Localized Scleroderma Patients Research Articles

Association of Black Race With Demographic, Comorbidities, and Outcome Variables in Localized Scleroderma Patients: A Retrospective Analysis of the 2017 US National Inpatient Sample

Association of Black Race With Demographic, Comorbidities, and Outcome Variables in Localized Scleroderma Patients: A Retrospective Analysis of the 2017 US National Inpatient Sample

"Comparative study of adipose-derived stem cells from localized scleroderma patients and healthy donors in treating skin fibrosis".

Localized scleroderma (LoS) is an autoimmune disease characterized by fibrosis of the skin and atrophy of the subcutaneous fat tissue. Adipose-derived mesenchymal stem cells (ASCs) is a promising treatment approach for LoS. However, ASCs from scleroderma patients (LoS-ASCs) have been shown to exhibit altered characteristics compared to ASCs from healthy donors (healthy-ASCs). This study aimed to compare the abilities of LoS-ASCs and healthy-ASCs in treating skin fibrosis. The paracrine ability of ASCs was tested with cytokine array. Bleomycin-challenged mice models received subcutaneous injection of LoS-ASCs and healthy-ASCs. Pathological staining and western blotting of COL1, α-SMA was performed. Fibroblasts derived from LoS lesions (LoS-FB) was co-cultured with ASCs, and subjected to RNA sequencing to further explore the similarities and differences in the treatment mechanism. In vivo comparison revealed that healthy ASCs had a stronger proliferation ability and secreted higher levels of growth factors and cytokines, including VEGFA, PDGFB, and IL-10. Pathological staining of the skin in mice models treated with ASCs demonstrated that healthy ASCs were more effective in reducing dermal thickness and collagen deposition, while increasing microvessel density and the proportion of M2 macrophages. Co-culture with both healthy-ASCs and LoS-ASCs reduced the proliferation and migration abilities of LoS-FB, as well as the protein expression of α-SMA and COL1. RNA sequencing and validation revealed potential difference in the canonical Wnt pathway. Healthy-ASCs exhibited stronger proliferation, paracrine, anti-fibrosis, pro-angiogenesis, and immunomodulation abilities in treating skin fibrosis in scleroderma mouse models. Allogenic ASCs obtained from healthy donors are more efficient in treating skin fibrosis, and could serve as a potential alternative for patients who are not suitable candidates for liposuction surgery in the future.

Characterization of Endothelial Cell Subclusters in Localized Scleroderma Skin with Single-Cell RNA Sequencing Identifies NOTCH Signaling Pathway

Localized scleroderma (LS) is an autoimmune disease characterized by inflammation and fibrosis, leading to severe cutaneous manifestations such as skin hardening, tightness, discoloration, and other textural changes that may result in disability. While LS shares similar histopathologic features and immune-fibroblast interactions with systemic sclerosis (SSc), its molecular mechanisms remain understudied. Endothelial cells (EC) are known to play a crucial role in SSc but have not been investigated in LS. Single-cell RNA sequencing (scRNA-seq) now allows for detailed examination of this cell type in the primary organ of interest for scleroderma, the skin. In this study, we analyzed skin-isolated cells from 27 LS patients (pediatric and adult) and 17 healthy controls using scRNA-seq. Given the known role of EC damage as an initial event in SSc and the histologic and clinical skin similarities to LS, we focused primarily on endothelial cells. Our analysis identified eight endothelial subclusters within the dataset, encompassing both disease and healthy samples. Interaction analysis revealed that signaling from diseased endothelial cells was predicted to promote fibrosis through SELE interaction with FGFBP1 and other target genes. We also observed high levels of JAG in arterial endothelial cells and NOTCH in capillary endothelial cells, indicating the activation of a signaling pathway potentially responsible for epidermal abnormalities and contributing to LS pathogenesis. In summary, our scRNA-seq analysis identified potential disease-propagating endothelial cell clusters with upregulated pathways in LS skin, highlighting their importance in disease progression.

National Registry for Childhood Onset Scleroderma I: Insights from the first 341 juvenile localized scleroderma patients

Objectives: There is an under recognition of juvenile-onset localized scleroderma and its extracutaneous manifestations leading to delay in systemic treatment. Our study aims to address this gap by describing the demographics, presentation, associated family history, concurrent autoimmune disease, extracutaneous manifestations, laboratory evaluation, treatment, and course of disease in juvenile-onset localized scleroderma patients enrolled in the National Registry for Childhood Onset Scleroderma. Methods: Participants for this study were derived from the National Registry for Childhood Onset Scleroderma and included 341 patients with juvenile-onset localized scleroderma. Demographic, and prospectively collected outcome measures, such as the Localized Scleroderma Cutaneous Assessment Tool, physical exam findings, laboratory values, and patient-reported outcomes were reviewed. Results: Most patients were female (71%), Caucasian (94%), had a linear subtype (56%), and had the onset of disease at age 7.5 (±4.2) years, and diagnosis 1.9 (±2.6) years after symptom onset. Most patients experienced at least one extracutaneous manifestation (70%), most commonly musculoskeletal (57%), followed by neurological (46%), and ophthalmological (11%). Those with musculoskeletal extracutaneous manifestation have significantly abnormal inflammatory and antibody laboratory values. Of patients with 1-year follow-up, a majority were treated with systemic therapy and globally improved with significant reduction in both modified Localized Scleroderma Skin Index ( p < 0.001) and Localized Scleroderma Damage Index ( p = 0.001). Conclusion: The study highlights need for earlier recognition of juvenile-onset localized scleroderma after demonstrating the delay in diagnosis and frequent extracutaneous manifestations with significant disease burden in a juvenile-onset localized scleroderma cohort. The benefits of systemic treatment and full extracutaneous manifestation screening in juvenile-onset localized scleroderma is supported.

Endpoints and outcomes for localized scleroderma/morphea: a scoping literature review

BackgroundCurrent treatment for localized scleroderma (LS) has been shown to halt disease activity, but little is still known about patient experiences with these treatments, nor is there consensus about optimal measurement strategies for future clinical trials.ObjectiveConduct a scoping review of the literature for the types of outcomes and measures (i.e. clinician-, patient-, and caregiver-reported) utilized in published treatment studies of LS.MethodsOnline databases were searched for articles related to the evaluation of treatment efficacy in LS with a special focus on pediatrics.ResultsOf the 168 studies, the most common outcomes used were cutaneous disease activity and damage measured via clinician-reported assessments. The most frequently cited measure was the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT). Few patient-reported outcome measures (PROMs) were used.LimitationsSome studies only vaguely reported the measures utilized, and the review yielded a low number of clinical trials.ConclusionIn addition to evaluating disease activity with clinician-reported measures, the field could obtain critical knowledge on the patient experience by including high-quality PROMs of symptoms and functioning. More clinical trials using a variety of outcomes and measures are necessary to determine the most suitable course of treatment for LS patients.

Advances in the Management of Localized Scleroderma: A Systematic Review of Laser Therapy and Injectable Filler Approaches.

Localized scleroderma (LS), commonly known as morphea, presents a significant clinical challenge due to its chronic, inflammatory nature affecting the skin and potentially underlying tissues. This systematic review explores the innovative approach of combining laser therapy and injectable fillers, specifically hyaluronic acid, for the treatment of LS. We conducted a comprehensive literature review following PRISMA guidelines, examining articles from MEDLINE/PubMed to assess the combined efficacy of these treatments in improving both esthetic and functional outcomes for LS patients. The search yielded 64 articles, with six selected for in-depth analysis for a total of nine patients, covering a range of patient demographics and treatment types. Our review highlights cases where fractional CO2 laser therapy promoted long-term tissue remodeling and instances where hyaluronic acid fillers effectively addressed skin atrophy and volume loss, enhancing both immediate and long-lasting esthetic improvements. The synergy between these treatments suggests a promising dual approach, aiming to maximize esthetic outcomes and to improve the quality of life for LS patients. This review underscores the necessity of further research to establish a comprehensive, evidence-based clinical pathway integrating both treatments for managing LS, thereby enhancing patient satisfaction and addressing the multifaceted nature of this challenging dermatological condition.

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

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

Automated anatomical landmark detection on 3D facial images using U-NET-based deep learning algorithm.

Facial anthropometry based on 3-dimensional (3D) imaging technology, or 3D photogrammetry, has gained increasing popularity among surgeons. It outperforms direct measurement and 2-dimensional (2D) photogrammetry because of many advantages. However, a main limitation of 3D photogrammetry is the time-consuming process of manual landmark localization. To address this problem, this study developed a U-NET-based deep learning algorithm to enable automated and accurate anatomical landmark detection on 3D facial models. The main structure of the algorithm stacked 2 U-NETs. In each U-NET block, we used 3×3 convolution kernel and rectified linear unit (ReLU) as activation function. A total of 200 3D images of healthy cases, acromegaly patients, and localized scleroderma patients were captured by Vectra H1 handheld 3D camera and input for algorithm training. The algorithm was tested to detect 20 landmarks on 3D images. Percentage of correct key points (PCK) and normalized mean error (NME) were used to evaluate facial landmark detection accuracy. Among healthy cases, the average NME was 1.4 mm. The PCK reached 90% when the threshold was set to the clinically acceptable limit of 2 mm. The average NME was 2.8 and 2.2 mm among acromegaly patients and localized scleroderma patients, respectively. This study developed a deep learning algorithm for automated facial landmark detection on 3D images. The algorithm was innovatively validated in 3 different groups of participants. It achieved accurate landmark detection and improved the efficiency of 3D image analysis.

Letter on Fat Grafting Reduces Skin Hyperpigmentation of Localized Scleroderma Patients: A Prospective Self-controlled Study

Letter on Fat Grafting Reduces Skin Hyperpigmentation of Localized Scleroderma Patients: A Prospective Self-controlled Study

Fat Grafting Reduces Skin Hyperpigmentation of Localized Scleroderma Patients: A Prospective Self-controlled Study.

Localized scleroderma (LS) is characterized by skin fibrosis, hyperpigmentation and soft tissue atrophy. Fat grafting has been widely used to correct LS deformity. To investigate the effect of fat grafting on the skin pigmentation of LS lesions. A prospective self-controlled study was conducted. Skin melanin and erythema indexes were measured by Mexameter® MX18 before and 3months after surgery. Differences between lesions and contralateral normal sites were compared to evaluate changes induced by fat grafting. Localized Scleroderma Cutaneous Assessment Tool and PUMC Localized Scleroderma Facial Aesthetic Index were used for clinical evaluation. Fourteen frontal linear LS patients participated in the study. Before surgery, the melanin index of the lesions was significantly higher than the contralateral sites (p = 0.023), while the erythema indexes were not significantly different (p = 0.426). Three months post-operation, the melanin index of the lesions significantly decreased (p = 0.008). There was no significant change in the erythema index of the lesions before and after fat grafting (p = 0.322). The LoSCAT and PUMC LSFAI scores demonstrated improved disease condition and facial esthetics after surgery. Fat grafting could alleviate skin hyperpigmentation and skin damage of LS lesions while having little effect on skin erythema and disease activity. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Platelet-Rich Plasma Combined Fat Transplantation for the Treatment of Bleomycin-Induced Murine Scleroderma.

Low-fat retention induced by inflammation limits the clinical application of fat grafting for treating localized scleroderma (LS) patients. Novel methods to improve the therapeutic outcome are needed. The aim of the study is to investigate the effect of platelet-rich plasma (PRP)-assisted fat transplantation on skin fibrosis and adipose survival in the LS model. The LS model was established by the injection of bleomycin into BALB/C nude mice, which were randomly divided into the following 4 groups: healthy control, LS disease group model, fat transplantation group, and PRP+ fat transplantation group. The mice received a subcutaneous injection at back with phosphate-buffered saline, fat, or 20% PRP+ fat. Factors of immunoregulation, angiogenesis and adipogenesis were measured. Platelet-rich plasma-combined fat transplantation significantly attenuated dermis fibrosis by reducing the production of type III collagen. The fat retention in the PRP+ fat transplantation group was 43 ± 4 mg, significantly higher than 22 ± 15 mg in the fat transplantation group (P = 0.0416). The level of tumor necrosis factor α and interleukin 2 showed no significant difference between the groups. The expression of angiogenesis factors, vascular endothelial growth factor, hepatocyte growth factor, platelet-derived growth factor, and CD31, significantly increased in the PRP+ fat transplantation group. The expression of adipogenesis factors, insulin-like growth factor 1 receptor, extracellular signal-regulated kinase, anti-CCAAT-enhancer-binding proteins, and peroxisome proliferator-activated receptor γ, also significantly increased in the PRP+ fat transplantation group. The results demonstrated that PRP-combined fat transplantation attenuated dermis fibrosis and raised fat survival in the LS model by promoting angiogenesis and adipogenesis through insulin-like growth factor 1 receptor/extracellular signal-regulated kinase signaling pathway.

Barriers to care in juvenile localized and systemic scleroderma: an exploratory survey study of caregivers’ perspectives

BackgroundJuvenile localized scleroderma (LS) and systemic sclerosis (SSc) are rare pediatric conditions often associated with severe morbidities. Delays in diagnosis are common, increasing the risk for permanent damage and worse outcomes. This study explored caregiver perspectives on barriers they encountered while navigating diagnosis and care for their child’s scleroderma.MethodsIn this cross-sectional study, caregivers of juvenile LS or SSc patients were recruited from a virtual family scleroderma educational conference and a juvenile scleroderma online interest group. The survey queried respondents about their child’s condition and factors affecting diagnosis and treatment.ResultsThe response rate was 61% (73/120), with 38 parents of LS patients and 31 parents of SSc patients. Most patients were female (80%) and over half were non-Hispanic white (55%). Most families had at least one person with a college education or higher (87%), traveled ≤ 2 h to see their rheumatologist (83%), and had private insurance (75%). Almost half had an annual household income ≥ $100,000 (46%). Families identified the following factors as barriers to care: lack of knowledge about scleroderma in the medical community, finding reliable information about pediatric scleroderma, long wait times/distances for a rheumatology/specialist appointment, balance of school/work and child’s healthcare needs, medication side effects, and identifying effective medications. The barrier most identified as a major problem was the lack of knowledge about juvenile scleroderma in the medical community. Public insurance, household income less than $100,000, and Hispanic ethnicity were associated with specific barriers to care. Lower socioeconomic status was associated with longer travel times to see the rheumatologist/specialist. Diagnosis and systemic treatment initiation occurred at greater than one year from initial presentation for approximately 28% and 36% of patients, respectively. Families of LS patients were commonly given erroneous information about the disease, including on the need and importance of treating active disease with systemic immunosuppressants in patients with deep tissue or rapidly progressive disease.ConclusionCaregivers of children with LS or SSc reported numerous common barriers to the diagnosis, treatment, and ongoing care of juvenile scleroderma. The major problem highlighted was the lack of knowledge of scleroderma within the general medical community. Given that most of the caregiver respondents to the survey had relatively high socioeconomic status, additional studies are needed to reach a broader audience, including caregivers with limited English proficiency, geographical limitations, and financial constraints, to determine if the identified problems are generalizable. Identifying key care barriers will help direct efforts to address needs, reduce disparities in care, and improve patient outcomes.

UVA1 irradiation attenuates collagen production via Ficz/AhR/MAPK signaling activation in scleroderma

Scleroderma is an autoimmune disease mainly characterized by progressive fibrosis of the skin. There are two types of scleroderma, namely localized scleroderma (LS) and systemic sclerosis (SSc); skin lesions in both types of scleroderma are histologically identical. Progressive skin sclerosis induces psychological and ecological burden for scleroderma patients. However, there is no effective treatment for scleroderma due to its unclear etiology. Aryl hydrocarbon receptor (AhR) is recognized as an environmental chemical effector that can respond to ultraviolet radiation, which has been demonstrated to participate in the pathogenesis of SSc in our previous study. In this study, we verify whether the anti-fibrosis effect of ultraviolet A1 (UVA1) phototherapy could be partially induced through Ficz/AhR/MAPK signaling activation for fibrotic lesions in both SSc and LS patients. This is the first study to show the association between the AhR pathway and the anti-fibrotic mechanism of UVA1 phototherapy, which provides additional evidence of the role of AhR in the fibrotic mechanism of systemic scleroderma from different perspectives. Ficz and other AhR agonists may replace UVA1 phototherapy as anti-fibrotic agents in scleroderma.

Adipose-Derived Stem Cells Attenuate Skin Fibrosis and Improve Fat Retention of a Localized Scleroderma Mouse Model.

Although autologous fat grafting is a feasible surgical technique to improve facial deformity in patients with localized scleroderma, its success is limited by the low graft retention induced by the local inflammatory environment. This study investigated the potential effect of adipose-derived stem cells (ASCs) on skin fibrosis and fat retention in a localized scleroderma mouse model. BALB/C nude mice that were induced by bleomycin to establish a localized scleroderma model were divided randomly into five groups: blank control; fat grafting; and low, moderate, and high doses of ASC-assisted fat grafting. The backs of the mice were subcutaneously injected with phosphate-buffered saline or fat, or fat with low, moderate, and high doses of ASCs (1 × 10 5 /mL, 5 × 10 5 /mL, and 25 × 10 5 /mL, respectively). The skin fibrosis and fat retention were analyzed after 1 month or 3 months, respectively. Compared to the disease model group, the fat-grafting group, and the low- and moderate-dose ASC-enriched groups, the high-dose ASCs significantly attenuated skin fibrosis, inhibited the production of type III collagen and transforming growth factor-β1, increased fat graft retention, enhanced the expression of angiogenesis-related cytokines and angiogenesis, and increased the expression of adipogenesis-related cytokines. The results demonstrated that high-dose ASCs attenuated skin fibrosis and improved fat retention in a localized scleroderma model by reducing inflammation and by promoting angiogenesis and adipogenesis. The authors further demonstrated that ASCs enhanced adipogenesis through the AKT/ERK signaling pathway. Fat grafting has been used to treat localized scleroderma patients but with low fat retention. In this study, ASC attenuated skin fibrosis and improved fat retention in the localized scleroderma model, providing evidence for cell therapy in future application of localized scleroderma treatment.

Association Between Fat Graft Retention and Blood Flow in Localized Scleroderma Patients: A Pilot Study.

BackgroundMicrocirculation plays a vital role in scleroderma physiopathology and the mechanism of fat survival.ObjectiveThis study aims to assess the blood perfusion change after fat grafting and evaluate the relationship between blood perfusion and fat graft retention in patients with localized scleroderma (LS).MethodsA pilot study was conducted in patients with LS receiving autologous fat grafting (AFG). Fat graft retention measured by magnetic resonance imaging (MRI) analysis and blood flow perfusion measured by laser speckle contrast imaging 6 months postoperatively were noted. PUMC Localized Scleroderma Facial Aesthetic Index was used to assess the improvement of facial aesthetic impairment.ResultsThe fat retention at the 6-month follow-up was 34.56 ± 11.89 percent. At the 6th month of follow-up, the relative blood perfusion at the lesion area was 115.08 ± 14.39 PU, significantly higher than 100.42 ± 10.62 PU at the pre-operation (p = 0.010). The blood perfusion at follow-up increased by an average of 1.15 ± 0.14 times before the operation. No association between the increase in the blood flow perfusions and fat graft retention was found (r = −0.082, p = 0.811).ConclusionLocal blood perfusion in the lesion area relatively increased after AFG, but no direct relationship was found between fat retention and increased blood supply.

Clinical and laboratory characterization of patients with localized scleroderma and response to UVA-1 phototherapy: In vivo and in vitro skin models.

Localized scleroderma (LS) is a rare disease leading to progressive hardening and induration of the skin and subcutaneous tissues. LS is responsive to UVA-1 phototherapy, though its exact mechanism of action dermal fibrosis is yet to be fully elucidated. We aimed to investigate the molecular changes induced by UVA-1 rays in human primary fibroblasts cultures. A total of 16 LS patients were treated with medium-dose UVA-1 phototherapy. At baseline, during and after therapy, Localized Scleroderma Assessment Tool, Dermatology Life Quality Index and lesions' staging and mapping were performed along with high-frequency ultrasound (HFUS) examination for dermal thickness assessment. Gene expression analysis for 23 mRNA transcripts, in vitro UVA-1 irradiation and viability tests were realized on lesional fibroblasts' primary cultures, before and 3 months after therapy. The dermal thickness, the LoSCAT and the DLQI progressively decreased starting from the last phototherapy session up to the 6 and 9 month follow-ups (-57% and -60%, respectively). Molecular gene analysis (rt-PCR) revealed that UVA-1 phototherapy exerts multiple effects: the activation of specific anti-fibrotic pathways (e.g., overexpression of CTHRC1 and metalloproteases 1, 2, 7, 8, 9, 12, suppression of TIMP-1), the downregulation of peculiar pro-fibrotic pathways (e.g., downregulation of TGF-ß, TGF-ßrII, Grb2, SMAD 2/3, TNRSF12A, CTGF) through a significant overexpression of IL-1ß; the stabilization of collagen synthesis acting on genes COL1A1, COL3A1, COL8A1, COL10A1, COL12A1. UVA-1 phototherapy adds significant benefits in local tissue remodeling, rebalancing the alteration between pro-fibrotic and anti-fibrotic pathways; these changes can be well monitored by HFUS.

Abnormal expression of interleukin-6 is associated with epidermal alternations in localized scleroderma.

Localized scleroderma (LSc) is a disease characterized by the excessive deposition of collagen and thereby thickening of the dermis. In recent years, studies reported that LSc demonstrated compromised skin barrier related to the progression of the disease. However, human studies examining epidermis in scleroderma are still sparse and lack systematic research. This study aims to investigate the structural and functional changes in the LSc epidermis and further explore the underlying mechanisms, providing a new angle to treat LSc in the clinic. A total of 136 skin sites, including lesion and non-lesion control, from 27 LSc patients were analyzed. Ultrasonic testing, trans-epidermal water loss (TEWL), and epidermal hydration were assessed to investigate the structural and functional alternations; correlations between these parameters were analyzed. To explore the underlying mechanism, skin-fibrosis mouse model and cellular model by bleomycin (BLM) were deployed. The epidermal thickness was markedly increased, with a significant decline of hydration (dryness) in the LSc lesion skin. Epidermal hydration presented a negative correlation with the thickness. TEWL was not altered. The mouse model validated these morphological changes in the epidermis and indicated that interleukin-6 (IL-6) was significantly elevated. Furthermore, cellular study demonstrated that increased phosphorylation of p38 in keratinocyte promoted the secretion of IL-6, stimulating cell proliferation. This study characterized the epidermal alterations in LSc patients, suggesting that keratinocyte-derived abnormal IL-6 secretion can lead to the thickening of the epidermis, promoting dryness. The topical application of moisturizer may largely relieve dryness and related pruritus, thus improve the quality of life in LSc patients. Key Points • Epidermal thickness was increased in LSc lesion skin with declined hydration level. • Skin fibrosis mouse model validated the epidermal alteration in LSc patient. • p38-dependent IL-6 overexpression in keratinocyte result in epidermal thickening.

The Value of High-Resolution Ultrasound Combined with Shear-Wave Elastography under Artificial Intelligence Algorithm in Quantitative Evaluation of Skin Thickness in Localized Scleroderma.

The aim of this study was to explore the value of high-resolution ultrasound combined with shear-wave elastography (SWE) in measuring skin thickness in patients with localized scleroderma (LS). Fifty patients with LS diagnosed by pathology in the hospital were selected as the research object, with a total of 96 lesions. Healthy people (50 cases) in the same period were selected as the control group. The skin thickness of the abdomen, chest, and left finger of the two groups was compared. The traditional nonlocal means (NLM) algorithm was improved by changing the Euclidean distance and introducing a cosine function, which was applied to the ultrasonic imaging intelligent diagnosis of patients with localized scleroderma. SWE imaging was evaluated, and the results demonstrated that LS lesion edema stage accounted for 7.29%, hardening stage occupied 43.75%, and the proportion of atrophy stage reached 48.96%. When the size of shell was 1 mm, maximum elastic modulus (Emax) was 0.984, mean of elastic modulus (Emean) was 0.926, and electro-static discharge (Esd) was 0.965. When the size of shell was 2 mm, the elastic moduli around lesions were as follows: Emax was 0.998, Emean was 0.968, and Esd was 0.997. By comparing the skin thickness of the abdomen, chest, and left finger, it was found that there was a significant difference between the LS group and the control group (P < 0.05). When the shell was 2 mm, the effect of sensitivity specificity on SWE imaging was better than that when the shell was 1 mm. In summary, the improved NLM algorithm showed excellent denoising effects on the ultrasonic images of LS patients. Besides, it could assist clinicians in ultrasonic imaging diagnosis for LS patients and effectively improve the diagnostic accuracy of diseases.

Genetic Signatures From RNA Sequencing of Pediatric Localized Scleroderma Skin.

The purpose of this study was to explore the skin transcriptional profile in pediatric localized scleroderma (LS) to provide a better understanding of the altered immune and fibrotic pathways promoting disease. LS is a progressive disease of the skin and underlying tissue that causes significant functional disability and disfigurement, especially in developing children. RNA sequencing (RNAseq) technology allows for improved understanding of relevant cellular expression through transcriptome analysis of phases during LS disease progression (more active/inflammatory vs. inactive/fibrotic) and also permits the use of RNA extracted from existing paraffin-embedded skin tissue, which is important in pediatrics. A strong correlation was observed between the comparison of genes expressed between fresh (RNAlater) and paraffinized skin in healthy and LS subjects, supporting the use of paraffinized tissue. LS gene signatures compared to healthy controls showed a distinct expression of an inflammatory response gene signature (IRGS) composed of IFNγ-, IFNα-, and TNFα-associated genes. GSEA© enrichment analysis showed that the IRGS, including interferon-inducible chemokines such as CXCL9, CXCL10, CXCL11, and IFNγ itself, was more highly expressed in LS patients with more inflammatory lesions. The use of paraffinized skin for sequencing was proven to be an effective substitute for fresh skin by comparing gene expression profiles. The prevalence of the IFNγ signature in the lesion biopsies of active LS patients indicates that these genes reflect clinical activity parameters and may be the promoters of early, inflammatory disease.

A pilot study on ex vivo expanded autologous adipose-derived stem cells of improving fat retention in localized scleroderma patients.

In patients with localized scleroderma (LoS), facial deformity induced by subcutaneous atrophy greatly reduces life quality. Autologous fat grafting (AFG) is used for volume restoration but with low‐fat retention due to various reasons. Adipose‐derived stem cells (ADSCs) have shown potential effects in improving fat retention. We aimed to compare the feasibility and efficacy of improving fat retention in LoS patients among the ADSCs‐assisted, the stromal vascular fraction (SVF)‐assisted and conventional AFG methods. A pilot study with a 6‐month follow‐up among 18 LoS patients was conducted. Participants were randomly assigned into three AFG groups: conventional group, SVF‐assisted group, and ADSCs‐assisted group. The SVF‐assisted group received SVF‐assisted AFG at the SVF:fat ratio of 1:1. The ADSCs‐assisted group received the mixture of ADSCs‐enriched fat graft supplemented with 5 × 105 ADSCs/mL fat. Volume retention was measured by magnetic resonance imaging, and clinical photographs were taken for outcome evaluation. At sixth‐month follow‐up, the fat retention of ADSCs‐assisted group was 49.83 ± 3.61%, significantly higher than 31.75 ± 1.73% of SVF‐assisted group (P = .0004), and 21.86 ± 1.68% of the conventional group (P < .0001). A significant difference of the fat retention was also observed between the SVF‐assisted and conventional group (P = .0346). No severe adverse events occurred during the procedure and follow‐up. This pilot study suggests that ADSCs‐assisted AFG is a safe, feasible, and attractive alternative to conventional and SVF‐assisted AFG in the correction of facial atrophy of LoS patients. Future studies with large patient samples are needed for confirmation. (Chinese Clinical Trial Registry, ChiCTR1900025717).