Role In Systemic Lupus Erythematosus Research Articles

Do novel inflammation biomarkers arising from routine complete blood count play a role in patients with systemic lupus erythematosus?

Laboratory-based biomarkers accurately presenting systemic lupus erythematosus (SLE) disease activity may have a practical value in clinical routine. As shown in many other conditions, complete blood count (CBC)-derived biomarkers may also play a role in SLE. We aimed to study for the first time the pan-immune-inflammation value (PIV, monocytes x platelets x neutrophils/lymphocytes) and the more established systemic immune-inflammation index (SII, neutrophils x platelets /lymphocytes) in SLE patients and correlate it with serological and clinical findings including disease outcomes. In this retrospective multicentric investigation, we reviewed the clinical records of 148 SLE who had an available CBC at baseline. The latter served for the determination of the neutrophil-to-lymphocyte ratio (NLR), SII, and the PIV. Control groups were studied as well. Univariable as well as multivariable statistics were employed. The values for baseline systemic immune-inflammation biomarkers (SIIB) studied were significantly (p < 0.0001) higher than those observed in healthy controls but comparable to those obtained from patients with other inflammatory conditions. Multivariable analysis revealed that ANA titer > 1:640 remained the only significant (p < 0.0001) baseline predictor of SLE flare (odds ratio: 7.6, 95% CI 3.1 to 18.8). Improvement of SLE following treatment was associated with the absence of lymphopenia as well as ANA > 1:640 (p = 0.041). The SLEDAI-2K significantly correlated with NLR, SII, CRP, lymphocytes, and monocytes only on univariable testing. Compared to healthy controls the CBC-based SIIB investigated are significantly increased in SLE patients. However, SIIB do not appear to be useful in managing SLE clinically. Nevertheless, we confirm that higher ANA titers can predict flares of SLE.

Oxysterols contribute to immune cell recruitment in SLE skin lesions

BackgroundAbnormal oxysterol metabolism has been observed in the peripheral blood of SLE patients, but its role in systemic lupus erythematosus (SLE) skin lesions remains unclear.MethodsTargeted oxidized lipid metabolomics analysis using liquid chromatography-mass spectrometry (LC-MS) was performed to quantify oxysterols in SLE skin lesions. Immunohistochemical staining and single-cell sequencing data analysis confirmed the upregulation of oxysterol-encoding enzymes CH25H and CYP7B1. The impact on fibroblast-mediated PBMCs chemotaxis was assessed using a transwell chamber.ResultsWe identified aberrant oxidized cholesterol metabolism in SLE skin lesions, characterized by elevated levels of 7-ketocholesterol, 5α-6α-cholestane-3β,5α,6β-triol, and so on. Fibroblasts were the primary cells expressing oxysterol-encoding genes, with CH25H and CYP7B1 expression upregulated via the IL-1β-mediated p38 MAPK and NFκB pathways. Notably, IL-1β-stimulated fibroblasts demonstrated enhanced PBMCs recruitment, which was attenuated by a GPR183 inhibitor.ConclusionOur findings reveal a potential mechanism by which fibroblasts contribute to immune cell recruitment in SLE skin lesions by expression of CH25H and CYP7B1. This study underscores the significance of oxysterol metabolism in SLE skin lesion pathogenesis and highlights potential therapeutic targets for SLE skin lesion treatment.Graphical abstract

P-210 A new insight into the effects of systemic lupus erythematosus on oocyte and embryo development and female fertility

Abstract Study question Does SLE affect oocyte and embryo development and female fertility in female patients? Summary answer Patients with SLE present worse outcomes in oocyte and embryonic development, thus yielding compromised female fertility and clinical pregnancy. What is known already Systemic lupus erythematosus (SLE) is often associated with adverse reproductive outcomes. However, it’s currently unclear regarding the role of SLE in oocyte and embryonic development. Also, it’s controversial whether SLE hurts fertility. There is a lack of comprehensive understanding and assessment of fertility in patients with SLE. Study design, size, duration This study retrospectively investigated oocyte and embryo development, ovarian reserve, and clinical outcomes in SLE patients who underwent in vitro fertilization (IVF) treatment from January 2013 to September 2022 at the University Hospital. Participants/materials, setting, methods In this study, we collected data from 34 SLE patients who were previously diagnosed and in remission for a total of 44 IVF cycles and matched 102 infertile women with a total of 148 IVF cycles by Propensity Score Matching (PSM) of 1:3 ratio. We then evaluated baseline characteristics, ovarian reserve, IVF laboratory outcomes, and clinical outcomes between the two groups. Main results and the role of chance After PSM matching, baseline characteristics including age, infertility types, and duration, as well as infertility causes overall coincided between the two groups. Anti-müllerian hormone (AMH) was significantly lower in the SLE group vs comparison (1.9 vs. 3.3 ng/mL, P=0.001). The SLE group performed a significant reduction in available embryo rate (76.6% vs. 86.0%, P=0.001), good-quality blastocyst formation rate (35.1% vs. 47.0%, P=0.003), and blastocyst formation rate (51.0% vs. 67.7%, P=0.001) compared to the comparison. As for clinical outcomes, the implantation rate in the SLE group was notably lower (37.9% vs. 54.9%, P=0.022). The CLBR following every embryo-transfer procedure was distinctly lower (41.2% vs 68.6%, P=0.016) in the SLE group vs comparison. Also, the conservative and optimal CLBRs following every complete cycle procedure were significantly reduced in the SLE group vs the comparison (P=0.001, both) Limitations, reasons for caution It’s a retrospective and single-center study, which is relevant to an inevitable risk of bias. Due to its special population selection, the sample size of this study is quite small. Wider implications of the findings This study provides data support to explore further the impact of SLE or other autoimmune diseases on female fertility, and it also calls for more attention to be given to these special patients by reproductive physicians. Comprehensive fertility assessment and individualized fertility guidance are recommended for patients with SLE. Trial registration number TJ-IRB20211280

The Aconitate Decarboxylase 1/Itaconate Pathway Modulates Immune Dysregulation and Associates with Cardiovascular Disease Markers and Disease Activity in Systemic Lupus Erythematosus.

The Krebs cycle enzyme aconitate decarboxylase 1 (ACOD1) mediates itaconate synthesis in monocytes and macrophages. Previously, we reported that administration of 4-octyl itaconate to lupus-prone mice abrogated immune dysregulation and clinical features. In this study, we explore the role of the endogenous ACOD1/itaconate pathway in the development of TLR7-induced lupus (imiquimod [IMQ] model). We found that, invitro, ACOD1 was induced in mouse bone marrow-derived macrophages and human monocyte-derived macrophages following TLR7 stimulation. This induction was partially dependent on type I IFN receptor signaling and on specific intracellular pathways. In the IMQ-induced mouse model of lupus, ACOD1 knockout (Acod1-/-) displayed disruptions of the splenic architecture, increased serum levels of anti-dsDNA and proinflammatory cytokines, and enhanced kidney immune complex deposition and proteinuria, when compared with the IMQ-treated wild-type mice. Consistent with these results, Acod1-/- bone marrow-derived macrophages treated invitro with IMQ showed higher proinflammatory features. Furthermore, itaconate serum levels in systemic lupus erythematosus patients were decreased compared with healthy individuals, in association with disease activity and specific perturbed cardiometabolic parameters. These findings suggest that the ACOD1/itaconate pathway plays important immunomodulatory and vasculoprotective roles in systemic lupus erythematosus, supporting the potential therapeutic role of itaconate analogs in autoimmune diseases.

Double-filtration plasmapheresis reduces type I interferon bioavailability and inducing activity in systemic lupus erythematosus

Type I interferons (IFN-Is) play a significant role in systemic lupus erythematosus (SLE) pathogenesis. Double-filtration plasmapheresis (DFPP) is a treatment option for SLE; however, its effect on IFN-Is remains unclear. Therefore, we investigated the effects of DFPP on IFN-Is. Plasma from patients with SLE (n = 11) who regularly underwent DFPP was analysed using a cell-based reporter system to detect the bioavailability and inducing activity of IFN-I. The concentration of plasma dsDNA was measured, and western blotting analysis was used to assess the phosphorylation of the STING pathway. A higher IFN-I bioavailability and inducing activity were observed in patients compared to healthy controls, and both parameters decreased after DFPP. The reduction in IFN-I-inducing activity was particularly prominent in patients with high disease activity. Notably, this reduction was not observed in STING-knockout reporter cells. Additionally, plasma dsDNA levels decreased after DFPP treatment, suggesting that inhibition of the STING pathway was responsible for the observed decrease in activity. Western blotting analysis revealed suppression of STING pathway phosphorylation after DFPP. DFPP reduced IFN-I bioavailability and the inducing activity of plasma. This reduction is likely attributable to the inhibition of the STING pathway through the elimination of dsDNA.

USP18 induction regulates immunometabolism to attenuate M1 signal-polarized macrophages and enhance IL-4-polarized macrophages in systemic lupus erythematosus

Effective treatment of systemic lupus erythematosus (SLE) remains an unmet need. Different subsets of macrophages play differential roles in SLE and the modulation of macrophage polarization away from M1 status is beneficial for SLE therapeutics. Given the pathogenic roles of type I interferons (IFN-I) in SLE, this study investigated the effects and mechanisms of a mitochondria localization molecule ubiquitin specific peptidase 18 (USP18) preserving anti-IFN effects and isopeptidase activity on macrophage polarization. After observing USP18 induction in monocytes from SLE patients, we studied mouse bone marrow-derived macrophages and showed that USP18 deficiency increased M1signal (LPS + IFN-γ treatment)-induced macrophage polarization, and the effects involved the induction of glycolysis and mitochondrial respiration and the expression of several glycolysis-associated enzymes and molecules, such as hypoxia-inducible factor-1α. Moreover, the effects on mitochondrial activities, such as mitochondrial DNA release and mitochondrial reactive oxygen species production were observed. In contrast, the overexpression of USP18 inhibited M1signal-mediated and enhanced interleukin-4 (IL-4)-mediated polarization of macrophages and the related cellular events. Moreover, the levels of USP18 mRNA expression showed tendency of correlation with the expression of metabolic enzymes in monocytes from patients with SLE. We thus concluded that by preserving anti-IFN effect and downregulating M1 signaling, promoting USP18 activity may serve as a useful approach for SLE therapeutics.

The causal associations of inflammatory cytokines with obesity and systemic lupus erythematosus: A Mendelian randomization study.

Previous studies have partly discussed the roles of inflammatory cytokines in obesity and systemic lupus erythematosus (SLE), but the causal relationship among inflammatory cytokines, obesity, and SLE is unclear. It is challenging to comprehensively evaluate the causal relationship between these variables. This study aimed to investigate the role of cytokines as intermediates between obesity and SLE. The inverse-variance weighted method (IVW) of mendelian randomization (MR) is mainly used to explore the causal relationship between exposure and outcome by using the genetic variation of the open large genome-wide association studies (GWAS), namely single-nucleotide polymorphisms (SNPs) related to obesity (more than 600 000 participants), inflammatory cytokines (8293 healthy participants) and SLE (7219 cases). Methods such as weighted median, MR-Egger are used to evaluate the reliability of causality. Reverse analysis is performed for each MR analysis to avoid reverse causality. Cochran's Q statistic and funnel chart are used to detect heterogeneity, MR-Egger intercept test and leave-one-out sensitivity analyses evaluated pleiotropy. Obesity was associated with 25 cytokines, and 3 cytokines were associated with SLE, including CTACK (OR = 1.19, 95% CI: 1.06, 1.33, p = .002), IL-18 (OR = 1.13, 95% CI: 1.01, 1.26, p = .027), SCGFb (OR = 0.89, 95% CI: 0.79, 0.99, p = .044). In the opposite direction, SLE was associated with 18 cytokines, and 2 cytokines were associated with obesity, including IP-10 (βIVW = -.03, 95% CI: -0.05, -0.01, p = .002), MIP-1B (βIVW = -.03, 95% CI: -0.05, -0.01, p = .004). Our MR study suggested that CTACK, IL-18 and SCGFb may play an intermediary role in obesity to SLE, while IP-10 and MIP-1B may play an intermediary role in SLE to obesity.

Targeting Interferon Signalling in Systemic Lupus Erythematosus: Lessons Learned.

The development of new medicines for systemic lupus erythematosus (SLE) has not addressed unmet clinical need, with only three drugs receiving regulatory approval for SLE in the last 60years, one of which was specifically licensed for lupus nephritis. In the last 20years it has become clear that activation of type 1 interferons (IFN) is reproducibly detected in the majority of SLE patients, and the actions of IFN in the immune system and on target tissues is consistent with a pathogenic role in SLE. These findings led to considerable drug discovery activity, first with agents directly targeting IFN family cytokines, with results that were encouraging but underwhelming. In contrast, targeting the type I IFN receptor with the monoclonal antibody anifrolumab, thereby blocking all IFN family members, was effective in a phase II clinical trial. This led to a pair of phase III trials, one of which was negative and the other positive, reflecting the difficulty of obtaining outcomes from trials in this complex disease. Nonetheless, the balance of evidence resulted in approval of anifrolumab in multiple jurisdictions from 2021 onwards. Multiple approaches to targeting the type 1 IFN pathway have subsequently had positive phase II clinical trials, including antibodies targeting cells that produce IFN, and small molecules targeting the receptor kinase TYK2, required for IFN signalling. Despite multiple hurdles, it is clear that IFN targeting in SLE is here to stay. The story of IFN-targeting therapy in SLE has lessons for drug development overall in this disease.

#525 SGLT2 inhibition in non-diabetic CKD: results in experimental lupus nephritis

Abstract Background and Aims Sodium glucose cotransporter type 2 inhibitors (SGLT2i) potently attenuate cardiovascular morbidity and progression of CKD in patients with type 2 diabetes. It has been proposed that SGLT2 inhibition may also elicit renoprotective effects in non-diabetic CKD. The aim of this work is to evaluate whether the treatment with an SGLT2i improves kidney disease progression in a mouse model of lupus nephritis (LN). Method We performed a single center randomized controlled preclinical trial using female MRLlpr/lpr mice. The animals were randomly assigned to (1) vehicle or (2) empagliflozin (EMP, 10 mg/kg/day) treatment once signs of active systemic lupus erythematosus (SLE) appeared: proteinuria &amp;gt;100 mg/dL (++ in reactive strips) or lymphadenopathy in minimum 2 bilateral sites with proteinuria &amp;gt;30 mg/dL (+ in reactive strips). We included 13 mice per group that were treated during 4 weeks. Empagliflozin was given as an admix into standard chow diet. Reduction of urinary albumin to creatine ratio (UACR) was considered the primary endpoint whereas glomerular filtration rate (GFR), renal histology (LN activity/chronicity index, glomerulosclerosis, interstitial fibrosis) and SLE markers (total serum IgG, anti-dsDNA IgG, glomerular IgG deposits, lymph node weight, spleen weight) were considered secondary endpoints. Results After 4 weeks of treatment, no significant differences in fasting blood glucose levels were found between the experimental groups. As expected, empagliflozin administration notably inhibited SGLT2 in the tubular cells demonstrated by a significant increase of urinary glucose (p &amp;lt; 0.0001). This is consistent with the increased water intake observed in MRLlpr/lpr mice treated with empagliflozin (p &amp;lt; 0.0001). At the end of the experiment, vehicle treated MRLlpr/lpr mice showed a significant increase in UACR (p = 0.0012) consistent with LN progression that was not attenuated by empagliflozin. In line, empagliflozin did not modify GFR and LN activity/chronicity indexes, glomerulosclerosis or interstitial fibrosis in kidney. Finally, regarding SLE markers, 4-weeks empagliflozin treatment was not able to decrease total serum IgG, anti-dsDNA IgG, glomerular IgG deposits or lymph node weight. Only spleen weight was significantly decreased in empagliflozin treated MRLlpr/lpr mice (p = 0.003). Conclusion In our experimental setting, empagliflozin treatment reduced spleen weight suggesting a protective role in SLE in MRLlpr/lpr mice. However, empagliflozin did not modify LN progression in MRLlpr/lpr mice probably because the acute LN phase. It is expected that the positive effect in terms of reducing proteinuria will be observed in patients with LN and residual proteinuria

Characterizing inflammasome activation by bacterial amyloid curli complexes from biofilms in dendritic cells and its role in SLE

Abstract Bacterial infections are a crucial environmental trigger for flares in Systemic lupus erythematosus (SLE). Although these infections are common in lupus patients, a precise mechanism of action remains unknown. Bacteria protect themselves from stresses by embedding in an extracellular matrix to form biofilms. Biofilms from bacterial species such as E. coli and Salmonella contain an amyloid protein called curli. Previous work from our labs has shown that curli/DNA complexes can accelerate lupus-like disease in mice, and increased levels of anti-curli antibodies are associated with flares in SLE patients, making these complexes important in autoimmunity. We had previously found that curli/DNA is a potent trigger of immune activation in dendritic cells (DCs) and macrophages. In macrophages, curli/DNA was also reported to induce IL-1b production through activation of the NLRP3 inflammasome. Here we expand these studies to delineate how curli/DNA complexes regulate IL-1b in murine and human DCs. Using curli/DNA alone or in combination with inflammasome stimuli, we found that curli/DNA stimulate pro-IL1b expression and inflammasome assembly, leading to caspase 1 activation, cleavage and release of mature IL-1B by DCs. However, we observed no cell death post inflammasome activation, suggesting a hyperactivated state in stimulated DCs. A deeper knowledge of this molecular mechanism might shed light on the role of inflammasome activation by bacterial infections in escalating SLE.

Circulating TIGIT±PD1+TPH, TIGIT ± PD1+TFH cells are elevated and their predicting role in systemic lupus erythematosus

It is well established that increased peripheral helper T cells (TPH) and follicular helper T cells (TFH) was found in systemic lupus erythematosus (SLE) patients. However, the expression patterns and immunomodulatory roles of TIGIT and PD1 on TPH/TFH in SLE are poorly understood. The expression patterns of TIGIT and PD1 on TPH and TFH cells were examined using flow cytometry and their expression patterns in SLE patients were then further evaluated for their correlation with auto-antibodies, disease activity and severity, B cell differentiation. Logistic regression was used to analyze the risk factors. And the receiver operating characteristic curves and logistic regression model were created to evaluate the predicting role in SLE. TIGIT±PD1+TPH, TIGIT±PD1+TFH cells in the peripheral blood of SLE patients were upregulated, whereas TIGIT+PD1−TFH was downregulated. TIGIT ± PD1+TPH, TIGIT ± PD1+TFH cells positively correlated with auto-antibodies production, disease activity and severity, whereas TIGIT+PD1−TFH cells negatively correlated. TIGIT ± PD1+TPH, TIGIT−PD1+TFH were positively correlated with the frequency of plasmablasts. Furthermore, higher TIGIT+PD1+TPH and TIGIT+PD1+TFH were shown to be risk factors for SLE, whereas TIGIT+PD1−TFH was found to be a protective factor, according to logistic regression analysis. A further logistic regression model showed that combination of TPH/TFH and routine blood indicators may has potential predicting value for SLE, with AUC of 0.957. The increased TIGIT ± PD1+TPH, increased TIGIT ± PD1+TFH, decreased TIGIT+PD1−TFH correlates with disease severity and activity, may boost our comprehending of the role of TIGIT and PD1 on TPH/TFH in SLE, and a logistic regression model based on combination of TPH/TFH and routine blood indicators shows prominent value for predicting SLE.

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.

MicroRNA-98-5p Inhibits IFI44L-Mediated Differentiation of Dendritic Cells and Activation of Interferon Pathway in Systemic Lupus Erythematosus

ABSTRACT MicroRNA-98-5p (miR-98-5p) plays a protective role in the pathogenesis of autoimmune diseases through anti-inflammatory effects, but little is known about its role in Systemic lupus erythematosus (SLE). Our previous study suggested Interferon-inducible 44 like (IFI44L) overexpressed in monocytes which contributes to the pathogenesis of SLE by enhancing the maturation and functions of monocyte-derived dendritic cells (Mo-DCs), and miR-98-5p can regulate the expression of IFI44L. In this study, we identified miR-98-5p lowly expressed in both peripheral blood mononuclear cells (PBMCs) and monocytes of SLE patients along with high expression of IFI44L. IFI44L serves as target gene of miR-98-5p which inhibits differentiation of Mo-DCs and IFI44L-mediated activation of interferon pathway. We further showed that miR-98-5p promotes methylation of the IFI44L promoter to down-regulate its expression in SLE. Our results reveal an important role for miR-98-5p in the IFI44L-mediated immune imbalance of SLE and suggest a potential therapeutic target for SLE in the future.

Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice

Toll-like receptor 9 (TLR9) recognizes self-DNA and plays intricate roles in systemic lupus erythematosus (SLE). However, the molecular mechanism regulating the endosomal TLR9 response is incompletely understood. Here, we report that palmitoyl-protein thioesterase 1 (PPT1) regulates systemic autoimmunity by removing S-palmitoylation from TLR9 in lysosomes. PPT1 promotes the secretion of IFNα by plasmacytoid dendritic cells (pDCs) and TNF by macrophages. Genetic deficiency in or chemical inhibition of PPT1 reduces anti-nuclear antibody levels and attenuates nephritis in B6.Sle1yaa mice. In healthy volunteers and patients with SLE, the PPT1 inhibitor, HDSF, reduces IFNα production ex vivo. Mechanistically, biochemical and mass spectrometry analyses demonstrated that TLR9 is S-palmitoylated at C258 and C265. Moreover, the protein acyltransferase, DHHC3, palmitoylates TLR9 in the Golgi, and regulates TLR9 trafficking to endosomes. Subsequent depalmitoylation by PPT1 facilitates the release of TLR9 from UNC93B1. Our results reveal a posttranslational modification cycle that controls TLR9 response and autoimmunity.

Progress of rituximab in the treatment of systemic lupus erythematosus and lupus nephritis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with heterogeneous clinical manifestations, often leading to significant morbidity and mortality, particularly due to lupus nephritis (LN). The standard therapeutic approach involving mycophenolate mofetil, cyclophosphamide, and glucocorticoids has shown limitations due to cumulative toxicity and side effects. The introduction of biologic agents, especially rituximab (RTX), a chimeric monoclonal antibody targeting CD20+ B cells, has revolutionized the treatment landscape. This review synthesized the current understanding of B cells' role in SLE and LN and evaluates RTX's therapeutic impact. B cells contribute to disease pathogenesis through autoantibody production and immune complex formation, leading to tissue damage. RTX's mechanisms of action, including Complement-Dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and induction of apoptosis, have demonstrated efficacy in both SLE and LN treatment. Clinical studies have reported remission rates and improved renal outcomes with RTX use, although challenges such as human anti-chimeric antibody development and optimal dosing persist. The review emphasized the need for continued research to elucidate RTX's long-term benefits and risks, and to explore personalized treatment strategies that incorporate B cell biology for better disease management in SLE and LN.

Downregulation of circETS1 disrupts Th17/Treg homeostasis by inhibiting FOXP3 transcription: A new potential biomarker in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with an imbalance of T helper 17 (Th17) to regulatory T cells (Tregs). However, the underlying mechanism remains unclear. Increasing evidence suggests that circular RNAs play a crucial role in SLE. Although circETS1 was discovered 30years ago, detailed exploration of its functions remains limited. In this study, we measured the expression levels of circETS1 in peripheral blood mononuclear cells (PBMCs) and CD4+ T cells of patients with SLE by quantitative polymerase chain reaction. The impact of circETS1 expression on the Th17/Treg balance and underlying mechanism were evaluated using double-luciferase reporter, gain-/loss-of-function, and rescue assays. Receiver operating characteristic (ROC) curve analysis was conducted to assess the diagnostic value of circETS1. Both circETS1 and FOXP3 expression were downregulated in the PBMCs and CD4+ T cells of patients with SLE (n = 28) compared with those in the cells of healthy controls (n = 20). Mechanistically, we found that circETS1 can bind directly to the microRNA miR-1205, acting as a sponge to upregulate the transcription of FOXP3, thereby maintaining the Th17/Treg balance. Notably, ROC analysis showed that the expression level of circETS1 in PBMCs had an area under the curve of 0.873 (95% confidence interval: 0.771-0.976; p < .001) for diagnosing SLE, with a sensitivity of 80.00% and a specificity of 89.29%. Finally, we found negative correlations between the level of circETS1 in PBMCs and disease severity (according to the Systemic Lupus Erythematosus Disease Activity Index) in patients with SLE (r = -0.7712, 95% CI: -0.8910 to -0.5509; p < .001). The imbalance in Th17/Treg cells in SLE may be attributed, in part, to the circETS1/miR-1205/FOXP3 pathway. CircETS1 has potential to serve as a valuable biomarker for the diagnosis and evaluation of SLE.

Serum Prolactin Level in Women with Systemic Lupus Erythematosus and its Correlation with Disease Activity

Abstract Background: In the last decade, evidence supports the hypothesis that the prolactin (PRL) hormone plays an important role in systemic lupus erythematosus (SLE) clinical expression and pathogenesis. Objective: To evaluate the presence, clinical, and serological significance of elevated serum PRL in women with SLE. Materials and Methods: A case–control study included 30 women with SLE; with mean age and disease duration were 33.15 ± 6.7 and 10.9 ± 1.9, respectively, and 30 age-matched apparently healthy subjects served as controls. All patients were subjected to clinical and serological evaluation. Disease activity was measured using the SLE Disease Activity Index. Serum PRL level was estimated for all the participants. Results: Serum PRL levels were 36.2 ± 15.8 ng/ml and 8.9 ± 4.4 ng/ml in patients with SLE and controls, respectively. Malar rash, photosensitivity, and arthritis were associated with elevated serum PRL. Positive antinuclear antibodies ANA and low complements were associated with a high serum PRL level. In addition, 18 (85.7%) patients with high disease activity have hyperprolactinemia, while only 3 (14.3%) patients with high disease activity have a normal range of serum PRL levels. Conclusion: SLE patients were associated with higher serum PRL levels than the control group. There was a significant relationship between serological status and hypocomplementemia with high serum PRL levels. In addition, there was a significant relationship between active disease and hyperprolactinemia.

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.

Biomarkers of Oxidative Stress in Systemic Lupus Erythematosus Patients with Active Nephritis.

Oxidative stress plays an important role in systemic lupus erythematosus (SLE) and especially in lupus nephritis (LN). The aim of this study was to compare redox-related biomarkers between patients with active LN, quiescent SLE (Q-SLE) and healthy controls (HC) and to explore their association with clinical characteristics such as disease activity in patients. We investigated levels of plasma free thiols (R-SH, sulfhydryl groups), levels of soluble receptor for advanced glycation end products (sRAGE) and levels of malondialdehyde (MDA) in SLE patients with active LN (n = 23), patients with quiescent SLE (n = 47) and HC (n = 23). Data of LN patients who previously participated in Dutch lupus nephritis studies and longitudinal samples up to 36 months were analyzed. Thiol levels were lower in active LN at baseline and Q-SLE patients compared to HC. In generalized estimating equation (GEE) modelling, free thiol levels were negatively correlated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) over time (p < 0.001). sRAGE and MDA were positively correlated with the SLEDAI over time (p = 0.035 and p = 0.016, respectively). These results indicate that oxidative stress levels in LN patients are increased compared to HC and associated with SLE disease activity. Therefore, interventional therapy to restore redox homeostasis may be useful as an adjunctive therapy in the treatment of oxidative damage in SLE.

Systemic lupus erythematosus and antiphospholipid syndrome: past, present, future

Immune-inflammatory (autoimmune and autoinflammatory) rheumatic diseases are widespread severe chronic inflammatory diseases and also "models" for studying the fundamental mechanisms of pathogenesis and approach to pharmacotherapy of other diseases associated with autoimmunity and/or autoinflammation. Uncontrolled inflammation leading to hypercoagulation forms the basis of "thromboinflammation", which is considered a universal pathogenetic mechanism of organ involvement in immune-inflammatory rheumatic diseases, as well as in COVID-19 and atherosclerotic vascular lesions (atherothrombosis). Thrombo-inflammatory mechanisms play a crucial role in systemic lupus erythematosus and antiphospholipid syndrome. Russian rheumatology, under the leadership of academician Valentina Alexandrovna Nasonova, greatly contributed to the research of these disorders. This article addresses the current view about the overlapping pathogenetic mechanisms of thrombosis in systemic lupus erythematosus and antiphospholipid syndrome, the relevance of these studies during the COVID-19 pandemic, and the prospects for antithrombotic and anti-inflammatory therapy.