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Unveiling the Link Between Antiphospholipid Antibodies and Cognitive Dysfunction in Almenara Lupus Cohort
Abstract
Objective
Cognitive dysfunction is a prevalent manifestation of systemic lupus erythematosus (SLE). There is evidence for the role of antiphospholipid (aPL) antibodies on its etiopathogenesis. Our objective was to identify the association between aPL antibodies and cognitive dysfunction in SLE patients.
Methods
This cross-sectional study included 135 patients evaluated from March 2015 to October 2017 at one center. Cognitive deficit was measured using the NEUROPSI test. Disease activity and damage were ascertained using the SLEDAI-2K (SLE Disease Activity Index 2000) and the SDI (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index), respectively; aPL antibodies were measured by enzyme-linked immunosorbent assay. The association between cognitive dysfunction and aPL antibodies was evaluated using univariable and multivariable linear regression models adjusted for age, sex, education, socioeconomic status, disease duration, SLEDAI-2K, SDI, mean current dose of prednisone, time of exposure to glucocorticoids, and drug use (immunosuppressants, hydroxychloroquine, aspirin, and warfarin).
Results
One hundred thirty-one patients (97.1%) were women; their mean (SD) age was 46.6 (12.5) years; 59 patients (43.7%) had positivity for at least 1 aPL antibody. IgM anticardiolipin (aCL) was positive in 24.5%, IgG in 13.5%, IgM aβ2GP1 in 16.8%, IgG anti-β2 glycoprotein in 24.6%, and the lupus anticoagulant in 5.3%. Ninety patients (66.7%) had some cognitive dysfunction. In the univariable analysis, a significant correlation between the NEUROPSI score and IgM aCL antibodies was found (B = −20.87 [SE, 3.2]; p < 0.001), which remained significant in the multivariable model (B = −13.89 [SE, 3.14]; p < 0.001).
Conclusions
IgM aCL antibodies are associated with cognitive dysfunction in patients with SLE. Larger and longitudinal studies are needed to assess the impact of these findings.
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Objective:
Cognitive dysfunction in SLE is common, but clinical risk factors are poorly understood. This study aims to explore the associations of cognitive dysfunction in SLE with disease activity, organ damage, biomarkers and medications.
Methods:
We performed cross-sectional cognitive assessment using a conventional neuropsychological test battery, with normative values derived from demographically matched healthy subjects. Endpoints included two binary definitions of cognitive dysfunction and seven individual cognitive domain scores. Clinical parameters included disease activity (SLEDAI-2K) and organ damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). We performed regression analyses to determine associations between clinical parameters and cognitive endpoints.
Results:
89 patients with SLE were studied, with median age of 45 and disease duration of 15 years. Organ damage was significantly associated with severe cognitive dysfunction (OR 1.49, CI 1.01-2.22) and worse cognitive test performance in three of the seven individual cognitive domains. In contrast, no significant associations were found between SLEDAI-2K at the time of cognitive assessment and any cognitive endpoints on multivariate analysis. Higher time-adjusted mean SLEDAI-2K was associated with better verbal memory scores but had no significant associations with other cognitive endpoints. The presence of anti-dsDNA antibodies and high IFN gene signature were negatively associated with severe cognitive dysfunction; there were no significant associations with the other autoantibodies studied or any medications. Substance use was significantly associated with lower psychomotor speed. Only 8% of patients who had cognitive dysfunction on testing had been recognised by clinicians on their SDI score.
Conclusions:
In SLE, cognitive dysfunction was positively associated with organ damage, but not associated with disease activity, and serological activity and high IFN signature were negatively associated. Cognitive dysfunction was poorly captured by clinicians. These findings have implications for preventative strategies addressing cognitive dysfunction in SLE.
Background
There is an increasing interest in the study of non-criteria antiphospholipid antibodies (aPL) including antibodies targeting domain 1 of the B2 glycoprotein 1 (anti-D1 B2GP1) and antibodies anti phosphatidylserine/ prothrombin (PS/PT).
Objectives
Our aim was to analyze a panel of conventional and non-criteria aPL in a cohort of patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS), to describe if there are differences in aPL titers among groups, to evaluate clinical associations including risk of recurrent events of novel aPL.
Methods
Observational study that evaluated at baseline antibodies against anti-D1 B2GP1 and anti PS/PT. Anti-D1 B2GP1 antibodies were tested using a chemiluminescent immunoassay. IgG and IgM anti PS/PT, aCL and anti B2GP1 by ELISA techniques. Therefore, patients were followed in order to identify new thrombotic events.
Results
133 patients with SLE and 23 with primary APS patients were included. Main APS manifestations were DVT (27%), obstetric morbidity (22%) and arterial thrombosis (10.1%). IgM anti PS/PT antibodies levels were (20.6 - 127) vs 21.9 (11.2 - 39.2) U/ml, p<0.001 in primary APS vs SLE with APS, respectively. Anti-D1 B2GP1, IgG and IgM anti PS/PT were associated with thrombotic and non-thrombotic manifestations. During follow-up, IgG B2GP1 were related with a significant cumulative risk of thrombosis.
Conclusions
We found significant differences in serum titers of non-criteria aPL among patients with primary APS vs SLE with APS. Whether non-criteria aPL antibodies titers are useful to differentiate patients with primary and secondary APS requires further analysis in other populations.
La presente investigación tiene el objetivo de estimar las propiedades psicométricas del instrumento de evaluación neuro-psicológica – Neuropsi en pacientes atendidos en el área de neurología de un hospital público de Perú. Asimismo, el estudio es de tipo psicométrico, de diseño no experimental y de corte transversal, por ello, se orienta a través de un enfoque cuantitativo; se trabaja con una muestra no probabilística de 432 Historias Clínicas (HC) de pacientes adultos mayores que fueron diagnosticados con o sin alteraciones cognitivas o demencia, a quienes se les aplica el instrumento de evaluación neuropsicológica breve en español – Neuropsi. En este sentido, se halla un análisis factorial que reporta un buen ajuste en un modelo de 6 factores con X2=2,825, CFI=0,990, GFI=0,986, PNFI=0,460, AIC=47,774, SRMR=0,0196, RMSEA=0,065 y el rendimiento cognitivo difiere según el rango de edad del paciente, además, presenta una confiabilidad de alfa de Cronbach de 0,863. Estos hallazgos sugieren que el instrumento es válido, breve, preciso y adecuado para medir el rendimiento cognitivo.
Currently, the evaluation of mental disorders in patients with Systemic lupus erythematosus (SLE) is essential in the management of the illness because of their impact in morbimortality. The main purpose of this study was to determine the prevalence of mental disorders in a group of patients with SLE in a tertiary referral hospital in Quito-Ecuador. The main diffuse central nervous system psychiatric syndromes in SLE (psychosis, anxiety and mood disorders) and cognitive dysfunction were evaluated with the MINI International Neuropsychiatric Interview and the Montreal scale, respectively. This was a descriptive, cross-sectional study which included patients 15 years and older diagnosed with SLE in a tertiary referral hospital in Quito, Ecuador. 85 patients diagnosed with SLE attending the internal medicine outpatient clinic during October 2017–May 2018 were included. A bivariate analysis of possible associations between these mental disorders with corticosteroid use, antiphospholipid syndrome (APS), and quality of life was also studied. Eighty-five patients, with an average age of 34.12 ± 11.5 years were included, of which 94% were females. 71% of participants (60 patients) had at least one mental disorder evaluated in this study. The most frequent was cognitive impairment (n = 43, 51%) followed by anxiety disorders (n = 35, 41%), mood disorders (n = 34, 40%) and psychosis (n = 1; 1%). 38% presented mild cognitive impairment and 13% had moderate cognitive impairment. Memory and visuospatial/executive function were the most affected domains in the cognitive assessment. 38% of participants were previously diagnosed with antiphospholipid syndrome, of which 78% had a mental disorder (OR = 1.83, p = 0.2). Most patients (n = 84; 99%) were treated with corticosteroids, of these, 59 patients presented a mental disorder (OR = 0.9, p = 0.8). Associations with APS or corticosteroid use were not statistically significant. However, the multivariate regression suggests an association between presence of mental disease and quality of life. There were statistically significant alterations in anxiety/depression and pain. There is a high prevalence of neuropsychiatric syndromes in this cohort of patients. Almost ¾ of our cohort had at least one mental disorder, the most common was cognitive impairment.
Objective
Cognitive impairment (CI) has been described in 3–80% of Systemic lupus erythematosus (SLE) patients but only short-term studies evaluated its over-time changes, suggesting that CI is usually a stable finding. We aimed at evaluating the changes of SLE-related CI in a 10-years prospective single center cohort study.
Methods
We evaluated 43 patients (M/F 5/38; mean age = 45.7±10.1 years; mean disease duration = 230.8±74.3 months) at baseline (T0) and after 10 years (T1). A test battery designed to detect fronto-subcortical dysfunction across five domains (memory, attention, abstract reasoning, executive and visuospatial function) was administered. A global cognitive dysfunction score (GCD) was obtained and associated with clinical and laboratory features.
Results
Prevalence of CI was 20.9% at T0 and 13.9% at T1 (P = NS). This impairment was prevalently mild at T0 (55.5%) and mild or moderate at T1 (36.3% for both degrees). After 10 years, CI improved in 50% of patients, while 10% worsened. Impaired memory (P = 0.02), executive functions (P = 0.02) and abstract reasoning (P = 0.03) were associated with dyslipidemia at T0. Worsening of visuospatial functions was significantly associated with dyslipidemia and Lupus Anticoagulant (P = 0.04 for both parameters). Finally, GCD significantly correlated with chronic damage measured by SLICC/damage index at T0 (r = 0.3; P = 0.04) and T1 (r = 0.3; P = 0.03).
Conclusions
For the first time, we assessed CI changes over 10-years in SLE. CI improved in the majority of the patients. Furthermore, we observed an improvement of the overall cognitive functions. These results could suggest that an appropriate management of the disease during the follow-up could be able to control SLE-related CI.
Systemic lupus erythematosus (SLE) and antiphospholipid syndrome have an increased risk to develop cognitive impairment. A possible role for antiphospholipid antibodies (aPL) and antiglutamate receptor (anti-NMDA) antibodies in the pathogenesis of neurological manifestations of these two conditions, have been suggested. In particular, the role of anti-NMDA antibodies in the pathogenesis of neuropsychiatric SLE is supported by several experimental studies in animal models and by the finding of a correlation between anti-NMDA positivity in cerebrospinal fluid and neurological manifestations of SLE. However, data from the literature are controversial, as several studies have reported a correlation of these antibodies with mild cognitive impairment in SLE, but more recent studies have not confirmed this finding. The synergism between anti-NMDA and other concomitant autoantibodies, such as aPL, can be hypothesized to play a role in inducing the tissue damage and eventually the functional abnormalities. In line with this hypothesis, we have found a high incidence of at least one impaired cognitive domain in a small cohort of patients with primary APS (PAPS) and SLE. Interestingly, aPL were associated with low scoring for language ability and attention while anti-NMDA titers and mini-mental state examination scoring were inversely correlated. However, when patients were stratified according to the presence/absence of aPL, the correlation was confirmed in aPL positive patients only. Should those findings be confirmed, the etiology of the prevalent defects found in PAPS patients as well as the synergism between aPL and anti-NMDA antibodies would need to be explored.
Objetivos: El objetivo del presente estudio es examinar en el Perú la validez de una versión en español del Inventario de Depresión de Beck (BDI) en pacientes hospitalizados de medicina general. Material y Métodos: Se tomó una muestra de 136 pacientes internados en los pabellones de medicina general del Centro Médico Naval (Lima-Perú), a quienes se les administró el BDI y la sección para el diagnóstico de depresión mayor de la Entrevista Clínica Estructurada para el DSM-IV (SCID). Resultados: El coeficiente alfa de Cronbach fue 0,889. La puntuación promedio del BDI fue significativamente más alta en los pacientes con depresión mayor que en los que no la tenían (26,71 frente a 6,79, p<0,001). Tomando 18,5 o 19,5 como punto de corte del BDI para el diagnóstico de depresión mayor, la sensibilidad fue 87,5% y la especificidad 98,21%. Ningún paciente con BDI menor de 7,5 tuvo depresión, mientras que todos los sujetos con BDI mayor de 24,5 la presentaron. A excepción de la pérdida de peso, todos los ítems tuvieron puntajes significativamente más altos en los pacientes deprimidos, siendo los ítems que mejor predecían la presencia de depresión: la inconformidad con uno mismo, la autopercepción negativa del aspecto físico, la autocensura, el insomnio y el sentirse castigado. Conclusiones: La versión en español del BDI utilizada tiene propiedades psicométricas adecuadas para la evaluación de depresión en pacientes hospitalizados de medicina general.
Antiphospholipid antibodies (aPL) are associated with neurological diseases such as stroke, migraine, epilepsy and dementia and are thus associated with both vascular and non-vascular neurological disease. We have therefore examined the possibility that these antibodies interact directly with neuronal tissue by studying the electrophysiological effects of aPL on a brain synaptosoneurosome preparation. IgG from patients with high levels of aPL and neurological involvement was purified by protein-G affinity chromatography as was control IgG pooled from ten sera with low levels of aPL. Synaptoneurosomes were purified from perfused rat brain stem. IgG from the patient with the highest level of aPL at a concentration equivalent to 1:5 serum dilution caused significant depolarization of the synaptoneurosomes as determined by accumulation of the lipophylic cation [3H]-tetraphenylphosphonium. IgG from this patient as well as IgG from two elderly patients with high levels of aPL were subsequently shown to permeabilize the synaptosomes to labeled nicotinamide adenine dinucleotide (NAD) and pertussis toxin-ADP-ribose transferase (PTX-A protein) as assayed by labeled ADP-ribosylation of G-proteins in the membranes. No such effects were seen with the control IgG. aPL may thus have the potential to disrupt neuronal function by direct action on nerve terminals. These results may explain some of the non-thromboembolic CNS manifestations of the antiphospholipid syndrome.
The purpose of this research was to develop, standardize, and test the reliability of a short neuropsychological test battery in the Spanish language. This neuropsychological battery was named "NEUROPSI," and was developed to assess briefly a wide spectrum of cognitive functions, including orientation, attention, memory, language, visuoperceptual abilities, and executive functions. The NEUROPSI includes items that are relevant for Spanish-speaking communities. It can be applied to illiterates and low educational groups. Administration time is 25 to 30 min. Normative data were collected from 800 monolingual Spanish-speaking individuals, ages 16 to 85 years. Four age groups were used: (1) 16 to 30 years, (2) 31 to 50 years, (3) 51 to 65 years, and (4) 66 to 85 years. Data also are analyzed and presented within 4 different educational levels that were represented in this sample; (1) illiterates (zero years of school); (2) 1 to 4 years of school; (2) 5 to 9 years of school; and (3) 10 or more years of formal education. The effects of age and education, as well as the factor structure of the NEUROPSI are analyzed. The NEUROPSI may fulfill the need for brief, reliable, and objective evaluation of a broad range of cognitive functions in Spanish-speaking populations.
Health care professionals are now faced with a growing number of patients from different ethnic groups, and from different socioeconomical backgrounds. In the field of neuropsychology there is an increasing need of reliable and culturally fair assessment measures. Spanish is the official language in more than 20 countries and the second most spoken language in the world. The purpose of this research was to develop and standardize the neuropsychological battery NEUROPSI ATTENTION AND MEMORY, designed to assess orientation, attention and concentration, executive functions, working memory and immediate and delayed verbal and visual memory. The developmental sequences of attention and memory as well as the educational effects were analyzed in a sample of 521 monolingual Spanish Speaking subjects, aged 6 to 85 years. Educational level ranged from 0 to 22 years of education. The consideration of the developmental sequence, and the effects of education, can improve the sensitivity and specificity of neuropsychological measures.
Introduction:
Cognitive impairment is a common neuropsychiatric manifestation of systemic lupus erythematosus (SLE). However, it is not routinely assessed for despite its high prevalence and significant disease burden.
Aims:
This study aimed to determine the prevalence of mild cognitive impairment (MCI) using the Montreal Cognitive Assessment (MoCA) and its associated factors among patients diagnosed with SLE in Malaysia.
Methods:
A total of 200 SLE patients were recruited prospectively from the outpatient clinics of two tertiary hospitals in Malaysia. Standardized clinical interview was utilized to obtain information on socio-demographic characteristics. All patients were then assessed using the MoCA questionnaire for presence of cognitive impairment; the Patient Health Questionnaire 9 (PHQ-9) for presence of depressive symptoms; and the Wong-Baker Faces Pain Scale (WBFPS) for severity of pain. The evaluation of disease activity and severity were performed by the treating rheumatologists and nephrologists using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and Systemic Lupus International Collaborating Clinics Damage Index (SLICC DI).
Results:
The prevalence of MCI was 35%. The significant associated factors from the bivariate analysis were male gender ( p = 0.04), educational level ( p = 0.00), WBFPS score ( p = 0.035) and anticardiolipin IgM ( p = 0.01). Further analysis using logistic regression model found that male gender (OR = 7.43, 95% confidence interval 1.06-52.06, p = 0.04), lower educational level (OR = 4.4, 95% confidence interval 1.47-13.21, p = 0.01) and presence of anticardiolipin IgM (OR = 6.81, 95% confidence interval 1.45-32.01, p = 0.031) were associated with impaired MoCA scores. Also, increasing pain scores increased the risk of patients being affected by cognitive impairment.
Conclusion:
Over one-third of patients with SLE in our cohort were found to have MCI. Risk factors included male gender, lower educational level, higher pain score and presence of anticardiolipin IgM. Physicians are encouraged to perform routine screening to detect cognitive dysfunction in patients with SLE in their clinical practice as part of a more comprehensive management.
Antiphospholipid antibodies (aPL) are well-known risk factors for venous and arterial thrombosis, but their association with cognitive dysfunction has not been widely investigated in the general population and in patients with primary and secondary antiphospholipid syndrome (APS).We performed a systematic review searching MEDLINE via PubMed and Cochrane (CENTRAL) databases for observational studies reporting on the association between aPL and dementia in the general population, in subjects carrying aPL, in patients with cognitive disorder/dementia, and in primary and secondary APS.
Prevalence of anticardiolipin (aCL) IgG ranged from 5.9% to 31.1% in the general population, with aCL titers being more elevated in subjects with functional decline of cognitive functions or with neurological alterations as detected by imaging. The prevalence of aPL ranged from 6.0 to 56.6% in patients with vascular dementia. Regarding patients with primary and secondary APS, a severe cognitive deficit has been described in up to 60% of patients, 33.3% of systemic lupus erythematosus (SLE)-APS and 22.2% of SLE patients without aPL. Five studies included patients with primary APS with divergent results,
while 18 studies investigated the association between aPL and cognitive impairment in patients with SLE. Of these, 14 reported a positive association between aPL, mostly aCL and LAC, and cognitive impairment while little evidence on anti b2-Glycoprotein I exists. Mechanisms leading to cognitive dysfunction are not well characterized and may include vascular aPL-induced micro and macro-thrombosis and immune-mediated neuronal toxicity pathways in the cerebral district.
Objective:
To characterize cognitive function in patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) in comparison with other chronic conditions, and to investigate its association with disease activity, and other psychological factors.
Methods:
Cross-sectional study including patients with AAV, rheumatoid arthritis (RA) (n = 30), and chronic kidney disease (CKD) (n = 29). Patients underwent a standardized neuropsychological battery (NEUROPSI). Sleep quality, fatigue, depression, and anxiety levels were assessed.
Results:
A total of 60 patients with AAV were included, median age of 54 years, and disease duration of 5.6 years. Prevalence of cognitive dysfunction (CD) in AAV patients was similar to RA and CKD (35%, 40%, and 39.3%, respectively, p = .88). When AAV patients with (n = 21) and without (n = 39) CD were compared, significantly more patients with CD had high disease activity (67% vs. 31%, p = .009). Abnormal performance was more frequent in the executive functions in the three groups (45% AAV, 51.7% RA, and 50% CKD), followed by language (25%, 13.8%, and 25%, respectively). Verbal and visual attentional tests were more frequently impaired in patients from the CKD group (p = .021), and psychomotor functions were more frequently affected in AAV patients (p < .05). Hospital Anxiety and Depression Scale (HADS) total score (especially anxiety) was higher in patients with memory impairment than in those with normal memory function (M = 6.79, SD = 4.53 vs. M = 4.5, SD = 3.6, p < .01). Neither Sleep Quality Index nor fatigue scale scores differed between those cognitively impaired and not impaired.
Conclusions:
No statistically significant differences were found in the frequency of CD among the three clinical populations. (JINS, 2019, 25, 595-602).
Patients with systemic lupus erythematosus (SLE) frequently show symptoms of central nervous system (CNS) involvement, termed neuropsychiatric SLE (NPSLE). The CNS manifestations of SLE are diverse and have a broad spectrum of severity and prognostic implications. Patients with NPSLE typically present with nonspecific symptoms, such as headache and cognitive impairment, but might also experience devastating features, such as memory loss, seizures and stroke. Some features of NPSLE, in particular those related to coagulopathy, have been characterized and an evidence-based treatment algorithm is available. The cognitive and affective manifestations of NPSLE, however, remain poorly understood. Various immune effectors have been evaluated as contributors to its pathogenesis, including brain-reactive autoantibodies, cytokines and cell-mediated inflammation. Additional brain-intrinsic elements (such as resident microglia, the blood–brain barrier and other neurovascular interfaces) are important facilitators of NPSLE. As yet, however, no unifying model has been found to underlie the pathogenesis of NPSLE, suggesting that this disease has multiple contributors and perhaps several distinct aetiologies. This heterogeneity presents a challenge for clinicians who have traditionally relied on empirical judgement in choosing treatment modalities for patients with NPSLE. Improved understanding of this manifestation of SLE might yield further options for managing this disease.
Objectives:
aPL are frequently present in SLE. In a well characterized SLE cohort we aimed at investigating the prevalence of aPL and assessing their analytical performance and clinical association by testing criteria specificities including LA, aCL IgG and IgM, anti-β2-glycoprotein 1 (antiβ2GP1) IgG and IgM, as well as the non-criteria aPS-PT IgG and IgM and anti-β2GP1 domain 1 (aD1) IgG.
Methods:
We included 178 patients satisfying the ACR SLE classification criteria, from whom 283 samples and thrombotic events were collected longitudinally. Each sample was tested for criteria and non-criteria aPL using validated techniques in a single centre.
Results:
All assays provided highly reproducible results. Of the samples, 42.5% were positive for at least one criteria assay, 20.5% showed double positivity and 12.6% triple positivity. All criteria and non-criteria specificities persisted over time. Most antibody titres were only moderately correlated; however, strong correlation was observed on one hand between aD1 IgG, antiβ2GP1 IgG and aCL IgG, and on the other between aPS-PT IgG and LA. aD1 IgG titres were extremely elevated in triple-positive samples. aPS-PT IgG by itself, and jointly with LA, was associated with thrombosis, an association mostly driven by venous thrombotic events.
Conclusions:
In this SLE cohort, the non-criteria aPL aD1 IgG and aPS-PT IgG performed differently. aD1 IgG was highly enriched in triple-positive samples, and aPS-PT IgG, jointly with LA, was associated with thrombotic events.
Objectives:
The objective of this study was to assess the contribution of clinically significant antiphospholipid antibodies (aPL) to organ damage in systemic lupus erythematosus (SLE).
Methods:
Patients with disease duration of less than 10 years and at least 5 years of follow-up were identified from two SLE registries. A clinically significant antiphospholipid antibody (aPL) profile was defined as: positive lupus anticoagulant, anticardiolipin IgG/M ≥ 40 G phospholipid units (GPL)/M phospholipid units (MPL), and/or anti-β2-glycoprotein-I IgG/M ≥ 99th percentile on two or more occasions, at least 12 weeks apart. Organ damage was assessed by the Systemic Lupus International Collaborating Clinics Damage Index (SDI). Univariate and multivariate analysis compared SLE patients with and without SDI increase during a 15-year follow-up.
Results:
Among 262 SLE patients, 33% had a clinically significant aPL profile, which was associated with an increased risk of organ damage accrual during a 5-year follow-up in univariate analysis, and during a 15-year follow-up in the multivariate analysis adjusting for age, gender, race, disease duration at registry entry, and time. In the multivariate analysis, older age at diagnosis and male gender were also associated with SDI increase at each time point.
Conclusion:
A clinically significant aPL profile is associated with an increased risk of organ damage accrual during a 15-year follow-up in SLE patients.
Objective. To investigate the outcome of neuropsychiatric involvement in systemic lupus erythematosus patients (NPSLE) recruited from a defined population. Methods. All cases of adult SLE diagnosed during 1981‐1995 within the Lund-Orup Health Care District were followed prospectively and neuropsychiatric manifestations were recorded. The SLICCuACR (Systemic Lupus International Collaborating ClinicsuAmerican College of Rheumatology) Damage Index, mortality and working incapacity were recorded as measures of outcome. Results. NPSLE manifestations developed in 38% (44u117) of the patients. A high rate of organ damage (SLICCuACR Damage Index) was recorded in the NPSLE patients (P < 0.001). Compared with patients without neuropsychiatric involvement, NPSLE patients were treated more intensively, with glucocorticoids (P < 0.01) and cytostatic drugs (P < 0.01). When compared with the normal population in the same area, the NPSLE patients had a higher rate of working incapacity (relative risk 4.0, 95% confidence interval 2.06‐6.96), whereas mortality was not increased (standardized mortality rate 1.4, 95% confidence interval 0.5‐3.0). Conclusions. SLE patients with neuropsychiatric involvement have an increased rate of organ damage and a high degree of working incapacity, which illustrates the severity of disease in this subgroup.
Genetic factors seem to play a more important role early in the course of systemic lupus erythematosus (SLE), whereas nongenetic factors seem to play a more important role over the course of the disease. SLE is more frequent with less favorable outcomes in nonwhite populations. To overcome these differences and reduce the immediate-term, mediate-term, and long-term impact of SLE among disadvantaged populations, it is essential to increase disease awareness, to improve access to health care and to provide care to these patients in a consistent manner regardless of the severity of their disease.
Cognitive dysfunction and cardiovascular disease are common and debilitating manifestations of systemic lupus erythematosus (SLE). In this study, we evaluated the relationship between cardiovascular events, traditional cardiovascular risk factors, and SLE-specific risk factors as predictors of cognitive dysfunction in a large cohort of participants with SLE.
Subjects included 694 participants from the Lupus Outcomes Study (LOS), a longitudinal study of SLE outcomes based on an annual telephone survey querying demographic and clinical variables. The Hopkins Verbal Learning Test-Revised and the Controlled Oral Word Association Test were administered to assess cognitive function. Multiple logistic regression was used to identify cardiovascular events (myocardial infarction, stroke), traditional cardiovascular risk factors (hypertension, hyperlipidemia, diabetes mellitus, obesity, smoking), and SLE-specific risk factors (antiphospholipid antibodies [aPL], disease activity, disease duration) associated with cognitive impairment in year 7 of the LOS.
The prevalence of cognitive impairment as measured by verbal memory and verbal fluency metrics was 15%. In adjusted multiple logistic regression analyses, aPL (odds ratio [OR] 2.10, 95% confidence interval [95% CI] 1.3-3.41), hypertension (OR 2.06, 95% CI 1.19-3.56), and a history of stroke (OR 2.27, 95% CI 1.16-4.43) were significantly associated with cognitive dysfunction. In additional analyses evaluating the association between these predictors and severity of cognitive impairment, stroke was significantly more prevalent in participants with severe impairment when compared to those with mild or moderate impairment (P = 0.036).
These results suggest that the presence of aPL, hypertension, and stroke are key variables associated with cognitive impairment, which may aid in identification of patients at greatest risk.
Although antiphospholipid syndrome (APS) is a multisystem prothrombotic condition, its inflammatory nature has been increasingly recognized in recent years. Stroke and transitory ischemic attacks are the neurological manifestations included in APS criteria, however many other neurological involvements have been attributed to antiphospholipid antibodies (aPL), such as seizures, transverse myelitis, and cognitive impairment. In this article we will review evidence from animal model that explain the role of aPL in cognition.
The association between antiphospholipid antibodies (aPL) and clinical events is stronger with a positive lupus anticoagulant (LA) test, higher anticardiolipin antibody (aCL) titers, and/or higher anti-beta(2)-glycoprotein-I antibody (abeta( 2)GPI) titers. The objective of this study was to determine the clinical characteristics of persistently high-titer (> or =80 U) aCL-positive patients compared with those with persistent moderate aCL titers (40-79 U). Second, we analyzed whether high-titer abeta(2)GPI test adds predictive information in persistently moderate-to-high titer aCL-positive patients. In this cross-sectional study, the primary analysis compared the clinical and aPL characteristics of 58 patients with at least two moderate-titer aCL results to another 85 patients with at least two high-titer aCL results. In the secondary analysis of patients with at least two abeta(2)GPI test results, we compared 29 patients with 'aCL 40-79 U and abeta( 2)GPI < 80 U' profiles with 8 patients with 'aCL 40-79U and abeta(2)GPI > or = 80 U', and also compared 27 patients with 'aCL > 80 U and abeta(2)GPI < 80 U' with 32 patients with 'aCL > 80 U and abeta(2)GPI > or = 80 U'. Although aPL-related vascular and pregnancy events were similar between the moderate- and high-titer aCL groups, the number of patients with positive LA tests (RR 2.06, CI 1.38-3.08, p < 0.01) and with at least one non-criteria aPL manifestation (RR 1.66, CI 1.20-2.30, p = 0.0005) were significantly higher in the high-titer aCL group. While magnetic resonance imaging (MRI) white matter changes were statistically more common in the high-titer aCL group (RR 2.03, CI 1.04-3.94, p = 0.02), there was a trend towards increased prevalence of livedo reticularis, cardiac valve disease, and cognitive dysfunction occurring in the high-titer aCL group. The secondary analysis showed that MRI white matter changes, cardiac valve disease, and cognitive dysfunction were proportionally more common in the high-titer abeta( 2)GPI groups, suggesting a linear relationship between non-criteria aPL manifestations and aPL titers. Our results suggest that patients with high aCL titers, compared with those with moderate titers, are more likely to have a positive LA test and a higher prevalence of non-criteria aPL manifestations. Furthermore, high-titer abeta(2)GPI positivity may further increase the prevalence of non-criteria aPL manifestations in moderate- or high-titer aCL-positive patients.
Antiphospholipid antibodies (aPL) have been suggested to play a role in causing cognitive and behavioral impairments. In the present study we investigated the pathogenic potential of aPL by intracerebro-ventricular (ICV) administration of immunoglobulins (IgG) from patients with antiphospholipid syndrome (APS). IgG, purified from the sera of four APS patients, was tested for binding to normal mouse brain by immunohistological staining. These IgG (7.5 microg) were injected ICV unilaterally to male C3H mice. Mice injected with IgG purified from pooled sera derived from healthy subjects served as controls. The mice were examined neurologically for motor function and coordination, and cognitively in a Morris water maze. The cognitive tests were performed with the experimenter blinded to the treatment. The performance of the mice in four separate experiments was compared by analysis of variance with repeated measures. IgG from one APS patient was found to bind best to neuronal structures in the hippocampus and cerebral cortex. Mice (n = 43) injected with this IgG performed worse in the water maze compared to the controls (n = 45) with significant effects of the aPL IgG on the overall performance of the mice (treatment, P < 0.03), on learning throughout the experiment (treatment x day, P < 0.02) and on short term memory (treatment x day xtrial, P < 0.002). IgG injected from two of the three other patients also bound specifically to mouse brain neurons and produced an impairment in performance of the water maze. These results support the hypothesis that aPL that gain access to the central nervous system may play a direct role in the pathogenesis of neurological manifestations of APS.
To evaluate predictors of cognitive dysfunction in patients with systemic lupus erythematosus (SLE).
The authors evaluated 123 patients enrolled in the San Antonio Lupus Study of Neuropsychiatric Disease (SALUD) who had completed at least 3 years of follow-up. Study visits occurred every 4 months and included a standard medical history, physical examination, and cognitive testing. Blood was obtained at each study visit for autoantibody testing.
There were 116 (94.3%) women and 7 (5.7%) men (mean age = 41.5 [+/-12.0] years). Patients had the following vascular risk factors: hypercholesterolemia (17.1%), diabetes (21.1%), and hypertension (48.0%). Consistent medication use included aspirin (21.1%), prednisone (65.0%), nonsteroidal anti-inflammatories (42.3%), and hydroxychloroquine (58.5%). The numbers of patients with consistently positive autoantibody levels were as follows: antiphospholipid, 54%; anti-beta-2-glycoprotein 1, 73%; and anti-ribosomal P, 17%. Factors significantly associated with declining cognitive function were consistently positive antiphospholipid antibodies, consistent prednisone use, diabetes, higher depression scores, and less education. The association of prednisone and poorer cognitive function was seen primarily in the middle age group and could not be totally explained by SLE-associated disease activity. Consistent aspirin use was associated with improved cognitive function, primarily in the oldest age group, especially if diabetes was also present.
Regular aspirin use is associated with improved cognitive function in older patients with systemic lupus erythematosus (SLE) in conjunction with the presence of other vascular risk factors. Regular prednisone use is associated with decreased cognitive functioning in middle-aged patients with SLE. Although this prednisone effect was independent of measures of SLE-associated disease activity, the authors cannot exclude the possibility that consistent prednisone use is a surrogate for more severe disease.
To investigate the role of neuropsychiatric (NP), clinical, and laboratory variables in influencing the health related quality of life (HRQOL) of Chinese patients with systemic lupus erythematosus (SLE).
The Medical Outcomes Study Short Form-36 was applied in a cohort of 291 patients with SLE. At the time of HRQOL testing all patients underwent a clinical and laboratory evaluation together with measures of disease activity and damage. Patients also submitted to a battery of NP tests.
Using multivariate analysis, NP involvement-ever was associated with impairment of the general health subscale. Cerebrovascular disease and mononeuropathy were associated with impairment of the physical function subscale, while the latter was also associated with impairment of the role-emotional subscale. Cognitive impairment was associated with impairment of the mental health subscale. The Hospital Anxiety and Depression (HAD) depression score was associated with impairment of all the 8 subscales, physical, and mental summary scores. The HAD anxiety score was associated with impairment of predominantly mental function. Active arthritis, lower education level, and serum albumin levels were associated with impairment of predominantly physical function. Advancing age and damage were associated with impairment of both physical and mental function. Low hemoglobin level and female sex were associated with impairment of predominantly mental function.
NP involvement and low-grade inflammation as reflected by low serum albumin and hemoglobin concentrations were associated with impaired HRQOL in patients with SLE, independent of other sociodemographic and clinical variables.
Test Neuropsi: normas según edad y nivel de instrucción para Argentina
- A N Querejeta
- Y F Sarquís
- M A Moreno
Querejeta AN, Sarquís YF, Moreno MA, et al. Test Neuropsi: normas según
edad y nivel de instrucción para Argentina. Cuad Neuropsicol. 2012;6:48-58.
Estudio multicéntrico de deterioro cognitivo en lupus eritematoso sistémico
- M D'amico
- J Romero
- G Rodriguez
D'Amico M, Romero J, Rodriguez G, et al. Estudio multicéntrico de
deterioro cognitivo en lupus eritematoso sistémico: ECLES. Rev Arg
Reumatol. 2015;26:28-32.