Early Diagnosis Of Systemic Sclerosis Research Articles

Development and validation of a new diagnostic prediction model of ENHO and NOX4 for early diagnosis of systemic sclerosis.

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis. The challenge of early diagnosis, along with the lack of effective treatments for fibrosis, contribute to poor therapeutic outcomes and high mortality of SSc. Therefore, there is an urgent need to identify suitable biomarkers for early diagnosis of SSc. Three skin gene expression datasets of SSc patients and healthy controls were downloaded from Gene Expression Omnibus (GEO) database (GSE130955, GSE58095, and GSE181549). GSE130955 (48 early diffuse cutaneous SSc and 33 controls) were utilized to screen differentially expressed genes (DEGs) between SSc and normal skin samples. Least absolute shrinkage and selection operator (LASSO) regression and support vector machine recursive feature elimination (SVM-RFE) were performed to identify diagnostic genes and construct a diagnostic prediction model. The results were further validated in GSE58095 (61 SSc and 36 controls) and GSE181549 (113 SSc and 44 controls) datasets. Receiver operating characteristic (ROC) curves were applied for assessing the level of diagnostic ability. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to verify the diagnostic genes in skin tissues of out cohort (10 SSc and 5 controls). Immune infiltration analysis were performed using CIBERSORT algorithm. A total of 200 DEGs were identified between SSc and normal skin samples. Functional enrichment analysis revealed that these DEGs may be involved in the pathogenesis of SSc, such as extracellular matrix remodeling, cell-cell interactions, and metabolism. Subsequently, two critical genes (ENHO and NOX4) were identified by LASSO and SVM-RFE. ENHO was found down-regulated while NOX4 was up-regulated in skin of SSc patients and their expression levels were validated by above three datasets and our cohort. Notably, these differential expressions were more pronounced in patients with diffuse cutaneous SSc than in those with limited cutaneous SSc. Next, we developed a novel diagnostic model for SSc using ENHO and NOX4, which demonstrated strong predictive power in above three cohorts and in our own cohort. Furthermore, immune infiltration analysis revealed dysregulated levels of various immune cell subtypes within early SSc skin specimens, and a negative correlation was observed between the levels of ENHO and Macrophages M1 and M2, while a positive correlation was observed between the levels of NOX4 and Macrophages M1 and M2. This study identified ENHO and NOX4 as novel biomarkers that can be serve as a diagnostic prediction model for early detection of SSc and play a potential role in the pathogenesis of the disease.

Periostin expression in uninvolved skin as a potential biomarker for rapid cutaneous progression in systemic sclerosis patients: a preliminary explorative study.

This study aimed to evaluate periostin serum levels and skin expression in patients with systemic sclerosis (SSc). We enrolled 35 patients with diffuse (d-SSc) or limited (l-SSc) SSc, 15 patients with very early diagnosis of systemic sclerosis (VEDOSS), and 30 sex-matched healthy controls. Periostin serum levels were determined by an enzyme-linked immunosorbent assay (ELISA). Periostin skin expression was determined by immunohistochemistry (IHC) on paired involved and uninvolved 5-mm skin biopsy samples in a subgroup of 10 d-SSc and 10 L-SSc patients. A 12-month follow-up was considered. We included 50 patients (mean age 53.1 ± 16.1 years; women 94%; mean disease duration 38.2 ± 45.1 months; anti-centromere 50%; anti-Scl70 40%), 35 of them with a definite SSc (68.8% l-SSc; 31.4% d-SSc; mean mRSS 9.0 ± 7.2) and 15 with VEDOSS; 30 controls were also included in this study. Periostin serum levels were higher in SSc patients compared to controls (32.7 ± 8.0 ng/mL vs. 27.7 ± 7.3 ng/mL; p < 0.001), while these levels were comparable among different groups of patients (29.7 ± 6.9 ng/mL in VEDOSS, 33.4 ± 7.8 ng/mL in lc-SSc; and 34.0 ± 8.5 in dc-SSc; p = ns). SSc patients with digital ulcers had higher periostin serum levels (36.2 ± 7.9 ng/mL vs. 30.6 ± 7.3 ng/mL, p < 0.02). Samples from the involved skin of l-SSc and d-SSc patients showed a significant dermal expression of periostin; an identical periostin expression was evident in the uninvolved skin of patients with d-SSc. In 7 out of 10 L-SSc patients, periostin expression was absent on uninvolved skin. In the remaining three l-SSc patients, a mild periostin expression on IHC was detectable on uninvolved skin and all of these three l-SSc patients presented a dramatic skin progression. Periostin skin expression may be a useful biomarker to indicate the presence of a disease at a higher risk of rapid cutaneous involvement.

Evaluation of pulmonary artery stiffness in patients with systemic sclerosis

Objective: The study aims to investigate the use of pulmonary artery stiffness (PAS) parameter in early diagnosis of systemic sclerosis&#x0D; (SSc) and pulmonary hypertension in SSc patients.&#x0D; Patients and Methods: The study involved 102 SSc patients and 45 control group patients, who underwent transthoracic&#x0D; echocardiographic evaluations.&#x0D; Results: Pulmonary artery stiffness was measured as 25.7±7.6 (Hz/msn) in the SSc cases and 13.7 ±1.6 (Hz/msn) in the healthy&#x0D; subjects (P&lt; 0.001). TAPSE/sPAP ratio, which we used as an indicator of RV-PA coupling, was calculated as 0.65+0.28 in SSc cases and&#x0D; 1.12+0.33 in the control group (P

Capillaroscopic examination in the early diagnosis of systemic sclerosis

Capillaroscopic examination in the early diagnosis of systemic sclerosis

Vision transformer assisting rheumatologists in screening for capillaroscopy changes in systemic sclerosis: an artificial intelligence model.

The first objective of this study was to implement and assess the performance and reliability of a vision transformer (ViT)-based deep-learning model, an 'off-the-shelf' artificial intelligence solution, for identifying distinct signs of microangiopathy in nailfold capilloroscopy (NFC) images of patients with SSc. The second objective was to compare the ViT's analysis performance with that of practising rheumatologists. NFC images of patients prospectively enrolled in our European Scleroderma Trials and Research group (EUSTAR) and Very Early Diagnosis of Systemic Sclerosis (VEDOSS) local registries were used. The primary outcome investigated was the ViT's classification performance for identifying disease-associated changes (enlarged capillaries, giant capillaries, capillary loss, microhaemorrhages) and the presence of the scleroderma pattern in these images using a cross-fold validation setting. The secondary outcome involved a comparison of the ViT's performance vs that of rheumatologists on a reliability set, consisting of a subset of 464 NFC images with majority vote-derived ground-truth labels. We analysed 17 126 NFC images derived from 234 EUSTAR and 55 VEDOSS patients. The ViT had good performance in identifying the various microangiopathic changes in capillaries by NFC [area under the curve (AUC) from 81.8% to 84.5%]. In the reliability set, the rheumatologists reached a higher average accuracy, as well as a better trade-off between sensitivity and specificity compared with the ViT. However, the annotators' performance was variable, and one out of four rheumatologists showed equal or lower classification measures compared with the ViT. The ViT is a modern, well-performing and readily available tool for assessing patterns of microangiopathy on NFC images, and it may assist rheumatologists in generating consistent and high-quality NFC reports; however, the final diagnosis of a scleroderma pattern in any individual case needs the judgement of an experienced observer.

Insights into molecular and clinical characteristics of very early systemic sclerosis.

The early heterogenous presentation of systemic sclerosis (SSc), in particular without skin involvement, has been a confounding factor delaying early diagnosis. In fact, early signs of SSc as Raynaud's phenomenon and puffy fingers, are also typical of other connective tissue diseases (CTDs) such as mixed CTD and undifferentiated CTD. In the last decade, a significant effort has been dedicated in defining molecular characteristics that could be used as early SSc biomarkers. In this narrative review, we address the present situation where several clinical scenarios are in search of a correct positioning into the prescleroderma (pre-SSc) phase as well as in the very early phase of SSc. Literature data showed that a part of patients classified as sine scleroderma SSc (ssSSc), mixed CTD and undifferentiated CTD may already belong to the very early phase of SSc, thus having a different pattern of progression to SSc. Recently, the very early diagnosis of systemic sclerosis (VEDOSS) criteria has been validated. while the area of pre-SSc still remains fuzzy, the VEDOSS study has shown that a 'window of opportunity' does exist also for SSc. In the very next future, this may allow to start the treatment to prevent the disease progression to a more advanced fibrotic stage.

Practical management of Raynaud's phenomenon - a primer for practicing physicians.

Raynaud's phenomenon (RP) is a common vasospastic condition that results in digital hypoperfusion in response to cold and/or emotional stress and is associated with significant pain and disability. The aim of our review is to provide a practical approach for clinicians to inform assessment and management of patients with RP. Autoantibodies and nailfold capillaroscopy are key investigations to stratify the risk of progression to systemic sclerosis (SSc) in patients RP, which was recently confirmed in the multicenter, very early diagnosis of systemic sclerosis (VEDOSS) project. Research has explored the complex lived-patient experience of RP including digital vasculopathy in SSc and has highlighted the need for outcome measure development to facilitate research in the field. Pharmacological treatment strategies vary significantly internationally and there is continued interest in developing surgical approaches. We provide a practical and up-to-date approach to inform the assessment and management of patients with RP including guidance on drug initiation and escalation. Calcium channel blockers are first-line treatment and can be initiated by primary care physicians. We also highlight second-line drug therapies used for refractory RP and the potential role for surgical intervention.

Diffuse myocardial fibrosis precedes subclinical functional myocardial impairment and provides prognostic information in systemic sclerosis.

Myocardial involvement is common in patients with systemic sclerosis (SSc) and causes myocardial fibrosis and subtle ventricular dysfunction. However, the temporal onset of myocardial involvement during the progression of the disease and its prognostic value are yet unknown. We used cardiovascular magnetic resonance (CMR) to investigate subclinical functional impairment and diffuse myocardial fibrosis in patients with very early diagnosis of SSc (VEDOSS) and established SSc and examined whether this was associated with mortality. One hundred and ten SSc patients (86 established SSc, 24 VEDOSS) and 15 healthy controls were prospectively recruited. The patients were followed-up for a median duration of 7.0 years (interquartile range 6.0-7.3 years). Study subjects underwent CMR including assessment of myocardial fibrosis [native T1 and extracellular volume (ECV)] and measurement of global longitudinal (GLS) and circumferential (GCS) myocardial strain. Native T1 values and ECV were elevated in VEDOSS and SSc patients compared with controls (P < 0.001). GLS was similar in VEDOSS and controls but significantly impaired in patients with established SSc (P < 0.001). GCS was similar over all groups (P = 0.88). There were 12 deaths during follow-up. Elevated native T1 [hazard ratio (HR) 5.8, 95% confidence interval (CI): 1.7-20.4; P = 0.006] and reduced GLS (HR 6.1, 95% CI: 1.3-29.9; P = 0.038) identified subjects with increased risk of death. Only native T1 was predictive for cardiovascular mortality (P < 0.001). Subclinical myocardial involvement first manifests as diffuse myocardial fibrosis identified by the expansion of ECV and increased native T1 in VEDOSS patients while subtle functional impairment only occurs in established SSc. Native T1 and GLS have prognostic value for all-cause mortality in SSc patients.

P117 Nailfold capillaroscopy: a survey of current UK practice and ‘next steps’ to facilitate generalised uptake

Background/AimsNailfold capillaroscopy has a key role in the assessment of patients with Raynaud’s phenomenon (RP) providing a window of opportunity for the early diagnosis of systemic sclerosis (SSc). Anecdotal evidence indicates that this opportunity is not being fully realised across UK rheumatology centres. Reasons for apparent discrepancies in use of capillaroscopy may relate to a lack of expertise, confidence or equipment. Exploratory work has demonstrated the potential for an internet-based standardised system for clinical reporting of nailfold capillaroscopy images to mitigate current inequities in care provision. The overall aim of this study was to understand current practices in the diagnosis of SSc in UK rheumatology centres with specific reference to identifying barriers to the use of nailfold capillaroscopy. A secondary aim was to understand rheumatologists’ views on a standardised system to facilitate the timely diagnosis of SSc.MethodsAn online survey comprising closed and free-text questions was developed using expert (n = 7) opinion from clinicians, scientists and health service researchers. The survey was piloted (n = 5) and sent to UK-based rheumatologists using established electronic mailing lists between 2nd October 2020 and 8th March 2021. Respondents were asked to describe workloads and practices typically seen before the COVID-19 pandemic. Data were analysed using descriptive statistics and thematic analysis.ResultsSurvey responses were received from 104 rheumatologists representing centres across the UK. Wide variation in terms of workloads and practices were described (See Table 1). Only 41% (n = 43) of respondents reported using nailfold capillaroscopy provided at their centres. Key barriers were access to equipment and a lack of expertise in terms of acquiring and analysing images. Respondents indicated that a centralised internet-based system for storing images and sharing diagnoses would provide access to expertise and the possibility of timely diagnoses. P117 Table 1:Use of nailfold capillaroscopy (NFC) across UK centresNumber (n = 104)%Do you use nailfold capillaroscopy at your site?No6159Yes4341Total104100In what context are nailfold capillaroscopy images taken?At the general clinic appointment2251At a separate hospital appointment1637Other12Either general clinic or separate hospital appointment25Missing/unclear25Is there a dedicated room where imaging is done?No2354Yes1842Unclear/missing25What type of equipment do you use for NFC?Video microscope921Stereomicroscope12USB microscope1228Dermatoscope1330Ophthalmoscope12Stereomicroscope & dermatoscope12Don't know614Who usually does NFC imaging in your centre?I do it myself2047Another consultant or SpR921Nurse/AHP37Technician/medical physics614Medical photography49Clinical scientist12Who usually interprets the NFC imaging in your centre?I do it myself2558Another consultant or SpR819Nurse/AHP25Technician/medical physics512other12Clinical scientist12Technician & consultant/SpR12From how many RP patients do you obtain NFC images?0381 to 5386 to 1092311 to 2061521 to 30410more than 30923Not sure513How many of those patients imaged were diagnosed with SSc?04101 to 516416 to 1082111 to 203821 to 3025more than 3025Not sure410How are results of NFC reported to the patients?Face-to-face at imaging session1126Face-to-face at clinic appointment1433Letter / as part of treatment plan1330No specific nailfold capillaroscopy reporting25Other25Letter / face-to-face12Do you (also) refer patients to other centres for NFC?No6260Yes4240How many patients per year do you refer to other centres?1 to 526636 to 10112711 to 201221 to 3025more than 3012*participants asked to base answers on the situation in 2019 before the COVID-19 pandemicConclusionSubstantial variation in approaches to the diagnosis of SSc across the UK was identified. Potential benefits of a standardised system were described by respondents including the improved diagnosis and management of SSc, realising potential patient benefits and reducing current health inequalities. Survey findings provide evidence to help develop future studies to develop and evaluate the proposed new system.Disclosure M. Eden: None. S. Wilkinson: None. A. Murray: None. P. Gurunath Bharathi: None. C. Taylor: None. K. Payne: None. A.L. Herrick: None.

Forearm porphyrin levels evaluated by digital imaging system are increased in patients with systemic sclerosis compared with patients in pre-clinical stage

We hypothesized that changes in skin characteristics on the forearm could be useful for early diagnosis of systemic sclerosis (SSc). We used VISIA digital imaging system to investigate this possibility for the first time. Twenty-eight Japanese patients who were diagnosed with typical or very early diagnosis of SSc (VEDOSS) were enrolled in this study, and ten age- and gender-matched patients with other disorders were included as a control group. Eight skin characteristics were analyzed. Our method of evaluating forearm skin characteristics was shown to be reproducible. The scores of WRINKLES, TEXTURE, PORES, and PORPHYRINS were higher in SSc subjects with sclerotic forearm skin (SSc forearm+; 11.004, 5.116, 3.230, and 0.084, respectively) and those without (SSc forearm-: 11.915, 4.898, 2.624, 0.0616, respectively) than in the non-SSc control subjects (10.075, 4.496, 2.459, 0.0223, respectively). Also, the scores of SPOTS, TEXTURE, PORES, UV SPOTS, BROWN SPOTS, and PORPHYRINS were elevated in SSc forearm+ (3.182, 5.116, 3.230, 5.761, 6.704, 0.084, respectively) and SSc forearm- patients (2.391, 4.898, 2.624, 9.835, 5.798, 0.0616, respectively) compared with those with VEDOSS (2.362, 4.738, 2.234, 5.999, 4.898, 0.0169, respectively). We found statistical significance in the difference in score of PORPHYRINS between SSc forearm- and VEDOSS groups (p = 0.044), and between SSc forearm+ and VEDOSS groups (p = 0.012). Therefore, they can be used to differentiate VEDOSS from early or mild SSc cases, which is sometimes clinically problematic. Our study also suggests that the porphyrin research will lead to a better understanding of SSc pathogenesis.

Predictors of progression to systemic sclerosis: analysis of very early diagnosis of systemic sclerosis in a large single-centre cohort.

This study analysed the very early disease of SSc (VEDOSS) characteristics in a group of 217 patients with RP and at least one manifestation of SSc in search of predictors for the progression to SSc. This was a cross-sectional single-centre analysis of patients presenting with RP with a specific SSc clinical manifestation or SSc autoantibody or SD pattern at nailfold capillaroscopy (SD-NFC), without skin involvement, who attended a scleroderma outpatient clinic between 2010 and 2019. The performance of VEDOSS and the importance of the combination of VEDOSS characteristics to predict the progression to SSc were evaluated. Among 217 patients, 153 (70.5%) were classified as SSc, including 65 (30%) in the first investigation; 69.3% of the SSc patients met VEDOSS criteria compared with 6.3% of patients who did not progress to SSc. The combinations most associated with progression to SSc were RP + puffy fingers (PF) + positive ANA + SD-NFC and/or SSc-specific antibody (VEDOSS level 2), with an odds ratio (OR) of 19.52 (95% CI 4.48, 85.06; P < 0.001) and RP + PF + positive ANA (VEDOSS level 1; 'red flags') (OR 15.45; P < 0.001), while combinations without non-RP clinical symptoms, as RP + SD-NFC (OR 0.03; P < 0.001) and RP + anticentromere + SD-NFC (OR 0.06; P = 0.006) were associated with non-progression to SSc. Among patients with RP with at least one manifestation of SSc, without skin involvement, combinations of VEDOSS characteristics were the strongest predictors of progression to SSc at a median follow-up of 4 years.

Progression of patients with Raynaud's phenomenon to systemic sclerosis: a five-year analysis of the European Scleroderma Trial and Research group multicentre, longitudinal registry study for Very Early Diagnosis of Systemic Sclerosis (VEDOSS).

Preliminary criteria for the very early diagnosis of systemic sclerosis (VEDOSS) have been previously proposed to identify signs and symptoms in patients with Raynaud's phenomenon. Patients with all signs or symptoms of the VEDOSS criteria already fulfil the 2013 American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) classification criteria for systemic sclerosis. However, prospective data for the evolution to fulfilling these criteria do not exist. We therefore aimed to determine the clinical value of the VEDOSS criteria to identify patients with Raynaud's phenomenon who progress to systemic sclerosis within 5 years. The VEDOSS project was a multicentre, longitudinal registry study done in 42 European Scleroderma Trial and Research group centres located in 20 countries in Europe, North America, and South America. Patients with Raynaud's phenomenon were eligible for enrolment. Those who had fulfilled the 1980 ACR or the 2013 ACR-EULAR classification criteria for systemic sclerosis, as well as of any other ACR or EULAR classification criteria for other definite connective tissue diseases at enrolment were excluded. Data were recorded each year during follow-up visits and included the four VEDOSS criteria (ie, positivity for antinuclear antibodies [ANAs], puffy fingers, systemic sclerosis-specific autoantibodies, and abnormal nailfold capillaroscopy). The primary endpoint was the fulfilment of the 2013 ACR-EULAR classification criteria for systemic sclerosis (ie, progression from enrolment to follow-up). Proportion of progressors and VEDOSS criteria interaction were reported descriptively. Predictors of progression of the distinct VEDOSS criteria interactions were determined based on the point prevalence at 5 years. To investigate the intermediate course of progression of the distinct VEDOSS criteria and their combinations, Kaplan-Meier analysis was done. Between March 1, 2010, and Oct 4, 2018, we enrolled 1150 patients with Raynaud's phenomenon in the VEDOSS database. 764 (66·4%) of 1150 patients met the VEDOSS criteria for study inclusion. Of the 764 patients, 553 (72·4%) had at least one available follow-up visit and the median duration of follow-up was 3·6 years (IQR 1·7-5·8). The mean age was 45·9 years (SD 15·0), 507 (91·7%) of 553 participants were female, and the median time since the onset of Raynaud's phenomenon was 4·0 years (IQR 1·7-10·0). At baseline, 401 (73·7%) of 544 patients with Raynaud's phenomenon had detectable ANA, with 208 (39·5%) of 527 patients positive for systemic sclerosis-specific autoantibodies. Nailfold capillaroscopy abnormalities were present in 182 (36·0%) of 505 patients and puffy fingers were detected in 96 (17·8%) of 540 at baseline. 1885 follow-up visits were recorded. 254 (45·9%) of 553 patients completed the study with progression or a 5-year follow-up; of whom, 133 reached the primary endpoint, resulting in an overall progression rate of 52·4%. The absence of ANA at baseline was the factor most strongly associated with a lack of progression within 5 years, with only four (10·8%) of 37 ANA-negative patients progressing. Conversely, positivity at baseline for systemic sclerosis-specific autoantibodies and puffy fingers was the combination having the highest risk of progression (16 [94·1%] of 17). Our results from the VEDOSS project offers a useful tool for a stratified risk approach to patients with Raynaud's phenomenon. The absence of ANA is a strong protective factor that identifies patients with very low risk of developing systemic sclerosis whereas the presence of one or two VEDOSS criteria in patients with Raynaud's phenomenon confers a progressively higher risk for systemic sclerosis over time. This stratification tool can be used both for clinical management and to inform early interventional trials. European Scleroderma Trial And Research and World Scleroderma Foundation.

The frequency of Raynaud\u2019s phenomenon, very early diagnosis of systemic sclerosis, and systemic sclerosis in a large Veteran Health Administration database

BackgroundWe describe Raynauds phenomenon (RP), potential very early diagnosis of systemic sclerosis (VEDOSS), and systemic sclerosis (SSc) in Veterans deployed in support of Post-9/11 operations. We sought to describe the military occupation specialty, clinical features, and vasodilator use across the three diagnoses.MethodsIndividual Veterans medical records were assessed for RP (ICD-9443.0), VEDOSS with swelling of hands (ICD-9729.81) and RP (ICD-9443.0), and SSc (ICD-9710.1). The distribution of sociodemographic, military service branch, job classification, vasodilator use, and comorbidities were examined across the three classifications of disease. The chi-squared test and Fisher’s exact compared frequency of these categorical variables. Logistic regression assessed the likelihood of characteristics of the three classifications.ResultsIn this population of 607,665 individual Veteran medical records, 857 had RP, 45 met possible VEDOSS criteria, and 71 had a diagnosis of SSc. The majority of RP, potential VEDOSS and SSc cases were white males. Those in craftworks, engineering or maintenance, and healthcare had a greater likelihood of RP. Less than half of RP and VEDOSS patients were on vasodilators. The most common comorbidities in this population were the diagnostic code for pain (highest in the potential VEDOSS group [81.6%]), followed by depression in all groups.ConclusionThis is a unique Veteran population of predominately-male patients. Our data suggests that vasodilator medications are potentially being under-utilized for RP and potential VEDOSS. Our data highlights mood and pain management as an important aspect of SSc care.

The burden of systemic sclerosis in Switzerland - the Swiss systemic sclerosis EUSTAR cohort.

Characteristics of Swiss patients with systemic sclerosis have not been described so far. The aim of the current study was to identify unmet needs in comparison with other European countries that could inform specific interventions to improve the care of systemic sclerosis patients. We analysed Swiss and other European systemic sclerosis patients registered in European Scleroderma Trials And Research (EUSTAR) and the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) cohort. Demographics, clinical profiles, organ involvement and survival of established, early/mild and very early / very mild systemic sclerosis patients were described and compared between the cohorts. We included 679 Swiss and 8793 European systemic sclerosis patients in the analysis. Over 95% of patients in both cohorts were Caucasian, disease subsets were similar, and no age difference was found. The Swiss cohort had more male patients (25% vs 16% European, p = 0.005) and higher prevalence of early/mild and very early / very mild patients (26.1 vs 8.5% European and 14.9% vs 6.7% European, respectively, both p &lt;0.0001). Disease duration in established systemic sclerosis patients at first presentation was numerically shorter but not significant in the Swiss cohort: 5.0 years (1&ndash;12) Swiss vs 6.0 years (2&ndash;12) years European, p = 0.055). Despite the earlier referral of Swiss patients to systemic sclerosis expert centres, they showed evidence of more severe disease, particularly in the limited cutaneous systemic sclerosis subset, but no differences in overall survival on longitudinal follow-up were observed. This is the first report of the national Swiss EUSTAR cohort. It identifies earlier referral to systemic sclerosis expert centres, before major organ damage occurs, and when outcome can still be modified, as a priority to improve care of patients with systemic sclerosis.

Contribution to the peripheral vasculopathy and endothelial cell dysfunction by CXCL4 in Systemic Sclerosis

BackgroundCXCL4, a chemokine with anti-angiogenic property, is involved in systemic sclerosis (SSc) related pulmonary arterial hypertension (PAH). ObjectiveTo investigated the contribution of CXCL4 to SSc development by focusing on the correlation of circulatory CXCL4 levels with their peripheral vasculopathy, and the effect of CXCL4 on endothelial cell dysfunction and the potential signaling. MethodsWe measured the plasma CXCL4 levels in 58 patients with SSc, 10 patients with the very early diagnosis of SSc (VEDOSS), and 80 healthy controls (HCs). Then, CXCL4 concentrations were correlated with clinical features, especially the peripheral vasculopathy. These observations were further validated in an additional cohort. Moreover, we studied the anti-angiogenic effects of CXCL4 and the underlying downstream signaling in human umbilical vein endothelial cells (HUVECs) in vitro. ResultsCirculating CXCL4 levels were 103.62 % higher in patients with SSc and 201.51 % higher in patients with VEDOSS than matched HCs, which were confirmed in two independent cohorts. CXCL4 levels were associated with digital ulcers (DU) and nailfold videocapillaroscopy (NVC) abnormalities in SSc. The proliferation, migration, and tube formation of HUVECs were inhibited by CXCL4 or SSc derived plasma, which reversed by CXCL4 neutralizing antibody, but failed by CXCR3 inhibitor. CXCL4 downregulated the transcription factor Friend leukaemia integration factor‐1 (Fli-1) via c-Abl signaling. Furthermore, CXCL4 blocked the transforming growth factor (TGF) -β or platelet-derived growth factor (PDGF) induced cell proliferation of HUVECs. ConclusionsCXCL4 may contribute to peripheral vasculopathy in SSc by downregulating Fli-1 via c-Abl signaling in endothelial cells and interfering angiogenesis.

Diffuse myocardial fibrosis precedes impairment of myocardial strain in patients with systemic sclerosis

Abstract Funding Acknowledgements Type of funding sources: None. Background - Myocardial involvement is common in patients with systemic sclerosis (SSc) and causes myocardial fibrosis and subtle ventricular dysfunction. However, the temporal onset of myocardial involvement during the progression of the disease is yet unknown. Purpose - To investigated the presence of subclinical functional impairment and diffuse myocardial fibrosis in patients with very early diagnosis of SSc (VEDOSS) and to compared the findings to patients with established SSc and healthy controls. Methods - 110 SSc patients (86 with established SSc and 24 with VEDOSS) and 15 healthy controls were prospectively recruited. The study subjects underwent cardiovascular magnetic resonance on a clinical 1.5T system. Pre- and post-contrast T1 mapping was performed using a MOLLI (Modified Look-Locker Inversion Recovery) sequence. For extracellular volume (ECV) measurements, a single bolus protocol with image acquisition 15-20 min. post-contrast injection was used. For the assessment of subtle functional impairment, global longitudinal (GLS) and circumferential (GCS) myocardial strain were evaluated. Results - Native T1 values and ECV were elevated in VEDOSS and in patients with established SSc compared to controls (p &amp;lt; 0.001; Figure 1 A &amp; B). GLS was similar in VEDOSS and controls but significantly reduced in patients with established SSc (p &amp;lt; 0.001; Figure 1 C). GCS was similar over all groups (p = 0.88). Patients with clinical evidence of pulmonary or gastrointestinal involvement had higher ECV or T1 values, respectively. Patients with clinical signs of cardiac involvement had lower absolute GLS. SSc subtype, classification or disease duration were not associated with the extent of myocardial fibrosis or impaired strain. Conclusion - Subclinical myocardial involvement first manifests as diffuse myocardial fibrosis identified by expansion of ECV and increased native T1 in VEDOSS patients while subtle functional impairment as measured by GLS only occurs in established SSc. No single clinical feature of SSc shows a strong association with subtle myocardial involvement.

OP0150 MACHINE LEARNING APPROACHES FOR RISK MODELLING IN INTERSTITIAL LUNG DISEASE ASSOCIATED WITH SYSTEMIC SCLEROSIS USING HIGH DIMENSIONAL IMAGE ANALYSIS

Background:The interstitial lung disease (ILD) associated with connective tissue diseases including systemic sclerosis (SSc) is heterogenous disease characterized by reduced survival of approximately 3 years (1). “Radiomics’’ is a field of research which describes the in-depth analysis of tissues by computational retrieval of high-dimensional quantitative features from medical images (2). Our previous study suggested capacity of radiomics features to differentiate between “high” and “low” risk groups for lung function decline in two independent cohorts (3).Objectives: •bTo develop robust, machine learning (ML) workflow for “radiomics” data in SSc-ILD to select optimal methods for prediction. •oTo predict the time to individual lung function decline defined as defined by the time to a relative decline of ≥ 15% in Forced Vital Capacity (FVC)% as previously (3), using workflow.Methods:We investigated two cohorts of SSc-ILD: 90 patients (76.7% female, median age 57.5 years) from the University Hospital Zurich and 66 patients (75.8% female, median age 61.0 years) from Oslo University Hospital’s. Patients were retrospectively selected if (3): a) diagnosed with early/mild SSc according to the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) criteria, b) presence of ILD on HRCT as determined by a senior radiologist. For every subject, we defined 1,355 robust radiomic features from HRCT images. The follow-up period was defined as the time interval between baseline visit and the last available follow-up visit.We have developed a systematic computational workflow to build predictive ML models. To reduce the number of redundant radiomic features, we applied correlation thresholds. We applied distinct methods including 1) Lasso Penalized Regression for feature selection, and 2) Random Forest (RF) for modeling using the R package ‘caret’. To select the optimal ML model, we randomly divided derivation cohort into Training (70%) and Holdout (30%) sets and applied fivefold cross-validation (5kCV) for feature and classifier selection on Training set only.Results:We have investigated various methods to select the optimal set of predictive radiomic features. Since the ML model performance is affected by both, feature, and classifier selection, we assessed these factors first.Results from feature filtering and selection, suggested that the combination of correlation threshold of 0.9 with Lasso regression proved best. As we perform feature selection in 5k CV workflow, features present in at least 2 sets entered model optimization step.During model selection, we selected RF classifier. We detected positive correlation between actual and predicted values with Spearman’s rho = 0.313, p = 0.167 and Spearman’s rho = 0.341, p = 0.015 in Oslo and Holdout sets respectively, as shown on Figure 1. The percentage of variance remained modest for both Holdout (Rsq = 0.104) and Oslo (Rsq = 0.126) datasets.Figure 1.Performance of the best, RF classifier shown as scatterplot between actual and predicted values of individual time to lung decline.Conclusion:In summary, we: (1) developed ML workflow that allowed to select o optimal methodology for modeling (i.e., feature and classifier selection), and (2) provide models that predicted time to individual lung function decline, characterized by significant correlation between predicted and actual values.

Expert-Level Distinction of Systemic Sclerosis from Hand Photographs Using Deep Convolutional Neural Networks

Systemic sclerosis (SSc) is an autoimmune disease characterized by systemic autoimmunity and tissue fibrosis of the skin and internal organs (Medsger, 2003). Early clinical interventions for SSc lead to early detection of complications, resulting in improved patient prognosis (Denton and Khanna, 2017). Therefore, early diagnosis of SSc is important. SSc presents with characteristic skin manifestations such as Raynaud’s phenomenon and skin sclerosis from early onset (Gunnarsson et al., 2016; LeRoy, 1992).

New Autoantibody Specificities in Systemic Sclerosis and Very Early Systemic Sclerosis.

Chemokine (C-X-C motif) ligand 4 (CXCL4) is a biomarker of unfavorable prognosis in Systemic Sclerosis (SSc), a potentially severe autoimmune condition, characterized by vasculitis, fibrosis and interferon (IFN)-I-signature. We recently reported that autoantibodies to CXCL4 circulate in SSc patients and correlate with IFN-α. Here, we used shorter versions of CXCL4 and CXCL4-L1, the CXCL4 non-allelic variant, to search for autoantibodies exclusively reacting to one or the other CXCL4 form. Moreover, to address whether anti-CXCL4/CXCL4-L1 antibodies were present before SSc onset and predicted SSc-progression, we longitudinally studied two VEDOSS (Very Early Diagnosis of Systemic Sclerosis) patient cohorts, separating SSc-progressors from SSc-non-progressors. We found that anti-CXCL4-specific autoantibodies were present in both SSc and VEDOSS patients (both SSc-progressors and SSc-non-progressors). Anti-CXCL4-L1-specific autoantibodies were especially detected in long-standing SSc (lsSSc). Anti-CXCL4/CXCL4-L1 antibodies correlated with IFN-α and with specific SSc-skin features but only in lsSSc and not in early SSc (eaSSc) or VEDOSS. Thus, a broader antibody response, with reactivity spreading to CXCL4-L1, is characteristic of lsSSc. The early anti-CXCL4 autoantibody response seems qualitatively different from, and likely less pathogenic than, that observed in advanced SSc. Lastly, we confirm that anti-CXCL4 autoantibodies are SSc-biomarkers and uncover that also CXCL4-L1 becomes an autoantigen in lsSSc.

Early Diagnosis of Systemic Sclerosis by Skin Ultrasonography.

Early Diagnosis of Systemic Sclerosis by Skin Ultrasonography.