Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus (NPSLE): Can They Be Used as Biomarkers for the Differential Diagnosis of This Disease?

Systemic lupus erythematosus is a complex immunological disease where both environmental factors and genetic predisposition lead to the dysregulation of important immune mechanisms. Eventually, the combination of these factors leads to the production of self-reactive antibodies that can target any organ or tissue of the human body. Autoantibodies can form immune complexes responsible for both the organ damage and the most severe complications. Involvement of the central nervous system defines a subcategory of the disease, generally known with the denomination of neuropsychiatric systemic lupus erythematosus. Neuropsychiatric symptoms can range from relatively mild manifestations, such as headache, to more severe complications, such as psychosis. The evaluation of the presence of the autoantibodies in the serum of these patients is the most helpful diagnostic tool for the assessment of the disease. The scientific progresses achieved in the last decades helped researchers and physicians to discover some of autoepitopes targeted by the autoantibodies, although the majority of them have not been identified yet. Additionally, the central nervous system is full of epitopes that cannot be found elsewhere in the human body, for this reason, autoantibodies that selectively target these epitopes might be used for the differential diagnosis between patients with and without the neuropsychiatric symptoms. In this review, the most relevant data is reported with regard to mechanisms implicated in the production of autoantibodies and the most important autoantibodies found among patients with systemic lupus erythematosus with and without the neuropsychiatric manifestations.

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.

Clinical presentation of a neuropsychiatric lupus patient with symmetrical basal ganglia lesions containing cytotoxic oedema cores surrounded by vasogenic oedema.

Neuropsychiatric (NP) manifestations of systemic lupus erythematosus (SLE) are diverse, but involvement of basal ganglia is rare. We describe here a 28-year-old woman with NPSLE presenting aseptic meningitis accompanied by elevated interleukin-6 levels in the cerebrospinal fluid, who developed symmetrical basal ganglia lesions, containing a cytotoxic oedematous core, surrounded by vasogenic oedema upon magnetic resonance imaging. We were able to observe these lesions from a de novo appearance during the disease onset to its disappearance during immunosuppressive treatment. Reversibility upon immunosuppressive treatment indicated that autoimmune mediated mechanisms could contribute to the basal ganglia lesions in NPSLE.

HMGB1 in Systemic Lupus Erythematosus.

The high-mobility group box 1 (HMGB1) has been shown to exert proinflammatory effects on many cells of the innate immune system. Originally identified as a nuclear protein, HMGB1 has been found to play an important role in mediating inflammation when released from apoptotic or necrotic cells as a damage-associated molecular pattern (DAMP). Systemic lupus erythematosus (SLE) is a disease of non-resolving inflammation, characterized by the presence of autoantibodies and systemic inflammation involving multiple organ systems. SLE patients have impaired clearance of apoptotic debris, which releases HMGB1 and other DAMPs extracellularly. HMGB1 activity is implicated in multiple disease phenotypes in SLE, including lupus nephritis and neuropsychiatric lupus. Elucidating the various properties of HMGB1 in SLE provides a better understanding of the disease and opens up new opportunities for designing potential therapeutics.

Autoantibodies associated with neuropsychiatric systemic lupus erythematosus: the quest for symptom-specific biomarkers.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organs, including the central nervous system. Neuropsychiatric SLE (NPSLE) is a severe and potentially fatal condition. Several factors including autoantibodies have been implicated in the pathogenesis of NPSLE. However, definitive biomarkers of NPSLE are yet to be identified owing to the complexity of this disease. This is a major barrier to accurate and timely diagnosis of NPSLE. Studies have identified several autoantibodies associated with NPSLE;some of these autoantibodies are well investigated and regarded as symptom-specific. In this review, we discuss recent advances in our understanding of the manifestations and pathogenesis of NPSLE. In addition, we describe representative symptom-specific autoantibodies that are considered to be closely associated with the pathogenesis of NPSLE.

Diagnostic performance of aPS/PT antibodies in neuropsychiatric lupus and cardiovascular complications of systemic lupus erythematosus.

Background: Systemic lupus erythematosus (SLE) is associated with a constellation of complications affecting multiple organs, including neuropsychiatric manifestations (NPSLE) and ischaemic events, leading to increased long-term morbidity. Antiphospholipid antibodies (aPL) are a major determinant of vascular inflammation and thromboembolic risk. The diagnostic role of anti-phosphatidylserine/prothrombin (aPS/PT) antibodies in this setting is incompletely defined.Aim: To verify whether aPS/PT add to diagnostics and disease stratification in patients with SLE with or without other aPL.Methods: 131 consecutive patients were studied, including 20 patients with SLE and secondary antiphospholipid syndrome (APS). aPS/PT IgG and IgM were assessed through ELISA and patients were stratified based on the presence of other aPL, on their clinical and laboratory features at time of blood sampling and on their clinical history. Synthetic indices of disease activity, chronic damage and cardiovascular risk were calculated at time of venipuncture.Results: Fifty-one (38.9%) patients with SLE had aPS/PT and 15 (11.5%) patients had aPS/PT as the only aPL (aPS/PT-only). aPS/PT-only patients had a significantly higher prevalence of NPSLE than quadruple aPL-negative patients (p = .007). Patients with aPS/PT were more likely to have a history of ischaemia, thrombocytopenia and Libman-Sacks' endocarditis. The presence of aPS/PT also associated with previous accrual of at least one damage item (p = .043), but had limited predictive values for damage progression in the short term.Conclusion: aPS/PT antibodies provide non-redundant information that could contribute to risk assessment and stratification of patients with SLE.

Blood-brain barrier disruption and neuroinflammation as pathophysiological mechanisms of the diffuse manifestations of neuropsychiatric systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that can involve nervous system commitment known as neuropsychiatric systemic lupus erythematosus (NPSLE). The diagnostic of NPSLE is complex because the symptoms range from focal symptoms (e.g., strokes, thrombotic events) to diffuse disorders affecting cognition, mood and level of consciousness (e.g. acute confusional state, psychosis). Both type of manifestations of NPSLE differ in their pathological mechanisms. The focus of this review will be on the mechanisms that lead to the blood-brain barrier (BBB) disruption and to the neuroinflammation related with the diffuse manifestations of NPSLE.

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.

Neuroinflammation in systemic lupus erythematosus - a review.

Neuroinflammation is a complex process that contributes to the pathogenesis of both immune mediated and neurodegenerative pathologies. Systemic lupus erythematosus (SLE) is the prototype of connective tissue diseases that can present the complete spectrum of neurological and psychiatric dysfunctions. The precise etiological diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) is rather difficult to be established and it is still controversial the exact timing of neuropsychiatric (NPS) events: either central nervous system (CNS) is the initial target of autoimmune abnormalities, either NPS symptoms are a part of multisystem involvement. Ischemic and inflammatory mechanisms have an important input on NPSLE pathogenesis. Neuroinflammation, consequent to blood-brain barrier (BBB) damage, local and systemic production of autoantibodies, determine neuronal injury and apoptosis, further responsible for diffuse cerebral events, mostly cognitive dysfunction and psychotic disorder. Moreover, SLE complications or therapy complications can interfere and contribute to complex clinical manifestations that can be present in SLE patients. Understanding the role of each pathogenic way can provide not only an early diagnosis, but a more accurate therapeutic approach of these patients.

The role of ophthalmic imaging in central nervous system degeneration in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disorder that can involve any organ system. Central nervous system involvement can be a severe life threatening complication, ultimately resulting in severe neurodegenerative changes. Magnetic resonance imaging suggests that neurodegeneration, which may have deleterious effects on brain function, may occur early in SLE and experimental models suggest that neuroprotection may be feasible and beneficial. The retina is an extension of the brain. Recent ophthalmic imaging technologies are capable of identifying early changes in retinal and choroidal morphology and circulation that may reflect CNS degeneration. However, their utility in monitoring CNS involvement in SLE has been poorly studied as these have only been performed in small cohorts, in a cross-sectional design, non-quantitatively and without correlation to disease activity. The authors aim to review the current understanding of neurodegeneration associated with SLE, with particular focus on the visual pathway. We describe the neuropathology of the visual system in SLE and the evidence for retinal and choroidal neurodegenerative and microvascular changes using optical coherence tomography technology. We aim to describe the potential role of optical imaging modalities in NPSLE diagnosis and their likely impact on the study of neuronal function.

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.

Central Nervous System Manifestations of Systemic Lupus Erythematosus.

Neuropsychiatric systemic lupus erythematosus (NPSLE) encompasses a variety of phenomena. Manifestations are focal or diffuse, and correlate with disease mechanisms. Recent understanding of the contribution of blood-brain barrier dysfunction to the passage of circulating antineuronal antibodies into the brain parenchyma has shed light on pathogenesis. Correct attribution of neuropsychiatric manifestations to SLE remains a challenge, but validated attribution models will help. Diagnosis relies on characteristic clinical manifestations, SLE disease activity, antibody measurements, cerebrospinal fluid findings, specific neuroimaging findings, and exclusion of alternative etiologies. Current treatment encompasses the identification and management of the inciting event, symptomatic treatment, and anticoagulation or immunosuppression.

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.

[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.

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 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.

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.