Experts document on methotrexate use in combined therapy with biological or targeted synthetic disease modifying drugs in patients with rheumatoid arthritis.

OBJECTIVE: We aimed to develop recommendations for the management of methotrexate (MTX) when considering the combination with biological (b) or targeted synthetic (ts) disease modifying drugs (DMARDs) in rheumatoid arthritis (RA). METHODS: Eleven experts on RA were selected. Two coordinators formulated 13 questions about the combination therapy of MTX with bDMARDs or tsDMARDs. A systematic review was conducted to answer the questions. Inclusion and exclusion criteria were established as well as the search strategies (Medline, Embase and the Cochrane Library were searched up to January 2019). Two reviewers selected the articles and collected data. Simultaneously, EULAR and ACR meeting abstracts were evaluated. Based on this evidence, the coordinators proposed preliminary recommendations that the experts discussed and voted in a nominal group meeting. The level of evidence and grade of recommendation was established using the Oxford Center for Evidence Based Medicine and the level of agreement with a Delphi. Agreement was established if at least 80% of the experts voted 'yes' (yes/no). RESULTS: The systematic review retrieved 513 citations of which 61 were finally included. A total of 10 recommendations were generated, voted and accepted. The level of agreement was very high in all of them and it was achieved in the first Delphi round. Final recommendations cover aspects such as the optimal MTX dosage, tapering strategy or patients' risk management. CONCLUSIONS: This document is intended to help clinicians solve usual clinical questions and facilitate decision making when treating RA patients with MTX in combination with bDMARDs or tsDMARDs.

Experts document on methotrexate use in combined therapy with biological or targeted synthetic disease modifying drugs in patients with rheumatoid arthritis / Documento de expertos sobre el uso de terapia combinada de metotrexato con terapias biológicas o terapias dirigidas a pacientes con artritis reumatoide

Objective: We aimed to develop recommendations for the management of methotrexate (MTX) when considering the combination with biological (b) or targeted synthetic (ts) disease modifying drugs (DMARDs) in rheumatoid arthritis (RA). Methods: Eleven experts on RA were selected. Two coordinators formulated 13 questions about the combination therapy of MTX with bDMARDs or tsDMARDs. A systematic review was conducted to answer the questions. Inclusion and exclusion criteria were established as well as the search strategies (Medline, Embase and the Cochrane Library were searched up to January 2019). Two reviewers selected the articles and collected data. Simultaneously, EULAR and ACR meeting abstracts were evaluated. Based on this evidence, the coordinators proposed preliminary recommendations that the experts discussed and voted in a nominal group meeting. The level of evidence and grade of recommendation was established using the Oxford Center for Evidence Based Medicine and the level of agreement with a Delphi. Agreement was established if at least 80% of the experts voted ‘yes’ (yes/no). Results: The systematic review retrieved 513 citations of which 61 were finally included. A total of 10 recommendations were generated, voted and accepted. The level of agreement was very high in all of them and it was achieved in the first Delphi round. Final recommendations cover aspects such as the optimal MTX dosage, tapering strategy or patients’ risk management. Conclusions: This document is intended to help clinicians solve usual clinical questions and facilitate decision making when treating RA patients with MTX in combination with bDMARDs or tsDMARDs.(AU)

Objetivo: Desarrollar recomendaciones sobre el uso de metotrexato (MTX) en combinación con medicamentos modificadores de la enfermedad (DMARD) biológicos (b) o sintéticos específicos (ts) en la artritis reumatoide (AR). Métodos: Se seleccionaron 11 expertos en AR. Dos coordinadores formularon 13 preguntas sobre la terapia combinada de MTX con bDMARD o tsDMARD. Se realizó una revisión sistemática para responder las preguntas. Se establecieron criterios de inclusión y exclusión, así como las estrategias de búsqueda (se realizaron búsquedas en Medline, Embase y la Biblioteca Cochrane hasta enero de 2019). Dos revisores seleccionaron los artículos y recopilaron datos. Simultáneamente, se evaluaron los resúmenes de las reuniones EULAR y ACR. Con base en esta evidencia, los coordinadores propusieron recomendaciones preliminares que los expertos discutieron y votaron en una reunión de grupo nominal. El nivel de evidencia y el grado de recomendación se establecieron utilizando el Centro de Oxford para Medicina Basada en Evidencia y el nivel de acuerdo con un Delphi. El acuerdo se estableció si al menos el 80% de los expertos votaron «sí» (sí/no). Resultados: La revisión sistemática recuperó 513 citas, de las cuales finalmente se incluyeron 61. Se generaron, votaron y aceptaron un total de 10 recomendaciones. El nivel de acuerdo fue muy alto en todas ellas y se logró en la primera ronda de Delphi. Las recomendaciones finales cubren aspectos como la dosis óptima de MTX, la estrategia de reducción o la gestión del riesgo de los pacientes. Conclusiones: Este documento está destinado a ayudar a los médicos a resolver preguntas clínicas habituales y facilitar la toma de decisiones al tratar a pacientes con AR con MTX, en combinación con bDMARD o tsDMARD.(AU)

Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts.

We aimed to validate the association of 28 GWAS-identified genetic variants for response to TNF inhibitors (TNFi) in a discovery cohort of 1361 rheumatoid arthritis (RA) patients monitored in routine care and ascertained through the REPAIR consortium and DANBIO registry. We genotyped selected markers and evaluated their association with response to TNFi after 6 months of treatment according to the change in disease activity score 28 (ΔDAS28). Next, we confirmed the most interesting results through meta-analysis of our data with those from the DREAM cohort that included 706 RA patients treated with TNFi. The meta-analysis of the discovery cohort and DREAM registry including 2067 RA patients revealed an overall association of the LINC02549rs7767069 SNP with a lower improvement in DAS28 that remained significant after correction for multiple testing (per-allele ORMeta=0.83, PMeta=0.000077; PHet=0.61). In addition, we found that each copy of the LRRC55rs717117G allele was significantly associated with lower improvement in DAS28 in rheumatoid factor (RF)-positive patients (per-allele ORMeta=0.67, P=0.00058; PHet=0.06) whereas an opposite but not significant effect was detected in RF-negative subjects (per-allele ORMeta=1.38, P=0.10; PHet=0.45; PInteraction=0.00028). Interestingly, although the identified associations did not survive multiple testing correction, the meta-analysis also showed overall and RF-specific associations for the MAFBrs6071980 and CNTN5rs1813443 SNPs with decreased changes in DAS28 (per-allele ORMeta_rs6071980 = 0.85, P=0.0059; PHet=0.63 and ORMeta_rs1813443_RF+=0.81, P=0.0059; PHet=0.69 and ORMeta_rs1813443_RF-=1.00, P=0.99; PHet=0.12; PInteraction=0.032). Mechanistically, we found that subjects carrying the LINC02549rs7767069T allele had significantly increased numbers of CD45RO+CD45RA+ T cells (P=0.000025) whereas carriers of the LINC02549rs7767069T/T genotype showed significantly increased levels of soluble scavengers CD5 and CD6 in serum (P=0.00037 and P=0.00041). In addition, carriers of the LRRC55rs717117G allele showed decreased production of IL6 after stimulation of PBMCs with B burgdorferi and E coli bacteria (P=0.00046 and P=0.00044), which suggested a reduced IL6-mediated anti-inflammatory effect of this marker to worsen the response to TNFi. In conclusion, this study confirmed the influence of the LINC02549 and LRRC55 loci to determine the response to TNFi in RA patients and suggested a weak effect of the MAFB and CNTN5 loci that need to be further investigated.

Detección de barreras e implementación de procedimientos para reducir la demora en el tratamiento del síndrome coronario agudo con elevación del segmento ST mediante angioplastia primaria / Barriers and Procedures to Reduce Treatment Delay in ST-Segment Elevation Acute Coronary Syndrome with Primary Percutaneous Coronary Intervention

RESUMEN Introducción: La demora a la reperfusión del síndrome coronario agudo con elevación del segmento ST es un factor determinante en el pronóstico. Su reducción podría disminuir la morbimortalidad. Objetivo: Identificar y modificar las barreras detectadas en 20 años de tratamiento del síndrome coronario agudo con elevación del segmento ST en un centro de tercer nivel de una ciudad de alta densidad demográfica para evaluar su efecto en el resultado del procedimiento. Material y métodos: Incluimos prospectiva y consecutivamente del 01/01/2000 al 31/12/2019, 3007 pacientes con síndrome coronario agudo con elevación del segmento ST dentro de las 12 h de iniciados los síntomas para realizar angioplastia primaria. Se dividió el tiempo desde el comienzo de los síntomas hasta la insuflación del balón en intervalos. Luego de identificar las barreras (2000-2009) se incorporaron cambios al procedimiento. Se organizó a la población en 2 grupos (G) G1: preimplementación de cambios (2000-2009) y G2: posimplementación (2010- 2019). Resultados: Se incluyeron en G1 1409 pacientes y en G2 1598. Sin diferencias demográficas, excepto por el tipo de angioplastia. Se identificaron demoras al realizar el diagnóstico, de comunicación entre médicos, del traslado y del ingreso del paciente a hemodinamia. Con los cambios, disminuimos el intervalo consulta-contacto con el hemodinamista [G1: 90 min (36-168) vs. G2: 77 min (36-144) p -0,01] y el intervalo contacto hemodinamista-ingreso a Hemodinamia [G1: 75 min (55-100) vs. G2: 51 min (34-70) p -0,01]. Se redujo la mortalidad intrahospitalaria (G1: 9,2% vs. G2:6,7% p -0,01) y al 6to mes (G1: 13,1% vs. G2: 7,5% p -0,01). Conclusiones: El retraso al diagnóstico, la dificultad en la comunicación y la forma de traslado fueron las principales causas de demora. La implementación de un protocolo de procedimientos permitió reducir las demoras. La evaluación continua de resultados y la educación permanente, constituyen los pilares fundamentales para la optimización de programas de atención en red.

ABSTRACT Background: The delay to reperfusion of ST-segment elevation acute coronary syndrome (STEACS) is a key factor in its prognosis, and its reduction could reduce morbidity and mortality. Objective: The aim of this study was to identify and modify the barriers detected in 20 years of STEACS treatment in a tertiary care center of a densely populated city to evaluate their effect on the outcome of the procedure. Methods: A total of 3007 patients with STEACS within 12 hours of symptoms onset were prospectively and consecutively included to undergo primary percutaneous coronary intervention (PCI) from January 1, 2000 to December 31, 2019. Time from symptoms onset to balloon inflation was divided into intervals. After barriers were identified (2000-2009), the procedure was changed. The population was divided into two groups (G) G1: pre-implementation (2000-2009) and G2: post-implementation (2010-2019) of changes. Results: G1 included 1409 and G2 1598 patients with no demographic differences except for the type of PCI. Delays were identified in diagnosis, communication between physicians, transfer and admission of the patient to the hemodynamics lab. Procedural changes decreased first medical contact-hemodynamic team contact interval [G1: 90 min (36-168) vs. G2: 77 min (36-144) p -0.01] and hemodynamic team contact-hemodynamics lab admission interval [G1: 75 min (55-100) vs. G2: 51 min (34-70) p -0.01] and reduced in-hospital (G1: 9,2% vs. G2: 6,7% p -0,01) and 6-month (G1: 13.1% vs. G2: 7.5% p -0. 01) mortality. Conclusions: Delay in diagnosis, difficulty in communication and type of transfer were the most important causes of delay. Implementing a procedural protocol reduced delays. Continuous evaluation of results and permanent education constitute the fundamental cornerstones for optimizing network care programs.

Experts document on methotrexate use in combined therapy with biological or targeted synthetic disease modifying drugs in patients with rheumatoid arthritis.

OBJECTIVE: We aimed to develop recommendations for the management of methotrexate (MTX) when considering the combination with biological (b) or targeted synthetic (ts) disease modifying drugs (DMARDs) in rheumatoid arthritis (RA). METHODS: Eleven experts on RA were selected. Two coordinators formulated 13 questions about the combination therapy of MTX with bDMARDs or tsDMARDs. A systematic review was conducted to answer the questions. Inclusion and exclusion criteria were established as well as the search strategies (Medline, Embase and the Cochrane Library were searched up to January 2019). Two reviewers selected the articles and collected data. Simultaneously, EULAR and ACR meeting abstracts were evaluated. Based on this evidence, the coordinators proposed preliminary recommendations that the experts discussed and voted in a nominal group meeting. The level of evidence and grade of recommendation was established using the Oxford Center for Evidence Based Medicine and the level of agreement with a Delphi. Agreement was established if at least 80% of the experts voted 'yes' (yes/no). RESULTS: The systematic review retrieved 513 citations of which 61 were finally included. A total of 10 recommendations were generated, voted and accepted. The level of agreement was very high in all of them and it was achieved in the first Delphi round. Final recommendations cover aspects such as the optimal MTX dosage, tapering strategy or patients' risk management. CONCLUSIONS: This document is intended to help clinicians solve usual clinical questions and facilitate decision making when treating RA patients with MTX in combination with bDMARDs or tsDMARDs.

NFKB2 polymorphisms associate with the risk of developing rheumatoid arthritis and response to TNF inhibitors: Results from the REPAIR consortium.

This study sought to evaluate the association of 28 single nucleotide polymorphisms (SNPs) within NFKB and inflammasome pathway genes with the risk of rheumatoid arthritis (RA) and response to TNF inhibitors (TNFi). We conducted a case-control study in a European population of 1194 RA patients and 1328 healthy controls. The association of potentially interesting markers was validated with data from the DANBIO (695 RA patients and 978 healthy controls) and DREAM (882 RA patients) registries. The meta-analysis of our data with those from the DANBIO registry confirmed that anti-citrullinated protein antibodies (ACPA)-positive subjects carrying the NFKB2rs11574851T allele had a significantly increased risk of developing RA (PMeta_ACPA + = 0.0006) whereas no significant effect was found in ACPA-negative individuals (PMeta_ACPA- = 0.35). An ACPA-stratified haplotype analysis including both cohorts (n = 4210) confirmed that ACPA-positive subjects carrying the NFKB2TT haplotype had an increased risk of RA (OR = 1.39, P = 0.0042) whereas no effect was found in ACPA-negative subjects (OR = 1.04, P = 0.82). The meta-analysis of our data with those from the DANBIO and DREAM registries also revealed a suggestive association of the NFKB2rs1056890 SNP with larger changes in DAS28 (OR = 1.18, P = 0.007). Functional experiments showed that peripheral blood mononuclear cells from carriers of the NFKB2rs1005044C allele (in LD with the rs1056890, r2 = 1.00) showed increased production of IL10 after stimulation with LPS (P = 0.0026). These results provide first evidence of a role of the NFKB2 locus in modulating the risk of RA in an ACPA-dependent manner and suggest its implication in determining the response to TNFi. Additional studies are now warranted to further validate these findings.

Impacto de un sistema de evaluación de tiempos a la reperfusión en infarto agudo de miocardio con elevación del ST / Impact of an Evaluation System of Times to Reperfusion in ST-segment Elevation Acute Myocardial Infarction

RESUMEN • Introducción: El tratamiento del infarto con supradesnivel del ST (IAMCEST) es tiempo-dependiente, por lo que los centros con angioplastia primaria (ATCp) deben estar organizados para asegurar una rápida reperfusión. Objetivos: Evaluar el impacto de un sistema de evaluación sistemática de los tiempos de reperfusión y feedback de resultados en la reducción de las demoras. Material y métodos: Estudio observacional, prospectivo, realizado en 46 centros con ATCp 24/7 de la Iniciativa Stent-Save a Life! Argentina. Se incluyeron pacientes con IAMCEST sometidos a ATCp antes de las 12 h desde el inicio de los síntomas, asistidos entre marzo de 2016 y febrero de 2019. La población se dividió en tres etapas consecutivas de 1 año cada una desde la inclusión de cada centro. Resultados: Se incluyeron 3492 pacientes consecutivos (primer año: 1482; segundo año: 1166; tercer año: 844). Se observó una reducción significativa del tiempo puerta-balón (TPB) (68, 60 y 50 min; p < 0,0001) a lo largo de los años considerados, independientemente de dónde haya sido el primer contacto médico (PCM) y del tiempo desde el primer contacto médico (PCM) al balón (115, 112 y 98 min; p < 0,0001), sin diferencias en el tiempo desde el inicio de los síntomas al PCM ni en el tiempo total de isquemia (TTI). Asimismo, en aquellos pacientes que tuvieron su PCM en centros sin hemodinamia y fueron derivados para la realización de ATCp, se observó una disminución del TTI (274, 260 y 235 min; p < 0,001). Conclusiones: La implementación de un programa puerta-balón (PPB) en centros con ATCp permitió reducir los tiempos al tratamiento.

ABSTRACT • Background: Treatment of patients with ST-elevation myocardial infarction (STEMI) is time-dependent; therefore centers with primary percutaneous coronary intervention (pPCI) capability should be organized to achieve rapid reperfusion. Objectives: The aim of this study was to assess the impact of a systematic evaluation of reperfusion times with periodic feed-back of results in reducing delays to treatment. Methods: This was an observational, prospective study conducted in 46 centers with 24/7 pPCI capability participating in the Stent-Save a Life! Argentina Initiative. Patients with STEMI who underwent pPCI within 12 hours from the onset of symptoms were included from March 2016 to February 2019. The population was divided into three consecutive stages lasting one year each since the inclusion of each center in the Stent-Save a Life! Initiative. Results: A total of 3,492 patients were included (1st year: 1,482, 2nd year: 1,166, 3rd year: 844). There was a significant reduction in door-to-balloon (DTB) time (68, 60 and 50 min; p <0.0001), regardless of the type of first medical contact (FMC), and of the time from FMC to reperfusion (115, 112 and 98 min; p<0.0001), without differences in time from the onset of symptoms to FMC or total ischemic time (TIT). In addition, patients with FMC in centers without PCI capability who were referred for pPCI also evidenced a significant reduction of TIT (274, 260 and 235 min; p<0.001). Conclusion: The implementation of a DTB program in centers with pPCI capability resulted in a significant reduction of treatment times.

Is Dual-Axis Rotational Coronary Angiography Radiation Dose Reduction Achievable in a Population with 100% Suspected Coronary Artery Disease? A Randomized Trial.

BACKGROUND: Previous studies have shown a reduction in radiation dose and contrast volume using dual-axis rotational coronary angiography (DARCA), but this has not been replicated in a population with 100% coronary artery disease (CAD). OBJECTIVE: To find if DARCA dose reduction is achievable in this population, we sought to compare the radiation dose, contrast volume, and procedure time between DARCA and conventional coronary angiography (CCA) techniques in a setting characterized by a prevalence of 100% suspected coronary artery disease. METHODS: An all-comer, prospective, randomized, open-label trial was conducted. Cine acquisition dose-area product (DAP), cumulative air kerma (AK), effective dose (E), fluoroscopic time, contrast volume, AK, cine acquisition DAP (CADAP), fluoroscopic DAP (F-DAP), and total DAP were compared between DARCA and CCA groups. RESULTS: We included 503 consecutive patients with suspected CAD. 252 were assigned to DARCA and 251 to CCA. Stable coronary artery disease was reported in 465 cases and non-ST elevation acute coronary syndrome in 38. Mean age: 61.88 ± 11.2 years, male gender 70.2%. DARCA arm patients showed lower total E dose (6.85 [4.55-10.83] vs. 7.91 [5.58-11.94] Sv; P = .0023), and cine E (3.00 [2.00-4.00] vs. 4.00 [3.00-5.00] Sv; P < .0001). Total DAP was also lower (40.3 [26.8-63.7] vs. 46.5 [32.8-70.2] Gycm2; P = .0023), as a consequence of a lower CADAP (16.3 [10.5-22.9] vs. 23.4 [17.4-32.0] Gycm2; P < .0001), with lower AK (367 [248-1497] vs. 497 [381-1827] mGy; P < .0001), with less contrast medium used (90 [60.0-106.0] vs. 100 [75.0-120.0] mL; P = .014). CONCLUSION: In a population with 100% suspected coronary artery disease, DARCA provides accurate information required in CAD, is safe, and results in a significant decrease in contrast material volume and radiation dose compared with CCA. The required extra projections did not neutralize the DARCA radiation dose and contrast volume reduction achievements.

Steroid hormone-related polymorphisms associate with the development of bone erosions in rheumatoid arthritis and help to predict disease progression: Results from the REPAIR consortium.

Here, we assessed whether 41 SNPs within steroid hormone genes associated with erosive disease. The most relevant finding was the rheumatoid factor (RF)-specific effect of the CYP1B1, CYP2C9, ESR2, FcγR3A, and SHBG SNPs to modulate the risk of bone erosions (P = 0.004, 0.0007, 0.0002, 0.013 and 0.015) that was confirmed through meta-analysis of our data with those from the DREAM registry (P = 0.000081, 0.0022, 0.00074, 0.0067 and 0.0087, respectively). Mechanistically, we also found a gender-specific correlation of the CYP2C9rs1799853T/T genotype with serum vitamin D3 levels (P = 0.00085) and a modest effect on IL1ß levels after stimulation of PBMCs or blood with LPS and PHA (P = 0.0057 and P = 0.0058). An overall haplotype analysis also showed an association of 3 ESR1 haplotypes with a reduced risk of erosive arthritis (P = 0.009, P = 0.002, and P = 0.002). Furthermore, we observed that the ESR2, ESR1 and FcγR3A SNPs influenced the immune response after stimulation of PBMCs or macrophages with LPS or Pam3Cys (P = 0.002, 0.0008, 0.0011 and 1.97•10-7). Finally, we found that a model built with steroid hormone-related SNPs significantly improved the prediction of erosive disease in seropositive patients (PRF+ = 2.46•10-8) whereas no prediction was detected in seronegative patients (PRF- = 0.36). Although the predictive ability of the model was substantially lower in the replication population (PRF+ = 0.014), we could confirm that CYP1B1 and CYP2C9 SNPs help to predict erosive disease in seropositive patients. These results are the first to suggest a RF-specific association of steroid hormone-related polymorphisms with erosive disease.

Early restoration of immune and vascular phenotypes in systemic lupus erythematosus and rheumatoid arthritis patients after B cell depletion.

This translational multi-centre study explored early changes in serologic variables following B lymphocyte depletion by rituximab (RTX) treatment in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients and investigated in vitro effects on the activity of other immune cells and the vascular endothelium. Eighty-five SLE patients, seventy-five RA patients and ninety healthy donors were enrolled. Two additional cohorts of selected SLE and RA patients were treated with RTX for 3 months. Changes in circulating levels of inflammatory mediators, oxidative stress markers and NETosis-derived bioproducts were evaluated. Serum miRNomes were identified by next-generation sequencing, and RTX-induced changes were delineated. Mechanistic in vitro studies were performed to assess activity profiles. Altered inflammatory, oxidative and NETosis-derived biomolecules were found in SLE and RA patients, closely interconnected and associated to specific miRNA profiles. RTX treatment reduced SLE and RA patients' disease activity, linked to a prominent alteration in those biomolecules and the reversal of altered regulating miRNAs. In vitro studies showed inhibition of NETosis and decline of pro-inflammatory profiles of leucocytes and human umbilical vein endothelial cells (HUVECs) after B cell depletion. This study provides evidence supporting an early RTX-induced re-setting of the pro-inflammatory status in SLE and RA, involving a re-establishment of the homeostatic equilibrium in immune system and the vascular wall.

Iniciativa Stent-Save a Life! Argentina / Stent-Save a Life! Argentina Initiative

RESUMEN 31. Introducción: La iniciativa Stent-Save a Life! (SSL) es un programa europeo que busca mejorar el acceso de pacientes con infarto agudo de miocardio con elevación del ST (IAMCEST) a un tratamiento de reperfusión basado en las recomendaciones de las guías clínicas, reduciendo así su morbimortalidad. Objetivo: Describir los resultados de los primeros tres años de la iniciativa SSL Argentina Material y métodos: Se realizó inicialmente un mapeo para analizar la situación local y luego se desarrolló el Programa Puerta-Balón (PPB) como un proceso de mejora continua para centros con capacidad de realizar angioplastia primaria (ATCp). Resultados: Desde marzo de 2016 hasta marzo de 2018 se trataron 3041 pacientes con IAMCEST en 38 centros participantes del citado programa. El 20% (n = 610) de esos pacientes tuvo su primer contacto médico (PCM) con el servicio de emergencias médicas. Excluyendo los 184 pacientes sin lesiones coronarias (6% del total), el 93% fue reperfundido, principalmente con ATCp (95%). El tiempo global de isquemia fue de 117 minutos, variando según el momento del PCM. La mortalidad global intrahospitalaria fue del 7%. Conclusiones: La falta de una "cultura de reperfusión" fue la barrera en común de centros públicos y privados que motivó el desarrollo del PPB. La identificación de los puntos críticos que impiden un tratamiento a tiempo, junto con la organización de los centros puertas adentro, representan el primer paso para mejorar la atención de estos pacientes. Es necesario el trabajo integrado de todos los actores involucrados a partir de la organización de redes de atención, adaptadas a la realidad local de cada centro y región.

ABSTRACT 39. Introduction: The Stent-Save a Life! (SSL) initiative is a European program that seeks to improve the access of patients with ST-segment elevation acute myocardial infarction (STEMI) to reperfusion therapies based on clinical guideline recommendations, thus reducing morbidity and mortality. Objective: The aim of this study was to describe the results of the first three years of the SSL Argentina initiative. Methods: Initially, a mapping was carried out to analyze the local situation and then the Door-to- Balloon Program (DBP) was developed as a continuous improvement process for centers with primary percutaneous coronary intervention (pPCI) capability. Results: From March 2016 to March 2018, 3,041 patients with STEMI were treated in 38 centers participating in this program. In 20% of cases (n=610) patients had their first medical contact with the emergency medical services. After excluding 184 patients (6%) without coronary lesions, reperfusion therapy was performed in 93% of cases, mainly by pPCI (95%). Total ischemic time was 117 minutes, with differences according to the time of first medical contact. Overall in-hospital mortality was 7%. Conclusions: The lack of a "reperfusion culture" was the common barrier of public and private centers that motivated the development of the DBP. The identification of critical points that prevent treatment on time, together with enhancement of in-hospital organization, represent the first step to improve the care of these patients. The integrated work of all the involved parties is necessary to develop care networks adapted to the local reality of each center and region.

Correction: Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients.

The original version of this Article contained an error in the spelling of the author Ana Rodríguez-Ramos, which was incorrectly given as Ana Rodríguez Ramos. This has now been corrected in both the PDF and HTML versions of the Article.

Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients.

The aim of this case-control study was to evaluate whether 47 single-nucleotide polymorphisms (SNPs) in steroid hormone-related genes are associated with the risk of RA and anti-TNF drug response. We conducted a case-control study in 3 European populations including 2936 RA patients and 2197 healthy controls. Of those, a total of 1985 RA patients were treated with anti-TNF blockers. The association of potentially interesting markers in the discovery population was validated through meta-analysis with data from DREAM and DANBIO registries. Although none of the selected variants had a relevant role in modulating RA risk, the meta-analysis of the linear regression data with those from the DREAM and DANBIO registries showed a significant correlation of the CYP3A4rs11773597 and CYP2C9rs1799853 variants with changes in DAS28 after the administration of anti-TNF drugs (P = 0.00074 and P = 0.006, respectively). An overall haplotype analysis also showed that the ESR2GGG haplotype significantly associated with a reduced chance of having poor response to anti-TNF drugs (P = 0.0009). Finally, a ROC curve analysis confirmed that a model built with eight steroid hormone-related variants significantly improved the ability to predict drug response compared with the reference model including demographic and clinical variables (AUC = 0.633 vs. AUC = 0.556; PLR_test = 1.52 × 10-6). These data together with those reporting that the CYP3A4 and ESR2 SNPs correlate with the expression of TRIM4 and ESR2 mRNAs in PBMCs (ranging from P = 1.98 × 10-6 to P = 2.0 × 10-35), and that the CYP2C9rs1799853 SNP modulates the efficiency of multiple drugs, suggest that steroid hormone-related genes may have a role in determining the response to anti-TNF drugs.KEY POINTS• Polymorphisms within the CYP3A4 and CYP2C9 loci correlate with changes in DAS28 after treatment with anti-TNF drugs.• A haplotype including eQTL SNPs within the ESR2 gene associates with better response to anti-TNF drugs.• A genetic model built with eight steroid hormone-related variants significantly improved the ability to predict drug response.

Use of prognostic factors of rheumatoid arthritis in clinical practice and perception of their predictive capacity before and after exposure to evidence.

The aim of the study is to benchmark the use and attributed importance of well-established prognostic factors in rheumatoid arthritis (RA) in daily clinical practice, and to contrast the use of factors with their ability to predict outcome. Medline was searched (inception-Sep. 2016) for systematic reviews on factors predicting death, disability, structural damage or remission in RA. All factors identified were compiled in a matrix of factors × outcomes, and scoping reviews for each cell were then performed. A survey to 42 rheumatologists randomly selected explored the use of the list of prognostic factors and inquired about the perceived strength of association with poor prognosis. In a second round, participants were exposed to evidence from the matrix and to responses from other participants. Change on perceived strength of association was evaluated. Rheumatologists report using prognostic factors in clinical practice on a daily basis. Very young onset, joint counts at diagnosis, rheumatoid factor, ACPA, and radiographic erosions are used frequently and correctly recognized as strong predictors. Comorbidities and other associated problems, such as obesity, low bone mineral density, cardiovascular disease, or extra-articular manifestations, are perceived as moderately associated to prognosis but, nevertheless, rheumatologists also use them profusely. Genetic and other biomarkers and osteitis by magnetic resonance are less accessible in daily practice and they obtained better results on second round (probably after knowing the strength of association with prognosis). Rheumatologists use widely most prognostic factors with a strong predictive value. However, factors with low evidence of prognostic value are also used and some factors are not used despite good evidence.

Vitamin D is Related to Markers of Vulnerable Plaque in Acute Myocardial Infarction.

BACKGROUND: Vitamin D is a fat soluble vitamin involved in calcium and bone metabolism; recently its deficiency has been related to cardiovascular disease. In cardiac tissue, vitamin D suppresses metalloproteinases (MMPs) expression, enzymes directly associated with vulnerable plaque. OBJECTIVE: To investigate whether the association between vitamin D and leptin is related to markers of vulnerable plaque, such as MMPs in patients with acute myocardial infarction. METHODS: We studied 66 male patients with acute myocardial infarction, undergoing primary angioplasty. Blood samples were obtained at admission and 24hs after the surgery. Leptin and vitamin D concentrations in serum and MMP-2 and -9 activities in plasma were determined. RESULTS: MMP-2 activity was increased in Vitamin D deficient/insufficient patients at admission (p=0.04) and 24 hs later (p=0.05). In a linear regression model, vitamin D explained 24% of the variance of MMP-2 activity (F=2.839 p=0.04). At admission, vitamin D correlated with serum leptin (r=-0.302 p=0.033), and explained 39.5% of its variation (F=4.432 p=0.003). CONCLUSION: In the studied population, vitamin D was inversely related to MMP-2 and leptin which are involved in coronary artery disease and acute myocardial infarction. The decrease in this hormone levels would be associated with a worse metabolic profile in acute coronary syndrome patients.

[Simple mechanical reperfusion in acute myocardial infarction: determinants, prognostic implications and relation with thrombus histology]. / Reperfusión mecánica simple en el infarto agudo de miocardio. Determinantes, implicaciones en el pronóstico y relación con la histología del trombo.

Simple mechanical reperfusion (SMR) is defined as reperfusion achieved after wire insertion at the occluded infarct-related artery in primary angioplasty. The determinants and prognostic implications of SMR and its relationship with the histopathology of the rescued thrombus were evaluated in 601 patients with acute myocardial infarction showing ST elevation and pre-procedural total occlusion of the infarct-related artery (TIMI flow 0). Two groups were considered according to the presence of SMR, defined as the visualization of contrast material after crossing the occlusion with the guide wire. SMR was achieved in 303 patients (50.4%) and was found to be associated with less time to treatment (248 vs. 286 minutes; p = 0.001), less deteriorated initial left ventricular function and shock at admission (9.2 vs. 16.4%; p = 0.008), higher successful rate (94.7% vs. 78.5%; p < 0,0001) and of higher rate of thrombus rescue: 70/81 vs. 27/79 patients (p < 0.0001). The right coronary artery was the most frequent infarct-related artery. Histopathology of the retrieved thrombi was available for 160 patients treated with thrombus aspiration. SMR was associated with smaller thrombus, lower contents of leukocytes and erythrocytes, and higher thrombus content of inflammatory cells, cholesterol and collagen crystals from the atheromatous plaque. SMR is an independent predictor of procedure success and its relationship with the anatomy of the thrombus could redefine the indication of thrombus aspiration.

Reperfusión mecánica simple en el infarto agudo de miocardio: Determinantes, implicaciones en el pronóstico y relación con la histología del trombo / Simple mechanical reperfusion in acute myocardial infarction: determinants, prognostic implications and relation with thrombus histology

La reperfusión mecánica simple (RMS) es la lograda en la angioplastia primaria al atravesar la oclusión en la arteria responsable de infarto con la guía intracoronaria. Para evaluar los determinantes de la RMS, su implicación en el pronóstico y su relación con la histopatología del trombo rescatado, fueron analizados los casos de 601 pacientes con infarto agudo de miocardio con elevación del segmento ST y oclusión total de la arteria responsable de infarto (flujo TIMI 0). Se consideraron dos grupos según la presencia de RMS, definida por la visualización de contraste distal a la lesión luego de atravesarla con la guía intracoronaria. Se realizó el análisis histopatológico de los trombos en un subgrupo de 160 pacientes tratados con tromboaspiración. En 303 (50.4%) pacientes se obtuvo RMS. La RMS se asoció a menor ventana al tratamiento (248 vs. 286 minutos, p = 0.001), menor deterioro de la función sistólica ventricular izquierda inicial y shock al ingreso (9.2 vs.16.4%, p = 0.008), mayor tasa de éxito (94.7 vs. 78.5%, p < 0.0001) y de rescate de trombos (70/81 vs. 27/79 pacientes, p < 0.0001). La arteria responsable de infarto más frecuente fue la coronaria derecha. La RMS se asoció con menor tamaño del trombo, menor concentración de leucocitos y eritrocitos y mayor contenido de células inflamatorias, cristales de colesterol y colágeno provenientes de la placa. La RMS es un predictor independiente de éxito y su relación con la anatomía del trombo podría redefinir la indicación de la tromboaspiración.

Simple mechanical reperfusion (SMR) is defined as reperfusion achieved after wire insertion at the occluded infarct-related artery in primary angioplasty. The determinants and prognostic implications of SMR and its relationship with the histopathology of the rescued thrombus were evaluated in 601 patients with acute myocardial infarction showing ST elevation and pre-procedural total occlusion of the infarct-related artery (TIMI flow 0). Two groups were considered according to the presence of SMR, defined as the visualization of contrast material after crossing the occlusion with the guide wire. SMR was achieved in 303 patients (50.4%) and was found to be associated with less time to treatment (248 vs. 286 minutes; p = 0.001), less deteriorated initial left ventricular function and shock at admission (9.2 vs. 16.4%; p = 0.008), higher successful rate (94.7% vs. 78.5%; p < 0,0001) and of higher rate of thrombus rescue: 70/81 vs. 27/79 patients (p < 0.0001). The right coronary artery was the most frequent infarct-related artery. Histopathology of the retrieved thrombi was available for 160 patients treated with thrombus aspiration. SMR was associated with smaller thrombus, lower contents of leukocytes and erythrocytes, and higher thrombus content of inflammatory cells, cholesterol and collagen crystals from the atheromatous plaque. SMR is an independent predictor of procedure success and its relationship with the anatomy of the thrombus could redefine the indication of thrombus aspiration.