NPSLE Patients Research Articles

Neuropsychiatric involvement in juvenile-onset systemic lupus erythematosus: Data from the UK Juvenile-onset systemic lupus erythematosus cohort study.

IntroductionJuvenile-onset systemic lupus erythematosus (JSLE) is a rare autoimmune/inflammatory disease with significant morbidity and mortality. Neuropsychiatric (NP) involvement is a severe complication, encompassing a heterogeneous range of neurological and psychiatric manifestations.MethodsDemographic, clinical, and laboratory features of NP-SLE were assessed in participants of the UK JSLE Cohort Study, and compared to patients in the same cohort without NP manifestations.ResultsA total of 428 JSLE patients were included in this study, 25% of which exhibited NP features, half of them at first visit. Most common neurological symptoms among NP-JSLE patients included headaches (78.5%), mood disorders (48.6%), cognitive impairment (42%), anxiety (23.3%), seizures (19.6%), movement disorders (17.7%), and cerebrovascular disease (14.9%). Peripheral nervous system involvement was recorded in 7% of NP-SLE patients. NP-JSLE patients more frequently exhibited thrombocytopenia (<100 × 109/L) (p = 0.04), higher C-reactive protein levels (p = 0.01), higher global pBILAG score at first visit (p < 0.001), and higher SLICC damage index score at first (p = 0.02) and last (p < 0.001) visit when compared to JSLE patients without NP involvement.ConclusionsA significant proportion of JSLE patients experience NP involvement (25%). Juvenile-onset NP-SLE most commonly affects the CNS and is associated with increased overall disease activity and damage.

Disrupted resting-state interhemispheric functional connectivity in systemic lupus erythematosus patients with and without neuropsychiatric lupus.

The aim of the study is to explore interhemispheric homotopic functional connectivity alterations in systemic lupus erythematosus (SLE) patients with and without neuropsychiatric lupus (NPSLE and non-NPSLE, respectively) and their potential correlations with clinical characteristics and neuropsychological performance. Based on resting-state functional MRI (rs-fMRI) data collected from SLE patients and matched healthy controls (HCs), the voxel-mirrored homotopic connectivity (VMHC) analysis was conducted to measure functional homotopy. Subsequently, correlations between altered functional homotopy and clinical/neuropsychological data were analyzed. Compared with the HC group, both NPSLE and non-NPSLE groups showed attenuated homotopic connectivity in middle temporal gyrus (MTG), cuneus (CUN), middle occipital gyrus (MOG), angular gyrus (ANG), and postcentral gyrus (PoCG). NPSLE patients also exhibited decreased homotopic connectivity in inferior parietal gyrus (IPG) and middle frontal gyrus (MFG). Compared with non-NPSLE patients, NPSLE patients showed weaker interhemispheric homotopic functional connectivity in MOG. Decreased homotopic functional connectivity in PoCG, IPG, and MOG were associated with the anxiety state of SLE patients. Our findings revealed attenuated functional homotopy in both NPSLE and non-NPSLE groups compared to the HC group, which appeared to be more severe in patients with comorbid neuropsychiatric lupus. Interhemispheric homotopy dysconnectivity may participate in the neuropathology of anxiety symptoms in SLE.

Cerebrovascular changes in neuro-Behcet's disease and neuropsychiatric lupus by transcranial Doppler ultrasonography and magnetic resonance imaging

IntroductionTranscranial Doppler ultrasonography (TCD) is a technique that allows measurement of blood flow from the basal intracerebral vessels. It is relatively inexpensive, non-invasive, can be performed at the bedside, and allows monitoring in acute emergency settings and for prolonged periods with a high temporal resolution, making it ideal for studying the haemodynamics within the intracranial arteries in neuro-Behcet's disease (NBD) and neuro-psychiatric lupus (NPSLE). Our aim was to assess the cerebral haemodynamic patterns in patients with NBD and NPSLE using TCD, while brain lesions were examined using magnetic resonance imaging (MRI). Material and methodsCase–control prospective study of 30 neuro-Behcet's disease patients, 25 neuro-psychiatric lupus patients and 26 healthy age-matched volunteers. All patients and healthy controls were examined by TCD. Only the groups of patients underwent cranial magnetic resonance imaging (MRI). ResultsTranscranial Doppler (TCD) values for middle cerebral artery (MCA), anterior cerebral artery (ACA), posterior cerebral artery (PCA), vertebral artery (VA) and basilar artery (BA) in NBD, NPSLE and control groups were measured. The results showed that there was a significant decrease in mean blood flow velocities in all the arteries examined in NBD and NPSLE patients. There was also a significant increase in the pulsatile index of PCA, VA and BA between NBD and NPSLE patients. The same results were obtained when comparing NBD versus controls. However, there was no significant difference between the NPSLE patients and the control group. The MRI lesions described were parenchymal lesions in 14 patients (46.7%), and vascular lesions in 4 patients (13.3%). Vascular lesions co-existed with parenchymal lesions (mixed lesion). Parenchymal lesions were in white matter (40%), thalamus (26.7%), brain stem (26.7%) and cerebellum (20%). While, in NPSLE, 23 patients were normal (92%) and only two patients had a vascular lesion (8%). ConclusionThere was a significant decrease in mean blood flow and a significant increase in the pulsatile index among both NBD and NPSLE patients, according to the TCD values.

Distinct spatial profile of inflammatory gene expression in the brain of a mouse model of neuropsychiatric lupus

Abstract Systemic Lupus Erythematosus (SLE) is an incurable autoimmune disease that results in central nervous system (CNS) involvement in up to 80% of patients, with clinical manifestations ranging from anxiety and fatigue to overt psychosis. However, the mechanisms and cellular components underlying these neuropsychiatric symptoms (NPSLE) remain largely unknown. An elevated type 1 interferon (IFN) signature has been commonly observed in SLE patients, particularly within the CNS of NPSLE patients (Crow et. al., 2014, Shiozawa et. al., 1992). Given the diversity of clinical CNS manifestations, we hypothesized that type 1 interferon-mediated inflammation occurs in spatially distinct regions within the CNS, resulting in differential behavioral outcomes depending on the impacted brain region. To test this hypothesis, we first characterized behavioral phenotypes in the Sle1, Yaa mouse model, and show that these mice exhibit anxiety-like, and fatigue-like behaviors consistent with the major clinical manifestations of NPSLE. To assess the spatial distribution of inflammatory gene expression, we utilized MERFISH (Moffitt et. al., 2016), a multiplexed spatial transcriptomics platform, and observed strikingly distinct patches of interferon stimulated gene (ISG) expression within the subcortical regions of Sle1, Yaa mouse brains. Preliminary single nucleus sequencing (sNuc-Seq) and in situ hybridization results implicate astrocytes and oligodendrocytes as the major cell classes enriched in these ISG patches. In summary, our results validate a mouse behavioral model of NPSLE, and show spatially distinct regions of ISG expression within the CNS, opening up a new avenue of investigation into the fundamental mechanisms of NPSLE.

Structural Changes on MRI Demonstrate Specific Cerebellar Involvement in SLE Patients-A VBM Study.

The purpose of this study is to investigate possible differences in brain structure, as measured by T1-weighted MRI, between patients with systemic lupus erythematosus (SLE) and healthy controls (HC), and whether any observed differences were in turn more severe in SLE patients with neuropsychiatric manifestations (NPSLE) than those without (non-NPSLE). Structural T1-weighted MRI was performed on 69 female SLE patients (mean age = 35.8 years, range = 18–51 years) and 24 age-matched female HC (mean age = 36.8 years, range = 23–52 years) in conjunction with neuropsychological assessment using the CNS Vital Signs test battery. T1-weighted images were preprocessed and analyzed by FSL-VBM. The results show that SLE patients had lower grey matter probability values than the control group in the VIIIa of the cerebellum bilaterally, a region that has previously been implied in sensorimotor processing in human and non-human primates. No structural differences for this region were found between NPSLE and non-NPSLE patients. VBM values from the VIIIa region showed a weak positive correlation with the psychomotor speed domain from CNS Vital Signs (p = 0.05, r = 0.21), which is in line with its presumed role as a sensorimotor processing area.

Treatment of neuropsychiatric systemic lupus erythematosus: clinical challenges and future perspectives

ABSTRACT Introduction: Neuropsychiatric (NP) involvement represents an emerging frontier in systemic lupus erythematosus (SLE), posing significant challenges due to its clinical diversity and obscure pathophysiology. The authors herein discuss selected aspects in the management of NPSLE based on existing literature and our experience, aiming to facilitate routine medical care. Areas covered: Research related to diagnosis, neuroimaging, treatment and outcome is discussed, focusing on data published in PubMed during the last 5 years. Selected translational studies of clinical relevance are included. Expert opinion: Identification of NPSLE patients who may benefit from appropriate treatment can be facilitated by attribution algorithms. Immunosuppressants are typically indicated in recurrent seizures, optic neuritis, myelopathy, psychosis and peripheral nerve disease, although a low threshold is recommended for cerebrovascular disease and other NP manifestations, especially when SLE is active. With the exception of stroke with positive antiphospholipid antibodies, anti-coagulation is rarely indicated in other syndromes. Refractory NPSLE can be treated with rituximab, whereas the role of other biologics remains unknown. Advances in the fields of biomarkers, neuroimaging for brain structural, perfusion or functional abnormalities, and design of novel compounds targeting not only systemic autoimmunity but also inflammatory and regenerative pathways within the nervous system, hold promise for optimizing NPSLE management.

Clinical Features and Outcomes of Neuropsychiatric Systemic Lupus Erythematosus in China.

Objective To identify the clinical characteristics, magnetic resonance imaging (MRI) results, and prognostic factors of neuropsychiatric (NP) systemic lupus erythematosus (SLE; NPSLE) in a relatively large patient series in China. Methods Data of patients with NPSLE at Peking Union Medical College Hospital (PUMCH) were collected retrospectively from June 2012 to June 2016. NPSLE patients were compared with 220 non-NPSLE patients. Survival rates were evaluated using the Kaplan-Meier curves, log-rank test, and Cox proportional hazards modeling. Cranial MRI results were also studied. Results Of the 194 included patients, sixteen subtypes of NPSLE were identified, and the most common manifestations were seizure (36.6%), acute confusional state (25.3%), and cerebral vascular disease (15.5%). Compared with the non-NPSLE group, NPSLE patients were significantly more likely to have typical lupus symptoms, higher Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores (P = 0.002), and positive rate of anti-ribosomal P protein antibodies (P = 0.008). Patients with seizure were more likely to have higher SLEDAI-2K scores and positive anti-β2GP1 than non-NPSLE patients. Sixteen patients died during follow-up. The most common cause of death was infection (37.5%). NPSLE significantly decreased survival rates of SLE patients. Patients with elevated serum creatinine (P = 0.001), hypocomplementemia (P = 0.031), and SLEDAI − 2K scores ≥ 15 (P = 0.014) had shorter survival periods. Eighty-two patients underwent detailed cranial MRI analysis; of these, 50 (61.0%) had abnormal results. Small vessel disease was the most common abnormal finding, followed by inflammatory-like lesions and large vessel disease. Conclusions High disease activity and positive rate of anti-ribosomal P protein antibodies may be risk factors for NPSLE. NPSLE decreases survival rates of SLE patients. Renal insufficiency and high disease activity are predictive of poor prognoses for NPSLE patients.

Neuropsychiatric lupus in Malaysian children: clinical characteristics, imaging features and 12-month outcomes.

Neuropsychiatric lupus (NPSLE) serves as a marker of severe disease in children with juvenile onset systemic lupus erythematosus (JSLE). This study aims to characterise the clinical and imaging features at diagnosis; and outcomes after 12 months in Malaysian children with NPSLE. A retrospective study of all NPSLE patients seen at the Pediatric Rheumatology Unit, Selayang Hospital from January 2004 to May 2017. Twenty-eight (19.8%) of 141 JSLE patients had NPSLE with a median presenting age of 10 years (IQR 9 - 12), median follow-up of 7 years (IQR 4 - 11) and female: male ratio of 3.7:1. Twenty-three patients had single episodes of NPSLE and five patients had two distinct episodes each. The mean disease activity score (SLEDAI- 2K) was 24.9±11.8 at presentation with 81.8% having high disease activity (score > 12). Majority (60.6%) present with NPSLE within the first year of SLE diagnosis whilst the remainder occurred at a median of five years (IQR 3-7) post-SLE diagnosis. Majority (75.8%) had central nervous system (CNS) involvement commonly presenting with seizures, delirium and visual complaints whilst 24.2% had peripheral nervous system (PNS) involvement. Frequent accompanying features included hypocomplementemia, acute cutaneous lupus and lupus nephritis. Autoantibodies were common; ANA (100%), anti-dsDNA (78.8%) anti-RNP (39.4%) and anti-Sm (39.4%). Abnormalities were seen in 85.7% of the magnetic resonance imaging (MRI) studies performed, predominantly supratentorial white matter hyperintensities on T2 images whilst cerebrospinal fluid examination was normal in the majority. All patients with CNS involvement received corticosteroids with immunosuppressive therapy: Cyclophosphamide (20), Rituximab (2). Treatment for PNS involvement included corticosteroids with Azathioprine (6) or Mycophenolate mofetil (2). At 12 months post-NPSLE, majority (85.7%) recovered without any neurological sequelae. Juvenile-onset NPSLE presents with a myriad of clinical features. It is associated with high disease activity and non-specific MRI features. With early diagnosis and treatment, the majority had good prognosis.

Mortality in patients with systemic lupus erythematosus and neuropsychiatric involvement: A retrospective analysis from a tertiary referral center in the Netherlands.

ObjectiveWe aimed to evaluate all-cause and cause-specific mortality in patients with systemic lupus erythematosus (SLE) and neuropsychiatric (NP) symptoms in the Netherlands between 2007–2018.MethodsPatients visiting the tertiary referral NPSLE clinic of the Leiden University Medical Center were included. NP symptoms were attributed to SLE requiring treatment (major NPSLE) or to other and mild causes (minor/non-NPSLE). Municipal registries were checked for current status (alive/deceased). Standardized mortality ratios (SMRs) and 95% confidence intervals (CI) were calculated using data from the Dutch population. Rate ratio (RR) and 95% CI were calculated using direct standardization to compare mortality between major NPSLE and minor/non-NPSLE.Results351 patients were included and 149 patients were classified as major NPSLE (42.5%). Compared with the general population, mortality was increased in major NPSLE (SMR 5.0 (95% CI: 2.6–8.5)) and minor/non-NPSLE patients (SMR 3.7 (95% CI: 2.2–6.0)). Compared with minor/non-NPSLE, mortality was similar in major NPSLE patients (RR: 1.0 (95% CI: 0.5–2.0)). Cause-specific mortality rates demonstrated an increased risk of death due to infections in both groups, whereas death due to cardiovascular disease was only increased in minor/non-NPSLE patients.ConclusionMortality was increased in both major NPSLE and minor/non-NPSLE patients in comparison with the general population. There was no difference in mortality between major NPSLE and minor/non-NPSLE patients.

Prevalence and characteristics of neuropsychiatric involvement in an Egyptian cohort of systemic lupus erythematosus patients: a single-center retrospective cohort

BackgroundThe aim of this study was to retrospectively investigate the prevalence and characteristics of neuropsychiatric (NP) involvement in a cohort of systemic lupus erythematosus (SLE) patients from a single tertiary center.ResultsOf 301 included patients’ medical records, the prevalence of NPSLE, that was defined according to the American College of Rheumatology Nomenclature of 1999, was 33.5% (101/301), of whom 10 (9.9%) were males. The mean age at the last visit of patients with NP involvement was 29.1 ± 8.2 years, whereas the mean age at onset was 21.9 ± 7.3 years, and the mean disease duration was 89.8 ± 59.4 months. The most common NP manifestations were psychosis [34/101 (33.7%)], followed by seizures [22/101 (21.8%)]. Compared to those without NPSLE, patients with NP involvement were characterized by having a younger age of onset (p < 0.001) had a longer disease duration (p = 0.02). Of the cumulative characteristics recorded, NPSLE patients showed a higher prevalence of cutaneous vasculitis (p = 0.002), discoid rash (p = 0.03), pleurisy and pleural effusion (p = 0.004, p = 0.03, respectively), pericarditis (p = 0.007), thrombocytopenia (p = 0.04), and secondary antiphospholipid (APS) (p = 0.04); however, there was no difference in any of the included serologic features between the two groups. Patients with NPSLE had a higher median disease activity score [Systemic Lupus Erythematosus Disease Activity Index-2 K (SLEDAI-2 K)] at the disease onset (p = 0.008), yet it was comparable to those without NP involvement at the last visit (p = 0.3). NPSLE patients demonstrated a higher median damage score (p < 0.001) that was assessed according to the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score. NPSLE patients with secondary APS showed a higher prevalence of cerebrovascular accidents (CVA) (p < 0.001), while those without APS developed psychosis more frequently (p = 0.03).ConclusionNeuropsychiatric SLE patients (33.5%) demonstrated a younger age of onset, higher prevalence of secondary APS and distinct clinical characteristics, and had higher disease damage. APS-positive NPSLE patients had a higher prevalence of CVA, while APS-negative patients showed a higher prevalence of psychosis.

Comparative proteomics analysis of plasma protein in patients with neuropsychiatric systemic lupus erythematosus.

BackgroundThe aim of this study was to evaluate serum biomarkers of systemic lupus erythematous (SLE) patients, with and without neuropsychiatric (NP) manifestation by high-resolution proteomic analysis.MethodsSLE patients with NP (NPSLE, n=9), SLE patients without NP (non-NPSLE, n=9) and healthy controls (HC, n=9) were prospectively enrolled in this study, and their plasma samples were collected and pooled into 3 NPSLE, 3 non-NPSLE and 3 HC samples for discovery profile. The TMT-LC-MS/MS-based proteomics approach was used to identify the differential proteome among the three matched groups, and the data were analyzed by bioinformatics tools, including Gene Ontology (GO) categories, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, to explore canonical pathways and networks involved in the pathogenesis of NPSLE. To validation of differentially expressed proteomics results, four proteins were measured by ELISA.ResultsThere were altogether 223 differentially expressed proteins in NPSLE groups compared with healthy controls (HC), of which 96 proteins increased while 127 proteins decreased. Compared with non-NPSLE, there were only 49 differentially expressed proteins in NPSLE groups, of which 37 proteins increased while 12 proteins decreased. The significantly changed pathway that those proteins are involved in was complement and coagulation cascades in NPSLE group compared with health controls. However, we didn’t find significantly changed pathway between NPSLE group and non-NPSLE group. Five proteins were found significantly changed in all group-comparisons with consistent tendencies using Venn analysis, including Vitamin D binding protein (VDBP), C-reactive protein (CRP), KRT16, IGHV4-4 and CTRP3. Four proteins including CTRP3, VDBP, PAPPA and TRYP2 were selected to estimate the validity of the proteomics approach by ELISA. The expression levels of CTRP3 and TRYP2 were significantly changed in NPSLE patients compared with either HC or non-NPSLE patients.ConclusionsOur research has successfully established serum protein profiles of NPSLE and non-NPSLE patients through TMT technology and screened out five proteins significantly changed in group-comparisons with consistent tendencies. The pathway of complement and coagulation cascades may participate in pathogenesis of NPSLE and non-NPSLE.

The pathogenic role of choroid plexus infiltrating T cells in Neuropsychiatric Lupus

Abstract Neuropsychiatric systemic lupus erythematosus (NPSLE) manifests as a range of symptoms, including cognitive abnormalities, mood disorders, and psychosis. The pathogenesis is complex and not yet completely understood. We recently proposed that the choroid plexus (CP) could be an alternative entry site to the blood brain barrier for immune mediators to enter the central nervous system. In the MRL/lpr lupus mouse model, the CP is heavily infiltrated with T and B cells, which is reminiscent of human NPSLE patients whose autopsies revealed infiltrates in the CP. Nevertheless, the role of CP infiltrating T cells in the pathogenesis is not known and is the objective for this study. In two cohorts, we evaluated whether intracerebroventricularly (ICV) delivered MRL/lpr CP T cells accelerate neuropsychiatric disease in young female MRL/lpr mice. Six week old female MRL/lpr mice were injected with MRL/lpr CP CD3+ T cells, MRL/lpr splenic CD3+ T cells, or PBS. The T cells were pooled from the CP and spleen of 16 week old MRL/lpr mice and expanded with anti-CD3/CD28 antibodies (1 ug/mL) and mIL-2 (10 U/mL) for 4 days. About ~200,000 cells were injected into the lateral ventricle from the bregma at AP −0.34 mm, ML −1.0 mm, and depth −2.0 mm. After 4 weeks post-injection, we found that CP T cell recipient mice had increased cognitive deficits compared to PBS controls. Histological assessment revealed an increase in lymphocytic infiltration, the number of proliferating cells, and IgG and complement deposition, in the choroid plexus of CP T recipient mice. Our result indicate that T cells can migrate to and proliferate in the CP following ICV injection, and that brain infiltrating MRL/lpr T cells may be a key contributor to the pathogenesis of NPSLE.

Prevalence of Neuropsychiatric Disorders in Patients With Systemic Lupus Erythematosus (SLE).

BACKGROUNDNeuropsychiatric systemic lupus erythematosus (NPSLE) is a serious and well‐known complication of systemic lupus erythematosus (SLE). There are few studies on the population‐based estimates of the prevalence of NPSLE and its manifestations. Reliable prevalence estimates are needed to quantify the burden of the disease and to direct the attention of policy makers to magnitude of suffering associated with SLE. We aimed to quantify the prevalence of NPSLE in different population settings.METHODSWe searched PubMed from January 2009 to June 2019 to identify studies relevant to this review. Databases searches combined terms from three themes: all age groups/general population, psychosis, neuropsychiatric impairment, mental disorders and delusions; and SLE, lupus, and systemic lupus erythematosus. Terms were searched as both keywords (title/abstract words) and subject headings as appropriate. We also searched original papers relevant to this review from the retrieved articles. For case classification and case ascertainment, NPSLE was classified according to the American College of Rheumatology guidelines.RESULTWe excluded 79 from the initial 105 articles from the screening of titles and abstracts. The remaining 26 full text articles were reviewed and 9 were included in the review. The major neuropsychiatric comorbidities that were observed from the studies were major depression, headaches, seizures and cerebrovascular diseases. The prevalence estimates of neuropsychiatric disorders in NPSLE patients were as follows: major depression in patients (17%–52%) headaches (38.8%–60%), seizures (26.4%–63%), and cerebrovascular diseases (26%–38.8%). The overall prevalence estimates of NPSLE varies from 11% to 60% of all SLE patients.CONCLUSIONThis study confirms that the burden of neuropsychiatric manifestations of SLE, including major depression, seizures, cerebrovascular disease is high. Further studies are needed to elucidate the pathogenesis of neurological involvement in patients with SLE and to address the risk factors for NPSLE.Support or Funding InformationAmerican Association for Anatomists

Regional cerebral perfusion correlates with anxiety in neuropsychiatric SLE: evidence for a mechanism distinct from depression.

The study examined the hypothesis that hypoperfusion in brain areas known to be involved in emotional disturbances in primary psychiatric disorders is also linked to emotional difficulties in systemic lupus erythematosus (SLE) and that these are not secondary to the physical and social burden incurred by the disease. Nineteen SLE patients without overt neuropsychiatric manifestations (non-NPSLE), 31 NPSLE patients, and 23 healthy controls were examined. Dynamic susceptibility contrast MRI was used and cerebral blood flow and cerebral blood volume values were estimated in six manually selected regions of interest of brain regions suspected to play a role in anxiety and depression (dorsolateral prefrontal cortex, ventromedial prefrontal cortex, anterior cingulate cortex, hippocampi, caudate nuclei and putamen). NPSLE patients reported high rates of anxiety and depression symptomatology. Significantly reduced cerebral blood flow and cerebral blood volume values were detected in the NPSLE group compared to healthy controls in the dorsolateral prefrontal cortex and ventromedial prefrontal cortex, bilaterally. Within the NPSLE group, anxiety symptomatology was significantly associated with lower perfusion in frontostriatal regions and in the right anterior cingulate gyrus. Importantly, the latter associations appeared to be specific to anxiety symptoms, as they persisted after controlling for depression symptomatology and independent of the presence of visible lesions on conventional MRI. In conclusion, hypoperfusion in specific limbic and frontostriatal regions is associated with more severe anxiety symptoms in the context of widespread haemodynamic disturbances in NPSLE.

Different patterns of cerebral perfusion in SLE patients with and without neuropsychiatric manifestations.

To investigate brain perfusion patterns in systemic lupus erythematosus (SLE) patients with and without neuropsychiatric systemic lupus erythematosus (NPSLE and non‐NPSLE, respectively) and to identify biomarkers for the diagnosis of NPSLE using noninvasive three‐dimensional (3D) arterial spin labeling (ASL). Thirty‐one NPSLE and 24 non‐NPSLE patients and 32 age‐ and sex‐matched normal controls (NCs) were recruited. Three‐dimensional ASL‐MRI was applied to quantify cerebral perfusion. Whole brain, gray (GM) and white matter (WM), and voxel‐based analysis (VBA) were performed to explore perfusion characteristics. Correlation analysis was performed to find the relationship between the perfusion measures, lesion volumes, and clinical variables. Receiver operating characteristic (ROC) analysis and support vector machine (SVM) classification were applied to differentiate NPSLE patients from non‐NPSLE patients and healthy controls. Compared to NCs, NPSLE patients showed increased cerebral blood flow (CBF) within WM but decreased CBF within GM, while non‐NPSLE patients showed increased CBF within both GM and WM. Compared to non‐NPSLE patients, NPSLE patients showed significantly reduced CBF in the frontal gyrus, cerebellum, and corpus callosum. CBF within several brain regions such as cingulate and corpus callosum showed significant correlations with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborating Clinics (SLICC) damage index scores. ROC analysis showed moderate performance in distinguishing NPSLE from non‐NPSLE patients with AUCs > 0.7, while SVM analysis demonstrated that CBF within the corpus callosum achieved an accuracy of 83.6% in distinguishing NPSLE from non‐NPSLE patients. Different brain perfusion patterns were observed between NPSLE and non‐NPSLE patients. CBF measured by noninvasive 3D ASL could be a useful biomarker for the diagnosis and disease monitoring of NPSLE and non‐NPSLE patients.

P4440Assessment of left atrial function in patients with systemic lupus erythematosus with and without neuropsychiatric manifestations: association with cardiovascular events

Abstract Introduction Cardiac involvement in Systemic Lupus Erythematosus (SLE) may lead to left ventricular (LV) hypertrophy with possible impairment of LV diastolic function and left atrial (LA) function, particularly in patients with severe forms of SLE with neuropsychiatric manifestations (NPSLE) and can also be associated with cardiovascular outcome. Purpose We evaluated the prevalence of LV diastolic dysfunction and LA dysfunction in a large cohort of SLE patients including also NPSLE patients, and their association with the occurrence of cardiovascular events (cerebrovascular accidents, lung-embolism, coronary revascularisation, heart failure hospitalisations and development of supraventricular arrhythmias). Methods A total of 102 SLE patients (87% female, 42±15 years) were included, of which 43 (42%) with NPSLE according to a multidisciplinary team assessment. All patients fulfilled the American College of Rheumatology (ACR 1997) and Systemic Lupus Erythematosus International Collaborating Clinics (SLICC 2012) classification criteria for SLE. Echocardiography was performed at the first visit: LV diastolic function was assessed according to current recommendations and including Tissue Doppler Imaging measures; LA volume (LAVI) was also measured and LA function was assessed by LA reservoir strain using 2D speckle tracking imaging. Results In the SLE patients, mean LV mass index was 82±32 g/m2, 29% of patients showed an e'septal &lt;10, 7% an E/e'&gt;14, 16% a LAVI&gt;34 ml/m2 and 5% a tricuspid velocity &gt;2.8m/s. When applying the currently recommended multiparametric approach, only 4% of SLE patients showed LV diastolic dysfunction. In NPSLE patients, the prevalence of LV diastolic dysfunction was not significantly higher (5%). However, an impaired LA reservoir strain (based on the median value of 25%) was observed in 54% of the total SLE population and in 77% of NPSLE patients suggesting higher sensitivity of this parameter to detect impaired LA function and LV diastolic function. During a median follow up of 11 years (Interquartile range: 4–19 years), 43 (42%) patients developed a cardiovascular event. Kaplan-Meier curve analysis showed that SLE patients with impaired LA strain &lt;25% experienced higher cumulative rates of cardiovascular events, as compared to SLE patients with LA strain≥25% (Chi-square 4.350; Log rank p=0.037). At the uni- and multivariate Cox-regression models, LA strain showed significant association with cardiovascular events (hazard ratio [HR]:0.944; 95% confidence interval [CI]: 0.893–0.997; p=0.039) together with age (HR: 1.030; 95% CI: 1.002–1.059; p=0.039) after correcting for LV mass index and LV diastolic dysfunction. LA reservoir strain Conclusions LA dysfunction as assessed by LA reservoir strain is significantly impaired in SLE and particularly in NPSLE patients and improve detection of myocardial involvement in these patients. Furthermore, LA reservoir strain is independently associated with the development of cardiovascular events.

Proteomic Analysis of Cerebrospinal Fluid: A Search for Biomarkers of Neuropsychiatric Systemic Lupus Erythematosus

Background: Neuropsychiatric systemic lupus erythematosus or NPSLE, as its name suggests, refers to the neurological and psychiatric manifestations of Systemic Lupus Erythematosus (SLE). In clinical practice, it is often difficult to reach an accurate diagnosis, as this disease presents differently in different patients, and the available diagnostic tests are often not specific enough. Objectives: The aim of this study was to search for proteomic biomarkers in cerebrospinal fluid that could be proposed as diagnostic aids for this disease. Methods: The proteomic profile of cerebrospinal fluid samples of 19 patients with NPSLE, 12 patients with SLE and no neuropsychiatric manifestation (SLEnoNP), 6 patients with neuropsychiatric symptoms but no SLE (NPnoSLE), 5 with Other Autoimmune Disorders without neuropsychiatric manifestations (OADs), and 4 Healthy Controls (HC), were obtained by two-dimensional gel electrophoresis and compared using ImageMaster Platinum 7.0 software. Results: The comparative analysis of the different study groups revealed three proteins of interest that were consistently over-expressed in NPSLE patients. These were identified by mass spectrometry as albumin (spot 16), haptoglobin (spot 160), and beta-2 microglobulin (spot 161). Conclusion: This work is one of the few proteomic studies of NPSLE that uses cerebrospinal fluid as the biological sample. Albumin has previously been proposed as a potential biomarker of rheumatoid arthritis and SLE, which is coherent with these results; but this is the first report of haptoglobin and beta-2 microglobulin in NPSLE, although haptoglobin has been associated with increased antibody production and beta-2 microglobulin with lupus nephritis.

Peripheral levels of brain-derived neurotrophic factor and S100B in neuropsychiatric systemic lupus erythematous

The aim of this study was to investigate serum S100B and brain-derived neurotrophic factor (BDNF) in systemic lupus erythematous (SLE) patients, with and without neuropsychiatric (NP) manifestation activity. We assessed 47 SLE patients and 20 selected healthy individuals. Disease activity was assessed according to the SLE disease activity index (SLEDAI). Serum BDNF and S100B were measured by enzyme-linked immunosorbent assay. Serum S100B protein was significantly higher in SLE patients. BDNF levels were significantly decreased in active SLE, when compared with inactive SLE, but not when compared with controls. S100B was clearly higher in the NPSLE group, when compared with the non-NPSLE or control groups. Receiver operating characteristic analysis of S100B revealed an area under the curve of 0.706 that discriminated NPSLE patients with peripheral polyneuropathy. Our findings reinforce the use of serum S100B as a biomarker in SLE, particularly for NPSLE. Moreover, we found a strong association between serum S100B and peripheral neuropathy, indicating a specific utility for this biomarker in SLE that warrants clinical investigation.

Lipocalin-2 is a pathogenic determinant and biomarker of neuropsychiatric lupus

Neuropsychiatric manifestations in lupus (NPSLE) affect ∼20–40% of patients. In the central nervous system, lipocalin-2 (LCN2) can promote injury through mechanisms directly linked to NPSLE, including brain barrier disruption, neurotoxicity, and glial activation. Since LCN2 is elevated in lupus and has been implicated in neuroinflammation, we investigated whether LCN2 is required for the pathogenesis of NPSLE. Here, we investigated the effects of LCN2 deficiency on the development of neurobehavioral deficits in the B6.Sle1.Sle3 (Sle1,3) mouse lupus model. Sle1,3 mice exhibited depression-like behavior and impaired spatial and recognition memory, and these deficits were attenuated in Sle1,3-LCN2KO mice. Whole-brain flow cytometry showed a significant increase in brain infiltrating leukocytes in Sle1,3 mice that was not reduced by LCN2 deficiency. RNA sequencing on sorted microglia revealed that several genes differentially expressed between B6 and Sle1,3 mice were regulated by LCN2, and that these genes are key mediators of the neuroinflammatory cascade. Importantly, LCN2 is upregulated in the cerebrospinal fluid of NPSLE patients across 2 different ethnicities. Our findings establish the Sle1,3 strain as an NPSLE model, demonstrate that LCN2 is a major regulator of the detrimental neuroimmune response in NPSLE, and identify CSF LCN2 as a novel biomarker for NPSLE.

Identification of protein biomarkers in cerebrospinal fluid(CSF) of Neuro Psychiatric SLE(NPSLE) patients using SOMA scan assay.

Abstract Background Neurological manifestations of systemic lupus erythematosus (NPSLE) include a wide spectrum of symptoms like seizures, meningitis and psychosis. Clinical diagnosis of NPSLE is challenging due to the lack of objective diagnostic tests. Here, we explore if CSF proteins may have diagnostic value in NPSLE. Methods 24 CSF samples (8 healthy + 8 neuro controls (NC) + 8 NPSLE) were screened using an aptamer-based platform for about 1100 proteins. A subset of the differentially expressed CSF proteins was selected for validation in two different cohorts, Caucasian controls (N=54) &amp; NPSLE (N= 25) and Chinese controls (N=15) &amp; SLE (N= 17). Results The initial aptamer-based screen revealed 8 CSF proteins to be elevated in NPSLE vs healthy, at fold change &amp;gt;2, and p &amp;lt;0.05. All 8 proteins were validated by ELISA. Total IgM, Lipocalin 2, M-CSF were significantly elevated in the CSF of NPSLE when compared to controls, in both Caucasian and Chinese patients (range of fold change: 16–1.2; p &amp;lt; 0.05). CSF HCC-s, DAN and Angiostatin were significantly elevated in Caucasian NPSLE patients only (range of fold change: 2.3–1.8; p &amp;lt; 0.05). Total C3 and albumin in CSF did not show any difference in disease groups in both cohorts, as assayed by ELISA. Conclusion Several novel proteins were noted to be elevated in NPSLE CSF, relative to control subjects with other neurological symptoms. Further studies are warranted to establish the specificity of CSF IgM, Lipocalin 2, M-CSF, HCC-s, DAN and Angiostatin for NPSLE and to understand their pathogenic relevance.