Progress of exosome research in systemic lupus erythematosus

Nonstandard and adjunctive medical therapies for systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with various clinical manifestations affecting different tissues. A characteristic feature of SLE is the presence of autoantibodies against double-stranded (ds)DNA, histones and nucleosomes, and other chromatin components. SLE is a prototype type III hypersensitivity reaction. Local deposition of anti-nuclear antibodies in complex with released chromatin induces serious inflammatory conditions by activation of the complement system. The severe renal manifestation, lupus nephritis, is classified based on histological findings in renal biopsies. Apoptotic debris, including chromatin, is present in the extracellular matrix and circulation of patients with SLE. This may be due to an aberrant process of apoptosis and/or insufficient clearance of apoptotic cells/chromatin. The non-cleared apoptotic debris may lead to activation of both the innate and adaptive immune systems. In addition, an aberrant presentation of peptides by antigen-presenting cells, disturbed selection processes for lymphocytes, and deregulated lymphocyte responses may be involved in the development of autoimmunity. In the present review, we briefly will summarize current knowledge on the pathogenesis of SLE. We will also critically discuss and challenge central issues that need to be addressed in order to fully understand the pathogenic mechanisms involved in the development of SLE and in order to have an improved diagnosis for SLE. Disappointingly, in our opinion, there are still more questions than answers for the pathogenesis, diagnosis, and treatment of SLE.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by a diverse array of autoantibody production, complement activation and immune complex deposition, causing tissue and organ damage. Effective medical treatment for SLE is lacking because the etiology and pathogenesis of SLE are incompletely understood. It has been confirmed that cytokine-mediated immunity plays a crucial role in the pathogenesis of various autoimmune diseases including SLE. Recently, IL-27 was identified, which belongs to the IL-12 cytokine family. IL-27 exerts profound anti-inflammatory effects in several experimental autoimmune models. In particular, suppressive effects on TH17 cells, which are implicated in the pathogenesis of SLE. Moreover, administration of IL-27 or augmentation of IL-27 signaling suppresses some autoimmune diseases, including autoimmune diabetes and murine lupus, suggesting that IL-27 may be therapeutically relevant in SLE. In this article, we discuss the biological features of IL-27 and summarize recent advances on the role of IL-27 in the pathogenesis and treatment of SLE. Even though IL-27 has shown therapeutic potential in SLE, further research, particularly in humans, is needed in order to establish the precise role of IL-27 in SLE.

Dysregulation of the antiviral immune response may contribute to autoimmune diseases. Here, we hypothesized that altered expression or function of MAVS, a key molecule downstream of the viral sensors RIG-I and MDA-5, may impair antiviral cell signalling and thereby influence the risk for systemic lupus erythematosus (SLE), the prototype autoimmune disease. We used molecular techniques to screen non-synonymous single nucleotide polymorphisms (SNPs) in the MAVS gene for functional significance in human cell lines and identified one critical loss-of-function variant (C79F, rs11905552). This SNP substantially reduced expression of type I interferon (IFN) and other proinflammatory mediators and was found almost exclusively in the African-American population. Importantly, in African-American SLE patients, the C79F allele was associated with low type I IFN production and absence of anti-RNA-binding protein autoantibodies. These serologic associations were not related to a distinct, functionally neutral, MAVS SNP Q198K. Hence, this is the first demonstration that an uncommon genetic variant in the MAVS gene has a functional impact upon the anti-viral IFN pathway in vivo in humans and is associated with a novel sub-phenotype in SLE. This study demonstrates the utility of functional data in selecting rare variants for genetic association studies, allowing for fewer comparisons requiring statistical correction and for alternate lines of evidence implicating the particular variant in disease.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affecting all organ systems. The disease preferentially affects females of childbearing age. It runs a variable course. It may run a mild course that may never lead to severe disease and manifestations from critical organ systems. However, it may also run an undulating course with periods of mild and severe disease. It may run as a mild disease, quickly deteriorating to severe disease and affecting multiple organ systems. Various immune pathways related both to the innate and adaptive immune response are involved in the pathogenesis of SLE. Various drugs have been developed targeting cellular and molecular targets in these pathways. Interferons are involved in the pathogenesis of SLE, and various drugs have been developed to target this pathway. T and B lymphocytes are involved in the pathophysiology of SLE. Various treatment modalities targeting cellular targets are available for the treatment of SLE. These include biologic agents targeting B lymphocytes. However, some patients have disease refractory to these treatment modalities. For these patients, cell-based therapies may be used. Hematopoietic stem cell transplantation involving autologous cells is an option in the treatment of refractory SLE. Mesenchymal stem cells are also applied in the treatment of SLE. Chimeric antigen receptor (CAR)-T cell therapy is a novel treatment also used in SLE management. This novel treatment method holds major promise for the management of autoimmune diseases and, in particular, SLE. Major hurdles to be overcome are the logistics involved, as well as the need for specialized facilities. This review focuses on novel treatment modalities in SLE targeting cellular and molecular targets in the immune system.

Extracellular Vesicles (EVs) are small vesicles that can be actively secreted by most cell types into the extracellular environment. Evidence indicates that EVs can carry microRNAs (miRNAs), long non-coding RNAs (lncRNAs), tRNA-derived small RNAs (tsRNAs), proteins, and lipids to target cells or tissue organizations. Latest studies show that EVs play a vital role in the immune modulation and may contribute to the pathogenesis of autoimmune diseases. Systemic lupus erythematosus (SLE) is a common autoimmune disease characterized by abnormal T cell activation and sustained production of autoantibodies against self-antigens, resulting in inflammation and damage to multiple systems. Pathogenic mechanisms of SLE, however, are still not well understood. In this review, we summarize the latest research advances on the functions and mechanisms of EVs, and its role in the pathogenesis, diagnosis, and treatment of SLE.

Bibliometric analysis is a mature method for quantitative evaluation of academic productivity. In view of the rapid development of research in the field of systemic lupus erythematosus (SLE) in the past decade, we used bibliometric methods to comprehensively analyze the literature in the field of SLE from 2013 to 2022. The relevant literature in the field of SLE from 2013 to 2022 was screened in the Web of Science Core Collection database. After obtaining and sorting out the data, CiteSpace and VOSviewer software were used to visualize the relevant data, and SPSS software was used for scientific statistics. A total of 18,450 publications were included in this study. The number of articles published over the past 10years has generally shown an upward trend, while Altmetric attention scores have also shown a clear upward trend in general and in most countries. Citation analysis and Altmetric analysis can mutually prove and supplement the influence of papers. The USA, China, Japan, Italy, and the UK are the most productive countries, but China and Japan are significantly inferior to other countries in terms of research influence. Four of the top ten authors are at the center of the collaboration network. LUPUS is the most contributing journal. The theme of systemic lupus erythematosus research mainly focuses on the pathogenesis, treatment, and management of SLE, and the emerging trend is related research on machine learning and immune cells. This study shows the research status of SLE, clarifies the main contributors in this field, discusses and analyzes the research hotspots and trends in this field, and provides reference for further research in this field to promote the development of SLE research. Key Points • Through bibliometric analysis, Altmetric analysis, and visual analysis, we reveal the global productivity characteristics of SLE-related papers in the past 10years. • The number of global SLE-related studies has shown a significant increase, indicating that SLE is still a hot topic and deserves further study. • Citation analysis and Altmetric analysis can mutually prove and supplement the influence of papers, and the attention of related literature among non-professional researchers is increasing. • The theme of SLE research mainly focuses on the pathogenesis, treatment, and management of SLE. The emerging trend is machine learning and immune cells, which may provide new strategies for the diagnosis and treatment of SLE in the future.

Treatment of SLE: bridging the gap from clinical trials to the clinic - a meeting report

CXC ligand 13 (CXCL13) is known as B cell chemotactic factor (BLC), promoting the migration of B lymphocytes by communicating with its receptor CXCR5, which can be regarded as part of pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This meta-analysis was to evaluate the circulating CXCL13 levels in SLE and RA. All articles were respectively gathered from PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) (by the end of 10 April 2019). According to random effects model, standardized mean difference (SMD) and 95% confidence interval (CI) of CXCL13 levels in SLE and RA were calculated by Stata 12.0 software. Totally, 15 studies were selected (981 SLE patients and 380 healthy controls, 332 RA patients and 147 healthy controls). SLE and RA patients were significantly increased in circulating CXCL13 levels (SMD = 1.851, 95% CI 0.604-3.098; SMD = 1.801, 95% CI = 1.145-2.457). Subgroup analyses showed that SLE patients from the Chinese group and systemic lupus erythematosus disease activity index (SLEDAI) score ≥ 6 group had higher circulating CXCL13 levels (SMD = 2.182, 95% CI 0.135-4.229; SMD = 0.767, 95% CI 0.503-1.030). However, there were no significant changes in CXCL13 concentrations in SLE patients from the English and SLEDAI score < 6 group. Similarly, subgroup analyses presented that RA patients from different classifications showed higher circulating CXCL13 levels. There was no publication bias. This meta-analysis demonstrated increased circulating CXCL13 concentrations in SLE and RA patients. Circulating CXCL13 levels may act as biomarkers and therapy targets in the diagnosis and treatment of SLE and RA.Key Point• First, CXC ligand 13 (CXCL13) is closely related to the pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), Second, this study may provide novel therapeutic targets for the treatment of SLE and RA patients. This meta-analysis provides a comprehensive analysis of circulating CXCL13 levels in patients with SLE and RA and also explores related influencing factors.

Successful treatment of severe chronic cutaneous lupus with anifrolumab: A series of 6 cases

Autoimmune diseases are diseases caused by tissue damage caused by the body's immune response to autoantibodies. Circular RNAs (CircRNAs) are a kind of special endogenous non-coding RNA that play a biological role by regulating gene transcription. In this work, we searched the PubMed, Web of Science (SCIE), National Science and Technology Library (NSTL), and ScienceDirect Online (SDOL) databases to summarize the impact of circRNAs on autoimmune diseases, especially the results of circRNAs in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The study on the function of circRNAs and autoimmune diseases further deepened our understanding of the development and pathogenesis of autoimmune diseases. CircRNAs may act as miRNA sponges to regulate biological processes and affect the occurrence and development of autoimmune diseases. CircRNAs are closely related to the pathogenesis of RA and SLE and may become potential biomarkers for the diagnosis and treatment of RA and SLE. CircRNAs play an important role in the pathogenesis of RA, SLE and other autoimmune diseases, and are expected to provide new biomarkers for the diagnosis and treatment of autoimmune diseases. However, the function and mechanism of circRNAs in autoimmune diseases need more comprehensive research.

Atherosclerosis is an inflammatory disease and the major cause of cardiovascular disease (CVD) in general. Atherosclerotic plaques are characterized by the presence of activated immune competent cells, but antigens and underlying mechanisms causing this immune activation are not well defined. During recent years and with improved treatment of acute disease manifestations, it has become clear that the risk of CVD is very high in a prototypic autoimmune disease, systemic lupus erythematosus (SLE). SLE-related CVD and atherosclerosis are important clinical problems but may in addition also shed light on how immune reactions are related to premature atherosclerosis and atherothrombosis. A combination of traditional and nontraditional risk factors, including dyslipidaemia (and to a varying degree hypertension, diabetes and smoking), inflammation, antiphospholipid antibodies (aPL) and lipid oxidation are related to CVD in SLE. Premature atherosclerosis in some form leading to atherothrombosis is likely to be a major underlying mechanism, though distinctive features if any, of SLE-related atherosclerosis when compared with 'normal' atherosclerosis are not clear. One interesting possibility is that factors such as inflammation or aPL make atherosclerotic lesions in autoimmune disease more prone to rupture than in 'normal' atherosclerosis. Whether premature atherosclerosis is a general feature of SLE or only affects a subgroup of patients remains to be demonstrated. Treatment of SLE patients should also include a close monitoring of traditional risk factors for CVD. In addition, attention should also be paid to nontraditional risk factors such as inflammation and SLE-related factors such as aPL. Hopefully novel therapeutic principles will be developed that target the causes of the inflammation and immune reactions present in atherosclerotic lesions.

Background Systemic lupus erythematosus (SLE) is an autoimmune disease that causes inflammation in connective tissues and can involve multiple organs systems. Lupus nephritis (LN) is an inflammatory kidney disease caused by SLE. There is a gap in the literature regarding the standard of care in SLE and LN patients. Objectives This study generated real world medication use among SLE and LN patients. Methods This retrospective study used data from two large administrative databases in the US: Truven Health MarketScan® and Optum® databases to identify adult patients (≥18 years of age) with ≥2 medical claims on different dates for SLE or LN diagnoses from 01JAN2013-31DEC2015. SLE was identified using the International Classification of Diseases, 9th and 10th Revision, Clinical Modification [ICD-9-CM] codes (710.0) OR ICD-10-CM (M32.10-M32.19, 32.8, 32.9). LN was captured as a subset of SLE using [ICD-9-CM: 710.0 AND (581.81 or 582.81 or 583.81); OR (ICD-10-CM:M32.14)]. The first SLE or LN diagnosis was designated as the index date. Patients were required to have continuous health plan enrollment for 1 year pre-index date (baseline period) and 1 year post-index date (follow-up period) and no prior SLE/LN diagnosis claims or belimumab medical/prescription claim during the baseline period to ensure incident patients were captured. The Truven Health MarketScan® and Optum® databases were pooled together and duplicates were identified and retained in MarketScan® only. Patient demographics and clinical characteristics during the baseline period were assessed. SLE treatment used during the follow-up period was evaluated and the proportion of patients that used SLE medications and average number of medical/prescription claims (#Rx) for each medication were provided. Results A total of 31,345 patients were identified including 30,086 SLE and 1,259 LN patients. Key results are shown in Table 1. The mean age was 52.7 years for SLE and 48.3 years for LN patients. Over 80% of the patients were female, with a mean Charlson Comorbidity Index (CCI) score of 1.1 and 1.8 for SLE and LN patients respectively. The most common comorbidities at baseline were hypertension and infections. Corticosteroids (SLE= 58.3%, #Rx=4.5; LN=66.2%, #Rx=6.5) and hydroxychloroquine (SLE=43.4%, #Rx=5.8; LN=40.7% #Rx=6.2) were the most commonly used SLE medications during 1-year follow up period. Approximately 2% of patients used biologics including belimumab (SLE=1.1%, #Rx=8.8; LN=1.4%, #Rx=8.3) and rituximab (SLE=0.9%, #Rx=4.2; LN=2.1%, #Rx=4.0). Conclusion Our findings indicate a nominal use of biologics (∼2%) among SLE and LN patients. Corticosteroids and hydroxychloroquine were the most commonly used SLE treatments. These data reveal an unmet need for availability of advanced therapy to treat SLE and LN. Future studies are warranted to understand the underlying causes. Disclosure of Interests: Lin Xie Grant/research support from: Janssen Research & Development, LLC, Furaha Kariburyo Grant/research support from: Janssen Research & Development, LLC, Janvi Sah Grant/research support from: Janssen Research & Development, LLC, Jennifer H. Lofland Employee of: Janssen Global Commercial Strategic Organization, Nan Li Shareholder of: J&J, Employee of: Janssen Scientific Affairs, LLC

Systemic lupus erythematosus (SLE) is fairly common in Asians, with an overall crude incidence rates (per 100 000 population per year) ranging from 0.9 to 3.1 and crude prevalence rates ranging from 4.3 to 45.3 (per 100 000) in the Asia-Pacific countries.1 SLE is at least two to three times more prevalent in Asia than in the Caucasian countries. As the population in Asia is huge, the burden of SLE disease in the Asian Pacific region is considerable.2 SLE is a multi-systemic autoimmune disease that predominantly affects women of childbearing age. It is characterized by myriads of immunological aberrations that lead to inflammation, dysfunction and damage of multiple organ systems.3 The clinical course of SLE is highly variable and unpredictable, with periods of exacerbations and remissions. Immunosuppressive treatment in order to control SLE disease activity may also incur further complications to organ functions, leading to increased risk of mortality and morbidities such as pain, functional impairment, mood disorders and work disability. All these factors lead to a significant impairment in the quality of life.4 Despite the advancement in the diagnosis and treatment of SLE in the past few decades leading to the improvement in survival, the survival rates of SLE in various localities appear to be plateaued after the 1990s’, and the relative mortality of the disease as compared to the general population is still high.5 Treatment of refractory SLE manifestations is a challenge and more clinical and laboratory research is clearly necessary. The emergence and ongoing studies of the biological agents has added to the arsenal of treatment modalities for SLE. Early diagnosis and identification of disease flares by novel biomarkers, better monitoring of treatment adherence, efficacy and toxicities of immune-modulatory regimens will help to further improve the prognosis of this mysterious disease. In this issue of International Journal of Rheumatic Diseases, experts from different Asian Pacific countries were invited to summarize their views and research works on different aspects of SLE in Asian patients. Clinical topics include the epidemiology of SLE in different ethnic groups, childhood onset SLE, existing and emerging biological therapies for SLE, treatment of lupus nephritis in Asian patients, pregnancy issues of SLE, infective complications of SLE and research on the antiphospholipid antibody syndrome. In addition, basic scientific reviews on the pathogenesis of SLE, genetics, biomarkers in lupus nephritis, role of dendritic cells, lymphocyte subsets and the role of vitamin D and mesenchymal cells in SLE are also included. We hope this special issue of SLE in Asia will provide readers an overview of the works that are ongoing in the Asian Pacific region and an update on the clinical management of different aspects of the disease.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by the presence of antibodies that recognise and target both protein and nucleic acid autoantigens. In addition, elevated levels of IL-23 and type I IFN are a major hallmark of this disease, playing critical roles in disease pathogenesis. TRIM21, a member of the tripartite motif containing (TRIM) E3 ligase family of proteins, is a well characterised SLE-associated autoantigen. Polymorphisms in the TRIM21 gene have been associated with SLE susceptibility suggesting it plays a critical role in disease pathogenesis. Studies into the function of TRIM21 have unveiled a dual function for this protein in regulating immune responses. Initially TRIM21 sustains interferon regulatory factor 3 (IRF3) levels, thus promoting interferon (IFN) and cytokine production, whereas following TLR7/9 stimulation, TRIM21 ubiquitinates IRF3 leading to its degradation via the proteasome, thus negatively regulating IFN and proinflammatory cytokine production. Following TRIM21 gene disruption, the enhanced stability of IRF3 observed has been associated with enhanced type I IFN and also IL-23pl9 levels, cytokines that play pivotal roles in SLE pathogenesis. We therefore investigated and identified a role for IRF3 in regulating IL-23pl9 production, thus explaining the association of TRIM21 with IL-23pl9 expression. Results demonstrate that loss of IRF3 leads to abrogated production of IL-23pl9 in response to TLR stimulation, thus indicating that IRF3 is a novel positive regulator of IL-23pl9 production. We have also shown that IRF3 is stably bound to the human IL-23pl9 promoter in monocytes, an association which increases with TLR3 stimulation. Patients with SLE show increased levels of IRF3 bound to the IL-23pl9 promoter both endogenously and following TLR3 activation compared with control subjects. Enhanced IRF3 binding was associated with increased IL-23pl9 production in monocytes from patients with SLE, thus providing novel insights into the molecular pathogenesis of SLE and the potential role for TLR3 in driving this response. Despite the vast number of studies characterising the function of TRIM21, very little is known about the regulation of this protein particularly at a promoter level. Using Matlnspector, we identified a putative estrogen response element within the TRIM21 gene promoter, which ChIP analysis proved to be functional. Estrogen was seen to upregulate TRIM21 expression through an ERa-dependent mechanism, a pathway which we observed to be overactive in SLE patients. Treatment of resting monocytes with an ERa antagonist abrogated estrogeninduced TRIM21 expression and as a consequence decreased IL-23 expression. Thus these findings identify TRIM21 as a novel ERa-regulated gene and provide further insights into the link between estrogen and the molecular pathogenesis of SLE. In addition to promoter analysis, investigation into 3' untranslated region of TRIM21 led us to identify a number of putative microRNAs binding sites that hold potential in the regulation of TRIM21 expression. Investigation into one such microRNA, miR-381, revealed a novel role for this microRNA in the negative regulation of TRIM21. Patient analysis demonstrated that levels of miR-381 were altered in SLE immune cells leading to decreased TRIM21 expression following TLR7 activation. As TRIM21 in response to TLR stimulation, ubiquitinates and degrades both IRF3 and IRF7, the reduced levels of TRIM21 observed contributes to the overproduction of IL-23 observed in these patients thus highlighting the pathogenic role dysregulated miRNA expression plays in SLE. Taken together, this work has identified TRIM21 as a novel estrogen receptor regulated gene whose activity is altered in SLE leading to enhanced production of IL-23, a cytokine associated with the pathogenesis of SLE. Together with the identification of miR-381 as a novel regulator of TRIM21 expression, our findings have not only contributed to the understanding behind the molecular pathogenesis of SLE but also underlined the therapeutic potential in manipulating TRIM21 activity or levels for the treatment of SLE.