ObjectiveCurrent disease activity measures for systemic lupus erythematosus (SLE) are difficult to score or interpret and problematic for use in clinical practice. Lupus Foundation of America (LFA)-Rapid Evaluation of Activity in Lupus (REAL) is a pilot application composed of anchored visual analogue scores (0–100 mm each) for each organ affected by lupus. This study evaluated the use of LFA-REAL in capturing SLE disease activity.MethodsIn a preliminary test of LFA-REAL, this simplified, organ-based system was compared with the most widely used outcome measures in clinical trials, the British Isles Lupus Assessment Group 2004 Index (BILAG), the SLE Disease Activity Index (SLEDAI) and the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Physician's Global Assessment (SS-PGA). The level of agreement was analysed using Spearman rank correlations.Results91 patients with SLE with mild to severe disease activity were evaluated, their median SLEDAI score was 4.0 (range 0–28) and BILAG score 8.0 (0–32). The median SS-PGA was 38 mm (4–92) versus the total REAL 50 mm (0–268), which expands in range by additive organ scores. Thirty-three patients had moderate to severe disease activity (≥1.5 on SS-PGA landmarks). The median SS-PGA score of this group was 66 mm (50–92) versus median REAL score of 100 mm (59–268), confirming ability to detect a wider distribution of scores at higher disease activity. Total REAL correlated with SLEDAI, BILAG and SS-PGA (correlation coefficient=0.816, 0.933 and 0.903, respectively; p<0.001 for all). Individual LFA-REAL organ scores for musculoskeletal and mucocutaneous also correlated with corresponding BILAG domain scores (correlation coefficient=0.925 and 0.934, p<0.001).ConclusionsIn this preliminary exercise, there were strong correlations between LFA-REAL and validated lupus disease activity indices. Further development may be valuable for consistent scoring in clinical trials, grading optimal assessment of change in disease activity and reliable monitoring of patients in practice.
ObjectiveAlthough SLE disproportionately affects minority racial groups, they are significantly under-represented in clinical trials in the USA. This may lead to misleading conclusions in race-based subgroup analyses. We conducted focus groups to evaluate the perceptions of diverse patients with lupus about clinical trial participation.MethodsA qualitative research design employed three 90 min focus groups led by a trained moderator and guided by the Theory of Planned Behaviour. Open-ended questions about trial participation included advantages and disadvantages (behavioural beliefs), approving and disapproving significant others (normative beliefs), and participation enhancers and barriers (control beliefs). Discussions were recorded, transcribed and analysed to identify emerging themes.ResultsPatients with SLE (n=23) aged 21–72, with increased proportion of minority groups (65%), participated. Reported advantages of trial participation included altruism and personal benefit. Disadvantages included uncertainties, disappointment, information burden, and life–health balance. Although some patients had discussed research participation with approving or disapproving family or friends, self-approval superseded external approval. Barriers included logistics and time, and facilitators included flexibility in scheduling, advance notice of studies, streamlined forms, and hope for SLE improvement.ConclusionsKnowledge about potential benefits of clinical trial participation was high. Minority patients demonstrated confidence in making their own informed decisions, but major barriers for all participants included burdensome forms, travel, childcare, and work. These suggest a major impact on minority and all recruitment from behavioural and control aspects, which should be considered in the logistics of trial design. This does not minimise the potential importance of improved access and education about clinical research.
Results 104 patients were randomized. In the efficacy evaluable population, 42% of XmAb5871-treated subjects reached Day 225 without LOI vs 28.6% of the placebo group (p=0.18) with 40.4% vs 23.1% (p=0.06) achieving this endpoint in the ITT population. In those with LOI, no (0%) XmAb5871 patients vs 9 (30%) placebo had SLE-DAI increase 7 with 3 (13%) vs 7 (23%) developing BILAG A scores. Six XmAb5871-treated patients were withdrawn for infusion-related events. The efficacy evaluable population excluded 10 placebo patients vs 2 XmAb5871 for other reasons, increasing placebo response proportions compared to the ITT population. Time to LOI was significantly longer in XmAb5871-treated patients than placebo (p=0.025, see figure 1).The most common AEs in XmAb5871-treated patients were transient, infusion-related gastrointestinal side effects during the 1 st or 2nd infusion. There were 8 SAEs in 7 XmAbtreated subjects, 5 in 4 placebo patients, no opportunistic infections, and no deaths. Infection rate was low compared to other SLE trials.Conclusions Results from this small trial, designed to maximize interpretability, supports further evaluation of XmAb5871 in SLE. Funding Source(s): This study was funded by Xencor Inc.
Lupus develops when genetically predisposed people encounter environmental agents that initiate flares. Current evidence indicates that the environmental contribution is mediated by T-cell DNA demethylation. DNA methylation patterns are established during differentiation, and silence inappropriate or unnecessary genes by promoting a condensed chromatin configuration that is inaccessible to transcription factors. The methylation patterns are then replicated each time a cell divides by DNA methyltransferase 1 (Dnmt1). Dnmt1 is upregulated during mitosis, binds the replication fork, and catalyzes transfer of the methyl group from S-adenosylmethionine (SAM) to dC bases in the daughter DNA strand only where the parent strand is methylated. Environmental agents that block ERK pathway signaling prevent Dnmt1 upregulation, and low Dnmt1 levels synergize with dietary micronutrient deficiencies that decrease SAM pools to impair methylation of the daughter strand. This activates genes silenced only by DNA methylation. Inhibiting T-cell DNA methylation converts helper CD4 + T cells into autoreactive, cytotoxic, proinflammatory cells that cause lupus-like autoimmunity in mice. Similar changes in CD4 + T-cell DNA methylation and gene expression are found in patients with active lupus. Procainamide and hydralazine, which cause ANAs in a majority of patients and lupus in a genetically predisposed subset, also inhibit T-cell DNA methylation. The lupus T-cell DNA methylation defect has been traced to low Dnmt1 levels caused by decreased ERK pathway signaling, and the signaling defect has now been traced to PKCδ inactivation caused by oxidative damage. The importance of decreased ERK pathway signaling was confirmed by generating a transgenic mouse with an inducible dominant negative MEK. Inducing the signaling defect selectively in T cells decreases Dnmt1, causing anti-DNA antibodies in mice without lupus genes, and higher anti-DNA antibody levels and an immune complex glomerulonephritis in mice with lupus genes. Autoantibody levels and kidney disease are suppressed by dietary transmethylation micronutrient supplementation in these mice. Epigenetic mechanisms also contribute to the gender dimorphism in lupus.Immune genes on the normally silenced X chromosome demethylate in women with active lupus, contributing to flare severity. In contrast, men with only one X chromosome require a greater genetic predisposition and/ or greater degree of DNA demethylation to develop a lupus flare equal in severity to women. Together, these studies indicate that environmental agents including oxidative stress and diet combine to inhibit T-cell DNA methylation, and that the epigenetically modified cells cause lupus-like autoimmunity in genetically predisposed people and mice. Background: CD4 T cells help B cells produce antibodies following antigen challenge. This response classically occurs in germinal centers (GC) located in B-cell follicles of secondary lymphoid organs (SLO), a site of immunoglobulin isotype switching and affinity maturation. GC ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.