Systemic Sclerosis Patients Research Articles

Markers of Endotoxemia and Inflammation are Associated with Digital Ulcers in Systemic Sclerosis Patients

ABSTRACT Background The aim of this study was to evaluate the possible role of lipopolysaccharide-binding protein (LBP) and interleukin 6 (IL-6) in the development of digital ulcers (DUs) in Systemic sclerosis (SSc). Methods 60 SSc patients were enrolled and tested for serum levels of LBP and IL-6. The development of DUs was assessed in a 12-month follow-up period. Results Median LBP and IL-6 were 107.445 ng/mL and 10.8 pg/mL whilst 33.3% patients had LBP ≥ 11995 ng/mL and 51.7% patients had IL-6 ≥ 12.5 pg/mL. DUs history were present in 41.7% SSc patients and at follow-up 23.3% patients developed new DUs. Baseline LBP (14105 ng/mL vs 10355 ng/mL, p < .001) and IL-6 (195 pg/mL vs 9.4 ng/mL, p < .001) were higher in SSc patients with new DUs. The ROC curves showed a good diagnostic accuracy for a cut-off of LBP ≥ 11995 ng/mL [AUC = 0.804 (95% CI = 0.656–0.951), p < .001] and for a cut-off of IL-6 ≥ 12.5 pg/mL [AUC = 0.897 (95% CI = 0.783–1.000), p < .001]. Free survival from new DUs was shorter in SSc patients with increased LBP (p < .001) or IL-6 (p = .003). Conclusions LPB or IL-6 could play a role in digital microvascular damage of SSc patients.

Validity and psychometric characteristics of the Duruöz Hand Index (DHI) with systemic sclerosis

Objective: The Duruöz Hand Index (DHI) is a self-report questionnaire originally developed to assess hand function in rheumatoid arthritis patients and validated for various rheumatic conditions. The aim of the study is to evaluate the validity and psychometric features of the DHI in patients with systemic sclerosis (SSc). Methods: SSc patients diagnosed using EULAR/ACR 2013 criteria were included in study. Hand functionality was assessed using the DHI, Hand Functional Index (HFI) and visual analog scales (VAS) for disability and handicap. Overall disability and quality of life were measured using the Health Assessment Questionnaire (HAQ) and Short Form-36 (SF-36). Reliability (Cronbach’s alpha and ICC) and validity (face, content, convergent and divergent) were also analyzed and correlations with other measures assessed for construct validity of the DHI were examined. Results: Seventy-three patients were included in the study, 78.1% were female. The baseline mean DHI score was 31.2 (SD: 20.2). Completion and calculation of the questionnaire were easy and took 5 min and 30 s, respectively. The Cronbach’s alpha coefficient for internal consistency was 0.973 and the ICC for test-retest reliability was 0.993 (95%CI 0.981–0.997), suggesting that the DHI has high internal consistency and a high degree of reliability. Cognitive debriefing showed that the DHI is clear, understandable, relevant, and covers many domains of daily life, indicating good face and content validity. The DHI demonstrated good to moderate correlations with functional measures indicating convergent validity and moderate to non-significant correlations with non-functional parameters that supported divergent validity. Cronbach’s alpha was 0.973, indicating excellent internal consistency. Conclusion: In SSc patients, specific tools for assessing hand function are lacking. The DHI is a practical, reliable and valid measurement tool for both clinical assessment and research in this disease affecting skin, tendons, subcutaneous tissue and arthritis.

Long-term Prognostic Value of Left and Right Ventricular Systolic Function on Cardiovascular Magnetic Resonance Imaging in Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare autoimmune disorder associated with a high risk of cardiovascular diseases. We aimed to determine the long-term prognostic value of left and right ventricular (LV and RV) systolic dysfunction in SSc patients with clinically suspected cardiac disease. We conducted a retrospective cohort study of consecutive adults with SSc who had cardiovascular magnetic resonance imaging (CMR) for suspected cardiac disease. We assessed two CMR measures of LV and RV function, ejection fraction (EF) and feature tracking-derived global longitudinal strain (GLS), and investigated their associations with the long-term incidence of a composite endpoint of death or major adverse cardiac events (MACE). In 151 patients (median age 58 years, 81% women) who had CMR at a median of 3.6 years after diagnosis, the median LVEF was 58.0%, and the median LVGLS was -15.7%. The median RVEF was 57.0%, and the median RVGLS was -16.2%. Over a median follow-up of 4.7 years, 69 patients experienced the composite endpoint of death or MACE. LVGLS was independently associated with the composite endpoint (hazard ratio [HR] 1.08 per 1% worsening; 95% confidence interval [CI] 1.01-1.15; p = 0.018), while LVEF was not. Similarly, RVGLS was independently associated with the composite endpoint (HR 1.08 per 1% worsening; 95% CI 1.01-1.15; p = 0.017), while RVEF was not. In patients with SSc and clinically suspected cardiac disease, worse LVGLS and RVGLS on CMR were independently associated with death or MACE, while LVEF and RVEF were not.

Fibroblast activities are associated with prolonged QTc and pulmonary arterial hypertension in patients with systemic sclerosis.

In systemic sclerosis patients (SSc), we aimed at exploring the potential of serum biomarkers of fibrosis and immune-cell activity to detect subclinical heart involvement determined by electrocardiographic (ECG) alterations. A panel of extracellular matrix (ECM) turnover biomarkers quantifying type III and VI collagen formation (PRO-C3 and PRO-C6), type IV collagen turnover (PRO-C4), MMP-degraded type III, IV, VI and VII collagen (C3M, C4M, C6M and C7M), human neutrophil elastase degraded elastin and calprotectin (ELA-HNE and CPa9-HNE), MMP-degraded C-reactive protein (CRPM), MMP-degraded and citrullinated vimentin (VICM) were measured by competitive ELISAs in serum from 102 well-characterised systemic sclerosis patients. Correlations to ECG-changes as well as clinical and paraclinical manifestations were explored. PRO-C3 and PRO-C6, biomarkers of fibroblast activation, were significantly increased in patients with prolonged QTc (>450ms) (p=0.043 and p=0.027, respectively), while no difference was detected for PRO-C4, C3M, C4M, C6M, and C7M. The ELA-HNE biomarker was significantly reduced in patients with prolonged QTc (>450ms). No difference was found for the CPa9-HNE, CRPM, VICM, and C4G. The PRO-C3 and PRO-C6 biomarkers were also significantly increased in the patients with pulmonal arterial hypertension (PAH) (p=0.041 and p=0.019, respectively), and increased with NYHA class (p=0.024 and p=0.045, respectively). In addition, C6M were significantly increased with NYHA class (p=0.021). Patients with SSc and prolonged QTc, presence of PAH and high NYHA class presented an altered tissue turnover, particularly associated with increased fibroblast activation. Our study indicates that serum-based biomarkers could serve as convenient biomarkers of subtle cardiac disease in SSc but further studies are needed to confirm this.

Respiratory tract lining fluid copper content contributes to pulmonary oxidative stress in patients with systemic sclerosis

Background Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs, mostly affecting young and middle-aged women. Significant questions remain as to its pathogenesis, especially the triggers for the associated interstitial lung disease (SSc-ILD). We examined the extent to which SSc and SSc-ILD were related to oxidative stress and altered metal homeostasis at the air-lung interface. Methods In this case-control study, we recruited 20 SSc patients, of which 11 had SSc-ILD. Eighteen healthy individuals were recruited as age-matched healthy controls, for a total of 38 study participants. Low molecular weight antioxidants (ascorbate, urate and glutathione), metal transport and chelation proteins (transferrin and ferritin) and metals (Fe and Cu) concentrations, including a measure of the catalytically active metal pool, were determined in respiratory tract lining fluid (RTLF) collected by bronchoalveolar lavage from the SSc group and compared with healthy controls. Results In the SSc group, 14 individuals were of female sex (70%) and the median age was 57 years (range 35–75). We observed evidence of oxidative stress in the RTLFs of SSc patients, characterised by increased concentrations of glutathione disulphide (GSSG, P&lt;0.01), dehydroascorbate (DHA, P&lt;0.05) and urate (P&lt;0.01). This was associated with elevated RTLF Fe (P=0.07) and Cu (P&lt;0.001), and evidence of a catalytic metal pool, demonstrated by an enhanced rate of ascorbate oxidation in the recovered lavage fluid (p&lt;0.01). Cu concentrations were significantly associated with the ascorbate depletion rate (r=0.76, P&lt;0.001), and GSSG (r=0.38, P&lt;0.05) and protein carbonyl (r=0.44, P&lt;0.01) concentrations. Whilst these markers were all increased in SSc patients, we found no evidence for an association with SSc-ILD. Conclusions These data confirm the presence of oxidative stress in the airways of SSc patients and, for the first time, suggest that an underlying defect in metal homeostasis at the air-lung interface may play a role in disease progression.

Altered X-chromosome inactivation of the TLR7/8 locus and heterogeneity of pDCs in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease that has a strong female predominance. Both the X-linked TLR7 and TLR8 can induce type I IFN (IFN-I) by plasmacytoid DCs (pDCs), which can promote fibrosis. We identified five subclusters of pDCs, including ISGhigh clusters that were over-represented in SSc patients. We observed that both TLR7 and TLR8 genes escape from X chromosome inactivation (XCI) at higher frequency in pDCs of SSc patients, which was associated with changes in TLR7 protein profile. Combined DNA/RNA FISH analysis revealed that the TLR7/8 locus is preferentially located outside of the inactive X (Xi) territory when TLR7 is expressed, suggesting that higher-order loop formation is linked to TLR7/8 expression from the Xi. Furthermore, the expression levels of XIST and the transcriptional repressor SPEN were reduced in SSc pDCs. Hence, our data revealed the heterogeneity of pDCs in SSc and suggested that altered XCI at the TLR7/8 locus may contribute to the chronic IFN-I activity of pDCs in female SSc patients.

Is Myopenia or Myosteatosis Clinically Relevant in Systemic Sclerosis? Skeletal Muscle Assessment Using Computed Tomography.

Is Myopenia or Myosteatosis Clinically Relevant in Systemic Sclerosis? Skeletal Muscle Assessment Using Computed Tomography.

PDCs, type 1 IFN, and the female predileXion of SSc.

Systemic sclerosis (SSc) is a debilitating autoimmune disease that preferentially afflicts women. The molecular origins of this female bias are unclear. A new study of plasmacytoid dendritic cells from SSc patients by Du et al. (https://doi.org/10.1084/jem.20231809) suggests the X chromosome may play a key role.

Mechanosensing regulates pDC activation in the skin through NRF2 activation.

Plasmacytoid DCs (pDCs) infiltrate the skin, chronically produce type I interferon (IFN-I), and promote skin lesions and fibrosis in autoimmune patients. However, what controls their activation in the skin is unknown. Here, we report that increased stiffness inhibits the production of IFN-I by pDCs. Mechanistically, mechanosensing activates stress pathways including NRF2, which induces the pentose phosphate pathway and reduces pyruvate levels, a product necessary for pDC responses. Modulating NRF2 activity in vivo controlled the pDC response, leading to resolution or chronic induction of IFN-I in the skin. In systemic sclerosis (SSc) patients, although NRF2 was induced in skin-infiltrating pDCs, as compared with blood pDCs, the IFN response was maintained. We observed that CXCL4, a profibrotic chemokine elevated in fibrotic skin, was able to overcome stiffness-mediated IFN-I inhibition, allowing chronic IFN-I responses by pDCs in the skin. Hence, these data identify a novel regulatory mechanism exerted by the skin microenvironment and identify points of dysregulation of this mechanism in patients with skin inflammation and fibrosis.

Soluble oncostatin M receptor (sOSMR): A potential biomarker in systemic sclerosis diagnosis.

Soluble oncostatin M receptor (sOSMR): A potential biomarker in systemic sclerosis diagnosis.

Spectrum of Clinical Manifestations in Patients of Scleroderma and Correlation between Cutaneous and Pulmonary Involvement.

Our research aimed at characterizing the range of signs and symptoms observed in scleroderma patients at a tertiary care hospital and investigating potential correlations between pulmonary and cutaneous involvement. We obtained informed consent from scleroderma patients for conducting a comprehensive clinical assessment, including detailed medical histories and physical examinations. Standard diagnostic investigations like complete blood counts, erythrocyte sedimentation rate, renal function, liver function, electrocardiograms (ECG), high-resolution computed tomography (HRCT) scans, and pulmonary function tests were performed. The modified Rodnan skin score (mRSS) was used to assess skin involvement. About 74 (71.2%) patients had diffuse cutaneous systemic scleroderma (dcSSc), while 30 (28.8%) patients had limited cutaneous scleroderma (lcSSc). 96 (92.3%) patients had Raynaud's phenomenon. About 68 (65.4%) patients had mild mRSS, while 26 (25%) and 10 (9.6%) patients had moderate and severe mRSS, respectively. Skin tightening (88.4%) and sclerodactyly (88.4%) were the most common cutaneous manifestations, followed by digital ulcers and pits (57.7%), diffuse edema of hands and feet (38.4%), salt-and-pepper skin (38.4%), calcinosis (30.8%), telangiectasia (25%), and contractures (19.2%). Pulmonary manifestations showed interstitial lung disease (ILD) in 62 (59.6%) patients and pulmonary hypertension (PH) in 14 (13.5%) patients. 8 (7.7%) patients had ILD with PH. 48 (46.2%) and 18 (17.3%) patients with dcSSc had mild and moderate mRSS, respectively, while 8 (7.7%) patients had severe mRSS. About 20 (19.2%) and 8 (7.7%) patients with lcSSc had mild and moderate mRSS, respectively, while 2 (1.9%) patients had severe mRSS. There was no significant correlation of mRSS and subtypes of scleroderma patients. The mean mRSS score in ILD was low in comparison to the mRSS score in patients with PH (25.7 ± 8.90 vs 28.9 ± 7.62). There was a significant correlation of mRSS and pulmonary involvement as indicated by the Student's t-test (p < 0.05). In systemic sclerosis (SSc) patients, the emergence of severe systemic complications such as pulmonary arterial hypertension and ILD can manifest regardless of disease duration or subtype. Symptoms might not consistently align with disease advancement. Therefore, a thorough evaluation that incorporates symptoms and specialized diagnostic tests, such as pulmonary function tests, echocardiography (ECHO), and HRCT, is crucial for early identification, timely treatment, and better prognosis. The mRSS serves as a valuable clinical instrument for monitoring scleroderma progression.

Total lung capacity is predictive of disease severity and survival in systemic sclerosis: A longitudinal analysis in 2347 patients from the French National Cohort Study.

Total lung capacity is predictive of disease severity and survival in systemic sclerosis: A longitudinal analysis in 2347 patients from the French National Cohort Study.

Exosomes carrying adipose mesenchymal stem cells function alleviate scleroderma skin fibrosis by inhibiting the TGF-β1/Smad3 axis

Systemic sclerosis (SSc) is a connective tissue disease characterized by progressive fibrosis of the skin and visceral organs, to date, skin fibrosis remains a clinical therapeutic challenge. Adipose-derived mesenchymal stem cells (AMSCs) have been considered extremely promising for the treatment of SSc, and the biological effects of MSCs are partly attributed to the secretion of exosomes (exos). Our aim was to determine whether exosomes derived from AMSCs have parental biological effects to AMSCs in the therapy of SSc skin fibrosis. In vitro cellular experiments, AMSCs and SSc skin fibroblasts were cocultured in direct contact and transwell indirect contact at a ratio of 1:5 and 1:10, respectively, then exosomes were extracted from the cell culture supernatant of AMSCs and identified, and the exosomes were cocultured with fibroblasts to investigate the effects of AMSCs and exosomes on fibroblast collagen synthesis. Repeated subcutaneous injections of bleomycin (BLM) to construct a model of SSc skin fibrosis in vivo experiments, then AMSCs and exosomes were injected subcutaneously to investigate their effects on skin fibrosis in the BLM mice. The results revealed that exosomes had similar biological functions to AMSCs, by inhibiting the TGF-β1/Smad3 axis, which alleviated collagen synthesis in skin fibroblasts from SSc patients and skin fibrosis in BLM models. In conclusion, AMSCs-derived exosomes may be “rising star candidates” for the treatment of SSc skin fibrosis.

Neoplasm related mortality risk in Systemic Sclerosis: a nationwide study

BackgroundThe higher mortality rates in patients with Systemic sclerosis (SSc) are related to SSc activity, cardiovascular disease, and neoplasms, among other factors. Our objective was to assess the impact of solid organ neoplasms (SON) and hematological neoplasms (HN) on mortality among SSc patients.MethodsA retrospective, observational comparison of SON and HN-related deaths in SSc patients with those in the general Spanish population was conducted using data from the Spanish Hospital Discharge Database. Binary logistic regression was used to analyze the impact of SSc on mortality risk from each neoplasm.ResultsDuring 2016–2019, 139,531 in-hospital deaths from neoplasms were certified in Spain (67 in patients with SSc). Malignancies accounted for 9.7% of all deaths in SSc patients, and disease activity for 11.5% (p > 0.05). Compared to the general Spanish population, patients with SSc had a higher death ratio from lung neoplasms (18.6 vs. 25.4%, OR = 2.228, 95% CI 1.260–3.937), gynecological neoplasms (3 vs. 13.4%, OR = 4.804, 95%CI 2.372–9.730), attributable to the increased risk of uterine tumors (0.9 vs. 4.5%, OR = 6.177, 95% CI 1.931–19.758) and ovarian carcinomas (1.3 vs. 4.5%, OR = 3.456, 95% CI 1.083–11.032), and from T/NK lineage lymphomas (0.3 vs. 3.0%, OR = 8.955 95% CI: 2.181–36.767).ConclusionThe detection of chronic comorbidities such as cancer is emerging as a noteworthy component of standard care for SSc patients. This can be addressed during their follow up or even in specific screening programs aimed at achieving better long-term quality of life and prognosis.

Assessment of Factors Related to Sarcopenia in Patients with Systemic Sclerosis.

Objectives: Systemic sclerosis (SSc) patients exhibit a heightened vulnerability to sarcopenia, a condition characterized by the loss of muscle mass and strength. This study aims to determine the prevalence of sarcopenia in patients with SSc and to investigate the associated factors contributing to this condition. Methods: Eighty patients with SSc were included in the study, and their demographic and clinical characteristics, body composition by bioelectrical impedance analysis, SARC-F score, chair-stand test performance, and 4 m walking speed were recorded. Results: Among the 80 participants, 91.3% were female, with a median age of 56.5 years (range 45-65). The majority (70%) had limited SSc, and 71.3% reported at least one comorbidity. According to the International Physical Activity Questionnaire, only 12.5% of participants met the criteria for an active lifestyle. The SARC-F questionnaire indicated that 20% of patients were at risk for sarcopenia. The prevalence of sarcopenia among patients showed considerable variability: 5% (95% CI 0.1-9) were identified through the appendicular skeletal muscle index (ASMI), 8.8% (95% CI 2.4-15) via the fat-free mass index (FFMI), and a concerning 20% (95% CI 11-29) according to the skeletal muscle mass index (SSMI). A multivariate logistic regression analysis identified age as the only factor significantly influencing the SARC-F score, with an odds ratio of 1.081 (95% CI 1.012-1.154, p = 0.020). Additionally, the older age group demonstrated a lower level of physical activity, poorer chair-stand test outcome, and slower 4 m gait speeds (p = 0.013, p = 0.008, p = 0.001, respectively), as well as a higher reported frequency of falls (p = 0.039). Conclusions: Sarcopenia is a prevalent issue among individuals with SSc, particularly in the older population. This study did not identify a direct correlation between sarcopenia and SSc subtype, disease activity, or other clinical parameters. However, the need for an improved cut-off value for diagnosing sarcopenia in this specific cohort is evident.

The impact of systemic sclerosis on women's health evaluated with an ad hoc-developed patient-reported questionnaire.

The impact of disease on women's health-related quality of life has become increasingly important in patients with rheumatic diseases (RDs). Systemic sclerosis (SSc) mostly affects women with a broad spectrum of clinical presentations and severity, and a variable impact on daily living. The objective of the present study was to specifically address "women's health" in systemic sclerosis patients through a dedicated questionnaire. An anonymous self-reported questionnaire (only in Italian) was developed in collaboration with obstetricians and gynecologists and subsequently revised and approved by five patient representatives. The questionnaire was administered to SSc patients during scheduled visits in an outpatient Rheumatology SSc Clinic. Between April 2021 and March 2023, 168 patients accepted to participate; among them, 44.1% had received their SSc diagnosis during reproductive age (<45 years). The questionnaire was composed of 44 questions and included 5 sections encompassing different topics. A high rate of adherence to female cancer screening programs was recorded (86.9% for cervix and 93.6% for breast cancer), while a non-regular gynecological follow-up was observed in 36.4%, mostly in patients with more severe disease phenotype. Only 42.3% accepted to compile the Female Sexual Function Index (FSFI), which indicated a sexual dysfunction (score ⩽ 26.55) in 66.2% of patients. A worse sexual function was shown to be associated with different disease manifestations, including digital ulcers. More than 90% of patients who expressed a desire for pregnancy after diagnosis received medical pre-conception counseling and were satisfied with the information provided. In contrast, discussion about contraception occurred in 37.8% of patients who had been diagnosed during fertile age. Family planning still represents an unmet need, as 43.6% of patients did not achieve their desired family size, mainly due to concerns about their capacity to care for their children. The newly developed questionnaire provides a unique opportunity to comprehensively assess the experience of women with SSc. Disease burden was shown to negatively impact sexual function and adherence to regular gynecological visits. Furthermore, receiving a diagnosis during reproductive age may increase the likelihood of a reduced family size. Clinicians who take care of women with SSc should implement these domains into routine management, thus improving the health literacy of their patients.

Associations Between Soluble Cell Adhesion Molecules and Cardiovascular Comorbidities in Systemic Sclerosis: Implications for Insulin Resistance.

Background: Soluble cell adhesion molecules such as sICAM-1 (soluble intercellular adhesion molecule-1), sVCAM-1 (soluble vascular cell adhesion molecule-1), and P-selectin have been implicated in cardiovascular disease pathogenesis in the general population. Cardiovascular disease is prevalent among patients with systemic sclerosis (SSc). This study aims to investigate potential associations between the serum levels of these adhesion molecules and specific cardiovascular comorbidities in SSc patients. Methods: This cross-sectional study encompassed 81 individuals with SSc. All SSc patients underwent a complete clinical evaluation. Serum sICAM-1, sVCAM-1, and P-selectin levels, lipid profiles and insulin resistance indices, and carotid ultrasound were assessed. Multivariable linear regression analyses were employed to investigate potential associations between adhesion molecule levels (sICAM, sVCAM, and P-selectin) and both SSc-specific manifestations and cardiometabolic parameters. Results: The associations of disease-related parameters with sICAM-1, sVCAM-1, and P-selectin levels were limited. Notably, only the modified Rodnan skin score exhibited a significant positive association with sVCAM-1 levels, while no such associations were observed for sICAM-1 and P-selectin. Regarding cardiovascular disease-related data, sVCAM-1 significantly correlated with higher values of insulin resistance and beta-cell function indices. In the case of P-selectin, although a trend was observed, statistical significance was not reached. Conclusions: In patients with SSc, serum values of sVCAM-1 independently correlate with insulin resistance. The assessment of CAMs in patients with SSc could serve as a valuable clinical tool for identifying individuals with increased insulin resistance and a higher risk of cardiovascular disease.

Aberrant lipid profiles and lymphocyte counts in systemic sclerosis population, reassessing predictive value for concurrent cardiovascular diseases.

To investigate alterations in blood lipid profiles and T cell subsets among systemic sclerosis (SSc) patients, and to assess their potential utility in predicting cardiovascular disease (CVD) risk. 105 SSc patients and 80 age- and sex-matched healthy controls (HCs) were enrolled. Flow cytometry was employed to quantify T cell subsets. Multivariate logistic regression analysis investigated the association between blood lipid profile, T cell subsets, SSc occurrence, and CVD risk. Additionally, a prediction model was developed to assess the potential predictive value of CVD risk. In the SSc patients, low-density lipoprotein cholesterol (LDL-C) (OR = 3.212, 95%CI = 1.132-9.113, p= 0.028), ESR (OR = 1.218, 95%CI = 1.086-1.367, p= 0.001), CRP (OR = 2.156, 95% CI = 1.393-3.338, p = 0.001), T helper (Th)cells (OR = 1.004, 95% CI = 1.001-1.008, p = 0.034) were positively correlated with the risk of SSc. Further studies found that absolute increases in Th cells in SSc patients were positively associated with the risk of CVD (OR=1.002, 95%CI=1.001-1.005, p =0.011) and were independent predictors of CVD risk in SSc. When Th cells exceeded 866.53 cells/μL, the risk of CVD in SSc patients was greatly increased (p<0.001). Altered lipid profiles and dysregulated Th cell expression in SSc patients, with a significant elevation of Th cells specifically noted in SSc-CVD patients, suggesting that Th cells may serve as a potential predictive biomarker for CVD in SSc patients, thereby aiding in early diagnosis. The underlying mechanism of this association requires further investigation.

Distinct metabolic profiles of circulating plasmacytoid dendritic cells in systemic sclerosis patients stratified by clinical phenotypes

BackgroundPlasmacytoid dendritic cells (pDCs) play a key role in systemic sclerosis (SSc) pathophysiology. However, despite the recognised importance of metabolic reprogramming for pDC function, their metabolic profile in SSc remains to be elucidated. Thus, our study aimed to explore the metabolic profile of pDCs in SSc and their potential contribution to the disease.MethodsPeripheral blood mononuclear cells (PBMCs) were isolated from the blood of healthy donors and SSc patients. SCENITH™, a single-cell flow cytometry-based method, was applied to infer the metabolic profile of circulating pDCs from patients with SSc. pDCs (CD304+ Lin−) at steady-state or stimulated with CpG A were analysed. Toll-like receptor (TLR)9 activation was confirmed by ribosomal protein S6 phosphorylation.ResultsCirculating pDCs from ten healthy donors and fourteen SSc patients were analysed. pDCs from anti-centromere antibody-positive (ACA+) patients displayed higher mitochondrial dependence and lower glycolytic capacity than those from anti-topoisomerase I antibody-positive (ATA+) patients. Furthermore, cells from both ACA+ patients and limited cutaneous SSc (lcSSc) patients showed a stronger response towards TLR9 activation than cells from ATA+, anti-RNA polymerase III antibody-positive (ARA+) or diffuse cutaneous SSc (dcSSc) patients.ConclusionsAn innovative single cell flow cytometry-based methodology was applied to analyse the metabolic profile of pDCs from SSc patients. Our results suggest that pDCs from ACA+ patients rely more on oxidative phosphorylation (OXPHOS) and are more responsive to external stimuli, whereas pDCs from ATA+ patients may exhibit a more activated or exhausted profile.

Cell-free regenerative medicine: identifying the best source of mesenchymal stem cells for skin therapy in Systemic Sclerosis.

Systemic Sclerosis (SSc) is a rare chronic systemic autoimmune disease characterized by fibrosis of the skin and internal organs and vasculopathy. Raynaud's phenomenon is typically the earliest clinical manifestation accompanied by skin inflammation, finger ulcers, and organ manifestations, including pulmonary fibrosis. There is an urgent need for the development of effective targeted therapeutic intervention for SSc patients. A greater focus has been placed on bioactive factors secreted by Mesenchymal Stem Cells (MSCs), with immunomodulatory and regenerative potentials. Current data report a different secretion profile of MSCs, depending on the tissue of origin. Understanding of the secretion profile of different MSCs is necessary to identify the most efficient and useful source for SSc treatment. We analyzed the content of MSC-conditioned media (MSC-CM) obtained from MSCs isolated from adipose tissue (AT), bone marrow (BM), Wharton's jelly (WJ), and cord blood (CB) by ELISA method, and their effects on the wound healing process by fibroblast proliferation, migration, and ECM deposition assays, to compare regenerative potential of different MSC populations. WJ-MSC-conditioned medium (CM) and BM-MSC-CM show a greater regenerative profile, compared to CB-MSC-CM and AT-MSC-CM, due to the abundance of growth factors and immunomodulatory cytokines and the effects on fibroblast functions. In SSc fibroblasts, WJ-MSC-CM significantly promotes fibroblast-mediated wound healing processes and VEGF expression, compared to BM-MSC-CM. Our data indicate that WJ-MSC-CM could be considered an appealing strategy to both topical and systemic administrations in SSc patients.