Systemic Lupus Erythematosus Therapeutics Research Articles

Unveiling the dynamics of B lymphocytes in systemic lupus erythematosus patients treated with belimumab through longitudinal single-cell RNA sequencing.

Unraveling the mechanisms underlying treatment response for targeted therapeutics in systemic lupus erythematosus (SLE) patients is challenging due to the limited understanding of diverse responses of circulating immune cells, particularly B cells. We investigated B lymphocyte dynamics during anti-BAFF treatment, utilizing longitudinal single-cell transcriptome data. We conducted single-cell RNA sequencing on PBMCs in four Korean SLE patients before and after belimumab treatment at the following time points: 2 weeks, 1, 3, 6, and 12 months. Analyzing over 73 000 PBMCs, we identified 8 distinct subsets of B cells and plasmablasts and analyzed dynamic changes within these cell subsets: initial declines in naive and transitional B cells followed by an increase at three months, contrasted by an initial increase and subsequent decrease in memory B cells by the third month. Meanwhile, plasmablasts exhibited a consistent decline throughout treatment. B cell activation pathways, specifically in naive and memory B cells, were downregulated during the third and sixth months. These findings were validated at the protein level throughout the first four weeks of treatment using flow cytometry. Comparative analysis with bulk transcriptome data from 22 Japanese SLE patients showed increased NR4A1 expression six months post-belimumab treatment, indicating its role in restricting self-reactive B cells, thereby contributing to the biological responses of anti-BAFF treatment. The observed B cell dynamics provided insights into the immunological mechanisms underlying the therapeutic effects of anti-BAFF in SLE patients. Furthermore, it underscores the need for research in predicting drug responses based on immune profiling.

Exploring the Complex Relationship Between Microbiota and Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by various autoantibodies and multi-organ. Microbiota dysbiosis in the gut, skin, oral, and other surfaces has a significant impact on SLE development. This article summarizes relevant research and provides new microbiome-related strategies for exploring the mechanisms and treating patients with SLE. SLE patients have disruptions in multiple microbiomes, with the gut microbiota (bacteria, viruses, and fungi) and their metabolites being the most thoroughly researched. This dysbiosis can promote SLE progression through mechanisms such as the leaky gut, molecular mimicry, and epigenetic regulation. Notwithstanding study constraints on the relationship between microbiota and SLE, specific interventions targeting the gut microbiota, such as probiotics, dietary management, and fecal microbiota transplantation, have emerged as promising SLE therapeutics.

CAR T Cell Therapy: A New Hope for Refractory Lupus?

Systemic lupus erythematosus (SLE) is a complex multisystem, autoimmune disorder. The disease involves multiple inflammatory and immune pathways, posing several treatment challenges. The role of B cells in the pathogenesis and disease activity of SLE is well described, and treatments targeting B cells are now well established. Despite advances in therapeutics for SLE, the clinical course of SLE can be associated with significant morbidity and mortality. For many individuals, the management of SLE requires lifelong immunosuppression. Chimeric antigen receptor (CAR) T cell therapy is an emerging treatment for haematological malignancies that uses CAR T cells to target CD19+ B lymphocytes. CAR T cell therapy has shown promising results in murine models of SLE, and a case report and subsequent case series in people with SLE reporting drug-free remission following CAR T cell therapy against CD19+ B cells have recently been published. This review discusses CAR T cell therapy, comparing it with established B cell depletion therapies, such as rituximab, and exploring its safety, limitations and promise in the management of patients with SLE.

Editorial introductions.

Editorial introductions.

Editorial introductions

Editorial introductions

The Pathogenesis, Molecular Mechanisms, and Therapeutic Potential of the Interferon Pathway in Systemic Lupus Erythematosus and Other Autoimmune Diseases.

Therapeutic success in treating patients with systemic lupus erythematosus (SLE) is limited by the multivariate disease etiology, multi-organ presentation, systemic involvement, and complex immunopathogenesis. Agents targeting B-cell differentiation and survival are not efficacious for all patients, indicating a need to target other inflammatory mediators. One such target is the type I interferon pathway. Type I interferons upregulate interferon gene signatures and mediate critical antiviral responses. Dysregulated type I interferon signaling is detectable in many patients with SLE and other autoimmune diseases, and the extent of this dysregulation is associated with disease severity, making type I interferons therapeutically tangible targets. The recent approval of the type I interferon-blocking antibody, anifrolumab, by the US Food and Drug Administration for the treatment of patients with SLE demonstrates the value of targeting this pathway. Nevertheless, the interferon pathway has pleiotropic biology, with multiple cellular targets and signaling components that are incompletely understood. Deconvoluting the complexity of the type I interferon pathway and its intersection with lupus disease pathology will be valuable for further development of targeted SLE therapeutics. This review summarizes the immune mediators of the interferon pathway, its association with disease pathogenesis, and therapeutic modalities targeting the dysregulated interferon pathway.

The latest in systemic lupus erythematosus-accelerated atherosclerosis: related mechanisms inform assessment and therapy.

Accelerated atherosclerosis is a significant comorbidity and the leading cause of death for patients with systemic lupus erythematosus (SLE). It is now apparent that SLE-accelerated atherosclerosis is not driven solely by traditional cardiovascular risk factors, adding complexity to disease characterization and mechanistic understanding. In this review, we will summarize new insights into SLE-accelerated atherosclerosis evaluation, treatment, and mechanism. Recent work highlights the need to incorporate inflammatory biomarkers into cardiovascular disease (CVD) risk assessments. This is especially true for SLE patients, in which mechanisms of immune dysfunction likely drive CVD progression. There is new evidence that commonly prescribed SLE therapeutics hinder atherosclerosis development. This effect is achieved both by reducing SLE-associated inflammation and by directly improving measures of atherosclerosis, emphasizing the interconnected mechanisms of the two conditions. SLE-accelerated atherosclerosis is most likely the consequence of chronic autoimmune inflammation. Therefore, diligent management of atherosclerosis requires assessment of SLE disease activity as well as traditional cardiovascular risk factors. This supports why many of the therapeutics classically used to control SLE also modulate atherosclerosis development. Greater understanding of the mechanisms underlying this condition will allow for the development of more targeted therapeutics and improved outcomes for SLE patients.

Targeting the Protective Arm of the Renin-Angiotensin System to Reduce Systemic Lupus Erythematosus Related Pathologies in MRL-lpr Mice

Patients with Systemic Lupus Erythematosus (SLE) suffer from a chronic inflammatory autoimmune disease that results from the body's immune system targeting healthy tissues which causes damage to various organ systems. Patients with lupus are still in need of effective therapies to treat this complex, multi-system disease. Because polymorphisms in ACE are associated with the activity of SLE and lupus nephritis and based on well-documented renal-protective effects of Renin Angiotensin System (RAS)-modifying therapies, ACE-I are now widely used in patients with SLE with significant efficacy. Our research explores alternate ways of modifying the RAS as a potential for systemic therapeutic benefit in the MRL-lpr mouse model of SLE. These therapeutics include; angiotensin (1-7) [A(1-7)], Nor-Leu-3 Angiotensin (1-7) (NorLeu), Losartan (ARB), and Lisinopril (ACE-I). Daily systemic treatment with all of these RAS-modifying therapies significantly reduced the onset and intensity in rash formation and swelling of the paw. Further, histology showed a corresponding decrease in hyperkeratosis and acanthosis in skin sections. Important immunological parameters such as decreased circulating anti-dsDNA antibodies, lymph node size, and T cell activation were observed. As expected, the development of glomerular pathologies was also attenuated by RAS-modifying therapy. Improved number and health of mesenchymal stem cells (MSCs), as well as reduction in oxidative stress and inflammation may be contributing to the reduction in SLE pathologies. Several studies have already characterized the protective role of ACE-I and ARBs in mouse models of SLE, here we focus on the protective arm of RAS. A(1-7) in particular demonstrates several protective effects that go beyond those seen with ACE-Is and ARBs; an important finding considering that ACE-Is and ARBs are teratogenic and can cause hypotension in this population. These results offer a foundation for further pharmaceutical development of RAS-modifying therapies, that target the protective arm, as novel SLE therapeutics that do not rely on suppressing the immune system.

Integrated, multicohort analysis reveals unified signature of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that follows an unpredictable disease course and affects multiple organs and tissues. We performed an integrated, multicohort analysis of 7,471 transcriptomic profiles from 40 independent studies to identify robust gene expression changes associated with SLE. We identified a 93-gene signature (SLE MetaSignature) that is differentially expressed in the blood of patients with SLE compared with healthy volunteers; distinguishes SLE from other autoimmune, inflammatory, and infectious diseases; and persists across diverse tissues and cell types. The SLE MetaSignature correlated significantly with disease activity and other clinical measures of inflammation. We prospectively validated the SLE MetaSignature in an independent cohort of pediatric patients with SLE using a microfluidic quantitative PCR (qPCR) array. We found that 14 of the 93 genes in the SLE MetaSignature were independent of IFN-induced and neutrophil-related transcriptional profiles that have previously been associated with SLE. Pathway analysis revealed dysregulation associated with nucleic acid biosynthesis and immunometabolism in SLE. We further refined a neutropoiesis signature and identified underappreciated transcripts related to immune cells and oxidative stress. In our multicohort, transcriptomic analysis has uncovered underappreciated genes and pathways associated with SLE pathogenesis, with the potential to advance clinical diagnosis, biomarker development, and targeted therapeutics for SLE.

Inhibition of IL-17 ameliorates systemic lupus erythematosus in Roquinsan/san mice through regulating the balance of TFH cells, GC B cells, Treg and Breg

Systemic lupus erythematosus (SLE) is mediated by a chronic and dysregulated inflammatory response. Interleukin (IL)-17, a proinflammatory cytokine, and T helper (Th)17 cells are associated with chronic autoimmune diseases. We hypothesized that inhibition of IL-17 would decrease the numbers of T cell subsets that function as B-cell helpers, as well as B-cell differentiation into plasma cells and autoantibody expression. The IL-17 level was increased markedly in Roquinsan/san mice. Loss of IL-17 in Roquinsan/san mice improved nephritis by downregulating immunoglobulin (Ig)G, IgG1, and IgG2a production. Formation of germinal centers (GCs), and follicular B- and T-cell differentiation was reduced, whereas the number of regulatory T (Treg) cells and immature B cells was increased, by IL-17 deficiency in Roquinsan/san mice. These results suggest that IL-17 inhibition can ameliorate SLE by inhibiting B-cell differentiation into GCs. Therefore, IL-17–producing Th17 cells show promise as a target for development of novel therapeutics for SLE.

Systemic lupus erythematosus: Withdrawing standard of care therapies in SLE trials?

Clinical trials of novel therapeutics in systemic lupus erythematosus (SLE) have so far been disappointing. A high placebo response rate in these trials owing to continued use of background immunosuppressive therapy could be confounding results. Could patient stratification and minimization of entry medications improve the effect size and interpretability of SLE trials?

CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus.

Genetic variations in the ITGAM gene (encoding CD11b) strongly associate with risk for systemic lupus erythematosus (SLE). Here we have shown that 3 nonsynonymous ITGAM variants that produce defective CD11b associate with elevated levels of type I interferon (IFN-I) in lupus, suggesting a direct link between reduced CD11b activity and the chronically increased inflammatory status in patients. Treatment with the small-molecule CD11b agonist LA1 led to partial integrin activation, reduced IFN-I responses in WT but not CD11b-deficient mice, and protected lupus-prone MRL/Lpr mice from end-organ injury. CD11b activation reduced TLR-dependent proinflammatory signaling in leukocytes and suppressed IFN-I signaling via an AKT/FOXO3/IFN regulatory factor 3/7 pathway. TLR-stimulated macrophages from CD11B SNP carriers showed increased basal expression of IFN regulatory factor 7 (IRF7) and IFN-β, as well as increased nuclear exclusion of FOXO3, which was suppressed by LA1-dependent activation of CD11b. This suggests that pharmacologic activation of CD11b could be a potential mechanism for developing SLE therapeutics.

Failure of a systemic lupus erythematosus response index developed from clinical trial data: lessons examined and learned.

Background Our primary goal was to create an outcome change score index similar to a standard rheumatoid arthritis (RA) model utilizing real-world data in systemic lupus erythematosus (SLE) patients that occurred during their phase 3 trials with a Food and Drug Administration-approved drug. Methods We utilized raw data from trials of belimumab for the treatment of SLE. Data were split 80/20 into training/validation sets. Index variables present in a majority of patients and with face validity were selected. Variables were scored for each patient as percentage improvement from baseline after one year. The percentage of placebo- and drug-treated patients considered improved after the application of various criteria was ascertained. Logistic regression was employed to determine the ability of the new index to predict treatment assignment. Results A total of 1693 subjects had data for analyses. Eight variables were chosen: arthritis, rash, physician global assessment, fatigue, anti-double stranded DNA antibodies, C3, C4 and C-reactive protein. In the training dataset, ≥20% improvement in ≥4 of eight variables produced the largest difference between placebo- and drug-treated patients (22.1%) with an acceptable rate of improved placebo-treated patients (25%). This resulted in an odds ratio for belimumab (10 mg/kg) vs placebo of 2.7 (95% CI: 2.0-3.6; p < 0.001). However, in the validate dataset the odds ratio was not significant at 1.3 (95% CI: 0.8-2.2; p = 0.863). Conclusions The index created from training data did not achieve statistical significance when tested in the validation set. We have speculated why this happened. Is the lack of success of therapeutics for SLE caused by ineffective medications, study design and outcome instruments that fail to inform us, or is the heterogeneity of the disease too daunting? The lessons learned here can help direct future endeavors intended to improve SLE outcome instruments.

Clinical trials: The rise of IL-2 therapy - a novel biologic treatment for SLE.

An unmet need exists for more-effective and selective therapeutics in systemic lupus erythematosus. Advances in understanding of the pathogenetic mechanisms of this severe autoimmune disease have led to the clinical translation of low-dose IL-2 therapy, which primarily aims to restore the activity of regulatory T cells.

A cytotoxic anti-IL-3Rα antibody targets key cells and cytokines implicated in systemic lupus erythematosus.

To date, the major target of biologic therapeutics in systemic lupus erythematosus (SLE) has been the B cell, which produces pathogenic autoantibodies. Recently, targeting type I IFN, which is elaborated by plasmacytoid dendritic cells (pDCs) in response to endosomal TLR7 and TLR9 stimulation by SLE immune complexes, has shown promising results. pDCs express high levels of the IL-3Rα chain (CD123), suggesting an alternative potential targeting strategy. We have developed an anti-CD123 monoclonal antibody, CSL362, and show here that it affects key cell types and cytokines that contribute to SLE. CSL362 potently depletes pDCs via antibody-dependent cell-mediated cytotoxicity, markedly reducing TLR7, TLR9, and SLE serum-induced IFN-α production and IFN-α-upregulated gene expression. The antibody also inhibits TLR7- and TLR9-induced plasmablast expansion by reducing IFN-α and IL-6 production. These effects are more pronounced than with IFN-α blockade alone, possibly because pDC depletion reduces production of other IFN subtypes, such as type III, as well as non-IFN proinflammatory cytokines, such as IL-6. In addition, CSL362 depletes basophils and inhibits IL-3 signaling. These effects were confirmed in cells derived from a heterogeneous population of SLE donors, various IFN-dependent autoimmune diseases, and healthy controls. We also demonstrate in vivo activity of CSL362 following its s.c. administration to cynomolgus monkeys. This spectrum of effects provides a preclinical rationale for the therapeutic evaluation of CSL362 in SLE.

Targeted therapeutics in SLE: emerging strategies to modulate the interferon pathway.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by impaired immune tolerance, resulting in the generation of pathogenic autoantibodies and immune complexes. Although autoreactive B lymphocytes have been the first targets for biologic therapies in SLE, the importance of the innate immune system, and in particular, pathways involved in interferon (IFN) signaling, has emerged. There are now data supporting a central role for a plasmacytoid dendritic cell-derived type I IFN pathway in SLE, with a number of biologic therapeutics and small-molecule inhibitors undergoing clinical trials. Monoclonal antibodies targeting IFN-α have completed phase II clinical trials, and an antibody against the type I IFN receptor is entering a phase III trial. However, other IFNs, such as IFN gamma, and the more recently discovered type III IFNs, are also emerging as targets in SLE; and blockade of upstream components of the IFN signaling pathway may enable inhibition of more than one IFN subtype. In this review, we discuss the current understanding of IFNs in SLE, focusing on emerging therapies.

A critical link between Lyn-mediated suppression of the TLR-MyD88-IRF5 pathway and the development of SLE-like disease

Abstract The transcription factor interferon regulatory factor 5 (IRF5) is critical for innate immune responses downstream of Toll-like receptors (TLRs). IRF5 is also linked to the pathogenesis of systemic lupus erythematosus (SLE) in humans and mice. However, it remains elusive whether and how IRF5 activity can be negatively regulated. The Src family kinase Lyn is also implicated in human SLE, and Lyn−/− mice develop an SLE-like disease. Here we show that Lyn selectively inhibits IRF5 activity, while it does not affect the NF-κB pathway. Lyn physically interacted with IRF5, thereby suppressing the phosphorylation and ubiquitination of IRF5, post-translational modifications important for IRF5 activation. Interestingly, the kinase activity of Lyn was dispensable for the suppression of IRF5 activity. IRF5 was hyper-activated in TLR7/9-stimulated Lyn−/− bone marrow-derived dendritic cells (BMDCs), and these cells hyper-produced IRF5-dependent cytokines especially type-I interferons (IFNs). IRF5 was constitutively activated (phosphorylated and translocated into the nucleus) in splenic DCs isolated from Lyn−/− mice. Importantly, even monoallelic ablation of the Irf5 gene was sufficient to alleviate the hyper-production of type-I IFNs in TLR7/9-stimulated Lyn−/− BMDCs, and to ameliorate the development of SLE-like symptoms, such as autoantibody production and autoimmune glomerulonephritis, in Lyn−/− mice. Our results identify Lyn as a critical suppressor of the TLR-MyD88-IRF5 pathway, and implicate that the selective control of IRF5 activity may contribute to better therapeutics for SLE.

High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry.

Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,492 SLE cases and 12,675 controls from six East-Asian cohorts, to identify novel and better localize known SLE susceptibility loci. We identified 10 novel loci as well as 20 known loci with genome-wide significance. Among the novel loci, the most significant was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta=3.75×10−117, OR=2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We localized the most likely functional variants for each locus by analyzing epigenetic marks and gene regulation data. Ten putative variants are known to alter cis- or trans-gene expression. Enrichment analysis highlights the importance of these loci in B- and T-cell biology. Together with previously known loci, the explained heritability of SLE increases to 24%. Novel loci share functional and ontological characteristics with previously reported loci, and are possible drug targets for SLE therapeutics.

Detection of dynamic frequencies of Th17 cells and their associations with clinical parameters in patients with systemic lupus erythematosus receiving standard therapy.

Recent evidence implicated an important role of Th17 cells in the pathogenesis of systemic lupus erythematosus (SLE). However, the association between dynamic changes of Th17 cell frequency and clinical parameters in SLE patients receiving clinical managements remains unknown. Here, we sought to evaluate their correlation in Chinese new-onset SLE patients with standard therapy. We found that the frequency of Th17 cells was higher in SLE patients than that in healthy controls and could be decreased by standard care. In consistent, the level of serum IL-6, IL-1β, IL-23, and Stat3 activity was elevated in SLE patients and down-regulated by disease treatment. Of note, the frequency of Th17 cells was correlated with SLEDAI and serum C3 in SLE patients. The changes of Th17 cell frequency were associated with those of SLEDAI and serum C3 in SLE patients between pretreatment and posttreatment. Further, the Th17 cell frequency was positively correlated with serum anti-dsDNA antibody in SLE patients. The changes of Th17 cell frequency were associated with those of serum anti-dsDNA antibody in SLE patients. Our findings showed that dynamic frequencies of Th17 cells were closely correlated with clinical parameters in SLE patients receiving standard treatment, which could facilitate the efficient management and development of novel therapeutics for SLE.

New therapeutics in systemic lupus erythematosus

The purpose of this review is to discuss new therapeutics in systemic lupus erythematosus (SLE). We will concentrate on both approved and unapproved treatments that were published during the last year. Efforts have focused on the optimization of the use of Belimumab and Rituximab using information generated previously in clinical trials and the development of small new drugs inhibitors of the proteasome and immune cell signaling molecules such as Btk, ROCK and CaMK4. We cannot predict which biologics are going to be effective in humans, as many of the biologics that provide significant benefit in preclinical trials and lupus-prone mice have often proved noneffective in clinical trials. We now realize that lupus-prone mice do not represent human SLE. Yet, genetic or treatments studies in mice are valuable and help us to understand the role of immune or biochemical abnormalities identified in patients in a whole organism. 2012 was an exciting year for the field of novel therapeutics in SLE and was signified by the effort to target specific signaling pathways with small molecules and biological agents.