| 1. |
- 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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| 3. |
- 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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| 4. |
- Acosta-Herrera, M, et al.
(författare)
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Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases
- 2019
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:3, s. 311-319
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Tidskriftsartikel (refereegranskat)abstract
- Immune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies.MethodsWe meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases.ResultsOur analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study.ConclusionsWe have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.
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| 5. |
- Herrick, A. L., et al.
(författare)
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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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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 77:4, s. 563-570
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Tidskriftsartikel (refereegranskat)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. |
- Lopez-Isac, E, et al.
(författare)
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GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4955-
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Tidskriftsartikel (refereegranskat)abstract
- 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 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.
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