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1.  Prospective Analysis Of Neuropsychiatric Events In An International Disease Inception Cohort of SLE Patients 
Annals of the rheumatic diseases  2009;69(3):529-535.
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.
doi:10.1136/ard.2008.106351
PMCID: PMC2929162  PMID: 19359262
Lupus; Neuropsychiatric; Prospective; Inception cohort
2.  SF-36 summary and subscale scores are reliable outcomes of neuropsychiatric events in systemic lupus erythematosus 
Annals of the rheumatic diseases  2011;70(6):961-967.
Objective
To examine change in health-related quality of life (HRQoL) in association with clinical outcomes of neuropsychiatric (NP) events in SLE.
Methods
An international study evaluated newly diagnosed SLE patients for NP events attributed to SLE and non-SLE causes. Outcome of events was determined by physician-completed 7-point scale and compared to patient-completed SF-36 questionnaires. Statistical analysis used linear mixed-effects regression models with patient specific random effects.
Results
274 patients (92% female; 68% Caucasian), from a cohort of 1400, had ≥ 1 NP event where the interval between assessments was 12.3 ± 2 months. The overall difference in change between visits in mental component summary (MCS) scores of the SF-36 was significant (p<0.0001) following adjustments for gender, ethnicity, center and previous score. A consistent improvement in NP status (N=295) was associated with an increase in the mean(SD) adjusted MCS score of 3.66(0.89) in SF-36 scores. Between paired visits where NP status consistently deteriorated (N=30), the adjusted MCS score decreased by 4.00(1.96). For the physical component summary (PCS) scores the corresponding changes were +1.73(0.71) and −0.62(1.58) (p<0.05) respectively. Changes in SF-36 subscales were in the same direction (p<0.05; with the exception of role physical). Sensitivity analyses confirmed these findings. Adjustment for age, education, medications, SLE disease activity, organ damage, disease duration, attribution and characteristics of NP events did not substantially alter the results.
Conclusion
Changes in SF-36 summary and subscale scores, in particular those related to mental health, are strongly associated with the clinical outcome of NP events in SLE patients.
doi:10.1136/ard.2010.138792
PMCID: PMC3795436  PMID: 21342917
Systemic lupus erythematosus; Neuropsychiatric; Inception cohort; Health related quality of life; SF-36
3.  Selective Involvement of the Amygdala in Systemic Lupus Erythematosus 
PLoS Medicine  2006;3(12):e499.
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
doi:10.1371/journal.pmed.0030499
PMCID: PMC1702559  PMID: 17177602
4.  Systemic lupus erythematosus 
Clinical Evidence  2009;2009:1123.
Introduction
Systemic lupus erythematosus (SLE) occurs predominantly in young women, but also in children. The prevalence of SLE varies widely worldwide, ranging from about 1 in 3500 women (regardless of race) in the UK, to 1 in 1000 women in China, to 1 in 250 African-American women in the USA.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments on joint symptoms (arthralgia/arthritis) and other non-organ-threatening symptoms (such as serositis and fatigue) in people with systemic lupus erythematosus? What are the effects of interventions for cutaneous involvement in people with systemic lupus erythematosus? What are the effects of treatments in people with proliferative lupus nephritis (WHO grades 3–5)? What are the effects of treatments for neuropsychiatric involvement in people with systemic lupus nephritis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 11 systematic reviews or RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acitretin; antipsychotic drugs; chloroquine; combination corticosteroids plus immunosuppressants; corticosteroids; hydroxychloroquine; intravenous immunoglobulin; methotrexate; non-steroidal anti-inflammatory drugs (NSAIDs); plasmapheresis; and sunblock.
Key Points
Systemic lupus erythematosus (SLE) is a chronic, multi-system, inflammatory connective tissue disorder of unknown cause that can involve joints, kidneys, serous surfaces, skin, and vessel walls. It occurs predominantly in young women, but also in children. The course of SLE is highly variable, involving non-organ-threatening symptoms (such as arthritis, arthralgia, and rashes), organ-threatening symptoms (such as lupus nephritis), and neuropsychiatric disorders (such as seizures and cognitive dysfunction).
The prevalence of SLE varies widely worldwide, ranging from about 1 in 3500 women (regardless of race) in the UK, to 1 in 1000 women in China, to 1 in 250 African-American women in the USA.
There is consensus that NSAIDs and corticosteroids are useful in relieving pain caused by arthralgia/arthritis, and pleuritis and pericarditis associated with SLE. We found no evidence that the well-documented adverse effects of NSAIDs differ in people with SLE. There is also consensus that corticosteroids and sunscreens are effective in reducing cutaneous manifestations of SLE.
Hydroxychloroquine or chloroquine are likely to be effective in reducing arthritis, pleuritis, and pericarditis. They may also improve cutaneous symptoms. Methotrexate may also be effective for both joint and cutaneous symptoms, but is associated with adverse effects.
Combining immunosuppressants plus corticosteroids may be more effective than corticosteroids alone in people with lupus nephritis, but with an increase in adverse effects. We don't know how corticosteroids alone compare with immunosuppressants alone in people with proliferative lupus nephritis.
We don't know whether corticosteroids, immunosuppressants, plasmapheresis, or intravenous immunoglobulin are effective in people with neuropsychiatric symptoms of lupus. Most people with neuropsychiatric lupus and psychotic symptoms will be offered antipsychotic drugs to control symptoms unless there are contraindications, despite the lack of RCTs assessing their effectiveness.
PMCID: PMC2907829  PMID: 21696649
5.  Libman-Sacks Endocarditis and Embolic Cerebrovascular Disease 
JACC. Cardiovascular imaging  2013;6(9):973-983.
Objective
To determine whether Libman-Sacks endocarditis is a pathogenic factor for cerebrovascular disease (CVD) in systemic lupus erythematosus (SLE).
Background
A cardioembolic pathogenesis of SLE CVD manifested as 1) neuropsychiatric SLE (NPSLE) including stroke and transient ischemic attacks (TIA), 2) neurocognitive dysfunction, and 3) MRI focal brain lesions has not been established.
Methods
A 6-year study of 30 patients with acute NPSLE (27 women, age 38±12 years), 46 age-and-sex matched SLE controls without NPSLE (42 women, age 36±12 years), and 26 age-and-sex matched healthy controls (22 women, age 34±11 years) who underwent clinical and laboratory evaluations, TEE, carotid duplex, transcranial Doppler, neurocognitive testing, and brain MRI/MRA. NPSLE patients were re-evaluated after 4.5 months of therapy. All patients were followed clinically for a median of 52 months.
Results
Libman-Sacks vegetations (87%), cerebromicroembolism (27% with 2.5 times more events per hour), neurocognitive dysfunction (60%), and cerebral infarcts (47%) were more common in NPSLE than in SLE (28%, 20%, 33%, and 0%) and healthy controls (8%, 0%, 4%, and 0%, respectively) (all p≤0.009). Patients with vegetations had 3 times more cerebromicroemboli per hour, lower cerebral blood flow, more stroke/TIA and overall NPSLE events, neurocognitive dysfunction, cerebral infarcts, and brain lesion load than those without (all p≤0.01). Libman-Sacks vegetations were independent risk factors of NPSLE (OR=13.4, p<0.001), neurocognitive dysfunction (OR=8.0, p=0.01), brain lesions (OR=5.6, p=0.004), and all 3 outcomes combined (OR=7.5, p<0.001). Follow-up re-evaluations in 18 (78%) of 23 surviving NPSLE patients demonstrated improvement of vegetations, microembolism, brain perfusion, neurocognitive dysfunction, and lesion load (all p≤0.04). Finally, patients with vegetations had reduced event free survival time to stroke/TIA, cognitive disability, or death (p=0.007).
Conclusion
The presence of Libman-Sacks endocarditis in patients with SLE is associated with higher risk for embolic CVD. This suggests that Libman-Sacks endocarditis may be a source of cerebral emboli.
doi:10.1016/j.jcmg.2013.04.012
PMCID: PMC3941465  PMID: 24029368
Libman-Sacks endocarditis; cerebrovascular disease; stroke; microembolism; transesophageal echocardiography
6.  Neuropsychiatric systemic lupus erythematosus is associated with imbalance in interleukin 10 promoter haplotypes 
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
PMCID: PMC1752835  PMID: 10343522
7.  NEUROPSYCHIATRIC DISEASE IN MURINE LUPUS IS DEPENDENT ON THE TWEAK/Fn14 PATHWAY 
Journal of autoimmunity  2013;43:44-54.
Given the early onset of neuropsychiatric disease and the potential response to immunosuppressive therapy, neuropsychiatric disease is considered a primary disease manifestation in SLE. However, the pathogenesis is not fully understood and optimal treatment has yet to be determined. TWEAK is a TNF family ligand that mediates pleotropic effects through its receptor Fn14, including the stimulation of inflammatory cytokines by astrocytes, endothelial cells, and other non-hematopeotic cell types, and induction of neuronal death. Furthermore, TWEAK-inducible mediators are implicated in neuropsychiatric lupus. Thus, we hypothesized that the TWEAK/Fn14 pathway may be involved in the pathogenesis of neuropsychiatric SLE. We generated MRL-lpr/lpr (MRL/lpr) mice deficient for Fn14, the sole known signaling receptor for TWEAK. Neuropsychiatric disease was compared in age- and gender-matched MRL/lpr Fn14 wild type (WT) and knockout (KO) mice, using a comprehensive battery of neurobehavioral tests. We found that MRL/lpr Fn14WT mice displayed profound depression-like behavior as seen by increased immobility in a forced swim test and loss of preference for sweetened fluids, which were significantly ameliorated in Fn14KO mice. Similarly, MRL/lpr Fn14WT mice had impaired cognition, and this was significantly improved in Fn14KO mice. To determine the mechanism by which Fn14 deficiency ameliorates neuropsychiatric disease, we assessed the serum levels of autoantibodies and local expression of cytokines in the cortex and hippocampus of lupus mice. No significant differences were found in the serum levels of antibodies to nuclear antigens, or autoantibodies specifically associated with neuropsychiatric disease, between MRL/lpr Fn14WT and KO mice. However, MRL/lpr Fn14KO mice had significantly decreased brain expression of RANTES, C3, and other proinflammatory mediators. Furthermore, MRL/lpr Fn14KO mice displayed improved blood brain barrier integrity. In conclusion, several central manifestations of neuropsychiatric lupus, including depression-like behavior and altered cognition, are normalized in MRL/lpr mice lacking Fn14. Our results are the first to indicate a role for the TWEAK/Fn14 pathway in the pathogenesis of neuropsychiatric lupus, and suggest this ligand-receptor pair as a potential therapeutic target for a common and dangerous disease manifestation.
doi:10.1016/j.jaut.2013.03.002
PMCID: PMC3672366  PMID: 23578591
Systemic lupus erythematosus (SLE); neuropsychiatric lupus; TWEAK; Fn14
8.  Short-Term Perioperative All-Cause Mortality and Cardiovascular Events in Women with Systemic Lupus Erythematosus 
Arthritis care & research  2013;65(6):986-991.
Background
Persons with systemic lupus erythematosus (SLE) are at increased risk of cardiovascular disease (CVD) events, but this excess CVD burden in the perioperative setting is yet to be determined. We aimed to determine the risk of perioperative short-term all-cause mortality and CVD events among women with SLE compared to those without SLE.
Methods and Results
We conducted a cross-sectional analysis of pooled hospital discharge data from years 1998 to 2002 of the Nationwide Inpatient Sample. We abstracted diseases and procedures using International Classification of Diseases, Ninth Revision (ICD-9-CM) codes. The principal procedure was categorized into either a low, intermediate, or high risk level. Survey logistic regression adjusting for potential confounders provided estimates for stratum-specific odds of adverse events in women with SLE relative to those without SLE for each procedure risk level. All-cause mortality was significantly greater among women with SLE having a low (Odds Ratio [OR] 1.54; 95% Confidence Interval [CI] 1.00-2.37) or a high risk principal procedure (OR 2.52; 95% CI 1.34-4.75) relative to women without SLE, but did not differ significantly among persons with intermediate risk procedures. Women with SLE with a low risk procedure were also more likely to experience a composite CVD event relative to women without SLE (OR 1.40; 95% CI 1.04-1.87).
Conclusions
Women with SLE are at increased risk for short-term perioperative adverse events. These results highlight a need for greater scrutiny during perioperative evaluation and management of women with SLE.
Significance and Innovation
The perioperative setting represents a time of heightened risk for morbidity and mortality, especially in individuals at increased risk of cardiovascular disease. Women with SLE are at increased risk of premature morbidity and mortality attributed to atherosclerotic disease. The results of our study which revealed an increased risk of adverse perioperative events in women with SLE indicates a need for greater scrutiny in perioperative clinical care also in addition to further investigation as to the non-cardiovascular causes of increased perioperative mortality observed in women with SLE.
doi:10.1002/acr.21915
PMCID: PMC3674177  PMID: 23213026
9.  A Randomised, Blinded, Placebo-Controlled Trial in Dementia Patients Continuing or Stopping Neuroleptics (The DART-AD Trial)  
PLoS Medicine  2008;5(4):e76.
Background
There have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease.
Methods and Findings
Design: Randomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial.
Setting: Oxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom.
Participants: Patients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo.
Interventions: Continue neuroleptic treatment for 12 mo or switch to an identical placebo.
Outcome measures: Primary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI).
Results: 165 patients were randomised (83 to continue treatment and 82 to placebo, i.e., discontinue treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo). Of those, 26 were lost to follow-up (13 per arm), resulting in 51 patients per arm analysed for the primary outcome. There was no significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 6 mo; estimated mean difference in deterioration (favouring placebo) −0.4 (95% confidence interval [CI] −6.4 to 5.5), adjusted for baseline value (p = 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) −2.4 (95% CI −8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI ≥ 15 benefited on neuropsychiatric symptoms from continuing treatment.
Conclusions
For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy.
Trial registration: Cochrane Central Registry of Controlled Trials/National Research Register (#ISRCTN33368770).
In a randomized trial of patients with dementia, Clive Ballard and colleagues show that withdrawal of neuroleptics had no overall detrimental effect, and by some measures improved, functional and cognitive status.
Editors' Summary
Background
The number of people with dementia (currently 25 million worldwide) is expected to increase by 5 million each year. The risk of dementia, including Alzheimer disease, increases sharply with age: Alzheimer's Disease International estimates that 1.4% of people 65–69 have dementia, whereas almost a full quarter of those over the age of 85 years are affected. Almost all older dementia patients will experience, along with the cognitive and functional decline typical of the illness, some neuropsychiatric symptoms. These symptoms can include agitation, aggression, and psychosis, and are often devastating for the older patient and his or her family and caregiver. Managing these symptoms is often a prime concern for health-care providers and families. Neuroleptics (sometimes called antipsychotics) are the class of drugs often used to manage or control neuropsychiatric problems, but there have been questions about their safety and appropriateness. Safety concerns involve risk of stroke, parkinsonism, sedation, edema, and chest infections but also include a worsening of cognitive decline with prolonged use of neuroleptics.
Why Was the Study Done?
Previous studies on the effectiveness and safety of neuroleptics in older people have been short term. Ballard and colleagues wanted to study over a longer period of time the impact of neuroleptic drugs on elderly patients with dementia. Specifically, they wanted to know if being on a neuroleptic was associated with more cognitive decline than coming off the drug. They also wanted to investigate whether discontinuing the drug exacerbated any neuropsychiatric symptoms, Parkinson disease-like symptoms, or other functional, language, and cognition difficulties frequently associated with dementia.
What Did the Researchers Do and Find?
The researchers recruited older patients with Alzheimer disease from across England who had been on neuroleptics for at least three months. They randomised patients to one of two groups: the first group continued taking the same neuroleptic at the same dosage level while the second group was switched to an identical-looking placebo. The researchers assessed the patients' cognitive status and neuropsychiatric symptoms upon their entry into the study. Six and 12 months later the researchers assessed any cognitive decline and the level of neuropsychiatric and other problems that patients were experiencing.
At both 6 and 12 months, the researchers found that there were no differences between the two groups (continued treatment and placebo) in terms of cognitive decline. The placebo group may have had less cognitive decline, but this was not statistically significant. They also found no overall differences between the two groups in the change in the number of neuropsychiatric symptoms over these time periods. Patients with severe neuropsychiatric problems at the outset of the trial did better on continued neuroleptic therapy, but this advantage was not statistically significant. There was a significant decline on the verbal fluency language tests among the patients who continued on their neuroleptic.
What Do these Findings Mean?
The researchers report perhaps the first trial of this duration on continued versus withdrawn neuroleptic treatment among older dementia patients. The findings do not indicate any benefit of continuing neuroleptic therapies in older patients on either cognitive or neuropsychiatric outcomes. The researchers conclude that neuroleptics, with their known safety issues, should not be used as first-line treatment to manage problems such as agitation or aggression. For older dementia patients whose neuropsychiatric symptoms are not remedied by nonpharmaceutical treatments, the researchers advise caution. More studies are urgently needed to find better solutions to help older patients with dementia who have agitation, aggression, and psychosis.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050076.
Alzheimer's Disease International is an umbrella organisation of organisations worldwide
The Alzheimer's Research Trust in the UK is a charity funding research to cure or prevent dementias
The US National Institutes of Aging has information on Alzheimer Disease in English and Spanish
Two governmental regulatory agencies—the Medicines and Healthcare Products Regulatory Agency in the UK and the Food and Drug Administration in the US—offer information about antipsychotics in people with dementia
doi:10.1371/journal.pmed.0050076
PMCID: PMC2276521  PMID: 18384230
10.  Classification criteria for neuropsychiatric systemic lupus erythematosus: Do they need a discussion? 
Hippokratia  2008;12(2):103-107.
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.
PMCID: PMC2464312  PMID: 18923663
neuropsychiatric systemic lupus erythematosus; classification criteria
11.  Anti-ribosomal P protein IgG autoantibodies in patients with systemic lupus erythematosus: diagnostic performance and clinical profile 
BMC Medicine  2013;11:98.
Background
This study was devised to assess the performance of anti-ribosomal P (anti-Rib-P) antibodies in the diagnosis of systemic lupus erythematosus (SLE) and the association of these antibodies with the clinical features of SLE.
Methods
We used a fluorescence enzyme immunoassay to determine anti-Rib-P levels in an SLE group, a rheumatic disease control (RDC) group (rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis), and a healthy control (HC) group. We also determined anti-Smith antigen (anti-Sm) and anti-double-stranded DNA (anti-dsDNA) antibody levels. Receiver operating characteristic (ROC) curves were constructed and the best cut-off points for positivity were determined. Using regression analysis, the relationship between clinical variables and autoantibody levels was analyzed.
Results
In total, 127 patients with SLE, 256 controls with other rheumatic diseases, and 100 HCs were studied. Anti-Rib-P autoantibodies were positive in 18 (14.2%) of the patients with SLE (mean concentration of 30.6 ± 46.9 U/ml) and in 2 patients with RA (0.8% of the RDC group). In addition, 12 patients with SLE (9.4%) were positive for anti-Sm (31.1 ± 40.8 U/ml) and 63 (49.6%) were positive for anti-dsDNA autoantibodies (88.4 ± 88.5 U/ml). When we assessed the 18 patients with SLE who had tested positive for anti-Rib-P, we found that 4 of these were positive for anti-Rib-P only, whereas 12 were positive for anti-Rib-P plus anti-dsDNA, and 2 were positive for all three antibodies. There were no samples positive for anti-Rib-P plus anti-Sm. The specificity, sensitivity, positive likelihood ratio, and negative likelihood ratio of anti-Rib-P for SLE diagnosis were 99.4%, 14.2%, 23.7%, and 0.86%, respectively.
Caucasian ethnicity was associated with lower anti-Rib-P antibody levels. No relation was found between anti-Rib-P levels and neuropsychiatric or other clinical features.
Conclusions
Anti-Rib-P autoantibodies have high specificity for SLE, and measurement of these might improve the accuracy of SLE diagnosis. In this study, we found that Caucasian ethnicity was associated with lower anti-Rib-P antibody levels.
doi:10.1186/1741-7015-11-98
PMCID: PMC3616863  PMID: 23557114
Anti-Rib-P; Systemic lupus erythematosus; Antibodies
12.  Dependent Stressful Life Events and Prior Depressive Episodes in the Prediction of Major Depression 
Archives of general psychiatry  2010;67(11):1120-1127.
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.
doi:10.1001/archgenpsychiatry.2010.136
PMCID: PMC3081880  PMID: 21041613
13.  Functional neuronal network activity differs with cognitive dysfunction in childhood-onset systemic lupus erythematosus 
Introduction
Neuropsychiatric manifestations are common in childhood-onset systemic lupus erythematosus (cSLE) and often include neurocognitive dysfunction (NCD). Functional magnetic resonance imaging (fMRI) can measure brain activation during tasks that invoke domains of cognitive function impaired by cSLE. This study investigates specific changes in brain function attributable to NCD in cSLE that have potential to serve as imaging biomarkers.
Methods
Formal neuropsychological testing was done to measure cognitive ability and to identify NCD. Participants performed fMRI tasks probing three cognitive domains impacted by cSLE: visuoconstructional ability (VCA), working memory, and attention. Imaging data, collected on 3-Tesla scanners, included a high-resolution T1-weighted anatomic reference image followed by a T2*-weighted whole-brain echo planar image series for each fMRI task. Brain activation using blood oxygenation level-dependent contrast was compared between cSLE patients with NCD (NCD-group, n = 7) vs. without NCD (noNCD-group, n = 14) using voxel-wise and region of interest-based analyses. The relationship of brain activation during fMRI tasks and performance in formal neuropsychological testing was assessed.
Results
Greater brain activation was observed in the noNCD-group vs. NCD-group during VCA and working memory fMRI tasks. Conversely, compared to the noNCD-group, the NCD-group showed more brain activation during the attention fMRI task. In region of interest analysis, brain activity during VCA and working memory fMRI tasks was positively associated with the participants' neuropsychological test performance. In contrast, brain activation during the attention fMRI task was negatively correlated with neuropsychological test performance. While the NCD group performed worse than the noNCD group during VCA and working memory tasks, the attention task was performed equally well by both groups.
Conclusions
NCD in patients with cSLE is characterized by differential activation of functional neuronal networks during fMRI tasks probing working memory, VCA, and attention. Results suggest a compensatory mechanism allows maintenance of attentional performance under NCD. This mechanism appears to break down for the VCA and working memory challenges presented in this study. The observation that neuronal network activation is related to the formal neuropsychological testing performance makes fMRI a candidate imaging biomarker for cSLE-associated NCD.
doi:10.1186/ar4197
PMCID: PMC3672728  PMID: 23497727
14.  Increased Arterial Stiffness in Systemic Lupus Erythematosus (SLE) Patients at Low Risk for Cardiovascular Disease: A Cross-Sectional Controlled Study 
PLoS ONE  2014;9(4):e94511.
Cardiovascular disease (CVD) is a major cause of death in systemic lupus erythematosus (SLE) patients. Although the risk for cardiovascular events in patients with SLE is significant, the absolute number of events per year in any given cohort remains small. Thus, CVD risks stratification in patients with SLE focuses on surrogate markers for atherosclerosis at an early stage, such as reduced elasticity of arteries. Our study was designed to determine whether arterial stiffness is increased in SLE patients at low risk for CVD and analyze the role for traditional and non-traditional CVD risk factors on arterial stiffness in SLE. Carotid-femoral pulse wave velocity (PWV) was prospectively assessed as a measure of arterial stiffness in 41 SLE patients and 35 controls (CTL). Adjustment on age or Framingham score was performed using a logistic regression model. Factors associated with PWV were identified separately in SLE patients and in controls using Pearson's correlation coefficient for univariate analysis and multiple linear regression for multivariate analysis. SLE patients and controls displayed a low 10-year risk for CVD according to Framingham score (1.8±3.6% in SLE vs 1.6±2.8% in CTL, p = 0.46). Pulse wave velocity was, however, higher in SLE patients (7.1±1.6 m/s) as compared to controls (6.3±0.8 m/s; p = 0.01, after Framingham score adjustment) and correlated with internal carotid wall thickness (p = 0.0017). In multivariable analysis, only systolic blood pressure (p = 0.0005) and cumulative dose of glucocorticoids (p = 0.01) were associated with PWV in SLE patients. Interestingly, the link between systolic blood pressure (SBP) and arterial stiffness was also confirmed in SLE patients with normal systolic blood pressure. In conclusion, arterial stiffness is increased in SLE patients despite a low risk for CVD according to Framingham score and is associated with systolic blood pressure and glucocorticoid therapy.
doi:10.1371/journal.pone.0094511
PMCID: PMC3983200  PMID: 24722263
15.  Causes and outcome of hospitalisations in Tunisian patients with systemic lupus erythematosus 
Lupus Science & Medicine  2014;1(1):e000017.
Objective
To describe the most common reasons of admission of Tunisian patients with systemic lupus erythematosus (SLE) and the outcomes of these hospitalisations.
Method
The charts of patients with SLE who were hospitalised at our Department of Internal Medicine during a 2-year period from January 2011 to December 2012 were retrospectively reviewed, and the demographic characteristics, clinical and laboratory features, as well as all comorbidities, were collected.
Results
There were 128 episodes of hospitalisation of 87 patients with SLE. 25 patients (28.7%) were admitted twice or more. The median length of stay for all admissions was 11 days (2–76). The total number of days of hospitalisation was 1896 days, which represent 10.7% of the total number of days of hospitalisation in our department. The most common overall reason for hospitalisation was active SLE (55 events, 43%). In 29 patients, SLE was newly diagnosed during hospitalisation. Other causes of hospitalisation included assessment of the disease, infections (9.4%) and associated autoimmune disease (6.25%). Adverse drug reaction (3.1%) and thromboembolic events (1.25%) were uncommon causes of hospitalisations. There was a significant difference in length of stay between patients admitted with SLE flare and those admitted for non-SLE flare reasons (p<0.01). Four hospitalisations (3%) resulted in death. The principal cause of death was active SLE.
Conclusions
Hospitalisation of patients with SLE is common in our department. Our study of this North African SLE population confirms the findings of previous studies suggesting that active SLE and infection remain the most common causes of hospitalisation of patients with SLE.
doi:10.1136/lupus-2014-000017
PMCID: PMC4225742  PMID: 25396063
Autoimmune Diseases; Systemic Lupus Erythematosus; Epidemiology
16.  Patient-reported outcome measures for systemic lupus erythematosus clinical trials: a review of content validity, face validity and psychometric performance 
Background
Despite overall progress in treatment of autoimmune diseases, patients with systemic lupus erythematosus (SLE) experience many inflammatory symptoms representing an unmet medical need. This study aimed to create a conceptual model of the humanistic and economic burden of SLE, and review the patient-reported outcomes (PROs) used to measure such concepts in SLE clinical trials.
Methods
A conceptual model for SLE was developed from structured review of published articles from 2007 to August 2013 identified from literature databases (MEDLINE, EMBASE, PsycINFO, EconLit) plus other sources (PROLabels, FDA/EMA websites, Clinicaltrials.gov). PROs targeting key symptoms/impacts were identified from the literature. They were reviewed in the context of available guidance and assessed for face and content validity and psychometric properties to determine appropriateness for use in SLE trials.
Results
The conceptual model identified fatigue, pain, cognition, daily activities, emotional well-being, physical/social functioning and work productivity as key SLE concepts. Of the 68 articles reviewed, 38 reported PRO data. From these and the other sources, 15 PROs were selected for review, including SLE-specific health-related quality of life (HRQoL) measures (n = 5), work productivity (n = 1), and generic measures of fatigue (n = 3), pain (n = 2), depression (n = 2) and HRQoL (n = 2). The Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue), Brief Pain Inventory (BPI-SF) and LupusQoL demonstrated the strongest face validity, conceptual coverage and psychometric properties measuring key concepts in the conceptual model. All PROs reviewed, except for three Lupus-specific measures, lacked qualitative SLE patient involvement during development. The Hospital Anxiety and Depression Scale (HADS), Short Form [36 item] Health Survey version 2 (SF-36v2), EuroQoL 5-dimensions (EQ-5D-3L and EQ-5D-5L) and Work Productivity and Activity Impairment Questionnaire: Lupus (WPAI:Lupus) showed suitability for SLE economic models.
Conclusions
Based on the identification of key symptoms and impacts of SLE using a scientifically sound conceptual model, we conclude that SLE is a condition associated with high unmet need and considerable burden to patients. This review highlights the availability and need for disease-specific and generic patient-reported measures of relevant domains of disease signs and symptoms, HRQoL and work productivity, providing useful insight for SLE clinical trial design.
doi:10.1186/s12955-014-0116-1
PMCID: PMC4223409  PMID: 25048687
Systemic lupus erythematosus; Patient-reported outcomes; Conceptual model; Fatigue; Health-related quality of life
17.  Racial Disparities for Age at Time of Cardiovascular Events and Cardiovascular Death in SLE Patients 
Arthritis and rheumatism  2010;62(9):2767-2775.
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.
doi:10.1002/art.27551
PMCID: PMC2946465  PMID: 20506536
18.  Herpes Zoster Vaccination in SLE: A pilot study of Immunogenicity 
The Journal of rheumatology  2013;40(11):10.3899/jrheum.130170.
Background
Patients with systemic lupus erythematosus (SLE) are at increased risk of herpes zoster (HZ). Although a vaccine for HZ has been FDA approved, its use in immunocompromised individuals remains controversial because it is a live-attenuated virus vaccine. We performed a pilot study of the immunogenicity of Zostavax® in SLE patients.
Methods
Ten SLE patients and 10 controls ≥50 years old participated in this open label vaccination study. All were seropositive for varicella zoster virus (VZV). SLE patients were excluded for SLEDAI>4, use of mycophenolatemofetil, cyclophosphamide, biologics, or >10 mg prednisone daily. Follow-up visits occurred at 2, 6, and 12 weeks. Clinical outcomes included the development of adverse events, particularly HZ or vesicular lesions, and SLE flare. Immunogenicity was assessed with VZV-specific IFN-γ producing ELISPOT assays and with antibody concentrations.
Results
All subjects were women. SLE patients were slightly older than controls (60.5 vs. 55.3 years, p<0.05) Median baseline SLEDAI was 0 (range 0–2) for SLE patients. No episodes of HZ, vesicular rash, serious adverse events, or SLE flares occurred. Three injection site reactions occurred in each group: mild erythema or tenderness. The proportion of subjects with a >50% increase in ELISPOT results following vaccination was comparable between both groups, although absolute SLE responses were lower than controls. Antibody titers increased only among controls following vaccination (p<0.05).
Conclusions
Zostavax vaccination yielded a measurable immuneresponse in this cohort of mild SLE patients on mild-moderate immunosuppressive medications. No herpetiform lesions or lupus flares were seen in this small cohort of patients.
doi:10.3899/jrheum.130170
PMCID: PMC3867792  PMID: 24037550
Systemic lupus erythematosus; herpes zoster; vaccine; Zostavax; infection; clinical trial
19.  Obesity and Cytokines in Childhood-Onset Systemic Lupus Erythematosus 
Journal of Immunology Research  2014;2014:162047.
Background. In systemic lupus erythematosus (SLE), atherosclerosis is attributed to traditional and lupus related risk factors, including metabolic syndrome (MetS), obesity, and inflammation. Objective. To evaluate the association between obesity, measures of body fat content, serum tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6 and -10 levels in childhood-onset SLE (cSLE). Methods. We screened consecutive cSLE patients followed up in the Pediatric Rheumatology Outpatient Clinic of the State University of Campinas. cSLE patients were assessed for disease and damage. Obesity was definite as body mass index (BMI) ≥30 kg/m2. Serum TNF-α, IL-6, and IL-10 levels were measured by ELISA. Dual-energy X-ray absorptiometry was used to determine total fat mass, lean mass, and percent of body fat. Results. We included 52 cSLE patients and 52 controls. cSLE patients had higher serum TNF-α  (P = 0.004), IL-6 (P = 0.002), and IL-10 (P < 0.001) levels compared to controls. We observed higher serum TNF-α  (P = 0.036) levels in cSLE patients with obesity. An association between serum TNF-α levels and body fat percent (P = 0.046) and total fat mass on trunk region (P = 0.035) was observed. Conclusion. Serum TNF-α levels were associated with obesity and body fat content in cSLE. Our finding suggests that obesity may contribute to the increase of serum TNF-α levels in cSLE.
doi:10.1155/2014/162047
PMCID: PMC3987792  PMID: 24741576
20.  Association of Genetic Variants in Complement Factor H and Factor H-Related Genes with Systemic Lupus Erythematosus Susceptibility 
PLoS Genetics  2011;7(5):e1002079.
Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, Pmeta = 6.6×10−8, OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, Pmeta = 2.9×10−7, OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ∼146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (Pmeta = 3.2×10−7, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (Pmeta = 3.5×10−4, OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.
Author Summary
Systemic lupus erythematosus (SLE) is a complex autoimmune disease, associated with increased complement activation. Previous studies have provided evidence for the presence of SLE susceptibility gene(s) in the chromosome 1q31-32 locus. Within 1q32, genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) may contribute to the development of SLE, because genetic variants of these genes impair complement regulation and predispose to various human diseases. In this study, we tested association of genetic variants in the region containing CFH and CFHRs with SLE. We identified genetic variants predisposing to SLE in European American, African American, and Asian populations, which might be attributed to the deletion of CFHR3 and CFHR1 genes but not previously identified disease-associated exonic variants of CFH. This study provides the first evidence for consistent association between CFH/CFHRs and SLE across multi-ancestral SLE datasets, providing new insights into the role of complement regulators in the pathogenesis of SLE.
doi:10.1371/journal.pgen.1002079
PMCID: PMC3102741  PMID: 21637784
21.  Atherosclerotic Vascular Events in a Multinational Inception Cohort of Systemic Lupus Erythematosus (SLE) 
Arthritis care & research  2010;62(6):881-887.
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.
doi:10.1002/acr.20122
PMCID: PMC2989413  PMID: 20535799
22.  Neuropsychiatric Symptoms and the Use of Complementary and Alternative Medicine 
PM & R : the journal of injury, function, and rehabilitation  2012;5(1):10.1016/j.pmrj.2012.06.012.
Objectives
To assess the prevalence of complementary and alternative medicine (CAM) use by U.S. adults reporting neuropsychiatric symptoms and whether this prevalence changes based on the number of symptoms reported. Additional objectives include identifying patterns of CAM use, reasons for use, and disclosure of use with conventional providers in U.S. adults with neuropsychiatric symptoms.
Design
Secondary database analysis of a prospective survey.
Participants
A total of 23,393 U.S. adults from the 2007 National Health Interview Survey.
Methods
We compared CAM use between adults with and without neuropsychiatric symptoms. Symptoms included self-reported anxiety, depression, insomnia, headaches, memory deficits, attention deficits, and excessive sleepiness. CAM use was defined as use of mind—body therapies (eg, meditation), biological therapies (eg, herbs), or manipulation therapies (eg, massage) or alternative medical systems (eg, Ayurveda). Statistical analysis included bivariable comparisons and multivariable logistical regression analyses.
Main Outcome Measures
The prevalence of CAM use among adults with neuropsychiatric symptoms within the previous 12 months and the comparison of CAM use between those with and without neuropsychiatric symptoms.
Results
Adults with neuropsychiatric symptoms had a greater prevalence of CAM use compared with adults who did not have neuropsychiatric symptoms (43.8% versus 29.7%, P < .001); this prevalence increased with an increasing number of symptoms (trend, P < .001). Differences in the likelihood of CAM use as determined by the number of symptoms persisted after we adjusted for covariates. Twenty percent of patients used CAM because standard treatments were either too expensive or ineffective, and 25% used CAM because it was recommended by a conventional provider. Adults with at least one neuropsychiatric symptom were more likely to disclose the use of CAM to a conventional provider (47.9% versus 39.0%, P < .001).
Conclusion
More than 40% of adults with neuropsychiatric symptoms commonly observed in many diagnoses use CAM; an increasing number of symptoms was associated with an increased likelihood of CAM use.
doi:10.1016/j.pmrj.2012.06.012
PMCID: PMC3824364  PMID: 23098832
23.  Decreased levels of soluble amyloid β-protein precursor and β-amyloid protein in cerebrospinal fluid of patients with systemic lupus erythematosus 
Arthritis Research & Therapy  2004;6(2):R129-R136.
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.
doi:10.1186/ar1040
PMCID: PMC400431  PMID: 15059276
amyloid precursor protein; β-amyloid protein; cerebrospinal fluid; neuropsychiatric systemic lupus erythematosus; tau
24.  Serum nitrated nucleosome levels in patients with systemic lupus erythematosus: a retrospective longitudinal cohort study 
Introduction
Circulating nucleosomes released from apoptotic cells are important in the pathogenesis of systemic lupus erythematosus (SLE). Both nucleosomes and anti-nucleosome antibodies are deposited in inflamed tissues in patients with SLE. Active inflammation promotes nitration of tyrosine residues on serum proteins. Our hypothesis was that levels of nitrated nucleosomes would be elevated in patients with SLE and could be associated with disease activity. We therefore carried out a retrospective longitudinal study to investigate factors affecting levels of nitrated nucleosomes (NN) in patients with SLE.
Methods
A novel serum ELISA was developed to measure serum NN and modified to measure serum nitrated albumin (NA). Levels of both NN and NA were measured in 397 samples from 49 patients with SLE followed through periods of disease flare and remission for a mean of 89 months. Anti-nucleosome antibody (anti-nuc) levels were measured in the same samples. The effects of 24 different clinical, demographic and serological variables on NN, NA and anti-nuc levels were assessed by univariable and multivariable analysis.
Results
Patients with SLE had higher mean NN than healthy controls or patients with other autoimmune rheumatic diseases (P =0.01). Serum samples from 18 out of 49 (36.7%) of SLE patients were never positive for NN. This group of 18 patients was characterized by lower anti-double stranded DNA antibodies (anti-dsDNA), disease activity and use of immunosuppressants. In the remaining 63.3%, NN levels were variable. High NN was significantly associated with anti-Sm antibodies, vasculitis, immunosuppressants, hydroxychloroquine and age at diagnosis. NN levels were raised in neuropsychiatric flares. NN levels did not completely parallel NA results, thus providing additional information over measuring nitration status alone. NN levels were not associated with anti-nuc levels.
Conclusions
NN are raised in a subset of patients with SLE, particularly those who are anti-Sm positive. Elevated NN may be a marker of vascular activation and neuropsychiatric flares in these patients.
doi:10.1186/ar4477
PMCID: PMC3978622  PMID: 24502558
25.  Comparison of adverse events associated with use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: postal and telephone survey of travellers. 
BMJ : British Medical Journal  1996;313(7056):525-528.
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.
PMCID: PMC2351944  PMID: 8789977

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