Therapy For SLE Research Articles

Challenges and opportunities in access to care for systemic lupus erythematosus patients across Europe and worldwide.

SLE presents significant challenges for patients and health-care professionals (HCPs), both across Europe and worldwide. Improving health-care outcomes for patients with SLE requires a comprehensive understanding of patient disease pathways. In particular, the geographical distance between SLE patients and specialized care centres, combined with the scarcity of rheumatologists, exacerbates delays in diagnosis and management. Also, the initial SLE symptoms can often be non-specific, and providing guidelines for primary HCPs and other non-specialists is extremely important. Improvement in access to treatment is also important, with several recently approved therapies for SLE not being available in several European countries and many low- and middle-income countries (LMICs). Furthermore, in the LMICs in which these treatments are available, they are not always covered by the health-care system, making their access almost impossible for those of lower socio-economic status. A number of provisions are already in place within the European Union, to improve access to care for patients with rare and complex diseases, including those with SLE. In particular, European Reference Networks (ERNs), such the ERN for Autoimmune Diseases ReCONNET, are virtual networks involving HCPs across Europe with the aim of improving the care of patients with rare and complex diseases that require highly specialized treatment and a concentration of knowledge and resources. In addition, lupus patient organizations such as Lupus Europe play a crucial role in raising awareness of SLE and advocating for improved access to care. Together, we can work towards a future where all people living with lupus receive the comprehensive and timely care they deserve.

A Case Report and Literature Review of a Triple-Vaccinated, Rituximab-Treated Systemic Lupus Erythematosus patient with COVID-19 pneumonia

Introduction: Patients being on immunosuppressive treatment of any reason, along with other risk factors such as smoking and obesity, are vulnerable to be infected from SARS-CoV2. Aim of this report is to describe a case of a female patient under Rituximab therapy who experienced episodes of lung infection due to Severe Acute Coronavirus 2 (SARS-CoV-2) invasion although fully vaccinated. Case report: A 50-year-old woman, with a past medical history of lupus nephritis on rituximab was diagnosed with lung infection due to SARS-CoV-2. Eight months later, following her last infusion of Rituximab (RTX), she developed moderate Coronavirus Disease 2019 (COVID-19). After a partial recovery, she exhibited exacerbation of respiratory symptoms leading to readmission and invasive oxygenation. She was eventually discharged home after 31 days. Her monthly neurological evaluation did not reveal evidence of disease activity. She later received intravenous immunoglobulin and a decision was made to restart rituximab. Conclusions: This case raises the possibility of persistent virus shedding and reactivation of severe acute respiratory syndrome coronavirus in a patient with SLE and Rituximab therapy. We emphasize a precise consideration of management of patients with autoimmune disorders during the COVID-19 pandemic.

Global research trends in precision-targeted therapies for systemic lupus erythematosus (2003–2023): A bibliographic study

BackgroundSystemic lupus erythematosus (SLE) is a persistent inflammatory disease caused by an autoimmune response that predominantly affects multiple organs and systems. Growing evidence highlights the critical role of precision-targeted therapies in the management of SLE. Surprisingly, only a handful of bibliometric studies have thoroughly assessed this area. This study attempts to assess the global landscape of literature output and research trends related to precision-targeted therapy for SLE. MethodPublications related to precision-targeted therapy for SLE from 2003 to 2023 were searched in the Web of Science Core Collection (WoSCC) database. VOSviewers, CiteSpace and the R package “bibliometrix” were used to perform this bibliometric analysis. ResultsA total of 3700 papers were retrieved, showing a steady annual increase in publications from 2003 to 2022. The United States led the field with the highest number of papers (36.1 %) and secured the top position in terms of citation frequency (59,889) and H-index (115). Anhui Medical University System claimed the top spot with an impressive output of 70 papers. Principal investigators Tsokos, George C. C., and Lu, Qianjin led the research effort. Among the journals, Frontiers in Immunology stood out, publishing the highest number of articles with 191. In particular, precision-targeted therapy for SLE has become a major research focus in recent years, covering aspects such as T cells, B cells, oxidative stress, remission, and PHASE-III. ConclusionThis bibliometric study of ours systematically analyses research trends in precision targeted therapy for systemic lupus erythematosus, and this information identifies the research frontiers and hot directions in recent years and will serve as a reference for scientists working on targeted therapies.

Role of Ayurvedic medicines with Panchakarma therapy in SLE w.s.r. to Aamvata

Background: Autoimmune disorders occur when the body’s immune system is working hard to defend against potentially precarious substances our bodies such as allergens, toxins, infection or food but does not identify the difference between the invaders and own body cells. SLE is an autoimmune disease in which organs, tissues and cells undergo damage, mediated by tissues binding auto antibodies and immune complexes. SLE affects heart, joints, skin, lungs, blood vessels, liver, kidney and nervous system. Due to Piita Pradhantwa in SLE it can be correlated with Pitta Anubandhi Amavata as both are systemic autoimmune disease having involvement of mainly Pitta Dosha. Materials and Methods: A male patient with complaints of pain in multiple joints with swelling, recurrent mouth ulcers, weakness all over the body and erythematous rashes on both hands with some discharge came to OPD of PTKLS Hospital and diagnosed as Amavata and admitted in IPD of the Hospital and treated according to Ayurveda Protocol including oral medications and Panchakarma therapy. Result: Patient got symptomatic relief. Details of this will be discussed in full paper. Discussion: In Ayurveda, symptoms of Vata Kapha Anubandhi Amavata can be correlated with RA and symptoms of Pitta Anubandhi Amavata can be correlated with SLE as there is involvement of Pitta Dosha and Rakta Dhatu in SLE.

Evaluating the real-world effectiveness of belimumab in patients with SLE using SLE-related laboratory values and rheumatoid arthritis-derived disease activity measures: RAPID3, swollen joint count and tender joint count

ObjectiveTo investigate the real-world impact of intravenous belimumab treatment among patients with SLE using rheumatoid arthritis-derived disease activity measures and SLE-related laboratory values.MethodsThis retrospective cohort study used US electronic medical...

Risk of diabetes mellitus in systemic lupus erythematosus: systematic review and meta-analysis.

To investigate the risk of DM and evaluate the impact of SLE therapies on the risk of developing DM in patients with SLE. Electronic database searches of PubMed, Embase, Cochrane Library and Web of Science were performed from inception to February 2023. Cohort and cross-sectional studies that analysed the risk of DM in patients with SLE were included. The associations between diabetes and antirheumatic agents, such as antimalarials and glucocorticoids, were analysed in cohort studies. Data were pooled using fixed- or random-effects meta-analysis to estimate pooled odd ratios (OR), relative risks (RR) and 95% confidence intervals (CIs). This study was registered with PROSPERO (CRD42023402774). A total of 37 studies (23 cross-sectional and 14 cohort studies) involving 266 537 patients with SLE were included. The pooled analyses from cross-sectional studies and cohort studies did not show an increased risk of DM in SLE patients (OR = 1.05, 95% CI 0.87-1.27; P = 0.63 and RR = 1.32, 95% CI 0.93-1.87; P = 0.12, respectively). However, several cohort studies consistently demonstrated a reduced risk of diabetes with antimalarials, while glucocorticoid use has been associated with an increased risk of developing diabetes. Age, sex, hypertension and immunosuppressants have not been identified as risk factors for DM in SLE patients. Although there was no increased risk of DM in patients with SLE compared with controls, HCQ users or adherents had a decreased risk, whereas glucocorticoid users had an increased risk.

Systematic literature review on early clinical evidence for immune-resolution therapies and potential benefits to patients and healthcare providers.

Several current therapies for autoimmune diseases do not provide sustained remission. Therapies that focus on the restoration of homeostasis within the immune system (i.e., immune resolution) could overcome the limitations of current therapies and provide more durable remission. However, there is no established consensus on appropriate clinical trial designs and endpoints to evaluate such therapies. Therefore, we conducted a systematic literature review (SLR) focusing on five index diseases (asthma, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus [SLE], and ulcerative colitis) to explore published literature on 1) expert opinion on immune-resolution outcomes that should be measured in clinical trials; and 2) quantification of immune resolution in previous clinical trials. The SLR was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Embase and MEDLINE databases were systematically searched (2013-2023) for published English language articles. Conference proceedings (2020-2022) from American Academy of Dermatology, American College of Rheumatology, Digestive Disease Week, European Alliance of Associations for Rheumatology, and European Academy of Dermatology and Venereology were searched to include relevant abstracts. The study protocol was registered in PROSPERO (CRD42023406489). The SLR included 26 publications on 20 trials and 12 expert opinions. Expert opinions generally lacked specific recommendations on the assessment of immune resolution in clinical trials and instead suggested targets or biomarkers for future therapies. The targets included thymic stromal lymphopoietin (TSLP) in asthma; T helper (Th)2 and Th22 cells and their respective cytokines (interleukin [IL]-4R and IL-22) in atopic dermatitis; inhibitory/regulatory molecules involved in T-cell modulation, and protein tyrosine phosphatase, non-receptor type 22 (PTPN22) in rheumatoid arthritis; low-dose IL-2 therapy in SLE; and pro-resolution mediators in ulcerative colitis and asthma. In the interventional studies, direct biomarker assessments of immune resolution were the number/proportion of regulatory T-cells (Treg) and the ratio Th17/Treg in SLE and rheumatoid arthritis; the number of T follicular helper cells (Tfh), Th1, Th2, Th17, and Th22 in atopic dermatitis, rheumatoid arthritis, and SLE; and mucosal proinflammatory gene signatures (tumor necrosis factor [TNF], interleukin 1 alpha [IL1A], regenerating family member 1 alpha [REG1A], IL8, interleukin 1 beta [IL1B], and leukocyte immunoglobulin-like receptors A [LILRA]) in ulcerative colitis. Several studies reported a statistically significant relationship between clinical remission and immune-resolution biomarkers, suggesting a link between T-cell homeostasis, cytokine production, and disease activity in autoimmune diseases. Existing literature does not offer clear guidance on the evaluation of immune resolution in interventional studies. Further research and consensus are needed to assess a treatment's ability to induce long-term remission or low disease activity. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023406489, identifier CRD42023406489.

Immunotherapeutic approaches for systemic lupus erythematosus: early overview and future potential.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Current SLE therapies include immunosuppressants, antimalarial drugs, non-steroidal anti-inflammatory drugs (NSAIDs), and corticosteroids, but these treatments can cause substantial toxicities to organs and may not be effective for all patients. In recent years, significant progress has been made in the treatment of SLE using immunotherapy, including Benlysta and Saphnelo. These advances in immunotherapy hold promise for SLE patients, providing new therapeutic options that may offer better clinical benefit and effectiveness. Simultaneously, several new biological therapies focusing on cytokines, peptides, targeted antibodies, and cell-based approaches are under clinical evaluation and have shown immense potential for the treatment of SLE. However, the complexity of SLE immunopathogenesis and disease heterogeneity present significant challenges in the development of effective immunological therapies. This review aims to discuss past experiences and understanding of diverse immunological targeting therapies for SLE and highlight future perspectives for the development of novel immunological therapies.

Concurrent occurrence of acute pancreatitis and intracerebral hemorrhage as presenting manifestations in lupus: a case report.

The authors hereby present the case of an 18-year-old female with chief complaints of fever, abdominal pain, headache, vomiting, and loss of vision. She was diagnosed with acute pancreatitis (AP) and intracerebral hemorrhage (ICH) with an etiology linked to SLE. SLICC criterion was used to diagnosed SLE while ATLANTA criteria for AP and neuro-radiological findings for ICH. Emergency temporo- parietal-occipital-osteoplastic craniotomy was done for ICH as well as started with immunosuppressive therapy for SLE. On the 18th day of admission, she was discharge with maintenance medications for SLE. While the vision took over a month to come to a premorbid state, she was clinically improved within 2 weeks of admission. Clinical manifestation of SLE vary greatly. AP and intracranial bleeding are few of the rare presentation of SLE. Acute presentation of both conditions in an otherwise healthy individual in the initial course of disease left the clinician with a wide array of differentials. Literature shows very little evidence of co-occurrence of ICH and pancreatitis as an initial manifestation in SLE patients. The exclusive diagnosis of these potentially fatal condition is made holistically with clinical, biochemical, and radiological parameters. SLE may present with atypical, life-threatening initial manifestations. Early diagnosis and timely intervention in therapy can lead to successful management. The treating physician must consider, SLE when a straightforward diagnosis is associated with inexplicable multiple concomitant abnormalities, especially in young women.

#2733 TRANSPLANTATION OF MESENCHYMAL STEM CELLS - NEW FOCUS OF IMMUNE CORRECTION IN TREATMENT OF LUPUS NEPHRITIS

Abstract Background and Aims Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterised by the production of organ-specific autoantibodies to components of cell nucleus, immune complex lesions of the connective tissue, and the development of irreversible damage of internal organs. Chronic relapsing course of SLE, resistance to steroid and immunosuppressive therapy, toxic effects of drugs determine the need of search for new therapeutic approaches. Objective To evaluate the efficacy and safety of bone marrow mesenchymal stem cell (MSC) transplantation with high-dose immunosuppressive therapy (HIST) in SLE patients. Method A total amount of 15 patients with a diagnosis of SLE (ACR criteria) refractory to classical immunosuppressive therapy was examined. Patients were divided into 2 groups: patients from the main group underwent MSCs transplantation with HIST (n = 10), while the control group was observed on the background of traditional immunosuppressive therapy without cell transplantation (n = 5). Both groups were comparable in age, gender of patients, duration and severity of the disease. The SELENA-SLEDAI was used to determine SLE activity. Cytokines were examined by ELISA (IL-1Β, IL-4, IL-10, TNF-Α), antibodies to double-stranded DNA (anti-dsDNA) and anti-nuclear antibodies (ANA) by indirect immunofluorescence. Morphological examination of kidney included Masson-trichrome histochemistry for collagen fibers, silvering reaction for elastic and reticulin fibers, immunofluorescent and immunohistochemical methods. The safety assessment included registration of various adverse events during and after transplantation. Statistical analysis was carried out by Kruskal-Wallis test using STATISTICA 6.1. Results Monitoring the effectiveness of autologous stem cell transplantation in SLE patients showed a significant 2-fold decrease in activity by SELENA-SLEDAI score from 14.67±1.15 to 7.33±1.15 points after 12 months (p = 0.03). In the control group, this indicator remained unchanged and amounted to 15.0±0.87 points despite ongoing immunosuppressive therapy. Clinical efficacy was noted in all patients receiving HIST and MSC transplantation, which was confirmed by a significant decrease in daily proteinuria from 2,48±0,77 to 1,06±0,56 g/l, a decrease in the value of antibodies to DNA (from 443,28±547,53 to 187,8±146,60) and blood cytokines (significantly for TNF-Α), and an increase in the level of complement (though insignificantly). According to kidney biopsy data, after MSC transplantation with HIST, positive dynamics consisted in an increase in the number of reticulin fibers in the vascular loops of the glomeruli, as well as a decrease in the immune inflammatory process in the vascular loops of the glomeruli by immunofluorescence analysis for the spectrum of antibodies (Figure 1). In most patients of the main group, the doses of methylprednisolone and immune suppressants were reduced. Chills during transplantation was registered in one patient; no other unwanted adverse events were identified. Conclusion MSC transplantation in combination with HIST is significantly more effective than traditional immunosuppressive therapy in SLE according to clinical and laboratory data. The method is safe, allows decreasing signs of autoimmune aggression and can be used in cases of refractoriness, low efficiency or intolerance of standard therapy for SLE.

Cutaneous Lupus Erythematosus: An Update on Pathogenesis and Future Therapeutic Directions.

Lupus erythematosus comprises a spectrum of autoimmune diseases that may affect various organs (systemic lupus erythematosus [SLE]) or the skin only (cutaneous lupus erythematosus [CLE]). Typical combinations of clinical, histological and serological findings define clinical subtypes of CLE, yet there is high interindividual variation. Skin lesions arise in the course of triggers such as ultraviolet (UV) light exposure, smoking or drugs; keratinocytes, cytotoxic T cells and plasmacytoid dendritic cells (pDCs) establish a self-perpetuating interplay between the innate and adaptive immune system that is pivotal for the pathogenesis of CLE. Therefore, treatment relies on avoidance of triggers and UV protection, topical therapies (glucocorticosteroids, calcineurin inhibitors) and rather unspecific immunosuppressive or immunomodulatory drugs. Yet, the advent of licensed targeted therapies for SLE might also open new perspectives in the management of CLE. The heterogeneity of CLE might be attributable to individual variables and we speculate that the prevailing inflammatory signature defined by either T cells, B cells, pDCs, a strong lesional type I interferon (IFN) response, or combinations of the above might be suitable to predict therapeutic response to targeted treatment. Therefore, pretherapeutic histological assessment of the inflammatory infiltrate could stratify patients with refractory CLE for T-cell-directed therapies (e.g. dapirolizumab pegol), B-cell-directed therapies (e.g. belimumab), pDC-directed therapies (e.g. litifilimab) or IFN-directed therapies (e.g. anifrolumab). Moreover, Janus kinase (JAK) and spleen tyrosine kinase (SYK) inhibitors might broaden the therapeutic armamentarium in the near future. A close interdisciplinary exchange with rheumatologists and nephrologists is mandatory for optimal treatment of lupus patients to define the best therapeutic strategy.

P164 An emerging role of interferon targeted therapy in mucocutaneous SLE: a prospective real-world evaluation of anifrolumab for refractory cutaneous lupus

Abstract Background/Aims Advances in rational drug design and recent clinical trials are leading to emergence of a range of novel therapies for SLE and therapeutic options in clinical practice are expected to broaden rapidly. The optimal real-world place of emerging and established agents will be guided by understanding their differential efficacy on specific SLE manifestations as well as efficacy for more resistant disease. Anifrolumab, a type-I interferon receptor blocking monoclonal antibody, showed efficacy in SLE in phase III trials with a notable effect on mucocutaneous disease although specific lesion subtypes and chroncicity were not explored. Severe refractory mucocutaneous SLE such as scarring discoid lesions are an important and common clinical challenge in current practice. We therefore prospectively evaluated the real-world efficacy and quality of life impact of anifolumab for active mucocutaneous SLE, recalcitrant to multiple biologic and immunosuppressant therapies. Methods Seven patients commenced anifrolumab (300 mg by monthly iv infusion) following application to the manufacturer’s early access programme (NCT 04750057). Prior biologic therapies were discontinued at least 5 half-lives in advance. Mucocutaneous disease activity was captured by Cutaneous Lupus Disease Area and Severity Index (CLASI) activity score and medical photography. Patient reported health-related quality of life comprising the Dermatology Life Quality Index (DLQI); Lupus-QoL and EQ5D-5L were evaluated at baseline, three and six months. Results Seven female patients with active mucocutaneous SLE (Discoid LE n = 5, chilblain LE n = 1, subacute cutaneous LE n = 1) and median disease duration of 17 years were evaluated. Median baseline CLASI activity score was 17 (range 10-26; higher scores indicating severe disease). Median number of previously failed therapies was 7 and included rituximab in 6/7, belimumab in 2/7 and thalidomide in 4/7. Rapid resolution of scale and erythema in DLE was established within 1 month of anifrolumab treatment. Improvements to chilblain lupus were evident by three months. CLASI activity score was improved ≥75% in all patients at 3 months. Clinical responses were associated with significant improvements in DLQI (p < 0.001) and EQ5D-VAS (p = 0.002) by three months. Lupus-QoL trended toward improvement across all domains but most strongly for fatigue (p = 0.01) and pain (p = 0.002) by 6 months. One patient discontinued treatment after 4 months due to polydermatomal shingles complicated by sensorineural hearing loss. Infection coincided with background prednisolone dose >15 mg daily, recent COVID-19 infection and new on-treatment hypogammaglobulinaemia (IgG <5 g/L). Prolonged aciclovir treatment was required for lesion resolution. Conclusion We report rapid real-world efficacy and quality of life impact of anifrolumab on highly refractory mucocutaneous SLE, which exceeded that anticipated from existing clinical trial data. Findings suggest a unique role for emerging interferon targeting therapies in management of mucocutaneous SLE but emphasize need for enhanced VZV precautions among higher risk patients. Disclosure L. Carter: Consultancies; UCB. Z. Wigston: None. P. Laws: Consultancies; Amgen, Celgene, Janssen, Leo, Lilly and Sanofi. Member of speakers’ bureau; AbbVie, Actelion and BMS. Grants/research support; UCB, Almirall, and Novartis. E.M. Vital: Consultancies; Roche, GSK, AstraZeneca, Aurinia Pharmaceuticals, Lilly and Novartis. Grants/research support; Roche, AstraZeneca and Sandoz.

Dampened Inflammation and Improved Survival After CXCL5 Administration in Murine Lupus via Myeloid and Neutrophil Pathways.

To determine the efficacy of CXCL5 administration in lupus-prone MRL/lpr (Faslpr ) mice and elucidate its working mechanisms. CXCL5 expression in blood (obtained from SLE patients and Faslpr mice) and major internal organs (obtained from Faslpr mice) was examined by Luminex, real-time polymerase chain reaction, and immunofluorescent staining analyses. Pharmacokinetic studies were performed in Faslpr mice and healthy Institute of Cancer Research mice. Efficacy of CXCL5 administration was demonstrated in Faslpr mice, and the working mechanism of CXCL5 treatment was elucidated by flow cytometry, Luminex, and RNA sequencing. In SLE patients, serum CXCL5 levels were significantly lower than in healthy individuals (P < 0.0001) and negatively correlated with disease activity (P=0.004). In Faslpr mice, disease severity progressed with age and was negatively associated with plasma CXCL5 levels. Intravenous administration of CXCL5 to Faslpr mice restored endogenous circulatory CXCL5, improved mice survival, and reduced anti-double-stranded DNA antibodies, proteinuria, lupus nephritis activity and chronicity indices, renal complements, and neutrophil extracellular traps over short-term (10 weeks) and long-term (2 years) time periods. In vitro and in vivo assays demonstrated that CXCL5 dictated neutrophil trafficking and suppressed neutrophil activation, degranulation, proliferation, and renal infiltration. Renal and splenic RNA sequencing further showed that CXCL5-mediated immunomodulation occurred by promoting energy production in renal-infiltrated immune cells, activating certain T cells, and reducing tissue fibrosis, granulocyte extravasation, complement components, and interferons. Further factorial design results indicated that CXCL5 appears to enhance host tolerability to cyclophosphamide in vulnerable individuals. We found that serum CXCL5 levels were significantly lower in SLE patients than in healthy individuals and were negatively correlated with disease activity. By administering CXCL5 intravenously in a mouse model of lupus, mouse survival improved, and indices of disease activity reduced significantly. Taken together, these findings indicate CXCL5 administration may represent a novel myeloid/neutrophil-targeting therapy for SLE.

Intraperitoneally Delivered Umbilical Cord Lining Mesenchymal Stromal Cells Improve Survival and Kidney Function in Murine Lupus via Myeloid Pathway Targeting

To determine the therapeutic efficacy of human umbilical cord lining mesenchymal stromal cells (CL-MSCs) (US Patent number 9,737,568) in lupus-prone MRL/lpr (Faslpr) mice and elucidate its working mechanisms. A total of 4 doses of (20-25) × 106 cells/kg of CL-MSCs was given to 16-week-old female Faslpr mice by intraperitoneal injection. Three subsequent doses were given on 17 weeks, 18 weeks, and 22 weeks, respectively. Six-week-old Faslpr mice were used as disease pre-onset controls. Mice were monitored for 10 weeks. Mouse kidney function was evaluated by examining complement component 3 (C3) deposition, urinary albumin-to-creatinine ratio (ACR), and lupus nephritis (LN) activity and chronicity. Working mechanisms were elucidated by flow cytometry, Luminex/ELISA (detection of anti-dsDNA and isotype antibodies), and RNA sequencing. CL-MSCs improved mice survival and kidney function by reducing LN activity and chronicity and lymphocyte infiltration over 10 weeks. CL-MSCs also reduced urinary ACR, renal complement C3 deposition, anti-dsDNA, and isotype antibodies that include IgA, IgG1, IgG2a, IgG2b, and IgM. Immune and cytokine profiling demonstrated that CL-MSCs dampened inflammation by suppressing splenic neutrophils and monocytes/macrophages, reducing plasma IL-6, IL-12, and CXCL1 and stabilizing plasma interferon-γ and TNF-α. RNA sequencing further showed that CL-MSCs mediated immunomodulation via concerted action of pro-proinflammatory cytokine-induced chemokines and production of nitric oxide in macrophages. CL-MSCs may provide a novel myeloid (neutrophils and monocytes/macrophages)-targeting therapy for SLE.

Pattern of Hematological Manifestations in Patients with Systemic Lupus Erythematosus Attending in a Tertiary Care Hospital

Background: Systemic lupus erythematosus is characterized by a wide range of symptoms, and hematological abnormalities are a typical complication (SLE). There are some that are immediately life-threatening and need immediate attention, and then there are those that require more careful thought. Objective: The purpose of this research was to better understand the hematological symptoms experienced by people with SLE. Method: This cross sectional study was carried out at tertiary hospital, Bangladesh from January 2021 to October 2022. Where a total of 100 Patients of SLE as diagnosed according to American college of Rheumatology (ACR) criteria were included in the study and patients with hematological problems for due to other diseases were excluded. Results: During the study, 21-25 years age group, 30% and 90% were female. Most common presenting complaints were arthralgia (82%) followed by malar rash(70%) and myalgia (66%). 25% had hypertension, 16% had autoimmune thyroids, 5% had DM, 40% had no history of previous. 80%were taken sterios, followed by 30% were taken Mycophenolate Mofetil, 25% were taken Cyclophosphamide, 9% were taken Methotrexate. In addition to that, Anemia was the most common hematological abnormality detected in 70% patients. Normocytic normochromic anemia (NNA) was the most common peripheral blood film (PBF) findings found in 36% of the patients followed by microcytic hypochromicanemia (MHA) 30%. A positive direct Coomb’s test was found in 40% of the patients and antiphospholipid antibody (APLA) was positive in 20% of the patients. Conclusion: Patients with SLE often have haematological abnormalities. Differentiating haematological abnormalities as a symptom of SLE, a side effect of SLE therapy, or part of another blood dyscrasia is essential.

Efficacy of belimumab combined with rituximab in severe systemic lupus erythematosus: study protocol for the phase 3, multicenter, randomized, open-label Synbiose 2 trial

BackgroundBelimumab, an anti-B-cell activating factor antibody, is approved for the treatment of auto-antibody positive systemic lupus erythematosus with a high degree of disease activity. Anti-CD20 B cell depletion with rituximab is used in refractory SLE as well, although with variable responses. We hypothesized that incomplete B cell depletion, related to a surge in BAFF levels following rituximab treatment, can cause ongoing disease activity and flares. The Synbiose 1 study primarily focused on immunological effects and shows the preliminary clinical benefit of combined rituximab and belimumab in SLE. The Synbiose 2 study will evaluate the clinical efficacy of combining belimumab with rituximab in patients with severe SLE, allowing the tapering of prednisolone and mycophenolate.MethodsSynbiose 2 is a phase 3, multicenter, randomized, controlled, open-label 2-year clinical trial. Seventy adults with severe SLE including lupus nephritis will be randomized 1:1 to receive either standard of care consisting of prednisolone and mycophenolate as induction and maintenance treatment, or belimumab and rituximab combined with standard of care as induction treatment, followed by prednisolone and belimumab as maintenance treatment. The primary objective is to assess whether combined B cell therapy will lead to a reduction of treatment failure. Secondary endpoints are complete and partial clinical and renal response and the improvement of SLE-specific autoimmune phenomena. Safety endpoints include the incidence of adverse events, with a special interest in infections.DiscussionThe Synbiose 2 trial is the first multicenter phase 3 clinical trial investigating combined B cell targeted therapy in SLE, including lupus nephritis. The outcome of this study will provide further evidence for the clinical efficacy of this new treatment strategy in severe SLE.Trial registrationClinicalTrials.gov NCT03747159. Registered on 20 November 2018.

Hydroxychloroquine induces apoptosis of myeloid-derived suppressor cells via up-regulation of CD81 contributing to alleviate lupus symptoms

BackgroundSystemic lupus erythematosus (SLE) is a chronic autoimmune disorder that results from widespread immune complex deposition and secondary tissue injury. Hydroxychloroquine (HCQ) has been used clinically to treat SLE, while its exact mechanism has still remained elusive. Some studies have shown that myeloid-derived suppressor cells (MDSCs) play a vital role in the regulation of SLE. In this study, we aimed to explore the effects of HCQ on the apoptosis of MDSCs in lupus mice and its possible molecular regulatory mechanism.MethodsWe constructed the imiquimod (IMQ)-induced lupus model in mice. The proportion and apoptosis of MDSCs were measured by flow cytometry. CD81-overexpressed adeno-associated virus was intraperitoneally injected into the lupus mice. We also transfected the CD81 siRNA into bone marrow-derived MDSCs, and employed qRT-PCR and Western blotting to quantify the level of CD81.ResultsThe results showed that HCQ ameliorated IMQ-induced lupus symptoms, and simultaneously inhibited the expansion of MDSCs. In particular, HCQ induced the apoptosis of MDSCs, and also up-regulated the expression level of CD81 in MDSCs, which might indicate the relationship between the expression level of CD81 and the apoptosis of MDSCs. CD81 was further confirmed to participate in the apoptosis of MDSCs and lupus disease progression by overexpressing CD81 in vivo. Molecular docking experiment further proved the targeting effect of HCQ on CD81. And then we interfered CD81 in bone marrow derived MDSCs in vitro, and it was revealed that HCQ rescued the decreased expression level of CD81 and relieved the immune imbalance of Th17/Treg cells.ConclusionIn summary, HCQ promoted the apoptosis of MDSCs by up-regulating the expression level of CD81 in MDSCs, and ultimately alleviated lupus symptoms. Our results may assist scholars to develop further effective therapies for SLE.

Whole-genome sequencing identifies rare missense variants of WNT16 and ERVW-1 causing the systemic lupus erythematosus

Systemic lupus erythematosus (SLE, OMIM 152700) is a rare autoimmune disease with high heritability that affects ~0.1% of the population. Previous studies have revealed several common variants with small effects in European and East Asian SLE patients. However, there is still no rare variant study on Chinese SLE patients using the whole-genome sequencing technology (WGS). Here, we designed a family based WGS study to identify novel rare variants with large effects. Based on large-scale allele frequency data from the gnomAD database, we identified rare protein-coding gene variants with disruptive and sequence-altering impacts in SLE patients. We found that the burden of rare variants was significantly higher than that of common variants in patients, suggesting a larger effect of rare variants on the SLE pathogenesis. We identified the pathogenic risk of rare missense variants with significant odds ratios (p < 0.05) in two genes, including WNT16 (NC_000007.14:g.121329757G > C, NP_057171.2:p.(Ala86Pro) and 7 g.121329760G > C, NP_057171.2:p.(Ala87Pro)), which explains five out of seven patients covering all three families but are absent from all controls, and ERVW-1 (NC_000007.14:g.92469882A > G, NP_001124397.1:p.(Leu167Pro), rs74545114; NC_000007.14:g.92469907G > A, NP_001124397.1:p.(Arg159Cys), rs201142302; NC_000007.14:g.92469919G > A, NP_001124397.1:p.(His155Tyr), rs199552228), which explains the other two patients. None of these variants were identified in any of the controls. These associations are supported by known gene expression studies in SLE patients based on literature review. We further tested the wild and mutant types using the luciferase assays and qPCR in cells. We found that WNT16 can activate the canonical Wnt/β-catenin pathway while the mutant cannot. Additionally, the wild ERVW-1 expression can be significantly up-regulated by cAMP while the mutant cannot. Our study provides the first direct genetic and in vitro evidence for the pathogenic risk of mutant WNT16 and ERVW-1, which may facilitate the design of precision therapy for SLE.

Systemic lupus erythematosus patients contain B-cell receptor repertoires sensitive to immunosuppressive drugs.

Immune repertoire (IR) during treatment may be a surrogate biomarker for disease response. Changes of the IR in systemic lupus erythematosus patients in response to immunosuppressive drugs were identified in ten SLE patients. Patients provided peripheral blood mononuclear cells at two time points for sequencing. They were divided into sensitive and nonsensitive groups by their clinical responses to immunosuppressive drugs. After treatment, the BCR expression significantly decreased in patients from the sensitive group while there was no change in patients from the nonsensitive group. IgM comprised a dominant portion of the BCR repertoire and increased slightly in all patients in the sensitive group but decreased in the nonsensitive group. IgA also exhibited opposing changes between the two groups. Shorter CDR3 of TRB and TRG chains occurred in the sensitive group. CDR3 length of IGK decreased significantly in the sensitive group. CDR3 of TCR δ/γ changed distinctly between time points in the sensitive group. Six immune-related genes showed differential expression levels in sensitive and nonsensitive groups. Our study shows that it is BCR repertoire sensitivity to immunosuppressive drugs in SLE patients and sheds light on personalized therapy for SLE.

Reductions in circulating B cell subsets and immunoglobulin G levels with long-term belimumab treatment in patients with SLE

ObjectiveTo examine the long-term changes in circulating B cell subsets and IgG levels at 5+ years of continuous belimumab treatment and their correlations with efficacy and safety measures.MethodsThis was a...