Systemic Sclerosis Patients Research Articles

Gastrointestinal disorders in systemic sclerosis: cluster analysis and prognosis from a French prospective cohort.

The gastrointestinal tract (GIT) is frequently involved in systemic sclerosis (SSc) and is responsible for alteration of quality of life. Many complications can occur, including chronic intestinal pseudo-obstruction, digestive haemorrhage and small-intestinal bacterial overgrowth. Since early development of organ failure is associated with poor prognosis, we need to identify risk factors associated with severe GIT involvement to prevent severe forms of the disease. We conducted an observational prospective study, which included 90 SSc patients from December 2019 to September 2021. We collected questionnaires about digestive manifestations and quality of life, blood and stool samples, and performed imaging. At inclusion and throughout the study we assessed the occurrence of malnutrition and severe GIT disorders. We performed statistical analysis to highlight eventual risk factors associated with digestive manifestations, including hierarchical cluster analysis. A majority of our patients had gastro-oesophageal manifestations (93.3%), followed by intestinal manifestations (67.8%) and anorectal manifestations (18.9%). We found a correlation between anorectal disorders and cardiac disease, and between gastro-oesophageal involvement and impaired pulmonary function tests. Smoking was significantly associated with occurrence of severe GIT disorders. Malnutrition was frequent and associated with more cardiac and pulmonary disease. Cluster analysis identified three groups of patients, including one cluster with cardiac and digestive involvement. GIT manifestations are frequent and severe in SSc. Smoking appears to be associated with severe disease. Anorectal manifestations may be associated with cardiac disease, but we need more studies to validate these results.

Real-World Clinical Profile and Safety of Nintedanib in Systemic Sclerosis-Associated Interstitial Lung Disease: A Subgroup Analysis of Interstitial Lung Disease Data From an Interstitial Lung Disease (ILD) Specialty Clinic in India.

Systemic sclerosis (SSc) is a multisystem autoimmune disorder characterized by dysregulated innate and adaptive immunity. Interstitial lung disease (ILD) is a common and serious complication of SSc, often leading to significant morbidity and mortality. Consistent demographic characteristics that aid in the early diagnosis of ILD in SSc are lacking. This study aims to identify clinical and demographic parameters associated with ILD in SSc patients and assess the safety and tolerability of nintedanibwith other immunosuppressants. This study is a subgroup analysis of data from the ILD clinic at All India Institute of Medical Sciences Raipur, collected between January 2022 and January 2024. We assessed the clinical and demographic profiles, high-resolution computed tomography thorax patterns, autoantibody profiles, lung function, and treatments used in the patients. We enrolled 57 patients with SSc-associated ILD. The mean age of the participants was 39.0 ± 11.1 years, with 53 (92.9%) being women. The mean body mass index was 20.4 ± 4.32 kg/m². Dyspnea was the most common symptom, followed by skin tightening and cough. Antinuclear antibody tests were positive in 92.9% of patients, and anti-Scl-70 antibodies were positive in 57.9%. Rheumatoid arthritis-SSc overlap was observed in 15.8% of patients. The mean predicted forced vital capacity was 46.5 ± 19.9%, the mean predicted total lung capacity was 64.5 ± 20.4%, and the mean predicted diffusing capacity for carbon monoxide was 46.2 ± 15.7%. The mean six-minute walk distance was 360.3 ± 81.2 meters, and the mean King's Brief Interstitial Lung Disease score was 63.9 ± 10.7. Common radiological abnormalities included ground-glass opacities in 57.8%, traction bronchiectasis in 43.8%, and honeycombing in 28.07%. The predominant ILD pattern was nonspecific interstitial pneumonia. Patients received a combination of prednisolone (5 mg/day) with mycophenolate mofetil (63.2%), hydroxychloroquine (17.5%), cyclophosphamide (12.3%), and methotrexate (7.02%). Nintedanib, the only antifibrotic used, was administered to 17 (29.8%) patients. ILD is relatively common in SSc, particularly in patients with diffuse cutaneous SSc and those with anti-topoisomerase antibodies. Female patients comprised the predominant population in this study. Patients tolerated mycophenolate mofetil and cyclophosphamide well. Nintedanib was the only antifibrotic used, and all patients tolerated the combination of antifibrotics and immunosuppressants well. Early diagnosis is crucial to slow disease progression and preserve lung function. Our results highlight the need for vigilant screening in high-risk groups and suggest that MMF, cyclophosphamide, and nintedanib can be safely incorporated into treatment regimens, offering a potential strategy to improve patient outcomes.

Elevated neutrophil extracellular traps in systemic sclerosis-associated vasculopathy and suppression by a synthetic prostacyclin analog

ObjectivesNeutrophils and neutrophil extracellular traps (NETs) contribute to the vascular complications of multiple diseases, but their role in systemic sclerosis (SSc) is understudied. We sought to test the hypothesis that NETs are implicated in SSc vasculopathy and that treatment with prostacyclin analogs may ameliorate SSc vasculopathy not only through vasodilation but also by inhibiting NET release.MethodsBlood from 125 patients with SSc (87 diffuse cutaneous SSc and 38 limited cutaneous SSc) was collected at a single academic medical center. Vascular complications such as digital ulcers, pulmonary artery hypertension, and scleroderma renal crisis were recorded. The association between circulating NETs and vascular complications was determined using in vitro and ex vivo assays. The impact of the synthetic prostacyclin analog epoprostenol on NET release was determined.ResultsNeutrophil activation and NET release were elevated in patients with SSc-associated vascular complications compared to matched patients without vascular complications. Neutrophil activation and NETs positively correlated with soluble E-selectin and VCAM-1, circulating markers of vascular injury. Treatment of patients with digital ischemia with a synthetic prostacyclin analog boosted neutrophil cyclic AMP, which was associated with the blunting of NET release and reduced NETs in circulation.ConclusionOur study demonstrates an association between NETs and vascular complications in SSc. We also identified the potential for an additional therapeutic benefit of synthetic prostacyclin analogs, namely to reduce neutrophil hyperactivity and NET release in SSc patients.

Does therapy with immunosuppressive drugs improve gastrointestinal symptoms in patients with systemic sclerosis?

ObjectivesWhile important progress was made regarding the treatment of systemic sclerosis (SSc), there is still no evidence-based disease-modifying treatment available for SSc-related gastrointestinal (GI) manifestations. We aimed to identify an...

Inflammatory Response of Monocytes/Macrophages in Patients with Systemic Sclerosis.

Investigation of the inflammatory response of immune cells is a current focus of research on autoimmune disorders. The aim of this study was to evaluate the inflammatory status of monocytes/macrophages in systemic sclerosis (SSc). The study included 35 SSc and 25 healthy participants. The secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), interleukin-6 (IL-6) was measured by enzyme-linked immunosorbent assay (ELISA) in primary cultures of monocytes/macrophages after stimulation with lipopolysaccharide (LPS) on day 1 and on day 6 of incubation. Impaired tolerance of the immune response was characterized by increased secretion of the inflammatory mediators in response to restimulation. Basal secretion of all cytokines was significantly higher in SSc patients compared to healthy individuals. The secretion of TNF-α, IL-1β and IL-6 after the initial LPS stimulation, and secretion of IL-1β, MCP-1, IL-6, IL-8 after LPS restimulation, was significantly higher in the SSc group. Eleven SSc patients (31%) showed impaired immune tolerance in terms of MCP-1 secretion. These patients were significantly younger and had a higher level of anti-topoisomerase I (anti-Scl70) antibodies compared to SSc patients with immune tolerance. This study revealed pro-inflammatory activation and impaired immune tolerance in monocytes/macrophages from SSc patients. The violation of immune response in terms of MCP-1 secretion may be an important factor in the development of chronic inflammation in SSc. MCP-1 may thus be a potential therapeutic target for novel SSc treatment strategies.

Effect of ambrisentan in patients with systemic sclerosis and mild pulmonary arterial hypertension: long-term follow-up data from EDITA study

BackgroundIn the EDITA trial, patients with systemic sclerosis (SSc) and mild pulmonary vascular disease (PVD) treated with ambrisentan had a significant decline of pulmonary vascular resistance (PVR) but not of mean pulmonary arterial pressure (mPAP) vs. placebo after six months. The EDITA-ON study aimed to assess long-term effects of open label therapy with ambrisentan vs. no pulmonary arterial hypertension (PAH) therapy.MethodsPatients who participated in the EDITA study and received regular follow-up were included in EDITA-ON. Clinical, echocardiographic, laboratory, exercise and hemodynamic parameters during follow-up were analysed. The primary endpoint was to assess whether continued treatment with ambrisentan vs. no treatment prevented the development of PAH according to the new definition.ResultsOf 38 SSc patients included in the EDITA study four were lost to follow-up. Of the 34 remaining patients (age 55 ± 11 years, 82.1% female subjects), 19 received ambrisentan after termination of the blinded phase, 15 received no PAH medication. The mean follow-up time was 2.59 ± 1.47 years, during which 29 patients underwent right heart catheterization. There was a significant improvement of mPAP in catheterised patients receiving ambrisentan vs. no PAH treatment (-1.53 ± 2.53 vs. 1.91 ± 2.98 mmHg, p = 0.003). In patients without PAH treatment 6/12 patients had PAH vs. 1/17 of patients receiving ambrisentan (p < 0.0001).ConclusionIn SSc patients with early PVD, the development of PAH and/or deterioration was less frequent among patients receiving ambrisentan, indicating that early treatment and close follow-up could be beneficial in this high-risk group. Future trials in this field are needed to confirm these results.

Do functionality, strength, vascularization, inflammatory and biopsychosocial status improve by biopsychosocial model-based exercise in SSc?

This study aimed to investigation of the effects of the Cognitive Exercise Therapy Approach (Bilişsel Egzersiz Terapi Yaklaşımı-BETY), a supervised biopsychosocial model-based exercise intervention, on functionality, muscle strength, vascularization, anti-inflammatory and biopsychosocial status in Systemic Sclerosis (SSc) patients. Thirty-seven SSc patients were included. Twenty of them were recruited into the study group (SG) undergoing BETY group exercise sessions three times a week for three months and 17 were in the control group (CG) following a home exercise program. Assessments tools were the Modified Rodnan Skin Score (mRSS), Scleroderma Health Assessment Questionnaire (SHAQ), Modified Hand Mobility in Scleroderma (mHAMIS), Duruoz Hand Index (DHI), Six Minute Walk Test (6MWT), skeletal muscle strength measurements using an isokinetic dynamometer (Biodex System 3 Pro), Shear Wave Elastography (SWE), ELISA kits (for tumor necrosis factor-alpha, Interleukin-6, IL-10, serum irisin level), BETY-Biopsychosocial Questionnaire (BETY-BQ), Hospital Anxiety and Depression Scale (HADS), and Short Form-36 (SF-36). The SG demonstrated improvements in SHAQ, mHAMIS, 6MWT, BETY-BQ, HADS, and SF-36 values, excluding the DHI scores (p < 0.05). In contrast, CG showed worsening in SHAQ-general scleroderma symptoms and HADS scores compared to SG (p < 0.05). IL-10 and TNF-alpha increased in both groups, also various vascular parameters were significantly different changed in SG than CG (p < 0.05). Muscle strength values improved in the SG but decreased in the CG however this was statistically not significant (p > 0.05). BETY can be recommended as a nonpharmacologic approach to the disease management of SSc patients.

The Novel Cytokine Interleukin-41/Meteorin-like Is Reduced in Diffuse Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease with a triad of features that include vascular abnormalities, inflammation and skin and lung fibrosis. At the core of the disease is the activation of myofibroblasts from quiescent fibroblasts and this can be modified by various cytokines. IL-41 is a recently described cytokine that was initially characterised as an adipokine as it was highly expressed in adipocytes and adipose tissue. However, it has recently been identified as being widely expressed and has immunomodulatory functions. This study examined the circulating levels of IL-41 and its expression in skin biopsies. We demonstrated significantly reduced levels of IL-41 in diffuse SSc that was also mirrored in the skin of SSc patients. AMPK has been proposed as a downstream target of IL-41, so we also measure mammalian target of rapamycin in skin and found that this is elevated in SSc patients. We speculate that IL-41 maybe an antifibrotic cytokine and its reduction may facilitate the activation of fibroblasts.

Racial variability in immune responses only partially explains differential systemic sclerosis disease severity

ObjectiveTo understand if autoantibodies account for racial variation in disease severity, we compared autoantibody distribution and associated phenotype between self-identified black and white systemic sclerosis (SSc) patients.Methods803 black and 2178...

Outcomes of myocarditis in systemic sclerosis: A 3-year follow-up.

The clinical course, the outcomes of myocarditis, and the imaging progression of cardiac magnetic resonance imaging (MRI) in systemic sclerosis (SSc) are still unknown. We aimed at defining changes in cardiac MRI findings, the clinical course, and the outcomes of SSc patients previously defined as having myocarditis by cardiac MRI. Methods: This prospective cohort study included SSc patients, who had previously been diagnosed with myocarditis through cardiac MRI at the Scleroderma Clinic of Khon Kaen University, between 2018 and 2020 and had had annual follow-ups of cardiac MRI for at least 3 years. Data on demographics, clinical characteristics, cardiac MRI findings, treatment regimens, and outcomes were collected. Serial cardiac MRI on a yearly basis was analyzed to assess changes in myocardial involvement over the 3-year period. Ten SSc patients diagnosed with myocarditis via cardiac MRI were included. Most belonged to the diffuse cutaneous subset with a mean age of 58.3±8.6 years and were mildly symptomatic. Initial cardiac MRI findings showed myocardial edema and hyperemia in all patients and eight patients had had pre-existing myocardial scars, suggesting disease chronicity. Treatment for concomitant interstitial lung disease involved steroids with either cyclophosphamide or mycophenolate mofetil in 6 patients. Outcomes of myocarditis were stable, improving, and worsening in 4, 4, and 2 patients, respectively. There was no complete resolution of the cardiac MRI indices for myocarditis, and none had had major cardiac events. Although SSc myocarditis on cardiac MRI may improve or show stability, the changes remained persistent. Among patients with SSc and mildly symptomatic myocarditis, the efficacy of steroids and immunosuppressive therapy is inconclusive. Over a 3-year follow-up, the prognosis had been acceptably good with no cardiac events.

ACKR1+ Endothelial Cells Mediate Leukocyte Infiltration and Synergize with SFRP2/ASPN+ Fibroblasts to Promote Skin Fibrosis in Systemic Sclerosis.

Skin fibrosis is the most typical pathological manifestation of systemic sclerosis (SSc) and localized scleroderma (LS) with unclear etiology and few effective treatments. Though excessive collagen secretion by fibroblasts is the primary cause of skin fibrosis, many lines of evidence suggested that vascular damage was the initiating event and various cell types along with fibroblasts worked together to contribute to the pathogenesis of skin fibrosis. We sought to explore the relationships between vascular endothelial cell lesions and immune cell infiltration, along with the cell-cell interactions among various cell types within the fibrotic skin ecosystem. Single-cell RNA-seq (10x Genomics) was performed on skin biopsies of 3 healthy donors and 7 SSc patients in Chinese. The additional 3 localized scleroderma patients' data from NCBI database (GSE160536) were integrated by Harmony. CellChat package (v1.5.0) was applied to analyze cell communication network. Transwell assay and subcutaneous bleomycin (BLM) injection in mice were used to explore the role of ACKR1 on immune cell infiltration. Milo single-cell western blot was applied to show the activation of fibroblast subclusters. A total of 62,295 cells were obtained and subpopulations of stromal and immune cells were identified. Interaction network analysis revealed that multiple chemokines secreted by macrophages, pericytes, and pro-inflammatory fibroblasts could bind with Duffy antigen/receptor for chemokines (ACKR1), which is highly expressed on ACKR1+ endothelial cells of lesion skin. Transwell assay revealed that over-expressed ACKR1 in HUVEC facilitated leukocyte infiltration under the treatment of IL8. The BLM mice showed enhanced ACKR1 expression, massive immune cell infiltration, and fibrosis in skin, which could be attenuated by ACKR1 inhibition. Furthermore, infiltrated macrophages with TGFB1 or PDGFB high production could activate SFRP2/ASPN+ fibroblasts to contribute to excessive accumulation of extracellular matrix (ECM), and the SOX4-ASPN axis plays an important role in the TGF-β signaling cascade and the etiology of skin fibrosis. Our results reveal that highly expressed ACKR1 in endothelial cells of fibrotic skin tissue promotes immune cell infiltration, and SFRP2/ASPN+ fibroblasts synergize to exacerbate skin fibrosis.

Clinical courses and predictors of left ventricular systolic dysfunction in systemic sclerosis: A cohort study.

Left ventricular systolic dysfunction (LVSD) is a cardiac involvement that is the leading cause of death among patients with systemic sclerosis (SSc). We aimed to define the clinical course and predictors of LVSD among SSc patients. We conducted a cohort study among adult patients with SSc who were followed up from 2013 to 2020. Semiparametric Cox regression analysis with robust clustering by cohort identification number was used to evaluate the predictors of LVSD. Among the 3, 987 person-years, LVSD was defined in 35 of 419 SSc patients for an incidence of 0.88 per 100 person-years. The median duration of the disease was 8.5 (interquartile range (IQR) 4.9-12.9) years. Every 1-point increase in the modified Rodnan skin score (mRSS) and salt and pepper skin were strong predictors of LVSD, with a respective adjusted hazard ratio (HR) of 1.05 and 3.17. During follow-up, 26 cases (74.3%) had unimproved LVSD. The strong predictors of the unimprovement of LVSD were every 1-point increase in mRSS (HR 1.05), every 1 mg increase in prednisolone treatment (HR 1.05), and every 1 U/L increase in creatine kinase (CK) (HR 1.001). Mycophenolate treatment was a protective factor against the unimprovement of LVSD in SSc (HR 0.15). LVSD was frequently found in patients with diffuse cutaneous SSc, and in most cases, it remained unimproved during follow-up. High mRSS, steroid use, and high CK levels were predictors of unimproved LVSD, whereas mycophenolate treatment might prevent the progression of LVSD. Steroids should be prescribed with caution in patients with longer disease duration.

Can Combination Therapy with Endothelin Receptor Antagonist and PDE5 Inhibitors Prevent Echocardiographic Findings Suspicious for Pulmonary Arterial Hypertension? Description of a Real-Life Case Series.

To retrospectively evaluate the incidence rate (IR) of elevated echocardiographic estimated systolic pulmonary artery pressure (sPAP), suspected for pulmonary hypertension (PH), in systemic sclerosis (SSc) patients after the introduction of a combination therapy with bosentan and sildenafil for treatment or prevention of digital ulcers. Patients attending the Scleroderma Unit of the Universital Hospital of Careggi from July 2010 to July 2023 were enrolled. Patients older than 18 years old with a history of digital ulcers, treated with bosentan and sildenafil in combination for at least 12 months, were included. Patients with a diagnosis of PH preceding the introduction of the therapy were excluded. Demographical data, disease duration, laboratoristic, and instrumental data (pulmonary function tests, echocardiographic estimation of sPAP, and ultrasonographic value of renal resistive index) were collected. The IR of echocardiographic signs suspected of pulmonary hypertension and their 95% confidence interval were calculated in events/1000 patients-years. Thirty-five patients were enrolled; the mean disease duration was 12.82 years (SD 5.92). The mean duration of the combination treatment was 81.03 (SD 43.1.3) months, and the total at-risk time was 2674 months. Two patients (5.7%) presented echocardiographic signs of PH (sPAP 50 mmHg and 40 mmHg); the IR was calculated to be 9/1000 patients-years (95% CI 7.95-10.12). In one of the two patients, right heart catheterism (RHC) excluded PAH, while the other patient refused to undergo RHC, and PAH could not be confirmed/excluded. The stability of PFTs and echocardiographic sPAP was observed during the observation time. The results of this retrospective study suggest that combination therapy with endothelin receptor antagonists and phosphodiesterase-5 (PDE5) inhibitors could help in preventing PAH in SSc; prospective case-control studies on a larger population are needed to improve knowledge in this field.

Ultrasound for day-to-day clinical use: construction of a simple discriminator between healthy skin and thickened systemic sclerosis skin.

Distinction of dermal thickening at fingers is paramount in recognition of systemic sclerosis (SSc). Evaluation of skin thickening by modified Rodnan skin score (mRSS) might be challenging. Simple and practical tools are needed to help distinguishing (non-) thickened skin in daily practice. High frequency ultrasonography (HFUS) can reliably measure dermal thickness (DT). In this pilot study we search for a DT cut-off value (as a simple HFUS discriminator) to distinguish between healthy control (HC) and SSc skin at the left index finger (F2L). DT evaluated by HFUS (18MHz probe) in SSc patients (2013 ACR/EULAR criteria) was compared with HC in a cross-sectional study. A cut-off value was selected by receiver operating characteristic (ROC) curve analysis. 63 consecutive SSc patients (mean age 52±14 SD, 78% female) and 48 HC (mean age 36±14 SD, 62% female) underwent HFUS. Mean DT at F2L was 1.44 mm (± 0.39 SD) in SSc patients and 1.06 mm (± 0.19 SD) in HC. Based on ROC-curve analysis, a DT cut-off of 1.5 mm is proposed as simple HFUS discriminator between HC and SSc, at a specificity of 1 and a sensitivity of 0.32. The final model had an area under the curve of 0.83 (95%CI 0.75-0.90). A simple HFUS discriminator between skin thickness of HC versus SSc, i.e., DT as measured at F2L, at a cut-off of 1.5 mm, is proposed for daily use in rheumatology clinics. Further validation should be executed through prospective multicentric cohorts.

Relationships between systemic sclerosis and atherosclerosis: screening for mitochondria-related biomarkers.

Patients with systemic sclerosis (SSc) are known to have higher incidence of atherosclerosis (AS). Mitochondrial injuries in SSc can cause endothelial dysfunction, leading to AS; thus, mitochondria appear to be hubs linking SSc to AS. This study aimed to identify the mitochondria-related biomarkers of SSc and AS. We identified common differentially expressed genes (DEGs) in the SSc (GSE58095) and AS (GSE100927) datasets of the Gene Expression Omnibus (GEO) database. Considering the intersection between genes with identical expression trends and mitochondrial genes, we used the least absolute shrinkage and selection operator (LASSO) as well as random forest (RF) algorithms to identify four mitochondria-related hub genes. Diagnostic nomograms were then constructed to predict the likelihood of SSc and AS. Next, we used the CIBERSORT algorithm to evaluate immune infiltration in both disorders, predicted the transcription factors for the hub genes, and validated these genes for the two datasets. A total of 112 genes and 13 mitochondria-related genes were identified; these genes were then significantly enriched for macrophage differentiation, collagen-containing extracellular matrix, collagen binding, antigen processing and presentation, leukocyte transendothelial migration, and apoptosis. Four mitochondria-related hub DEGs (IFI6, FSCN1, GAL, and SGCA) were also identified. The nomograms showed good diagnostic values for GSE58095 (area under the curve (AUC) = 0.903) and GSE100927 (AUC = 0.904). Further, memory B cells, γδT cells, M0 macrophages, and activated mast cells were significantly higher in AS, while the resting memory CD4+ T cells were lower and M1 macrophages were higher in SSc; all of these were closely linked to multiple immune cells. Gene set enrichment analysis (GSEA) showed that IFI6 and FSCN1 were involved in immune-related pathways in both AS and SSc; GAL and SGCA are related to mitochondrial metabolism pathways in both SSc and AS. Twenty transcription factors (TFs) were predicted, where two TFs, namely BRCA1 and PPARγ, were highly expressed in both SSc and AS. Four mitochondria-related biomarkers were identified in both SSc and AS, which have high diagnostic value and are associated with immune cell infiltration in both disorders. Hence, this study provides new insights into the pathological mechanisms underlying SSc and AS. The specific roles and action mechanisms of these genes require further clinical validation in SSc patients with AS.

Progranulin, sICAM-1, and sVCAM-1 May Predict an Increased Risk for Ventricular Arrhythmias in Patients with Systemic Sclerosis.

In systemic sclerosis (SSc), fibrosis of the myocardium along with ongoing autoimmune inflammation can alter the electric function of the cardiac myocytes, which may increase the risk for ventricular arrhythmias and sudden cardiac death. We analyzed the electrocardiographic (ECG) variables describing ventricular repolarization such as QT interval, QT dispersion (QTd), T wave peak-to-end interval (Tpe), and arrhythmogeneity index (AIX) of 26 patients with SSc and 36 healthy controls. Furthermore, echocardiographic and laboratory parameters were examined, with a focus on inflammatory proteins like C-reactive ptotein (CRP), soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), and progranulin (PGRN). The CRP, sICAM-1, and sVCAM-1 levels were positively correlated with the length of the QT interval. Although the serum PGRN levels were not increased in the SSc group compared to the controls, in SSc patients, the PGRN levels were positively correlated with the QT interval and the AIX. According to our results, we conclude that there may be a potential association between autoimmune inflammation and the risk for ventricular arrhythmias in patients with SSc. We emphasize that the measurement of laboratory parameters of inflammatory activity including CRP, PGRN, sVCAM-1, and sICAM-1 could be helpful in the prediction of sudden cardiac death in patients with SSc.

Whole phenotype of patients with systemic sclerosis and sicca manifestations: Comparison with sicca manifestations from other causes

Introduction & objectivesThis study aimed to characterize the whole phenotype of Systemic sclerosis (SSc) patients with sicca symptoms, using major salivary glands Ultrasound (SGUS) parameters, minor salivary glands biopsies (mSGB) and clinical findings, and to compare these characteristics with those from patients with Sjogren's Disease (SjD), and patients with sicca manifestations from other causes. MethodsSixty SSc patients fulfilling the 2013 ACR/EULAR classification criteria and with subjective self-declared sicca symptoms were consecutively recruited and had SGUS and mSGB. Fifteen SSc patients without subjective sicca symptoms and 65 patients with sicca symptoms from other causes (including 37 SjD with no SSc). ResultsSSc patients with subjective sicca symptoms had frequent objective clinical (up to 83 %), histological (44 % of Focus score≥1/ mm2) and US anomalies (63 % of OMERACT ≥2). 53 % patients without subjective clinical complaint also had abnormal objective tests, suggesting the existence of a sub clinical involvement of salivary glands in SSc. SjD-SSc patients had more severe glandular involvement as compared to patients with isolated SjD and isolated Sicca-SSc patients (70%, 48,6 % and 38% of patients with OMERACT ≥2 respectively) suggesting additive impact of both diseases on glandular physiology and structure. ConclusionSjD-SSc overlap have more severe sicca features as compared to isolated sicca-SSc and isolated SjD, suggesting a specific impact of SSc on salivary gland physiology. Further translational studies are needed to identify the underlying pathways that could serve as therapeutic targets.

Assessment of Skin by High Frequency Musculoskeletal Ultrasound in Egyptian Patients with Systemic Sclerosis

Abstract Background Fibrotic involvement of the skin is a cardinal feature of systemic sclerosis (SSc). The extent of skin involvement is associated with internal organ involvement with severe disease course and poor prognosis. SSc skin involvement is characterized by three phases in temporal sequence: edematous, fibrotic, and atrophic. A palpation-based semi- quantitative score, the modified Rodnan skin score (mRSS) is widely used for the assessment of skin involvement. It is a quick, noninvasive clinical assessment that correlates with histological grading of skin fibrosis. However, it lacks the sensitivity to differentiate between clinically indistinguishable pathological phases such as inflammatory edema vs. established fibrosis. More objective approaches to measure skin involvement imaging have been developed in the past decades.In our study, we review the use of ultrasound for the assessment of early changes in skin thickness and echogenicity in patients with SSc, focusing. mainly on high frequency ultrasound. Aim of the Work to evaluate the role of high frequency ultrasound (HFUS) of skin in assessment of early changes in skin thickness and echogenicity in patients with SSc. Patients and Methods Our study is a cross-sectional, observational study involving homogenous groups consisting of 23 SSc patients and 21 healthy age and sex matched controls. Patients who fulfilled the 2013 ACR/EULAR Classification Criteria for SSc. Results DT was evaluated by both mRSS and HFUS at 5 skin areas in both patients and control. We found statistically significant difference between the two studied groups as regards in area 1 longitudinal (P = 0.017) and area 1 in transverse (P = 0.038), tendency to significance in area 2 (P = 0.054). Subclinical dermal involvement was detected by HFUS even in the skin areas in patients who had a normal local MRSS ( These areas were not planned to be assessed by high frequency ultrasound but added to the five areas to be assessed to evaluate for ultrasound detected subclinical involvement of skin in SSc patients ). In particular, DT was highly significantly greater in patients with area with Rodnan zero score at dorsum of hand than in healthy subjects (longitudinal and transverse) (P &amp;lt; 0.001, 0.005 ) respectively. Similar changes at the level of echogenicity occurred in determination of the stage of the disease, with increased skin thickness and decreased echogenicity occurring early and during skin disease activity due to edema; and decrease skin thickness and increased echogenicity occurring late with skin atrophy Conclusion that high frequency ultrasound is a useful tool in assessment of skin pathologic changes (even subclinical changes) in terms of thickness and echogenicity in patients with SSc both at disease onset and during follow up of response to therapy and disease stage. Moreover, it could be a useful screening tool with definite cutoff values at certain areas that differentiate normal from pathologic skin thickness.

Clinical outcomes and associated factors with mortality in systemic sclerosis patients with sarcopenia

BackgroundDespite the high incidence of sarcopenia in systemic sclerosis (SSc) patients, there is currently limited evidence on their outcomes. ObjectivesOur study aimed to determine clinical courses, outcomes, and identify factors associated with mortality in the SSc patients with sarcopenia. MethodsA historical cohort study was conducted in 180 adult SSc patients diagnosed with sarcopenia according to the criteria of Asian Working Group for Sarcopenia 2019, who were attending the Scleroderma Clinic at Khon Kaen University between July 2019 and November 2021. ResultsForty-one were diagnosed with sarcopenia. A total of 443.8 persons-year, the respective mortality rate for SSc patients with and without sarcopenia was 5.05 and 5.22 per 100-person-years, showing no statistical difference (p = 0.58). Sarcopenia was not a significant mortality risk in SSc patients with a hazard ratio (HR) of 1.34, 95 % CI 0.48–3.75. The survival rate from the baseline evaluation of sarcopenia to the last follow-up of the patients with sarcopenia at 6-, 12-, 18-, and 24-months were 97.6 %, 95.1 %, 92.7 %, and 87.8 %. Hospitalization was the sole factor significantly associated with the mortality risk, with a HR of 14.21 (95 % CI 2.36–85.60). Sarcopenia itself did not appear to be a significant predictor of disease progression, it did contribute significantly to the progression of salt and pepper skin (p=0.01). ConclusionsThe mortality rate of SSc patients with sarcopenia increased after a 2-year follow-up but no difference from non-sarcopenic patients. Once these patients required hospitalization, the mortality risk increased by over 10 times. Further long-term follow-up in a large cohort is suggested.

Sirtuin3 and Sirtuin7 are promising biomarkers in systemic sclerosis

BackgroundSystemic sclerosis (SSc) is an autoimmune disease that results in micro-vasculopathy, leading to organ dysfunction. Sirtuins are known for their role in cellular processes such as the cell cycle, aging, and inflammation, Sirtuins also play an important role in regulating fibrotic responses, inhibiting collagen production and myofibroblast differentiation, implying that its dysregulation is involved in the pathogenesis of systemic sclerosis. The aim of this study was to determine the circulating Sirtuin3 and Sirtuin7 levels in patients suffering from systemic sclerosis with a focus on how they might be associated with the different clinical features and subsets of the disease.MethodsThis prospective cross-sectional case–control study included 56 participants 41 SSc patients and 15 healthy controls. Demographics, clinical, and laboratory data were analyzed. Quantitative determination of human Sirtuin3 and Sirtuin7 concentrations was done.ResultsAmong systemic sclerosis patients, the age of SSc patients was 42.27 ± 10.46 years. The mean serum levels of Sirtuin3 and Sirtuin7 were significantly lower in SSc patients than in healthy controls (p < 0.001). SIRT3 and SIRT7 levels among SSc patients showed a statistically significant positive correlation (p < 0.001). SIRT7 level was insignificantly decreased in dcSSc (14.16 ± 5.93) than in lcSSc (20.01 ± 8.34). Regarding the SIRT3 level, there was an insignificant difference between dcSSc and lcSSc. Modified Rodnan’s skin score correlated negatively with Sirtuin3 and Sirtuin7 levels. In systemic sclerosis patients with interstitial lung disease (56.1%), there was an insignificant difference in SIRT3 and SIRT7 levels (0.12 ± 0.01and 21.23 ± 8.23) compared with systemic sclerosis patients without interstitial lung disease (0.10 ± 0.01 and 17.47 ± 8.57), with p = 0.408 and 0.258, respectively. The receiver operating characteristic curve for SSc prediction with Sirtuin3 has an accuracy of 83.0%, sensitivity of 85.4%, and specificity of 80.0% and p < 0.001. Regarding Sirtuin7, it has an accuracy of 89.5%, sensitivity of 85.4%, and specificity of 93.3% and p < 0.001.ConclusionSirtuin3 and Sirtuin7 levels were found to have a significant positive correlation in SSc patients. Sirtuin3 and Sirtuin7 levels are both good diagnostic biomarkers for detecting and diagnosing SSc, with Sirtuin7 being more accurate, specific, and predictive of the disease than Sirtuin3. Sirtuin7 is thought to be a new biomarker for SSc disease.