Patients with NPSLE experience poorer HRQoL and more fatigue than SLE patients with no neuropsychiatric involvement, irrespective of neuropsychiatric activity.

OBJECTIVES: Substantial proportions of patients with SLE report poor health-related quality of life (HRQoL). Our objective was to investigate the impact of neuropsychiatric involvement (NP) in SLE on patient-reported outcomes. METHODS: We analysed data from four phase III trials (BLISS-52, BLISS-76, BLISS-SC, EMBRACE; N = 2968). The NPSLE group comprised individuals with NP-BILAG A/B/C/D or score in any descriptor of the NP-SLEDAI-2K at baseline (N = 350), while the non-NPSLE group consisted of patients with NP-BILAG E (N = 2618). HRQoL was assessed with the SF-36, EQ-5D-3L, and FACIT-F. Full health state (FHS) was defined as 'no problems' in all EQ-5D dimensions. RESULTS: NPSLE patients reported lower scores in the SF-36 physical and mental component summary compared with the non-NPSLE population [mean (s.d.): 35.7 (9.1) vs 39.6 (9.6); P < 0.001 and 37.3 (12.1) vs 41.4 (11.0); P < 0.001, respectively]. NPSLE patients also exhibited impaired HRQoL in all EQ-5D dimensions compared with non-NPSLE patients (P < 0.05 for all). A substantially lower proportion of NPSLE patients experienced FHS in comparison with the non-NPSLE group (3.3% vs 14.5%; P < 0.001). NPSLE was associated with severe fatigue [23.8 (12.2) vs 31.5 (11.6); P < 0.001]. Notably, our findings revealed no discernible distinctions between active and inactive NPSLE patients with regard to SF-36, EQ-5D, FHS or FACIT-F scores. CONCLUSION: NP in patients with SLE has a detrimental effect on HRQoL experience and is associated with severe fatigue, regardless of the degree of neuropsychiatric disease activity. Early intervention is warranted in NPSLE patients to enhance long-term HRQoL experience.

Neuropsychiatric symptoms in Systemic Lupus Erythematosus: mixed methods analysis of patient-derived attributional evidence in the international INSPIRE project.

OBJECTIVE: Attribution of neuropsychiatric symptoms in systemic lupus erythematosus (SLE) relies heavily on clinician assessment. Limited clinic time, variable knowledge, and symptom under-reporting contributes to discordance between clinician assessments and patient symptoms. We obtained attributional data directly from patients and clinicians in order to estimate and compare potential levels of direct attribution to SLE of multiple neuropsychiatric symptoms using different patient-derived measures. METHODS: Quantitative and qualitative data analysed included: prevalence and frequency of neuropsychiatric symptoms, response to corticosteroids, and concurrence of neuropsychiatric symptoms with non-neuropsychiatric SLE disease activity. SLE patients were also compared with controls and inflammatory arthritis (IA) patients to explore attributability of neuropsychiatric symptoms to the direct disease effects on the brain/nervous system. RESULTS: We recruited 2,817 participants, including 400 clinicians. SLE patients (n = 609) reported significantly higher prevalences of neuropsychiatric symptoms than controls (n = 463) and IA patients (n = 489). SLE and IA patients' quantitative data demonstrated multiple neuropsychiatric symptoms relapsing/remitting with other disease symptoms such as joint pain. Over 45% of SLE patients reported resolution/improvement of fatigue, positive sensory symptoms, severe headache, and cognitive dysfunction with corticosteroids. Evidence of direct attributability in SLE was highest for hallucinations and severe headache. SLE patients had greater reported improvement from corticosteroids (p= 0.008), and greater relapsing-remitting with disease activity (p< 0.001) in the comparisons with IA patients for severe headache. Clinician and patients reported insufficient time to discuss patient-reported attributional evidence. Symptoms viewed as indirectly related/non-attributable were often less prioritised for discussion and treatment. CONCLUSION: We found evidence indicating varying levels of direct attributability of both common and previously unexplored neuropsychiatric symptoms in SLE patients, with hallucinations and severe headache assessed as the most directly attributable. There may also be-currently under-estimated-direct effects on the nervous system in IA and other systemic rheumatological diseases.

Attribution of neuropsychiatric symptoms and prioritisation of evidence in the diagnosis of neuropsychiatric lupus: mixed methods analysis of patient and clinician perspectives from the international INSPIRE study.

OBJECTIVE: Neuropsychiatric lupus (NPSLE) is challenging to diagnose. Many neuropsychiatric symptoms, such as headache and hallucinations, cannot be verified by tests or clinician assessment. We investigated prioritisations of methods for diagnosing NPSLE and attributional views. METHODS: Thematic and comparative analyses were used to investigate how clinicians prioritise sources of evidence from a 13-item list, and explore discordances in clinician and patient perspectives on attribution. RESULTS: We identified high levels of variability and uncertainty in clinicians' assessments of neuropsychiatric symptoms in SLE patients. In attributional decisions, clinicians (surveys n = 400, interviews n = 50) ranked clinicians' assessments above diagnostic tests (many of which they reported were often unenlightening in NPSLE). Clinicians ranked patient opinion of disease activity last, and 46% of patients reported never/rarely having been asked if their SLE was flaring, despite experienced patients often having "attributional insight". SLE Patients (surveys n = 676, interviews n = 27) estimated higher attributability of neuropsychiatric symptoms to the direct effects of SLE on the nervous system than clinicians (p < 0.001 for all symptoms excluding mania), and 24% reported that their self-assessment of disease activity was never/rarely concordant with their clinicians. Reports of misattributions were common, particularly of non-verifiable diffuse symptoms. Terminology differed between clinicians and influenced attribution estimates. CONCLUSION: NPSLE diagnostic tests and clinician assessments have numerous limitations, particularly in detecting diffuse neuropsychiatric symptoms that can be directly attributable and benefit from immunosuppression. Our findings suggest that incorporating patient attributional insights-although also subject to limitations-may improve attribution decision-making. Consensus regarding terminology and interpretations of "direct attributability" is required.

Bortezomib is efficacious in the treatment of severe childhood-onset neuropsychiatric systemic lupus erythematosus with psychosis: a case series and mini-review of B-cell immunomodulation in antibody-mediated diseases.

Childhood-onset neuropsychiatric systemic lupus erythematosus (cNPSLE) with psychosis is a challenging manifestation of SLE. Pathogenic long-lived plasma cells (LLPCs) are not specifically targeted by standard immunosuppression and their persistence contributes to chronic autoimmunity. Bortezomib is approved for the treatment of multiple myeloma and has shown benefits in a variety of other antibody-mediated diseases. Bortezomib may be efficacious for severe or treatment-refractory cNPSLE through eradication of LLPCs, decreasing autoantibody production. We describe the first pediatric case series of five patients with unrelenting cNPSLE with psychosis who were treated safely and effectively with bortezomib between 2011 and 2017. Most patients had persistent cNPSLE with psychosis despite aggressive immunosuppression with methylprednisolone, cyclophosphamide, rituximab, and usually plasmapheresis. All patients demonstrated rapid clinical improvement in their psychotic manifestations with the ability to quickly taper immunosuppression after the introduction of bortezomib. No patient had a recurrence of overt psychosis during a follow-up period of 1-10 years. Secondary hypogammaglobulinemia developed in all five patients and required immunoglobulin replacement. No other severe side effects or adverse events were observed. Bortezomib-mediated LLPC depletion is a promising therapy for severe recalcitrant cNPSLE with psychosis when used as adjunctive therapy to conventional immunosuppression, B-cell, and antibody-depleting therapies. After initiation of bortezomib, patients had rapid, demonstrable improvement in psychosis as well as reduction in glucocorticoids and antipsychotics. Further investigation is needed to determine the therapeutic role of bortezomib in severe cNPSLE and cSLE. We present a mini-review of the rationale for bortezomib use and novel B-cell immunomodulation in rheumatic disease.

Neuropsychiatric Systemic Lupus Erythematosus: A 2021 Update on Diagnosis, Management, and Current Challenges.

Patients with systemic lupus erythematosus (SLE) experience neuropsychiatric symptoms. The term neuropsychiatric SLE (NPSLE) is a generic term that refers to a series of neurological and psychiatric symptoms directly related to SLE. In approximately 30% of patients with neuropsychiatric symptoms, SLE is the primary cause (NPSLE), and symptoms manifest more frequently around SLE onset. Neurovascular and psychotic conditions can also lead to NPSLE. Pathogenesis of NPSLE is implicated in both neuroinflammatory and ischemic mechanisms, and it is associated with high morbidity and mortality. After diagnosing and assigning causality, NPSLE treatment is individualized according to the type of neuropsychiatric manifestations, type of the predominant pathway, activity of SLE, and severity of the clinical manifestations. There are many problems to be addressed with regards to the diagnosis and management of NPSLE. Controlled clinical trials provide limited guidance for management, and observational cohort studies support symptomatic, antithrombotic, and immunosuppressive agents. The purpose of this review was to provide a detailed and critical review of the literature on the pathophysiology, diagnosis, and treatment of NPSLE. This study aimed to identify the shortcoming in diagnostic biomarkers, novel therapies against NPSLE, and additional research needs.

Thrombosis of a basilar perforator aneurysm associated with pontine infarction in a patient with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect multiple organ systems. Cerebral aneurysm formation is a rare central nervous system manifestation of SLE and tends to present as subarachnoid hemorrhage. Here, we report a 34-year-old woman with SLE complicated by a thrombosed aneurysm that had arose at the origin of a perforating artery, thereby causing obstruction of the artery and subsequent development of pontine infarction. Detailed examination of thin-slice CT and magnetic resonance imaging scans led to the correct diagnosis of uncommon cause of stroke.

Assessment of cognitive impairment in Systemic Lupus Erythematosus using the Mini-Mental Status Exam and the Montreal Cognitive Assessment Test-Filipino Version

Introduction@#Cognitive impairment (CI) in patients with systemic lupus erythematosus (SLE) presents with or without overt signs of central nervous involvement. The prevalence of CI is variable, ranging from 19-80%. It is often overlooked, leading to high healthcare costs and productivity loss. The usual tools for detection are expensive, time-consuming and not locally available. Detection of CI using the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment Test (MoCA) is more clinically relevant and practical. The objectives of this study are to determine the prevalence of CI in SLE patients using MMSE/MoCA, to determine the degree of impairment in the different cognitive domains, and to characterize patients with CI in terms of disease activity, education, and employment.@*Methods@#This is a cross-sectional study of 62 SLE patients, 19 years or older, at a rheumatology clinic. Demographic and disease characteristics were collected. The validated Filipino versions of the MMSE/MoCA test were administered. Descriptive and non-parametric statistics were applied.@*Results@#Most patients are female (96.77%), below collegiate level of education (58.06%), and unemployed (70.97%). Mean disease duration is 8.92 (SD±7.03) years. Mean age at diagnosis is 28 (SD±10.30) years. Hypertension is the most common co-morbidity. Most have low lupus disease activity or are in remission (80.65%). Most are on prednisone (72.58%), with an average dose of 11.88mg/day (SD±10.66). The prevalence of CI is 38.71% (MMSE-P) and 77.42% (MoCA-P). The presence of CI is not related to educational level, employment, and disease activity.@*Conclusion@#Cognitive impairment (CI) is common in this cohort of SLE patients. Disease activity, level of education and employment do not seem to affect its occurrence. The MMSE-P and MoCA-P are rapid tools to assess the presence of CI and should be used in clinical practice to improve the quality of care for patients with lupus.

Mycophenolate mofetil and deflazacort combination in neuropsychiatric lupus: a decade of experience from a tertiary care teaching hospital in southern India.

Mycophenolate mofetil (MMF) is an effective therapeutic agent with high safety profile in the management of lupus nephritis. This retrospective study was conducted to assess the efficacy and side effect profile of MMF as induction as well as maintenance therapeutic agent along with tapering steroids in neuropsychiatric lupus (NPSLE). Hospital electronic medical records of patients with SLE diagnosed by ACR 1990 and/or SLICC 2012 criteria between January 2005 and May 2015 were retrieved. Among them, patients fulfilling ACR 1999 criteria for NPSLE were identified. Data of NPSLE patients treated with MMF as upfront second line immunosuppressive agent, both for induction and maintenance, were analyzed. Of the 140 patients with NPSLE, 88 fulfilled the inclusion criteria. Mean age of the cohort was 25.51 ± 7.82 years with female to male ratio of 84:4. Median duration of follow-up was 33 months (3-129 months). Seizure was the most common NPSLE manifestation (n = 37, 42.05%). Of the 88 patients, 18 had NPSLE solely due to secondary antiphospholipid syndrome. Of the remaining 70 patients, 61 (87.1%) had improved, 7 remained unchanged with no worsening and 3 patients had worsening or developed new symptoms during follow up after 3 months from baseline. At last follow-up, 55 out of 57 patients (97.1%) with detailed data had improved, while 2 patients had relapsed. Side effects were significantly more common in patients on prednisolone as compared to those on deflazacort. In patients with NPSLE, MMF along with tapering steroids is an efficacious combo in inducing remission and preventing relapse of disease.

Numerous Fusiform and Saccular Cerebral Aneurysms in Central Nervous System Lupus Presenting with Ischemic Stroke.

Central nervous system (CNS) involvement occurs in up to 50% of patients with systemic lupus erythematosus (SLE). Cerebral aneurysm formation is a rare complication of CNS lupus. The majority of these patients present with subarachnoid hemorrhage. We report a patient with an active SLE flare who presented with a recurrent ischemic stroke and was found to have numerous unruptured fusiform and saccular aneurysms in multiple vascular territories. He was treated with high-dose steroid and rituximab along with aspirin and blood pressure control for stroke prevention.

Sustained Immunosuppression Alters Olfactory Function in the MRL Model of CNS Lupus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is frequently accompanied by diverse neuropsychiatric manifestations. An increased frequency of olfactory deficits has been recently reported as another marker of CNS involvement in SLE patients. Similarly, we observed that spontaneous development of lupus-like disease in MRL/lpr mice is accompanied by altered olfaction-related behaviors. However, it remained unclear whether the behavioral deficits are due to systemic autoimmunity, or the distinct genetic make-up. To address this question, we presently examine whether prolonged treatment with the immunosuppressive drug cyclophosphamide (CY) restores odor-guided behaviors in MRL/lpr mice. Over 12 weekends, MRL/lpr and control MRL +/+ males were given ad lib access to a sweetened CY solution or a vehicle. Their responsiveness to different scents was assessed at ages corresponding to mild, modest, and severe disease. Odor-guided exploratory behavior was further examined in the novel object test at 21 weeks of age, shortly before terminal assessment of immunopathology. In comparison to control groups, MRL/lpr mice exposed to CY exhibited normal spleen size and antibody levels, as well as increased responsiveness to an attractant and a novel object. However, CY treatment also exacerbated their aberrant response to a repellent, suggesting a dual mode of action on brain olfactory systems. The present results reveal that generalized immunosuppression modulates odor-guided behaviors in lupus-prone animals. Although key pathogenic mechanisms are not clear, the findings strengthen the construct validity of the MRL model by supporting the hypothesis that onset of systemic autoimmunity alters the activity of olfactory circuits.

Catatonia - An unusual presenting clinical manifestation of systemic lupus erythematosus.

A 24-year-old female presented with catatonia and symptoms suggestive of Depressive Disorder. She also gave history of undocumented low grade irregular fever. The patient was worked up to rule out any organic cause or psychiatric illness. However, further investigations revealed immunological profile diagnostic of Systemic Lupus Erythematosus (SLE) with CNS involvement (CNS lupus). The diagnosis of SLE in this patient presenting with catatonia was of practical importance because catatonia as one of the manifestations of SLE or as a standalone presenting symptom is extremely rare. Hence, clinicians should be aware of this rarity so that diagnosis of Neuropsychiatric SLE (NPSLE) or catatonia as a presenting feature of SLE is never missed.

Seizures associated with Lupus during pregnancy.

A sudden flare of previously stable SLE may give rise to CNS lupus. During pregnancy, seizures associated with CNS lupus can cause hypoxic-ischemic encephalopathy (HIE) in the infant.

Bilateral reversible basal ganglia changes associated with dystonia and hemifacial spasms in central nervous system lupus.

We report a 40-year-old woman with systemic lupus erythematosus (SLE) and associated inflammatory polyarthritis who presented with acute facial dystonic spasms. Her speech was also affected. An MRI brain showed bilateral symmetrical basal ganglia signal change on T2. This movement disorder was due to an acute manifestation of her lupus. Her symptoms resolved rapidly following treatment with (oral) steroids. Repeat MRI brain at 1 month showed complete resolution of the basal ganglia signal change. This is the first time that facial spasms and dystonia with corresponding MRI changes are reported as a presentation of lupus affecting the central nervous system (CNS lupus).

A case of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with lupus erythematosus in the central nervous system.

We report on a case of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with lupus erythematosus in the central nervous system (CNS). A 73-year-old woman with essential hypertension suddenly demonstrated consciousness disturbance. Upon her admission, laboratory data showed significant hyponatremia (114 mEq/L) and a lack of body fluid loss. Diminished free water excretion (urine osmolality 684 mOsm/kg) and normal urine Na excretion (FENa 1.70 %) were consistent with the diagnosis of SIADH, which was confirmed by an inappropriately high concentration of plasma antidiuretic hormone (ADH) (15.3 pg/mL at 256 mOsm/kg of plasma osmolality). The hyponatremia was corrected by a combination of oral water intake restriction and saline infusion with furosemide administration until the 20th hospital day. Simultaneously, the presence of exudative pleural effusion in both chest cavities, suggesting the existence of pleuritis, and high titer of anti-nuclear antibody (ANA, 5120×) and anti-double-strand DNA antibody (6500 IU/mL), indicated the subclinical development of systemic lupus erythematosus (SLE), although the diagnostic criteria were not satisfied at that time. On the 34th hospital day, the sudden onset of unknown consciousness disturbance confirmed the diagnosis of SLE as CNS lupus. In previous case reports on SLE and/or SIADH, a few cases in which SLE and SIADH developed concomitantly regularly showed high immunological activities, as in our case. Some common pathophysiological bases might be involved in the concomitant appearance of those disorders.

Effects of prolonged treatment with memantine in the MRL model of CNS lupus.

OBJECTIVES: Neuropsychiatric manifestations and brain atrophy of unknown etiology are common and severe complications of systemic lupus erythematosus (SLE). An autoantibody that binds to N-methyl-D-aspartate (NMDA) receptor NR2 has been proposed as a key factor in the etiology of central nervous system (CNS) SLE. This hypothesis was supported by evidence suggesting memantine (MEM), an uncompetitive NMDA receptor antagonist, prevents behavioral dysfunction and brain pathology in healthy mice immunized with a peptide similar to an epitope on the NR2 receptor. Given that SLE is a chronic condition, we presently examine the effects of MEM in MRL/lpr mice, which develop behavioral deficits alongside SLE-like disease. METHODS: A broad behavioral battery and 7-Tesla MRI were used to examine whether prolonged treatment with MEM (~25 mg/kg b.w. in drinking water) prevents CNS involvement in this spontaneous model of SLE. RESULTS: Although MEM increased novel object exploration in MRL/lpr mice, it did not show other beneficial, substrain-specific effects. Conversely, MEM was detrimental to spontaneous activity in control MRL +/+ mice and had a negative effect on body mass gain. Similarly, MRI revealed comparable increases in the volume of periventricular structures in MEM-treated groups. CONCLUSIONS: Sustained exposure to MEM affects body growth, brain morphology, and behavior primarily by pharmacological, and not autoimmunity-dependant mechanisms. Substrain-specific improvement in exploratory behavior of MEM-treated MRL/lpr mice may indicate that the NMDA system is merely a constituent of a complex pathogenenic cascade. However, it was evident that chronic administration of MEM is unable to completely prevent the development of a CNS SLE-like syndrome.

Systemic lupus erythematosus / 소아과

Systemic lupus erythematosus (SLE) is an episodic, multi-system, autoimmune disease characterized by widespread inflammation of blood vessels and connective tissues and by the presence of antinuclear antibodies (ANAs), especially antibodies to native (double-stranded) DNA (dsDNA). Its clinical manifestations are extremely variable, and its natural history is unpredictable. Untreated, SLE is often progressive and has a significant fatality rate. The most widely used criteria for the classification of SLE are those of the American College of Rheumatology (ACR), which were revised in 1982 and modified in 1997. The presence of four criteria have been diagnosed as a SLE. Rashes are common at onset and during active disease. The oral mucosa is the site of ulceration with SLE. Arthralgia and arthritis affect most children and these symptoms are short in duration and can be migratory. Lupus nephritis may be more frequent and of greater severity in children than in adults. The initial manifestation of nephritis is microscopic hematuria, followed by proteinuria. The most common neuropsychiatric symptoms are depression, psychosis(hallucination and paranoia) and headache. CNS disease is a major cause of morbidity and mortality. Pericarditis is the most common cardiac manifestation. Libman-Sacks endocarditis is less common in children. The most frequently described pleuropulmonary manifestations are pleural effusions, pleuritis, pneunonitis and pulmonary hemorrhage. During the active phase ESR, CRP, gamma globulin, ferritin and anti-dsDNA are elevated. Antibodies to dsDNA occur in children with active nephritis. Antibodies to the extractable nuclear antigens (Sm, Ro/SS-A, La/SS-B) are strongly associated with SLE. Specific treatment should be individualized and based on the severity of the disease. Sepsis has replaced renal failure as the most common cause of death.

A Case of Optic Neuritis in Systemic Lupus Erythematosus / 대한내과학회지

Systemic lupus erythematosus (SLE) is a disease of unknown etiology in which tissues and cells are damaged by pathogenic autoantibodies and immune complexes. Optic neuritis in SLE is very rare and the prevalence can be estimated to be approximately 1% of the patients of SLE. The main pathogenesis of optic neuritis with SLE is that of a vaso-occlusive disease in small vessels and the histopathologic appearance has varied from demyelination to definite vascular disease with axonal necrosis. The visual outcome of optic neuritis in SLE has often been poor. The treatments of optic neuritis in SLE are intravenous methylprednisolone, immunosuppressive agents and plasmapheresis. The authors experienced a case of lupus nephritis and CNS lupus which was complicated by optic neuritis in 18-year-old female patient who complained of sudden visual disturbance of the both eyes After treatment with plasmapheresis and systemic corticosteroid, her visual deficit was gradually recovered.

Two Cases of Systemic Lupus Erythematosus with Cerebrovascular Involvement / 영남의대학술지

Systemic lupus erythematosus(SLE) is an autoimmune disease which may affect many different organs and disclose various clinical manifestations. Recently central nervous system(CNS) involvement has been recognized as an increasingly significant contributor to morbidity and mortality of SLE. The clinical manifestations of CNS-lupus are highly variable and range from mild cognitive dysfunction, movement disorder, headache, psychosis to life-threatening stroke and coma. Among the neuropsychiatric disorders encountered in patients with SLE, cerebrovascular disease has been a relatively rare complication. The diagnosis and management of CNS-lupus is difficult because of the lack of useful diagnostic methods. If, cerebrovascular involvement is suspected, then aggressive treatment such as high dose steroid, immunosuppressive therapy, plasma exchange, may be required to reduce high mortality rate. We experienced 2 cases cerebrovascular disease occurring in SLE patients which presented with various neuropsychiatric manifestations. They were diagnosed as CNS-lupus by neuropsychiatric symptoms, brain MRI, and EEG, and showed good response to high dose steroid pulse therapy.