Rituximab in Rheumatoid Arthritis: A Systematic Review of Efficacy and Safety

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(A) Percentage of EULAR response. B) Frequency of adverse events." ] ] ] "textoCompleto" => "IntroductionRituximab (RTX) was approved in Spain for the treatment of lymphoma in June 1998 and rheumatoid arthritis (RA) in June 2006.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Research in RA was initially based on evidence of efficacy and safety of the drug in patients with lymphoma, which has a particular clinical development. The first detailed clinical data on the use of RTX in RA was published in 2001<a class="elsevierStyleCrossRef" href="#bib0010">2</a> and included: patients with no prior exposure to methotrexate (MTX), patients that failed MTX and/or other disease-modifying drugs (DMARDs), and patients failing treatment with drugs that block tumor necrosis factor alpha (anti-TNF-α). Currently, there are more than 7 years of experience with the use of RTX in patients with RA<a class="elsevierStyleCrossRef" href="#bib0015">3</a> and Spain has an increasingly larger number of patients with RTX, not only with RA but patients with severe and refractory manifestations of lupus erythematosus, vasculitis, Sjogren's syndrome, and other indications, showing good results. A recent meta-analysis showed that the number of patients needed to treat (NNT) with RTX vs placebo for ACR50 improvement was 4.1 (2.02–8.33).<a class="elsevierStyleCrossRef" href="#bib0020">4</a> While the number of patients needed to harm (NNH) and see an adverse event, as well as non-compliance was not significant: 1.34 (0.65–2.76). This data is similar to that of other biologicals such as anti-TNF.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> As part of the “Rituximab Consensus. Evidence based recommendation”<a class="elsevierStyleCrossRef" href="#bib0025">5</a> we decided to conduct a systematic review<a class="elsevierStyleCrossRef" href="#bib0030">6</a> following Cochrane methodology. The aim of the review was to assess the efficacy and safety of treatment with RTX in RA patients, using clinical practice outcome measures and with the intention to assist the physician when making treatment decisions in difficult cases during everyday patient consultation.Patients and MethodsSelection of studies: We searched for publications during the period of January 1, 2003 to September 30, 2009 in the following electronic databases: Medline through Pubmed,<a class="elsevierStyleCrossRef" href="#bib0035">7</a> and the Cochrane EMBASE<a class="elsevierStyleCrossRef" href="#bib0040">8</a> Library.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> We also performed a manual search of EULAR and ACR meeting abstracts from 2003 to 2009, and Roche Pharma<a class="elsevierStyleCrossRef" href="#bib0050">10</a> data, as well as reviewing the Mabthera 2009<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Summary. The search strategy was similar for all bases: MESH terms and free text for the following terms: rituximab, rheumatoid arthritis, anti-CD20, and biologics; we did not select any publication language filter or type of study. In a first stage, 2 authors (BHC and MGH) searched the literature independently and reviewed the title and abstract. In a second step 2 reviewers independently (BHC and RAA) selected papers after an at-length review. The final selection of items was made after consensus for any lack of agreement, considering the following criteria:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-Inclusion of patients over 18 years of age.</li><li class="elsevierStyleListItem" id="lsti0010">-RA according to 1987 criteria of the American College of Rheumatology.<a class="elsevierStyleCrossRef" href="#bib0055">11</a></li><li class="elsevierStyleListItem" id="lsti0015">-Randomized clinical trials of RTX vs placebo.</li></ul>We removed subanalysis studies, observational studies and duplicate studies, in the latter choosing the most recent study.Once articles were selected, data was extracted for analysis and carried out in paper format and independently by 2 reviewers (BHC and RAA) with the Cochrane<a class="elsevierStyleCrossRef" href="#bib0030">6</a> Collaboration tool for data extraction, which includes information on the type of clinical trial, patient characteristics, number of centers, type of intervention, efficacy and safety outcomes, and features analysis. Finally, selected studies were those whose quality score, assigned by each reviewer and according to the GRADE scale and independently graded was good or very good.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>The estimate of the possibility of bias was performed using the Cochrane collaboration<a class="elsevierStyleCrossRef" href="#bib0030">6</a> tool, which includes assessment of: (1) identification of randomization sequence generation; (2) quality of randomization masking; (3) masking the patient and assessors; (4) similarity of the treatment groups; (5) differences between groups in follow-up; (6) differences reported in outcomes between groups; (7) differences in the presence of adverse events in the groups; and (8) evaluation of the study quality.Outcome measures: Proposals were selected by OMERACT<a class="elsevierStyleCrossRef" href="#bib0065">13</a> (Outcome Measurements in Rheumatoid Arthritis Clinical Trials) and the Cochrane musculoskeletal diseases study, which are detailed below:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020">-Clinical efficacy:<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0025">1.Remission considered as DAS28 (Disease Activity Score), DAS28≤2.6.<a class="elsevierStyleCrossRef" href="#bib0070">14</a></li><li class="elsevierStyleListItem" id="lsti0030">2.Patients with good clinical response according to EULAR criteria (European League Against Rheumatism), those with change >1.2 and final DAS28≤3.2.<a class="elsevierStyleCrossRef" href="#bib0075">15</a></li><li class="elsevierStyleListItem" id="lsti0035">3.ACR (American College of Rheumatology) 50% (ACR50) and 70% (ACR70) criteria.<a class="elsevierStyleCrossRef" href="#bib0080">16</a></li><li class="elsevierStyleListItem" id="lsti0040">4.Physical function as measured by the HAQ (Health Assessment Questionnaire), considering an improvement in HAQ≥0.2units.<a class="elsevierStyleCrossRef" href="#bib0085">17</a></li></ul></li><li class="elsevierStyleListItem" id="lsti0045">-Radiographic outcome:<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0050">1.Percentage of patients without radiographic progression defined as a change in the Genant–Sharp index≤0.</li><li class="elsevierStyleListItem" id="lsti0055">2.Mean change in Genant–Sharp<a class="elsevierStyleCrossRef" href="#bib0090">18</a> radiographic index.</li></ul></li><li class="elsevierStyleListItem" id="lsti0060">-Safety:<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0065">1.Death.</li><li class="elsevierStyleListItem" id="lsti0070">2.Serious infections (infections that required patient admission to the hospital for treatment and/or endangered the life of the patient).</li><li class="elsevierStyleListItem" id="lsti0075">3.Serious adverse events (those requiring hospitalization, resulting in patient death, threatened the life of the patient or left organ damage).</li><li class="elsevierStyleListItem" id="lsti0080">4.Withdrawals from the study for any reason.</li><li class="elsevierStyleListItem" id="lsti0085">5.Withdrawals from the study for serious adverse effects.</li><li class="elsevierStyleListItem" id="lsti0090">6.Withdrawals from the study because of infusion reactions (any reaction that occurred within 24h after the infusion).</li><li class="elsevierStyleListItem" id="lsti0095">7.Severe reactions associated with infusion (those that endangered the patient's life, lead to patient death, forced hospitalization or prolongation of hospitalization).</li></ul></li></ul>Statistical AnalysisFort he outcomes considered we calculated the relative risk and odds ratio (OR) for dichotomous variables and mean difference from baseline compared to endline for continuous variables. For rare events, the calculation of the difference in risk was performed using a Mantel Haenszel, obtaining 95%confidence intervals (95%CI), with continuity correction when necessary. The analysis was performed using a fixed effects model and in the case of significant heterogeneity between the studies we also performed a random effects model with RevMan 5 software.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> Heterogeneity was considered as a I2≥50%.The absolute risk difference was defined as the difference in risk of the RTX-treated group minus the difference in the risk of the placebo treated group. The NNT for efficacy outcomes of clinical and radiographic scores and the safety NNH for each outcome were calculated using the inverse of the absolute risk difference, with the Cates formulas and calculator.<a class="elsevierStyleCrossRef" href="#bib0100">20</a>A priori, we considered the following subgroup analysis: (1) treatment with/without MTX, (2) duration of RA <2 years, (3) doses of RTX 2 cycles of 500mg vs 2 cycles of 1000mg, and (4) results at week 52.ResultsThe search identified 445 publications, of which 176 (40%) were discarded after an initial review of titles and abstracts and 234 (48%) because they were basic research studies, review papers or observational studies. We selected 55 (11%) papers for a second review, to which 84 items from 3 sources were added: a manual search, studies provided by the pharmaceutical industry, and drug data in the Archives of Pharma<a class="elsevierStyleCrossRef" href="#bib0050">10</a> Roche. A detailed review of 139 studies was conducted and allowed the identification of 10 controlled clinical trials. Sixty-seven papers were excluded because they related to basic research, case series or were not be related to the subject; 18 were duplicate reports, 12 subanalysis or extensions of the selected clinical trials, and 32 observational studies. Finally, we selected 5 for systematic review,<a class="elsevierStyleCrossRefs" href="#bib0105">21–25</a> eliminating 5 for not having a control group or whose primary objective was not effectiveness and/or safety.<a class="elsevierStyleCrossRefs" href="#bib0130">26–38</a> The flowchart of study selection for the review is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The characteristics of the 5 included trials and quality assessment in accordance with GRADE<a class="elsevierStyleCrossRef" href="#bib0060">12</a> criteria are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Excluded studies and the causes are summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<a class="elsevierStyleCrossRefs" href="#bib0130">26–38</a> The reasons for exclusion were methodological problems in the case of clinical trials (no placebo group, primary objective unrelated to efficacy and safety, and insufficient data to review). The papers considered included RA patients with a mean age of 51.4 years, 80% women, 84% FR +, and 8.1 years since onset of RA. All studies except the work of Tak et al.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> featured patients with failure to MTX. Two studies allowed the inclusion of patients with prior exposure to anti-TNF drugs.<a class="elsevierStyleCrossRefs" href="#bib0110">22,23</a> The patients had a high level of activity, baseline DAS28 6.7, and poor physical function (HAQ >1). Outcomes measured were clinical efficacy according to ACR, EULAR criteria, and safety outcomes in all and 2 studies included a radiographic outcome measurement.<a class="elsevierStyleCrossRefs" href="#bib0110">22,25</a> The methodological quality of the study according to the GRADE level was good, considering the quality of evidence (study design, study quality, consistency of results, and direction) and pooled within the different outcomes.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>The primary efficacy results at 24 weeks are summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>. The efficacy outcomes are presented for all patients and 2 subtypes of patients with RA included in the articles: DMARD failure patients and patients with failure to anti-TNF. Analyzing all patients, an ACR50 response was found in 40% of patients treated with RTX vs 19% in the placebo group, the absolute risk difference was 21% and NNT with RTX vs placebo for an ACR50 response was 5 (4–6). There was an ACR70 response in 24% of patients treated with RTX vs 10% in the placebo group, the absolute risk difference was 14% and NNT with RTX vs placebo for an ACR70 response was 7 (5–10).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Considering the outcomes that are assessed in clinical practice, we found a DAS28 <2.6 at 24 weeks of treatment in 17% of patients treated with RTX vs 5% in the placebo group; the absolute risk difference was 12% and NNT with RTX vs placebo for an DAS28 <2.6 response was 9 (6–15). The frequency of patients with a good EULAR response at 24 weeks of treatment was 17% in patients treated with RTX vs 3% in the placebo group; the absolute risk difference was 14% and NNT with RTX vs placebo for a good EULAR response was 8 (5–15). The improvement in physical function, 1 of the most relevant domains of quality of life, measured as the percentage of patients with improvement in HAQ >0.2 at 24 weeks of the first cycle of treatment with RTX was 74% vs 57% in the placebo group, with an absolute risk difference of 21% and the NNT with RTX vs placebo for an improvement in HAQ>0.2 was 6 (4–8).The radiographic outcome was assessed in 2 of the 5 papers. The percentage of patients showing no radiographic progression at week 24 was 66% in the RTX-treated group compared with 59% of the placebo group, OR 1.34 (1.04–1.71). At 52 weeks, the percentage of patients without radiographic progression was 60% in the RTX treated group vs 50% in the placebo group, the absolute risk difference was 10%, OR 1.53 (1.20–1.95) and the NNT with RTX vs placebo and not have radiographic progression was 10 (7–22). The mean difference in the Genant–Sharp Index at week 24 was 0.57 for the RTX-treated group vs 0.95 for the placebo group and at week 52 of 0.563 vs 1.05, respectively for a mean difference of −0.6 (−1.14 to −0.06). Problems of heterogeneity found in ACR50 and HAQ improvement≥0.2 with I2=59% and 56% respectively. For the rest of the outcomes of effectiveness the I2 was 13%–42%.When we analyzed the data including only studies with DMARD failure<a class="elsevierStyleCrossRefs" href="#bib0105">21,23,24</a> the direction and magnitude of response were similar but with higher NNT and wider confidence intervals, as shown in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>. The heterogeneity also increased with an I2=62% for remission and DAS28 response and an I2=82% for changes in HAQ. The same happened when the analysis was performed with patients with RA and failure to anti-TNF. In this analysis, the assessment of DAS28remission was not possible, because 27 of 298 (9%) patients in the RTX-treated group and none in the placebo group (0/201) showed remission.Safety results are summarized in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>. The evaluation of safety outcomes was only possible at 24 weeks due to study designs. The frequency of any infusion reaction was higher in the group treated with RTX. The NNH of RTX vs placebo in order to present a reaction to the first infusion, when patients receive premedication with corticosteroids was 12 (8–26). In the case of serious infusion reactions, they only occurred in the group treated with RTX (0.74%), making it impossible to estimate absolute risk difference, OR and NNH. No significant differences between both groups were found regarding the number of serious adverse events, mortality, severe infections and withdrawals due to serious adverse effects. A greater number of study withdrawals due to adverse events were seen in the placebo group, due to disease activity. This estimate showed the most heterogeneity (I2=93%) and in the rest with a lower I2 it was lower than 50%.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>SubanalysisA second meta-analysis objective was to investigate the efficacy of cycles with different doses of RTX: 500mg×2 vs 1000mg×2. Patients with RA and who had anti-TNF failure received cycles of RTX at doses of 1000mg×2.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> Dose analysis included only 2 studies<a class="elsevierStyleCrossRefs" href="#bib0115">23,24</a> of patients with failure to MTX and found no significant differences in efficacy or safety variables between the 2 doses used, as shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>The administration of RTX monotherapy vs combination therapy RTX+MTX was evaluated in a single randomized trial<a class="elsevierStyleCrossRef" href="#bib0105">21</a> including 40 patients per group; this study had the greatest risk of bias and heterogeneity and it was not possible to perform the analysis. Something similar happened when trying to assess RTX+DMARD treatment different from MTX, as the only combination found was RTX+CFM.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> A fourth sub-analysis was performed with clinical data at 52 weeks; the efficacy results were similar to those occurring at week 24 (data not shown). The safety data could be assessed only at week 24.DiscussionThe purpose of a systematic review of therapeutic intervention is to find the best available evidence on the efficacy and safety of a drug compared to standard therapy. A meta-analysis including 5 controlled trials of adequate methodological quality was performed to insure its internal validity.Patients included were predominantly women over 50 years of age, with established RA defined by ACR criteria, with high activity and poor physical function. Most had failed DMARD treatment (at least MTX) and/or anti-TNF, similar to those seen in clinical practice.The findings of the meta-analysis related to efficacy outcomes have a good level of evidence. It was found that 2 cycles of RTX 1000mg each administered IV on days 0 and 15, were better than placebo in achieving a response at week 24 considering: ACR50 with NNT of 5 (4–6), ACR70 response with NNT of 7 (5–10), DAS28 remission as ≤2.6 with NNT of 9 (6–15), EULAR response with NNT of 8 (5–15), improvement in HAQ≥0.2 with NNT 5 (4–8), no radiographic progression 1.5 (1.2–1.9) and less change in the Genant–Sharp index 0.6 (−1.14 to −0.06). The methodological quality according to the GRADE scale and nature of the models used for the estimates were moderate to good; problems of heterogeneity were found for the ACR50 response and improvement in HAQ. When performing the corresponding analysis of efficacy in 2 subpopulations of patients with RA: failure to DMARD and to anti-TNF, the results were similar, but the data less robust due to an increase in model heterogeneity, with estimates of lower quality.The quality of the results of the evaluation of the safety outcome was a major problem and was moderated by the following considerations:<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0100">1.Possibility of selection bias: Trials included patients without comorbidity and exclude patients with significant comorbidity who present worse safety outcomes; also, consider that the selection process chooses high-activity patients, including patients from various geographical areas, where access to the drug may condition the entry of the patient.</li><li class="elsevierStyleListItem" id="lsti0105">2.The sample size of trials was calculated for outcomes of efficacy and not safety and that is important in rare safety outcomes (mortality and severe infection).</li><li class="elsevierStyleListItem" id="lsti0110">3.Methodological aspects: In the trials included in the meta-analysis, the placebo phase was 24 weeks, allowing rescue medication, which further reduced the sample size. Safety monitoring is completed when the trial ended, usually at 4 weeks after the last follow-up visit and not done in the long term, a fact particularly important when talking about a drug that can cause sustained depletion of B lymphocytes.</li><li class="elsevierStyleListItem" id="lsti0115">4.Problems were found related to significant heterogeneity for withdrawals from the study for any adverse events and serious adverse events. With all these considerations, the quality of evidence for safety outcomes was moderate and this should be considered when interpreting the results. There were more infusion-related reactions of any kind (NNH 12; 8–26) and especially severe reactions related to infusion into the RTX-treated group (0.7% vs 0%, respectively), in the later case, there were no reactions in the placebo group and estimation of the NNT was impossible. The possibility of reactions during the infusion of the drug is more when undergoing the first infusion and is reduced by premedication and proper administration of the drug; serious infusion reactions will occur in approximately 0.5% of patients.<a class="elsevierStyleCrossRefs" href="#bib0005">1,10</a> There were no reports of infusion-related mortality. The methodological quality to make this assertion was moderate. For other safety outcomes: number of serious adverse effects, mortality, severe infections and withdrawal from the study due to serious adverse events, no differences were found between the RTX and the placebo group. There were a greater number of withdrawals from the trial for any cause in the placebo group vs the group treated with RTX, a low level of evidence given the heterogeneity of the estimate.</li></ul>As in other previous meta-analysis, there were no significant differences in serious infections in patients treated with RTX vs placebo.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> This finding deserves a special comment: the absence of difference in serious infections between the treated and placebo groups could be a type II statistical error, i.e., assuming that no differences between groups exist when in fact there are. Similar difficulties occur in the meta-analysis of patients with RA and anti-TNF,<a class="elsevierStyleCrossRefs" href="#bib0200">40,41</a> as shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>A, where the results are contradictory. A recent meta-analysis of observational studies has shown an increased risk of serious infections in patients with RA receiving anti-TNF vs DMARD.<a class="elsevierStyleCrossRef" href="#bib0210">42</a> Patients in the prospective observational studies are similar to those in routine clinical practice and could eliminate selection bias. This data is consistent with the impression of clinicians; we observed that anti-TNF drugs increase the risk of severe infections.<a class="elsevierStyleCrossRef" href="#bib0215">43</a> The incidence of serious infections per 100 patient-years in patients treated with RTX is similar to that seen with other biologics (anti-TNF or other therapeutic targets) (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>B).<a class="elsevierStyleCrossRefs" href="#bib0155">31–34</a> Despite finding no difference in infections among patients treated with RTX vs placebo in the systematic review, we believe that the frequency of serious infections with RTX is similar to that observed with anti-TNF and other biologics.<a class="elsevierStyleCrossRefs" href="#bib0195">39–43</a><elsevierMultimedia ident="fig0015"></elsevierMultimedia>In addition to these limitations, another limitation was the timeline; and only estimates were made at week 24 for efficacy and safety variables, and in week 52 for X-ray outcomes. Other interesting questions arose when comparing efficacy at doses of 500×2 vs 1000×2, vs monotherapy. Combination therapy with DMARDs, concomitant use of different DMARDs or efficacy of MTX in patients with antibodies to citrullinated peptides and/or rheumatoid factor could not be answered given the lack of data for analysis.The implications of these findings in clinical practice are that RTX is an effective treatment in patients with active RA, considering clinical and radiographic outcome measures. The number needed to treat was 7 (5–10) RTX patients compared with placebo for an ACR70 response, 9 (6–15) to achieve a DAS28 <2.6 and 6 (4–8) for a HAQ <0.2. The safety of the drug was similar to that of placebo, except for the first infusion reactions. The NNH for reactions to the first infusion was 12 (8–26). It was not possible to identify an increase in other safety outcomes, including the number of serious infections, possibly due to methodological problems. However, the risk of developing serious infections in patients treated with RTX seems to be comparable to other anti-TNF biologics.Conflict of InterestThis document was financed through an unrestricted grant to the department of Rheumatology of the del Hospital Universitario La Paz (AREPAZ). The choice of reviewers was the sole responsibility of the study coordinator (EMM). No Roche Pharma employee participated in the scientific meeting or had knowledge of their development until the project was finished. The meeting organization and expert fees were the sole responsibility of the Hospital Universitario La Paz (AREPAZ)." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres125542" "titulo" => array:4 [ 0 => "Abstract" 1 => "Introduction" 2 => "Methods" 3 => "Results" ] ] 1 => array:2 [ "identificador" => "xpalclavsec112835" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres125541" "titulo" => array:4 [ 0 => "Resumen" 1 => "Introducción" 2 => "Metodología" 3 => "Resultados" ] ] 3 => array:2 [ "identificador" => "xpalclavsec112834" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Patients and Methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Statistical Analysis" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Results" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Subanalysis" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Discussion" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflict of Interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2010-10-12" "fechaAceptado" => "2011-03-04" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec112835" "palabras" => array:3 [ 0 => "Rituximab" 1 => "Rheumatoid arthritis" 2 => "Meta-analysis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec112834" "palabras" => array:3 [ 0 => "Rituximab" 1 => "Artritis reumatoide" 2 => "Metaanálisis" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "IntroductionThe aim of the systematic review was to evaluate the safety and efficacy of rituximab for the treatment of rheumatoid arthritis patients, as part of the Consensus on the use of rituximab in rheumatoid arthritis. A document with evidence based recommendations.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> MethodsAll papers published from January 2003 to September 2009 were reviewed in a systematic way in Medline, EMBASE, and Cochrane Library database. The Mesh terms used were: “Rituximab”, “Rheumatoid arthritis” “Anti-CD20”, and “Biologics”. The abstracts of the EULAR and ACR congress of 2003–2009 were also reviewed, as well as data of Roche Pharma. Two rheumatologists (BHC and MGH) made the bibliographic review by title and summary of each work. Two authors (BHC and RAA) selected them by quality according to the GRADE SCALE after review. The data was collected on paper. The outcomes evaluated were of efficacy in agreement with OMERACT<a class="elsevierStyleCrossRef" href="#bib0065">13</a> (Outcome Measurements in Rheumatoid Arthritis Clinical Trials) and The Musculoskeletal Cochrane Study Group. The outcomes of safety evaluated were: mortality, severe infections, severe adverse events, and withdrawal for any cause, severe adverse events, and infusion related reactions. The review was conducted with Cochrane methodology. The odds ratio and relative risk for dichotomist variables, mean difference between baseline and final measurements for continuous variables, and risk differences were calculated with RevMan 5.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> The number of patients needed to treat was calculated with Cates’ calculator.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> ResultsRTX is an effective drug in 3 groups of patients with RA: patients who fail to MTX, those who fail anti-TNF and in patients with no prior exposure to MTX. It is necessary to treat 7 (5–10) patients with RTX vs placebo to obtain an ACR70 response; 9 (6–15) to achieve a DAS28 <2.6; and 5 (4–8) to achieve a HAQ improvement >0.2. The safety of the drug was similar to that of placebo except for infusion reactions where 12 (8–26) patients need to be treated with RTX vs placebo to see a reaction to the first infusion with steroid premedication. Severe adverse events to the infusion had an incidence of 0.7% in patients of the RTX treated group. It was impossible to identify a larger increase in the number of severe infections, probably due to methodological problems, however, the risk of developing infections in patients treated with RTX seems to be comparable to that of other anti-TNF and biologics." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "IntroducciónEl objetivo de la revisión sistemática fue evaluar la eficacia y la seguridad del tratamiento con RTX en pacientes con AR para la elaboración del Documento de consenso de uso de rituximab en artritis reumatoide, un documento con recomendaciones basadas en la evidencia<a class="elsevierStyleCrossRef" href="#bib0025">5</a> sobre el empleo del fármaco en situaciones clínicas difíciles en práctica clínica habitual. MetodologíaSe realizaron búsquedas de los trabajos publicados desde enero de 2003 hasta septiembre de 2009 en Medline, EMBASE y la Cochrane Library y revisión manual de los resúmenes de los congresos de EULAR y ACR de 2003 a 2009 y de datos proporcionados por Roche Pharma. En la estrategia de búsqueda se emplearon los siguientes términos: «Rituximab», «Rheumatoid arthritis», «Anti-CD20», «Biologics». Dos autores (BHC y MGH) efectuaron la búsqueda bibliográfica por título y resumen. Después dos autores (BHC y RAA) calificaron los trabajos según la escala GRADE y los seleccionaron tras su revisión en extenso. La extracción de los datos para el análisis se realizó en formato en papel. Las medidas de desenlace evaluadas fueron para eficacia las propuestas por OMERACT<a class="elsevierStyleCrossRef" href="#bib0065">13</a> (Outcome Measurements in Rheumatoid Arthritis Clinical Trials) y el grupo Cochrane de Estudio de Enfermedades Musculoesqueléticas, relevantes en práctica clínica. Para seguridad se evaluaron: mortalidad, presencia de infecciones graves, efectos adversos graves, retiradas del estudio por cualquier causa, retiradas del estudio por efectos adversos graves, retiradas del estudio por reacciones a la infusión y reacciones graves relacionadas con la infusión. El análisis estadístico se realizó con el cálculo del riesgo relativo y la odds ratio para variables dicotómicas (OR) y de la diferencia media entre el valor basal frente al final para variables continuas, se estimó la diferencia absoluta de riesgo con el programa RevMan 5<a class="elsevierStyleCrossRef" href="#bib0095">19</a> y el número de pacientes necesario que tratar con las fórmulas y la calculadora de Cates<a class="elsevierStyleCrossRef" href="#bib0100">20</a>. ResultadosEl RTX es un medicamento eficaz en el tratamiento de tres grupos de pacientes con artritis reumatoide: en fallo a MTX, fallo a anti-TNF y en pacientes sin exposición previa a MTX. Es necesario tratar a 7 (5-10) pacientes con RTX frente a placebo para obtener una respuesta ACR70; 9 (6-15) para conseguir un DAS28<2,6 y 5 (4-8) para una mejoría en el HAQ>0,2. La seguridad del fármaco fue similar a la del placebo, excepto para reacciones a la primera infusión en donde se necesita tratar 12 (8-26) pacientes con RTX frente a placebo para observar alguna reacción a la primera infusión con premedicación con corticoides. Las reacciones graves a la infusión tuvieron una incidencia de 0,7% en los pacientes del grupo tratado con RTX. No fue posible identificar un mayor incremento en el número de infecciones graves posiblemente debido a problemas metodológicos, no obstante el riesgo de desarrollar infecciones graves en pacientes tratados con RTX parece ser comparable al de otros anti-TNF y biológicos." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Hernández-Cruz B, et al. Rituximab en artritis reumatoide: una revisión sistemática de eficacia y seguridad. Reumatol Clin. 2011. doi:10.1016/j.reuma.2011.03.004." ] ] "multimedia" => array:7 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2681 "Ancho" => 2125 "Tamanyo" => 267210 ] ] "descripcion" => array:1 [ "en" => "Search strategy. Survey of the studies selected for review." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1972 "Ancho" => 2750 "Tamanyo" => 333632 ] ] "descripcion" => array:1 [ "en" => "Outcome estimation of the RTX 500mg×2 vs RTX 1000mg×2 groups. (A) Percentage of EULAR response. B) Frequency of adverse events." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2708 "Ancho" => 2410 "Tamanyo" => 183712 ] ] "descripcion" => array:1 [ "en" => "(A) Relative risk for developing serious infections in patients with anti-TNF therapy from clinical trials and observational studies unrelated to the meta-analysis. (B) Incidence of infections per 100 patient-years in those receiving biologic treatment." ] ] 3 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "RA: rheumatoid arthritis; ACR: ACR response; DAS28ESR: disease activity score calculated using ESR; CCT: controlled clinical trial; EULAR: EULAR criteria for improvement using DAS28; DMARD: disease modifying anti-rheumatic drugs; FR+: positive rheumatoid factor; MTX: methotrexate; TJC: tender joint count out of 68; SJC: swollen joint count out of 66; ND: no data; CRP: C reactive protein mg/dl; RTX: rituximab; ESR: erythrocyte sedimentation rate, mm/h; 2×1000: 2 cycles of 1000mg each, on days 0 and 15; 2×500: 2 cycles 500mg each on days 0 and 15.aQuality evaluation using Cochrane methodology." "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">Author, Year \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">Type \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">Target Population \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">RA Characteristics \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">Outcomes \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">Treatment 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 " colspan="10" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Baseline</td></tr><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="" 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="" 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="" 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="" 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="" 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">Age, Years \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">Female % \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">RF+% \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">RA Duration, Years \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">DAS28ESR \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">HAQ \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">ESR mmHra \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">CRP mg/dl \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">X-ray Genant–Sharp \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">Quality of evidence (DRADE)* \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 " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Edwards et al.<a class="elsevierStyleCrossRef" href="#bib0105">21</a>, 2004n=161 \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">CCT \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">RA, MTX fail \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">Active: ≥8 TJC, ≥8 SJC and /or ESR≥28mmHr or CRP≥1.5mg/dl,RF+ \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">ACREULARSafety \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">Placebo+MTXRTX 2×1000RTX 2×1000+CFMRTX 2×1000+MTX \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">53.7±10.7 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">78 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">100 \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="char" 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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.85±0.8 \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">ND \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">51 \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">3.1 \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">ND \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">Good \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">Cohen et al.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>, 2006n=517 \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">CCT \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">RA Anti-TNF fail1=60%, 2=31%, 3=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">Active: ≥8 TJC, ≥8 SJC and/or ESR≥28mmHr or CRP ≥1,5mg/dlAt least one erosion \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">ACREULAR, X-ray,Safety \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">Placebo+MTXRTX 2×1000+MTX \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">52.5±12.4 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">81 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">79 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.9±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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.85±1.0 \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">1.9±0.5 \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">48 \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">3.7 \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">48.1±35.4 \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">Good \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">Emery et al.<a class="elsevierStyleCrossRef" href="#bib0115">23</a>, 2006n=465 \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">CCT \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">RA activeFailure to a 2–5 DMARD(≈30% anti-TNF) \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">Active: ≥8 TJC, ≥8 SJC, and/or ESR ≥28 mmHra o CRP ≥1,5mg/dl \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">ACREULARSafety \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">Placebo+MTXRTX 2×500+MTXRTX 2×1000+MTX \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51.2 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">82 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10.4 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.75 \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">1.75 \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">45 \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">3.1 \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">ND \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">Good \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">Emery et al.<a class="elsevierStyleCrossRef" href="#bib0120">24</a>, 2010n=512 \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">CCT \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">RA active, MTX fail, no previous biologic \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">Active: ≥8 TJC, ≥8 SJC and /or ESR ≥28 mmHr or CRP ≥0,6mg/dl \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">EULARACRSafety \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">Placebo+MTXRTX 2×500+MTXRTX 2×1000+MTX \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51.7±12.6 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">82 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">74 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.06±7.2 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.4±1.0 \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">ND \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">ND \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">ND \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">ND \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">Good \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">Tak et al.<a class="elsevierStyleCrossRef" href="#bib0125">25</a>, 2009n=755 \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">CCT \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">RA active, >4 years, No prior MTX \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">Active: ≥8 TJC, ≥8 SJC and CRP ≥1,0mg/dl \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">X-rayACREULARSafety \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">Placebo+MTXRTX+MTX 2×500RTX+MTX 2×1000 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">47.9±13.1 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">81 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">86 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.9±1.1 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.1±1.0 \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">1.8±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">ND \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">3.2 \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">7.6±11.0 \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">Good \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab212074.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Evidence Table. Characteristics of the Studies Included in the Meta-analysis." ] ] 4 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "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">Author, Year \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">Type \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">Target Population \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">Outcome \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">Motive for Exclusion \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 " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rubber Roth et al.,<a class="elsevierStyleCrossRef" href="#bib0130">26</a> 2010 \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">CT \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">Active RA, MTX fail \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">ACR response, EULAR response \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">No placebo group \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">Bingham III et al.,<a class="elsevierStyleCrossRef" href="#bib0135">27</a> 2009 \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">CT \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">Active RA \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">Response to vaccine \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">Open CT, objective other than efficacy \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">Loveless et al.,<a class="elsevierStyleCrossRef" href="#bib0140">28</a> 2009 \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">CT \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">Active RA, ≥1 DMARD fail \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">Safety and efficacy \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">Open trial, no placebo group \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">Genwald et al.,<a class="elsevierStyleCrossRef" href="#bib0145">29</a> 2009 \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">CT \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">Active RA in spite of MTX+etanercept or MTX+adalimumab \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">Safety (infections)efficacy \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">Patients treated with RTX in combination with anti-TNF \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">Mease et al.,<a class="elsevierStyleCrossRef" href="#bib0150">30</a> 2008 \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">CT \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">RA+≥1 anti-TNF fail \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">Efficacy and safety of a 2nd round of RTX vs placebo \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">No placebo group \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">Cohen et al.,<a class="elsevierStyleCrossRef" href="#bib0155">31</a> 2009 \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">CT<a class="elsevierStyleCrossRef" href="#bib0110">22</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">Active RA, anti-TNF fail \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">ACR, EULAR, X-ray, safety \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">Extension \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">Issacs et al.,<a class="elsevierStyleCrossRef" href="#bib0160">32</a> 2009 \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">CT<a class="elsevierStyleCrossRefs" href="#bib0110">22,23</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">In FR+ and/or CCP+ patients \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">Subanalysis \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">Subanalysis \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">Keystone et al.,<a class="elsevierStyleCrossRef" href="#bib0165">33</a> 2009 \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">CT<a class="elsevierStyleCrossRefs" href="#bib0110">22,23</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">1000mg×2+MTX \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">Subanalysis, open phase, patients with initial response \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">Subanalysis \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">Keystone et al.,<a class="elsevierStyleCrossRef" href="#bib0170">34</a> 2007 \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">CT<a class="elsevierStyleCrossRefs" href="#bib0110">22,24</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">1000mg×2+MTX \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">Subanalysis of open phase, patients with initial response \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">Subanalysis \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">Mariette et al.,<a class="elsevierStyleCrossRef" href="#bib0175">35</a> 2009 \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">CT<a class="elsevierStyleCrossRef" href="#bib0125">25</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">500×2+MTX1000×2+MTXPlacebo+MTX \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">Subanalysis RF+and/or CCP+and poor prognosis \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">Subanalysis \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">Emery et al.,<a class="elsevierStyleCrossRef" href="#bib0180">36</a> 2009 \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">CT<a class="elsevierStyleCrossRef" href="#bib0115">23</a> vs <a class="elsevierStyleCrossRefs" href="#bib0110">22,24</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">1000×2+MTX \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">Phase II and III subanalysis \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">Subanalysis \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">Kremer et al.,<a class="elsevierStyleCrossRef" href="#bib0185">37</a> 2006 \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">CT<a class="elsevierStyleCrossRef" href="#bib0115">23</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">RTX 1000×2+MTX vs Placebo+MTX \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">Subanalysis of REFLEX \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">Subanalysis \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">Vollenhoven et al.,<a class="elsevierStyleCrossRef" href="#bib0190">38</a> 2009 \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">CT<a class="elsevierStyleCrossRefs" href="#bib0110">22–27</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">At least 1 cycle of RTX \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">Safety \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">Subanalysis \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab212072.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Articles Excluded From the Meta-Analysis and the Motive for Exclusion." ] ] 5 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "NE: not evaluated. Frequency of events in control group is 0 making calculations impossible." "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">Outcome (Week 24) \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">No. of CCT \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">No. \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">Frequency in RTX GroupNo. of Events/Total (%) \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">Frequency in PBO GroupNo. of Events/Total (%) \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">Odds Ratio (95% CI) \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">NNT (95% CI) \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="7" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">All scenarios</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">ACR50 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2251 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">597/1484 (40) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">144/762 (19) \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">3.1 (2.5–4.0) \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">5 (4–6) \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">ACR70 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2251 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">358/1484 (24) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">78/767 (10) \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">3.0 (2.3–4.0) \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">7 (5–10) \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 <2.6 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1723 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">194/1118 (17) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33/605 (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">3.5 (2.4–5.2) \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 (6–15) \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">Good EULAR response \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1497 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">164/982 (17) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18/515 (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">5.2 (3.2–8.7) \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">8 (5–15) \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"> HAQ improvement >0.2 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">876 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">789/1065 (74) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">302/526 (57) \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">2.3 (1.7–3.1) \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">5 (4–8) \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">% of patients with no X-ray progression at week 52 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1179 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">460/761 (60) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">208/418 (50) \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 (1.2–1.9) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 (7–22) \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="7" 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 " colspan="7" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DMARD fail</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">ACR50 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">956 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">170/582 (29) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32/294 (13) \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">3.3 (2.2–5.11) \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 (4–9) \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">ACR70 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">876 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62/582 (11) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15/294 (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">2.2 (1.2–3.9) \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">19 (9–88) \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<2.6 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">876 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32/377 (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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4/172 (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">4.4 (1.5–12.6) \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">18 (13–29) \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">HAQ improvement >0.2 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">876 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">366/582 (63) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">123/294 (42) \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">2.3 (1.7–3.1) \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">5 (4–8) \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="7" 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 " colspan="7" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-TNF fail</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">ACR50 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">499 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">80/298 (27) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10/201 (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">7.01 (3.5–13.9) \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 (3–10) \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">ACR70 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">499 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36/298 (12) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2/201 (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">13.6 (3.2–57.4) \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">10 (3–47) \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<2.6 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">499 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27/298 (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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0/201 (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">NE \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">NE \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">EULAR response \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">499 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">149/298 (50) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40/201 (20) \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">4.0 (2.6–6.0) \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">4 (3–6) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab212073.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Grouped Results of Treatment Efficacy of 2 Cycles of RTX vs Placebo for All Patients and for the Groups of Patients with RA and Failure to Anti-TNF." ] ] 6 => array:7 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "SAE: severe adverse event; NE: not evaluated. Frequency of adverse events in control group is 0, making calculations impossible; NNH: number seeded to harm; NS: not significant.Infusion reactions (any reaction occurring in the 24h post-infusion.Severe reactions related to the infusion: those that put the patients life in danger, led to death, merited hospitalization or prolonged hospital stay.Serious infection: infections requiring hospitalization of patient for treatment and/or put the patients life in danger.Severe adverse events: those requiring hospitalization, caused patients death, put the life of the patient in danger or led to long term complications." "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">Outcome (Week 24) \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">No. of CCT \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">No. \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">Frequency in RTX Group (%)No. of Events/Total (%) \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">Frequency in PBO Group (%)No. of Events/Total (%) \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">Odds ratio (95% CI) \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">NNH (95% CI) \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 " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Severe adverse events \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2327 \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">123/1565 (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">66/762 (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">0.94 (0.68–1.30) \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">Death \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2367 \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">2/1565 (0.13) \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">3/80 (0.37) \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">0.33 (0.08–1.37) \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="7" 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 " colspan="7" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Reactions to first infusion<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a></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">Any \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1652 \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">272/1082 (25) \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">92/570 (16) \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">1.70 (1.31–2.22) \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 (8–26) \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">Severe \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1652 \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">18/1082 (0.74) \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">0/570 (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">NE \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">NE \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="7" 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">Serious infection \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1652 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18/1082 (1.7) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10/570 (1.8) \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">0.93 (0.45–2.05) \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">Study dropout, any cause \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1652 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">99/1083 (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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">85/569 (15) \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">0.6 (0.44–0.81) \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">19 (13–41) \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">Dropout due to SAE \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1652 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23/1084 (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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5/370 (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">2,23 (0.87–5.69) \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></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab212075.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "In patients who received steroid premedication." ] ] ] "descripcion" => array:1 [ "en" => "Grouped Results Regarding Safety of Treatment in a Cycle of 2 RTX Infusions vs Placebo." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:43 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Ficha técnica de Mabthera. 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Original Article

Rituximab in Rheumatoid Arthritis: A Systematic Review of Efficacy and Safety

Rituximab en artritis reumatoide: una revisión sistemática de eficacia y seguridad

Blanca Hernández-Cruza,

Corresponding author

blancahcruz@gmail.com

Corresponding author.

, Miriam García-Ariasb, Rafael Ariza Arizac, Emilio Martín Molab

a Unidad de Investigación e i+D+I, Servicio de Reumatología, Hospital Universitario Virgen Macarena, Sevilla, Spain

b Servicio de Reumatología, Hospital Universitario La Paz, Madrid, Spain

c Servicio de Reumatología, Hospital Universitario Virgen Macarena, Sevilla, Spain

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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Outcome estimation of the RTX 500<span class="elsevierStyleHsp" style=""></span>mg&#215;2 vs RTX 1000<span class="elsevierStyleHsp" style=""></span>mg&#215;2 groups&#46; &#40;A&#41; Percentage of EULAR response&#46; B&#41; Frequency of adverse events&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Rituximab &#40;RTX&#41; was approved in Spain for the treatment of lymphoma in June 1998 and rheumatoid arthritis &#40;RA&#41; in June 2006&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Research in RA was initially based on evidence of efficacy and safety of the drug in patients with lymphoma&#44; which has a particular clinical development&#46; The first detailed clinical data on the use of RTX in RA was published in 2001<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> and included&#58; patients with no prior exposure to methotrexate &#40;MTX&#41;&#44; patients that failed MTX and&#47;or other disease-modifying drugs &#40;DMARDs&#41;&#44; and patients failing treatment with drugs that block tumor necrosis factor alpha &#40;anti-TNF-&#945;&#41;&#46; Currently&#44; there are more than 7 years of experience with the use of RTX in patients with RA<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and Spain has an increasingly larger number of patients with RTX&#44; not only with RA but patients with severe and refractory manifestations of lupus erythematosus&#44; vasculitis&#44; Sjogren&#39;s syndrome&#44; and other indications&#44; showing good results&#46; A recent meta-analysis showed that the number of patients needed to treat &#40;NNT&#41; with RTX vs placebo for ACR50 improvement was 4&#46;1 &#40;2&#46;02&#8211;8&#46;33&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> While the number of patients needed to harm &#40;NNH&#41; and see an adverse event&#44; as well as non-compliance was not significant&#58; 1&#46;34 &#40;0&#46;65&#8211;2&#46;76&#41;&#46; This data is similar to that of other biologicals such as anti-TNF&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> As part of the &#8220;Rituximab Consensus&#46; Evidence based recommendation&#8221;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> we decided to conduct a systematic review<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> following Cochrane methodology&#46; The aim of the review was to assess the efficacy and safety of treatment with RTX in RA patients&#44; using clinical practice outcome measures and with the intention to assist the physician when making treatment decisions in difficult cases during everyday patient consultation&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Patients and Methods</span><p id="par0010" class="elsevierStylePara elsevierViewall">Selection of studies&#58; We searched for publications during the period of January 1&#44; 2003 to September 30&#44; 2009 in the following electronic databases&#58; Medline through Pubmed&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and the Cochrane EMBASE<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Library&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> We also performed a manual search of EULAR and ACR meeting abstracts from 2003 to 2009&#44; and Roche Pharma<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> data&#44; as well as reviewing the Mabthera 2009<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Summary&#46; The search strategy was similar for all bases&#58; MESH terms and free text for the following terms&#58; rituximab&#44; rheumatoid arthritis&#44; anti-CD20&#44; and biologics&#59; we did not select any publication language filter or type of study&#46; In a first stage&#44; 2 authors &#40;BHC and MGH&#41; searched the literature independently and reviewed the title and abstract&#46; In a second step 2 reviewers independently &#40;BHC and RAA&#41; selected papers after an at-length review&#46; The final selection of items was made after consensus for any lack of agreement&#44; considering the following criteria&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0015" class="elsevierStylePara elsevierViewall">Inclusion of patients over 18 years of age&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0020" class="elsevierStylePara elsevierViewall">RA according to 1987 criteria of the American College of Rheumatology&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0025" class="elsevierStylePara elsevierViewall">Randomized clinical trials of RTX vs placebo&#46;</p></li></ul></p><p id="par0030" class="elsevierStylePara elsevierViewall">We removed subanalysis studies&#44; observational studies and duplicate studies&#44; in the latter choosing the most recent study&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Once articles were selected&#44; data was extracted for analysis and carried out in paper format and independently by 2 reviewers &#40;BHC and RAA&#41; with the Cochrane<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Collaboration tool for data extraction&#44; which includes information on the type of clinical trial&#44; patient characteristics&#44; number of centers&#44; type of intervention&#44; efficacy and safety outcomes&#44; and features analysis&#46; Finally&#44; selected studies were those whose quality score&#44; assigned by each reviewer and according to the GRADE scale and independently graded was good or very good&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The estimate of the possibility of bias was performed using the Cochrane collaboration<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> tool&#44; which includes assessment of&#58; &#40;1&#41; identification of randomization sequence generation&#59; &#40;2&#41; quality of randomization masking&#59; &#40;3&#41; masking the patient and assessors&#59; &#40;4&#41; similarity of the treatment groups&#59; &#40;5&#41; differences between groups in follow-up&#59; &#40;6&#41; differences reported in outcomes between groups&#59; &#40;7&#41; differences in the presence of adverse events in the groups&#59; and &#40;8&#41; evaluation of the study quality&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Outcome measures&#58; Proposals were selected by OMERACT<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> &#40;Outcome Measurements in Rheumatoid Arthritis Clinical Trials&#41; and the Cochrane musculoskeletal diseases study&#44; which are detailed below&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">Clinical efficacy&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">1&#46;</span><p id="par0055" class="elsevierStylePara elsevierViewall">Remission considered as DAS28 &#40;Disease Activity Score&#41;&#44; DAS28<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>2&#46;6&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">2&#46;</span><p id="par0060" class="elsevierStylePara elsevierViewall">Patients with good clinical response according to EULAR criteria &#40;European League Against Rheumatism&#41;&#44; those with change &#62;1&#46;2 and final DAS28<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>3&#46;2&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">3&#46;</span><p id="par0065" class="elsevierStylePara elsevierViewall">ACR &#40;American College of Rheumatology&#41; 50&#37; &#40;ACR50&#41; and 70&#37; &#40;ACR70&#41; criteria&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">4&#46;</span><p id="par0070" class="elsevierStylePara elsevierViewall">Physical function as measured by the HAQ &#40;Health Assessment Questionnaire&#41;&#44; considering an improvement in HAQ<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>0&#46;2<span class="elsevierStyleHsp" style=""></span>units&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">-</span><p id="par0075" class="elsevierStylePara elsevierViewall">Radiographic outcome&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">1&#46;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Percentage of patients without radiographic progression defined as a change in the Genant&#8211;Sharp index<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">2&#46;</span><p id="par0085" class="elsevierStylePara elsevierViewall">Mean change in Genant&#8211;Sharp<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> radiographic index&#46;</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">-</span><p id="par0090" class="elsevierStylePara elsevierViewall">Safety&#58;<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">1&#46;</span><p id="par0095" class="elsevierStylePara elsevierViewall">Death&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">2&#46;</span><p id="par0100" class="elsevierStylePara elsevierViewall">Serious infections &#40;infections that required patient admission to the hospital for treatment and&#47;or endangered the life of the patient&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">3&#46;</span><p id="par0105" class="elsevierStylePara elsevierViewall">Serious adverse events &#40;those requiring hospitalization&#44; resulting in patient death&#44; threatened the life of the patient or left organ damage&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">4&#46;</span><p id="par0110" class="elsevierStylePara elsevierViewall">Withdrawals from the study for any reason&#46;</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">5&#46;</span><p id="par0115" class="elsevierStylePara elsevierViewall">Withdrawals from the study for serious adverse effects&#46;</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">6&#46;</span><p id="par0120" class="elsevierStylePara elsevierViewall">Withdrawals from the study because of infusion reactions &#40;any reaction that occurred within 24<span class="elsevierStyleHsp" style=""></span>h after the infusion&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">7&#46;</span><p id="par0125" class="elsevierStylePara elsevierViewall">Severe reactions associated with infusion &#40;those that endangered the patient&#39;s life&#44; lead to patient death&#44; forced hospitalization or prolongation of hospitalization&#41;&#46;</p></li></ul></p></li></ul></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Statistical Analysis</span><p id="par0130" class="elsevierStylePara elsevierViewall">Fort he outcomes considered we calculated the relative risk and odds ratio &#40;OR&#41; for dichotomous variables and mean difference from baseline compared to endline for continuous variables&#46; For rare events&#44; the calculation of the difference in risk was performed using a Mantel Haenszel&#44; obtaining 95&#37;confidence intervals &#40;95&#37;CI&#41;&#44; with continuity correction when necessary&#46; The analysis was performed using a fixed effects model and in the case of significant heterogeneity between the studies we also performed a random effects model with RevMan 5 software&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Heterogeneity was considered as a <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span>&#8805;50&#37;&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The absolute risk difference was defined as the difference in risk of the RTX-treated group minus the difference in the risk of the placebo treated group&#46; The NNT for efficacy outcomes of clinical and radiographic scores and the safety NNH for each outcome were calculated using the inverse of the absolute risk difference&#44; with the Cates formulas and calculator&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">A priori&#44; we considered the following subgroup analysis&#58; &#40;1&#41; treatment with&#47;without MTX&#44; &#40;2&#41; duration of RA &#60;2 years&#44; &#40;3&#41; doses of RTX 2 cycles of 500<span class="elsevierStyleHsp" style=""></span>mg vs 2 cycles of 1000<span class="elsevierStyleHsp" style=""></span>mg&#44; and &#40;4&#41; results at week 52&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><p id="par0145" class="elsevierStylePara elsevierViewall">The search identified 445 publications&#44; of which 176 &#40;40&#37;&#41; were discarded after an initial review of titles and abstracts and 234 &#40;48&#37;&#41; because they were basic research studies&#44; review papers or observational studies&#46; We selected 55 &#40;11&#37;&#41; papers for a second review&#44; to which 84 items from 3 sources were added&#58; a manual search&#44; studies provided by the pharmaceutical industry&#44; and drug data in the Archives of Pharma<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Roche&#46; A detailed review of 139 studies was conducted and allowed the identification of 10 controlled clinical trials&#46; Sixty-seven papers were excluded because they related to basic research&#44; case series or were not be related to the subject&#59; 18 were duplicate reports&#44; 12 subanalysis or extensions of the selected clinical trials&#44; and 32 observational studies&#46; Finally&#44; we selected 5 for systematic review&#44;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#8211;25</span></a> eliminating 5 for not having a control group or whose primary objective was not effectiveness and&#47;or safety&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#8211;38</span></a> The flowchart of study selection for the review is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">The characteristics of the 5 included trials and quality assessment in accordance with GRADE<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> criteria are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Excluded studies and the causes are summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#8211;38</span></a> The reasons for exclusion were methodological problems in the case of clinical trials &#40;no placebo group&#44; primary objective unrelated to efficacy and safety&#44; and insufficient data to review&#41;&#46; The papers considered included RA patients with a mean age of 51&#46;4 years&#44; 80&#37; women&#44; 84&#37; FR &#43;&#44; and 8&#46;1 years since onset of RA&#46; All studies except the work of Tak et al&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> featured patients with failure to MTX&#46; Two studies allowed the inclusion of patients with prior exposure to anti-TNF drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> The patients had a high level of activity&#44; baseline DAS28 6&#46;7&#44; and poor physical function &#40;HAQ &#62;1&#41;&#46; Outcomes measured were clinical efficacy according to ACR&#44; EULAR criteria&#44; and safety outcomes in all and 2 studies included a radiographic outcome measurement&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;25</span></a> The methodological quality of the study according to the GRADE level was good&#44; considering the quality of evidence &#40;study design&#44; study quality&#44; consistency of results&#44; and direction&#41; and pooled within the different outcomes&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">The primary efficacy results at 24 weeks are summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46; The efficacy outcomes are presented for all patients and 2 subtypes of patients with RA included in the articles&#58; DMARD failure patients and patients with failure to anti-TNF&#46; Analyzing all patients&#44; an ACR50 response was found in 40&#37; of patients treated with RTX vs 19&#37; in the placebo group&#44; the absolute risk difference was 21&#37; and NNT with RTX vs placebo for an ACR50 response was 5 &#40;4&#8211;6&#41;&#46; There was an ACR70 response in 24&#37; of patients treated with RTX vs 10&#37; in the placebo group&#44; the absolute risk difference was 14&#37; and NNT with RTX vs placebo for an ACR70 response was 7 &#40;5&#8211;10&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0160" class="elsevierStylePara elsevierViewall">Considering the outcomes that are assessed in clinical practice&#44; we found a DAS28 &#60;2&#46;6 at 24 weeks of treatment in 17&#37; of patients treated with RTX vs 5&#37; in the placebo group&#59; the absolute risk difference was 12&#37; and NNT with RTX vs placebo for an DAS28 &#60;2&#46;6 response was 9 &#40;6&#8211;15&#41;&#46; The frequency of patients with a good EULAR response at 24 weeks of treatment was 17&#37; in patients treated with RTX vs 3&#37; in the placebo group&#59; the absolute risk difference was 14&#37; and NNT with RTX vs placebo for a good EULAR response was 8 &#40;5&#8211;15&#41;&#46; The improvement in physical function&#44; 1 of the most relevant domains of quality of life&#44; measured as the percentage of patients with improvement in HAQ &#62;0&#46;2 at 24 weeks of the first cycle of treatment with RTX was 74&#37; vs 57&#37; in the placebo group&#44; with an absolute risk difference of 21&#37; and the NNT with RTX vs placebo for an improvement in HAQ<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;2 was 6 &#40;4&#8211;8&#41;&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">The radiographic outcome was assessed in 2 of the 5 papers&#46; The percentage of patients showing no radiographic progression at week 24 was 66&#37; in the RTX-treated group compared with 59&#37; of the placebo group&#44; OR 1&#46;34 &#40;1&#46;04&#8211;1&#46;71&#41;&#46; At 52 weeks&#44; the percentage of patients without radiographic progression was 60&#37; in the RTX treated group vs 50&#37; in the placebo group&#44; the absolute risk difference was 10&#37;&#44; OR 1&#46;53 &#40;1&#46;20&#8211;1&#46;95&#41; and the NNT with RTX vs placebo and not have radiographic progression was 10 &#40;7&#8211;22&#41;&#46; The mean difference in the Genant&#8211;Sharp Index at week 24 was 0&#46;57 for the RTX-treated group vs 0&#46;95 for the placebo group and at week 52 of 0&#46;563 vs 1&#46;05&#44; respectively for a mean difference of &#8722;0&#46;6 &#40;&#8722;1&#46;14 to &#8722;0&#46;06&#41;&#46; Problems of heterogeneity found in ACR50 and HAQ improvement<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>0&#46;2 with <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span>&#61;59&#37; and 56&#37; respectively&#46; For the rest of the outcomes of effectiveness the <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> was 13&#37;&#8211;42&#37;&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">When we analyzed the data including only studies with DMARD failure<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;23&#44;24</span></a> the direction and magnitude of response were similar but with higher NNT and wider confidence intervals&#44; as shown in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46; The heterogeneity also increased with an <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span>&#61;62&#37; for remission and DAS28 response and an <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span>&#61;82&#37; for changes in HAQ&#46; The same happened when the analysis was performed with patients with RA and failure to anti-TNF&#46; In this analysis&#44; the assessment of DAS28remission was not possible&#44; because 27 of 298 &#40;9&#37;&#41; patients in the RTX-treated group and none in the placebo group &#40;0&#47;201&#41; showed remission&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Safety results are summarized in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#46; The evaluation of safety outcomes was only possible at 24 weeks due to study designs&#46; The frequency of any infusion reaction was higher in the group treated with RTX&#46; The NNH of RTX vs placebo in order to present a reaction to the first infusion&#44; when patients receive premedication with corticosteroids was 12 &#40;8&#8211;26&#41;&#46; In the case of serious infusion reactions&#44; they only occurred in the group treated with RTX &#40;0&#46;74&#37;&#41;&#44; making it impossible to estimate absolute risk difference&#44; OR and NNH&#46; No significant differences between both groups were found regarding the number of serious adverse events&#44; mortality&#44; severe infections and withdrawals due to serious adverse effects&#46; A greater number of study withdrawals due to adverse events were seen in the placebo group&#44; due to disease activity&#46; This estimate showed the most heterogeneity &#40;<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span>&#61;93&#37;&#41; and in the rest with a lower <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> it was lower than 50&#37;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Subanalysis</span><p id="par0180" class="elsevierStylePara elsevierViewall">A second meta-analysis objective was to investigate the efficacy of cycles with different doses of RTX&#58; 500<span class="elsevierStyleHsp" style=""></span>mg&#215;2 vs 1000<span class="elsevierStyleHsp" style=""></span>mg&#215;2&#46; Patients with RA and who had anti-TNF failure received cycles of RTX at doses of 1000<span class="elsevierStyleHsp" style=""></span>mg&#215;2&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Dose analysis included only 2 studies<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24</span></a> of patients with failure to MTX and found no significant differences in efficacy or safety variables between the 2 doses used&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0185" class="elsevierStylePara elsevierViewall">The administration of RTX monotherapy vs combination therapy RTX&#43;MTX was evaluated in a single randomized trial<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> including 40 patients per group&#59; this study had the greatest risk of bias and heterogeneity and it was not possible to perform the analysis&#46; Something similar happened when trying to assess RTX&#43;DMARD treatment different from MTX&#44; as the only combination found was RTX&#43;CFM&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> A fourth sub-analysis was performed with clinical data at 52 weeks&#59; the efficacy results were similar to those occurring at week 24 &#40;data not shown&#41;&#46; The safety data could be assessed only at week 24&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0190" class="elsevierStylePara elsevierViewall">The purpose of a systematic review of therapeutic intervention is to find the best available evidence on the efficacy and safety of a drug compared to standard therapy&#46; A meta-analysis including 5 controlled trials of adequate methodological quality was performed to insure its internal validity&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Patients included were predominantly women over 50 years of age&#44; with established RA defined by ACR criteria&#44; with high activity and poor physical function&#46; Most had failed DMARD treatment &#40;at least MTX&#41; and&#47;or anti-TNF&#44; similar to those seen in clinical practice&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">The findings of the meta-analysis related to efficacy outcomes have a good level of evidence&#46; It was found that 2 cycles of RTX 1000<span class="elsevierStyleHsp" style=""></span>mg each administered IV on days 0 and 15&#44; were better than placebo in achieving a response at week 24 considering&#58; ACR50 with NNT of 5 &#40;4&#8211;6&#41;&#44; ACR70 response with NNT of 7 &#40;5&#8211;10&#41;&#44; DAS28 remission as &#8804;2&#46;6 with NNT of 9 &#40;6&#8211;15&#41;&#44; EULAR response with NNT of 8 &#40;5&#8211;15&#41;&#44; improvement in HAQ&#8805;0&#46;2 with NNT 5 &#40;4&#8211;8&#41;&#44; no radiographic progression 1&#46;5 &#40;1&#46;2&#8211;1&#46;9&#41; and less change in the Genant&#8211;Sharp index 0&#46;6 &#40;&#8722;1&#46;14 to &#8722;0&#46;06&#41;&#46; The methodological quality according to the GRADE scale and nature of the models used for the estimates were moderate to good&#59; problems of heterogeneity were found for the ACR50 response and improvement in HAQ&#46; When performing the corresponding analysis of efficacy in 2 subpopulations of patients with RA&#58; failure to DMARD and to anti-TNF&#44; the results were similar&#44; but the data less robust due to an increase in model heterogeneity&#44; with estimates of lower quality&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">The quality of the results of the evaluation of the safety outcome was a major problem and was moderated by the following considerations&#58;<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">1&#46;</span><p id="par0210" class="elsevierStylePara elsevierViewall">Possibility of selection bias&#58; Trials included patients without comorbidity and exclude patients with significant comorbidity who present worse safety outcomes&#59; also&#44; consider that the selection process chooses high-activity patients&#44; including patients from various geographical areas&#44; where access to the drug may condition the entry of the patient&#46;</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">2&#46;</span><p id="par0215" class="elsevierStylePara elsevierViewall">The sample size of trials was calculated for outcomes of efficacy and not safety and that is important in rare safety outcomes &#40;mortality and severe infection&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">3&#46;</span><p id="par0220" class="elsevierStylePara elsevierViewall">Methodological aspects&#58; In the trials included in the meta-analysis&#44; the placebo phase was 24 weeks&#44; allowing rescue medication&#44; which further reduced the sample size&#46; Safety monitoring is completed when the trial ended&#44; usually at 4 weeks after the last follow-up visit and not done in the long term&#44; a fact particularly important when talking about a drug that can cause sustained depletion of B lymphocytes&#46;</p></li><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">4&#46;</span><p id="par0225" class="elsevierStylePara elsevierViewall">Problems were found related to significant heterogeneity for withdrawals from the study for any adverse events and serious adverse events&#46; With all these considerations&#44; the quality of evidence for safety outcomes was moderate and this should be considered when interpreting the results&#46; There were more infusion-related reactions of any kind &#40;NNH 12&#59; 8&#8211;26&#41; and especially severe reactions related to infusion into the RTX-treated group &#40;0&#46;7&#37; vs 0&#37;&#44; respectively&#41;&#44; in the later case&#44; there were no reactions in the placebo group and estimation of the NNT was impossible&#46; The possibility of reactions during the infusion of the drug is more when undergoing the first infusion and is reduced by premedication and proper administration of the drug&#59; serious infusion reactions will occur in approximately 0&#46;5&#37; of patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;10</span></a> There were no reports of infusion-related mortality&#46; The methodological quality to make this assertion was moderate&#46; For other safety outcomes&#58; number of serious adverse effects&#44; mortality&#44; severe infections and withdrawal from the study due to serious adverse events&#44; no differences were found between the RTX and the placebo group&#46; There were a greater number of withdrawals from the trial for any cause in the placebo group vs the group treated with RTX&#44; a low level of evidence given the heterogeneity of the estimate&#46;</p></li></ul></p><p id="par0230" class="elsevierStylePara elsevierViewall">As in other previous meta-analysis&#44; there were no significant differences in serious infections in patients treated with RTX vs placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> This finding deserves a special comment&#58; the absence of difference in serious infections between the treated and placebo groups could be a type II statistical error&#44; i&#46;e&#46;&#44; assuming that no differences between groups exist when in fact there are&#46; Similar difficulties occur in the meta-analysis of patients with RA and anti-TNF&#44;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;41</span></a> as shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A&#44; where the results are contradictory&#46; A recent meta-analysis of observational studies has shown an increased risk of serious infections in patients with RA receiving anti-TNF vs DMARD&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> Patients in the prospective observational studies are similar to those in routine clinical practice and could eliminate selection bias&#46; This data is consistent with the impression of clinicians&#59; we observed that anti-TNF drugs increase the risk of severe infections&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> The incidence of serious infections per 100 patient-years in patients treated with RTX is similar to that seen with other biologics &#40;anti-TNF or other therapeutic targets&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>B&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#8211;34</span></a> Despite finding no difference in infections among patients treated with RTX vs placebo in the systematic review&#44; we believe that the frequency of serious infections with RTX is similar to that observed with anti-TNF and other biologics&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#8211;43</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0235" class="elsevierStylePara elsevierViewall">In addition to these limitations&#44; another limitation was the timeline&#59; and only estimates were made at week 24 for efficacy and safety variables&#44; and in week 52 for X-ray outcomes&#46; Other interesting questions arose when comparing efficacy at doses of 500&#215;2 vs 1000&#215;2&#44; vs monotherapy&#46; Combination therapy with DMARDs&#44; concomitant use of different DMARDs or efficacy of MTX in patients with antibodies to citrullinated peptides and&#47;or rheumatoid factor could not be answered given the lack of data for analysis&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">The implications of these findings in clinical practice are that RTX is an effective treatment in patients with active RA&#44; considering clinical and radiographic outcome measures&#46; The number needed to treat was 7 &#40;5&#8211;10&#41; RTX patients compared with placebo for an ACR70 response&#44; 9 &#40;6&#8211;15&#41; to achieve a DAS28 &#60;2&#46;6 and 6 &#40;4&#8211;8&#41; for a HAQ &#60;0&#46;2&#46; The safety of the drug was similar to that of placebo&#44; except for the first infusion reactions&#46; The NNH for reactions to the first infusion was 12 &#40;8&#8211;26&#41;&#46; It was not possible to identify an increase in other safety outcomes&#44; including the number of serious infections&#44; possibly due to methodological problems&#46; However&#44; the risk of developing serious infections in patients treated with RTX seems to be comparable to other anti-TNF biologics&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of Interest</span><p id="par0245" class="elsevierStylePara elsevierViewall">This document was financed through an unrestricted grant to the department of Rheumatology of the del Hospital Universitario La Paz &#40;AREPAZ&#41;&#46; The choice of reviewers was the sole responsibility of the study coordinator &#40;EMM&#41;&#46; No Roche Pharma employee participated in the scientific meeting or had knowledge of their development until the project was finished&#46; The meeting organization and expert fees were the sole responsibility of the Hospital Universitario La Paz &#40;AREPAZ&#41;&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The aim of the systematic review was to evaluate the safety and efficacy of rituximab for the treatment of rheumatoid arthritis patients&#44; as part of the Consensus on the use of rituximab in rheumatoid arthritis&#46; A document with evidence based recommendations&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p> <span class="elsevierStyleSectionTitle">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">All papers published from January 2003 to September 2009 were reviewed in a systematic way in Medline&#44; EMBASE&#44; and Cochrane Library database&#46; The Mesh terms used were&#58; &#8220;Rituximab&#8221;&#44; &#8220;Rheumatoid arthritis&#8221; &#8220;Anti-CD20&#8221;&#44; and &#8220;Biologics&#8221;&#46; The abstracts of the EULAR and ACR congress of 2003&#8211;2009 were also reviewed&#44; as well as data of Roche Pharma&#46; Two rheumatologists &#40;BHC and MGH&#41; made the bibliographic review by title and summary of each work&#46; Two authors &#40;BHC and RAA&#41; selected them by quality according to the GRADE SCALE after review&#46; The data was collected on paper&#46; The outcomes evaluated were of efficacy in agreement with OMERACT<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> &#40;Outcome Measurements in Rheumatoid Arthritis Clinical Trials&#41; and The Musculoskeletal Cochrane Study Group&#46; The outcomes of safety evaluated were&#58; mortality&#44; severe infections&#44; severe adverse events&#44; and withdrawal for any cause&#44; severe adverse events&#44; and infusion related reactions&#46; The review was conducted with Cochrane methodology&#46; The odds ratio and relative risk for dichotomist variables&#44; mean difference between baseline and final measurements for continuous variables&#44; and risk differences were calculated with RevMan 5&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> The number of patients needed to treat was calculated with Cates&#8217; calculator&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">RTX is an effective drug in 3 groups of patients with RA&#58; patients who fail to MTX&#44; those who fail anti-TNF and in patients with no prior exposure to MTX&#46; It is necessary to treat 7 &#40;5&#8211;10&#41; patients with RTX vs placebo to obtain an ACR70 response&#59; 9 &#40;6&#8211;15&#41; to achieve a DAS28 &#60;2&#46;6&#59; and 5 &#40;4&#8211;8&#41; to achieve a HAQ improvement &#62;0&#46;2&#46; The safety of the drug was similar to that of placebo except for infusion reactions where 12 &#40;8&#8211;26&#41; patients need to be treated with RTX vs placebo to see a reaction to the first infusion with steroid premedication&#46; Severe adverse events to the infusion had an incidence of 0&#46;7&#37; in patients of the RTX treated group&#46; It was impossible to identify a larger increase in the number of severe infections&#44; probably due to methodological problems&#44; however&#44; the risk of developing infections in patients treated with RTX seems to be comparable to that of other anti-TNF and biologics&#46;</p>"
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        "resumen" => "<span class="elsevierStyleSectionTitle">Introducci&#243;n</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">El objetivo de la revisi&#243;n sistem&#225;tica fue evaluar la eficacia y la seguridad del tratamiento con RTX en pacientes con AR para la elaboraci&#243;n del Documento de consenso de uso de rituximab en artritis reumatoide&#44; un documento con recomendaciones basadas en la evidencia<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> sobre el empleo del f&#225;rmaco en situaciones cl&#237;nicas dif&#237;ciles en pr&#225;ctica cl&#237;nica habitual&#46;</p> <span class="elsevierStyleSectionTitle">Metodolog&#237;a</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Se realizaron b&#250;squedas de los trabajos publicados desde enero de 2003 hasta septiembre de 2009 en Medline&#44; EMBASE y la Cochrane Library y revisi&#243;n manual de los res&#250;menes de los congresos de EULAR y ACR de 2003 a 2009 y de datos proporcionados por Roche Pharma&#46; En la estrategia de b&#250;squeda se emplearon los siguientes t&#233;rminos&#58; &#171;Rituximab&#187;&#44; &#171;Rheumatoid arthritis&#187;&#44; &#171;Anti-CD20&#187;&#44; &#171;Biologics&#187;&#46; Dos autores &#40;BHC y MGH&#41; efectuaron la b&#250;squeda bibliogr&#225;fica por t&#237;tulo y resumen&#46; Despu&#233;s dos autores &#40;BHC y RAA&#41; calificaron los trabajos seg&#250;n la escala GRADE y los seleccionaron tras su revisi&#243;n en extenso&#46; La extracci&#243;n de los datos para el an&#225;lisis se realiz&#243; en formato en papel&#46; Las medidas de desenlace evaluadas fueron para eficacia las propuestas por OMERACT<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> &#40;Outcome Measurements in Rheumatoid Arthritis Clinical Trials&#41; y el grupo Cochrane de Estudio de Enfermedades Musculoesquel&#233;ticas&#44; relevantes en pr&#225;ctica cl&#237;nica&#46; Para seguridad se evaluaron&#58; mortalidad&#44; presencia de infecciones graves&#44; efectos adversos graves&#44; retiradas del estudio por cualquier causa&#44; retiradas del estudio por efectos adversos graves&#44; retiradas del estudio por reacciones a la infusi&#243;n y reacciones graves relacionadas con la infusi&#243;n&#46; El an&#225;lisis estad&#237;stico se realiz&#243; con el c&#225;lculo del riesgo relativo y la odds ratio para variables dicot&#243;micas &#40;OR&#41; y de la diferencia media entre el valor basal frente al final para variables continuas&#44; se estim&#243; la diferencia absoluta de riesgo con el programa RevMan 5<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> y el n&#250;mero de pacientes necesario que tratar con las f&#243;rmulas y la calculadora de Cates<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#46;</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">El RTX es un medicamento eficaz en el tratamiento de tres grupos de pacientes con artritis reumatoide&#58; en fallo a MTX&#44; fallo a anti-TNF y en pacientes sin exposici&#243;n previa a MTX&#46; Es necesario tratar a 7 &#40;5-10&#41; pacientes con RTX frente a placebo para obtener una respuesta ACR70&#59; 9 &#40;6-15&#41; para conseguir un DAS28<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>2&#44;6 y 5 &#40;4-8&#41; para una mejor&#237;a en el HAQ<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#44;2&#46; La seguridad del f&#225;rmaco fue similar a la del placebo&#44; excepto para reacciones a la primera infusi&#243;n en donde se necesita tratar 12 &#40;8-26&#41; pacientes con RTX frente a placebo para observar alguna reacci&#243;n a la primera infusi&#243;n con premedicaci&#243;n con corticoides&#46; Las reacciones graves a la infusi&#243;n tuvieron una incidencia de 0&#44;7&#37; en los pacientes del grupo tratado con RTX&#46; No fue posible identificar un mayor incremento en el n&#250;mero de infecciones graves posiblemente debido a problemas metodol&#243;gicos&#44; no obstante el riesgo de desarrollar infecciones graves en pacientes tratados con RTX parece ser comparable al de otros anti-TNF y biol&#243;gicos&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Hern&#225;ndez-Cruz B&#44; et al&#46; Rituximab en artritis reumatoide&#58; una revisi&#243;n sistem&#225;tica de eficacia y seguridad&#46; Reumatol Clin&#46; 2011&#46; <span class="elsevierStyleInterRef" href="doi:10.1016/j.reuma.2011.03.004">doi&#58;10&#46;1016&#47;j&#46;reuma&#46;2011&#46;03&#46;004</span>&#46;</p>"
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">RA&#58; rheumatoid arthritis&#59; ACR&#58; ACR response&#59; DAS28ESR&#58; <span class="elsevierStyleItalic">disease activity score</span> calculated using ESR&#59; CCT&#58; controlled clinical trial&#59; EULAR&#58; EULAR criteria for improvement using DAS28&#59; DMARD&#58; disease modifying anti-rheumatic drugs&#59; FR&#43;&#58; positive rheumatoid factor&#59; MTX&#58; methotrexate&#59; TJC&#58; tender joint count out of 68&#59; SJC&#58; swollen joint count out of 66&#59; ND&#58; no data&#59; CRP&#58; C reactive protein mg&#47;dl&#59; RTX&#58; rituximab&#59; ESR&#58; erythrocyte sedimentation rate&#44; mm&#47;h&#59; 2&#215;1000&#58; 2 cycles of 1000<span class="elsevierStyleHsp" style=""></span>mg each&#44; on days 0 and 15&#59; 2&#215;500&#58; 2 cycles 500<span class="elsevierStyleHsp" style=""></span>mg each on days 0 and 15&#46;</p><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">a</span>Quality evaluation using Cochrane methodology&#46;</p>"
          "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">Author&#44; Year&nbsp;\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">Type&nbsp;\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">Target Population&nbsp;\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">RA Characteristics&nbsp;\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">Outcomes&nbsp;\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">Treatment Groups&nbsp;\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  " colspan="10" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Baseline</td></tr><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">&nbsp;\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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\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">Age&#44; Years&nbsp;\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">Female &#37;&nbsp;\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">RF&#43;&#37;&nbsp;\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">RA Duration&#44; Years&nbsp;\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">DAS28ESR&nbsp;\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">HAQ&nbsp;\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">ESR mmHra&nbsp;\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">CRP mg&#47;dl&nbsp;\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">X-ray Genant&#8211;Sharp&nbsp;\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">Quality of evidence &#40;DRADE&#41;&#42;&nbsp;\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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Edwards et al&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#44; 2004n&#61;161&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">CCT&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">RA&#44; MTX fail&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">Active&#58; &#8805;8 TJC&#44; &#8805;8 SJC and &#47;or ESR<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>28<span class="elsevierStyleHsp" style=""></span>mmHr or CRP<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#44;RF&#43;&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">ACREULARSafety&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">Placebo&#43;MTXRTX 2&#215;1000RTX 2&#215;1000&#43;CFMRTX 2&#215;1000&#43;MTX&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&#46;7&#177;10&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">78&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#46;5&#177;6&#46;5&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;85&#177;0&#46;8&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">ND&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">51&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">3&#46;1&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">ND&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">Good&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">Cohen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#44; 2006n&#61;517&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">CCT&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">RA Anti-TNF fail1&#61;60&#37;&#44; 2&#61;31&#37;&#44; 3&#61;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">Active&#58; &#8805;8 TJC&#44; &#8805;8 SJC and&#47;or ESR<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>28<span class="elsevierStyleHsp" style=""></span>mmHr or CRP &#8805;1&#44;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dlAt least one erosion&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">ACREULAR&#44; X-ray&#44;Safety&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">Placebo&#43;MTXRTX 2&#215;1000&#43;MTX&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&#46;5&#177;12&#46;4&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">81&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">79&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#46;9&#177;8&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;85&#177;1&#46;0&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">1&#46;9&#177;0&#46;5&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">48&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">3&#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">48&#46;1&#177;35&#46;4&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">Good&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">Emery et al&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&#44; 2006n&#61;465&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">CCT&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">RA activeFailure to a 2&#8211;5 DMARD&#40;&#8776;30&#37; anti-TNF&#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">Active&#58; &#8805;8 TJC&#44; &#8805;8 SJC&#44; and&#47;or ESR &#8805;28 mmHra o CRP &#8805;1&#44;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&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">ACREULARSafety&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">Placebo&#43;MTXRTX 2&#215;500&#43;MTXRTX 2&#215;1000&#43;MTX&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">82&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#46;4&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;75&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">1&#46;75&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">45&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">3&#46;1&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">ND&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">Good&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">Emery et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>&#44; 2010n&#61;512&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">CCT&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">RA active&#44; MTX fail&#44; no previous biologic&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">Active&#58; &#8805;8 TJC&#44; &#8805;8 SJC and &#47;or ESR &#8805;28 mmHr or CRP &#8805;0&#44;6<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&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">EULARACRSafety&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">Placebo&#43;MTXRTX 2&#215;500&#43;MTXRTX 2&#215;1000&#43;MTX&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&#46;7&#177;12&#46;6&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">82&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">74&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;06&#177;7&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;4&#177;1&#46;0&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">ND&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">ND&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">ND&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">ND&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">Good&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">Tak et al&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&#44; 2009n&#61;755&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">CCT&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">RA active&#44; &#62;4 years&#44; No prior MTX&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">Active&#58; &#8805;8 TJC&#44; &#8805;8 SJC and CRP &#8805;1&#44;0<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&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">X-rayACREULARSafety&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">Placebo&#43;MTXRTX&#43;MTX 2&#215;500RTX&#43;MTX 2&#215;1000&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&#46;9&#177;13&#46;1&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">81&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">86&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;9&#177;1&#46;1&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;1&#177;1&#46;0&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">1&#46;8&#177;0&#46;6&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">ND&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">3&#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">7&#46;6&#177;11&#46;0&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">Good&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab212074.png"
              ]
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Evidence Table&#46; Characteristics of the Studies Included in the Meta-analysis&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "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">Author&#44; Year&nbsp;\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">Type&nbsp;\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">Target Population&nbsp;\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">Outcome&nbsp;\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">Motive for Exclusion&nbsp;\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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rubber Roth et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> 2010&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">CT&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">Active RA&#44; MTX fail&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">ACR response&#44; EULAR response&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">No placebo group&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">Bingham III et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> 2009&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">CT&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">Active RA&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">Response to vaccine&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">Open CT&#44; objective other than efficacy&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">Loveless et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> 2009&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">CT&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">Active RA&#44; &#8805;1 DMARD fail&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">Safety and efficacy&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">Open trial&#44; no placebo group&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">Genwald et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> 2009&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">CT&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">Active RA in spite of MTX&#43;etanercept or MTX&#43;adalimumab&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">Safety &#40;infections&#41;efficacy&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">Patients treated with RTX in combination with anti-TNF&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">Mease et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> 2008&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">CT&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">RA&#43;&#8805;1 anti-TNF fail&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">Efficacy and safety of a 2nd round of RTX vs placebo&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">No placebo group&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">Cohen et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> 2009&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">CT<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</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">Active RA&#44; anti-TNF fail&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">ACR&#44; EULAR&#44; X-ray&#44; safety&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">Extension&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">Issacs et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> 2009&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">CT<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</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">In FR&#43; and&#47;or CCP&#43; patients&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">Subanalysis&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">Subanalysis&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">Keystone et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> 2009&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">CT<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</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">1000<span class="elsevierStyleHsp" style=""></span>mg&#215;2&#43;MTX&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">Subanalysis&#44; open phase&#44; patients with initial response&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">Subanalysis&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">Keystone et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> 2007&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">CT<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;24</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">1000<span class="elsevierStyleHsp" style=""></span>mg&#215;2&#43;MTX&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">Subanalysis of open phase&#44; patients with initial response&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">Subanalysis&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">Mariette et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> 2009&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">CT<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</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">500&#215;2&#43;MTX1000&#215;2&#43;MTXPlacebo&#43;MTX&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">Subanalysis RF&#43;and&#47;or CCP&#43;and poor prognosis&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">Subanalysis&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">Emery et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> 2009&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">CT<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> vs <a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;24</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">1000&#215;2&#43;MTX&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">Phase II and III subanalysis&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">Subanalysis&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">Kremer et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> 2006&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">CT<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</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">RTX 1000&#215;2&#43;MTX vs Placebo&#43;MTX&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">Subanalysis of REFLEX&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">Subanalysis&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">Vollenhoven et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> 2009&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">CT<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#8211;27</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">At least 1 cycle of RTX&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">Safety&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">Subanalysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab212072.png"
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Articles Excluded From the Meta-Analysis and the Motive for Exclusion&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">NE&#58; not evaluated&#46; Frequency of events in control group is 0 making calculations impossible&#46;</p>"
          "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">Outcome &#40;Week 24&#41;&nbsp;\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">No&#46; of CCT&nbsp;\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">No&#46;&nbsp;\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">Frequency in RTX GroupNo&#46; of Events&#47;Total &#40;&#37;&#41;&nbsp;\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">Frequency in PBO GroupNo&#46; of Events&#47;Total &#40;&#37;&#41;&nbsp;\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">Odds Ratio &#40;95&#37; CI&#41;&nbsp;\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">NNT &#40;95&#37; CI&#41;&nbsp;\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="7" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">All scenarios</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>ACR50&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2251&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">597&#47;1484 &#40;40&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">144&#47;762 &#40;19&#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">3&#46;1 &#40;2&#46;5&#8211;4&#46;0&#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 &#40;4&#8211;6&#41;&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>ACR70&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2251&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">358&#47;1484 &#40;24&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">78&#47;767 &#40;10&#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"><span class="elsevierStyleHsp" style=""></span>Good EULAR response&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span> HAQ improvement &#62;0&#46;2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#37; of patients with no X-ray progression at week 52&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>DAS28<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>2&#46;6&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>HAQ improvement &#62;0&#46;2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>ACR50&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">SAE&#58; severe adverse event&#59; NE&#58; not evaluated&#46; Frequency of adverse events in control group is 0&#44; making calculations impossible&#59; NNH&#58; number seeded to harm&#59; NS&#58; not significant&#46;</p><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Infusion reactions &#40;any reaction occurring in the 24<span class="elsevierStyleHsp" style=""></span>h post-infusion&#46;</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Severe reactions related to the infusion&#58; those that put the patients life in danger&#44; led to death&#44; merited hospitalization or prolonged hospital stay&#46;</p><p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Serious infection&#58; infections requiring hospitalization of patient for treatment and&#47;or put the patients life in danger&#46;</p><p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Severe adverse events&#58; those requiring hospitalization&#44; caused patients death&#44; put the life of the patient in danger or led to long term complications&#46;</p>"
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                  \t\t\t\t" style="border-bottom: 2px solid black">Frequency in RTX Group &#40;&#37;&#41;No&#46; of Events&#47;Total &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 21735743
Original language: English

DOI:10.1016/j.reumae.2011.03.001

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Year/Month	Html	Pdf	Total

2024 November	11	14	25
2024 October	75	37	112
2024 September	137	41	178
2024 August	121	53	174
2024 July	94	35	129
2024 June	108	47	155
2024 May	113	44	157
2024 April	97	29	126
2024 March	65	54	119
2024 February	55	47	102
2024 January	59	38	97
2023 December	55	68	123
2023 November	69	59	128
2023 October	58	43	101
2023 September	199	50	249
2023 August	259	34	293
2023 July	49	43	92
2023 June	52	36	88
2023 May	44	35	79
2023 April	46	28	74
2023 March	115	54	169
2023 February	63	40	103
2023 January	69	40	109
2022 December	65	48	113
2022 November	78	47	125
2022 October	90	48	138
2022 September	60	46	106
2022 August	65	56	121
2022 July	71	52	123
2022 June	52	50	102
2022 May	75	67	142
2022 April	72	54	126
2022 March	85	59	144
2022 February	65	62	127
2022 January	79	50	129
2021 December	56	47	103
2021 November	63	45	108
2021 October	59	62	121
2021 September	44	52	96
2021 August	47	48	95
2021 July	41	42	83
2021 June	47	47	94
2021 May	72	71	143
2021 April	114	109	223
2021 March	60	45	105
2021 February	28	26	54
2021 January	39	31	70
2020 December	27	26	53
2020 November	31	25	56
2020 October	27	11	38
2020 September	44	40	84
2020 August	21	25	46
2020 July	15	23	38
2020 June	33	28	61
2020 May	26	25	51
2020 April	19	22	41
2020 March	21	8	29
2020 February	2	0	2
2020 January	4	0	4
2019 September	6	0	6
2019 June	2	0	2
2019 March	2	0	2
2019 January	1	0	1
2018 June	0	1	1
2018 May	6	13	19
2018 April	42	15	57
2018 March	83	22	105
2018 February	45	11	56
2018 January	45	9	54
2017 December	49	11	60
2017 November	56	11	67
2017 October	41	15	56
2017 September	61	11	72
2017 August	68	24	92
2017 July	72	15	87
2017 June	96	34	130
2017 May	80	25	105
2017 April	69	41	110
2017 March	70	16	86
2017 February	41	22	63
2017 January	61	8	69
2016 December	107	23	130
2016 November	96	15	111
2016 October	120	28	148
2016 September	138	23	161
2016 August	84	18	102
2016 July	71	17	88
2016 June	0	17	17
2016 May	0	14	14
2016 April	1	29	30
2016 March	0	9	9
2016 February	1	0	1
2015 December	2	0	2
2015 September	1	0	1
2015 August	2	12	14
2015 July	35	12	47
2015 June	80	22	102
2015 May	109	22	131
2015 April	80	15	95
2015 March	73	15	88
2015 February	81	8	89
2015 January	78	8	86
2014 December	81	10	91
2014 November	78	13	91
2014 October	61	14	75
2014 September	47	14	61
2014 August	60	21	81
2014 July	58	23	81
2014 June	67	10	77
2014 May	56	22	78
2014 April	64	9	73
2014 March	54	28	82
2014 February	51	20	71
2014 January	63	19	82
2013 December	49	12	61
2013 November	47	15	62
2013 October	87	21	108
2013 September	61	23	84
2013 August	70	34	104
2013 July	55	27	82
2013 June	59	25	84
2013 May	60	30	90
2013 April	58	25	83
2013 March	39	31	70
2013 February	40	23	63
2013 January	83	25	108
2012 December	72	23	95
2012 November	238	34	272
2012 October	206	29	235
2012 September	18	5	23
2012 July	4	0	4
2012 June	4	0	4
2012 May	2	0	2
2012 April	10	0	10
2012 March	8	0	8
2012 February	9	0	9
2012 January	8	0	8
2011 December	7	0	7
2011 November	8	0	8
2011 October	6	0	6

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