Review Article
Efficacy and Safety of Abatacept in Patients With Rheumatoid Arthritis and No Prior Treatment With Biologics
Eficacia y seguridad de abatacept en pacientes con artritis reumatoide sin tratamiento biológico previo
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"documento" => "article" "crossmark" => 0 "subdocumento" => "fla" "cita" => "Reumatol Clin. 2011;7:389-91" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 3929 "formatos" => array:3 [ "EPUB" => 60 "HTML" => 3385 "PDF" => 484 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>" "titulo" => "Systemic Autoimmune Diseases and Depressive Disorders" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "389" "paginaFinal" => "391" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Enfermedades autoinmunitarias sistémicas y trastornos depresivos" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Sylvia Arias, Victoria Fonsalía, Nicolás Asteggiante, Verónica Bartesaghi" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Sylvia" "apellidos" => "Arias" ] 1 => array:2 [ "nombre" => "Victoria" "apellidos" => "Fonsalía" ] 2 => array:2 [ "nombre" => "Nicolás" "apellidos" => "Asteggiante" ] 3 => array:2 [ "nombre" => "Verónica" "apellidos" => "Bartesaghi" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1699258X11001446" "doi" => "10.1016/j.reuma.2011.04.010" "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/S1699258X11001446?idApp=UINPBA00004M" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574311000591?idApp=UINPBA00004M" "url" => "/21735743/0000000700000006/v1_201305061631/S2173574311000591/v1_201305061631/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review Article</span>" "titulo" => "Efficacy and Safety of Abatacept in Patients With Rheumatoid Arthritis and No Prior Treatment With Biologics" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "392" "paginaFinal" => "396" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Alejandro Escudero Contreras, M. Carmen Castro-Villegas, M. Vanesa Hernández-Hernández, Federico Díaz-González" "autores" => array:4 [ 0 => array:3 [ "nombre" => "Alejandro" "apellidos" => "Escudero Contreras" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "M. Carmen" "apellidos" => "Castro-Villegas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "M. Vanesa" "apellidos" => "Hernández-Hernández" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:4 [ "nombre" => "Federico" "apellidos" => "Díaz-González" "email" => array:1 [ 0 => "federico.diaz.gonzalez@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Reumatología, Hospital Universitario Reina Sofía, Córdoba, Spain" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Reumatología, Hospital Universitario de Canarias, Tenerife, Spain" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Eficacia y seguridad de abatacept en pacientes con artritis reumatoide sin tratamiento biológico previo" ] ] "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" => 1311 "Ancho" => 1586 "Tamanyo" => 92947 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">ACR response at 6 and 12 months in the abatacept group compared to placebo. <span class="elsevierStyleSup">a</span><span class="elsevierStyleItalic">P</span><.001 for abatacept vs placebo; <span class="elsevierStyleSup">b</span><span class="elsevierStyleItalic">P</span><.001 for abatacept alone, 12 vs 6 months; <span class="elsevierStyleSup">c</span>ITT population, in which all dropouts were considered as non responders regarding ACR after dropout. ACR: American College of Rheumatology response criteria; ITT: intention to treat; MTX: methotrexate.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Available epidemiological data on the Spanish Society of Rheumatology put the prevalence of rheumatoid arthritis (RA) in the Spanish population at 0.5%,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> which means that at least 200<span class="elsevierStyleHsp" style=""></span>000 people are suffering from this disease in our country. The annual incidence of RA in Spain is 8.3 cases/100<span class="elsevierStyleHsp" style=""></span>000 inhabitants, similar to the two neighboring countries.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The disease affects mainly women (3:1, female/male) with a predilection for the 4th and 5th decades of life, with a long period of joint involvement and a significant increase in morbidity and mortality, which is globally increased over the general population.</p><p id="par0010" class="elsevierStylePara elsevierViewall">In recent decades it has been suggested that RA is presenting with a more benign clinical course. However, this finding is probably due to recent advances in the knowledge of its natural history and pathogenesis, leading to a much earlier diagnosis and more aggressive treatment and not to real changes in the intrinsic aggressiveness of the disease. Regarding therapy, during the last decade the therapeutic arsenal of RA has been strongly reinforced by new biological drugs. These include abatacept (ABA), a recombinant human fusion protein consisting of the extracellular fraction of CTLA-4 receptor and the Fc domain of human IgG1. This molecule allows in vivo blocking of co-stimulation signals by preventing activation of the T lymphocyte (TL). The efficacy and safety of ABA in patients with RA have been supported by the results of randomized controlled trials in patients with RA and data from long-term follow up. This review will focus on the efficacy and safety data obtained from the AGREE, AIM, ATTEST clinical trials, and the 101-100 IM Phase IIb study in which ABA was studied in methotrexate naïve RA patients or those with an inadequate response to methotrexate (MTX) who had not received treatment with anti-tumor necrosis factor (TNF)—a agent.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results of Clinical Efficacy</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">AIM Study (Abatacept in Inadequate Response to Methotrexate)</span><p id="par0015" class="elsevierStylePara elsevierViewall">AIM was a double-blind, randomized, placebo-controlled, multicenter phase III, one-year parallel dose trial that included patients with active RA (No.=656) and with an inadequate response to disease modifying antirheumatic drugs (DMARDs) including methotrexate (MTX) and had never been treated with anti-TNF. The primary objectives were assessed at 6 months and then patients went to an open-label extension follow-up phase lasting 2–5 years.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The response rates obtained by ACR and DAS28 composite indices in the ABA+MTX group (No.=433) were high even from the sixth month cutpoint compared to placebo+MTX group (PLB) (No.=219) (<span class="elsevierStyleItalic">ACR50</span> 39.9% vs 16.8%; <span class="elsevierStyleItalic">ACR70</span> 19.8% vs 6.5%, <span class="elsevierStyleItalic">P</span><.001) and increased progressively each year, showing differences from the control group (<span class="elsevierStyleItalic">ACR50</span> 48.3% vs 18.2%; <span class="elsevierStyleItalic">ACR70</span> 28.8% vs 6.1%, <span class="elsevierStyleItalic">P</span><.001) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Regarding the data obtained in the assessment by DAS28 at the start of treatment both groups showed high clinical activity (mean DAS28=6.4). At 6 months these figures were reduced in the ABA+MTX group compared to control when considered either low activity (DAS28≤3.2; 30.1% vs 10.0%, <span class="elsevierStyleItalic">P</span><.001) or remission (DAS28≤2.6; 14.8% vs 2.8%, <span class="elsevierStyleItalic">P</span><.001). Upon completion of the study year, 44.1% were in the low activity group and more than a quarter of patients (25.4%) in the treatment arm were in remission compared to only 1.9% in the PLB+MTX group.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">In relation to physical function, both treatment groups showed high HAQ-DI (1.7) scores at baseline. Those considered as responders achieved at least a ≥0.3<span class="elsevierStyleHsp" style=""></span>units from baseline difference in the HAQ-DI. Following this criterion, the ABA+MTX group showed statistically significant improvements compared to placebo (63.7% vs 39.3%, <span class="elsevierStyleItalic">P</span><.001) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Moreover, there was improvement in the physical and mental components, in the quality of life test, in the sleep quality test measured by a sleep problem index (SPI) and fatigue determined by visual analog scale (VAS) during first year monitoring of patients in the ABA+MTX group with respect to the control group.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The importance of this trial lies not only in the good results obtained in response rates, but above all, radiographic progression data regarding joint damage. They evaluated structural joint damage changes from baseline with both the total Sharp score (TSS) as modified by Genant and its two components, erosion and impingement. At one year, the ABA+MTX group showed a delay in radiological progression with about half the total score compared with PLB+MTX (0.25 vs 0.53, <span class="elsevierStyleItalic">P</span><.029).<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">After the first year, the trial continued with an open-label extension phase lasting 2 and 5 years. At 5 years, 70.4% of patients in the ABA+MTX remained in the study. In this period, ACR figures, rather than diminishing or stabilizing, gradually increased, showing high levels of <span class="elsevierStyleItalic">ACR50</span>: 61.7% and 61.1% and <span class="elsevierStyleItalic">ACR70</span>: 38% and 39.6% and at 2 and 5 years, respectively. These percentages were stable up to 7 years after (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Similar results occurred with the DAS28 response during the follow-up period: DAS28≤3.2: 56.1% and 54.7% and DAS28≤2.6: 30.9% and 33.7% also at 2 and 5 years, respectively.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">In parallel with the clinical responses, there was a significant improvement in HAQ-DI and SF-36 that was maintained at 2 and 5 years.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,6</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">With regard to structural damage at 2 years, there was a 57% reduction of joint damage (66% reduction in erosion and impingement 47%). In subsequent years there was a continued slowing of total structural damage (0.37, 0.34, and 0.26), erosions (0.23, 0.23, and 0.11), and impingement (0.14, 0.11, and 0.14). At 5 years, 45.1% of patients remained without progression of structural damage.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">All these data confirm the clinical efficacy of abatacept, both associated with MTX and in those patients naïve to anti-TNF therapy.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">The ATTEST Study (Abatacept or Infliximab vs Placebo, Tolerance Test, Efficacy, and Safety in the Treatment of RA)</span><p id="par0055" class="elsevierStylePara elsevierViewall">This was a randomized, double-blind, multicenter phase III trial comparing directly the efficacy of two biologic therapies, ABA (10<span class="elsevierStyleHsp" style=""></span>mg/kg/4 week, No.=156) and infliximab (IFB) (3<span class="elsevierStyleHsp" style=""></span>mg/kg/8 week, No.=165) against PLB (No.=110) in combination with MTX in RA patients with inadequate response to MTX alone. The primary endpoint was ACR20 response rate and DAS28 at 6 months.</p><p id="par0060" class="elsevierStylePara elsevierViewall">At 6 months, in both treatment arms (ABA and IFB), about twice as many patients reached a DAS28≤3.2 (ABA 20.7% vs IFB 25.6%) compared to MTX+PLB (10.8%) and more than three achieved remission (DAS28≤2.6) (ABA 11.3% vs IFB 12.8%) compared to MTX (2.9%). Interestingly, at one year the ABA group data tended to increase (low activity 35.3% and remission 18.7%) compared to the stagnation of the results obtained with IFB (22.4% and 12.2%, respectively) with a mean reduction in DAS28 values at 6 and 12 months to −2.55 and −2.88<span class="elsevierStyleHsp" style=""></span>units in the ABA group and −2.25 vs −2.25<span class="elsevierStyleHsp" style=""></span>units in the IFB group (vs −1.48 in the placebo group, <span class="elsevierStyleItalic">P</span><.001). ACR data at all times were similar in both treatment groups and superior to MTX, even from the 6th month (ACR50 and 70: ABA: 40.4% and 20.5%, IFB: 37% and 24.2%, MTX: 20% and 9.1%, <span class="elsevierStyleItalic">P</span><.05), but at one year they were increased significantly in the group treated with ABA (ABA: 45.5% and 26.3%) while stagnated in the case of IFB (36.4% and 20.6%).<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Despite the limitations in this study on the systematic use of IFB only 3<span class="elsevierStyleHsp" style=""></span>mg/kg, the effectiveness of ABA was clear, behaving similarly to IFB in the first months, with a trend in to overcome it in efficacy in the follow-up.</p><p id="par0070" class="elsevierStylePara elsevierViewall">The 2-year follow-up data were presented in EULAR 2009 in Copenhagen, which included more than 90% of patients initially treated, showing an increase in the low-activity (42% at 2nd year for 35.3% in the first) and remission data (26% vs 18.7%) in the ABA+MTX group. These results were similar in the group treated with MTX+IFB who after completing a year changed to ABA+MTX, increasing the rate of responders in both low activity (45% vs 22.4%) and remission (29% vs 12.2%), as in the ACR of 2nd compared to the 1st year (ACR50 71% vs 36.4%, ACR70 45% vs 20.6%).<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,10</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Phase IIb Trial</span><p id="par0075" class="elsevierStylePara elsevierViewall">This was a multicenter, randomized, placebo-controlled study to evaluate the safety and clinical efficacy at 12 months of two different doses of ABA: 2<span class="elsevierStyleHsp" style=""></span>mg/kg (No.=105) and 10<span class="elsevierStyleHsp" style=""></span>mg/kg (No.=115) or placebo (No.=119), in combination with MTX and administered intravenously in patients with active RA with inadequate response to MTX.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> At one year follow up, patients were switched to a fixed dose of 10<span class="elsevierStyleHsp" style=""></span>mg/kg/4 week, as the dose of 2<span class="elsevierStyleHsp" style=""></span>mg/kg/4 week showed no significant differences to PLB, with an open-label 5 year<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> and 7 year<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> extension.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Clinical response data increased gradually over time (DAS28≤3.2: 48.2%, 58.5%, and 69.7% and DAS28≤2.6: 25.3%, 45.3%, and 51.5% for 1, 5, and 7 years, respectively). The same occurred with the ACR70 response rates, which were significant from 1st to the 7th year (28.9% vs 51.4%).</p><p id="par0085" class="elsevierStylePara elsevierViewall">Note the high rates of remission (DAS28≤2.6) and ACR70 responses achieved at seven years in more than half of patients (51.5% and 51.4%) (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">AGREE Study</span><p id="par0090" class="elsevierStylePara elsevierViewall">This study was performed in patients with RA, who were MTX naïve, had <2 years of disease progression and poor prognostic factors (≥12 tender joints, ≥10 swollen joints, CRP≥0.45<span class="elsevierStyleHsp" style=""></span>mg/dl, rheumatoid factor and/or anti-CCP positive and radiographic evidence of erosion in the hands, wrists or feet). In this study, patients were randomized 1:1 to receive 10<span class="elsevierStyleHsp" style=""></span>mg/kg/4 weeks ABA+MTX or PLB+MTX.</p><p id="par0095" class="elsevierStylePara elsevierViewall">At one year, the treatment group (ABA+MTX) reached ACR50 57.4% vs 42.3% in the MTX+PLB, and a DAS28 remission rate≤2.6 from 41.4% vs 23.3%, achieving global reductions in DAS28 of −3.22 (vs −2.49) (<span class="elsevierStyleItalic">P</span><.001).<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">In this study, progression of structural damage data using radiographic follow up was obtained. The data were similar to those obtained in the AIM study, and, at one year, the ABA+MTX group had a mean change in total score of 0.63 vs 1.06 in the MTX group+PLB using a Genant modified TSS. It was also noted that patients in ABA+MTX group had a change greater than or equal to 0.3<span class="elsevierStyleHsp" style=""></span>units compared to the baseline data in the HAQ-DI and a significant improvement in the physical and mental component SF-36.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results of Clinical Safety</span><p id="par0105" class="elsevierStylePara elsevierViewall">Safety studies have always occupied a very important role in the development of biological drugs in rheumatology. In the AIM, ATTEST, AGREE, and Phase IIb trial, ABA safety data were also widely reported. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the data on infections, symptoms and autoimmune diseases, malignancies and deaths observed in these studies and in periods of extension.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">AIM Study</span><p id="par0110" class="elsevierStylePara elsevierViewall">In this study, ABA was well tolerated, with more frequent mild adverse effects (AE) (headache, nasopharyngitis and nausea).<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The overall incidence of AE remained stable at 5 years (cumulative incidence rate of 300.2 and 242.3 per 100 patient-years).<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Severe adverse effects (SAE) (17.7/100 patient-years at 12 months and 13.9/100 patient-years to 5 years) were more frequent in the ABA+MTX group (15%) than in the PLB+MTX (11.9%). The most common, excluding outbreaks of arthritis, were pneumonia, basal cell carcinoma and chest pain that occurred in more than 0.5% of patients during the 5-year extension period.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">ATTEST Study</span><p id="par0120" class="elsevierStylePara elsevierViewall">As already mentioned, the ATTEST trial is interesting because it assesses the safety profiles of biological agents with 2 different mechanisms of action (ABA and IFB) under the same conditions of study. During the 12-month double-blind period, the AE related to the administration of treatment (infusions) and discontinuations due to SAE were lower in the ABA treated group than in the IFB treated one (total AE 89.1% vs 93.3%, treatment-related AE 46.2% vs 58.2%, and discontinuations due to SAE 3.2% vs 7.3%). The same applies to the SAE, which were up to 2 times more frequent in the IFB group (total SAE: 9.6% vs 18.2%, treatment-related SAE 3.2% vs 8.5%; SAE treatment interruptions 2.6% vs 3.6%).<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> This frequency was maintained during the second year of follow-up of these patients, and in the extension period (AE: 15.76 in the double blind phase vs 9.96/100 patient-years in the extension period).<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> In addition, there were 3 times less acute infusion reactions in the ABA group than in the IFB group (7.1% vs 24.8%). The most common infusion reactions were hypotension and urticaria that occurred only in the group treated with IFB (0% vs 4.8%), followed by headache and nausea (1.3% vs 4.2% and 1.9% vs 4.2%, respectively).<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Phase IIb Trial</span><p id="par0125" class="elsevierStylePara elsevierViewall">According to data from this study, ABA was well tolerated and the safety profiles of both doses used (2<span class="elsevierStyleHsp" style=""></span>mg/kg and 10<span class="elsevierStyleHsp" style=""></span>mg/kg) were similar to those in the placebo group.</p><p id="par0130" class="elsevierStylePara elsevierViewall">The incidence of AE and SAE remained similar after 7 years of follow up as compared to the double-blind period (AE 366.1 and SAE 17.4/100 patient-years vs AE 489.7 and SAE 20/100 patient-years).<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The most frequent adverse effects were: nasopharyngitis (30.3%), respiratory infections (23%), cough (22.3%), headache (23.7%), nausea (15.3%) and diarrhea (19.9%).<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">AGREE Study</span><p id="par0135" class="elsevierStylePara elsevierViewall">During follow up, the frequency of AE, SAE, and SAE treatment discontinuations was similar in both groups (AE: 84.8% vs 83.4%; SAE: 7.8% vs 7.9%; SAE discontinuations: 1.2% vs 1.2%). The most frequent AE were mild nausea, upper respiratory tract infection and headache. Up to 16 patients (6.3%) experienced an acute infusional reaction in the treatment group, whereas in the MTX group there were only 5 (2%), all mild or moderate, except for a severe case of urticaria that presented in the group treated with ABA.</p><p id="par0140" class="elsevierStylePara elsevierViewall">Two patients in the group treated with ABA became pregnant during the study. One patient who had received a dose of ABA submitted a positive urine pregnancy test on day 1 and suffered a spontaneous abortion between days 1 and 30. The other patient had received 9 infusions of the drug when she had a positive urine pregnancy test (day 253), confirmed by ultrasound, and then proceeded to an induced abortion at 281 days. Both patients were withdrawn from the study.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0145" class="elsevierStylePara elsevierViewall">From the efficacy and safety of these studies data we concluded that ABA associated with methotrexate is an effective treatment option with a good safety profile for patients with rheumatoid arthritis, including those with an aggressive onset, or those who have not been previously treated with other biologic therapies.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of Interest</span><p id="par0150" class="elsevierStylePara elsevierViewall">Dr. AEC has participated as an advisor to BMS, lecturing in national forums on efficacy and safety of abatacept. Dr. FDG has participated as an advisor to BMS in national and international forums and has lectured on efficacy and safety of abatacept and has received funding for clinical and basic research from MSD, Pfizer, Roche and UCB. The remaining authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:2 [ "identificador" => "xres125631" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec112924" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres125632" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec112925" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Results of Clinical Efficacy" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "AIM Study (Abatacept in Inadequate Response to Methotrexate)" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "The ATTEST Study (Abatacept or Infliximab vs Placebo, Tolerance Test, Efficacy, and Safety in the Treatment of RA)" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Phase IIb Trial" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "AGREE Study" ] ] ] 6 => array:3 [ "identificador" => "sec0035" "titulo" => "Results of Clinical Safety" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "AIM Study" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "ATTEST Study" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Phase IIb Trial" ] 3 => array:2 [ "identificador" => "sec0055" "titulo" => "AGREE Study" ] ] ] 7 => array:2 [ "identificador" => "sec0060" "titulo" => "Conclusions" ] 8 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflict of Interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-03-31" "fechaAceptado" => "2011-06-17" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec112924" "palabras" => array:4 [ 0 => "Rheumatoid arthritis" 1 => "Abatacept" 2 => "Efficacy" 3 => "Safety" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec112925" "palabras" => array:4 [ 0 => "Artritis reumatoide" 1 => "Abatacept" 2 => "Eficacia" 3 => "Seguridad" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Abatacept (ABA) is a recombinant human fusion protein that blocks co-stimulation signals on T lymphocytes, impeding their activation. Randomized and controlled trials examining efficacy and safety have been performed with ABA combined with methotrexate (MTX), vs MTX monotherapy and vs infliximab (IFB) combined with MTX in patients with rheumatoid arthritis and who are naïve to biologic therapy. ABA has shown to be more effective than MTX and at least as effective as IFB+MTX, in terms of activity and clinical remission, physical function and reduction in radiological progression. Safety data at 7 years have shown that the drug is comparable to MTX in monotherapy and safer than the IFB+MTX combination, although infections still constitute the main risk when using ABA. This review summarizes the safety and efficacy data of the AIM, ATTEST, Phase IIb IM101-100, and AGREE trials.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El abatacept (ABA) es una proteína de fusión recombinante humana que permite el bloqueo de la señal co-estimuladora del linfocito T, evitando su activación. Se han realizado estudios aleatorizados y controlados de eficacia y seguridad del ABA combinado con metotrexato (MTX), frente a MTX en monoterapia y frente a infliximab (IFB) combinado con MTX en pacientes con artritis reumatoide naive a terapia biológica. ABA ha demostrado ser más eficaz que el MTX y al menos igual que IFB+MTX, en términos de actividad y remisión clínica, funcionalidad física y disminución de la progresión radiológica. Los datos de seguridad a 7 años han demostrado que el fármaco es equiparable al MTX en monoterapia y más seguro que la combinación IFB+MTX, aunque las infecciones continúan siendo el principal riesgo del uso de ABA. En esta revisión se resumen los datos de seguridad y eficacia de los estudios AIM, ATTEST, fase IIb IM101-100 y AGREE.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Escudero Contreras A, et al. Eficacia y seguridad de abatacept en pacientes con artritis reumatoide sin tratamiento biológico previo. Reumatol Clin. 2011;7:392–6.</p>" ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1311 "Ancho" => 1586 "Tamanyo" => 92947 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">ACR response at 6 and 12 months in the abatacept group compared to placebo. <span class="elsevierStyleSup">a</span><span class="elsevierStyleItalic">P</span><.001 for abatacept vs placebo; <span class="elsevierStyleSup">b</span><span class="elsevierStyleItalic">P</span><.001 for abatacept alone, 12 vs 6 months; <span class="elsevierStyleSup">c</span>ITT population, in which all dropouts were considered as non responders regarding ACR after dropout. ACR: American College of Rheumatology response criteria; ITT: intention to treat; MTX: methotrexate.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1222 "Ancho" => 1537 "Tamanyo" => 82395 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Percentage of patients treated with abatacept who reached an HAQ-DI response at 12 months. *<span class="elsevierStyleItalic">P</span><.001 for abatacept vs placebo; based on an ITT population, where dropouts considered as non responders; responders according to HAQ reached a mean baseline reduction of 0.3<span class="elsevierStyleHsp" style=""></span>units. HAQ: health assessment questionnaire; ITT: intention to treat; MTX: methotrexate.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1267 "Ancho" => 1699 "Tamanyo" => 125055 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Percentage of ACR response at 7 years. Shown are response rates at 0–6 months; ITT population: analysis of cases based on all of the patients randomized to abatacept who entered LTE and who had visit data. ITT: intention to treat; DB: double blind; LTE: long term extension.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 864 "Ancho" => 1621 "Tamanyo" => 100365 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">LDAS and DAS28 remission at 7 years in patients treated with abatacept. Data are based on all of the patients originally randomized to abatacept 10<span class="elsevierStyleHsp" style=""></span>mg/kg who entered LTE, with visit data (analysis “observed cases”); remission defined as DAS28 (PCR)=DAS28<2.6; LDAS=DAS28 (CRP)≤3.2. DAS28: disease activity score; DB: double blind; LTE: long term extension; CI: confidence interval; LDAS: low disease activity score.</p>" ] ] 4 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Groups \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Infections \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Severe Infections \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Autoimmune Symptoms and Diseases \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Neoplasia \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Deaths \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="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">AIM</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="elsevierStyleHsp" style=""></span>PLB+MTX<span class="elsevierStyleHsp" style=""></span>No.=219<span class="elsevierStyleHsp" style=""></span>1 year \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 pat (2.3%) \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">2 pat (0.9%) \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">10 pat (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">2 pat (0.9%) \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">1 pat (0.2%) \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>ABA+MTX<span class="elsevierStyleHsp" style=""></span>No.=433<span class="elsevierStyleHsp" style=""></span>1 year \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 pat (3.9%); 90.5/100 pat-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">11 pat (2.5%); 4.2/100 pat-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">20 pat (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">4 pat (0.9%) \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">1 pat (0.2%) \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>ABA+MTX<span class="elsevierStyleHsp" style=""></span>No.=593<span class="elsevierStyleHsp" style=""></span>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"><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>67.1/100 pat-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">2.8/100 pat-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">49 pat (8.2%) \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"><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>33 pat (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">3 pat (0.5%) \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="6" 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 " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">ATTEST</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="elsevierStyleHsp" style=""></span>IFB+MTX<span class="elsevierStyleHsp" style=""></span>No.=165<span class="elsevierStyleHsp" style=""></span>1 year \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">14 pat (8.5%) \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">1 pat (0.6%) \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">2 pat (1.2%) \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">2 pat (1.2%) \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>ABA+MTX<span class="elsevierStyleHsp" style=""></span>No.=156<span class="elsevierStyleHsp" style=""></span>1 year \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"><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>3 pat (1.9%) \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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 pat (1.3%) \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">1 pat (0.6%) \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">1 pat (0.6%) \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="6" 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 " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">IIb</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="elsevierStyleHsp" style=""></span>ABA+MTX<span class="elsevierStyleHsp" style=""></span>No.=120<span class="elsevierStyleHsp" style=""></span>1 year \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">94.2/100 pat-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">2.1/100 pat-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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">2.1/100 pat-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">1 pat (0.5%) \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>ABA+MTX<span class="elsevierStyleHsp" style=""></span>No.=130<span class="elsevierStyleHsp" style=""></span>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"><a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>77.3/100 pat-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">3/100 pat-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 pat (9.2%) \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">1.5/100 pat-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">5/100 pat-years \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>ABA+MTX<span class="elsevierStyleHsp" style=""></span>No.=114<span class="elsevierStyleHsp" style=""></span>7 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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">3.18/100 pat-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"><a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a>13 pat (4.5%) \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">20 pat (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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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="6" 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 " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">AGREE</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="elsevierStyleHsp" style=""></span>PLB+MTX<span class="elsevierStyleHsp" style=""></span>No.=256<span class="elsevierStyleHsp" style=""></span>1 year \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">139 pat (54.9%) \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">5 pat (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">5 pat (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">0 pat (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">4 pat (1.6%) \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>ABA+MTX<span class="elsevierStyleHsp" style=""></span>No.=253<span class="elsevierStyleHsp" style=""></span>1 year \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">132 pat (51.6%) \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 pat (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">6 pat (2.3%) \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"><a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">f</span></a>1 pat (0.4%) \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">2 pat (0.8%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab212137.png" ] ] ] "notaPie" => array:6 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara">The most common serious infections recorded during the first 2 years of the follow up period were pneumonia, acute bronchitis, cellulitis, and urinary<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> tract infection.</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara">Within tumor diagnoses reported during the 5 years of the extension period are non-melanocytic skin tumors, tumors of solid organ and hematologic malignancies.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara">The most common serious infection was pneumonia (1.3 ABA vs IFB 1.8%) as well as 5 cases of serious opportunistic infections (including 2 cases of tuberculosis) in the IFB arm, while ABA was associated to none.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p>" ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "<p class="elsevierStyleNotepara">The most common infections were pneumonia (1%) and diverticulitis (1%). There were no opportunistic infections or cases of tuberculosis.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p>" ] 4 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "e" "nota" => "<p class="elsevierStyleNotepara">In the cumulative period of 7 years, a total of 13 patients developed autoimmunity or autoimmune disease. The most frequent was psoriasis, but cutaneous vasculitis, rheumatoid vasculitis, erythemanodosum, sicca syndrome, and multiple sclerosis<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> were also seen.</p>" ] 5 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "f" "nota" => "<p class="elsevierStyleNotepara">One case of pancreatic cancer appeared in a patient who had received 12 infusions of ABA, although it was considered unlikely to be treatment related.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">ABA: Abatacept; IFB: Infliximab; MTX: Methotrexate; Pat: Patients; PLB: Placebo.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The prevalence of rheumatoid arthritis in the general population of Spain" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "L. Carmona" 1 => "V. Villaverde" 2 => "C. Hernandez-Garcia" 3 => "J. Ballina" 4 => "R. Gabriel" 5 => "A. Laffon" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2002" "volumen" => "41" "paginaInicial" => "88" "paginaFinal" => "95" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The incidence of rheumatoid arthritis in Spain: results from a nationwide primary care registry" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "SERAP Study Group" "etal" => false "autores" => array:5 [ 0 => "J. Carbonell" 1 => "T. Cobo" 2 => "A. Balsa" 3 => "M.A. Descalzo" 4 => "L. Carmona" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2008" "volumen" => "47" "paginaInicial" => "1088" "paginaFinal" => "1092" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.M. Kremer" 1 => "H.K. Genant" 2 => "L.W. Moreland" 3 => "A.S. Russell" 4 => "P. Emery" 5 => "C. Abud-Mendoza" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Intern Med" "fecha" => "2006" "volumen" => "144" "paginaInicial" => "865" "paginaFinal" => "876" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16785475" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Abatacept demonstrates consistent safety and sustained improvements in efficacy through 5 years of treatment in biologic-naive patients with RA" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.M. Kremer" 1 => "A.S. Russell" 2 => "P. Emery" 3 => "C. Abud-Mendoza" 4 => "J. Szechinski" 5 => "J.C. Becker" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2009" "volumen" => "68" "paginaInicial" => "FRI0263" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Results of a two-year followup study of patients with rheumatoid arthritis who received a combination of abatacept and methotrexate" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.M. Kremer" 1 => "H.K. Genant" 2 => "L.W. Moreland" 3 => "A.S. Russell" 4 => "P. Emery" 5 => "C. Abud-Mendoza" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.23397" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2008" "volumen" => "58" "paginaInicial" => "953" "paginaFinal" => "963" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18383390" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Disease remission, radiographic non-progression and normalization of function achieved at year 1 are sustained long-term in a majority of patients: 5-year outcomes with abatacept in biologic-naive patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Westhovens" 1 => "M. Dougados" 2 => "S. Hall" 3 => "D. Moniz Reed" 4 => "J.C. Becker" 5 => "J. Teng" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2009" "volumen" => "60" "paginaInicial" => "TUE1657" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Abatacept increases the proportion of patients who remain free from structural damage progression through 5 years in methotrexate inadequate responders with RA" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Genant" 1 => "C. Peterfy" 2 => "R. Westhovens" 3 => "J.C. Becker" 4 => "G. Vratsanos" 5 => "X. Zhou" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2009" "volumen" => "68" "paginaInicial" => "FRI0253" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Schiff" 1 => "M. Keiserman" 2 => "C. Codding" 3 => "S. Songcharoen" 4 => "A. Berman" 5 => "S. Nayiager" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/ard.2007.080002" "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2008" "volumen" => "67" "paginaInicial" => "1096" "paginaFinal" => "1103" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18055472" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Two-year efficacy and safety in abatacept-treated patients with RA who received continuous therapy or switched from infliximab to abatacept: the attest trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Schiff" 1 => "M. Keiserman" 2 => "C. Codding" 3 => "S. Songcharoen" 4 => "A. Berman" 5 => "S. Nayiager" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2009" "volumen" => "68" "paginaInicial" => "SAT0103" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluation of abatacept in biologic-naive patients with active rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M. Schiff" 1 => "L. Bessette" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10067-009-1363-0" "Revista" => array:6 [ "tituloSerie" => "Clin Rheumatol" "fecha" => "2010" "volumen" => "29" "paginaInicial" => "583" "paginaFinal" => "591" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20099018" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase IIb, double-blind, randomized, placebo-controlled trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.M. Kremer" 1 => "M. Dougados" 2 => "P. Emery" 3 => "P. Durez" 4 => "J. Sibilia" 5 => "W. Shergy" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.21201" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2005" "volumen" => "52" "paginaInicial" => "2263" "paginaFinal" => "2271" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16052582" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Safety and efficacy of the selective costimulation modulator abatacept in patients with rheumatoid arthritis receiving background methotrexate: a 5-year extended phase IIB study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Westhovens" 1 => "J.M. Kremer" 2 => "L.W. Moreland" 3 => "P. Emery" 4 => "A.S. Russell" 5 => "T. Li" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3899/jrheum.080813" "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "2009" "volumen" => "36" "paginaInicial" => "736" "paginaFinal" => "742" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19273451" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Consistent safety and sustained improvement in disease activity and treatment response over 7 years of abatacept treatment in biologic-naive patients with RA" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Westhovens" 1 => "J.M. Kremer" 2 => "P. Emery" 3 => "A.S. Russell" 4 => "T. Li" 5 => "R. Aranda" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2009" "volumen" => "67" "paginaInicial" => "SAT0108" ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Westhovens" 1 => "M. Robles" 2 => "A.C. Ximenes" 3 => "S. Nayiager" 4 => "J. Wollenhaupt" 5 => "P. Durez" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/ard.2008.101121" "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2009" "volumen" => "68" "paginaInicial" => "1870" "paginaFinal" => "1877" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19124524" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sustained and clinically meaningful improvements in physical function and fatigue and reductions in activity limitation are observed in MTX-naive patients with early rheumatoid arthritis treated with abatacept over 2 years of the AGREE trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Westhovens" 1 => "J. Wollenhaupt" 2 => "B. Haraoui" 3 => "J.C. Becker" 4 => "A. Covucci" 5 => "L. Rosenblatt" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2010" "volumen" => "62" "paginaInicial" => "WED1837" ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Abatacept treatment for rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M. Schiff" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2011" "volumen" => "50" "paginaInicial" => "437" "paginaFinal" => "449" ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/21735743/0000000700000006/v1_201305061631/S2173574311000621/v1_201305061631/en/main.assets" "Apartado" => array:4 [ "identificador" => "8383" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Review Article" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735743/0000000700000006/v1_201305061631/S2173574311000621/v1_201305061631/en/main.pdf?idApp=UINPBA00004M&text.app=https://reumatologiaclinica.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574311000621?idApp=UINPBA00004M" ]
| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Octubre | 29 | 24 | 53 |
| 2024 Septiembre | 38 | 14 | 52 |
| 2024 Agosto | 63 | 36 | 99 |
| 2024 Julio | 39 | 34 | 73 |
| 2024 Junio | 53 | 28 | 81 |
| 2024 Mayo | 46 | 28 | 74 |
| 2024 Abril | 52 | 16 | 68 |
| 2024 Marzo | 43 | 29 | 72 |
| 2024 Febrero | 50 | 31 | 81 |
| 2024 Enero | 47 | 28 | 75 |
| 2023 Diciembre | 23 | 26 | 49 |
| 2023 Noviembre | 45 | 20 | 65 |
| 2023 Octubre | 52 | 32 | 84 |
| 2023 Septiembre | 95 | 33 | 128 |
| 2023 Agosto | 57 | 19 | 76 |
| 2023 Julio | 48 | 26 | 74 |
| 2023 Junio | 37 | 23 | 60 |
| 2023 Mayo | 45 | 14 | 59 |
| 2023 Abril | 23 | 11 | 34 |
| 2023 Marzo | 49 | 32 | 81 |
| 2023 Febrero | 40 | 22 | 62 |
| 2023 Enero | 20 | 25 | 45 |
| 2022 Diciembre | 74 | 33 | 107 |
| 2022 Noviembre | 48 | 30 | 78 |
| 2022 Octubre | 26 | 30 | 56 |
| 2022 Septiembre | 39 | 26 | 65 |
| 2022 Agosto | 38 | 52 | 90 |
| 2022 Julio | 37 | 38 | 75 |
| 2022 Junio | 39 | 29 | 68 |
| 2022 Mayo | 27 | 50 | 77 |
| 2022 Abril | 38 | 43 | 81 |
| 2022 Marzo | 37 | 44 | 81 |
| 2022 Febrero | 25 | 47 | 72 |
| 2022 Enero | 37 | 31 | 68 |
| 2021 Diciembre | 21 | 46 | 67 |
| 2021 Noviembre | 35 | 50 | 85 |
| 2021 Octubre | 72 | 54 | 126 |
| 2021 Septiembre | 50 | 38 | 88 |
| 2021 Agosto | 53 | 41 | 94 |
| 2021 Julio | 29 | 42 | 71 |
| 2021 Junio | 47 | 35 | 82 |
| 2021 Mayo | 54 | 30 | 84 |
| 2021 Abril | 103 | 99 | 202 |
| 2021 Marzo | 60 | 41 | 101 |
| 2021 Febrero | 42 | 17 | 59 |
| 2021 Enero | 36 | 14 | 50 |
| 2020 Diciembre | 22 | 18 | 40 |
| 2020 Noviembre | 29 | 21 | 50 |
| 2020 Octubre | 16 | 12 | 28 |
| 2020 Septiembre | 30 | 16 | 46 |
| 2020 Agosto | 16 | 15 | 31 |
| 2020 Julio | 18 | 17 | 35 |
| 2020 Junio | 28 | 15 | 43 |
| 2020 Mayo | 24 | 22 | 46 |
| 2020 Abril | 20 | 18 | 38 |
| 2020 Marzo | 9 | 7 | 16 |
| 2020 Febrero | 2 | 0 | 2 |
| 2020 Enero | 13 | 0 | 13 |
| 2019 Septiembre | 4 | 0 | 4 |
| 2019 Junio | 2 | 0 | 2 |
| 2019 Marzo | 2 | 0 | 2 |
| 2019 Enero | 1 | 0 | 1 |
| 2018 Mayo | 5 | 0 | 5 |
| 2018 Abril | 36 | 6 | 42 |
| 2018 Marzo | 46 | 7 | 53 |
| 2018 Febrero | 22 | 4 | 26 |
| 2018 Enero | 22 | 4 | 26 |
| 2017 Diciembre | 33 | 2 | 35 |
| 2017 Noviembre | 29 | 9 | 38 |
| 2017 Octubre | 30 | 8 | 38 |
| 2017 Septiembre | 42 | 6 | 48 |
| 2017 Agosto | 48 | 6 | 54 |
| 2017 Julio | 55 | 7 | 62 |
| 2017 Junio | 81 | 1 | 82 |
| 2017 Mayo | 73 | 16 | 89 |
| 2017 Abril | 62 | 8 | 70 |
| 2017 Marzo | 61 | 3 | 64 |
| 2017 Febrero | 37 | 2 | 39 |
| 2017 Enero | 52 | 6 | 58 |
| 2016 Diciembre | 71 | 18 | 89 |
| 2016 Noviembre | 49 | 7 | 56 |
| 2016 Octubre | 66 | 15 | 81 |
| 2016 Septiembre | 91 | 6 | 97 |
| 2016 Agosto | 88 | 7 | 95 |
| 2016 Julio | 55 | 12 | 67 |
| 2016 Mayo | 0 | 10 | 10 |
| 2016 Abril | 2 | 0 | 2 |
| 2016 Marzo | 1 | 6 | 7 |
| 2016 Febrero | 1 | 0 | 1 |
| 2015 Diciembre | 2 | 0 | 2 |
| 2015 Octubre | 0 | 17 | 17 |
| 2015 Septiembre | 1 | 0 | 1 |
| 2015 Agosto | 6 | 0 | 6 |
| 2015 Julio | 12 | 0 | 12 |
| 2015 Junio | 46 | 7 | 53 |
| 2015 Mayo | 62 | 11 | 73 |
| 2015 Abril | 45 | 12 | 57 |
| 2015 Marzo | 42 | 5 | 47 |
| 2015 Febrero | 41 | 9 | 50 |
| 2015 Enero | 29 | 9 | 38 |
| 2014 Diciembre | 49 | 7 | 56 |
| 2014 Noviembre | 41 | 8 | 49 |
| 2014 Octubre | 46 | 9 | 55 |
| 2014 Septiembre | 40 | 6 | 46 |
| 2014 Agosto | 43 | 8 | 51 |
| 2014 Julio | 43 | 11 | 54 |
| 2014 Junio | 39 | 10 | 49 |
| 2014 Mayo | 46 | 11 | 57 |
| 2014 Abril | 29 | 4 | 33 |
| 2014 Marzo | 53 | 18 | 71 |
| 2014 Febrero | 32 | 11 | 43 |
| 2014 Enero | 48 | 10 | 58 |
| 2013 Diciembre | 41 | 7 | 48 |
| 2013 Noviembre | 26 | 12 | 38 |
| 2013 Octubre | 51 | 11 | 62 |
| 2013 Septiembre | 34 | 13 | 47 |
| 2013 Agosto | 32 | 14 | 46 |
| 2013 Julio | 32 | 6 | 38 |
| 2013 Junio | 35 | 12 | 47 |
| 2013 Mayo | 46 | 13 | 59 |
| 2013 Abril | 39 | 14 | 53 |
| 2013 Marzo | 32 | 11 | 43 |
| 2013 Febrero | 29 | 16 | 45 |
| 2013 Enero | 23 | 10 | 33 |
| 2012 Diciembre | 21 | 12 | 33 |
| 2012 Noviembre | 18 | 10 | 28 |
| 2012 Octubre | 14 | 6 | 20 |
| 2012 Septiembre | 6 | 2 | 8 |
| 2012 Julio | 1 | 0 | 1 |
| 2012 Junio | 5 | 0 | 5 |
| 2012 Abril | 6 | 0 | 6 |
| 2012 Marzo | 3 | 0 | 3 |
| 2012 Febrero | 8 | 0 | 8 |
| 2012 Enero | 11 | 0 | 11 |
| 2011 Diciembre | 4 | 0 | 4 |
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