Hydroxychloroquine is associated with a lower risk of polyautoimmunity: data from the RELESSER Registry

Objectives. This article estimates the frequency of polyautoimmunity and associated factors in a large retrospective cohort of patients with SLE. Methods. RELESSER (Spanish Society of Rheumatology Lupus Registry) is a nationwide multicentre, hospital-based registry of SLE patients. This is a cross-sectional study. The main variable was polyautoimmunity, which was defined as the co-occurrence of SLE and another autoimmune disease, such as autoimmune thyroiditis, RA, scleroderma, inflammatory myopathy and MCTD. We also recorded the presence of multiple autoimmune syndrome, secondary SS, secondary APS and a family history of autoimmune disease. Multiple logistic regression analysis was performed to investigate possible risk factors for polyautoimmunity. Results. Of the 3679 patients who fulfilled the criteria for SLE, 502 (13.6%) had polyautoimmunity. The most frequent types were autoimmune thyroiditis (7.9%), other systemic autoimmune diseases (6.2%), secondary SS (14.1%) and secondary APS (13.7%). Multiple autoimmune syndrome accounted for 10.2% of all cases of polyautoimmunity. A family history was recorded in 11.8%. According to the multivariate analysis, the factors associated with polyautoimmunity were female sex [odds ratio (95% CI), 1.72 (1.07, 2.72)], RP [1.63 (1.29, 2.05)], interstitial lung disease [3.35 (1.84, 6.01)], Jaccoud arthropathy [1.92 (1.40, 2.63)], anti-Ro/SSA and/or anti-La/SSB autoantibodies [2.03 (1.55, 2.67)], anti-RNP antibodies [1.48 (1.16, 1.90)], MTX [1.67 (1.26, 2.18)] and antimalarial drugs [0.50 (0.38, 0.67)]. Conclusion. Patients with SLE frequently present polyautoimmunity. We observed clinical and analytical characteristics associated with polyautoimmunity. Our finding that antimalarial drugs protected against polyautoimmunity should be verified in future studies

A novel genetic variant in PTGS1 affects N-glycosylation of cyclooxygenase-1 causing a dominant-negative effect on platelet function and bleeding diathesis.

During platelet activation, arachidonic acid (AA) is released from membrane phospholipids and metabolized to thromboxane A2 (TXA2) through the actions of cyclooxygenase-1 (COX-1) and TXA2 synthase. Note, TXA2 binds to the platelet TXA2 receptor, causing shape change, secretion and platelet aggregation.1 Also, COX-1 (599aa; 70 kDa) has cyclooxygenase and peroxidase activities and it is functionally active as a homodimer, with each COX-1 monomer consisting of four highly conserved domains: an N-terminal signal peptide, a dimerization domain, a membrane-binding domain (MBD) and a large C-terminal catalytic domain2 (Figure 1A). Irreversible COX-1 inhibition by aspirin is a widely established anti-platelet therapy in cardiovascular disease.Fundación Mutua Madrileña, Grant/Award Number: AP172142019; Fundación Séneca, Grant/Award Number: 19873/GERM/15; Gerencia Regional de Salud, Grant/Award Numbers: 1647/A/17, 2061A/19; Instituto de Salud Carlos III (ISCIII) & Feder, Grant/Award Numbers: CB15/00055, PI17/01966, PI18/00598, PI20/00926, PI17/01311; Junta de Castilla y León; British Heart Foundation, Grant/Award Number: PG/17/40/33028; Ayuda a Grupos de Trabajo en Patología Hemorrágica; Premio López Borrasca 2019; Sociedad Española de Trombosis y Hemostasia

Relevance of gastrointestinal manifestations in a large Spanish cohort of patients with systemic lupus erythematosus: what do we know?

SLE can affect any part of the gastrointestinal (GI) tract. GI symptoms are reported to occur in >50% of SLE patients. To describe the GI manifestations of SLE in the RELESSER (Registry of SLE Patients of the Spanish Society of Rheumatology) cohort and to determine whether these are associated with a more severe disease, damage accrual and a worse prognosis. METHODS: We conducted a nationwide, retrospective, multicentre, cross-sectional cohort study of 3658 SLE patients who fulfil =4 ACR-97 criteria. Data on demographics, disease characteristics, activity (SLEDAI-2K or BILAG), damage (SLICC/ACR/DI) and therapies were collected. Demographic and clinical characteristics were compared between lupus patients with and without GI damage to establish whether GI damage is associated with a more severe disease. RESULTS: From 3654 lupus patients, 3.7% developed GI damage. Patients in this group (group 1) were older, they had longer disease duration, and were more likely to have vasculitis, renal disease and serositis than patients without GI damage (group 2). Hospitalizations and mortality were significantly higher in group 1. Patients in group 1 had higher modified SDI (SLICC Damage Index). The presence of oral ulcers reduced the risk of developing damage in 33% of patients. CONCLUSION: Having GI damage is associated with a worse prognosis. Patients on a high dose of glucocorticoids are at higher risk of developing GI damage which reinforces the strategy of minimizing glucocorticoids. Oral ulcers appear to decrease the risk of GI damage. © The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology

Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders

Inherited platelet disorders are a heterogeneous group of rare diseases, caused by inherited defects in platelet production and/or function. Their genetic diagnosis would benefit clinical care, prognosis and preventative treatments. Until recently, this diagnosis has usually been performed via Sanger sequencing of a limited number of candidate genes. High-throughput sequencing is revolutionizing the genetic diagnosis of diseases, including bleeding disorders. We have designed a novel high-throughput sequencing platform to investigate the unknown molecular pathology in a cohort of 82 patients with inherited platelet disorders. Thirty-four (41.5%) patients presented with a phenotype strongly indicative of a particular type of platelet disorder. The other patients had clinical bleeding indicative of platelet dysfunction, but with no identifiable features. The high-throughput sequencing test enabled a molecular diagnosis in 70% of these patients. This sensitivity increased to 90% among patients suspected of having a defined platelet disorder. We found 57 different candidate variants in 28 genes, of which 70% had not previously been described. Following consensus guidelines, we qualified 68.4% and 26.3% of the candidate variants as being pathogenic and likely pathogenic, respectively. In addition to establishing definitive diagnoses of well-known inherited platelet disorders, high-throughput sequencing also identified rarer disorders such as sitosterolemia, filamin and actinin deficiencies, and G protein-coupled receptor defects. This included disease-causing variants in DIAPH1 (n=2) and RASGRP2 (n=3). Our study reinforces the feasibility of introducing high-throughput sequencing technology into the mainstream laboratory for the genetic diagnostic practice in inherited platelet disorders.This study was supported by research grants from the Gerencia Regional de Salud (GRS 1370/A/16), ISCIII & Feder (PI14/01956), CIBERER CB15/00055, Fundación Séneca (19873/GERM/15) and Sociedad Española de Trombosis y Hemostasia (SETH). SPW holds a British Heart Foundation chair.Peer Reviewe

Lack of evidence for KRAS oncogenic mutations in triple-negative breast cancer

<p>Abstract</p> <p>Background</p> <p>Mutational analysis of the <it>KRAS </it>gene has recently been established as a complementary <it>in vitro </it>diagnostic tool for the identification of patients with colorectal cancer who will not benefit from anti-epidermal growth factor receptor (EGFR) therapies. Assessment of the mutation status of <it>KRAS </it>might also be of potential relevance in other EGFR-overexpressing tumors, such as those occurring in breast cancer. Although <it>KRAS </it>is mutated in only a minor fraction of breast tumors (5%), about 60% of the basal-like subtype express EGFR and, therefore could be targeted by EGFR inhibitors. We aimed to study the mutation frequency of <it>KRAS </it>in that subtype of breast tumors to provide a molecular basis for the evaluation of anti-EGFR therapies.</p> <p>Methods</p> <p>Total, genomic DNA was obtained from a group of 35 formalin-fixed paraffin-embedded, triple-negative breast tumor samples. Among these, 77.1% (27/35) were defined as basal-like by immunostaining specific for the established surrogate markers cytokeratin (CK) 5/6 and/or EGFR. <it>KRAS </it>mutational status was determined in the purified DNA samples by Real Time (RT)-PCR using primers specific for the detection of wild-type <it>KRAS </it>or the following seven oncogenic somatic mutations: Gly12Ala, Gly12Asp, Gly12Arg, Gly12Cys, Gly12Ser, Gly12Val and Gly13Asp.</p> <p>Results</p> <p>We found no evidence of <it>KRAS </it>oncogenic mutations in all analyzed tumors.</p> <p>Conclusions</p> <p>This study indicates that <it>KRAS </it>mutations are very infrequent in triple-negative breast tumors and that EGFR inhibitors may be of potential benefit in the treatment of basal-like breast tumors, which overexpress EGFR in about 60% of all cases.</p

Impacto de las enfermedades autoinmunes en el manejo y pronóstico del síndrome coronario agudo

ntroducción: Los pacientes con enfermedades autoinmunes (EAI) presentan una carga importante de afectación cardiovascular que conducen tanto a una morbilidad como a una mortalidad prematura. Pero no queda claro si ello se debe a una mayor prevalencia de enfermedad cardiovascular establecida, a una mayor letalidad en la presentación de los casos o bien a un manejo diferente durante el episodio índice. Objetivos: El objetivo primario del estudio fue determinar las implicaciones pronósticas derivadas de la presencia de EAI tanto a nivel intrahospitalario como tras el alta en pacientes ingresados tras síndrome coronario agudo (SCA). Los objetivos secundarios incluyeron el análisis de la prevalencia de EAI en pacientes ingresados tras SCA, su perfil clínico así como el manejo realizado en el ingreso y los tratamientos prescritos al alta. Métodos: El estudio incluyó a pacientes consecutivos ingresados tras SCA en el Hospital Universitario Virgen de la Arrixaca desde Enero de 2011 a Diciembre de 2015. Se compararon las características basales socio-demográficas entre pacientes con y sin EAI así como la presentación clínica y el manejo realizado. Se analizó la aparición de eventos cardiovasculares adversos tanto durante la hospitalización como durante el seguimiento tras el alta hospitalaria que incluyó la muerte total, el infarto no fatal, el ictus y la aparición de hemorragias mayores. Mediante un modelo de regresión multivariante de Cox se estableció el papel de la presencia de EAI en el riesgo de aparición de los eventos de interés. Resultados: De los 2236 pacientes incluidos con SCA, 78 tenían EAI (3.3%): 24 Artritis Reumatoide, 10 Enfermedad Inflamatoria Intestinal, 7 Espondilitis Anquilosante, 6 Artropatía Psoriásica, 5 Polimialgia Reumática, 2 Lupus Eritematoso Sistémico y 20 miscelánea. La edad media de los pacientes con EAI fue de 67 ± 13 años y la mediana de evolución de la enfermedad fue de 10 [4-14] años. El 70% de los pacientes con EAI estaban tomando corticoides, el 50% fármacos modificadores de la enfermedad, el 22% antiinflamatorios no esteroideos y el 8% terapia biológica. No se encontraron diferencias en las características clínicas o demográficas excepto por una mayor prevalencia de fibrilación auricular y enfermedad pulmonar obstructiva crónica en pacientes con EAI. Tampoco encontramos diferencias relevantes tanto en la presentación clínica del SCA como del manejo realizado del mismo en cuanto a estrategias de revascularización o tratamientos al alta. Respecto al pronóstico intrahospitalario la tasa de eventos adversos combinados fue similar en ambos grupos (10% vs 10%, p=0,920), sin haber tampoco diferencias en cada evento por separado. Sin embargo tras un seguimiento de 397 [375-559] días, los pacientes con EAI tuvieron de forma global una mayor tasa de eventos (44% vs 28% p<0,001). Tras el ajuste multivariable, la presencia de EAI se asoció de forma independiente a una mayor mortalidad total (Hazard Ratio 2,1, IC95% 1,2 a 3,7, p=0,008) y en el límite de la significación como factor de riesgo independiente de hemorragias mayores (Hazard Ratio 2,2, IC95% 0,9 a 5,5). La presencia de EAI no se asoció a un incremento de riesgo de infarto no fatal e ictus en el seguimiento. Conclusiones: La presencia de EAI no cambia la forma de presentación del SCA ni el manejo realizado del mismo. Aunque la EAI no incrementa el riesgo de complicaciones intrahospitalarias, si que constituye un factor de riesgo independiente que duplica la mortalidad tras el alta y en el límite de la significación en cuanto a la aparición de hemorragias mayores. Background: Patients with autoimmune diseases (AID) have a high burden of cardiovascular disease leading to premature morbidity and mortality. But it is unclear if it is due to a higher prevalence of cardiovascular disease, to a worse case fatality or to a different management after an index event. Objectives: The primary aim of the study is to assess the prognostic implications of the presence of AID both during the hospitalization and after discharge after an acute coronary syndrome (ACS). The secondary objectives included the assessment of the prevalence of AID in patients with ACS, their clinical profile and the management of this index event. Methods: The study included consecutive patients admitted after ACS from January 2011 to December 2015 at the University Hospital Virgen de la Arrixaca, Murcia (Spain). For AID patients, in-hospital management and ACS presentation was compared to non-AID patients. We also compared in-hospital and major adverse events during follow-up (death, recurrent non-fatal myocardial infarction, stroke and major bleeding, between groups). A multivariate Cox regression model was performed to assess the independent role of the presence of AID in the occurrence of the events of interest. Results: Of 2236 patients included with ACS, 78 had AID (3.3%): 24 Rheumatoid arthritis, 10 Inflammatory Bowel Disease, 7 Ankylosing Spondylitis, 6 Psoriatic Arthritis, 5 Polymyalgia Rheumatica, 2 Systemic Lupus Erythematosus and 20 miscellanea. Mean age of AID patients was 67 ± 13 years and median evolution of the disease was 10 [4-14] years. Seventy percent of AID patients were taking corticosteroids, 50% disease modifying antirheumatic drugs, 22% non-steroidal anti-inflammatory drugs and 8% biological therapy. No significant differences were found in clinical and demographics characteristics between groups except for a higher percentage of atrial fibrillation and chronic obstructive pulmonary disease in AID patients. Compared to non-AID patients, AID patients had similar clinical ACS presentation and no differences were found with respect to revascularization strategies or medical treatment at discharge. With respect to prognosis the two groups had comparable rates of adverse events during hospitalization (10% vs 10%, p=0.920) with no statistically significant differences in any single event studied. However after a follow-up of 397 [375-559] days, AID patients had higher rate of combined adverse events (44% vs 28% p<0,001). After multivariate adjustment the presence of AID was associated with increased total mortality (Hazard Ratio 2.1, 95% CI 1.2 to 3.7, p=0.008) and it was also a borderline risk factor for higher major bleeding complications (Hazard Ratio 2.2, 95% CI 0.9 to 5.5). The presence of AID was not an independent risk factor for neither stroke or recurrent non-fatal myocardial infarction. Conclusions: The presence of AID did not change ACS presentation and clinical management. Although AID is not associated with worse outcomes during hospitalization it is independently linked to higher total mortality and a trend to an increased risk of major bleeding during follow-up

A microRNA Signature Associated with Early Recurrence in Breast Cancer

<div><p>Recurrent breast cancer occurring after the initial treatment is associated with poor outcome. A bimodal relapse pattern after surgery for primary tumor has been described with peaks of early and late recurrence occurring at about 2 and 5 years, respectively. Although several clinical and pathological features have been used to discriminate between low- and high-risk patients, the identification of molecular biomarkers with prognostic value remains an unmet need in the current management of breast cancer. Using microarray-based technology, we have performed a microRNA expression analysis in 71 primary breast tumors from patients that either remained disease-free at 5 years post-surgery (group A) or developed early (group B) or late (group C) recurrence. Unsupervised hierarchical clustering of microRNA expression data segregated tumors in two groups, mainly corresponding to patients with early recurrence and those with no recurrence. Microarray data analysis and RT-qPCR validation led to the identification of a set of 5 microRNAs (the 5-miRNA signature) differentially expressed between these two groups: miR-149, miR-10a, miR-20b, miR-30a-3p and miR-342-5p. All five microRNAs were down-regulated in tumors from patients with early recurrence. We show here that the 5-miRNA signature defines a high-risk group of patients with shorter relapse-free survival and has predictive value to discriminate non-relapsing versus early-relapsing patients (AUC = 0.993, p-value<0.05). Network analysis based on miRNA-target interactions curated by public databases suggests that down-regulation of the 5-miRNA signature in the subset of early-relapsing tumors would result in an overall increased proliferative and angiogenic capacity. In summary, we have identified a set of recurrence-related microRNAs with potential prognostic value to identify patients who will likely develop metastasis early after primary breast surgery.</p></div

Wiskott–Aldrich syndrome in a child presenting with macrothrombocytopenia

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease resulting from variants in the WAS gene, characterized by a triad of immunodeficiency, eczema, and thrombocytopenia. Despite the fact that WAS is traditionally differentiated from immune thrombocytopenia (ITP) by small size of WAS platelets, in practice, microthrombocytopenia may occasionally not be present, and in certain cases, WAS patients exhibit some parallelism to ITP patients. We characterized one patient presenting with the classic form of the disease but increased mean platelet volume. Molecular studies revealed a novel hemizygous 1-bp deletion in WAS gene, c.802delC, leading to a frameshift and stop codon at amino acid 308 (p.Arg268Glyfs*40). Next-generation sequencing of a total of 70 additional genes known to harbor variants implicated in inherited platelet disorders did not identify additional defects. The pathogenesis of macrothrombocytopenia in this case is not known, but probably the coexistence of a still unidentified additional genetic variant might be involved