Analysis of local spontaneous neuronal activity by resting - state functional MRI in patients with neuropsychiatric systemic lupus erythematosus

In order to establish if neuropsychiatric systemic lupus erythematosus (NPSLE) can be identified by any characteristic other than those used to diagnose the neuropsychiatric (NP) disease itself, we retrospectively reviewed 98 systemic lupus erythematosus (SLE) patients followed over a mean period of 10 years. NPSLE was identified in 22 patients. Stroke and generalized seizures were the most frequent NP manifestations. The NPSLE and non-NPSLE groups were similar with regard to demographic characteristics, ACR criteria, serum autoantibodies, and frequency of hypertension and hypercholesterolemia. Of note, compared to the non-NPSLE group, NPSLE was associated with a higher frequency of smoking (78 versus 26%), organ damage (73 versus 34%), and cumulative mortality rate (14 versus 7%). The series of patients was further analysed according to the presence of antiphospholipid syndrome (APS). Significantly, the interval between the onset of NP disease and SLE diagnosis was shorter in the APS− (0.3 ± 1 years) than in the APS+ (5 ± 7 years) groups. Recurrence and/or persistence of NP events were only documented in the APS− group. Overall cumulative mortality was highest in NPSLE and in APS+ patients with inadequate anticoagulation control, identifying an aspect that requires improved vigilance and the development of novel therapeutic modalities.

The aims of this study are to investigate the cytokine, chemokine and adhesion molecule profiles in cerebrospinal fluid from patients with neuropsychiatric systemic lupus erythematosus and systemic lupus erythematosus with central nervous system infection. Experimental sets were established which included 108 patients and 132 cerebrospinal fluid samples. The patients were grouped as neuropsychiatric systemic lupus erythematosus (n = 54), systemic lupus erythematosus with central nervous system infection (n = 16), systemic lupus erythematosus controls (n=20), and non-inflammatory neurological disease (n=18). The dynamic changes of 21 patients in the neuropsychiatric systemic lupus erythematosus group before and after induction therapy were further analyzed. IL-1 beta, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, TNFalpha, IFN gamma, IP-10, MCP-1, RANTES, VCAM-1, and P-selectin were measured in cerebrospinal fluid samples by using a fluorescent bead-based assay. Cerebrospinal fluid levels of IL-8, MCP-1, P-selectin and VCAM-1 were significantly increased in neuropsychiatric systemic lupus erythematosus compared with systemic lupus erythematosus controls. IL-6, IL-17, IL-8 and VCAM-1 were higher in systemic lupus erythematosus with central nervous system infection than in systemic lupus erythematosus controls. Among systemic lupus erythematosus with central nervous system infection, the IL-6, IL-17, IL-8 and IP-10 levels were higher than those in neuropsychiatric systemic lupus erythematosus. After sufficient induction therapy, IL-8, MCP-1, P-selectin, VCAM-1 and IL-6 in patients with neuropsychiatric systemic lupus erythematosus decreased significantly. Levels of all molecules tested in non-inflammatory central nervous system disease were not different from those of systemic lupus erythematosus controls. From our data, the intrathecal cytokine/chemokine profile is different among patients with neuropsychiatric systemic lupus erythematosus, systemic lupus erythematosus complicated with central nervous system infection and systemic lupus erythematosus controls. IL-8, MCP-1, VCAM-1, P-selectin and IL-6 in cerebrospinal fluid are effective parameters to monitor neuropsychiatric systemic lupus erythematosus disease activity and response to treatment. Significantly elevated IL-17, IL-6, and to a lesser extent, IL-8, favors central nervous system infection in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. Its most prevalent manifestation is neuropsychiatric SLE (NP-SLE), which is characterized by increased involvement of the nervous system, with relevant symptoms, such as marked cognitive deficits, which are directly involved in subsequent functional disability. The objective of this study is to identify and compare the profile of cognitive deficits in patients with NP-SLE and patients with non-neuropsychiatric SLE (nonNP-SLE) by means of a systematic review and meta-analysis. We performed a systematic literature search based on the key words "cogn* OR neurocogn* AND lupus AND neuropsychiatry*" and included articles published between April 1999 and December 2016. A total of 244 articles were retrieved. We excluded reviews and meta-analyses, experiments not performed in humans, and single case reports. We included studies that used standardized cognitive measures and had included at least the subgroups NP-SLE and non NP-SLE. The meta-analysis was finally based on six studies, and 10 neuropsychological variables were examined. Significant differences were observed between the groups for six variables. In the remaining four variables, we observed marked heterogeneity between the groups or a low number of studies. The data obtained indicate greater cognitive impairment among NP-SLE patients than among nonNP-SLE patients, at least for the cognitive domains of visuomotor coordination, attention, executive function, visual learning and memory, and phonetic fluency. The identification and definition of cognitive deficits in SLE patients is necessary to develop adequate cognitive remediation programs to improve functional outcomes. (JINS, 2018, 24, 629-639).

Introduction: Systemic lupus erythematosus is an autoimmune disease affecting up to 210 per 100,000 people in Europe, more often among women. The inflammatory process in lupus causes changes in various organs. However, somatic changes are not the only effects of lupus. The neuropsychiatric manifestations of this disease have been given a separate name – neuropsychiatric lupus. Material and methods: A review of the literature available on the PubMed platform in the period of 1987-2023 was performed using the key words: neuropsychiatric systemic lupus erythematosus, mental disorders, mood disorders, sleep disorders, systemic lupus erythematosus. Original studies, review works, meta-analyses and Internet sources were analyzed. Results: Psychotic disorders in lupus occur with a frequency of up to 3%. Risk factors include young age, male gender and glucocorticoids treatment. Mood disorders occur in several to several dozen percent of lupus patients, including depression affecting up to ⅓ of patients. Belimumab, psychotherapy and improving the quality of sleep, the disturbance of which is observed in most patients with lupus, have potential in treatment. Anxiety disorders are seen primarily in the teenage age group, where social phobia predominates – the fear of rejection due to the disease – and they worsen and are exacerbated by rheumatic disease. Cognitive dysfunctions occur in up to 80% of lupus patients. They are probably related to enzymes of metabolic pathways, dyslipidemia and thyroid dysfunction. Conclusions: Mental disorders develop more often in patients with lupus than in the general population and they predispose to autoimmune diseases. Comprehensive diagnosis and psychiatric care of patients with lupus are necessary. Keywords: systemic lupus erythematosus, sleep disorders, mood disorders, neuropsychiatric systemic lupus erythematosus, mental disorders

Neuropsychiatric systemic lupus erythematosus (NPSLE) has varied manifestations. To study the pattern of neuropsychiatric (NP) involvement in systemic lupus erythematosus (SLE). Hospital based cross sectional and retrospective study. Patients admitted with a diagnosis of SLE, during a period of 16 months, were evaluated and any NP syndrome present classified as per the American College of Rheumatology (ACR) nomenclature. SPSS software Version 10 was used for descriptive analysis and correlative study. Out of 50 patients with SLE, all the patients with NPSLE [39 (78%)] were females, mean age 25.66 years (range: 11-44). The commonest manifestation was headache [20 (55.6%)]. Seizures were seen in 8 (20.51%) and psychosis in 6 (16.2%). Fine distal tremor was seen in 8 (20.51%) of patients. Headache is a frequent NP syndrome. Fine distal tremor is a syndrome not included in ACR classification but seen is 20% of our patients with NPSLE.

Background: Serum immunoglobulin G targeting the astrocyte water channel aquaporin-4 (AQP4) in the central nervous system (CNS) is a biomarker for neuromyelitis optica spectrum disease (NMOSD). Co-existence of NMOSD with systemic lupus erythematosus (SLE) putatively suggests susceptibility to antibody-mediated autoimmune disease. Objective: To estimate the prevalence of NMOSD in SLE and investigate the immunogenetic background for an association of NMOSD and SLE. Methods: The study included a predominantly population-based cohort with clinical and serological investigations of 208 patients with SLE, followed prospectively since 1995. All patients received immunosuppressive treatment. NMOSD was evaluated retrospectively based on the 2015 International Panel for NMOSD Diagnosis (IPND) criteria. Polymorphisms in programmed cell death protein 1 (PDCD-1) PD-1.3 G/A were genotyped. AGP4-IgG and other autoantibodies, including myelin oligodendrocyte glycoprotein (MOG), was determined blinded to clinical diagnosis. Results: Of 208 patients with SLE, 45(22%) had neuropsychiatric (NP) SLE, and CNS involvement predominated in 30 of 45 (67%) patients. Serum AQP4-IgG was detected in 2 of 30 (6.7%) neuropsychiatric SLE (NPSLE) patients both of whom had myelitis and antiphospholipid syndrome; one patient also had myasthenia gravis. None had MOG-IgG. PD-1.3A allele was not associated with SLE nor with NPSLE. Conclusion: AQP4-IgG autoimmune syndrome may rarely co-exist with SLE, and such patients have other NMOSD-typical syndromes such as myelitis.

The management of neuropsychiatric systemic lupus erythematosus (NPSLE) remains challenging because of clinical heterogeneity and the complexity of pathophysiologic mechanisms involved. We sought to determine the molecular signature of NPSLE and its endotypes towards novel biomarkers and targeted therapies. Whole-blood RNA sequencing from 308 patients with systemic lupus erythematosus (119 with NPSLE, 189 non-NPSLE) and 72-matched healthy controls (HCs) were performed. Supervised pathway enrichment analysis and unsupervised weighted gene coexpression network analysis were applied to distinguish clinically and molecularly defined NPSLE endotypes. Compared with HCs, patients with NPSLE demonstrated dysregulation of adaptive immune responses along with upregulation of interleukin (IL)-1, IL-6, IL-17, and IL-12/IL-23 signalling pathways. The comparison between NPSLE and non-NPSLE groups revealed a robust upregulation of complement cascade, DNA damage response, adaptive immunity, and IL-1 and IL-6 signalling. Furthermore, active NPSLE exhibited a strong autophagy signature. The B cell and complement cascade signatures exhibited a gradual upregulation across the non-NPSLE, inactive NPSLE, and active NPSLE subgroups. Within NPSLE, diffuse syndromes correlated positively with the oxidative phosphorylation module, while antiphospholipid antibody-positive NPSLE was not associated with specific signatures by unsupervised analysis. NPSLE endotypes such as cognitive dysfunction, seizures, psychosis, and optic neuritis were associated with distinct transcriptomic signatures namely IL-6 signalling and leukocyte migration, DNA damage response, inflammation, and type-I interferon, respectively. The clinical heterogeneity of NPSLE appears to be associated with molecular diversity, with certain endotypes or syndromes exhibiting distinct gene signatures. Upregulation of adaptive immune response and complement cascade suggests that complement inhibitors and B cell-targeted therapies could be further explored in NPSLE.

FRI0184 ATTRIBUTION OF NEUROPSYCHIATRIC MANIFESTATIONS TO SYSTEMIC LUPUS ERYTHEMATOSUS IN POLISH COHORT OF PATIENTS WITH THE USE OF THE ITALIAN MODEL

Background and Objective Neuropsychiatric manifestations are frequently reported in 75% of Systemic Lupus Erythematosus (SLE) patients and that varied from mild subtle signs: headache or mood disturbance to life threatening conditions: acute confusional state, major fits, stroke or transverse myelitis. Electroencephalography (EEG) was used to determine whether there is a lateralized pattern of electrophysiologic dysfunction in SLE patients or not. So, this study was done to describe EEG findings in a cohort of Egyptian SLE patients with Neuropsychiatric SLE (NPSLE), its possible correlation with any of the disease activity parameters and comparing them to patients with Non-NPSLE. Patients and Methods This case-control study was conducted on 60 SLE patients who fulfilled the 2015 ACR/SLICC Classification Criteria for SLE. They were classified into 2 groups: 30 patients with NPSLE as cases and 30 patients without NPSLE (Non-NPSLE) as controls. All patients were subjected to detailed medical history taking together with full clinical examination and calculations of SLE disease activity using the SLE disease activity index (SLEDAI) score. Laboratory investigations including CBC, ESR, CRP, BUN, creatinine, urine analysis, P/C ratio, C3, C4, Lupus Anticoagulant (LAC) and Anticardiolipin (ACL) antibodies and EEG were done for all patients. MRI brain was done for patients with NPSLE. Results There were 6 neuropsychiatric manifestations in the NPSLE group; the commonest was seizure disorders (43.3%), followed by psychosis (20.0%), cerebrovascular disease (16.7%), acute confusional state (13.3%), headache (10.0%) and lastly demyelinating syndrome (6.7%). SLEDAI score was higher in NPSLE group (Median=16) than nonNPSLE group (Median=4) (P < 0.01). ACL IgM positivity was higher in NPSLE group (P < 0.05). 53.3% of NPSLE group had abnormal MRI brain findings, the most common finding was periventricular white matter lesion (23.3%), followed by infarction (13.3%), subcortical white matter lesion and demyelinating lesion (6.7%). Lastly was sinus thrombosis, cerebral edema and encephalomalacia (3.3% each). 12 patients out of 30 (40.0%) with NPSLE had EEG abnormalities, while all 30 patients with non-NPSLE had no EEG abnormalities. The most common EEG abnormalities in NPSLE group were diffuse slowing (20.0%), followed by generalized epileptiform activity (13.3%), and lastly temporal epileptiform activity (6.7% each). 50% of patients with abnormal EEG had normal MRI. 13 patients out of 30 with NPSLE had seizure disorders (43.3%), 8 of them had abnormal EEG (61.5%). Conclusion Not all patients with NPSLE must have abnormal brain MRI or EEG. EEG is a useful assistant tool in diagnosing and studying the different manifestations of NPSLE especially seizure disorder and acute confusional state, but it cannot be used as a screening test alone for detecting NPSLE and must be supplemented by neuroimaging studies.

Comprehensive analysis of disease activity, neuropsychiatric symptoms, imaging features and risk factors for seizure in hospitalized patients with juvenile-onset neuropsychiatric systemic lupus erythematosus.

Objective: Previous reports indicate that serum anti-microtubule-associated protein 2 (MAP-2) antibodies are common in sera from patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Differential diagnosis of NPSLE is occasionally difficult because of differential diagnosis which can mimic NPSLE. Therefore, specific biomarkers for NPSLE are needed. We conducted this study to clarify whether cerebrospinal fluid (CSF) anti-MAP-2 antibodies are a useful diagnostic biomarker for NPSLE.Methods: Enzyme-linked immunosorbent assay was conducted to measure CSF concentrations of anti-MAP-2 and anti-ribosomal P antibodies and of IL-6 in NPSLE patients (n = 24) and non-NPSLE controls (n = 17). The non-NPSLE controls consisted of systemic lupus erythematosus patients with neuropsychiatric symptoms caused by non-NPSLE conditions (n = 10) and patients with other connective tissue diseases (n = 7).Results: Significantly higher anti-MAP-2 antibody titers were found in the CSF of patients with NPSLE versus non-NPSLE controls. The prevalence of anti-MAP-2 antibodies was 33.3% (8/24) in NPSLE patients when a positive cutoff value was 3 standard deviations above the mean optical density of non-NPSLE controls. None of the controls had anti-MAP-2 antibodies in their CSF. Both anti-ribosomal P antibody titers and concentration of IL-6 in the CSF were significantly higher in patients with NPSLE having anti-MAP-2 antibodies than in patients with non-NPSLE controls.Conclusion: Anti-MAP-2 antibodies could be detected in the CSF of 33.3% of patients with NPSLE, and its presence was highly specific for NPSLE. We propose that CSF anti-MAP-2 antibodies are a novel and useful diagnostic biomarker for NPSLE.

Neuropsychiatric Lupus: The Prevalence and Autoantibody Associations Depend on the Definition: Results from the 1000 Faces of Lupus Cohort

Development of the American College of Rheumatology (ACR) criteria for neuropsychiatric systemic lupus erythematosus (NPSLE) was a major step in understanding these disorders. Without biomarkers confirming a direct relationship between systemic lupus erythematous and the neuropsychiatric diagnoses, skeptics may view the ACR classification as mere semantics. However, by allowing neurologists and rheumatologists in different centers to use standardized terms, the criteria are useful in caring for patients and in assembling homogeneous groups of research participants. In pediatric systemic lupus erythematous cohorts, the prevalence of NPSLE in general, and movement disorders in particular, ranged from 34.6% and 0% in a retrospective study in Taiwan1 to 95% and 7% in a prospective study in the United States.2 For many patients, diagnosis and treatment are delayed as mimicking infectious, toxic, and metabolic conditions are ruled out. A diagnostic biomarker would be immensely helpful. Although history, examination, magnetic resonance imaging, cerebrospinal fluid (CSF) analysis, and standard autoantibody profiles are important, none are sufficiently sensitive or specific to be considered a diagnostic biomarker for NPSLE. The search for informative biomarkers in neuro-immunological conditions including NPSLE has been hampered by the use of techniques which alter the target antigen’s structure. Studies using cell-based assays, which preserve antigenic structure, have produced more clinically useful and scientifically valid results. At least two prior studies have used cell-based, flow cytometry assays in NPSLE. In adult patients with NPSLE, Alosachie et al.3 found antibodies to a neuroblastoma cell line in 63% (36/57) of serum samples and 83% (5/6) of CSF samples, but none using a glioma cell line. In a cohort of 17 adult patients with NPSLE, Kang et al.4 detected antibodies to the same neuroblastoma cell line in 77% (13) of serum and 88% (15) of CSF samples. In the latter study, abnormalities in magnetic resonance imaging and CSF anti-ribosomal P antibody assays were found in only 59% and 18% of patients with NPSLE respectively. In both studies, patients with systemic lupus erythematous without neuropsychiatric symptoms, and disease and healthy controls rarely harbored such antibodies, thus yielding good positive and negative predictive values, particularly for the CSF assays.3,4 Dale et al.,5 the first group to apply these techniques to pediatric NPSLE patients, found elevated serum immunoglobulin G binding to the surface of cells with dopaminergic neuronal characteristics in six females with chorea (n=4) or parkinsonism (n=2) associated with lupus and/or anti-phospholipid antibodies compared with healthy and disease controls. The fact that similar levels of antibodies were detected in patients with lupus without neuropsychiatric symptoms contrasts with the prior reports and is somewhat troubling. This finding suggests a difference between pediatric and adult NPSLE and/or the requirement for a ‘second hit’ to cause clinical expression, but ultimately remains unexplained in the current study. From the above studies, several points emerge. First, anti-neuronal autoantibodies appear to be important in NPSLE. Secondly, based on the two adult studies, measurement of such antibodies in CSF may be more meaningful than in serum. The lack of testing in CSF in the current study is an important limitation. Lastly, the target cell type chosen for the antibody assays may be critically important. An elegant feature of the current study is that the authors used a cell line with dopaminergic characteristics to detect antibodies in the subgroup of patients with movement disorders within NPSLE. This raises several questions. Does this approach explain why Dale et al. found elevated antibodies in all of the patients, compared with prior studies with lower sensitivity? Would the dopaminergic cell assay detect antibodies in other NPSLE subgroups? What is the best cell type to use for other, more common NPSLE diagnoses, such as headaches, seizures, and mood disorders? Future research will hopefully identify the specific antigen targeted by the autoantibodies in patients with NPSLE, perhaps within diagnostic subgroups. Such identification is necessary to elevate the status of the currently identified autoantibodies from an informative, but not definitive, finding, to the next big diagnostic biomarker in the field.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can have detrimental effects on many different systems in the body, including the central nervous system. Neuropsychiatric SLE (NPSLE) refers to several different neurological and/or behavioral clinical syndromes, and has been reported as having a prevalence rate of approximately 30−40%, while manifestation of myelitis or optic neuritis of NPSLE is rare (~1%). Myelitis and optic neuritis are easily identifiable since myelitis is frequently transverse, and manifests as severe disturbances in both motor and sensory pathways, while optic neuritis is often both bilateral and severe. At least 85% of patients experience relapses in the form of optic neuritis, transverse myelitis, or both. Furthermore, some cases of NPSLE with optic neuritis are often complicated by myelitis. Interestingly, the characteristics of myelitis or optic neuritis in NPSLE are quite similar to neuromyelitis optica (NMO), a disease characterized by bilateral optic neuropathy and transverse myelopathy. In fact, magnetic resonance imaging (MRI) of patients with NPSLE has demonstrated longitudinal spinal involvement showing cord swelling and hyperintense lesions in central regions. These findings are also typically observed in MRIs of patients with NMO. Additionally, anti-aquaporin 4 (AQP4) antibodies have been discovered in patients with NMO and with NPSLE with myelitis and/or optic neuritis. Therefore, complications that are often encountered with NMO should be considered when treating cases of NPSLE with myelitis and/or optic neuritis. Moreover, since the treatment of NMO closely resembles the therapeutic approaches taken for NPSLE, corticosteroids alone or in combination with immunosuppressants could prove effective in reducing incidents of relapse. Some patients, however, may be refractory to steroid therapy; in such cases, plasma exchange may have priority over other second-line therapeutic strategies, such as intravenous immunoglobulin and rituximab, because of treatment approaches typically employed in NMO. In this review, I will discuss pathological similarities between NPSLE with myelitis and/or optic neuritis and NMO with the aim of demonstrating that our knowledge of NMO should be considered when treating NPSLE with myelitis and/or optic neuritis.

Objective To analyze the laboratory indexes and clinical symptoms of patients with neuropsychiatric systemic lupus erythematosus (NPSLE), so as to provide the basis for the condition judgment and individual treatment of NPSLE patients. Methods The laboratory indexes and clinical manifestations of 136 cases of NPSLE and 146 cases of non-NPSLE were compared and analyzed. Results The distribution of C-reactive protein, neutrophils, neutrophil rate, antinuclear antibodies (ANA) and hepatitis B virus DNA copies in NPSLE group were higher than those in non-NPSLE group (P<0.05), while the distribution of serum albumin, erythrocyte sedimentation rate, immune globulin G, and immune globulin E concentrations, lymphocytes and lymphocyte ratio were lower than those in non-NPSLE group (P<0.05). The systemic lupus erythematosus disease activity index (SLEDAI) score in NPSLE group was significantly higher than in that non-NPSLE group (P<0.05). In addition to the neuropsychological manifestations, the clinical symptoms of low complement (89.71%), 24 hours proteinuria (59.50%) and fever (58.82%) are also common in NPSLE group. Conclusions The activity of NPSLE patients was related to the decrease of lymphocyte count and proportion while ANA was positive in serum. Hepatitis B virus infection may be related to NPSLE, which should be paid more attention in clinical diagnosis and treatment. Key words: Lupus; Nervous system; Laboratory index; Clinical symptoms