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- Elhai, M, et al.
(författare)
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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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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:7, s. 979-987
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Tidskriftsartikel (refereegranskat)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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- Becker, M, et al.
(författare)
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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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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:9, s. 1242-1248
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Tidskriftsartikel (refereegranskat)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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- Van Gompel, E, et al.
(författare)
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DELINEATING THE IMMUNOGENIC DOMAINS OF MDA5 USING PATIENT DERIVED AUTOANTIBODIES
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 196-197
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The presence of myositis specific anti-melanoma differentiation associated protein 5 (MDA5) autoantibodies is associated with mucocutaneous ulcerations, rapidly progressing interstitial lung disease (RPILD), arthritis and mild muscle involvement in patients. RPILD is the major cause of mortality. At present it is unknown which domain of the MDA5 protein is the main elicitor of an immunogenic response.Objectives:The aim of this study is to delineate the domains in the MDA5 protein that are the target of autoantibodies.Methods:Anti-MDA5 IgG were isolated from MDA5(+) patient plasma (7 UPMC, 1 KI and 1 KULeuven) by affinity chromatography using an in-house affinity column as described earlier in Ossipova et al, 2014(1). 8 constructs covering different regions of the MDA5 protein were recombinantly produced in E.coli (Uniprot ID Q9BYX4, Figure 1). An in-house ELISA was developed to identify the domains with the main epitope(s) by measuring the reactivity of the plasma samples and purified autoantibodies against these MDA5 protein constructs, similar to what was reported by Fernandes-Cerqueira et al, 2018(2). The biotinylated MDA5 proteins were immobilized on streptavidin coated plates and subsequently incubated with primary antibodies (purified autoantibodies(2) or original plasma) and a HRP-conjugated secondary antibody. The ELISA was developed by the addition of TMB substrate and the optical density (OD) was measured at 450 nm.Figure 1.Graphical presentation of the constructs representing different (combinations of) domains of the MDA5 protein.Results:The preliminary data suggest the main reactivity of the plasma samples and the corresponding purified autoantibodies is directed towards the helicase domains and that there is variability between the patients in the reactivity towards domains located at the end of the protein.Conclusion:The study aims to resolve the main immunogenic domain of the MDA5 protein, which will lead to more insight in the disease mechanisms. The preliminary results suggest this domain is in the center of the MDA5 protein, but further experiments are necessary. We will use this set up to study differences in reactivity between patients (from different cohorts) and assess if differences in antibody reactivity could be linked to clinical features such as RPILD. Such correlations might be beneficial to predict the disease progression and to apply personal treatment approaches.References:[1]Ossipova E, Cerqueira CF, Reed E, Kharlamova N, Israelsson L, et al. Affinity purified anti-citrullinated protein/peptide antibodies target antigens expressed in the rheumatoid joint. Arthritis Res Ther. 2014;16(4):R167.[2]Fernandes-Cerqueira C, Renard N, Notarnicola A, Wigren E, Gräslund S, et al. Patients with anti-Jo1 antibodies display a characteristic IgG Fc-glycan profile which is further enhanced in anti-Jo1 autoantibodies. Scientific reports. 2018;8(1):17958.Disclosure of Interests:Eveline Van Gompel: None declared, Catia Cerqueira: None declared, Edvard Wigren: None declared, Susanne Gräslund: None declared, Karine Chemin: None declared, Begum Horuluoglu: None declared, Ellen De Langhe: None declared, Olivier Benveniste: None declared, Ingrid E. Lundberg Consultant of: Consulting fees from Corbus Pharmaceuticals, Inc, Grant/research support from: Research grants from Bristol Myers Squibb and AstraZeneca.
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