Minimum Effective Dosages of Anti-TNF in Rheumatoid Arthritis: A Cross-sectional Study

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ETN: etanercept; ADA; adalimumab; IFX: infliximab. Reduced (the time between doses was longer or the doses were lower than the standard ones). Standard (according to the approved prescribing information): ETN 25mg twice a week or 50mg weekly, ADA 40mg every other week, and IFX 3mg/kg every 8 weeks. Escalated (the time between doses was shorter or the doses were higher than the standard ones)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Inmaculada de la Torre, Lara Valor, Juan Carlos Nieto, María Montoro, Luis Carreño" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Inmaculada" "apellidos" => "de la Torre" ] 1 => array:2 [ "nombre" => "Lara" "apellidos" => "Valor" ] 2 => array:2 [ "nombre" => "Juan Carlos" "apellidos" => "Nieto" ] 3 => array:2 [ "nombre" => "María" "apellidos" => "Montoro" ] 4 => array:2 [ "nombre" => "Luis" "apellidos" => "Carreño" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2173574314000379" "doi" => "10.1016/j.reumae.2013.07.004" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574314000379?idApp=UINPBA00004M" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1699258X13001976?idApp=UINPBA00004M" "url" => "/1699258X/0000001000000002/v2_201404030117/S1699258X13001976/v2_201404030117/en/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2173574313001378" "issn" => "21735743" "doi" => "10.1016/j.reumae.2013.12.006" "estado" => "S300" "fechaPublicacion" => "2014-03-01" "aid" => "596" "copyright" => "Elsevier España, S.L." "documento" => "simple-article" "crossmark" => 0 "subdocumento" => "crp" "cita" => "Reumatol Clin. 2014;10:105-8" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 2560 "formatos" => array:3 [ "EPUB" => 56 "HTML" => 2106 "PDF" => 398 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Brief Report" "titulo" => "Comparative Study of Both Versions of an Immunoassay Commercialized for Therapeutic Drug Monitoring of Adalimumab in Rheumatoid Arthritis" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "105" "paginaFinal" => "108" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Estudio comparativo de las 2 versiones de un inmunoanálisis comercializado para la monitorización terapéutica de adalimumab en artritis reumatoide" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1551 "Ancho" => 1564 "Tamanyo" => 132359 ] ] "descripcion" => array:1 [ "en" => "Comparison study by correlation analysis of adalimumab concentrations determined with the 2 versions of marketed kits (n=140). A correlation coefficient of 0.896 (Version 2=0.907, Version 1 2536+) and a concordance correlation coefficient of 0.85 (95% CI: 0.80–0.89) has been obtained. gr1 Version Version Y: Concentration of adalimumab determined with V2 X: Concentration of adalimumab determined with V1." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Francisca Llinares-Tello, José Rosas, Inmaculada de la Torre, Lara Valor, Xavier Barber, José Miguel Senabre" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Francisca" "apellidos" => "Llinares-Tello" ] 1 => array:2 [ "nombre" => "José" "apellidos" => "Rosas" ] 2 => array:2 [ "nombre" => "Inmaculada" "apellidos" => "de la Torre" ] 3 => array:2 [ "nombre" => "Lara" "apellidos" => "Valor" ] 4 => array:2 [ "nombre" => "Xavier" "apellidos" => "Barber" ] 5 => array:2 [ "nombre" => "José Miguel" "apellidos" => "Senabre" ] 6 => array:1 [ "colaborador" => "the AIR-MB-HUGM Group" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1699258X13001794" "doi" => "10.1016/j.reuma.2013.07.007" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1699258X13001794?idApp=UINPBA00004M" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574313001378?idApp=UINPBA00004M" "url" => "/21735743/0000001000000002/v2_201403290120/S2173574313001378/v2_201403290120/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2173574313001494" "issn" => "21735743" "doi" => "10.1016/j.reumae.2013.12.018" "estado" => "S300" "fechaPublicacion" => "2014-03-01" "aid" => "581" "copyright" => "Elsevier España, S.L." "documento" => "article" "crossmark" => 0 "subdocumento" => "fla" "cita" => "Reumatol Clin. 2014;10:94-100" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 2882 "formatos" => array:3 [ "EPUB" => 55 "HTML" => 2256 "PDF" => 571 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Original Article" "titulo" => "Tocilizumab in Patients With Active Rheumatoid Arthritis and Inadequate Response to Disease-modifying Antirheumatic Drugs or Tumor Necrosis Factor Inhibitors: Subanalysis of Spanish Results of an Open-label Study Close to Clinical Practice" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "94" "paginaFinal" => "100" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tocilizumab en pacientes con artritis reumatoide activa y respuesta inadecuada a fármacos antirreumáticos modificadores de la enfermedad o antagonistas del factor de necrosis tumoral: subanálisis de los datos españoles de un estudio abierto cercano a la práctica clínica habitual" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 969 "Ancho" => 2100 "Tamanyo" => 96078 ] ] "descripcion" => array:1 [ "en" => "Percentage of patients in clinical remission (DAS28<2.6) or low disease activity (DAS28≤3.2) at 6 months of starting treatment with tocilizumab." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "José M. Álvaro-Gracia, Antonio Fernández-Nebro, Alicia García-López, Manuel Guzmán, Francisco J. Blanco, Francisco J. Navarro, Sagrario Bustabad, Yolanda Armendáriz, José A. Román-Ivorra" "autores" => array:10 [ 0 => array:2 [ "nombre" => "José M." "apellidos" => "Álvaro-Gracia" ] 1 => array:2 [ "nombre" => "Antonio" "apellidos" => "Fernández-Nebro" ] 2 => array:2 [ "nombre" => "Alicia" "apellidos" => "García-López" ] 3 => array:2 [ "nombre" => "Manuel" "apellidos" => "Guzmán" ] 4 => array:2 [ "nombre" => "Francisco J." "apellidos" => "Blanco" ] 5 => array:2 [ "nombre" => "Francisco J." "apellidos" => "Navarro" ] 6 => array:2 [ "nombre" => "Sagrario" "apellidos" => "Bustabad" ] 7 => array:2 [ "nombre" => "Yolanda" "apellidos" => "Armendáriz" ] 8 => array:2 [ "nombre" => "José A." "apellidos" => "Román-Ivorra" ] 9 => array:1 [ "colaborador" => "ACT SURE" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1699258X13001496" "doi" => "10.1016/j.reuma.2013.07.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1699258X13001496?idApp=UINPBA00004M" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574313001494?idApp=UINPBA00004M" "url" => "/21735743/0000001000000002/v2_201403290120/S2173574313001494/v2_201403290120/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Brief Report" "titulo" => "Minimum Effective Dosages of Anti-TNF in Rheumatoid Arthritis: A Cross-sectional Study" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "101" "paginaFinal" => "104" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Inmaculada De La Torre, Lara Valor, Juan Carlos Nieto, María Montoro, Luis Carreño" "autores" => array:5 [ 0 => array:4 [ "nombre" => "Inmaculada" "apellidos" => "De La Torre" "email" => array:1 [ 0 => "Inma.torre.ortega@googlemail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "¿" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Lara" "apellidos" => "Valor" ] 2 => array:2 [ "nombre" => "Juan Carlos" "apellidos" => "Nieto" ] 3 => array:2 [ "nombre" => "María" "apellidos" => "Montoro" ] 4 => array:2 [ "nombre" => "Luis" "apellidos" => "Carreño" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Rheumatology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Dosis efectiva mínimas de anti-TNF en artritis reumatoide: un estudio transversal" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1358 "Ancho" => 2328 "Tamanyo" => 220121 ] ] "descripcion" => array:1 [ "en" => "Percentage of responders (DAS28 ≤3.2) and non-responders (DAS28 >3.2) in the different dosage regimens of anti-TNF treatments. ETN: etanercept; ADA; adalimumab; IFX: infliximab. Reduced (the time between doses was longer or the doses were lower than the standard ones). Standard (according to the approved prescribing information): ETN 25mg twice a week or 50mg weekly, ADA 40mg every other week, and IFX 3mg/kg every 8 weeks. Escalated (the time between doses was shorter or the doses were higher than the standard ones)." ] ] ] "textoCompleto" => "IntroductionRheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease with a fluctuant but progressive course, leading, without treatment, to cartilage damage, bone erosions, and joint destruction, the main causes of long-term disability.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>Although the registered doses of anti-TNFs are at the top of the group dose response curve and under-treatment is not expected to be very frequent, the use of standard dosages in clinical practice may result in under or over treatment<a class="elsevierStyleCrossRef" href="#bib0010">2</a> once remission or low disease activity have been achieved, making it reasonable to attempt treating patients on an individualized schedule.Clinical experience confirms the long-term efficacy of standard dosages for anti-TNF drugs, evaluation is still necessary to determine if reduced dosages could maintain clinically controlled patients. There are some reports addressing the issue of stopping, lowering, or increasing the dosages inpatients in remission,<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> showing that up to 50% of patients relapse if the drug is stopped, and reintroduction of the therapy might not achieve previous results. However, tapering anti-TNF dosages seems to preserve the clinical efficacy in most patients.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Consequently, RA patients treated with anti-TNF who are in maintained remission<a class="elsevierStyleCrossRef" href="#bib0030">6</a> could benefit from treatment adjustment in order to find the lowest effective dose.The aim of the study was to assess the anti-TNF dosages in RA patients, evaluating whether modified patterns could control patients clinically under our daily clinical practice.Patients and MethodsStudy Design and Patient PopulationA cross-sectional, non-interventional study was conducted in the Hospital General Universitario Gregorio Marañón (HGUGM) in Madrid (Spain), from October 2010 to October 2011. During the study period, patients receiving anti-TNF for a minimum period of 12 months, and attending per routine follow-up the Biological Therapy Unit at the Rheumatology Department, were subsequently included. Requirements included being diagnosed with RA, according to the American College of Rheumatology's (ACR) 1987 revised criteria,<a class="elsevierStyleCrossRef" href="#bib0035">7</a> and treated with any of the following anti-TNF drugs: etanercept (ETN), adalimumab (ADA), or infliximab (IFX),administered either at standard or modified doses. Standard therapy was that in accordance with the approved prescribing information: ETN 25mg twice a week or 50mg weekly, ADA40mg every other week, and IFX 3mg/kg every 8 weeks. Modified therapy was either escalated (the time between doses was shorter or the doses were higher than the standard ones) or reduced (the time between doses was longer or the doses were lower than the standard ones). Dose tapering was adopted if the patient was in remission by DAS28 <2.6 or low activity <3.2 for those with very established and chronic disease for at least 1 year, based on a clinician and patient agreement, and not following any standardized protocol.Study VariablesThe variables studied were the percentage of patients treated with each drug (IFX, ADA, and ETN), the prescribed dosages, the distribution of patients in clinical categories according to the Disease Activity Score (DAS28):<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Remission (DAS28 <2.6); Low activity (DAS28: 2.6–3.2); Moderate activity (DAS28: 3.2–5.1); or High activity (DAS28 >5.1) in each treatment group, and the concomitant treatment with DMARDs: methotrexate (MTX), leflunomide (LF), sulfasalazine, andhydroxychloroquine.EthicsThe study was approved by the HGUGM Ethics Committee and all participants provided written informed consent.Statistical AnalysesData was analyzed with the SPSS 17.0 statistical program. Continuous variables were described using mean and standard deviation (SD) or median and range. Categorical variables were described with frequencies and percentages. Statistical analyses including parametric and non-parametric tests in relation with variables distribution were performed comparing the 3 groups (ANOVA or Kruskal–Wallis test). Additional comparisons between IFX-ADA, IFX-ETN, and ETN-ADA groups were carried out using non-parametric or parametric tests (U Mann–Whitney, Chi square).ResultsDemographic and Clinical Data (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>)195 RA patients were included. Participants were predominantly women (79%) and the global mean age was 58.1 (±14.9) years. Patients were distributed into 3 groups, according to the anti-TNF drug used: 81 patients in the ETN group (41.5%), 56 in the ADA group (28.7%), and 58 in the IFX group (29.7%). Mean disease duration (years) was statistically different between groups (P=.01) although most patients (42.2%) had a mean disease duration between 10 and 20 years. In the 2–5 year range of duration, however, the percentage of patients in the ADA group was significantly higher when compared to ETN and IFX (P=.03). There were also significant differences between groups in terms of time from diagnosis to the administration of the first biological treatment. IFX was most commonly used as first-line biological treatment, whereas ETN was the option most commonly used as second-line.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Dosage Regimen and Clinical Disease ActivityMost patients in ETN (72.8%) and ADA (69.6%) groups were treated with the standard dosages. In the ETN group there were no patients in escalated doses while most patients in IFX had an escalated regimen (69%). The percentage of patients with reduced doses were 27.1% and 25% for both the ETN and ADA groups respectively, with less than 4% in the IFX group.The distribution of patients in the ETN and ADA groups were similar, with most patients receiving the standard therapy, whereas in the IFX group there was a considerable proportion of patients with an escalated regimen. We found more than 60% of responders (DAS28 ≤3.2) in the ETN and ADA groups and less than 50% in the IFX one. <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> shows the distribution of responder and non-responder patients within the different treatment regimens (standard, escalated, and reduced) of the evaluated drugs. Both ETN (61.7%) and ADA (64.3%) groups had more responders than non-responders in any of the dosage regimens, even in the reduced one. On the other hand, the IFX group, despite having the higher number of patients in an escalated regimen, had globally less responders (48.3%), even at increased doses, where responders and non-responders were distributed at 50%. However, mean DAS28 value was similar for all anti-TNF (ETN: 2.8±1.5, ADA: 2.7±1.5,IFX: 3.3±1.5; P=.6). ETN patients, regardless of biologic line, were less likely to use concomitant DMARD than ADA or IFX patients. The drug more frequently used in association was methotrexate (MTX) followed by leflunomide (LEF).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>DiscussionAlthough clinical experience confirms the long-term efficacy of standard dosages for anti-TNF drugs, this study, based on our daily clinical experience, provides real-life data on the use of different dosage regimens. While the mean DAS28 value was similar between groups, we found more responders by DAS28 among patients in ETN and ADA groups when compared to IFX group, despite the higher percentage of patients with dose escalation in the latter group. IFX dose escalation in clinical practice has been reported elsewhere.<a class="elsevierStyleCrossRefs" href="#bib0040">8–15</a> Nevertheless, in our cohort IFX was mainly used as a first line therapy, having a longer disease duration as well as a longer delay until biological treatment. The election of the drug and the different efficacies between anti-TNFs might be related to the patient's clinical and demographic characteristics, as well as the drugs available at the moment of starting biological treatment as well as the recent tendency to treat to target.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>Nevertheless, when patients achieve clinical response, physicians can be constrained by the dosages specified in the summary of product characteristics (SPC). Real-life clinical practice supports the benefits of tailoring RA treatment, considering the severity of the condition, the effectiveness of each specific drug, and the risk of side effects. In our study over 40% of the patients were treated with either higher or lower dosages than those recommended in the approved prescribing information.Considering the cross-sectional design of the study, the interpretation of the results is limited since we cannot differentiate cause and effect from a simple association. In this sense, we have no information regarding patients in which dose reduction had been previously attempted without maintaining clinical response, and those who never tried dose titration. Also, we have identified some patients with very active disease or moderate disease activity on reduced dosage regimens. Even though this finding might be contradictory, those patients presented very established RA with chronic damage due to long-term disease duration, but no current clinical activity.DMARD use was lower for patients on ETN when compared to ADA and IFX. Better clinical efficacy of anti-TNF in combination with DMARD is broadly accepted,<a class="elsevierStyleCrossRef" href="#bib0085">17</a> however it is interesting to highlight the increased possibility of clinical control in our ETN group without concomitant DMARD, in accordance with other reports which give data of up to 50% of patients on ETN treatment inmonotherapy.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> However, non use of DMARDs have been broadly showed in patients after various biologics, and taking into account that ETN was the second line for most of the patients included n this study we cannot firmly conclude monotherapy as a good option only for ETN.Despite its limitations, this study has some strengths, since cross-sectional studies are useful at identifying associations and generating hypotheses.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> This study may be considered a good start point for controlled long-term trials that further investigate our findings. When a drug is effective at achieving disease control, it is important to consider the possibility of tapering doses whenever possible to reduce the cost and the possible long-term side effects.ConclusionsRegarding our results, it seems reasonable, when clinical response has been achieved, to try to reduce the standard dosage in order to establish the minimum effective dose, because tapered doses do not seem to lead to high disease activity in some patients.Conflict of InterestThe authors declare no conflict of interest.Ethical ResponsibilitiesProtection of Human and Animal SubjectsThe authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration.Confidentiality of DataThe authors declare that they have followed the protocols of their work centre on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study.Right to Privacy and Informed ConsentThe authors have obtained the informed consent of the patients and/or subjects mentioned in the article. The author for correspondence is in possession of this document." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres326257" "titulo" => array:5 [ 0 => "Abstract" 1 => "Aims" 2 => "Patients and methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec307736" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres326256" "titulo" => array:5 [ 0 => "Resumen" 1 => "Objetivos" 2 => "Pacientes y métodos" 3 => "Resultados" 4 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec307737" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Patients and Methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Study Design and Patient Population" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Study Variables" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Ethics" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Statistical Analyses" ] ] ] 6 => array:3 [ "identificador" => "sec0035" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Demographic and Clinical Data (Table 1)" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Dosage Regimen and Clinical Disease Activity" ] ] ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflict of Interest" ] 10 => array:3 [ "identificador" => "sec0065" "titulo" => "Ethical Responsibilities" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "Protection of Human and Animal Subjects" ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Confidentiality of Data" ] 2 => array:2 [ "identificador" => "sec0080" "titulo" => "Right to Privacy and Informed Consent" ] ] ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-07-18" "fechaAceptado" => "2013-07-24" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec307736" "palabras" => array:7 [ 0 => "Rheumatoid arthritis" 1 => "Anti-TNF" 2 => "Dosage titration" 3 => "DAS28" 4 => "Etanercept" 5 => "Adalimumab" 6 => "Infliximab" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec307737" "palabras" => array:7 [ 0 => "Artritis reumatoide" 1 => "Anti-TNF" 2 => "Ajuste de la dosis" 3 => "DAS28" 4 => "Etanercep" 5 => "Adalimumab" 6 => "Infliximab" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "AimsTo evaluate the modified dosages of anti-TNF in controlling disease activity in rheumatoid arthritis (RA) measured by DAS28-ESR. Patients and methodsCross-sectional study: RA patients treated with etanercept (ETN), adalimumab (ADA) or infliximab (IFX), at standard or modified doses. Main variables: dosage, concomitant disease modifying drugs (DMARDs), DAS28-ESR. Results195 RA patients included (79% women, mean age 58.1 years): ETN=81, ADA=56, IFX=58. Mean disease duration and time to first biological treatment was higher in IFX group (P=.01). Patients distribution by dosage: standard: ETN (72.8%), ADA (69.6%), IFX (27.6%); escalated: IFX (69%), ADA (5.4%), ETN (0%); reduced: ETN (27.1%), ADA (25%), IFX (3.4%). Concomitant DMARDs use was lower in ETN (58.2%) than ADA (66.07%) and IFX (79.31%). Higher proportion of responders (DAS28 ≤3.2) in ADA (65.3%) and ETN (61.7%) than IFX (48.3%). ConclusionsRA clinical control can be preserved with modified anti-TNF dosages. Controlled prospective studies should be performed to define when therapy can be tailored and for which patients." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "ObjetivosAvaluar dosis modificadas de anti-TNF en el control de actividad de la enfermedad en la artritis reumatoide (AR) medida por DAS28-VSG. Pacientes y métodosEstudio transversal: pacientes con AR tratados con etanercept (ETN), adalimumab (ADA) o infliximab (IFX), en dosis estándar o modificada. Principales variables: dosis, enfermedad concomitante, fármacos modificadores (DMARDs), DAS28-VSG. Resultados195 pacientes con AR fueron incluidos (79% mujeres, edad media 58,1 años): ETN = 81, ADA = 56, IFX = 58. La duración de la enfermedad y el tiempo medio hasta el primer tratamiento biológico fue mayor en el grupo con IFX (p = 0,01). Distribución de los pacientes por dosis estándar: ETN (72,8%), ADA (69,6%), IFX (27,6%); incremento: IFX (69%), ADA (5,4%), ETN (0%), reducción: ETN (27,1%), ADA (25%), IFX (3,4%). Uso concomitante DMARD fue menor en ETN (58,2%) que ADA (66,07%) e IFX (79,31%). La mayor proporción de respondedores (DAS28 ≤ 3,2) se vio en ADA (65,3%) y ETN (61,7%) que en IFX (48,3%). ConclusionesEl control clínico de la AR se puede preservar con dosis modificadas de anti-TNF. Estudios prospectivos controlados deben realizarse para definir cuando la terapia se puede adaptar y en que pacientes." ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1358 "Ancho" => 2328 "Tamanyo" => 220121 ] ] "descripcion" => array:1 [ "en" => "Percentage of responders (DAS28 ≤3.2) and non-responders (DAS28 >3.2) in the different dosage regimens of anti-TNF treatments. ETN: etanercept; ADA; adalimumab; IFX: infliximab. Reduced (the time between doses was longer or the doses were lower than the standard ones). Standard (according to the approved prescribing information): ETN 25mg twice a week or 50mg weekly, ADA 40mg every other week, and IFX 3mg/kg every 8 weeks. Escalated (the time between doses was shorter or the doses were higher than the standard ones)." ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "NS: no significant. ETN: etanercept; ADA: adalimumab; IFX: infliximab; DAS28: Disease Activity Score.P value: ANOVA test between the 3 groups." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">ETN (n: 81) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">ADA (n: 56) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">IFX (n: 58) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">P value \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Demographics</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Female; n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 (80) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38 (67.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">52 (89.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age (years; mean±SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">53.2 (±15.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59.9 (±15.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">61.3 (±10.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DAS28 (mean±SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.75 (±1.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.69 (±1.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.25 (±1.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Concomitant DMARD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">58.0% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">66.1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">79.3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">P=.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clinical disease duration (years; mean±SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.3 (±6.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10.5 (±6.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13.2 (±6.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">P=.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><2 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.7% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2–5 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.8% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21.6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10.9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">P=.03 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5–10 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36.5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31.4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18.2% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10–20 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41.9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37.3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">47.3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>20 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.2% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9.8% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23.6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Time from diagnosis to first anti-TNF treatment (years; mean±SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.7 (±5.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.9 (±5.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.5 (±4.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">P=.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><2 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17.6%<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.8%<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">P=.02<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2–5 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25.7% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31.4%<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23.6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">P=.02<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5–10 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27.0% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31.4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29.1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10–20 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18.9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23.5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40.0% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>20 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.0% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">First-line biological option (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">63.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">70.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">87.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">P=.02 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Second-line biological option (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">P=.02 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab476177.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "U-Mann–Whitney comparison group per group." ] ] ] "descripcion" => array:1 [ "en" => "Demographic and clinical characteristics of patients." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:19 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Biologic agents in rheumatoid arthritis: an update for managed care professionals" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "S.K. Agarwal" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.18553/jmcp.2011.17.s9-b.S14" "Revista" => array:7 [ "tituloSerie" => "J Manag Care Pharm" "fecha" => "2011" "volumen" => "17" "numero" => "9 Suppl. B" "paginaInicial" => "S14" "paginaFinal" => "S18" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22073935" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dose titration using the Disease Activity Score (DAS28) in rheumatoid arthritis patients treated with anti-TNFalpha" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A.A. Den Broeder" 1 => "M.C. Creemers" 2 => "A.M. Van Gestel" 3 => "P.L. Van Riel" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2002" "volumen" => "41" "paginaInicial" => "638" "paginaFinal" => "642" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Is there a need for immunopharmacologic guidance of anti-tumor necrosis factor therapies?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "K. Bendtzen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.30207" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2011" "volumen" => "63" "paginaInicial" => "867" "paginaFinal" => "870" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21452309" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Differences in biologic dose-escalation non-biologic and steroid intensification among three anti-TNF agents: evidence from clinical practice" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.J. Moots" 1 => "B. Haraoui" 2 => "M. Matucci-Cerinic" 3 => "P.L. van Riel" 4 => "J. Kekow" 5 => "T. Schaeverbeke" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Exp Rheumatol" "fecha" => "2011" "volumen" => "29" "paginaInicial" => "26" "paginaFinal" => "34" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21345289" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The effects of low dose etanercept on disease control and radiographic progression in moderate to severe rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "B. Raffeiner" 1 => "C. Botsios" 2 => "P. Sfriso" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.27185" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2010" "volumen" => "62" "numero" => "10 Suppl." "paginaInicial" => "290" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20039398" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.S. Smolen" 1 => "R. Landewe" 2 => "F.C. Breedveld" 3 => "M. Buch" 4 => "G. Burmester" 5 => "M. Dougados" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/ard.2009.126532" "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2010" "volumen" => "69" "paginaInicial" => "964" "paginaFinal" => "975" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20444750" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F.C. Arnett" 1 => "S.M. Edworthy" 2 => "D.A. Bloch" 3 => "D.J. McShane" 4 => "J.F. Fries" 5 => "N.S. Cooper" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "1988" "volumen" => "31" "paginaInicial" => "315" "paginaFinal" => "324" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3358796" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Patterns of biologic agent utilization among patients with rheumatoid arthritis: a retrospective cohort study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "S. Ogale" 1 => "E. Hitraya" 2 => "H.J. Henk" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1471-2474-12-204" "Revista" => array:5 [ "tituloSerie" => "BMC Musculoskelet Disord" "fecha" => "2011" "volumen" => "12" "paginaInicial" => "204" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21929807" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evidence for differential acquired drug resistance to anti-tumour necrosis factor agents in rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A. Finckh" 1 => "J.F. Simard" 2 => "C. Gabay" 3 => "P.A. Guerne" 4 => "S. 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Brief Report

Minimum Effective Dosages of Anti-TNF in Rheumatoid Arthritis: A Cross-sectional Study

Dosis efectiva mínimas de anti-TNF en artritis reumatoide: un estudio transversal

Inmaculada De La Torre

Corresponding author

Inma.torre.ortega@googlemail.com

Corresponding author.

, Lara Valor, Juan Carlos Nieto, María Montoro, Luis Carreño

Rheumatology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Rheumatoid arthritis &#40;RA&#41; is a chronic&#44; systemic&#44; inflammatory disease with a fluctuant but progressive course&#44; leading&#44; without treatment&#44; to cartilage damage&#44; bone erosions&#44; and joint destruction&#44; the main causes of long-term disability&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Although the registered doses of anti-TNFs are at the top of the group dose response curve and under-treatment is not expected to be very frequent&#44; the use of standard dosages in clinical practice may result in under or over treatment<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> once remission or low disease activity have been achieved&#44; making it reasonable to attempt treating patients on an individualized schedule&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Clinical experience confirms the long-term efficacy of standard dosages for anti-TNF drugs&#44; evaluation is still necessary to determine if reduced dosages could maintain clinically controlled patients&#46; There are some reports addressing the issue of stopping&#44; lowering&#44; or increasing the dosages inpatients in remission&#44;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> showing that up to 50&#37; of patients relapse if the drug is stopped&#44; and reintroduction of the therapy might not achieve previous results&#46; However&#44; tapering anti-TNF dosages seems to preserve the clinical efficacy in most patients&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Consequently&#44; RA patients treated with anti-TNF who are in maintained remission<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> could benefit from treatment adjustment in order to find the lowest effective dose&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of the study was to assess the anti-TNF dosages in RA patients&#44; evaluating whether modified patterns could control patients clinically under our daily clinical practice&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study Design and Patient Population</span><p id="par0025" class="elsevierStylePara elsevierViewall">A cross-sectional&#44; non-interventional study was conducted in the Hospital General Universitario Gregorio Mara&#241;&#243;n &#40;HGUGM&#41; in Madrid &#40;Spain&#41;&#44; from October 2010 to October 2011&#46; During the study period&#44; patients receiving anti-TNF for a minimum period of 12 months&#44; and attending per routine follow-up the Biological Therapy Unit at the Rheumatology Department&#44; were subsequently included&#46; Requirements included being diagnosed with RA&#44; according to the American College of Rheumatology&#39;s &#40;ACR&#41; 1987 revised criteria&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and treated with any of the following anti-TNF drugs&#58; etanercept &#40;ETN&#41;&#44; adalimumab &#40;ADA&#41;&#44; or infliximab &#40;IFX&#41;&#44;administered either at standard or modified doses&#46; <span class="elsevierStyleItalic">Standard therapy</span> was that in accordance with the approved prescribing information&#58; ETN 25<span class="elsevierStyleHsp" style=""></span>mg twice a week or 50<span class="elsevierStyleHsp" style=""></span>mg weekly&#44; ADA40<span class="elsevierStyleHsp" style=""></span>mg every other week&#44; and IFX 3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 8 weeks&#46; <span class="elsevierStyleItalic">Modified therapy</span> was either <span class="elsevierStyleItalic">escalated</span> &#40;the time between doses was shorter or the doses were higher than the standard ones&#41; or <span class="elsevierStyleItalic">reduced</span> &#40;the time between doses was longer or the doses were lower than the standard ones&#41;&#46; Dose tapering was adopted if the patient was in remission by DAS28 &#60;2&#46;6 or low activity &#60;3&#46;2 for those with very established and chronic disease for at least 1 year&#44; based on a clinician and patient agreement&#44; and not following any standardized protocol&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Study Variables</span><p id="par0030" class="elsevierStylePara elsevierViewall">The variables studied were the percentage of patients treated with each drug &#40;IFX&#44; ADA&#44; and ETN&#41;&#44; the prescribed dosages&#44; the distribution of patients in clinical categories according to the Disease Activity Score &#40;DAS28&#41;&#58;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Remission &#40;DAS28 &#60;2&#46;6&#41;&#59; Low activity &#40;DAS28&#58; 2&#46;6&#8211;3&#46;2&#41;&#59; Moderate activity &#40;DAS28&#58; 3&#46;2&#8211;5&#46;1&#41;&#59; or High activity &#40;DAS28 &#62;5&#46;1&#41; in each treatment group&#44; and the concomitant treatment with DMARDs&#58; methotrexate &#40;MTX&#41;&#44; leflunomide &#40;LF&#41;&#44; sulfasalazine&#44; andhydroxychloroquine&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Ethics</span><p id="par0035" class="elsevierStylePara elsevierViewall">The study was approved by the HGUGM Ethics Committee and all participants provided written informed consent&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Statistical Analyses</span><p id="par0040" class="elsevierStylePara elsevierViewall">Data was analyzed with the SPSS 17&#46;0 statistical program&#46; Continuous variables were described using mean and standard deviation &#40;SD&#41; or median and range&#46; Categorical variables were described with frequencies and percentages&#46; Statistical analyses including parametric and non-parametric tests in relation with variables distribution were performed comparing the 3 groups &#40;ANOVA or Kruskal&#8211;Wallis test&#41;&#46; Additional comparisons between IFX-ADA&#44; IFX-ETN&#44; and ETN-ADA groups were carried out using non-parametric or parametric tests &#40;<span class="elsevierStyleItalic">U</span> Mann&#8211;Whitney&#44; Chi square&#41;&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Demographic and Clinical Data &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;</span><p id="par0045" class="elsevierStylePara elsevierViewall">195 RA patients were included&#46; Participants were predominantly women &#40;79&#37;&#41; and the global mean age was 58&#46;1 &#40;&#177;14&#46;9&#41; years&#46; Patients were distributed into 3 groups&#44; according to the anti-TNF drug used&#58; 81 patients in the ETN group &#40;41&#46;5&#37;&#41;&#44; 56 in the ADA group &#40;28&#46;7&#37;&#41;&#44; and 58 in the IFX group &#40;29&#46;7&#37;&#41;&#46; Mean disease duration &#40;years&#41; was statistically different between groups &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;01&#41; although most patients &#40;42&#46;2&#37;&#41; had a mean disease duration between 10 and 20 years&#46; In the 2&#8211;5 year range of duration&#44; however&#44; the percentage of patients in the ADA group was significantly higher when compared to ETN and IFX &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;03&#41;&#46; There were also significant differences between groups in terms of time from diagnosis to the administration of the first biological treatment&#46; IFX was most commonly used as first-line biological treatment&#44; whereas ETN was the option most commonly used as second-line&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Dosage Regimen and Clinical Disease Activity</span><p id="par0050" class="elsevierStylePara elsevierViewall">Most patients in ETN &#40;72&#46;8&#37;&#41; and ADA &#40;69&#46;6&#37;&#41; groups were treated with the standard dosages&#46; In the ETN group there were no patients in escalated doses while most patients in IFX had an escalated regimen &#40;69&#37;&#41;&#46; The percentage of patients with reduced doses were 27&#46;1&#37; and 25&#37; for both the ETN and ADA groups respectively&#44; with less than 4&#37; in the IFX group&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The distribution of patients in the ETN and ADA groups were similar&#44; with most patients receiving the standard therapy&#44; whereas in the IFX group there was a considerable proportion of patients with an escalated regimen&#46; We found more than 60&#37; of responders &#40;DAS28 &#8804;3&#46;2&#41; in the ETN and ADA groups and less than 50&#37; in the IFX one&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> shows the distribution of responder and non-responder patients within the different treatment regimens &#40;standard&#44; escalated&#44; and reduced&#41; of the evaluated drugs&#46; Both ETN &#40;61&#46;7&#37;&#41; and ADA &#40;64&#46;3&#37;&#41; groups had more responders than non-responders in any of the dosage regimens&#44; even in the reduced one&#46; On the other hand&#44; the IFX group&#44; despite having the higher number of patients in an escalated regimen&#44; had globally less responders &#40;48&#46;3&#37;&#41;&#44; even at increased doses&#44; where responders and non-responders were distributed at 50&#37;&#46; However&#44; mean DAS28 value was similar for all anti-TNF &#40;ETN&#58; 2&#46;8&#177;1&#46;5&#44; ADA&#58; 2&#46;7&#177;1&#46;5&#44;IFX&#58; 3&#46;3&#177;1&#46;5&#59; <span class="elsevierStyleItalic">P</span>&#61;&#46;6&#41;&#46; ETN patients&#44; regardless of biologic line&#44; were less likely to use concomitant DMARD than ADA or IFX patients&#46; The drug more frequently used in association was methotrexate &#40;MTX&#41; followed by leflunomide &#40;LEF&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0060" class="elsevierStylePara elsevierViewall">Although clinical experience confirms the long-term efficacy of standard dosages for anti-TNF drugs&#44; this study&#44; based on our daily clinical experience&#44; provides real-life data on the use of different dosage regimens&#46; While the mean DAS28 value was similar between groups&#44; we found more responders by DAS28 among patients in ETN and ADA groups when compared to IFX group&#44; despite the higher percentage of patients with dose escalation in the latter group&#46; IFX dose escalation in clinical practice has been reported elsewhere&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#8211;15</span></a> Nevertheless&#44; in our cohort IFX was mainly used as a first line therapy&#44; having a longer disease duration as well as a longer delay until biological treatment&#46; The election of the drug and the different efficacies between anti-TNFs might be related to the patient&#39;s clinical and demographic characteristics&#44; as well as the drugs available at the moment of starting biological treatment as well as the recent tendency to treat to target&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Nevertheless&#44; when patients achieve clinical response&#44; physicians can be constrained by the dosages specified in the summary of product characteristics &#40;SPC&#41;&#46; Real-life clinical practice supports the benefits of tailoring RA treatment&#44; considering the severity of the condition&#44; the effectiveness of each specific drug&#44; and the risk of side effects&#46; In our study over 40&#37; of the patients were treated with either higher or lower dosages than those recommended in the approved prescribing information&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Considering the cross-sectional design of the study&#44; the interpretation of the results is limited since we cannot differentiate cause and effect from a simple association&#46; In this sense&#44; we have no information regarding patients in which dose reduction had been previously attempted without maintaining clinical response&#44; and those who never tried dose titration&#46; Also&#44; we have identified some patients with very active disease or moderate disease activity on reduced dosage regimens&#46; Even though this finding might be contradictory&#44; those patients presented very established RA with chronic damage due to long-term disease duration&#44; but no current clinical activity&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">DMARD use was lower for patients on ETN when compared to ADA and IFX&#46; Better clinical efficacy of anti-TNF in combination with DMARD is broadly accepted&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> however it is interesting to highlight the increased possibility of clinical control in our ETN group without concomitant DMARD&#44; in accordance with other reports which give data of up to 50&#37; of patients on ETN treatment inmonotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> However&#44; non use of DMARDs have been broadly showed in patients after various biologics&#44; and taking into account that ETN was the second line for most of the patients included <span class="elsevierStyleItalic">n</span> this study we cannot firmly conclude monotherapy as a good option only for ETN&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Despite its limitations&#44; this study has some strengths&#44; since cross-sectional studies are useful at identifying associations and generating hypotheses&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> This study may be considered a good start point for controlled long-term trials that further investigate our findings&#46; When a drug is effective at achieving disease control&#44; it is important to consider the possibility of tapering doses whenever possible to reduce the cost and the possible long-term side effects&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conclusions</span><p id="par0085" class="elsevierStylePara elsevierViewall">Regarding our results&#44; it seems reasonable&#44; when clinical response has been achieved&#44; to try to reduce the standard dosage in order to establish the minimum effective dose&#44; because tapered doses do not seem to lead to high disease activity in some patients&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of Interest</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Ethical Responsibilities</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Protection of Human and Animal Subjects</span><p id="par0095" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Confidentiality of Data</span><p id="par0100" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work centre on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Right to Privacy and Informed Consent</span><p id="par0105" class="elsevierStylePara elsevierViewall">The authors have obtained the informed consent of the patients and&#47;or subjects mentioned in the article&#46; 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          "identificador" => "xpalclavsec307737"
          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
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        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Patients and Methods"
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            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Study Design and Patient Population"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Study Variables"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Ethics"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Statistical Analyses"
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          ]
        ]
        6 => array:3 [
          "identificador" => "sec0035"
          "titulo" => "Results"
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            0 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Demographic and Clinical Data &#40;Table 1&#41;"
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            1 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Dosage Regimen and Clinical Disease Activity"
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        7 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Discussion"
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        8 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Conclusions"
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        9 => array:2 [
          "identificador" => "sec0060"
          "titulo" => "Conflict of Interest"
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        10 => array:3 [
          "identificador" => "sec0065"
          "titulo" => "Ethical Responsibilities"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Protection of Human and Animal Subjects"
            ]
            1 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Confidentiality of Data"
            ]
            2 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Right to Privacy and Informed Consent"
            ]
          ]
        ]
        11 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2013-07-18"
    "fechaAceptado" => "2013-07-24"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec307736"
          "palabras" => array:7 [
            0 => "Rheumatoid arthritis"
            1 => "Anti-TNF"
            2 => "Dosage titration"
            3 => "DAS28"
            4 => "Etanercept"
            5 => "Adalimumab"
            6 => "Infliximab"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec307737"
          "palabras" => array:7 [
            0 => "Artritis reumatoide"
            1 => "Anti-TNF"
            2 => "Ajuste de la dosis"
            3 => "DAS28"
            4 => "Etanercep"
            5 => "Adalimumab"
            6 => "Infliximab"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Aims</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To evaluate the modified dosages of anti-TNF in controlling disease activity in rheumatoid arthritis &#40;RA&#41; measured by DAS28-ESR&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Cross-sectional study</span>&#58; RA patients treated with etanercept &#40;ETN&#41;&#44; adalimumab &#40;ADA&#41; or infliximab &#40;IFX&#41;&#44; at standard or modified doses&#46; <span class="elsevierStyleItalic">Main variables</span>&#58; dosage&#44; concomitant disease modifying drugs &#40;DMARDs&#41;&#44; DAS28-ESR&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">195 RA patients included &#40;79&#37; women&#44; mean age 58&#46;1 years&#41;&#58; ETN&#61;81&#44; ADA&#61;56&#44; IFX&#61;58&#46; Mean disease duration and time to first biological treatment was higher in IFX group &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;01&#41;&#46; Patients distribution by dosage&#58; standard&#58; ETN &#40;72&#46;8&#37;&#41;&#44; ADA &#40;69&#46;6&#37;&#41;&#44; IFX &#40;27&#46;6&#37;&#41;&#59; escalated&#58; IFX &#40;69&#37;&#41;&#44; ADA &#40;5&#46;4&#37;&#41;&#44; ETN &#40;0&#37;&#41;&#59; reduced&#58; ETN &#40;27&#46;1&#37;&#41;&#44; ADA &#40;25&#37;&#41;&#44; IFX &#40;3&#46;4&#37;&#41;&#46; Concomitant DMARDs use was lower in ETN &#40;58&#46;2&#37;&#41; than ADA &#40;66&#46;07&#37;&#41; and IFX &#40;79&#46;31&#37;&#41;&#46; Higher proportion of responders &#40;DAS28 &#8804;3&#46;2&#41; in ADA &#40;65&#46;3&#37;&#41; and ETN &#40;61&#46;7&#37;&#41; than IFX &#40;48&#46;3&#37;&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">RA clinical control can be preserved with modified anti-TNF dosages&#46; Controlled prospective studies should be performed to define when therapy can be tailored and for which patients&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Avaluar dosis modificadas de anti-TNF en el control de actividad de la enfermedad en la artritis reumatoide &#40;AR&#41; medida por DAS28-VSG&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio transversal&#58; pacientes con AR tratados con etanercept &#40;ETN&#41;&#44; adalimumab &#40;ADA&#41; o infliximab &#40;IFX&#41;&#44; en dosis est&#225;ndar o modificada&#46; Principales variables&#58; dosis&#44; enfermedad concomitante&#44; f&#225;rmacos modificadores &#40;DMARDs&#41;&#44; DAS28-VSG&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">195 pacientes con AR fueron incluidos &#40;79&#37; mujeres&#44; edad media 58&#44;1 a&#241;os&#41;&#58; ETN &#61; 81&#44; ADA &#61; 56&#44; IFX &#61; 58&#46; La duraci&#243;n de la enfermedad y el tiempo medio hasta el primer tratamiento biol&#243;gico fue mayor en el grupo con IFX &#40;p &#61; 0&#44;01&#41;&#46; Distribuci&#243;n de los pacientes por dosis est&#225;ndar&#58; ETN &#40;72&#44;8&#37;&#41;&#44; ADA &#40;69&#44;6&#37;&#41;&#44; IFX &#40;27&#44;6&#37;&#41;&#59; incremento&#58; IFX &#40;69&#37;&#41;&#44; ADA &#40;5&#44;4&#37;&#41;&#44; ETN &#40;0&#37;&#41;&#44; reducci&#243;n&#58; ETN &#40;27&#44;1&#37;&#41;&#44; ADA &#40;25&#37;&#41;&#44; IFX &#40;3&#44;4&#37;&#41;&#46; Uso concomitante DMARD fue menor en ETN &#40;58&#44;2&#37;&#41; que ADA &#40;66&#44;07&#37;&#41; e IFX &#40;79&#44;31&#37;&#41;&#46; La mayor proporci&#243;n de respondedores &#40;DAS28 &#8804; 3&#44;2&#41; se vio en ADA &#40;65&#44;3&#37;&#41; y ETN &#40;61&#44;7&#37;&#41; que en IFX &#40;48&#44;3&#37;&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El control cl&#237;nico de la AR se puede preservar con dosis modificadas de anti-TNF&#46; Estudios prospectivos controlados deben realizarse para definir cuando la terapia se puede adaptar y en que pacientes&#46;</p>"
      ]
    ]
    "multimedia" => array:2 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1358
            "Ancho" => 2328
            "Tamanyo" => 220121
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Percentage of responders &#40;DAS28 &#8804;3&#46;2&#41; and non-responders &#40;DAS28 &#62;3&#46;2&#41; in the different dosage regimens of anti-TNF treatments&#46; ETN&#58; etanercept&#59; ADA&#59; adalimumab&#59; IFX&#58; infliximab&#46; Reduced &#40;the time between doses was longer or the doses were lower than the standard ones&#41;&#46; Standard &#40;according to the approved prescribing information&#41;&#58; ETN 25<span class="elsevierStyleHsp" style=""></span>mg twice a week or 50<span class="elsevierStyleHsp" style=""></span>mg weekly&#44; ADA 40<span class="elsevierStyleHsp" style=""></span>mg every other week&#44; and IFX 3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 8 weeks&#46; Escalated &#40;the time between doses was shorter or the doses were higher than the standard ones&#41;&#46;</p>"
        ]
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      1 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">NS&#58; no significant&#46; ETN&#58; etanercept&#59; ADA&#58; adalimumab&#59; IFX&#58; infliximab&#59; DAS28&#58; Disease Activity Score&#46;</p><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">P</span> value&#58; ANOVA test between the 3 groups&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">ETN &#40;<span class="elsevierStyleItalic">n</span>&#58; 81&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">IFX &#40;<span class="elsevierStyleItalic">n</span>&#58; 58&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Female&#59;</span> n <span class="elsevierStyleItalic">&#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">64 &#40;80&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38 &#40;67&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">52 &#40;89&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">ns&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Age &#40;years&#59; mean&#177;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">53&#46;2 &#40;&#177;15&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">59&#46;9 &#40;&#177;15&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">61&#46;3 &#40;&#177;10&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">DAS28 &#40;mean&#177;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2&#46;75 &#40;&#177;1&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">2&#46;69 &#40;&#177;1&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">3&#46;25 &#40;&#177;1&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Concomitant DMARD</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">79&#46;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">P</span>&#61;&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Clinical disease duration &#40;years&#59; mean&#177;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">11&#46;3 &#40;&#177;6&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">10&#46;5 &#40;&#177;6&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">13&#46;2 &#40;&#177;6&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">P</span>&#61;&#46;01&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;2 years</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2&#46;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">2&#8211;5 years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&#46;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">P</span>&#61;&#46;03&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">5&#8211;10 years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#46;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">10&#8211;20 years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&#46;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&#46;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#62;20 years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#46;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&#46;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Time from diagnosis to first anti-TNF treatment &#40;years&#59; mean&#177;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;7 &#40;&#177;5&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;9 &#40;&#177;5&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;5 &#40;&#177;4&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">P</span>&#61;&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;2 years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#46;6&#37;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#46;8&#37;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">P</span>&#61;&#46;02<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">2&#8211;5 years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&#46;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&#46;4&#37;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&#46;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">P</span>&#61;&#46;02<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">5&#8211;10 years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&#46;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">10&#8211;20 years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&#46;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#62;20 years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">First-line biological option &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">70&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">87&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">P</span>&#61;&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Second-line biological option &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">P</span>&#61;&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                      "titulo" => "Biologic agents in rheumatoid arthritis&#58; an update for managed care professionals"
                      "autores" => array:1 [
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                        "tituloSerie" => "J Manag Care Pharm"
                        "fecha" => "2011"
                        "volumen" => "17"
                        "numero" => "9 Suppl&#46; B"
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Article information

ISSN: 21735743
Original language: English

DOI:10.1016/j.reumae.2013.07.004

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Year/Month	Html	Pdf	Total

2024 November	3	4	7
2024 October	37	24	61
2024 September	33	15	48
2024 August	68	30	98
2024 July	74	35	109
2024 June	71	27	98
2024 May	78	40	118
2024 April	55	22	77
2024 March	56	24	80
2024 February	26	31	57
2024 January	23	17	40
2023 December	22	24	46
2023 November	29	15	44
2023 October	36	40	76
2023 September	84	27	111
2023 August	33	25	58
2023 July	34	20	54
2023 June	31	23	54
2023 May	48	24	72
2023 April	31	18	49
2023 March	70	26	96
2023 February	50	25	75
2023 January	33	18	51
2022 December	58	30	88
2022 November	60	23	83
2022 October	53	27	80
2022 September	33	26	59
2022 August	29	46	75
2022 July	25	39	64
2022 June	38	40	78
2022 May	56	55	111
2022 April	31	46	77
2022 March	39	39	78
2022 February	41	28	69
2022 January	28	36	64
2021 December	23	51	74
2021 November	24	53	77
2021 October	30	40	70
2021 September	23	31	54
2021 August	13	34	47
2021 July	22	25	47
2021 June	21	34	55
2021 May	23	27	50
2021 April	84	54	138
2021 March	39	24	63
2021 February	22	27	49
2021 January	44	22	66
2020 December	23	15	38
2020 November	22	15	37
2020 October	14	6	20
2020 September	14	10	24
2020 August	17	16	33
2020 July	32	9	41
2020 June	25	16	41
2020 May	35	11	46
2020 April	24	10	34
2020 March	16	8	24
2020 February	2	0	2
2018 May	5	1	6
2018 April	20	14	34
2018 March	32	10	42
2018 February	25	5	30
2018 January	17	13	30
2017 December	28	4	32
2017 November	26	7	33
2017 October	19	8	27
2017 September	24	5	29
2017 August	42	7	49
2017 July	25	8	33
2017 June	49	8	57
2017 May	36	12	48
2017 April	22	7	29
2017 March	38	17	55
2017 February	25	7	32
2017 January	20	3	23
2016 December	39	18	57
2016 November	20	0	20
2016 October	37	12	49
2016 September	30	7	37
2016 August	33	7	40
2016 July	14	3	17
2016 April	1	0	1
2015 December	2	0	2
2015 September	1	0	1
2015 August	3	0	3
2015 July	10	5	15
2015 June	29	11	40
2015 May	41	21	62
2015 April	22	16	38
2015 March	18	9	27
2015 February	12	14	26
2015 January	12	10	22
2014 December	23	15	38
2014 November	28	9	37
2014 October	26	16	42
2014 September	29	20	49
2014 August	21	17	38
2014 July	35	16	51
2014 June	43	20	63
2014 May	41	30	71
2014 April	36	29	65
2014 March	27	21	48

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