Hydroxychloroquine Dose per Ophthalmology Guidelines and the Risk of Systemic Lupus Erythematosus Flares.

This study of an academic medical center patient cohort with systemic lupus erythematosus (SLE) investigates the association between hydroxychloroquine dose based on current guidelines and risk of lupus flares.

Association of a Combination of Healthy Lifestyle Behaviors With Reduced Risk of Incident Systemic Lupus Erythematosus.

OBJECTIVE: While previous studies have demonstrated an association between individual factors related to lifestyle and the risk of systemic lupus erythematosus (SLE), it is unclear how the combination of these factors might affect the risk of incident SLE. This study was undertaken to prospectively evaluate whether a combination of healthy lifestyle factors is associated with a lower risk of incident SLE and its subtypes (anti-double-stranded DNA [anti-dsDNA]-positive and anti-dsDNA-negative SLE). METHODS: The study included 185,962 women from the Nurses' Health Study (NHS) and NHSII cohorts, among whom there were 203 incident cases of SLE (96 with anti-dsDNA-positive SLE, 107 with anti-dsDNA-negative SLE) during 4,649,477 person-years of follow-up. The Healthy Lifestyle Index Score (HLIS) was calculated at baseline and approximately every 2 years during follow-up, with scores assigned for 5 healthy lifestyle factors: alcohol consumption, body mass index, smoking, diet, and exercise. A time-varying Cox proportional hazards regression model was used to estimate the adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) for the risk of SLE. In addition, the percentage of partial population attributable risk (PAR%) of SLE development was calculated. RESULTS: A higher HLIS was associated with a lower risk of SLE overall (HR 0.81 [95% CI 0.71-0.94]) and a lower risk of anti-dsDNA-positive SLE (HR 0.78 [95% CI 0.63-0.95]). Women with ≥4 healthy lifestyle factors had the lowest risk of SLE overall (HR 0.42, 95% CI 0.25-0.70) and lowest risk of anti-dsDNA-positive SLE (HR 0.35, 95% CI 0.17-0.75) as compared to women with only 1 healthy behavior or no healthy behaviors. The PAR% of SLE development was 47.7% (95% CI 23.1-66.6%), assuming that the entire population had adhered to at least 4 healthy lifestyle behaviors. CONCLUSION: These results indicate that the risk of developing SLE, a disease in which significant evidence of genetic involvement has been established, might be reduced by nearly 50% with adherence to modifiable healthy lifestyle behaviors.

The Effects of Vitamin D on Immune System and Inflammatory Diseases.

Immune cells, including dendritic cells, macrophages, and T and B cells, express the vitamin D receptor and 1α-hydroxylase. In vitro studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, has an anti-inflammatory effect. Recent epidemiological evidence has indicated a significant association between vitamin D deficiency and an increased incidence, or aggravation, of infectious diseases and inflammatory autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. However, the impact of vitamin D on treatment and prevention, particularly in infectious diseases such as the 2019 coronavirus disease (COVID-19), remains controversial. Here, we review recent evidence associated with the relationship between vitamin D and inflammatory diseases and describe the underlying immunomodulatory effect of vitamin D.

The DNA co-vaccination using Sm antigen and IL-10 as prophylactic experimental therapy ameliorates nephritis in a model of lupus induced by pristane.

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies such as anti-Sm. Studies in patients with SLE and murine models of lupus reveal that the most critical anti-Sm autoantibodies are predominantly direct against D1(83-119), D2, and B´/B epitopes. OBJECTIVES: The present study aimed to analyze the induction of antigen-specific tolerance after prophylactic immunization with a DNA vaccine encoding the epitopes: D183-119, D2, B´/B, and B´/BCOOH in co-vaccination with IFN-γ or IL-10 in a murine model of lupus induced by pristane. MATERIAL AND METHODS: To obtain endotoxin-free DNA vaccines, direct cloning techniques using pcDNA were performed: D183-119, D2, B´/B, B´/BCOOH, IFN-γ, or IL-10. Lupus was induced by 0.5 mL of pristane via intraperitoneal in BALB/c female mice. Immunoprecipitation with K562 cells was metabolically labeled with 35S and ELISA to detect serum antibodies or mice IgG1, IgG2a isotypes. ELISA determined IL-10 and IFN-γ from splenocytes supernatants. Proteinuria was assessed monthly, and lupus nephritis was evaluated by immunofluorescence, and electron microscopy. RESULTS: The prophylactic co-vaccination with D2/IL-10 reduced the expression of kidney damage observed by electron microscopy, direct immunofluorescence, and H & E, along with reduced level of anti-nRNP/Sm antibodies (P = 0.048). CONCLUSION: The prophylactic co-vaccination of IL-10 with D2 in pristane-induced lupus ameliorates the renal damage maybe by acting as prophylactic DNA tolerizing therapy.

SMS2 deficiency impairs PKCδ-regulated B cell tolerance in the germinal center.

B cell tolerance prevents autoimmunity by deleting or deactivating autoreactive B cells that otherwise may cause autoantibody-driven disorders, including systemic lupus erythematosus (lupus). Lupus is characterized by immunoglobulin Gs carrying a double-stranded (ds)-DNA autospecificity derived mainly from somatic hypermutation in the germinal center (GC), pointing to a checkpoint breach of GC B cell tolerance that leads to lupus. However, tolerance mechanisms in the GC remain poorly understood. Here, we show that upregulated sphingomyelin synthase 2 (SMS2) in anti-dsDNA GC B cells induces apoptosis by directly activating protein kinase C δ (PKCδ)'s pro-apoptotic activity. This tolerance mechanism prevents lupus autoimmunity in C57/BL6 mice and can be stimulated pharmacologically to inhibit lupus pathogenesis in lupus-prone NZBWF1 mice. Patients with lupus consistently have substantially reduced SMS2 expression in B cells and to an even greater extent in autoimmune-prone, age-associated B cells, suggesting that patients with lupus have insufficient SMS2-regulated B cell tolerance.

Influenza A/Singapore (H3N2) component vaccine in systemic lupus erythematosus: A distinct pattern of immunogenicity.

INTRODUCTION: Influenza A (H3N2) virus is the most important cause of seasonal influenza morbidity and mortality in the last 50 years, surpassing the impact of H1N1. Data assessing immunogenicity and safety of this virus component are lacking in systemic lupus erythematosus (SLE) and restricted to small reports with other H3N2 strains. OBJECTIVE: This study aims to evaluate short-term immunogenicity and safety of influenza A/Singapore (H3N2) vaccine in SLE. METHODS: 81 consecutive SLE patients and 81 age- and sex-matched healthy controls (HC) were vaccinated with the influenza A/Singapore/INFIMH-16-0019/2016(H3N2)-like virus. Seroprotection (SP) and seroconversion (SC) rates, geometric mean titers(GMT), and factor increase in GMT(FI-GMT) and adverse events were assessed before and 4 weeks post-vaccination. Disease activity and therapies were also evaluated. RESULTS: Before immunization, SLE and HC groups had high SP rates (89% vs 77%, p = 0.061) and elevated GMT titer with higher levels in SLE (129.1(104.1-154.1) vs 54.8(45.0-64.6), p < 0.001). Frequency of two previous years' influenza vaccination was high and comparable in SLE and HC (89% vs 90%, p = 1.000). Four weeks post-vaccination, median GMT increased for both groups and remained higher in SLE compared to HC (239.9(189.5-290.4) vs 94.5(72.6-116.4), p < 0.0001) with a comparable FI-GMT (2.3(1.8-2.9) vs 1.9(1.5-2.3), p = 0.051). SC rates were low and comparable for both groups (16% vs 11%, respectively, p = 0.974). Disease activity scores remained stable throughout the study (p = 1.000) and severe adverse events were not identified. CONCLUSION: Influenza A/Singapore (H3N2) vaccine has an adequate safety profile. The distinct immunogenicity pattern from other influenza A components characterized by a remarkably high pre- and post-vaccination SP rate and high GMT levels may be associated with previous influenza A vaccination. (www.clinicaltrials.gov, NCT03540823).

Dietary Supplementation With Eicosapentaenoic Acid Inhibits Plasma Cell Differentiation and Attenuates Lupus Autoimmunity.

Accumulating evidence suggests that cholesterol accumulation in leukocytes is causally associated with the development of autoimmune diseases. However, the mechanism by which fatty acid composition influences autoimmune responses remains unclear. To determine whether the fatty acid composition of diet modulates leukocyte function and the development of systemic lupus erythematosus, we examined the effect of eicosapentaenoic acid (EPA) on the pathology of lupus in drug-induced and spontaneous mouse models. We found that dietary EPA supplementation ameliorated representative lupus manifestations, including autoantibody production and immunocomplex deposition in the kidneys. A combination of lipidomic and membrane dynamics analyses revealed that EPA remodels the lipid composition and fluidity of B cell membranes, thereby preventing B cell differentiation into autoantibody-producing plasma cells. These results highlight a previously unrecognized mechanism by which fatty acid composition affects B cell differentiation into autoantibody-producing plasma cells during autoimmunity, and imply that EPA supplementation may be beneficial for therapy of lupus.

Resolvin D1 Improves the Treg/Th17 Imbalance in Systemic Lupus Erythematosus Through miR-30e-5p.

Resolvin D1 (RvD1) prompts inflammation resolution and regulates immune responses. We explored the effect of RvD1 on systemic lupus erythematosus (SLE) and investigated the correlation between RvD1 and Treg/Th17 imbalance, which is one of the major factors contributing to the pathogenesis of disease. SLE patients and healthy controls were recruited to determine plasma RvD1 levels. MRL/lpr lupus model was used to verify rescue of the disease phenotype along with Treg/Th17 ratio. Purified naive CD4+ T cells were used to study the effect of RvD1 on Treg/Th17 differentiation in vitro. Furthermore, small RNA Sequencing and transfection were performed successively to investigate downstream microRNAs. The result showed that the RvD1 level was significantly lower in active SLE patients compared with inactive status and controls. Moreover, The SLE disease activity index (SLEDAI) score had a significant negative correlation with RvD1 level. As expected, RvD1 treatment ameliorated disease phenotype and inflammatory response, improved the imbalanced Treg/Th17 in MRL/lpr mice. In addition, RvD1 increased Treg while reduced Th17 differentiation in vitro. Furthermore, miR-30e-5p was verified to modulate the Treg/Th17 differentiation from naïve CD4+ T cells as RvD1 downstream microRNA. In conclusion, RvD1 effectively ameliorates SLE progression through up-regulating Treg and down-regulating Th17 cells via miR-30e-5p.

Association between alcohol intake and the risk of systemic lupus erythematosus: A systematic review and meta-analysis.

OBJECTIVES: Previous studies have reported inconsistent results on the relationship between alcohol intake and the risk of systemic lupus erythematosus (SLE). Therefore, we conducted a systematic review and meta-analysis to illustrate the potential role of alcohol intake on the progression of SLE. METHODS: An electronic search of the PubMed, EmBase, and the Cochrane library databases was conducted from their inception up to March 2020. Observational studies that investigated the role of alcohol intake on the risk of SLE were eligible for inclusion in this study. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated as an effect estimate using the random-effects model. RESULTS: Seven case-control studies (n = 3, 251) and three cohort studies (n = 322, 479) were selected for the final meta-analysis. Mild (OR: 0.85; 95% CI: 0.53-1.38; p = 0.515) or heavy (OR: 0.63; 95% CI: 0.37-1.09; p = 0.102) alcohol intake were not associated with the risk of SLE, while moderate alcohol intake could protect against the risk of SLE (OR: 0.71; 95% CI: 0.55-0.93; p = 0.012). Sensitivity analysis suggested that heavy alcohol intake was associated with a reduced risk of SLE (OR: 0.47; 95% CI: 0.32-0.67; p < 0.001). CONCLUSIONS: This study found that moderate alcohol intake could protect against the risk of SLE, while mild or heavy alcohol intake did not significantly affect the risk of SLE.

Blockade of anti-dsDNA ameliorates systemic lupus erythematosus in MRL/Faslpr mice through ameliorating inflammation via the PKCδ-NLRC4 axis.

Anti-double-stranded DNA (anti-dsDNA) is closely associated with the inflammatory burden in the brain after ischemic stroke. Here, we studied the inflammatory cascade and investigated the mechanisms behind the pro-inflammatory role of dsDNA in systemic lupus erythematosus (SLE). The serum levels of interleukin-1beta (IL-1ß) and IL-6 in SLE patients and the corresponding controls were evaluated using ELISA, and the expression level of caspase-1 was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). We found that the serum levels of IL-1ß and IL-6 were increased in the SLE patients. The expression of caspase-1 was upregulated and positively correlated with the levels of pro-inflammatory factors. The level of anti-dsDNA was also elevated and positively correlated with the results for the mean fluorescence intensity (MFI) of caspase-1. Additionally, we evaluated the functions of PRKCD encoding protein kinase c delta (PKCδ) and NLRC4, in vivo, in MRL/Faslpr mice. We found that renal injury was aggravated, and the levels of pro-inflammatory factors were increased in the MRL/Faslpr mice. We also found that increased levels of NLRC4 in the mice exacerbated renal injury and increased the levels of pro-inflammatory factors, whereas inhibition of PKCδ had the opposite results. These findings provide unique perspectives on pathogenesis of SLE and indicate that inhibition of anti-dsDNA could attenuate renal inflammatory burden, representing a promising therapeutic opportunity for SLE.

Bcl-3 inhibits lupus-like phenotypes in BL6/lpr mice.

Bcl-3 is an atypical member of the IκB family that modulates NF-κB activity in nuclei. lpr mice carry the lpr mutation in Fas, resulting in functional loss of this death receptor; they serve as models for lupus erythematosus and autoimmune lymphoproliferation syndrome (ALPS). To explore the biologic roles of Bcl-3 in this disease model, we generated BL6/lpr mice lacking Bcl-3. Unlike lpr mice on an MRL background, BL6/lpr mice present with very mild lupus- or ALPS-like phenotypes. Bcl-3 KO BL6/lpr mice, however, developed severe splenomegaly, dramatically increased numbers of double negative T cells - a hallmark of human lupus, ALPS, and MRL/lpr mice - and exhibited inflammation in multiple organs, despite low levels of autoantibodies, similar to those in BL6/lpr mice. Loss of Bcl-3 specifically in T cells exacerbated select lupus-like phenotypes, specifically organ infiltration. Mechanistically, elevated levels of Tnfα in Bcl-3 KO BL6/lpr mice may promote lupus-like phenotypes, since loss of Tnfα in these mice reversed the pathology due to loss of Bcl-3. Contrary to the inhibitory functions of Bcl-3 revealed here, this regulator has also been shown to promote inflammation in different settings. Our findings highlight the profound, yet highly context-dependent roles of Bcl-3 in the development of inflammation-associated pathology.

Lupus eritematoso sistémico 2020 / Systemic lupus erythematosus 2020

El lupus eritematoso sistémico (LES) es una enfermedad autoinmunitaria multisistémica compleja, con una gran heterogeneidad en su presentación clínica y una alta morbimortalidad. Aunque su pronóstico ha mejorado de forma notable a lo largo de las últimas décadas, aún siguen existiendo necesidades no cubiertas en esta enfermedad. En esta actualización realizamos una puesta al día de los principales avances en esta enfermedad en los últimos años. Concretamente revisamos los nuevos criterios de clasificación propuestos por la Liga Europea de Reumatología y el Colegio Americano de Reumatología, la búsqueda de nuevos biomarcadores, las nuevas definiciones de remisión y de baja actividad de la enfermedad, así como las estrategias actuales de abordaje y tratamiento del LES y la situación actual de las nuevas terapias

Systemic lupus erythematosus (SLE) is a complex autoimmune multisystemic disease of great clinical heterogeneity and significant potential morbidity and mortality. Although the outlook for patients with SLE has greatly improved, many unmet needs remain. In this review we aim to summarize the most relevant data on SLE that have emerged in recent years. In particular we discuss the new classification criteria from the European League Against Rheumatism and American College of Rheumatology, new biomarkers, novel definitions of remission and low lupus disease activity and what has emerged on new drugs and new therapeutic strategies

DNA vaccine encoding heat shock protein 90 protects from murine lupus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies to multiple self-antigens, including heat shock proteins (HSP). Because of the increased expression of HSP90 and abnormal immune responses to it in SLE, we investigated whether an HSP90 DNA vaccine could modulate the development and clinical manifestations of SLE in lupus-prone mice. METHODS: (NZB x NZW)F1 (NZB/W) mice were vaccinated with DNA constructs encoding HSP90 or control plasmids or vehicle. The mice were then monitored for survival, circulating anti-dsDNA autoantibodies, and immune phenotypes. Renal disease was evaluated by immunohistochemistry and by the measurement of proteinuria. RESULTS: Vaccination with HSP90 DNA reduced lupus disease manifestations and prolonged the survival of NZB/W mice. The protective effects of the HSP90 DNA vaccine associated with the induction of tolerogenic dendritic cells (DCs) and an expansion of T regulatory cells (Tregs). CONCLUSIONS: The beneficial effects of DNA vaccination with HSP90 in murine SLE support the possibility of HSP90-based therapeutic modalities of intervention in SLE.

Effect of early eradication therapy on systemic lupus erythematosus risk in patients with Helicobacter pylori infection: a nationwide population-based cohort study.

BACKGROUND: This study aimed to investigate whether early eradication therapy influences systemic lupus erythematosus (SLE) risk in patients with Helicobacter pylori (HP) infection. METHODS: We identified 41,653 patients with HP infection in Taiwan from 2000 to 2013. The patient population was divided into early (within three months) and late (after three months) eradication cohorts. age, sex, co-morbidities and medical visits were matched at a 1:1 ratio. Multiple Cox regression, sensitivity analysis and stratified analysis were used to estimate SLE adjusted hazard ratios (aHR). RESULTS: The relative risk of SLE was 0.75 (95% confidence interval 0.43-1.31) in the early eradication cohort. After multivariate adjustment, the SLE risk was non-significantly lower in the early eradication cohort than in the late eradication cohort (aHR = 0.74, 95% CI 0.42-1.29). Stratified analysis revealed that early eradication could significantly reduce SLE risk during the three-year follow-up period (aHR = 0.16, 95% CI 0.05-0.53, p for interaction = 0.0013). Compared to eradication within three months of diagnosis, eradication within 3-36 months and >36 months corresponded with SLE aHRs of 4.78 (95% CI 1.19-19.20) and 7.66 (95% CI 2.17-27.05), respectively, when the follow-up period was less than three years. CONCLUSION: Early HP eradication could significantly reduce SLE risk, especially in the first three-year follow-up.

B cell-intrinsic TLR9 expression is protective in murine lupus.

Toll-like receptor 9 (TLR9) is a regulator of disease pathogenesis in systemic lupus erythematosus (SLE). Why TLR9 represses disease while TLR7 and MyD88 have the opposite effect remains undefined. To begin to address this question, we created 2 alleles to manipulate TLR9 expression, allowing for either selective deletion or overexpression. We used these to test cell type-specific effects of Tlr9 expression on the regulation of SLE pathogenesis. Notably, Tlr9 deficiency in B cells was sufficient to exacerbate nephritis while extinguishing anti-nucleosome antibodies, whereas Tlr9 deficiency in dendritic cells (DCs), plasmacytoid DCs, and neutrophils had no discernable effect on disease. Thus, B cell-specific Tlr9 deficiency unlinked disease from autoantibody production. Critically, B cell-specific Tlr9 overexpression resulted in ameliorated nephritis, opposite of the effect of deleting Tlr9. Our findings highlight the nonredundant role of B cell-expressed TLR9 in regulating lupus and suggest therapeutic potential in modulating and perhaps even enhancing TLR9 signals in B cells.

2020 Chinese guidelines for the diagnosis and treatment of systemic lupus erythematosus

Systemic lupus erythematosus (SLE), a complex and heterogeneous autoimmune disease, represents a significant challenge for both diagnosis and treatment. In 2019, under the leadership of the Chinese Rheumatology Association, a multidisciplinary guideline development group was established. The objective was to develop an evidence-based diagnosis and treatment guideline for SLE in China based on emerging new evidence. The guideline was registered at International Practice Guidelines Registry Platform (IPGRP-2019CN022). The grading of recommendations assessment, development and evaluation (GRADE) approach was used to rate the quality of evidence and the strength of recommendations, and the RIGHT (Reporting Items for Practice Guidelines in Healthcare) checklist was followed to report the guideline. The guideline provides recommendations for the SLE classification criteria, disease activity monitoring and assessing, medication principles and considerations organ and system involvement and management of patients during pregnancy. This guideline is intended to serve as a tool for Chinese clinicians for the best decisions-making on diagnosis and treatment of SLE.

DNA Vaccination With Hsp70 Protects Against Systemic Lupus Erythematosus in (NZB × NZW)F1 Mice.

OBJECTIVE: To address whether a targeted modulation of the abnormal expression of Hsp70 and autoantibodies against this molecule in systemic lupus erythematosus can influence disease. METHODS: Lupus-prone (NZB × NZW)F1 mice that had been DNA-vaccinated with plasmids encoding Hsp70 and controls were monitored for lupus disease parameters including anti-double stranded DNA (anti-dsDNA) autoantibodies and cytokines using enzyme-linked immunosorbent assay, and for kidney function and pathology. The phenotypic and numerical changes in relevant immune cells were evaluated by flow cytometry, and cell function was assessed. RESULTS: Mice that had been DNA-vaccinated with Hsp70 displayed marked suppression of anti-dsDNA antibody production, reduced renal disease, and antiinflammatory responses that are associated with a significantly extended survival, compared to controls. These protective effects in Hsp70-vaccinated mice were associated with an induction of tolerogenic immune responses and an expansion of functional Treg cells. CONCLUSION: DNA vaccination with Hsp70 suppresses murine lupus by inducing tolerogenic immune responses and antiinflammatory immune responses associated with reduced disease manifestations and increased mouse survival.

Suppression of systemic lupus erythematosus in NZBWF1 mice infected with Hymenolepis microstoma.

Intestinal helminths induce immune suppressive responses thought to regulate inflammatory diseases including allergies and autoimmune diseases. This study was designed to evaluate whether helminthic infections suppress the natural development of systemic lupus erythematosus (SLE) in NZBWF1 mice. Infection of NZBWF1 SLE-prone mice with two nematodes failed to establish long-lasting settlement. However, the Hymenolepis microstoma (Hm) rodent tapeworm successfully established long-term parasitization of NZBWF1 mice and was used to evaluate the suppressive effects of helminth infection. Ten-month-old NZBWF1 mice developed symptoms including autoantibody generation, proteinuria, glomerular histopathology, and splenomegaly, but mice infected with Hm at 2 months of age did not show any clinical signs. Furthermore, infection with Hm reduced lymphocyte activation and increased regulatory T cells in the spleen and mesenteric lymph nodes. These results indicate that infection with Hm protects NZBWF1 mice from naturally developing SLE and suggest that pathological immunity is attenuated, presumably because of the induction of regulatory T cells.

Lupus, Silica, and Dietary Omega-3 Fatty Acid Interventions.

Two environmental factors, crystalline silica (cSiO2), a toxic airborne particle encountered occupationally, and docosahexaenoic acid (DHA), a dietary omega-3 highly unsaturated fatty acid (HUFA), have the potential to influence the development of systemic lupus erythematosus (lupus). Using the NZBWF1 mouse, which spontaneously develops lupus, we found that intranasal exposure to cSiO2 significantly decreases latency and promotes rapid progression of the disease. Specifically, cSiO2 induces the development of ectopic lymphoid structures (ELS) containing germinal centers in the lungs that yield vigorous and diverse autoantibody responses locally and systemically. Transcriptomic analysis revealed that cSiO2 promotes a robust type I interferon gene signature that likely precipitates ELS neogenesis. Intriguingly, dietary supplementation with human-relevant doses of DHA impedes cSiO2-induced gene expression, ELS neogenesis, autoantibody elevation, and glomerulonephritis in this lupus-prone mouse model. Together, our findings point to the feasibility of enhancing tissue omega-3 HUFAs as a personalized nutritional intervention to impede onset and progression of environment-triggered autoimmune disease.