Treatment with lysophosphatidic acid prevents microglial activation and depression-like behaviours in a murine model of neuropsychiatric systemic lupus erythematosus.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is an incurable disease characterised by neuropsychiatric symptoms, particularly depression. Novel therapeutic options for NPSLE are urgently needed. Several previous reports have suggested that both microglial activation and impaired neurogenesis may be involved in the progression of depression. In contrast, the administration of lysophosphatidic acid (LPA) ameliorates depression and anxiety. Therefore, in the present study, we determined whether treatment with LPA affects microglial activation, impaired neurogenesis, and abnormal behaviour in MRL/lpr mice. In both tail suspension test and forced swim test, the MRL/lpr mice exhibited a significant increase in total immobility time compared with MRL/+ mice. Treatment with LPA significantly suppressed the prolonged immobility time in MRL/lpr mice. In contrast, pretreatment with ki16425 (a specific antagonist of LPA receptor 1 and 3) significantly reversed the effects of LPA. Furthermore, MRL/lpr mice exhibited impairments in spatial working memory and visual cognitive memory, which were suppressed by LPA treatment. The expression levels of TMEM119, CD68, GFAP, and caspase-3 in the hippocampus and prefrontal cortex of MRL/lpr mice were significantly higher than those in MRL/+ mice. Treatment with LPA inhibited these increases in MRL/lpr mice. Pretreatment with ki16425 reversed LPA-mediated inhibition of microglial activation. The quantity of sodium fluorescein that leaked into the brain tissues in MRL/lpr mice were significantly higher than that in MRL/+ mice. Treatment with LPA tended to decrease the sodium fluorescein leakage. These findings suggest that treatment with LPA may regulate microglial activation, which is important in the pathogenesis of NPSLE, as well as blood-brain-barrier weakening and abnormal behaviour.

Central nervous system involvement in systemic lupus erythematosus: Data from the Spanish Society of Rheumatology Lupus Register (RELESSER).

OBJECTIVES: To analyze the prevalence, incidence, survival and contribution on mortality of major central nervous system (CNS) involvement in systemic lupus erythematosus (SLE). METHODS: Patients fulfilling the SLE 1997 ACR classification criteria from the multicentre, retrospective RELESSER-TRANS (Spanish Society of Rheumatology Lupus Register) were included. Prevalence, incidence and survival rates of major CNS neuropsychiatric (NP)-SLE as a group and the individual NP manifestations cerebrovascular disease (CVD), seizure, psychosis, organic brain syndrome and transverse myelitis were calculated. Furthermore, the contribution of these manifestations on mortality was analysed in Cox regression models adjusted for confounders. RESULTS: A total of 3591 SLE patients were included. Of them, 412 (11.5%) developed a total of 522 major CNS NP-SLE manifestations. 61 patients (12%) with major CNS NP-SLE died. The annual mortality rate for patients with and without ever major CNS NP-SLE was 10.8% vs 3.8%, respectively. Individually, CVD (14%) and organic brain syndrome (15.5%) showed the highest mortality rates. The 10% mortality rate for patients with and without ever major CNS NP-SLE was reached after 12.3 vs 22.8 years, respectively. CVD (9.8 years) and organic brain syndrome (7.1 years) reached the 10% mortality rate earlier than other major CNS NP-SLE manifestations. Major CNS NP-SLE (HR 1.85, 1.29-2.67) and more specifically CVD (HR 2.17, 1.41-3.33) and organic brain syndrome (HR 2.11, 1.19-3.74) accounted as independent prognostic factors for poor survival. CONCLUSION: The presentation of major CNS NP-SLE during the disease course contributes to a higher mortality, which may differ depending on the individual NP manifestation. CVD and organic brain syndrome are associated with the highest mortality rates.

High Prevalence but Low Impact of Cognitive Dysfunction on Quality of Life in Patients With Lupus and Neuropsychiatric Symptoms.

OBJECTIVE: To evaluate the prevalence and impact of cognitive impairment on health-related-quality of life (HRQoL) in patients with systemic lupus erythematosus (SLE) and neuropsychiatric (NP) symptoms. METHODS: Patients with SLE and NP symptoms referred to the Leiden NPSLE clinic (2007-2019) were included. In a multidisciplinary evaluation, NP symptoms were attributed to SLE (NPSLE: inflammatory, ischemic, or both combined) or other causes. Four cognitive domains were determined: global cognitive function (score 0-30), learning and memory, executive function and complex attention, and psychomotor speed (all T scores). HRQoL was determined using the mental component score and physical component score of the Short Form 36 health survey. The associations between cognition and NPSLE phenotype and cognition and HRQoL were assessed with multiple regression analyses and linear mixed models corrected for confounding and expressed in SDs. RESULTS: A total of 357 patients (86% female, mean age 44 years) were included. Of those 357 patients, 169 had a follow-up visit (median follow-up 11 months). Impairment in global cognitive function was present in 8% of patients, and in all other cognitive domains in ±50%. The most severe impairment (all domains) was seen in patients with a combined NPSLE phenotype. Diffuse cognitive impairment (learning and memory, executive function and complex attention, and psychomotor speed) was most common and was present more often in patients with an inflammatory phenotype. A weak association between cognition and HRQoL was found both cross-sectionally and longitudinally. In general, 1 SD lower scores on the cognitive domains were associated with at most one-fifth SD lower HRQoL. CONCLUSION: Objective cognitive impairment is common in SLE patients with NP symptoms, but may have a limited influence on HRQoL.

Autoimmune RNA dysregulation and seizures: therapeutic prospects in neuropsychiatric lupus.

Lupus autoimmunity frequently presents with neuropsychiatric manifestations, but underlying etiology remains poorly understood. Human brain cytoplasmic 200 RNA (BC200 RNA) is a translational regulator in neuronal synapto-dendritic domains. Here, we show that a BC200 guanosine-adenosine dendritic transport motif is recognized by autoantibodies from a subset of neuropsychiatric lupus patients. These autoantibodies impact BC200 functionality by quasi irreversibly displacing two RNA transport factors from the guanosine-adenosine transport motif. Such anti-BC autoantibodies, which can gain access to brains of neuropsychiatric lupus patients, give rise to clinical manifestations including seizures. To establish causality, naive mice with a permeabilized blood-brain barrier were injected with anti-BC autoantibodies from lupus patients with seizures. Animals so injected developed seizure susceptibility with high mortality. Seizure activity was entirely precluded when animals were injected with lupus anti-BC autoantibodies together with BC200 decoy autoantigen. Seizures are a common clinical manifestation in neuropsychiatric lupus, and our work identifies anti-BC autoantibody activity as a mechanistic cause. The results demonstrate potential utility of BC200 decoys for autoantibody-specific therapeutic interventions in neuropsychiatric lupus.

Prevalence of Neuropsychiatric Lupus in Psychosis Patients Who Have Tested Positive for Antinuclear Antibodies.

OBJECTIVE: Psychosis is a rare manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE). Current guidelines do not make a recommendation regarding the use of antinuclear antibody (ANA) testing in the assessment of patients with psychosis. The present study was undertaken to determine the prevalence of NPSLE in patients with psychosis who were positive for ANAs. METHODS: A retrospective review of patients who were admitted to the mental health service of 2 metropolitan tertiary referral centers with a diagnosis of psychosis and had been tested for ANAs was conducted. A diagnosis of SLE was made when the 2019 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) classification criteria were fulfilled. Attribution of psychosis-related events to NPSLE were made according to validated criteria. RESULTS: There were 10,205 mental health admissions with diagnoses of psychosis representing 4,766 individual patients, 911 patients (19%) were tested for ANAs, 135 (15%) of those tests returned a positive result with a titer of ≥1:160. The mean ± SD follow-up time was 47 ± 26 months. At discharge, there were 4 patients who met 2019 ACR/EULAR criteria for SLE, 2 of whom met criteria for NPSLE (2 patients had other manifestations of SLE), yielding an NPSLE prevalence of 1.5% (2 of 135) among patients who were positive for ANAs, and 0.2% (2 of 911) among all patients who underwent testing for ANAs. CONCLUSION: The prevalence of NPSLE in patients with psychosis who were positive for ANAs was low, at 1.5%. The low rate of clinically significant positive results would argue against routine testing for ANAs in patients with psychosis.

CXCL13 Neutralization Attenuates Neuropsychiatric Manifestations in Lupus-Prone Mice.

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.

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

INTRODUCTION: Juvenile-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. METHODS: Demographic, 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. RESULTS: A 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. CONCLUSIONS: A 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.

Fatigue in patients with systemic lupus erythematosus and neuropsychiatric symptoms is associated with anxiety and depression rather than inflammatory disease activity.

INTRODUCTION: We aimed to investigate risk factors for fatigue in patients with systemic lupus erythematosus (SLE) and neuropsychiatric symptoms in order to identify potential interventional strategies. METHODS: Patients visiting the neuropsychiatric SLE (NPSLE) clinic of the Leiden University Medical Center between 2007-2019 were included. In a multidisciplinary consensus meeting, SLE patients were classified as having neuropsychiatric symptoms of inflammatory origin (inflammatory phenotype) or other origin (non-inflammatory phenotype). Fatigue was assessed with the SF-36 vitality domain (VT) since 2007 and the multidimensional fatigue inventory (MFI) and visual analogue scale (VAS) since 2011. Patients with a score on the SF-36 VT ≥1 standard deviation (SD) away from the mean of age-related controls of the general population were classified as fatigued; patients ≥2 SD away were classified as extremely fatigued. Disease activity was measured using the SLE disease activity index-2000. The influence of the presence of an inflammatory phenotype, disease activity and symptoms of depression and anxiety as measured by the hospital anxiety and depression scale (HADS) was analyzed using multiple regression analyses corrected for age, sex and education. RESULTS: 348 out of 371 eligible patients filled in questionnaires and were included in this study . The majority was female (87%) and the mean age was 43 ± 14 years. 72 patients (21%) had neuropsychiatric symptoms of an inflammatory origin. Fatigue was present in 78% of all patients and extreme fatigue was present in 50% of patients with an inflammatory phenotype vs 46% in the non-inflammatory phenotype. Fatigue was similar in patients with an inflammatory phenotype compared to patients with a non-inflammatory phenotype on the SF-36 VT (ß: 0.8 (95% CI -4.8; 6.1) and there was less fatigue in patients with an inflammatory phenotype on the MFI and VAS (ß: -3.7 (95% CI: -6.9; -0.5) and ß: -1.0 (95% CI -1.6; -0.3)). There was no association between disease activity and fatigue, but symptoms of anxiety and depression (HADS) associated strongly with all fatigue measurements. CONCLUSION: This study suggests that intervention strategies to target fatigue in (NP)SLE patients may need to focus on symptoms of anxiety and depression rather than immunosuppressive treatment.

Transition to severe phenotype in systemic lupus erythematosus initially presenting with non-severe disease: implications for the management of early disease.

OBJECTIVE: Changes in the care of patients with SLE dictate a re-evaluation of its natural history and risk factors for disease deterioration and damage accrual. We sought to decipher factors predictive of a deterioration in phenotype ('transition') in patients initially presenting with non-severe disease. METHODS: Patients from the 'Attikon' cohort with disease duration ≥1 year were included. Disease at diagnosis was categorised as mild, moderate or severe, based on the British Isles Lupus Assessment Group manifestations and physician judgement. 'Transition' in severity was defined as an increase in category of severity at any time from diagnosis to last follow-up. Multivariable logistic regression was performed to identify baseline factors associated with this transition. RESULTS: 462 patients were followed for a median (IQR) of 36 (120) months. At diagnosis, more than half (56.5%) had a mild phenotype. During disease course, transition to more severe forms was seen in 44.2%, resulting in comparable distribution among severity patterns at last follow-up (mild 28.4%, moderate 33.1%, severe 38.5%). Neuropsychiatric involvement at onset (OR 6.33, 95% CI 1.22 to 32.67), male sex (OR 4.53, 95% CI 1.23 to 16.60) and longer disease duration (OR 1.09 per 1 year, 95% CI 1.04 to 1.14) were independently associated with transition from mild or moderate to severe disease. Patients with disease duration ≥3 years who progressed to more severe disease had more than 20-fold increased risk to accrue irreversible damage. CONCLUSION: Almost half of patients with initially non-severe disease progress to more severe forms of SLE, especially men and patients with positive anti-double-stranded DNA or neuropsychiatric involvement at onset. These data may have implications for the management of milder forms of lupus.

Low C4 as a risk factor for severe neuropsychiatric flare in patients with systemic lupus erythematosus.

OBJECTIVE: This study aimed to explore the risk factors for 'severe' neuropsychiatric (NP) flare in patients with systemic lupus erythematosus (SLE). METHODS: This retrospective study comprised newly diagnosed 184 adult SLE patients who visited Hokkaido University Hospital between 2006 and 2017. In this study, severe NP flare was defined as the occurrence of at least one newly developed British Isles Lupus Assessment Group A score in the neurological domain. Overall severe NP flare-free survival was estimated by Kaplan-Meier analysis. Clinical and demographic profiles at SLE diagnosis were assessed as potential risk items in the adjusted multivariate Cox regression model. RESULTS: The median follow-up period was 7.9 years (interquartile range (IQR) 4.6-12.3) years. A total of 28 (15.2%) patients had one or more severe NP flares during the observation period. The median time from patient enrolment date to severe NP flare occurrence was 3.1 years (IQR 0.9-6.3 year). The 2- and 10-year severe NP flare-free survival rates were 92.7% and 86.0%, respectively. Among the manifestations of severe NP flare, psychosis was the most frequent (19.1%). In the multivariate model, low serum levels of C4 (hazard ratio (HR) = 3.67, p = 0.013) and severe NP manifestations at SLE diagnosis (HR = 7.11, p < 0.001) emerged as independent risk factors for developing severe NP flare. CONCLUSION: The first severe NP flare presented early in the course of SLE. Low C4 level and severe NP manifestations at SLE diagnosis could predict the development of severe NP flare.

Neuropsychiatric Lupus Erythematosus: Future Directions and Challenges; a Systematic Review and Survey.

This study aimed to systematically review neuropsychiatric lupus erythematosus (NPSLE) and establish a simplified diagnostic criterion for NPSLE. Publications from 1994 to 2018 in the database (Wanfang data (http://www.wanfangdata.com.cn/index.html) and China National Knowledge Internet (http://www.cnki.net)) were included. In total, 284 original case reports and 24 unpublished cases were collected, and clinical parameters were analyzed. An attempt was made to develop a set of simplified diagnostic criteria for NPSLE based on cases described in the survey and literature; moreover, and pathophysiology and management guidelines were studied. The incidence rate of NPSLE was estimated to be 12.4% of SLE patients in China. A total of 408 NPSLE patients had 652 NP events, of which 91.2% affected the central nervous system and 8.8% affected the peripheral nervous system. Five signs (manifestations, disease activity, antibodies, thrombosis, and skin lesions) showed that negative and positive predictive values were more than 70%, included in the diagnostic criteria. The specificity, accuracy, and positive predictive value (PPV) of the revised diagnostic criteria were significantly higher than those of the American College of Rheumatology (ACR) criteria (χ2=13.642, 15.591, 65.010, p<0.001). The area under the curve (AUC) for revised diagnostic criteria was 0.962 (standard error=0.015, 95% confidence intervals [CI] =0.933-0.990), while the AUC for the ACR criteria was 0.900 (standard error=0.024, 95% CI=0.853-0.946). The AUC for the revised diagnostic criteria was different from that for the ACR criteria (Z=2.19, p<0.05). Understanding the pathophysiologic mechanisms leading to NPSLE is essential for the evaluation and design of effective interventions. The set of diagnostic criteria proposed here represents a simplified, reliable, and cost-effective approach used to diagnose NPSLE. The revised diagnostic criteria may improve the accuracy rate for diagnosing NPSLE compared to the ACR criteria.

Is serum TWEAK a useful biomarker of neuropsychiatric systemic lupus erythematosus?

The aim of this study was to determine the role of the tumor necrosis factor like weak inducer of apoptosis (TWEAK) as a serum biomarker of neuropsychiatric involvement in systemic lupus erythematosus (NPSLE). Levels of TWEAK levels were measured in sera of 92 patients with systemic lupus erythematosus (SLE), including 28 patients with neuropsychiatric lupus, and in 59 healthy controls using ELISA. All SLE patients underwent rheumatological, neurological and psychiatric assessment. We found no significant differences in TWEAK levels, between SLE patients and the healthy controls (p=0.2411). Similarly, no difference was observed between subgroup of NPSLE and healthy controls (p=0.7658). The mean SLE disease activity (SLEDAI) was 13.25. No correlations between TWEAK levels with disease activity (SLEDAI, r=0.2113, p=0.2805) or the most common NPSLE manifestations such as headache (r=0.2079), seizures (r=0.1101), cerebrovascular disease (r= 0.2347), cognitive dysfunction (r=0.1597) and anxiety (r=0.1397) were observed. Our data do not support the use of serum TWEAK as a discriminating biomarker for NPSLE. The role of the TWEAK in NPSLE remains to be investigated.

Accelerated immune aging was correlated with lupus-associated brain fog in reproductive-age systemic lupus erythematosus patients.

AIMS: Cognitive impairment is common in systemic lupus erythematosus (SLE) patients with substantial adverse effects on function and quality of life. One hypothesis to understand the mechanisms of cognitive impairment in SLE is accelerated immunosenescence. The aim of this study is to observe the correlation between immunosenescence with cognitive impairment in patients with SLE. METHODS: Sixty-one female SLE patient were measured for CD4 and CD8 T cell-associated senescence markers, including percentage of end-stage differentiated T cells (CD4 and CD8 T cells expressing CD57+ or loss of CD28 expression), of naïve T cells (CD4+ CD45RA+ and CD8+ CD45RA+ ), memory T cells (CD4+ CD45RO+ and CD8+ CD45RO+ ), and antigen-experienced T cells (CD4+ KLRG1+ and CD8+ KLRG1+ ) which were measured using flow cytometry. One hallmark of immunosenescence called immune risk profile (IRP) was defined by an inverted ratio of CD4 and CD8. Cognitive functions were measured by Mini-Mental State Examination (MMSE) and Montréal Cognitive Assessment (MOCA) questionnaire. RESULTS: Thirty-six (59.1%) SLE patients who had IRP develop significantly lower attention and recall from both MMSE (P = .005 and P = .000) and MOCA (P = .017 and P = .000) examinations. Decreased visuospatial ability was also found in patients with IRP measured by MOCA (P = .046). There was a negative correlation between memory CD4+ CD45RO+ T cells with recall and visuospatial domain (R = -0.204, P = .039 and R = -0.250, P = .033; respectively), and negative correlation between CD8+ CD28- T cells with recall and attention domain (R = -0.249, P = .027 and R = -0.145, P = .048, respectively). CONCLUSION: Systemic lupus erythematosus patients develop an accelerated immunosenescence which contributes to cognitive dysfunction, especially in attention, recall, and visuospatial domains.

Neuropsychiatric events in systemic lupus erythematosus: a longitudinal analysis of outcomes in an international inception cohort using a multistate model approach.

OBJECTIVES: Using a reversible multistate model, we prospectively examined neuropsychiatric (NP) events for attribution, outcome and association with health-related quality of life (HRQoL), in an international, inception cohort of systemic lupus erythematosus (SLE) patients. METHODS: Annual assessments for 19 NP events attributed to SLE and non-SLE causes, physician determination of outcome and patient HRQoL (short-form (SF)-36 scores) were measured. Time-to-event analysis and multistate modelling examined the onset, recurrence and transition between NP states. RESULTS: NP events occurred in 955/1827 (52.3%) patients and 592/1910 (31.0%) unique events were attributed to SLE. In the first 2 years of follow-up the relative risk (95% CI) for SLE NP events was 6.16 (4.96, 7.66) and non-SLE events was 4.66 (4.01, 5.43) compared with thereafter. Patients without SLE NP events at initial assessment had a 74% probability of being event free at 10 years. For non-SLE NP events the estimate was 48%. The majority of NP events resolved over 10 years but mortality was higher in patients with NP events attributed to SLE (16%) versus patients with no NPSLE events (6%) while the rate was comparable in patients with non-SLE NP events (7%) compared with patients with no non-SLE events (6%). Patients with NP events had lower SF-36 summary scores compared with those without NP events and resolved NP states (p<0.001). CONCLUSIONS: NP events occur most frequently around the diagnosis of SLE. Although the majority of events resolve they are associated with reduced HRQoL and excess mortality. Multistate modelling is well suited for the assessment of NP events in SLE.

Neuropsychiatric lupus erythematosus: future directions and challenges; a systematic review and survey

This study aimed to systematically review neuropsychiatric lupus erythematosus (NPSLE) and establish a simplified diagnostic criterion for NPSLE. Publications from 1994 to 2018 in the database (Wanfang data (http://www.wanfangdata.com.cn/index.html) and China National Knowledge Internet (http://www.cnki.net)) were included. In total, 284 original case reports and 24 unpublished cases were collected, and clinical parameters were analyzed. An attempt was made to develop a set of simplified diagnostic criteria for NPSLE based on cases described in the survey and literature; moreover, and pathophysiology and management guidelines were studied. The incidence rate of NPSLE was estimated to be 12.4% of SLE patients in China. A total of 408 NPSLE patients had 652 NP events, of which 91.2% affected the central nervous system and 8.8% affected the peripheral nervous system. Five signs (manifestations, disease activity, antibodies, thrombosis, and skin lesions) showed that negative and positive predictive values were more than 70%, included in the diagnostic criteria. The specificity, accuracy, and positive predictive value (PPV) of the revised diagnostic criteria were significantly higher than those of the American College of Rheumatology (ACR) criteria (χ2=13.642, 15.591, 65.010, p<0.001). The area under the curve (AUC) for revised diagnostic criteria was 0.962 (standard error=0.015, 95% confidence intervals [CI] =0.933-0.990), while the AUC for the ACR criteria was 0.900 (standard error=0.024, 95% CI=0.853-0.946). The AUC for the revised diagnostic criteria was different from that for the ACR criteria (Z=2.19, p<0.05). Understanding the pathophysiologic mechanisms leading to NPSLE is essential for the evaluation and design of effective interventions. The set of diagnostic criteria proposed here represents a simplified, reliable, and cost-effective approach used to diagnose NPSLE. The revised diagnostic criteria may improve the accuracy rate for diagnosing NPSLE compared to the ACR criteria.

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.

Clinical, neuroimaging and immunological phenotype of South African neuropsychiatric systemic lupus erythematosus patients.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is an important cause of morbidity and mortality. We undertook this observational retrospective study of patients with NPSLE who had brain magnetic resonance imaging (MRI) to determine the indications for MRI and the correlation of clinical and laboratory findings with MRI. We identified 83 NPSLE patients (84.3% women) seen at Inkosi Albert Luthuli Central Hospital in Durban, South Africa, between June 2003 and May 2017. The mean age at SLE diagnosis was 26.24 ± 12.81 years and the median interval to NPSLE was 11.0 (interquartile range, 4.0-39.0) months. The most common indications for MRI were seizures (45.8%), psychosis (18.1%) and cerebrovascular disease (18.1%). The MRI was abnormal in 68 (81.9%) with small-vessel disease in 65 (78.3%) and large-vessel disease in eight (9.6%). The small-vessel abnormalities were white-matter hyperintensities (WMH) (59.0%), atrophy (55.4%) and lacunae (4.6%). Our patients had high disease activity at NPSLE. Cerebrovascular disease was associated with an abnormal MRI ( p = 0.018) and large-vessel disease ( p = 0.014) on MRI. Our NPSLE patients were younger and had high disease activity, and seizures were more common compared with other studies. The most common MRI abnormalities were WMH and cortical atrophy, in agreement with other studies.

Cognitive impairment, event-related potentials and immunological status in patients with systemic lupus erythematosus.

BACKGROUND: Cognitive impairment (CI) is a frequent problem in lupus patients, regardless of their overt neuropsychiatric (NP) involvement. OBJECTIVES: The aim of our study was to test cognitive abilities in systemic lupus erythematosus (SLE) patients by means of neuropsychological testing and event-related potentials (ERPs), and to search for their cognitive abilities correlations with a wide range of auto-antibodies. MATERIAL AND METHODS: A total of 37 SLE patients were subjected to a battery of neuropsychological tests, recommended by the American College of Rheumatology (ACR), and to ERPs. They were also tested for a wide range of auto-antibodies (anti-cardiolipin (aCL), anti-ß2-glycoprotein I (anti-ß2-GPI), lupus anticoagulant, anti-dsDNA, anti-nucleosome, anti-ribosomal P (anti-Rib-P), anti-ganglioside, anti-Ro/SS-A, and anti-La/SS-B. RESULTS: Cognitive impairment was found in 35% of patients, mostly with NP SLE (NPSLE), and was associated with higher disease activity, measured by the SLE Disease Activity Index (SLEDAI), and with a longer duration of central nervous system (CNS) involvement. There were no differences in the immunological status between CI patients and those without cognitive decline, but some antibodies were correlated with worse results in certain neuropsychological tests (anti-dsDNA and worse results of Rey Complex Figure Test - RCFTc for copying and RCFTr for recall, and of verbal fluency test (VFT); aCL IgG and worse results in Digit Span (DS) and in RCFTc). Event-related potentials showed prolonged N200 and P300 latencies in SLE patients in comparison to controls, but no differences were found between SLE and NPSLE patients. Mean P300 latency was significantly longer in patients without anti-nucleosome antibodies. CONCLUSIONS: Event-related potentials can be used as a complementary tool in assessing CI in SLE patients. The immunological status of patients with CI did not differ from that of patients without cognitive problems.

Neuropsychiatric Systemic Lupus Erythematosus Is Dependent on Sphingosine-1-Phosphate Signaling.

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.