Systemic Lupus Erythematosus Therapy Research Articles

P162 Dimethyl fumarate modulates T cell metabolism and function in systemic lupus erythematosus patient samples

Abstract Background/Aims Activated CD4+T cells make a significant contribution to inflammation in systemic lupus erythematosus (SLE) through secretion of proinflammatory cytokines such as IFN-γ and TNF-α. CD4+T cells can also express activating NK receptors such as NKG2D that can engage with stress-induced ligands such as MICA, as noted in lupus nephritis, and mediate nonspecific tissue injury. We know that cellular metabolism regulates the activation of T cells. Evidence from patients with multiple sclerosis indicates that dimethyl fumarate (DMF), an electrophile, targets cellular metabolism to modulate CD4+T cell activation and function. Here, we investigated whether DMF modulates T cell metabolism and function in samples from patients with SLE in a series of in vitro experiments. Methods All experiments were performed using isolated T cells from freshly drawn whole blood samples from patients with SLE. T cells were isolated using negative selection using stem cell or Miltenyei magnetic bead separation kit. Isolated T cells were activated with anti-CD3 and IL-2 and incubated with either DMF at 25μM concentration or DMSO alone for three or seven days at 37 °C and 5% CO2 before harvesting. Results In Seahorse experiments, after three days of incubation, dimethyl fumarate (DMF) inhibited Figure A-i) the oxygen consumption rate (OCR) and A-ii) extra cellular acidification rate (ECAR) in isolated T cells when compared with samples incubated with vehicle, dimethyl sulfoxide (DMSO). Our results revealed that DMF significantly inhibited: 1) aerobic glycolysis and oxidative phosphorylation in activated T cells from patients with SLE (n = 4) (Figure A- i and ii) in vitro; 2) T cell activation and proliferation as assessed by a reduction in the frequency of CD69 (n = 4) and D) Ki67 (n = 2) positivity, respectively (Figure B-E); 3) Collectively, these results suggest that DMF inhibits T cell activation and proliferation in samples from patients with SLE. After 7 days of incubation, DMF significantly inhibited the expression of activating NK receptors CD158a and NKG2D on T cells whereas there was a trend toward enhancing the expression of inhibitory NK receptors NKG2A and CD158b (Figure F-I). After 7 days of incubation, DMF significantly reduced intracellular expression of IFN-γ, TNF-α, IL-17 and secretion of pro-inflammatory cytokines IFN-γ and TNF-α in supernatants (Figure J - N). Conclusion Our preliminary data indicated that, in SLE patient samples, DMF modulates metabolic programming of CD4+ T cells and inhibits glycolysis and oxidative phosphorylation of activated CD4+ T cells. In vitro, DMF inhibited: T cell activation; proliferation; the expression of activating NK receptors; and secretion of proinflammatory cytokines from T cells patients with SLE. Taken together with the existing safety data in humans, these data provide mechanistic rationale for investigating the potential of dimethyl fumarate, with a distinct mechanism of action, as a novel therapy for SLE. Disclosure L. Kell: None. K. Shah: None. S. Taylor: None. R. De Maeyer: None. D.A. Isenberg: None. D. Sen: None. M. Castelino: None. M. Leandro: None. A. Akbar: None. V. Reddy: Grants/research support; UCLH Biomedical research centre funded this work, Dr.Reddy's work was supported through MR/T024968/1 MRC-CARP Fellowship.

Comparison of Low-Dose Interleukin 2 Therapy in Conjunction With Standard Therapy in Patients With Systemic Lupus Erythematosus vs Rheumatoid Arthritis: A Systematic Review.

This systematic review aims to compare the efficacy and safety of a novel immunotherapy with low-dose interleukin 2 (IL2) across two of the most prevalent autoimmune diseases i.e. systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Contemporary therapeutic practices have not been able to achieve complete remission from these autoimmune disorders. In contrast, low-dose IL2has shown promise in achieving this therapeutic goal via inducing self-tolerance in patients with autoimmune diseases; however, due to variable irregularities among autoimmune processes of variable diseases, the benefit of low-dose IL2 could not be determined among different autoimmune diseases. Therefore, we conducted a study to compare low-dose IL2 therapy effects on SLE and RA. We systematically screened four databases: PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), PubMed Central (PMC), and Google Scholar. Inclusion and exclusion criteria were implemented. Quality appraisal of studies chosen for the review was done using the Cochrane Risk-of-Bias (RoB) assessment tool for randomized controlled trials, and the Newcastle-Ottawa Scale (NOS) and JBI critical appraisal tool for non-randomized clinical trials. Information was gathered from seven articles: three randomized controlled trials and four non-randomized clinical trials. Our review concluded that low-dose IL2 therapy in conjunction with respective standard therapies for SLE and RA has a higher efficacy and safety profile as compared to standard therapy alone and the therapeutic effects were comparable in both SLE and RA patients treated with low-dose IL2; however, this novel intervention does not seem to have a significant corrective effect on the biomarkers of RA as it does for SLE biomarkers.

BCD020 rituximab bioanalog compared to standard treatment in juvenile systemic lupus erythematosus: The data of 12 months case-control study.

Systemic lupus erythematosus (SLE) is the most frequent and serious systemic connective tissue disease. Nowadays there is no clear guidance on its treatment in childhood. There are a lot of negative effects of standard-of-care treatment (SOCT), including steroid toxicity. Rituximab (RTX) is the biological B-lymphocyte-depleting agent suggested as a basic therapy in pediatric SLE. To compare the benefits of RTX above SOCT. The data from case histories of 79 children from the Saint-Petersburg State Pediatric Medical University from 2012 to 2022 years, were analyzed. The diagnosis of SLE was established with SLICC criteria. We compared the outcomes of treatment of SLE in children treated with and without RTX. Laboratory data, doses of glucocorticosteroids, disease activity measured with SELENA-SLEDAI, and organ damage were assessed at the time of initiation of therapy and one year later. Patients, treated with RTX initially had a higher degree of disease activity with prevalence of central nervous system and kidney involvement, compared to patients with SOCT. One year later the disease characteristics became similar between groups with a more marked reduction of disease activity (SELENA-SLEDAI activity index) in the children who received RTX [-19 points (17; 23) since baseline] compared to children with SOCT [-10 (5; 15.5) points since baseline, P = 0.001], the number of patients with active lupus nephritis, and daily proteinuria. During RTX therapy, infectious diseases had three patients; one patient developed a bi-cytopenia. RTX can be considered as the option in the treatment of severe forms of SLE, due to its ability to arrest disease activity compared to SOCT.

MDSC-derived S100A8/9 contributes to lupus pathogenesis by promoting TLR7-mediated activation of macrophages and dendritic cells

Toll-like receptors (TLRs), especially TLR7, play an important role in systemic lupus erythematosus (SLE) pathogenesis. However, the regulatory mechanism underlying the abnormal activation of TLR pathways in patients with SLE has not been elucidated. Notably, accumulating evidence indicates that myeloid-derived suppressor cells (MDSCs) are important regulators of inflammation and autoimmune diseases. Compared with healthy control subjects, patients with SLE have a greater proportion of MDSCs among peripheral blood mononuclear cells (PBMCs); however, the effect of MDSCs on TLR7 pathway activation has not been determined. In the present study, lupus MDSCs significantly promoted TLR7 pathway activation in macrophages and dendritic cells (DCs), exacerbating the imiquimod-induced lupus model. RNA-sequencing analysis revealed significant overexpression of S100 calcium-binding protein A8 (S100A8) and S100A9 in MDSCs from diseased MRL/lpr mice. In vitro and in vivo studies demonstrated that S100A8/9 effectively promoted TLR7 pathway activation and that S100A8/9 deficiency reversed the promoting effect of MDSCs on TLR7 pathway activation in lupus. Mechanistically, MDSC-derived S100A8/9 upregulated interferon gamma (IFN-γ) secretion by macrophages and IFN-γ subsequently promoted TLR7 pathway activation in an autocrine manner. Taken together, these findings suggest that lupus MDSCs promote TLR7 pathway activation and lupus pathogenesis through the S100A8/9-IFN-γ axis. Our study identified an important target for SLE therapy.

T Cell Dysfunction in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune inflammatory disease that can affect many organs in the body with very diverse clinical appearances. The prevalence of SLE in each country varies. The Lupus Foundation of America estimates that around 1.5 million cases occur in America and at least 5 million cases occur worldwide. The pathophysiology of SLE is very complex. The involvement of innate and adaptive immunity in the initiation and pathophysiology of SLE disease shows that there are interactions between leukocytes, cytokines, chemokines and tissue cells. T cells are the main component of the adaptive immune system which can kill infected host cells, activate other immune cells, produce cytokines and regulate immune responses. T cell dysfunction in SLE includes triggering inflammation through the secretion of pro-inflammatory cytokines, helping B cells produce autoantibodies and the accumulation of autoreactive T cells. Aberrations in T cells could be a therapeutic target for development and a potential SLE therapy.

Smith-specific regulatory T cells halt the progression of lupus nephritis

Antigen-specific regulatory T cells (Tregs) suppress pathogenic autoreactivity and are potential therapeutic candidates for autoimmune diseases such as systemic lupus erythematosus (SLE). Lupus nephritis is associated with autoreactivity to the Smith (Sm) autoantigen and the human leucocyte antigen (HLA)-DR15 haplotype; hence, we investigated the potential of Sm-specific Tregs (Sm-Tregs) to suppress disease. Here we identify a HLA-DR15 restricted immunodominant Sm T cell epitope using biophysical affinity binding assays, then identify high-affinity Sm-specific T cell receptors (TCRs) using high-throughput single-cell sequencing. Using lentiviral vectors, we transduce our lead Sm-specific TCR into Tregs derived from patients with SLE who are anti-Sm and HLA-DR15 positive. Compared with polyclonal mock-transduced Tregs, Sm-Tregs potently suppress Sm-specific pro-inflammatory responses in vitro and suppress disease progression in a humanized mouse model of lupus nephritis. These results show that Sm-Tregs are a promising therapy for SLE.

Association between the Duration of Steroid Therapy with Hyperglycemia in Patients with Systemic Lupus Erythematosus (SLE)

Introduction: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease which primary treatment consists of steroid drugs administration. Prolonged steroid administration is often associated with an increase in blood glucose, a condition known as hyperglycemia. Hence, this study aimed to evaluate the association between the duration of steroid therapy with hyperglycemia in patients with SLE treated at a tertiary healthcare center in Surabaya, Indonesia.Methods: A cross-sectional study was conducted under a purposive sampling frame from January to December of 2022 by utilizing secondary data from electronic medical health records in Dr. Soetomo General Academic Hospital, a tertiary healthcare center in Surabaya, Indonesia. The association between variables were analyzed using Fisher’s exact test, chi square test, independent T-test, one-way ANOVA, Mann-Whitney, and Spearman's rank correlation.Results: Out of 150 included patients, 2.67% experienced hyperglycemia following steroid therapy for SLE. There were no significant associations between clinical variables and hyperglycemia occurence in SLE patients (p>0.05). Patients that received higher doses of steroid did not experience any significant difference in hyperglycemia (p=0.727 for <6 months; p=0.865 for ≥6 months). Daily steroid dose was also not significantly associated with the severity of SLE manifestations based on the SLEDAI score (p=0.081). Overall, no significant association was identified between the duration of steroid therapy with hyperglycemia among SLE patients in the hospital (p=0.365). Conclusion: The study found no significant correlation between clinical variables, hyperglycemia incidence, daily steroids dosage, methylprednisolone dosage, SLE severity, or steroid use duration in patients with Systemic Lupus Erythematosus.

CD19 Chimeric Antigen Receptor T Cell Treatment: Unraveling the Role of B Cells in Systemic Lupus Erythematosus.

B cell generation of autoantibodies is a crucial step in the pathogenesis of systemic lupus erythematosus (SLE). After their differentiation in the bone marrow, B cells populate the secondary lymphatic organs, where they undergo further maturation leading to the development of memory B cells as well as antibody-producing plasmablasts and plasma cells. Targeting B cells is an important strategy to treat autoimmune diseases such as SLE, in which B cell tolerance is disturbed and autoimmune B cells and autoantibodies emerge. This review discusses the functional aspects of antibody- and cell-based B cell-depleting therapy in SLE. It thereby particularly focuses on lessons learned from chimeric antigen receptor (CAR) T cell treatment on the role of B cells in SLE for understanding B cell pathology in SLE. CAR T cells model a deep B cell depletion and thereby allow understanding the role of aberrant B cell activation in the pathogenesis of SLE. Furthermore, the effects of B cell depletion on autoantibody production can be better described, ie, explaining the concept of different cellular sources of (auto-) antibodies in the form of short-lived plasmablasts and long-lived plasma cells, which differ in their susceptibility to B cell depletion and require different targeted therapeutic approaches. Finally, the safety of deep B cell depletion in autoimmune disease is discussed.

Study on the expression changes of lncRNA in patients with systemic lupus erythematosus and its correlation with Treg cells.

We initially explored the link between the differentially expressed long non-coding RNAs (lncRNAs) and the number of regulatory T (Treg) cells by detecting the lncRNA expression profiles in patients with systemic lupus erythematosus (SLE), then analyzed the correlation between Treg-related lncRNAs and the clinical features of SLE patients, predicting the mechanism by which lncRNAs regulate the differentiation and development of Treg cells, and provided new ideas for the treatment of SLE. Peripheral blood of 9 active SLE patients were collected and mononuclear cells (PBMCs) were extracted; the lncRNA expression profiles of PBMCs were analyzed by whole transcriptome sequencing. Nine healthy people were used as controls to screen the differentially expressed lncRNAs, to analyze the correlation between lncRNAs and Treg cell number. Pearson test was used to analyze the correlation between lncRNAs and the number of Treg cell, and the correlation between Treg-associated lncRNA and SLEDAI score, ESR, C3, and C4 in SLE patients. The targeted genes of Treg-associated lncRNAs were predicted with miRcode and Targetscan databases and coexpression network. There were 240 differentially expressed lncRNAs in SLE patients compared with healthy controls, including 134 highly expressed lncRNAs (p < 0.05) and 106 lowly expressed lncRNAs (p < 0.05). The expression of ANKRD44-AS1 (r = 0.7417, p = 0.0222), LINC00200 (r = 0.6960, p = 0.0373), AP001363.2 (r = 0.7766, p = 0.0138), and LINC02824 (r = 0.7893, p = 0.0114) were positively correlated with the number of Treg cell, and the expression of AP000640.1 (r = - 0.7225, p = 0.0279), AC124248.1 (r = - 0.7653, p = 0.0163), LINC00482 (r = - 0.8317, p = 0.0054), and MIR503HG (r = - 0.7617, p < 0.05) were negatively correlated with the number of Treg cell. Among these Treg-associated lncRNAs, the expression of LINC00482 (r = - 0.7348, p < 0.05) and MIR503 HG (r = - 0.7617, p < 0.05) were negatively correlated with C3. LINC00200, ANKRD44 - AS1, and AP000640.1 related to Treg cells regulate the expression of signal transducer and activator of transcription 5 (STAT5), phospholipase D1 (PLD1), homeodomain-only protein X (HOPX), and runt-related transcription factor 3 (RUNX3) through competitive binding of miRNA or trans-regulatory mechanism, thereby regulating the differentiation and development of Treg cell. The lncRNA expression profiles were changed in SLE patients, the differentially expressed lncRNAs were associated with abnormal number and function of Treg cells in SLE, and Treg-associated lncRNAs were associated with SLE-disease activity, which may affect the expression of STAT5, PLD1, HOPX, RUNX3 and regulate Treg cell function and participate in the pathogenesis and progression of SLE by competitively binding to miRNAs or trans-regulatory mechanism. Key points • Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs and systems. lncRNAs may affect Treg cells function by regulating genes expression, which may be an important pathogenesis of SLE. • This study, taking SLE as an example, preliminarily analyzed the correlation between lncRNA and Treg cells in SLE patients, analyzed the correlation between Treg-related lncRNA and the clinical characteristics of SLE, and speculated that lncRNA could regulate the differentiation and development of Treg cells through competitive combination with miRNA or trans-regulatory mechanisms. • It is possible to target epigenetic therapy for SLE.

Diagnostic Values of METTL1-Related Genes and Immune Characteristics in Systemic Lupus Erythematosus.

Methyltransferase like 1 (METTL1) regulates epitranscriptomes via the m7G modification in mammalian mRNA and microRNA. Systemic lupus erythematosus (SLE) is caused by abnormal immune reactivity and has diverse clinical manifestations. RNA methylation as a mechanism to regulate gene expression is widely implicated in immune regulation. However, the role of m7G in immune response of SLE has not been extensively studied. Expression of METTL1 was identified in the public dataset GSE122459 and validated in an independent cohort of SLE patients. We investigated the association between METTL1-expression and clinical manifestations of SLE. Subsequently, differentially expressed genes (DEG) that were correlated with METTL1-expression in GSE122459 were used for functional enrichment analysis. The correlation between infiltrating immune cells and METTL1, as well as candidate biomarkers identified to be correlated with either METTL1 or immune cell infiltration were assessed by single-sample GSEA. Potential mechanisms were explored with Gene ontology and KEGG pathway enrichment. Diagnostic performances of candidate biomarkers in SLE were analyzed. The mRNA and protein expression of METTL1 in SLE patients were significantly decreased in both datasets. METTL1-coexpressed DEGs were enriched in several key immune-related pathways. Activated CD8 T cells, activated CD4 T cells, memory B cells and type 2 helper T cells were different between patients with high and low METTL1 expression. Further, activated CD8 T-cells, activated CD4 T-cells, memory B-cells were correlated with METTL1. The genes of LAMP3, CD83, PDCD1LG2, IGKVD3D-20, IGKV5-2, IGKV2D-30, IGLV3-19 and IGLV4-60 were identified as candidate targets that were correlated with immune cell proportion. Moreover, LAMP3, CD83, and PDCD1LG2 expression were of diagnostic value in SLE as indicated by ROC analysis. Our findings suggested that METTL1 and its candidate targets LAMP3, CD83, PDCD1LG2 may be used for diagnosing SLE and could be explored for developing targeted molecular therapy for SLE.

Symposium 6

The ultimate goal of treatment of systemic lupus erythematosus (SLE) is to prolong survival without compromising the quality of life. The survival rates of SLE have plateaued since the 2000s’ and morbidities related to disease activity and treatment are still problematic. A big unmet need for SLE therapy is to develop strategies that can enhance efficacy, reduce disease flares and drug related complications. Cocktail immunosuppressive therapies for the synergistic effect of individual drugs may enhance efficacy and enable dosage reduction. However, risk of infective complications, adoption of a step-up or step-down approach and the choice of agents are still controversial, partly because of the issue of cost-effectiveness. Belimumab is the first biological agent licensed for pediatric and adult patients with renal and non-renal SLE, based on several pivotal randomized controlled trials (BLISS-52, BLISS-76, BLISS-NEA, BLISS-SC, BLISS-LN). The continuous use of belimumab enables reduction of disease flares, glucocorticoid doses and organ damage. Anifrolumab, a monoclonal antibody against type I interferon receptors, has shown efficacy for non-renal SLE in the TULIP studies. It is recently licensed for moderate to severe SLE patients who are receiving standard therapies. Although rituximab did not show benefit in renal and non-renal SLE, it is commonly used off-label to treat refractory lupus manifestations. The newer generation anti-CD20 biologic, obinutuzumab, shows promising preliminary results in a phase 2 lupus nephritis (LN) trial. Combination of anti-CD20 and anti-BAFF is being studied in LN but the results are conflicting hitherto. Ianalumab, a monoclonal antibody against BAFF receptor that exhibits dual mechanisms of action (BAFF inhibition and B cell depletion), is being studied in LN. The updated 2023 EULAR recommendations for SLE have included the role of biological agents in the treatment algorithm. Belimumab and anifrolumab may be considered in non-major organ SLE, including skin disease, that is refractory to hydroxychloroquine with or without other immunosuppressive agents. Initial combination therapy of glucocorticoids, mycophenolate mofetil or low dose cyclophosphamide, with belimumab is an option for the treatment of severe LN, and belimumab may be used as long-term maintenance therapy of SLE/LN. In this talk, the evidence and the role of the older and newer biologic and targeted agents in SLE/LN will be reviewed.

FRI045 Impact Of Morbid Obesity On Lupus Hospitalizations: A Nationwide Analysis

Abstract Disclosure: F. Sami: None. S. Sami: None. K.N. Patolia: None. T. Ayub: None. Background: Obesity is a risk factor for Systemic Lupus erythematosus(SLE) and reduces quality of life in SLE patients because of disease activity and damage accrual. We aim to define the epidemiology of obese SLE patients, impact of morbid obesity on lupus hospitalizations &amp; assess healthcare economic burden from obesity. Methods: The National Inpatient Sample (NIS) was used to obtain data. Data was optimized to reflect national estimates. Patients hospitalized with a principal diagnosis of SLE with and without morbid obesity as a comorbidity were obtained from 2016-2019 NIS. Epidemiological characteristics were analyzed. Primary outcomes of mortality, length of hospital stay (LOS), &amp; total hospital charges(THC) were compared for both groups. Univariate logistic analysis was used to identify confounders and adjusted odds ratio was calculated using the multivariate logistic regression model. Results: Of 721,090 SLE hospitalizations, 7.96% had obesity as a comorbidity. For obese SLE patients, mean age was significantly lower than nonobese SLE patients(51.94 years [SD 13.86] vs 52.55 years [SD 17.30]). There were significantly more females (93.1% vs. 88%), were from age group of 40-60 years (47.5% vs 36.3%), were caucasians (50.64% vs 48.62%) and blacks (34.5% vs 30.7%)Obesity was less frequent in Hispanic and Asian lupus patients (odds ratio [OR] 0.79 and 0.33, respectively). It was significantly more in low socioeconomic SLE patients (income $1-$55,999) (38.18% vs. 33.87%) and less prevalent in high socioeconomic class with income &amp;gt; $94000 (13.3% vs 49.56%). Mortality rate was significantly higher for obese SLE patients (1.54 % vs. 1.20%, OR 1.03). Obese group had mean LOS 5.79 days vs. 5.42 days (p-value 0.009) and higher THC ($66265 vs $63742, p-value &amp;lt; 0.001). Charlson comorbidity index was higher for obese SLE (3.33 vs 2.98, p-value &amp;lt; 0.001). Obese SLE patients were significantly more common to have sepsis (10.24% vs 8.67%, OR 1.20), heart failure (6.50% vs 5.05%, OR 1.31) pulmonary embolism/deep vein thrombosis (PE/DVT) (3.86% vs. 2.69%,OR 1.45) and respiratory failure (17.91% vs 12.68%, OR 1.50), with p-value &amp;lt; 0.001 for all.It was not an independent predictor of mortality for SLE patients. Other significant predictors of mortality identified for SLE patients were age (OR 1.02), Charlson comorbidity index (OR 1.06), renal failure (OR 2.75), sepsis (OR 2.74), PE/DVT (OR 2.22), respiratory failure (OR 12.75), and stroke (OR 1.82), most of which were more common with obesity. Conclusion: Obesity with SLE is more widely seen in females, relatively younger age, low socioeconomic class, Caucasians and African-Americans. Obese SLE patients have greater mortality, THC &amp; LOS, reflecting more healthcare burden. Respiratory failure, stroke, sepsis, PE/DVT and heart failure are more common in obese patients. Therefore, weight optimization therapies for SLE may improve outcomes. Presentation: Friday, June 16, 2023

B Cell Tolerance and Targeted Therapies in SLE.

Systemic Lupus Erythematosus (SLE) is a chronic systemic autoimmune disease of high clinical and molecular heterogeneity, and a relapsing-remitting pattern. The disease is currently without cure and more prevalent in women. B cell tolerance and production of autoantibodies are critical mechanisms that drive SLE pathophysiology. However, how the balance of the immune system is broken and how the innate and adaptive immune systems are interacting during lupus-specific autoimmune responses are still largely unknown. Here, we review the latest knowledge on B cell development, maturation, and central versus peripheral tolerance in connection to SLE and treatment options. We also discuss the regulation of B cells by conventional T cells, granulocytes, and unconventional T cells, and how effector B cells exert their functions in SLE. We also discuss mechanisms of action of B cell-targeted therapies, as well as possible future directions based on current knowledge of B cell biology.

Low-dose interleukin-2 therapy in systemic lupus erythematosus.

In systemic lupus erythematosus (SLE), T regulatory cells (Tregs) contribute to the inhibition of autoimmune responses by suppressing self-reactive immune cells. Interleukin (IL)-2 plays an essential role in the generation, function and homeostasis of the Tregs and is reduced in SLE. Several clinical studies, including randomized trials, have shown that low-dose IL-2 therapy in SLE patients is safe and effective and can reduce disease manifestations. This review discusses the rationale for the use of low-dose IL-2 therapy in SLE, the clinical responses in patients, and the effects of this therapy on different types of T cells. Considerations are made on the current and future directions of use of low-dose IL-2 regimens in SLE.

Cytokines in Systemic Lupus Erythematosus-Focus on TNF-α and IL-17.

Systemic lupus erythematosus (SLE) is an autoimmune disorder known for its complex pathogenesis, in which cytokines play an essential role. It seems that the modulation of these cytokines may impact disease progression, being considered potential biomarkers. Thus, TNF (tumor necrosis factor)-α and IL (interleukin)-17 are molecules of great interest in SLE. TNF-α plays a dual role in SLE, with both immunosuppressive and proinflammatory functions. The role of IL-17 is clearly described in the pathogenesis of SLE, having a close association with IL-23 in stimulating the inflammatory response and consecutive tissue destruction. It appears that patients with elevated levels of these cytokines are associated with high disease activity expressed by the SLE disease activity index (SLEDAI) score, although some studies do not confirm this association. However, TNF-α and IL-17 are found in increased titers in lupus patients compared to the general population. Whether inhibition of these cytokines would lead to effective treatment is under discussion. In the case of anti-TNF-α therapies in SLE, the possibility of ATIL (anti-TNF-induced lupus) is a serious concern that limits their use. The use of anti-IL-17 therapies in SLE is a promising option, but not yet approved. Future studies of these cytokines in large cohorts will provide valuable information for the management of SLE.

Cytokine and reactivity profiles in SLE patients following anti-CD19 CART therapy

Chimeric antigen receptor (CAR) Tcells targeting CD19+ B cells have demonstrated efficacy in refractory systemic lupus erythematosus (SLE). Although initial clinical data suggest that anti-CD19 CAR Tcell therapy is well tolerated and highly effective, the immunologic consequences of CAR Tcell therapy in SLE patients remain unclear. We profiled serum in six refractory SLE patients prior to and 3months following CAR Tcell infusion. Three months post Tcell infusion, the inflammatory cytokines IL-6 and TNFα decreased in patient sera. This was accompanied by elevations in serum IL-7 and BAFF. Furthermore, SLE-associated antibodies dropped profoundly in five of six patients. Last, consistent with other reports of CD19 CAR T therapy in B cell malignancies, we were able to show marginal impact of anti-CD19 CART therapy on pre-existing humoral immune responses in SLE patients. Together, these results provide insights into the mechanisms of efficacy of anti-CD19 CAR Tcell therapy in SLE.

Overexpressed CD44 is associated with B-cell activation via the HA-CD44-AIM2 pathway in lupus B cells

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by aberrant development of B cells and excess production of autoantibodies. Our team previously reported that absent in melanoma 2 (AIM2) regulates B-cell differentiation via the Bcl-6-Blimp-1 axis. Notably, in keyhole limpet hemocyanin (KLH)-immunized CD19creAim2f/f mice, the frequency of CD19+CD44+ B cells was decreased, accompanied by a weakened KLH response, indicating that AIM2 deficiency suppressed the antigen-induced B-cell immune response by downregulating the expression of CD44. CD44, a surface marker of T-cell activation and memory, was overexpressed in T cells of SLE patients, but its roles and mechanism in B cells have not been elucidated. In the current work, we revealed that CD44 expression was upregulated in the B cells of SLE patients and MRL/lpr mice, accompanied by elevated AIM2 expression in CD19+CD44+ B-cell subsets, and that its ligand hyaluronan (HA) was also abnormally increased in the serum of SLE patients. Notably, the extrafollicular (EF) region serves as an important site of B-cell activation and differentiation separate from the germinal center, while CD44 expression is concentrated in EF B cells. In addition, in vitro experiments demonstrated that the HA-CD44 interaction stimulated B-cell activation and upregulated the expression of AIM2 and the transcription factor STAT3. Either blocking CD44, knocking down AIM2 expression or suppressing the activity of STAT3 in B cells suppressed B-cell activation and proliferation. Moreover, blocking CD44 downregulated the expression of STAT3 and AIM2, while suppressing the activity of STAT3 decreased the expression of CD44 and AIM2. In summary, overexpressed CD44 in B cells might participate in B-cell activation and proliferation in the EF region via the HA-CD44-AIM2 pathway, providing potential targets for SLE therapy.

Efficacy and Safety of New B Cell-Targeted Biologic Agent for the Treatment of Systemic Lupus Erythematosus: A Systematic Review and Meta-Analysis.

B cells are central to the pathogenesis of systemic lupus erythematosus (SLE). We aimed to analyze the efficacy and safety of new B cell-targeted drug therapies for SLE. A systematic review of randomized controlled trials (RCTs) and reference lists of relevant articles published from inception to 2022 were selected from PubMed, Scopus and Web of Science databases. Random effects meta-analyses were performed to estimate an overall effect size for the risk of adverse events (AEs) and serious adverse events (SAEs) with belimumab and tabalumab treatment. Heterogeneity was assessed using the I2 statistic and meta-regression. Funnel asymmetry was evaluated using Egger's test. This study included 13 RCTs, of which three showed high risk of bias. Egger's test showed no asymmetry. The risk of SAEs and AEs was lower in the treatment group with belimumab treatment. The risk of AEs for tabalumab treatment was lower in the treatment group and lower for SAEs. Belimumab and tabalumab therapies are effective and safe in the treatment of SLE, although tabalumab does not show sufficient statistical power. Advances in understanding the underlying mechanisms of SLE will be directed towards correlating clinical manifestations with specific pathogenic pathways and the development of precision medicine.

Janus kinase inhibitors in systemic lupus erythematosus: implications for tyrosine kinase 2 inhibition.

Aberrant activation of the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway is common in systemic lupus erythematosus (SLE), conferring immune-mediated properties in target tissues. Multiple cytokines activate different combinations of JAKs and STATs to alter the cell fate of target tissue and induce end-organ damage. Thus, the simultaneous blockade of several different cytokines by small molecules acting downstream intracellular signalling has gained traction. JAK inhibitors have been approved for the treatment of several rheumatic diseases, yet hitherto not for SLE. Nevertheless, JAK inhibitors including tofacitinib, baricitinib, and deucravacitinib have shown merit as treatments for SLE. Tofacitinib, a JAK1/3 inhibitor, reduced cholesterol levels, improved vascular function, and decreased the type I interferon signature in SLE patients. Baricitinib, a JAK1/2 inhibitor, demonstrated significant improvements in lupus rashes and arthritis in a phase 2 and a phase 3 randomised controlled trial, but the results were not replicated in another phase 3 trial. Deucravacitinib, a selective tyrosine kinase 2 (TYK2) inhibitor, yielded greater response rates than placebo in a phase 2 trial of SLE and will be investigated in larger phase 3 trials. TYK2 is activated in response to cytokines actively involved in lupus pathogenesis; this review highlights the potential of targeting TYK2 as a promising therapy for SLE.

Triptoquinone A and B exercise a therapeutic effect in systemic lupus erythematosus by regulating NLRC3.

The autoimmune disorder systemic lupus erythematosus (SLE) is multifaceted, with limited therapeutic alternatives and detrimental side effects, particularly on bones and joints. This research endeavors to examine the curative potential and underlying mechanisms of in addressing SLE-associated bone and joint complications. Triptoquinone A and triptoquinone B, constituents of Tripterygium wilfordii polyglycoside tablets (TGTs), exhibit antioxidant and anti-inflammatory attributes; nonetheless, its function in SLE therapy remains elusive. This investigation delves into the role of oxidative stress in systemic lupus erythematosus (SLE) and probes the prospective remedial effects of triptoquinone A and triptoquinone B on inflammation and cartilage deterioration in SLE-affected joints. Employing bioinformatics analyses, differentially expressed genes (DEGs) and protein-protein interactions were discerned in SLE, rheumatoid arthritis (RA), and osteoarthritis (OA) datasets. Enrichment analyses unveiled shared genes implicated in immune system regulation and toll-like receptor signaling pathways, among others. Subsequent examination of triptoquinone A and triptoquinone B revealed their capacity to diminish NLRC3 expression in chondrocytes, resulting in decreased pro-inflammatory cytokine levels and cartilage degradation enzyme expression. Suppression of NLRC3 augmented the protective effects of triptoquinone A and B, implying that targeting NLRC3 may constitute a potential therapeutic strategy for inflammation and cartilage degeneration-associated conditions in SLE patients. Our discoveries indicate that triptoquinone A and triptoquinone B may impede SLE progression via the NLRC3 axis, offering potential benefits for SLE-affected bone and joint health.