Background and Objectives: In SSc, ILD is a major cause of morbidity and mortality. We aimed to investigate the performance of DLCO (diffusing capacity of lung carbon monoxide) and FVC (forced... Show moreBackground and Objectives: In SSc, ILD is a major cause of morbidity and mortality. We aimed to investigate the performance of DLCO (diffusing capacity of lung carbon monoxide) and FVC (forced vital capacity) delta change (Delta) and baseline values in predicting the development of SSc-ILD. Methods: Longitudinal data of DLCO, FVC, and ILD on the HRCT of SSc patients from the EUSTAR database were evaluated at baseline (t0) and after 12 (+/- 4) (t1) and 24 (+/- 4) (t(2)) months. Results: 474/17805 patients were eligible for the study (403 females); 46 (9.7%) developed ILD at t(2). Positivity for anti-topoisomerase antibodies (117 patients) showed an association with ILD development at t(2) (p = 0.0031). Neither the mean t0 to t1 change (Delta) of DLCO nor the mean t(0) to t(1) FVC Delta predicted the appearance of ILD at t(2). Investigating the possible role of baseline DLCO and FVC values in predicting ILD appearance after 24 (+/- 4) months, we observed a moderate predictive capability of t(0) DLCO < 80%, stronger than that of FVC < 80%. Conclusions: We suggest that an impaired baseline DLCO may be predictive of the appearance of ILD after 2 years of follow-up. This result advances the hypothesis that a reduction in gas exchange may be considered an early sign of lung involvement. However, further rigorous studies are warranted to understand the predictive role of DLCO evaluation in the course of SSc. Show less
Deibel, E.; Carreira, P.E.; Vonk, M.; Papa, N. del; Becvár, R.; Guillén-Del-Castillo, A.; ... ; Hoffmann-Vold, A.M. 2023
ObjectiveThe outcome of patients with COVID-19 improved over the pandemic, including patients with systemic rheumatic diseases. However, data on patients with systemic sclerosis (SSc) are lacking.... Show moreObjectiveThe outcome of patients with COVID-19 improved over the pandemic, including patients with systemic rheumatic diseases. However, data on patients with systemic sclerosis (SSc) are lacking. This study aimed to assess the outcome of patients with both SSc and COVID-19 over several waves.MethodsPatients with both SSc and COVID-19 who were registered in the European Scleroderma Trials and Research group (EUSTAR) were collected between April 2020 and April 2021. Patients were assigned to waves 1, 2, or 3 depending on the date of their COVID-19 diagnosis. Primary endpoints were death, intensive care unit stay, or ventilatory support (severe outcome). Subgroup analyses of patients who were hospitalized or died were conducted. General and SSc-specific characteristics and treatment were compared over the waves. Descriptive statistics and multivariate logistic regression were applied.ResultsA total of 333 patients were included; 57 patients (17%) had a severe outcome, and 30 patients (9%) died. Compared to wave 1, significantly fewer patients with SSc suffered from severe COVID-19 in waves 2 and 3 (28.2% vs 9.8% and 12.7%; P < 0.001), fewer patients required hospitalization (46.7% vs 19.6% and 25.5%; P < 0.001) or ventilatory support (24.0% vs 8.7% and 10.9%; P = 0.001), and fewer patients died (15.7% vs 5.0% and 7.5%; P = 0.011). Patients were significantly younger, more often men, had less frequent arterial hypertension, and less SSc cardiac involvement over waves 1 to 3. Patients received significantly less medium to high doses of corticosteroids as they did SSc treatment.ConclusionThe outcome of patients with both SSc and COVID-19 improved significantly over time because of intrinsic and extrinsic factors. Show less
Importance Systemic sclerosis (SSc) sine scleroderma (ssSSc) is a subset of SSc defined by the absence of skin fibrosis. Little is known about the natural history and skin manifestations among... Show moreImportance Systemic sclerosis (SSc) sine scleroderma (ssSSc) is a subset of SSc defined by the absence of skin fibrosis. Little is known about the natural history and skin manifestations among patients with ssSSc.Objective To characterize the clinical phenotype of patients with ssSSc compared with patients with limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) within the EUSTAR database.Design, Setting, and Participants This longitudinal observational cohort study based on the international EUSTAR database included all patients fulfilling the classification criteria for SSc assessed by the modified Rodnan Skin score (mRSS) at inclusion and with at least 1 follow-up visit; ssSSc was defined by the absence of skin fibrosis (mRSS = 0 and no sclerodactyly) at all available visits. Data extraction was performed in November 2020, and data analysis was performed from April 2021 to April 2023.Main Outcomes and Measures Main outcomes were survival and skin manifestations (onset of skin fibrosis, digital ulcers, telangiectasias, puffy fingers).Results Among the 4263 patients fulfilling the inclusion criteria, 376 (8.8%) were classified as having ssSSc (mean [SD] age, 55.3 [13.9] years; 345 [91.8%] were female). At last available visit, in comparison with 708 patients with lcSSc and 708 patients with dcSSc with the same disease duration, patients with ssSSc had a lower prevalence of previous or current digital ulcers (28.2% vs 53.1% in lcSSc; P < .001; and 68.3% in dcSSc; P < .001) and puffy fingers (63.8% vs 82.4% in lcSSc; P < .001; and 87.6% in dcSSc; P < .001). By contrast, the prevalence of interstitial lung disease was similar in ssSSc and lcSSc (49.8% and 57.1%; P = .03) but significantly higher in dcSSc (75.0%; P < .001). Skin telangiectasias were associated with diastolic dysfunction in patients with ssSSc (odds ratio, 4.778; 95% CI, 2.060-11.081; P < .001). The only independent factor for the onset of skin fibrosis in ssSSc was the positivity for anti–Scl-70 antibodies (odds ratio, 3.078; 95% CI, 1.227-7.725; P = .02). Survival rate was higher in patients with ssSSc (92.4%) compared with lcSSc (69.4%; P = .06) and dcSSc (55.5%; P < .001) after up to 15 years of follow-up.Conclusions and Relevance Systemic sclerosis sine scleroderma should not be neglected considering the high prevalence of interstitial lung disease (>40%) and SSc renal crisis (almost 3%). Patients with ssSSc had a higher survival than other subsets. Dermatologists should be aware that cutaneous findings in this subgroup may be associated with internal organ dysfunction. In particular, skin telangiectasias in ssSSc were associated with diastolic heart dysfunction. Show less
Elhai, M.; Sritharan, N.; Boubaya, M.; Balbir-Gurman, A.; Siegert, E.; Hachulla, E.; ... ; USTAR Collaborators 2022
Background The current subclassification of systemic sclerosis into cutaneous subtypes does not fully capture the heterogeneity of the disease. We aimed to compare the performances of... Show moreBackground The current subclassification of systemic sclerosis into cutaneous subtypes does not fully capture the heterogeneity of the disease. We aimed to compare the performances of stratification into LeRoy's cutaneous subtypes versus stratification by autoantibody status in systemic sclerosis. Methods For this cohort study, we assessed people with systemic sclerosis in the multicentre international European Scleroderma Trials and Research (EUSTAR) database. Individuals positive for systemic-sclerosis autoantibodies of two specificities were excluded, and remaining individuals were classified by cutaneous subtype, according to their systemic sclerosis-specific autoantibodies, or both. We assessed the performance of each model to predict overall survival, progression-free survival, disease progression, and different organ involvement. The three models were compared by use of the area under the curve (AUC) of the receiver operating characteristic and the net reclassification improvement (NRI). Missing data were imputed. Findings We assessed the database on July 26, 2019. Of 16 939 patients assessed for eligibility, 10 711 patients were included: 1647 (15middot4%) of 10 709 were male, 9062 (84middot6%) were female, mean age was 54middot4 (SD 13middot8) years, and mean disease duration was 7middot9 (SD 8middot2) years. Information regarding cutaneous subtype was available for 10 176 participants and antibody data were available for 9643 participants. In the prognostic analysis, there was no difference in AUC for overall survival (0middot82, 95% CI 0middot81-0middot84 for cutaneous only vs 0middot84, 0middot82-0middot85 for antibody only vs 0middot84, 0middot83-0middot86 for combined) or for progression-free survival (0middot70, 0middot69-0middot71 vs 0middot71, 0middot70-0middot72 vs 0middot71, 0middot70-0middot72). However, at 4 years the NRI showed substantial improvement for the antibody-only model compared with the cutaneous-only model in prediction of overall survival (0middot57, 0middot46-0middot71 for antibody only vs 0middot29, 0middot19-0middot39 for cutaneous only) and disease progression (0middot36, 0middot29-0middot46 vs 0middot21, 0middot14-0middot28). The antibody -only model did better than the cutaneous-only model in predicting renal crisis (AUC 0middot72, 0middot70-0middot74 for antibody only vs 0middot66, 0middot64-0middot69 for cutaneous only) and lung fibrosis leading to restrictive lung function (AUC 0middot76, 0middot75-0middot77 vs 0middot71, 0middot70-0middot72). The combined model improved the prediction of digital ulcers and elevated systolic pulmonary artery pressure, but did poorly for cardiac involvement. Interpretation The autoantibody-only model outperforms cutaneous-only subsetting for risk stratifying people with systemic sclerosis in the EUSTAR cohort. Physicians should be aware of these findings at the time of decision making for patient management. Copyright (C) 2022 Elsevier Ltd. All rights reserved. Show less
Objectives The prevalence and characteristics of SSc-associated interstitial lung disease (SSc-ILD) vary between geographical regions worldwide. The objectives of this study were to explore the... Show moreObjectives The prevalence and characteristics of SSc-associated interstitial lung disease (SSc-ILD) vary between geographical regions worldwide. The objectives of this study were to explore the differences in terms of prevalence, phenotype, treatment and prognosis in patients with SSc-ILD from predetermined geographical regions in the EUSTAR database. Material and methods Patients were clustered into seven geographical regions. Clinical characteristics and survival of patients with SSc-ILD were compared among these pre-determined regions. Results For baseline analyses, 9260 SSc patients were included, with 6732 for survival analyses. The prevalence of SSc-ILD in the overall population was 50.2%, ranging from 44.0% in 'Western Europe and Nordic countries' to 67.5% in 'Eastern European, Russia and Baltic countries'. In all regions, anti-topoisomerase antibodies were associated with SSc-ILD. Management also significantly differed; mycophenolate mofetil was prescribed at baseline in 31.6% of patients with SSc-ILD in 'America (North and South)' and 31.7% in 'Middle East' but only 4.3% in 'Asia and Oceania' (P <0.0001). Patients from 'America (North and South)' and 'Middle East' had the highest survival rate at the end of follow-up (85.8% and 85.2%, respectively). Conclusions Our study highlights key differences among regions in terms of clinical presentation and prognosis of SSc-ILD. This work also demonstrates that the management of SSc-ILD is highly variable among the different regions considered, suggesting that efforts are still needed for the standardization of medical practice in the treatment of this disease. Show less
Background Nintedanib is a tyrosine kinase inhibitor used in the treatment of progressive fibrosing interstitial lung diseases (ILDs). We assessed the safety and tolerability of nintedanib in... Show moreBackground Nintedanib is a tyrosine kinase inhibitor used in the treatment of progressive fibrosing interstitial lung diseases (ILDs). We assessed the safety and tolerability of nintedanib in patients with autoimmune disease-related ILDs and with other ILDs in subgroups by sex.Methods In this post-hoc analysis, we pooled data from the two INPULSIS trials in patients with idiopathic pulmonary fibrosis (IPF), the SENSCIS trial in patients with fibrosing ILDs associated with systemic sclerosis, and the INBUILD trial in patients with progressive fibrosing ILDs other than IPF. In each trial, patients were randomly assigned to receive oral nintedanib 150 mg twice daily or matched placebo. We assessed adverse events reported over 52 weeks in patients with autoimmune disease-related ILDs and other ILDs in subgroups by sex.Findings In these analyses, we included 746 patients with autoimmune disease-related ILDs (523 [70%] were female, 223 [30%] were male; 615 [82%] had systemic sclerosis), of whom 370 (50%) received nintedanib (268 [72%] female and 102 [28%] male patients) and 376 (50%) received placebo (255 [68%] female and 121 (32%] male patients); and 1554 patients with other ILDs (437 [28%J female, 1117 [72%] male; 1061 [68%] with IPF), of whom 888 (57%) received nintedanib (237 [27%] female and 651 [73%] male patients) and 666 (43%) received placebo (200 [30%]female and 466 [70%] male patients). Of 102 male and 268 female patients with autoimmune disease-related ILDs treated with nintedanib, nausea was reported in 21 (21%) male and 92 (34%) female patients, vomiting in 12 (12%) male and 73 (27%) female patients, alanine aminotransferase increase in four (4%) male and 31(12%) female patients, aspartate aminotransferase increase in three (3%) male and 23 (9%) female patients, and adverse events leading to dose reduction in 18 (18%) male and 101 (38%) female patients; 28 (27%) male and 107 (40%) female patients had at least one treatment interruption. Of 651 male and 237 female nintedanib-treated patients with other ILDs, nausea was reported in 135 (21%) male and 95 (40%) female patients, vomiting in 51 (8%) male and 70 (30%) female patients, alanine aminotransferase increase in 19 (3%) male and 31 (13%) female patients, aspartate aminotransferase increase in 17 (3%) male and 26 (11%) female patients, and adverse events leading to dose reduction in 106 (16%) male and 84 (35%) female patients; 155 (24%) male and 82 (35%) female patients had at least one treatment interruption. The proportions of patients with adverse events leading to discontinuation of nintedanib were similar between female and male patients with autoimmune disease-related ILDs (44 [16%] of 268 vs 17 [17%] of 102), but were greater among female than male patients with other ILDs (62 [26%] of 237 vs 112 [17%] of 651). Across subgroups by diagnosis and sex, diarrhoea was the most frequent adverse event associated with nintedanib (autoimmune-related ILDs: 198 [74%] of 268 female and 73 [72%] of 102 male patients; other ILDs: 155 [65%] of 237 female and 408 [63%] of 651 male patients), and was the event that most frequently led to treatment discontinuation (autoimmune-related ILDs: 20 [7%] female and five [5%] male patients; other ILDs: 16 [7%] female and 27 [4%] male patients).Interpretation The adverse event profile of nintedanib was generally similar between male and female patients with autoimmune disease-related ILDs, and between male and female patients with other ILDs, but nausea, vomiting, liver enzyme elevations, dose reductions, and treatment interruptions were more frequent in female patients than in male patients. Sex should be considered in the monitoring and management of adverse events that might be associated with nintedanib. Copyright (C) 2022 Elsevier Ltd. All rights reserved. Show less
Liem, S.I.E.; Boonstra, M.; Cessie, S. le; Riccardi, A.; Airo, P.; Distler, O.; ... ; EUSTAR Collaborators 2022
Background We aimed to evaluate sex-specific risk of anti-topoisomerase I antibodies (ATA) on mortality, diffuse cutaneous systemic sclerosis, interstitial lung disease, and pulmonary hypertension... Show moreBackground We aimed to evaluate sex-specific risk of anti-topoisomerase I antibodies (ATA) on mortality, diffuse cutaneous systemic sclerosis, interstitial lung disease, and pulmonary hypertension in two cohorts of people with systemic sclerosis.Methods This study was a 10-year analysis of the prospective Leiden Combined Care in Systemic Sderosis (CCISS) cohort in the Netherlands and the international European Scleroderma Trials and Research (EUSTAR) cohort. We included participants with systemic sderosis according to the 2013 American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) classification criteria; available autoantibody status; available skin subtyping; at least one available radiographic assessment of interstitial lung disease; and with a known date of disease onset. People with systemic sclerosis were categorised in six risk groups by sex and autoantibody status (anti-centromere antibody [ACA]-positive female, ACA-positive male, ACA and ATA-negative female, ACA and ATA-negative male, ATA-positive female, and ATA-positive male). We constructed Kaplan-Meier curves and Cox proportional hazard models, accounting for left-truncated survival to prevent bias because the date of disease onset (first non-Raynaud's symptom) preceded the date of cohort entry for all patients. The primary outcome was all-cause mortality and the secondary outcomes were diffuse cutaneous systemic sclerosis, interstitial lung disease, and pulmonary hypertension.Findings 445 (63%) of 708 participants between April 1,2009, and Jan 1,2022, in CCISS (101 [23%] male and 344[77%] female) and 4263 (50%) of 8590 between June 1, 2004, and March 28,2018, in EUSTAR (783[18%] male and 3480 [82%] female) were eligible for this study. In both cohorts, ATA expression occurred significantly more often in males than in females (39 [39%] of 101 males vs 67 [19%] of 344 females in CCISS; p<0.0001 and 381 [49%] of 783 males vs 1323 [38%] of 3480 females in EUSTAR; p<0. 0001). According to estimated survival rates, 30% of ATA-positive males versus 12% of ATA-positive females died in the CCISS cohort and 33% versus 15% died in the EUSTAR cohort within 10 years. After adjustment for age, race, and autoantibody status, male sex remained the most important risk factor for all-cause mortality (HR 2.9 [95% CI 1.5-5.5] in CCISS, 0.0018; and HR 2.6 [2.0-3.4] in EUSTAR, p<0.0001).Interpretation We show that the association between male sex and increased mortality in systemic sclerosis cannot be explained by higher ATA prevalence. However, additional research on the effect of sex-specific characteristics on people with systemic sclerosis is required. Copyright (C) 2022 Elsevier Ltd. All rights reserved. Show less
Objective To develop and validate the prognostic prediction model DU-VASC to assist the clinicians in decision-making regarding the use of platelet inhibitors (PIs) for the management of digital... Show moreObjective To develop and validate the prognostic prediction model DU-VASC to assist the clinicians in decision-making regarding the use of platelet inhibitors (PIs) for the management of digital ulcers in patients with systemic sclerosis. Secondly, to assess the incremental value of PIs as predictor. Methods We analysed patient data from the European Scleroderma Trials and Research group registry (one time point assessed). Three sets of derivation/validation cohorts were obtained from the original cohort. Using logistic regression, we developed a model for prediction of digital ulcers (DUs). C-Statistics and calibration plots were calculated to evaluate the prediction performance. Variable importance plots and the decrease in C-statistics were used to address the importance of the predictors. Results Of 3710 patients in the original cohort, 487 had DUs and 90 were exposed to PIs. For the DU-VASC model, which includes 27 predictors, we observed good calibration and discrimination in all cohorts (C-statistic = 81.1% [95% CI: 78.9%, 83.4%] for the derivation and 82.3% [95% CI: 779.3%, 85.3%] for the independent temporal validation cohort). Exposure to PIs was associated with absence of DUs and was the most important therapeutic predictor. Further important factors associated with absence of DUs were lower modified Rodnan skin score, anti-Scl-70 negativity and normal CRP. Conversely, the exposure to phosphodiesterase-5 inhibitor, prostacyclin analogues or endothelin receptor antagonists seemed to be associated with the occurrence of DUs. Nonetheless, previous DUs remains the most impactful predictor of DUs. Conclusion The DU-VASC model, with good calibration and discrimination ability, revealed that PI treatment was the most important therapy-related predictor associated with reduced DU occurrence. Show less
Acosta-Herrera, M.; Kerick, M.; Lopez-Isac, E.; Assassi, S.; Beretta, L.; Simeon-Aznar, C.P.; ... ; Australian Scleroderma Inter 2021
Objective The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we... Show moreObjective The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes. Methods 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA). Results Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1*11:04 and HLA-DPB1*13:01, and revealed a novel association of HLA-B*08:01. Stratified analyses showed specific associations of HLA-DQA1*02:01 with lcSSc, and an exclusive association of HLA-DQA1*05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1*08:01 and confirmed the previously reported association of HLA-DRB1*07:01 with ACA-positive patients, as opposed to the HLA-DPA1*02:01 and HLA-DQB1*03:01 alleles associated with ATA presentation. Conclusions This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression. Show less
Vries-Bouwstra, J.K. de; Allanore, Y.; Matucci-Cerinic, M.; Balbir-Gurman, A. 2020
Objective. To evaluate agreement of the updated European League Against Rheumatism and European Scleroderma Trials and Research group (EUSTAR) recommendations for treatment of systemic sclerosis ... Show moreObjective. To evaluate agreement of the updated European League Against Rheumatism and European Scleroderma Trials and Research group (EUSTAR) recommendations for treatment of systemic sclerosis (SSc) among international experts. In addition, to determine factors that might influence agreement.Methods. Level of agreement (10-point scale: 0 = not at all, 10 = completely agree) and local drug availability (yes/no) were assessed using an online survey. The Web link to the survey was shared with 481 unique e-mail addresses and SSc networks (Scleroderma Clinical Trials Consortium, Australian Scleroderma Interest Group, International Systemic Sclerosis Inception Cohort). Level of agreement was compared between subgroups stratified for participant characteristics.Results. In total, 263 experts participated, of whom n = 209 (79%) completed each single item. The majority were rheumatologists (n = 200, 76%) working in Europe (n = 185; 71%); 59% (n = 156) were EUSTAR members; and 57% (n = 151) had > 10 years of clinical experience. Overall level of agreement was high (mean 8.0, SD 2.5). The 3 highest mean agreements included (1) angiotensin-converting enzyme inhibitors for scleroderma renal crisis (9.2, SD 2.1); (2) blood pressure control in SSc-patients treated with corticosteroids (9.0, SD 2.2); (3) proton pump inhibitors to prevent reflux complications (9.0, SD 2.2). The 3 lowest mean agreements included (1) fluoxetine for Raynaud phenomenon (RP; 4.6, SD 2.8); (2) hematopoietic stem cell transplantation (HSCT) for severe SSc (7.1, SD 2.9); (3) phosphodiesterase inhibitors 5 for RP (7.3, SD 2.7). Agreement differed between Europe and non-Europe for the use of iloprost, bosentan, methotrexate, HSCT, and cyclophosphamide. Treatment availability could partially explain differential agreement for iloprost, bosentan, and HSCT.Conclusion. In general, worldwide expert agreement on updated recommendations for treatment of SSc is high, supporting their value. Differences in agreement are partially explained by geographical area and treatment availability. Show less
Lopez-Isac, E.; Acosta-Herrera, M.; Kerick, M.; Assassi, S.; Satpathy, A.T.; Granja, J.; ... ; ASIG 2019
Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis... Show moreSystemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments. Show less
Mihai, C.; Landewe, R.; Heijde, D. van der; Walker, U.A.; Constantin, P.I.; Gherghe, A.M.; ... ; EUSTAR 2016
