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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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- Shepherd, L., et al.
(författare)
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Infection-related and -unrelated malignancies, HIV and the aging population
- 2016
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Ingår i: HIV Medicine. - : Wiley. - 1464-2662 .- 1468-1293. ; 17:8, s. 590-600
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: HIV-positive people have increased risk of infection-related malignancies (IRMs) and infection-unrelated malignancies (IURMs). The aim of the study was to determine the impact of aging on future IRM and IURM incidence. Methods: People enrolled in EuroSIDA and followed from the latest of the first visit or 1 January 2001 until the last visit or death were included in the study. Poisson regression was used to investigate the impact of aging on the incidence of IRMs and IURMs, adjusting for demographic, clinical and laboratory confounders. Linear exponential smoothing models forecasted future incidence. Results: A total of 15 648 people contributed 95 033 person-years of follow-up, of whom 610 developed 643 malignancies [IRMs: 388 (60%); IURMs: 255 (40%)]. After adjustment, a higher IRM incidence was associated with a lower CD4 count [adjusted incidence rate ratio (aIRR) CD4 count < 200 cells/μL: 3.77; 95% confidence interval (CI) 2.59, 5.51; compared with ≥ 500 cells/μL], independent of age, while a CD4 count < 200 cells/μL was associated with IURMs in people aged < 50 years only (aIRR: 2.51; 95% CI 1.40–4.54). Smoking was associated with IURMs (aIRR: 1.75; 95% CI 1.23, 2.49) compared with never smokers in people aged ≥ 50 years only, and not with IRMs. The incidences of both IURMs and IRMs increased with older age. It was projected that the incidence of IRMs would decrease by 29% over a 5-year period from 3.1 (95% CI 1.5–5.9) per 1000 person-years in 2011, whereas the IURM incidence would increase by 44% from 4.1 (95% CI 2.2–7.2) per 1000 person-years over the same period. Conclusions: Demographic and HIV-related risk factors for IURMs (aging and smoking) and IRMs (immunodeficiency and ongoing viral replication) differ markedly and the contribution from IURMs relative to IRMs will continue to increase as a result of aging of the HIV-infected population, high smoking and lung cancer prevalence and a low prevalence of untreated HIV infection. These findings suggest the need for targeted preventive measures and evaluation of the cost−benefit of screening for IURMs in HIV-infected populations.
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- Fripiat, F., et al.
(författare)
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Macro-nutrient concentrations in Antarctic pack ice: Overall patterns and overlooked processes
- 2017
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Ingår i: Elementa. - : University of California Press. - 2325-1026. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Antarctic pack ice is inhabited by a diverse and active microbial community reliant on nutrients for growth. Seeking patterns and overlooked processes, we performed a large-scale compilation of macro-nutrient data (hereafter termed nutrients) in Antarctic pack ice (306 ice-cores collected from 19 research cruises). Dissolved inorganic nitrogen and silicic acid concentrations change with time, as expected from a seasonally productive ecosystem. In winter, salinity-normalized nitrate and silicic acid concentrations (C∗) in sea ice are close to seawater concentrations (Cw), indicating little or no biological activity. In spring, nitrate and silicic acid concentrations become partially depleted with respect to seawater (C∗ < Cw), commensurate with the seasonal build-up of ice microalgae promoted by increased insolation. Stronger and earlier nitrate than silicic acid consumption suggests that a significant fraction of the primary productivity in sea ice is sustained by flagellates. By both consuming and producing ammonium and nitrite, the microbial community maintains these nutrients at relatively low concentrations in spring. With the decrease in insolation beginning in late summer, dissolved inorganic nitrogen and silicic acid concentrations increase, indicating imbalance between their production (increasing or unchanged) and consumption (decreasing) in sea ice. Unlike the depleted concentrations of both nitrate and silicic acid from spring to summer, phosphate accumulates in sea ice (C∗ > Cw). The phosphate excess could be explained by a greater allocation to phosphorus-rich biomolecules during ice algal blooms coupled with convective loss of excess dissolved nitrogen, preferential remineralization of phosphorus, and/or phosphate adsorption onto metal-organic complexes. Ammonium also appears to be efficiently adsorbed onto organic matter, with likely consequences to nitrogen mobility and availability. This dataset supports the view that the sea ice microbial community is highly efficient at processing nutrients but with a dynamic quite different from that in oceanic surface waters calling for focused future investigations. Copyright © 2017 The Author(s).
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- Le Bas-Bernardet, S, et al.
(författare)
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Bortezomib, C1-Inhibitor and Plasma Exchange Do Not Prolong the Survival of Multi-Transgenic GalT-KO Pig Kidney Xenografts in Baboons.
- 2015
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Ingår i: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. - : Elsevier BV. - 1600-6143. ; 15:2, s. 358-70
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Tidskriftsartikel (refereegranskat)abstract
- Galactosyl-transferase KO (GalT-KO) pigs represent a potential solution to xenograft rejection, particularly in the context of additional genetic modifications. We have performed life supporting kidney xenotransplantation into baboons utilizing GalT-KO pigs transgenic for human CD55/CD59/CD39/HT. Baboons received tacrolimus, mycophenolate mofetil, corticosteroids and recombinant human C1 inhibitor combined with cyclophosphamide or bortezomib with or without 2-3 plasma exchanges. One baboon received a control GalT-KO xenograft with the latter immunosuppression. All immunosuppressed baboons rejected the xenografts between days 9 and 15 with signs of acute humoral rejection, in contrast to untreated controls (n=2) that lost their grafts on days 3 and 4. Immunofluorescence analyses showed deposition of IgM, C3, C5b-9 in rejected grafts, without C4d staining, indicating classical complement pathway blockade but alternate pathway activation. Moreover, rejected organs exhibited predominantly monocyte/macrophage infiltration with minimal lymphocyte representation. None of the recipients showed any signs of porcine endogenous retrovirus transmission but some showed evidence of porcine cytomegalovirus (PCMV) replication within the xenografts. Our work indicates that the addition of bortezomib and plasma exchange to the immunosuppressive regimen did not significantly prolong the survival of multi-transgenic GalT-KO renal xenografts. Non-Gal antibodies, the alternative complement pathway, innate mechanisms with monocyte activation and PCMV replication may have contributed to rejection.
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