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Abstract Background The Manhattan Lupus Surveillance Program (MLSP), a population-based retrospective registry of patients with systemic lupus erythematosus (SLE), was used to investigate the prevalence of cardiovascular disease events (CVE) and compare rates among sex, age and race/ethnicity to population-based controls. Methods Patients with prevalent SLE in 2007 aged ≥ 20 years in the MLSP were included. CVE required documentation of a myocardial infarction or cerebrovascular accident. We calculated crude risk ratios and adjusted risk ratios (ARR) controlling for sex, age group, race and ethnicity, and years since diagnosis. Data from the 2009–2010 National Health and Nutrition Examination Survey (NHANES) and the 2013–2014 NYC Health and Nutrition Examination Survey (NYC HANES) were used to calculate expected CVE prevalence by multiplying NHANES and NYC HANES estimates by strata-specific counts of patients with SLE. Crude prevalence ratios (PRs) using national and NYC estimates and age standardized prevalence ratios (ASPRs) using national estimates were calculated. Results CVE occurred in 13.9% of 1,285 MLSP patients with SLE, and risk was increased among men (ARR:1.7, 95%CI:1.2–2.5) and older adults (age > 60 ARR:2.5, 95%CI:1.7–3.8). Compared with non-Hispanic Asian patients, CVE risk was elevated among Hispanic/Latino (ARR:3.1, 95%CI:1.4-7.0) and non-Hispanic Black (ARR:3.5, 95%CI1.6-7.9) patients as well as those identified as non-Hispanic and in another or multiple racial groups (ARR:4.2, 95%CI:1.1–15.8). Overall, CVE prevalence was higher among patients with SLE than nationally (ASPR:3.1, 95%CI:3.0-3.1) but did not differ by sex. Compared with national race and ethnicity-stratified estimates, CVE among patients with SLE was highest among Hispanics/Latinos (ASPR:4.3, 95%CI:4.2–4.4). CVE was also elevated among SLE registry patients compared with all NYC residents. Comparisons with age-stratified national estimates revealed PRs of 6.4 (95%CI:6.2–6.5) among patients aged 20–49 years and 2.2 (95%CI:2.1–2.2) among those ≥ 50 years. Male (11.3, 95%CI:10.5–12.1), Hispanic/Latino (10.9, 95%CI:10.5–11.4) and non-Hispanic Black (6.2, 95%CI:6.0-6.4) SLE patients aged 20–49 had the highest CVE prevalence ratios. Conclusions These population-based estimates of CVE in a diverse registry of patients with SLE revealed increased rates among younger male, Hispanic/Latino and non-Hispanic Black patients. These findings reinforce the need to appropriately screen for CVD among all SLE patients but particularly among these high-risk patients.

IntroductionApproximately 20-40% of patients with systemic lupus erythematosus (SLE) experience neuropsychiatric SLE (NPSLE), which often manifests as cognitive dysfunction and depression. Currently, there are no approved treatments for NPSLE because its underlying mechanisms are unclear. Identifying relevant mediators and understanding their contribution to pathogenesis are crucial for developing targeted treatment options. Lipocalin 2 (LCN2) is a multifunctional acute-phase protein that plays important roles in immune cell differentiation, migration, and function. LCN2 has been implicated in models of neuroinflammatory disease.MethodsWe generated an LCN2-deficient MRL/lpr mouse to evaluate the effects of LCN2 on this classic NPSLE model. To evaluate the effects of LCN2 deficiency on behavior, the mice underwent a battery of behavioral tests evaluating depression, memory, and anxiety. Flow cytometry was used to quantify immune cell populations in the brain, blood, and secondary lymphoid organs. Cutaneous disease was quantified by scoring lesional skin, and skin infiltrates were quantified through immunofluorescent staining. Systemic disease was evaluated through measuring anti-nuclear antibodies by ELISA.ResultsIn this study, we found that LCN2 deficiency significantly attenuates neuropsychiatric and cutaneous disease in MRL/lpr lupus prone mice, likely by decreasing local infiltration of immune cells into the brain and skin and reducing astrocyte activation in the hippocampus. Anti-nuclear antibodies and kidney disease were not affected by LCN2.DiscussionAs there was no effect on systemic disease, our results suggest that the inflammatory effects of LCN2 were localized to the skin and brain in this model. This study further establishes LCN2 as a potential target to ameliorate organ injury in SLE, including neuropsychiatric and cutaneous disease.

Abstract Background Neuropsychiatric lupus (NPSLE) describes the cognitive, memory, and affective emotional burdens faced by many lupus patients. While NPSLE’s pathogenesis has not been fully elucidated, clinical imaging studies and cerebrospinal fluid (CSF) findings, namely elevated interleukin-6 (IL-6) levels, point to ongoing neuroinflammation in affected patients. Not only linked to systemic autoimmunity, IL-6 can also activate neurotoxic glial cells the brain. A prior pre-clinical study demonstrated that IL-6 can acutely induce a loss of sucrose preference; the present study sought to assess the necessity of chronic IL-6 exposure in the NPSLE-like disease of MRL/lpr lupus mice. Methods We quantified 1308 proteins in individual serum or pooled CSF samples from MRL/lpr and control MRL/mpj mice using protein microarrays. Serum IL-6 levels were plotted against characteristic NPSLE neurobehavioral deficits. Next, IL-6 knockout MRL/lpr (IL-6 KO; n = 15) and IL-6 wildtype MRL/lpr mice (IL-6 WT; n = 15) underwent behavioral testing, focusing on murine correlates of learning and memory deficits, depression, and anxiety. Using qPCR, we quantified the expression of inflammatory genes in the cortex and hippocampus of MRL/lpr IL-6 KO and WT mice. Immunofluorescent staining was performed to quantify numbers of microglia (Iba1 +) and astrocytes (GFAP +) in multiple cortical regions, the hippocampus, and the amygdala. Results MRL/lpr CSF analyses revealed increases in IL-17, MCP-1, TNF-α, and IL-6 (a priori p-value

AbstractSystemic lupus erythematosus (SLE) poses formidable challenges due to its multifaceted etiology while impacting multiple tissues and organs and displaying diverse clinical manifestations. Genetic and environmental factors contribute to SLE complexity, with relatively limited approved therapeutic options. Murine models offer insights into SLE pathogenesis but do not always replicate the nuances of human disease. This review critically evaluates spontaneous and induced animal models, emphasizing their validity and relevance to neuropsychiatric SLE (NPSLE). While these models undoubtedly contribute to understanding disease pathophysiology, discrepancies persist in mimicking some NPSLE intricacies. The lack of literature addressing this issue impedes therapeutic progress. We underscore the urgent need for refining models that truly reflect NPSLE complexities to enhance translational fidelity. We encourage a comprehensive, creative translational approach for targeted SLE interventions, balancing scientific progress with ethical considerations to eventually improve the management of NPSLE patients. A thorough grasp of these issues informs researchers in designing experiments, interpreting results, and exploring alternatives to advance NPSLE research.

Abstract Background Leveraging the Accelerating Medicines Partnership (AMP) Lupus Nephritis (LN) dataset, we evaluated longitudinal patterns, rates, and predictors of response to standard-of-care therapy in patients with lupus nephritis. Methods Patients from US academic medical centers with class III, IV, and/or V LN and a baseline urine protein/creatinine (UPCR) ratio ≥ 1.0 (n = 180) were eligible for this analysis. Complete response (CR) required the following: (1) UPCR 50% reduction in UPCR; (2) normal serum creatinine or, if abnormal, ≤ 125% of baseline; and (3) prednisone dose ≤ 15 mg/day. Results Response rates to the standard of care at week 52 were CR = 22.2%; PR = 21.7%; non-responder (NR) = 41.7%, and not determined (ND) = 14.4%. Only 8/180 (4.4%) patients had a week 12 CR sustained through week 52. Eighteen (10%) patients attained a week 12 PR or CR and sustained their responses through week 52 and 47 (26.1%) patients achieved sustained PR or CR at weeks 26 and 52. Week 52 CR or PR attainment was associated with baseline UPCR > 3 (ORadj = 3.71 [95%CI = 1.34–10.24]; p = 0.012), > 25% decrease in UPCR from baseline to week 12 (ORadj = 2.61 [95%CI = 1.07–6.41]; p = 0.036), lower chronicity index (ORadj = 1.33 per unit decrease [95%CI = 1.10–1.62]; p = 0.003), and positive anti-dsDNA antibody (ORadj = 2.61 [95%CI = 0.93–7.33]; p = 0.069). Conclusions CR and PR rates at week 52 were consistent with the standard-of-care response rates observed in prospective registrational LN trials. Low sustained response rates underscore the need for more efficacious therapies and highlight how critically important it is to understand the molecular pathways associated with response and non-response.

ObjectiveLeveraging the Manhattan Lupus Surveillance Program (MLSP), a population-based registry of cases of systemic lupus erythematosus (SLE) and related diseases, we investigated the proportion of SLE with concomitant rheumatic diseases, including Sjögren’s disease (SjD), antiphospholipid syndrome (APLS), and fibromyalgia (FM), as well as the prevalence of autoantibodies in SLE by sex and race/ethnicity.MethodsPrevalent SLE cases fulfilled one of three sets of classification criteria. Additional rheumatic diseases were defined using modified criteria based on data available in the MLSP: SjD (anti-SSA/Ro positive and evidence of keratoconjunctivitis sicca and/or xerostomia), APLS (antiphospholipid antibody positive and evidence of a blood clot), and FM (diagnosis in the chart).Results1,342 patients fulfilled SLE classification criteria. Of these, SjD was identified in 147 (11.0%, 95% CI 9.2–12.7%) patients with women and non-Latino Asian patients being the most highly represented. APLS was diagnosed in 119 (8.9%, 95% CI 7.3–10.5%) patients with the highest frequency in Latino patients. FM was present in 120 (8.9%, 95% CI 7.3–10.5) patients with non-Latino White and Latino patients having the highest frequency. Anti-dsDNA antibodies were most prevalent in non-Latino Asian, Black, and Latino patients while anti-Sm antibodies showed the highest proportion in non-Latino Black and Asian patients. Anti-SSA/Ro and anti-SSB/La antibodies were most prevalent in non-Latino Asian patients and least prevalent in non-Latino White patients. Men were more likely to be anti-Sm positive.ConclusionData from the MLSP revealed differences among patients classified as SLE in the prevalence of concomitant rheumatic diseases and autoantibody profiles by sex and race/ethnicity underscoring comorbidities associated with SLE.

3-hydroxy-L-kynurenamine (3-HKA) is a metabolite deriving from a lateral pathway of tryptophan catabolism. Here the authors identify 3-HKA as a biogenic amine and show it has anti-inflammatory properties that can protect mice against psoriasis and nephrotoxic nephritis.

Objective To evaluate the usefulness of biomarkers to predict the evolution of patients suspected of systemic lupus erythematosus (SLE), designated as probable SLE (pSLE), into classifiable SLE according to the American College of Rheumatology (ACR) classification criteria. Methods Patients suspected of SLE were enrolled by lupus experts if they fulfilled three ACR criteria for SLE and were followed for approximately 1‐3 years to evaluate transition into ACR‐classifiable SLE. Individual cell‐bound complement activation products (CB‐CAPs), serum complement proteins (C3 and C4), and autoantibodies were measured by flow cytometry, turbidimetry, and enzyme‐linked immunosorbent assay, respectively. Blood levels of hydroxychloroquine (HCQ) were measured by mass spectrometry. A multianalyte assay panel (MAP), which includes CB‐CAPs, was also evaluated. A MAP of greater than 0.8 reflected the optimal cutoff for transition to SLE. Time to fulfillment of ACR criteria was evaluated by Kaplan‐Meier analysis and Cox proportional hazards model. Results Of the 92 patients with pSLE enrolled, 74 had one or two follow‐up visits 9‐35 months after enrollment for a total of 128 follow‐up visits. Overall, 28 patients with pSLE (30.4%) transitioned to ACR‐classifiable SLE, including 16 (57%) in the first year and 12 (43%) afterwards. A MAP score of greater than 0.8 at enrollment predicted transition to classifiable SLE during the follow‐up period (hazard ratio = 2.72; P = 0.012), whereas individual biomarkers or fulfillment of Systemic Lupus International Collaborating Clinics criteria did not. HCQ therapy was not associated with the prevention of transition to SLE. Conclusion Approximately one‐third of patients with pSLE transitioned within the study period. MAP of greater than 0.8 predicted disease evolution into classifiable SLE.

Abstract Background The immune system undergoes a myriad of changes with age. While it is known that antibody-secreting plasma and long-lived memory B cells change with age, it remains unclear how the binding profile of the circulating antibody repertoire is impacted. Results To understand humoral immunity changes with respect to age, we characterized serum antibody binding to high density peptide microarrays in a diverse cohort of 1675 donors. We discovered thousands of peptides that bind antibodies in age-dependent fashion, many of which contain di-serine motifs. Peptide binding profiles were aggregated into an “immune age” by a machine learning regression model that was highly correlated with chronological age. Applying this regression model to previously-unobserved donors, we found that a donor’s predicted immune age is longitudinally consistent over years, suggesting it could be a robust long-term biomarker of humoral immune ageing. Finally, we assayed serum from donors with autoimmune disease and found a significant association between “accelerated immune ageing” and autoimmune disease activity. Conclusions The circulating antibody repertoire has increased binding to thousands of di-serine peptide containing peptides in older donors, which can be represented as an immune age. Increased immune age is associated with autoimmune disease, acute inflammatory disease severity, and may be a broadly relevant biomarker of immune function in health, disease, and therapeutic intervention.

Developing noninvasive diagnostic biomarkers for lupus nephritis (LN) diagnosis is an important clinical goal. Here the authors identify urinary proteins correlated with active LN and disease severity, which differ across ethnicities but collectively outperform the current clinical method.

Abstract For people with chronic autoimmune rheumatic diseases (AIRD), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or systemic sclerosis (SSc), normal cognitive functions are essential for performing daily activities. These diseases may be associated with cognitive dysfunction (CD). In RA, CD has been associated with age, lower education and disease duration and activity. Great advances have been achieved in neuropsychiatric SLE in the identification of pathogenic pathways, assessment and possible treatment strategies. SSc rarely exerts direct effects on the brain and cognitive function. However, the psychological burden that includes depression, anxiety and social impact may be high. AIRD patients with sustained disease activity, organ damage or lower education should be evaluated for CD. The control of systemic inflammation together with tailored behavioural cognitive therapies may benefit these patients.

T cells are central to the pathogenesis of lupus nephritis (LN), a common complication of systemic lupus erythematosus (SLE). CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM), are involved in T cell activation and trafficking. Previously, we showed that soluble ALCAM is increased in urine (uALCAM) of patients with LN, suggesting that this pathway contributes to disease. To investigate, uALCAM was examined in 1038 patients with SLE and LN from 5 ethnically diverse cohorts; CD6 and ALCAM expression was assessed in LN kidney cells; and disease contribution was tested via antibody blockade of CD6 in murine models of SLE and acute glomerulonephritis. Extended cohort analysis offered resounding validation of uALCAM as a biomarker that distinguishes active renal involvement in SLE, irrespective of ethnicity. ALCAM was expressed by renal structural cells whereas CD6 expression was exclusive to T cells, with elevated numbers of CD6+ and ALCAM+ cells in patients with LN. CD6 blockade in models of spontaneous lupus and immune-complex glomerulonephritis revealed significant decreases in immune cells, inflammatory markers, and disease measures. Our data demonstrate the contribution of the CD6/ALCAM pathway to LN and SLE, supporting its use as a disease biomarker and therapeutic target.

Neuropsychiatric lupus (NPSLE), the nervous system presentation of systemic lupus erythematosus (SLE), remains challenging to treat due to its unclear pathogenesis and lack of available targeted therapies. A potential contributor to disease progression is brain tertiary lymphoid structures (TLS); these ectopic lymphoid follicles that can develop tissue-targeted antibodies have recently been described in the MRL/lpr lupus mouse strain, a classic model for studying NPSLE. The brains of MRL/lpr mice show a significant increase of CXCL13, an important chemokine in lymphoid follicle formation and retention that may also play a role in the disease progression of NPSLE. The aim of the present study was to inhibit CXCL13 and examine the effect of this intervention on lymphoid formation and the development of neurobehavioral manifestations in lupus mice. Female MRL/lpr mice were injected with an anti-CXCL13 antibody, an IgG1 isotype-matched antibody, or PBS either three times a week for 12 weeks intraperitoneally (IP) starting at 6-8 weeks of age, or continuously intracerebroventricularly (ICV) with an osmotic pump over a two-week period starting at 15 weeks of age. Cognitive dysfunction and depression-like behavior were assessed at the end of treatment. When treatment was delivered IP, anti-CXCL13 treated mice showed significant improvement in cognitive function when compared to control treated mice. Depression-like behavior was attenuated as well. Furthermore, mice that received anti-CXCL13 by the ICV route showed similar beneficial effects. However, the extent of lymphocyte infiltration into the brain and the general composition of the aggregates were not substantively changed by anti-CXCL13 irrespective of the mode of administration. Nevertheless, analysis of brain gene expression in anti-CXCL13 treated mice showed significant differences in key immunological and neuro-inflammatory pathways that most likely explained the improvement in the behavioral phenotype. Our results indicate that CXCL13 affects the behavioral manifestations in the MRL/lpr strain and is important to the pathogenesis of murine NPSLE, suggesting it as a potential therapeutic target.

Objectives In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis.Methods 475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines.Results 34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved.Conclusions Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required.

Engagement of Fcγ receptor IIb (FcγRIIb) suppresses B cell activation and represents a promising target for therapy in autoimmunity. Obexelimab is a non-depleting anti-human CD19 mAb with an Fc region engineered to have high affinity for human FcγRIIb, thereby co-engaging BCR and FcγRIIb. To assess its ability to suppress B cell activation in vivo, we generated non-autoimmune-prone C57BL/6 (B6) and SLE-prone NZM 2328 (NZM) mice in which the human FcγRIIb extracellular domain was knocked into the mouse Fcgr2b locus (B6.hRIIb and NZM.hRIIb mice, respectively, the latter retaining features of SLE). XENP8206, a mAb which bears the same FcγRIIb-enhanced human Fc domain as does obexelimab but which recognizes murine CD19 rather than human CD19, inhibited in vitro BCR-triggered activation of B cells from both B6.hRIIb and NZM.hRIIb mice. Following administration of XENP8206 to B6.hRIIb or NZM.hRIIb mice, B cell numbers in the spleen and lymph nodes remained stable but became hyporesponsive to BCR-triggered activation for at least 14 days. These findings demonstrate proof-of-principle that pharmacologic co-engagement of BCR and human FcγRIIb inhibits B cell activation in non-autoimmune and SLE-prone hosts while preserving B cell numbers. These observations lay a strong foundation for clinical trials in human SLE with agents that co-engage BCR and FcγRIIb. Moreover, B6.hRIIb and NZM.hRIIb should serve as powerful in vivo models in the elucidation of the cellular and molecular underpinnings of the changes induced by BCR/FcγRIIb co-engagement.

Objectives To evaluate the association between lupus severity and cell-bound complement activation products (CB-CAPs) or low complement proteins C3 and C4.Methods All subjects (n=495) fulfilled the American College of Rheumatology (ACR) classification criteria for SLE. Abnormal CB-CAPs (erythrocyte-bound C4d or B-lymphocyte-bound C4d levels >99th percentile of healthy) and complement proteins C3 and C4 were determined using flow cytometry and turbidimetry, respectively. Lupus severity was estimated using the Lupus Severity Index (LSI). Statistical analysis consisted of multivariable linear regression and groups comparisons.Results Abnormal CB-CAPs were more prevalent than low complement values irrespective of LSI levels (62% vs 38%, respectively, p

Objective: In systemic lupus erythematosus (SLE), widespread T cell infiltration into target organs contributes to inflammation and organ damage. Autoreactive T cells become aberrantly activated in this disease due to dysfunctional T cell receptor signaling that lowers the activation threshold. Characterizing the T cell repertoire can provide further insight into the specific homing and proliferation of these T cells into lupus target organs. In the spontaneous lupus model, MRL/lpr, the TCR repertoire has not been fully elucidated, especially for T cells infiltrating the brain. Our aim was to investigate and compare the TCR repertoire between MRL/lpr mice and its congenic controls, MRL/MpJ, and within MRL/lpr tissues.Methods: Spleen, salivary gland, and brain choroid plexus were isolated from female MRL/lpr mice and MRL/MpJ mice. The TCRβ CDR3 region was analyzed by multiplex PCRs and sequencing.Results: Significant differences were seen not only between the MRL/lpr and MRL/MpJ spleens, but also between MRL/lpr tissues. The TCR repertoire in MRL/lpr choroid plexus tissues had significantly increased clonality and sequence homology compared to MRL/lpr spleen and salivary gland. The consensus sequence, CASSQDWGGYEQYFF, was identified in the MRL/lpr choroid plexus repertoire.Conclusions: The TCR repertoire in lupus prone mice is not uniform between target organs, and suggests that T cells are specifically recruited into the choroid plexus of MRL/lpr mice. Further studies are needed to determine the antigen specificities for these infiltrating T cells in target organs of lupus mice, and their possible contribution to the pathogenesis of neuropsychiatric disease and other lupus manifestations.

Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) affect over one-half of SLE patients, yet underlying mechanisms remain largely unknown. We demonstrate that SLE-prone mice (CReCOM) develop NP-SLE, including behavioral deficits prior to systemic autoimmunity, reduced brain volumes, decreased vascular integrity, and brain-infiltrating leukocytes. NP-SLE microglia exhibit numerical expansion, increased synaptic uptake, and a more metabolically active phenotype. Microglia from multiple SLE-prone models express a “NP-SLE signature” unrelated to type I interferon. Rather, the signature is associated with lipid metabolism, scavenger receptor activity and downregulation of inflammatory and chemotaxis processes, suggesting a more regulatory, anti-inflammatory profile. NP-SLE microglia also express genes associated with disease-associated microglia (DAM), a subset of microglia thought to be instrumental in neurodegenerative diseases. Further, expression of “NP-SLE” and “DAM” signatures correlate with the severity of behavioral deficits in young SLE-prone mice prior to overt systemic disease. Our data are the first to demonstrate the predictive value of our newly identified microglia-specific “NP-SLE” and “DAM” signatures as a surrogate for NP-SLE clinical outcomes and suggests that microglia-intrinsic defects precede contributions from systemic SLE for neuropsychiatric manifestations.

Cognitive impairment is frequently reported among anti-phospholipid syndrome (APS) patients as well as anti-phospholipid antibody (aPL) carriers, but it is less studied than other manifestations of this condition. Moreover, the exact prevalence of cognitive impairment in these patients has not been accurately determined, mainly due to inconsistency in the tools used to identify impairment, small sample sizes, and variability in the anti-phospholipid antibodies measured and positivity cutoffs. The notion of a direct pathogenic effect is supported by the observation that the higher the number of aPLs present and the higher the load of the specific antibody, the greater the risk of cognitive impairment. There is some evidence to suggest that besides the thrombotic process, inflammation-related pathways play a role in the pathogenesis of cognitive impairment in APS. The cornerstone treatments of APS are anti-coagulant and anti-thrombotic medications. These treatments have shown some favorable effects in reversing cognitive impairment, but solid evidence for the efficacy and safety of these treatments in the context of cognitive impairment is still lacking. In this article, we review the current knowledge regarding the epidemiology, pathophysiology, clinical associations, and treatment of cognitive impairment associated with APS and aPL positivity.

Abstract Background Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects different end organs, including skin and brain. We and others have previously shown the importance of macrophages in the pathogenesis of cutaneous and neuropsychiatric lupus. Additionally, autoantibodies produced by autoreactive B cells are thought to play a role in both the skin and central nervous system pathologies associated with SLE. Methods We used a novel inhibitor of Bruton’s tyrosine kinase (BTK), BI-BTK-1, to target both macrophage and B cell function in the MRL-lpr/lpr murine model of SLE, and examined the effect of treatment on skin and brain disease. Results We found that treatment with BI-BTK-1 significantly attenuated the lupus associated cutaneous and neuropsychiatric disease phenotypes in MRL/lpr mice. Specifically, BI-BTK-1 treated mice had fewer macroscopic and microscopic skin lesions, reduced cutaneous cellular infiltration, and diminished inflammatory cytokine expression compared to control mice. BTK inhibition also significantly improved cognitive function, and decreased accumulation of T cells, B cells, and macrophages within the central nervous system, specifically the choroid plexus. Conclusions Directed therapies may improve the response rate in lupus-driven target organ involvement, and decrease the dangerous side effects associated with global immunosuppression. Overall, our results suggest that inhibition of BTK may be a promising therapeutic option for cutaneous and neuropsychiatric disease associated with SLE.

To date, the treatment of immune-mediated kidney diseases has only marginally benefited from highly specific biological drugs that have demonstrated remarkable effects in many other diseases. What accounts for this disparity? In April 2016, the International Society of Nephrology held a Nexus meeting on Translational Immunology in Nephrology in Berlin, Germany, to identify and discuss hurdles that block the translational flow of target identification, and preclinical and clinical target validation in the domain of immune-mediated kidney disease. A broad panel of experts including basic scientists, translational researchers, clinical trialists, pharmaceutical industry drug developers, and representatives of the American and European regulatory authorities made recommendations on how to overcome such hurdles at all levels of the translational research process. The results of these discussions are presented here, which may serve as a roadmap for how to optimize the process of developing more innovative and effective drugs for patients with immune-mediated kidney diseases.

OBJECTIVES/GOALS: Tubulointerstitial damage in lupus nephritis (LN) is a strong predictor of progression to chronic kidney disease and end stage renal disease (ESRD). While complement activation mediates glomerular injury, the role of complement in renal tubular damage has not been evaluated. We investigated the association between complement activation and tubulointerstitial fibrosis. METHODS/STUDY POPULATION: Patients with LN were selected randomly between July 2014 - July 2016. Chromogenic immunohistochemistry was performed on formalin-fixed, paraffin-embedded, 4-µm human renal biopsy sections using unconjugated, murine anti-human Complement C9 (Hycult Biotech, clone X197) as a marker of the terminal complement activation. Positive control is C3 glomerulopathy and negative control is normal kidney. Tubular basement membrane C9 staining intensity were analyzed on semiquantitative scale 0 to 3 by a renal pathologist. Interstitial fibrosis/tubular atrophy were categorized into low (0–10%), medium (11–20%), or high (≥21%). Clinical parameters were assessed at time of biopsy and 6 months post biopsy. Bivariate associations were assessed between presence of tubular C9 (C9+) and other covariates. RESULTS/ANTICIPATED RESULTS: Renal biopsies from 30 LN studied, 23 (77%) of which had proliferative LN. There were 24 (80%) women, mean (SD) age 33 (12) years. Positive tubular C9 staining was observed in 7/30 (23%) biopsies. At time of renal biopsy, C9+ patients had significantly higher urine protein, compared to C9- patients: median (IQR) 6.2g (3.3-13.1) vs. 2.4g (1.3-4.6), p

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About 40% of patients with systemic lupus erythematosus experience diffuse neuropsychiatric manifestations, including impaired cognition and depression. Although the pathogenesis of diffuse neuropsychiatric SLE (NPSLE) is not fully understood, loss of brain barrier integrity, autoreactive antibodies, and pro-inflammatory cytokines are major contributors to disease development. Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, prevents lymphocyte egress from lymphoid organs through functional antagonism of S1P receptors. In addition to reducing the circulation of autoreactive lymphocytes, fingolimod has direct neuroprotective effects such as preserving brain barrier integrity and decreasing pro-inflammatory cytokine secretion by astrocytes and microglia. Given these effects, we hypothesized that fingolimod would attenuate neurobehavioral deficits in MRL-lpr/lpr (MRL/lpr) mice, a validated neuropsychiatric lupus model. Fingolimod treatment was initiated after the onset of disease, and mice were assessed for alterations in cognitive function and emotionality. We found that fingolimod significantly attenuated spatial memory deficits and depression-like behavior in MRL/lpr mice. Immunofluorescent staining demonstrated a dramatic lessening of brain T cell and macrophage infiltration, and a significant reduction in cortical leakage of serum albumin, in fingolimod treated mice. Astrocytes and endothelial cells from treated mice exhibited reduced expression of inflammatory genes, while microglia showed differential regulation of key immune pathways. Notably, cytokine levels within the cortex and hippocampus were not appreciably decreased with fingolimod despite the improved neurobehavioral profile. Furthermore, despite a reduction in splenomegaly, lymphadenopathy, and circulating autoantibody titers, IgG deposition within the brain was unaffected by treatment. These findings suggest that fingolimod mediates attenuation of NPSLE through a mechanism that is not dependent on reduction of autoantibodies or cytokines, and highlight modulation of the S1P signaling pathway as a novel therapeutic target in lupus involving the central nervous system.

Neuropsychiatric symptoms in systemic lupus erythematosus (SLE) are not uncommon, yet the mechanisms underlying disease initiation and progression in the brain are incompletely understood. Although the role of T cells in other lupus target organs such as the kidney is well defined, which T cells contribute to the pathogenesis of neuropsychiatric SLE is not known. The present study was aimed at characterizing the CD4 T cell populations that are present in the choroid plexus (CP) of MRL/MpJ-faslpr mice, the primary site of brain infiltration in this classic lupus mouse model which exhibits a prominent neurobehavioral phenotype. T cells infiltrating the CP of MRL/MpJ-faslpr mice were characterized and subset identification was done by multiparameter flow cytometry. We found that the infiltrating CD4 T cells are activated and have an effector phenotype. Importantly, CD4 T cells have a T follicular helper cell (TFH) like phenotype, as evidenced by their surface markers and signature cytokine, IL-21. In addition, CD4 TFH cells also secrete significant levels of IFN-γ and express Bcl-6, thereby conforming to a potentially pathogenic T helper population that can drive the disease progression. Interestingly, the regulatory axis comprising CD4 T regulatory cells is diminished. These results suggest that accumulation of CD4 TFH in the brain of MRL/MpJ-faslpr mice may contribute to the neuropsychiatric manifestations of SLE, and point to this T cell subset as a possible novel therapeutic candidate.

Ten ongoing studies designed to test the possibility that extracellular RNAs may serve as biomarkers in human disease are described. These studies, funded by the NIH Common Fund Extracellular RNA Communication Program, examine diverse extracellular body fluids, including plasma, serum, urine and cerebrospinal fluid. The disorders studied include hepatic and gastric cancer, cardiovascular disease, chronic kidney disease, neurodegenerative disease, brain tumours, intracranial haemorrhage, multiple sclerosis and placental disorders. Progress to date and the plans for future studies are outlined.

Kidney biopsy remains the mainstay of Lupus Nephritis (LN) diagnosis and prognostication. The objective of this study is to identify non-invasive biomarkers that closely parallel renal pathology in LN. Previous reports have demonstrated that serum Insulin-like growth factor binding protein 4 (IGFBP-4) was increased in diabetic nephropathy in both animal models and patients. We proceeded to assess if IGFBP4 could be associated with LN. We performed ELISA using the serum of 86 patients with LN. Normal healthy adults (N = 23) and patients with other glomerular diseases (N = 20) served as controls. Compared to the healthy controls or other glomerular disease controls, serum IGFBP-4 levels were significantly higher in the patients with LN. Serum IGFBP-4 did not correlate well with systemic lupus erythematosus disease activity index (SLEDAI), renal SLEDAI or proteinuria, but it did correlate with estimated glomerular filtration rate (R = 0.609, P < 0.0001). Interestingly, in 18 patients with proliferative LN whose blood samples were obtained at the time of renal biopsy, serum IGFBP-4 levels correlated strongly with the chronicity index of renal pathology (R = 0.713, P < 0.001). IGFBP-4 emerges a potential marker of lupus nephritis, reflective of renal pathology chronicity changes.