RESUMEN
BACKGROUND: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a poorly understood and heterogeneous manifestation of SLE. Common major NPSLE syndromes include strokes, seizures, myelitis, and aseptic meningitis. Easily obtainable biomarkers are needed to assist in early diagnosis and improve outcomes for NPSLE. A frequent end-result of major syndromes is neuronal or glial injury. Blood-based neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) have been utilized as markers for monitoring disease activity and/or severity in other neurodegenerative and neuroinflammatory diseases; however, they have not been evaluated in active major NPSLE. METHODS: This was a case-control study. We enrolled patients aged 12-60 years with active major NPSLE, SLE without active major NPSLE, and healthy controls. Active NPSLE was defined as being <6 months from last new or worsening neuropsychiatric symptom. Demographics, clinical data, and serum or plasma biosamples were collected. RESULTS: Thirteen patients with active major NPSLE, 13 age/sex/kidney function matched SLE controls without active major NPSLE, and 13 age/sex matched healthy controls (mean ages 26.8, 27.3, 26.6 years) were included. 92% of each group were female. Major syndromes included stroke (5), autonomic disorder (3), demyelinating disease (2), aseptic meningitis (2), sensorimotor polyneuropathy (2), cranial neuropathy (1), seizures (1), and myelopathy (2). Mean (standard deviation) blood NfL and GFAP were 3.6 pg/ml (2.0) and 50.4 pg/ml (15.0), respectively, for the healthy controls. Compared to healthy controls, SLE without active major NPSLE had mean blood NfL and GFAP levels 1.3 pg/ml (p = .42) and 1.2 pg/ml higher (p = .53), respectively. Blood NfL was on average 17.9 pg/ml higher (95% CI: 9.2, 34.5; p < .001) and blood GFAP was on average 3.2 pg/ml higher (95% CI: 1.9, 5.5; p < .001) for cases of active major NPSLE compared to SLE without active major NPSLE. In a subset of 6 patients sampled at multiple time points, blood NfL and GFAP decreased after immunotherapy. CONCLUSIONS: Blood NfL and GFAP levels are elevated in persons with SLE with active major NPSLE compared to disease matched controls and may lower after immunotherapy initiation. Larger and longitudinal studies are needed to ascertain their utility in a clinical setting.
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Biomarcadores , Proteína Ácida Fibrilar de la Glía , Vasculitis por Lupus del Sistema Nervioso Central , Proteínas de Neurofilamentos , Humanos , Femenino , Biomarcadores/sangre , Estudios de Casos y Controles , Adulto , Masculino , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Proteína Ácida Fibrilar de la Glía/sangre , Proteínas de Neurofilamentos/sangre , Adulto Joven , Adolescente , Persona de Mediana Edad , Niño , Neuroglía/patología , Neuroglía/metabolismo , Neuronas/patologíaRESUMEN
OBJECTIVES: This study aimed to investigate disparities in clinical profiles and autoantibody patterns between patients with and without neuropsychiatric systemic lupus erythematosus (NPSLE) in a cohort and to identify risk factors associated with NPSLE in the Chinese population. METHODS: SLE patients were retrospectively reviewed from two tertiary hospitals. The relationships between NPSLE and immunological biomarkers were explored. RESULTS: Among the 945 SLE patients, 75 (7.94%) were diagnosed with NPSLE. The most prevalent NP manifestations involved cognitive disorder (30.67%), headache (26.67%), seizure disorder (26.67%), and psychosis (26.67%).We observed significant associations between psychosis and anti-ß2GPI antibodies (F = 6.092, p = 0.015), polyneuropathy and anti-Scl70 antibodies (F = 20.161, p < 0.001), demyelinating syndrome and anti-cardiolipin antibodies (F = 6.637, p = 0.011), myasthenia gravis and anti-RNP (F = 5.864, p = 0.017), and anti-Smith antibodies (F = 5.096, p = 0.026). Multivariate logistics analysis showed that anti-prothrombin (aPT) IgM antibodies (OR = 10.985, CI 1.279-94.343, p = 0.029), age (OR = 1.169, CI 1.032-1.325, p = 0.014), and serum creatinine (SCr) (OR = 1.014, CI 1.003-1.025, p = 0.009) were independent risk factors of NPSLE, while anti-Sjogren syndrome antigen B (SSB) antibodies (OR 0.023, CI 0.002-0.622, p = 0.023) and high complement C3 (OR = 0.001, CI 0-0.045, p < 0.001) indicated reduced risk of NPSLE. CONCLUSION: Various neuropsychiatric manifestations in SLE were found to be correlated with specific autoantibodies. Independent risk factors for NPSLE included aPT IgM antibodies, age, and elevated serum creatinine, while the absence of anti-SSB antibodies and low complement C3 levels were associated with increased risk. KEY POINTS: â¢Significant associations were found between specific autoantibodies and neuropsychiatric symptoms, shedding light on potential biomarkers for predicting and understanding NPSLE. â¢The study identifies independent risk factors for NPSLE in the Chinese population, including the presence of anti-prothrombin IgM antibodies, older age, elevated serum creatinine, and lower complement C3 levels.
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Autoanticuerpos , Biomarcadores , Vasculitis por Lupus del Sistema Nervioso Central , Humanos , Femenino , Masculino , Estudios Retrospectivos , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Adulto , Biomarcadores/sangre , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Persona de Mediana Edad , China , Factores de Riesgo , Adulto Joven , Complemento C3/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Protrombina/inmunologíaRESUMEN
Surface-enhanced Raman spectroscopy (SERS) is a powerful optical technique for non-invasive and label-free bioanalysis of liquid biopsy, facilitating to diagnosis of potential diseases. Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the subgroups of systemic lupus erythematosus (SLE) with serious manifestations for a high mortality rate. Unfortunately, lack of well-established gold standards results in the clinical diagnosis of NPSLE being a challenge so far. Here we develop a novel Raman fingerprinting machine learning (ML-) assisted diagnostic method. The microsphere-coupled SERS (McSERS) substrates are employed to acquire Raman spectra for analysis via convolutional neural network (CNN). The McSERS substrates demonstrate better performance to distinguish the Raman spectra from serums between SLE and NPSLE, attributed to the boosted signal-to-noise ratio of Raman intensities due to the multiple optical regulation in microspheres and AuNPs. Eight statistically-significant (p-value <0.05) Raman shifts are identified, for the first time, as the characteristic spectral markers. The classification model established by CNN algorithm demonstrates 95.0% in accuracy, 95.9% in sensitivity, and 93.5% in specificity for NPSLE diagnosis. The present work paves a new way achieving clinical label-free serum diagnosis of rheumatic diseases by enhanced Raman fingerprints with machine learning.
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Vasculitis por Lupus del Sistema Nervioso Central , Aprendizaje Automático , Microesferas , Espectrometría Raman , Humanos , Espectrometría Raman/métodos , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Vasculitis por Lupus del Sistema Nervioso Central/diagnóstico , Técnicas Biosensibles/métodos , Nanopartículas del Metal/química , Oro/química , Redes Neurales de la Computación , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/diagnósticoRESUMEN
OBJECTIVE: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a form of SLE associated with severe NP syndromes causing mortality and morbidity. Respecting the fundamental of BAFF in NPSLE pathophysiology, we investigated its clinical value. METHODS: Totally 105 NPSLE and 101 SLE cases without NPSLE (non-NPSLE, control) were included. Serum BAFF/TNF-α/IL-6/IL-10 levels were measured using ELISA kits. T lymphocytes were detected by flow cytometry. The independent influencing factors for NPSLE, and the auxiliary diagnostic efficacy and the ability of BAFF levels to predict adverse prognosis of NPSLE patients were analyzed by multiple factor logistic regression, and ROC curve and survival curve. RESULTS: In NPSLE patients, serum BAFF level was increased and positively correlated with SLEDAI-2k, serum proinflammatory cytokines, while negatively correlated with CD4+T/CD8+T cells, and anti-inflammatory cytokine. High serum BAFF protein level was associated with a higher risk of developing NPSLE. The AUC of serum BAFF > 301.7 assisting in NPSLE diagnosis was 0.8196. Furthermore, high levels of serum BAFF were associated with a higher risk of adverse outcomes in NPSLE patients. . CONCLUSION: Serum BAFF level in NPSLE patients was correlated with lymphocytes and high serum BAFF protein level could assist in diagnosis and to predict adverse outcomes in NPSLE patients.
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Factor Activador de Células B , Vasculitis por Lupus del Sistema Nervioso Central , Humanos , Factor Activador de Células B/sangre , Femenino , Masculino , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Vasculitis por Lupus del Sistema Nervioso Central/diagnóstico , Adulto , Persona de Mediana Edad , Biomarcadores/sangre , Pronóstico , Citocinas/sangre , Inflamación/sangre , Inflamación/inmunología , Inflamación/diagnóstico , Adulto JovenRESUMEN
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.
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Anticuerpos Antinucleares/sangre , Vasculitis por Lupus del Sistema Nervioso Central/epidemiología , Trastornos Psicóticos/epidemiología , Adulto , Anciano , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Vasculitis por Lupus del Sistema Nervioso Central/psicología , Masculino , Servicios de Salud Mental/estadística & datos numéricos , Persona de Mediana Edad , Prevalencia , Trastornos Psicóticos/sangre , Trastornos Psicóticos/etiología , Estudios RetrospectivosRESUMEN
CD226 is an activating receptor expressed on the cell surface of natural killer cells and T cells. Although CD226 polymorphism is known to be involved in systemic lupus erythematosus (SLE), the involvement of soluble CD226 (sCD226) in SLE is still unknown. In the present study, we measured serum sCD226 levels using an enzyme-linked immunosorbent assay in 58 SLE patients and 33 healthy controls (HCs) and evaluated their associations with SLE Disease Activity Index 2000 (SLEDAI-2K), clinical manifestations, laboratory data, and the cumulative probability of flare. Serum sCD226 levels showed no significant differences between SLE patients and HCs. However, sCD226 levels were significantly elevated in active SLE patients with a SLEDAI-2K score of ≥ 20 compared with HCs. In SLE patients, sCD226 levels were significantly correlated with SLEDAI-2K scores and anti-dsDNA antibody titers. Moreover, the cumulative probability of flare was markedly higher in patients with high sCD226 than in those with low sCD226. In patients with neuropsychiatric involvement, sCD226 levels were elevated and reflected neuropsychiatric disease activity. These findings indicate that serum sCD226 levels are associated with disease activity and flares of SLE. Thus, it may be a useful biomarker for SLE, and its monitoring allows for more precise SLE management.
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Antígenos de Diferenciación de Linfocitos T/sangre , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Adulto , Anticuerpos Antinucleares/sangre , Biomarcadores/sangre , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Lupus Eritematoso Sistémico/clasificación , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Vasculitis por Lupus del Sistema Nervioso Central/clasificación , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , SolubilidadRESUMEN
BACKGROUND: Autoantibodies (auto Abs) and inflammatory mediators (IMs) in cerebrospinal fluid (CSF) may be involved in the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE). It is suggested that anti-N-methyl D-aspartate receptor NR2 subunit (NR2) Ab can develop NP manifestation after blood-brain barrier (BBB) abruption. We also reported the association between NPSLE and CSF anti-U1RNP Ab. In the present study, combined effects of CSF anti-NR2 and anti-U1RNP Abs on IMs in patients with NPSLE were examined. METHODS: CSF samples were collected from 69 patients with NPSLE and 13 non-NPSLE controls. CSF anti-NR2 and anti-U1RNP Abs were determined using ELISA. Levels of IL-6, IL-8, and monokine induced by IFN-γ (MIG) in CSF were measured by quantitative multiplex cytokine analysis. RESULTS: CSF IL-6 levels were higher in CSF anti-NR2-positive than in CSF anti-NR2-negative patients (p = 0.003) and non-NPSLE controls (p = 0.015) and were positively correlated with anti-NR2 titer (r = 0.42). CSF IL-8 levels were higher in CSF anti-U1RNP-positive than in CSF anti-U1RNP-negative patients (p = 0.041). CSF MIG levels were more elevated in CSF anti-NR2-positive (p = 0.043) and anti-U1RNP-positive patients (p = 0.029) than in non-NPSLE controls. Additionally, in double positive (DP; both anti-NR2 and U1RNP Ab positive) group, CSF IL-6 and MIG levels were significantly higher than in the double negative (DN; both anti-NR2 and U1RNP Ab negative) group. However, combined effect of both Abs on IM elevation and clinical manifestation was not clear. CONCLUSIONS: CSF anti-NR2 and anti-U1RNP Abs have different effects on the elevation of CSF IM levels in patients with NPSLE. Additional effect of anti-U1RNP Abs on anti-NR2 Ab-mediated NP manifestation, however, was not recognized in our study.
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Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Receptores de N-Metil-D-Aspartato/inmunología , Ribonucleoproteína Nuclear Pequeña U1/inmunología , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Inflamación/sangre , Inflamación/líquido cefalorraquídeo , Mediadores de Inflamación/sangre , Mediadores de Inflamación/líquido cefalorraquídeo , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Vasculitis por Lupus del Sistema Nervioso Central/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
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.
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Complemento C4/metabolismo , Vasculitis por Lupus del Sistema Nervioso Central/psicología , Adulto , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Masculino , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
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.
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Citocina TWEAK/sangre , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Vasculitis por Lupus del Sistema Nervioso Central/diagnóstico , Adulto , Ansiedad/sangre , Ansiedad/diagnóstico , Ansiedad/psicología , Biomarcadores/sangre , Femenino , Humanos , Vasculitis por Lupus del Sistema Nervioso Central/psicología , Masculino , Persona de Mediana EdadRESUMEN
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.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Cognición , Disfunción Cognitiva/inmunología , Inmunosenescencia , Lupus Eritematoso Sistémico/inmunología , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Adolescente , Adulto , Atención , Biomarcadores/sangre , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/diagnóstico , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Vasculitis por Lupus del Sistema Nervioso Central/diagnóstico , Vasculitis por Lupus del Sistema Nervioso Central/psicología , Recuerdo Mental , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVES: To identify specific cerebrospinal fluid (CSF) biomarkers for the diagnosis and disease severity evaluation of neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Patients presented with neuropsychiatric symptoms were recruited and categorised as 36 NPSLE, 19 SLE controls, 4 other connective tissue disease (CTD) controls and 10 nervous system disorder (NSD) controls. The NPSLE group consisted of severe NPSLE (sNPSLE) and mild NPSLE (mNPSLE). Potential biomarkers were determined by Luminex multiplex assay and enzyme-linked immunosorbent assay. RESULTS: 1) Among a variety of neurological disease-related proteins, only ubiquitin carboxyl hydrolase L1 (UCH-L1) levels were significantly elevated in the CSF samples of sNPSLE patients compared with those of mNPSLE patients (p=0.020) and SLE controls (p=0.037). CSF UCH-L1 levels were significantly positively correlated with SLE disease activity index and overlap number of NPSLE manifestations. 2) CSF anti-UCH-L1 autoantibodies were significantly elevated in patients with NPSLE in comparison to all of the control groups, with a sensitivity of 53% and a specificity of 91% for NPSLE. CSF anti-UCH-L1 levels were associated with organ involvement and were positively correlated with serum anti-UCH-L1 levels in the NPSLE patients (r=0.4551, p=0.0382). CONCLUSIONS: Anti-UCH-L1 is a promising CSF biomarker for NPSLE diagnosis with high specificity, and the elevated levels of CSF UCH-L1 reflect the clinical severity of NPSLE. The elevation of UCH-L1 and its autoantibody in NPSLE patients showed us novel aetiological insights on NPSLE.
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Anticuerpos Antifosfolípidos/sangre , Hidrolasas/metabolismo , Vasculitis por Lupus del Sistema Nervioso Central , Ubiquitina , Autoanticuerpos , Ensayo de Inmunoadsorción Enzimática , Humanos , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Vasculitis por Lupus del Sistema Nervioso Central/etiología , Vasculitis por Lupus del Sistema Nervioso Central/inmunologíaRESUMEN
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.
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Anticuerpos Antinucleares/inmunología , Trastornos del Conocimiento/inmunología , Trastornos del Conocimiento/fisiopatología , Potenciales Evocados , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/fisiopatología , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Vasculitis por Lupus del Sistema Nervioso Central/fisiopatología , Pruebas Neuropsicológicas , Trastornos del Conocimiento/sangre , Humanos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/psicología , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Vasculitis por Lupus del Sistema Nervioso Central/psicología , beta 2 Glicoproteína IRESUMEN
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.
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Autoanticuerpos/sangre , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Mortalidad , Adolescente , Adulto , Anciano , Autoanticuerpos/inmunología , Femenino , Humanos , Vasculitis por Lupus del Sistema Nervioso Central/mortalidad , Masculino , Persona de Mediana Edad , Proteínas Ribosómicas/inmunologíaRESUMEN
BACKGROUND: Anti-DNA/N-methyl-D-aspartate receptor 2 (NR2) antibodies (anti-DNA/NR2 antibodies) are a subset of anti-DNA autoantibodies that cross-react with the extracellular domain of the GluN2A/GluN2B subunits of NR2. These antibodies induce apoptosis of hippocampus neurons and psychiatric disorder in mice and humans. Neuropsychiatric system lupus erythematosus (NPSLE) can develop after initiation of corticosteroids (post-steroid neuropsychiatric manifestation: PSNP) or before treatment (de novo NPSLE); however, pathophysiological differences between these subtypes remain unclear. The objective of this study was to clarify the prevalence of anti-DNA/NR2 antibodies in patients with NPSLE. METHODS: This study involved a cohort of patients with NPSLE admitted to our hospital. NPSLE patients were classified into two groups, de novo NPSLE and PSNP-SLE. Serum anti-DNA antibodies and anti-DNA/NR2 antibodies were measured by enzyme-linked immunosorbent assays. RESULTS: Serum samples were obtained from 24 patients with de novo NPSLE, 25 with PSNP-SLE and 76 healthy controls (HC). The level of anti-DNA/NR2 antibodies in patients with de novo NPSLE and PSNP-SLE were also higher than those in HC. Positive correlation between anti-DNA antibodies and anti-DNA/NR2 antibodies were found in PSNP-SLE, but was not significant in de novo NPSLE. CONCLUSION: The levels of anti-DNA/NR2 antibodies in PSNP-SLE were similar to those in de novo NPSLE. Anti-DNA/NR2 antibodies in PSNP-SLE were suggested as a dominant subset of anti-DNA antibodies, indicating that anti-DNA/NR2 antibodies may be a predictive factor in PSNP-SLE.
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Anticuerpos Antinucleares/inmunología , Autoanticuerpos/inmunología , Autoinmunidad , ADN/inmunología , Lupus Eritematoso Sistémico/tratamiento farmacológico , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Receptores de N-Metil-D-Aspartato/inmunología , Esteroides/efectos adversos , Adolescente , Adulto , Anticuerpos Antinucleares/sangre , Autoanticuerpos/sangre , Diagnóstico Diferencial , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/inmunología , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Vasculitis por Lupus del Sistema Nervioso Central/diagnóstico , Masculino , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Factor Neurotrófico Derivado del Encéfalo/sangre , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Subunidad beta de la Proteína de Unión al Calcio S100/sangre , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Cuba , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Masculino , Persona de Mediana Edad , Curva ROC , Índice de Severidad de la EnfermedadRESUMEN
A 14-year-old boy presented to our institution with a 1-month history of neurocognitive decline and intermittent fevers. His history was significant for fevers, headaches, and a 10-lb weight loss. Previous examinations by multiple medical providers were significant only for bilateral cervical lymphadenopathy. Previous laboratory workup revealed leukopenia, neutropenia, and elevated inflammatory markers. Despite improvement in his laboratory values after his initial presentation, his fevers persisted, and he developed slowed and "jerky" movements, increased sleep, slurred speech, delusions, visual hallucinations, and deterioration in his school performance. A brain MRI performed at an outside hospital before admission at our institution was concerning for patchy, increased T2 and fluid-attenuated inversion recovery signal intensity in multiple areas, including the basal ganglia. After transfer to our institution and admission to the pediatric hospital medicine team, the patient had an acute decompensation. Our subspecialists will discuss the initial evaluation, workup, differential diagnosis, definitive diagnosis, and subsequent management of this patient.
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Fiebre/diagnóstico por imagen , Leucopenia/diagnóstico por imagen , Vasculitis por Lupus del Sistema Nervioso Central/diagnóstico por imagen , Trastornos Neurocognitivos/diagnóstico por imagen , Neutropenia/diagnóstico por imagen , Adolescente , Diagnóstico Diferencial , Fiebre/sangre , Fiebre/psicología , Humanos , Leucopenia/sangre , Leucopenia/psicología , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Vasculitis por Lupus del Sistema Nervioso Central/psicología , Masculino , Trastornos Neurocognitivos/sangre , Trastornos Neurocognitivos/psicología , Neutropenia/sangre , Neutropenia/psicologíaRESUMEN
OBJECTIVES: The present study was carried out to elucidate the roles of serum autoantibodies in the development of blood-brain barrier (BBB) damages in neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Paired serum and CSF samples were obtained from 101 SLE patients when they presented active neuropsychiatric manifestations (69 patients with diffuse psychiatric/neuropsychological syndromes [diffuse NPSLE] and 32 patients with neurologic syndromes or peripheral neuropathy [focal NPSLE]). IgG anti-NR2 subunit of NMDA receptor (anti-NR2), anti-Sm, anti-ribosomal P and IgG anti-cardiolipin in sera and albumin in CSF and sera were measured by ELISA. Blood-brain barrier (BBB) function was evaluated by Q albumin (CSF/serum albumin quotient x 1,000). RESULTS: Q albumin was significantly higher in acute confusional state (ACS) than in non-ACS diffuse NPSLE (anxiety disorder, cognitive dysfunction, mood disorder and psychosis) or in focal NPSLE. Anti-Sm, but not anti-NR2, anti-P or anticardiolipin, was significantly elevated in ACS compared with the other 2 groups of NPSLE, although serum anti-NR2 was significantly higher in ACS than that in focal NPSLE. Multiple regression analysis confirmed the significant contribution of anti-Sm (p=0.0040), but not anti-NR2 (p=0.5023), anti-P (p=0.2651), or anti-cardiolipin (p=0.6769) in the elevation of Q albumin. CONCLUSIONS: The data demonstrate that serum anti-Sm antibodies play a most important role in the disruption of BBB in NPSLE.
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Anticuerpos Antinucleares/sangre , Barrera Hematoencefálica/metabolismo , Permeabilidad Capilar , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Proteínas Nucleares snRNP/inmunología , Adulto , Anticuerpos Antinucleares/líquido cefalorraquídeo , Anticuerpos Antinucleares/inmunología , Biomarcadores/sangre , Barrera Hematoencefálica/patología , Femenino , Humanos , Vasculitis por Lupus del Sistema Nervioso Central/líquido cefalorraquídeo , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Vasculitis por Lupus del Sistema Nervioso Central/patología , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
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.
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Síndrome Antifosfolípido , Acuaporina 4/inmunología , Autoanticuerpos/sangre , Lupus Eritematoso Sistémico , Vasculitis por Lupus del Sistema Nervioso Central , Neuromielitis Óptica , Adulto , Síndrome Antifosfolípido/sangre , Síndrome Antifosfolípido/epidemiología , Síndrome Antifosfolípido/inmunología , Autoinmunidad/inmunología , Comorbilidad , Dinamarca/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/epidemiología , Lupus Eritematoso Sistémico/inmunología , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Vasculitis por Lupus del Sistema Nervioso Central/epidemiología , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Masculino , Persona de Mediana Edad , Neuromielitis Óptica/sangre , Neuromielitis Óptica/epidemiología , Neuromielitis Óptica/inmunología , Estudios RetrospectivosRESUMEN
BACKGROUND: In patients with systemic lupus erythematosus (SLE) there is no serological test that will reliably distinguish neuropsychiatric (NP) events due to active SLE from those due to other causes. Previously we showed that serum levels of nitrated nucleosomes (NN) were elevated in a small number of patients with NPSLE. Here we measured serum NN in samples from a larger population of patients with SLE and NP events to see whether elevated serum NN could be a marker for NPSLE. METHODS: We obtained serum samples from patients in the Systemic Lupus International Collaborative Clinics (SLICC) inception cohort. This included 216 patients with NP events and two matched controls with SLE but no NP events for each of these patients. For the NP patients we tested samples taken before, during and after the NP event. RESULTS: Twenty-six patients had events attributed to SLE according to the most stringent SLICC attribution rule. In these patients there was no association between onset of event and elevated serum NN. In 190 patients in whom events were not attributed to SLE by the SLICC rules, median serum NN was elevated at the onset of event (P = 0.006). The predominant clinical features in this group of 190 patients were headache, mood disorders and anxiety. CONCLUSIONS: Serum NN levels rise at the time of an NP event in a proportion of patients with SLE. Further studies are needed to determine the value of serum NN as a biomarker for NPSLE.
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Lupus Eritematoso Sistémico/sangre , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Nucleosomas/metabolismo , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
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.