Approach For Systemic Lupus Erythematosus Research Articles

Preferences for diagnostic pathways and treatment choice in systemic lupus erythematosus: a patient-based discrete choice experiment.

Starting from the unmet need of early diagnosis and treatment in systemic lupus erythematosus (SLE), the study aims to explore patient preferences in diagnostic pathways and treatment modalities. It seeks to integrate clinical priorities with patient perspectives, providing an optimal approach to SLE treatment that remains uncertain. A discrete choice experiment (DCE) has been conducted to investigate whether patient preferences align while maintaining consistent attributes and levels, providing a direct assessment of relative preferences and hypothetical treatment approaches in SLE. DCE results demonstrated that obtaining an early diagnosis is the most crucial attribute for patients. Additionally, a multidisciplinary care team, capable of enhancing clinical outcomes and patient satisfaction, is essential, along with a clinical centre conveniently located within 30 minutes of the patient's home. Lastly, patients prefer the opportunity to reduce glucocorticoid to a dosage ≤5 mg/day, and eventually discontinue, aligning with the new EULAR recommendations, and favour oral and subcutaneous routes of administration for new course of treatment. Patient preferences contribute to enhancing the care pathway for SLE by optimising disease management, with a focus on multidisciplinarity and psychological support.

Identification of T cell Autoantigens in a mouse model of Lupus Nephritis

Abstract Lupus nephritis (LN) is the most common severe organ manifestation of Systemic lupus erythematosus (SLE). Autoreactive CD4+ T cells play a key role in SLE, but the mechanism of loss of self-tolerance and antigen specificity of CD4+ T cells is unclear. CD4+ αβ T cells use their T cell receptor (TCR) to recognize 12–20 residue-long epitopes presented on class II MHC molecules. Identifying CD4+ T cell epitopes has been challenging due to lack of efficient and easy-to-implement methods for epitope discovery. We developed a robust T cell antigen discovery technology that uses chimeric receptors called SABR-II (Signaling and Antigen-presenting Bifunctional Receptors) to express large peptide antigen libraries in the context of MHC molecules. Using SABR-IIs, we sought to identify the autoantigens recognized by kidney-infiltrating CD4+ T cells in a mouse mode of LN – MRL/lpr mice. We used a high-throughput single cell TCR cloning to clone and express 93 TCRs from CD4+ T cells sorted from kidneys of 26-week-old MRL/lpr mice. For antigen discovery, we constructed SABR-IIs with I-Ek and I-Ak (class II MHC allele of MRL/lpr mice) and confirmed their functionality. We built libraries of ~25,000 epitopes derived from nuclear proteins and validated them using a known antigen-specific TCR. We have identified novel putative autoantigens, which will be validated in vitro. This study will lead to identification of novel self-antigens, providing the groundwork for understanding the biology of LN and for development of preventative and therapeutic approaches in SLE.

Emerging concepts of type I interferons in SLE pathogenesis and therapy.

Type I interferons have been suspected for decades to have a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). Evidence has now overturned several long-held assumptions about how type I interferons are regulated and cause pathological conditions, providing a new view of SLE pathogenesis that resolves longstanding clinical dilemmas. This evidence includes data on interferons in relation to genetic predisposition and epigenetic regulation. Importantly, data are now available on the role of interferons in the early phases of the disease and the importance of non-haematopoietic cellular sources of type I interferons, such as keratinocytes, renal tubular cells, glial cells and synovial stromal cells, as well as local responses to type I interferons within these tissues. These local effects are found not only in inflamed target organs in established SLE, but also in histologically normal skin during asymptomatic preclinical phases, suggesting a role in disease initiation. In terms of clinical application, evidence relating to biomarkers to characterize the type I interferon system is complex, and, notably, interferon-blocking therapies are now licensed for the treatment of SLE. Collectively, the available data enable us to propose a model of disease pathogenesis that invokes the unique value of interferon-targeted therapies. Accordingly, future approaches in SLE involving disease reclassification and preventative strategies in preclinical phases should be investigated.

The association between lupus serology and disease outcomes: A systematic literature review to inform the treat-to-target approach in systemic lupus erythematosus.

Serological markers such as anti-double stranded (ds)DNA antibodies and complement fractions C3/C4, are integral components of disease activity assessment in patients with systemic lupus erythematosus (SLE). However, it remains uncertain whether treatment should aim at restoration of serological abnormalities. To analyze and critically appraise the literature on the prognostic impact of active lupus serology despite clinical disease quiescence. A systematic literature review was performed in PubMed and EMBASE using the PICOT(S) (population, index, comparator, outcome(s), timing, setting) system to identify studies evaluating the association of serum anti-dsDNA, C3 and C4 levels assessed at the time of clinical remission or during the disease course, against the risk for impending flares and organ damage. Risk of bias was determined by the Quality in Prognosis Studies and ROB2 tools for observational and randomized controlled studies, respectively. Fifty-three studies were eligible, the majority having moderate (70.6%) or high (11.8%) risk of bias and not adequately controlling for possible confounders. C3 hypocomplementemia during stable/inactive disease was associated with increased risk (2.0 to 3.8-fold) for subsequent flare in three out of seven relevant studies. Three out of four studies reported a significant effect of C4 hypocomplementemia on flare risk, including one study in lupus nephritis (likelihood ratio-positive 12.0). An increased incidence of flares (2.0 to 2.8-fold) was reported in 11 out of 16 studies assessing the prognostic effect of high anti-dsDNA, and similarly, the majority of studies yielded significant relationships with renal flares. Six studies examined the effect of combined (rather than individual) serological activity, confirming the increased risk (2.0 to 2.7-fold) for relapses. No consistent association was found with organ damage. Notwithstanding the heterogeneity and risk of bias, existing evidence indicates a modest association between abnormal serology and risk for flare in patients with stable/inactive SLE. These findings provide limited support for inclusion of serology in the treat-to-target approach but rationalize to further investigate their prognostic implications especially in lupus nephritis.

A novel computational drug repurposing approach for Systemic Lupus Erythematosus (SLE) treatment using Semantic Web technologies.

A novel computational drug repurposing approach for Systemic Lupus Erythematosus (SLE) treatment using Semantic Web technologies.

New therapeutic approaches in systemic lupus erythematosus.

This review gives an overview of the recently published clinical trials in systemic lupus erythematosus (SLE). Our continuously improving understanding of the cellular and molecular mechanisms, which are involved in the pathogenesis of SLE, has inspired the performance of multiple clinical trials in an attempt to modify recognized targets. Here, we summarize results obtained from recent trials, which used monoclonal antibodies blocking cytokines, blockers of costimulatory molecules or deleting immune cells, small drug inhibitors of kinases and replenishment of cytokines. The therapeutic options for patients with SLE grow continuously and in parallel it raises the need for pathogenetic mechanism-based precision medicine so that we may select the right treatment for the right patient.

Conversion of T Follicular Helper Cells to T Follicular Regulatory Cells by Interleukin-2 Through Transcriptional Regulation in Systemic Lupus Erythematosus.

This study was undertaken to identify characteristics of follicular regulatory T (Tfr) cells and elucidate the mechanisms by which follicular helper T (Tfh) cells convert to Tfr cells. We probed the phenotype of T helper cells in patients with systemic lupus erythematosus (SLE) and underlying transcriptional regulation using cytokine-induced STAT family factors. Peripheral blood mononuclear cells from 41 patients with SLE and 26 healthy donors were used to sort out the memory Tfh cell subset, and Tfh cells were cultured under various conditions. The phenotype of T helper cells and underlying mechanisms of transcriptional regulation were probed using flow cytometry and quantitative polymerase chain reaction analyses. These analyses evaluated the expression of characteristic markers and phosphorylation of STATs. Chromatin immunoprecipitation was used to evaluate histone modifications. In patients with SLE, the proportion of CD4+CXCR5+FoxP3-PD-1high Tfh cells was increased (P < 0.01), whereas the proportion of CD4+CXCR5+CD45RA-FoxP3high activated Tfr cells was decreased (P < 0.05). Serum interleukin-2 (IL-2) levels were also reduced in patients with SLE. IL-2 induced conversion of memory Tfh cells to functional Tfr cells, which was characterized by CXCR5+Bcl-6+FoxP3high pSTAT3+pSTAT5+ cells. The loci of FOXP3 and BCL6 at STAT binding sites were marked by bivalent histone modifications. Following IL-2 stimulation, STAT3 and STAT5 selectively bound to FOXP3 and BCL6 gene loci accompanied by suppression of H3K27me3. Finally, IL-2 stimulation suppressed the generation of CD38+CD27high plasmablasts in Tfh and B cell coculture assays ex vivo. Impaired function of Tfr cellsmight beattributed to defective IL-2 production. ExogenousIL-2 restores the function of Tfr cells through the conversion of Tfh cells to Tfr cells in patients with SLE. Thus, restoring balance between Tfh and Tfr cells may provide new therapeutic approaches in SLE.

Prolonged clinical remission and low disease activity statuses are associated with better quality of life in systemic lupus erythematosus.

The objective of this study was to determine the association between disease activity status and health-related quality of life (HRQoL) in systemic lupus erythematosus (SLE) patients. SLE patients in an out-patient clinic during the previous 12 months were included in the study. The Systemic Lupus Erythematosus-specific Quality-of-Life questionnaire (SLEQoL) was administered at the last visit. Disease activity status was determined retrospectively during the previous year. The categories of disease activity status were defined as: clinical remission (CR): clinical quiescent disease according to Systemic Lupus Erythematosus Disease Activity Index 2000, prednisolone ≤ 5 mg/day; low disease activity (LDA): SLEDAI-2K (without serological domain) ≤ 2, prednisolone ≤ 7.5 mg/day; and non-optimally controlled status: for those who were not in CR/LDA. Immunosuppressive drugs (maintenance dose) and antimalarials were allowed. Prolonged CR or LDA was defined as those with sustained CR or LDA for at least one year. The association between disease activity status and HRQoL was assessed by using regression analysis adjusting for other covariates. Of 237 SLE patients, 100 patients (42.2%) achieved prolonged CR, 46 patients (19.4%) achieved prolonged LDA and 91 patients (38.4%) were not in CR/LDA. Non-CR/LDA patients had significantly higher total SLEQoL score and in all domains compared to CR/LDA patients. No significant difference in SLEQoL domain scores was found between CR and LDA groups. Multivariable analysis revealed that non-CR/LDA was positively associated with SLEQoL score compared with CR/LDA (β 20.02, 95% confidence interval (CI) 6.81-33.23, p < 0.003). Moreover, non-CR/LDA was at a higher risk of impaired QoL (SLEQoL score > 80) compared with CR (hazard ratio 3.8; 95% CI 1.82-7.95; p < 0.001). However, there was no significant difference between CR and LDA in terms of SLEQoL score or impaired QoL. Other factors associated with higher SLEQoL score were damage index (β 9.51, 95% CI 3.52-15.49, p = 0.002) and anemia (β 24.99, 95% CI 5.71-44.27, p = 0.01). Prolonged CR and LDA are associated with better HRQoL in SLE patients and have a comparable effect. Prolonged CR or optional LDA may be used as the treatment goal of a treat to target approach in SLE.

New therapeutic strategies in systemic lupus erythematosus management.

The current treatment approach for systemic lupus erythematosus (SLE), as outlined inthe recommendations by international medical associations including EULAR and the ACR, is mostly eminence-based rather than evidence-based. However, knowledge on SLE is growing quickly, and such new advances need to be translated into clinical practice. Questions remain regarding the choice and timing of drug administration and tapering until withdrawal, which both can affect the balance between the control of disease activity and damage to organs triggered by long-standing and/or disproportionate immunosuppression. Currently, the treating physicians of patients with SLE are required to weigh the present with the future situation of their patients in an optimized balance between therapeutic harm and benefit. In this Review, the available therapeutic strategies and main challenges in the approach to SLE treatment are discussed. Remission and low disease activity are desirable therapeutic goals. Although the drug armamentarium for SLE has not expanded much in the past few decades, there are nonetheless opportunities to make better choices and explore combination therapies; such opportunities offer the potential of a personalized medicine strategy.

Regulatory T Cells and Their Association with Serum Markers and Symptoms in Systemic Lupus Erythematosus and Rheumatoid Arthritis

ABSTRACTPurpose: Impairment in number and functions of regulatory T cells (Treg) has been found to be associated with many autoimmune diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This study was conducted to identify and compare Treg by flow cytometry using two different staining approaches.Methods: Treg were identified by using CD4+CD25+high and CD4+CD25+CD127dim staining approaches in SLE and RA patients and healthy controls. Association of both identified Treg levels with various serum markers and clinical presentation was also examined.Results: Blood CD4+CD25+CD127dim cells levels were 11.4+3.57 %, 9.76+2.37 % and 6.95+1.16 %; while CD4+CD25+high cells were 1.46+1.09 %, 0.95+0.59 % and 1.87+1.14 % in SLE patients, RA patients and healthy controls respectively. Number of CD4+CD25+CD127dim cells was higher than CD4+CD25+high cells in blood samples of all three study groups. Levels of CD4+CD25+CD127dim cells were significantly higher in SLE and RA patients, compared to healthy controls, but this difference was not observed for CD4+CD25+high Treg. CD4+CD25+high levels showed significant correlation with serum C4, IFN-γ and IL-10 levels in healthy subjects and with C4 levels and fever in SLE patients. CD4+CD25+CD127dim levels showed significant association with alopecia and oral ulcers in SLE patients only, but no correlation with measured serum markers.Conclusion: Results suggest that both staining approaches detect Treg differently and also that Treg play different role in pathogenesis of SLE and RA.

Treat to target, remission and low disease activity in SLE.

Despite improvements in survival, outcomes of contemporary treatment of systemic lupus erythematosus (SLE) are unacceptable. Unlike in many diseases, treat-to-target (T2T) approaches have not been adopted in SLE, owing to a lack of validated targets to treat towards. Therefore, it is a key goal to validate target state definitions such as low disease activity and remission, and test their implementation in clinical practice and clinical trials. In this article, we review recent advances in T2T approaches in SLE, and emerging evidence-based consensus on definitions of remission and low disease activity that are needed to underpin such approaches. We conclude that, while more work is needed, much has been achieved and at least for low disease activity the lupus low disease activity state definition appears to have utility and validity for the study of SLE. Application to routine clinical care awaits validation of improved outcomes from T2T studies based on these targets.

Dietary hydroxytyrosol and hydroxytyrosyl acetate supplementation prevent pristane-induced systemic lupus erythematous in mice

Current experimental studies suggest a beneficial role of dietary phenolic compounds on prevention and management of immune-inflammatory disorders. Systemic lupus erythematosus (SLE), a multisystemic autoimmune chronic disease, remains without an effective and safe treatment. Thus, diet therapy could be a promising approach in SLE due to its potential prophylactic effects without the side effects of classical pharmacology. This study evaluates the effects of diets supplemented with phenolic compounds: hydroxytyrosol (HTy) and hydroxytyrosyl acetate (HTy-Ac) in pristane-induced SLE mice. Peritoneal macrophages and spleens were isolated and cultured to evaluate cytokines levels by Enzyme-Linked Immunosorbent Assay (ELISA). Renal changes of inflammatory markers and signaling pathways were determined by western blot. Dietary phenol supplementation significantly reduced pro-inflammatory cytokines and prevented renal damage with a considerably blockage of different inflammatory-related pathways suggesting that HTy and HTy-Ac supplementation might provide a basis for developing a new dietary strategy for prevention and management of SLE.

Systemic Lupus Erythematosus: Review of Cardiovascular Aspects

Systemic lupus erythematosus (SLE) is an autoimmune condition with a complex pathophysiological process in which its inflammatory activity is an enhancer of coronary disease by systemic inflammation, endothelial dysfunction and predisposition to thrombosis. The cardiovascular involvement in SLE is not a diagnostic criterion and is considered only as damage established in the long-term of the disease. The objective of this study is to highlight the importance of clinical vision for the early identification of cardiovascular involvement in SLE. A critical analysis of the cardiac approach in SLE, with emphasis on clinical aspects, cardiovascular biomarkers and genetics and rational request of additional tests. The particularity of patients with lupus nephritis and antiphospholipid antibody syndrome is also highlighted. The perception of subclinical cardiac damage is critical for interrupting the cycle of myocardial injury and to avoid progression of heart disease.

Stat3 and Stat5 govern IL-10 expression in T cells through trans-activation and epigenetic remodelling in health and disease

IL-10 is an immune-regulatory cytokine that plays a central role during innate and adaptive immune responses. T cells are a major source of IL-10. The molecular mechanisms governing IL-10 expression remain only partially understood. The autoimmune disorder systemic lupus erythematosus (SLE) is characterized by autoantibody production, immune complex formation, and altered cytokine expression. IL-10 is elevated in the serum and tissues of SLE patients. Next to its anti-inflammatory capacities, IL-10 promotes the differentiation, survival, and activity of B cells. Thus, IL-10 contributes to autoantibody production and tissue damage in SLE. The molecular events contributing to the increased expression of IL-10 in SLE patients remain to be determined. We aimed to determine molecular mechanisms controlling IL10 in health and disease. In T cells, DNA methylation of the IL10 promoter and the 4th intron governs the recruitment of Stat transcription factors. Both Stat3 and Stat5, which are recruited to the 5’ proximal promoter and the 4th intron, regulate IL-10. Stat3 and Stat5 mediate both trans-activation and epigenetic remodelling through their interaction with the histone acetyltransferase p300. In T cells from SLE patients, activation of Stat3 is increased, resulting in a replacement of Stat5, subsequently promoting IL-10 expression. Understanding the molecular events contributing to cytokine deregulation in SLE will offer new therapeutic options. Correcting the imbalanced activation of Stat transcription factors may be a promising candidate in the search for novel therapeutic approaches in SLE.

B cell biology: implications for treatment of systemic lupus erythematosus

B cells are critical players in the orchestration of properly regulated immune responses, normally providing protective immunity without autoimmunity. Balance in the B cell compartment is achieved through the finely regulated participation of multiple B cell populations with different antibody-dependent and independent functions. Both types of functions allow B cells to modulate other components of the innate and adaptive immune system. Autoantibody-independent B cell functions include antigen presentation, T cell activation and polarization, and dendritic cell modulation. Several of these functions are mediated by the ability of B cells to produce immunoregulatory cytokines and chemokines and by their critical contribution to lymphoid tissue development and organization including the development of ectopic tertiary lymphoid tissue. Additionally, the functional versatility of B cells enables them to play either protective or pathogenic roles in autoimmunity. In turn, B cell dysfunction has been critically implicated in the pathophysiology of systemic lupus erythematosus (SLE), a complex disease characterized by the production of autoantibodies and heterogeneous clinical involvement. Thus, the breakdown of B cell tolerance is a defining and early event in the disease process and may occur by multiple pathways, including alterations in factors that affect B cell activation thresholds, B cell longevity, and apoptotic cell processing. Once tolerance is broken, autoantibodies contribute to autoimmunity by multiple mechanisms including immune-complex mediated Type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines including IFNα, TNF and IL-1. The complexity of B cell functions has been highlighted by the variable success of B cell-targeted therapies in multiple autoimmune diseases, including those conventionally viewed as T cell-mediated conditions. Given the widespread utilization of B cell depletion therapy in autoimmune diseases and the need for new therapeutic approaches in SLE, a better understanding of human B cell subsets and the balance of pathogenic and regulatory functions is of the essence.

Anticytokine Therapies in Systemic Lupus Erythematosus

The dysfunctional immune response that characterizes systemic lupus erythematosus (SLE) associates with an unbalanced production of soluble mediators that are crucial in promoting and sustaining chronic inflammation. The successful use of biologics in several autoimmune diseases has led to studies in SLE aimed at contrasting the proinflammatory responses that contribute to tissue and organ damage in the disease. Several approaches have been developed and tested as potential therapeutic agents in SLE in preclinical studies and in clinical trials. This article provides an overview on antibody-based approaches in SLE that, although preliminary, have the potential to expand the current therapeutic possibilities in the disease.

Update on emerging drug therapies for systemic lupus erythematosus

Importance of the field: Despite the improvement in survival of systemic lupus erythematosus (SLE), a cure for this chronic and disabling disease is still a myth. Refractory manifestations and treatment-related complications are still major causes for mortality and morbidity. More effective but less toxic therapies through modification of existing regimens, combination strategies or more specific targeting at the immunopathogenetic pathways are necessary.Areas covered in this review: The availability of biotechnology has led to the emergence of targeted therapies for SLE. In the past 5 years, there have been a number of clinical trials in the pipeline that involve existing drugs or novel biological agents. This article updates different novel therapeutic approaches in SLE that have emerged since 2006.What the readers will gain: Readers will read the latest information and critical appraisals regarding recent clinical trials in lupus. Expert opinions on future directions of SLE treatment trials are also provided.Take home message: SLE is a clinically and immunologically heterogeneous disease. Targeted therapies are currently available but to the disappointment of the lupus community, data from many recent clinical trials are unfavorable. While flaws and limitations in the study design and outcome measures may contribute to the futility of these trials, selection of SLE subsets by serum and cellular biomarkers may identify those who will benefit from these targeted therapies.

Novel therapeutic approaches in systemic lupus erythematosus

Systemic lupus erythematosus is a prototypical systemic autoimmune disease, affecting multiple organs and organ-systems, leading to a wide variety of symptoms, serological and clinical features. The pathogenesis of the disease encompasses a complex interplay among various immune-competent cells and inflammatory mediators, which gives ground to target numerous potentially harmful players in this system. The aim of the present review was to depict certain aspects on the pathogenesis of SLE and to highlight pathways that can be promising targets of novel therapeutic approaches. T-cell, B-cell targeting, modification of co-stimulatory pathways, anti-cytokine therapy, soluble mediators, as well as autologous stem cell transplantation have been addressed. Finally, we described potential side effects of these biologics.

Pathogenesis of kidney disease in systemic lupus erythematosus

A combination of systemic autoimmunity and tissue response to immune injury underlie renal involvement in lupus erythematosus. In this review, we discuss recent literature investigating pathogenetic mechanisms of lupus glomerulonephritis. In lupus glomerulonephritis, glomerular immune complexes were believed to be the primary mediators of renal disease. Recent studies make it apparent that autoantibodies of multiple specificities participate in the formation of immune complexes, deposited in the kidneys. Renal infiltration by T cells, macrophages, and dendritic cells have a dominant role in the progression of lupus glomerulonephritis leading to renal failure. Activation of Toll-like receptors modulates autoantibody production and systemic interferon responses. However, glomerular cell responses to immune injury influence disease outcome. In addition, new insights on the genetics of susceptibility to end-organ damage in lupus glomerulonephritis have been discovered. Differential glomerular responses reflected in gene expression profiles during disease progression provide potential markers for diagnosis of lupus glomerulonephritis progression and flares. In addition, studies of end-organ responses provide new targets for therapeutic interventions. Lupus glomerulonephritis is a prototype of immune complex disease mediated by autoantibodies of multiple specificities, one of which is anti-DNA. Murine models of spontaneous systemic lupus erythematosus have been critical for understanding the underlying disease. Recent studies demonstrate that in addition to systemic autoimmunity, end-organ responses, and end-organ resistance to damage are also critical in determining disease outcome. This understanding should influence design of novel therapeutic approaches in systemic lupus erythematosus.

Rituximab in systemic lupus erythematosusA systematic review of off-label use in 188 cases

The complexity of the therapeutic approach in systemic lupus erythematosus (SLE) is increased by the large number of patients who do not respond to the first-line therapies and by relapses after initial clinical remission. In these patients, second-line drugs are often prescribed according to individual clinical decisions. The emergence of biological therapies has increased the therapeutic armamentarium available in these complex situations, but their use is limited by the lack of licensing. Available data on the use of rituximab in SLE rely on a large number of case reports and some observational studies. We analyzed current evidence on the therapeutic use of rituximab in adult SLE patients by a systematic review of reports included in the PubMed database between 2002 and 2007. A total of 188 SLE patients treated with rituximab were identified; 171 (91%) patients showed a significant improvement in one or more of the systemic SLE manifestations. There were 103 patients with lupus nephritis, with an overall rate of therapeutic response of renal involvement of 91%. Adverse events were reported in 44 (23%) patients; the most frequent were infections (19%). Although it is not yet possible to make definite recommendations, the global analysis of all cases reported to date support the off-label use of rituximab in severe, refractory SLE cases, whereas its use as a first-line therapy or in patients with a predominantly mild form of the disease is not advised.