Fibrosis In Systemic Sclerosis Patients Research Articles

Silica's silent threat: Contributing to skin fibrosis in systemic sclerosis by targeting the HDAC4/Smad2/3 pathway

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.

Levels of anti-topoisomerase I antibody correlated with short onset of cardiopulmonary involvement in Thai systemic sclerosis patients

Anti-topoisomerase-I antibody (ATA) is associated with disease severity and internal organ involvement in patients with systemic sclerosis (SSc). The correlation between ATA levels and the clinical course of SSc is unclear. We aimed to determine the correlation between ATA level and survival time and the onset of internal organ fibrosis in SSc patients. This historical cohort study was conducted in adult SSc patients with quantitative tests of ATA between January 2019 and December 2022. Patients with overlap syndrome and no quantitative ATA test were excluded. According to the sample size calculation, and 10% compensated for missing data, a total of 153 patients were needed. The respective mean age on the study date and median ATA level was 59.9 ± 11.3 years and 370 U/mL (range 195–652). Most cases (107 cases; 69.9%) were the diffuse cutaneous SSc subset. According to a multivariable analysis, the ATA titer had a negative correlation with the onset of cardiac involvement (Rho − 0.47, p = 0.01), and had a positive correlation with skin thickness progression (Rho 0.39, p = 0.04). Eleven cases exhibited ATA levels < 7 U/mL and outlier ATA levels were excluded, 142 cases were included in the sensitivity analysis, and multivariable analysis showed the correlation between early onset of ILD and cardiac involvement (Rho − 0.43, p = 0.03 and Rho − 0.51, p = 0.01, respectively). The ATA level was correlated with neither the survival time nor the onset of renal crisis in both analyses. High ATA levels were correlated with a short onset of ILD and cardiac involvement and the presence of extensive skin tightness. Quantitative tests of ATA could serve as an effective tool for identifying patients at risk of an unfavorable prognosis.

The Role of IRF8 Polymorphisms in Systemic Sclerosis Development and Pathogenesis

The Role of IRF8 Polymorphisms in Systemic Sclerosis Development and Pathogenesis

Therapeutic management of fibrosis in systemic sclerosis patients - an analysis from the Swiss EUSTAR cohort.

Systemic sclerosis is a chronic autoimmune connective tissue disease leading to microvascular and fibrotic manifestations in multiple organs. Several treatment options and recommendations from different European countries are available. In this study, for which the ambit is Switzerland specifically, we aim to describe the treatment patterns of systemic sclerosis patients with fibrotic manifestations. Systemic sclerosis patients were selected from six Swiss tertiary centres recorded in the multicentre, prospective European Scleroderma Trials and Research (EUSTAR) registry. Patients fulfilling the 2013 ACR/EULAR systemic sclerosis classification criteria at baseline were included. To determine the differences in treatment of varying degrees of fibrosis, four groups were identified: (1) patients with a modified Rodnan skin score (mRSS) >0; (2) those with mRSS ≥7; (3) those with interstitial lung disease (SSc-ILD), diagnosed by either chest X-Ray or high-resolution computed tomography; and (4) patients fulfilling one of the additional criteria for extensive interstitial lung disease, defined as interstitial lung disease involvement of >20% in high-resolution computed tomography, dyspnea NYHA-stage 3/4, or a predicted forced vital capacity (FVC) of <70%. A total of 590 patients with systemic sclerosis fulfilled the inclusion criteria. In this cohort, 421 (71.4%) had mRSS >0, of whom 195 (33.1%) had mRSS ≥7; interstitial lung disease was diagnosed in 198 of 456 (43.4%), of whom 106 (18.0 %) showed extensive interstitial lung disease. Regarding non-biologic disease-modifying medications (DMARDs), the most frequently prescribed was methotrexate, followed by hydroxychloroquine and mycophenolate mofetil. Rituximab and tocilizumab were most frequently used among the biologic DMARDs. Specifically, 148/372 (39.8%) of treated patients with skin fibrosis received methotrexate, mycophenolate mofetil or rituximab, and 80/177 (45.2%) with interstitial lung disease received cyclophosphamide, mycophenolate mofetil, tocilizumab or rituximab. Most patients received a proton-pump inhibitor, and few patients underwent hematopoietic stem cell transplantation. Overall, in Switzerland, a wide range of medications is prescribed for systemic sclerosis patients. This includes modern, targeted treatments for which randomised controlled clinical trial have been recently reported.

Spatial frequency domain imaging for the assessment of scleroderma skin involvement.

Systemic sclerosis (SSc) is an autoimmune disease characterized by the widespread deposition of excess collagen in the skin and internal organs, as well as vascular dysfunction. The current standard of care technique used to quantify the extent of skin fibrosis in SSc patients is the modified Rodnan skin score (mRSS), which is an assessment of skin thickness based on clinical palpation. Despite being considered the gold standard, mRSS testing requires a trained physician and suffers from high inter-observer variability. In this study, we evaluated the use of spatial frequency domain imaging (SFDI) as a more quantitative and reliable method for assessing skin fibrosis in SSc patients. SFDI is a wide-field and non-contact imaging technique that utilizes spatially modulated light to generate a map of optical properties in biological tissue. The SFDI data were collected at six measurement sites (left and right forearms, hands, and fingers) of eight control subjects and ten SSc patients. mRSS were assessed by a physician, and skin biopsies were collected from subject's forearms and used to assess for markers of skin fibrosis. Our results indicate that SFDI is sensitive to skin changes even at an early stage, as we found a significant difference in the measured optical scattering () between healthy controls and SSc patients with a local mRSS score of zero (no appreciable skin fibrosis by gold standard). Furthermore, we found a strong correlation between the diffuse reflectance (Rd) at a spatial frequency of 0.2 mm-1 and the total mRSS between all subjects (Spearman correlation coefficient = -0.73, p-value < 0.0028), as well as high correlation with histology results. The healthy volunteer results show excellent inter- and intra-observer reliability (ICC > 0.8). Our results suggest that the measurement of tissue and Rd at specific spatial frequencies and wavelengths can provide an objective and quantitative assessment of skin involvement in SSc patients, which could greatly improve the accuracy and efficiency of monitoring disease progression and evaluating drug efficacy.

Liver Involvement in Patients with Systemic Sclerosis: Role of Transient Elastography in the Assessment of Hepatic Fibrosis and Steatosis.

Background Systemic sclerosis (SSc) is a rare, multisystemic disorder of connective tissue characterized by widespread inflammation, vascular abnormalities, and both skin and visceral organ fibrosis. Tissue fibrosis is the final phase of a complex biological process of immune activation and vascular damage. Objectives The aim of the study was to assess hepatic fibrosis and steatosis in SSc patients by transient elastography (TE). Methods Fifty-nine SSc patients fulfilling the 2013 ACR/EULAR classification criteria were recruited. Clinical and laboratory findings, modified Rodnan skin score (mRSS), activity index, videocapillaroscopy, echocardiography, and lung function data were analyzed. Liver stiffness (LS) was measured by transient elastography (TE), with 7 kPa used as the cut-off value for significant liver fibrosis. In addition, hepatic steatosis was evaluated by means of controlled attenuation parameter (CAP) findings. Specifically, CAP values ≥ 238 ≤ 259 dB/m were considered consistent with mild steatosis (S1), values ≥ 260 ≤ 290 dB/m were compatible with moderate steatosis (S2), and values ≥ 291 dB/m were indicative of severe steatosis (S3). Results The median age of patients was 51 years, with a median disease duration of 6 years. The median LS was 4.5 (2.9-8.3) kPa; 69.5% of patients had no evidence of fibrosis (F0); 27.1% displayed LS values between 5.2 and 7 kPa; and only 3.4% of patients had LS values > 7 kPa (F3). The median CAP value for liver steatosis was 223 dB/m (IQR: 164-343). Overall, 66.1% of patients did not show evidence of steatosis (CAP values < 238 dB/m); 15.2% showed values consistent with mild (S1) steatosis (CAP value ≥ 238 ≤ 259 dB/m); 13.5% had moderate (S2) steatosis (CAP value ≥ 260 ≤ 290 dB/m); and 5.1% were deemed to have severe steatosis (S3) due to CAP values ≥ 291 dB/m. Conclusions Although systemic sclerosis is associated with fibrosis of the skin and several organs, only 3.4% of our patient population showed evidence of marked liver fibrosis, which is the same prevalence as that expected in the general population. Therefore, fibrosis of the liver did not appear to be a significant concern in SSc patients, albeit moderate fibrosis could still be detected in a significant proportion of subjects. A prolonged follow-up may clarify whether liver fibrosis in SSc patients may still progress. Likewise, the prevalence of significant steatosis was low (5.1%) and depended on the same variables associated with fatty liver disease in the general population. TE was shown to be an easy and valuable method for detection and screening of hepatic fibrosis in SSc patients with no additional risk factors for liver disease and may be useful to assess the potential progression of liver fibrosis over time.

Autoantibodies against PIP4K2B and AKT3 Are Associated with Skin and Lung Fibrosis in Patients with Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare autoimmune systemic disease that leads to decreased survival and quality of life due to fibrosis, inflammation, and vascular damage in the skin and/or vital organs. Early diagnosis is crucial for clinical benefit in SSc patients. Our study aimed to identify autoantibodies in the plasma of SSc patients that are associated with fibrosis in SSc. Initially, we performed a proteome-wide screening on sample pools from SSc patients by untargeted autoantibody screening on a planar antigen array (including 42,000 antigens representing 18,000 unique proteins). The selection was complemented with proteins reported in the literature in the context of SSc. A targeted antigen bead array was then generated with protein fragments representing the selected proteins and used to screen 55 SSc plasma samples and 52 matched controls. We found eleven autoantibodies with a higher prevalence in SSc patients than in controls, eight of which bound to proteins associated with fibrosis. Combining these autoantibodies in a panel could lead to the subgrouping of SSc patients with fibrosis. Anti-Phosphatidylinositol-5-phosphate 4-kinase type 2 beta (PIP4K2B)- and anti-AKT Serine/Threonine Kinase 3 (AKT3)-antibodies should be further explored to confirm their association with skin and lung fibrosis in SSc patients.

Altered pathways of keratinization, extracellular matrix generation, angiogenesis, and stromal stem cells proliferation in patients with systemic sclerosis.

Systemic sclerosis is characterized by endothelial dysfunction, autoimmunity abnormalities, and fibrosis of the skin and internal organs. The pathogenetic mechanisms underlying systemic sclerosis vasculopathy are still not clarified. A complex cellular and extracellular network of interactions has been studied, but it is currently unclear what drives the activation of fibroblasts/myofibroblasts and the extracellular matrix deposition. Using RNA sequencing, the aim of the work was to identify potential functional pathways implied in systemic sclerosis pathogenesis and markers of endothelial dysfunction and fibrosis in systemic sclerosis patients. RNA-sequencing analysis was performed on RNA obtained from biopsies from three systemic sclerosis patients and three healthy controls enrolled in our University Hospital. RNA was used to generate sequencing libraries that were sequenced according to proper transcriptomic analyses. Subsequently, we performed gene set enrichment analysis of differentially expressed genes on the entire list of genes that compose the RNA-sequencing expression matrix. Gene set enrichment analysis revealed that healthy controls were characterized by gene signatures related to stromal stem cells proliferation, cytokine-cytokine receptor interaction, macrophage-enriched metabolic network, whereas systemic sclerosis tissues were enriched in signatures associated with keratinization, cornification, retinoblastoma 1 and tumor suppressor 53 signaling. According to our data, RNA-sequencing and pathway analysis revealed that systemic sclerosis subjects display a discrete pattern of gene expression associated with keratinization, extracellular matrix generation, and negative regulation of angiogenesis and stromal stem cells proliferation. Further analysis on larger numbers of patients is needed; however, our findings provide an interesting framework for the development of biomarkers useful to explore potential future therapeutic approaches.

Circulatory cytokeratin 17, marginal zone B1 protein and leucine-rich α2-glycoprotein-1 as biomarkers for disease severity and fibrosis in systemic sclerosis patients.

IntroductionSystemic sclerosis (Ssc) is a multiorgan debilitating autoimmune disease that associates the triad: vascular involvement, tissue fibrosis and profound immune response alterations. Numerous previous studies focused on identification of candidate proteomic Ssc biomarkers using mass-spectrometry techniques and a large number of candidate Ssc biomarkers emerged. These biomarkers must firstly be confirmed in independent patient groups. The aim of the present study was to investigate the association of cytokeratin 17 (CK17), marginal zone B1 protein (MZB1) and leucine-rich α2-glycoprotein-1 (LRG1) with clinical and biological Ssc characteristics.Material and methodsSerum CK17, MZB1 and LRG1 were assessed in samples of the available Ssc biobank comprising of samples from 53 Ssc patients and 26 matched age and gender controls.ResultsCirculatory CK17, LRG1 and MZB1 concentrations were increased in Ssc patients. Cytokeratin 17 is independently associated with Ssc disease activity. Patients with pulmonary fibrosis expressed higher LRG1 and MZB1 concentrations. Serum MZB1 concentrations were also associated with extensive skin fibrosis.ConclusionsSerum CK17, MZB1 and LRG1 were confirmed biomarkers for Ssc. LRG1 seems a good biomarker for pulmonary fibrosis, while MZB1 is a good biomarker for extensive skin fibrosis. CK17 proved to be independently associated with Ssc disease severity, higher CK17 values being protective for a more active disease.

The Relationship Between Modified Rodnan Skin Score (mRSS) With Pulmonal Hypertension and Lung Fibrosis in Systemic Sclerosis Patients

Background: Systemic sclerosis (SSc) is a connective tissue disease, which affects the skin, blood vessels, heart, lungs, kidneys, gastrointestinal tract and musculoskeletal system. The manifestations in blood vessels include pulmonary hypertension which can be seen from echocardiography, while the manifestations to the lungs in the form of pulmonary fibrosis are examined by high-resolution computed tomography (HRCT). Modified Rodnan Skin Score (mRSS) a method for measuring skin thickness in SSc patients.&#x0D; Objective: This study aims to determine the relationship between mRSS and pulmonary hypertension and pulmonary fibrosis in SSc patients.&#x0D; Methods and Materials: Research with a cross sectional approach at Dr Kariadi Hospital. There were 23 study subjects with SSc patients having their mRSS measured by a rheumatologist and an HRCT examination by a radiologist to see the percent of lung damage and echocardiographic examination by a cardiologist to measure the Tricuspid Regurgitation Velocity Maximum (TRV Max) as a marker of pulmonary hypertension. Normality test using Saphiro-Wilk. The Spearman rank correlation test was used to analyze the relationship between the mRSS score, pulmonary hypertension and pulmonary fibrosis.&#x0D; Results: The proportion of study subjects with a mean age of 40.39 years, women, and 4.43 years of illness. The mean mRSS score was 17.43. Examination of pulmonary hypertension from echocardiography found most of the light category 95.6%, heavy category 4.4%, while the HRCT examination found pulmonary fibrosis of 86.9%, normal 13.1%. There are significant relationship between mRSS and pulmonary fibrosis (r = 0.485, p = 0.019), and significant relationship between pulmonary hypertension (r = 0.63, p = 0.001)&#x0D; Conclusion: There is a significant relationship between mRSS, pulmonary fibrosis and pulmonary hypertension.

Serum IGFBP-2 in systemic sclerosis as a prognostic factor of lung dysfunction

Systemic sclerosis (SSc) is a rare connective tissue disease associated with rapid evolving interstitial lung disease (ILD), driving its mortality. Specific biomarkers associated with the progression of this lung disease are highly needed. We aimed to identify specific biomarkers of SSc-ILD to predict the evolution of the disease. For this, we compared prospectively serum levels of several biomarkers associated with lung fibrosis in SSc patients (n = 102), among which SSc-no ILD (n = 63) and SSc-ILD (n = 39), compared to healthy subjects (HS) (n = 39). We also performed a longitudinal study in a subgroup of 28 patients analyzing biomarkers variations and pulmonary function tests over a period of 2 years. Serum level of IGFBP-2 was significantly increased in SSc patients compared to HS, and negatively correlated with pulmonary function (assessed by carbon monoxide transfer coefficient (KCO)) (r = − 0.29, p < 0.01). Two-year longitudinal analysis in a subgroup of 28 SSc patients determined that IGFBP-2 variation was positively correlated with KCO at 2-year follow-up (r = 0.6, p < 0.001). SSc patients with a lower variation of IGFBP-2 (less than 22%) presented significant deterioration of pulmonary function at 2-year follow-up (p < 0.01). ROC curve analysis enabled us to identify that baseline IGFBP-2 > 105 ng/ml was associated with a poor outcome (KCO < 70% predicted) at 2-year follow-up (AUC = 0.75, p < 0.05). We showed for the first time that serum levels of IGFBP-2 might be a prognostic factor of the development of SSc-ILD.

Bushen Yijing Decoction (BSYJ) exerts an anti-systemic sclerosis effect via regulating MicroRNA-26a /FLI1 axis

ABSTRACT Systemic sclerosis (SSc) refers to a group of autoimmune rheumatic diseases. Bushen Yijing decoction (BSYJ) is used for treating SSc. However, its underlying mechanism remains unknown. The present study aims to investigate potential roles of Friend leukemia integration factor 1 (FLI1) and microRNA in the beneficial effects of BSYJ on SSc. Primary skin fibroblasts were isolated from healthy individuals and SSc patients through tissue-explant technique and validated by immunocytochemistry. mRNA and microRNA levels were determined by quantitative RT-PCR. Protein expression was measured by western blotting. MiR-26a mimics or inhibitor were transfected to induce miR-26a overexpression or knockdown in vitro and in vivo, respectively. Histological changes of skin tissues from SSc mouse were evaluated by H&E and Masson trichrome staining. Results showed that FLI1 expression significantly decreased in primary skin fibroblasts of SSc patients. MiR-26a was predicted to target FLI1 untranslated region. Transfection of miR-26 mimics in SSc skin fibroblasts (SFB) leads to decrease in FLI1 expression and increase in collagen I gene expression and fibronectin accumulation. On the other hand, miR-26a knockdown increased FLI1 expression and decreased collagen I and fibronectin expression in SFB. In addition, BSYJ-containing rat serum suppressed miR-26a expression, while it elevated FLI1 expression and inhibited fibronectin and collagen I accumulation in SFB. In the mouse SSc model, BSYJ-containing serum inhibited dermal fibrosis by suppressing miR-26a expression and restoring FLI1 protein levels. Overall, our study demonstrates that BSYJ decoction exerts anti-dermal fibrosis in SSc patients via suppressing miR-26a level and thus to increase FLI1 expression in fibroblasts.

Validation of the suction device Nimble for the assessment of skin fibrosis in systemic sclerosis

ObjectivesSkin fibrosis is a main hallmark of systemic sclerosis (SSc). Clinical assessment is done semi-quantitatively using the modified Rodnan skin score (mRSS). Objective measurements for quantifying skin fibrosis could complement the mRSS to achieve higher reproducibility. The aim of this study was to explore the potential of suction measurements to detect structural changes in the skin that are associated with skin fibrosis.MethodsThis clinical trial included 30 SSc patients and 30 healthy volunteers (HC). We validated a novel suction device—the Nimble—to quantify skin stiffness in comparison to the Cutometer using the OMERACT filter.ResultsA significant difference (p < 0.05) between the skin stiffness of HC and SSc patient groups was found for each location measured. The correlation between the measurements of forearm skin stiffness and the mRSS values was high for the Nimble (r = 0.82) and moderate for the Cutometer (r = 0.58). A ROC analysis showed good ability for the Nimble to distinguish between SSc patients with and without skin involvement (AUC = 0.82). Both suction devices provided excellent reliability in all measurements on HC and SSc patients and proved face validity and feasibility.ConclusionSuction devices assessing skin stiffness, such as the Nimble, show clear potential to objectively quantify skin fibrosis in SSc patients and might be promising outcome measures complementing established methods such as the mRSS.Trial registrationClinicaltrials.gov, NCT03644225, Registered 23 August 2018—Retrospectively registered, http://www.clinicaltrials.gov

Scleroderma as a paraneoplastic syndrome and tumors associated with scleroderma

Patients with systemic scleroderma, or systemic sclerosis (SS), have an increased risk of developing malignant neoplasms. Cancer can be diagnosed immediately prior to SS symptoms, at the stage of diagnosis and years after SS diagnosis. The first two cases may indicate scleroderma-like paraneoplastic syndrome. In this case, the main mechanism of paraneoplastic syndrome development is associated with immune system activation by antigens, expressed by tumor cells, which leads to the development of antibodies that cross-react with body tissues, causing damage and secondary regeneration. Thus, cancer induces autoimmunity – mutation-specific T-cell immune response, and pathogenetic mechanisms can be the same for fibrogenesis and oncogenesis.SS clinical and laboratory characteristics that indicate paraneoplastic etiology include minimum time difference between diagnosing scleroderma and cancer, as well as oncopathology in a patient’s or family cancer history, late disease onset (after 50 years), SS symptoms in a man, sudden onset and rapid progression of clinical symptoms, expressed or atypical SS symptoms (malaise, fever, significant weight loss), asymmetric or absent Raynaud syndrome, antibodies against RNA polymerase III, absence of anticentromeric antibodies and anti-Scl70, deviations in laboratory tests indicating possible oncopathology (anemia, hypercalcemia, hypergammaglobulinemia), no response to SS treatment, disappearance of SS symptoms after anticancer treatment and their appearance when cancer reactivation. On the other hand, patients with scleroderma have an increased risk of all types of cancer, with men at higher risk than women. Continuous autoimmune stimulation, B-cell activation, chronic inflammatory process and fibrosis in SS patients can lead to malignant transformation in certain organ systems, especially in lungs.The most important risk factor for lung cancer in SS patients is interstitial lung disease, requiring special attention from a physician. In addition to lung cancer, SS patients more likely than the general population suffer from malignant hematologic diseases, esophageal cancer, hepatocellular carcinoma and bladder cancer. Scleroderma-like skin changes are also possible when cytotoxic drugs are used to treat cancer (docetaxel, paclitaxel, bleomycin, etc.), as well as during radiation therapy.

Anti‐C1q antibodies in scleroderma

Systemic sclerosis (SSc) is an autoimmune condition which means that the body's immune system, which usually fights off disease, wrongly targets healthy parts of the body, and SSc patients produce antibodies to their own tissues (‘autoantibodies’). Extensive thickening and scarring of tissues (fibrosis) is the main feature of the condition and is due to over‐production of collagen. Changes in small blood vessels also occur. When fibrosis occurs in the lungs (pulmonary fibrosis) it can lead to high blood pressure in the arteries going to the lungs, and this may be life‐threatening. The condition is commoner in women. SSc can be localised or disseminated (generalised), depending on the extent of skin involvement. Although the cause of SSc has not been fully worked out, many of the autoantibodies associated with the condition are believed to be involved in one way or another. Autoantibodies called ‘anti‐C1q’ are certainly found in another autoimmune condition called systemic lupus erythematosus, so the aim of this study from Greece and the USA was to see if they were also present in SSc. Anti‐C1q autoantibodies were found in 16.1% of the 124 SSc patients in the study, occurring as often as the third most frequently found autoantibody, known as anti‐RNA polymerase III. They were found particularly in men and in patients with disseminated SSc. Presence of anti‐C1q antibodies was associated with pulmonary fibrosis but not with any of the other features of SSc. The authors therefore suggest that anti‐C1q autoantibodies could be looked at as a marker for (sign of) pulmonary fibrosis in SSc patients.

T1 mapping cardiac magnetic resonance imaging frequently detects subclinical diffuse myocardial fibrosis in systemic sclerosis patients

Objectivescardiac involvement is the second most frequent systemic sclerosis (SSc) related cause of death. It remains mostly asymptomatic in the early stage and is underdiagnosed with routine screening. Cardiac magnetic resonance imaging (CMR) could improve cardiac assessment of patients and noteworthily, new sequences allow the detection of diffuse myocardial fibrosis (DMF) by native T1 mapping. The aim of this study was to determine the prevalence of cardiac involvement by CMR native T1 mapping and its correlation with echocardiography data and non-cardiac manifestations in SSc patients. Methodspatients fulfilling the ACR/EULAR classification criteria for SSc were prospectively included between 2014 and 2016. They underwent CMR at 1.5T, including native T1 and T2 mapping, and Late Gadolinium Enhancement (LGE) as a part of routine follow up. Routine biological tests (mainly BNP and CRP) were centralized in the hospital laboratory. Resultsseventy-two unselected patients were included. Thirty six patients (50%) had elevated T1 (ET1) (mean T1 1097±14 ms). CMR cardiac functional parameters were similar in ET1 and normal T1 (NT1). Echocardiography was normal in 18 (50%) of ET1. ET1 and NT1 groups were similar for cardiovascular risk factors and ischemic heart disease. ET1 was not correlated with any clinical or echocardiographic parameter or antibody profile. Thirty-six percent of patients with ET1 had no cardiac symptoms, normal echocardiography and CMR LVEF, and no LGE. Conclusionnative T1 mapping detects left ventricular ET1 (potential DMF) in 50% of patients with SSc and a third of them had a normal conventional screening including standard CMR. In the future, further studies are needed to confirm the benefit of use of native T1 mapping as a part of routine follow up to detect earlier pejorative cardiac involvement in SSc patients.

Suppressive Regulation by MFG-E8 of Latent Transforming Growth Factor β-Induced Fibrosis via Binding to αv Integrin: Significance in the Pathogenesis of Fibrosis in Systemic Sclerosis.

Several studies have demonstrated that the secreted glycoprotein and integrin ligand milk fat globule-associated protein with epidermal growth factor- and factor VIII-like domains (MFG-E8) negatively regulates fibrosis in the liver, lungs, and respiratory tract. However, the mechanisms and roles of MFG-E8 in skin fibrosis in systemic sclerosis (SSc) have not been characterized. We undertook this study to elucidate the role of MFG-E8 in skin fibrosis in SSc. We assessed expression of MFG-E8 in the skin and serum in SSc patients. We examined the effect of recombinant MFG-E8 (rMFG-E8) on latent transforming growth factor β (TGFβ)-induced gene/protein expression in SSc fibroblasts. We examined the effects of deficiency or administration of MFG-E8 on fibrosis mouse models. We demonstrated that MFG-E8 expression around dermal blood vessels and the serum MFG-E8 level in SSc patients (n = 7 and n = 44, respectively) were lower than those in healthy individuals (n = 6 and n = 28, respectively). Treatment with rMFG-E8 significantly inhibited latent TGFβ-induced expression of type I collagen, α-smooth muscle actin, and CCN2 in SSc fibroblasts (n = 3-8), which suggested that MFG-E8 inhibited activation of latent TGFβ as well as TGFβ signaling via binding to αv integrin. In a mouse model of bleomycin-induced fibrosis (n = 5-8) and in a TSK mouse model (a genetic model of SSc) (n = 5-10), deficient expression of MFG-E8 significantly enhanced both pulmonary and skin fibrosis, and administration of rMFG-E8 significantly inhibited bleomycin-induced dermal fibrosis. These results suggest that vasculopathy-induced dysfunction of pericytes and endothelial cells, the main cells secreting MFG-E8, may be associated with the decreased expression of MFG-E8 in SSc and that the deficient inhibitory regulation of latent TGFβ-induced skin fibrosis by MFG-E8 may be involved in the pathogenesis of SSc and may be a therapeutic target for fibrosis in SSc patients.

Innate immunity and Toll-like receptor signaling in the pathogenesis of scleroderma: advances and opportunities for therapy.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease in which inflammation and cytokine dysregulation leads to skin fibrosis. Toll-like receptors (TLRs) are conserved pattern recognition receptors, recognizing pathogens danger-associated molecular patterns (DAMPs) that elicit a cascade of proinflammatory signaling. Recently, TLRs have been found to be critically important in SSc pathogenesis, with increased levels of the TLRs and their ligands present in the disease. Animal models have also been pivotal in delineating the role of these innate immune receptors in SSc. This current review examines the role of TLRs and the most recent evidence of the role of DAMPs and how these may be exploited therapeutically. Increasingly, studies have demonstrated the key roles of TLR4 and other intracellular TLRs in mediating fibrosis in SSc patients and animal models. TLR4 activation appears a key point and novel DAMPs, expressed upon tissue damage, appear critical in mediating the profibrotic effect through a downstream enhancement of transforming growth factor β. Deletion of Tenascin-C or a splice variant of fibronectin ameliorates animal models of skin fibrosis. Intracellular, nucleic acid sensing, TLR8 is critical in activating macrophages to secrete profibrotic molecules. The mechanism involves histone modification through epigenetic modifying enzymes. TLRs are key therapeutic targets in SSc.

Inhibitory Regulation of Skin Fibrosis in Systemic Sclerosis by Apelin/APJ Signaling.

Apelin/APJ signaling has been determined to regulate cardiac and arterial fibrosis and to be involved in the pathogenesis of pulmonary arterial hypertension. Our objective was to elucidate the role of apelin in skin fibrosis in systemic sclerosis (SSc). Expression of apelin/APJ in normal and SSc fibroblasts was compared. Effects of small interfering RNA depletion and the addition of apelin in fibroblasts were analyzed. The effect of apelin injections on bleomycin-induced dermal fibrosis in mice was investigated. We analyzed the effects of the biased agonist of APJ, MM07, on skin fibrosis in vitro and in vivo. The expression of apelin in SSc fibroblasts was significantly lower than that in normal fibroblasts. Serum apelin levels were negatively correlated with the modified Rodnan skin thickness score in SSc patients. Stimulation with transforming growth factor β1 (TGFβ1) inhibited apelin expression in fibroblasts, suggesting that activation of TGFβ1 signaling in SSc might be responsible for reduced apelin expression in SSc fibroblasts. Small interfering RNA depletion of apelin from fibroblasts significantly enhanced fibrosis-related gene expression, and treatment with apelin protein significantly inhibited TGFβ1 signaling in fibroblasts. Administration of apelin significantly inhibited bleomycin-induced dermal fibrosis in mice. We demonstrated that MM07 had greater potential than apelin to inhibit fibrosis in vivo and in vitro. Collectively, TGFβ1 signaling and apelin signaling may counteract each other in the fibrotic process of SSc. Inhibitory regulation of TGFβ1-induced skin fibrosis by apelin/APJ signaling may be involved in the pathogenesis of SSc and could be a therapeutic target for fibrosis in SSc patients.

Correlation of sCD40L Level with Force Vital Capacity Value in Restrictive Lung Disease of Systemic Sclerosis Patients

Background: Interstitial Lung Disease (ILD) is one of the major cause of morbidity and mortality in Systemic Sclerosis (SSc). The gold standard to diagnose ILD is using High Resolution Computed Tomography (HRCT) scan. HRCT scan need a lot of cost and not always available, so another diagnosing test is needed as an alternative modality to diagnose ILD. ILD is a restrictive lung disease caused by lung fibrosis which is proved by the decrease of Forced Vital Capacity (FVC) in spirometry, and followed by the increase of soluble CD40L (sCD40L) level in plasma. This sCD40L may become a potential biomarker to evaluate lung fibrosis in SSc patients. The aim of this study is to analyze the correlation of sCD40L levels with FVC score in SSc patients with restrictive lung disease.Method:This cross sectional study was enrolled by the SSc patient who has restrictive lung disease based on spirometry test, at Rheumatology outpatient clinic dr. Hasan Sadikin Hospital from May 2015 to May 2016. All subject took underwent history, physical examination, spirometry and blood test for sCD40L. Data were analyzed using Pearson correlation.Result:There were 38 subjects involved in this study, dominated bywoman (92.1%) with mean age 41(±11) years. Subjects consist of 22(57,9%) with limited SSc, 16(42,1%) with diffuse SSc patients and 33 subjects treated with DMARD. Mean sCD40L serum in this study was 6.690,3(±2.377,3) pg/mL, with no statistical difference between limited and diffuse type (p=0.154). Mean FVC score in this study was 58.2(±10,8). There was no significant correlation between sCD40L serum with FVC (r=0.058; p=0.366). There was weak correlation on DMARD naïve subject between sCD40L serum and FVC (r=0.058; p=0.366) but statistically insignificant. There was no significant correlation between sCD40L serum with mRSS (r=0,066; p=0,346).Conclusion: This study founds no correlation between sCD40L with FVC in SSc at dr. Hasan Sadikin Hospital. Keyword : sCD40L, Forced Vital Capacity, Restrictive Lung Disease, Systemic Sclerosis