Neuropsychiatric Features of a Cohort of Patients with Systemic Lupus Erythematosus

In order to establish if neuropsychiatric systemic lupus erythematosus (NPSLE) can be identified by any characteristic other than those used to diagnose the neuropsychiatric (NP) disease itself, we retrospectively reviewed 98 systemic lupus erythematosus (SLE) patients followed over a mean period of 10 years. NPSLE was identified in 22 patients. Stroke and generalized seizures were the most frequent NP manifestations. The NPSLE and non-NPSLE groups were similar with regard to demographic characteristics, ACR criteria, serum autoantibodies, and frequency of hypertension and hypercholesterolemia. Of note, compared to the non-NPSLE group, NPSLE was associated with a higher frequency of smoking (78 versus 26%), organ damage (73 versus 34%), and cumulative mortality rate (14 versus 7%). The series of patients was further analysed according to the presence of antiphospholipid syndrome (APS). Significantly, the interval between the onset of NP disease and SLE diagnosis was shorter in the APS(-) (0.3 ± 1 years) than in the APS(+) (5 ± 7 years) groups. Recurrence and/or persistence of NP events were only documented in the APS(-) group. Overall cumulative mortality was highest in NPSLE and in APS(+) patients with inadequate anticoagulation control, identifying an aspect that requires improved vigilance and the development of novel therapeutic modalities.

Juvenile Systemic Lupus Erythematosus in Portugal: Clinical and Immunological Patterns of Disease Expression in a Cohort of 56 Patients

Objective: To define the pattern of disease expression and to gain better understanding in patients with juvenile onset systemic lupus erythematosus (SLE) in Portugal. Methods: The features of unselected patients with systemic lupus erythematosus who had disease onset before the age of 18 years were retrospectively analysed in three Portuguese centres with Pediatric Rheumatology Clinic over a 24-year period (1987-2011). Demographic, clinical and laboratory manifestations, therapy and outcome were assessed. Results: A cohort of 56 patients with a mean age at disease onset of 12.6±4.04 years (mean±1SD) (range, 1.0-17.0 years) and a mean period of follow-up of 5.5±5.4 years. Forty six (82.1%) patients were female. The most common disease manifestations were musculoskeletal (87.5%), mucocutaneous (80.3%) and haematological abnormalities (75%). Lupus nephritis was diagnosed in 46.4% of patients and consisted of glomerular ne - phritis in all cases. Neuropsychiatric manifestations occurred in 21.4% but severe central nervous system complications were uncommon, as brain infarcts and organic brain syndrome in 4 (7.1%) patients. Antinuclear antibodies and anti-double stranded DNA were positive in most patients in (98.2% and 71.4% respectively), as well as low C3 and/or C4 were observed frequently (85.7%). Generally, most patients had a good response to therapy as demonstrated by a significant decreasing of SLEDAI score from disease presentation to the last evaluation. The SLEDAI at diagnosis, the maximum SLEDAI and the incidence of complications were significantly higher in patients with neurolupus and/or lupus nephritis. Therapy included oral steroids (87.5%), hydroxychloroquine (85.7%), azathioprine (55.4%), IV cyclophosphamide (28.6%) along with other drugs. Six (10.7%) patients were treated with rituximab. Long-term remission was achieved in 32%, disease was active in 68%, adverse reactions to therapy occurred in 53.6% and complications/severe manifestations in 23.2%. Two patients died, being active disease and severe infection the causes of death. Conclusions: This study suggests that in our patients the clinical and laboratory features observed were similar to juvenile systemic lupus erythematosus patients from other series. Clinical outcome was favourable in the present study. Complications from therapy were frequent. Objective: To define the pattern of disease expression and to gain better understanding in patients with juvenile onset systemic lupus erythematosus (SLE) in Portugal. Methods: The features of unselected patients with systemic lupus erythematosus who had disease onset before the age of 18 years were retrospectively analysed in three Portuguese centres with Pediatric Rheumatology Clinic over a 24-year period (1987-2011). Demographic,clinical and laboratory manifestations, therapy and outcome were assessed. Results: A cohort of 56 patients with a mean age at disease onset of 12.6±4.04 years (mean±1SD) (range, 1.0-17.0 years) and a mean period of follow-up of 5.5±5.4 years. Forty six (82.1%) patients were female. The most common disease manifestations were musculoskeletal (87.5%), mucocutaneous (80.3%) and haematological abnormalities (75%). Lupus nephritis was diagnosed in 46.4% of patients and consisted of glomerular ne - phritis in all cases. Neuropsychiatric manifestations occurred in 21.4% but severe central nervous system complications were uncommon, as brain infarcts and organic brain syndrome in 4 (7.1%) patients. Antinuclear antibodies and anti-double stranded DNA were positive in most patients in (98.2% and 71.4% respectively), as well as low C3 and/or C4 were observed frequently (85.7%). Generally, most patients had a good response to therapy as demonstrated by a significant decreasing of SLEDAI score from disease presentation to the last evaluation. The SLEDAI at diagnosis, the maximum SLEDAI and the incidence of complications were significantly higher in patients with neurolupus and/or lupus nephritis. Therapy included oral steroids (87.5%), hydroxychloroquine (85.7%), azathioprine (55.4%), IV cyclophosphamide (28.6%) along with other drugs. Six (10.7%) patients were treated with rituximab. Long-term remission was achieved in 32%, disease was active in 68%, adverse reactions to therapy occurred in 53.6% and complications/severe manifestations in 23.2%. Two patients died, being active disease and severe infection the causes of death. Conclusions: This study suggests that in our patients the clinical and laboratory features observed were similar to juvenile systemic lupus erythematosus patients from other series. Clinical outcome was favourable in the present study. Complications from therapy were frequent.

Atteintes cardiaques dans les connectivites: l'exemple du lupus érythémateux systémique [Cardiac involvement in connective tissue disease: the example of systemic lupus erythematosus]

When we think of cardiac affection in the context of systemic lupus erythematosus (SLE), we usually refer to pericarditis first. As frequent as this affection is, it is actually not the only cardio-vascular problem that occurs with this systemic inflammatory disease. Are the cardiac events--ranging from multiple heart valve involvements to increased cardiovascular risks--clinically significant? And are they involving a specific follow-up, treatment or support? We are therefore trying to evaluate these questions in order to give some recommendations to any practitioners following up a lupus patient, or a patient suffering from any other inflammatory systemic disease.

High ACSL5 transcript levels associate with systemic lupus erythematosus and apoptosis in Jurkat T lymphocytes and peripheral blood cells

BACKGROUND: Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease in which increased apoptosis and decreased apoptotic cells removal has been described as most relevant in the pathogenesis. Long-chain acyl-coenzyme A synthetases (ACSLs) have been involved in the immunological dysfunction of mouse models of lupus-like autoimmunity and apoptosis in different in vitro cell systems. The aim of this work was to assess among the ACSL isoforms the involvement of ACSL2, ACSL4 and ACSL5 in SLE pathogenesis. FINDINGS: With this end, we determined the ACSL2, ACSL4 and ACSL5 transcript levels in peripheral blood mononuclear cells (PBMCs) of 45 SLE patients and 49 healthy controls by quantitative real time-PCR (q-PCR). We found that patients with SLE had higher ACSL5 transcript levels than healthy controls [median (range), healthy controls =16.5 (12.3-18.0) vs. SLE = 26.5 (17.8-41.7), P = 3.9x10 E-5] but no differences were found for ACSL2 and ACSL4. In in vitro experiments, ACSL5 mRNA expression was greatly increased when inducing apoptosis in Jurkat T cells and PBMCs by Phorbol-Myristate-Acetate plus Ionomycin (PMA+Io). On the other hand, short interference RNA (siRNA)-mediated silencing of ACSL5 decreased induced apoptosis in Jurkat T cells up to the control levels as well as decreased mRNA expression of FAS, FASLG and TNF. CONCLUSIONS: These findings indicate that ACSL5 may play a role in the apoptosis that takes place in SLE. Our results point to ACSL5 as a potential novel functional marker of pathogenesis and a possible therapeutic target in SLE

Association study of genetic variants of pro-inflammatory chemokine and cytokine genes in systemic lupus erythematosus

BACKGROUND. Several lines of evidence suggest that chemokines and cytokines play an important role in the inflammatory development and progression of systemic lupus erythematosus. The aim of this study was to evaluate the relevance of functional genetic variations of RANTES, IL-8, IL-1alpha, and MCP-1 for systemic lupus erythematosus. METHODS. The study was conducted on 500 SLE patients and 481 ethnically matched healthy controls. Genotyping of polymorphisms in the RANTES, IL-8, IL-1alpha, and MCP-1 genes were performed using a real-time polymerase chain reaction (PCR) system with pre-developed TaqMan allelic discrimination assay. RESULTS. No significant differences between SLE patients and healthy controls were observed when comparing genotype, allele or haplotype frequencies of the RANTES, IL-8, IL-1alpha, and MCP-1 polymorphisms. In addition, no evidence for association with clinical sub-features of SLE was found. CONCLUSION. These results suggest that the tested functional variation of RANTES, IL-8, IL-1alpha, and MCP-1 genes do not confer a relevant role in the susceptibility or severity of SLE in the Spanish population.

Evidence of new risk genetic factor to systemic lupus erythematosus: the UBASH3A gene

The ubiquitin associated and Src-homology 3 (SH3) domain containing A (UBASH3a) is a suppressor of T-cell receptor signaling, underscoring antigen presentation to T-cells as a critical shared mechanism of diseases pathogenesis. The aim of the present study was to determine whether the UBASH3a gene influence the susceptibility to systemic lupus erythematosus (SLE) in Caucasian populations. We evaluated five UBASH3a polymorphisms (rs2277798, rs2277800, rs9976767, rs13048049 and rs17114930), using TaqMan® allelic discrimination assays, in a discovery cohort that included 906 SLE patients and 1165 healthy controls from Spain. The SNPs that exhibit statistical significance difference were evaluated in a German replication cohort of 360 SLE patients and 379 healthy controls. The case-control analysis in the Spanish population showed a significant association between the rs9976767 and SLE (Pc = 9.9E-03 OR = 1.21 95%CI = 1.07-1.37) and a trend of association for the rs2277798 analysis (P = 0.09 OR = 0.9 95%CI = 0.79-1.02). The replication in a German cohort and the meta-analysis confirmed that the rs9976767 (Pc = 0.02; Pc = 2.4E-04, for German cohort and meta-analysis, respectively) and rs2277798 (Pc = 0.013; Pc = 4.7E-03, for German cohort and meta-analysis, respectively) UBASH3a variants are susceptibility factors for SLE. Finally, a conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs9976767 polymorphism. Our results suggest that UBASH3a gene plays a role in the susceptibility to SLE. Moreover, our study indicates that UBASH3a can be considered as a common genetic factor in autoimmune diseases.

The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis

Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P  = 1.34×10(-8), OR  = 1.22, CI 95%  = 1.14-1.30; rs2004640: P  = 4.60×10(-7), OR  = 0.84, CI 95%  = 0.78-0.90; rs10488631: P  = 7.53×10(-20), OR  = 1.63, CI 95%  = 1.47-1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P  = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P  = 9.04×10(-22), OR  = 1.75, CI 95%  = 1.56-1.97) better explained the observed association (likelihood P-value  = 1.48×10(-4)), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific.

Diagnosis of latent tuberculosis in patients with systemic lupus erythematosus: T.SPOT.TB versus tuberculin skin test.

Early studies in patients with systemic lupus erythematosus (SLE) reported increased incidence of tuberculosis. The tuberculin skin test (TST) is the technique of choice to detect latent tuberculosis infection (LTBI) but has several limitations. OBJECTIVES We compared TST and the newer T.SPOT.TB test to diagnose LTBI in SLE patients. METHODS In this observational cohort study conducted between August 2009 and February 2012, we recruited 92 patients from those attending the SLE clinic of our university hospital. Data recorded were epidemiological and sociodemographic characteristics. Laboratory analyses included TST and T.SPOT.TB tests. RESULTS Of the patients studied, 92% were women with an average age of 42.7 years. Overall, the degree of correlation between the two tests was low (Kappa index = 0.324) but was better in patients not receiving corticosteroids (CTC)/immunosuppressive (IS) therapy (Kappa = 0.436) and in those receiving hydroxychloroquine (Kappa = 0.473). While TST results were adversely affected by those receiving CTC and/or IS drugs (P = 0.021), the T.SPOT.TB results were not. CONCLUSION Although the TST test remains a useful tool for diagnosing LTBI in SLE patients, the T.SPOT.TB test is perhaps better employed when the patient is receiving CTC and/or IS drugs.

Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a severe and incurable autoimmune disease characterized by chronic activation of plasmacytoid dendritic cells (pDCs) and production of autoantibodies against nuclear self-antigens by hyperreactive B cells. Neutrophils are also implicated in disease pathogenesis; however, the mechanisms involved are unknown. Here, we identified in the sera of SLE patients immunogenic complexes composed of neutrophil-derived antimicrobial peptides and self-DNA. These complexes were produced by activated neutrophils in the form of web-like structures known as neutrophil extracellular traps (NETs) and efficiently triggered innate pDC activation via Toll-like receptor 9 (TLR9). SLE patients were found to develop autoantibodies to both the self-DNA and antimicrobial peptides in NETs, indicating that these complexes could also serve as autoantigens to trigger B cell activation. Circulating neutrophils from SLE patients released more NETs than those from healthy donors; this was further stimulated by the antimicrobial autoantibodies, suggesting a mechanism for the chronic release of immunogenic complexes in SLE. Our data establish a link between neutrophils, pDC activation, and autoimmunity in SLE, providing new potential targets for the treatment of this devastating disease.

Influence of cholecalciferol (Vitamin D3) on the course of experimental systemic lupus erythematosus in F1 (NZBxW) mice

The course of systemic lupus erythematosus (SLE), an autoimmune disease, is markedly affected by hormones such as estrogen and prolactin. It is well known that heavy exposure to sunlight has deleterious effects on SLE, triggering episodes of the disease. Classical explanations for this occurrence suggest that UV radiation damages DNA, which becomes immunogenic, or induces exposure of the Ro antigen in keratinocytes. In recent years, it has been shown that vitamin D3 has important effects on the immune system. Thus, we proposed an alternative hypothesis, suggesting that UV radiation, by promoting vitamin D3 synthesis, could be a factor aggravating the course of SLE after exposure to sunlight. To test this hypothesis, we injected F1(NZBxW) mice, which are prone to developing SLE, with vitamin D3, and we demonstrated a worsening of the histopathological findings in the kidney. (C) 2000 Wiley-Liss, Inc.

Preliminary core sets of measures for disease activity and damage assessment in juvenile systemic lupus erythematosus and juvenile dermatomyositis

Objective. To identify preliminary core sets of outcome variables for disease activity and damage assessment in juvenile systemic lupus erythematosus (JSLE) and juvenile dermatomyositis (JDM). Methods. Two questionnaire surveys were mailed to 267 physicians from 46 different countries asking each member to select and rank the response variables used when assessing clinical response in patients with JSLE or JDM. Next, 40 paediatric rheumatologists from 34 countries met and, using the nominal group technique, selected the domains to be included in the disease activity and damage core sets for JSLE and JDM. Results. A total of 41 response variables for JSLE and 37 response variables for JDM were selected and ranked through the questionnaire surveys. In the consensus conference, domains selected for both JSLE and JDM activity or damage core sets included the physician and parent/patient subjective assessments and a global score tool. Domains specific for JSLE activity were the immunological tests and the kidney function parameters. Concerning JDM, functional ability and muscle strength assessments were indicated for both activity and damage core sets, whereas serum muscle enzymes were included only in the activity core set. A specific paediatric domain called 'growth and development' was introduced in the disease damage core set for both diseases and the evaluation of health-related quality of life was advised in order to capture the influence of the disease on the patient lifestyle. Conclusions. We developed preliminary core sets of measures for disease activity and damage assessment in JSLE and JDM. The prospective validation of the core sets is in progress.

Long-term cardiac changes in patients with systemic lupus erythematosus

Background: The aim of this study was evaluate the late-onset repercussions of heart alterations of patients with systemic lupus erythematosus (SLE) after a 13-year follow up. Methods. A historical prospective study was carried out involving the analysis of data from the charts of patients with a confirmed diagnosis of lupus in follow up since 1998. The 13-year evolution was systematically reviewed and tabulated to facilitate the interpretation of the data. Results: Forty-eight patient charts were analyzed. Mean patient age was 34.5 ± 10.8 years at the time of diagnosis and 41.0 ± 10.3 years at the time of the study (45 women and 3 men). Eight deaths occurred in the follow-up period (two due to heart problems). Among the alterations found on the complementary exams, 46.2% of cases demonstrated worsening at reevaluation and four patients required a heart catheterization. In these cases, coronary angioplasty was performed due to the severity of the obstructions and one case required a further catheterization, culminating in the need for surgical myocardial revascularization. Conclusion: The analysis demonstrated progressive heart impairment, with high rates of alterations on conventional complementary exams, including the need for angioplasty or revascularization surgery in four patients. These findings indicate the need for rigorous cardiac follow up in patients with systemic lupus erythematosus. © 2013 de Godoy et al.; licensee BioMed Central Ltd.

Long-term cardiac changes in patients with systemic lupus erythematosus

Abstract Background The aim of this study was evaluate the late-onset repercussions of heart alterations of patients with systemic lupus erythematosus (SLE) after a 13-year follow up. Methods A historical prospective study was carried out involving the analysis of data from the charts of patients with a confirmed diagnosis of lupus in follow up since 1998. The 13-year evolution was systematically reviewed and tabulated to facilitate the interpretation of the data. Results Forty-eight patient charts were analyzed. Mean patient age was 34.5 ± 10.8 years at the time of diagnosis and 41.0 ± 10.3 years at the time of the study (45 women and 3 men). Eight deaths occurred in the follow-up period (two due to heart problems). Among the alterations found on the complementary exams, 46.2% of cases demonstrated worsening at reevaluation and four patients required a heart catheterization. In these cases, coronary angioplasty was performed due to the severity of the obstructions and one case required a further catheterization, culminating in the need for surgical myocardial revascularization. Conclusion The analysis demonstrated progressive heart impairment, with high rates of alterations on conventional complementary exams, including the need for angioplasty or revascularization surgery in four patients. These findings indicate the need for rigorous cardiac follow up in patients with systemic lupus erythematosus.

A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus.

A gain-of-function R620W polymorphism in the PTPN22 gene, encoding the lymphoid tyrosine phosphatase LYP, has recently emerged as an important risk factor for human autoimmunity. Here we report that another missense substitution (R263Q) within the catalytic domain of LYP leads to reduced phosphatase activity. High-resolution structural analysis revealed the molecular basis for this loss of function. Furthermore, the Q263 variant conferred protection against human systemic lupus erythematosus, reinforcing the proposal that inhibition of LYP activity could be beneficial in human autoimmunity.

EULAR Recommendations for Women's Health and the Management of Family Planning, Assisted Reproduction, Pregnancy and Menopause in Patients with Systemic Lupus Erythematosus and/or Antiphospholipid Syndrome

OBJECTIVES: Develop recommendations for women's health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). METHODS: Systematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus. RESULTS: Family planning should be discussed as early as possible after diagnosis. Most women can have successful pregnancies and measures can be taken to reduce the risks of adverse maternal or fetal outcomes. Risk stratification includes disease activity, autoantibody profile, previous vascular and pregnancy morbidity, hypertension and the use of drugs (emphasis on benefits from hydroxychloroquine and antiplatelets/anticoagulants). Hormonal contraception and menopause replacement therapy can be used in patients with stable/inactive disease and low risk of thrombosis. Fertility preservation with gonadotropin-releasing hormone analogues should be considered prior to the use of alkylating agents. Assisted reproduction techniques can be safely used in patients with stable/inactive disease; patients with positive antiphospholipid antibodies/APS should receive anticoagulation and/or low-dose aspirin. Assessment of disease activity, renal function and serological markers is important for diagnosing disease flares and monitoring for obstetrical adverse outcomes. Fetal monitoring includes Doppler ultrasonography and fetal biometry, particularly in the third trimester, to screen for placental insufficiency and small for gestational age fetuses. Screening for gynaecological malignancies is similar to the general population, with increased vigilance for cervical premalignant lesions if exposed to immunosuppressive drugs. Human papillomavirus immunisation can be used in women with stable/inactive disease. CONCLUSIONS: Recommendations for women's health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus.