Whole blood transcriptome profiling in patients treated with deucravacitinib and novel mechanistic insights into TYK2 inhibition in lupus: results from a post hoc analysis of the PAISLEY SLE phase 2 trial.

Background:Deucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with moderate to severe plaque psoriasis. Deucravacitinib inhibits TYK2-mediated...

Background:A key feature of Systemic Lupus Erythematosus (SLE) is the female predominance, as women present with this disease 9-fold more than men. In addition, the phenotype of the disease in...

While tau and aging have highly overlapping differential gene expression signatures, they diverge in the affected cell types, with aging having a wide-ranging impact and tau-triggered changes instead polarized to excitatory neurons and glia.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by immune dysregulation and chronic inflammation across various organ systems. While anti-dsDNA and anti-Sm antibodies are commonly associated with SLE, the presence of anti-RNP antibodies is often linked to unique gene expression profiles and immune responses. This study aims to investigate the gene expression profiles in ribonucleoprotein (RNP) autoantibody-positive SLE patients by analyzing publicly available transcriptomic data. This study analyzed transcriptomic data from the GEO dataset GSE61635, which includes gene expression profiles from 79 anti-RNP-positive SLE patients and 30 healthy controls. Differentially expressed genes (DEGs) were identified using the GEO2R tool with a p-value < 0.05 and |log2fold change| > 1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. Tissue-specific and cell-type enrichment analyses highlighted the involvement of immune tissues. A total of 1891 DEGs were identified between anti-RNP-positive SLE patients and healthy controls. Among the identified DEGs, SLC4A1 and EPB42 were notably downregulated, while PIP4K2A was highly upregulated. Enrichment analyses revealed significant dysregulation in antiviral response and immune regulation pathways. PPI network analysis highlighted key hub genes, suggesting a heightened antiviral state in these patients. Tissue-specific enrichment and cell-type enrichment identified the bone marrow and immune tissues as being highly affected by the altered gene expression. Additionally, gene frequency analysis highlighted RASD2 as being recurrently significant across multiple studies. The findings suggest that anti-RNP-positive SLE patients exhibit distinct gene expression and immune dysregulation profiles, particularly in antiviral and immune regulation pathways. These results provide insights into the molecular mechanisms driving SLE in this patient subset and may guide future therapeutic interventions.

Several investigational agents are under evaluation in systemic lupus erythematosus (SLE) clinical trials but quantitative frameworks to enable comparison of their efficacy to reference benchmark treatments are lacking. To benchmark SLE treatment effects and identify clinically important covariates, we developed a model-based meta-analysis (MBMA) within a latent variable model framework for efficacy end points and SLE composite end point scores (BILAG-based Composite Lupus Assessment and Systemic Lupus Erythematosus Responder Index) using aggregate-level data on approved and investigational therapeutics. SLE trials were searched using PubMed and www.clinicaltrials.gov for treatment name, SLE and clinical trial as search criteria that resulted in four data structures: (1) study and investigational agent, (2) dose and regimen, (3) baseline descriptors, and (4) outcomes. The final dataset consisted of 25 studies and 81 treatment arms evaluating 16 different agents. A previously developed (K Goteti etal. 2022) SLE latent variable model of data from placebo arms (placebo + standard of care treatments) was used to describe aggregate SLE end points over time for the various SLE placebo and treatment arms in a Bayesian MBMA framework. Continuous dose-effect relationships using a maximum effect model were included for anifrolumab, belimumab, CC-220 (iberdomide), epratuzumab, lulizumab pegol, and sifalimumab, whereas the remaining treatments were modeled as discrete dose effects. The final MBMA model was then used to benchmark these compounds with respect to the maximal efficacy on the latent variable compared to the placebo. This MBMA illustrates the application of latent variable models in understanding the trajectories of composite end points in chronic diseases and should enable model-informed development of new investigational agents in SLE.

This study aims to investigate the molecular differences and commonalities between systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) by analyzing RNA-sequencing (RNA-seq) data. By focusing on differentially expressed genes and enriched pathways, the investigation seeks to identify unique biomarkers, shared pathways, and potential therapeutic targets for these autoimmune diseases. This study involved 10 patients with SSc and 24 with SLE who did not receive immunosuppressants. RNA-seq data from patients with SSc and SLE were analyzed using DESeq2 to identify differentially expressed genes. Functional and pathway enrichment analyses were conducted and comparative analyses were performed. We identified 2055 differentially expressed genes (DEGs) between patients with SSc and controls. Notably, the expression of the shared gene RGS5 was significantly downregulated in both SLE and SSc, with a more pronounced downregulation in SSc. Additionally, the expression of the key transcription factor EGR1 was upregulated in SSc, whereas that of BLK, ITGAM, and IFNG was upregulated in SLE. Network analysis identified hub genes-AP3D1, FTX, USP47, CUX1, ZC3H4, CAND1, INTS1, TRNT1, MTERF1, and SETD1B-that may play critical roles in the progression of both SLE and SSc. These findings suggest that RGS5 could serve as a shared biomarker for vascular dysfunction, while EGR1 and BLK may represent therapeutic targets in SSc and SLE. Overall, this analysis enhances understanding of distinct and overlapping gene expression signatures in SSc and SLE, providing a foundation for future targeted treatment strategies and requiring further validation in larger cohorts.

EULAR points to consider for conducting clinical trials in systemic lupus erythematosus

In a study of a herpes simplex virus (HSV) vaccine, the combination of sex and prior exposure to the virus resulted in HSV naive women mounting a prominent type I interferon response associated with reduced neutralizing titers to HSV.

Clinician-reported outcome measures in lupus trials: a problem worth solving.

This study aimed to identify differentially expressed genes (DEGs) of systemic lupus erythematosus (SLE) using gene expression-based computational methodologies to analyze disease-immune interactions, which affect the development and progression of SLE. Twenty-six patients with SLE and 46 healthy controls were selected from the Gene Expression Omnibus (GEO) database. The significantly enriched immune and virus-related gene lists were computed and visualized by using the DEGs from the gene set enrichment analysis (GSEA). Quantification of 38 immune cells was performed in determining the impact of immune cells on the virus mediated immunity in SLE by using ImmQuant algorithm. Thirty-nine upregulated and 57 downregulated were identified in SLE patient compared to the healthy controls. Upregulated genes were significantly implicated in Gene Ontology gene sets as cytokine mediated signaling, secretion, and exocytosis in immune response pathways in 26 female SLE patients. In addition, these genes were enriched in hepatitis C, influenza A, measles, Epstein-Barr virus, and herpes simplex virus 1 infection in Kyoto Encyclopedia of Genes and Genomes pathways. Especially, FCGR1A, IRF7, OAS2, CAMP, MX1, OAS3, OAS1, DEFA3, ISG15, and RSAD2 were involved in virus mediated SLE mechanism, and the expression for OAS1, OAS2, and IRF7 was closely associated with the quantities of colony forming unit-monocyte and colony forming unit-granulocyte. Identifying virus-mediated SLE genes and quantifies of immune cells were used to understand the pathological process and perform early diagnosis of female SLE, and will lead to clinical tools for treating SLE in patients. Key Points • Using gene expression-based computational methodologies,the 57immune and viral genes were significantly upregulated in 26 SLE patients. • The identifiedthree key viral genessuch as OAS1, OAS2, and IF7 were closely associated with colony-forming unit-monocytes and colony-forming unit-granulocytes, which affect the virus mediated immunity in SLE. • The viral genes and quantifies of immune cells are useful in understanding pathogenesis of SLE, and this will provide clinical strategiesof potential treatment choicesin SLE patients.

BackgroundAbatacept (ABA or CTLA4Ig) is a fusion protein that interferes with co-stimulation of T cells and antigen-presenting cells by inhibiting interactions between CD28 and CD80/86. ABA is effective in rheumatoid...

Integrated analysis of ATAC-seq and RNA-seq reveals the transcriptional regulation network in SLE

PV264 / #825Poster Topic:AS24 - SLE-TreatmentBackground/PurposeRegulatory T cell (Treg) dysfunction is a key feature of systemic lupus erythematosus (SLE). Preliminary studies expanding Tregs in patients with SLE using low-dose interleukin 2 (IL-2) have demonstrated promising results. However, use of IL-2 is limited due to its short half-life requiring frequent injections and the narrow therapeutic window for Treg selectivity poses the risk of activating other immune responses (eg, pathogenic T effector, natural killer [NK] cells). Compounding these challenges, SLE is immunologically and clinically heterogenous with a high variability in disease activity and organ system involvement. Interpretation of SLE trial results is further complicated by various background treatments, imperfect outcome measures, and need for experienced investigators. Therefore, there are challenges to the development of treatments for Treg expansion in SLE. MK-6194 is an IL-2 mutein with enhanced Treg selectivity, increased affinity for the alpha chain of the IL-2 receptor (CD25) and decreased affinity for the beta chain (CD122), which is Fc-conjugated for increased half-life. In a phase 1 trial, subcutaneous (SC) MK-6194 was generally well tolerated (up to a single dose of 10 mg; up to doses of 5 mg every 2 or 4 weeks) by healthy participants with no serious adverse events (AEs) or dose-limiting toxicities. Injection site erythema was the most common AE. A dose-dependent increase in Treg number was observed, peaking between Days 8–11 with no attenuation after repeated injections and minimal impact on non-Treg or NK cell numbers. These data support further evaluation of MK-6194 as a potential treatment for SLE. To test this hypothesis in a phase 2a SLE trial, analysis of past trials highlights the importance of accurate assessment of eligible patients with clinically significant disease activity and limited background therapy.MethodsThis multicenter, randomized, double-blind, placebo-controlled phase 2a trial is currently enrolling eligible adults (Table) with moderate-to-severe SLE (Figure) randomized (1:1:1) to receive SC placebo or MK-6194 in 1 of 2 dosing regimens for 52 weeks (main trial period) followed by a double-blind long-term extension (NCT06161116). The primary efficacy endpoint is the proportion of participants with Systemic Lupus Erythematosus Responder Index-4 (SRI-4) response at Week 28. The primary safety endpoint is the number of AEs and AEs leading to trial discontinuation. Secondary endpoints include SRI-4 response at Week 52, British Isles Lupus Assessment Group-Based Composite Lupus Assessment (BICLA) and Cutaneous Lupus Erythematosus Disease Area and Severity Index-50 (CLASI-50) responses at Weeks 28 and 52, and change from baseline in tender/swollen joint counts. Exploratory endpoints include immunologic parameters, pharmacokinetics/pharmacodynamics, anti-drug antibodies, and biomarker parameters. Patient eligibility and accuracy of disease activity scoring throughout the trial will be adjudicated by an experienced, blinded clinical team.Table.Inclusion/exclusion criteriaFigure.Trial design and key endpointsResultsThe trial is actively recruiting approximately 270 participants in 17 countries across North America, Latin America, Europe, the Middle East and Asia-Pacific regions. Estimated primary trial completion will be April 2027.ConclusionsThis currently recruiting phase 2a trial was designed to address challenges in the development of Treg expansion therapy for SLE. MK-6194, a novel IL-2 mutein, was developed for Treg selectivity with longer half-life. The trial protocol utilized knowledge gained from past SLE publications to increase the likelihood of interpretable data.

Nex-T TM Cluster of Differentiation 19 (CD19) Chimeric Antigen Receptor (CAR) T-Cell Therapy BMS-986353 (CC-97540): Comparative Analysis of Baseline Patient Data from Trials in Systemic Lupus Erythematosus (SLE) and Relapsed/Refractory Large B-Cell Lymphoma (R/R LBCL) Related to Manufacturability and Potential Safety

BackgroundCharacterizing differentially expressed genes (DEGs) of systemic lupus erythematosus (SLE) is necessary to understand immunogenic interactions, and how several key immune genes were closely associated with the susceptibility of SLE.ObjectivesThis...