Mortality In Systemic Sclerosis Research Articles

All-cause mortality in systemic rheumatic diseases under treatment compared with the general population, 2015–2019

ObjectivesTo compare current all-cause mortality rates in rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) versus general population.MethodsIn this population-based, retrospective...

Mortality in Systemic Sclerosis-Associated Interstitial Lung Disease in Brazil: A Real-Life, Long-Term Follow-up Observational Study.

The aim of this study was to identify risk factors associated with mortality in patients with systemic sclerosis (SSc), particularly those with interstitial lung disease (ILD), over a long-term follow-up in a large Brazilian SSc cohort. We conducted a medical records review study of 380 scleroderma patients from 1982 to 2019. Systemic sclerosis ILD was considered in those with evidence of ILD on chest high-resolution computed tomography (HRCT). Causes of death were determined. Among the 380 SSc patients, SSc-ILD on chest HRCT was observed in 227 patients (59.7%). Seventy-two patients (18.9%) died during a mean follow-up of 7.2 years since the SSc diagnosis; among them, 57 (79.2%) had SSc-ILD, compared with 15 (20.8%) without SSc-ILD (p < 0.001). Of the 72 deaths, 51.4% were considered related to SSc, and ILD was the leading cause of death. The overall survival rates at 5, 10, and 15 years were 87.9%, 81.5%, and 74.9%, respectively. Kaplan-Meier analysis showed a significantly worse prognosis among patients with SSc-ILD than among those without ILD (p < 0.001). Among patients with SSc-ILD, disease duration of less than 4 years (p < 0.001), forced vital capacity <80% at baseline (p = 0.017), and pulmonary systolic arterial pressure ≥40 mm Hg on echocardiography (p < 0.001) were significantly associated with mortality by multivariate analysis. In Brazilian SSc patients, the presence of ILD was associated with a worse prognosis. The higher mortality among SSc-ILD patients, especially those with a shorter disease duration and forced vital capacity <80%, highlights the need for early screening and closer monitoring before irreversible lung function deterioration occurs.

TO ASSESS DIFFERENT PROGNOSIS INTERVALS FOR PATIENTS WITH SYSTEMIC SCLEROSIS- INTERSTITIAL LUNG DISEASE

TOPIC: Diffuse Lung Disease TYPE: Original Investigations PURPOSE: Systemic sclerosis (SSc) is a multisystem autoimmune disease. Pulmonary alterations are the major cause of mortality in SSc. SSc-ILD has heterogeneous disease progression: many patients will have a chronic, indolent course while others may develop progressive, life-threatening disease.Objectives: To assess prognosis intervals for pts with SSc-ILD. METHODS: It was a longitudinal study involving 140 pts with SSc-ILD. The mean age was 46.7±13.9years, females 82%, SSc duration 6.2±5.8 years, diffuse subset - 54%. The mean duration of follow up was 73,2±27,8 months. Clinical, laboratory, and immunologic data were collected on all patients. Based on analysis of discrimination function the equation of prognosis was developed. The equation is 3.14GGO (ground glass opacities) + 0,7 index EScSG – 1,326 FVC - 0,1 the maximum daily dose of glucocorticoids + 0,136 Gamma globulins + 1.066 CYP – 1.075 DLCO ≤ 5,8. Value of equation of prognosis to 5.8 corresponds to stabilization or good prognosis and value after 5.8 corresponds to poor prognosis. The equation of prognosis had 86% sensitivity and 56% specificity. The cut-off point 4.7 was represented 65% sensitivity and 67% specificity. The prognosis intervals were following: value of equation to 4.7 corresponds to good prognosis; value from 4.8 to 5.8 corresponds to stabilization and value after 5.8 corresponds to poor prognosis. RESULTS: Pts were distributed into groups depending on results of discrimination function: 14 pts (10%) - zone of good prognosis; 8 pts (6%) - zone of stabilization and 118 (84%) - zone of poor prognosis. We have decided to join pts from zone good prognosis and zone stabilization into united group (U-group) - 22 pts (16 %). Tab. Comparative characteristics of the groups.Parameters Group 1 (n=14) Group 2 (n=8) U-Group (n=22) Group 3 (n=118)Age years 45,4±16,4 50,2±15,8 47,2±16 47,5±13 P>0,05Male 3(21%) 1(12,5%) 4(18%) 21(18%) P>0,05Female 11(79%) 7(87,5%) 18(82%) 97(82%) P>0,05Limited form 8(57%) 2(35%) 10(46%) 54(46%) P>0,05Diffuse form 6(43%) 6(75%) 12(54%) 64(54%) P>0,05Duration of 6,8±7,6 5±4,2 6,2±6,4 6,5±5,7 P>0,05disease yearsCRP mg/ml 10±10 8,5±10,6 9,4±10,4 12,6±23,9 P>0,05ESR mm/h 16,7±13,1 17,4±21,9 17±16,3 23,5±16,7 P>0,05ANA-hep-2 525±322* 420±190** 487±281 *** 774±430* ** *** p: Gr1 vs Gr3 =0,038; Gr2 vs Gr3=0,02; U-Gr vs Gr3 =0,032a-Scl-70 u/ml 59,9±82,7* 67±94,5 116±93** 62,5±85* ** p: Gr1 vs Gr3 =0,03; U-Gr vs Gr3 =0,013Ejectionfraction(EF)(%) 67,3±5,3* 65,5±6,1 66,7±5,5** 63±6,8* ** p: Gr1 vs Gr3 =0,02; U-Gr vs Gr3 =0,017PAP mm hg 31,6±5,8 32,4±9,3 31,9±7 36,4±14 P>0,056MWT m(6 Minutewalk test) 490±110 477±104 485±104 430±100 P>0,05The age, SSc duration, gender proportion and SSc forms, were similar in the all groups (p>0,05). In the study mean dates of ANF-hep-2, a-Scl-70 were significantly lower and EF was significantly higher in groups 1 and U-group than in group 3. In groups 1,2 and U-group the mean levels of ESR, CRP, PAP were lower and value of 6MWT were higher than mean levels in group 3 accordingly. So separately group 2 didn’t have significant differences with group 1 and 3. CONCLUSIONS: In the study we didn’t find any correlation between meanings of group 2 and groups 1,3 but the meanings of group 1 and U-group have had the same correlation. It would be rational to highlight only one zone of prognosis before and after 5,8. CLINICAL IMPLICATIONS: . DISCLOSURES: No relevant relationships by Lidia Ananyeva, source=Web Response No relevant relationships by Oxana Desinova, source=Web Response No relevant relationships by Liudmila Garzanova, source=Web Response No relevant relationships by Olga Koneva, source=Web Response No relevant relationships by Olga Ovsynnikova, source=Web Response No relevant relationships by Mayya Starovoytova, source=Web Response

Troponin elevation independently associates with mortality in systemic sclerosis.

Cardiac involvement is common in systemic sclerosis (SSc), and elevated troponin may be the only sign of ongoing myocardial disease. The objective was to determine whether the presence of elevated troponin associates with unique SSc characteristics and poor outcomes. This retrospective, cross-sectional study included patients in the Johns Hopkins Scleroderma Center Research Registry with any troponin measurement in the past 10 years. Clinical data were compared between those with elevated versus normal troponin. Survival analyses including Cox proportional hazards and regression analyses were performed. 272 patients with a troponin measurement were identified. 83 (31%) had elevated troponin. Compared to those with a normal troponin level, those with elevated troponin level were more likely to have the diffuse SSc subtype (p=0.005), lower left ventricular ejection fraction (57.7 ± 20% vs. 64.4 ± 17.4%, p=0.007), lower forced vital capacity percent predicted (61.1 ± 18.8% vs. 66.8 ± 20.4%, p=0.03), higher right ventricular systolic pressure (51.4 ± 20.9 vs. 43.4 ± 15.9 mmHg, p=0.001), higher Medsger muscle and heart severity scores (p≤0.001), and higher frequency of mortality (28% vs. 9.5%, p≤0.0001). Patients with elevated troponin also have a 2.16-fold (95% CI 1.01-4.63, p=0.046) increased risk of death compared to those without elevated troponin even after adjusting for age, sex, disease duration, and cardiopulmonary risk factors. Troponin may be a useful prognostic biomarker that may identify a subset of patients with heart disease that may warrant closer clinical investigation.

CD19 + CD21lo/neg cells are increased in systemic sclerosis-associated interstitial lung disease

Interstitial lung disease (ILD) represents a significant cause of morbidity and mortality in systemic sclerosis (SSc). The purpose of this study was to examine recirculating lymphocytes from SSc patients for potential biomarkers of interstitial lung disease (ILD). Peripheral blood mononuclear cells (PBMCs) were isolated from patients with SSc and healthy controls enrolled in the Vanderbilt University Myositis and Scleroderma Treatment Initiative Center cohort between 9/2017–6/2019. Clinical phenotyping was performed by chart abstraction. Immunophenotyping was performed using both mass cytometry and fluorescence cytometry combined with t-distributed stochastic neighbor embedding analysis and traditional biaxial gating. This study included 34 patients with SSc-ILD, 14 patients without SSc-ILD, and 25 healthy controls. CD21lo/neg cells are significantly increased in SSc-ILD but not in SSc without ILD (15.4 ± 13.3% vs. 5.8 ± 0.9%, p = 0.002) or healthy controls (5.0 ± 0.5%, p < 0.0001). While CD21lo/neg B cells can be identified from a single biaxial gate, tSNE analysis reveals that the biaxial gate is comprised of multiple distinct subsets, all of which are increased in SSc-ILD. CD21lo/neg cells in both healthy controls and SSc-ILD are predominantly tBET positive and do not have intracellular CD21. Immunohistochemistry staining demonstrated that CD21lo/neg B cells diffusely infiltrate the lung parenchyma of an SSc-ILD patient. Additional work is needed to validate this biomarker in larger cohorts and longitudinal studies and to understand the role of these cells in SSc-ILD.

Performance of the DETECT Algorithm for Pulmonary Hypertension Screening in a Systemic Sclerosis Cohort.

Pulmonary arterial hypertension (PAH) is one of the leading causes of mortality in systemic sclerosis (SSc). This study was undertaken to assess predictive accuracies of the DETECT algorithm and the 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines in SSc patients who underwent right-sided heart catheterization (RHC) for pulmonary hypertension (PH) evaluation. Patients with SSc who had diagnostic RHC, had no PH or had PAH, and had available data on variables to allow application of the DETECT and 2015 ESC/ERS guidelines were included for analysis. PH classification was based on hemodynamics using the 2018 revised criteria and extent of lung fibrosis shown on high-resolution computed tomography. Sensitivity and predictive accuracies of the DETECT algorithm and 2015 ESC/ERS guidelines were calculated, including analysis of subjects with a diffusing capacity for carbon monoxide (DLco) of ≥60% predicted. Sixty-eight patients with SSc had RHC, of whom 58 had no PH and 10 had PAH. The mean age was 60.0 years, and 58.8% had limited cutaneous SSc. The DETECT algorithm had a sensitivity of 1.00 (95% confidence interval [95% CI] 0.69-1.00) and a negative predictive value (NPV) of 1.00 (95% CI 0.80-1.00), whereas the 2015 ESC/ERS guidelines had a sensitivity of 0.80 (95% CI 0.44-0.97) and an NPV of 0.94 (95% CI 0.81-0.99). In patients with a DLco of ≥60% (n = 27), the DETECT algorithm had a sensitivity of 1.00 (95% CI 0.29-1.00) and an NPV of 1.00 (95% CI 0.59-1.00), whereas the 2015 ESC/ERS guidelines had a sensitivity of 0.67 (95% CI 0.09-0.99) and an NPV of 0.94 (95% CI 0.71-1.00). The DETECT algorithm has high sensitivity and NPV for diagnosis of PAH, including among individuals with a DLco of ≥60%.

Endothelial Progenitor Cells: Relevant Players in the Vasculopathy and Lung Fibrosis Associated with the Presence of Interstitial Lung Disease in Systemic Sclerosis Patients.

Endothelial progenitor cells (EPC), which are key effectors in the physiologic vascular network, have been described as relevant players in autoimmune diseases. We previously showed that EPC frequency may help to identify the presence of interstitial lung disease (ILD) in rheumatoid arthritis patients. Given that ILD constitutes the main cause of mortality in systemic sclerosis (SSc) patients, we aimed to determine the EPC contribution to the pathogenic processes of vasculopathy and lung fibrosis in SSc-ILD+. EPC quantification was performed by flow cytometry on blood from 83 individuals: 21 SSc-ILD+ patients and subjects from comparative groups (20 SSc-ILD− and 21 idiopathic pulmonary fibrosis (IPF) patients and 21 healthy controls (HC)). EPC were considered as CD34+, CD45low, CD309+, and CD133+. A significant increase in EPC frequency was found in SSc-ILD+ patients when compared to HC (p < 0.001). SSc-ILD+ patients exhibited a higher EPC frequency than SSc-ILD− patients (p = 0.012), whereas it was markedly reduced compared to IPF patients (p < 0.001). EPC frequency was higher in males (p = 0.04) and negatively correlated to SSc duration (p = 0.04) in SSc-ILD+ patients. Our results indicate a role of EPC in the processes of vasculopathy and lung fibrosis in SSc-ILD+. EPC frequency may be considered as a biomarker of ILD in SSc patients.

French recommendations for the management of systemic sclerosis

Systemic sclerosis (SSc) is a generalized disease of the connective tissue, arterioles, and microvessels, characterized by the appearance of fibrosis and vascular obliteration. There are two main phenotypical forms of SSc: a diffuse cutaneous form that extends towards the proximal region of the limbs and/or torso, and a limited cutaneous form where the cutaneous sclerosis only affects the extremities of the limbs (without passing beyond the elbows and knees). There also exists in less than 10% of cases forms that never involve the skin. This is called SSc sine scleroderma. The prognosis depends essentially on the occurrence of visceral damage and more particularly interstitial lung disease (which is sometimes severe), pulmonary arterial hypertension, or primary cardiac damage, which represent the three commonest causes of mortality in SSc. Another type of involvement with poor prognosis, scleroderma renal crisis, is rare (less than 5% of cases). Cutaneous extension is also an important parameter, with the diffuse cutaneous forms having less favorable prognosis.

POS0842 LUNG ULTRASOUND TO ASSESS THE SEVERITY OF INTERSTITIAL LUNG DISEASE IN SYSTEMIC SCLEROSIS

Background:Interstitial lung disease (ILD) is one of the most common complications and one of the main causes of morbidity and mortality in Systemic Sclerosis (SSc). High-resolution computed tomography (HRCT) is the gold standard for the diagnosis of ILD and it allows its quantification. Among semi-quantitative methods, Goh et al proposed a semi-quantitative scoring system to visually quantify ILD extent, with categorical cut-off of 20% to distinguish limited and extensive parenchymal involvement with prognostic implications. More recently, the use of radiomics has allowed the objective quantification of ILD through the use of dedicated software, which calculate different parameters of lung density.Given the exposure to ionizing radiation that the procedure entails, other methods of ILD evaluation are being studied, among which lung ultrasound (LUS) identifies the B-lines as a main feature of ILD. So far, different evidences have proposed the use of LUS for the screening of ILD, even in the early phases of the disease and in subclinical lung involvement.Objectives:the aim of this study is to test the role of LUS in quantifying the severity of SSc-ILD, evaluated with both semi-quantitative visual radiological and quantitative radiomic scores.Methods:Adult SSc patients classified according to the ACR/EULAR 2013 criteria patients were assessed with pulmonary function test (PFTs), lung ultrasound and HRCT over 60 days. CT images were analysed qualitatively (by presence/absence of ILD), semi-quantitatively (categorical Goh score &lt;20% vs&gt; 20% of extent and the continuous extent Goh score made from 5 levels’ assessment– 0 to 100%) and quantitatively [with the densitometric radiomic data obtained through the Horos software - Mean lung attenuation (MLA), Standard Deviation (SD), Kurtosis, Skewness and Lung volume (LV)]. LUS was used to quantify the B-lines detected in each patient by scanning a total of 13 intercostal spaces, on both anterior and posterior chest wall.Results:Among 59 SSc patients (81% women, mean age 48±14 years, 45% anti-Scl70 positive), 23 (39%) presented ILD on HRCT, of which 14 limited and 9 extensive. The mean visual semi-quantitative score was 6%, ranging from 0 to 66%. Our data showed a significantly different number of B-Lines in ILD vs non-ILD patients (median 38 vs 9, p &lt;.005), a result which was further confirmed among non-ILD vs ILD&gt; 20% (median 47 vs 9, p=.001) and ILD &lt;20% (median 36 vs 9, p=.001) patients. Conversely, the number of B-lines was not statistically different between patients with ILD &lt;20% and &gt;20% (median 47 vs 36, p=.78). We observed a significant negative correlation between the number of B-lines and FVC (r=-.472, p&lt;.05) TLC (r=-.436, p=.003), DLco (r=-.515, p&lt;.001), DLCO/VA (r=.-306, p=.03). Finally, the number of B-lines showed a statistically significant correlation with the Goh score on 5 levels (r=.437, p=.001), MLA (r=.571, p&lt;.001), kurtosis (r=-.285, p=.028), skewness (r=-.370, p = .004) and LV (r=-.277, p=.033). All data were confirmed analysing anterior and posterior B-Lines separately.Conclusion:Our study confirms that LUS represents a useful tool for the identification of SSc-ILD. In addition, we showed that LUS may be useful also for the quantification of the severity of SSc-ILD, by correlating with PFT parameters, radiomics parameters and visual radiological evaluation. Together with the PFTs, LUS could be used to increase the accuracy of the screening and, potentially, of the follow-up of SSc-ILD patients.Disclosure of Interests:Cosimo Bruni: None declared, Lavinia Mattolini: None declared, Lorenzo Tofani: None declared, Luna Gargani Consultant of: GE Healthcare, Philips Healthcare and Caption Health, Nicholas Landini: None declared, Gemma Lepri: None declared, Martina Orlandi: None declared, Serena Guiducci: None declared, Silvia Bellando Randone: None declared, Marco Matucci-Cerinic: None declared

AB0413 HIGH-RESOLUTION COMPUTED TOMOGRAPHY FOR THE SCREENING, RE-SCREENING AND FOLLOW-UP OF SYSTEMIC SCLEROSIS RELATED INTERSTITIAL LUNG DISEASE: RESULTS OF A EUSTAR-SCTC SURVEY

Background:High-resolution computed tomography (HRCT) is the gold standard diagnostic test for Interstitial lung disease (ILD), a significant cause of morbidity and mortality in systemic sclerosis (SSc). Different algorithms have been proposed for the screening of SSc-ILD, including the use of pulmonary function tests (Forced Vital Capacity - FVC, Lung Diffusion of Carbone Monoxyde - DLCO). A prior survey reported that 50-66% of general rheumatologists and SSc experts ordered HRCT for ILD screening in newly diagnosed SSc patients (1).Objectives:Given the recent availability of on-label treatment for SSc-ILD (2), the publication of consensus recommendations for the identification of SSc-ILD (3) and recent awareness programs for the use of HRCT to detect SSc-ILD, we aimed to re-evaluate the use of HRCT for screening, re-screening and follow-up of SSc-ILD.Methods:An invitation was sent to the European Scleroderma Trials and Research (EUSTAR) and Scleroderma Clinical Trials Consortium (SCTC) members, also advertised through social media. Answers were recorded between Nov 25th and Dec 31st 2020. Questions were asked on the use of chest HRCT at baseline, the re-screening of patients with a negative baseline HRCT and the follow-up of HRCT positive SSc-ILD patients. When HRCT was not routinely requested, additional details were collected about the parameters guiding its use. The results of the survey were tested for association with geographical origin, medical specialty, working environment, SSc referral institute and scientific group membership of the responders, using Chi-squared test.Results:205/630 (32.5%) physicians replied to the survey. Participants were widely distributed in terms of geographical origin (130 Europe, 23 Asia, 23 North America, 31 other continents), medical specialty (156 rheumatology, 21 internal medicine, 14 clinical immunology, 14 other), working environment (176 University Hospital, 12 community hospital, 17 other), SSc dedicated clinic (179 referral and 26 non-referral) and scientific group membership (98 EUSTAR, 42 SCTC, 42 EUSTAR and SCTC, 23 not declared).At SSc diagnosis, 95.7% of responders would perform HRCT: 66.7% as routine screening for ILD (67,4% of SSc referral and 62% for non-referral physicians) and 29% for diagnostic purposes (among the latter, if crackles on auscultation – 92.5%, FVC&lt;80% predicted - 86.6%, FVC±DLCO relative decline reaching the current definition of ILD progression, 86.6% or dyspnea at rest/exercise - 85.1/83.3%).During follow-up, 78.8% of responders would repeat an HRCT in baseline negative cases: 20.3% as a yearly routine screening and 64.5% for diagnostic aims (decision on the latter group was more frequently driven by FVC±DLCO relative decline indicative of ILD progression– 90.6%, new onset or worsening of dyspnoea at rest/exercise – 80.5/86.6%, new onset or worsening of lung crackles on auscultation – 82.6%).Finally, 94.5% of responders would repeat a chest HRCT after SSc-ILD diagnosis: 36.8% as a yearly routine and 56.7% according to clinical evaluation (driven by new FVC±DLCO relative decline based ILD progression – 90.8%, new onset or worsening of dyspnoea at rest/exercise – 83.2/81.7%; 5.2% to evaluate treatment effects). We found no difference in the distribution of answers among groups.Conclusion:The use of baseline HRCT for the screening of SSc-ILD has slightly increased in non-referral and remained stable in referral centers compared to previous surveys, indicating that the implementation of guidelines might be successful and awareness programs should be continued. In addition, we provide new data on use of HRCT in re-screening and follow-up. The development of validated algorithms to further support the appropriate application of HRCT at follow-up is highly needed.

Endocan and Circulating Progenitor Cells in Women with Systemic Sclerosis: Association with Inflammation and Pulmonary Hypertension.

Background: Systemic sclerosis (SSc) is characterized by early vasculopathy and fibrosis in the skin, lungs, and other tissues. Vascular manifestations of SSc include Raynaud’s phenomenon, digital ulcers, and pulmonary artery hypertension (PAH). PAH is the second most common cause of mortality in SSc. Circulating CD34+ cells associated with cardiovascular health status in several conditions, including chronic immune-inflammatory disease. CD34+ cell numbers have been found inconstantly reduced in SSc. Endocan, a proteoglycan expressed by endothelial cells, was recently suggested as a marker of vascular stress. We tested the relationships among CD34+ cells, endocan, inflammatory markers, vitamin D levels, and clinical parameters in SSc patients with PAH. METHODS: Standard echocardiography was performed. Vitamin D levels, CD34+ cells, inflammatory markers, endocan plasma levels were determined in 36 female SSc patients (24 diffuse/12 limited) and 36 matched controls (HC). RESULTS: We found no difference in CD34+ and vitamin D levels in SSc as compared to controls; ESR, CRP, fibrinogen, endocan, sPAP were higher in SSc with respect to controls. We found a correlation between endocan and: CD34+ cells (r: −0.540, p = 0.002), pulmonary arterial pressure (sPAP) (r: 0.565, p < 0.001), tricuspid annular plane excursion (TAPSE) (r: −0.311, p < 0.01), and E/A ratio (r: −0.487, p < 0.001), but not with ejection fraction (r: −0.057, p = 0.785) in SSc. CD34+ cells correlate with fibrinogen (r: −0.619, p < 0.001), sPAP (r: −0.404, p = 0.011), E/A (r: 0.470, p < 0.005 in SSc. CONCLUSION: CD34+ cell number was significantly correlated with endocan levels and with sPAP in SSc; endocan and CD34+ progenitor cells might be suggested as a potential marker of disease status.

Aerosol components associated with hospital mortality in systemic sclerosis: an analysis from a nationwide Thailand healthcare database

Occupational and environmental associations with systemic sclerosis (SSc) have been confirmed; however, the association between aerosol components and mortality is uncertain. The study aimed to define the association between aerosol components and hospital mortality among Thai SSc patients. A study was conducted using a national database of patients covered by the National Health Security Office, hospitalised between 2014 and 2018. Data included all patients over 18 having a primary diagnosis of SSc (ICD-10: M34). Spatial resources used map information based on GPS coordinates of Thailand. Aerosol components—including organic carbon, black carbon, dust particulate matter diameter < 2.5 µm (PM2.5), and sulfate—were assessed using the NASA satellite MERRA-2 Model M2TMNXFLX v5.12.4. Spatial modelling with R Package Integrated Nested Laplace Approximation (R-INLA) was used to analyse the association between the incidence of mortality and the 5-year accumulation of each aerosol component adjusted by age, sex, and comorbid diseases. The study included 2,094 SSc patients with 3,684 admissions. Most (63.8%) were female. During admission, 1,276 cases died. R-INLA analysis indicated an increase of 1 µg/m3 of dust PM2.5 was associated with a respective increase in the risk of overall mortality and death due to pneumonia of 96% and 79%. An increase of 1 µg/m3 of dust PM2.5 resulted in 1.17, 1.18, 1.64, and 2.15 times greater risk of mortality due to pulmonary fibrosis, cardiac involvement, renal involvement, and cancer, respectively. Aerosol components—particularly dust PM2.5 exposures—increased the risk of overall, cardio-pulmonary-renal, and cancer mortality among SSc patients.

Nailfold Capillaroscopy in Systemic Sclerosis Patients with and without Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis

Systemic sclerosis (SSc)-related pulmonary arterial hypertension (SSc-PAH) is a leading cause of mortality in SSc. The extent of peripheral microvasculopathy assessed through nailfold capillaroscopy might correlate with the presence of PAH in SSc patients. We searched the PubMed, Cochrane Library, Scopus, and Web of Science databases and performed a random effects meta-analysis of observational studies comparing nailfold capillaroscopic alterations in SSc-PAH versus SSc-noPAH patients. Weighted mean differences (WMD) with the corresponding confidence intervals (CIs) were estimated. The quality of the included studies was evaluated using a modified Newcastle–Ottawa scale. Seven studies with 101 SSc-PAH and 277 SSc-noPAH participants were included. Capillary density was marginally reduced in the SSc-PAH group (WMD: −1.0, 95% CI: −2.0 to 0.0, I2 = 86%). This effect was strengthened once PAH diagnosis was confirmed by right heart catheterization (WMD: −1.2, 95% CI: −2.3 to −0.1, I2 = 85%). An increase in capillary loop width was observed in SSc-PAH compared to SSc-noPAH patients (WMD: 10.9, 95% CI: 2.5 to 19.4, I2 = 78%). Furthermore, SSc-PAH patients had a 7.3 times higher likelihood of active or late scleroderma pattern (95% CI: 3.0 to 18.0, I2 = 4%). SSc-PAH patients presented with worse nailfold capillaroscopic findings compared to SSc-noPAH patients.

Estimated glomerular filtration rate and renal resistive index as possible predictive markers of mortality in systemic sclerosis

ObjectiveSubclinical nephropathy is underestimated in systemic sclerosis (SSc). Study aim is to evaluate the role of renal resistance indices (RRI) and estimated glomerular filtration rate (eGFR) assessed by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) as predictive markers of mortality during 10 years of follow-up in SSc patients. Methods181 SSc patients (60 years, 152 females) were enrolled. At baseline, the GFR was estimated in 181 SSc patients and RRI was measured in 122 SSc patients. During a follow-up of 10 years we recorded the main complications of disease, date and causes of death. ResultseGFR shows a linear negative correlation with RRI. RRI showed a correlation with systolic pulmonary artery pressure (sPAP). Overall survival is lower in SSc patients with eGFR<60 ml/min and RRI ≥0.70 than in SSc patients with eGFR≥60 ml/min (p<0.0001) and with RRI<0.70 (p<0.01) both for mortality due to SSc and all causes. In multivariate analysis, eGFR<60 ml/min [HR 6.429, 95%CI (1.006-41.08), p<0.05] and forced vital capacity (FVC) [HR 0.954, 95%CI (0.911-1), p<0.05] are predictive markers of mortality due to SSc, while eGFR [HR 3.617, 95%CI (1.370-9.554), p<0.01], RRI [HR 0.210, 95% CI (0.068-0.649), p<0.01], age [HR 1.062, 95%CI (1.023-1.103), p<0.01], FVC [HR 0.967, 95%CI (0.946-0.989), p<0.01] and disease activity index (DAI) [HR 1.663, 95%CI (1.262-2.191), p<0.0001] are predictive markers of mortality due to all causes. ConclusionWe demonstrate that eGFR is a predictive marker of mortality due to SSc and to all causes, conversely RRI is predictive marker of mortality due to all causes.

Identification of Autoimmunity to Peptides of Collagen V α1 Chain as Newly Biomarkers of Early Stage of Systemic Sclerosis.

Patients with Systemic sclerosis (SSc) presents immune dysregulation, vasculopathy, and fibrosis of the skin and various internal organs. Pulmonary fibrosis leads to SSc-associated interstitial lung disease (ILD), which is the main cause of morbidity and mortality in SSc. Recently autoimmunity to type V collagen (Col V) has been characterized in idiopathic pulmonary fibrosis and show promise to be related to the development in SSc. Our aim was to evaluate autoimmunity to Col V α1(V) and α2(V) chains and to the antigenic peptides of these Col V chains in early-SSc sera employing lung tissue of SSc-ILD, as antigen source. We found that sera samples from patients with early-SSc were reactive to Col V (41.18%) and presented immunoreactivity for Col5A1(1.049) and Col5A1(1.439) peptides. The IgG isolated from early-SSc patients-anti-Col V positive sera (anti-ColV IgG) was adsorbed with α1(V) chain (anti-ColV IgG/ads-α1(V)) and α2(V) chain (anti-ColV IgG/ads-α2(V)) and biotinylated to evaluate the spectrum of reactivity in SSc-ILD patients lung biopsies by immunofluorescence. The SSc-ILD lung tissue samples immunostained with anti-ColV IgG showed increased green fluorescence in the vascular basement membrane, bronchiolar smooth muscle, and adventitial layer, contrasting with the tenue immunostaining in control lungs. Col V protein expression in these pulmonary compartments immunostained with early-SSc anti-ColV IgG was confirmed by immune colocalization assays with commercial anti-human Col V antibodies. In addition, SSc-ILD lung tissues immunostained with anti-ColV IgG/ads-α1(V) (sample in which Col V α1 chain-specific antibodies were removed) showed decreased green fluorescence compared to anti-ColV IgG and anti-ColV IgG/ads-α2(V). Our data show that autoimmunity to Col V in early-SSc was related to peptides of the α1(V) chain, suggesting that these antibodies could be biomarkers of SSc stages and potential target of immunotherapy with Col V immunogenic peptides.

Characterising Breathlessness in Systemic Sclerosis: Peak Exercise Performance is Linked to Workload-Indexed Blood Pressure Response

Cardiopulmonary involvement from systemic sclerosis (SSc) is common and 50% of patients report feeling breathless. Dyspnoea in SSc is an important determinant of quality of life and function [1]. Exercise capacity is a predictor of mortality in SSc [2], but the underlying mechanisms of the observed functional impairment are not yet elucidated. We hypothesised that vascular dysfunction, measured by the rate of change of systolic blood pressure (SBP) relative to exercise intensity (Watts), would correlate with the degree of exercise impairment in SSc.

Osteopontin Links Myeloid Activation and Disease Progression in Systemic Sclerosis

SummaryProgressive lung fibrosis is a major cause of mortality in systemic sclerosis (SSc) patients, but the underlying mechanisms remain unclear. We demonstrate that immune complexes (ICs) activate human monocytes to promote lung fibroblast migration partly via osteopontin (OPN) secretion, which is amplified by autocrine monocyte colony stimulating factor (MCSF) and interleukin-6 (IL-6) activity. Bulk and single-cell RNA sequencing demonstrate that elevated OPN expression in SSc lung tissue is enriched in macrophages, partially overlapping with CCL18 expression. Serum OPN is elevated in SSc patients with interstitial lung disease (ILD) and prognosticates future lung function deterioration in SSc cohorts. Serum OPN levels decrease following tocilizumab (monoclonal anti-IL-6 receptor) treatment, confirming the connection between IL-6 and OPN in SSc patients. Collectively, these data suggest a plausible link between autoantibodies and lung fibrosis progression, where circulating OPN serves as a systemic proxy for IC-driven profibrotic macrophage activity, highlighting its potential as a promising biomarker in SSc ILD.

Prognostic role of right ventricular and atrial mechanics in systemic sclerosis

Abstract Background Left ventricular diastolic dysfunction implies a worse prognosis in systemic sclerosis (SSc). Little is known, however, about the prognostic value of right ventricular (RV) and right atrial (RA) mechanics in this disease. Thus we aimed to investigate the long term prognostic value of the traditional and modern echocardiographic parameters of the RV and RA function as well as N-terminal pro B-type natriuretic peptide (NT-proBNP) levels in SSc patients. Patients and methods Seventy SSc patients (age: 57±12 years) were enrolled into the study. They underwent echocardiography in the years 2014–15. Parameters of the RV systolic function (tricuspid annular plane systolic excursion /TAPSE/, RV fractional area change /RVFAC/), inferior vena cava, collapsibility index, RV wall thickness were measured. Doppler data were collected: tricuspid E and A, peak velocity of tricuspid regurgitation (TR), tricuspid annular myocardial systolic (S), early- (e') and late- (a') diastolic velocities, tricuspid E/e' ratio. Maximal RA volume index as well as RA reservoir (εR), conduit (εCD) and contractile (εCT) strain were measured with the speckle tracking method. RA stiffness was calculated as ratio of E/e' to εR. Survival was assessed after 5 years. Since in some cases the cause of death was unknown, all-cause mortality was chosen as outcome. Results During the follow-up period of 4.7±0.9 years, 6 patients (8.6%) died. In univariate Cox regression analysis TAPSE, peak velocity of TR, tricuspid annular a' and S, tricuspid E/e' ratio, maximal RA volume index, RA stiffness and lnNT-proBNP were significantly associated with outcome. In multivariate Cox regression analysis RA stiffness was proved to be the only independent predictor of mortality (p=0.013). Using ROC analysis, RA stiffness ≥0.156 was the strongest predictor of the mortality (sensitivity=83.3%, specificity =89.1%, AUC=0.859). Conclusion Our results suggest that RA stiffness is an independent predictor of all-cause mortality in SSc. Larger prospective validation studies are required to prove our findings. ROC and Kaplan-Meier survival curve Funding Acknowledgement Type of funding source: None

Incidence, prevalence and mortality of systemic sclerosis in Italy: a nationwide population-based study using administrative health data.

To study incidence, prevalence and mortality of systemic sclerosis (SSc) in Italy, assessing epidemiological differences between men and women and in distinct age groups. We performed a nationwide population-based study using administrative health data from regional co-payment exemption registries. Patients entitled with SSc-specific co-payment exemption were included. Fourteen of the 20 Italian regions contributed data covering a population of over 45 million individuals. Crude annual incidence rate, annual prevalence, crude annual mortality rate and standardised mortality ratio (SMR) were calculated. In 2016, the overall crude incidence rate of SSc was 18.5 (95% CI 16.9-20.2) per million per year. Incidence rate was 31.0 (95% CI 28.1-34.1) per million in women, and 4.3 (95% CI 3.2-5.6) per million in men. Peak incidence was observed in the age range 55-69years. Overall annual prevalence was 306.1 (95% CI 301.1-311.2) per million. Prevalence was 530.8 (95% CI 521.5-540.2) per million in women and 67.8 (95% CI 64.4-71.3) per million in men, with a female to male ratio of 7.8:1. Highest prevalence was observed in the range 70-84years. Crude annual mortality rate was 27.9 (95% CI 24.9-31.1) per 1000 patients. Overall SMR in patients with SSc was 2.8 (95% CI 1.9-3.8). SMR was 3.8 (95% CI 2.9-5.1) in men and 2.6 (95% CI 1.8-3.6) in women. We provided updated estimates on epidemiology of SSc in Italy. Our findings on incidence, prevalence and mortality of SSc are consistent with previously published literature.

SYSTEMIC SCLEROSIS-ASSOCIATED PRECAPILLARY PULMONARY HYPERTENSION WITH AND WITHOUT INTERSTITIAL LUNG DISEASE: OBSERVATIONS FROM A SINGLE REFERRAL CENTER COHORT

SESSION TITLE: Diffuse Lung Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Interstitial lung disease (ILD) and precapillary pulmonary hypertension (PH) are the leading causes of morbidity and mortality in systemic sclerosis (SSc). However, whether PH is more frequent in SSc in the presence of ILD, and whether it confers an increased risk of death remains incompletely understood. METHODS: Analysis of data from SSc patients followed between 2017-2019 at the UCMC. Details regarding the presence, type and severity of ILD were obtained from HRCTs and PFTs. Precapillary pulmonary hypertension was diagnosed by RHC in accordance with guidelines (mPAP >25 mmHg, PCWP =15 mmHg and a PVR >3 WU). Continuous data were summarized as median(IQR), and count data were summarized as percentages. Cox proportional-hazards model was used to calculate hazard ratios for survival. RESULTS: We reviewed data from 184 SSc patients. Median age was 58 years (IQR 19), and the majority of the subjects were women (84%). HRCT scans were available for 169/184 (92%) of patients, with 78/169 (46%) having radiological ILD. Non-specific interstitial pneumonia was the most frequent radiographic pattern, seen in 60% of patients. Patients with ILD had worse pulmonary function compared to patients without ILD. Indeed, both FVC (76% predicted, IQR 31 vs 82% predicted, IQR 31) and DLCO (52% predicted, IQR 27 vs 72%predicted, IQR 41) were significantly lower in SSc patients with ILD compared to those without ILD. PH was more common in patients with ILD (35% vs 21%, p<0.05). However, the median mPAP was similar between both subsets (35mmHg vs 31mmmHg, in patients with versus without ILD, respectively). Similarly, we did not find a statistically significant difference in PVR, right atrial pressure or cardiac index. Amongst patients with ILD, 51% received an immunomodulator other than prednisone. Mycophenolate mofetil (MMF) was used in 36/78 (46%) of patients. Although numerically higher, there was no statistical difference in FVC between ILD patients who took MMF versus those who did not (74% predicted, IQR 36 vs 70% predicted, IQR 32, p = 0.361). In patients with combined ILD-PH, we found no correlation between mPAP and DLCO or FVC. We found no differences in mPAP or PVR between patients taking MMF versus those not taking it. Similarly, we found no difference in the percentage change in FVC between patients taking MMF versus those without. During our follow-up time, 15/78 (19.2%) ILD patients died and 8/78 (10.3%) were lost to follow up. The presence of PH was associated with a significantly higher risk of death (HR 3.69, 95%CI 1.26-10.81) in SSc patients with ILD. However, this increased hazard risk was no longer statistically significant when adjusted for FVC and DLCO. CONCLUSIONS: PH was more common in SSc patients with ILD compared to those without. Although the presence of PH may confer an increased risk of death, it does not appear to be independent of low FVC or DLCO. CLINICAL IMPLICATIONS: Prognosis of SSc-ILD DISCLOSURES: No relevant relationships by Yousef Ahmad, source=Web Response Chair of a Committee relationship with PHA Please note: PHA Medically Led Sessions, PHA Preceptorship Added 05/22/2020 by Jean Elwing, source=Web Response Removed 05/22/2020 by Jean Elwing, source=Web Response Educator relationship with PH CME Programs - PHA, Simply Speaking, Impact PH Please note: Intermittent, Ongoing Added 05/22/2020 by Jean Elwing, source=Web Response, value=Honoraria Principal Investigator relationship with Actelion, Arena, Reata, United Therapeutics Please note: Ongoing - University is Paid Directly Added 05/22/2020 by Jean Elwing, source=Web Response, value=Grant/Research Support Advisory Committee Member relationship with United Therapeutics Please note: $5001 - $20000 Added 06/05/2020 by Jean Elwing, source=Web Response, value=Consulting fee Principal Investigator relationship with Lung LLC, Liquidia, Phase Bio, Complexa, Gossamer Bio Please note: Ongoing - University is Paid Directly Added 05/22/2020 by Jean Elwing, source=Web Response, value=Grant/Research Support Member of a Committee relationship with PHA Please note: PHA Education Committee Added 05/22/2020 by Jean Elwing, source=Web Response Removed 05/22/2020 by Jean Elwing, source=Web Response Advisory Committee Member relationship with Liquidia, Acceleron Please note: $1001 - $5000 Added 06/05/2020 by Jean Elwing, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Acceleron Please note: $5001 - $20000 Added 06/05/2020 by Jean Elwing, source=Web Response, value=Consulting fee Removed 06/05/2020 by Jean Elwing, source=Web Response No relevant relationships by Jose Gomez-Arroyo, source=Web Response No relevant relationships by Nishant Gupta, source=Web Response No relevant relationships by Sarah Khan, source=Web Response No relevant relationships by Keegan Olmstead, source=Web Response No relevant relationships by Julie Windholz, source=Web Response No relevant relationships by Christine Zhou, source=Web Response