Mortality In Systemic Sclerosis Research Articles

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 <20% vs> 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 <.005), a result which was further confirmed among non-ILD vs ILD> 20% (median 47 vs 9, p=.001) and ILD <20% (median 36 vs 9, p=.001) patients. Conversely, the number of B-lines was not statistically different between patients with ILD <20% and >20% (median 47 vs 36, p=.78). We observed a significant negative correlation between the number of B-lines and FVC (r=-.472, p<.05) TLC (r=-.436, p=.003), DLco (r=-.515, p<.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<.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

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

Exercise Pulmonary Resistances Predict Long-Term Survival in Systemic Sclerosis

Pulmonary hemodynamics during exercise may reveal early pulmonary vascular disease and may be of clinical and prognostic relevance in systemic sclerosis (SSc). We aimed to assess the prognostic relevance of exercise pulmonary resistances in patients with SSc with no or mildly increased mean pulmonary arterial pressure (mPAP). Are pulmonary resistances at peak exercise independent predictors of mortality in systemic sclerosis? All SSc patients with resting mPAP< 25mmHg and at least one year of follow-up data who underwent symptom-limited exercise right heart catheterization between April 2005 and December 2018 were analyzed retrospectively. Age-adjusted Cox regression analysis was used to evaluate the association between pulmonary resistances and all-cause mortality. The cohort consisted of 80 patients: 73 women and 7 men with a mean age of 57 years (interquartile range [IQR], 47-67 years) and a mean follow-up time of 10.4 years (IQR, 8.5-11.8 years). At baseline, resting mPAP of≤ 20mmHg and 21 to 24mmHg was found in 68 and 12 patients, respectively. Pulmonary vascular resistance (PVR) and total pulmonary resistance (TPR) at peak exercise were associated significantly with mortality (P= .006 [hazard ratio (HR), 2.20; 95%CI, 1.26-3.87] and P= .026 [HR, 1.56; 95%CI, 1.06-2.29]), whereas resting PVR and TPR were not (P= .087 [HR, 2.27; 95%CI, 0.89-5.83] and P= .079 [HR, 1.88; 95%CI, 0.93-3.80]). The mPAP per cardiac output (CO) and transpulmonary gradient (TPG) per CO slopes were associated significantly with mortality (P= .047 [HR, 1.14; 95%CI, 1.002-1.286] and P= .034 [HR, 1.34; 95%CI, 1.02-1.76]) as well. The area under the receiver operating characteristic curve for exercise PVR to predict 10-year mortality was 0.917 (95%CI, 0.797-1.000). PVR and TPR at peak exercise, mPAP/CO slope, and TPG/CO slope are predictors of age-adjusted long-term mortality in SSc patients with no or mildly increased pulmonary arterial pressure.

Systemic sclerosis is an independent risk factor for ischemic heart disease, especially in patients carrying certain antiphospholipid antibodies: A large cross-sectional study

BackgroundA higher prevalence of ischemic heart disease (IHD) in patients with systemic sclerosis (SSc) was reported. However, contrasting findings were published concerning the role of SSc-related autoantibodies in IHD risk which remains controversial. The current study explored the link between SSc and IHD, impact of putative links on SSc mortality and the role of SSc-related and antiphospholipid autoantibodies in disease associated IHD. MethodsA large cohort study utilising the Clalit-Health-Service (CHS) database was conducted on 2431 SSc patients and 12,710 age- and sex matched controls. The proportion of IHD was compared between patients diagnosed with SSc and age- and gender-matched controls. The role of SSc-linked and antiphospholipid autoantibodies in disease associated IHD was assessed. ResultsThe prevalence rate of IHD was significantly higher in SSc than controls (20.4% vs 15.0%, p <0.001). At the multivariate analysis, SSc was an independent predictor of IHD with an OR of 1.91 (95%CI 1.57–2.31, p < 0.0001). SSc patients with IHD had a higher mortality rate with an HR of 2.67 (95%CI 2.03–3.53, p < 0.0001) than those without IHD. In SSc patients positivity for anti-beta2GPI (IgM-isotype) or anti-cardiolipin (aCL) (IgA-isotype) represented a risk factor for IHD with an OR 1.89 (95% 1.04–3.45, p = 0.0369) and OR of 3.72 (95% 1.25–11.11, p = 0.0184), respectively. ConclusionsPatients with SSc are at higher risk for developing IHD with an additional risk for the latter in those positive for aCL or anti-beta2GPI. A high degree of suspicion is needed during routine patient follow-up and pre-emptive screening should be considered.

Overall mortality.

Systemic sclerosis is a highly morbid, complex autoimmune disease that is variable both in its phenotype and the attendant mortality driven by such manifestations. This review article synthesizes mortality data from the best available meta-analyses, subgroup analyses of single cohorts, and subjective comparisons of individual cohort studies, which in aggregate suggest that mortality in systemic sclerosis has been gradually improving over the past several decades. This review also summarizes the literature describing various risk factors for mortality in systemic sclerosis.

Polyporus Polysaccharide Ameliorates Bleomycin-Induced Pulmonary Fibrosis by Suppressing Myofibroblast Differentiation via TGF-β/Smad2/3 Pathway.

Pulmonary fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc) with no effective medication. Polyporus polysaccharide (PPS), extracted from Chinese herbs, has immune regulation, anticancer, antioxidant and antiinflammatory activities. This study aims to investigate antifibrotic effects of PPS. We show that PPS markedly ameliorates bleomycin-induced lung fibrosis in mice. Myofibroblasts are the effector cells responsible for excessive deposition of extracellular matrix (ECM) proteins in fibrotic diseases. In vitro evidence reveals that PPS exerts potent antifibrotic effects by inhibiting fibroblast-to-myofibroblast transition, suppressing ECM deposition, and repressing lung fibroblast proliferation and migration. We also find that PPS inhibits TGF-β1-induced Smad2/3 activating. This study is the first to demonstrate an antifibrotic role of PPS in lungs, thus warranting further therapeutic evaluation.

Update on Morbidity and Mortality in Systemic Sclerosis-Related Interstitial Lung Disease.

Contemporary studies of systemic sclerosis (SSc) consistently demonstrate that interstitial lung (ILD) is a leading cause of disease-related death. This review summarizes morbidity and mortality outcomes in SSc-ILD patients from high-quality observational and interventional studies over the last 50 years. The data presented suggest a trend for improved morbidity and mortality outcomes among present day SSc-ILD patients. Specifically, SSc-ILD patients appear to be living longer from the time of the initial diagnosis. Despite improved survival, the number one cause of death for most SSc-ILD patients remains respiratory failure from ILD. This review describes the most important demographic, clinical, and biological factors, which affect mortality in SSc-ILD, and could be used to help stratify patients for closer monitoring and more aggressive initial treatment. The review concludes with an overview of future research needed to (1) understand how to personalize the care of SSc-ILD patients to improve morbidity and mortality outcomes; and (2) investigate whether novel therapeutic interventions (e.g., anti-fibrotics, hematopoetic stem-cell transplantation) offer any meaningful long-term survival advantage over the current standard of care.

Spanish scleroderma risk score (RESCLESCORE) to predict 15-year all-cause mortality in scleroderma patients at the time of diagnosis based on the RESCLE cohort: Derivation and internal validation.

A few scores predicting the short-term risk of mortality in Systemic sclerosis (SSc) have been reported to date. Our study aimed to create a predictive 15-year all-cause mortality score at the time of the diagnosis of SSc. The study was based on the Spanish Scleroderma Registry (RESCLE). The cohort was split up in derivation (DC) and validation cohort (VC). A multivariate analysis to detect variables related to all-cause mortality within the first 15years from SSc diagnosis was performed, assigning points to the rounded beta values to create the score (RESCLESCORE). 1935 SSc patients were included. The variables in the final model were as follows: age at diagnosis (+2 points>65years-old), male gender (+1 point), lcSSc subset (-1 point), mode of onset other than Raynaud's (+1 point), cancer (+1 point) and visceral involvement, such as ILD (+1 point), PAH (+1 point), heart (+1 point) and renal involvement (+2 points). Autoantibodies did not achieve statistical significance in the multivariate analysis. The 3 categories of risk to predict 15-year all-cause mortality at the time of diagnosis were as follows: low risk (5% vs. 7%, p=.189), intermediate risk (26.5% vs. 25.5%, p=.911) and high risk (47.8% vs. 59%, p=.316). The AUC was 0.799 (DC) vs. 0.778 (VC) (p=.530). In conclusion, the RESCLESCORE demonstrated an excellent ability to categorize SSc patients at the time of diagnosis in separate 15-year all-cause mortality risk strata at the time of diagnosis.

Early trajectories of skin thickening are associated with severity and mortality in systemic sclerosis

BackgroundSystemic sclerosis (SSc) is a severe and highly heterogeneous disease. The modified Rodnan skin score (mRSS) is a widely used tool for the assessment of the extent and degree of skin thickness. This study aimed to identify the classes of patients with early similar skin thickening trajectories without any a priori assumptions and study their associations with organ involvement and survival.MethodsFrom the French SSc national cohort, patients with a disease duration of less than 2 years at inclusion and with at least 2 mRSS available within the first 4 years of follow-up were enrolled. Classes of patients with similar mRSS trajectories were identified based on a latent class mixed model. The clinical characteristics and survival rate were compared between the obtained classes.ResultsA total of 198 patients fulfilled the inclusion criteria, with a total of 641 mRSS available. The median disease duration and follow-up were 0.8 (interquartile range 0.4; 1.2) and 6.3 (3.8; 8.9) years, respectively. Individual trajectories of mRSS were highly heterogeneous between patients. Models with 1–6 latent classes of trajectories were sequentially assessed, and the 5-class model represented the best fit to data. Each class was characterized by a unique global trajectory of mRSS. The median disease duration did not differ significantly between classes. Baseline organ involvement was more frequent in classes with significant change over time (classes 2–5) than in class 1 (low baseline mRSS without significant change over time). Using Cox regression, we observed a progressively increasing risk of death from classes 1 to 5.ConclusionsEarly identification of clinical phenotype based on skin thickening trajectories could predict morbi-mortality in SSc. This study suggested that mRSS trajectories characterization might be pivotal for clinical practice and future trial designs.

Assessment of interstitial lung disease in systemic sclerosis using the quantitative CT algorithm CALIPER.

Interstitial lung disease (ILD) remains a major cause of morbidity and mortality in systemic sclerosis (SSc). Study aim is to characterize and quantify SSc-ILD by using Computer-Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER). Secondly, our objective is to evaluate which radiological pattern is predictive of lung function decline at 12months follow-up. In the prospective study (IRB 5435), 66 SSc patients underwent high-resolution computerized tomography (HRCT) at baseline. HRCT was performed according to standard protocol using a CT 64GE light speed VCT power scanner. CALIPER classified lung parenchyma on volume units. Every volume unit was classified into radiological parenchymal patterns (honeycombing, reticular and ground glass). Pulmonary function tests (PFTs) were performed at baseline and after 12months of follow-up. Cigarette smoking and other lung diseases unrelated to SSc are exclusion criteria. CALIPER analysis showed normal lung parenchyma 87.4± 9.8%, ground glass 2.8± 5.3%, reticular 4 ± 5.7%, and honeycombing 1 ± 1%. In multiple regression analysis, FEV1 (p < 0.0001), FVC (p = 0.001), and DLCO (p < 0.0001) measurements at baseline showed a negative correlation with the reticular pattern percentage. At follow-up, DLCO reduction showed a positive correlation (p < 0.001) with the percentage of ground glass pattern (r = 0.33, beta coefficient = 0.51). In the ROC curve analysis, ground glass score is a good predictor (0.75, p = 0.009; 95% CI 0.59-0.91) of DLCO worsening, defined as a decrease of more than 10% of DLCO. Using a cutoff ≥ 4.5 for ground glass score, the RR for DLCO worsening is 6.8 (p < 0.01; 95% CI 1.6-29.2). The results of this study show that CALIPER is useful not only for quantifying lung damage but also for assessing worsening PFTs, but larger studies are needed to confirm these preliminary data.Key Points• At baseline reticular pattern showed negative correlation with PFTs• At follow-up ground glass pattern predicts worsening of DLCO• CALIPER is a useful to quantify lung damage.

Cardiovascular Magnetic Resonance Identifies High-Risk Systemic Sclerosis Patients with Normal Echocardiograms and Provides Incremental Prognostic Value.

Background: Acute cardiac events are a significant contributor to mortality in systemic sclerosis (SSc). However, echocardiographic evaluation may be deceptively normal during an acute presentation. We hypothesized that in diffuse SSc patients presenting with acute cardiac events and a normal echocardiogram, cardiovascular magnetic resonance (CMR) would have incremental diagnostic/prognostic value. Methods. 50 consecutive diffuse SSc patients with normal echocardiograms were evaluated using a 1.5T system. A total of 27 (63%) had experienced an acute cardiac event three to tendays before CMR evaluation (rhythm disturbances, angina pectoris, shortness of breath). Left/right ventricular (LV/RV) volumes and ejection fractions (EF), as well as LV mass, the T2-signal ratio, early/late gadolinium enhancement (EGE/LGE), native/post-contrast T1-mapping, T2-mapping and extracellular volume fraction (ECV) were compared between the event and no-event groups. Results: No differences were identified in LV/RV volumes/EF/mass. In logistic regression analyses, independent predictors of belonging to the event group were EGE (odds ratio (95% CI): 1.55 (1.06–2.26), p = 0.024), LGE (1.81 (1.23–2.67), p = 0.003), T2 mapping (1.20 (1.06–1.36), p = 0.004) and native/post-contrast T1 mapping (1.17 (1.04–1.32), p = 0.007 and 0.86 (0.75–0.98), p = 0.025). At a median follow-up of ~1.2 years, 42% vs. 11% of the event/no-event group respectively reached a combined endpoint of event occurrence/recurrence or cardiovascular mortality. Of the independent predictors resulting from logistic regression analyses, only LGE (hazard ratio (95% CI): 1.20 (1.11–1.30), p < 0.001), T2-mapping (1.07 (1.01–1.14), p = 0.025) and native T1-mapping (1.08 (1.01–1.15), p = 0.017) independently predicted the combined endpoint. Conclusions: A normal echocardiogram does not preclude myocardial lesions in diffuse SSc patients, which can be detected by CMR especially in symptomatic patients.