Thymic stromal lymphopoietin and digital microvascular damage in systemic sclerosis patients: A pilot study.

BACKGROUND: Systemic sclerosis (SSc) is a complex autoimmune connective-tissue disease, characterised by vasculopathy and fibrosis of the skin and internal organs. Activation of microvascular endothelial cells (ECs) causes the intimal hyperplasia that characterises the vascular remodelling in SSc. The most frequent complication of SSc is the development of digital ulcers (DUs). Thymic stromal lymphopoietin (TSLP) may trigger fibrosis and sustain vascular damage. Aim of this study was to evaluate the correlation between serum level of TSLP and DUs. METHODS: 75 consecutive SSc patients were enrolled and serum TSLP levels were measured. The presence of history of DUs (HDU) was evaluated. Recurrent new DUs were defined as the presence of at least 3 episodes of DUs in a 12-months follow up period. The risk of developing new DUs was calculated by applying the capillaroscopic skin ulcer risk index (CSURI). RESULTS: The median value of TSLP was higher in patients with HDU than patients without HDU [181.67 pg/ml (IQR 144.67; 265.66) vs 154.67 pg/ml (IQR 110.67; 171.33), p < 0.01]. The median value of TSLP was higher in patients with an increased CSURI index than patients without an increased CSURI [188 pg/ml (IQR 171.33; 246.33) vs 159.33 pg/ml (IQR 128.67; 218), p < 0.01]. Kaplan-Meier curves demonstrated that free survival from new DUs was significantly (p < 0.01) lower in SSc patients with increased TSLP serum levels. CONCLUSION: TSLP might have a key role in digital microvascular damage of SSc patients.

Epidemiology of systemic sclerosis in Quebec, Canada: a population-based study.

Background: Systemic sclerosis (SSc) is a systemic life-threatening autoimmune rheumatic disease. We aimed to assess the incidence, prevalence, mortality and spatiotemporal trends of SSc in Quebec, Canada with stratification by sex and age. Methods: SSc cases were identified from Quebec populational databases from 1989 to 2019. Negative Binomial (NB) Generalized Linear Models were used for age-standardized incidence rates (ASIR) analyses and NB random walk for prevalence and mortality. A Poisson Besag-York-Mollié regression model was used for spatial analysis. Findings: 8180 incident SSc cases were identified between 1996 and 2019 with an average age of 57.3 ± 16.3 years. The overall ASIR was 4.14/100,000 person-years (95%, Confidence Interval (CI) 4.05-4.24) with a 4:1 female predominance. ASIR increased steadily over time with an Average Annual Percent Change (AAPC) of 3.94% (95% CI 3.49-4.38). While the highest incidence rates were in those aged 60-79 years old among females and >80 years old among males, the highest AAPC (∼10%) was seen in children. Standarized incidence ratios varied geographically between 0.52 to 1.64. The average prevalence was 28.96/100,000 persons (95% CI 28.72-29.20). The Standardized Mortality Ratio (SMR) decreased from 4.18 (95% CI 3.64-4.76) in 1996 to 2.69 (95% CI 2.42-2.98) in 2019. Females had a greater SMR until 2007 and males thereafter. The highest SMR was in children and young adults [31.2 (95% CI 8.39-79.82) in the 0-19-year age group]. Interpretation: We showed an increasing trend in SSc incidence and prevalence and a decline in SMR over a 25-year period in Quebec. An uneven geographic distribution of SSc incidence was demonstrated. Funding: National Scleroderma Foundation, Canadian Dermatology Foundation/Canadian Institutes of Health Research.

Cross-sectional study using the University of California, Los Angeles, Scleroderma Clinical Trials Consortium Gastrointestinal Tract Instrument 2.0 (UCLA SCTC GIT 2.0) for gastrointestinal disorders of systemic sclerosis.

This study aimed to identify severe gastrointestinal ailments in patients with systemic sclerosis (SSc), investigate the role of antibodies in gastrointestinal disorders, and explore the relationship between limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) in terms of gastrointestinal involvement and its association with skin stiffness. We used the University of California, Los Angeles, Scleroderma Clinical Trials Consortium Gastrointestinal Tract Instrument 2.0 (UCLA SCTC GIT 2.0) questionnaire to assess gastrointestinal disturbances in 100 patients with SSc. Gastrointestinal impairment was categorized into three levels: absence of or minor symptoms, moderate symptoms, and severe symptoms, as indicated by the total gastrointestinal tract (GIT) score. Comparing 27 patients with dcSSc and 73 patients with lcSSc, severe gastrointestinal disturbances were found in 7.4% of patients with dcSSc and 4.1% of patients with lcSSc. A total of 18.0% of anticentromere antibody (ACA)-positive patients exhibited moderate to severe symptoms, while 9.1% of antitopoisomerase 1 antibody-positive patients displayed similar symptoms. The average disease duration in patients with severe symptoms was 15.0 years, in those with moderate symptoms was 10.3 years, and in those who were symptom-free or mildly affected was 8.5 years. Among 16 patients with moderate to severe gastrointestinal disorders, a positive correlation was observed between the modified Rodnan skin thickness score (mRSS) and total GIT score. In addition, a positive correlation was identified between fecal incontinence and mRSS, with weaker correlations for reflux and bloating symptoms. Patients with gastrointestinal disorders showed a tendency to worsen over time, particularly in ACA-positive patients with dcSSc. Furthermore, a correlation was observed between mRSS and fecal incontinence, reflux, and abdominal bloating in patients with moderate to severe gastrointestinal disturbances.

Role of intravenous immunoglobulins in systemic sclerosis (SSc): A systematic literature review.

BACKGROUND: Systemic sclerosis (SSc) is a heterogenous, multi-system autoimmune disease that causes progressive fibrosis of the skin and internal organs, resulting in high morbidity and mortality. Intravenous Immunoglobulin (IVIG) is a therapeutic option for SSc; however, reports of its efficacy have been variable, and its use across multiple organ manifestations of SSc has not been comprehensively reviewed. AIM: The aim of this study was to systematically assess the existing literature on the role of IVIG use across a range of SSc manifestations. METHODS: Medline, Embase, Cochrane, Web of Science and Scopus were searched from 01/01/2003-15/04/2024 using terms related to SSc and IVIG. Included studies were English-language full texts, where ≥5 adults with SSc received IVIG, and where a reportable outcome was documented. RESULTS: Of 418 potentially relevant records, 12 were included in this review, comprising 266 patients across one randomised control trial, two pilot studies, one open label study, seven retrospective studies and one case control study. Eighteen outcomes were documented across five different organ systems: cutaneous, respiratory, musculoskeletal, gastrointestinal, and other (clinical improvement and corticosteroid sparing benefit). Results showed a favourable effect of IVIG in reducing the extent of skin thickening, muscle and joint pain, gastrointestinal symptoms, steroid dosing and improving patient/physician reported quality of life. Whilst IVIG may appear to be less beneficial for respiratory disease, the stabilisation in pulmonary function tests and radiological features may be considered a positive outcome in itself. Limitations included a lack of high-quality studies, and the use of concomitant therapies in many studies, rendering the efficacy of IVIG alone difficult to ascertain. CONCLUSION: IVIG showed benefit in treating some manifestations of SSc, however there was a lack of convincing evidence for the efficacy in others. The lack of high-quality data highlights the need for further well-designed clinical trials to confirm these findings and inform guidelines for IVIG use.

A study of the reliability and construct validity of the 1-minute sit-to-stand test for individuals with systemic sclerosis.

OBJECTIVE: This study seeks to assess the reliability and construct validity of the 1-minute sit-to-stand test as an efficient tool for evaluating the functional capacity of individuals with systemic sclerosis, considering its time and space effectiveness. METHODS: This cross-sectional study recruited forty-nine individuals with systemic sclerosis from a university hospital in Denmark. The 1-minute sit-to-stand test was conducted twice on the same day, with an interval of approximately 10 to 15 minutes between administrations, followed by a single administration of the 6-minute walk test. Reliability and validity were estimated using Bland-Altman statistics, intraclass correlation coefficient (ICC2,1), paired t-test, and Spearman's rank correlation coefficient (ρ). RESULTS: The 1-minute sit-to-stand test exhibited excellent test-retest reliability with an ICC2,1 (CI) of 0.97 (0.95-0.99). The minimal metrically detectable change between separate measures on a subject for the difference in the measures to be considered real at the 95% confidence level was 2.9 repetitions and 11%, respectively. A learning effect of one repetition was observed between repeated measures. High construct validity was observed between the 1-minute sit-to-stand and 6-minute walk test (ρ = 0.78, p < .001). CONCLUSIONS: This study demonstrates the 1-minute sit-to-stand test as highly reliable, with an 11% change indicating a true outcome change. It also demonstrates robust construct validity compared to the 6-minute walk test. The 1-minute sit-to-stand test appears feasible for assessing functional capacity in well-functioning individuals with systemic sclerosis, but prior familiarization with the task is recommended, as a small learning effect was observed with one repetition.

Exploring the complexity of systemic sclerosis etiology by trio whole genome sequencing.

Systemic sclerosis (SSc) is a heterogeneous rare autoimmune fibrosing disorder affecting connective tissue. The etiology of systemic sclerosis is largely unknown and many genes have been suggested as susceptibility loci of modest impact by genome-wide association study (GWAS). Multiple factors can contribute to the pathological process of the disease, which makes it more difficult to identify possible disease-causing genetic alterations. In this study, we have applied whole genome sequencing (WGS) in 101 indexed family trios, supplemented with transcriptome sequencing on cultured fibroblast cells of four patients and five family controls where available. Single nucleotide variants (SNVs) and copy number variants (CNVs) were examined, with emphasis on de novo variants. We also performed enrichment test for rare variants in candidate genes previously proposed in association with systemic sclerosis. We identified 42 exonic and 34 ncRNA de novo SNV changes in 101 trios, from a total of over 6000 de novo variants genome wide. We observed higher than expected de novo variants in PRKXP1 gene. We also observed such phenomenon along with increased expression in patient group in NEK7 gene. Additionally, we also observed significant enrichment of rare variants in candidate genes in the patient cohort, further supporting the complexity/multi-factorial etiology of systemic sclerosis. Our findings identify new candidate genes including PRKXP1 and NEK7 for future studies in SSc. We observed rare variant enrichment in candidate genes previously proposed in association with SSc, which suggest more efforts should be pursued to further investigate possible pathogenetic mechanisms associated with those candidate genes.

Exploring the mechanism of luteolin improving immune and inflammatory responses in systemic sclerosis based on systems biology and cell experiments.

There is a growing trend of applying traditional Chinese medicine (TCM) to treat immune diseases. This study reveals the possible mechanism of luteolin, an active ingredient in the core prescription of TCM, in alleviating systemic sclerosis (SSc) inflammation. Bibliometrics was performed to retrieve the core keywords of SSc inflammation. The key inflammatory indicators in the serum samples of 50 SSc patients were detected by ELISA. Data mining was applied for correlation analysis, association rule analysis, and binary logistic regression analysis on the clinical indicators and medication of 50 SSc patients before and after treatment to determine the core prescription. Network pharmacology was used for identifying candidate genes and pathways; molecular docking was conducted to determine the core monomer components of the prescription, providing a basis for subsequent in vitro molecular mechanism research. The effect of luteolin on SSc-human dermal fibroblasts (HDF) viability and inflammatory factors was evaluated by means of ELISA, RT-PCR, and Western blot. The role of TNF in inflammation was explored by using a TNF overexpression vector, NF-κB inhibitor (PKM2), and SSc-HDF. The involvement of TNF/NF-κB pathway was validated by RT-PCR, Western blot, and immunofluorescence. TCM treatment partially corrected the inflammatory changes in SSc patients, indicating its anti-inflammatory effects in the body. Atractylodes, Yam, Astragalus root, Poria cocos, Pinellia ternata, Salvia miltiorrhiza, Safflower, Cassia twig, and Angelica were identified as the core prescriptions for improving inflammatory indicators. Luteolin was the main active ingredient in the prescription and showed a strong binding energy with TNF and NF-κB. Luteolin exerted anti-inflammatory effects in vitro by reducing inflammatory cytokines in SSc-HDF and inhibiting the activation of TNF/NF-κB. Mechanistically, luteolin inhibited the activation of the TNF/NF-κB pathway in SSc-HDF, as manifested by an increase in extranuclear p-P65 and TNF but a decrease in intranuclear p-P65. Interestingly, the addition of PKM2 augmented the therapeutic function of luteolin against inflammation in SSc-HDF. Our study showed the TCM alleviates the inflammatory response of SSc by inhibiting the activation of the TNF/NF-κB pathway and is an effective therapeutic agent for the treatment of SSc.

Seasonal fluctuation of serum Krebs von den Lungen-6 levels in systemic sclerosis-associated interstitial lung disease.

AIM: To evaluate whether seasonal changes influence fluctuations in serum Krebs von den Lungen-6 (KL-6) levels in systemic sclerosis-related interstitial lung disease (SSc-ILD). METHODS: Summer was defined as the period between July and September, and winter as between December and February. The study was conducted between 2015 and 2016, with a focus on these two seasons. A diagnosis of ILD and ILD progression overtime were evaluated using chest computed tomography. Among patients with SSc-ILD, those with data on serum KL-6 and lactate dehydrogenase (LDH) levels in the 2015 winter, 2015 summer, and 2016 winter seasons were included. Patients with comorbidities that could affect serum KL-6 levels were excluded. RESULTS: Of 60 patients with SSc-ILD, 52 (86.7%) had stable ILD, 5 (8.3%) had worsened ILD, and 3 (5.0%) had improved ILD. Serum KL-6 levels were significantly higher during the winter than those during the summer (2015 winter vs. 2015 summer: 649 U/mL vs. 585 U/mL, p < .0001; 2016 winter vs. 2015 summer: 690 U/mL vs. 585 U/mL, p < .0001). No significant differences were observed between the winters of 2015 and 2016 (649 U/mL vs. 690 U/mL, p = .78). However, serum LDH levels did not exhibit seasonal fluctuations (2015 winter vs. 2015 summer: 203 U/L vs. 199 U/L, p = .3; 2016 winter vs. 2015 summer: 201 U/L vs. 199 U/L, p = .6; 2015 winter vs. 2016 winter: 203 U/L vs. 201 U/L, p = .24). CONCLUSION: Seasonal fluctuations in serum KL-6 levels were observed in patients with SSc-ILD.

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

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

Metabolomics in systemic sclerosis.

Systemic sclerosis is a rare autoimmune condition leading to incurable complications. Therefore fast and precise diagnosis is crucial to prevent patient death and to maintain quality of life. Unfortunately, currently known biomarkers do not meet this need. To address this problem researchers use diverse approaches to elucidate the underlying aberrations. One of the methods applied is metabolomics. This modern technique enables a comprehensive assessment of multiple compound concentrations simultaneously. As it has been gaining popularity, we found it necessary to summarize metabolomic studies presented so far in a narrative review. We found 11 appropriate articles. All of the researchers found significant differences between patients and control groups, whereas the reported findings were highly inconsistent. Additionally, we have found the investigated groups in most studies were scarcely described, and the inclusion/exclusion approach was diverse. Therefore, further study with meticulous patient assessment is necessary.

2023 Brazilian Society of Rheumatology guidelines for the treatment of systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a rare chronic autoimmune disease with heterogeneous manifestations. In the last decade, several clinical trials have been conducted to evaluate new treatment options for SSc. The purpose of this work is to update the recommendations of the Brazilian Society of Rheumatology in light of the new evidence available for the pharmacological management of SSc. METHODS: A systematic review including randomized clinical trials (RCTs) for predefined questions that were elaborated according to the Patient/Population, Intervention, Comparison, and Outcomes (PICO) strategy was conducted. The rating of the available evidence was performed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. To become a recommendation, at least 75% agreement of the voting panel was needed. RESULTS: Six recommendations were elaborated regarding the pharmacological treatment of Raynaud's phenomenon, the treatment (healing) and prevention of digital ulcers, skin involvement, interstitial lung disease (ILD) and gastrointestinal involvement in SSc patients based on results available from RCTs. New drugs, such as rituximab, were included as therapeutic options for skin involvement, and rituximab, tocilizumab and nintedanib were included as therapeutic options for ILD. Recommendations for the pharmacological treatment of scleroderma renal crisis and musculoskeletal involvement were elaborated based on the expert opinion of the voting panel, as no placebo-controlled RCTs were found. CONCLUSION: These guidelines updated and incorporated new treatment options for the management of SSc based on evidence from the literature and expert opinion regarding SSc, providing support for decision-making in clinical practice.

Systemic Sclerosis With a Normotensive Scleroderma Renal Crisis: A Diagnostic Dilemma.

Systemic sclerosis (SSc), also called scleroderma, is an auto-immune rheumatic disease that is characterized by fibrosis of the skin and internal organs and vasculopathy. Three of the severe manifestations of the disease include a scleroderma renal crisis (SRC), pulmonary arterial hypertension, and digital ulceration. Vascular manifestations like Raynaud's phenomenon are an almost universal symptom in patients with SSc and are often the earliest manifestation of the disease. An SRC occurs in approximately 10% of all patients with scleroderma. It is characterized by malignant hypertension and progressive renal failure. However, about 10% of SRC cases present with normal blood pressure or a normotensive renal crisis. A 65-year-old man with a history of peripheral vascular disease and newly diagnosed heart failure presented to the emergency department on account of progressive discoloration of the left big toe and intermittent confusion. Initially, he was noted to be hemodynamically stable, with bluish discoloration of his left lower extremity and left big toe, which was tender to palpation with palpable distal pulses. His left toe progressively became dusky and gangrenous, necessitating ray amputation by vascular surgery. His hospital course was further complicated by worsening acute kidney injury, requiring initiation of hemodialysis, and progressive hypoxia with the transition from room air to high-flow oxygen. As part of his workup for acute kidney injury (AKI), his antinuclear antibody (ANA) was found to be positive, with high titers, as well as elevated SCl-70 IgG. Despite the initiation of hemodialysis, and post-surgical revision, he continued to deteriorate. His family opted for comfort care measures, and he died a few days later. Although SSc is a rare disease, it is associated with significant morbidity and has one of the highest mortality rates among connective tissue diseases. SSc can present with heterogeneous manifestations, mimicking several isolated organ-specific conditions. This makes the diagnosis challenging, especially early in the course of the disease. A high index of suspicion, especially in the setting of rapidly progressing multi-organ involvement without a clear cause, should prompt further evaluation of systemic sclerosis.

Extracellular Vesicles Derived from Adipose Stem Cells Alleviate Systemic Sclerosis by Inhibiting TGF-ß Pathway.

Systemic sclerosis is an autoimmune disease characterized by inflammatory reactions and fibrosis. Myofibroblasts are considered therapeutic targets for preventing and reversing the pathogenesis of fibrosis in systemic sclerosis. Although the mechanisms that differentiate into myofibroblasts are diverse, transforming growth factor ß (TGF-ß) is known to be a key mediator of fibrosis in systemic sclerosis. This study investigated the effects of extracellular vesicles derived from human adipose stem cells (ASC-EVs) in an in vivo systemic sclerosis model and in vitro TGF-ß1-induced dermal fibroblasts. The therapeutic effects of ASC-EVs on the in vivo systemic sclerosis model were evaluated based on dermal thickness and the number of α-smooth muscle actin (α-SMA)-expressing cells using hematoxylin and eosin staining and immunohistochemistry. Administration of ASC-EVs decreased both the dermal thickness and α-SMA expressing cell number as well as the mRNA levels of fibrotic genes, such as Acta2, Ccn2, Col1a1 and Comp. Additionally, we discovered that ASC-EVs can decrease the expression of α-SMA and CTGF and suppress the TGF-ß pathway by inhibiting the activation of SMAD2 in dermal fibroblasts induced by TGF-ß1. Finally, TGF-ß1-induced dermal fibroblasts underwent selective death through ASC-EVs treatment. These results indicate that ASC-EVs could provide a therapeutic approach for preventing and reversing systemic sclerosis.

Evaluation of oral health in 148 patients with systemic sclerosis-data from a prospective interdisciplinary monocentric cohort.

In daily rheumatology practice, systemic sclerosis is primarily regarded as a potentially life-threatening disease characterized by fibrosis of various organs. Therefore, other manifestations, such as orofacial involvement, are often not of primary concern. Furthermore, due to its rarity, the disease might not be well known by dentists, which contrasts with the increased risk of various problems in the oral cavity. Periodontitis in particular is a known risk factor for morbidity and mortality and is associated with various systemic diseases. The risk of periodontitis appears to be increased in patients with systemic sclerosis, but little is known about the gender-specific differences. This study aims to elucidate the health-conscious behaviour of patients, their dental care and the risk of periodontitis with regard to gender-specific differences. This descriptive study of the Interdisciplinary Centre of Rheumatic Diseases (INDIRA) in collaboration with the Department of Orthodontics at the University Hospital of Tuebingen, Germany, examined the data of 148 patients with systemic sclerosis with regard to their oral health using a questionnaire and evaluating the risk of periodontitis with the DG Paro self-assessment score in this cohort. Among the participating patients, 90% reported regular visits to the dentist and good dental care. Nevertheless, more than half of the patients had missing teeth and problems opening their mouths. Sicca symptoms in the oral cavity were also common (40%). The risk of periodontitis among female participants was high (around 60%), and even higher among male study participants (around 80%). Gingival bleeding as a surrogate parameter for periodontitis was associated with salivary flow and the modified Rodnan skin score (mRSS). Despite a high awareness of dental health, we observed a high risk of periodontitis, especially in male patients with systemic sclerosis. In addition, the association between xerostomia and missing teeth as well as gingival bleeding and mRSS may indicate an increased risk in patients with a more progressive disease. We would therefore recommend regular dental consultations and careful oral hygiene for patients with systemic sclerosis in addition to the-more organ-focused-regular examinations of patients.

Topical Application of Nitrate Ameliorates Skin Fibrosis by Regulating ST2+CD4+ T Cells in Systemic Sclerosis Mouse Model.

Systemic sclerosis (SSc) is characterized by intractable multiorgan fibrosis caused by vascular and immune dysfunction. Currently, effective therapeutic options for patients with SSc are limited. Nitrate, an abundant nutrient in the diet, has been demonstrated to be preventative and therapeutic for several diseases. To determine whether nitrate can slow or reverse SSc progression, topical application of nitrate delivered by dissolving microneedles was used to treat a bleomycin (BLM)-induced dermal fibrosis mouse model. In this study, nitrate considerably attenuated dermal thickness, stiffness, and collagen deposition. Bulk RNA sequencing of skin revealed that Cd4 was a key hub gene in SSc nitrate therapy. Additionally, BLM-induced cytokines and chemokines were inhibited by nitrate, and CD4+ T cells infiltration markedly declined. Il4, Il6, Il13, and Tgfb expression in CD4+ T cells isolated from skin biopsies also significantly decreased. Mechanistically, Il1rl1, a type2 immune response inducer, was markedly repressed in isolated CD4+ T cells and dermal tissues after nitrate treatment. Remarkably, compared with wild type mice, mice lacking Il1rl1 showed impaired transcriptional profiles after intradermal BLM injection. Adoptive transfer of ST2+CD4+ T cells promoted bleomycin-induced Rag2-/- mice dermal fibrosis. Collectively, these findings demonstrate that nitrate targeting ST2+CD4+ T cells is an effective therapeutic option for SSc.

Macrophages as determinants and regulators of systemic sclerosis-related interstitial lung disease.

BACKGROUND: Interstitial lung disease (ILD) is the primary cause of mortality in systemic sclerosis (SSc), an autoimmune disease characterized by tissue fibrosis. SSc-related ILD (SSc-ILD) occurs more frequently in females aged 30-55 years, whereas idiopathic pulmonary fibrosis (IPF) is more prevalent in males aged 60-75 years. SSc-ILD occurs earlier than IPF and progresses rapidly. FCN1, FABP4, and SPP1 macrophages are involved in the pathogenesis of lung fibrosis; SPP1 macrophages demonstrate upregulated expression in both SSc-ILD and IPF. To identify the differences between SSc-ILD and IPF using single-cell analysis, clarify their distinct pathogeneses, and propose directions for prevention and treatment. METHODS: We performed single-cell RNA sequencing on NCBI Gene Expression Omnibus (GEO) databases GSE159354 and GSE212109, and analyzed lung tissue samples across healthy controls, IPF, and SSc-ILD. The primary measures were the filtered genes integrated with batch correction and annotated cell types for distinguishing patients with SSc-ILD from healthy controls. We proposed an SSc-ILD pathogenesis using cell-cell interaction inferences, and predicted transcription factors regulating target genes using SCENIC. Drug target prediction of the TF gene was performed using Drug Bank Online. RESULTS: A subset of macrophages activates the MAPK signaling pathway under oxidative stress. Owing to the lack of inhibitory feedback from ANNEXIN and the autoimmune characteristics, this leads to an earlier onset of lung fibrosis compared to IPF. During initial lung injury, fibroblasts begin to activate the IL6 pathway under the influence of SPP1 alveolar macrophages, but IL6 appears unrelated to other inflammatory and immune cells. This may explain why tocilizumab (an anti-IL6-receptor antibody) only preserves lung function in patients with early SSc-ILD. Finally, we identified BCLAF1 and NFE2L2 as influencers of MAPK activation in macrophages. Metformin downregulates NFE2L2 and could serve as a repurposed drug candidate. CONCLUSIONS: SPP1 alveolar macrophages play a role in the profibrotic activity of IPF and SSc-ILD. However, SSc-ILD is influenced by autoimmunity and oxidative stress, leading to the continuous activation of MAPK in macrophages. This may result in an earlier onset of lung fibrosis than in IPF. Such differences could serve as potential research directions for early prevention and treatment.

Low-Carbon Monoxide Diffusing Capacity, Patient-Reported Measures and Reduced Nailfold Capillary Density Are Associated with Interstitial Lung Disease in Systemic Sclerosis.

The aim of this paper is to identify factors associated with interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) and build an algorithm to better define this association for a personalised application in clinical practice. METHODS: A total of 78 SSc patients underwent HRCT to assess ILD. Demographic, clinical and laboratory variables were collected, focusing on those associated either directly or indirectly with lung involvement. The discriminant value of each variable was determined using the operating characteristic curves (ROC) and included in a model to estimate the strength of ILD association in SSc. RESULTS: Thirty-three (42.31%) patients showed ILD on HRCT. DLco, M-Borg, GERD-Q and capillary density were significantly associated with the presence of ILD-SSc. A model including these variables had a coefficient of determination (R2) of 0.697. DLco had an AUC of 0.861 (p < 0.001) with a cut-off of ≤72.3% (sensitivity 78.8%, specificity 91.1%, +LR 8.86). The m-Borg Scale showed an AUC of 0.883 (p < 0.001) with a cut-off >2 (sensitivity 84.8%, specificity 82.2%, +LR 4.77), GERD-Q had an AUC of 0.815 (p < 0.001) with a cut-off >7 (sensitivity 72.7%, specificity 86.7%, +LR 5.45). The capillary density showed an AUC of 0.815 (p < 0.001) with a cut-off of ≤4.78 (sensitivity 87.9%, specificity 68.9%, +LR 2.82). Based on the pre-test probability values, these four variables were applied to Fagan's nomogram to calculate the post-test probability of this association. CONCLUSIONS: Our study identified four associated clinical factors of ILD in SSc patients. Moreover, their inclusion in an algorithm for the post-test probability, tailored to the specific patients' characteristics, significantly increases the ability to find out the presence of SSc-ILD.

Calcinosis Prevalence in Autoimmune Connective Tissue Diseases-A Retrospective Study.

Background/Objectives: Calcinosis cutis is the deposition of insoluble calcium salts, which may cause inflammation, ulceration, pain, and restricted joint mobility. It rarely develops in damaged tissues (dystrophic subtype), most frequently in autoimmune connective tissue diseases (CTDs), but there is very limited data on the prevalence. Also, therapy remains an unsolved issue. In this study, we aimed to collect data on the prevalence of calcinosis in CTD patients to highlight that it is a considerable problem. Methods: A retrospective study was conducted in our department to assess the epidemiology of dystrophic calcinosis in CTDs between January 2003 and January 2024. Results: A total of 839 CTD patients were identified, of whom 56 had calcinosis (6.67%). The mean age of the calcinosis patients at diagnosis of underlying CTD was 41.16 ± 19.47 years. The mean time interval from the onset of calcinosis was 5.96 ± 8.62 years. Systemic sclerosis was the most common CTD complicated by calcinosis (n = 22). Conclusions: Our results are comparable to those reported previously in the literature. Although calcinosis is rare in the overall population, it is a present and unsolved problem in CTD patients. Therefore, further studies are needed on the factors involved in the development and progression of calcinosis as well as its treatment.

Protocol for the development of a tool to map systemic sclerosis pain sources, patterns, and management experiences: a Scleroderma Patient-centered Intervention Network patient-researcher partnership.

INTRODUCTION: Systemic sclerosis (SSc) is a rare, complex autoimmune rheumatic disease with multiple factors that contribute to pain. People with SSc emphasize the effect pain has on their quality of life, but no studies have systematically examined the frequency and relative importance of different SSc pain sources, patterns of pain from different sources, and pain management experiences. Our objectives are to (1) develop a tool, jointly with researchers, health care providers, and patients, to map sources of pain in SSc, determine patterns of pain from different sources, and understand pain management experiences; and (2) administer the final tool version to participants in the large multinational Scleroderma Patient-centered Intervention Network (SPIN) Cohort. METHODS: First, we will use validated pain assessment tools as templates to develop an initial version of our pain assessment tool, and we will obtain input from patient advisors to adapt it for SSc. The tool will include questions on pain sources, pain patterns, pain intensity, pain management techniques, and barriers to pain management in SSc. Second, we will conduct nominal group technique sessions with people living with SSc and health care providers who care for people with SSc to further refine the tool. Third, we will conduct individual usability testing sessions with SPIN Cohort participants. Once the tool has been finalized, we will administer it to individuals in the multinational SPIN Cohort, which currently includes over 1,300 active participants from 54 sites in 7 countries. We will perform unsupervised clustering using the KAy-Means for MIxed LArge data (KAMILA) method to identify participant subgroups with similar profiles of pain sources (present or absent) and to evaluate predictors of subgroup membership. We will use latent profile analysis to identify subgroups of participants with similar profiles based on pain intensity scores for each pain source and evaluate predictors. DISCUSSION: Once completed, our pain assessment tool will allow our team and other researchers to map sources of pain in SSc and to understand pain management experiences of people living with SSc. This knowledge will provide avenues for studies on the pathophysiology of pain in SSc and studies of interventions to improve pain management.