A successful plasma exchange in bridging to rituximab for severe neuropsychiatric lupus and lupus nephritis with viral infections and aspiration pneumonia.

Systematic lupus erythematosus (SLE) is a chronic autoimmune disease involving several organs such as the kidneys, skin, vessels, and central nervous system. Neuropsychiatric SLE (NPSLE) is a life-threatening condition that needs treatment with the combination of glucocorticoids and Immunosuppressants (IS). This includes cyclophosphamide and rituximab (RTX) which can lead to several infections. Therapeutic apheresis is an optional treatment for inflammatory diseases and has less risks of infections than IS. Plasma exchange (PE) is one of the most common apheresis, and is recommended for the management of NPSLE. We report a refractory NPSLE case with bacterial pneumonia and cytomegalovirus antigenemia. PE was performed prior to RTX. After the initiation of RTX which was incompatible due to infection such as aspiration pneumonia and cytomegalic virus, PE was scheduled considering the pharmacokinetics of RTX. Her SLE activity was well managed after PE and RTX without flare. PE treatment plan bridging to IS and RTX may effectively work in refractory SLE patients with infections.

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.

[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.

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.

Neuro-ophthalmologic manifestations of systemic lupus erythematosus: a systematic review.

Herein we summarize the clinical presentation, treatment and outcome of neuro-ophthalmologic manifestations in patients with systemic lupus erythematosus (SLE). We performed a systematic review of the neuro-ophthalmologic manifestations of SLE reported in the English literature from 1970 to 2010 by a Medline search. The prevalence of neuro-ophthalmologic manifestations is 3.6% in adult and 1.6% in childhood SLE patients. Neuro-ophthalmologic manifestations of SLE are highly variable, with the commonest presentation being optic neuritis, followed by myasthenia gravis, visual field defects and pseudotumor cerebri. The underlying pathology was thought to be either SLE activity or its vascular complications. Most neuro-ophthalmologic manifestations of SLE are responsive to high-dose glucocorticoids. Anticoagulation is indicated when there is concomitant antiphospholipid syndrome. SLE-related neuromyelitis optica is often refractory to treatment and 92% of patients require multiple immunosuppressive protocols. Neuro-ophthalmologic manifestations of SLE are uncommon but heterogeneous. The prognosis of neuro-ophthalmologic manifestations in SLE is generally good because of their rapid response to glucocorticoids. Relapses of these manifestations may be reduced by the use of maintenance immunosuppression. Cyclophosphamide, azathioprine, plasmapheresis, intravenous immunoglobulin and rituximab can be considered in glucocorticoid-dependent or refractory cases. Anticoagulation is indicated when there is concomitant antiphospholipid syndrome.

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.

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.

Focal neurological deficits due to a contrast enhancing lesion in a patient with systemic lupus erythematosus: case report and review of literature.

Neuropsychiatric (NP) systemic lupus erythematosus (SLE) is a complex entity comprising 19 different discrete syndromes. We report a case of a 32-year-old female with SLE and new onset neurological symptoms and radiographic evidence of a contrast enhancing lesion on brain MRI. The lesion was successfully excised and found to be granulomatous in nature. Infection and malignant etiologies were ruled out suggesting that the lesion was due to SLE. Subsequently, the development of multiple reversible hyperintense signal abnormalities on brain MRI suggested the possibility of posterior reversible encephalopathy syndrome (PRES). The lesions resolved after the withdrawal of immunosuppression. This article reviews both the clinical and pathological complexity of PRES in SLE and the state of the current literature. We conclude that more data is required to understand the spectrum of PRES and its management in SLE patients.

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.

Lupus cerebritis after visiting a tanning salon.

A 53-year-old female was admitted to the intensive care unit for lupus cerebritis; she had a 15-year history of stable lupus. Over the prior 1 to 2 months, the patient visited a tanning salon and this triggered the exacerbation of lupus. Her initial symptoms were cutaneous in the form of an erythematous rash. Within 2 weeks she started to have headaches and was admitted for seizure and psychosis. Ultraviolet A exposure in the tanning salon is known to exacerbate lupus by modulation of the immune system at the level of the skin. It has also been found that ultraviolet light can lead to the formation of antinuclear antibodies. This case illustrates the need to emphasize the danger of the tanning salon to patients with systemic lupus erythematous; the risk is not only cutaneous, it can also be systemic.

Pathogenesis of neuropsychiatric systemic lupus erythematosus and potential biomarkers.

Systemic lupus erythematosus is a chronic, multisystemic, autoimmune disease that may involve the central, peripheral, and autonomic nervous systems and can present with a wide variety of neurological and psychiatric manifestations. In this article, we review the recent literature pertaining to the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE). We searched the PUBMED database with no chronological constraints using the following terms: "neuropsychiatric systemic lupus erythematosus" cross-referenced with the terms "pathogenesis" and "biomarkers" for full-text articles in English. The etiology of NPSLE is as yet unknown, though numerous autoantibodies and cytokines have been suggested as possible mediators. Of the numerous autoantibodies and biomarkers examined, anti-phospholipid, anti-ribosomal P, anti-neuronal, anti-glial fibrillary acidic protein (GFAP), anti-endothelial cell, anti-N-methyl-D: -aspartate (NMDA), microtubule-associated protein 2 (MAP-2), and matrix metalloproteinase-9 (MMP-9) appear to be elevated in patients with NPSLE. Cytokines that may be involved in the pathology of NPSLE include interleukin (IL)-2, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, and interferons (IFN)-alpha and -gamma. With continued advances in immunological research, new insights into the pathophysiologic mechanisms of NPSLE may lead to the development of biomarkers and new treatment strategies.

New directions in the treatment of systemic lupus erythematosus.

OBJECTIVE: The aim of this review is to provide an up-to-date overview of treatment approaches for systemic lupus erythematosus (SLE), highlighting the multiplicity and heterogeneity of clinical symptoms that underlie therapeutic decisions. Discussion will focus on the spectrum of currently available therapies, their mechanisms and associated side-effects. Finally, recent developments with biologic treatments including rituximab, epratuzumab, tumor necrosis factor (TNF) inhibitors, and belimumab, will be discussed. RESEARCH DESIGN AND METHODS: A MEDLINE literature search for 'systemic lupus erythematosus' and 'damage' and 'treatment' was undertaken for 1996-2008. Secondary citations were obtained from selected manuscripts. Individual case studies were excluded. FINDINGS: SLE is an autoimmune disease involving multiple organ systems, a clinical pattern of flares and remissions, and the presence of anti-nuclear autoantibodies. Whereas early symptoms most frequently involve the skin and joints, disease morbidity and mortality are usually associated with cardiovascular events and damage to major organs, particularly the kidneys. Many of the current therapeutic options are considered to be inadequate because of toxicities, accrual of organ damage, and insufficient control of the underlying disease pathology. Improved understanding of SLE pathogenesis and immunology has led to the identification of new treatment targets. Current interest is mainly focused on the targeted immunosuppressive actions provided by biologic therapy. Although the potential long-term beneficial or harmful effects of the new molecular treatments are unclear, their precise molecular targeting may reveal key relationships within the immune system and advance the cause of individualized molecular medicine. CONCLUSIONS: Biologic compounds that target specific immunologic mechanisms offer a new paradigm in the treatment of SLE, one that may, at best, reverse the course of the disease and, at the very least, might provide some new alternatives to reduce symptoms and limit tissue damage without undue contribution to overall morbidity and mortality.

Raised intrathecal levels of APRIL and BAFF in patients with systemic lupus erythematosus: relationship to neuropsychiatric symptoms.

INTRODUCTION: The tumour necrosis factor (TNF) family ligands BAFF (B-cell activating factor of TNF family) and APRIL (a proliferation-inducing ligand) are essential for B-cell survival and function. Elevated serum levels of BAFF and APRIL have been reported earlier in patients with systemic lupus erythematosus (SLE). Since autoantibody formation in the central nervous system (CNS) is a distinct feature of neuropsychiatric SLE (NPSLE), we have investigated whether NPSLE is associated with an enhanced intrathecal production of APRIL and BAFF. METHODS: Levels of BAFF and APRIL in cerebrospinal fluid (CSF) and serum from healthy controls, SLE patients without CNS involvement, and patients with NPSLE were determined by enzyme-linked immunosorbent assay. Interleukin-6 (IL-6) levels were determined by an IL-6-specific bioassay. RESULTS: SLE patients had levels of APRIL in CSF that were more than 20-fold higher and levels of BAFF in CSF that were more than 200-fold higher than those of healthy controls. Separate analyses of SLE patients with and without CNS involvement revealed that NPSLE patients had enhanced levels of APRIL in CSF. BAFF and APRIL were likely produced locally in the CNS as CSF and serum levels did not correlate. Moreover, CSF levels of APRIL correlated with BAFF but not with IL-6, suggesting that APRIL and BAFF in the CNS are regulated together but that they are produced independently of IL-6. CONCLUSION: To our knowledge this is the first study to show elevated levels of BAFF and APRIL in CSF of SLE patients. APRIL was augmented in NPSLE patients compared with SLE patients without CNS involvement. APRIL and BAFF antagonists breeching the blood-brain barrier therefore could have beneficial effects on SLE patients, in particular patients with NPSLE.

Autoantibody-mediated neuroinflammation: pathogenesis of neuropsychiatric systemic lupus erythematosus in the NZM88 murine model.

Autoantibodies play an important role in central nervous system manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE). Previous studies have shown that the lupus-prone NZM88 strain has major neural deficits and high titers of serum IgG to brain antigens. ELISA was performed to detect the presence of IgG in different brain regions of NZM88 mice and to compare the levels with NZM2758 mice and control strains (NZW and BALB/c). There was a substantial increase of IgG in the substantia nigra (SN) and hypothalamus (HT) of brains from NZM88 mice compared to control NZW and BALB/c mice, whereas NZM2758 mice had more IgG in the cortex. The increased presence of IgG in the NPSLE-prone NZM88 mouse brain was paralleled by increased TNF-alpha and IL-12 in the SN and HT regions; significantly elevated expression of MHC Class-II was also observed in the SN of NZM88 mice and cortex of NZM2758 mice. A co-culture system of dopaminergic neurons and microglia was used to demonstrate that NZM88 sera modifies dopaminergic cell activity only in the presence of microglia and that TNF-alpha is synthesized and released in this co-culture. This study demonstrates a functional link between the autoantibodies, the activation of microglia, and neuronal function associated dopamine production, which is suggested to be causally related to the predominant NPSLE syndromes.

Diagnosis and treatment of vasculitis of the central nervous system in a patient with systemic lupus erythematosus.

BACKGROUND: A 23-year-old white woman with a 3-year history of systemic lupus erythematosus and a 15-month history of lupus nephritis and retinal vasculitis was successfully treated with antibiotics for Pseudomonas aeruginosa pneumonia while on moderate doses of corticosteroids. Even though her pneumonia had improved, she developed acute changes in her mental status that rapidly progressed to encephalopathy with coma. INVESTIGATIONS: Physical examination, fundoscopic examination, laboratory tests for metabolic abnormalities, cerebrospinal fluid analysis, microbiology and serologic testing, electroencephalogram, tests for IgM and IgG anticardiolipin antibodies, neuroimaging including CT of the brain and T1-weighted MRI before and after gadolinium contrast, and flow-attenuated inversion recovery MRI. DIAGNOSIS: Vasculitis of the central nervous system associated with systemic lupus erythematosus. MANAGEMENT: Intravenous methylprednisolone 1,000 mg/day for 3 days, one dose of intravenous pulse cyclophosphamide 750 mg/m(2), intravenous immunoglobulin 400 mg/kg/day for 4 days, plasmapheresis on alternate days for five cycles, and prednisone 40 mg/day. She continued monthly doses of intravenous pulse cyclophosphamide and intravenous pulse methylprednisolone for 6 months, followed by maintenance infusions every 3 months over 2 years. Prednisone was tapered over 18 months. Cyclophosphamide was discontinued after 2 years because of poor bone-marrow tolerance, and was replaced with mycophenolate mofetil 3,000 mg/ day and ciclosporin 50 mg twice daily.

[Appearance of central nervous system lupus during corticosteroid therapy and warfarinization in a patient with pure red cell aplasia and antiphospholipid syndrome].

A 48-year-old woman presented to our hospital with epigastralgia and erythema on the left dorsalis pedis. Her medical history included deep venous thrombosis three months prior to admission to our hospital. Upon admission it was determined that she had severe anemia (hemoglobin level 4.6 g/dl). Bone marrow analysis indicated a markedly decreased number of erythroid progenitor cells. A skin biopsy specimen of the erythema revealed microthrombus. Anticardiolipin-beta2GPI antibody and lupus anticoagulant were positive. The patient was diagnosed with pure red cell aplasia (PRCA) and antiphospholipid syndrome (APS). After steroid pulse therapy and warfarinization, her anemia and purpura improved. Three months later she developed depression with positive anti-ribosomal P protein antibody that was indicative of central nervous system lupus. Although her psychometric condition did not respond to steroid pulse therapy, improvement was seen after she received three courses of cyclophosphamide pulse therapy. We report a rare case of CNS lupus that developed during corticosteroid therapy and warfarinization in a patient with PRCA and APS.

Overwhelming leukoencephalopathy as the only sign of neuropsychiatric lupus.

We describe a patient with diffuse leukoencephalopathy, a rare central nervous system complication of systemic lupus erythematosus, who died of brain herniation despite aggressive management. Brain magnetic resonance imaging revealed diffuse white matter hyperintensities consistent with vasogenic edema. Autopsy revealed only widespread cerebral edema. Early recognition and persistent, aggressive treatment will be required to avoid this fatal and rare manifestation of neuropsychiatric lupus.

[Central nervous system involvement in connective tissue diseases].

Neuropsychiatric manifestations are relatively common and serious complications in systemic lupus erythematosus (CNS lupus). Overall, in patients with CNS lupus, CSF IgM, IgA, IgG indexes (indicators of intrathecal Ig synthesis) as well as CSF IL-6 activities were significantly elevated. Of note, especially in patients lupus psychosis, but not in those with focal CNS lesions, anti-ribosomal P antibody (anti-P) in the sera as well as anti-neuronal antibody (anti-N) in the CSF was significantly elevated in relation to their CNS disease activities. These data indicate that the immune system activation within the CNS, possibly resulting in the elevation of CSF anti-N, plays an important role in the pathogenesis of CNS lupus, including lupus psychosis. CNS involvement in Behçet's disease, usually called neuro-Behçet's syndrome (NB), includes acute type and chronic progressive type. Acute NB is characterized by acute meningoencephalitis with focal lesions, presenting high intensity areas in T2-weightened images or Flare images on MRI scans, whereas chronic progressive NB is characterized by intractable slowly progressive dementia, ataxia and dysarthria with persistent elevation of CSF IL-6 activity. Chronic progressive NB is resistant to conventional treatment with steroid, cyclophosphamide, or azathioprine, but responds to low dose methotrexate. As for ANCA-related vasculitis, pachymeningitis has been found to be associated with P-ANCA as well as C-ANCA.