Diffuse Neuropsychiatric Systemic Lupus Erythematosus Research Articles

Impaired serotonin synthesis in hippocampus of murine lupus represents an early neuropsychiatric event.

Despite significant progress in understanding the mechanisms underlying hippocampal involvement in neuropsychiatric systemic lupus erythematosus (NPSLE), our understanding of how neuroinflammation affects the brain neurotransmitter systems is limited. To date, few studies have investigated the role of neurotransmitters in pathogenesis of NPSLE with contradictory results. Hippocampal tissue from NZB/W-F1 lupus-prone mice and age-matched control strains were dissected in both pre-nephritic (3-month-old) and nephritic (6-month-old) stages. High-Performance Liquid Chromatography (HPLC) was used to evaluate the level of serotonin (5-HT), dopamine (DA), and their metabolites 5-HIAA and DOPAC, respectively, in mouse hippocampi. Lupus mice exhibit decreased levels of serotonin at the early stages of the disease, along with intact levels of its metabolite 5-HIAA. The 5-HT turnover ratio (5-HIAA/5-HT ratio) was increased in the hippocampus of lupus mice at pre-nephritic stage suggesting that low hippocampal serotonin levels in lupus are attributed to decreased serotonin synthesis. Both DA and DOPAC levels remained unaffected in lupus hippocampus at both early and late stages. Impaired hippocampal serotonin synthesis in the hippocampus of lupus-prone mice represents an early neuropsychiatric event. These findings may have important implications for the use of symptomatic therapy in diffuse NPSLE.

Brain-Reactive Antibodies are Potential Biomarkers for Evaluating Therapeutic Efficacy in NPSLE Patients.

PurposeNeuropsychiatric systemic lupus erythematosus (NPSLE) is the main cause of disability and death in systemic lupus erythematosus (SLE). It can cause cognitive impairment and organic brain syndrome. Brain-reactive antibodies, such as anti-DNA/anti-N-methyl-D-aspartate receptor (NMDAR) antibodies (DNRAbs), anti-microtubule-associated protein 2 (anti-MAP2) antibodies, and anti-glial fibrillary acidic protein (anti-GFAP) antibodies are thought to participate in the progression of NPSLE and thus considered potential diagnostic biomarkers, but whether they can be used for evaluating therapeutic efficacy in NPSLE is unknown.Patients and methodsOverall, 17 NPSLE patients and 10 non-SLE controls were included in this study. All the patients were treated with glucocorticoid (GC) pulse therapy. Serum and cerebrospinal fluid (CSF) concentrations of DNRAbs and anti-MAP2 and anti-GFAP antibodies were measured using enzyme-linked immunosorbent assay. The differences between the CSF concentrations of these antibodies in NPSLE patients before and after GC pulse therapy were analyzed.ResultsCSF concentrations of DNRAbs and anti-MAP2 and anti-GFAP antibodies were significantly higher in NPSLE patients compared to the non-SLE controls. Among the patients, CSF concentration of DNRAbs was significantly higher in the patients with acute confusional state (ACS) than in those with non-ACS diffuse NPSLE or focal NPSLE. Additionally, CSF concentration of DNRAbs was significantly correlated with QIgG (r=0.4884, P=0.0467) and IgG index (r=0.5319, P=0.0280) in NPSLE patients. Moreover, CSF concentrations of DNRAbs, anti-MAP2, and anti-GFAP antibodies and QIgG were significantly decreased after GC pulse therapy in NPSLE patients.ConclusionThese results indicate that CSF DNRAbs and anti-MAP2 and anti-GFAP antibodies are potential biomarkers for evaluating therapeutic efficacy in NPSLE.

Role of Serum IL-6 in Neuropsychiatric Systemic lupus Erythematosus.

ObjectiveThe present study was designed in order to elucidate the roles of serum interleukin 6 (IL‐6) in the pathogenesis in neuropsychiatric systemic lupus erythematosus (NPSLE).MethodsPaired serum and cerebrospinal fluid (CSF) samples were obtained from 101 patients with SLE when they presented active neuropsychiatric manifestations (69 patients with diffuse psychiatric/neuropsychological syndromes [diffuse NPSLE] and 32 patients with neurologic syndromes or peripheral nervous system involvement [focal NPSLE]) and from 22 control patients without SLE with noninflammatory neurological diseases. The levels of albumin and IL‐6 in CSF and sera were measured by enzyme‐linked immunosorbent assay.ResultsSerum IL‐6 and CSF IL‐6 were elevated in NPSLE compared with non‐SLE controls. Among NPSLE, serum IL‐6 and CSF IL‐6 were significantly elevated in acute confusional state (ACS) compared with non‐ACS diffuse NPSLE (anxiety disorder, cognitive dysfunction, mood disorder, and psychosis) or focal NPSLE. Q albumin (CSF/serum albumin quotient) was also significantly higher in ACS than in the other two groups of NPSLE. Of note, serum IL‐6 (r = 0.2801, p = 0.0207), but not CSF IL‐6 (r = 0.1602, p = 0.1918), was significantly correlated with Q albumin in patients with diffuse NPSLE, including ACS and non‐ACS.ConclusionThese results indicate that serum IL‐6 as well as CSF IL‐6 is involved in the pathogenesis of NPSLE. Moreover, it is suggested that serum IL‐6 might play a most important role in blood‐brain barrier breakdown in NPSLE.

Differential expression of antibodies to NMDA receptor in anti-NMDA receptor encephalitis and in neuropsychiatric systemic lupus erythematosus

ObjectiveAnti-NMDA receptor encephalitis is the most prevalent autoimmune encephalitis having characteristic clinical features with autoantibodies against tetrameric transmembrane channels composed of combinations of NR1 subunits of NMDA receptors with NR2...

Prevalence, outcome and prognostic factors of neuropsychiatric systemic lupus erythematosus: A real world single center study

Objectives: To investigate the prevalence, outcome and prognostic factors of neuropsychiatric systemic lupus erythematosus (NPSLE).Methods: SLE inpatients from 2005 to 2016 were included. Information on survival duration and causes of death was collected. Data were analyzed using Kaplan–Meier curves, log-rank tests and Cox proportional hazards modeling.Results: Among 1589 SLE patients, 101 (6.4%) were diagnosed with NPSLE. The overall survival rates of the NPSLE patients were 89%, 85% and 84% at 1, 3 and 5 years, respectively. The standardized mortality ratio of NPSLE patients was 11.14. The most common cause of death was NPSLE related conditions (7, 47%), including intracranial hypertension syndrome, cerebrovascular disease and motor neuron disease. The following variables were associated with death: cardiac involvement, renal involvement, diffuse NPSLE, acute confusional state, more than one NPSLE manifestation, low lymphocyte count, elevated C-reactive protein, abnormal cerebrospinal fluid (CSF) and high systemic lupus erythematosus disease activity index. Acute confusional state (p = .001), elevated intracranial pressure (p = .010) and C-reactive protein (CRP) (p = .032) were independently predictive factors of death.Conclusion: Our study demonstrates an 11.14-fold increased mortality of NPSLE patients compared with general population. NPSLE related disorders are main causes of death. Acute confusional state is the most significant predictive factor for poor prognosis.

Anti-ribosomal P protein antibodies influence mortality of patients with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematous involving a severe form of the disease

Objectives: The aim of this study is to clarify the effect of various autoantibodies on overall mortality in patients with diffuse psychiatric/neuropsychological syndromes in SLE (diffuse NPSLE).Methods: Fifty-five patients with diffuse NPSLE admitted from 1992 to 2017 had met inclusion criteria and were recruited for this study. The relationship of various serum autoantibodies with mortality was retrospectively analyzed based on the medical charts.Results: Of 55 patients, 14 patients [25.5%] had died during the observation period (2728 [22-8842] days (median [range])). The 5-year, 10-year, 15-year and 20-year mortality rates were 18.8%, 21.9%, 36.9% and 47.4%, respectively. Among various serum autoantibodies at the onset of diffuse NPSLE, only the presence of anti-ribosomal P protein antibodies (anti-ribo P) significantly increased the risk for death (relative risk 2.262, 95% confidence interval 1.276–4.417, p = 0.005). Of 14 fatal patients, 10 patients had died within 1 y after the onset of diffuse NPSLE. Remarkably, 7 of 10 patients with positive anti-ribo P had died of the severe complication primarily attributed to SLE except for one patient.Conclusions: The presence of anti-ribo P is a significant risk factor for overall poor prognosis in patients with diffuse NPSLE, involving a fatal complication by SLE.

Evaluation of blood-brain barrier function by quotient alpha2 macroglobulin and its relationship with interleukin-6 and complement component 3 levels in neuropsychiatric systemic lupus erythematosus.

Although quotient of alpha2 macroglobulin (Qα2MG) was previously reported to be useful for the evaluation of blood–brain barrier (BBB) function, it is not commonly used. We therefore evaluated BBB function among the various subsets of neuropsychiatric systemic lupus erythematosus (NPSLE) using quotient Q α2MG. Furthermore, we determined the correlation between Q α2MG and cerebrospinal (CSF) interleukin (IL)-6 level and quotient complement component 3 (Q C3). To determine intrathecal production of C3, the C3 index (Q C3/Q α2MG) was also calculated. Fifty-six patients with SLE were included in this study. Of these, 48 were diagnosed with NPSLE, consisting of 30 diffuse NPSLE patients (acute confusional state (ACS): n = 14, non-ACS: n = 16) and 18 patients with focal NPSLE. CSF IL-6 concentration, and paired serum and CSF levels of α2MG and C3, were measured by enzyme-linked immuno solvent assay (ELISA). The Q α2MG, Q C3, and C3 index were then calculated. Q α2MG, Q C3, and IL-6 concentrations in the CSF were significantly elevated in NPSLE compared with non-NPSLE. Among the subsets of NPSLE, significant increases in Q α2MG, CSF IL-6, and Q C3 were observed in ACS compared with non-ACS or focal NPSLE. There was a positive correlation between CSF IL-6 level and Q α2MG, as well as between Q C3 and Q α2MG, in diffuse NPSLE. There were no significant differences in C3 index between NPSLE and non-NPSLE, as well as among the subgroups of NPSLE. Our study suggests that BBB disruption is present in ACS, and elevated levels of IL-6 and C3 in CSF in diffuse NPSLE, especially in ACS, might result from their entry to the CSF from the systemic circulation through the damaged BBB, as well as increased intrathecal production. Furthermore, Q α2MG might be useful for the evaluation of BBB integrity.

Elevated levels of soluble fractalkine and increased expression of CX3CR1 in neuropsychiatric systemic lupus erythematosus

The aim of the present study was to determine the levels of soluble fractalkine (sFKN) and expression of CX3CR1 in neuropsychiatric systemic lupus erythematosus (NPSLE). Disease activity of SLE was assessed using the SLE Disease Activity Index (SLEDAI). The mRNA expression levels of CX3CR1 and FKN were quantified using reverse transcription-quantitative polymerase chain reaction. Levels of sFKN in the serum and cerebrospinal fluid (CSF) were measured using enzyme-linked immunosorbent assays. The mRNA expression levels of CX3CR1 in peripheral blood mononuclear cells from patients with NPSLE, non-NPSLE and Behcet's disease were significantly higher than that of rheumatoid arthritis and healthy persons. Levels of sFKN in the serum and CSF of cells with diffuse NPSLE (DNPSLE) were significantly higher than those of focal NPSLE (FNPSLE) cells. Serum levels of sFKN were higher in patients with NPSLE or non-NPSLE than heathy persons. sFKN in CSF were significantly higher in DNPSLE than non-NPSLE cells, but there were no significant difference between FNPSLE and control. Treatment reduced sFKN in serum and CSF in patients with NPSLE. There was significant correlation between sFKN in the serum of patients with SLE and the SLEDAI. sFKN levels were correlated with IgG in CSF from patients with NPSLE. The mRNA expression levels of CX3CR1 in the brain tissue of lupus mice were significantly higher than normal mice; however, the mRNA expression of FKN was lower than normal mice. These results suggest that sFKN and CX3CR1 may be involved in vasculitis and SLE, particularly in DNPSLE, which may occur by damaging the blood-brain barrier or recruiting expression microglial cells of CX3CR1. Additionally, sFKN appears to be a serological marker in patients with SLE, and may be useful for the diagnosis and treatment of NPSLE.

Differential activation mechanisms of serum C5a in lupus nephritis and neuropsychiatric systemic lupus erythematosus

Objective: To explore the role of C5a in the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) and lupus nephritis (LN).Methods: Sera were obtained from 29 patients with NPSLE, 25 with LN, 26 without NPSLE or LN [SLE alone], and 21 healthy donors. Cerebrospinal fluid (CSF) was obtained from 29 NPSLE patients. C5a and C5 were measured by ELISA. Blood-brain barrier (BBB) function was evaluated by Q albumin ([CSF albumin/serum albumin] × 103).Results: Serum C5a, but not C5, was significantly increased in SLE compared with healthy control. Serum C5a, but not C5, was significantly higher in NPSLE and in LN than in SLE alone. Serum C4, but not C3, was lower in LN than in NPSLE. Q albumin was significantly higher in diffuse NPSLE than in focal NPSLE, whereas there were no significant differences in CSF or serum C5a between both groups. Notably, CSF C5 and C5a were significantly correlated with Q albumin, whereas serum C5a, but not C5, appeared to be inversely correlated with Q albumin.Conclusion: These results disclosed that serum C5a was elevated not only in NPSLE but also in LN through different mechanisms. Moreover, it is suggested that C5a might be consumed during BBB damages.

Complement levels and anti-C1q autoantibodies in patients with neuropsychiatric systemic lupus erythematosus.

The objective of this paper is to analyse serum levels of anti-C1q, C1q circulating immune complexes (CIC), complement activation and complement components in systemic lupus erythematosus (SLE) patients during the first central nervous system neuropsychiatric (NP) event and to define the possible association between these results and clinical and laboratory characteristics. A total of 280 patients suspected of having NP involvement due to SLE were recruited in the Leiden NPSLE-clinic. All SLE patients were classified according to the ACR 1982 revised criteria for the classification of SLE. The clinical disease activity was measured by the SLE Disease Activity Index 2000 (SLEDAI-2K) and NP diagnoses were classified according to the 1999 ACR case definitions for NPSLE. We measured in serum of all patients anti-C1q and C1q CIC levels, the activation capacity of complement (CH50 and AP50) and different complement components (C1q, C3, C4). In 92 patients the symptoms were attributed to SLE. NPSLE patients consisted of 63 patients with focal NPSLE and 34 patients with diffuse NPSLE. Anti-C1q antibodies were significantly higher and CH50, AP50 and C3 were significantly lower in NPSLE patients compared with SLE patients without NPSLE. This association was specially marked for diffuse NPSLE while no differences were found for focal NPSLE. After using potential predictors, decreased C4 remained significantly associated with focal NPSLE, but only when antiphospholipid antibodies (aPL) were included in the model. C3 and AP50 were independently associated with diffuse NPSLE. When SLEDAI-2K was included in the model these two associations were lost. When individual NPSLE syndromes were analysed, psychosis and cognitive dysfunction showed significantly lower values of complement activation capacity and all complement components. No significant associations were seen for other individual NPSLE syndromes. The associations between diffuse NPSLE and anti-C1q, C3/AP50 and focal NPSLE and C4 may be explained by disease activity and the presence of aPL, respectively. The role of complement activation and complement components in lupus psychosis and cognitive dysfunction merits further research.

Association of antibodies to the NR1 subunit of N-methyl-D-aspartate receptors with neuropsychiatric systemic lupus erythematosus

Objective: To determine epitope reactivity of autoantibodies to N-methyl-D-aspartate (NMDA) receptor NR1 subunit and their association with neuropsychiatric systemic lupus erythematosus (NPSLE).Methods: Paired serum and CSF specimens were obtained from 41 patients with NPSLE (22 with diffuse psychiatric/neuropsychological syndromes [diffuse NPSLE] and 19 with neurologic syndromes or polyneuropathy [focal NPSLE]), 21 patients with various rheumatic diseases other than SLE (non-SLERD). Sera were also obtained from 27 SLE patients without neuropsychiatric manifestations (non-CNS SLE). Antibodies to murine NR1 (mNR1) or to 4 different preparations of synthetic 25-amino-acid (AA) peptides of human NR1 were measured by enzyme-linked immune sorbent assay (ELISA).Results: Serum anti-mNR1 levels were significantly higher in NPSLE than in non-SLERD. Sera from NPSLE patients bound efficiently to the AA residues 19–44 from the N-terminus of NR1 (NR1-A) or 56–81 (NR1-C). Accordingly, serum anti-NR1-A and anti-NR1-C were also elevated in NPSLE compared with non-SLERD. Of note, anti-NR1-A as well as anti-NR1-C levels in CSF, but not in sera, were significantly elevated in diffuse NPSLE compared with focal NPSLE or with non-SLERD.Conclusion: These results suggest that autoantibodies to NMDA receptor NR1, especially to the AA residues 19–44 and 56–81 from the N-terminus play a pivotal role in the pathogenesis of diffuse NPSLE.

Cognitive and White Matter Tract Differences in MS and Diffuse Neuropsychiatric Systemic Lupus Erythematosus.

Multiple sclerosis and neuropsychiatric systemic lupus erythematosus are autoimmune diseases with similar CNS inflammatory and neurodegenerative characteristics. Our aim was to investigate white matter tract changes and their association with cognitive function in patients with MS and those with neuropsychiatric systemic lupus erythematosus compared with healthy controls by using diffusion tensor imaging. Thirty patients with relapsing-remitting MS and 23 patients with neuropsychiatric systemic lupus erythematosus matched for disease severity and duration and 43 healthy controls were scanned with 3T MR imaging. The DTI was postprocessed, corrected for lesions, and analyzed with tract-based spatial statistics. Cognitive assessment included examination of processing speed; visual, auditory/verbal, and visual-spatial memory; and sustained attention and executive function. Differences were considered significant at P < .05. Tract-based spatial statistics analysis revealed significantly decreased fractional anisotropy and increased mean diffusivity in patients with MS compared with healthy controls, decreased fractional anisotropy in patients with MS compared with those with neuropsychiatric systemic lupus erythematosus, and an increased mean diffusivity in patients with neuropsychiatric systemic lupus erythematosus compared with healthy controls. Patients with MS showed decreased fractional anisotropy throughout central WM pathways, including the corpus callosum and the inferior longitudinal and fronto-occipital fasciculi compared with those with neuropsychiatric systemic lupus erythematosus. Altered cognitive scores in patients with MS were significantly associated with decreased fractional anisotropy and increased mean diffusivity in all examined domains, while in patients with diffuse neuropsychiatric systemic lupus erythematosus, only decreased fractional anisotropy in the superior WM pathways showed significant association with executive function. Patients with MS and neuropsychiatric systemic lupus erythematosus showed widespread WM tract alterations outside overt lesions, though more severe changes were identified in patients with MS. The WM tract changes were associated with cognitive dysfunction in all explored domains only in patients with MS.

Pathogenicity of lupus anti-ribosomal P antibodies: role of cross-reacting neuronal surface P antigen in glutamatergic transmission and plasticity in a mouse model.

To assess whether autoantibodies against ribosomal P (anti-P), which are possibly pathogenic in neuropsychiatric systemic lupus erythematosus (NPSLE), alter glutamatergic synaptic transmission and to what extent the cross-reacting neuronal surface P antigen (NSPA) is involved. We analyzed glutamatergic transmission and long-term potentiation (LTP) mediated by AMPA receptor (AMPAR) and N-methyl-d-aspartate receptor (NMDAR) by field excitatory postsynaptic potential (EPSP) at the CA3-CA1 synapse. AMPAR activation by patch-clamp recordings in primary ventral spinal cord neurons was analyzed. In primary hippocampal neurons, NSPA distribution was assessed by double immunofluorescence, and intracellular calcium changes were evaluated using Fura-2 AM. NSPA-LacZ reporter-knockin mice expressing a truncated NSPA were used to assess NSPA expression pattern and function in the brain using β-galactosidase staining and comparative electrophysiology, calcium responses, and water maze memory tests. NSPA was expressed in the brain in hippocampal CA1, dentate gyrus and ventral, but not dorsal, CA3 regions, encompassing postsynaptic regions and partial colocalization with NMDAR. Notably, NSPA-LacZ reporter-knockin mice showed impaired memory, and decreased NMDAR activity and LTP, with neurons insensitive to anti-P autoantibodies. Anti-P autoantibodies enhanced CA1 postsynaptic transmission, increasing AMPAR and NMDAR activity and leading to LTP abrogation after prolonged (20-minute) incubation. Our findings indicate that the neuronal cell surface target of anti-P, NSPA, is involved in glutamatergic synaptic transmission and plasticity related to memory in the hippocampus, and mediates the deleterious effects of anti-P on these processes. Cognitive impairment, as well as other diffuse NPSLE manifestations, may develop when anti-P autoantibodies have access to brain regions coexpressing NSPA, AMPAR, and NMDAR.

Brain MRI in patients with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus

BackgroundManifestations in neuropsychiatric systemic lupus erythematosus (NPSLE), especially active diffuse NPSLE syndromes, are some of the most difficult complications of the disease. For the evaluation and the diagnosis of central...

OP0215 Association of Cerebrospinal Fluid Anti-Sm Antibodies with Acute Confusional State in Systemic Lupus Erythematosus

BackgroundNeuropsychiatric manifestation in systemic lupus erythematosus (NPSLE) is one of the most serious complications of the disease. Previous studies disclosed the strong association between serum anti-Sm antibodies and organic brain...

FRI0402 Cluster Analysis of an ARRAY of Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus (NPSLE)

BackgroundNeuropsychiatric complaints in systemic lupus erythematosus (SLE) patients present a challenge to the clinician due to the lack of specific diagnostic tests. To date, reports on the associations between specific...

Blood-brain barrier damages and intrathecal synthesis of anti-N-methyl-D-aspartate receptor NR2 antibodies in diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus

IntroductionAlthough neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the recalcitrant complications of the disease, its pathogenesis still remains unclear. Previous studies revealed that antibodies reactive with NMDA (N-methyl-D-aspartate) receptor NR2 (anti-NR2) are elevated in cerebrospinal fluid (CSF) of patients with diffuse psychiatric/neuropsychological syndromes (diffuse NPSLE), which is usually more recalcitrant than neurologic syndromes of NPSLE (focal NPSLE). Two mechanisms have been implicated for the elevation of CSF IgG, including intrathecal synthesis and transudation through the damaged blood-brain barrier (BBB). The present study was designed in order to elucidate the roles of BBB function and intrathecal synthesis of anti-NR2 in the elevation of CSF anti-NR2 with regard to the severity in NPSLE.MethodsPaired serum and CSF samples were obtained from 81 systemic lupus erythematosus (SLE) patients when they presented active neuropsychiatric manifestations, and from 22 non-SLE control patients with non-inflammatory neurological diseases. The 81 SLE patients consisted of 55 patients with diffuse NPSLE, including 23 patients with acute confusional state (ACS), the severest form of diffuse NPSLE, and 26 patients with neurologic syndromes or peripheral nervous system involvement (focal NPSLE). IgG anti-NR2 and albumin were measured by ELISA. BBB function and intrathecal synthesis of anti-NR2 were evaluated by Q albumin and by CSF anti-NR2 index, respectively.ResultsCSF anti-NR2 levels, Q albumin and CSF anti-NR2 index were significantly higher in NPSLE than in non-SLE control. CSF anti-NR2 levels and Q albumin were significantly higher in ACS than in non-ACS diffuse NPSLE (anxiety disorder, cognitive dysfunction, mood disorder and psychosis) or in focal NPSLE, whereas there was no significant difference in CSF anti-NR2 index among the 3 groups. CSF anti-NR2 levels were significantly correlated with Q albumin in diffuse NPSLE (r = 0.3754, P = 0.0053).ConclusionsThese results demonstrate that the severity of BBB damages plays a crucial role in the development of ACS, the severest form of diffuse NPSLE, through the accelerated entry of larger amounts of anti-NR2 into the central nervous system.

Pathogenesis and treatment of CNS lupus

Neuropsychiatric manifestations pose diagnostic and therapeutic challenges in systemic lupus erythematosus (SLE). We review recently published studies on the epidemiology, pathogenesis, neuroimaging, and treatment of NPSLE. Generalized SLE activity or damage and antiphospholipid antibodies are identified as major risk factors for neuropsychiatric involvement. NPSLE patients have increased genetic burden and novel genomic approaches are expected to elucidate its pathogenesis. Animal data suggest that, in cases of disturbed blood-brain barrier, autoantibodies against the NR2 subunits of the N-methyl-D-aspartate receptor and 16/6 idiotype antibodies may cause diffuse neuropsychiatric manifestations through neuronal apoptosis or brain inflammation; data in humans are still circumstantial. In NPSLE, advanced neuroimaging uncovers structural and metabolic abnormalities in brain regions with normal appearance on conventional MRI. Treatment includes corticosteroids/immunosuppressants for inflammatory manifestations or generalized SLE activity, and antiplatelets/anticoagulation for manifestations related to antiphospholipid antibodies. In refractory cases, uncontrolled studies suggest a beneficial role of rituximab. We have begun to better understand how brain-reactive autoantibodies, present in a proportion of SLE patients, can cause brain injury and diffuse NPSLE. Further testing will be required to determine the clinical utility of advanced neuroimaging. Controlled trials are needed to guide therapeutic decisions.

FRI0327 Brain mri findings in patients with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus

BackgroundNeuropsychiatric manifestations in systemic lupus erythematosus (NPSLE) are one of the most difficult complications of the disease, especially diffuse psychiatric/neuropsychological syndromes (diffuse NPSLE). For the evaluation and the diagnosis of...

Association of cerebrospinal fluid anti–NR2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus

To explore the association of antibodies directed against N-methyl-D-aspartate receptor subunit NR2 (anti-NR2) in cerebrospinal fluid (CSF) with neuropsychiatric manifestations in systemic lupus erythematosus (NPSLE). Paired serum and CSF specimens were obtained from 56 patients with NPSLE (38 with diffuse psychiatric/neuropsychological syndromes [diffuse NPSLE] and 18 with neurologic syndromes or peripheral neuropathy [focal NPSLE]) and from 20 control patients with noninflammatory neurologic diseases. IgG anti-NR2 antibodies were measured by enzyme-linked immunosorbent assay using synthetic peptide containing the extracellular ligand-binding domain of NR2. The binding of affinity-purified anti-NR2 to human neuroblastoma cell line SK-N-MC was examined by flow cytometry. Purified anti-NR2 bound to the surface of SK-N-MC cells. Levels of anti-NR2 antibodies in CSF were significantly elevated in patients with diffuse NPSLE compared with levels in control patients or those with focal NPSLE, whereas there were no significant differences in serum anti-NR2 levels among the 3 groups. In 31 of the 38 patients with diffuse NPSLE (81.6%) and 8 of the 18 patients with focal NPSLE (44.4%), CSF anti-NR2 levels were more than 3 SD above the mean level in the control patients (P=0.0120 by chi-square test). These results indicate that anti-NR2 is a constituent of antineuronal antibodies and, more importantly, that anti-NR2 antibodies in CSF, but not in serum, are associated with diffuse NPSLE.