Are serum autoantibodies associated with brain changes in systemic lupus erythematosus? MRI data from the Leiden NP-SLE cohort.

OBJECTIVE: The effect of serum autoantibodies on the brain of systemic lupus erythematosus (SLE) patients remains unclear. We investigated whether serum autoantibodies, individually and assessed in groups, are associated with specific brain-MRI abnormalities or whether these structural changes are associated with other SLE-related or traditional cardiovascular disease risk factors. METHODS: All patients underwent brain 3Tesla-MRI. White matter hyperintensities (WMHs), ischemic lesions, inflammatory-like lesions and cerebral atrophy were scored. Serum autoantibodies analyzed included lupus anticoagulant (LAC), anticardiolipine (aCL) IgG and IgM (first 3 also grouped into antiphospholipid autoantibodies (aPL)), anti-dsDNA, anti-SSA, anti-SSB, anti-RNP, and anti-Sm (the latter 5 grouped into SLE-related autoantibodies). Associations were assessed using logistic regression analysis adjusted for potential confounders. Furthermore, a sensitivity analysis including anti-Beta2 glycoprotein-1 antibodies (anti-ß2GP1) in the aPL group was performed and the potential modification role of the neuropsychiatric clinical status in the model was assessed. RESULTS: 325 patients (mean age 42 years (SD 14), 89% female) were included. The following MRI-brain abnormalities were found: WMHs (71%), lacunar infarcts (21%), gliosis (11%), micro-hemorrhages (5%), large hemorrhages (2%), inflammatory-like lesions (6%) and atrophy (14%). No associations were found between individual or total SLE-related autoantibodies and inflammatory-like lesions. A higher number of positive aPL was associated with lacunar infarcts (OR 1.37 (95%CI 1.02-1.99) and gliosis (OR 2.15 (1.37-3.37)). LAC was associated with lacunar infarcts in white matter (OR 3.38 (1.32-8.68)) and atrophy (OR 2.49 (1.01-6.15)), and aCL IgG with gliosis (OR 2.71 (1.05-7.02)). Among other variables, SLE patients with hypertension presented a higher chance for WMHs (OR 5.61 (2.52-12.48)) and lacunar infarcts in WM (OR 2.52 (1.10-5.74)) and basal ganglia (OR 8.34 (2.19-31.70)), while cumulative SLE-damage was correlated with lacunar infarcts in WM (OR 1.43 (1.07-1.90)), basal ganglia (OR 1.72 (1.18-2.51)) and cerebellum (OR 1.79 (1.33-2.41)). These associations were confirmed in the sensitivity analysis. CONCLUSIONS: Brain abnormalities in SLE represent different underlying pathogenic mechanisms. aPL are associated with ischemic brain changes in SLE, while the presence of SLE-related serum autoantibodies is not related to inflammatory-like lesions. Hypertension and cumulative SLE-damage associate with ischemic MRI-brain changes in SLE, suggesting the importance of accelerated atherosclerosis in this process.

Neuropsychiatric symptoms in systemic lupus erythematosus: impact on quality of life.

Objective Assess quality of life in patients with systemic lupus erythematosus (SLE) presenting with neuropsychiatric symptoms (neuropsychiatric SLE, NPSLE). Methods Quality of life was assessed using the Short-Form 36 item Health Survey (SF-36) in patients visiting the Leiden NPSLE clinic at baseline and at follow-up. SF-36 subscales and summary scores were calculated and compared with quality of life of the general Dutch population and patients with other chronic diseases. Results At baseline, quality of life was assessed in 248 SLE patients, of whom 98 had NPSLE (39.7%). Follow-up data were available for 104 patients (42%), of whom 64 had NPSLE (61.5%). SLE patients presenting neuropsychiatric symptoms showed a significantly reduced quality of life in all subscales of the SF-36. Quality of life at follow-up showed a significant improvement in physical functioning role ( p = 0.001), social functioning ( p = 0.007), vitality ( p = 0.023), mental health ( p = 0.014) and mental component score ( p = 0.042) in patients with neuropsychiatric symptoms not attributed to SLE, but no significant improvement was seen in patients with NPSLE. Conclusion Quality of life is significantly reduced in patients with SLE presenting neuropsychiatric symptoms compared with the general population and patients with other chronic diseases. Quality of life remains considerably impaired at follow-up. Our results illustrate the need for biopsychosocial care in patients with SLE and neuropsychiatric symptoms.

Outcomes of neuropsychiatric events in systemic lupus erythematosus based on clinical phenotypes; prospective data from the Leiden NP SLE cohort.

Objective The objective of this study was to assess whether clinical and patient's reported outcomes are associated with a different pathophysiological origin of neuropsychiatric events presenting in systemic lupus erythematosus. Methods A total of 232 neuropsychiatric events presenting in 131 systemic lupus erythematosus patients were included. Neuropsychiatric systemic lupus erythematosus diagnosis was established per event by multidisciplinary evaluation. All neuropsychiatric events were divided according to a suspected underlying pathophysiological process into one of the following: non-neuropsychiatric systemic lupus erythematosus related, inflammatory and ischaemic neuropsychiatric systemic lupus erythematosus. The clinical outcome of all neuropsychiatric events was determined by a physician-completed four-point Likert scale. Health-related quality of life was measured with the subscales of the patient-generated Short Form 36 (SF-36) health survey questionnaire. The change between scores at paired visits of all domain scores, mental component summary (SF-36 MCS) and physical component summary (SF-36 PCS) scores were retrospectively calculated and used as patient-reported outcome. The association among these outcomes and the different origin of neuropsychiatric events was obtained using multiple logistic regression analysis. Results The clinical status of 26.8% non-neuropsychiatric systemic lupus erythematosus events, 15.8% ischaemic neuropsychiatric systemic lupus erythematosus and 51.6% inflammatory neuropsychiatric systemic lupus erythematosus improved after re-assessment. Almost all SF-36 domains had a positive change at re-assessment in all groups independently of the origin of neuropsychiatric events. Neuropsychiatric systemic lupus erythematosus ( B = 0.502; p < 0.001) and especially inflammatory neuropsychiatric systemic lupus erythematosus ( B = 0.827; p < 0.001) had better clinical outcome, with change in disease activity being the only important predictor. The change in SF-36 MCS was also independently associated with neuropsychiatric systemic lupus erythematosus ( B = 5.783; p < 0.05) and inflammatory neuropsychiatric systemic lupus erythematosus ( B = 11.133; p < 0.001). Disease duration and change in disease activity were the only predictors in both cases. The change in SF-36 PCS was only negatively associated with age. Conclusion Inflammatory neuropsychiatric systemic lupus erythematosus events have better clinical outcome and meaningful improvement in SF-36 MCS than ischaemic neuropsychiatric systemic lupus erythematosus or non-neuropsychiatric systemic lupus erythematosus.

Increased expression of microRNA-155 in peripheral blood mononuclear cells from psoriasis patients is related to disease activity.

BACKGROUND: MicroRNAs (miRNAs) gene expression regulators are altered in psoriasis suggesting their role in the pathogenesis. OBJECTIVE: To study expression changes of inflammation and toll-like receptor (TLR)-related miRNAs, miRNA-155, let-7i, miRNA-21, miRNA-146a and miRNA-223 in peripheral mononuclear cells (PBMCs) and miRNA-21, miRNA-146a and miRNA-223 in plasma, from chronic plaque-type psoriasis patients who were treatment-naive or had undergone a washout period (n = 11). MiRNAs were evaluated at baseline and after 11 (9-12) months [median (25th-75th percentile range)] of methotrexate (MTX) or topical (betamethasone plus calcipotriene) treatment. METHODS: MiRNA expression was analysed with quantitative real-time reverse transcription-polymerase chain reaction. Matched controls were studied. RESULTS: Psoriasis patients presented, at baseline, increased expression of miRNA-155, let-7i, miRNA-146a, miRNA-21 and miRNA-223 in PBMCs, plus miRNA-21, miRNA-146a and miRNA-223 in plasma. Receiver-operator characteristic (ROC) curve analysis and area under the curve (AUC) showed that expression of these miRNAs have the potential to distinguish between psoriasis and controls. At baseline, miRNA-155 expression in PBMCs correlated with Psoriasis Area Severity Index (PASI) [12 (8-14)] (Spearman r: 0.7140, P < 0.05) suggesting a role in psoriasis. After MTX or topical treatment, reduction in PASI was observed [87.5% (75-100)]; miRNA-155 expression in PBMCs decreased; plasma miRNA-21, miRNA-146a and miRNA-223 were down-regulated. ROC analysis showed that miRNA-155 expression in PBMCs from psoriasis patients have the potential to distinguish between patients' samples at baseline and after treatment (AUC: 0.942, sensitivity: 0.91; specificity: 0.91 values; maximum likelihood ratio =10). After treatment, miRNA-146a expression in PBMCs increased; miRNA-155/miRNA-146a ratio decreased, suggestive of a regulatory feedback; let-7i expression decreased; miRNA-21 and miRNA-223 remained elevated. CONCLUSION: In this exploratory study, psoriasis patients presented increased expression of miRNA-155 in PBMCs that correlated with PASI and decreased with disease remission. MiRNA-21, miRNA-146a and miRNA-223 in PBMCs and plasma were increased at baseline and differentially modulated, underscoring different roles of TLR-related miRNAs in psoriasis.

Complement levels and anti-C1q autoantibodies in patients with neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: The objective of this paper is to analyse serum levels of anti-C1q, C1q circulating immune complexes (CIC), complement activation and complement components in systemic lupus erythematosus (SLE) patients during the first central nervous system neuropsychiatric (NP) event and to define the possible association between these results and clinical and laboratory characteristics. METHODS: A total of 280 patients suspected of having NP involvement due to SLE were recruited in the Leiden NPSLE-clinic. All SLE patients were classified according to the ACR 1982 revised criteria for the classification of SLE. The clinical disease activity was measured by the SLE Disease Activity Index 2000 (SLEDAI-2K) and NP diagnoses were classified according to the 1999 ACR case definitions for NPSLE. We measured in serum of all patients anti-C1q and C1q CIC levels, the activation capacity of complement (CH50 and AP50) and different complement components (C1q, C3, C4). RESULTS: In 92 patients the symptoms were attributed to SLE. NPSLE patients consisted of 63 patients with focal NPSLE and 34 patients with diffuse NPSLE. Anti-C1q antibodies were significantly higher and CH50, AP50 and C3 were significantly lower in NPSLE patients compared with SLE patients without NPSLE. This association was specially marked for diffuse NPSLE while no differences were found for focal NPSLE. After using potential predictors, decreased C4 remained significantly associated with focal NPSLE, but only when antiphospholipid antibodies (aPL) were included in the model. C3 and AP50 were independently associated with diffuse NPSLE. When SLEDAI-2K was included in the model these two associations were lost. When individual NPSLE syndromes were analysed, psychosis and cognitive dysfunction showed significantly lower values of complement activation capacity and all complement components. No significant associations were seen for other individual NPSLE syndromes. CONCLUSION: The associations between diffuse NPSLE and anti-C1q, C3/AP50 and focal NPSLE and C4 may be explained by disease activity and the presence of aPL, respectively. The role of complement activation and complement components in lupus psychosis and cognitive dysfunction merits further research.

Replication of PTPRC as genetic biomarker of response to TNF inhibitors in patients with rheumatoid arthritis.

Genetic biomarkers could be useful for orienting treatment of patients with rheumatoid arthritis (RA), but none has been convincingly validated yet. Putative biomarkers include 14 single nucleotide polymorphisms that have shown association with response to TNF inhibitors (TNFi) in candidate gene studies and that we assayed here in 755 RA patients. Three of them, in the PTPRC, IL10 and CHUK genes, were significantly associated with response to TNFi. The most significant result was obtained with rs10919563 in PTPRC, which is a confirmed RA susceptibility locus. Its RA risk allele was associated with improved response (B=0.33, P=0.006). This is the second independent replication of this biomarker (P=9.08 × 10(-8) in the combined 3003 RA patients). In this way, PTPRC has become the most replicated genetic biomarker of response to TNFi. In addition, the positive but weaker replication of IL10 and CHUK should stimulate further validation studies.

Angioedema adquirido por déficit de C1 inhibidor secundario a linfoma B esplénico de la zona marginal / Acquired angioedema with C1 inhibitor deficiency secondary to splenic marginal zone B-cell lymphoma

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Alteraciones en los niveles de expresión del microARN-33 en plasma de pacientes con psoriasis / Abnormal Levels of Expression of Plasma MicroRNA-33 in Patients With Psoriasis

INTRODUCCIÓN Y OBJETIVOS: Se han identificado microARN (miARN) circulantes implicados en la regulación postranscripcional de genes del metabolismo de lípidos (miARN-33) y de la función vascular y angiogénesis (miARN-126). El objetivo de este estudio exploratorio ha sido evaluar los niveles plasmáticos de miARN-33 y miARN-126 en pacientes con psoriasis en placas y su relación con parámetros clínicos. MATERIAL Y MÉTODOS: Se estudiaron once pacientes con psoriasis en placas (PASI [mediana] [25 - 75% percentil] 13 [9-14] y BSA 12 [11-15]) y un grupo pareado en edad y sexo de 11 controles sanos. Se analizaron factores de riesgo cardiovascular y la ateromatosis carotídea subclínica. Los miARN plasmáticos se evaluaron mediante la reacción en cadena de la polimerasa cuantitativa a tiempo real (qRT-PCR). RESULTADOS: La media del grosor de la íntima carotídea (GIM) estaba aumentada en pacientes (0,57 mm [0,54-0,61], n = 11) respecto a controles (0,50 mm [0,48-0,54], datos disponibles n = 9) (test Mann-Whitney, p = 0,0055). La expresión de miARN-33 en pacientes (5,34 [3,12-7,96], n = 11) estaba significativamente aumentada respecto a controles (2,33 [1,71-2,84], n = 7; solo se pudo detectar en 7 de 11) (test de Wilcoxon signed Rank, p = 0,0049). No se observaron diferencias en los niveles de miARN-126 entre pacientes y controles. En pacientes se observó una correlación positiva entre miARN-33 e insulina (r = 0,7289, p = 0,0109, n = 11); y una correlación negativa entre miARN-126 y GIM (r = -0,6181, p = 0,0426, n = 11). CONCLUSIÓN: Los pacientes con psoriasis presentaban niveles plasmáticos aumentados de miARN-33 (metabolismo de lípidos y glucosa), que se correlacionaban con los niveles de insulina. La valoración de miARN-33 circulante puede contribuir al conocimiento de las alteraciones inflamatorias sistémicas en psoriasis

INTRODUCTION AND OBJECTIVES: Circulating microRNAs (miRNA) are involved in the posttranscriptional regulation of genes associated with lipid metabolism (miRNA-33) and vascular function and angiogenesis (miRNA-126). The objective of this exploratory study was to measure plasma levels of miRNA-33 and miRNA-126 in patients with plaque psoriasis and evaluate their association with clinical parameters. MATERIAL AND METHODS: We studied 11 patients with plaque psoriasis. The median Psoriasis Area Severity Index (PASI) was 13 (interquartile range [IQR], 9-14) and body surface area involvement was 12 (IQR, 11-15). Eleven healthy controls matched for age and sex were also included. We analyzed cardiovascular risk factors and subclinical carotid atheromatosis. Plasma miRNAs were evaluated using quantitative real-time polymerase chain reaction. RESULTS: Carotid intima-media thickness was greater in patients (0.57 mm; IQR, 0.54-0.61; n = 11) than in controls (0.50 mm; IQR, 0.48-0.54; data available for 9 controls) (P = 0.0055, Mann-Whitney). Expression of miRNA-33 in patients (5.34; IQR, 3.12-7.96; n = 11) was significantly higher than in controls (2.33; IRQ, 1.71-2.84; only detected in 7 of 11 controls) (P = 0.0049, Wilcoxon signed rank). No differences in miRNA-126 levels were observed between patients and controls. In patients (n = 11), we observed a positive correlation between miRNA-33 and insulin levels (r = 0.7289, P = 0.0109) and a negative correlation between miRNA-126 and carotid intima-media thickness (r = -0.6181, P = 0.0426). CONCLUSION: In psoriasis patients plasma levels of lipid and glucose metabolism-related miRNA-33 are increased and correlated with insulin. The study of circulating miRNA-33 in psoriasis may provide new insights about the associated systemic inflammatory abnormalities

Abnormal levels of expression of plasma microRNA-33 in patients with psoriasis.

INTRODUCTION AND OBJECTIVES: Circulating microRNAs (miRNA) are involved in the posttranscriptional regulation of genes associated with lipid metabolism (miRNA-33) and vascular function and angiogenesis (miRNA-126). The objective of this exploratory study was to measure plasma levels of miRNA-33 and miRNA-126 in patients with plaque psoriasis and evaluate their association with clinical parameters. MATERIAL AND METHODS: We studied 11 patients with plaque psoriasis. The median Psoriasis Area Severity Index (PASI) was 13 (interquartile range [IQR], 9-14) and body surface area involvement was 12 (IQR, 11-15). Eleven healthy controls matched for age and sex were also included. We analyzed cardiovascular risk factors and subclinical carotid atheromatosis. Plasma miRNAs were evaluated using quantitative real-time polymerase chain reaction. RESULTS: Carotid intima-media thickness was greater in patients (0.57mm; IQR, 0.54-0.61; n=11) than in controls (0.50mm; IQR, 0.48-0.54; data available for 9 controls) (P=.0055, Mann-Whitney). Expression of miRNA-33 in patients (5.34; IQR, 3.12-7.96; n=11) was significantly higher than in controls (2.33; IQR, 1.71-2.84; only detected in 7 of 11 controls) (P=.0049, Wilcoxon signed rank). No differences in miRNA-126 levels were observed between patients and controls. In patients (n=11), we observed a positive correlation between miRNA-33 and insulin levels (r=0.7289, P=.0109) and a negative correlation between miRNA-126 and carotid intima-media thickness (r=-0.6181, P=.0426). CONCLUSION: In psoriasis patients plasma levels of lipid and glucose metabolism-related miRNA-33 are increased and correlated with insulin. The study of circulating miRNA-33 in psoriasis may provide new insights about the associated systemic inflammatory abnormalities.

Cardiovascular risk assessment in rheumatoid arthritis: impact of the EULAR recommendations on a national calibrated score risk index.

OBJECTIVES: To evaluate the impact of the application of the EULAR task force recommendations in the cardiovascular (CV) risk assessment of rheumatoid arthritis (RA) patients according to a national calibrated SCORE. METHODS: Two hundred and one consecutive RA patients seen at the rheumatology outpatient clinics of the University Hospital 'San Cecilio', Granada, Southern Spain, were studied. Information on demographic, classic CV risk factors, history of CV events and disease clinical features were obtained. Both the systematic coronary risk evaluation (SCORE) risk index and the modified SCORE (mSCORE) following the EULAR recommendations were performed. RESULTS: Based on the classic CV risk factors the mean ± standard deviation SCORE was 2.2 ± 2.6 (median 2). Twenty-two (11%) patients were above the threshold of high risk for the Spanish population. Following the EULAR recommendations 52 of the 124 patients (41.93%) initially classified as having intermediate risk were reclassified as having high CV risk. Therefore, the mean mSCORE was 3.3 ± 4 (median 3) and, due to this, 74 (36.8%) patients were above the threshold of high CV risk for the Spanish population. As expected, patients who had experienced CV events were older, had more CV risk factors and higher mSCORE than those without CV events. CONCLUSIONS: These observations support the claim that the mSCORE should be specifically adapted to the population to be assessed. However, the use of additional tools should be considered in an attempt to fully identify high-risk RA patients.