Related Articles

Objectives

To determine the frequency, accrual, attribution and outcome of neuropsychiatric (NP) events and impact on quality of life over 3 years in a large inception cohort of SLE patients.

Methods

The study was conducted by the Systemic Lupus International Collaborating Clinics. Patients were enrolled within 15 months of SLE diagnosis. NP events were identified using the ACR case definitions and decision rules were derived to determine the proportion of NP disease attributable to SLE. The outcome of NP events was recorded and patient perceived impact determined by the SF-36.

Results

There were 1206 patients (89.6% female) with a mean (±SD) age of 34.5±13.2 years. The mean disease duration at enrollment was 5.4±4.2 months. Over a mean follow-up of 1.9±1.2 years 486/1206 (40.3%) patients had ≥1 NP events which were attributed to SLE in 13.0%–23.6% of patients using two a priori decision rules. The frequency of individual NP events varied from 47.1% (headache) to 0% (myasthenia gravis). The outcome was significantly better for those NP events attributed to SLE especially if they occurred within 1.5 years of the diagnosis of SLE. Patients with NP events, regardless of attribution, had significantly lower summary scores for both mental and physical health over the study.

Conclusions

NP events in SLE patients are variable in frequency, most commonly present early in the disease course and adversely impact patients’ quality of life over time. Events attributed to non-SLE causes are more common than those due to SLE, although the latter have a more favourable outcome.

Context

Most environmental risk factors for psychiatric disorders cannot be studied experimentally, making causal attributions difficult. Can we address this question by using together 2 major methods for causal inference: natural experiments and specialized statistical methods?

Objective

To determine the causal relationship between dependent stressful life events (dSLEs) and prior depressive episodes (PDEs) and major depression (MD).

Design

Assessment of risk factors and episodes of MD at interview. Statistical analyses used the co-twin control and propensity score–matching methods.

Setting

General community.

Participants

Four thousand nine hundred ten male and female twins from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders.

Main Outcome Measure

Episodes of MD.

Results

We found that dSLEs were strongly associated with risk for MD in female (odds ratio [OR], 5.85) and male (4.55) twins in the entire sample and, at considerably lower levels, in female (2.29) and male (2.19) monozygotic twins discordant for dSLE exposure. A case-control sample matched on propensity score showed a moderate association in female (OR, 1.79) and male (1.53) twins. A PDE strongly predicted risk for MD in female (OR, 3.68) and male (5.20) twins in the entire sample. In monozygotic pairs discordant for exposure, the association was weaker in male (OR, 1.41) and absent in female (1.00) twins. A case-control sample matched on propensity score showed a moderate association between PDE and depressive episodes in male (OR, 1.58) and female twins (1.66).

Conclusions

Although dSLEs have a modest causal effect on the risk for MD, a large proportion of the observed association is noncausal. The same pattern is seen for PDEs, although the causal impact is somewhat more tenuous. For environmental exposures in psychiatry that cannot be studied experimentally, co-twin control and propensity scoring methods—which have complementary strengths and weaknesses—can provide similar results, suggesting their joint use can help with the critical question of causal inference.

OBJECTIVE—To investigate the association of interleukin 10 (IL10) promoter polymorphisms and neuropsychiatric manifestations of systemic lupus erythematosus (SLE).
METHODS—IL10 haplotypes of 11 healthy volunteers were cloned to confirm that in the Dutch population, only the three common haplotypes (-1082/-819/-592) GCC, ACC and ATA exist. The IL10 promoter polymorphisms of 92 SLE patients and 162 healthy controls were determined. The medical records of the SLE patients were screened for the presence of neuropsychiatric involvement.
RESULTS—All cloned haplotypes were either GCC, ACC or ATA. Forty two SLE patients had suffered from neuropsychiatric manifestations (NP-SLE). In NP-SLE patients, the frequency of the ATA haplotype is 30% versus 18% in the controls and 17% in the non-NP-SLE group (odds ratios 1.9, p=0.02, and 2.1, p=0.04, respectively), whereas the GCC haplotype frequency is lower in the NP-SLE group compared with controls and non-NP-SLE patients (40% versus 55% and 61%, odds ratios 0.6, p=0.02 and 0.4 p=0.006). The odds ratio for the presence of NP-SLE is inversely proportional to the number of GCC haplotypes per genotype when the NP-SLE group is compared with non-NP-SLE patients.
CONCLUSIONS—The IL10 locus is associated with neuropsychiatric manifestations in SLE. This suggests that IL10 is implicated in the immunopathogenesis of neuropsychiatric manifestations in SLE.

 Keywords: systemic lupus erythematosus; neuropsychiatric manifestations; genetics; interleukin 10 promoter haplotypes

Neuropsychiatric manifestations in systemic lupus erythematosus (SLE) are common; however, psychosis per se is bit uncommon. They may be cognitive deficit, lupus headache, psychoses, seizures, peripheral neuropathy, and cerebrovascular events. Psychiatric symptoms in SLE can be functionally independent psychiatric disorders. It can be due to drugs (steroids) used for SLE or secondary to SLE because of its brain involvement, which is termed as neuropsychiatric systemic lupus erythematosus (NPSLE). No single clinical, laboratory, neuropsychological, and imaging test can be used to differentiate NPSLE from non-NPSLE patients with similar neuropsychiatric manifestations. Presently we are discussing about three cases of SLE with psychosis and which had different clinical presentation. The present reports also depict the approach to case differential diagnosis and management of the same.

Background: At the current stage, the criteria for making the diagnosis of SLE (ARA, 1982) include only two neuropsychiatric manifestations: seizures and psychoses. In view of the need for early detection of the lesions of the nervous system, we set ourselves to the task of developing an approach for making the diagnosis of NPSLE (neuropsychiatric SLE) on the basis of criteria with high sensitivity and specificity.

Methods: In view of determining the type and incidence of the lesions of the nervous system (NS), clinical, laboratory, and instrumental examinations were performed within the period from 1998 to 2006 in 225 patients with SLE. Depending on the specific features of the clinical course, these patients were divided into three groups: with clinically manifested lesions of NS; without clinically manifested lesions of NS; and with incomplete SLE.

Results and conclusions: The results from the performed examinations showed a high percentage (64.44%) of neuropsychiatric lesions in the patients with SLE. According our results, NPSLE diagnosis should be made in the presence of at least one indicator from the first group of criteria (seizures, psychosis, cerebrovascular event, lesion of cranial nerves, motor disturbances, quantitative alterations of consciousness) and at least two indicators from the second group of criteria (cognitive dysfunction, headache due to lupus, peripheral neuropathy, MRI changes, EEG changes, ENMG changes, positive aRPA, positive aPL) after ruling out other causes (except for SLE) for their occurrence.

Objective:

To determine some of the neuropsychiatric manifestations of systemic lupus erythematosus (SLE) by applying multimodal neurophysiological and psychometric studies.

Patients and methods:

Twenty-six SLE patients were evaluated for neurological and psychiatric disorders and compared with 26 healthy controls matched for age, sex, education, and social class. The severity of SLE disease was assessed. Each subject was subjected to the following examinations: laboratory, neurophysiology, magnetic resonance imaging of the brain, transcranial duplex, Modified Mini-mental State Examination, Cognitive Assessment Scale Inventory, Hamilton Depression Scale, and Hamilton Anxiety Scale.

Results:

The mean age of subjects was 25.9 ± 8.9 years. The most prevalent neurological manifestations were (in order of frequency) anxiety in 17 cases (65.4%), depression in 15 cases (57.7%), headache in 10 cases (38.5%), peripheral neuropathy in 7 cases (26.9%), seizures in 6 cases (23.1%), psychosis in 5 cases (19.2%), dementia in 4 cases (15.4%), radiculopathy in 4 cases (15.4%), myositis in 3 cases (11.5%), and stroke in 2 cases (7.7%). There was a significant affection in amplitude of the ulnar nerve, cognitive function impairment, and electroencephalography changes. There was a significant increased mean velocity and decreased Pulsatility Index of the most studied intracranial vessels in the patients.

Conclusion:

The use of multimodal neurophysiological, transcranial duplex, and psychometric scales increases the sensitivity for detecting nervous system involvement.

Pseudotumor cerebri is an uncommon manifestation of neuropsychiatric systemic lupus erythematosus (SLE), and is characterized by an elevated intracranial pressure, papilledema with occasional abducens nerve paresis, absence of a space-occupying lesion or ventricular enlargement, and normal cerebrospinal fluid chemical and hematological constituents. Pseudotumor cerebri has been reported in a few sporadic cases in patients with systemic lupus erythematosus. However, the recurrent pseudotumor cerebri in patients with systemic lupus erythematosus which has been rarely reported, has not been reported in Korea. We experienced a 30-yr-old female patient with SLE who was presented with second attack of severe intractable headache. She was diagnosed pseudotumor cerebri twice and successfully treated with corticosteroid. Headache is the common symptom in patients with neuropsychiatric SLE and attributable to various causes. We suggest that it is important to define the cause of headache in patients with SLE and pseudotumor cerebri should be included in the spectrum of clinical manifestations during the course of SLE as a cause of headache.

Objective

The aim of this study was to determine if there are racial disparities in regard to the age at which SLE patients experience CVD and CVD associated death.

Methods

Using the 2003–2006 National Inpatient Sample, we calculated the age difference between SLE patients and their race and gender-matched controls at the time of hospitalization for a cardiovascular (CVD) event and for CVD-associated death. In addition, we also calculated the age difference for the same outcomes between White SLE patients and gender-matched controls for each minority group.

Results

The mean age difference at the time of CVD event between women with and without SLE was 10.5 years. All age differences between women with SLE (n=3,625) and women without SLE admitted for CVD were significant (p<0.0001). Black women were the youngest female SLE racial group to be admitted with CVD (53.9 years) and have a CVD associated inhospital mortality (52.8 years; n=218). Black SLE women were 19.8 years younger than race and gender-matched controls at the time of CVD associated death. Admission trends for CVD were reversed for Black women such that the highest proportions of these patients were admitted before age 55 and then steadily decreased across age categories. There were 805 men with SLE admitted with a CVD event, with Black and Hispanic groups being the youngest.

Conclusions

There are significant racial disparities with regard to age at the time of hospital admission for CVD events and a CVD-related hospitalization resulting in death in patients with SLE.

OBJECTIVE: To compare the frequency of adverse events, particularly neuropsychiatric effects, from mefloquine and from chloroquine plus proguanil as used for malaria chemoprophylaxis. DESIGN: Retrospective questionnaire to travellers taking either regimen between November 1993 and February 1995; telephone interview with those reporting pronounced side effects. SETTING: Travellers from Britain who consulted an advisory helpline. SUBJECTS: 1214 adults taking mefloquine and 1181 taking chloroquine plus proguanil. MAIN OUTCOME MEASURES: Reported presence of and degree of disability from 12 neuropsychiatric and other symptoms, as assessed by the subjects and by referees and on the basis of behaviour change. RESULTS: There were equal rates of any side effects (40%) and of stopping or changing medication. Overall, neuropsychiatric adverse events were significantly more common in travellers taking mefloquine. In all, 333 neuropsychiatric adverse events were reported by 1214 travellers taking mefloquine, compared with 189 such events in 1181 travellers taking proguanil plus chloroquine (P < 0.001). In all, 0.7% of travellers taking mefloquine had disabling neuropsychiatric adverse effects, compared with 0.09% of those taking proguanil plus chloroquine (P = 0.021). Two travellers taking mefloquine (1 in 607) were admitted to hospital as a result of the adverse event, compared with 1 in 1181 travellers taking proguanil plus chloroquine. CONCLUSION: There is a significant excess of adverse neuropsychiatric events of intermediate degrees of severity associated with the use of mefloquine compared with proguanil plus chloroquine. This finding may also explain the discrepant findings between earlier studies and clinical experience.

Background

Despite the uncertainty in the diagnosis of neuropsychiatric involvement in systemic lupus erythematosus (SLE), attempts have been made to record the association of certain antibodies in serum with neuropsychiatric (NP) manifestations. We aimed to assess the behaviour and the association of serum and cerebrospinal fluid (CSF) autoantibodies with NP manifestations in SLE patients (NPSLE).

Methodology/Principal Findings

Forty-seven SLE patients, hospitalized because of NP manifestations were included. They were evaluated at hospitalization and six months later, and serum and CSF samples were obtained at each evaluation. As controls, serum samples were taken from 49 non-NPSLE patients at hospitalization and six months later; serum and CSF samples were also obtained from 6 SLE patients with septic meningitis, 16 surgical SLE patients and 25 patients without autoimmune diseases. Antinuclear, anti-dsDNA, anti-ribosomal P, Anti-N-Methyl-D-Aspartate receptor (NMDAR), anti-cardiolipin, and anti-β2 glycoprotein-I antibodies were measured. In serum, anti-ribosomal P, anti-NMDAR, and other antibodies did not differentiate among SLE groups, and the levels of all antibodies were similar among the SLE groups. Six-months later, this scenario remained unchanged and the decrease in the levels of some autoantibodies reflected a decline in disease activity, rather than a change in NPSLE. In CSF, only the presence and the levels of anti-NMDAR antibodies showed a characteristic distribution in central NPSLE and septic meningitis patients. Six months later the prevalence of most antibodies in CSF did not change, however the levels of anti-dsDNA, anti-ribosomal P, and anti-NMDAR decreased.

Conclusion

In NPSLE, autoantibodies in serum do not reflect their behaviour in CSF. All autoantibodies were elevated in septic meningitis reflecting the global penetration of serum antibodies into the CSF in this condition. Anti-NMDAR antibodies in CSF identified patients with central NPSLE; their continued presence in CSF 6 months after neurologic symptoms raise questions regarding the conditions under which they are pathogenic.

Background

Antibodies specifically affect the amygdala in a mouse model of systemic lupus erythematosus (SLE). The aim of our study was to investigate whether there is also specific involvement of the amygdala in human SLE.

Methods and Findings

We analyzed a group of 37 patients with neuropsychiatric SLE (NP-SLE), 21 patients with SLE, and a group of 12 healthy control participants with diffusion weighted imaging (DWI). In addition, in a subset of eight patients, plasma was available to determine their anti-NMDAR antibody status. From the structural magnetic resonance imaging data, the amygdala and the hippocampus were segmented, as well as the white and gray matter, and the apparent diffusion coefficient (ADC) was retrieved. ADC values between controls, patients with SLE, and patients with NP-SLE were tested using analysis of variance with post-hoc Bonferroni correction. No differences were found in the gray or white matter segments. The average ADC in the amygdala of patients with NP-SLE and SLE (940 × 10−6 mm2/s; p = 0.006 and 949 × 10−6 mm2/s; p = 0.019, respectively) was lower than in healthy control participants (1152 × 10−6 mm2/s). Mann-Whitney analysis revealed that the average ADC in the amygdala of patients with anti-NMDAR antibodies (n = 4; 802 × 10−6 mm2/s) was lower (p = 0.029) than the average ADC of patients without anti-NMDAR antibodies (n = 4; 979 × 10−6 mm2/s) and also lower (p = 0.001) than in healthy control participants.

Conclusions

This is the first study to our knowledge to observe damage in the amygdala in patients with SLE. Patients with SLE with anti-NMDAR antibodies had more severe damage in the amygdala compared to SLE patients without anti-NMDAR antibodies.

Patients with SLE who also had antibodies against the NMDA receptor had more severe damage in the amygdala as compared with patients with SLE without these antibodies.

Editors' Summary

Background.

The human body is continually attacked by viruses, bacteria, fungi, and parasites, but the immune system usually prevents these pathogens from causing disease. To be effective, the immune system has to respond rapidly to foreign antigens (bits of proteins that are unique to the pathogen) but ignore self-antigens. In autoimmune diseases, this ability to discriminate between self and nonself fails for unknown reasons, and the immune system begins to destroy human tissues. In the chronic autoimmune disease systemic lupus erythematosus (SLE or lupus), the immune system attacks the skin, joints, nervous system, and many other organs. Patients with SLE make numerous “autoantibodies” (antibodies are molecules made by the immune system that recognize and attack antigens; autoantibodies attack self-antigens). These autoantibodies start the attack on the body; then other parts of the immune system join in, causing inflammation and forming deposits of immune cells, both of which damage tissues. Common symptoms of SLE include skin rashes and arthritis, but some patients develop NP-SLE, a form of SLE that includes neuropsychiatric symptoms such as amnesia, dementia, mood disorders, strokes, and seizures. There is no cure for SLE, but mild cases are controlled with ibuprofen and other non-steroidal anti-inflammatory drugs; severe cases are kept in check with corticosteroids and other powerful immunosuppressants.

Why Was This Study Done?

In most of the tissues affected by SLE, the damage done by autoantibodies and immune cells can be seen when the tissues are examined with a microscope. But there is little microscopic damage visible in the brains of patients with NP-SLE. More generally, it is unclear how or even whether the immune system affects mental functions and emotion. In this study, researchers used magnetic resonance imaging (MRI) to investigate whether there are any structural changes in the brains of patients with NP-SLE that could explain their neuropsychiatric symptoms. They have also examined whether any changes in the brain can be linked to the presence of autoantibodies that recognize a protein called the NMDA receptor (anti-NMDAR antibodies) that is present on brain cells.

What Did the Researchers Do and Find?

The researchers used an MRI technique called diffusion weighted imaging to examine the brains of several patients with NP-SLE or SLE and the brains of several healthy individuals. Using this technique, it is possible to quantify the amount of structural damage in different regions of the brain. The researchers found no differences in most areas of the brain between the two groups of patients and the healthy controls. However, there were clear signs of damage in the amygdala (the part of the brain that regulates emotions and triggers responses to danger) in the patients with SLE or NP-SLE when compared to the control individuals. The researchers also found that the damage was more severe in the patients who had anti-NMDAR autoantibodies than in those that did not have these autoantibodies.

What Do These Findings Mean?

These findings suggest that autoantibodies produced by patients with SLE specifically damage the amygdala, a discovery that helps to explain some of the neuropsychiatric symptoms of this condition. Previous work has shown that the treatment of mice with anti-NMDAR antibodies and epinephrine, a stress hormone that causes leaks in the blood-brain barrier (antibodies can't usually get into the brain because of this barrier), results in damage to the amygdala and a deficient response to dangerous stimuli. The researchers suggest that a similar series of events might happen in SLE—patients often mention that a period of major stress precedes the development of symptoms. To provide stronger evidence for such a scenario, a detailed study of how stress relates to neuropsychiatric symptoms is needed. The damage to the amygdala (and the lack of damage elsewhere in the brain) and the possible association between brain damage and anti-NMDAR antibodies seen in this small study also need to be confirmed in more patients. Nevertheless, these findings provide an intriguing glimpse into the interplay between the immune system and the brain and into how stress might lead to physical damage in the brain.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030499.

MedlinePlus encyclopedia pages on autoimmunity and on systemic lupus erythematosus

US National Institute of Arthritis and Musculoskeletal and Skin Diseases booklet for patients with SLE

American College of Rheumatology information for patients on SLE

NHS Direct Online Health Encyclopedia pages on SLE

The Lupus Foundation of America information and support for patients with SLE

The hypothesis that lymphocytotoxic antibodies are associated with neuropsychiatric involvement in systemic lupus erythematosus (NP-SLE) is re-evaluated in this study. In an unselected cohort of 98 women with SLE a cross-sectional study has been performed to analyse associations among standardised clinical, neurological, and neuropsychological assessments and lymphocytotoxic antibodies measured by microcytotoxicity assay. Fifty patients showed objective clinical evidence of continuing or past NP-SLE and 54 patients had cognitive impairment. In accordance with previous observations 44% (24/54) of the cognitively impaired group did not have clinically detectable evidence of NP-SLE. Although lymphocytotoxic antibodies were found to be only marginally more prevalent in those patients with a clinical diagnosis of NP-SLE than in those without (32% v 23%), these antibodies were significantly associated with cognitive impairment (chi 2 = 5.42; p less than 0.02). No association was detected between lymphocytotoxic antibodies and either overall systemic disease activity or other organ system involvement, suggesting that the association between lymphocytotoxic antibodies and cognitive dysfunction in SLE is specific.

Physicians’ awareness about neuropsychiatric syndromes in systemic lupus erythematosus (SLE) is not rarely limited to seizures and psychoses included in the American College of Rheumatology (ACR) classification. Involvement of the central nervous system (CNS) with its rich symptomatology still belongs to the faintly recognised and understood aspects of lupus. The objective was to investigate prevalence and clinical correlations of psychiatric disorders in SLE patients. Fifty-two SLE patients were included. Disease duration and current and cumulative corticosteroid doses were calculated. Disease activity was assessed with the Systemic Lupus Activity Measure (SLAM). All subjects were examined by a psychiatrist. Psychiatric disorders were classified according to ACR criteria for neuropsychiatric systemic lupus erythematosus (NPSLE). Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT) were used to screen for cognitive impairments. Mental disorders were diagnosed in 16 (30.77%), depressive disorder in 6 (11.54%), cognitive dysfunction in 5 (9.62%), anxiety disorder in 4 (7.69%) and psychosis in one patient (1.92%). SLE duration was shorter in patients diagnosed with anxiety disorder (P < 0.05), and cumulative dose of corticosteroids was lower in patients with anxiety disorder (P < 0.01). There was high positive correlation between SLE duration and cumulative dose of corticosteroids (r = 0.684, P < 0.001). Shorter SLE duration in patients with anxiety disorder seems to reflect its adaptative nature.

Objective

To describe vascular events during an 8 year follow-up in a multicentre SLE inception cohort and their attribution to atherosclerosis.

Methods

Clinical data including co-morbidities are recorded yearly. Vascular events are recorded and attributed to atherosclerosis or not. All events met standard clinical criteria. Factors associated with atherosclerotic vascular events were analysed using descriptive statistics, t-tests and χ2. Stepwise multivariate logistic regression was used to assess the association of factors with vascular events attributed to atherosclerosis.

Results

Since 2000, 1249 patients have been entered into the cohort. There have been 97 vascular events in 72 patients. These include: myocardial infarction (13), angina (15), congestive heart failure (24), peripheral vascular disease (8), transient ischemic attack (13), stroke (23), pacemaker insertion (1). Fifty of the events were attributed to active lupus, 31events in 22 patients were attributed to atherosclerosis, and 16 to other causes. Time from diagnosis to first atherosclerotic event was 2.0 ± 1.5 years. Compared to patients followed for 2 years without atherosclerosis events (615), at enrolment patients with AVE were more frequently Caucasian, male, older at diagnosis of SLE, obese, smokers, hypertensive and had a family history of coronary artery disease. On multivariate analysis only male gender and older age at diagnosis were associated factors.

Conclusion

In an inception cohort with SLE followed for up to 8 years there were 97 vascular events but only 31 were attributable to atherosclerosis. Patients with atherosclerotic events were more likely to be male and to be older at diagnosis of SLE.

Introduction

The tumour necrosis factor (TNF) family ligands BAFF (B-cell activating factor of TNF family) and APRIL (a proliferation-inducing ligand) are essential for B-cell survival and function. Elevated serum levels of BAFF and APRIL have been reported earlier in patients with systemic lupus erythematosus (SLE). Since autoantibody formation in the central nervous system (CNS) is a distinct feature of neuropsychiatric SLE (NPSLE), we have investigated whether NPSLE is associated with an enhanced intrathecal production of APRIL and BAFF.

Methods

Levels of BAFF and APRIL in cerebrospinal fluid (CSF) and serum from healthy controls, SLE patients without CNS involvement, and patients with NPSLE were determined by enzyme-linked immunosorbent assay. Interleukin-6 (IL-6) levels were determined by an IL-6-specific bioassay.

Results

SLE patients had levels of APRIL in CSF that were more than 20-fold higher and levels of BAFF in CSF that were more than 200-fold higher than those of healthy controls. Separate analyses of SLE patients with and without CNS involvement revealed that NPSLE patients had enhanced levels of APRIL in CSF. BAFF and APRIL were likely produced locally in the CNS as CSF and serum levels did not correlate. Moreover, CSF levels of APRIL correlated with BAFF but not with IL-6, suggesting that APRIL and BAFF in the CNS are regulated together but that they are produced independently of IL-6.

Conclusion

To our knowledge this is the first study to show elevated levels of BAFF and APRIL in CSF of SLE patients. APRIL was augmented in NPSLE patients compared with SLE patients without CNS involvement. APRIL and BAFF antagonists breeching the blood-brain barrier therefore could have beneficial effects on SLE patients, in particular patients with NPSLE.

Accelerated atherosclerosis represents a major problem in both systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients, and endothelial damage is a key feature of atherogenesis. We aimed to assess early endothelial changes in SLE and RA female patients (127 SLE and 107 RA) without previous CV events. Biomarkers of endothelial cell activation (intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), thrombomodulin (TM), and tissue factor (TF)) were measured and endothelial function was assessed using peripheral artery tonometry. Reactive hyperemia index (RHI), an indicator of microvascular reactivity, and augmentation index (AIx), a measure of arterial stiffness, were obtained. In addition, traditional CV risk factors, disease activity and medication were determined. Women with SLE displayed higher sICAM-1 and TM and lower TF levels than women with RA (p = 0.001, p<0.001 and p<0.001, respectively). These differences remained significant after controlling for CV risk factors and medication. Serum levels of vascular biomarkers were increased in active disease and a moderate correlation was observed between sVCAM-1 levels and lupus disease activity (rho = 0.246) and between TF levels and RA disease activity (rho = 0.301). Although RHI was similar across the groups, AIx was higher in lupus as compared to RA (p = 0.04). Also in active SLE, a trend towards poorer vasodilation was observed (p = 0.06). In conclusion, women with SLE and RA present with distinct patterns of endothelial cell activation biomarkers not explained by differences in traditional CV risk factors. Early vascular alterations are more pronounced in SLE which is in line with the higher CV risk of these patients.

Symptoms originating from the central nervous system (CNS) frequently occur in patients with systemic lupus erythematosus (SLE). These symptoms are extremely diverse, including a state of dementia. The aim of this study was to examine the cerebrospinal fluid (CSF) content of soluble molecules indicating axonal degeneration and amyloidogenesis.

One hundred and fourteen patients with SLE and age-matched controls were evaluated clinically, with magnetic resonance imaging of the brain and CSF analyses. Levels of tau, amyloid precursor protein (APP), β-amyloid protein (Aβ42), and transforming growth factor beta (TGF-β) were all determined using sandwich ELISAs.

APP and Aβ42 levels were significantly decreased in SLE patients irrespective of their CNS involvement, as compared with healthy controls. Patients with neuropsychiatric SLE who underwent a second lumbar puncture following successful cyclophosphamide treatment showed further decreases of Aβ42. CSF-tau levels were significantly increased in SLE patients showing magnetic resonance imaging-verified brain pathology as compared with SLE patients without such engagement. Importantly, tau levels displayed significant correlation to Aβ42 levels in the CSF. Finally, TGF-β levels were significantly increased in patients with neuropsychiatric SLE as compared with those without.

Low intrathecal levels of Aβ42 found in SLE patients seem to be a direct consequence of a diminished production of APP, probably mediated by heavy anti-inflammatory/immuno-suppressive therapy. Furthermore, our findings suggest that CSF tau can be used as a biochemical marker for neuronal degeneration in SLE. Finally, the increased TGF-β levels observed may support a notion of an ongoing anti-inflammatory response counteracting tissue injury caused by CNS lupus.

Although systemic lupus erythematosis (SLE) is usually evaluated with regard to autoimmune reactivity toward the kidney, there are multiple psychiatric abnormalities associated with this autoimmune disease. Lupus-prone male NZM88 mice, derived from NZB/NZW F1 mice, develop early neuropsychiatric manifestations without any signs of nephritis. In addition to the usual repertoire of antibody specificities, including autoantibodies to dsDNA and renal antigens, mice of this inbred strain express autoantibodies to numerous brain antigens. Here, we show that autoantibodies to brain antigens, assessed by Western analysis, are as individually varied as are the diverse neuropsychiatric manifestations observed in SLE patients. Additionally, a monoclonal antibody derived from the spleen of an untreated NZM88 male when injected into healthy BALB/cByJ, but not C57BL/6J, mice induced behaviors similar to those of lupus-prone NZM88 mice. This monoclonal antibody, which is specific to dynamin-1, binds preferentially in BALB/cByJ cortex and induces substantial expression of cytokines mainly in the hypothalamus. Thus, an antibody to just one brain antigen can induce multiple behavioral changes, and multiple autoantibodies to different brain antigens exist in lupus-prone mice; however, susceptibility to the induction of neurobehavioral deficits is dependent on host genetics.

Objective

Racial differences are known to account for a higher incidence of systemic lupus erythematosus (SLE), as well as increased disease severity and mortality. The purpose of this study was to determine if there are any race-specific risk factors that affect measures of subclinical atherosclerosis in SLE patients.

Methods

Traditional and SLE-related cardiovascular disease (CVD) risk factors were assessed in 106 female SLE patients. Carotid medial intimal medial thickness (mIMT) and coronary artery calcification (CAC) were measured on all subjects. Differences were evaluated between races for all clinical, serologic, and CVD risk factors and the racial interactions with all covariables. Outcomes included mIMT and CAC.

Results

There were no significant differences between races with regard to mIMT or CAC. Significant covariables in the final model for mIMT included age, triglycerides, glucose, and race-age and race-smoking interactions. A prediction model with fixed significant covariables demonstrated that Black subjects with a smoking history had a significantly higher mIMT than Blacks who had never smoked, an effect not seen in Whites. There were no differences between having CAC or with the CAC scores between the races. In the final model for CAC, age and SLE disease duration were significant covariables impacting CAC.

Conclusion

When controlling for other significant CVD covariables and interactions, Black women, but not White, with SLE with a history of smoking have higher mIMT measurements than those who have never smoked. This is the first report documenting the race-specific effect of smoking on subclinical measures of CVD in SLE.

Objective

To test serum S100B protein levels in patients with and without neuropsychiatric systemic lupus erythematosus (NPSLE) and controls.

Methods

87 patients with SLE, 23 with and 64 without neuropsychiatric involvement, and 25 control subjects were prospectively evaluated. NPSLE diagnosis was made according to the American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Serum S100B protein levels were determined with a luminescence immunoassay. Statistical analysis was performed using Mann‐Whitney and Kruskal‐Wallis tests.

Results

Among the patients with NPSLE, 9 presented psychosis; 4, cranial neuropathy; 3, cerebrovascular disease; 1, seizures; 1, chorea; 1, peripheral polyneuropathy; 1, multiplex mononeuropathy; 3, dementia. Serum concentrations of S100B protein were significantly higher in patients with NPSLE (median 0.164 ng/ml, interquartile range 0.113–0.332) than in non‐NPSLE patients (0.062 ng/ml, 0.026–0.109) and controls (0.088 ng/ml, 0.013–0.124) (p<0.001). Patients with anti‐dsDNA antibodies had higher S100B protein levels (p = 0.001). No significant associations were found of lupus activity (among non‐NPSLE cases), antiphospholipid antibodies, and reduced complement levels with S100B concentration.

Conclusions

Serum S100B protein level is raised in NPSLE, reflecting continuing neurological damage. The association of anti‐dsDNA antibodies with higher S100B protein concentration deserves further study.

OBJECTIVES: To analyse frequency of HLA class II antigens (DR and DQ) and lymphocytotoxic autoantibodies in patients with systemic lupus erythematosus (SLE) and subsets with or without neuropsychiatric involvement. METHODS: Ninety three patients with SLE (42 with neuropsychiatric features) were typed for HLA class II antigens and investigated for the presence of lymphocytotoxic autoantibodies by a complement dependent microlymphocytotoxicity assay. A total of 191 controls of similar ethnic background were also typed for HLA antigens. RESULTS: HLA-DR3 antigen was increased in the total group of patients with SLE (p = 0.003) and in the neuropsychiatric group (p = 0.002). HLA-DR4 antigen frequency was increased in non-neuropsychiatric patients (p = 0.001) and decreased in patients with neuropsychiatric SLE (p = 0.0005). Comparisons of HLA frequencies between subgroups of patients showed decreased HLA-DR4 (p < 0.0001) and increased HLA-DR9 and HLA-DQ2 antigens (p = 0.0008 and 0.005 respectively) in the neuropsychiatric group. The frequency of lymphocytotoxic autoantibodies was increased in neuropsychiatric patients with SLE having HLA-DR9 specificity (p = 0.04). CONCLUSION: HLA-DR4 may have a protective specificity for the development of neuropsychiatric features of SLE and HLA-DR9, in addition to HLA-DR3, and the presence of lymphocytotoxic auto-antibodies may predispose to neuropsychiatric abnormalities.

A rare manifestation of systemic lupus erythematosus (SLE) is cerebral venous sinus thrombosis (CVST), in which early diagnosis and aggressive therapy are of prime importance for favorable outcome. The pathogenesis of CVST is largely unknown, but it is thought to be caused by cerebral vasculitis, antiphospholipid antibodies or other conditions associated with enhanced coagulability. We describe two cases of SLE with CVST which were not associated with antiphospholipid antibodies. Both cases were treated with immunosuppressants (intravenous methylprednisolone and cyclophosphamide pulse therapy) and anticoagulant drugs (heparin and subsequent maintenance therapy with warfarin). There was a marked improvement of neurologic symptoms with the disappearance of thrombus in a follow-up MRI. The possibility of CVST should be considered in any patients with SLE who show neuropsychiatric manifestations.

Objective

There is increasing evidence of the impact of SLE on employment, but few studies have had sufficient sample size and longitudinal follow-up to estimate the impact of specific manifestations or of increasing disease activity on employment.

Methods

Data derive from the UCSF Lupus Outcomes Study, a longitudinal cohort of 1204 persons with SLE sampled between 2002 and 2009. Of the 1204, 484 were working at baseline and had at least one follow-up interview. We used the Kaplan-Meier method to estimate the time between onset of thrombotic, neuropsychiatric, or musculoskeletal manifestations or of increased disease activity and work loss, and Cox proportional hazards regression to estimate the risk of work loss associated with the onset of specific manifestations, the number of manifestations, and increased activity, with and without adjustment for sociodemographic, employment, and SLE duration.

Results

By four years of follow-up, 57%, 34%, and 38% of those with thrombotic, musculoskeletal, and neuropsychiatric manifestations, respectively, had stopped working as had 42% of those with increased disease activity. On a bivariable basis, the risk of work loss was significantly higher among persons 55–64, and those with increased disease activity and each kind of manifestation. In multivariable analysis, older age, shorter job tenure, thrombotic and musculoskeletal manifestations, greater number of manifestations, and high levels of activity increased the risk of work loss.

Conclusions

Incident thrombosis and musculoskeletal manifestations, multiple manifestations, and increased disease activity are associated with the risk of work loss in SLE.

Introduction

Systemic lupus erythematosus (SLE) is characterized by frequent neuropsychiatric involvement, which includes cognitive impairment (CI). We aimed at assessing CI in a cohort of Italian SLE patients by using a wide range of neurocognitive tests specifically designed to evaluate the fronto-subcortical dysfunction. Furthermore, we aimed at testing whether CI in SLE is associated with serum autoantibodies, disease activity and chronic damage.

Methods

Fifty-eight consecutive patients were enrolled. Study protocol included data collection, evaluation of serum levels of ANA, anti-dsDNA, anti-cardiolipin, anti-β2-glycoprotein I, anti-P ribosomal, anti-endothelial cell, and anti-Nedd5 antibodies. SLEDAI-2000 and SLICC were used to assess disease activity and chronic damage. Patients were administered a test battery specifically designed to detect fronto-subcortical dysfunction across five domains: memory, attention, abstract reasoning, executive function and visuospatial function. For each patient, the raw scores from each test were compared with published norms, then transformed into Z scores (deviation from normal mean), and finally summed in the Global Cognitive Dysfunction score (GCDs).

Results

Nineteen percent of patients had mild GCDs impairment (GCDs 2–3), 7% moderate (GCDs 4–5) and 5% severe (GCDs≥6). The visuospatial domain was the most compromised (MDZs = −0.89±1.23). Anti-cardiolipin IgM levels were associated with visuospatial domain impairment (r = 0.331, P = 0.005). SLEDAI correlated with GCDs, and attentional and executive domains; SLICC correlated with GCDs, and with visuospatial and attentional domains impairment.

Conclusions

Anti-phospholipids, disease activity, and chronic damage are associated with cognitive dysfunction in SLE. The use of a wide spectrum of tests allowed for a better selection of the relevant factors involved in SLE cognitive dysfunction, and standardized neuropsychological testing methods should be used for routine assessment of SLE patients.

Introduction

The clinical outcome and therapeutic response to immunosuppressive agents vary among patients with lupus nephritis of different ethnic populations. Thus, we evaluated the efficacy of two established treatment protocols for lupus nephritis (low-dose versus standard-dose cyclophosphamide) in Puerto Ricans with systemic lupus erythematosus (SLE).

Methods

A retrospective cohort of 49 adult patients with SLE treated with intravenous low or standard-dose cyclophosphamide for clinical or biopsy confirmed lupus nephritis was studied. Demographic parameters, clinical manifestations, autoantibodies and pharmacological treatments were determined prior to cyclophosphamide treatment. Renal parameters, disease activity, damage accrual and corticosteroid use were determined before and after treatment. Cyclophosphamide-associated adverse events were also examined. Univariable and bivariable analyses were used to evaluate group differences.

Results

Thirty-nine SLE patients received the standard-dose treatment and ten patients the low-dose therapy. Prior to cyclophosphamide infusion, demographic parameters, clinical manifestations, autoantibodies profile, disease damage and pharmacologic treatments were similar in both groups. Disease activity was higher in the low-dose group. After cyclophosphamide therapy, significant improvement of renal parameters (increase in the glomerular filtration rate and decrease in hematuria, pyuria, urinary cellular casts, proteinuria and hypertension) were observed only for patients that received the standard-dose therapy. Disease activity and corticosteroids requirement decreased in both groups after treatment. No differences were observed for adverse events associated with cyclophosphamide.

Conclusions

The standard-dose cyclophosphamide therapy appears to be more effective, and similar in terms of drug safety, than the low-dose regime for lupus nephritis in Puerto Ricans with SLE.