Association of elevated serum soluble CD226 levels with the disease activity and flares of systemic lupus erythematosus.

CD226 is an activating receptor expressed on the cell surface of natural killer cells and T cells. Although CD226 polymorphism is known to be involved in systemic lupus erythematosus (SLE), the involvement of soluble CD226 (sCD226) in SLE is still unknown. In the present study, we measured serum sCD226 levels using an enzyme-linked immunosorbent assay in 58 SLE patients and 33 healthy controls (HCs) and evaluated their associations with SLE Disease Activity Index 2000 (SLEDAI-2K), clinical manifestations, laboratory data, and the cumulative probability of flare. Serum sCD226 levels showed no significant differences between SLE patients and HCs. However, sCD226 levels were significantly elevated in active SLE patients with a SLEDAI-2K score of ≥ 20 compared with HCs. In SLE patients, sCD226 levels were significantly correlated with SLEDAI-2K scores and anti-dsDNA antibody titers. Moreover, the cumulative probability of flare was markedly higher in patients with high sCD226 than in those with low sCD226. In patients with neuropsychiatric involvement, sCD226 levels were elevated and reflected neuropsychiatric disease activity. These findings indicate that serum sCD226 levels are associated with disease activity and flares of SLE. Thus, it may be a useful biomarker for SLE, and its monitoring allows for more precise SLE management.

Diagnostic criteria for systemic lupus erythematosus: a critical review.

Systemic lupus erythematosus is a multi-organ system autoimmune disease with clinical and serological heterogeneity. The formulation of initial criteria for SLE was first proposed by the American College of Rheumatology and appeared in 1971. Although the original purpose of the criteria was to classify the disease, it became widely used as a diagnostic criteria in clinical situations. Since then the ACR criteria have undergone at least two changes (in 1982 and 1997). Clinical manifestations that can differentiate SLE patients from healthy people such as skin lesions, arthritis, renal disorder, neurologic disorder, hematologic changes and others are included in these criteria. Serum anti-nuclear antibody, anti-ds-DNA antibody and anti-Sm antibody are important biomarkers of SLE patients. In 2012, the Systemic Lupus Collaborating Clinics proposed the SLICC criteria for SLE in view of new knowledge of autoantibodies and the importance of low complement. Future biomarkers may be useful in distinguishing SLE from other diseases and in monitoring of disease activity.

Neuropsychiatric lupus: classification criteria in neuroimaging studies.

This systematic review described the criteria and main evaluations methods procedures used to classify neuropsychiatric systemic lupus erythematosus (NPSLE) patients. Also, within the evaluations methods, this review aimed to identify the main contributions of neuropsychological measurements in neuroimaging studies. A search was conducted in PubMed, EMBASE and SCOPUS databases with the terms related to neuropsychiatric syndromes, systemic lupus erythematosus, and neuroimaging techniques. Sixty-six abstracts were found; only 20 were completely analyzed and included. Results indicated that the 1999 American College of Rheumatology (ACR) criteria is the most used to classify NPSLE samples together with laboratorial, cognitive, neurological and psychiatric assessment procedures. However, the recommended ACR assessment procedures to classify NPSLE patients are being used incompletely, especially the neuropsychological batteries. Neuropsychological instruments and neuroimaging techniques have been used mostly to characterize NPSLE samples, instead of contributing to their classifications. The most described syndromes in neuroimaging studies have been seizure/cerebrovascular disease followed by cognitive dysfunctions as well as headache disorder.

Neuropsychiatric systemic lupus erythematosus: lessons learned from magnetic resonance imaging.

OBJECTIVE: The clinical manifestations of nervous system involvement in systemic lupus erythematosus (neuropsychiatric SLE [NPSLE]) are highly diverse, and their etiology is incompletely understood. The aim of this study was to provide an inventory of abnormalities on conventional brain magnetic resonance imaging (MRI) in NPSLE and to interpret the findings in relation to possible underlying pathogenetic mechanisms. METHODS: MR images of the first episode of active NPSLE in 74 patients were retrospectively reviewed. All patients fulfilled the American College of Rheumatology (ACR) 1982 revised criteria for the classification of SLE and were classified according to the 1999 ACR case definitions for NPSLE syndromes. We excluded patients with a history of brain disease and patients in whom other mechanisms unrelated to SLE caused the neuropsychiatric symptoms. RESULTS: The principal findings were: 1) focal hyperintensities in white matter (WM) (49% of all patients) or both WM and gray matter (GM) (5% of all patients), suggestive of vasculopathy or vasculitis; 2) more widespread, confluent hyperintensities in the WM, suggestive of chronic hypoperfusion due to the same mechanisms; 3) diffuse cortical GM lesions (12% of all patients), compatible with an immune response to neuronal components or postseizure changes; and 4) absence of MRI abnormalities, despite signs and symptoms of active disease (42% of all patients). CONCLUSION: Several distinct brain MRI patterns were observed in patients with active NPSLE, suggestive of different pathogenetic mechanisms. To advance our understanding of the various processes leading to NPSLE, the radiographic manifestations may be a good starting point and useful for categorization of patients in further research.

Identify biomarkers of neuropsychiatric systemic lupus erythematosus by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry combined with weak cation magnetic beads.

OBJECTIVE: To identify proteomic biomarkers in cerebrospinal fluid (CSF) and develop a diagnostic proteomic model for neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: CSF proteomic spectra were generated by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) combined with weak cation exchange (WCX) magnetic beads. The spectra were taken from 27 patients with NPSLE before and after treatment, and 27 controls including 17 patients with scoliosis and 10 patients with SLE but without neuropsychiatric manifestation. Discriminating peaks were processed by Biomarker Patterns Software to build a decision tree model for NPSLE classification. In addition, CSF samples of 12 patients with NPSLE, 12 patients with lumbar disc herniation, and 9 patients with other neurological conditions were used as a blind test group to verify the accuracy of the model. RESULTS: Twelve discriminating mass-to-charge (m/z) peaks were identified between NPSLE and controls: m/z peaks 7740, 11962, 8065, 7661, 6637, 5978, 11384, 11744, 8595, 10848, 7170, and 5806. The diagnostic decision tree model, built with a panel of m/z peaks 8595, 7170, 7661, 7740, and 5806, recognized NPSLE with both sensitivity and specificity of 92.6%, based on training group samples, and sensitivity and specificity of 91.7% and 85.7%, respectively, based on the blind test group. In addition, the root node m/z peak 8595 protein, which was downregulated in the CSF of patients with NPSLE after treatment, was identified and confirmed as ubiquitin by immunoprecipitation and ELISA. CONCLUSION: Potential CSF biomarkers for NPSLE are identified by MALDI-TOF-MS combined with WCX magnetic beads. The novel diagnostic proteomic model with m/z peaks 8595, 7170, 7661, 7740, and 5806 is highly sensitive and relatively specific for NPSLE diagnosis. The level of ubiquitin in CSF is a promising biomarker for active NPSLE.

[Does cutaneous lupus erythematodes really exist?]. / Gibt es wirklich einen kutanen Lupus erythematodes?

It should be obvious today that systemic lupus erythematosus (SLE) patients are better treated in an interdisciplinary approach. Nonetheless, the question remains as to whether cutaneous lupus erythematosus (CLE) indeed constitutes a disease entity of its own rather than the only recognized manifestation of oligosymptomatic SLE. The ACR criteria, designed for classification rather than diagnosis, are of limited value in answering this question. However, the concept of specific autoantibodies and immune complexes as inducers of various organ manifestations and analogous ideas on other autoantibody-mediated problems within and outside SLE argue for CLE as an existing entity. This is relevant for understanding the underlying immunopathogenesis, while less important for the appropriate therapy.

Demystifying neuropsychiatric lupus--is it possible?

The occurrence of nervous system events in patients with systemic lupus erythematosus (SLE) remains a diagnostic and therapeutic challenge due to the diversity of clinical manifestations, the correction attribution of events to SLE or other causes, and the lack of clinical trial data to facilitate the selection of treatment options. Over the past decade the classifcation and attribution of neuropsychiatric (NP) events has received more rigorous attention and new insights into the pathogenetic mechanisms have emerged through neuroimaging studies and elucidation of autoimmune and infammatory mechanisms. Although much work remains to be done on this complex and fascinating aspect of lupus, there is an emerging consensus on the pathogenesis and treatment of NP-SLE.

[Neuropsychiatric lupus (CNS lupus and PNS lupus)].

Patients with SLE show in a variety of neuropsychiatric symptoms, although we could not use standardized methods for evaluating and making diagnosis of the syndromes. ACR felt to develop objective and valuable tools for the diagnosis and classification of neuropsychiatric lupus, therefore, they proposed a new tentative set of nomenclatures describing neuropsychiatric lupus syndromes in accordance with 4th edition of Diagnostic and Statistical Manual of Mental Disorders provided by American Psychiatric Association. For this purpose, The Ad Hoc Committee collected and evaluated 108 case presentations of neuropsychiatric lupus from USA, Canada, and UK. Re-evaluation of the tentative nomenclatures selected 19 neuropsychiatric syndrome to facilitate and enhance clinical research. They grouped into peripheral and central nervous system lupus, and central nervous system lupus was divided into neurologic syndromes and diffuse psychiatric/ neuropsychological syndromes. Instead of organic brain syndrome, a term of acute confusional state was introduced.

ACR classification criteria for systemic lupus erythematosus: limitations and revisions to neuropsychiatric variables.

There are a wide variety of neurologic (N) and psychiatric (P) manifestations of systemic lupus erythematosus (SLE) which extend beyond those identified in the current American College of Rheumatology (ACR) classification criteria for SLE. Several attempts have been made to devise a classification of NP-SLE manifestations. The most recent is the ACR nomenclature and case definitions for 19 NP lupus syndromes which currently provides the best means of a standardized approach to categorize NP events in SLE patients. Data from a number of studies has indicated a wide variability in the prevalence of the 19 NP syndromes. On the basis of these findings and utilizing the guidelines provided in the case definitions for diagnosis and exclusion of confounding variables, it is proposed to examine a number of NP manifestations for possible inclusion in revised classification and diagnostic criteria for SLE.

The ACR nomenclature for CNS lupus revisited.

Neuropsychiatric systemic lupus erythematosus (NPSLE) involves a wide range of peripheral and central nervous system manifestations. These manifestations are complex and their pathophysiology is poorly understood. NPSLE can precede the onset of lupus or occur at any time during its course. The American College of Rheumatology (ACR) developed a standardized nomenclature system providing case definitions for the neuropsychiatric syndromes of systemic lupus erythematosus (SLE) to facilitate and enhance patient classification and reporting requirements in clinical research. Estimates of NPSLE prevalence have ranged widely and most are based on research conducted before the introduction of ACR case definitions. This paper reviews the early experience with the ACR nomenclature use and possible future directions for its improvement. The identification and categorization of the major neuropsychiatric syndromes in SLE using ACR case definitions seems to be adequate, however the mildest and most subjective of the syndromes are the most problematic. Even if the definitions in their present form might have drawbacks the only way forward is further use of ACR nomenclature, pooling data from different populations, and collection of experience as a basis for improvement. The acquisition of normative data for ethnic, age and sex stratification would extend their usefulness.

Validity of the new American College of Rheumatology criteria for neuropsychiatric lupus syndromes: a population-based evaluation.

OBJECTIVE: To assess the validity of the recently developed American College of Rheumatology (ACR) nomenclature for neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: We conducted a cross-sectional, population-based study covering an area with 440,000 people. A total of 46 patients aged 16 to 65 years fulfilled the criteria for a definite diagnosis of SLE. One control for each patient matched by age, sex, education, and place of residence was randomly identified from the population register. All patients and controls underwent a clinical neurologic examination and neuropsychological testing. The data were analyzed using conditional logistic regression methods. RESULTS: Forty-two patients (91%) and 25 controls (56%) fulfilled at least one of the ACR NPSLE criteria, which gave an odds ratio (OR) of 9.5 (95% confidence interval [CI] 2.2-40.8) but low specificity (0.46). Cognitive dysfunction was the most common syndrome detected in 37 patients (80%). A revised set of 16 criteria excluding the syndromes without evidence for neuronal damage resulted in improved specificity (OR 7.0, 95% CI 2.1-23.5, specificity 0.93). CONCLUSION: The proposed 19 ACR criteria did not differentiate SLE patients from controls, nor NPSLE patients from other SLE patients. The revised NPSLE criteria proposed by us performed well in our population but should be evaluated in a larger patient population.

Imaging modalities in central nervous system systemic lupus erythematosus.

Within the past few years, a clearly defined case definition system for central nervous system systemic lupus erythematosus (CNS-SLE) has been established. This has allowed cross-study comparisons of patients fulfilling the specific case definitions. New imaging techniques used on the subgroup of CNS-SLE patients that did not have any evidence for infarctions suggest that in these patients symptoms are associated with a diffuse process in the brain. Most likely this process leads to axonal damage and demyelination, ultimately leading to cerebral atrophy. With respect to the diagnostic work-up of SLE patients with neuropsychiatric symptoms, it has become clear that cranial magnetic resonance imaging is the technique of choice. Preliminary studies using quantitative magnetic resonance imaging techniques suggest that patients with neuropsychiatric symptoms caused by active CNS-SLE can be differentiated from patients with the same symptoms caused by residual disease.

Lúpus neuropsiquiátrico de acordo com a nova nomenclatura e definição de casos do Colégio Americano de Reumatologia (ACR): análise de 527 pacientes / Neuropsychiatric lupus according to the new nomenclature and case definition given by the American College of Rheumatology (ACR): review of 527 patients

Objetivo: Testar a nova classificação proposta pelo Colégio Americano de Reumatologia (ACR) para a nomenclatura das manifestações neuropsiquiátricas (MNP) do LES e definição de 19 síndromes em uma coorte de 527 pacientes com LES, previamente estudados quanto a estas manifestações e determinar a sua frequência. Pacientes e métodos: As 19 definições de síndromes estabelecidas pelo ACR incluindo os critérios diagnósticos, exclusões importantes e métodos diagnósticos foram aplicados à coorte de 527 pacientes. Todas as MNP secundárias foram excluídas. Uma bateria de testes neuropsicológicos para o diagnóstico de distúrbios cognitivos e questionários específicos para cefaléia, desordens do humor e de ansiedade foram aplicados a 40 pacientes desta coorte e comparados com normais, pareados de acordo com sexo, idade, condição socioeconômica e escolaridade. Resultados: O estudo da coorte revelou convulsões em 39 pacientes (7,4 por cento), psicose em 28 (5,3 por cento), polineuropatia em 20 (quatro por cento), estado confusional agudo em 15 (3 por cento), doença cerebrovascular em 13 (2,5 por cento), neuropatia craniana em oito (1,5 por cento), mononeuropatia em sete (1,3 por cento), mielopatia em seis (1 por cento), coréia em quatro (0,8 por cento), meningite asséptica em dois (0,4 por cento), síndrome de Guillan-Barré, síndrome desmielinizante e miastenia grave, um caso cada (0,2 por cento). Nenhum caso foi observado de desordens autonômicas e plexopatia. Dos 40 pacientes que foram submetidos aos testes neuropsicológicos, 75 por cento apresentaram distúrbios cognitivos em pelo menos um dos testes realizados. Desordens de ansiedade e desordens do humor (depressão) ocorreram em 70 por cento e 75 por cento, respectivamente. Cefaléia ocorreu em 62,5 por cento dos pacientes. Conclusões: A nomenclatura do ACR com definição das 19 síndromes pode ser útil para pesquisa clínica, em estudos multicêntricos, com grande número de doentes. Algumas condições, como desordens autonômicas e plexopatia, são bastante raras. Para detecção de distúrbios cognitivos, desordens de humor e de ansiedade são necessários testes e questionários específicos. Cefaléia é um sintoma comum como no LES, principalmente migrânea, mas é incerto se é relacionada ou não à doença

Neuropsychiatric lupus.

Neuropsychiatric (NP) manifestations of systemic lupus erythematosus (SLE) have been recognized for more than 100 years but continue to pose a diagnostic and therapeutic challenge for rheumatologists and other physicians involved in the care of SLE patients. NP-SLE includes a plethora of clinical manifestations and the reported prevalence has varied widely between 14% and 75%. The recent introduction of a standard nomenclature, case definitions, and diagnostic criteria for 19 NP-SLE syndromes should facilitate a more consistent approach to the classification of patients and to the execution of large multicenter clinical studies. The etiology of NP-SLE is likely multifactorial and includes microangiopathy, autoantibody production, and the intrathecal production of proinflammatory cytokines. Newer imaging modalities of brain structure and function provide novel ways of understanding pathogenic mechanisms. The use of standardized neuropsychometric techniques to evaluate cognitive function has identified a high prevalence of cognitive impairment in SLE patients. The management of patients with NP-SLE includes symptomatic and immunosuppressive therapies, evidence for which is largely limited to uncontrolled clinical trials and anecdotal experience. Multicenter initiatives are required to address important issues on prognosis and management.