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Background: Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular and immunity alterations and skin/internal organ fibrosis. Aberrant levels of plasma CXCL4, CXCL4–RNA/DNA complexes, type I IFN (IFN-I) and anti-CXCL4 antibodies characterize SSc. These parameters influence each other: CXCL4–self-DNA/RNA complexes are triggers of IFN-I in plasmacytoid dendritic cells (pDCs), and anti-CXCL4 autoantibodies amplify this effect. Here, we assess the modulation over time of plasma CXCL4 and the related parameters of CXCL4–DNA/RNA complexes, anti-CXCL4 antibodies, IFN-α and TNF-α in an SSc cohort under the synthetic analogue of prostacyclin PGI2 (iloprost) treatment to address contribution of these parameters to pathogenesis and their role as biomarkers. Methods: We analyzed immunological parameters at baseline (T0) and after 3 (T3) and 6 (T6) months in 30 SSc patients. Responders were the patients that lowered their disease activity parameters after six months of treatment. Results: Anti-CXCL4 autoantibodies correlated with both IFN-α and TNF-α levels in SSc plasma. Responders significantly down-regulated serum IFN-α. In seven patients with a shorter disease duration, improvement coincides with a decrease in plasma IFN-α, CXCL4 and TNF-α. Iloprost efficiently blocks pDCs IFN-α production induced by CXCL4–DNA/RNA complexes in vitro. Conclusions: The data suggest a possible role of iloprost as a disease-modifying drug, mainly accompanied by down-regulation of plasma IFN-I levels. Since CXCL4, IFN-I and TNF-α down-modulation was evident and significant in improving SSc patients with a shorter disease duration, these results warrant future investigations on the early use of iloprost to slow SSc progression. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a chronic disease of the connective tissue characterized by its multifaceted impact on various bodily systems, yet its precise cause remains elusive. Central to its pathology are abnormal immune activation, vasculopathy, and consequent fibrosis affecting both the skin and internal organs. The intricate interplay between the innate and adaptive immune systems significantly influences the pathogenesis of SSc. Despite substantial research, the role of neutrophils, key players in innate immunity, in the context of SSc has remained enigmatic. Emerging evidence suggests that neutrophils not only contribute to the initiation and perpetuation of SSc but also inflict damage on organs and promote fibrosis—a hallmark of the disease in many patients. This review aims to investigate the nuanced involvement of neutrophils in the development of SSc. By shedding light on the intricate mechanisms through which neutrophils influence the pathogenesis of SSc, we can gain deeper insights into the disease process and potentially identify novel therapeutic targets. Understanding the precise role of neutrophils may pave the way for more targeted and effective interventions to alleviate the burden of SSc on affected individuals. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a collagen disease with immune abnormalities, vasculopathy, and fibrosis. Ca blockers and prostaglandins are used to treat peripheral circulatory disturbances. Chronic limb‐threatening ischemia (CLTI) is a disease characterized by extremity ulcers, necrosis, and pain due to limb ischemia. Since only a few patients present with coexistence of CLTI and SSc, the treatment outcomes of revascularization in these cases are unknown. In this study, we evaluated the clinical characteristics and treatment outcomes of seven patients with CLTI and SSc, and 35 patients with uncomplicated CLTI who were hospitalized from 2012 to 2022. A higher proportion of patients with uncomplicated CLTI had diabetes and male. There were no significant differences in the age at which ischemic ulceration occurred, other comorbidities, or in treatments, including antimicrobial agents, revascularization and amputation, improvement of pain, and the survival time from ulcer onset between the two subgroups. EVT or amputation was performed in six or two of the seven patients with CLTI and SSc, respectively. Among those who underwent EVT, 33% (2/6) achieved epithelialization and 67% (4/6) experienced pain relief. These results suggest that the revascularization in cases with CLTI and SSc should consider factors such as infection and general condition, since revascularization improve the pain of these patients. [ABSTRACT FROM AUTHOR]

ABSTRACTSystemic sclerosis (SSc) is a chronic autoimmune disease characterized by skin and internal organ fibrosis and obliterative vasculopathy. Few effective treatments are currently available for fibrosis in SSc, therefore, demand persists for novel therapies. Although use of Ginkgo biloba extract (GBE) has been reported to improve blood circulation and alleviate liver and lung fibrosis, its effect on skin fibrosis in SSc remains unclear. In this study, the effects and underlying mechanisms of GBE on skin fibrosis in bleomycin (BLM)-induced mouse model of SSc was investigated. GBE significantly reduced dermal thickness and protein levels of profibrotic factors in the BLM-induced SSc mouse model. Moreover, GBE inhibited the gene expression of profibrotic factors, such as COL1A1, α-SMA, and connective tissue growth factor (CTGF), in fibroblasts by suppressing transforming growth factor (TGF)-β signaling. Furthermore, GBE inhibited the transdifferentiation of adipocytes into myofibroblasts. Thus, our findings suggest that GBE is a promising therapeutic candidate for the treatment of SSc.

Systemic sclerosis (SSc) is a rare autoimmune disease whose molecular mechanisms are not yet fully understood. There is no definitive cure, and the main causes of death are pulmonary fibrosis and pulmonary arterial hypertension. Here, we focus on the interferon regulators factor 8 (IRF8), a factor involved in the type I interferon (IFN-I) signature, which is present in about half of SSc patients. Variants of this factor may play a role in autoimmunity, but little is known regarding the role of IRF8 in SSc pathogenesis. We carried out a literature search to address the association between the IRF8 factor and SSc susceptibility and clinical manifestations. The current studies appear to confirm a possible association between the alteration of the gene for IRF8 and SSc susceptibility. A link between IRF8 mutations and expression of a pro-fibrotic phenotype at the cellular level also emerges. Additional investigations are needed to confirm the role of IRF8 in SSc. However, IRF8 is worth consideration as a possible new disease marker of fibrosis in SSc patients.

Objectives Pulmonary arterial hypertension (PAH) occurs in various connective tissue diseases (CTDs). We sought to assess contemporary treatment patterns and survival of patients with various forms of CTD-PAH. Methods We analysed data from COMPERA, a European pulmonary hypertension registry, to describe treatment strategies and survival in patients with newly diagnosed PAH associated with SSc, SLE, MCTD, UCTD and other types of CTD. All-cause mortality was analysed according to the underlying CTD. For patients with SSc-PAH, we also assessed survival according to initial therapy with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5is) or a combination of these two drug classes. Results This analysis included 607 patients with CTD-PAH. Survival estimates at 1, 3 and 5 years for SSc-PAH (n  = 390) were 85%, 59% and 42%; for SLE-PAH (n  = 34) they were 97%, 77% and 61%; for MCTD-PAH (n  = 33) they were 97%, 70% and 59%; for UCTD-PAH (n  = 60) they were 88%, 67% and 52%; and for other CTD-PAH (n  = 90) they were 92%, 69% and 55%, respectively. After multivariable adjustment, the survival of patients with SSc-PAH was significantly worse compared with the other conditions (P  = 0.001). In these patients, the survival estimates were significantly better with initial ERA–PDE5i combination therapy than with initial ERA or PDE5i monotherapy (P  = 0.016 and P  = 0.012, respectively). Conclusions Mortality remains high in patients with CTD-PAH, especially for patients with SSc-PAH. However, for patients with SSc-PAH, our results suggest that long-term survival may be improved with initial ERA–PDE5i combination therapy compared with initial monotherapy. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a rare autoimmune disease whose molecular mechanisms are not yet fully understood. There is no definitive cure, and the main causes of death are pulmonary fibrosis and pulmonary arterial hypertension. Here, we focus on the interferon regulators factor 8 (IRF8), a factor involved in the type I interferon (IFN-I) signature, which is present in about half of SSc patients. Variants of this factor may play a role in autoimmunity, but little is known regarding the role of IRF8 in SSc pathogenesis. We carried out a literature search to address the association between the IRF8 factor and SSc susceptibility and clinical manifestations. The current studies appear to confirm a possible association between the alteration of the gene for IRF8 and SSc susceptibility. A link between IRF8 mutations and expression of a pro-fibrotic phenotype at the cellular level also emerges. Additional investigations are needed to confirm the role of IRF8 in SSc. However, IRF8 is worth consideration as a possible new disease marker of fibrosis in SSc patients. [ABSTRACT FROM AUTHOR]

Background: Metoclopramide and domperidone are prokinetic agents commonly used to treat gastrointestinal dysmotility disorders. This study aimed to evaluate the safety and associated side effects of prolonged-use metoclopramide and domperidone as treatment for chronic gastrointestinal dysmotility disorders in patients with systemic sclerosis (SSc). Methods: A quantitative observational survey was conducted by interview questionnaire in rheumatology outpatients at a tertiary teaching hospital in Riyadh, Saudi Arabia. The study included all patients aged 25–80 years diagnosed with SSc. All patients were on metoclopramide or domperidone for the treatment of chronic gastrointestinal dysmotility symptoms over at least 12 weeks. Results: Eighteen eligible patients were included. Most study participants were diagnosed with SSc complicated by interstitial lung disease (n = 13; 72.2 %). The most frequently reported side effect that occurred while taking prokinetic drugs was shortness of breath (n = 12; 66.7 %). None of the participants reported experiencing depression, galactorrhea, or syncope. CNS side effects were reported in 5.6 %. There were no differences in side effects based on the type and dosage of prokinetic drug used. Conclusions: Use of metoclopramide and domperidone for the treatment of chronic gastrointestinal dysmotility in SSc patients for 12 weeks or longer was not associated with any troublesome side effects. Further studies with more participants are needed to confirm our findings.

Background: Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular and immunity alterations and skin/internal organ fibrosis. Aberrant levels of plasma CXCL4, CXCL4–RNA/DNA complexes, type I IFN (IFN-I) and anti-CXCL4 antibodies characterize SSc. These parameters influence each other: CXCL4–self-DNA/RNA complexes are triggers of IFN-I in plasmacytoid dendritic cells (pDCs), and anti-CXCL4 autoantibodies amplify this effect. Here, we assess the modulation over time of plasma CXCL4 and the related parameters of CXCL4–DNA/RNA complexes, anti-CXCL4 antibodies, IFN-α and TNF-α in an SSc cohort under the synthetic analogue of prostacyclin PGI2 (iloprost) treatment to address contribution of these parameters to pathogenesis and their role as biomarkers. Methods: We analyzed immunological parameters at baseline (T0) and after 3 (T3) and 6 (T6) months in 30 SSc patients. Responders were the patients that lowered their disease activity parameters after six months of treatment. Results: Anti-CXCL4 autoantibodies correlated with both IFN-α and TNF-α levels in SSc plasma. Responders significantly down-regulated serum IFN-α. In seven patients with a shorter disease duration, improvement coincides with a decrease in plasma IFN-α, CXCL4 and TNF-α. Iloprost efficiently blocks pDCs IFN-α production induced by CXCL4–DNA/RNA complexes in vitro. Conclusions: The data suggest a possible role of iloprost as a disease-modifying drug, mainly accompanied by down-regulation of plasma IFN-I levels. Since CXCL4, IFN-I and TNF-α down-modulation was evident and significant in improving SSc patients with a shorter disease duration, these results warrant future investigations on the early use of iloprost to slow SSc progression.

Systemic sclerosis (SSc) is a chronic disease of the connective tissue characterized by its multifaceted impact on various bodily systems, yet its precise cause remains elusive. Central to its pathology are abnormal immune activation, vasculopathy, and consequent fibrosis affecting both the skin and internal organs. The intricate interplay between the innate and adaptive immune systems significantly influences the pathogenesis of SSc. Despite substantial research, the role of neutrophils, key players in innate immunity, in the context of SSc has remained enigmatic. Emerging evidence suggests that neutrophils not only contribute to the initiation and perpetuation of SSc but also inflict damage on organs and promote fibrosis—a hallmark of the disease in many patients. This review aims to investigate the nuanced involvement of neutrophils in the development of SSc. By shedding light on the intricate mechanisms through which neutrophils influence the pathogenesis of SSc, we can gain deeper insights into the disease process and potentially identify novel therapeutic targets. Understanding the precise role of neutrophils may pave the way for more targeted and effective interventions to alleviate the burden of SSc on affected individuals.

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by significant fibrosis of the skin and internal organs, with the main involvement of the lungs, kidneys, heart, esophagus, and intestines. SSc is also characterized by macro- and microvascular damage with reduced peripheral blood perfusion. Several studies have reported more than 240 pathways and numerous dysregulation proteins, giving insight into how the field of biomarkers in SSc is still extremely complex and evolving. Antinuclear antibodies (ANA) are present in more than 90% of SSc patients, and anti-centromere and anti-topoisomerase I antibodies are considered classic biomarkers with precise clinical features. Recent studies have reported that trans-forming growth factor β (TGF-β) plays a central role in the fibrotic process. In addition, interferon regulatory factor 5 (IRF5), interleukin receptor-associated kinase-1 (IRAK-1), connective tissue growth factor (CTGF), transducer and activator of transcription signal 4 (STAT4), pyrin-containing domain 1 (NLRP1), as well as genetic factors, including DRB1 alleles, are implicated in SSc damage. Several interleukins (e.g., IL-1, IL-6, IL-10, IL-17, IL-22, and IL-35) and chemokines (e.g., CCL 2, 5, 23, and CXC 9, 10, 16) are elevated in SSc. While adiponectin and maresin 1 are reduced in patients with SSc, biomarkers are important in research but will be increasingly so in the diagnosis and therapeutic approach to SSc. This review aims to present and highlight the various biomarker molecules, pathways, and receptors involved in the pathology of SSc.

Human parvovirus B19 (B19V) is a single-stranded non-enveloped DNA virus of the family Parvoviridae that has been associated with various autoimmune disorders. Systemic sclerosis (SSc) is an autoimmune connective tissue disorder with high mortality and has been linked to B19V infection. However, the precise mechanism underlying the B19V contribution to the development of SSc remains uncertain. This study investigated the impacts of the functional B19V-VP1 unique region (VP1u) in macrophages and bleomycin (BLE)-induced SSc mice. Cell experimental data showed that significantly decreased viability and migration of both B19V-VP1u-treated U937 and THP-1 macrophages are detected in the presence of celastrol. Significantly increased MMP9 activity and elevated NF-kB, MMP9, IL-6, TNF-α, and IL-1β expressions were detected in both B19V-VP1u-treated U937 and THP-1 macrophages. Conversely, celastrol revealed an inhibitory effect on these molecules. Notably, celastrol intervened in this pathogenic process by suppressing the sPLA2 activity of B19V-VP1u and subsequently reducing the inflammatory response. Notably, the administration of B19V-VP1u exacerbated BLE-induced skin fibrosis in mice, with augmented expressions of TGF-β, IL-6, IL-17A, IL-18, and TNF-α, ultimately leading to α-SMA and collagen I deposits in the dermal regions of BLE-induced SSc mice. Altogether, this study sheds light on parvovirus B19 VP1u linked to scleroderma and aggravated dermal fibrosis. [ABSTRACT FROM AUTHOR]

A comparative analysis of flow-mediated vasodilation (FMD), vasoactive angiogenic, and fibrogenic mediators between treatment-naive and treated systemic sclerosis (SSc) patients is an unmet need. (1)To assess the FMD and different pathogenic mediators in SSc patients about endothelial dysfunction. (2) To assess the proportion of circulating endothelial cells (CECs) in treatment-naïve patients. SSc patients were grouped into treatment-naïve (Group-I, n = 24) on vasodilator (Group-II, n = 10), on vasodilator + immunosuppressive (Group-III, n = 22)]. Age-sex matched healthy controls (n = 20) were included. Endothelial dysfunction (ED) was measured radiologically using FMD. Serum levels of NO, ET1, NO/ET1, sVCAM, sICAM, TGF, IL-6, and VEGF, as well as gene expressions of eNOS, iNOS, ET-1, and TGF, were measured to assess the status of ED in various study groups. CEC was measured in Group-I and HC. CEC was used as a marker to identify a key regulator of ED in SSc. FMD was significantly decreased in all SSc patients through receiving treatment. Upregulation of serum NO and ET concentrations was noted post-treatment with an unaltered NO/ET1 ratio. NO was positively correlated with FMD (r = 0.6) and negatively with TGFβ (r = − 0.5). ET-1 showed a negative correlation with TGFβ (r = − 0.5) but no significant correlation with FMD. Circulating endothelial cell (CEC) was significantly higher in Group-I (3.2%) than HC (0.8%) (p = 0.002), and it showed a good correlation with NO (r = − 0.7, p = 0.0001) and NO/ET1 (r = − 0.6, p = 0.007). Persistent ED was observed in all SSc patients irrespective of treatment. Dysbalance in NO/ET1 ratio might be the considering factor for the underlying progression of ED. Based on our findings, it may be hypothesized that reduced NO may be a contributing factor in the pathogenesis of endothelial dysfunction in SSc. [ABSTRACT FROM AUTHOR]

Background & Aims: Systemic sclerosis is an autoimmune disease of unknown cause and is very difficult to treat. Scleroderma, or systemic sclerosis (SSc), is a multifocal systemic disorder characterized by overactive immune system, systemic inflammation, vascular damage, and tissue fibrosis. The pathogenesis of the disease is mainly based on autoimmune inflammatory processes, systemic vasculopathy and collagen deposition in the skin and internal organs, which leads to tissue fibrosis with severe functional disorders and can be one of the major causes of mortality in these patients. SSc-associated interstitial lung disease (ILD) is a common complication of SSc, which can lead to significant morbidity and mortality. As with other pulmonary fibrotic diseases, damage to epithelial cells, activation of innate and acquired immunity, and activation of fibroblasts may lead to overproduction of the matrix and ulceration of the SSc-ILD. New studies speculate that differentiation and proliferation Myofibroblasts are a key pathological mechanism that increases fibrosis in SSc-ILD. According to EULAR recommendations, cyclophosphamide is the first choice for the treatment of SSc-ILD. Cyclophosphamide acts as a cytotoxic immunosuppressive agent by modulating lymphocyte function, reducing suppression of the inflammatory response and fibrosis. Cyclophosphamide (CYC) is an immunosuppressive alkalizing drug that inhibits the function of lymphocytes in the cellular environment. Moreover, bronchoalveolar lavage and pulmonary function testing are shown. Systemic and intravenous injection of immunosuppressive drugs may be associated with more potential systemic complications. A study published in the New England Journal of Medicine in 2006 found that treatment with cyclophosphamide for one year resulted in significant improvement in lung function and symptoms in patients with SSc-ILD. However, the use of cyclophosphamide is associated with potential side effects, such as increased risk of infection and cancer, and its use should be carefully evaluated on a case-by-case basis.Therefore, choosing the best method of drug administration with the aim of improving the symptoms and skin involvement in patients with systemic sclerosis can be very important and vital. In this study, the effects and immunotherapy of oral cyclophosphamide in the treatment of skin lesions and interstitial lung disease were studied. Methods: The type of study is quasi-experimental, and 21 patients who received cyclophosphamide and had a follow-up of 12 months were included in the study.Twenty-one selected patients included in this retrospective cohort were treated with oral CYC (up to 2 mg/kg/day). Additionally, they received an additional low dose of prednisolone (≤10 mg) for 6 months. Skin score, forced vital capacity (FVC) and diffusion lung capacity for carbon monoxide (DLCO) were assessed as outcome measures. At entry and after 12 months Modified Rodnan Skin Score (MRSS), pulmonary function tests and DLCO have been evaluated. Inclusion criteria include the following: 1- Treatment with cyclophosphamide 2- Follow-up for at least one year from the start of the first dose of the drug 3- The use of oral cyclophosphamide for at least six months 4- Filling the diagnostic criteria of ACR (American College of Rheumatology) 5. Existence Documents related to High-resolution computed tomography (HRCT), PFT and DLCO at the beginning of treatment and 12 months after treatment. Exclusion criteria also included the following: Patients who, in addition to ILD, had pulmonary artery hypertension (PAH) or severe left ventricular failure (EF <50%) were excluded from the study. Patients with normal HRCT and FEV <20% were also excluded from the study, provided that the volume reduction was due to thickening of the skin. The patients received cyclophosphamide at a maximum dose of 2 mg/kg/day (50-100 mg/day) for 12 months. In addition, prednisolone 10-15 mg / day was initially administered for 2 months and then for 10 months at a dose of 5 mg / day. GhRh agonist and oocyte cryopreservation were used for 4 and 8 in 16 patients under 45 years of age, respectively. The major limitations of our study were the small population, and the retrospective nature of the study, which inevitably renders the study unblinded with selection biases. Other limitations included the lack of a comparative control group and the short follow-up period. An advantage of the present study is that all patients completed 1 year of treatment. We also presented all clinical and serological variables in detail, providing sufficient data for future comparative studies. The study was conducted after approval by the Ethics Committee of the University of Iran with the ethics code IRIUMS.FMD.REC.1396.9511288002. Results: The patients’ age at the time of ILD need to treatment/months median (IQR) were 34.0 (29.6–48.5) years, 18 (85%) had female gender, and 8 (38%) had a diffuse subtype of the disease. The mean (SD) FVC percentages obtained at baseline 59.5 ±10.7 and post-treatment 63.1 ± 16.2 with mean difference 2.9 ± 11.5, p=0.19. DLCO% in CYC treated patients at base was 67.7 ± 27.5 and post treatment was 60.0 ±22.9 with a mean difference of −8.0 ± 23.7 (p = 0.12). Following 12 months of treatment mean difference of changes in MRSS was −1.4 ± 4.5 in CYC-treated patients. In the twelfth month, 5 out of 21 patients showed improvement, while 14 patients had stable FVC. Among the patients, only one patient showed improvement in DLCO and 14 patients had stable DLCO. The non-significance of P indicates no change in the parameters and prevention of deterioration of the patient's condition in terms of the investigated parameters following the intervention. After one year of treatment with CYC, two patients showed symptoms of leukopenia, which led to a temporary reduction in the dose of the received drug to improve the condition. Conclusion: Based on our findings, the use of cyclophosphamide as an immunosuppressive drug can prevent the deterioration of patients with SSc-ILD in terms of FVC, DLCO, and MRSS factors. [ABSTRACT FROM AUTHOR]

The platelet-derived growth factor receptor (PDGFR) is a membrane tyrosine kinase receptor involved in several metabolic pathways, not only physiological but also pathological, as in tumor progression, immune-mediated diseases, and viral diseases. Considering this macromolecule as a druggable target for modulation/inhibition of these conditions, the aim of this work was to find new ligands or new information to design novel effective drugs. We performed an initial interaction screening with the human intracellular PDGFRα of about 7200 drugs and natural compounds contained in 5 independent databases/libraries implemented in the MTiOpenScreen web server. After the selection of 27 compounds, a structural analysis of the obtained complexes was performed. Three-dimensional quantitative structure–activity relationship (3D-QSAR) and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses were also performed to understand the physicochemical properties of identified compounds to increase affinity and selectivity for PDGFRα. Among these 27 compounds, the drugs Bafetinib, Radotinib, Flumatinib, and Imatinib showed higher affinity for this tyrosine kinase receptor, lying in the nanomolar order, while the natural products included in this group, such as curcumin, luteolin, and epigallocatechin gallate (EGCG), showed sub-micromolar affinities. Although experimental studies are mandatory to fully understand the mechanisms behind PDGFRα inhibitors, the structural information obtained through this study could provide useful insight into the future development of more effective and targeted treatments for PDGFRα-related diseases, such as cancer and fibrosis. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is a chronic progressive cholestatic liver disease of uncertain etiology. Although PBC is frequently complicated by Sjögren's syndrome and chronic thyroiditis, it can also be associated with a variety of other autoimmune disorders. We herein describe a rare case of immune thrombocytopenic purpura (ITP) coexistence with PBC and localized cutaneous systemic sclerosis (LcSSc). A 47-year-old woman with PBC and LcSSc who was positive for antiphospholipid antibody experienced a rapid decrease in platelet count to 1.8 × 104/µL during follow-up. After clinical findings ruled out thrombocytopenia from cirrhosis, a diagnosis of ITP was made following bone marrow examination. Her human leukocyte antigen (HLA) type was HLA-DPB1*05:01, which has been associated with disease susceptibility to PBC and LcSSc, but not to ITP. A careful review of similar reports suggested that in PBC, other collagen disease complications, positive antinuclear antibody, and positive antiphospholipid antibody may all support a diagnosis of ITP. Clinicians should be vigilant for ITP when rapid thrombocytopenia is observed during the course of PBC. [ABSTRACT FROM AUTHOR]

FLT3/CDK inhibitor, FN-1501, scleroderma, systemic sclerosis (SSc), tyrosine kinase, metastatic colon adenocarcinoma Keywords: FLT3/CDK inhibitor; FN-1501; metastatic colon adenocarcinoma; scleroderma; systemic sclerosis (SSc); tyrosine kinase EN FLT3/CDK inhibitor FN-1501 metastatic colon adenocarcinoma scleroderma systemic sclerosis (SSc) tyrosine kinase e272 e274 3 08/14/23 20230801 NES 230801 Scleroderma refers to a heterogeneous group of rare autoimmune skin disorders characterised by hardening and tightening of the skin.[[1]] Multiple drugs have been implicated in the formation of scleroderma-like lesions, including chemotherapeutic agents.[3] Scleroderma can also develop in a paraneoplastic fashion.[4] We present a case of sclerodermatous eruption following the administration of the experimental chemotherapy drug FN-1501, a tyrosine kinase inhibitor intended to treat metastatic colon adenocarcinoma that acts on the FLT3 receptor and cyclin-dependent kinase (FLT3/CDK inhibitor).[5] A 78-year-old male patient with a 7-year history of metastatic colon adenocarcinoma was admitted for acute kidney injury 8 days after starting a phase I clinical trial of FN-1501, an FLT3/CDK inhibitor.[5] His symptoms started 3 days after completing three doses of FN-1501 with sensations of heat in his hands and feet that self-resolved in 24 h followed by swelling, red blotches on the torso and extremities, skin tightening, and dysphagia. [Extracted from the article]

To assess the frequency of thyroid dysfunction and thyroid auto-antibodies in systemic sclerosis (SSc) patients. This study included thirty-three SSc patients and 30 matching controls. Thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), anti thyroglobulin (ATG) and anti thyroid peroxidase autoantibodies (ATPO) were measured in the sera of patients and controls. The mean age of the patients was 45.9 ± 13.05 years; 28 females and 5 males (F: M 5.6:1) and a disease duration of 4.58 ± 3.84 years. The FT3, FT4, TSH tended to be higher in patients (T3: 2.8 ± 0.66 pg/ml; T4: 1.5 ± 0.65 ng/ml; TSH: 1.9 ± 2.1 ul/ml) than in controls (p = 0.07, p = 0.21 and p = 0.24 respectively) while the ATG level in patients was 40 ± 21.3 IU/ml and ATPO 36.7 ± 88.2 IU/ml. Four patients had hypothyroidism (12 %); 3 (9 %) subclinical hypothyroidism (SCHT) and 1 (3 %) clinical hypothyroidism (CHT). ATG was positive in one patient and in 2 controls while ATPO was positive in two patients compared to one control. Both antibodies were positive in one patient. ATPO was associated with SCHT in one (3 %) and with overt hypothyroidism in another (3 %). The thyroid profile, ATG and ATPO were comparable between females and males (p = 0.34, p = 0.23, p = 0.96, p = 0.77 and p = 0.35 respectively) and all were similar between lcSSc and dcSSc except TSH (lower in dcSSc; p = 0.03). Muscle weakness was significantly higher among ATPO positive patients (p = 0.005) while thyroid dysfunction was significantly associated with arthralgia (p = 0.007). Thyroid dysfunction mainly hypothyroidism is more frequent among SSc patients. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) or scleroderma, is a rare, systemic autoimmune connective tissue disease that can cause fibrosis of cutaneous tissue and visceral organs. Facial involvement can have a deleterious effect on patients' function, cosmetic appearance and quality of life. This study describes our experience and results with total facial autologous fat grafting for treating scleroderma. It includes 14 women and 3 men with SSc, at an average age of 51.3 years who underwent 32 autologous fat grafting surgeries between 2017–2022. The surgical technique is further described and demographic and surgical data, including preoperative and postoperative measurements were analyzed. Patients who had multiple surgeries ultimately received grafts with twice the volume of fat than in the first procedure. The oral opening increased an average of 33%. All patients reported improvement in quality of life and were very satisfied with the aesthetic outcomes. The use of autologous fat grafting to treat SSc patients successfully increased oral openings and improved facial manifestations. The procedure is reproducible, safe and leads to improvement in facial manifestations and patients' quality of life. It can be repeated over time to preserve or enhance the results. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Silica exposure boosts proliferation, migration, and activation of skin fibroblasts. • Silica exposure induces DNA hypomethylation of HDAC4 and increase its expression. • Silica induces and exacerbates skin fibrosis by targeting the HDAC4/Smad2/3 pathway. • HDAC4 inhibition alleviates silica-induced skin fibrosis in systemic sclerosis. [ABSTRACT FROM AUTHOR]

Despite advancements in managing autoimmune rheumatic diseases (ARDs) with existing treatments, many patients still encounter challenges such as inadequate responses, difficulty in maintaining remission, and side effects. Chimeric Antigen Receptor (CAR) T-cell therapy, originally developed for cancer, has now emerged as a promising option for cases of refractory ARDs. A search of the literature was conducted to compose a narrative review exploring the current evidence, potential safety, limitations, potential modifications, and future directions of CAR-T cells in ARDs. CAR-T cell therapy has been administered to patients with refractory ARDs, including systemic lupus erythematosus, antisynthetase syndrome, and systemic sclerosis, demonstrating significant improvement. Notable responses include enhanced clinical symptoms, reduced serum autoantibody titers, and sustained remissions in disease activity. Preclinical and in vitro studies using both animal and human samples also support the efficacy and elaborate on potential mechanisms of CAR-T cells against antineutrophil cytoplasmic antibody-associated vasculitis and rheumatoid arthritis. While cautious monitoring of adverse events, such as cytokine release syndrome, is crucial, the therapy appears to be highly tolerable. Nevertheless, challenges persist, including cost, durability due to potential CAR-T cell exhaustion, and manufacturing complexities, urging the development of innovative solutions to further enhance CAR-T cell therapy accessibility in ARDs. CAR-T cell therapy for refractory ARDs has demonstrated high effectiveness. While no significant warning signs are currently reported, achieving a balance between therapeutic efficacy and safety is vital in adapting CAR-T cell therapy for ARDs. Moreover, there is significant potential for technological advancements to enhance the delivery of this treatment to patients, thereby ensuring safer and more effective disease control for patients. [ABSTRACT FROM AUTHOR]

Human parvovirus B19 (B19V) is a single-stranded non-enveloped DNA virus of the family Parvoviridae that has been associated with various autoimmune disorders. Systemic sclerosis (SSc) is an autoimmune connective tissue disorder with high mortality and has been linked to B19V infection. However, the precise mechanism underlying the B19V contribution to the development of SSc remains uncertain. This study investigated the impacts of the functional B19V-VP1 unique region (VP1u) in macrophages and bleomycin (BLE)-induced SSc mice. Cell experimental data showed that significantly decreased viability and migration of both B19V-VP1u-treated U937 and THP-1 macrophages are detected in the presence of celastrol. Significantly increased MMP9 activity and elevated NF-kB, MMP9, IL-6, TNF-α, and IL-1β expressions were detected in both B19V-VP1u-treated U937 and THP-1 macrophages. Conversely, celastrol revealed an inhibitory effect on these molecules. Notably, celastrol intervened in this pathogenic process by suppressing the sPLA2 activity of B19V-VP1u and subsequently reducing the inflammatory response. Notably, the administration of B19V-VP1u exacerbated BLE-induced skin fibrosis in mice, with augmented expressions of TGF-β, IL-6, IL-17A, IL-18, and TNF-α, ultimately leading to α-SMA and collagen I deposits in the dermal regions of BLE-induced SSc mice. Altogether, this study sheds light on parvovirus B19 VP1u linked to scleroderma and aggravated dermal fibrosis.

ABSTRACTBackground Autoimmune rheumatologic disease associated interstitial lung diseases (ARD-ILD) are rare conditions and the association between ARDs and respiratory symptoms often goes unrecognised by ARD patients and general practitioners (GPs). The diagnostic trajectory from the first respiratory symptoms to an ARD-ILD diagnosis is often delayed and may increase the burden of symptoms and allow further disease progression.The aim of this study was to 1) characterise the diagnostic trajectories of ARD-ILD patients and to 2) identify barriers for obtaining a timely ILD diagnosis based on the experiences and perceptions of both patients and healthcare professionals.Method Semi-structured qualitative interviews were conducted with Danish ARD-ILD patients, rheumatologists, pulmonologists and ILD nurses.Results Sixteen patients, six rheumatologists, three ILD nurses and three pulmonologists participated. Five characteristics of diagnostic trajectories were identified in the patient interviews: 1) early referral to lung specialists; 2) early delay; 3) delay or shortcut depending on specific circumstances; 4) parallel diagnostic trajectories connected late in the process; 5) early identification of lung involvement without proper interpretation. With the exception of early referral to lung specialists, all of the diagnostic trajectory characteristics identified led to delayed diagnosis. Delayed diagnostic trajectories resulted in patients experiencing increased uncertainty. Inconsistent disease terminology, insufficient knowledge and lack of awareness of ARD-ILD among central healthcare professionals and delayed referral to ILD specialists were main contributors to the diagnostic delay identified by the informants.Conclusion Five characteristics of the diagnostic trajectories were identified, four of which led to diagnostic delay of ARD-ILD. Improved diagnostic trajectories can shorten the diagnostic trajectory and increase early access to appropriate specialist medical care. Improved awareness and expertise in ARD-ILD across different medical specialties, especially among GPs, may contribute to more efficient and timely diagnostic trajectories and improved patient experiences.

Purpose: A study of shear wave elastography (SWE) for evaluation of skin stiffness in systemic sclerosis (SSc) patients. The purpose of this study was to measure the skin stiffness and thickness in patients with scleroderma using shear wave elastography. Methods: Prospective data collections of skin stiffness and thickness using SWE in SSc and control groups. Results: Skin stiffness and thickness were done in 29 patients with SSc and a 29 control population using SWE on bilateral forearms. The SSc patients had thicker skin and higher stiffnesses than the control group. The mean of skin thickness and stiffness using SWE of SSc are 1.74 mm and 47.32 kPa while normal subjects were 1.5 mm and 19.5 kPa. Mean differences were 0.023 mm (95% CI 0.15–0.3, p < 0.001) and 27.82 kPa (95% CI 22.63–33.01, p < 0.001). The dorsal forearms tend to have a higher SWE than the volar forearms in SSc. No statistically significant differences between gender, age or dominancy of skin stiffness were found. SWE has a good correlation with clinical manual palpation of forearms (mRSS) with Spearman rho's of 0.550 (p = 0.002) and 0.508 (p = 0.005) of dominant and non-dominant forearms. Conclusion: The application of SWE can be used for evaluation of skin involvement in scleroderma patients with good correlations with the mRSS that was used in the current patients. Furthermore, SWE is a safe technique for either diagnosis or follow up. [ABSTRACT FROM AUTHOR]

Background: Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, abnormal inflammation, and fibrosis of the skin and internal organs, notably the skin and lungs, significantly impairing quality of life. There is currently no cure for SSc, and its etiology remains largely unknown, presenting a primary barrier to effective treatment. We investigated the role of interleukin-21 (IL-21) in the pathogenesis of SSc., Methods: We assessed the expression levels of fibrosis-related genes in human dermal fibroblasts exposed to IL-21 and TGF beta. We also induced SSc in wild-type C57BL/6 mice and IL-21 knockout (KO) mice with a C57BL/6 background using bleomycin (Bleomycin). Histological analyses were conducted on skin and lung tissues from these mice. The distribution and expression levels of fibrosis-related proteins in the tissues were examined via immunohistochemistry and quantitative real-time PCR. Furthermore, we measured the frequency of Th1, Th2, and Th17 cells among splenocytes through flow cytometry., Results: IL-21 activation led to STAT3 phosphorylation more than TGF beta in dermal fibroblasts. In IL-21 KO mice with BLM-induced SSc, skin thickness and lung fibrosis were reduced. The absence of IL-21 in these mice resulted in suppressed expression of fibrosis-related genes, including Col1a1, Col1a2, Col3a1, CTGF, α-SMA, STAT3, and TGFβ, in the skin and lungs. It also led to a decreased frequency of Th1, Th2, and Th17 cells, as well as a lower Th17/Treg ratio among splenocytes, factors known to contribute to the development of SSc., Conclusions: IL-21 contributes to the development of SSc by promoting the expression of fibrosis-related genes and modulating the levels of CD4+ T cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The platelet-derived growth factor receptor (PDGFR) is a membrane tyrosine kinase receptor involved in several metabolic pathways, not only physiological but also pathological, as in tumor progression, immune-mediated diseases, and viral diseases. Considering this macromolecule as a druggable target for modulation/inhibition of these conditions, the aim of this work was to find new ligands or new information to design novel effective drugs. We performed an initial interaction screening with the human intracellular PDGFRα of about 7200 drugs and natural compounds contained in 5 independent databases/libraries implemented in the MTiOpenScreen web server. After the selection of 27 compounds, a structural analysis of the obtained complexes was performed. Three-dimensional quantitative structure–activity relationship (3D-QSAR) and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses were also performed to understand the physicochemical properties of identified compounds to increase affinity and selectivity for PDGFRα. Among these 27 compounds, the drugs Bafetinib, Radotinib, Flumatinib, and Imatinib showed higher affinity for this tyrosine kinase receptor, lying in the nanomolar order, while the natural products included in this group, such as curcumin, luteolin, and epigallocatechin gallate (EGCG), showed sub-micromolar affinities. Although experimental studies are mandatory to fully understand the mechanisms behind PDGFRα inhibitors, the structural information obtained through this study could provide useful insight into the future development of more effective and targeted treatments for PDGFRα-related diseases, such as cancer and fibrosis.

Systemic Sclerosis (SSc) is a chronic autoimmune disease with high morbidity and mortality. Autologous Hematopoietic Stem Cell Transplantation (AHSCT) is the best therapeutic option for rapidly progressive SSc, allowing increased survival with regression of skin and lung fibrosis. The immune determinants of the clinical response after AHSCT have yet to be well characterized. In particular, the pivotal role of the Human Leukocyte Antigen (HLA) system is not well understood, including the role of non-classical immuno-modulatory HLA-E and HLA-G molecules in developing tolerance and the role of Natural Killer cells (NK) in the immunomodulation processes. We retrospectively tested whether the genetic and/or circulating expression of the non-classical HLA-E and HLA-G loci, as well as the imputed classical HLA determinants of HLA-E expression, influence the observed clinical response to AHSCT at 12- and 24-month follow-up. In a phenotypically well-defined sample of 46 SSc patients classified as clinical responders or non-responders, we performed HLA genotyping using next-generation sequencing and circulating levels of HLA-G and quantified HLA-E soluble isoforms by ELISA. The -21HLA-B leader peptide dimorphism and the differential expression level of HLA-A and HLA-C alleles were imputed. We observed a strong trend towards better clinical response in HLA-E*01:03 or HLA-G 14bp Del allele carriers, which are known to be associated with high expression of the corresponding molecules. At 12-month post-AHSCT follow-up, higher circulating levels of soluble HLA-E were associated with higher values of modified Rodnan Skin Score (mRSS) (p = 0.0275), a proxy of disease severity. In the non-responder group, the majority of patients carried a double dose of the HLA-B Threonine leader peptide, suggesting a non-efficient inhibitory effect of the HLA-E molecules. We did not find any correlation between the soluble HLA-G levels and the observed clinical response after AHSCT. High imputed expression levels of HLA-C alleles, reflecting more efficient NK cell inhibition, correlated with low values of the mRSS 3 months after AHSCT (p = 0.0087). This first pilot analysis of HLA-E and HLA-G immuno-modulatory molecules suggests that efficient inhibition of NK cells contributes to clinical response after AHSCT for SSc. Further studies are warranted in larger patient cohorts to confirm our results. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc), and its early detection and treatment may prevent deterioration of lung function. Different vendors have recently made larger image matrices available as a post-processing option for computed tomography (CT), which could facilitate the diagnosis of SSc-ILD. Therefore, the objective of this study was to assess the effect of matrix size on lung image quality in patients with SSc by comparing a 1024-pixel matrix to a standard 512-pixel matrix and applying different reconstruction kernels. Methods: Lung scans of 50 patients (mean age 54 years, range 23–85 years) with SSc were reconstructed with these two different matrix sizes, after determining the most appropriate kernel in a first step. Four observers scored the images on a five-point Likert scale regarding image quality and detectability of clinically relevant findings. Results: Among the eight tested kernels, the Br59-kernel (sharp) reached the highest score (19.48 ± 3.99), although differences did not reach statistical significance. The 1024-pixel matrix scored higher than the 512-pixel matrix HRCT overall (p = 0.01) and in the subcategories sharpness (p < 0.01), depiction of bronchiole (p < 0.01) and overall image impression (p < 0.01), and lower for the detection of ground-glass opacities (GGO) (p = 0.04). No significant differences were found for detection of extent of reticulations/bronchiectasis/fibrosis (p = 0.50) and image noise (p = 0.09). Conclusions: Our results show that with the use of a sharp kernel, the 1024-pixel matrix HRCT, provides a slightly better subjective image quality in terms of assessing interstitial lung changes, whereby GGO are more visible on the 512-pixel matrix. However, it remains to be answered to what extent this is related to the improved representation of the smallest structures. [ABSTRACT FROM AUTHOR]

Metoclopramide and domperidone are prokinetic agents commonly used to treat gastrointestinal dysmotility disorders. This study aimed to evaluate the safety and associated side effects of prolonged-use metoclopramide and domperidone as treatment for chronic gastrointestinal dysmotility disorders in patients with systemic sclerosis (SSc). A quantitative observational survey was conducted by interview questionnaire in rheumatology outpatients at a tertiary teaching hospital in Riyadh, Saudi Arabia. The study included all patients aged 25–80 years diagnosed with SSc. All patients were on metoclopramide or domperidone for the treatment of chronic gastrointestinal dysmotility symptoms over at least 12 weeks. Eighteen eligible patients were included. Most study participants were diagnosed with SSc complicated by interstitial lung disease (n = 13; 72.2 %). The most frequently reported side effect that occurred while taking prokinetic drugs was shortness of breath (n = 12; 66.7 %). None of the participants reported experiencing depression, galactorrhea, or syncope. CNS side effects were reported in 5.6 %. There were no differences in side effects based on the type and dosage of prokinetic drug used. Use of metoclopramide and domperidone for the treatment of chronic gastrointestinal dysmotility in SSc patients for 12 weeks or longer was not associated with any troublesome side effects. Further studies with more participants are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a clinically heterogeneous disorder of the connective tissue characterized by vascular alterations, immune/inflammatory manifestations, and organ fibrosis. SSc pathogenesis is complex and still poorly understood. Therefore, effective therapies are lacking and remain nonspecific and limited to disease symptoms. In the last few years, many molecular and cellular mediators of SSc fibrosis have been described, providing new potential options for targeted therapies. In this review: (i) we focused on the PDGF/PDGFR pathway as key signaling molecules in the development of tissue fibrosis; (ii) we highlighted the possible role of stimulatory anti-PDGFRα autoantibodies in the pathogenesis of SSc; (iii) we reported the most promising PDGF/PDGFR targeting therapies. [ABSTRACT FROM AUTHOR]

Background: Literature regarding trends for incidence and mortality of scleroderma renal crisis (SRC) in systemic sclerosis (SSc) within the United States (US) emergency departments (EDs) is limited.Objective: To study the mortality of SRC among SSc patient encounters within the US EDs.Methods: Data from the National Emergency Department Sample (NEDS) constitutes 20% sample of hospital-owned EDs and inpatient sample in the US were analyzed for SSc with and without SRC using ICD-9 codes. A linear p-trend was used to assess the trends.Results: Of the total 180,435 encounters with the diagnosis of SSc in NEDS for the years 2009 2014, 771 or 4.27/1000 patients (mean age 59.6 ± 15.5 years, 75.4% females) were recorded with SRC. The numerical differences in mortality among SRC (32 or 4.1%) and non-SRC subgroups (5487 or 3.1%) did not reach statistical significance (p = 0.3). Major complications among SRC in comparison to non-SRC subgroup include ischemic stroke (5.6% vs 0.98%, p = 0.001), new-onset AF (8% vs 6.9%, p = 0.001), new-onset congestive heart failure (24.1% vs 8.8%, p = 0.001), pulmonary arterial hypertension (15.8% vs 10.9%, p = 0.001), respiratory failure (27.5% vs 10.5%, p = 0.001), and deep vein thrombosis (4.7% vs 4.6%, p = 0.001). Congestive heart failure (CHF) was strongly associated with SRC among SSc (OR 4.3 95%CI 2.7-6.7; p < 0.001). The absolute yearly rate of SRC had increased over the study years from 2.11/1000 to 5.79/1000 (linear p-trend 0.002) while the mortality trend remained steady.Conclusion: SRC is a relatively rare medical emergency. Although there has been a significant rise in the rate of SRC among SSc patients over the study years, mortality rates had remained steady. SSc patients with CHF should be considered to have low threshold for admission to inpatient services from EDs. [ABSTRACT FROM AUTHOR]

Background: Serum fibrosis markers for systemic sclerosis (SSc) remain limited. The Enhanced Liver Fibrosis (ELF) score is a collagen marker set consisting of procollagen type III amino terminal propeptide (PIIINP), tissue inhibitor of metalloproteinases 1 (TIMP-1), and hyaluronic acid (HA). This longitudinal study aimed to examine the performance of the ELF score and its single analytes as surrogate outcome measures of fibrosis in SSc. Methods: Eighty-five SSc patients fulfilling the 2013 ACR/EULAR criteria with the absence of chronic liver diseases were enrolled. Serum PIIINP, TIMP-1, HA, and the ELF score were measured and correlated with clinical variables including the modified Rodnan skin score (mRSS) and interstitial lung disease (ILD). Twenty SSc patients underwent a follow-up serological testing and mRSS evaluation during treatment with immunosuppressants and/or anti-fibrotic drugs. Results: Serum PIIINP, TIMP-1, and ELF score were significantly higher in patients with SSc than in healthy controls [PIIINP: 10.31 (7.83–14.10) vs. 5.61 (4.69–6.30), p <.001; TIMP-1: 110.73 (66.21–192.45) vs. 61.81 (48.86–85.24), p <.001; ELF: 10.34 (9.91–10.86) vs. 9.68 (9.38–9.99), p <.001]. Even higher levels of PIIINP, TIMP-1, and ELF score were found in patients with diffuse cutaneous SSc than those with limited cutaneous SSc. At baseline, both PIIINP and ELF score showed good correlation with mRSS (PIIINP: r =.586, p <.001; ELF: r =.482, p <.001). Longitudinal analysis showed that change in PIIINP positively correlated with change in mRSS (r = 0.701, p =.001), while change in ELF score were not related, in a statistical context, to the change in mRSS (ELF: r =.140, p =.555). Serum TIMP-1 was significantly higher in SSc patients with ILD, compared to the matched group of patients without ILD [109.45 (93.05–200.09) vs. 65.50 (40.57–110.73), p = 0.007]. Conclusion: In patients with SSc, the ELF score well correlates with the extent of skin fibrosis, while serum PIIINP is a sensitive marker for longitudinal changes of skin fibrosis. In the future, circulating collagen metabolites may potentially be used to evaluate therapeutic effects of anti-fibrotic treatments in the disease. [ABSTRACT FROM AUTHOR]

Hyperspectral imaging (HSI) is an optical remote sensing technology that has the advantages of high spatial and spectral resolution. Aside from its use in geographical research, HSI has been widely used in medical diagnosis. Systemic sclerosis (SSc) is a multiorgan autoimmune disease that leads to skin tightness, thickness, and fibrosis. Internal organ involvement and mortality in this progressive disease are strongly correlated with the extent and severity of abnormal skin thickness. Our prior study demonstrated that HSI can outperform conventional assessment tools as a diagnostic modality to evaluate the severity of skin sclerosis in SSc patients. However, the analysis algorithm has its limitations. This study aimed to investigate a novel soft abundance score for HSI. We also explored the influence of band selection on the HSI analysis of SSc patients. In total, we enrolled 30 SSc patients (male: 10; female: 20, median age±range, 49.9±17.0 years) and 24 healthy controls (male: 12; female: 12, median age±range, 37.0±11.0 years). We found that most of the spectral bands generated by different band selection methods were similar. Moreover, in the task of distinguishing SSc patients from healthy controls, the soft abundance scores calculated from these bands exhibited greater discriminative power than a spectral angle mapper (SAM), skin scores determined by clinical assessments, or skin thickness determined through ultrasonography. Our results suggest that the spectral bands selected in this study should be taken into consideration to guide future hardware improvement. The analytic algorithm can also be applied as a new clinical method.

Objectives: To evaluate changes in microbial composition and the evolution of gastrointestinal tract (GIT) symptoms in systemic sclerosis (SSc). Methods: Adult SSc patients provided stool specimens every 3 months over the course of 1 year. Participants completed the University of California, Los Angeles (UCLA) GIT 2.0 questionnaire to assess GIT symptom severity at each stool collection. The microbiota from these samples were determined by Illumina HiSeq 2500 16S ribosomal RNA sequencing (Illumina, Inc., San Diego, California, USA). Mixed effect models evaluated changes in GIT symptoms and microbial composition over time. Results: Among 19 patients with SSc (female; 89.5%; median age: 51.3 years), the median disease duration was 7 years and the baseline total GIT 2.0 score was 0.7 (standard deviation: 0.6). The majority of participants (63%) provided at least four stool samples over the course of the 12-month study. Patients with longer disease durations had increased GIT symptoms over the course of the study. There was no difference in the course of GIT symptoms over time between patients with limited versus diffuse cutaneous disease. The relative abundances of specific genera did not change over time within individual subjects. After controlling for age, sex, ethnicity, disease duration, and SSc subtype (i.e., limited versus diffuse), low abundance of Bacteroides was associated with increased GIT symptoms over time. Conclusion: This study is the first to have longitudinally characterised the lower GIT microbiome in SSc patients and demonstrated relative stability of genera abundance over the course of 1 year. The findings provide additional evidence that specific genera are associated with SSc-GIT symptoms and warrant further evaluation in larger SSc studies.

Background. Systemic sclerosis (SSc) is an incurable connective tissue disease characterized by decreased peripheral blood perfusion due to microvascular damage and skin thickening/hardening. The microcirculation deficit is typically secondary to structural vessel damage, which can be assessed morphologically and functionally in a variety of ways, exploiting different technologies. Objective. This paper focuses on reviewing new studies regarding the correlation between microvascular damage, endothelial dysfunction, and internal organ involvement, particularly pulmonary changes in SSc. Methods. We critically reviewed the most recent literature on the correlation between blood perfusion and organ involvement. Results. Many papers have demonstrated the link between structural microcirculatory damage and pulmonary involvement; however, studies that have investigated correlations between microvascular functional impairment and internal organ damage are scarce. Overall, the literature supports the correlation between organ involvement and functional microcirculatory impairment in SSc patients. Conclusions. Morphological and functional techniques appear to be emerging biomarkers in SSc, but obviously need further investigation.

Systemic sclerosis (SSc) or scleroderma, is a rare, systemic autoimmune connective tissue disease that can cause fibrosis of cutaneous tissue and visceral organs. Facial involvement can have a deleterious effect on patients’ function, cosmetic appearance and quality of life. This study describes our experience and results with total facial autologous fat grafting for treating scleroderma. It includes 14 women and 3 men with SSc, at an average age of 51.3 years who underwent 32 autologous fat grafting surgeries between 2017–2022. The surgical technique is further described and demographic and surgical data, including preoperative and postoperative measurements were analyzed. Patients who had multiple surgeries ultimately received grafts with twice the volume of fat than in the first procedure. The oral opening increased an average of 33%. All patients reported improvement in quality of life and were very satisfied with the aesthetic outcomes. The use of autologous fat grafting to treat SSc patients successfully increased oral openings and improved facial manifestations. The procedure is reproducible, safe and leads to improvement in facial manifestations and patients’ quality of life. It can be repeated over time to preserve or enhance the results.

• CXCL4 as a biomarker in the VEDOSS and related with peripheral vasculopathy in SSc. • CXCL4 exerts its anti-angiogenesis effects by downregulating Fli-1 via the c-Abl pathway. • CXCL4 blocked the TGF -β or PDGF induced cell proliferation of HUVECs. CXCL4, a chemokine with anti-angiogenic property, is involved in systemic sclerosis (SSc) related pulmonary arterial hypertension (PAH). To investigated the contribution of CXCL4 to SSc development by focusing on the correlation of circulatory CXCL4 levels with their peripheral vasculopathy, and the effect of CXCL4 on endothelial cell dysfunction and the potential signaling. We measured the plasma CXCL4 levels in 58 patients with SSc, 10 patients with the very early diagnosis of SSc (VEDOSS), and 80 healthy controls (HCs). Then, CXCL4 concentrations were correlated with clinical features, especially the peripheral vasculopathy. These observations were further validated in an additional cohort. Moreover, we studied the anti-angiogenic effects of CXCL4 and the underlying downstream signaling in human umbilical vein endothelial cells (HUVECs) in vitro. Circulating CXCL4 levels were 103.62 % higher in patients with SSc and 201.51 % higher in patients with VEDOSS than matched HCs, which were confirmed in two independent cohorts. CXCL4 levels were associated with digital ulcers (DU) and nailfold videocapillaroscopy (NVC) abnormalities in SSc. The proliferation, migration, and tube formation of HUVECs were inhibited by CXCL4 or SSc derived plasma, which reversed by CXCL4 neutralizing antibody, but failed by CXCR3 inhibitor. CXCL4 downregulated the transcription factor Friend leukaemia integration factor‐1 (Fli-1) via c-Abl signaling. Furthermore, CXCL4 blocked the transforming growth factor (TGF) -β or platelet-derived growth factor (PDGF) induced cell proliferation of HUVECs. CXCL4 may contribute to peripheral vasculopathy in SSc by downregulating Fli-1 via c-Abl signaling in endothelial cells and interfering angiogenesis. [ABSTRACT FROM AUTHOR]

• 2-APB induces dedifferentiation in TGF-β1-induced myofibroblasts. • Inhibition of intracellular Ca2+ regulation by 2-APB restrains the expression of fibrotic markers through inhibiting TGF-β1/SMAD3 signaling. • Treatment with 2-APB in the bleomycin-induced SSc mice alleviates SSc pathogenesis. • 2-APB is a potential candidate for treating fibrotic diseases. Systemic sclerosis (SSc) causes progressive fibrosis of multiple organs with the low efficacy of immunosuppressive therapies. Our previous study indicated the SSc pathological pathways are closely correlated with Ca2+ signals, and blockage of the intracellular Ca2+ elevation facilitates inhibition of SSc pathogenesis. Transforming growth factor β (TGF-β)-modulated SMAD signaling is crucial in regulating SSc pathogenesis. Whether Ca2+ signals are involved in TGF-β1/SMAD signaling-induced fibrotic process has been further investigated. We utilized TGF-β1-induced myofibroblasts as a model to detect how Ca2+ signals affected SSc pathogenesis, and investigated the combination of treatment with store-operated Ca2+ entry (SOCE) associated inhibitors, 2-aminoethyl diphenylborinate (2-APB) and SKF96365 to restrain the increased Ca2+ signaling in myofibroblasts. In addition, the SSc bleomycin mouse model was used to detect the effect of 2-APB on SSc pathogenesis in vivo. Our findings revealed increased levels of TGF-β1 production in SSc was associated with intracellular Ca2+ activity, and inhibition of intracellular Ca2+ regulation by 2-APB resulted in the dedifferentiation of TGF-β1-induced myofibroblasts. This was due to the fact that 2-APB restrained the expression fibrotic markers, α-SMA, fibronectin and vimentin through inhibiting TGF-β1/SMAD3 signaling. Thus, subcutaneous injection of 2-APB improved bleomycin-induced skin and pulmonary fibrosis. 2-APB is a potential candidate for treating fibrosis, by disrupting intracellular Ca2+ regulation in SSc to induce the dedifferentiation of myofibroblasts and meliorates fibrosis pathogenesis via inhibiting TGF-β1/SMAD3 signaling. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a systemic autoimmune condition of unknown cause. Yes-Associated Protein/Tafazzin (YAP/TAZ) are transcriptional coactivators previously demonstrated to be involved in cellular stretch biology, and form the principal effector molecules of the Hippo signalling pathway. The association between YAP/TAZ and stretch is contingent upon their cytoplasmic localisation (with nuclear translocation, the cell adopts a relaxed state). The author weighs the evidence for a central role for YAP/TAZ signalling in scleroderma spanning the major clinical features of the condition. Several of the features unique to SSc are mediated by cytoplasmic localisation of YAP/TAZ, including the stretch phenotype (through binding to NF-2), arterial lumenal obliteration (through their binding to angiomotin), the promotion of hypergammaglobulinaemia (via feedback to the upstream Hippo signalling molecule Mammalian Ste20-like Kinase 1), and the induction of B-Lymphocyte-Induced Maturation Protein-1 leading to the adoption of Th2 lineage, prominent in SSc. One observes that the induction of the fibrotic phenotype of scleroderma is mediated through GLI1/GLI2 (the effector molecules of the Hedgehog pathway). GLI1/GLI2 are induced to reciprocally enter the nucleus when YAP/TAZ is intracytoplasmic. The latter explains the characteristically increased connective tissue growth factor 2 and endothelin-1 expression. In this article, the author references some examples of the role of YAP/TAZ in the biophysically similar condition nephrogenic systemic fibrosis and suggests a role of YAP/TAZ cytoplasmic sequestration in programmed cell death protein 1-ligand antagonist-induced scleroderma.

Abstract Background Up to 12% of patients with systemic sclerosis (SSc) have anti-neutrophil cytoplasmic antibodies (ANCA). However, the majority of these patients do not manifest ANCA-associated vasculitis (AAV) and the significance of ANCA in these patients is unclear. The aim of this study is to determine the prevalence of ANCA in a well-characterised SSc cohort and to examine the association between ANCA and SSc clinical characteristics, other autoantibodies, treatments and mortality. Methods Clinical data were obtained from 5 centres in the Australian Scleroderma Cohort Study (ASCS). ANCA positive was defined as the presence of any one or combination of cytoplasmic ANCA (c-ANCA), perinuclear ANCA (p-ANCA), atypical ANCA, anti-myeloperoxidase (anti-MPO) or anti-proteinase-3 (anti-PR3). Associations of demographic and clinical features with ANCA were investigated by logistic or linear regression. Survival analysis was performed using Kaplan-Meyer curves and Cox regression models. Results Of 1303 patients, 116 (8.9%) were ANCA positive. Anti-PR3 was more common than anti-MPO (13.8% and 11.2% of ANCA-positive patients, respectively). Only 3 ANCA-positive patients had AAV. Anti-Scl-70 was more common in ANCA positive vs ANCA negative (25% vs 12.8%, p

Background: Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc), and its early detection and treatment may prevent deterioration of lung function. Different vendors have recently made larger image matrices available as a post-processing option for computed tomography (CT), which could facilitate the diagnosis of SSc-ILD. Therefore, the objective of this study was to assess the effect of matrix size on lung image quality in patients with SSc by comparing a 1024-pixel matrix to a standard 512-pixel matrix and applying different reconstruction kernels. Methods: Lung scans of 50 patients (mean age 54 years, range 23–85 years) with SSc were reconstructed with these two different matrix sizes, after determining the most appropriate kernel in a first step. Four observers scored the images on a five-point Likert scale regarding image quality and detectability of clinically relevant findings. Results: Among the eight tested kernels, the Br59-kernel (sharp) reached the highest score (19.48 ± 3.99), although differences did not reach statistical significance. The 1024-pixel matrix scored higher than the 512-pixel matrix HRCT overall (p = 0.01) and in the subcategories sharpness (p < 0.01), depiction of bronchiole (p < 0.01) and overall image impression (p < 0.01), and lower for the detection of ground-glass opacities (GGO) (p = 0.04). No significant differences were found for detection of extent of reticulations/bronchiectasis/fibrosis (p = 0.50) and image noise (p = 0.09). Conclusions: Our results show that with the use of a sharp kernel, the 1024-pixel matrix HRCT, provides a slightly better subjective image quality in terms of assessing interstitial lung changes, whereby GGO are more visible on the 512-pixel matrix. However, it remains to be answered to what extent this is related to the improved representation of the smallest structures.

Systemic Sclerosis (SSc) is a chronic autoimmune disease with high morbidity and mortality. Autologous Hematopoietic Stem Cell Transplantation (AHSCT) is the best therapeutic option for rapidly progressive SSc, allowing increased survival with regression of skin and lung fibrosis. The immune determinants of the clinical response after AHSCT have yet to be well characterized. In particular, the pivotal role of the Human Leukocyte Antigen (HLA) system is not well understood, including the role of non-classical immuno-modulatory HLA-E and HLA-G molecules in developing tolerance and the role of Natural Killer cells (NK) in the immunomodulation processes. We retrospectively tested whether the genetic and/or circulating expression of the non-classical HLA-E and HLA-G loci, as well as the imputed classical HLA determinants of HLA-E expression, influence the observed clinical response to AHSCT at 12- and 24-month follow-up. In a phenotypically well-defined sample of 46 SSc patients classified as clinical responders or non-responders, we performed HLA genotyping using next-generation sequencing and circulating levels of HLA-G and quantified HLA-E soluble isoforms by ELISA. The -21HLA-B leader peptide dimorphism and the differential expression level of HLA-A and HLA-C alleles were imputed. We observed a strong trend towards better clinical response in HLA-E*01:03 or HLA-G 14bp Del allele carriers, which are known to be associated with high expression of the corresponding molecules. At 12-month post-AHSCT follow-up, higher circulating levels of soluble HLA-E were associated with higher values of modified Rodnan Skin Score (mRSS) (p = 0.0275), a proxy of disease severity. In the non-responder group, the majority of patients carried a double dose of the HLA-B Threonine leader peptide, suggesting a non-efficient inhibitory effect of the HLA-E molecules. We did not find any correlation between the soluble HLA-G levels and the observed clinical response after AHSCT. High imputed expression levels of HLA-C alleles, reflecting more efficient NK cell inhibition, correlated with low values of the mRSS 3 months after AHSCT (p = 0.0087). This first pilot analysis of HLA-E and HLA-G immuno-modulatory molecules suggests that efficient inhibition of NK cells contributes to clinical response after AHSCT for SSc. Further studies are warranted in larger patient cohorts to confirm our results.

Abstract Background Sympathetic skin response (SSR) is a technique to assess the sympathetic cholinergic pathways. Sympathetic dysfunction may participate in the development of pain, which is the major complaint in patients with systemic sclerosis (SSc) and rheumatoid arthritis (RA). Objectives In this study, we aimed to assess the autonomic dysfunction in patients with (SSc) and (RA) using SSR as a simple neurophysiologic test. Methods Palmar SSR to median nerve electrical stimulation was recorded in 21 patients with SSc, 39 patients with RA, and in 60 healthy age and sex-matched control subjects. Results Palmar SSR to median nerve stimulation (of SSc patients and RA patients) shows significantly delayed latency and reduced amplitude in comparison to the control group. SSR of SSc patients has significantly delayed latency and reduced amplitude when compared to RA patients. Moreover, six SSc patients have delayed SSR in spite of the absence of manifestations of polyneuropathy. Conclusions Patients with SSc and RA have features of autonomic dysfunction with more affection of SSc patients.

Systemic sclerosis (SSc) is a clinically heterogeneous disorder of the connective tissue characterized by vascular alterations, immune/inflammatory manifestations, and organ fibrosis. SSc pathogenesis is complex and still poorly understood. Therefore, effective therapies are lacking and remain nonspecific and limited to disease symptoms. In the last few years, many molecular and cellular mediators of SSc fibrosis have been described, providing new potential options for targeted therapies. In this review: (i) we focused on the PDGF/PDGFR pathway as key signaling molecules in the development of tissue fibrosis; (ii) we highlighted the possible role of stimulatory anti-PDGFRα autoantibodies in the pathogenesis of SSc; (iii) we reported the most promising PDGF/PDGFR targeting therapies.