Factors associated with neuropsychiatric involvement in Latin American patients with systemic lupus erythematosus.

INTRODUCTION: Factors related to presentation of neuropsychiatric (NP) SLE manifestations, early in the course of the disease, and during follow up have not been clearly established. PURPOSE: To identify disease and non-disease related factors associated with NP manifestations in early SLE. METHODS: We included 1193 patients from the GLADEL inception cohort free of NP involvement at cohort entry. We evaluated the association of demographic, clinical and laboratory data with NP involvement during follow-up. STATISTICAL METHODS: Independent factors associated with NP involvement were identified using a multivariable Cox regression model. RESULTS: Factors independently associated with NP manifestations were: mestizo ethnicity (HR 1.701, 95% CI 1.282-2.258, p = 0.0002), myalgias/myositis (HR 1.832, 95% CI 1.335-2.515, p = 0.0002), pneumonitis (HR 2.476, 95% CI 1.085-5.648, p = 0.0312), shrinking lung (HR 2.428, 95% CI 1.074-5.493, p = 0.0331) and hemolytic anemia (HR 1.629, 95% CI 1.130-2.347, p = 0.0089). Longer disease duration at cohort entry (13 to 24 months) was associated with a lower risk of developing NP manifestations (HR 0.642, 95% CI 0.441-0.934, p = 0.0206). CONCLUSIONS: Patients with myalgias/myositis, pneumonitis, shrinking lung and hemolytic anemia are at higher risk of NP involvement, whereas longer disease duration at cohort entry is associated with a lower risk of developing NP involvement.

The management of neuropsychiatric lupus in the 21st century: still so many unmet needs?

Neuropsychiatric (NP) events occur in the majority of patients with SLE and predominantly affect the CNS in addition to the peripheral and autonomic systems. Approximately 30% of all NP events are attributable to SLE (NPSLE) and present most frequently around the time of SLE onset. NPSLE is associated with increased morbidity and mortality and the proposed pathogenesis includes both ischaemic and neuroinflammatory mechanisms. Following diagnosis and causal attribution, the treatment of NPSLE is tailored to the type of NP event, the predominant putative pathogenic pathway and the activity and severity of the clinical event. There is a dearth of controlled clinical trials to guide management, but therapeutic options include symptomatic, antithrombotic and immunosuppressive agents that are supported by observational cohort studies. Our objective was to review what is currently known about NPSLE and to identify deficiencies in diagnostic biomarkers, novel therapies and clinical trials for this manifestation of SLE.

The clinical significance of ubiquitin carboxyl hydrolase L1 and its autoantibody in neuropsychiatric systemic lupus erythematosus.

OBJECTIVES: To identify specific cerebrospinal fluid (CSF) biomarkers for the diagnosis and disease severity evaluation of neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Patients presented with neuropsychiatric symptoms were recruited and categorised as 36 NPSLE, 19 SLE controls, 4 other connective tissue disease (CTD) controls and 10 nervous system disorder (NSD) controls. The NPSLE group consisted of severe NPSLE (sNPSLE) and mild NPSLE (mNPSLE). Potential biomarkers were determined by Luminex multiplex assay and enzyme-linked immunosorbent assay. RESULTS: 1) Among a variety of neurological disease-related proteins, only ubiquitin carboxyl hydrolase L1 (UCH-L1) levels were significantly elevated in the CSF samples of sNPSLE patients compared with those of mNPSLE patients (p=0.020) and SLE controls (p=0.037). CSF UCH-L1 levels were significantly positively correlated with SLE disease activity index and overlap number of NPSLE manifestations. 2) CSF anti-UCH-L1 autoantibodies were significantly elevated in patients with NPSLE in comparison to all of the control groups, with a sensitivity of 53% and a specificity of 91% for NPSLE. CSF anti-UCH-L1 levels were associated with organ involvement and were positively correlated with serum anti-UCH-L1 levels in the NPSLE patients (r=0.4551, p=0.0382). CONCLUSIONS: Anti-UCH-L1 is a promising CSF biomarker for NPSLE diagnosis with high specificity, and the elevated levels of CSF UCH-L1 reflect the clinical severity of NPSLE. The elevation of UCH-L1 and its autoantibody in NPSLE patients showed us novel aetiological insights on NPSLE.

The role of septin 7 in physiology and pathological disease: A systematic review of current status.

Septins are a conserved family of cytoskeletal GTPases present in different organisms, including yeast, drosophila, Caenorhabditis elegans and humans. In humans, septins are involved in various cellular processes, including exocytosis, apoptosis, leukemogenesis, carcinogenesis and neurodegeneration. Septin 7 is unique out of 13 human septins. Mammalian septin 6, septin 7, septin 2 and septin 9 coisolate together in complexes to form the core unit for the generation of the septin filaments. Physiological septin filaments are hetero-oligomeric complexes consisting of core septin hexamers and octamers. Furthermore, septin 7 plays a crucial role in cytokinesis and mitosis. Septin 7 is localized to the filopodia and branches of developing hippocampal neurons, and is the most abundant septin in the adult rat forebrain as well as a structural component of the human and mouse sperm annuli. Septin 7 is crucial to the spine morphogenesis and dendrite growth in neurons, and is also a structural constituent of the annulus in human and mouse sperm. It can suppress growth of some tumours such as glioma and papillary thyroid carcinoma. However, the molecular mechanisms of involvement of septin 7 in human disease, especially in the development of cancer, remain unclear. This review focuses on the structure, function and mechanism of septin 7 in vivo, and summarizes the role of septin 7 in cell proliferation, cytokinesis, nervous and reproductive systems, as well as the underlying molecular events linking septin 7 to various diseases, such as Alzheimer's disease, schizophrenia, neuropsychiatric systemic lupus erythematosus, tumour and so on.

Facial and limb angioedema with parotitis and Kikuchi-like necrotizing lymphadenitis preceding neuropsychiatric systemic lupus erythematosus in a young African American male.

Angioedema has been observed in a few cases secondary to systemic lupus erythematosus (SLE). Herein, we report a rare case where a young healthy male initially presented with angioedema, lymphadenopathy and parotitis and later on developed neuropsychiatric manifestations at the very onset of his SLE disease. This case illustrates the importance of prompt clinical consideration of lupus with unusual and atypical preceding manifestations.

Diagnosing and attributing neuropsychiatric events to systemic lupus erythematosus: time to untie the Gordian knot?

Neurological and psychiatric syndromes, collectively referred to as NPSLE, occur frequently in SLE. The frequency of NPSLE varies from 21 to 95%; however, only 13-38% of neuropsychiatric (NP) events could be attributable to SLE in the NPSLE SLICC inception cohort. This variability in the frequency of NPSLE is attributable to the low specificity of the ACR case definitions for SLE-attributed NP syndromes, inclusion of minor NP events in the ACR nomenclature, difficulty in ascertainment of NP events and diverse experience of rheumatologists in the clinical assessment of NP events. Making the correct and early attribution of NP events to SLE is important to institute appropriate immunosuppressive treatment for favourable outcomes. Various attribution models using composite decision rules have been developed and used to ascribe NP events to SLE. This review will focus on the various clinical presentations, diagnostic work-up and attributions of the common NPSLE syndromes, including other NP events not included in the ACR nomenclature but which have come to attention in recent years.

Update on the pathogenesis and treatment of childhood-onset systemic lupus erythematosus.

PURPOSE OF REVIEW: This article will provide an update of studies published in the last year regarding epidemiology, pathogenesis, major disease manifestations and outcomes, and therapies in childhood-onset systemic lupus erythematosus (cSLE). RECENT FINDINGS: Recent studies on cSLE epidemiology supported previous findings that cSLE patients have more severe disease and tend to accumulate damage rapidly. Lupus nephritis remains frequent and is still a significant cause of morbidity and mortality. In the past year unfortunately there were no new reproducible, biomarker studies to help direct therapy of renal disease. However, some progress was made in neuropsychiatric disease assessment, with a new and promising automated test to screen for cognitive dysfunction reported. There were no prospective interventional treatment trials designed for patients with cSLE published in the last year, but some studies involving children are currently active and might improve the therapeutic options for patients with cSLE. SUMMARY: There is a need to get a better understanding of pathogenesis and identify new biomarkers in cSLE to more accurately predict outcomes. New insights into characterization of different clinical manifestations may enable to optimize individual interventions and influence the prognosis.

The diagnosis and clinical management of the neuropsychiatric manifestations of lupus.

Neuropsychiatric (NP) involvement in Systemic Lupus Erythematosus (SLE), can be a severe and troubling manifestation of the disease that heavily impacts patient's health, quality of life and disease outcome. It is one of the most complex expressions of SLE which can affect central, peripheral and autonomous nervous system. Complex interrelated pathogenetic mechanisms, including genetic factors, vasculopathy, vascular occlusion, neuroendocrine-immune imbalance, tissue and neuronal damage mediated by autoantibodies, inflammatory mediators, blood brain barrier dysfunction and direct neuronal cell death can be all involved. About NPSLE a number of issues are still matter of debate: from classification and burden of NPSLE to attribution and diagnosis. The role of neuroimaging and new methods of investigation still remain pivotal and rapidly evolving as well as is the increasing knowledge in the pathogenesis. Overall, two main pathogenetic pathways have been recognized yielding different clinical phenotypes: a predominant ischemic-vascular one involving large and small blood vessels, mediated by aPL, immune complexes and leuko-agglutination which it is manifested with more frequent focal NP clinical pictures and a predominantly inflammatory-neurotoxic one mediated by complement activation, increased permeability of the BBB, intrathecal migration of autoantibodies, local production of immune complexes and pro-inflammatory cytokines and other inflammatory mediators usually appearing as diffuse NP manifestations. In the attempt to depict a journey throughout NPSLE from diagnosis to a reasoned therapeutic approach, classification, epidemiology, attribution, risk factors, diagnostic challenges, neuroimaging techniques and pathogenesis will be considered in this narrative review based on the most relevant and recent published data.

Autoimmunity, neuroinflammation, pathogen load: A decisive crosstalk in neuropsychiatric SLE.

Depicting the cellular and molecular bases of the continuous dialogue existing between the peripheral immune and the central nervous systems, as in neurolupus, is fundamental to improve, and better apprehend the role played by immune cells and mediators in the initiation and progression of neurological and psychiatric diseases, which nowadays remain a major public health issue. The relative frequency of neurological symptoms occurring in systemic autoimmunity is particularly worrying as, for example, two-thirds of patients with lupus will eventually experience the disabling effects of neuropsychiatric lupus. Neurolupus is a particularly severe form of lupus with wide-ranging symptoms, which contribute to increased mortality and morbidity in patients. In this context, infections, which suddenly trigger exacerbations of the otherwise mild lupus disease, may drive the progression of neuroinflammation and neurodegeneration via different mechanisms involving a network of effector molecules and cells. The complex interaction of neuroimmunology and neuroinfectiology represents a genuine challenge for basic scientists and clinicians to understand the mechanisms that are implicated, and identify possible biomarkers of severity that might predict the development of this devastating form of lupus. The ultimate goal is to design appropriate, personalised therapeutic strategies to improve the outcome of the disease.

Is it primary neuropsychiatric systemic lupus erythematosus? Performance of existing attribution models using physician judgment as the gold standard.

OBJECTIVES: Models for the attribution of neuropsychiatric manifestations to systemic lupus erythematosus (NPSLE) that incorporate timing and type of manifestation, exclusion/confounding or favouring factors have been proposed. We tested their diagnostic performance against expert physician judgment. METHODS: SLE patients with neuropsychiatric manifestations were identified through retrospective chart review. Manifestations were classified according to physician judgment as attributed to SLE, not attributed or uncertain. Results were compared against the Systemic Lupus International Collaborating Clinics (SLICC) attribution models A and B, and one introduced by the Italian Study Group on NPSLE. RESULTS: 191 patients experienced a total 242 neuropsychiatric manifestations, 136 of which were attributed to SLE according to physician. Both SLICC models showed high specificity (96.2% and 79.2% for model A and B, respectively) but low sensitivity (22.8% and 34.6%, respectively) against physician judgment. Exclusion of cases of headache, anxiety disorders, mild mood and cognitive disorders and polyneuropathy without electrophysiologic confirmation led to modest increases in sensitivity (27.7% and 42.0% for SLICC models A and B, respectively) and reductions in specificity (94.8% and 65.5%, respectively). The Italian Group model showed good accuracy in NPSLE attribution with an area under the curve of the receiver operating characteristics analysis of 0.862; values ≥7 showed the best combination of sensitivity and specificity (82.4% and 82.9%, respectively). CONCLUSIONS: Attribution models can be useful in NPSLE diagnosis in routine clinical practice and their performance is superior in major neuropsychiatric manifestations. The Italian Study Group model is accurate, with values ≥7 showing the best combination of sensitivity and specificity.

[The 452th case: rash, hypotension, abdominal pain and headache].

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized with multiple organ involvements. Acute acalculous cholecystitis(AAC) is an extremely rare manifestation of digestive system involvement in SLE. We reported a case of 32-year-old woman who complained skin rashes for two weeks and stomachache and oliguria for one day. She had rashes at onset, and developed fever, stomachache, hypotension and headache. Physical examination at admission indicated blood pressure 76/47 mmHg(1 mmHg=0.133 kPa), heart rate 107 beats/min, warm acra. Murphy's sign was positive. Ultrasound suggested the enlarged gallbladder with surrounding hypoecho band yet no biliary calculi were found. A diagnosis of SLE was made, characteristic with distributive shock at the onset and AAC, complicated with neuropsychiatric lupus and lupus nephritis. She had an acute and severe course of disease, which had been relieved after treatment of high dose glucocorticoid and immunosuppressants. This case arouses clinicians to pay more attention to AAC as a rare form of disease flare in SLE. Early diagnosis of AAC is crucial to a favorable prognosis and in avoid of abdominal surgery.

Vasculitis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex heterogeneous autoimmune disease with a wide variety of clinical and serological manifestations that may affect any organ. Vasculitis prevalence in SLE is reported to be between 11% and 36%. A diverse clinical spectrum, due to inflammatory involvement of vessels of all sizes, is present. Even though cutaneous lesions, representing small vessel involvement, are the most frequent, medium and large vessel vasculitis may present with visceral affection, with life-threatening manifestations such as mesenteric vasculitis, pulmonary hemorrhage, or mononeuritis multiplex, with detrimental consequences. Early recognition and an appropriate treatment are crucial. Recent studies have shown that vasculitis in patients with SLE may present different clinical forms based on the organ involved and the size of the affected vessel. It is noteworthy that the episodes of vasculitis are not always accompanied by high disease activity. Recent articles on this topic have focused on new treatments for the control of vascular disease, such as biological therapies such as Rituximab and Belimumab, among others.

Pathogenesis and treatment of CNS lupus.

PURPOSE OF REVIEW: Neuropsychiatric manifestations pose diagnostic and therapeutic challenges in systemic lupus erythematosus (SLE). We review recently published studies on the epidemiology, pathogenesis, neuroimaging, and treatment of NPSLE. RECENT FINDINGS: Generalized SLE activity or damage and antiphospholipid antibodies are identified as major risk factors for neuropsychiatric involvement. NPSLE patients have increased genetic burden and novel genomic approaches are expected to elucidate its pathogenesis. Animal data suggest that, in cases of disturbed blood-brain barrier, autoantibodies against the NR2 subunits of the N-methyl-D-aspartate receptor and 16/6 idiotype antibodies may cause diffuse neuropsychiatric manifestations through neuronal apoptosis or brain inflammation; data in humans are still circumstantial. In NPSLE, advanced neuroimaging uncovers structural and metabolic abnormalities in brain regions with normal appearance on conventional MRI. Treatment includes corticosteroids/immunosuppressants for inflammatory manifestations or generalized SLE activity, and antiplatelets/anticoagulation for manifestations related to antiphospholipid antibodies. In refractory cases, uncontrolled studies suggest a beneficial role of rituximab. SUMMARY: We have begun to better understand how brain-reactive autoantibodies, present in a proportion of SLE patients, can cause brain injury and diffuse NPSLE. Further testing will be required to determine the clinical utility of advanced neuroimaging. Controlled trials are needed to guide therapeutic decisions.

Neuropsychiatric manifestations in patients with systemic lupus erythematosus: epidemiology and radiology pointing to an immune-mediated cause.

BACKGROUND: Different pathogenetic pathways have been proposed for neuropsychiatric (NP) manifestations in systemic lupus erythematosus (SLE). OBJECTIVE: To describe the patient characteristics of a large cohort of patients with SLE with NP manifestations (NPSLE) in a single centre and to review whether these and other data are compatible with immune-mediated mechanisms. METHODS: A total of 212 patients were identified from MRI scans of the brain ordered for suspected NPSLE. Data were collected from the medical records. NP syndromes were classified according to the American College of Rheumatology (ACR) nomenclature and case definitions. RESULTS: 155 patients fulfilled the criteria for SLE. In 102 patients NP manifestations were attributed to SLE itself (primary NPSLE) whereas, in the remaining patients, the NP symptoms were due to other causes. The median age at the time of SLE diagnosis in patients with primary NPSLE was 27.5 years and the median duration prior to NPSLE was 2.8 years. Forty patients (39%) had a NP manifestation in the first year of the disease. Cerebrovascular disease, cognitive dysfunction, seizures and headache were the most prevalent syndromes. In 47% of patients with primary NPSLE the MRI scan of the brain showed no abnormalities. CONCLUSIONS: Most NP manifestations in SLE occur early in the disease. This finding, as well as data from quantitative imaging studies and recent pathological studies, point to an immune-mediated pathogenesis.

Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway.

Given the early onset of neuropsychiatric disease and the potential response to immunosuppressive therapy, neuropsychiatric disease is considered a primary disease manifestation in systemic lupus erythematosus (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 cytokine production 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.

Development of systemic lupus erythematosus in a male-to-female transsexual: the role of sex hormones revisited.

Systemic lupus erythematosus (SLE) predominantly affects women of childbearing age. The infrequency of SLE in men and disease onset in prepubertal or postmenopausal women suggests a role of estrogen in the predisposition to the disease. Patients with hypergonadotrophic hypogonadism are prone to the development of SLE, and the use of exogenous estrogens in women increases the relative risk of SLE onset and disease flares. These observations provide indirect evidence for an opposite role of estrogens and androgens in the pathogenesis of SLE. We report on a male-to-female transsexual who developed SLE 20 years after sex-reassignment surgery and prolonged estrogen therapy. The role of sex hormones in SLE is revisited.

Vocal cords palsy in systemic lupus erythematosus patient: diagnostic and therapeutic difficulties.

Vocal cords palsy is a rare complication in the course of systemic lupus erythematosus (SLE). A 38-year-old female patient with a history of SLE presented with chronic voice hoarseness resistant to standard treatment. High levels of antinuclear antibodies including dsDNA, Ro52, SSA, SSB were confirmed, while antiphospholipid antibodies were absent. While other causes of voice hoarseness were excluded, bilateral vocal cords palsy was diagnosed. Moreover, the patient revealed features of obvious Hashimoto thyroiditis with high levels of antithyroid antibodies and also developed a convergent squint as a result of fatigability of oculomotor muscles. Electrophysiology test of peripheral nerves detected myasthenic type nerve-muscle conduction impairment which was suspected as the cause of reported symptoms. Possible reasons for emerging signs and symptoms of neuropsychiatric systemic lupus erythematosus were discussed as well as the presence of vasculitis, neuropathy, significance of thyroiditis and coexistence of myasthenia. All that reasons of similar autoimmune background were also raised in this case report.

Secondary neuropsychiatric manifestations caused by Epstein-Barr virus encephalitis in a new onset systemic lupus erythematosus patient.

Abnormal manifestations of central nervous system in system lupus erythematosus (SLE) patients are mainly caused by primary neuropsychiatric SLE (NP-SLE). We reported a new onset SLE patient who had secondary neuropsychiatric manifestations caused by Epstein-Barr virus (EBV) encephalitis. Although EBV has an uncertain association with SLE, Epstein-Barr virus encephalitis occurred in active SLE patients was not reported previously. Our report may be the first case about EBV encephalitis occurred in active SLE.

Predictors for neuropsychiatric development in Chinese adolescents with systemic lupus erythematosus.

The aim of our study is to investigate the relationship between neuropsychiatric systemic lupus erythematosus (NPSLE) development and clinical factors to elucidate potential predictors at the time of SLE onset as well as during NP flares. Sixty-seven adolescents between the ages of 10 and 18 years with SLE were retrospectively reviewed, and their clinical characteristics and laboratory findings were analyzed. Twenty-four (35.82%) patients with NPSLE were included in the analysis. Renal involvement at the time of SLE onset was significantly less common in patients who developed NP symptoms (P = 0.0038), but renal involvement during the entire follow-up (FU) period was not significantly different between patients with NP and those without NP. Photosensitivity at the time of SLE diagnosis was significantly more common in patients with NP (P = 0.0080). No differences were found in the clinical and laboratory results between the time of SLE onset and NP onset in the same late-onset NP group. Our results suggest that NP development is negatively correlated with renal involvement at the onset of SLE, but not during the entire FU period, and NP development is positively correlated with photosensitivity at the time of SLE onset. We could not identify any factors that might predict the occurrence of NP symptoms during an NP flare.