Pragmatic treatment of patients with Systemic Lupus Erythematosus with rituximab: Long-term effects on serum immunoglobulins

OBJECTIVE: B cell depletion therapy based on rituximab is a therapeutic option for refractory disease in patients with Systemic Lupus Erythematosus (SLE). The aim of this observational study was to document long-term effects on B cell function by following serum immunoglobulin levels in patients with SLE treated with rituximab in routine clinical practice. METHODS: We included 57 consecutive patients with SLE treated with rituximab and concomitant/sequential immunosuppressants and measured serum total IgG, IgM, and IgA and IgG anti-dsDNA antibodies over a median of 48 months most recent follow-up. Flow cytometry was used prospectively to assess B-cell phenotypes in 17/57 patients. RESULTS: Twelve patients (21%) had persistent IgM hypogammaglobulinemia (1000IU/ml; normal<50IU/ml). Factors predictive of low serum IgM included: baseline serum IgM ≤0.8g/L (receiver-operated-curve analysis) and subsequent therapy with mycophenolate mofetil (MMF) (odds ratio=6.8 compared with other immunosuppressants). In patients maintaining normal IgM levels (9/17), the frequency of circulating IgD+CD27+ B cells was significantly higher (p=0.05). At 12 months after rituximab, 7/30 SLE patients with baseline anti-dsDNA≤1000 IU/ml had lost seropositivity. CONCLUSIONS: Lower baseline serum IgM levels and sequential therapy with MMF were predictive of IgM hypogammaglobulinemia after rituximab in SLE, but this was not associated with higher levels of anti-dsDNA antibodies or an increased risk of infections. This provides useful directions for clinicians regarding rituximab and sequential immunosuppressive treatment for patients with SLE. This article is protected by copyright. All rights reserved

Adverse infusion reactions to rituximab in systemic lupus erythematosus: a retrospective analysis

Background To undertake a retrospective review of patients with SLE who had received Rituximab in order to determine the rates and associated patient characteristics of clinically significant adverse infusion reactions. Methods A descriptive analysis was undertaken of each infusion reaction, which was then assessed using the clinical information available to hypothesise on the possible underlying mechanism(s). Results Records of 136 SLE patients previously treated with 481 individual infusions of Rituximab were reviewed. A total of 22 patients (17.6%) had 28 (5.8% of total infusions) documented clinically significant adverse infusion reactions. Average age at first Rituximab infusion in patients without a reaction was 37 years (range 16–73) compared with 30 years (range 18–56) in those with a reaction. A high proportion of men (18.2%) experienced an infusion reaction. Severity and type of reaction varied. 6.4% of those who had a reaction were not retreated. Conclusions While Rituximab remains an important tool in the treatment of SLE it is important to be aware that rates of infusion reactions may be more significant in SLE than in other diseases. A prospective study is required to better characterise the reactions

Breaking the Silence of Mainstream Teachers\u27 Attitude towards Inclusive Education in the Bahamas: High School Teachers\u27 Perceptions

There has been a paradigm shift globally regarding the adoption of inclusive education policies and procedures. However, teachers still have varying views, anxieties, and preconceive misconceptions about the successful implementation of inclusive education practices in the general education classroom. This study utilized a qualitative approach to provide an informative exploration of teachers’ attitudes toward inclusive education and its implementation, possible factors that influence teachers\u27 attitude, and recommendations for promoting best practices in inclusive education. Data was collected utilizing semi-structured interviews from eight teachers throughout the New Providence District in the Bahamas. The results of the study revealed that teachers generally had positive attitudes toward inclusion. However, lack of funding, administrative support and minimal opportunities for training and development were identified as negative influential factors regarding teachers’ attitude towards inclusive education

Long-term persistence of rituximab in patients with rheumatoid arthritis: an evaluation of the UCL cohort from 1998 to 2020

OBJECTIVES: B cell depletion therapy based on rituximab in patients with RA was pioneered at University College London Hospitals/University College London in 1998. The objective of this study was to evaluate long-term persistence of rituximab and identify factors associated with discontinuation of treatment. METHODS: Retrospective review of medical records from all rituximab-treated RA patients followed up in a dedicated clinic (1998–2020). Data collected included gender, disease duration, previous DMARDs, autoantibody status, age and concomitant therapy at first cycle, length of follow-up, and number of cycles. Drug survival and factors associated with drug discontinuation were analysed using Kaplan–Meier survival curves, log-rank test and Cox regression analysis. RESULTS: A total of 404 patients were included. Median disease duration and age at time of first rituximab cycle were 10 and 57 years, respectively. Median total follow-up was 55 months and median number of cycles five. 93.1% of patients were seropositive. Overall, 31.2% of patients stopped rituximab, with the largest reason for discontinuing being primary inefficacy (42.1%). Comparison of Kaplan–Meier curves showed that rituximab drug survival was lower in seronegative patients and in patients who had previously failed at least one biologic DMARD (bDMARD). Cox regression analysis revealed that rituximab discontinuation was associated with a greater number of previous bDMARDs. CONCLUSION: Many patients with RA achieve good control of their disease with repeated cycles of rituximab treatment. The most common reasons for treatment discontinuation were either primary or secondary inefficacy. Patients who were seronegative and who had previously failed other bDMARDs were more at risk of drug discontinuation

Serum markers of B-cell activation in pregnancy during late gestation, delivery, and the postpartum period

B cells are vital for the normal evolution of pregnancy due to their humoral and possible regulatory activities. Our group and others have documented that circulating B-cell subsets undergo changes from normal late pregnancy to the postpartum period. However, the underlying mechanisms are poorly understood. Therefore, this study examined the degree of B-cell activation in normal pregnancy by analyzing the levels of serum markers in healthy pregnant women during the third trimester of pregnancy, the day of delivery, and the postpartum period. METHOD OF STUDY: A prospective study including pregnant and non-pregnant women attending routine care was undertaken at a hospital clinic. Sociodemographic and clinical data were collected, along with peripheral blood samples. The serum levels of soluble CD23 (sCD23), B-cell-activating factor (BAFF), kappa (κ) and lambda (λ) free light chains (FLC), IgA, IgG, and IgM were quantified. RESULTS: Our study included 43 third trimester pregnant and 35 non-pregnant women. In the pregnant women, the median levels of sCD23, BAFF, IgG, and κ FLC were significantly higher during the postpartum period than during the third trimester of pregnancy. Compared to the non-pregnant women, the third trimester pregnant women had higher median BAFF levels and lower sCD23, IgA, IgG, and FLC levels. CONCLUSION: Changes in serum markers of B-cell kinetics that occur during pregnancy often persist into the postpartum period and affect the secretion of immunoglobulins from different classes. Further studies are needed to clarify the biological significance of our observations.info:eu-repo/semantics/publishedVersio

In vitro B cell experiments explore the role of CD24, CD38, and energy metabolism in ME/CFS

Introduction: Disturbances of energy metabolism contribute to the clinical manifestations of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Previously, we found that B cells from ME/CFS patients have an increased expression of CD24, a modulator of many cellular functions including those of cell stress. The relative ability of B cells from ME/CFS patients and healthy controls (HC) to respond to rapid changes in energy demand was compared. Methods: CD24, the ectonucleotidases CD39 and CD73, the NAD-degrading enzyme CD38, and mitochondrial mass (MM) were measured following cross-linking of the B cell receptor and costimulation with either T-cell-dependent or Toll-like-receptor-9-dependent agonists. The levels of metabolites consumed/produced were measured using 1H-NMR spectroscopy and analyzed in relation to cell growth and immunophenotype. Results: Proliferating B cells from patients with ME/CFS showed a lower mitochondrial mass and a significantly increased usage of essential amino acids compared with those from HC, with a significantly delayed loss of CD24 and an increased expression of CD38 following stimulation. Discussion: The immunophenotype results suggested the triggering of a stress response in ME/CFS B cells associated with the increased usage of additional substrates to maintain necessary ATP levels. Disturbances in energy metabolism in ME/CFS B cells were thus confirmed in a dynamic in vitro model, providing the basis for further mechanistic investigations

Hawking radiation and thermodynamics of dynamical black holes in phantom dominated universe

The thermodynamic properties of dark energy-dominated universe in the presence of a black hole are investigated in the general case of a varying equation-of-state-parameter $w(a)$. We show that all the thermodynamics quantities are regular at the phantom divide crossing, and particularly the temperature and the entropy of the dark fluid are always positive definite. We also study the accretion process of a phantom fluid by black holes and the conditions required for the validity of the generalized second law of thermodynamics. As a results we obtain a strictly negative chemical potential and an equation-of-state parameter $w<-5/3.$Comment: 22 pages,3 figure

1D vs. 2D shape selectivity in the crystallization-driven self-assembly of polylactide block copolymers

yes2D materials such as graphene, LAPONITE® clays or molybdenum disulfide nanosheets are of extremely high interest to the materials community as a result of their high surface area and controllable surface properties. While several methods to access 2D inorganic materials are known, the investigation of 2D organic nanomaterials is less well developed on account of the lack of ready synthetic accessibility. Crystallization-driven self-assembly (CDSA) has become a powerful method to access a wide range of complex but precisely-defined nanostructures. The preparation of 2D structures, however, particularly those aimed towards biomedical applications, is limited, with few offering biocompatible and biodegradable characteristics as well as control over self-assembly in two dimensions. Herein, in contrast to conventional self-assembly rules, we show that the solubility of polylactide (PLLA)-based amphiphiles in alcohols results in unprecedented shape selectivity based on unimer solubility. We use log Poct analysis to drive solvent selection for the formation of large uniform 2D diamond-shaped platelets, up to several microns in size, using long, soluble coronal blocks. By contrast, less soluble PLLA-containing block copolymers yield cylindrical micelles and mixed morphologies. The methods developed in this work provide a simple and consistently reproducible protocol for the preparation of well-defined 2D organic nanomaterials, whose size and morphology are expected to facilitate potential applications in drug delivery, tissue engineering and in nanocomposites.University of Warwick, Materials GRP, EPSRC, The Royal Society, ER