Diagnosis and Management of Pediatric Neuropsychiatric Systemic Lupus Erythematosus: An Update.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a potentially serious and life-threatening complication of SLE. The presentation and severity of neuropsychiatric involvement in SLE may show considerable variability. The disease can affect the neural tissue directly or may be associated with vascular involvement, mainly associated with anti-phospholipid (aPL) antibodies. A direct causal link with SLE may sometimes be challenging since there are many confounding factors and the symptoms may be non-specific. Despite its remarkable sensitivity in detecting hemorrhagic and ischemic stroke, transverse myelitis and ischemic infarction, magnetic resonance imaging (MRI) lacks the spatial resolution required to identify microvascular involvement. When standard MRI fails to detect a suspicious lesion, it is advisable to use advanced imaging modalities such as positron emission tomography (PET), single photon emission computed tomography (SPECT) or quantitative MRI, if available. Even with these advanced modalities, the specificity of neuroimaging in NPSLE remains inadequate (60-82% for MRI). Neuropsychiatric syndromes, such as cerebrovascular events, seizures and cognitive impairments appear to be associated with serum aPL antibodies. Some studies have shown that anti-ribosomal P antibodies have a low sensitivity for NPSLE and a limited contribution to the differentiation of different clinical entities. Treatment has two main goals: symptomatic relief and treatment of the disease itself. Commonly used immunosuppressants for NPSLE include cyclophosphamide (CYC), azathioprine (AZA), and mycophenolate mofetil (MMF). According to EULAR's current recommendation, strong immunosuppressants such as CYC and rituximab (RTX) should be preferred. Biologics have also been used in NPSLE. Fingolimod, eculizumab, and JAK inhibitors are potential drugs in the pipeline. Developing targeted therapies will be possible by a better understanding of the pathological mechanisms.

Animal models of neuropsychiatric systemic lupus erythematosus: deciphering the complexity and guiding therapeutic development.

Systemic lupus erythematosus (SLE) poses formidable challenges due to its multifaceted etiology while impacting multiple tissues and organs and displaying diverse clinical manifestations. Genetic and environmental factors contribute to SLE complexity, with relatively limited approved therapeutic options. Murine models offer insights into SLE pathogenesis but do not always replicate the nuances of human disease. This review critically evaluates spontaneous and induced animal models, emphasizing their validity and relevance to neuropsychiatric SLE (NPSLE). While these models undoubtedly contribute to understanding disease pathophysiology, discrepancies persist in mimicking some NPSLE intricacies. The lack of literature addressing this issue impedes therapeutic progress. We underscore the urgent need for refining models that truly reflect NPSLE complexities to enhance translational fidelity. We encourage a comprehensive, creative translational approach for targeted SLE interventions, balancing scientific progress with ethical considerations to eventually improve the management of NPSLE patients. A thorough grasp of these issues informs researchers in designing experiments, interpreting results, and exploring alternatives to advance NPSLE research.

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.

Neuropsychiatric lupus in Malaysian children: clinical characteristics, imaging features and 12-month outcomes.

BACKGROUND: Neuropsychiatric lupus (NPSLE) serves as a marker of severe disease in children with juvenile onset systemic lupus erythematosus (JSLE). This study aims to characterise the clinical and imaging features at diagnosis; and outcomes after 12 months in Malaysian children with NPSLE. METHODS: A retrospective study of all NPSLE patients seen at the Pediatric Rheumatology Unit, Selayang Hospital from January 2004 to May 2017. RESULTS: Twenty-eight (19.8%) of 141 JSLE patients had NPSLE with a median presenting age of 10 years (IQR 9 - 12), median follow-up of 7 years (IQR 4 - 11) and female: male ratio of 3.7:1. Twenty-three patients had single episodes of NPSLE and five patients had two distinct episodes each. The mean disease activity score (SLEDAI- 2K) was 24.9±11.8 at presentation with 81.8% having high disease activity (score > 12). Majority (60.6%) present with NPSLE within the first year of SLE diagnosis whilst the remainder occurred at a median of five years (IQR 3-7) post-SLE diagnosis. Majority (75.8%) had central nervous system (CNS) involvement commonly presenting with seizures, delirium and visual complaints whilst 24.2% had peripheral nervous system (PNS) involvement. Frequent accompanying features included hypocomplementemia, acute cutaneous lupus and lupus nephritis. Autoantibodies were common; ANA (100%), anti-dsDNA (78.8%) anti-RNP (39.4%) and anti-Sm (39.4%). Abnormalities were seen in 85.7% of the magnetic resonance imaging (MRI) studies performed, predominantly supratentorial white matter hyperintensities on T2 images whilst cerebrospinal fluid examination was normal in the majority. All patients with CNS involvement received corticosteroids with immunosuppressive therapy: Cyclophosphamide (20), Rituximab (2). Treatment for PNS involvement included corticosteroids with Azathioprine (6) or Mycophenolate mofetil (2). At 12 months post-NPSLE, majority (85.7%) recovered without any neurological sequelae. CONCLUSIONS: Juvenile-onset NPSLE presents with a myriad of clinical features. It is associated with high disease activity and non-specific MRI features. With early diagnosis and treatment, the majority had good prognosis.

[Therapeutic Strategies of Neuropsychiatric Systemic Lupus Erythematosus].

Damage of the central and peripheral nervous systems associated with systemic lupus erythematosus (SLE) is termed neuropsychiatric SLE (NPSLE). In this review, we have discussed SLE encephalopathy, which is associated with neurological symptoms in particular. At the time of diagnosis, disease severity should be evaluated based on clinical findings, imaging, laboratory tests, including cerebrospinal fluid tests and neurophysiological tests, of the patient. Subsequently, treatment involving both definitive therapy and symptomatic treatment is initiated. After introducing definitive therapy, it is further desirable to adopt an appropriate treatment approach by identifying the predominant type of pathogenesis (inflammatory or vascular). A collaborative approach involving specialists in collagen vascular disease, neurologists, and psychiatrists is important for appropriate management of NPSLE.

Exercise alleviates symptoms of CNS lupus.

Systemic lupus erythematosus (lupus) is a global health problem where 20-80% patients display cognitive problems and central nervous system (CNS) dysfunction. Early diagnosis and treatment of lupus remains a clinical challenge. Exercise improves experimental lupus nephritis. However, the effects of exercise in CNS lupus remains unknown. This study investigates the effects of controlled exercise (CE) that consisted of treadmill walking (5 m/min for 10 min everyday) on experimental CNS lupus using the well-established mouse model, MRL/lpr mice. The MRL/lpr mice were subjected to CE from 8 weeks (preclinical) to 16 weeks (disease). Multiplex gene expression analysis revealed significant upregulation of genes involved in neurite growth, proliferation and synaptic plasticity, and a decrease in inflammatory genes including complement proteins, NFkB, chemokines and cytokines in exercised mice compared to the unmanipulated, age-matched controls. The loss of blood-brain barrier integrity, astrogliosis and edema seen in MRL/lpr mice were reduced with exercise. Exercised mice performed better in behavioral assessments such as open field, nesting, and tail suspension test. For the first time our results show that a supervised, well-regulated and controlled exercise regimen alleviates CNS lupus and could potentially serve as an intervention strategy to improve the quality of life. Exercise could also serve as an adjunct therapy for lupus and other neuroinflammatory diseases, thereby reducing the need for the current therapies with toxic side effects. The validity of the findings and a safe exercise regimen needs to be established by additional studies in patients.

Treatment of neuropsychiatric systemic lupus erythematosus: clinical challenges and future perspectives.

Introduction: Neuropsychiatric (NP) involvement represents an emerging frontier in systemic lupus erythematosus (SLE), posing significant challenges due to its clinical diversity and obscure pathophysiology. The authors herein discuss selected aspects in the management of NPSLE based on existing literature and our experience, aiming to facilitate routine medical care.Areas covered: Research related to diagnosis, neuroimaging, treatment and outcome is discussed, focusing on data published in PubMed during the last 5 years. Selected translational studies of clinical relevance are included.Expert opinion: Identification of NPSLE patients who may benefit from appropriate treatment can be facilitated by attribution algorithms. Immunosuppressants are typically indicated in recurrent seizures, optic neuritis, myelopathy, psychosis and peripheral nerve disease, although a low threshold is recommended for cerebrovascular disease and other NP manifestations, especially when SLE is active. With the exception of stroke with positive antiphospholipid antibodies, anti-coagulation is rarely indicated in other syndromes. Refractory NPSLE can be treated with rituximab, whereas the role of other biologics remains unknown. Advances in the fields of biomarkers, neuroimaging for brain structural, perfusion or functional abnormalities, and design of novel compounds targeting not only systemic autoimmunity but also inflammatory and regenerative pathways within the nervous system, hold promise for optimizing NPSLE management.

Relevant domains and outcome measurement instruments in neuropsychiatric systemic lupus erythematosus: a systematic literature review.

OBJECTIVES: Although neuropsychiatric involvement in SLE (NPSLE) is one of the most complex and troubling manifestations of the disease, validated outcome instruments to be used as sensitive endpoints in controlled clinical trials are lacking. We performed a systematic literature review (SLR) to identify outcome measurement instruments and domains used to assess NPSLE. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were used. Articles available in English (1967-2020), listed in PubMed, Embase, PsycINFO, Cochrane Library and the EULAR outcome measures library were screened. All domains and outcome measurement instruments were characterized according to the OMERACT Filter 2.1, considering core areas (manifestations/abnormalities, life impact, death/lifespan, societal/resource use) and contextual factors. RESULTS: Of 3392 abstracts evaluated, 83 studies were included in the SLR (15 974 patients, females 89.9%). Eligible studies included domains and instruments pertinent to all core areas defined by the OMERACT, except for 'societal/resource use'. The most common core areas were 'manifestations/abnormalities', covering 10 domains pertinent to laboratory and instrumental markers, indexes and neuropsychiatric dimension (cognitive, neurologic and psychiatric field), and 'life impact', covering 7 domains related to physical function (from both the perspective of the patient and the physician), pain and quality of life. CONCLUSION: Our study revealed great heterogeneity in the instruments derived from populations with NPSLE and none of these had high-quality evidence. This supports the need to develop and further validate a core domain set and outcome measurement instruments to promote clinical research in this field, enhancing comparability across studies.

Neuropsychiatric involvement in systemic lupus erythematosus: A review.

The neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) is a challenge for clinicians, both at a diagnostic and therapeutic level. Although in 1999 the American College of Rheumatology (ACR) proposed a set of definitions for 19 NPSLE syndromes, with the intention of homogenizing the terminology for research purposes and clinical practice, the prevalence of NPSLE varies widely according to different series and is estimated to be between 37 and 95%. This is due to multiple factors such as the unalike definitions used, the diverse design of the studies, type of population, race, type and severity of symptoms, and follow-up of the different cohorts of patients with SLE. In recent years, some authors have tried excluding minor neuropsychiatric manifestations in order to try to reduce this wide variation in the prevalence of NPSLE since they are very prevalent in the general population; others authors have developed various models for the attribution of neuropsychiatric events to SLE that can assist clinicians in this diagnostic process, and finally, some authors developed and validated in 2014 a new algorithm based on the definitions of the ACR that includes the evaluation of the patient's lupus activity together with imaging techniques and the analysis of cerebrospinal fluid (CSF), with the aim of trying to differentiate the true neuropsychiatric manifestations attributable to SLE. In 2010, the European League Against Rheumatism (EULAR) developed recommendations for the management of NPSLE. We found abundant literature published later where, in addition to the recommendations for the management of the 19 NPSLE syndromes defined by the ACR, additional recommendations are given for other neurological and/or psychiatric syndromes, conditions, and complications that have been associated to SLE in recent years. We review below the diagnostic and therapeutic management of the different entities.

Management of inflammatory neurologic and psychiatric manifestations of systemic lupus erythematosus: A systematic review.

BACKGROUND: The neurological and psychiatric manifestations of systemic lupus erythematosus (NPSLE) are a heterogeneous group of conditions with variable clinical presentation and significant morbidity and mortality. OBJECTIVES: Our aim was to comprehensively assess and present the evidence for treatments used in the management of inflammatory NPSLE. METHODS: Medline, Embase, CINHAL and Cochrane CENTRAL were searched from 1990 to end of March 2019 using key words that related to NPSLE and treatment. Included studies comprised clinical trials, observational studies or case series with ≥5 patients and sufficient data related to treatment and outcome in NPSLE patients. RESULTS: There were 7222 studies identified in the search, of which 90 were included in the review. There was a notable paucity of clinical trials, with only two randomised controlled trials and one pilot study. Treatment categories included corticosteroids (14 studies), cyclophosphamide (18 studies), synthetic DMARDs (7 studies), biologic therapies (14 studies), therapeutic plasma exchange (6 studies), intravenous immunoglobulin (2 studies), autologous stem cell transplant (3 studies), other therapies (8 studies), combination therapies (6 studies), studies with grouped outcome data (5 studies) and observational studies with therapy-specific associations (7 studies). Corticosteroids are accepted as first line treatment in NPSLE and there is low-moderate evidence supporting their benefit. Moderate evidence, based on consistent data in numerous studies and some trial data, supports the use of cyclophosphamide in the treatment of NPSLE. Limited data support some synthetic DMARDs such as mycophenolate, azathioprine and intrathecal methotrexate. In refractory disease, low-moderate evidence supports rituximab therapy and limited evidence supports benefit following autologous stem cell transplant. Regarding adjuvant treatments, limited evidence favours addition of plasma exchange, intravenous immunoglobulin and hydroxychloroquine. There exists very limited data for other therapies. CONCLUSION: There are multiple therapeutic options for the management of inflammatory NPSLE including systemic, biologic and interventional therapies; however, currently there is a paucity of high-quality trial data to guide firm recommendations. In order to better understand the optimal treatment of NPSLE and its different subtypes, further well-designed clinical trials are needed.

Update οn the diagnosis and management of systemic lupus erythematosus.

Clinical heterogeneity, unpredictable course and flares are characteristics of systemic lupus erythematosus (SLE). Although SLE is-by and large-a systemic disease, occasionally it can be organ-dominant, posing diagnostic challenges. To date, diagnosis of SLE remains clinical with a few cases being negative for serologic tests. Diagnostic criteria are not available and classification criteria are often used for diagnosis, yet with significant caveats. Newer sets of criteria (European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019) enable earlier and more accurate classification of SLE. Several disease endotypes have been recognised over the years. There is increased recognition of milder cases at presentation, but almost half of them progress overtime to more severe disease. Approximately 70% of patients follow a relapsing-remitting course, the remaining divided equally between a prolonged remission and a persistently active disease. Treatment goals include long-term patient survival, prevention of flares and organ damage, and optimisation of health-related quality of life. For organ-threatening or life-threatening SLE, treatment usually includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses. Management of disease-related and treatment-related comorbidities, especially infections and atherosclerosis, is of paramount importance. New disease-modifying conventional and biologic agents-used alone, in combination or sequentially-have improved rates of achieving both short-term and long-term treatment goals, including minimisation of glucocorticoid use.

Lupus Eritematoso Sistémico y Manifestaciones en el Sistema Nervioso Central: Un desafío diagnóstico permanente: casos Clínicos / Systemic lupus erythematosus and manifestations in the Central Nervous System: a permanent diagnostic challenge. Clinical cases

La presencia de manifestaciones neuropsiquiátricas en pacientes reumatológicos trae consigo un gran desafío diagnóstico que exige una mirada amplia, desde las bases de la medicina interna, a fin de poder orientar un estudio adecuado y el tratamiento oportuno. Junto con ello, el permanente diálogo e intercambio de miradas clínicas con otras especialidades permite tener un enfoque multidisciplinario que enriquece el abordaje de estas presentaciones complejas.

The presence of neuropsychiatric manifestations in rheumatological patients brings with it a great diagnostic challenge that requires a broad view, from the foundations of internal medicine, in order to guide the appropriate study and timely treatment of these patients. Along with this, the permanent dialogue and exchange of clinical views with other specialties allows for a multidisciplinary approach that enriches the approach to these complex presentations.

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.

Prevalence, outcome and prognostic factors of neuropsychiatric systemic lupus erythematosus: A real world single center study.

Objectives: To investigate the prevalence, outcome and prognostic factors of neuropsychiatric systemic lupus erythematosus (NPSLE).Methods: SLE inpatients from 2005 to 2016 were included. Information on survival duration and causes of death was collected. Data were analyzed using Kaplan-Meier curves, log-rank tests and Cox proportional hazards modeling.Results: Among 1589 SLE patients, 101 (6.4%) were diagnosed with NPSLE. The overall survival rates of the NPSLE patients were 89%, 85% and 84% at 1, 3 and 5 years, respectively. The standardized mortality ratio of NPSLE patients was 11.14. The most common cause of death was NPSLE related conditions (7, 47%), including intracranial hypertension syndrome, cerebrovascular disease and motor neuron disease. The following variables were associated with death: cardiac involvement, renal involvement, diffuse NPSLE, acute confusional state, more than one NPSLE manifestation, low lymphocyte count, elevated C-reactive protein, abnormal cerebrospinal fluid (CSF) and high systemic lupus erythematosus disease activity index. Acute confusional state (p = .001), elevated intracranial pressure (p = .010) and C-reactive protein (CRP) (p = .032) were independently predictive factors of death.Conclusion: Our study demonstrates an 11.14-fold increased mortality of NPSLE patients compared with general population. NPSLE related disorders are main causes of death. Acute confusional state is the most significant predictive factor for poor prognosis.

Anti-IFNAR treatment does not reverse neuropsychiatric disease in MRL/lpr lupus mice.

OBJECTIVE: Many systemic lupus erythematosus patients display a type I interferon (IFN) signature, and IFNα levels positively correlate with disease severity. Previous studies blocking the type I IFN pathway systemically in lupus models showed some beneficial effects. However, its effects on neuropsychiatric manifestations have yet to be carefully assessed, even though IFNα has been associated with induction of depression. Our aim was to investigate whether disrupting the type I IFN pathway would attenuate the development of murine neuropsychiatric lupus. METHODS: Female MRL/lpr mice were administered an antitype I IFN receptor (IFNAR) antibody or a control antibody intraperitoneally three times weekly for 12 weeks starting at age 4-5 weeks. Behavior was assessed during and at the end of the treatment schedule. RESULTS: No significant differences were seen between the anti-IFNAR- and control-treated mice when assessing for depression-like behavior or cognitive dysfunction, although anti-IFNAR antibody-treated mice displayed significant decreases in levels of IFN-stimulated genes. Anti-IFNAR treatment also did not significantly improve brain histology, cellular infiltration, or blood-brain barrier integrity. CONCLUSIONS: Surprisingly, our results showed no improvement in neuropsychiatric disease and suggest that the role of IFNAR signaling in the pathogenesis of neuropsychiatric lupus continues to need to be carefully assessed.

Characteristics and risk factors of an emergency department visit in patients with systemic lupus erythematosus.

This study aimed to examine the characteristics of patients with systemic lupus erythematosus (SLE) visiting the emergency department (ED) and the risk factors of an ED visit by these patients. This 4-year retrospective study was performed at a tertiary care center in Japan. We included all 205 patients with SLE who were treated in our outpatient clinic between April 1, 2008 and March 31, 2012 and divided them into two groups: those who visited the ED (the ED-user group) and those who did not (the ED-non-user group). We statistically compared the patient backgrounds and characteristics of the groups and identified the risk factors of an ED visit. Of all the patients, 118 visited the ED during study period and 87 did not. In total, 269 events were identified in the ED-user group. Of these, 91 (33.8%) were cases of infection, 32 (11.9%) were orthopedic problems, 32 (11.9%) were cases of gastrointestinal disease, 31 (11.5%) were cases of neurological disease, and 25 (9.3%) were cardiovascular events. Twenty-four events (8.9%) were due to SLE flares, of which ten (41.7%) were cases of neuropsychiatric lupus (NPSLE). The glucocorticoid dosage and the presence of a psychiatric illness, NPSLE, and lupus nephritis were higher among the ED-user group. Multivariate logistic regression analysis demonstrated high glucocorticoid dosage to be a risk factor of an ED visit. Among SLE patients, infections were the principal reason for visiting the ED. The most common reasons for an ED visit were common diseases rather than flares.

[Neuropsychiatric Systemic Lupus Erythematosus].

Systemic lupus erythematosus (SLE) is a representative autoimmune disease that is characterized by a variety of manifestations affecting multiple organs. Damage to the central nervous system is one example of how SLE can manifest and cause significant morbidity and mortality. The American College of Rheumatology defines neuropsychiatric SLE (NPSLE) as involving the central and peripheral nervous systems, which can include overt symptoms such as stroke, seizures, and psychosis. Recommendations from the international task force regarding the treat-to-target approach in SLE include targeting remission, preventing further damage, and improving quality of life. When a patient exhibits high disease activity and organ damage, treatment is initiated with a high dose of glucocorticoid and immunosuppressants. Recent innovative approaches to treatment include using biologics and JAK inhibitors, with high expectations of improving SLE management.