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.

Neuropsychiatric Lupus in clinical practice / Lúpus neuropsiquiátrico na prática clínica

ABSTRACT Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs, characterized by the production of autoantibodies and the development of tissue injury. The etiology of SLE is partially known, involving multiple genetic and environmental factors. As many as 50% of patients with SLE have neurological involvement during the course of their disease. Neurological manifestations are associated with impaired quality of life, and high morbidity and mortality rates. Nineteen neuropsychiatric syndromes have been identified associated with SLE, and can be divided into central and peripheral manifestations. This article reviews major neuropsychiatric manifestations in patients with SLE and discusses their clinical features, radiological findings and treatment options.

RESUMO Lúpus eritematoso sistêmico (LES) é uma doença autoimune crônica que envolve múltiplos órgãos e sistemas, caracterizada pela produção de auto anticorpos e lesão tecidual. A etiologia do LES é parcialmente conhecida e envolve interação entre fatores genéticos e ambientais. Até 50% dos pacientes com LES apresentam envolvimento neurológico no decorrer da doença. Manifestações neurológicas estão associadas a prejuízo na qualidade de vida e altas taxas de mortalidade e morbidade. Foram identificadas 19 síndromes neuropsiquiátricas em pacientes com LES, divididas entre manifestações do sistema nervoso central e periférico. O objetivo deste artigo é revisar as manifestações neuropsiquiátricas mais importantes. Serão abordadas as características clínicas, os aspectos radiológicos e opções de tratamento dos eventos neuropsiquiátricos.

Immunotherapies for Neurological Manifestations in the Context of Systemic Autoimmunity.

Neurological involvement is relatively common in the majority of systemic autoimmune diseases and may lead to severe morbidity and mortality, if not promptly treated. Treatment options vary greatly, depending on the underlying systemic pathophysiology and the associated neurological symptoms. Selecting the appropriate therapeutic scheme is further complicated by the lack of definite therapeutic guidelines, the necessity to differentiate primary neurological syndromes from those related to the underlying systemic disease, and to sort out adverse neurological manifestations caused by immunosuppressants or the biological agents used to treat the primary disease. Immunotherapy is a sine qua non for treating most, if not all, neurological conditions presenting in the context of systemic autoimmunity. Specific agents include classical immune modulators such as corticosteroids, cyclophosphamide, intravenous immunoglobulin, and plasma exchange, as well as numerous biological therapies, for example anti-tumor necrosis factor agents and monoclonal antibodies that target various immune pathways such as B cells, cytokines, and co-stimulatory molecules. However, experience regarding the use of these agents in neurological complications of systemic diseases is mainly empirical or based on small uncontrolled studies and case series. The aim of this review is to present the state-of-the-art therapies applied in various neurological manifestations encountered in the context of systemic autoimmune diseases; evaluate all treatment options on the basis of existing guidelines; and compliment these data with our personal experience derived from a large number of patients.

Utility of TWEAK to assess neuropsychiatric disease activity in systemic lupus erhytematosus.

OBJECTIVE: The purpose of this study was to assess the utility of tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) in serum and cerebrospinal fluid (CSF) as a biomarker in neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Thirty three NPSLE patients were evaluated at hospitalization and six months later. As controls, five SLE patients with septic meningitis, 51 hospitalized SLE patients without a history of neuropsychiatric (NP) manifestations and without infections, 16 SLE patients without NP manifestations (surgical-SLE), four patients with primary neuropsychiatric disorders, and 25 patients with non-autoimmune diseases were also studied. Serum and CSF samples were drawn at hospitalization, except non-NPSLE patients, in whom only serum was studied, and six months later in 19 NPSLE and 27 non-NPSLE patients. Serum and CSF TWEAK levels were measured by ELISA; values are expressed in pg/mL. RESULTS: The mean ± SD age of NPSLE patients was 31 ± 13.1 years, which was similar across study groups (p = 0.54). TWEAK levels in serum were not different across the study groups. In CSF, TWEAK levels were higher in NPSLE, surgical-SLE and primary neuropsychiatric groups than in non-autoimmune patients: median (IQR) 159.2 (94.1-374.9), 172.3 (125.3-421.9), 371.3 (143-543) vs. 122.1 (76.1-212.4), respectively; all p < 0.05. Six months later, when the neuropsychiatric manifestations were clinically in remission, serum or CSF TWEAK did not vary from baseline in NPSLE patients. CONCLUSIONS: TWEAK levels are slightly elevated in CSF in SLE patients compared with non-autoimmune controls, irrespective of the presence of NP manifestations. TWEAK levels in serum and CSF do not seem to be a useful biomarker of CNS involvement in SLE.

Electroconvulsive therapy for catatonia in juvenile neuropsychiatric lupus.

Neuropsychiatric manifestations are serious and frequent complications of systemic lupus erythematous (SLE). Catatonia is a neuropsychiatric disorder characterized by motor disturbance (including waxy flexibility and catalepsy), stupor, excitement, negativism, mutism, echopraxia and echolalia. Catatonia associated with SLE has been only rarely reported, especially in children. Here we present a case of a 14-year-old patient encountered in consultation-liaison psychiatry who presented catatonia associated with SLE. Her catatonia was refractory to treatment with pulse methylprednisolone, intravenous cyclophosphamide and rituximab. The patient responded to a combined therapy of electroconvulsive therapy and benzodiazepines. The present case suggests that although rarely reported, catatonia seen in the background of SLE should be promptly identified and treated to reduce the morbidity.

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

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

Analysis of JC virus DNA in NPSLE patients treated with different immunomodulatory agents.

OBJECTIVE: The objective of this report is to assess the presence and viral load of JC polyomavirus (JCV) DNA in cerebrospinal fluid (CSF) and plasma from neuropsychiatric systemic lupus erythematosus (NPSLE) patients in comparison to controls and to investigate if different types of immunosuppressive treatments were correlated to detection and viral load of JCV DNA in SLE. BACKGROUND: Reactivation of a latent JCV infection with subsequent development of the fatal disease progressive multifocal leukoencephalopathy (PML) has become an increasing problem in patients with autoimmune diseases treated with newer immunosuppressants. Accumulating data point out that SLE patients are at particular risk for PML compared to patients with other rheumatic diseases. METHODS: CSF samples (n = 69) and plasma samples (n = 51) from 71 SLE patients and 58 controls (53 CSF samples and 50 plasma samples) with other non-inflammatory neurological disease (OND) were analyzed for JCV DNA with a quantitative PCR method. RESULTS: All CSF and plasma samples from NPSLE patients and controls were negative for JCV DNA. CONCLUSION: JCV DNA was absent in CSF and plasma in NPSLE patients and controls and consequently we were not able to identify any correlation between the occurrence of JCV DNA and type of immunosuppressive medication.

The use of electroconvulsive therapy in a patient with juvenile systemic lupus erythematosus and catatonia.

Catatonia is a rare manifestation in patients with systemic lupus erythematosus (SLE). As catatonia can be associated with both psychiatric and organic conditions, this could create a diagnostic dilemma once this occurs in SLE patients. The report describes a 15-year-old female with SLE who developed catatonia three days after the diagnosis of SLE was made. Her catatonia was refractory to the treatment with immunosuppressive therapy, which included pulse methylprednisolone, intravenous cyclophosphamide, rituximab, intravenous immunoglobulin (IVIG) and plasmapheresis. Given her persistent catatonia, electroconvulsive therapy (ECT) was initiated three months after the onset of her symptoms. After the third ECT treatment, her mental status dramatically improved and returned nearly to baseline while she was continued on the immunosuppression. This is the first report of a successful ECT therapy in catatonic lupus in children.

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

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

Neuropsychiatric lupus: clinical challenges, brain-reactive autoantibodies and treatment strategies.

Neurological manifestations in lupus can be due to active lupus disease affecting the brain or to other reasons. Reversible posterior leucoencephalopathy syndrome, primary lymphoma of the central nervous system, cerebral infections by bacteria (e.g. mycobacteria), viruses (e.g. JC virus), fungi (e.g. Cryptococcus) and parasites (e.g. Acanthamoeba), steroid-induced psychosis and reactive depression need to be excluded. Brain-reactive autoantibodies have been described as associating with neuropsychiatric lupus. The strongest associations described to date are with antiribosomal P protein and antiphospholipid antibodies. However these autoantibodies have not been shown to play significant roles in the pathogenesis. Treatment strategy for severe neuropsychiatric lupus include establishing definitive diagnosis, early identification and treatment of aggravating factors, appropriate symptomatic treatment, adequate immunosuppression, selective B-cell depletion and autologous haematopoietic stem cell transplant. Systematic reviews have shown that cyclophosphamide administration is superior to pulse methylprednisolone as a maintenance therapy. Mycophenolate mofetil has been shown to have modest effect and should only be considered if cyclophosphamide cannot be administered.

Electroconvulsive therapy for catatonia in neuropsychiatric systemic lupus erythematosus.

Neuropsychiatric systemic lupus erythematosus encompasses neurological syndromes of the central, peripheral, and autonomic nervous system and a variety of psychiatric syndromes. Neuropsychiatric systemic lupus erythematosus presenting as catatonia is uncommon, and treatment of this condition is not well defined. Here we describe a case of neuropsychiatric systemic lupus erythematosus with catatonia and our treatment approach focusing on electroconvulsive therapy in conjunction with cyclophosphamide. We also discuss the pathophysiological underpinnings of the condition and the basis for treatment.

[Clinical manifestations, laboratory test, treatment and outcome of neuropsychiatric involvement in pediatric systemic lupus erythematosus patients].

OBJECTIVE: To investigate the clinical manifestations, laboratory test, treatment and outcome of neuropsychiatric (NP) involvement in pediatric systemic lupus erythematosus (SLE) patients. METHODS: Seventy-seven patients with NP syndromes of SLE (NPSLE) seen from 1987 to 2007 were retrospectively reviewed. The relationship between the relative factors and the relapse of NPSLE was analyzed with logistic regression model. RESULTS: NPSLE was found in 17.3% of the SLE patients and 75% of the NPSLE patients the NP involvements occurred in the first 2 years of the onset of SLE. The most frequent NP manifestations were headache (31.8%) and seizure disorder (29.1%). In the active phases, the levels of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores of the 92.2% patients were higher than 15 and belonged to severe lupus. The patients were accompanied frequently with fever (88.3%) and rash (84.4%). The most frequently involved organs were kidney (76.6%) and blood system (67.5%). In the active phases, the ANA was positive (98.7%), the level of ESR increased (86.3%), the level of complement profile decreased (72.7%). The cerebrospinal fluid (CSF) study, the CT, the MRI and the EEG were abnormal (90.1%, 60.7%, 54.8%, 73.9%, respectively). All the patients received glucocorticoids and immunodepressant treatment in which 79.2% received IV high-dose methylprednisolone (MP), 51.9% received intrathecal (IT) methotrexate (MTX) and dexamethasone (DXM), 26.0% received IVIG, 2 patients received autologous peripheral blood stem cell transplantation. The mortality was 9.0%. The rate of relapse was 22.0% and in 75.0% of relapsed patients the relapse occurred within 24 months from the onset of NPSLE. The SLEDAI scores related to the relapse of the NPSLE (chi(2) = 3.987, P = 0.0459, OR = 1.172, 95% CI 1.003 and 1.370). CONCLUSION: SLEDAI scores were significantly helpful in predicting recurrence of NPSLE.

New directions in the treatment of systemic lupus erythematosus.

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

Autologous blood stem cell transplantation in refractory systemic lupus erythematodes with recurrent longitudinal myelitis and cerebral infarction.

Autologous hematopoietic stem cell transplantation (ASCT) has the potential to eliminate autoreactive lymphocytes and may represent a therapeutic option for patients with refractory autoimmune diseases. We describe a 19-year old woman with neuropsychiatric systemic lupus erythematodes (NPSLE) presenting with acute longitudinal myelitis and aseptic meningitis. Despite therapy with methylprednisolone and cyclophosphamide (CYC), recurrence of longitudinal myelitis and a disabling stroke-like relapse occurred. Hematopoietic stem cells were mobilized by CYC at 2 g/m2 and G-CSF. The patient was conditioned by CYC at 200 mg/kg and anti-thymocyte globulin and 3.6 x 10(6) CD34+ cells/kg were infused. Hematopoietic regeneration was observed on day 12 after ASCT. Currently, 18 months after ASCT, the patient is in clinical remission with no evidence for residual serological or neuroradiological activity of SLE. Although a longer follow-up will be needed to reliably assess the efficacy of ASCT in this patient, the present case demonstrates that ASCT may represent a therapeutic option for patients with severe NPSLE.

Overwhelming leukoencephalopathy as the only sign of neuropsychiatric lupus.

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

A severe case of systemic lupus erythematosus with cerebral involvement.

We describe an 18-year-old girl who presented with severe systemic lupus erythematosus with multiple organ involvement. The disease was further complicated by recurrent seizures and intracerebral left parieto-occipital bleeding that required neurosurgical treatment. Postoperative rebleeding occurred due to disseminated intravascular coagulation and platelet dysfunction. Catastrophic antiphospholipid syndrome was suspected, but could not be confirmed during follow-up. Additional treatment with plasmapheresis and intravenous pulse cyclophosphamide in combination with corticosteroids was started. Liquor drainage via a ventriculo-peritoneal (vp)-shunt was necessary because of a hydrocephalus malresorptivus. The patient's recovery was slow and incomplete (cachexia and amaurosis persisted). Follow-up was further complicated by an intraperitoneal vp-shunt cyst, which was initially treated conservatively, but finally had to be revised operatively.