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Neutrophilic dermatoses (NDs) refer to a group of cutaneous conditions histologically characterized by the dense accumulation of neutrophils in the skin in the absence of infection. NDs have been associated with underlying autoimmune connective tissue disorders (CTDs) such as systemic lupus erythematosus (SLE), Sjogren's syndrome, and dermatomyositis. We describe a case of neutrophilic dermatoses as a manifestation of a SLE flare.

Aims Methods Results Conclusions The pharmacokinetics (PK) of belimumab, a human immunoglobulin G1λ (IgG1λ) monoclonal antibody treatment for systemic lupus erythematosus (SLE), have been well reported. Clinical PK data in healthy participants and patients with SLE from Mainland China suggest lower‐than‐expected belimumab exposure. This study assessed inter‐regional differences in belimumab exposure and efficacy via the exposure–response relationship to inform any dose‐adjustment requirements.Data from nine interventional belimumab studies in healthy participants and patients with SLE were used to update two‐compartment PK models with first‐order subcutaneous (SC) absorption, and a logistic regression model characterizing the 52‐week SLE Responder Index (SRI) response in adult and paediatric patients with SLE. Covariates of belimumab PK and efficacy were identified using forward selection (P > .05) and backward elimination (P < .01). The models were evaluated using statistical tests and visual predictive checks.Baseline fat‐free mass was the most significant covariate affecting belimumab PK; baseline albumin and IgG concentrations were also PK covariates. After adjusting for covariates, Mainland Chinese patients had significantly higher observed belimumab clearance (28%) and central volume of distribution (20%) than other populations, leading to lower‐than‐expected exposures. Despite this, following the same dose, they were expected to have almost identical SRI response rates vs. other populations from the exposure–response analysis.Belimumab 10 mg kg−1 intravenously every 4 weeks, or 200 mg SC every week, would achieve the maximum treatment effect for North East Asian patients with SLE (including Mainland Chinese) and similar responses to patients from other regions, despite lower reported exposures in Chinese patients. [ABSTRACT FROM AUTHOR]

Wilson's disease (WD) is a rare, autosomal recessive disorder of copper metabolism caused by pathogenic mutations in the ATP7B gene. Cellular copper overload is associated with impaired iron metabolism. Oxidative stress, cuproptosis, and ferroptosis are involved in cell death in WD. The clinical picture of WD is variable. Hepatic/neuropsychiatric/other symptoms may manifest in childhood/adulthood and even old age. It has been shown that phenotypic variability may be determined by the type of ATP7B genetic variants as well as the influence of various genetic/epigenetic, environmental, and lifestyle modifiers. In 1976, immunological abnormalities were first described in patients with WD. These included an increase in IgG and IgM levels and a decrease in the percentage of T lymphocytes, as well as a weakening of their bactericidal effect. Over the following years, it was shown that there is a bidirectional relationship between copper and inflammation. Changes in serum cytokine concentrations and the relationship between cytokine gene variants and the clinical course of the disease have been described in WD patients, as well as in animal models of this disease. Data have also been published on the occurrence of antinuclear antibodies (ANAs), antineutrophil cytoplasmic antibodies (ANCAs), anti-muscle-specific tyrosine kinase antibodies, and anti-acetylcholine receptor antibodies, as well as various autoimmune diseases, including systemic lupus erythematosus (SLE), myasthenic syndrome, ulcerative colitis, multiple sclerosis (MS), polyarthritis, and psoriasis after treatment with d-penicillamine (DPA). The occurrence of autoantibodies was also described, the presence of which was not related to the type of treatment or the form of the disease (hepatic vs. neuropsychiatric). The mechanisms responsible for the occurrence of autoantibodies in patients with WD are not known. It has also not been clarified whether they have clinical significance. In some patients, WD was differentiated or coexisted with an autoimmune disease, including autoimmune hepatitis or multiple sclerosis. Various molecular mechanisms may be responsible for immunological abnormalities and/or the inflammatory processes in WD. Their better understanding may be important for explaining the reasons for the diversity of symptoms and the varied course and response to therapy, as well as for the development of new treatment regimens for WD. [ABSTRACT FROM AUTHOR]

Immunology and microbiology research has witnessed remarkable growth and innovation globally, playing a pivotal role in advancing our understanding of immune mechanisms, disease pathogenesis, and therapeutic interventions. This manuscript presents a comprehensive exploration of the key areas in immunology research, spanning from the utilisation of bacterial proteins as antibody reagents to the intricate realms of clinical immunology and disease management. The utilisation of bacterial immunoglobulin-binding proteins (IBPs), including protein A (SpA), protein G (SpG), and protein L (SpL), has revolutionised serological diagnostics, showing promise in early disease detection and precision medicine. Microbiological studies have shed light on antimicrobial resistance patterns, particularly the emergence of extended-spectrum beta-lactamases (ESBLs), guiding antimicrobial stewardship programmes and informing therapeutic strategies. Clinical immunology research has elucidated the molecular pathways underlying immune-mediated disorders, resulting in tailored management strategies for conditions such as severe combined immunodeficiency (SCID), neuropsychiatric systemic lupus erythematosus (NPSLE), etc. Additionally, significant efforts in vaccine development against tuberculosis and HIV are highlighted, underscoring the ongoing global pursuit of effective preventive measures against these infectious diseases. In summary, immunology and microbiology research have provided significant contributions to global healthcare, fostering collaboration, innovation, and improved patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Micro RNA155 (miR-155) was identified as an essential determinant in immunological responses, and its genetic variants have increasing attention due to their ability to modulate its expression and potentially influence the susceptibility to autoimmune illnesses including rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, etc. Objectives: To examine the impact of miR-155 gene polymorphism (rs767649A>T) and miR-155 gene expression and their association with multiple sclerosis (MS) in a sample of Iraqi patients. Materials and methods: A total of 75 blood specimens were obtained from individuals diagnosed with MS. While an additional 75 blood specimens were collected from evidently healthy participants serving as a control group, with an age ranged 20-71 years. miR-155 gene polymorphism (rs767649 A>T) was determined utilizing Tetra-ARMS Polymerase Chain Reaction (Tetra-ARMS PCR) and miR-155 expression was evaluated using Real-time Polymerase Chain Reaction (RT-PCR). Results: The females experienced MS at a higher rate (69.33%) compared to the males. Furthermore, the age group 30-39 years showed a greater susceptibility to the disease (54.67%). The analysis of miR-155 (rs767649 A>T) SNP in MS patients indicated that 7 (9.34%) had the wild genotype (AA), 31 (41.33%) had the heterogeneous genotype (AT), and 37 (49.33%) had the mutant genotype (TT). These differences were statistically significant (P-value = 0.040). A allele frequency was 45 (0.3) (OR: 0.25; CI: 0.15-0.41) and T allele frequency was 105 (0.7) (OR: 3.91; CI: 2.42-6.33) in MS patients. While analysis of miR-155 gene expression demonstrated a significant increase in the patient group (1.82 ± 0.25 fold) compared to the healthy control group (0.33 ± 0.13 fold). The relationship between miR-155 gene expression and miR-155 genotypes in MS patients, revealed a notable elevation in miR-155 gene expression at the TT genotype (3.15 ± 0.73 fold), followed by TA genotype (1.29 ±0.65fold) and finally AA genotype (0.37 ± 0.19 fold) with highly statistically significant difference (P-value = 0.001). Conclusion: There was a significant positive correlation between miR-155 (rs767649 A>T) genotypes and miR-155 expression and susceptibility to MS in Iraqi patients. These findings suggests that miR-155 may hold potential as a diagnostic and therapeutic marker for the disease. [ABSTRACT FROM AUTHOR]

ObjectivesWe compared the outcomes of patients with or without systemic lupus erythematosus (SLE) who were diagnosed with coronavirus disease 19 (COVID-19) and evaluated factors within patients with SLE associated with severe outcomes.MethodsThis retrospective cohort study used the deidentified Optum COVID-19 electronic health record dataset to identify patients with COVID-19 from 1/1/2020 to 31/12/2020. Cases with SLE were matched with general controls at a ratio of 1:10 by age, sex, race and ethnicity and COVID-19 diagnosis date. Outcomes included 30-day mortality, mechanical ventilation, hospitalisation and intensive care unit admission. We evaluated the relationship between COVID-19-related outcomes and SLE using multivariable logistic regression. In addition, within SLE cases, we examined factors associated with COVID-19 related outcomes, including disease activity and SLE therapy.ResultsWe included 687 patients matched with 6870 controls. Unadjusted rates of outcomes for patients with SLE were significantly worse than for matched controls including mortality (3.6% vs 1.8%), mechanical ventilation (6% vs 2.5%) and hospitalisation (31% vs 17.7%) (all p

Biological agents are those preparations made of carbon-based biological agents with medical research value using traditional processes or modern biotechnology, which have the functions of prevention (health care), treatment, and diagnosis of various physiological symptoms of human body. At present, biological agents used in systemic lupus erythematosus (SLE) management include inhibition of B cell activation and blocking of therapeutic autoantibodies, inhibition of T cell activation and induction of T cell tolerance, activation and regulation of cytokines, and synthetic peptide immunogens. Each biological agent has its specific indications. Biological therapy can relieve the disease quickly, which is a good adjuvant therapy for refractory and severe SLE. However, the long-term treatment needs to be combined with traditional treatments. [ABSTRACT FROM AUTHOR]

ObjectiveDelayed detection of LN associates with worse outcomes. There are conflicting recommendations regarding a threshold level of proteinuria at which biopsy will likely yield actionable management. This study addressed the association of urine protein:creatinine ratios (UPCR) with clinical characteristics and investigated the incidence of proliferative and membranous histology in patients with a UPCR between 0.5 and 1.MethodsA total of 275 SLE patients (113 first biopsy, 162 repeat) were enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership across 15 US sites at the time of a clinically indicated renal biopsy. Patients were followed for 1 year.ResultsAt biopsy, 54 patients had UPCR

ObjectivesA perception derived from cross-sectional studies of small systemic lupus erythematosus (SLE) cohorts is that there is a marked discrepancy between antinuclear antibody (ANA) assays, which impacts on clinicians' approach to diagnosis and follow-up. We compared three ANA assays in a longitudinal analysis of a large international incident SLE cohort retested regularly and followed for 5 years.MethodsDemographic, clinical and serological data was from 805 SLE patients at enrolment, year 3 and 5. Two HEp-2 indirect immunofluorescence assays (IFA1, IFA2), an ANA ELISA, and SLE-related autoantibodies were performed in one laboratory. Frequencies of positivity, titres or absorbance units (AU), and IFA patterns were compared using McNemar, Wilcoxon and kappa statistics, respectively.ResultsAt enrolment, ANA positivity (≥1:80) was 96.1% by IFA1 (median titre 1:1280 (IQR 1:640-1:5120)), 98.3% by IFA2 (1:2560 (IQR 1:640-1:5120)) and 96.6% by ELISA (176.3 AU (IQR 106.4 AU-203.5 AU)). At least one ANA assay was positive for 99.6% of patients at enrolment. At year 5, ANA positivity by IFAs (IFA1 95.2%; IFA2 98.9%) remained high, while there was a decrease in ELISA positivity (91.3%, p91% agreement in ANA positivity at all time points and ≥71% agreement in IFA patterns between IFA1 and IFA2.ConclusionIn recent-onset SLE, three ANA assays demonstrated commutability with a high proportion of positivity and titres or AU. However, over 5 years follow-up, there was modest variation in ANA assay performance. In clinical situations where the SLE diagnosis is being considered, a negative test by either the ELISA or HEp-2 IFA may require reflex testing.

Objective: Elevated double-stranded DNA (dsDNA) antibody levels in blood serum are considered a disease-specific marker in systemic lupus erythematosus (SLE), correlate with disease activity and the incidence of lupus nephritis, and can be detected in up to 86% of all SLE cases. Despite the high clinical relevance, the variety of dsDNA antibody testing methods with heterogenous performance in clinical use remains challenging. This study is the first to prospectively investigate the performance of two of today's most commonly applied anti-dsDNA testing methods head-to-head under real-world conditions, as well as their correlation with other clinical and serological disease parameters in SLE patients. Methods: In this prospective study, all SLE patients undergoing treatment at the Department of Rheumatology at the University Hospital Bonn within a 13-months period (n=41) and control patients without connective-tissue disease (n=51) were consecutively enrolled and examined. For all study participants' serum samples both anti-dsDNA-NcX enzyme-linked immunoassay testing EUROIMMUN, Luebeck, Germany) and the fluorescence immunoassay ELiA dsDNA (Thermo Fisher Scientific, Waltham, USA) were performed. In addition, demographic data, further laboratory values and disease activity parameters were recorded. Clinical disease activity was assessed by SLEDAI-2K. Results: Both assays showed high specificity (anti-dsDNA-NcX ELISA: 0.9, ELiA dsDNA: 0.959), but there were notable differences in sensitivity (anti-dsDNA-NcX ELISA: 0.51, ELiA dsDNA: 0.38). Pearsons's correlation yielded a positive correlation between anti-dsDNA concentrations and CRP concentrations for the anti-dsDNA-NcX ELISA (R=0.22; p=0.038) and a mild-to-moderate inverse correlation between concentrations of anti-dsDNA and complement C4 for the ELiA dsDNA test (R=-0.22; p=0.045) when SLE and control patients were considered together. Other than, no significant correlation between anti-dsDNA concentrations and clinical or laboratory findings was found for either test procedure. Conclusion: Both anti-dsDNA antibody assays represent reliable examination methods with high specificity for the diagnosis of SLE that fulfill EULAR/ACR requirements. However, the anti-dsDNA-NcX ELISA showed superior sensitivity and significant correlation with disease activity (as measured by CRP concentrations). [ABSTRACT FROM AUTHOR]

Studying the human immune system is challenging. These challenges stem from the complexity of the immune system itself, the heterogeneity of the immune system between individuals, and the many factors that lead to this heterogeneity including the influence of genetics, environment, and immune experience. Studies of the human immune system in the context of disease are increased in complexity as multiple combinations and variations in immune pathways can lead to a single disease. Thus, although individuals with a disease may share clinical features, the underlying disease mechanisms and resulting pathophysiology can be diverse among individuals with the same disease diagnosis. This has consequences for the treatment of diseases, as no single therapy will work for everyone, therapeutic efficacy varies among patients, and targeting a single immune pathway is rarely 100% effective. This review discusses how to address these challenges by identifying and managing the sources of variation, improving access to high‐quality, well‐curated biological samples by building cohorts, applying new technologies such as single‐cell omics and imaging technologies to interrogate samples, and bringing to bear computational expertise in conjunction with immunologists and clinicians to interpret those results. The review has a focus on autoimmune diseases, including rheumatoid arthritis, MS, systemic lupus erythematosus, and type 1 diabetes, but its recommendations are also applicable to studies of other immune‐mediated diseases. [ABSTRACT FROM AUTHOR]

ObjectivesTo evaluate systemic lupus erythematosus (SLE) flares following hydroxychloroquine (HCQ) reduction or discontinuation versus HCQ maintenance.MethodsWe analysed prospective data from the Systemic Lupus International Collaborating Clinics (SLICC) cohort, enrolled from 33 sites within 15 months of SLE diagnosis and followed annually (1999-2019). We evaluated person-time contributed while on the initial HCQ dose ('maintenance'), comparing this with person-time contributed after a first dose reduction, and after a first HCQ discontinuation. We estimated time to first flare, defined as either subsequent need for therapy augmentation, increase of ≥4 points in the SLE Disease Activity Index-2000, or hospitalisation for SLE. We estimated adjusted HRs (aHRs) with 95% CIs associated with reducing/discontinuing HCQ (vs maintenance). We also conducted separate multivariable hazard regressions in each HCQ subcohort to identify factors associated with flare.ResultsWe studied 1460 (90% female) patients initiating HCQ. aHRs for first SLE flare were 1.20 (95% CI 1.04 to 1.38) and 1.56 (95% CI 1.31 to 1.86) for the HCQ reduction and discontinuation groups, respectively, versus HCQ maintenance. Patients with low educational level were at particular risk of flaring after HCQ discontinuation (aHR 1.43, 95% CI 1.09 to 1.87). Prednisone use at time-zero was associated with over 1.5-fold increase in flare risk in all HCQ subcohorts.ConclusionsSLE flare risk was higher after HCQ taper/discontinuation versus HCQ maintenance. Decisions to maintain, reduce or stop HCQ may affect specific subgroups differently, including those on prednisone and/or with low education. Further study of special groups (eg, seniors) may be helpful.

NETosis is a form of neutrophil cell death during which extracellular fibrillary structures composed of cytosolic and granule proteins assembled on scaffolds of decondensed chromatin, called neutrophil extracellular traps (NETs), are released. NETs normally contribute to host immune defense. Accumulating evidence implicates aberrant NET production and/or reduced NET clearance, along with alterations of molecules involved in NETosis pathway, in humans and animals with lupus. The extruded nuclear antigens released by NET are a source of autoantigens, which can contribute to the breakdown of self-tolerance in lupus. Excessive NET can also promote the production of pro-inflammatory cytokine interferon-α, elicit direct cytotoxic effect on various renal cells, and cause capillary necrosis and podocyte loss. Additionally, NET can induce endothelial-to-mesenchymal transdifferentiation, which can promote activated myofibroblasts leading to extracellular matrix production. Thus, aberrant NETosis can play diverse roles, including autoantibody production, inflammation, and tissue damage, at different stages of lupus pathogenesis. Evidence suggests that treatments currently used in lupus may reduce NETosis, suggesting a potential utility of targeting NETosis to treat lupus. In fact, several approaches are being experimented to therapeutically target pathways of NETosis. Future studies should precisely delineate distinct roles of NETosis at different stages of lupus pathogenesis in humans, which would offer a rational basis for NETosis-targeting treatments in the clinic.

ObjectivesVitamin D (25(OH)D) deficiency and metabolic syndrome (MetS) may both contribute to increased cardiovascular risk in SLE. We aimed to examine the association of demographic factors, SLE phenotype, therapy and vitamin D levels with MetS and insulin resistance.MethodsThe Systemic Lupus International Collaborating Clinics (SLICC) enrolled patients recently diagnosed with SLE (

Case Description: We describe a case of presumptive acquired systemic lupus erythematosus secondary to phenobarbital administration in a dog, which resolved with withdrawal of the drug. Clinical Findings: A 3.5 year‐old poodle presented to a veterinary teaching hospital for Tier 1 idiopathic epilepsy and was treated with phenobarbital. The dog experienced fever, multiple cytopenias, and proteinuria in conjunction with a positive antinuclear antibody (ANA) titer. Diagnostics: Serial CBCs, urine protein : creatinine ratios, and sternal bone marrow aspirates were performed to evaluate improvement. Treatment and Outcome: Phenobarbital was withdrawn and levetiracetam initiated. All abnormalities resolved with supportive care, without initiation of immunosuppressive drugs. All cytopenias and proteinuria resolved and ANA test results became negative within 3 months. The patient recovered and did well clinically. Clinical Relevance: Systemic lupus erythematosus is a disease of multiple autoimmune syndromes occurring concurrently or sequentially in conjunction with the presence of circulating ANA. It has been well described in dogs as an idiopathic condition, but in human medicine may occur secondary to drug reactions (drug‐associated lupus) including as a reaction to phenobarbital. The findings in our case are consistent with the criteria for drug‐induced lupus in humans and we suggest it as the first report of phenobarbital‐induced lupus in a dog. [ABSTRACT FROM AUTHOR]

BackgroundThere is limited information regarding the impact of dose and gestational timing of oral corticosteroid (OCS) use on preterm birth (PTB), especially among women with asthma.ObjectivesTo evaluate OCS dose and timing on PTB for asthma and, as a comparison, systemic lupus erythematosus (SLE).MethodsWe used health care data from California Medicaid enrollees linked to birth certificates (2007-2013), identifying women with asthma (n = 22,084) and SLE (n = 1174). We estimated risk ratios (RR) for OCS cumulative dose trajectories and other disease-related medications before gestational day 140 and hazard ratios (HR) for time-varying exposures after day 139.ResultsFor asthma, PTB risk was 14.0% for no OCS exposure and 14.3%, 16.8%, 20.5%, and 32.7% in low, medium, medium-high, and high cumulative dose trajectory groups, respectively, during the first 139 days. The high-dose group remained associated with PTB after adjustment (adjusted RR [aRR]: 1.46; 95% confidence interval [CI]: 1.00, 2.15). OCS dose after day 139 was not clearly associated with PTB, nor were controller medications. For SLE, PTB risk for no OCS exposure was 24.9%, and it was 39.1% in low- and 61.2% in high-dose trajectory groups. aRR were 1.80 (95% CI: 1.34, 2.40) for high and 1.24 (95% CI: 0.97, 1.58) for low groups. Only prednisone equivalent dose >20 mg/day after day 139 was associated with increased PTB (adjusted HR: 2.54; 95% CI: 1.60, 4.03).ConclusionsFor asthma, higher OCS doses early in pregnancy, but not later, were associated with increased PTB. For SLE, higher doses early and later in pregnancy were associated with PTB.

BACKGROUND:Systemic lupus erythematous (SLE) disproportionately impacts patients of color and socioeconomically disadvantaged patients. Similar disparities in HIV were reduced through a World Health Organization-endorsed Care Continuum strategy targeting "retention in care," defined as having at least two annual visits or viral load lab tests. Using similar definitions, this study aimed to examine predictors of lupus retention in care, to develop an SLE Care Continuum and inform interventions to reduce disparities. We hypothesized that Black patients and those residing in disadvantaged neighborhoods would have lower retention in care. METHODS:Abstractors manually validated 545 potential adult cases with SLE codes in 2013-2014 using 1997 American College of Rheumatology (ACR) or 2012 Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria. We identified 397 SLE patients who met ACR or SLICC criteria for definite lupus, had at least one baseline rheumatology visit, and were alive through 2015. Retention in care was defined as having two ambulatory rheumatology visits or SLE labs (e.g., complement tests) during the outcome year 2015, analogous to HIV retention definitions. Explanatory variables included age, sex, race, ethnicity, smoking status, neighborhood area deprivation index (ADI), number of SLE criteria, and nephritis. We used multivariable logistic regression to test our hypothesis and model predictors of SLE retention in care. RESULTS:Among 397 SLE patients, 91% were female, 56% White, 39% Black, and 5% Hispanic. Notably, 51% of Black versus 5% of White SLE patients resided in the most disadvantaged ADI neighborhood quartile. Overall, 60% met visit-defined retention and 27% met complement lab-defined retention in 2015. Retention was 59% lower for patients in the most disadvantaged neighborhood quartile (adjusted OR 0.41, CI 0.18, 0.93). No statistical difference was seen based on age, sex, race, or ethnicity. More SLE criteria and non-smoking predicted greater retention. CONCLUSIONS:Disadvantaged neighborhood residence was the strongest factor predicting poor SLE retention in care. Future interventions could geo-target disadvantaged neighborhoods and design retention programs with vulnerable populations to improve retention in care and reduce SLE outcome disparities.

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

Introduction and aim. Autoimmune rheumatic diseases are a group of disorders with similar clinical, laboratory and immunological manifestations. Connective tissue diseases include systemic scleroderma, dermatomyositis or polymyositis, Sjögren's syndrome, rheumatoid arthritis, and systemic lupus erythematosus. If the patient meets the diagnostic criteria for at least two of these diseases and has specific serologic markers, a diagnosis of overlap syndrome is possible. Description of the case. This case describes a 27-year-old man who had a history of paroxysmal fever, night sweats, erythema- like skin lesions on the forearms and lower legs, a feeling of progressive muscle weakness especially in the proximal muscles, and dry mouth. The patient was diagnosed with an overlap syndrome: systemic lupus erythematosus, dermatomyositis, and Sjögren's syndrome. Conclusion. Overlap syndrome is difficult to treat due to its multisystem nature, requiring a symptomatic therapeutic approach and careful control of medication doses to reduce side effects while controlling disease activity. [ABSTRACT FROM AUTHOR]

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Cutaneous lupus erythematosus (CLE) in humans encompasses multiple subtypes that exhibit a wide array of skin lesions and, in some cases, are associated with the development of systemic lupus erythematosus (SLE). We investigated dogs with exfoliative cutaneous lupus erythematosus (ECLE), a dog-specific form of chronic CLE that is inherited as a monogenic autosomal recessive trait. A genome-wide association study (GWAS) with 14 cases and 29 controls confirmed a previously published result that the causative variant maps to chromosome 18. Autozygosity mapping refined the ECLE locus to a 493 kb critical interval. Filtering of whole genome sequence data from two cases against 654 controls revealed a single private protein-changing variant in this critical interval, UNC93B1:c.1438C>A or p.Pro480Thr. The homozygous mutant genotype was exclusively observed in 23 ECLE affected German Shorthaired Pointers and an ECLE affected Vizsla, but absent from 845 controls. UNC93B1 is a transmembrane protein located in the endoplasmic reticulum and endolysosomes, which is required for correct trafficking of several Toll-like receptors (TLRs). The p.Pro480Thr variant is predicted to affect the C-terminal tail of the UNC93B1 that has recently been shown to restrict TLR7 mediated autoimmunity via an interaction with syndecan binding protein (SDCBP). The functional knowledge on UNC93B1 strongly suggests that p.Pro480Thr is causing ECLE in dogs. These dogs therefore represent an interesting spontaneous model for human lupus erythematosus. Our results warrant further investigations of whether genetic variants affecting the C-terminus of UNC93B1 might be involved in specific subsets of CLE or SLE cases in humans and other species.

ObjectiveTo construct a Frailty Index (FI) as a measure of vulnerability to adverse outcomes among patients with systemic lupus erythematosus (SLE), using data from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort.MethodsThe SLICC inception cohort consists of recently diagnosed patients with SLE followed annually with clinical and laboratory assessments. For this analysis, the baseline visit was defined as the first study visit at which sufficient information was available for construction of an FI. Following a standard procedure, variables from the SLICC database were evaluated as potential health deficits. Selected health deficits were then used to generate a SLICC-FI. The prevalence of frailty in the baseline dataset was evaluated using established cutpoints for FI values.ResultsThe 1683 patients with SLE (92.1% of the overall cohort) eligible for inclusion in the baseline dataset were mostly female (89%) with mean (SD) age 35.7 (13.4) years and mean (SD) disease duration 18.8 (15.7) months at baseline. Of 222 variables, 48 met criteria for inclusion in the SLICC-FI. Mean (SD) SLICC-FI was 0.17 (0.08) with a range from 0 to 0.51. At baseline, 27.1% (95% CI 25.0-29.2) of patients were classified as frail, based on SLICC-FI values > 0.21.ConclusionThe SLICC inception cohort permits feasible construction of an FI for use in patients with SLE. Even in a relatively young cohort of patients with SLE, frailty was common. The SLICC-FI may be a useful tool for identifying patients with SLE who are most vulnerable to adverse outcomes, but validation of this index is required prior to its use.

Background: Exploring the human microbiome in multiple body niches is beneficial for clinicians to determine which microbial dysbiosis should be targeted first. We aimed to study whether both the fecal and vaginal microbiomes are disrupted in SLE patients and whether they are correlated, as well as their associations with immunological features. Methods: A group of 30 SLE patients and 30 BMI-age-matched healthy controls were recruited. Fecal and vaginal samples were collected, the 16S rRNA gene was sequenced to profile microbiomes, and immunological features were examined. Results: Distinct fecal and vaginal bacterial communities and decreased microbial diversity in feces compared with the vagina were found in SLE patients and controls. Altered bacterial communities were found in the feces and vaginas of patients. Compared with the controls, the SLE group had slightly lower gut bacterial diversity, which was accompanied by significantly higher bacterial diversity in their vaginas. The most predominant bacteria differed between feces and the vagina in all groups. Eleven genera differed in patients' feces; for example, Gardnerella and Lactobacillus increased, whereas Faecalibacterium decreased. Almost all the 13 genera differed in SLE patients' vaginas, showing higher abundances except for Lactobacillus. Three genera in feces and 11 genera in the vagina were biomarkers for SLE patients. The distinct immunological features were only associated with patients' vaginal microbiomes; for example, Escherichia-Shigella was negatively associated with serum C4. Conclusions: Although SLE patients had fecal and vaginal dysbiosis, dysbiosis in the vagina was more obvious than that in feces. Additionally, only the vaginal microbiome interacted with patients' immunological features. [ABSTRACT FROM AUTHOR]

ObjectivesTo assess the prevalence of combined hormonal contraceptives (CHCs) in reproductive-age women with SLE with and without possible contraindications and to determine factors associated with their use in the presence of possible contraindications.MethodsThis observational cohort study included premenopausal women ages 18-45 years enrolled in the SLICC Registry ⩽15 months after SLE onset, with annual assessments spanning 2000-2017. World Health Organization Category 3 or 4 contraindications to CHCs (e.g. hypertension, aPL) were assessed at each study visit. High disease activity (SLEDAI score >12 or use of >0.5 mg/kg/day of prednisone) was considered a relative contraindication.ResultsA total of 927 SLE women contributed 6315 visits, of which 3811 (60%) occurred in the presence of one or more possible contraindication to CHCs. Women used CHCs during 512 (8%) visits, of which 281 (55%) took place in the setting of one or more possible contraindication. The most frequently observed contraindications were aPL (52%), hypertension (34%) and migraine with aura (22%). Women with one or more contraindication were slightly less likely to be taking CHCs [7% of visits (95% CI 7, 8)] than women with no contraindications [9% (95% CI 8, 10)].ConclusionCHC use was low compared with general population estimates (>35%) and more than half of CHC users had at least one possible contraindication. Many yet unmeasured factors, including patient preferences, may have contributed to these observations. Further work should also aim to clarify outcomes associated with this exposure.

European League Against Rheumatism and are jointly supporting multiphase development of systemic lupus erythematosus (SLE) classification criteria based on weighted criteria and a continuous probability scale. Prior steps included item generation, item reduction and hierarchical organisation of candidate criteria using an evidence-based approach. Our objectives were to determine relative weights using multicriteria decision analysis (MCDA) and to set a provisional threshold score for SLE classification. An SLE Expert Panel (8 European, 9 North American) submitted 164 real, unique cases with a wide range of SLE probability in a standardised format. Using the candidate criteria, experts scored and rank-ordered 20 representative cases. At an in-person meeting, experts reviewed inter-rater reliability of scoring, further refined criteria definitions and participated in an MCDA exercise. Based on expert consensus decisions on pairwise comparisons of criteria, 1000minds software calculated criteria weights and rank-ordered the remaining 144 cases based on their additive scores. The score of the lowest-ranked case for which complete expert consensus was achieved defined the provisional threshold classification score. Inter-rater reliability of scoring cases with the candidate criteria was good. MCDA involved 74 pairwise decisions and was repeated for the arthritis and mucocutaneous domains when the initial ranking of some cases did not match expert opinion. After criteria weights and additive scores were recalculated once, experts reached consensus for SLE classification for all cases scoring>83. Using an iterative process, the candidate criteria definitions were refined, preliminary weights were calculated and a provisional threshold score for SLE classification was determined.

ObjectiveIn cross-sectional studies, elevated osteopontin (OPN) levels have been proposed to reflect, and/or precede, progressive organ damage and disease severity in systemic lupus erythematosus (SLE). We aimed, in a cohort of patients with recent-onset SLE, to determine whether raised serum OPN levels precede damage and/or are associated with disease activity or certain disease phenotypes.MethodsWe included 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who had 5 years of followup data available. All patients fulfilled the 1997 American College of Rheumatology (ACR) criteria. Baseline sera from patients and from age- and sex-matched population-based controls were analyzed for OPN using ELISA. Disease activity and damage were assessed at each annual followup visit using the SLE Disease Activity Index 2000 (SLEDAI-2K) and the SLICC/ACR damage index (SDI), respectively.ResultsCompared to controls, baseline OPN was raised 4-fold in SLE cases (p < 0.0001). After relevant adjustments in a binary logistic regression model, OPN levels failed to significantly predict global damage accrual defined as SDI ≥ 1 at 5 years. However, baseline OPN correlated with SLEDAI-2K at enrollment into the cohort (r = 0.27, p < 0.0001), and patients with high disease activity (SLEDAI-2K ≥ 5) had raised serum OPN (p < 0.0001). In addition, higher OPN levels were found in patients with persistent disease activity (p = 0.0006), in cases with renal involvement (p < 0.0001) and impaired estimated glomerular filtration rate (p = 0.01).ConclusionThe performance of OPN to predict development of organ damage was not impressive. However, OPN associated significantly with lupus nephritis and with raised disease activity at enrollment, as well as over time.

Objective: Analyse the integrated safety profile of evobrutinib, a Bruton's tyrosine kinase inhibitor (BTKi), using pooled data from multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) trials.Methods: Phase II, randomised, double-blind, placebo-controlled trial data were analysed (N=1083; MS: n=213, 48 weeks (W); RA: n=390, 12W; SLE: n=480, 52W). The analysis included all patients who received ≥1 dose of evobrutinib (25 mg or 75 mg once daily, or 50 mg or 75 mgtwice daily) or placebo. Descriptive statistics and exposure-adjusted incidence rates (EAIR) were used to report treatment-emergent adverse events (TEAEs).Results: Data from 1083 patients were pooled: evobrutinib, n=861; placebo, n=271 (sum >1083 due to MS trial design: n=49 received both placebo (W0-24) and evobrutinib 25 mg (W25-48)); median follow-up time (pt-years): evobrutinib, 0.501; placebo, 0.463. Across indications, the proportion of patients with TEAEs and the EAIR were similar for evobrutinib and placebo (66.2% (247.6 events/100 pt-years) vs 62.4% (261.4 events/100 pt-years)). By indication, the EAIR (events/100 pt-years) of TEAEs for evobrutinib versus placebo were: MS: 119.7 vs 148.3; RA: 331.8 vs 306.8; SLE: 343.0 vs 302.1. Two fatal events occurred (in SLE). The serious infections EAIR was 2.7 and 2.1 events/100 pt-years for evobrutinib and placebo. For previously reported BTKi-class effects, the EAIR of transient elevated alanine aminotransferase/aspartate aminotransferase TEAEs (events/100 pt-years) with evobrutinib versus placebo was 4.8 vs 2.8/3.5 vs 0.7, respectively. IgG levels were similar in evobrutinib/placebo-treated patients.Conclusions: This is the first BTKi-integrated safety analysis that includes patients with MS. Overall, evobrutinib treatment (all doses) was generally well tolerated across indications.Trial Registration Numbers: NCT02975349, NCT03233230, NCT02975336. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the proof of concept for using Raman spectroscopy as a diagnostic platform in the setting of systemic lupus erythematosus (SLE). We sought to identify unique Raman signatures in serum blood samples to successfully segregate SLE patients from healthy controls (HC). In addition, a retrospective audit was undertaken to assess the clinical utility of current testing platforms used to detect anti-double stranded DNA (dsDNA) antibodies (n = 600). We examined 234 Raman spectra to investigate key variances between SLE patients (n = 8) and HC (n = 4). Multi-variant analysis and classification model construction was achieved using principal component analysis (PCA), PCA-linear discriminant analysis and partial least squares-discriminant analysis (PLS-DA). We achieved the successful segregation of Raman spectra from SLE patients and healthy controls (p-value < 0.0001). Classification models built using PLS-DA demonstrated outstanding performance characteristics with 99% accuracy, 100% sensitivity and 99% specificity. Twelve statistically significant (p-value < 0.001) wavenumbers were identified as potential diagnostic spectral markers. Molecular assignments related to proteins and DNA demonstrated significant Raman intensity changes between SLE and HC groups. These wavenumbers may serve as future biomarkers and offer further insight into the pathogenesis of SLE. Our audit confirmed previously reported inconsistencies between two key methodologies used to detect anti-dsDNA, highlighting the need for improved laboratory testing for SLE. Raman spectroscopy has demonstrated powerful performance characteristics in this proof-of-concept study, setting the foundations for future translation into the clinical setting. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by dysregulated immune responses leading to widespread inflammation and damage in various organs. Environmental factors such as infections, hormonal influences and exposure to ultraviolet light can trigger the disease in genetically predisposed individuals. Genome-wide association studies have identified over 100 susceptibility loci linked to immune regulation, interferon (IFN) signaling and antigen presentation in SLE. In addition, rare cases of monogenic lupus have been instrumental in understanding critical underlying disease mechanisms. Several immunological abnormalities contribute to the loss of self-tolerance and the perpetuation of autoimmune responses in SLE. In particular, defective clearance of apoptotic cells due to defective phagocytosis and complement activation leads to accumulation of self-antigens. Dysregulated innate immune responses activate the adaptive immune system, amplifying the inflammatory response with an important role for type I IFNs. Abnormalities in B cell development and activation lead to the production of autoreactive antibodies, forming immune complexes that cause tissue damage. Similarly, disturbances in T-cell compartments, altered regulatory T-cell functions and altered cytokine production, particularly IFN-α, contribute to tissue damage. Understanding of the immunopathogenesis of SLE is evolving rapidly, with ongoing research identifying new molecular pathways and potential therapeutic targets. Future classifications of SLE are likely to be based on underlying biological pathways rather than clinical and serological signs alone. This review aims to provide a detailed update on the most recent findings regarding the immunopathogenesis of SLE, focusing on the variability of biological pathways and the implications for future therapeutic strategies, in particular chimeric antigen receptor T (CAR T) cells. [ABSTRACT FROM AUTHOR]

ObjectivesRheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) disproportionately affect women during and following childbearing years. Antihuman leucocyte antigen (HLA) alloantibody responses are common in healthy parous women, and as these diseases are both linked with HLA and immune dysregulation, we sought to evaluate anti-HLA antibodies in RA and SLE.MethodsAnti-HLA antibodies were measured among parous SLE cases (n=224), parous RA cases (n=202) and healthy parous controls (n=239) and compared with each other as well as with nulliparous female and male controls. Antibody specificities were identified and compared against subject HLA types to determine autoreactivity versus alloreactivity. The association of anti-HLA antibodies with clinical outcomes was evaluated.ResultsLevels and frequencies of anti-HLA antibodies were significantly higher among parous females with SLE (52%) or RA (46%) compared with controls (26%), and anti-HLA antibodies were also found among nulliparous females and males with SLE and RA. Autoreactive anti-HLA antibodies were observed among SLE and RA antibody-positive subjects, but not healthy controls, with the highest frequency of autoreactive anti-HLA antibodies found in the SLE subjects. Higher levels of anti-HLA antibodies were associated with nephritis among the nulliparous SLE cases (p

ObjectiveTo evaluate response duration and identify predictors of transitioning into and out of the response state in patients with SLE receiving standard of care (SoC) in 52-week clinical trials.MethodsA multistate model (MSM) allowing for bidirectional transitions between response and non-response states was fit to data on 759 patients with SLE with active disease randomised to SoC. The probability of being in response at 52 weeks, average duration of response (sojourn time) and mean total time in response for SLE Responder Index (SRI-4, SRI-5, SRI-6) and BILAG-based Composite Lupus Assessment (BICLA) were estimated. Predictors of attainment and loss of SRI-5 response were also assessed.ResultsThe MSM estimated probability of being in response at 52 weeks ranged from 42% (SRI-6) to 61% (SRI-4). Mean duration of response ranged from 20.4 weeks (BICLA) to 31.5 weeks (SRI-4). Mean total time in response was 16.4-24.8 weeks. Baseline characteristics predictive of shorter SRI-5 response duration were African descent (p=0.005), longer history of disease (p=0.03), higher anti-dsDNA antibody titres (p=0.039), lower lymphocyte count (p=0.008) and lower haemoglobin (p=0.006). Younger age (p

Inclusion of patient-reported outcomes is important in SLE clinical trials as they allow capture of the benefits of a proposed intervention in areas deemed pertinent by patients. We aimed to compare the measurement properties of health-related quality of life (HRQoL) measures used in adults with SLE and to evaluate their responsiveness to interventions in randomised controlled trials (RCTs). A systematic review was undertaken using full original papers in English identified from three databases: MEDLINE, EMBASE and PubMed. Studies describing the validation of HRQoL measures in English-speaking adult patients with SLE and SLE drug RCTs that used an HRQoL measure were retrieved. Twenty-five validation papers and 26 RCTs were included in the indepth review evaluating the measurement properties of 4 generic (Medical Outcomes Study Short-Form 36 (SF36), Patient Reported Outcomes Measurement Information System (PROMIS) item-bank, EuroQol-5D, and Functional Assessment of Chronic Illness Therapy-Fatigue) and 3 disease-specific (Lupus Quality of Life (LupusQoL), Lupus Patient Reported Outcomes, Lupus Impact Tracker (LIT)) instruments. All measures had good convergent and discriminant validity. PROMIS provided the strongest evidence for known-group validity and reliability among generic instruments; however, data on its responsiveness have not been published. Across measures, standardised response means were generally indicative of poor-moderate sensitivity to longitudinal change. In RCTs, clinically important improvements were reported in SF36 scores from baseline; however, between-arm differences were frequently non-significant and non-important. SF36, PROMIS, LupusQoL and LIT had the strongest evidence for acceptable measurement properties, but few measures aside from the SF36 have been incorporated into clinical trials. This review highlights the importance of incorporating a broader range of SLE-specific HRQoL measures in RCTs and warrants further research that focuses on longitudinal responsiveness of newer instruments.

This article describes three complicated cases in rheumatology and pregnancy. The first case elucidates the challenges in treating SLE in conjunction with pulmonary arterial hypertension, while the second case features an SLE-affected pregnancy with development of portal hypertension secondary to portal vein thrombosis related to APS. The third case is a pregnant woman with stable SLE who developed thrombotic microangiopathy caused by atypical haemolytic uraemic syndrome, and failed to improve despite multiple measures including biopsy and elective preterm delivery. There are grave and unique challenges for women with autoimmune disease, but adverse outcomes can sometimes be avoided with careful and multidisciplinary medical management. Pre-conception counselling with regard to medications and disease treatment should also include discussion of the advisability of pregnancy, which may be difficult for a patient, but present the best course for optimizing health outcomes.

SLE is a complex autoimmune disease that results from the interplay of genetics, epigenetics and environmental exposures. DNA methylation is an epigenetic mechanism that regulates gene expression and tissue differentiation. Among all the epigenetic modifications, DNA methylation perturbations have been the most widely studied in SLE. It mediates processes relevant to SLE, including lymphocyte development, X-chromosome inactivation and the suppression of endogenous retroviruses. The establishment of most DNA methylation marks occurs in utero; however, a small percentage of epigenetic marks are dynamic and can change throughout a person's lifetime and in relation to exposures. In this review, we discuss the current understanding of the biology of DNA methylation and its regulators, the measurement and interpretation of methylation marks, the effects of genetics on DNA methylation and the role of environmental exposures with relevance to SLE. We also summarise research findings associated with SLE disease risk and heterogeneity. The robust finding of hypomethylation of interferon-responsive genes in patients with SLE and new associations beyond interferon-responsive genes such as cell-specific methylation abnormalities are described. We also discuss methylation changes associated with lupus nephritis, autoantibody status and disease activity. Lastly, we explore future research directions, emphasising the need for longitudinal studies, cell tissue and context-specific profiling, as well as integrative approaches. With new technologies, DNA methylation perturbations could be targeted and edited, offering novel therapeutic approaches.

ObjectivesTo describe how immunosuppressant use and hospitalisation patterns for SLE have evolved by comparing admission statistics at one academic centre between 2005 and 2013.MethodsWe identified admissions for SLE and for all hospitalised patients by using the hospital electronic database. For adult patients with SLE, a comprehensive chart review was conducted to identify primary indications for hospitalisation, in-hospital mortality, mean length of stay and immunosuppressant use.ResultsThe number of yearly SLE patient hospitalisations decreased from 178 to 86 between the two times of observation. Infection was the most common reason for hospitalisation accounting for 39.9% of hospitalisations in 2005 versus 31.4% of hospitalisations in 2013 (p=0.29). Lupus flare accounted for 9.6% of admissions in 2005 versus 8.1% of admissions in 2013 (p=0.72). Seven patients died during their hospitalisation (3.9% of admissions) in 2005 as opposed to no inpatient deaths in 2013. Of the 261 admissions between 2010 and 2013, six admissions resulted in death (2.3% of admissions). SLE patient mean length of hospital stay decreased from 7.6 days to 6.4 days (p=0.36) compared with all patient length of stay, which decreased from 6 days to 5.8 days. Corticosteroid use decreased (79.8% to 61.6%, p=0.11) while hydroxychloroquine (27.0% to 59.3%, p

BACKGROUND:Targeted inhibitors of B-cell activating factor (BAFF) have been evaluated in phase III trials in over 4000 patients with systemic lupus erythematosus (SLE). Post hoc analyses of these studies identify greater treatment effect in patients entering with higher disease activity, greater corticosteroid doses, anti double-stranded DNA (dsDNA) and low complement C3 or C4. OBJECTIVES:To evaluate the efficacy and safety of blisibimod, a BAFF inhibitor, in a population of patients with SLE enriched for high disease activity. METHODS:442 patients with SLE with antinuclear antibodies or anti-dsDNA and Safety of Estrogen in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥10 on standard-of-care medications were randomised to receive weekly subcutaneous blisibimod (200 mg) or placebo. Corticosteroid taper was encouraged from week 8. The primary end point was the week 52 SLE Responder Index-6 (SRI-6). RESULTS:The SRI-6 primary end point was not met. There was a statistically significant steroid-sparing effect, and significantly more blisibimod-treated subjects achieved corticosteroid taper. Increased blisibimod treatment effect on SRI-6 was observed in subjects who achieved a concomitant decrease in corticosteroid dose from baseline. In subjects with baseline urinary protein:creatinine ratio (UPCR) ≥56.5 mg/mmol, significantly higher proportions of blisibimod subjects achieved >50% reduction in UPCR and/or UPCR

BackgroundWe examined the usefulness of erythrocyte-bound C4d (EC4d) to monitor disease activity in SLE.MethodsData and blood samples were collected from three different studies, each of which included longitudinal evaluations using the Physicians Global Assessment (PGA) of disease activity and the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE Disease Activity Index (SLEDAI), which was assessed without anti-double-stranded DNA (dsDNA) and low complement C3/C4 (clinical SELENA-SLEDAI). EC4d levels were determined using flow cytometry; other laboratory measures included antibodies to dsDNA, C3 and C4 proteins. Relationships between clinical SELENA-SLEDAI, PGA and the laboratory measures were analysed using linear mixed effect models.ResultsThe three studies combined enrolled 124 patients with SLE (mean age 42 years, 97% women, 31% Caucasians and 34% African-Americans) followed for an average of 5 consecutive visits (range 2-13 visits). EC4d levels and low C3/C4 status were significantly associated the clinical SELENA-SLEDAI or PGA in each of the three study groups (p

ObjectivesTo describe glucocorticoid (GC) use in the SLICC inception cohort and to explore factors associated with GC use. In particular we aimed to assess temporal trends in GC use and to what extent physician-related factors may influence use.MethodsPatients were recruited within 15 months of diagnosis of SLE from 33 centres between 1999 and 2011 and continue to be reviewed annually. Descriptive statistics were used to detail oral and parenteral GC use. Cross sectional and longitudinal analyses were performed to explore factors associated with GC use at enrolment and over time.ResultsWe studied 1700 patients with a mean (s.d.) follow-up duration of 7.26 (3.82) years. Over the entire study period, 1365 (81.3%) patients received oral GCs and 447 (26.3%) received parenteral GCs at some point. GC use was strongly associated with treatment centre, age, race/ethnicity, sex, disease duration and disease activity. There was no change in the proportion of patients on GCs or the average doses of GC used over time according to year of diagnosis.ConclusionGCs remain a cornerstone in SLE management and there have been no significant changes in their use over the past 10-15 years. While patient and disease factors contribute to the variation in GC use, between-centre differences suggest that physician-related factors also contribute. Evidence-based treatment algorithms are needed to inform a more standardized approach to GC use in SLE.

Purpose of reviewAberrant epigenetic changes in DNA methylation, histone marks, and noncoding RNA expression regulate the pathogenesis of many rheumatic diseases. The present article will review the recent advances in the epigenetic profile of inflammatory arthritis and discuss diagnostic biomarkers and potential therapeutic targets.Recent findingsMethylation signatures of fibroblast-like synoviocytes not only distinguish rheumatoid arthritis (RA) and osteoarthritis (OA), but also early RA from late RA or juvenile idiopathic arthritis. Methylation patterns are also specific to individual joint locations, which might explain the distribution of joint involvement in some rheumatic diseases. Hypomethylation in systemic lupus erythematosus (SLE) T cells is, in part, because of active demethylation and 5-hydroxymethylation. The methylation status of some genes in SLE is associated with disease severity and has potential as a diagnostic marker. An integrative analysis of OA methylome, transcriptome, and proteome in chondrocytes has identified multiple-evidence genes that might be evaluated for therapeutic potential. Class-specific histone deacetylase inhibitors are being evaluated for therapy in inflammatory arthritis.SummaryDisease pathogenesis is regulated by the interplay of genetics, environment, and epigenetics. Understanding how these mechanisms regulate cell function in health and disease has implications for individualized therapy.

Despite the increasing use of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) cardiovascular (CV) risk score in clinical practice, few studies have compared this score to the Framingham risk score among rheumatologic patients. We calculated Framingham and 2013 ACC/AHA risk scores in subjects with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and assessed demographic, CV, and rheumatologic characteristics associated with discordant scores (high-risk ACC/AHA scores but low-risk Framingham scores). SLE and RA subjects drawn from two population-based cohort studies were assessed during in-person study visits. We used chi-squared tests and t tests to examine the association of discordant CV risk scores with baseline characteristics. Eleven (7.0%) of 157 SLE subjects and 11 (11.5%) of 96 RA subjects had discordant CV risk scores with high ACC/AHA scores and low Framingham scores. These findings did not significantly change when a 1.5 multiplier was applied to the Framingham score. Rheumatologic disease duration, high-sensitivity CRP levels, African-American race, diabetes, current use of anti-hypertensive medication, higher age, and higher systolic blood pressure were each significantly associated with discordant risk scores. Approximately 10% of SLE and RA subjects had discordant 10-year CV risk scores. Our findings suggest that the use of the 2013 ACC/AHA risk score could result in changes to lipid-lowering therapy recommendations in a significant number of rheumatologic patients. Prospective studies are needed to compare which score better predicts CV events in rheumatologic patients, especially those with risk factors associated with discordant risk scores.

BackgroundOur aim is to study the existence of the TLR9/TGF-β1/PDGF-B pathway in healthy humans and patients with systemic lupus erythematosus (SLE), and to explore its possible involvement in the pathogenesis of lupus nephritis (LN).MethodsProtein levels of the cytokines were detected by ELISA. mRNA levels of the cytokines were analyzed by real-time PCR. MTT assay was used to test the proliferation of mesangial cells under different treatments.ResultsCompared to healthy controls (N Control = 56), levels of Toll-like receptor (TLR)9, transforming growth factor (TGF)-β1, and platelet-derived growth factor B (PDGF-B) were increased significantly in the peripheral blood of SLE patients (N SLE = 112). Significant correlations between the levels of TLR9, TGF-β1, and PDGF-B were observed in both healthy controls and SLE patients. The levels of TGF-β1 and PDGF-B were greatly enhanced by TLR9 activation in primary cell cultures. The proliferation of mesangial cells induced by the plasma of SLE patients was significantly higher than that induced by healthy controls; PDGF-B was involved in this process. The protein levels of PDGF-B homodimer correlated with the levels of urine protein in SLE patients with LN (N LN =38).ConclusionsThe TLR9/TGF-β1/PDGF-B pathway exists in humans and can be excessively activated in SLE patients. High levels of PDGF-B may result in overproliferation of mesangial cells in the kidney that are involved in the development of glomerulonephritis and LN. Further studies are necessary to identify TLR9, TGF-β1, and PDGF-B as new therapeutic targets to prevent the development of glomerulonephritis and LN.

BackgroundIn patients with systemic lupus erythematosus (SLE) there is no serological test that will reliably distinguish neuropsychiatric (NP) events due to active SLE from those due to other causes. Previously we showed that serum levels of nitrated nucleosomes (NN) were elevated in a small number of patients with NPSLE. Here we measured serum NN in samples from a larger population of patients with SLE and NP events to see whether elevated serum NN could be a marker for NPSLE.MethodsWe obtained serum samples from patients in the Systemic Lupus International Collaborative Clinics (SLICC) inception cohort. This included 216 patients with NP events and two matched controls with SLE but no NP events for each of these patients. For the NP patients we tested samples taken before, during and after the NP event.ResultsTwenty-six patients had events attributed to SLE according to the most stringent SLICC attribution rule. In these patients there was no association between onset of event and elevated serum NN. In 190 patients in whom events were not attributed to SLE by the SLICC rules, median serum NN was elevated at the onset of event (P = 0.006). The predominant clinical features in this group of 190 patients were headache, mood disorders and anxiety.ConclusionsSerum NN levels rise at the time of an NP event in a proportion of patients with SLE. Further studies are needed to determine the value of serum NN as a biomarker for NPSLE.

FcγRIIB is an inhibitory receptor expressed throughout B cell development. Diminished expression or function is associated with lupus in mice and humans, in particular through an effect on autoantibody production and plasma cell (PC) differentiation. Here, we analyzed the effect of B cell-intrinsic FcγRIIB expression on B cell activation and PC differentiation. Loss of FcγRIIB on B cells in Fcgr2b-conditional KO (Fcgr2b-cKO) mice led to a spontaneous increase in autoantibody titers. This increase was most striking for IgG3, suggestive of increased extrafollicular responses. Marginal zone (MZ) B cells had the highest expression of FcγRIIB in both mice and humans. This high expression of FcγRIIB was linked to increased MZ B cell activation, Erk phosphorylation, and calcium flux in the absence of FcγRIIB triggering. We observed a marked increase in IgG3+ PCs and B cells during extrafollicular PC responses in Fcgr2b-cKO mice. The increased IgG3 response following immunization of Fcgr2b-cKO mice was lost in MZ-deficient Notch2 Fcgr2b-double KO mice. Importantly, patients with systemic lupus erythematosus (SLE) had a decrease in FcγRIIB expression that was strongest in MZ B cells. Thus, we present a model in which high FcγRIIB expression in MZ B cells prevented their hyperactivation and ensuing autoimmunity. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor was previously known as an environmental receptor that modulates the cellular response to external environmental changes. In essence, the aryl hydrocarbon receptor is a cytoplasmic receptor and transcription factor that is activated by binding to the corresponding ligands, and they transmit relevant information by binding to DNA, thereby activating the transcription of various genes. Therefore, we can understand the development of certain diseases and discover new therapeutic targets by studying the regulation and function of AhR. Several autoimmune diseases, including systemic lupus erythematosus (SLE), have been connected to AhR in previous studies. SLE is a classic autoimmune disease characterized by multiorgan damage and disruption of immune tolerance. We discuss here the homeostatic regulation of AhR and its ligands among various types of immune cells, pathophysiological roles, in addition to the roles of various related cytokines and signaling pathways in the occurrence and development of SLE. [ABSTRACT FROM AUTHOR]

Introduction: Childhood systemic lupus erythematosus (cSLE) is a complex multisystem autoimmune disease. In 2019, belimumab was approved for the clinical treatment for cSLE, making it the only biological agent approved for cSLE children aged 5 and older in 60 years. Objective: To review emerging evidence on belimumab in cSLE published up to April 2022, so as to provide information for clinical decision-making. Method: A comprehensive search of relevant publications up to the date of April 2022 in PUBMED, EMBASE, WOS, COCHRANE, ClinicalTrials.gov, CBM, CNKI and WANFANG was performed using the following criteria: (a) English and Chinese language studies; (b) RCT studies, cohort studies, or case-control studies; (c) patients with age <18; (d) Observational studies or case series studies contain more than 5 patients. All relevant literature was independently screened and reviewed by at least two reviewers and the obtained literature data were extracted and reviewed by two authors. Results: Five publications met the inclusion/exclusion criteria for cSLE: one randomized controlled trial, one retrospective cohort study, and three case series. There was a high degree of heterogeneity among several studies, and the availability of baseline and outcome data provided was uneven. Conclusion: At present, there is a lack of high-quality clinical trials of belimumab in the treatment of cSLE. Based on the current research, it is believed that the use of belimumab can inhibit cSLE activity, reduce the dose of corticosteroids and immunosuppressants, and delay kidney damage. Also it shows clinical benefit in alleviating symptoms of monogenic cSLE refractory to standard therapy. More studies are urgently needed to validate the clinical efficacy of belimumab in cSLE and to evaluate its long-term safety in pediatric populations to promote evidence-based practice. [ABSTRACT FROM AUTHOR]

Objective To evaluate the dysfunction of B-cell metabolism and its involvement in SLE pathology. Methods We assessed the expression of metabolic markers of B cells in the peripheral blood of healthy controls (HCs) and SLE patients by using flow cytometry. In vitro, peripheral B cells were isolated from HCs and SLE patients to investigate the metabolic regulation mechanisms involved in their differentiation. Results The expression level of DiOc6 (mitochondrial membrane hyperpolarization) was higher in B cells from SLE patients than in HCs, and correlated to the percentage of plasmablasts in CD19+ cells and with SLEDAI, a disease activity score. Stimulation of CD19+ cells with the Toll-like receptor 9 (TLR9) ligand CpG and IFN-α enhanced glycolysis, oxidative phosphorylation (OXPHOS), DiOc6 expression, and plasmablast differentiation in vitro. In the absence of glutamine, both glycolysis and OXPHOS were reduced, and plasmablast differentiation was suppressed, whereas there was no change in the absence of glucose. As glutamine is an important nutrient for protein synthesis, we further investigated the effect of the glutaminase inhibitor BPTES, which inhibits glutamine degradation, on metabolic regulation. BPTES reduced DiOc6 expression, OXPHOS, reactive oxygen species (ROS) production, adenosine triphosphate (ATP) production, plasmablast differentiation without affecting glycolysis. Metformin inhibited CpG- and IFN-α-induced glutamine uptake, mitochondrial functions and suppressed plasmablast differentiation. Conclusions Mitochondrial dysfunction in B cells is associated with plasmablast differentiation and disease activity in SLE. Enhanced mitochondrial functions mediated by glutamine metabolism are important for plasmablast differentiation, which may be a potential therapeutic target for SLE. [ABSTRACT FROM AUTHOR]