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Disruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C-terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full-length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.

ObjectiveInfections are a common complication of SLE. Our objective was to evaluate their causes and impact on the survival of patients with SLE.MethodsAnalysis of the admissions and death causes in patients diagnosed with SLE from the Spanish Hospital Discharge Database and the infection-related deaths of the Spanish population from the National Statistical Institute, between 2016 and 2018.Only infections recorded as the main diagnosis were analysed (severe or clinically relevant infection).ResultsAmong 18 430 admissions in patients with SLE, disease activity was the cause of admission in 19% of all patients and infection in 15%. However, infection was the main cause of death (25%) while SLE activity was responsible for only 6% of deaths (pConclusionOur nationwide study confirms that infections are the leading cause of death in SLE in Spain, with the highest proportion occurring in young patients with lupus compared with the general population of the same age range.

Background: the admission and death causes of SLE patients might have changed over the last years. Methods: Analysis of the Spanish National Hospital Discharge database. All individuals admitted with SLE, according to ICD-9, were selected. The following five admission categories were considered: SLE, cardiovascular disease (CVD), neoplasm, infection, and venous-thromboembolic disease (VTED), along four periods of time (1997–2000, 2001–2005, 2006–2010, and 2011–2015). Results: The admissions (99,859) from 43.432 patients with SLE were included. The absolute number of admissions increased from 15,807 in 1997–2000 to 31,977 in 2011–2015. SLE decreased as a cause of admission (from 47.1% to 20.8%, p < 0.001), while other categories increased over the time, as follows: 5% to 8.6% for CVD, 8.2% to 13% for infection, and 1.4% to 5.5% for neoplasm (p < 0.001 for all). The admission mortality rate rose from 2.22% to 3.06% (p < 0.001) and the causes of death evolved in parallel with the admission categories. A significant trend to older age was observed over time in the overall population and deceased patients (p < 0.001). Conclusions: Better control of SLE over the past two decades has led to a decrease in early admissions, and disease chronification. As a counterpart, CVD, infections, and neoplasm have become the main causes of admissions and mortality.

espanolIntroduccion La arteritis de la temporal es un proceso infrecuente en paciente jovenes. Se presenta el caso de una paciente de 39 anos con arteritis de la temporal con revision de casos descritos hasta el momento. Presentacion del caso Mujer de 39 anos sin antecedentes de interes que consulta por un nodulo subcutaneo temporal derecho, sin otros sintomas ni hallazgos a la exploracion. En las pruebas realizadas destacaba la presencia de signo del halo ecografico alrededor de la arteria temporal en la localizacion del nodulo. Se realizo escision con curacion de la paciente y la histopatologia mostro hallazgos de arteritis temporal juvenil. Conclusiones La arteritis temporal en pacientes jovenes es una entidad infrecuente, ante la cual siempre hay que descartar manifestaciones sistemicas mediante una anamnesis, exploracion fisica reglada y pruebas complementarias. La anatomia patologica establecera el diagnostico definitivo. El tratamiento suele ser quirurgico. Tras dicho tratamiento, se debera seguir a la paciente por el posible desarrollo posterior de otras enfermedades. EnglishIntroduction Temporal arteritis is an uncommon disorder in young people. A 39-year-old woman with juvenile temporal arteritis is described and we performed a literature review of all cases of juvenile temporal arteritis described to date. Case presentation A 39-year-old woman presented with a subcutaneous temporal nodule in the right temple with no other associated symptoms or background and unremarkable physical examination. Ultrasonography of the nodule revealed an anechoic perivascular halo surrounding the temporal artery. The nodule was excised resulting in the patient's recovery. The results of the histopathological study showed features of juvenile temporal arteritis. Conclusions Juvenile temporal arteritis is a very uncommon disorder. Systemic manifestations should be ruled out by physical examination and complementary tests. Histopathology establishes the definitive diagnosis. Treatment is surgical excision and a follow-up should be conducted to rule out complications.

Introduction Temporal arteritis is an uncommon disorder in young people. A 39-year-old woman with juvenile temporal arteritis is described and we performed a literature review of all cases of juvenile temporal arteritis described to date. Case presentation A 39-year-old woman presented with a subcutaneous temporal nodule in the right temple with no other associated symptoms or background and unremarkable physical examination. Ultrasonography of the nodule revealed an anechoic perivascular halo surrounding the temporal artery. The nodule was excised resulting in the patient’s recovery. The results of the histopathological study showed features of juvenile temporal arteritis. Conclusions Juvenile temporal arteritis is a very uncommon disorder. Systemic manifestations should be ruled out by physical examination and complementary tests. Histopathology establishes the definitive diagnosis. Treatment is surgical excision and a follow-up should be conducted to rule out complications.

To determine the burden and impact of cardiovascular risk factors (CRF) in antiphospholipid syndrome (APS) patients.Analysis of the patients diagnosed with APS identified in the Spanish Hospital Discharge Database between 2016 and 2017. We analysed the admissions due to arterial (ATE) and venous thromboembolic events (VTE) and evaluated the incidence and the attributed risk of each CRF.5424 admissions in patients diagnosed with APS were identified. 64.6% were women and the mean age was 54.6. The mortality rate was 3.1%. Overall, 35.8% of patients had hypertension, 14% were diabetic, 21.7% hypercholesterolaemic, 9.9% obese and 26.7% smokers. Thromboembolic events (67.9% arterial and 32.1% venous) accounted for 11.9% of admissions and 7.1% of deaths. Male sex (OR 1.83, 95% CI 1.41-2.21), cholesterol (OR 1.25, 95% CI 1.01-1.54) and smoking (OR 1.49, 95% CI 1.22-1.81) were independently associated with thromboembolic events. Meanwhile, patients with ATE were older (57 vs. 54.1 years p=0.033), and presented more secondary APS (17.1% vs. 10.6%, p=0.034), hypertension (47.7% vs. 33.5%, p=0.001), diabetes (16.9% vs. 9.6%, p=0.017), cholesterol (34.3% vs. 17.8%, p0.001) and smoking habit (41.2% vs. 24%, p0.001) when compared with VTE. Risk factors independently associated with ATE events were male sex (OR=1.61, 95% CI=1.30-2.03), hypertension (OR=1.30, 95% CI=1.03-1.64), cholesterol (OR=1.51, 95% CI=1.18-1.94) and smoking habit (OR=1.84, 95% CI=1.47-2.32), while VTE events were determined by male sex (OR=2.06, 95% CI=1.53-2.77) and obesity (OR=1.61, CI=1.02-2.52).Thromboembolic events in APS were in part determined by a high prevalence of CRF. The identification of distinct profiles may allow us to undertake a more personalised approach to reduce thromboembolic events and to individualise anticoagulant and antiplatelet therapy.

Low serum levels of 25-hydroxyvitamin D (25(OH)D) have been associated with a higher frequency of risk factors and cardiovascular disease. The aim of this study is to evaluate the association of 25(OH)D, cardiovascular risk factors, and subclinical atherosclerosis in systemic lupus erythematosus (SLE) patients. Forty-seven female SLE patients were studied. Data collected included demographics, SLE activity, disease damage, cardiovascular risk factors, and markers of subclinical atherosclerosis. Patient treatments and vitamin D and calcium supplementation (VitD-Ca) were recorded. Vitamin D deficiency was defined as serum 25(OH)D

Cystatin C (CysC) is a protein considered as an excellent marker of renal function, and it has been suggested as an independent predictor of cardiovascular (CV) risk. We evaluated the association of serum CysC with renal function, CV risk factors, inflammation, and subclinical atherosclerosis in Systemic Lupus Erythematosus (SLE) patients. Sixty-one SLE female patients were selected according to estimated glomerular filtration rate (GFR) > 60 ml/min/1.73m2. Renal function parameters, SLE specific factors, CV risk factors, and inflammatory markers were assessed. Subclinical atherosclerosis was assessed by measuring the carotid-femoral pulse wave velocity (PWV) by Doppler velocimetry. Serum CysC concentration was measured using a particle-enhanced immunonephelometric assay that established 0.59–1.01 mg/l as reference values. Patients with high CysC showed significantly altered creatinine, microalbuminuria, and GFR in addition to a significant higher presence of traditional CV risk factors such as arterial hypertension (p

Objectives Statins have been proposed as a potential treatment for systemic lupus erythematosus (SLE) due to their immunomodulatory properties, their role restoring endothelial function and preventing atherosclerosis. We evaluate the effect of a short period treatment with a low dose of atorvastatin and its withdrawal on early stage subclinical atherosclerosis. Methods Thirty-seven SLE females received 20 mg/day atorvastatin during eight weeks. At baseline, at the end of treatment and six months after atorvastatin withdrawal, disease activity, subclinical atherosclerosis –assessed by measuring carotid-femoral pulse wave velocity (PWV) – and quantification of circulating endothelial progenitor cells (EPC) – as a surrogate biological marker of subclinical atherosclerosis – were carried out. Results The group of SLE patients with baseline pathological arterial stiffness showed a significant decrease of PWV after atorvastatin therapy (8.43 ± 1.45 m/s vs 7.42 ± 1.06 m/s; p = 0.002) that is maintained six months after treatment finished. Only patients of the middle-aged group showed a nearly significant decrease in the PWV measured along the study (7.16 ± 1.23 m/s vs 6.76 ± 0.82 m/s; p = 0.05). Atorvastatin induced a significant decrease in the circulating EPC percentage (0.65 ± 0.67 vs 0.40 ± 0.31; p = 0.023) as well as a downward trend of disease activity that it is observed by a decrease in SLE disease activity index simultaneously with an increase in C3 complement and significant decrease in serum concentration of vascular endothelial grow factor (VEGF) and sVCAM-1. Conclusions Short-term atorvastatin therapy reduces arterial stiffness of SLE patients with baseline pathological PWV, who are mainly in the group of middle-aged patients. Further studies are needed to determine whether these patients would benefit from statin therapy in preventing cardiovascular events.

Objectives Metabolic syndrome (MetS) is highly prevalent in patients with systemic lupus erythematosus (SLE) and it has been associated with increased cardiovascular risk. We examined the contribution of MetS to inflammatory markers, arterial stiffness and circulating endothelial progenitor cells (EPCs) as surrogates of subclinical atherosclerosis. Methods Cardiovascular risk factors, SLE-specific factors and peripheral blood EPCs were assessed in 50 female SLE patients. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III. Simultaneously, atherosclerosis was assessed by measuring the carotid–femoral pulse wave velocity (PWV) by doppler velocimetry. Results Beyond the factors included in the definition, SLE patients with MetS have a significantly higher serum level of uric acid (6.88 ± 2.20 vs 4.45 ± 1.17, p Conclusions MetS may contribute to the development of atherosclerosis by significantly increasing inflammation levels and arterial stiffness and decreasing circulating EPCs. This finding would justify close monitoring of these patients.

Endothelial progenitor cells (EPCs) play an important role in vascular damage repair and it has been suggested that a decreased number of these cells is associated with increased subclinical atherosclerosis. Our study aim was to evaluate whether the number of circulating EPCs in patients with SLE is associated with subclinical atherosclerosis, the presence of cardiovascular (CV) risk factors and SLE-specific factors.Forty-six female SLE patients were included. At the time of each patient's appointment, CV risk factors, SLE-specific factors and EPCs were assessed in peripheral blood by flow cytometry. Simultaneously, atherosclerosis was assessed by measuring the carotid-femoral pulse wave velocity (PWV) by Doppler velocimetry, intima media thickness (IMT) and carotid plaque by B-mode US scanning.Patients were classificated according to PWV following the reference values adjusted by age and blood pressure published by the European Society of Cardiology. Patients with pathological values of PWV showed a significant decrease of circulating EPC percentage compared with normal PWV patients. Decreased EPC counts were also associated with certain risk factors, including hypertension, tobacco use, impaired glucose metabolism, and metabolic syndrome, and correlate with high levels of high-sensitivity CRP (hsCRP) or fibrinogen. The presence of carotid plaque and IMT measurement were unrelated with EPC quantification.Patients with a reduced percentage of EPCs showed pathological arterial stiffness and association with certain CV risk factors, suggesting that the measurement of circulating EPCs can be used as a biological marker to determine subclinical atherosclerosis in SLE.

The purpose of this study was to examine the expression of human leukocyte antigen-G (HLA-G) in patients with systemic lupus erythematosus (SLE) and its relation with interleukin-10 (IL-10) production. The study included 50 female SLE patients and 59 healthy female donors. HLA-G expression in peripheral blood and cutaneous biopsies was determined by flow cytometry and immunohistochemistry, respectively. Soluble HLA-G (sHLA-G) and IL-10 were quantified in serum samples by enzyme-linked immunosorbent assay. SLE patients presented with serum sHLA-G and IL-10 levels significantly higher than that observed in controls (median [interquartile range (IQR)] = 43.6 U/ml [23.2-150.2] vs 26.84 U/ml [6.0-45.2], p = 0.004; and 1.4 pg/ml [0-2.3] vs 0 pg/ml [0-1.5], p = 0.01, respectively). But no correlation was observed between sHLA-G and both IL-10 levels and the disease activity index for SLE patients. The expression of membrane HLA-G in peripheral lymphocytes from SLE patients was low, but higher than in controls (median [IQR] = 1.5% [0.6-1.8] and 0.3% [0.2-0.8], respectively; p = 0.02). Finally, these findings were in accordance with the weak expression of HLA-G in skin biopsies. Despite the fact that patients present higher levels of HLA-G than healthy controls, which suggests a possible relevance of this molecule in SLE, it seems not to be related to IL-10 production or disease activity.

Objective The development of common variable immunodeficiency (CVID) or hypogammaglobulinemia in systemic lupus erythematosus (SLE) is rare. The purpose of this article is to provide a detailed review of lupus-associated CVID and to identify clinical characteristics and laboratory features in patients with SLE-associated CVID. Methods We describe 2 patients with SLE and CVID and review the cases published in the English literature highlighting both the demographic and the clinical characteristics and the laboratory and therapeutic aspects of this disorder. Results Detailed descriptions of 18 patients were available; 89% were females with a mean age at the onset of SLE of 23.8 years. In 50% of patients CVID developed within the first 5 years after the diagnosis of SLE. All patients had been treated with corticosteroids and 72% had also received immunosuppressive therapy. Sinopulmonary infections were the most frequent symptom. SLE disease activity decreased after the development of CVID in 67% of patients. Most patients (89%) were treated with gammaglobulin therapy. The most notable immunological feature was a reduced number or percentage of B-cells in 60% of patients. Conclusions CVID should be suspected in any SLE patient with recurrent sinopulmonary infections in the absence of SLE activity and/or immunosuppressive treatment.

Genetic variants of endosomal toll like receptors (TLR) have been associated with many infectious, autoimmune and inflammatory diseases, but few studies have been reported in the Spanish population. The aim of this study was to describe the allelic and genotypic distributions of some common nucleotide substitutions of endosomal TLRs in healthy Spanish women and to compare them with those already published in other population groups. Nine substitutions were analysed in 150 DNA samples from 150 Spanish, non-related healthy females: TLR3 rs3775291 and rs5743305; TLR7 rs179008 and rs5743781; TLR8 rs3764880 and TLR9 rs187084, rs5743836, rs352139 and rs352140. Genotyping was carried out by real time PCR and melting curve analysis in a LightCycler 480. A systematic review was performed in order to compare the genotypic distributions in our cohort with those previously published in other population groups. The comparative study was performed with the two tailed Fisher's test or the Yates continuity correction for the Chi-square test when appropriate. No homozygotes for rs5743781 in TLR7 were found, and rs352139 and rs352140 of TLR9 were in strong linkage disequilibrium. Genotype distributions in endosomal TLR are similar to other Spanish series previously reported. As expected, most differences were found when comparing our distributions with Asiatics, but differences were also found with other Caucasian populations. Since there are significant variations in genotypic distributions of TLRs in both interracial groups and within the same ethnic group, to carry out studies of disease susceptibility in more restricted groups is mandatory.

Cryofibrinogenemia is a rare clinical finding with a yet unknown physiopathogenic mechanism. We describe the case of a woman with cold-induced extensive necrotic lesions that responded poorly to initial corticosteroid and anticoagulant therapies. Serum cryoglobulin determinations were persistently negative. After several years of evolution, she developed severe cold-related skin lesions that required left-leg amputation. Further analysis disclosed the presence of cryofibrinogen and an apparently insignificant serum monoclonal immunoglobulin Gκ peak. We additionally demonstrate that the cold precipitation of fibrinogen was directly related to the monoclonal paraprotein presence. The lesions responded dramatically to a B cell-targeted therapy with intravenous cyclophosphamide and dexamethasone.

Objective To investigate the contribution of T lymphocytes and monocytes to cytokine production in systemic lupus erythematosus (SLE). Methods Forty-five SLE patients and 19 healthy volunteers were included. Serum levels of tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), interleukin (IL)-6, and IL10 were quantified by ELISA. The cytokine production capacities of peripheral blood mononuclear cells were assessed by culturing in vitro with PMA+Ionomycin or LPS. The intracellular cytokine expression was measured by flow cytometry in T lymphocytes and monocytes, respectively. The influence of the disease activity (measured as the SLE-disease activity index; SLEDAI) and the treatment the patients were receiving was evaluated. Results Serum IL10, IL6, and TNFα levels were increased in patients (P ≤ 0.01), and a higher spontaneous (without stimuli) intracellular expression of IL10 in CD4+ and CD8+ T lymphocytes (P < 0.05) and of IL6 in monocytes (P = 0.01) were found. After stimulation, patients presented a higher percentage of CD4+ and CD8+ T lymphocytes producing IL4 and IL10 (P ≤ 0.01), and of monocytes producing IL6 (P = 0.04) and IL10 (P = 0.008). The SLEDAI score was positively correlated with the percentage of CD4+IL10+ and CD8+IL10+ T lymphocytes (P < 0.01), and inversely correlated with CD8+TNFα+ (P= 0.02), CD4+IFNγ+ (P = 0.04) and CD8+ IFNγ+ (P = 0.002) T lymphocytes. Patients receiving high dose prednisone produced higher IL10, but they also were the patients with a more active disease. Conclusion Monocytes and T lymphocytes (CD4+ and CD8+) contribute to an overproduction of IL6 and IL10 in SLE; this correlates with the disease activity but is independent of the treatment the patients are receiving. © 2009 Clinical Cytometry Society

Background: Not all the patients with sarcoidosis need pharmacological therapy, and the decision to start therapy is based mainly on clinical conditions. The aim of this study was to evaluate the prognostic value of the leukocyte and lymphocyte subpopulations in the bronchoalveolar lavage fluid from these patients. Methods: Thirty-three nonsmoking patients with sarcoidosis were included and classified based on the presence of Lofgren's syndrome (n = 11), the radiological stage (12 at Stage I, 17 at Stage II, and 4 at Stage III), and their follow-up. Differential leukocyte subsets and the lymphocyte subpopulations were determined by flow cytometry. Results: The percentage of neutrophils was lower in patients with Lofgren's syndrome (P = 0.038) and in patients at Stage I (P = 0.002). Patients with a poor outcome had a higher percentage of neutrophils (P = 0.004) and NK cells (P = 0.023) than those with a stable disease. Finally, a higher percentage of NK cells was found in those patients who needed a steroid treatment (P = 0.012). Conclusions: Increased percentages of neutrophils and NK cells in the bronchoalveolar lavage fluid from patients with sarcoidosis are associated with a poor outcome and a higher probability to need steroids treatment. The percentage of neutrophils was also lower in patients with Lofgren's syndrome. © 2006 International Society for Analytical Cytology

Current evidence indicates that regulatory T cells (Tregs) actively suppress autoreactive lymphocytes that escape central tolerance.1,2 Tregs are characterised by a high intensity CD25 constitutive expression3 on the surface of CD4 T lymphocytes, which distinguishes them from the non-regulatory CD4+CD25+ T lymphocytes.4 Because of their important role in the maintenance of tolerance, it has been suggested that Tregs are decreased in patients with systemic lupus erythematosus (SLE).5 We have quantified Tregs in patients with SLE and controls and evaluated their association with disease activity and treatment. Thirty three patients with SLE (26 women, 7 men) and 14 healthy volunteers matched for age and sex (11 women, 3 men) with a mean age of 39.9 and 36 years, respectively, were studied. All patients fulfilled at least four of the American College of Rheumatology 1982 revised criteria for the classification of SLE.6 Disease activity at the time of blood sampling was assessed using the SLE Disease Activity Index (SLEDAI).7 …

Transverse myelitis (TM) is a rare complication of systemic lupus erythematosus (SLE). Although usually a late manifestation of SLE, it can occur at presentation. We investigated the clinical presentation, treatment and outcome of 15 patients with TM as the presenting manifestation of SLE or lupus-like disease.All patients received corticosteroids, while 13 also received immunosuppressive therapy. Five patients were fully anticoagulated with warfarin.A sensory level with spastic lower limb weakness and sphincter disturbance was the most common presentation: 14/15 patients had a thoracic or cervical sensory level. Cerebrospinal fluid examination showed high protein concentrations in 3 patients and oligoclonal bands in 8. Eleven of the 15 (73%) had antiphospholipid antibodies (aPL). Of the 15 patients, 3 had complete resolution of the symptoms, 6 had good functional improvements, 5 had good to fair outcome with some functional deficit, and one patient who received corticosteroids alone later died from pneumonia.We describe 15 patients with TM as the presenting manifestation of SLE or lupus-like disease with a high prevalence of aPL. Our data support the view that early diagnosis and immunosuppressive therapy may be superior to corticosteroids alone in improving functional outcome. In those patients with aPL, antiplatelet agents and/or warfarin should also be considered.

e19520 Background: Many patients with Hodgkin´s Lymphoma (HL) are cured but they have an increased risk of developing second neoplasms (SN). We analyzed and compared their long-term risk of develop...

Background. Prospective study based on measuring the left ventricular ejection function (LVEF) of lymphoma patients treated with rapid infusion Rituximab (one hour). Patients and Methods. 42 patients with non-Hodgkin lymphoma were treated with rapid infusion Rituximab-based chemotherapy (mostly CHOP-R). Basal LVEF was measured before chemotherapy and every six months after treatment. Results. An average of 6.5 infusions per patient were administered (total of 273 infusions). Twenty-four (57%) patients had at least one cardiovascular risk factor. In 13 patients (31%) we observed a decreased in the post-treatment LVEF of over 10%. Patients (3) with drop > 10% recovered normally, but when LVEF decreased by over 15% (6 patients), no one recovered until normal level. None of them developed clinical congestive failure. Conclusion. Rapid infusion Rituximab added to chemotherapy does not cause clinical cardiac toxicity. Patients recover LVEF when it decreased less than 15%.