[Update on systemic sclerosis]. / Update zur systemischen Sklerose.

BACKGROUND: The updates to the European recommendations and the German guidelines for the treatment of systemic sclerosis are expected shortly, which are very good evidence-based guidelines for all those treating the disease; however, there are still disease manifestations with insufficient studies and current study results that were published after the review of the literature for the guidelines and might be of interest to the reader. OBJECTIVE AND METHODS: The aim of this work is to provide an overview of the publications in the last year that are interesting from the authors' point of view. The aim is to provide practically relevant information on the current state of knowledge that can supplement the guidelines. RESULTS: The pathogenesis of systemic sclerosis (SSc) is becoming better understood in its interplay between environmental factors and the development of autoantibodies. There have also been overviews of the manifestation and prognosis of cardiac involvement in the last year. The American Thoracic Society issued the first guidelines for the treatment of interstitial lung disease in SSc. There are an increasing number of studies that suggest that disease-modulating combination therapies, such as rituximab and mycophenolate mofetil (MMF) are beneficial. Work addressing the involvement of joints suggests that inflammatory changes are common. Current options for the treatment of gastrointestinal involvement are presented. CONCLUSION: The diagnosis and treatment of systemic sclerosis is making progress and many symptoms and complications are treatable. Nevertheless, much remains to be done to improve the quality of life of the patients.

Investigating the trajectory of functional disability in systemic sclerosis: group-based trajectory modelling of the Health Assessment Questionnaire-Disability Index.

OBJECTIVES: To identify the trajectories and clinical associations of functional disability in systemic sclerosis (SSc). METHODS: Australian Scleroderma Cohort Study (ASCS) participants meeting ACR/EULAR criteria for SSc recruited within 5 years of disease onset, with ≥2 Health Assessment Questionnaire-Disability Index (HAQ-DI) scores were included. Group based trajectory modelling (GBTM) was used to identify the number and shape of HAQ-DI trajectories. Between group comparisons were made using the chi-squared test, two-sample t-test or Wilcoxon rank-sum test as appropriate. Multiple logistic regression was used to identify features associated with trajectory group membership. Survival analyses were performed using Kaplan Meier and Cox proportional hazard modelling. RESULTS: We identified two HAQ-DI trajectory groups within 426 ASCS participants with incident SSc: low-stable disability (n=221, 52%), and high-increasing disability (n=205, 48%). Participants with high-increasing disability were older at disease onset, more likely to have diffuse SSc (dcSSc), cardiopulmonary disease, multimorbidity, digital ulcers, and gastrointestinal involvement (all p≤0.01), as was use of immunosuppression (p<0.01). Multimorbidity was associated with high-increasing trajectory group membership (OR3.1, 95%CI1.1-8.8, p=0.04); independently, multiple SSc features were also strongly associated including dcSSc (OR2.3, 95%CI1.3-4.2, p<0.01), proximal weakness (OR7.3, 95%CI2.0-27.1, p<0.01) and joint contractures (OR2.7, 95%CI1.3-5.3, p<0.01). High-increasing physical disability was associated with an almost two-fold increased risk of mortality (HR1.9, 95%CI1.0-3.8, p=0.05), and higher symptom burden. CONCLUSIONS: Two trajectories of functional disability in SSc were identified. Those with high-increasing functional disability had a distinct clinical phenotype and worse survival compared to those with low-stable functional disability. These data highlight the pervasive nature of physical disability in SSc, and its prognostic importance.

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

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

The burden and determinants of fatigue in incident and prevalent systemic sclerosis.

OBJECTIVES: To investigate the burden and clinical associations of fatigue in systemic sclerosis (SSc) as measured by FACIT-Fatigue scores. METHODS: Australian Scleroderma Cohort Study participants with ≥1 FACIT-Fatigue score were included. Participants were divided into those with incident SSc (≤5 years SSc duration at recruitment and FACIT-Fatigue score recorded within 5 years of disease onset) or prevalent SSc (first FACIT-Fatigue score recorded >5 years after SSc onset). Generalised estimating equations were used to model change in FACIT-Fatigue scores over time, expressed as an increasing (improving) or decreasing (worsening) score. RESULTS: Of 859 participants, 215 had incident SSc and 644 prevalent SSc. First-recorded FACIT-Fatigue scores were similar in those with incident (37 units, IQR 25-45.5) and prevalent SSc (36 units, IQR 23-44; p=0.17), as were lowest-ever recorded FACIT-Fatigue scores (incident 23 units; prevalent 22 units, p=0.75). In incident SSc, higher skin scores (regression coefficient (RC) -1.5 units, 95%CI -2.3 to -0.8), PAH (RC -8.2, 95%CI -16.5 to 0.1) and reduced left ventricular function (RC -10.6, 95%CI -18.3 to -2.8) were associated with more severe fatigue. In prevalent SSc, higher skin scores (RC -0.6, 95%CI -1.3 to 0), gastrointestinal symptoms (RC -6.6, 95%CI -9.0 to -4.2), hypoalbuminaemia (RC -2.8, 95%CI -5.0 to -0.7), BMI<18.5kg/m2 (RC -6.3, 95%CI -10.3 to -2.2), raised CRP (RC -3.1, 95%CI -4.7 to -1.5), and anaemia (RC -1.7, 95%CI -3.5 to 0.1) were associated with more severe fatigue. CONCLUSIONS: The burden of fatigue is substantial in both incident and prevalent SSc. Cardiopulmonary and gastrointestinal involvement are associated with worse fatigue.

PSGL-1, ADAM8, and selectins as potential biomarkers in the diagnostic process of systemic lupus erythematosus and systemic sclerosis: an observational study.

Background: Early diagnosis and treatment of Systemic lupus erythematosus (SLE) and Systemic sclerosis (SSc) present significant challenges for clinicians. Although various studies have observed changes in serum levels of selectins between healthy donors and patients with autoimmune diseases, including SLE and SSc, their potential as biomarkers has not been thoroughly explored. We aimed to investigate serum profiles of PSGL-1 (sPSGL-1), ADAM8 (sADAM8) and P-, E- and L-selectins (sP-, sE- and sL-selectins) in defined SLE and SSc patient cohorts to identify disease-associated molecular patterns. Methods: We collected blood samples from 64 SLE patients, 58 SSc patients, and 81 healthy donors (HD). Levels of sPSGL-1, sADAM8 and selectins were analyzed by ELISA and leukocyte membrane expression of L-selectin and ADAM8 by flow cytometry. Results: Compared to HD, SLE and SSc patients exhibited elevated sE-selectin and reduced sL-selectin levels. Additionally, SLE patients exhibited elevated sPSGL-1 and sADAM8 levels. Compared to SSc, SLE patients had decreased sL-selectin and increased sADAM8 levels. Furthermore, L-selectin membrane expression was lower in SLE and SSc leukocytes than in HD leukocytes, and ADAM8 membrane expression was lower in SLE neutrophils compared to SSc neutrophils. These alterations associated with some clinical characteristics of each disease. Using logistic regression analysis, the sL-selectin/sADAM8 ratio in SLE, and a combination of sL-selectin/sE-selectin and sE-selectin/sPSGL-1 ratios in SSc were identified and cross-validated as potential serum markers to discriminate these patients from HD. Compared to available diagnostic biomarkers for each disease, both sL-selectin/sADAM8 ratio for SLE and combined ratios for SSc provided higher sensitivity (98% SLE and and 67% SSc correctly classified patients). Importantly, the sADAM8/% ADAM8(+) neutrophils ratio discriminated between SSc and SLE patients with the same sensitivity and specificity than current disease-specific biomarkers. Conclusion: SLE and SSc present specific profiles of sPSGL-1, sE-, sL-selectins, sADAM8 and neutrophil membrane expression which are potentially relevant to their pathogenesis and might aid in their early diagnosis.

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.

Systemic sclerosis: one year in review 2024.

Systemic sclerosis (SSc) is a rare and chronic connective tissue disease of unknown aetiology and characterised by three main pathogenetic events represented by endothelial damage, inflammation with activation of the immune system leading to production of specific autoantibodies and finally fibrosis. SSc is a heterogeneous disease and the classification in two subsets, the limited cutaneous (lcSSc) subset and the diffuse cutaneous one (dcSSc), is not capable of capturing the broad and different phenotypic expression of the disease. In the last years progress has been made in the knowledge of SSc pathogenesis, in its early diagnosis and new therapeutic strategies have been proposed, however, the management of SSc still represents a challenge for the clinician. For this reason, every year several studies investigate new insights of disease pathogenesis, internal organ involvement and therapeutic approaches. The purpose of this review is to provide an overview of the literature published in 2023.

2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Screening and Monitoring of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease. METHODS: We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation. RESULTS: Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs. CONCLUSION: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.

Acute Kidney Injury in Systemic Sclerosis Beyond Scleroderma Renal Crisis: A Case-Control Study.

BACKGROUND AND OBJECTIVES: Renal involvement in systemic sclerosis remains a significant concern with the focus often centered on scleroderma renal crisis (SRC). However, the broader spectrum of renal manifestations, beyond SRC, remains underrecognized. In our case-control analysis, we describe other causes, risk factors, and renal outcomes of acute kidney injury (AKI) in systemic sclerosis other than SRC. METHODS: Patients diagnosed with SSC, with and without AKI, between 2017 and 2023 at Albany Medical Center, were included in the case-control study using International Classification of Diseases , 10th Revision codes and electronic medical records. Patients with SRC were carefully excluded. Data were collected and compared between AKI and non-AKI groups for patients' demographics, clinical characteristics, and baseline treatment. Additionally, data were collected for baseline, peak, and follow-up creatinine, etiology of AKI, treatment, and outcomes. Statistical analysis was performed using R (version 4.3.0) and Minitab (V19). Categorical variables were presented as frequencies/percentages, and continuous variables as means/standard deviations. Associations between categorical variables were assessed by χ 2 test and Fisher exact test. Odds ratios and 95% confidence intervals were calculated using binary logistic regression to separately assess the effect of each independent variable on the odds of AKI. Statistical significance was set at p < 0.05. RESULTS: A total of 74 cases were identified. Out of these 74 cases, 27 had AKI and 47 did not have AKI. Out of the 27 AKI cases, 4 with SRC were excluded. Advanced age, chronic kidney disease, and heart failure were identified as risk factors for AKI development. The predominant cause of AKI was prerenal etiology, accounting for 47.8% (n = 11) of cases. This was followed by cardiorenal syndrome and acute tubular necrosis, accounting for 21.7% and 17.3% of the cases, respectively. Most of the cases with AKI had complete renal recovery 78% (n = 18), whereas 17% (n = 4) had progression of the underlying chronic kidney disease. One patient progressed to end-stage renal disease requiring hemodialysis. CONCLUSIONS: This analysis highlights the risk factors and variable clinicopathological courses of renal involvement in patients with scleroderma. This may range from mild AKI with good prognosis to life-threatening SRC.

Evaluation of Monocyte Subpopulations in Patients with Systemic Sclerosis and its Association with Clinical Manifestations of the Disease: a Cross-sectional Controlled Study.

Background: Systemic sclerosis (SSc) is a chronic autoimmune disorder characterized not only by fibrosis and vasculopathy but also by inflammation. Previous studies have demonstrated monocyte involvement in SSc development, suggesting a role for immune dysfunction in SSc pathogenesis. Objective: To investigate the relationship between SSc's clinical manifestations and altered levels of monocyte subpopulations. Methods: Twenty-six patients meeting the ACR/EULAR SSc criteria along with twenty healthy individuals as the control group, were enrolled in the study. Peripheral blood mononuclear cells (PBMCs) were obtained from heparinized blood samples of both the SSc patients and the control group. Subpopulations of monocytes were assessed based on HLA-DR, CD14, and CD16 expression using multi-color flow cytometry. The one-way ANOVA, Student's t-test, and Mann-Whitney U test were employed for normally and non-normally distributed data. The Spearman correlation test was utilized to identify correlations between the variables. Results: The SSc patients showed a significant increase in the number of circulating peripheral blood monocytes (p<0.001). The percentage of CD16+ monocyte subpopulations was higher in the SSc cases compared to the control group. A significant decrease in the ratio of classic to non-classic monocytes was observed in SSc cases (7.43%) compared to the control group (52.09%, p<0.001). No association was observed between monocyte subpopulations and clinical characteristics of SSC. Conclusion: Our results showed an increase in the level of CD16+ monocytes in patients with SSc compared to healthy individuals. Further investigation is required to determine the clinical significance of this alteration.

Assessing the quality of forced vital capacity measurement in patients with systemic sclerosis.

INTRODUCTION: Forced vital capacity (FVC) is an important tool for monitoring lung functions in patients with systemic sclerosis (SSc). However, several disease manifestations may influence the quality of FVC test in SSc. We aimed to assess the quality of FVC measurements according to current guidelines in patients with SSc and determine the factors that may affect results. METHOD: In this cross-sectional study, SSc patients and age/sex matched controls underwent spirometry. Quality of FVC measurements were graded according to updated American Thoracic Society (ATS) and European Respiratory Society (ERS) guidelines. Demographics, clinical features and parameters that may affect FVC test quality were compared between SSc patients with high and low quality FVC test. RESULTS: 98 SSc patients (90 female) and 100 controls were included. The rate of high quality FVC measurement in SSc patients was significantly lower in SSc patients compared to controls. (80 % vs 60.2 % p = 0.002). Among SSc patients; diffuse disease, ILD, anti-topoisomerase 1 antibody positivity, immunosuppressive use, flexion contractures of hands, reduced mouth opening and decreased chest expansion were more frequent in patients with low quality FVC (p < 0.05 for all). Patients with muscle weakness and medium/high risk of malnutrition were also numerically higher in low quality FVC group. Presence of more than one condition that may affect FVC quality was significantly higher among patients with low quality FVC. CONCLUSION: A significant percent of SSc patients had low quality FVC measurement. Physicians should be aware of this point while interpreting FVC test results especially in SSc patients with more than one condition that may affect the quality of the test.

[An artificial neural network diagnostic model for scleroderma and immune cell infiltration analysis based on mitochondria-associated genes].

OBJECTIVE: To establish a diagnostic model for scleroderma by combining machine learning and artificial neural network based on mitochondria-related genes. METHODS: The GSE95065 and GSE59785 datasets of scleroderma from GEO database were used for analyzing expressions of mitochondria-related genes, and the differential genes were identified by Random forest, LASSO regression and SVM algorithms. Based on these differential genes, an artificial neural network model was constructed, and its diagnostic accuracy was evaluated by 10-fold crossover verification and ROC curve analysis using the verification dataset GSE76807. The mRNA expressions of the key genes were verified by RT-qPCR in a mouse model of scleroderma. The CIBERSORT algorithm was used to estimate the bioinformatic association between scleroderma and the screened biomarkers. RESULTS: A total of 24 differential genes were obtained, including 11 up-regulated and 13 down-regulated genes. Seven most relevant mitochondria-related genes (POLB, GSR, KRAS, NT5DC2, NOX4, IGF1, and TGM2) were screened using 3 machine learning algorithms, and the artificial neural network diagnostic model was constructed. The model showed an area under the ROC curves of 0.984 for scleroderma diagnosis (0.740 for the verification dataset and 0.980 for cross-over validation). RT-qPCR detected significant up-regulation of POLB, GSR, KRAS, NOX4, IGF1 and TGM2 mRNAs and significant down-regulation of NT5DC2 in the mouse models of scleroderma. Immune cell infiltration analysis showed that the differential genes in scleroderma were associated with follicular helper T cells, immature B cells, resting dendritic cells, memory activated CD4+T cells, M0 macrophages, monocytes, resting memory CD4+T cells and mast cell activation. CONCLUSION: The artificial neural network diagnostic model for scleroderma established in this study provides a new perspective for exploring the pathogenesis of scleroderma.

Imaging of Pulmonary Manifestations of Connective Tissue Disease.

The majority of connective tissue diseases (CTDs) are multisystem disorders that are often heterogeneous in their presentation and do not have a single laboratory, histologic, or radiologic feature that is defined as the gold standard to support a specific diagnosis. Given this challenging situation, the diagnosis of CTD is a process that requires the synthesis of multidisciplinary data which may include patient clinical symptoms, serologic evaluation, laboratory testing, and imaging. Pulmonary manifestations of connective tissue disease include interstitial lung disease as well as multicompartmental manifestations. These CT imaging patterns and features of specific diseases will be discussed in this article.

Identification and management of interstitial lung disease associated with systemic sclerosis (SSc-ILD), rheumatoid arthritis (RA-ILD), and polymyositis/dermatomyositis (PM/DM-ILD): development of expert consensus-based clinical algorithms.

BACKGROUND: Clinical guidance on the identification and management of connective tissue disease-associated interstitial lung disease (CTD-ILD) is needed for optimal clinical practice. We aimed to develop clinical algorithms for identifying and managing three common CTD-ILDs: those associated with systemic sclerosis (SSc-ILD), rheumatoid arthritis (RA-ILD), and polymyositis/dermatomyositis (PM/DM-ILD). RESEARCH DESIGN AND METHODS: Meetings were held October-November 2023 to create consensus-based algorithms for identifying and managing SSc-ILD, RA-ILD, and PM/DM-ILD in clinical practice, based on expert consensus statements for identification and management of CTD-ILD previously derived from a Delphi process. RESULTS: We developed clinical algorithms for SSc-ILD, RA-ILD, and PM/DM-ILD that highlight both commonalities and differences in the identification and management of these CTD-ILDs. Importantly, ILD should be suspected in patients with SSc, RA, or PM/DM who have respiratory symptoms. Chest high-resolution computed tomography has utility for screening, diagnosis and assessment of severity. Furthermore, regular follow-up and multidisciplinary management are important. Disease-specific considerations include unique risk factors such as anti-topoisomerase I antibodies in SSc-ILD, high-titer cyclic citrullinated peptide antibodies in RA, anti-aminoacyl tRNA synthetase antibodies in PM/DM, and anti-melanoma differentiation-associated gene 5 antibody in DM. CONCLUSIONS: These algorithms may help physicians to identify and manage patients with SSc-ILD, RA-ILD, or PM/DM-ILD.

Dysregulation of circulating collagen turnover markers in very early systemic sclerosis.

OBJECTIVE: Clinical observation suggests that vascular activation and autoimmunity precede remodelling of the extracellular matrix (ECM) in systemic sclerosis (SSc). We challenge this paradigm by hypothesising that ECM biomarkers are already disturbed in patients with very early SSc (veSSc) when fibrosis is not yet clinically detectable. METHODS: 42 patients with veSSc, defined as the presence of Raynaud's phenomenon and at least one of puffy fingers, positive antinuclear antibodies or pathological nailfold capillaroscopy, not meeting the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for SSc, were compared with healthy controls (HCs, n=29). ECM degradation (BGM, C3M, C4M and C6M) and ECM formation biomarkers (PRO-C3, PRO-C4 and PRO-C5) were measured in serum using ELISAs. A cross-sectional analysis at baseline and a longitudinal analysis was performed. RESULTS: Compared with HC, veSSc patients showed a strongly dysregulated turnover of type III and IV collagens (higher C3M, C4M, both p<0.0001 and PRO-C3, p=0.004, lower turnover ratios PRO-C3/C3M and PRO-C4/C4M, both p<0.0001). The biglycan degradation biomarker BGM was higher in veSSc than in HC (p=0.006), whereas the degradation biomarker for type VI collagen, C6M, was lower (p=0.002). In an ROC analysis, biomarkers of type III and IV collagen excellently distinguished between veSSc and HC: C3M, AUC=0.95, p<0.0001; C4M, AUC=0.97, p<0.0001; turnover ratios PRO-C3/C3M, AUC=0.80, p<0.0001; PRO-C4/C4M, AUC=0.97; p<0.0001. CONCLUSION: These findings indicate ECM remodelling as a very early phenomenon of SSc occurring in parallel with microvascular and autoimmune changes. Biomarkers of type III and IV collagens distinguished between veSSc patients and HC, indicating them as potential biomarkers for the detection of veSSc.