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Resumen Objetivo Identificar herramientas disenadas para evaluar la gravedad global de los pacientes con artritis reumatoide (AR) para su uso en la investigacion de marcadores pronosticos de artritis precoz. Metodos Revision sistematica de estudios cuyo objetivo fuera el desarrollo o validacion de indices de gravedad en AR. Se valoro la calidad metodologica mediante la lista de comprobacion COSMIN. Ademas, se evaluo la claridad de definicion, viabilidad y probabilidad de estar presente durante los 2 primeros anos de evolucion. Resultados Despues de revisar 3.519 articulos, se identificaron 3 indices de gravedad. La Patient Activity Scale (PAS) valoro si el tratamiento previo o actual predecia la gravedad de la AR, medida mediante el patient-reported PAS. Las variables de tratamiento no permitieron distinguir entre los cuartiles superior e inferior de la PAS. El CIRAS incluye las variables edad, sexo, sindrome de Felty, numero de visitas al reumatologo y al rehabilitador, factor reumatoide (FR), recuento de plaquetas, marcadores inflamatorios y paneles bioquimicos solicitados. Su correlacion fue baja (r = 0,56), con un indice previamente validado por el mismo grupo investigador, el RARBIS, con el DAS28-PCR (r = 0,07) y el Multidimensional Health Assesment Questionnaire (MD-HAQ) (r = 0,008). Por ultimo, el RARBIS, utilizado para validar el CIRAS, fue ideado como un indice de gravedad de AR basado en registros medicos. Incluye como dominios cirugia, radiologia, manifestaciones extraarticulares, clinica y variables de laboratorio, elegidas previamente por un panel de expertos. Este indice presento una correlacion debil con la intensidad de tratamiento (r = 0,35) y con el DAS 28 (r = 0,41). Conclusion No existe ningun indice para valorar la gravedad de la AR sobre la base del curso evolutivo de los 2 primeros anos de seguimiento y que se adapte a la estrategia terapeutica actual. Por lo tanto, creemos razonable el desarrollo de un nuevo indice de gravedad ad hoc para pacientes con artritis de reciente comienzo.

Resumen Objetivo Analizar el efecto de polimorfismos de nucleotido unico (SNPs) de la metilen-tetrahidrofolatorreductasa (MTHFR; rs1801131 y rs1801133), el transportador de membrana que une ATP B1 (ABCB1; rs1045642), la aicartransformilasa/IMP ciclohidrolasa (ATIC; rs2372536) y la folilpoliglutamatosintetasa (FPGS; rs1544105) en la toxicidad hepatica y medular de metotrexato (MTX). Pacientes y metodos Se analizaron 1.415 visitas (732 con MTX, 683 sin MTX) de 350 pacientes del Princesa Early Arthritis Register Longytudinal study . El genotipo de los diferentes SNP se determino mediante sondas TaqMan (Applied Biosystems). Se realizaron analisis multivariables mediante modelos lineales generalizados en los que las variables dependientes fueron los niveles sericos de transaminasa glutamico-piruvica (toxicidad hepatica), leucocitos, plaquetas o hemoglobina (toxicidad hematologica) y se ajustaron por variables clinicas (actividad de la enfermedad, etc.), analiticas (funcion renal, etc.), sociodemograficas (edad, sexo, etc.) y las variantes geneticas de MTHFR, ABCB1, ATIC y FPGS. Tambien se analizaron las variables que influyeron en las dosis de MTX administradas a lo largo del seguimiento. Resultados Cuando recibian MTX los portadores del genotipo CC del SNP rs1045642 de ABCB1 presentaron niveles significativamente mayores de GPT (7,1 ± 2,0 U/l; p Discusion Nuestros datos sugieren que variantes geneticas de las enzimas FGPS y MTHFR, y del transportador ABCB1, podrian ayudar a detectar pacientes con mayor riesgo de toxicidad por MTX.

Objetivo Establecer recomendaciones para el manejo de pacientes con artritis reumatoide (AR) centrado en el papel de los farmacos antirreumaticos modificadores de enfermedad (FAME) sinteticos y biologicos disponibles, que sirvan de referencia para todos los profesionales implicados en la atencion de estos pacientes. Metodos Las recomendaciones se consensuaron a traves de un panel de 14 expertos previamente seleccionados por la Sociedad Espanola de Reumatologia (SER). Se recogio la evidencia disponible mediante la actualizacion de las 3 revisiones sistematicas (RS) que se utilizaron para las recomendaciones EULAR 2013, a las que se anadio una nueva RS para dar respuesta a una pregunta adicional. Todas fueron realizadas por miembros del grupo de revisores de la SER. La clasificacion del nivel de la evidencia y del grado de la recomendacion se realizo utilizando el sistema del Centre for Evidence-Based Medicine de Oxford. Se utilizo la metodologia Delphi para evaluar el grado de acuerdo entre los panelistas para cada recomendacion. Resultados Se emiten un total de 13 recomendaciones sobre el manejo terapeutico de pacientes con AR del adulto. El objetivo terapeutico debe ser tratar al paciente en fases precoces de la enfermedad, con el objetivo de la remision clinica, teniendo un papel central el metotrexato como FAME sintetico de referencia. Se actualizan las indicaciones de los FAME biologicos disponibles, se enfatiza la importancia de los factores pronosticos y se incide en el concepto de optimizacion de biologicos. Conclusiones Se presenta la quinta actualizacion de las recomendaciones SER para el manejo de la AR con FAME sinteticos y biologicos.

Objective To identify tools designed to evaluate the severity of patients with rheumatoid arthritis (RA) in order to use them in the investigation of prognostic markers in early arthritis. Methods We conducted a systematic review of studies that developed/validated an index for RA disease severity. They were analysed using the COSMIN checklist to assess their methodological quality. In addition, all the variables included were evaluated for their clarity of definition, feasibility and probability of being present in each outcome during the first 2 years of the disease course. To estimate redundancy, variables were grouped by domains. Results After reviewing 3519 articles, 3 studies were included. The first study, the PAS, assessed whether current and lifetime treatment with disease-modifying antirheumatic drugs and/or biologics accurately predicted RA severity, as measured by the patient-reported PAS. Treatment variables did not fully distinguish patients in the highest and lowest quartiles of PAS scores. Another severity index, the Claims-Based Index for RA Severity (CIRAS), included the variables age, sex, Felty's syndrome, number of rehabilitation and rheumatology visits, test for inflammatory markers, number of chemistry panels/platelet counts ordered and rheumatoid factor test. The correlation was low (r = 0.56) with an index previously validated by the same research group, the RA medical records-based index of severity (RARBIS), with Disease Activity Score- C -reactive protein (DAS28-PCR) (r = 0.07) and Multidimensional Health Assessment Questionnaire (MD-HAQ) (r = 0.008). Finally, the RARBIS, used to validate the CIRAS, was devised as an RA severity index based on medical records. It includes as domains surgery, radiology, extra-articular manifestations, clinical and laboratory variables, previously chosen by an expert panel. RARBIS had a weak correlation with treatment intensity (r = 0.35) and with DAS28 (r = 0.41). Conclusion There is no index to assess the severity of RA based on the course of the first 2 years of follow-up that is adapted to the current strategy of therapeutic management of this disease. Therefore, we believe it is reasonable to develop a new ad hoc severity index for patients with early arthritis.

To analyze the effect of single nucleotide polymorphisms (SNPs) with well-known functional impact of methylenetetrahydrofolatereductase (MTHFR; rs1801131 and rs1801133), the membrane transporter ABCB1 (rs1045642), the AICAR transformylase/IMP cyclohydrolase (ATIC; rs2372536) and folyl-polyglutamatesynthetase (FPGS; rs1544105), on liver and bone marrow toxicity of methotrexate (MTX).We analyzed 1415 visits from 350 patients of the PEARL (Princesa Early Arthritis Register Longitudinal) study: (732 with MTX, 683 without MTX). The different SNPs were genotyped using specific TaqMan probes (Applied Biosystems). Multivariate analyzes were performed using generalized linear models in which the dependent variables were the levels of serum alanine aminotransferase (liver toxicity), leukocytes, platelets or hemoglobin (hematologic toxicity) and adjusted for clinical variables (disease activity, etc.), analytical (renal function, etc.), sociodemographic (age, sex, etc.) and genetic variants of MTHFR, ABCB1, ATIC and FPGS. The effect of these variables on the MTX doses prescribed throughout follow-up was also analyzed through multivariate analysis nested by visit and patient.When taking MTX, those patients carrying the CC genotype of rs1045642 in ABCB1 showed significantly higher GPT levels (7.1±2.0 U/L; P.001). Carrying at least one G allele of rs1544105 in FPGS was associated with lower leukocyte (-0.67±0.32; 0.038), hemoglobin (-0.34±0.11g/dL; P=.002), and platelet (-11.8±4.7; P=.012) levels. The presence of the G allele of rs1544105 in FPGS, and the T allele of rs1801133 in MTHFR, was significantly associated with the use of lower doses of MTX.Our data suggest that genotyping functional variants in FGPS and MTHFR enzymes and the transporter ABCB1 could help to identify patients with increased risk of MTX toxicity.

Objetivo Analizar el efecto de la estructura del afecto en las siguientes herramientas de evaluacion de la artritis reumatoide: escala visual analogica (EVA) de dolor, HAQ y DAS28. Pacientes y metodos Se estudiaron 86 pacientes con artritis reumatoide de reciente comienzo, de los que el 75,7% eran mujeres, con una mediana de edad al inicio de la enfermedad de 55 anos. A todos los pacientes se les aplico la version adaptada a poblacion espanola del cuestionario PANAS que evalua las componentes de afecto positivo (AP) y negativo (AN). Los pacientes pertenecian al registro de artritis de reciente comienzo de nuestro centro por lo que se disponia de informacion clinica de los enfermos en 282 visitas. Para determinar el efecto de AP y AN en cada una de nuestras variables dependientes se estimaron 3 modelos de regresion lineal multivariable mediante modelos lineales generalizados usando el comando glm del programa Stata 10.1. Resultados El promedio de la puntuacion de AP y AN en nuestros pacientes fue similar al descrito para la poblacion espanola sana. Las puntuaciones elevadas en la subescala de AN se asociaron a peores puntuaciones, tanto en la EVA de dolor, como en el HAQ. Por el contrario, puntuaciones elevadas en AP se asociaron con una mejor evolucion de la actividad de la enfermedad medida por el DAS28. Conclusion La estructura del afecto puede influir en las herramientas que utilizamos para la evaluacion de los pacientes con artritis reumatoide, por lo que podria ser recomendable incluir la realizacion del PANAS como parte de dicha evaluacion

Resumen Objetivo Dado el creciente uso de las terapias biologicas en distintas enfermedades reumatologicas, y la importancia de la gestion de riesgo de las mismas, desde la Sociedad Espanola de Reumatologia (SER) se ha impulsado el desarrollo de recomendaciones basadas en la mejor evidencia posible. Estas deben de servir de referencia para reumatologos e implicados en el tratamiento de pacientes en tratamiento o en los que se quiere indicar la terapia biologica independientemente de su enfermedad de base. Metodos Las recomendaciones se emitieron siguiendo la metodologia de grupos nominales. El nivel de evidencia y el grado de recomendacion se clasificaron segun el modelo del Center for Evidence Based Medicine de Oxford y el grado de acuerdo se extrajo por tecnica Delphi. Se utilizo toda la informacion de consensos y guias de practica clinica previas. Resultados Se realizan recomendaciones sobre la gestion del riesgo del uso de las terapias biologicas en pacientes con enfermedades reumatica. Incluyen la gestion del riesgo de la indicacion, gestion del riesgo antes de iniciar el tratamiento, gestion del riesgo durante el seguimiento, actitud ante acontecimientos adversos, y actitud en situaciones especiales. Conclusiones Se presentan las recomendaciones SER sobre la gestion del riesgo del tratamiento con terapias biologicas.

Resumen Objetivo Valorar las diferencias de respuesta al tratamiento mediante DAS28 calculado mediante velocidad de sedimentacion globular (VSG) y proteina C reactiva teniendo en cuenta el genero del paciente y analizar el comportamiento individual de cada uno de sus componentes en una cohorte de pacientes de artritis precoz en el area 2 de la Comunidad de Madrid. Pacientes y metodos Se estudiaron un total de 134 pacientes (77,6% mujeres) que cumplian criterios del Colegio Americano de Reumatologia para el diagnostico de artritis reumatoide del registro de artritis precoz del Hospital de La Princesa. En dicho registro se realizaron 4 visitas protocolizadas en las que se recogen de forma sistematica los datos necesarios para calcular el DAS28 con VSG y proteina C reactiva, asi como el tratamiento prescrito a los pacientes. Se analizaron las diferencias por genero en la respuesta al tratamiento mediante ambos indices compuestos, asi como de las variables que los componen y la valoracion de la enfermedad por el medico. Resultados Las mujeres presentaron mayor actividad de la enfermedad y discapacidad al inicio del seguimiento. A pesar de que estas recibieron un tratamiento mas intenso, su valor promedio de DAS28 no llego a igualarse con el de los hombres a lo largo del seguimiento. Por el contrario, la valoracion de la enfermedad por parte del paciente y del medico si llego a igualarse. Al analizar los componentes del DAS28 por separado, se observo que esta discordancia era debida principalmente a las variables VSG y recuento de articulaciones dolorosas. Conclusiones La VSG y el recuento de articulaciones dolorosas causan un sesgo en la evaluacion de la actividad de la artritis reumatoide con el DAS28 que puede afectar a la evaluacion de la respuesta al tratamiento.

Objetivo: analizar el efecto de la terapia con agentes inhibidores del factor de necrosis tumoral (TNF) en la concentracion serica de interleucina 15 (IL-15) y determinar si los valores basales de esta o su variacion con el tratamiento predicen la respuesta clinica a los anti-TNF. Pacientes y metodo: se estudio a 75 pacientes con artritis reumatoide que iban a iniciar tratamiento con anti-TNF. Se recogieron muestras de suero previas y a los 3 meses de tratamiento. La concentracion de IL-15 se cuantifico mediante enzimoinmunoanalisis. Tanto en la visita basal como en la final se recogieron parametros clinicos y analiticos que permitieran calcular el DAS28. Tambien se recogieron variables sociodemograficas y otras relacionadas con la enfermedad, como factor reumatoide, numero de farmacos previos, etc. Se definio remision como un DAS28 1,2. Resultados: la concentracion de IL-15 se relaciono de forma significativa con un mayor uso de farmacos modificadores de la enfermedad durante el seguimiento de los pacientes. Tambien se observo una disminucion significativa de la IL-15 a los 3 meses de tratamiento con anti-TNF. Sin embargo, los valores basales de IL-15 y su disminucion con el tratamiento no se relacionaron con la respuesta a los anti-TNF o la consecucion de remision clinica. Conclusiones: nuestros datos parecen confirmar los obtenidos in vitro, que indican que el TNF esta implicado en la modulacion de la expresion de IL-15. No obstante, la medicion de la concentracion serica de IL-15 no parece ser de utilidad para seleccionar a los pacientes candidatos a terapia anti-TNF. © 2008 Elsevier Espana, S.L. Todos los derechos reservados.

Objective To establish recommendations for the management of patients with rheumatoid arthritis (RA) to serve as a reference for all health professionals involved in the care of these patients, and focusing on the role of available synthetic and biologic disease-modifying antirheumatic drugs (DMARDs). Methods Consensual recommendations were agreed on by a panel of 14 experts selected by the Spanish Society of Rheumatology (SER). The available scientific evidence was collected by updating three systematic reviews (SR) used for the EULAR 2013 recommendations. A new SR was added to answer an additional question. The literature review of the scientific evidence was made by the SER reviewer's group. The level of evidence and the degree of recommendation was classified according to the Oxford Centre for Evidence-Based Medicine system. A Delphi panel was used to evaluate the level of agreement between panellists (strength of recommendation). Results Thirteen recommendations for the management of adult RA were emitted. The therapeutic objective should be to treat patients in the early phases of the disease with the aim of achieving clinical remission, with methotrexate playing a central role in the therapeutic strategy of RA as the reference synthetic DMARD. Indications for biologic DMARDs were updated and the concept of the optimisation of biologicals was introduced. Conclusions We present the fifth update of the SER recommendations for the management of RA with synthetic and biologic DMARDs.

vasculitides. We present two patients with rheumatoid arthritis who subsequently developed systemic vasculitis. ANCA determination was decisive in the early diagnosis of these patients.

The development of biologic therapies has improved the prognosis of rheumatoid arthritis (RA). However, at present there is not enough evidence supporting that TNF antagonists, anti CD20 therapy or abatacept used as first line therapy provide relevant long-term benefits in daily clinical practice. Furthermore, clinical trials that analyze the effect of the combination of methotrexate (MTX) plus TNF antagonists against MTX monotherapy have shown that the later provides significant clinical responses and relevant radiological damage arrest in patients with early RA. Therefore, considering that in 5-6 months we can detect which patients do not respond adequately to MTX, we can select those patients for biologic therapy avoiding the exposure to the putative adverse events of combination therapy to those patients with optimal response to MTX monotherapy.

Objective Due to the increasing use of biologic therapy in rheumatic diseases and the importance of its risk management, the Spanish Society of Rheumatology (SER) has promoted the development of recommendations based on the best evidence available. These recommendations should be a reference to rheumatologists and those involved in the treatment of patients who are using, or about to use biologic therapy irrespectively of the rheumatic disease. Methods Recommendations were developed following a nominal group methodology and based on systematic reviews. The level of evidence and degree of recommendation were classified according to the model proposed by the Center for Evidence Based Medicine at Oxford. The level of agreement was established through a Delphi technique. Evidence from previous consensus and clinical guidelines was used. Results We have produced recommendations on risk management of biologic therapy in rheumatic patients. These recommendations include indication risk management, risk management before the use of biologic therapy, risk management during follow-up, attitude to adverse events, and attitude to special situations. Conclusions We present the SER recommendations related to biologic therapy risk management.

Objective To provide a reference to rheumatologists and to those involved in the treatment of RA who are using, or about to use biologic therapy. Methods Recommendations were developed following a nominal group methodology and based on systematic reviews. The level of evidence and grade of recommendation were classified according to the model proposed by the Center for Evidence Based Medicine at Oxford. The level of agreement was established through Delphi technique. Results We have produced recommendations on the use of the seven biologic agents available for RA in our country. The objective of treatment is to achieve the remission of the disease as quickly as possible. Indications and nuances regarding the use of biologic therapy were reviewed as well as the evaluation that should be performed prior to administration and the follow up of patients undergoing this therapy. Conclusions We present an update on the SER recommendations for the use of biologic therapy in patients with RA.

The development of biologic therapies has improved the prognosis of rheumatoid arthritis (RA). However, at present there is not enough evidence supporting that TNF antagonists, anti CD20 therapy or abatacept used as first line therapy provide relevant long-term benefits in daily clinical practice. Furthermore, clinical trials that analyze the effect of the combination of methotrexate (MTX) plus TNF antagonists against MTX monotherapy have shown that the later provides significant clinical responses and relevant radiological damage arrest in patients with early RA. Therefore, considering that in 5-6 months we can detect which patients do not respond adequately to MTX, we can select those patients for biologic therapy avoiding the exposure to the putative adverse events of combination therapy to those patients with optimal response to MTX monotherapy.

To analyze the effect of the TNF blocking agents (aTNF) on the serum levels of interleukin 15 (IL-15). To determine whether baseline IL15 serum levels or their response to aTNF therapy can predict the clinical response to this treatment.We studied 75 patients suffering from rheumatoid arthritis that were selected to start aTNF therapy. Serum samples were obtained at baseline visit and after three months of aTNF treatment. Measurement of IL-15 serum concentration was performed through immune-enzyme assay. We collected the clinical and analytical parameters needed to calculate DAS28 both at baseline and final visit, as well as sociodemographic variables and other such as rheumatoid factor, previous disease modifying anti-rheumatic drugs (DMARD), etc. We defined remission as a DAS282.6 and clinical response when the decrease in DAS28 value was higher than 1.2.There was a significant correlation between IL-15 serum level and the number of previous DMARD. We also detected a significant decrease in the concentration of serum IL-15 after three months of treatment with aTNF. However, neither the baseline IL-15 serum level nor the decrease in the concentration of IL-15 were associated with a specific pattern of response to aTNF.Our data seem to support previous in vitro findings suggesting that TNF is involved in the regulation of IL-15 expression. Nevertheless, the measurement of IL-15 serum levels does not seem to be a useful tool to select those patients that should be treated with aTNF therapy.