| 1. |
- Elhai, M, et al.
(author)
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Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study
- 2019
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In: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:7, s. 979-987
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Journal article (peer-reviewed)abstract
- To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice.MethodsWe performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab.Results254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47–5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55–1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56–3.53], p<0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83–9.62]; p=0.019 as compared with controls vs 3 [0.66–5.35]; p=0.012).ConclusionRituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.
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| 2. |
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| 3. |
- Becker, M, et al.
(author)
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Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis
- 2019
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In: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:9, s. 1242-1248
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Journal article (peer-reviewed)abstract
- Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database.MethodsInclusion criteria were diagnosis of diffuse SSc and follow-up over 12±3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression.ResultsOf 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model.ConclusionsThe use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials.
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| 4. |
- Gossec, L., et al.
(author)
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European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies : 2015 update
- 2016
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In: Annals of the Rheumatic Diseases. - London : BMJ Books. - 0003-4967 .- 1468-2060. ; 75:3, s. 499-510
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Journal article (peer-reviewed)abstract
- BACKGROUND: Since the publication of the European League Against Rheumatism recommendations for the pharmacological treatment of psoriatic arthritis (PsA) in 2012, new evidence and new therapeutic agents have emerged. The objective was to update these recommendations.METHODS: A systematic literature review was performed regarding pharmacological treatment in PsA. Subsequently, recommendations were formulated based on the evidence and the expert opinion of the 34 Task Force members. Levels of evidence and strengths of recommendations were allocated.RESULTS: The updated recommendations comprise 5 overarching principles and 10 recommendations, covering pharmacological therapies for PsA from non-steroidal anti-inflammatory drugs (NSAIDs), to conventional synthetic (csDMARD) and biological (bDMARD) disease-modifying antirheumatic drugs, whatever their mode of action, taking articular and extra-articular manifestations of PsA into account, but focusing on musculoskeletal involvement. The overarching principles address the need for shared decision-making and treatment objectives. The recommendations address csDMARDs as an initial therapy after failure of NSAIDs and local therapy for active disease, followed, if necessary, by a bDMARD or a targeted synthetic DMARD (tsDMARD). The first bDMARD would usually be a tumour necrosis factor (TNF) inhibitor. bDMARDs targeting interleukin (IL)12/23 (ustekinumab) or IL-17 pathways (secukinumab) may be used in patients for whom TNF inhibitors are inappropriate and a tsDMARD such as a phosphodiesterase 4-inhibitor (apremilast) if bDMARDs are inappropriate. If the first bDMARD strategy fails, any other bDMARD or tsDMARD may be used.CONCLUSIONS: These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion. © 2015 BMJ Publishing Group Ltd & European League Against Rheumatism.
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| 5. |
- Herrick, A. L., et al.
(author)
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Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study
- 2018
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 77:4, s. 563-570
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Journal article (peer-reviewed)abstract
- Objectives Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). Methods The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). Results 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Conclusions Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. Trial registration number NCT02339441. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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| 6. |
- Adewumi, Oluseun, et al.
(author)
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Characterization of human embryonic stem cell lines by the International Stem Cell Initiative
- 2007
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In: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 25:7, s. 803-816
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Journal article (peer-reviewed)abstract
- The International Stem Cell Initiative characterized 59 human embryonic stem cell lines from 17 laboratories worldwide. Despite diverse genotypes and different techniques used for derivation and maintenance, all lines exhibited similar expression patterns for several markers of human embryonic stem cells. They expressed the glycolipid antigens SSEA3 and SSEA4, the keratan sulfate antigens TRA-1-60, TRA-1-81, GCTM2 and GCT343, and the protein antigens CD9, Thy1 (also known as CD90), tissue- nonspecific alkaline phosphatase and class 1 HLA, as well as the strongly developmentally regulated genes NANOG, POU5F1 (formerly known as OCT4), TDGF1, DNMT3B, GABRB3 and GDF3. Nevertheless, the lines were not identical: differences in expression of several lineage markers were evident, and several imprinted genes showed generally similar allele-specific expression patterns, but some gene-dependent variation was observed. Also, some female lines expressed readily detectable levels of XIST whereas others did not. No significant contamination of the lines with mycoplasma, bacteria or cytopathic viruses was detected.
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| 7. |
- Colic, J, et al.
(author)
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ALTERED FIBRIN CLOT PROPERTIES IN PATIENTS WITH SYSTEMIC SCLEROSIS
- 2020
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 695-696
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Conference paper (other academic/artistic)abstract
- Vasculopathy in Systemic sclerosis (SSc) is connected with the activation of coagulation. However, the fibrinolytic activity still remains unclear since the most preliminary evidences are discordant (1, 2).Objectives:To assess the haemostatic function, fibrin clot density and clot lysis time in SSc patients and healthy controls (HC) to determine their relation to disease findings.Methods:Patients who fulfilled the 2013 ACR/EULAR SSc criteria and have never been treated with endothelin receptor antagonist, phosphodiesterase 5 inhibitors or prostanoids were eligibile. Our study included 58 SSc patients [36 limited (lcSSc) and 22 diffuse cutaneous SSc (dcSSc)] and 46 sex/age-matched HC. Clinical evaluation of patients was performed, including high-resolution CT (HRCT), pulmonary function tests and the revised EUSTAR activity index. The interstitial lung disease (ILD) group (n = 15) was defined as moderate or severe changes on HRCT, with a forced vital capacity (FVC) < 85% predicted, without evidence of significant pulmonary arterial hypertension. The serum concentration of ICAM1 and von Willebrand factor antigen (VWF) were measured by ELISA. Haemostatic potential parameters; including overall haemostasis (OHP), overall coagulation (OCP) and overall fibrinolysis (OFP) potential, were assessed and endogenous thrombin potential (ETP) was determined. Maximum absorbance (Cmax), reflects the fibrin clot density and clot lysis time (Lys50t0), reflects fibrinolytic susceptibility, were calculated from OHP and OCP curves (3). Fibrin structure was visualised using scanning electron microscopy (SEM).Results:The OFP value was significantly decreased, Lys50t0 prolonged (p<0.05), while OHP and ETP were increased (p<0.05) in patients. In dSSc group ETP, OHP, Cmax and Lys50t0 were higher compared to HC (p<0.05). In SSc group, a positive association was found between coagulation parameters (OCP, OHP, Cmax) and the erythrocyte sedimentation rate (ESR), fibrinogen and ICAM1 (respectively p<0.05). Lys50t0 was positively correlated with ICAM1, ESR and VWF (respectively p<0.001, p<0.05, p<0.05). An inverse correlation was found between Cmax and both the diffusing capacity of the lungs for carbon monoxide (r=-0.408, p<0.01) and FVC (r=-0.318, p<0.01). Increased Cmax was found in ILD respect to HC (p<0.01). Denser plasma clot was associated with active disease (p<0.01). Longer Lys50t0 was observed in pitting scars group (p<0.01). Prolonged Lys50t0 was independently predicted by ICAM1 (OR 1.12, 95% CI 1.03–1.2, p<0.01).Conclusion:Our results provide evidences of denser plasma fibrin clot among patients with lung involvement and impaired fibrinolysis, selectively presented among SSc patients with piting scars. Thus, these patients might be at risk for thrombotic complications. Raised ICAM-1 levels could reflect impaired fibrinolysis, giving insight the important role of this molecule in endothelial homeostasis.References:[1]Cerinic MM, et al. Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis. Semin Arthritis Rheum. 2003;32:285–95[2]Lippi G, et al. Plasma D-dimer concentration in patients with systemic sclerosis.Thromb J. 2006;4:2.[3]Carter AM, et al. Heritability of clot formation, morphology, and lysis: the EuroCLOT study. Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2783-9Figure 1.SEM images of fibrin network in 1 representative sample from a SSc (A) and 1from HC sample (B).Disclosure of Interests:Jelena Colic: None declared, Aleksandra Antovic: None declared, Iva Pruner: None declared, Jelena Vojinovic Consultant of: Roche, Abbvie, Pfizer, MSD, Speakers bureau: Roche, Abbvie, Pfizer, MSD, Mirjana Sefik Bukilica: None declared, Nemanja Damjanov Grant/research support from: from AbbVie, Pfizer, and Roche, Consultant of: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Speakers bureau: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche
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| 8. |
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| 9. |
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| 10. |
- Colic, J, et al.
(author)
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CLOT LYSIS TIME PREDICTS RECURRENT DIGITAL ULCERS IN SYSTEMIC SCLEROSIS AFTER ONE YEAR OF FOLLOW-UP: A NESTED CASE-CONTROL STUDY
- 2021
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 693-693
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Conference paper (other academic/artistic)abstract
- Digital ulcers (DU) are a common visible manifestation of vasculopathy in systemic sclerosis (SSc), which could be recurrent and associated with disability and mortality (1). Although vasculopathy is connected with impaired coagulation/fibrinolysis system and aberrant expression of adhesion molecules, there are few data about their role in developing recurrent DU.Objectives:To evaluate the possible role of Fibrin generation/Fibrinolysis parameters and adhesion molecules in the prediction of new ischaemic DU oncet during a 1-year follow-up and their impact on the time to new DU onset (TD).Methods:From 58 consecutive patients with SSc who fulfilled the 2013 ACR/EULAR SSc criteria and have never been treated with endothelin receptor antagonist, phosphodiesterase 5 inhibitors or prostanoids, a total of 38 patients with ever had DU, either active at inclusion or in past, were enrolled in a prospective cohort study. Each patient was given a “DU diary”. Demografic, clinical and serologycal data were recorded. The serum concentration of ICAM1 and E selectin were measured by ELISA. Haemostatic potential parameters: overall haemostasis (OHP), overall coagulation (OCP) and overall fibrinolysis (OFP) potential were assessed. Maximum absorbance (Cmax), reflects the fibrin clot density and clot lysis time (Lys50t0, time from initiation of clot formation to the time at which a 50% fall in absorbance from Cmax in the lysis assay), reflects fibrinolytic susceptibility, were calculated (2). Fibrin structure was visualised using scanning electron microscopy (SEM).Results:Over the follow-up period,18 patients (45.5%) developed new DU with the average TD of 7.4±2.9 months. There was no differance in ASA and CCB treatment among two groups (p>0.05). The OFP value was significantly decreased (p<0.01), Lys50t0 prolonged (p<0.05), while OHP was increased (p<0.05) in patients experienced new DU. Lys50t0 showed good validity in identifying patients with new DU oncet (AUC 0.683 95% CI 0.5 - 0.9). By multivariate analysis including clinical data in model the Lys50t0 (HR 1.2, 95% CI 1.1-1.3, p=0.018) and active DU at enrollment (HR 9.6, 95% CI 1.4-66.8, p=0.022) were identified as independent risk factors for the occurrence of new DU. TD was inversly correlated with ICAM1(p<0.001), E selectin (p<0.05), Cmax (p <0.05) and Lys50t0 (p<0.001). Model explaining 81.6% of the TD variability included Lys50t0 (β=- 0.55,p=0.003), E selectin (β=- 0.44,p=0.014) and fibrinogen (β=- 0.49,p=0.017). SEM revealed denser fibrin clots with thinner fibres in group experienced new DU compared to clots formed in plasma of patient without DU.Conclusion:Our results provide evidence that impaired fibrinolysis has critical role in the progression of microvascular disease, identifing clot lysis time as a strong predictor in the oncet of new digital ulcers in Systemic sclerosis. The higher level of E selectin and the longer lysis time are, the shorter is time until the onset of new digital ulcer. These results could be used in selection of patients at high risk of developing recurrent digital ulcer and therefore allow earlier therapeutic intervention.References:[1]Allanore Y, Distler O, Matucci-Cerinic M, Denton CP. Review: Defining a Unified Vascular Phenotype in Systemic Sclerosis. Arthritis Rheumatol. 2018 Feb;70(2):162-170[2]Carter AM, et al. Heritability of clot formation, morphology, and lysis: the EuroCLOT study. Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2783-9.Figure 1.SEM images of fibrin network in 1 representative sample from a SSc patient with (A) and 1from patient without (B) new DU oncetDisclosure of Interests:None declared
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| 11. |
- Colic, J, et al.
(author)
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EXTRACELLULAR VESICLES AS POTENTIAL BIOMARKERS OF EARLY DISEASE STAGE IN SYSTEMIC SCLEROSIS
- 2022
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 761-761
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Conference paper (other academic/artistic)abstract
- Extracellular vesicles (EVs) are membrane-coated vesicles most often generated from the vasculature and circulating blood cells upon cell activation and during the early phase of apoptosis (1).ObjectivesTo evaluate the concentration of different subpopulations of EVs in plasma from patients with SSc in relation to the disease duration and to the markers of endothelial injury.MethodsOur study included 59 SSc patients (36 limited (lSSc) and 23 diffuse cutaneous subset (dSSc)) and 46 healthy age and gender matched controls subjects. Disease duration less than 3 years in patients with dSSc and less than 5 years in those with lSSc was considered as early disease stage. Clinical evaluation of patients was performed. EVs were analysed with flow cytometry after staining platelet poor plasma with fluorescent cell-specific monoclonal antibodies. The concentration of following phosphatidylserine-positive EVs (PS+ EVs) were analyzed: total EVs, endothelial EVs (EEVs; CD144+), platelet EVs (PEVs; CD42b+), monocytes EVs (LEVs; CD14+), EVs expressing ICAM1 (CD54+), VCAM1 (CD106+) and P selectin (CD62p+). Serum levels of ICAM1, VCAM1 and P selectin were determined with ELISA.ResultsMedian disease duration of our cohort was 4 (0-29) years (early lSSc [20/36]: 2.5 (0-4.5) years; early dSSc [11/23]: 10 (1-30) months). All types of investigated EVs were significantly elevated in SSc patients compared to controls (p<0.05). Patients with early disease stage had significantly increased levels of all PS+EVs compared to HC (p<0.05). Moreover, the levels of EVs expressing ICAM1 and VCAM1 showed good validity in identifying patients with early disease stage (AUC 0.7, p<0.01). PEVs were increased in early dSSc compared to early lSSc, but the difference did not reach statistical significance (p=0.07). There was a correlation between serum levels and the levels of EVs expressing specific adhesion molecules (ICAM1: r=0.7, p<0.01; VCAM1: r=0.7, p<0.01; P selectin: r=-0.7, p<0.01), only within the group with early dSSc subtype of the disease. Further correlations were detected between ICAM1+EVs with either mRSS (r=0.07, p< 0.01) or EUSTAR activity index (r=0.07, p= 0.02) among patients with early dSSc.ConclusionIncreased levels of circulating EVs of different cell origin were present in patients with early SSc. EVs expressing either ICAM1 or VCAM1 could be novel biomarkers of early disease. EVs expressing ICAM1 showed association with severity of skin involvement and disease activity in patients with early dSSc giving insight into their role in the pathogenesis of SSc.References[1]J Colic, M Matucci-Cerinic, S Guiducci and N Damjanov. Review: Microparticles in systemic sclerosis, targets or tools to control fibrosis: This is the question!. Journal of Scleroderma and Related Disorders. 2019; 5(34):239719831985735Disclosure of InterestsNone declared
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| 12. |
- Colic, J, et al.
(author)
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Impaired Fibrinolysis Is Linked With Digital Vasculopathy and Onset of New Digital Ulcers in Systemic Sclerosis
- 2022
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In: The Journal of rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 49:6, s. 598-606
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Journal article (peer-reviewed)abstract
- To assess thrombin generation, fibrin formation, and structure together with the fibrinolytic status in patients with systemic sclerosis (SSc) in relation to the occurrence of digital ulcers (DUs) during the course of disease.Methods.We studied variables of endothelial dysfunction, thrombin generation, overall hemostatic potential, and fibrin clot turbidity in plasma from 58 patients with SSc (39 with DU history and 19 DU-naïve) and 46 matched healthy controls (HCs). Fibrin structure was visualized using scanning electron microscopy (SEM). Finally, 39 patients with a history of DUs were followed for 1.5 years and the predictive value of all investigated markers for new DU onset was explored.Results.Significantly enhanced endogenous thrombin potential (ETP) and prolonged clot lysis time (CLT) were found in patients with DUs compared to HCs. CLT was prolonged in patients with DUs compared to those without, showing good validity in identifying DUs with an area under the curve of 0.7 (95% CI 0.6–0.8). The levels of ETP and intercellular adhesion molecule 1 were independently associated with CLT. Over the follow-up period, 20 patients developed new DUs. CLT was prolonged (P < 0.001) in patients with new DU episodes, especially those with recurrent DUs. Regression analysis showed that the Raynaud phenomenon visual analog scale and CLT were predictors of new DUs (OR 1.1, 95% CI 1.0–1.1 and OR 1.2, 95% CI 1.1–1.3, respectively). SEM confirmed denser fibrin clots in patients with new DUs.Conclusion.Our results suggest that impaired fibrinolysis might have an emerging role in underlying digital vasculopathy and its progression in SSc.
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| 13. |
- Ingegnoli, Francesca, et al.
(author)
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A comparison between nailfold capillaroscopy patterns in adulthood in juvenile and adult-onset systemic sclerosis: A EUSTAR exploratory study
- 2015
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In: Microvascular Research. - : Elsevier BV. - 1095-9319 .- 0026-2862. ; 102, s. 19-24
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Journal article (peer-reviewed)abstract
- Objective: Qualitative capillaroscopy patterns in juvenile- and adult-onset systemic sclerosis (SSc) were studied in adulthood using data from the EULAR Scleroderma Trials and Research (EUSTAR) database. Methods: Data collected between June 2004 and April 2013 were examined with focus on capillaroscopy. In this retrospective exploratory study, series of patients with juvenile-onset SSc were matched with series of adult-onset SSc having the same gender and autoantibody profile. Results: 30 of 123 patients with juvenile-onset and 2108 of 7133 with adult-onset SSc had data on capillaroscopy. Juvenile-onset SSc showed scleroderma pattern more frequently than adult-onset SSc (93.3% and 88%). The OR was 2.44 and 95% Cl 0.57-10.41. An active scleroderma pattern was present in 58% of juvenile- and 61% of adult-onset SSc. The OR was 0.91 and 95% Cl 0.28-2.93. The late scleroderma pattern was present in 61% of juvenile- and 55.5% of adult-onset SSc. The OR was 1.06 and 95% Cl 0.34-3.56. Conclusion: This is the first exploratory study on the comparison of capillaroscopy between juvenile- and adult-onset SSc in adulthood. Juvenile-onset SSc had an increase prevalence of sderoderma pattern, but a similar distribution of the three patterns was suggested. Further studies are needed to define this issue. (C) 2015 Elsevier Inc. All rights reserved.
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