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BackgroundPhysical activity is an adjunctive therapy that improves symptoms in people living with systemic lupus erythematosus (SLE), yet the mechanisms underlying this benefit remain unclear.MethodsWe carried out a cohort study of 123 patients with SLE enrolled in the California Lupus Epidemiology Study (CLUES). The primary predictor variable was self-reported physical activity, which was measured using a previously validated instrument. We analyzed peripheral blood mononuclear cell (PBMC) single-cell RNA sequencing (scRNA-seq) data available from the cohort. From the scRNA-seq data, we compared immune cell frequencies, cell-specific gene expression, biological signalling pathways, and upstream cytokine activation states between physically active and inactive patients, adjusting for age, sex and race.FindingsWe found that physical activity influenced immune cell frequencies, with sedentary patients most notably demonstrating greater CD4+ T cell lymphopenia (Padj = 0.028). Differential gene expression analysis identified a transcriptional signature of physical inactivity across five cell types. In CD4+ and CD8+ T cells, this signature was characterized by 686 and 445 differentially expressed genes (Padj

ObjectiveThere is an established yet unexplained link between interferon (IFN) and systemic lupus erythematosus (SLE). The expression of sequences derived from transposable elements (TEs) may contribute to SLE phenotypes, specifically production of type I IFNs and generation of autoantibodies.MethodsWe profiled cell-sorted RNA-sequencing data (CD4+ T cells, CD14+ monocytes, CD19+ B cells, and natural killer cells) from peripheral blood mononuclear cells of 120 patients with SLE and quantified TE expression identifying 27,135 TEs. We tested for differential TE expression across 10 SLE phenotypes, including autoantibody production and disease activity.ResultsWe found 731 differentially expressed (DE) TEs across all SLE phenotypes that were mostly cell specific and phenotype specific. DE TEs were enriched for specific families and open reading frames of viral genes encoded in TE sequences. Increased expression of DE TEs was associated with genes involved in antiviral activity, such as LY6E, ISG15, and TRIM22, and pathways such as IFN signaling.ConclusionThese findings suggest that expression of TEs contributes to activation of SLE-related mechanisms in a cell-specific manner, which can impact disease diagnostics and therapeutics.

BACKGROUND: Neuropsychiatric symptoms in SLE and other systemic autoimmune rheumatic diseases (SARDs) are challenging to diagnose, attribute and manage. We investigated the timings of onset of a broad range of neuropsychiatric (NP) symptoms in relation to timing of SLE onset. In addition, we explored whether NP symptoms may be a prodrome to SARD onset and to subsequent flares. METHODS: We collected patient reports of the timing of their first episode of 29 NP symptoms relative to SLE non-NP symptom onset. Surveys (n = 676 SLE patients and n = 400 clinicians) and interviews (n = 50 clinicians; and n = 69 SARD patients, including 27 SLE patients) were completed from 2022 to 2023, and analysed using mixed methods. FINDINGS: The majority of NP symptoms did not first present around the time of SLE onset, contrary to the prevailing view among many rheumatology participants and in the literature. For example, among patients who experienced hallucinations, 54% reported first presentation >1 year after disease onset. Patient interviews also revealed that a range of NP symptoms may be a prodrome to SLE/SARDs onset and later flares, including symptoms not represented in existing classification criteria. Evidence of a possible prodromal syndrome was elicited from those patients who experienced hallucinations. Of these, 61% (SLE) and 34% (other SARDs) reported increasingly disrupted dreaming sleep (usually nightmares) prior to their hallucinations. In-depth interviews revealed that progression of symptoms in flares showed a high degree of inter-patient variation, whilst symptom progression was often similar in individual patients recurrent flares. INTERPRETATION: Neuropsychiatric symptoms can first present at any stage in the SLE disease course. Attributional decisions should evaluate timings of NP symptoms in relation to timing of SLE/SARD symptom onset rather than time of diagnosis due to frequent diagnostic delays. Greater recognition of prodromal/early NP symptoms indicating impending SLE flares (and potentially other SARD flares) could enable quicker flare identification and treatment. FUNDING: The Lupus Trust.

ObjectiveAccurate identification of lupus nephritis (LN) cases is essential for patient management, research and public health initiatives. However, LN diagnosis codes in electronic health records (EHRs) are underused, hindering efficient identification. We investigated the current performance of International Classification of Diseases (ICD) codes, 9th and 10th editions (ICD9/10), for identifying prevalent LN, and developed scoring systems to increase identification of LN that are adaptable to settings with and without LN ICD codes.MethodsTraining and test sets derived from EHR data from a large health system. An external set comprised data from the EHR of a second large health system. Adults with ICD9/10 codes for SLE were included. LN cases were ascertained through manual chart reviews conducted by rheumatologists. Two definitions of LN were used: strict (definite LN) and inclusive (definite, potential or diagnostic uncertainty). Gradient boosting models including structured EHR fields were used for predictor selection. Two logistic regression-based scoring systems were developed ('LN-Code' included LN ICD codes and 'LN-No Code' did not), calibrated and validated using standard performance metrics.ResultsA total of 4152 patients from University of California San Francisco Medical Center and 370 patients from Zuckerberg San Francisco General Hospital and Trauma Center met the eligibility criteria. Mean age was 50 years, 87% were female. LN diagnosis codes demonstrated low sensitivity (43-73%) but high specificity (92-97%). LN-Code achieved an area under the curve (AUC) of 0.93 and a sensitivity of 0.88 for identifying LN using the inclusive definition. LN-No Code reached an AUC of 0.91 and a sensitivity of 0.95 (0.97 for the strict definition). Both scoring systems had good external validity, calibration and performance across racial and ethnic groups.ConclusionsThis study quantified the underutilisation of LN diagnosis codes in EHRs and introduced two adaptable scoring systems to enhance LN identification. Further validation in diverse healthcare settings is essential to ensure their broader applicability.

Mitochondria are eukaryotic cellular organelles that function in energy metabolism, ROS production, and programmed cell death. Cutaneous epithelial and hair follicle dermal papilla cells are energy-rich cells that thereby may be affected by mitochondrial dysfunction and DNA mutation accumulation. In this review, we aimed to summarize the medical literature assessing dermatologic conditions and outcomes associated with mitochondrial dysfunction. A search of PubMed and Embase was performed with subsequent handsearching to retrieve additional relevant articles. Mitochondrial DNA (mtDNA) deletions, mutation accumulation, and damage are associated with phenotypic signs of cutaneous aging, hair loss, and impaired wound healing. In addition, several dermatologic conditions are associated with aberrant mitochondrial activity, such as systemic lupus erythematosus, psoriasis, vitiligo, and atopic dermatitis. Mouse model studies have better established causality between mitochondrial damage and dermatologic outcomes, with some depicting reversibility upon restoration of mitochondrial function. Mitochondrial function mediates a variety of dermatologic conditions, and mitochondrial components may be a promising target for therapeutic strategies.

BackgroundSocial determinants of health are consistently associated with systemic lupus erythematosus (SLE) outcomes. However, social determinants of health are typically measured with conventional socioeconomic status factors such as income or education. We assessed the association of economic insecurities (ie, food, housing, health care, and financial insecurity) with patient-reported outcomes in a cohort of patients with SLE.MethodsIn this cross-sectional analysis, data were derived from the California Lupus Epidemiology Study based in the San Francisco Bay Area, CA, USA. Participants were recruited between Feb 25, 2015, and Jan 10, 2018, from rheumatology clinics. Inclusion criteria were Bay Area residency; oral fluency in English, Spanish, Cantonese, or Mandarin; 18 years or older; ability to provide informed consent; and a physician confirmed SLE diagnosis. Food, housing, health care, and financial economic insecurities were assessed by validated screening tools. Patient-reported outcomes were obtained using PROMIS, Quality of Life in Neurological Disorders (known as Neuro-QoL) Cognitive Function short form, Patient Health Questionnaire (PHQ)-8, and General Anxiety Disorder (GAD)-7 instruments. Poverty was defined as household income of 125% or less of the federal poverty limit. Lower education was defined as less than college-graduate education. The association of economic insecurities with patient-reported outcomes was assessed by multivariable linear regression models adjusting for demographics, SLE disease characteristics, and comorbidities. We tested for interactions of insecurities with poverty and education.FindingsThe final cohort included 252 participants. Mean age was 49·7 (SD 13·4) years, 228 (90%) of 252 were women and 24 (10%) were men. 80 (32%) individuals self-identified as Asian, 26 (10%) as Black, 101 (40%) as White, eight (3%) as mixed race, and 37 (15%) as other race; 59 (23%) self-identified as Hispanic. 135 (54%) individuals had at least one insecurity. Insecurities were highly prevalent, and more common in those with poverty and lower education. Adjusted multivariate analyses revealed that participants with any insecurity had significantly worse scores across all measured patient-reported outcomes. For physical function, no insecurity had an adjusted mean score of 48·9 (95% CI 47·5-50·3) and any insecurity had 45·7 (44·3-47·0; p=0·0017). For pain interference, no insecurity was 52·0 (50·5-53·5) and any insecurity was 54·4 (53·0-55·8; p=0·031). For fatigue, no insecurity was 50·5 (48·8-52·3) and any insecurity was 54·9 (53·3-56·5; p=0·0005). For sleep disturbance, no insecurity was 49·9 (48·3-51·6) and any insecurity was 52·9 (51·4-54·5; p=0·012). For cognitive function, no insecurity was 49·3 (47·7-50·9) and any insecurity was 45·6 (44·1-47·0; p=0·0011). For PHQ-8, no insecurity was 4·4 (3·6-5·1) and any insecurity was 6·1 (5·4-6·8; p=0·0013). For GAD-7, no insecurity was 3·3 (2·6-4·1) and any insecurity was 5·2 (4·5-5·9; p=0·0008). Individuals with more insecurities had worse patient-reported outcomes. There were no statistically significant interactions between insecurities and poverty or education.InterpretationHaving any economic insecurity was associated with worse outcomes for people with SLE regardless of poverty or education. The findings of this study provide insight into the relationship between economic insecurities and SLE outcomes and underscore the need to assess whether interventions that directly address these insecurities can reduce health disparities in SLE.FundingUS Centers for Disease Control, Rheumatology Research Foundation, and National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL-16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.

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.

This study focuses on understanding the transcriptional heterogeneity of activated platelets and its impact on diseases such as sepsis, COVID-19, and systemic lupus erythematosus (SLE). Recognizing the limited knowledge in this area, our research aims to dissect the complex transcriptional profiles of activated platelets to aid in developing targeted therapies for abnormal and pathogenic platelet subtypes. We analyzed single-cell transcriptional profiles from 47,977 platelets derived from 413 samples of patients with these diseases, utilizing Deep Neural Network (DNN) and eXtreme Gradient Boosting (XGB) to distinguish transcriptomic signatures predictive of fatal or survival outcomes. Our approach included source data annotations and platelet markers, along with SingleR and Seurat for comprehensive profiling. Additionally, we employed Uniform Manifold Approximation and Projection (UMAP) for effective dimensionality reduction and visualization, aiding in the identification of various platelet subtypes and their relation to disease severity and patient outcomes. Our results highlighted distinct platelet subpopulations that correlate with disease severity, revealing that changes in platelet transcription patterns can intensify endotheliopathy, increasing the risk of coagulation in fatal cases. Moreover, these changes may impact lymphocyte function, indicating a more extensive role for platelets in inflammatory and immune responses. This study identifies crucial biomarkers of platelet heterogeneity in serious health conditions, paving the way for innovative therapeutic approaches targeting platelet activation, which could improve patient outcomes in diseases characterized by altered platelet function.

The TREX1 gene encodes a highly efficient DNA exonuclease that plays an important role in maintaining DNA homeostasis in the cytoplasm. TREX1 mutations lead to a spectrum of type I interferonopathies that are characterized by systemic inflammation, high blood levels of autoantibodies, and spontaneously activated immunity. The TREX1‐P212fs mutation is thought to be linked to systemic lupus erythematosus (SLE). Here, we analyzed the functions of 20 TREX1 mutants and found that the TREX1‐P212fs mutant was able to reduce DNA enzyme activity and missed endoplasmic reticulum localization. Mouse‐derived in situ Trex1 models of transcoding mutations have not been reported. We successfully constructed Trex1‐P212fs mice by CRISPR‐Cas9 technology. Trex1P212fs/P212fs mice exhibit systemic inflammation, lymphocytosis, vasculitis, and kidney disease. The excessive autoantibody production was also present in these mice. We further demonstrated that TREX1 (1–212) protein lost its interaction with RPN1, the subunit that makes up the oligosaccharyl transferase (OST) complex. These data suggest an important role of TREX1‐C‐terminal association with the endoplasmic reticulum in inducing immune activation and the Trex1‐P212fs model may provide theoretical support for a better understanding of SLE treatment and defense. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by immune system dysfunction that can lead to serious health issues and mortality. Recent investigations highlight the role of gut microbiota alterations in modulating inflammation and disease severity in SLE. This review specifically summaries the variations in gut microbiota composition across various murine models of lupus. By focusing on these differences, we aim to elucidate the intricate relationship between gut microbiota dysbiosis and the development and progression of SLE in preclinical settings. [ABSTRACT FROM AUTHOR]

Introduction: Heterogeneity of the clinical manifestations of systemic lupus erythematosus (SLE) may lead to diagnostic delays. This study is aimed at determining the health-seeking behaviour patterns and factors associated with diagnostic delays in a multi-ethnic SLE cohort in Malaysia. Methodology: This was a cross-sectional study involving SLE patients who visited our institute between January 2020 and June 2021. A review of the medical records and face-to-face interviews were conducted to obtain sociodemographics, SLE disease characteristics and the intervals from the first symptoms to the diagnosis. Health-seeking behaviours were assessed by asking about the patients' first action during the initial symptoms and were divided into: (i) seeking professional health personnel; (ii) self-treatment; and (iii) the use of the internet as a primary source of information. Diagnostic delays were defined as the interval between initial symptoms and SLE diagnosis of more than 6 months. Low-level disease activity state (LLDAS) at 12 months was assessed from the medical records. Univariate and multivariate logistic regression analysis was subsequently conducted to determine factors associated with diagnostic delays. Results: Among the 154 patients included in the study, 24% (n = 37) had delayed diagnosis. The delay was significantly higher among the Indian versus Malay versus Chinese (42.9% vs 28% vs 10.8%, p = 0.037). Patients with rash tend to have delayed diagnosis (37.8% vs 22.2%, p = 0.08) while fewer patients with frothy urine had delayed diagnosis (8.1% vs 21.4%, p = 0.09). No significant association was found between health-seeking behaviours and diagnostic delays. The rate of LLDAS at 12 months was significantly lower among patients with delayed diagnosis (43.2% vs 70.0%, p = 0.006). Chinese ethnicity remained the only significant factor associated with lesser diagnostic delays in the multivariate analysis, with OR 0.30 (CI 0.09–0.93), p = 0.037. Conclusion: There were ethnic disparities in the early diagnosis of SLE in Malaysia, with Indian patients having a longer interval between the first symptom and diagnosis while the Chinese were associated with lower diagnostic delays. Early diagnosis predicted early attainment of LLDAS, suggesting that prompt recognition of the initial SLE symptoms is important. [ABSTRACT FROM AUTHOR]

Objectives: This multicenter longitudinal study investigated the prevalence of gastrointestinal (GI) manifestations in lupus patients and determined the risk factors associated with mortality. Methods: This study is part of the Oman Lupus Study, which included 1160 patients who met the classification criteria for systemic lupus erythematosus (SLE) from January 2006 to February 2020. All patients were screened for GI symptoms and involvement. Results: We identified 91 patients with GI manifestations, with a prevalence rate of 8.53% in the pediatric group and 7.75% in the adult group, and this difference was not statistically significant (p =.755). Ischemic colitis was significantly associated with longer disease duration (p <.001) and positivity for B2-glycoprotein I (B2GPI) autoantibodies (p <.0001). Moreover, a significant correlation was found between ischemic colitis and hematologic manifestations (p =.001), lupus nephritis (p =.007), pulmonary complications (p =.000-.039), and some cardiac complications (p =.012-.269). Mortality rates were greater in patients with GI involvement (24.37%), including those with ischemic colitis (p =.005), chronic peritonitis (p <.001), and spleen/liver infarction (p =.001). Sepsis, thrombocytopenia, and different internal organ involvement rates were significantly associated with increased mortality. Conclusion: This research provides significant insights into GI manifestations in lupus patients. A higher mortality rate was found to be associated with organ involvement, disease duration, autoantibody profile, and specific complications. Considering this fact, it is vital to prioritize management strategies to improve clinical outcomes in this group of patients. [ABSTRACT FROM AUTHOR]

Objectives To study the effect of SARS-CoV2 infection on flares of systemic lupus erythematosus (SLE). Methods Patients who fulfilled the ACR/SLICC criteria for SLE and had documented COVID-19 between February and November 2022 were identified retrospectively from our hospital COVID-19 registry. SLE controls who did not have SARS-CoV2 infection were randomly matched for age, sex and the time of infection in a 2:1 ratio with those infected. The primary outcome of interest was clinical flare of SLE within 90 days of COVID-19. The rate of SLE flares (mild/moderate or severe) was compared between SARS-CoV2-infected SLE patients and controls. Results Ninety-one SLE patients with COVID-19 (age 48.6 (14.0) years; 95.6% women) and 182 SLE controls (age 48.7 (13.8) years; 95.6% women) were studied. Eleven of 91 (12.1%) SARS-CoV2-infected patients had serious manifestations. One (1.1%) patient died and 7 (7.7%) developed severe complications. Within 90 days of SARS-CoV2 infection, 14 (15.4%) patients developed mild/moderate clinical SLE flares and two (2.2%) patients had severe SLE flares. The incidence of SLE flares in SARS-CoV2-infected patients was significantly higher than in those without the infection (17.6% vs 5.5%; odds ratio 3.67 [95% CI: 1.59, 8.46]; P  = 0.001). The changes in anti-dsDNA and complement levels, however, were not significantly different between the two groups. Among SARS-CoV2-infected SLE patients, those with clinical SLE flares had significantly lower C3 values (P  = 0.004) before the infection than those without. Conclusion Clinical flares within 90 days were significantly more common in SLE patients infected with SARS-CoV2 than matched non-infected SLE controls. [ABSTRACT FROM AUTHOR]

• Characteristics and treatment patterns of 11,255 systemic lupus erythematosus patients analysed across four countries. • Glucocorticoids and hydroxychloroquine were the most common first-line treatments. • Mycophenolate mofetil was the most common second-line treatment for both adults and pediatric patients. • Higher glucocorticoid doses were often prescribed to pediatric patients compared to adults. Multiple treatment options are recommended for Systemic Lupus Erythematosus (SLE) by clinical guidelines. This study aimed to explore SLE treatment patterns as there is limited real-world data of SLE medication utilisation, especially in childhood-onset SLE (cSLE). We conducted a longitudinal cohort study using five routinely collected healthcare databases from four European countries (United Kingdom, France, Germany, and Spain). We described the characteristics of adult and paediatric patients at time of SLE diagnosis. We calculated the percentage of patients commencing SLE treatments in the first month and year after diagnosis, reported number of prescriptions, starting dose, cumulative dose, and duration of each treatment, and characterised the line of therapy. We characterised 11,255 patients with a first diagnosis of SLE and included 5718 in our medication utilisation analyses. The majority of adult SLE patients were female (range 80–88 %), with median age of 49 to 54 years at diagnosis. In the paediatric cohort (n = 378), 66–83 % of SLE patients were female, with median age of 12 to 16 years at diagnosis. Hydroxychloroquine and glucocorticoids were common first-line treatments in both adults and children, with second-line treatments including mycophenolate mofetil and methotrexate. Few cases of monoclonal antibody use were seen in either cohort. Initial glucocorticoid dosing in paediatric patients was often higher than in adults. Treatment choices for adult SLE patients across four European countries were in line with recent therapeutic consensus guidelines. High glucocorticoid prescriptions in paediatric patients suggests the need for steroid-sparing treatment alternatives and paediatric specific guidelines. [Display omitted] [ABSTRACT FROM AUTHOR]

To examine the association between clinical personnel's general attitudes towards new interventions and implementation outcomes related to an evidence-based individualized, culturally tailored, computerized decision aid (DA) for the management of lupus. To assess attitudes, the validated Evidence-Based Practice Attitudes Scale (EBPAS) survey was emailed to personnel in 15 rheumatology clinics across the U.S. The survey also included questions related to three validated implementation outcomes: lupus DA acceptability, appropriateness and feasibility. The baseline round of the survey was fielded from August 2019 to January 2020 and yielded a 56.8% response rate (n = 76 respondents). We also collected organizational characteristics from each clinic and personnel-level control variables. Overall, respondents reported modest levels of lupus DA acceptability, appropriateness and feasibility (3.54, 3.45 and 3.40, respectively, on a scale of 1–5). Multilevel regression analyses demonstrated statistically significant positive relationships between a respondent's openness to new practices/interventions and perceived lupus DA acceptability (β = 0.31, p <.01) and feasibility (β = 0.28, p <.05). Divergence (a respondent's perceived difference between current and new practices) was not associated with clinic personnel perceptions of the DA. These findings suggest that understanding clinic personnel general attitudes toward new interventions is an important precursor to implementing evidence-based practices and may provide important diagnostic information about places to intervene in preparation for implementation and improving shared decision-making with patients. [ABSTRACT FROM AUTHOR]

Introduction: Systemic Lupus Erythematosus, an autoimmune disease, can target various organs of the human body. Lupus nephritis (LN) is a major complication affecting almost half of all SLE patients, with classes "III and IV" being the most aggressive. The severity and prognosis of LN can be influenced by different biomarkers, some of which are used as therapeutic targets. One such target is the B-cell activating factor (BAFF), a key figure in the pathophysiology of SLE. New add-on treatments have emerged in the treatment of LN targeting BAFF as well as other pathways. Assortment of patients to suitable treatment combinations needs more precision using guiding markers. Methods: This prospective study aims to explore BAFF-expression in patients with active-proliferative LN and its possible association with the response after induction therapy. Peripheral blood mononuclear cells (PBMC) and renal tissue samples (if applicable) were collected from participants before the initiation of induction treatment. RNA was extracted, and the expression levels of BAFF-mRNA were measured using quantitative real-time polymerase chain reaction. Clinical and laboratory data, including disease activity indices and renal functions, were recorded at baseline and 6-months after the commencement of the induction treatment. Results: The study included 24 patients,14 responders and 10 non-responders. At baseline, median PBMC BAFF-mRNA expression was nearly identical in responders and non-responders. Renal BAFF-expression was found to be higher in non-responders, although non-significant (p = 0.21). Contrary to PBMC BAFF expression, renal BAFF-mRNA was negatively correlated with baseline glomerular filtration rate and with the primary endpoint of response, which was reduction of proteinuria to≥50% of baseline (p = 0.07). Conclusions: Renal BAFF expression could be a better representative of severity and therapeutic response than blood expression. We acknowledge that the use of BAFF expression as a predictive for early refractoriness to therapy in LN is not yet conclusive. [ABSTRACT FROM AUTHOR]

We report a pediatric patient with prolidase deficiency, caused by a mutation in the PEPD gene, which encodes the enzyme prolidase D, with a lupus-like clinic and marked dysmorphic features along with pulmonary, neurological, skeletal, and immune system involvement. In addition to being the first known case in the literature where Friedrich's ataxia and prolidase deficiency were observed together, we aimed to highlight that this diagnosis should be considered in patients with autoimmunity and additional systemic findings such as treatment-resistant skin lesions, intellectual disability, and pulmonary manifestations. Furthermore, we sought to compare this case with others documented in the literature. [ABSTRACT FROM AUTHOR]

The cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway has been identified as a significant modulator of inflammation in various clinical contexts, including infection, cellular stress, and tissue injury. The extensive participation of the cGAS-STING pathway can be attributed to its ability to detect and control the cellular reaction to DNAs originating from both microorganisms and hosts. These DNAs are well recognized as molecules linked with potential risks. At physiological levels, the STING signaling system exhibits protective effects. However, prolonged stimulation of this pathway contributes to autoimmune disorder pathogenesis. The present paper provides an overview of the activation mechanism of the cGAS-STING signaling pathways and their associated significant functions, as well as therapeutic interventions in the context of systemic lupus erythematosus (SLE). The primary objective is to enhance our comprehension of SLE and facilitate more effective diagnosis and treatment strategies for this condition. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with protean manifestations. There is little understanding of why some organs are specifically impacted in patients and the mechanisms of disease persistence remain unclear. While much work has been done characterizing the DNA methylation status in SLE, there is less information on histone modifications, a more dynamic epigenetic feature. This study identifies two histone marks of activation and the binding of p300 genome-wide in three cell types and three clinical subsets to better understand cell-specific effects and differences across clinical subsets. Results: We examined 20 patients with SLE and 8 controls and found that individual chromatin marks varied considerably across T cells, B cells, and monocytes. When pathways were examined, there was far more concordance with conservation of TNF, IL-2/STAT5, and KRAS pathways across multiple cell types and ChIP data sets. Patients with cutaneous lupus and lupus nephritis generally had less dramatically altered chromatin than the general SLE group. Signals also demonstrated significant overlap with GWAS signals in a manner that did not implicate one cell type more than the others. Conclusions: The pathways identified by altered histone modifications and p300 binding are pathways known to be important from RNA expression studies and recognized pathogenic mechanisms of disease. NFκB and classical inflammatory pathways were strongly associated with increased peak heights across all cell types but were the highest-ranking pathway for all three antibodies in monocytes according to fgsea analysis. IL-6 Jak/STAT3 signaling was the most significant pathway association in T cells marked by H3K27ac change. Therefore, each cell type experiences the disease process distinctly although in all cases there was a strong theme of classical inflammatory pathways. Importantly, this NFκB pathway, so strongly implicated in the patients with generalized SLE, was much less impacted in monocytes when cutaneous lupus was compared to the general SLE cohort and also less impacted in lupus nephritis compared to general SLE. These studies define important cell type differences and emphasize the breadth of the inflammatory effects in SLE. [ABSTRACT FROM AUTHOR]

Antigen-specific antibodies are generated by antibody-secreting cells (ASCs). How RNA post-transcriptional modification affects antibody homeostasis remains unclear. Here, we found that mRNA polyadenylations and N6-methyladenosine (m6A) modifications maintain IgG1 antibody production in ASCs. IgG heavy-chain transcripts (Ighg) possessed a long 3′ UTR with m6A sites, targeted by the m6A reader YTHDF1. B cell-specific deficiency of YTHDF1 impaired IgG production upon antigen immunization through reducing Ighg1 mRNA abundance in IgG1+ ASCs. Disrupting either the m6A modification of a nuclear-localized splicing intermediate Ighg1 or the nuclear localization of YTHDF1 reduced Ighg1 transcript stability. Single-cell RNA sequencing identified an ASC subset with excessive YTHDF1 expression in systemic lupus erythematosus patients, which was decreased upon therapy with immunosuppressive drugs. In a lupus mouse model, inhibiting YTHDF1-m6A interactions alleviated symptoms. Thus, we highlight a mechanism in ASCs to sustain the homeostasis of IgG antibody transcripts by integrating Ighg1 mRNA polyadenylation and m6A modification. [Display omitted] • m6A-modified Ighg1 RNA acts as a precursor for secretory Ighg1 • Loss of YTHDF1 in B cells decreases IgG response by reducing IgG transcript life in ASCs • YTHDF1 and Ighg1 mRNA form nuclear granules for Ighg1 stability in ASCs • YTHDF1 accumulation in ASCs promotes the pathogenesis of SLE IgG antibody production must be tightly maintained for appropriate antibody immunity. Wang et al. reveal a mechanism to sustain the homeostasis of IgG antibody transcripts by integrating Ighg1 mRNA polyadenylation and m6A modification in antibody-secreting cells (ASCs). Data from individuals with SLE and from a lupus mouse model highlight the clinical relevance of the mechanism. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is characterised by generalised immune dysfunction, including infection susceptibility. Infection-associated flares (IAFs) are common and might rapidly self-resolve, paralleling infection resolution, but their specific clinical phenotype is poorly understood. Therefore, we screened 2039 consecutive visits and identified 134 flares, defined as a loss of the lupus low disease activity state (LLDAS), from 1089 visits at risk spanning over multiple follow-up years, yielding an average yearly LLDAS deterioration rate of 17%. Thirty-eight IAFs were isolated from the total flares and were mostly related to bacterial and herpesvirus infections. When compared to other flares (OFs; n = 98), IAFs showed no milder patterns of organ involvement and similar rates of long-term damage accrual, as estimated by conventional clinimetrics. Arthritis in IAFs was more severe than that in OFs [median (interquartile range) DAS-28 2.6 (2.3–4.1) vs. 2.0 (1.6–2.7); p = 0.02]. Viral IAFs were characterised by atypically lower levels of anti-DNA antibodies (p < 0.001) and possibly abnormally high complement levels when compared to flares of different origin. These data suggest that IAFs are of comparable or even higher severity than OFs and may subtend distinct pathophysiological mechanisms that are poorly tackled by current treatments. Further research is needed to confirm these data. [ABSTRACT FROM AUTHOR]

Background: Monogenic lupus is defined as systemic lupus erythematosus (SLE)/SLE-like patients with either dominantly or recessively inherited pathogenic variants in a single gene with high penetrance. However, because the clinical phenotype of monogenic SLE is extensive and overlaps with that of classical SLE, it causes a delay in diagnosis and treatment. Currently, there is a lack of early identification models for clinical practitioners to provide early clues for recognition. Our goal was to create a clinical model for the early identification of pediatric monogenic lupus, thereby facilitating early and precise diagnosis and treatment for patients. Methods: This retrospective cohort study consisted of 41 cases of monogenic lupus treated at the Department of Pediatrics at Peking Union Medical College Hospital from June 2012 to December 2022. The control group consisted of classical SLE patients recruited at a 1:2 ratio. Patients were randomly divided into a training group and a validation group at a 7:3 ratio. A logistic regression model was established based on the least absolute shrinkage and selection operator to generate the coefficient plot. The predictive ability of the model was evaluated using receiver operator characteristic curves and the area under the curve (AUC) index. Results: A total of 41 cases of monogenic lupus patients and 82 cases of classical SLE patients were included. Among the monogenic lupus cases (with a male-to-female ratio of 1:1.05 and ages of onset ranging from birth to 15 years), a total of 18 gene mutations were identified. The variables included in the coefficient plot were age of onset, recurrent infections, intracranial calcifications, growth and developmental delay, abnormal muscle tone, lymphadenopathy/hepatosplenomegaly, and chilblain-like skin rash. Our model demonstrated satisfactory diagnostic performance through internal validation, with an AUC value of 0.97 (95% confidence interval = 0.92–0.97). Conclusions: We summarized and analyzed the clinical characteristics of pediatric monogenic lupus and developed a predictive model for early identification by clinicians. Clinicians should exercise high vigilance for monogenic lupus when the score exceeds − 9.032299. [ABSTRACT FROM AUTHOR]

ABSTRACT Background/Objectives Methods Results Conclusions Integrated care models, like combined rheumatology/dermatology clinics (RDCs), facilitate efficient coordination between specialists and provide comprehensive care. Given the limited literature on pediatric RDC logistics, outcomes, benefits and, challenges, we comprehensively characterized our patient cohort at the UCSF Benioff Children's Hospital RDC and surveyed pediatric dermatologists participating in RDCs.We retrospectively reviewed 71 patients new to the UCSF Pediatric RDC between September 2017 and September 2023. A survey was distributed in 2024 to 17 dermatologists in North America, each representing a unique pediatric RDC.69% of patients (49/71) were female. Seventeen (24%) presented without a known diagnosis; the first RDC visit established a diagnosis for 7 of them (41%). Of patients with a previously established diagnosis, initial RDC evaluation confirmed it in 52 (96%) and revised it for 2 (4%). The most encountered diagnoses were linear morphea (33%), lupus (23%), and psoriasis (13%). New systemic therapy was prescribed for 23% of patients, and additional work‐up was recommended via skin biopsy (8%) and imaging (28%). Survey results revealed all pediatric RDCs include trainees, but only 59% (10/17) receive administrative support. All agreed that RDCs are valuable for patient care and most (15/17, 88%) felt that the RDC was a valuable use of their time.Pediatric RDCs are valuable for consensus diagnosis, streamlined evaluation, and management of complex patients. Though clinical and administrative support for RDCs is generally poor, RDCs are valuable to patients, a good use of time for clinicians, and offer educational opportunities for team members. [ABSTRACT FROM AUTHOR]

This narrative review aims specifically to explore the relationship between tobacco exposure and systemic sclerosis (SSc), idiopathic inflammatory myositis (IIM), and systemic lupus erythematosus (SLE). Relevant articles were obtained by searching key terms such as "tobacco," "smoking," "scleroderma," "myositis," "lupus," and "Sjögren's" in PubMed and Google Scholar databases. The selected articles ranged from the years 2010 to 2023. Inclusion criteria were based on the relevance and contribution to the field of study. Systemic sclerosis is a complex condition involving multiple immune cell lines that can be influenced by tobacco. However, the existing literature does not provide sufficient evidence to support an increased risk of SSc in smokers or the impact on treatment options. Cigarette smoking does increase the risk of skin ulcerations in SSc patients. In addition, cigarette smoking has been associated with IIM through genetic and molecular mechanisms. Smokers with dermatomyositis or polymyositis are at an elevated risk of atherosclerosis and interstitial lung disease. Similarly, smoking in patients with SLE increases the risk of organ damage, thrombosis, and disease severity compared with non-smokers. Smokers with SLE also have more difficulty in controlling disease flares compared with non-smokers. Tobacco exposure can lead to secondary complications in patients with IIM and SLE, although the course of treatment may not differ significantly. No definitive conclusions can be drawn to the clear relationship between tobacco smoking and Sjögren's's syndrome. [ABSTRACT FROM AUTHOR]

Multifaceted interrogation of the proteome deepens the system‐wide understanding of biological systems; however, mapping the redox changes in the proteome has so far been significantly more challenging than expression and solubility/stability analyses. Here, the first high‐throughput redox proteomics approach integrated with expression analysis (REX) is devised and combined with the Proteome Integral Solubility Alteration (PISA) assay. The whole PISA‐REX experiment with up to four biological replicates can be multiplexed into a single tandem mass tag TMTpro set. For benchmarking this compact tool, HCT116 cells treated with auranofin are analyzed, showing great improvement compared with previous studies. PISA‐REX is then applied to study proteome remodeling upon stimulation of human monocytes by interferon α (IFN‐α). Applying this tool to study the proteome changes in plasmacytoid dendritic cells (pDCs) isolated from wild‐type versus Ncf1‐mutant mice treated with interferon α, shows that NCF1 deficiency enhances the STAT1 pathway and modulates the expression, solubility, and redox state of interferon‐induced proteins. Providing comprehensive multifaceted information on the proteome, the compact PISA‐REX has the potential to become an industry standard in proteomics and to open new windows into the biology of health and disease. [ABSTRACT FROM AUTHOR]

Objective: In Africa, the treatment outcomes of lupus nephritis (LN) are not well known. This is especially true in the current era where contemporary treatment options are more widely available. This retrospective study aimed to measure the outcomes of biopsy-proven LN treated at the Livingstone Tertiary Hospital (LTH) Renal Unit in Gqeberha (formerly Port Elizabeth), South Africa and to identify predictors of a poor outcome. Methods: A retrospective cohort study of 131 patients with biopsy-proven LN who had a kidney biopsy between 01 January 2012 to 31 December 2021 as identified from the biopsy register. A sub-analysis of 107 patients with proliferative and/or membranous LN was performed. Results: Mean age was 31.4 ± 12.7 years with a female predominance of 86.3%. At 6-month follow-up, 69.6% of patients had complete or partial response to treatment. This increased to 70.3% and 72.6% at 18 and 30 months, respectively. Twenty-seven patients were lost to follow-up, while 7 (5.3%) patients progressed to kidney failure (KF). There were 3 (2.3%) deaths. Predictors of poor response were an elevated baseline serum creatinine (OR = 2.53, 95% CI 0.99 – 6.52, p =.054), a decreased eGFR (OR = 2.92, 95% CI 0.94 – 9.09, p =.065) and an elevated blood pressure (OR = 6.06, 95% CI 1.11 – 33.33, p =.038) at the time of biopsy. Infections were the most common adverse event with 50 infections seen in 39 (29.8%) patients. Herpes viral infections were frequently noted (n = 12) accounting for 24.0% of all documented infections. Conclusion: Response rates were similar in this cohort when compared to other contemporary studies. Predictors of poor response were an elevated baseline serum creatinine, a decreased eGFR and an elevated blood pressure at time of the biopsy. Infections were the most common occurring adverse event, although the mortality rate remained low at 2.3%. [ABSTRACT FROM AUTHOR]

Introduction: Antimalarials (AMs) are old drugs with a wide range of beneficial effects in systemic lupus erythematosus (SLE) beyond the control of activity. The most recent debate is focused on defining the optimal doses to assure the best benefit/risk ratio. Areas covered: We have reviewed the pharmacological basis underlying the various therapeutic effects of AMs and the beneficial and toxic effects of HCQ, also discussing the role of mepacrine not only as a substitute in cases of maculopathy, but also as a very effective therapy combined with HCQ. We searched PubMed and Embase for articles published in English at any time. We used the terms "hydroxychloroquine" or "mepacrine" or "chloroquine" or "antimalarials", "pharmacokinetics", "efficacy", "remission", "toxicity", "adherence". We reviewed original research articles, large observational studies, systematic reviews, and expert consensus statements. Additionally, studies were identified through the assessment of the reference lists of the evaluated manuscripts. Expert opinion: We advocate for the widespread use of HCQ at stable doses of 200 mg/d (≤4 mg/kg/d for most patients) and also for the early combination therapy with mepacrine to assure a good control of SLE activity, and also a durable and safe use of these essential drugs for the management of SLE. [ABSTRACT FROM AUTHOR]

Although the role of low-density granulocytes (LDGs), neutrophils in the peripheral blood mononuclear cell (PBMC) fraction, and neutrophil extracellular traps (NETs) in assessing lupus disease severity is acknowledged, data specific to childhood-onset lupus remains scarce. This study analyzed 46 patients with childhood-onset systemic lupus erythematosus (82.6% females, mean age 14.5 ± 0.3 years), including 26 cases with normal complement levels and 20 with low complement levels, along with 20 healthy adult volunteers. Key parameters that distinguished healthy volunteers from lupus patients and differentiated between lupus patients with low and normal complement were serum interferon (IFN)-α, serum citrullinated histone 3 (CitH3), and extracellular traps (ETs) in LDGs. However, NETs (assessed by nuclear staining morphology), LDG abundance, and other parameters (such as endotoxemia, cytokines, and double-stranded (ds) DNA) did not show such differentiation. When lipopolysaccharide (LPS) was administered to LDGs in the PBMC fraction, it induced ETs in both low and normal complement groups, indicating the inducible nature of ETs. In adult healthy volunteers, activation by recombinant IFN-α or dsDNA in isolated neutrophils induced LDGs and NETs (identified using immunofluorescent staining for CitH3, myeloperoxidase, and neutrophil elastase) at 45 min and 3 h post-stimulation, respectively. Additionally, approximately half of the LDGs underwent late apoptosis at 3 h post-stimulation, as determined by flow cytometry analysis. Activation by IFN-α or dsDNA in LDGs also led to a more pronounced expression of CD66b, an adhesion molecule, compared to regular-density neutrophils, suggesting higher activity in LDGs. In conclusion, IFN-α and/or dsDNA in serum may transform regular-density neutrophils into LDGs before progressing to NETosis and apoptosis, potentially exacerbating lupus severity through cell death-induced self-antigens. Therefore, LDGs and ETs in LDGs could provide deeper insights into the pathophysiology of childhood-onset lupus. [ABSTRACT FROM AUTHOR]

Simple Summary: Mouse models of disease are commonly used to generate compelling data which are the basis for biological conviction in drug discovery. Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease which can often lead to kidney failure, and there are many mouse models that claim to mimic the disease, but none can completely reproduce all aspects of human SLE. To effectively utilize these models for drug development, we must understand which biological similarities they share with human SLE patients. Here, we compared a select number of lupus mouse models to see how well immune pathways in kidney samples mimic human disease in kidney samples from lupus patients. The mouse models vary in the type and intensity of immune responses that were observed. Each mouse model shares various aspects of immune response with human SLE patients and should be utilized based on drug targets and shared biological pathways. Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease which can present with mixed organ involvement. Kidney involvement in lupus nephritis (LN) is a severe complication and major cause of mortality in SLE patients, second only to cardiovascular disease. While mouse models have helped uncover some molecular pathways involved in SLE/LN, we need a better understanding of the connection of these pathways and the immune cells involved in disease pathogenesis to develop new and effective therapies. Furthermore, models used for studying SLE/LN in mice have a heterogeneous immune response and may not always represent disease manifestations observed in patients. Identifying models that have shared pathways with human disease would allow for better translation for developing effective SLE/LN therapies. The molecular pathways of five different SLE/LN models (MRL/lpr, poly (I:C)-induced, interferon-α-induced, bm12 GvHD, and spontaneous NZB/W F1) were compared to characterize the immune response in mouse kidneys. These models demonstrated varied magnitudes in immune responses and proportions of innate vs. adaptive cell involvement. These findings were compared to human molecular pathways and cell types from public databases, including the Accelerating Medicine Partnership–Systemic Lupus Erythematosus Program (AMP-SLE), to help corelate mechanisms involved in mouse models to human disease. [ABSTRACT FROM AUTHOR]

The BAFF-APRIL system is crucial for the pathogenesis of systemic lupus erythematosus (SLE) by promoting B cell survival, differentiation and the maintenance of humoral autoimmunity. Here, we investigated the relationship of BCMA expression on B cell subsets with its ligands BAFF and APRIL, together with soluble BCMA, and with clinical and serologic variables in a cohort of 100 SLE patients (86 under conventional and 14 under belimumab therapy) and 30 healthy controls (HCs) using multicolor flow cytometry and ELISA. We found that BCMA expression in SLE patients was significantly increased on all B cell subsets compared to HCs, with all examined components of the BAFF-APRIL system being upregulated. BCMA expression was significantly increased on switched and unswitched memory B cells compared to naïve B cells, both in HCs and SLE. BCMA expression on B cells correlated with plasmablast frequencies, serum anti-dsDNA antibodies and complement consumption, while soluble BCMA correlated with plasmablast frequency, highlighting its potential as a clinical biomarker. Belimumab treatment significantly reduced BCMA expression on most B cell subsets and soluble TACI and contributed to the inhibition of almost the entire BAFF-APRIL system and restoration of B cell homeostasis. These results provide insights into the complex dysregulation of the BAFF-APRIL system in SLE and highlight the therapeutic potential of targeting its components, particularly BCMA, in addition to its use as a biomarker for disease activity. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to explore the treatment pattern of systemic lupus erythematosus (SLE) in Aotearoa/New Zealand. Methods: SLE patients were linked to the pharmaceutical dispensing data. The use of publicly funded anti-malarials, immunomodulators, biologics, glucocorticoids and bisphosphonates were compared by gender, ethnicity, age group, socioeconomic status and year of SLE identification. Adherence to hydroxychloroquine was examined using the medication possession ratio (MPR), with a MPR of ≥0.8 considered as high adherence. Results: Of the 2631 SLE patients, 73.8% used hydroxychloroquine, 64.1% used immunomodulators/biologics and 68.0% used 5 mg or more prednisone daily for at least 90 days. Women were more likely to use hydroxychloroquine than men. Asian patients had a different treatment pattern than other ethnic groups, and Māori were less likely to use hydroxychloroquine. The proportions of patients using different treatments decreased with age. Of the patients using hydroxychloroquine, 54.5% had high adherence. For patients over 40 years old and on long term prednisone, 47.3% had bisphosphonates and this figure was 17.8% for patients under the age of 40 years old. Patients with better socioeconomic status had a higher probability of using bisphosphonates than patients with lower socioeconomic status. Conclusions: Adherence to hydroxychloroquine in these patients varied and was lower in men and in Māori. Prednisone is commonly prescribed and used long term. Half of those over the age of 40 years old co-administered bisphosphonate. Further research is needed to identify the reasons for these discrepancies on SLE treatments by gender, ethnicity, age and socioeconomic status. [ABSTRACT FROM AUTHOR]

Background: Macrophage activation syndrome (MAS) is an acquired form of hemo phagocytic lymphohistiocytosis (HLH) and is usually associated with infections, autoimmune, auto inflammatory syndromes and malignancies. Case details: A 14 year old girl presented with sub-acute onset of fever with lymphadenopathy, pancytopenia,high ferritin values and a falling erythrocyte sedimentation rate. She was evaluated with relevant laboratory tests that was suggestive of systemic Lupus erythematosus and associated macrophage activation syndrome She recovered with immunosuppressive therapy and other supportive care. Conclusion: There is a need for a high index of suspicion of occult MAS and MAS in patients with systemic lupus erythematosus as it may be an initial presentation. Delay in diagnosis and initiation of treatment can lead to a higher mortality. [ABSTRACT FROM AUTHOR]

The presence of anxiety and depression symptoms in patients with lupus is common, and some research reports that psychological interventions can reduce them, therefore we conducted a systematic review and meta-analysis of the efficacy of psychological interventions in adults with systemic lupus erythematosus. Randomized and non-randomized clinical trials with adult population diagnosed with lupus, treated with psychological intervention, and compared with similar groups were selected. Several databases were searched in July 2023. Fourteen studies were included in the meta-analysis, with moderate effect sizes for anxiety and depression in group intervention modalities. Factors such as percentage of sample with lupus, gender, medication, and interventions with relaxation components influenced the results. Group psychological intervention programs are effective in reducing symptoms in patients with lupus, although further research on treatment modulating variables is needed. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, that mainly affects skin, joints and kidneys but can affect any organ in the body. It is characterized by presence of multiple autoantibodies like ANA, antibodies to dsDNA and RNA associated proteins. The major mechanism leading to tissue damage includes immune complex mediated complement activation, interferon alpha release by plasmacytoid dendritic cells, NETosis by neutrophils as well as defects in monocytes leading to poor clearance of cellular debris and direct cellular dysfunction mediated by antibodies. A child can present with pyrexia of unknown origin, immune mediated cytopenias, malar rash, oral ulcers, serositis, glomerulonephritis or nervous system dysfunction. As renal disease has a bearing on the long term impact, all children should have urine exam and blood pressure measurement done to rule out renal disease. The treatment varies depending on the severity and organs involved. In life or organ threatening situations, pulse methylprednisolone is used. Hydroxychloroquine, Mycophenolate mofetil, Azathioprine and Cyclophosphamide are the commonly used drugs in SLE. Over the years the prognosis of SLE has improved probably due to early diagnosis and better use of immunosuppressive treatment, regular follow up and treatment of co-morbidities. The 10-year survival now approaches 90% and with advent of new and targeted therapy it is hoped that the morbidity and organ damage can also be minimized. [ABSTRACT FROM AUTHOR]

Purpose of Review: Childhood-onset systemic lupus erythematosus (cSLE) is a severe and potentially life-threatening chronic autoimmune disease. cSLE is more aggressive and has poorer outcomes than adult-onset disease. The global burden of cSLE is poorly understood, with most publications on cSLE originating from high-resourced settings. The reports from less resourced settings indicate high morbidity and mortality in these populations. Recent Findings: In this article, we review the disparities in global access to rheumatology care and research for patients with cSLE. We highlight recent cSLE advances from all regions of the globe. We describe current obstacles to cSLE clinical care and research in all settings. Finally, we propose a path forward for high quality, equitable and accessible care to individuals with cSLE everywhere. Summary: Individuals with cSLE are at risk for morbidity and death, yet patients worldwide face challenges to adequate access to care and research. Sustained, collaborative efforts are needed to create pathways to improve care and outcomes for these patients. [ABSTRACT FROM AUTHOR]

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Introduction Systemic Lupus Erythematosus, an autoimmune disease, can target various organs of the human body. Lupus nephritis (LN) is a major complication affecting almost half of all SLE patients, with classes “III and IV” being the most aggressive. The severity and prognosis of LN can be influenced by different biomarkers, some of which are used as therapeutic targets. One such target is the B-cell activating factor (BAFF), a key figure in the pathophysiology of SLE. New add-on treatments have emerged in the treatment of LN targeting BAFF as well as other pathways. Assortment of patients to suitable treatment combinations needs more precision using guiding markers.Methods This prospective study aims to explore BAFF-expression in patients with active-proliferative LN and its possible association with the response after induction therapy. Peripheral blood mononuclear cells (PBMC) and renal tissue samples (if applicable) were collected from participants before the initiation of induction treatment. RNA was extracted, and the expression levels of BAFF-mRNA were measured using quantitative real-time polymerase chain reaction. Clinical and laboratory data, including disease activity indices and renal functions, were recorded at baseline and 6-months after the commencement of the induction treatment.Results The study included 24 patients,14 responders and 10 non-responders. At baseline, median PBMC BAFF-mRNA expression was nearly identical in responders and non-responders. Renal BAFF-expression was found to be higher in non-responders, although non-significant (p = 0.21). Contrary to PBMC BAFF expression, renal BAFF-mRNA was negatively correlated with baseline glomerular filtration rate and with the primary endpoint of response, which was reduction of proteinuria to≥50% of baseline (p = 0.07).Conclusions Renal BAFF expression could be a better representative of severity and therapeutic response than blood expression. We acknowledge that the use of BAFF expression as a predictive for early refractoriness to therapy in LN is not yet conclusive.

Abstract Background Systemic lupus erythematosus (SLE) is an autoimmune disease with protean manifestations. There is little understanding of why some organs are specifically impacted in patients and the mechanisms of disease persistence remain unclear. While much work has been done characterizing the DNA methylation status in SLE, there is less information on histone modifications, a more dynamic epigenetic feature. This study identifies two histone marks of activation and the binding of p300 genome-wide in three cell types and three clinical subsets to better understand cell-specific effects and differences across clinical subsets. Results We examined 20 patients with SLE and 8 controls and found that individual chromatin marks varied considerably across T cells, B cells, and monocytes. When pathways were examined, there was far more concordance with conservation of TNF, IL-2/STAT5, and KRAS pathways across multiple cell types and ChIP data sets. Patients with cutaneous lupus and lupus nephritis generally had less dramatically altered chromatin than the general SLE group. Signals also demonstrated significant overlap with GWAS signals in a manner that did not implicate one cell type more than the others. Conclusions The pathways identified by altered histone modifications and p300 binding are pathways known to be important from RNA expression studies and recognized pathogenic mechanisms of disease. NFκB and classical inflammatory pathways were strongly associated with increased peak heights across all cell types but were the highest-ranking pathway for all three antibodies in monocytes according to fgsea analysis. IL-6 Jak/STAT3 signaling was the most significant pathway association in T cells marked by H3K27ac change. Therefore, each cell type experiences the disease process distinctly although in all cases there was a strong theme of classical inflammatory pathways. Importantly, this NFκB pathway, so strongly implicated in the patients with generalized SLE, was much less impacted in monocytes when cutaneous lupus was compared to the general SLE cohort and also less impacted in lupus nephritis compared to general SLE. These studies define important cell type differences and emphasize the breadth of the inflammatory effects in SLE.

Abstract Although the role of low-density granulocytes (LDGs), neutrophils in the peripheral blood mononuclear cell (PBMC) fraction, and neutrophil extracellular traps (NETs) in assessing lupus disease severity is acknowledged, data specific to childhood-onset lupus remains scarce. This study analyzed 46 patients with childhood-onset systemic lupus erythematosus (82.6% females, mean age 14.5 ± 0.3 years), including 26 cases with normal complement levels and 20 with low complement levels, along with 20 healthy adult volunteers. Key parameters that distinguished healthy volunteers from lupus patients and differentiated between lupus patients with low and normal complement were serum interferon (IFN)-α, serum citrullinated histone 3 (CitH3), and extracellular traps (ETs) in LDGs. However, NETs (assessed by nuclear staining morphology), LDG abundance, and other parameters (such as endotoxemia, cytokines, and double-stranded (ds) DNA) did not show such differentiation. When lipopolysaccharide (LPS) was administered to LDGs in the PBMC fraction, it induced ETs in both low and normal complement groups, indicating the inducible nature of ETs. In adult healthy volunteers, activation by recombinant IFN-α or dsDNA in isolated neutrophils induced LDGs and NETs (identified using immunofluorescent staining for CitH3, myeloperoxidase, and neutrophil elastase) at 45 min and 3 h post-stimulation, respectively. Additionally, approximately half of the LDGs underwent late apoptosis at 3 h post-stimulation, as determined by flow cytometry analysis. Activation by IFN-α or dsDNA in LDGs also led to a more pronounced expression of CD66b, an adhesion molecule, compared to regular-density neutrophils, suggesting higher activity in LDGs. In conclusion, IFN-α and/or dsDNA in serum may transform regular-density neutrophils into LDGs before progressing to NETosis and apoptosis, potentially exacerbating lupus severity through cell death-induced self-antigens. Therefore, LDGs and ETs in LDGs could provide deeper insights into the pathophysiology of childhood-onset lupus.

Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide library for phage display immunoprecipitation and sequencing (PhIP-seq) in profiling mouse autoantibodies. This library was validated using 7 genetically distinct mouse lines across a spectrum of autoreactivity. Mice deficient in antibody production (Rag2-/- and μMT) were used to model nonspecific peptide enrichments, while cross-reactivity was evaluated using anti-ovalbumin B cell receptor-restricted OB1 mice as a proof of principle. The PhIP-seq approach was then utilized to interrogate 3 distinct autoimmune disease models. First, serum from Lyn-/- IgD+/- mice with lupus-like disease was used to identify nuclear and apoptotic bleb reactivities. Second, serum from nonobese diabetic (NOD) mice, a polygenic model of pancreas-specific autoimmunity, was enriched in peptides derived from both insulin and predicted pancreatic proteins. Lastly, Aire-/- mouse sera were used to identify numerous autoantigens, many of which were also observed in previous studies of humans with autoimmune polyendocrinopathy syndrome type 1 carrying recessive mutations in AIRE. These experiments support the use of murine proteome-wide PhIP-seq for antigenic profiling and autoantibody discovery, which may be employed to study a range of immune perturbations in mouse models of autoimmunity profiling.

BackgroundSystemic lupus erythematosus (SLE) patients are prone to frequent emergency department (ED) visits. This study explores the epidemiology and outcomes of ED visits by patients with SLE utilizing the Nationwide Emergency Department Sample (NEDS).MethodsUsing NEDS (2019), SLE ED visits identified using ICD-10 codes (M32. xx) were compared with non-SLE ED visits in terms of demographic and clinical features and primary diagnoses associated with the ED visits. Factors associated with inpatient admission were analyzed using logistic regression. Variations in ED visits by age and race were assessed.ResultsWe identified 414,139 (0.35%) ED visits for adults ≥ 18 years with SLE. ED visits with SLE comprised more women, Black patients, ages 31-50 years, Medicare as the primary payer, and had higher comorbidity burden. A greater proportion of Black and Hispanic SLE patients who visited the ED were in the youngest age category of 18-30 years (around 20%) compared to White patients (less than 10%). Non-White patients had higher Medicaid utilization (27%-32% vs 19% in White patients). Comorbidity patterns varied based on race, with more White patients having higher rates of hyperlipidemia and ischemic heart disease (IHD) and more Black patients having chronic kidney disease (CKD), hypertension, and heart failure. Categorizing by race, SLE/connective tissue disease (CTD) and infection were the most prevalent primary ED diagnosis in non-White and White patients, respectively. Age ≥ 65 years, male sex, and comorbidities were linked to a higher risk of admission. Black race (OR 0.86, p = .01) and lowest income quartile (OR 0.78, p = .003) had lower odds of inpatient admission.ConclusionInfection and SLE/CTD were among the top diagnoses associated with ED visits and inpatient admission. Despite comprising a significant proportion of SLE ED visits, Black patients had lower odds of admission. While the higher prevalence of older age groups, hyperlipidemia, and IHD among White patients may partly explain the disparate results, and further study is needed to understand the role of other factors including reliance on the ED for routine care compared among Black patients, differences in insurance coverage, and potential socioeconomic biases among healthcare providers.

ObjectiveWe aimed to develop readily measurable digital quality measure statements for clinical care in systemic lupus erythematosus (SLE) using a multistep process guided by consensus methods.MethodsUsing a modified Delphi process, an American College of Rheumatology (ACR) workgroup of SLE experts reviewed all North American and European guidelines from 2000 to 2020 on treatment, monitoring, and phenotyping of patients with lupus. Workgroup members extracted quality constructs from guidelines, rated these by importance and feasibility, and generated evidence-based quality measure statements. The ACR Rheumatology Informatics System for Effectiveness (RISE) Registry was queried for measurement data availability. In 3 consecutive Delphi sessions, a multidisciplinary Delphi panel voted on the importance and feasibility of each statement. Proposed measures with consensus on feasibility and importance were ranked to identify the top 3 measures.ResultsReview of guidelines and distillation of 57 quality constructs resulted in 15 quality measure statements. Among these, 5 met high consensus for importance and feasibility, including 2 on treatment and 3 on laboratory monitoring measures. The 3 highest-ranked statements were recommended for further measure specification as SLE digital quality measures: 1) hydroxychloroquine use, 2) limiting glucocorticoid use >7.5 mg/day to

Disseminated histoplasmosis is a rare yet serious fungal infection that primarily affects individuals with compromised immune systems. While it is widely known for its endemicity in the Midwest region of the USA, recent studies have indicated a noteworthy increase in sporadic cases, suggesting a widening of the endemic region for the pathology. This report describes a case of disseminated histoplasmosis in a 39-year-old female with a history of lupus, hypertension, anxiety, asthma, idiopathic edema, and fibromyalgia from a nonendemic region, who presented with cyclic fevers of unknown origin, peripheral edema, and oral sores. On admission, she was diagnosed with acute pyelonephritis and started on levofloxacin. She continued to develop worsening leukopenia and thrombocytopenia in addition to bone and joint pain. Bone marrow biopsy results were consistent with hemophagocytic lymphohistiocytosis (HLH) triggered by histoplasmosis confirmed by PCR. Despite an initial negative urine antigen test for Histoplasma, subsequent tests showed rising levels. The patient's clinical course was marked by a protracted hospital stay, multiple systems involvement, severe de-conditioning, drug side effects requiring adjustments in anti-fungal medications, and interdisciplinary care. The patient gradually improved and was discharged home with follow-ups. This study underscores the role of timely diagnosis of disseminated histoplasmosis in patients with underlying autoimmune diseases for favorable outcomes, thereby emphasizing the necessity of heightened clinical suspicion. By addressing the nuanced challenges that arise in managing multiple complications in the domain of disseminated histoplasmosis, advocates a comprehensive interdisciplinary approach to optimize patient care.

Abstract Background Rituximab (RTX) has been utilised off‐label for a variety of dermatological indications beyond pemphigus vulgaris. Efficacy has been reported in other immunobullous disorders, inflammatory dermatoses and connective tissue diseases. Objectives To assess the off‐label use of RTX in our centre with respect to indications, frequency and duration of treatment, efficacy, and adverse events. Methods Charts were retrospectively reviewed for all patients who received dermatologist‐prescribed RTX infusions off‐label at our centre between 2009 and 2022. Efficacy was categorised based on reported percentage reduction of disease activity: very good (75%–100%), good (50%–74%), partial (25%–49%) and none (0%–24%). Results Twenty‐nine patients received RTX off‐label during this time period. Infusions were discontinued in 28% (n = 8), due to insufficient clinical response. Median treatment duration for those on 6‐12‐monthly regular infusions was 2.4 years (range 0.5–11 years). Indications included cutaneous lupus (n = 9), mucous membrane pemphigoid (n = 5), pyoderma gangrenosum (n = 6), lichen planus (n = 2), dermatomyositis (n = 1), livedoid vasculitis (n = 1), sarcoidosis (n = 1), bullous pemphigoid (n = 1), pemphigus vulgaris, foliaceus and vegetans (n = 1 each). Clinical improvement was documented in 79% (n = 23); very good in 48% (n = 14), good in 17% (n = 5), and moderate in 14% (n = 4). Clinical efficacy in immunobullous disorders was 100% (9/9), 67% in cutaneous lupus (6/9), 33% in pyoderma gangrenosum (2/6), and 50% in lichen planus (1/2). No side effects were documented for 79% (n = 23). Adverse peri‐infusion events were seen in three patients (10%). Four patients died during follow up; one due to neutropenic sepsis with a background of advanced malignancy, and three due to Covid‐19. Conclusions RTX was prescribed for multiple off‐label dermatological indications, often for recalcitrant disease. Responses were good overall, with a reassuring safety profile. Three patients died of Covid‐19; knowledge of the impact of RTX on the immune response and efficacy of vaccines is expanding and will continue to inform guidelines for RTX use in the post‐Covid era.

Introduction The aim of this study was to investigate the effects of ujjayi pranayama on non-lethal problems and cardiorespiratory functions in women with systemic lupus erythematosus (SLE). Methods This randomized controlled trial involved a home-based training of ujjayi pranayama for 6 weeks. Forty SLE women were randomly assigned to either the ujjayi-pranayama group ( n = 20), who performed 30 min of ujjayi pranayama daily (15 min in the morning and evening), or the waitlist control group ( n = 20). Various measures, including State-Trait Anxiety Inventory (STAI), cortisol, Stress Vulnerability Scale (SVS), Beck Depression Inventory II (BDI-II), Fatigue Severity Scale (FSS), Pittsburgh Sleep Quality Index (PSQI), pulse rate (Pul-r), respiratory rate (Res-r), systolic blood pressure (SBPr), and diastolic blood pressure (DBPr) were assessed. Results Significant reductions were observed via paired tests in Pul-r (75.95 ± 3.63 vs 72.95 ± 3.17; p < 0.001), Res-r (16.70 ± 3.62 vs 14.80 ± 2.94; p < 0.001), SBPr (126.60 ± 4.75 vs 121.30 ± 4.30; p < 0.001), DBPr (82.15 ± 3.57 vs 78.05 ± 3.44; p < 0.001), PSQI (7.45 ± 1.27 vs 5.10 ± 1.20; p < 0.001), FSS (4.80 ± 1 vs 3.75 ± 1.11; p < 0.001), BDI-II (13.70 ± 2.77 vs 6.80 ± 1.50; p < 0.001), STAI (66.70 ± 4.72 vs 47.55 ± 6.15; p < 0.001), cortisol (8.51 ± 1.36 vs 6.34 ± 1.36; p < 0.001), and SVS (12.65 ± 1.78 vs 6.45 ± 1.57; p < 0.001) in the ujjayi pranayama group only. Conclusions Ujjayi pranayama significantly improved non-lethal problems and cardiorespiratory functions in women with lupus.

Abstract Systemic lupus erythematosus (SLE) is a multifactorial disease characterized by the convergence of genetic, immunological, and viral elements resulting in a complex interaction of both internal and external factors. The role of the Epstein-Barr virus (EBV) and human endogenous retroviruses (HERV-E) as triggers and maintenance elements in the pathogenesis of SLE has been widely recognized. Previous studies have independently evaluated the effects of EBV and HERV-E in this disease. In this work, for the first time, these viral factors are jointly investigated in SLE patients. This study aimed at assessing the differential expression of immune regulatory genes and the incidence of specific viral pathogens (EBV and HERV-E), alongside the detailed characterization of surface markers in T- and B-lymphocytes in patients with SLE and control participants. A comparative analysis between patients with SLE and control participants was performed, evaluating the expression of phenotypic markers and genes involved in the immune response (TNF-α, IL-2, IL-6, IL-10, IFNG, TLR3), as well as HERV-E gag and EBV viral genes (LMP1 and BZLF1).A significant association between SLE and EBV was found in this study. A notable increase in EBV LMP1 gene expression was observed in patients with SLE . Also, a significant overexpression of HERV-E was observed, in addition to a considerable increase in the distribution of the cell surface marker CD27 + on T- and B-lymphocytes, observed in individuals with SLE compared to the control group. This study provides evidence regarding the role that EBV virus plays in lymphocytes in the context of SLE, highlighting how both the virus and the host gene expression may influence disease pathogenesis by altering immune regulatory pathways mediated by TNF-α, IFN-γ, and IL-10, as well as parallel overexpression of HERV-E gag. The decrease in TLR3 could indicate a compromised antiviral response, which could facilitate viral reactivation and contribute to disease activity.