationship between ferroptosis and SSC skin fibroblasts. We observed that erastin-induced ferroptosis was suppressed in SSC fibroblasts. RSL3, a direct inhibitor of Glutathione Peroxidase 4 (GPX4), significantly reduced the viability of the fibroblasts, and upregulation of GPX4 in the SSC fibroblasts contributed to ferroptosis resistance. Furthermore, we demonstrated that transferrin receptor 1 (TfR1) was a crucial transporter for iron deposition in the fibroblasts. Collectively, our results highlight that GPX4 inhibition could enhance the sensitivity to ferroptosis by SSC fibroblasts, which showed distinct characteristics of iron metabolism that were not observed in normal fibroblasts in this study. Taken together, these results suggest that targeting ferroptosis could be a therapeutic strategy for the treatment of SSC.

Single-Cell RNA-Sequencing Analyses Identify APLNR, INS-IGF2, RGCC Genes May Be Involved in the Pathogenesis of Systemic Sclerosis Skin.

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. 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. 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 (APLNR, INS-IGF2, RGCC) 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. APLNR, INS-IGF2 and RGCC serve as potential key players in the pathogenesis of SSc skin through EndMT-dependent mechanisms.

Serum levels of AGGF1: Potential association with cutaneous and cardiopulmonary involvements in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, aberrant immune activation, and extensive tissue fibrosis of the skin and internal organs. Because of the complicated nature of its pathogenesis, the underlying mechanisms of SSc remain incompletely understood. Angiogenic factor with a G-patch domain and a Forkhead-associated domain 1 (AGGF1) is a critical factor in angiogenesis expressed on vascular endothelial cells, associated with inflammatory and fibrotic responses. To elucidate the possible implication of AGGF1 in SSc pathogenesis, we investigated the association between serum AGGF1 levels and clinical manifestations in SSc patients. We conducted a cross-sectional analysis of AGGF1 levels in sera from 60 SSc patients and 19 healthy controls with enzyme-linked immunosorbent assay. Serum AGGF1 levels in SSc patients were significantly higher than those in healthy individuals. In particular, diffuse cutaneous SSc patients with shorter disease duration had higher levels compared to those with longer disease duration and limited cutaneous SSc patients. Patients with higher serum AGGF1 levels had a higher incidence of digital ulcers, higher modified Rodnan Skin Scores (mRSS), elevated serum Krebs von den Lungen-6 (KL-6) levels, C-reactive protein levels, and right ventricular systolic pressures (RVSP) on the echocardiogram, whereas they had reduced percentage of vital capacity (%VC) and percentage of diffusing capacity of the lungs for carbon monoxide (%DLCO) in pulmonary functional tests. In line, serum AGGF1 levels were significantly correlated with mRSS, serum KL-6 and surfactant protein D levels, RVSP, and %DLCO. These results uncovered notable correlations between serum AGGF1 levels and key cutaneous and vascular involvements in SSc, suggesting potential roles of AGGF1 in SSc pathogenesis.

Interferon-γ Induces Interleukin-6 Production and Alpha-smooth Muscle Actin Expression in Systemic Sclerosis Fibroblasts


 Systemic sclerosis (SSc) is an autoimmune systemic disease that is characterized by immune dysregulation, inflammation, vasculopathy, and fibrosis. Tissue fibrosis plays an important role in SSc and can affect several organs such as the dermis, lungs, and heart. Dysregulation of interferon (IFN) signaling contributes to the SSc pathogenesis and interferon regulatory factor 1 (IRF1) has been indicated as the main regulator of type I IFN.
 This study aimed to clarify the effect of IFN-gamma (-γ) and dexamethasone (DEX) on the IRF1, extracellular signal-regulated kinase 1/2 (ERK1/2), and the expression of alpha-smooth muscle actin (α-SMA) in myofibroblasts and genes involved in the inflammation and fibrosis processes in early diffuse cutaneous systemic sclerosis (dcSSc). A total of 10 early dcSSc patients (diffuse cutaneous form) and 10 unaffected control dermis biopsies were obtained to determine IFNγ and DEX effects on inflammation and fibrosis. Fibroblasts were treated with IFNγ and DEX at optimum time and dose. The expression level of genes and proteins involved in the fibrosis and inflammation processes have been quantified by quantitative real-time PCR (RT-qPCR) and western blot, respectively.
 IFNγ could up-regulate some of the inflammation-related genes (Interleukin-6; IL6) and down-regulate some of the fibrosis-related genes (COL1A1) in cultured fibroblasts of patients with early dcSSc compared to the untreated group. Besides, it has been revealed that IFNγ can induce fibroblast differentiation to the myofibroblast that expresses α-SMA.
 Concerning the inhibitory effect of IFNγ on some fibrotic genes and its positive effect on the inflammatory genes and myofibroblast differentiation, it seems that IFNγ may play a dual role in SSc.

The deficiency of DNASE1L3 does not affect systemic sclerosis pathogenesis in two inducible murine models of the disease.

We induced systemic sclerosis (SSc)-like disease in both wild-type and Dnase1l3-deficient mice using two distinct approaches involving bleomycin and hypochlorous acid injections. Our observations revealed that the deficiency in DNASE1L3 did not affect tissue fibrosis or inflammation caused by these treatments. Despite the association of single nucleotide polymorphisms in humans with SSc pathogenesis, our study demonstrates that DNASE1L3 is dispensable in two inducible murine models of SSc-like pathogenesis.

Neutrophil-Driven M2-Like Macrophages Are Critical for Skin Fibrosis in a Systemic Sclerosis Model

Systemic sclerosis (SSc) is a challenging autoimmune disease characterized by progressive fibrosis affecting the skin and internal organs. Despite the known infiltration of macrophages and neutrophils, their precise contributions to SSc pathogenesis remain elusive. In this study, we elucidated that CD206hiMHCIIlo M2-like macrophages constitute the predominant pathogenic immune cell population in the fibrotic skin of a bleomycin (BLM)-induced SSc mouse model. These cells emerged as pivotal contributors to the profibrotic response by orchestrating the production of TGF-β1 through a MerTK signaling-dependent manner. Notably, we observed that neutrophil infiltration was a prerequisite for the accumulation of M2-like macrophages. Strategies such as neutrophil depletion or inhibition of CXCR1/2 were proven effective in reducing M2-like macrophages, subsequently mitigating SSc progression. Detailed investigations revealed that in fibrotic skin, neutrophil-released neutrophil extracellular traps (NETs) were responsible for the differentiation of M2-like macrophages. Our findings illuminate the significant involvement of the neutrophil-macrophage-fibrosis axis in SSc pathogenesis, offering critical information for the development of potential therapeutic strategies.

Immune profiling analysis of double-negative T cells in patients with systemic sclerosis.

To construct a molecular immune map of patients with systemic sclerosis (SSc) by mass flow cytometry, and compare the number and molecular expression of double-negative T (DNT) cell subsets between patients and healthy controls (HC). Peripheral blood mononuclear cells (PBMCs) were extracted from the peripheral blood of 17 SSc patients and 9 HC. A 42-channel panel was set up to perform mass cytometry by time of flight (CyTOF) analysis for DNT subgroups. Flow cytometry was used to validate subpopulation functions. The clinical data of patients were collected for correlation analysis. Compared with HC, the number of total DNT cells decreased in SSc patients. Six DNT subsets were obtained from CyTOF analysis, in which the proportion of cluster1 increased, while the proportion of cluster3 decreased. Further analysis revealed that cluster1 was characterized by high expression of CD28 and CCR7, and cluster3 was characterized by high expression of CD28 and CCR5. After in vitro stimulation, cluster1 secreted more IL-4 and cluster3 secreted more IL-10 in SSc patients compared to HC. Clinical correlation analysis suggested that cluster1 may play a pathogenic role while cluster3 may play a protective role in SSc. ROC curve analysis further revealed that cluster3 may be a potential indicator for determining disease activity in SSc patients. We found a new CCR5+CD28+ DNT cell subset, which played a protective role in the pathogenesis of SSc. Key Points • The number of DNT cells decreased in SSc patients' peripheral blood. • DNT cells do not infiltrate in the skin but secrete cytokines to participate in the pathogenesis of SSc. • A CCR5+CD28+ DNT cell population may play a protective role in SSc.

The Role of IRF8 Polymorphisms in Systemic Sclerosis Development and Pathogenesis

The Role of IRF8 Polymorphisms in Systemic Sclerosis Development and Pathogenesis

Fibroblasts and Endothelial Cells in Three-Dimensional Models: A New Tool for Addressing the Pathogenesis of Systemic Sclerosis as a Prototype of Fibrotic Vasculopathies.

Two-dimensional in vitro cultures have represented a milestone in biomedical and pharmacological research. However, they cannot replicate the architecture and interactions of in vivo tissues. Moreover, ethical issues regarding the use of animals have triggered strategies alternative to animal models. The development of three-dimensional (3D) models offers a relevant tool to investigate disease pathogenesis and treatment, modeling in vitro the in vivo environment. We aimed to develop a dynamic 3D in vitro model for culturing human endothelial cells (ECs) and skin fibroblasts, simulating the structure of the tissues mainly affected in systemic sclerosis (SSc), a prototypical autoimmune fibrotic vasculopathy. Dermal fibroblasts and umbilical vein ECs grown in scaffold or hydrogel, respectively, were housed in bioreactors under flow. Fibroblasts formed a tissue-like texture with the deposition of a new extracellular matrix (ECM) and ECs assembled tube-shaped structures with cell polarization. The fine-tuned dynamic modular system allowing 3D fibroblast/EC culture connection represents a valuable model of the in vivo interplay between the main players in fibrotic vasculopathy as SSc. This model can lead to a more accurate study of the disease's pathogenesis, avoiding the use of animals, and to the development of novel therapies, possibly resulting in improved patient management.

In Silico Prediction of NOS2, NOS3 and Arginase 1 Genes Targeting by Micro RNAs Upregulated in Systemic Sclerosis

Introduction: Systemic sclerosis (SSc) is a chronic disorder, characterised by endothelial dysfunction and fibrosis of skin and internal organs. Endothelium dysfunction leads to a decrease in nitric oxide levels, consequent to reduced Nitric Oxide synthase 3 (NOS3) activity due to decreased NOS3 gene function. Besides endothelium, macrophages too play an important role in the pathogenesis of SSc; classically activated M1 macrophages (express NOS2) and alternatively activated M2 macrophages (express Arginase1) are differentially altered in favour of M2 macrophages. Micro-RNAs (miRNAs) regulate expression of various genes and may favour disease phenotype. Aim: Our aim was to identify differentially expressed micro-RNAs in SSc, which target NOS2, NOS3 and Arginase1 genes by in-silico approach. Methods: Data on miRNAs upregulation reported in various studies was collected and their sequence ID from miRBase was identified in FASTA format from NCBI. Binding strength of these miRNAs against NOS2, NOS3 and Arginase1 genes was evaluated by RNA22. Results: After scanning 39 publications reporting miRNA expression in SSc, a total of 13 miRNAs were found to be up-regulated for NOS2 (Gibbs free energy ≤18.0Kj/mol) and 15 miRNAs up-regulated for NOS3 (Gibbs free energy ≤18.0Kj/mol) whereas for Arginase1 only 2 miRNAs were up-regulated. Conclusion: There is differential upregulation of miRNAs in SSc. Micro RNAs targeting NOS2 and NOS3 genes are highly up-regulated in comparison to Arginase 1. Role of epigenetic regulation of genes by miRNAs may play a key role in pathogenesis of SSc.

Systemic sclerosis

Systemic sclerosis (SSc) is avery heterogeneous, chronic, rare, but socioeconomically important disease with asevere disease course and severe impairment of the quality of life of affected patients. Overview of the current state of research on the pathogenesis, diagnosis and therapy of SSc. A literature search was performed. The pathogenesis of SSc is not fully understood. ACR/EULAR criteria allow the diagnosis of early forms of SSc. Classification into limited cutaneous SSc and diffuse cutaneous SSc is of prognostic and therapeutic relevance. New organ-specific treatment options for SSc have led to improved quality of life and prognosis.

Adeno-Associated Virus Type 5 Infection via PDGFRα Is Associated With Interstitial Lung Disease in Systemic Sclerosis and Generates Composite Peptides and Epitopes Recognized by the Agonistic Immunoglobulins Present in Patients With Systemic Sclerosis.

The etiopathogenesis of systemic sclerosis (SSc) is unknown. Platelet-derived growth factor receptors (PDGFRs) are overexpressed in patients with SSc. Because PDGFRα is targeted by the adeno-associated virus type 5 (AAV5), we investigated whether AAV5 forms a complex with PDGFRα exposing epitopes that may induce the immune responses to the virus-PDGFRα complex. The binding of monomeric human PDGFRα to the AAV5 capsid was analyzed by in silico molecular docking, surface plasmon resonance (SPR), and genome editing of the PDGFRα locus. AAV5 was detected in SSc lungs by in situ hybridization, immunohistochemistry, confocal microscopy, and molecular analysis of bronchoalveolar lavage (BAL) fluid. Immune responses to AAV5 and PDGFRα were evaluated by SPR using SSc monoclonal anti-PDGFRα antibodies and immunoaffinity-purified anti-PDGFRα antibodies from sera of patients with SSc. AAV5 was detected in the BAL fluid of 41 of 66 patients with SSc with interstitial lung disease (62.1%) and in 17 of 66 controls (25.75%) (P < 0.001). In SSc lungs, AAV5 localized in type II pneumocytes and in interstitial cells. A molecular complex formed of spatially contiguous epitopes of the AAV5 capsid and of PDGFRα was identified and characterized. In silico molecular docking analysis and binding to the agonistic anti-PDGFRα antibodies identified spatially contiguous epitopes derived from PDGFRα and AAV5 that interacted with SSc agonistic antibodies to PDGFRα. These peptides were also able to bind total IgG isolated from patients with SSc, not from healthy controls. These data link AVV5 with the immune reactivity to endogenous antigens in SSc and provide a novel element in the pathogenesis of SSc.

Autoantibodies Targeting G-Protein-Coupled Receptors: Pathogenetic, Clinical and Therapeutic Implications in Systemic Sclerosis.

Systemic sclerosis (SSc) is a multifaceted connective tissue disease whose aetiology remains largely unknown. Autoimmunity is thought to play a pivotal role in the development of the disease, but the direct pathogenic role of SSc-specific autoantibodies remains to be established. The recent discovery of functional antibodies targeting G-protein-coupled receptors (GPCRs), whose presence has been demonstrated in different autoimmune conditions, has shed some light on SSc pathogenesis. These antibodies bind to GPCRs expressed on immune and non-immune cells as their endogenous ligands, exerting either a stimulatory or inhibitory effect on corresponding intracellular pathways. Growing evidence suggests that, in SSc, the presence of anti-GPCRs antibodies correlates with specific clinical manifestations. Autoantibodies targeting endothelin receptor type A (ETAR) and angiotensin type 1 receptor (AT1R) are associated with severe vasculopathic SSc-related manifestations, while anti-C-X-C motif chemokine receptors (CXCR) antibodies seem to be predictive of interstitial lung involvement; anti-muscarinic-3 acetylcholine receptor (M3R) antibodies have been found in patients with severe gastrointestinal involvement and anti-protease-activated receptor 1 (PAR1) antibodies have been detected in patients experiencing scleroderma renal crisis. This review aims to clarify the potential pathogenetic significance of GPCR-targeting autoantibodies in SSc, focusing on their associations with the different clinical manifestations of scleroderma. An extensive examination of functional autoimmunity targeting GPCRs might provide valuable insights into the underlying pathogenetic mechanisms of SSc, thus enabling the development of novel therapeutic strategies tailored to target GPCR-mediated pathways.

Effect of Anti-S100A4 Monoclonal Antibody Treatment on Experimental Skin Fibrosis and Systemic Sclerosis-Specific Transcriptional Signatures in Human Skin.

S100A4 is a DAMP protein. S100A4 is overexpressed in patients with systemic sclerosis (SSc), and levels correlate with organ involvement and disease activity. S100A4-/- mice are protected from fibrosis. The aim of this study was to assess the antifibrotic effects of anti-S100A4 monoclonal antibody (mAb) in murine models of SSc and in precision cut skin slices of patients with SSc. The effects of anti-S100A4 mAbs were evaluated in a bleomycin-induced skin fibrosis model and in Tsk-1 mice with a therapeutic dosing regimen. In addition, the effects of anti-S100A4 mAbs on precision cut SSc skin slices were analyzed by RNA sequencing. Inhibition of S100A4 was effective in the treatment of pre-established bleomycin-induced skin fibrosis and in regression of pre-established fibrosis with reduced dermal thickening, myofibroblast counts, and collagen accumulation. Transcriptional profiling demonstrated targeting of multiple profibrotic and proinflammatory processes relevant to the pathogenesis of SSc on targeted S100A4 inhibition in a bleomycin-induced skin fibrosis model. Moreover, targeted S100A4 inhibition also modulated inflammation- and fibrosis-relevant gene sets in precision cut SSc skin slices in an ex vivo trial approach. Selected downstream targets of S100A4, such as AMP-activated protein kinase, calsequestrin-1, and phosphorylated STAT3, were validated on the protein level, and STAT3 inhibition was shown to prevent the profibrotic effects of S100A4 on fibroblasts in human skin. Inhibition of S100A4 confers dual targeting of inflammatory and fibrotic pathways in complementary mouse models of fibrosis and in SSc skin. These effects support the further development of anti-S100A4 mAbs as disease-modifying targeted therapies for SSc.

The role of B cells in systemic sclerosis.

Systemic sclerosis (SSc) is a rare and refractory systemic disease characterized by fibrosis and vasculopathy in the presence of autoimmune abnormalities. While the exact cause of SSc is incompletely understood, the specific autoantibodies identified in SSc are closely linked to disease severity and prognosis, indicating a significant role of autoimmune abnormalities in the pathogenesis of SSc. Although the direct pathogenic mechanisms of autoantibodies in SSc are not fully elucidated, numerous prior investigations have demonstrated the involvement of B cells in the pathogenesis of SSc through various mechanisms. Additionally, several clinical trials have explored the efficacy of B-cell depletion therapy for SSc, with many reporting positive outcomes. However, the role of B cells in SSc pathogenesis is multifaceted, as they can both promote inflammation and exert inhibitory functions. This article provides an overview of the involvement of B cells in SSc development, incorporating the latest research findings.

Advances in the Understanding, Diagnosis, and Treatment of Systemic Sclerosis A Comprehensive Review of Recent Developments

Systemic sclerosis (SSc) is a multifaceted autoimmune disorder characterized by widespread organ involvement, impacting the skin, lungs, gastrointestinal tract, and blood vessels. Patients often confront a reduced lifespan, primarily attributed to pulmonary complications. Current therapeutic strategies concentrate on organ-specific interventions to mitigate inflammation and alleviate symptoms. Immunosuppressive drugs, vasodilators, and anti-fibrotic agents are commonly employed, but ongoing research explores novel drugs and therapeutic approaches. Autologous stem cell transplantation is considered in rapidly progressing interstitial lung disease, although potential complications must be carefully weighed. Recent studies delve into the intricate pathogenesis of SSc, revealing abnormalities in metabolic pathways and protein regulation. The disease manifests with diverse symptoms affecting various organs, with vascular involvement significantly contributing to morbidity, especially pulmonary arterial hypertension. Complications, including heightened susceptibility to infections, are exacerbated by the disease and its treatments. Ongoing research investigates potential treatments such as GPR68 antagonists, soluble guanylate cyclase activators, and melanocortin 1 receptor agonists, displaying promising results in improving pulmonary function. Multiple clinical trials for various drugs are currently underway. In conclusion, addressing the complexities of systemic sclerosis requires a multidisciplinary approach. Understanding its intricate pathogenesis and developing targeted therapies are pivotal for enhancing patient outcomes and extending survival.

SLC39A7 upregulation links to skin fibrosis in systemic sclerosis via TGF-β/SMAD pathway.

Systemic sclerosis (SSc) is a multisystem connective tissue disease. Skin fibrosis, the hallmark of this disease, is defined as the excess deposition and accumulation of extracellular matrix, mainly type 1 collagen, in the dermis. SLC39A7 is an intracellular zinc transporter that plays a unique role in connective tissue formation. Therefore, we investigated the expression and role of SLC39A7 in SSc. Using immunohistochemical staining we demonstrated the overexpression of SLC39A7 in the skin of SSc patients. Quantitative real-time PCR and western blot data analysis showed that both SLC39A7 mRNA and protein levels were significantly upregulated in dermal fibroblasts from SSc patients compared to healthy controls. We used the shRNA lentiviral particle transduction system to stably knockdown the expression of SLC39A7 in SSc fibroblasts. The results showed that knockdown of SLC39A7 suppressed the production of type 1 collagen. These findings provide evidence that SLC39A7 is involved in the pathogenesis of SSc and that SLC39A7 plays a positive role in its progression.

Systemic Sclerosis and Atherosclerosis: Potential Cellular Biomarkers and Mechanisms.

Systemic sclerosis (SSc) is a rare systemic autoimmune disease of unknown etiology, which is characterized by endothelial dysfunction, pathologic vasculopathy, and increased tissue fibrosis. Traditionally, SSc has been regarded as a prototypical fibrotic disease in the family of systemic autoimmune diseases. Traditionally, emphasis has been placed on the three components of the pathogenesis of SSc: vascular, immune, and mesenchymal. Microvascular lesions, including endothelial dysfunction and smooth muscle cell migration into the intima of vessels in SSc, resemble the atherosclerotic process. Although microvascular disease is a hallmark of SSc, understanding the role of atherosclerotic vascular lesions in patients with SSc remains limited. It is still unknown whether the increased cardiovascular risk in SSc is related to specific cardiac complications (such as myocardial fibrosis) or the accelerated development of atherosclerosis. Different immune cell types appear to be involved in the immunopathogenesis of SSc via the activation of other immune cells, fibrosis, or vascular damage. Macrophages, B cells, T cells, dendritic cells, neutrophils, and endothelial cells have been reported to play the most important role in the pathogenesis of SSc and atherosclerosis. In our article, we reviewed the most significant and recent studies on the pathogenetic links between the development of SSc and the atherosclerotic process.

Steroid hormones in systemic sclerosis: associations with disease characteristics and modifications during scleroderma renal crisis.

The renin-angiotensin-aldosterone system (RAAS) and glucocorticoids (GCs) are involved in vascular remodeling and fibrosis, but have not been extensively studied in systemic sclerosis (SSc). Our aim was to investigate the RAAS and GC hormones in SSc patients. Serum levels of renin (dosage and activity), aldosterone and its precursors (DOC, B, 18-OH-DOC, 18-OH-B), and GCs (cortisol, cortisone, 11-deoxycortisol, 18-OH-F) were assessed in 122 SSc patients and 52 healthy controls. After applying stringent inclusion criteria aimed at ensuring accurate hormone assessments (exclusion of interfering drugs, strict sampling conditions), we analyzed RAAS hormones in 61 patients, and GCs in 96 patients. Hormone levels were compared between patients and controls; and associations with disease characteristics were assessed in patients. Regarding RAAS hormones, SSc patients displayed significantly lower aldosterone levels (although within normal range), similar renin levels, and higher B levels than controls. Abnormal RAAS hormone levels were associated with a more severe SSc phenotype (lung and skin fibrosis, heart and pulmonary vascular involvements, inflammation). Regarding GC hormones, SSc patients had higher levels of cortisol, 11-desoxycortisol (precursor) and 18-OH-F (metabolite) but lower levels of cortisone (inactive counterpart) than controls.RAAS hormone levels were assessed in 5 SSc patients before and during scleroderma renal crisis (SRC): concentrations varied considerably between patients, but consistently included normal/increased aldosterone levels and elevated renin levels. RAAS and GC hormones are abnormally produced in SSc patients, especially in patients with severe SSc and during SRC. This could suggest a participation of these hormonal systems in SSc pathogenesis.