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CT-P13 trough levels, an infliximab biosimilar, in the management of inflammatory bowel disease" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "475" "paginaFinal" => "480" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Alfonso Elosua González, Patricia Sanz Segura, Daniel Oyón Lara, Santiago López García, Maria Teresa Arroyo Villarino, Maria José Alcalá Escriche, Leticia Ollero Domenche, Cristina Rodríguez Gutiérrez, Óscar Nantes Castillejo" "autores" => array:9 [ 0 => array:4 [ "nombre" => "Alfonso" "apellidos" => "Elosua González" "email" => array:1 [ 0 => "alfonso.elosua@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Patricia" "apellidos" => "Sanz Segura" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Daniel" "apellidos" => "Oyón Lara" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Santiago" "apellidos" => "López García" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 4 => array:3 [ "nombre" => "Maria Teresa" "apellidos" => "Arroyo Villarino" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 5 => array:3 [ "nombre" => "Maria José" "apellidos" => "Alcalá Escriche" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 6 => array:3 [ "nombre" => "Leticia" "apellidos" => "Ollero Domenche" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] 7 => array:3 [ "nombre" => "Cristina" "apellidos" => "Rodríguez Gutiérrez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 8 => array:3 [ "nombre" => "Óscar" "apellidos" => "Nantes Castillejo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Servicio de Aparato Digestivo, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Aparato Digestivo, Hospital Universitario Miguel Servet, Zaragoza, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Aparato Digestivo, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Aparato Digestivo, Hospital Obispo Polanco, Teruel, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Servicio de Aparato Digestivo, Hospital Ernest Lluch Martin, Calatayud, Zaragoza, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Utilidad clínica de la determinación de niveles de CT-P13, biosimilar de infliximab, en el control de la enfermedad inflamatoria intestinal" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Infliximab (IFX) is an intravenously administered chimeric IgG1 monoclonal antibody against tumour necrosis factor alpha (TNF-α), a proinflammatory cytokine with an important role in rheumatoid arthritis, ankylosing spondylitis, psoriasis, ulcerative colitis (UC) and Crohn's disease (CD).</p><p id="par0010" class="elsevierStylePara elsevierViewall">In 1997, Targan et al.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a> published the first study demonstrating the efficacy of IFX in treating CD. Since then, many studies have corroborated its usefulness in CD and UC.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">2,3</span></a> This drug has improved the quality of life of patients with inflammatory bowel disease (IBD), reducing the need for hospitalization and surgery, which results in better work, academic performance and less absenteeism.<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4,5</span></a> Although biologics were initially considered the last step on the therapeutic ladder, their use has progressively increased. Also, an early use seems to alter the natural course of the disease, slowing or preventing its progression.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In June 2013 the European Medicines Agency approved the use of CT-P13 (Remsima®, Celltrion, Republic of Korea, and Inflectra®, Hospira, UK), the first IFX biosimilar, for all the indications of the original product, and since then several studies have shown its efficacy and safety in IBD.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">7,8</span></a> Biosimilars are versions of an original biologic drug whose patent has expired, and its entry into the market leads to price reductions that can facilitate access to these treatments. However, the high price of these drugs is far from being the only factor to take into account, and among healthcare professionals the concern is to use them correctly, to maximize their efficacy, minimize their toxicity and avoid unnecessary costs.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">9</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">There is increasing evidence that a therapeutic strategy based on monitoring the levels of IFX and its antibodies could optimize treatment compared to the classic strategy based exclusively on the clinical or biochemical response to the biologic drug.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">10,11</span></a> So much so, that today level monitoring can be considered as an integral component of close IBD control.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a> Studies have shown that optimal levels of IFX are associated with both clinical and endoscopic remission, while subtherapeutic levels are associated and even cause a decrease in its efficacy and an increased risk of disease reactivation.<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">13–15</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Monitoring IFX and anti-IFX antibody levels in a patient with an inadequate response allows us to classify the drug failure subtype as pharmacokinetic, pharmacodynamic or immunological failure.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a> Knowing the therapeutic ranges adequately would not only allow a dose increase in those with insufficient clinical response but could prevent loss of response by proactively adjusting the doses before symptoms reoccur. It would also allow reducing the doses in those patients with good response and levels above the range, saving costs and perhaps minimizing risks. The scarce data published to date regarding levels of CT-P13 support the same conclusions.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">7,8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">So far, most of the studies focus on monitoring the levels of IFX during the maintenance phase and the most significant evidence regarding level-based strategies has to do with a specific scenario, that of the loss of secondary response.<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">11,16,17</span></a> There is less data for the induction phase<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">18,19</span></a>; among them, the study by Ungar et al.,<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">9</span></a> where 2 groups of patients were analyzed, one with a severe cortico-refractory exacerbation versus the other with a moderate UC exacerbation, and despite the fact that the drug levels were lower in severe exacerbations, there was no difference in mean drug levels in the week 14 in responding patients versus non-responding ones. Other scenarios are still to be analyzed, among them, the systematic monitoring of post-induction levels.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Taking into account the above, and with the hypothesis that patients with subtherapeutic levels of IFX after induction (week 14) would have a higher risk of loss of secondary response over follow-up, the objective of our study was to analyze if a proactive strategy based on post-induction IFX levels would improve the results compared to a standard clinical strategy with no level monitoring one year after treatment.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Patients and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Study design and patients</span><p id="par0040" class="elsevierStylePara elsevierViewall">We conducted a prospective, multicenter, cohort study that included all adult patients with IBD (<span class="elsevierStyleItalic">European Crohn's and Colitis Organization</span> criteria) consecutively treated with CT-P13 from its introduction in the different participating hospitals throughout 2015 until 30th March 2017. Patients whose indication for treatment was prevention of post-surgical recurrence or treatment of perianal disease were excluded.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Method</span><p id="par0045" class="elsevierStylePara elsevierViewall">The induction dose was 5<span class="elsevierStyleHsp" style=""></span>mg/kg of IFX at weeks 0, 2 and 6. Two comparison groups were established, the clinical approach (CLN) and the proactive (PRO), depending on the availability of the hospital in routine practice to perform drug level monitoring. In the PRO group, the patients belonged to a centre where drug level monitoring was available, while in the CLN group, the hospital did not include the possibility of requesting them within their lab tests.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Intensification of the biologic therapy was carried out by increasing the dose to 10<span class="elsevierStyleHsp" style=""></span>mg/kg or by decreasing the interval to 6 weeks, at the discretion of the treating physician.</p><p id="par0055" class="elsevierStylePara elsevierViewall">In the PRO group, post-induction trough levels of IFX and anti-IFX antibodies were measured systematically at week 14, using the ELISA technique (Promonitor® IFX, Progenika Biopharma, Spain), and were intensified in those patients with subtherapeutic IFX levels, regardless of their clinical situation (remission or activity), checking the dose-escalating response and dose re-escalating if necessary until reaching correct levels. Patients with levels within range and no primary response underwent a therapeutic target change.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Subtherapeutic levels were considered when values were lower than 3<span class="elsevierStyleHsp" style=""></span>μg/ml, as published in previous series,<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a> values in agreement with current revisions.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Clinical indices were used to establish the response to the drug. In CD, a partial response (PR) was considered to be a decrease of ≥3 points in the Harvey–Bradshaw Index (HBI) and clinical remission (CR) an HBI<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>5. In UC, a decrease of ≥3 points in the partial Mayo Scoring Index (pMSI) was considered a PR and a score ≤2 points in pMSI for CR. A primary response at week 14 was considered to be PR or CR. Loss of secondary response was considered to be the transition from CR to PR or no response (NR) in patients who had obtained a primary response.</p><p id="par0070" class="elsevierStylePara elsevierViewall">The present study was approved by the Navarre Clinical Research Ethics Committee. All patients were given a patient information leaflet and they all gave their informed consent.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0075" class="elsevierStylePara elsevierViewall">The SPSS® version 20 software was used for the statistical analysis of the data. An analysis was first performed comparing both groups, describing their epidemiological and disease characteristics until the start of treatment. Proportions were used for the categorical variables, the mean and standard deviation or the median and the interquartile range were used for quantitative variables, as appropriate.</p><p id="par0080" class="elsevierStylePara elsevierViewall">The comparability of the groups was analyzed using the chi square or Fisher's exact test, as appropriate for qualitative variables, and using the Student's <span class="elsevierStyleItalic">t</span> test for independent samples or the Wilcoxon test for quantitative variables, as appropriate.</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Baseline characteristics and indication of CT-P13</span><p id="par0085" class="elsevierStylePara elsevierViewall">A total of 77 patients (23 UC, 54 CD) treated in tertiary hospitals with reference IBD units were included, of whom only one had IFX level determination and underwent a proactive approach. Both groups (41 PRO, 36 CLN) had comparable baseline characteristics (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), with the exception of more prior bowel resection-type surgeries in CD or strictureplasty in the PRO group (38.7 vs. 8.7%; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.01) and a greater previous use of steroids in the CLN group (80.5 vs. 100%; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.05). <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the indication for CT-P13 therapy and concomitant treatment. There was a significantly higher proportion of patients on immunomodulatory treatment in the PRO group than in the CLN group (68.3 vs. 41.7%; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.03).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Initial efficacy (week 14)</span><p id="par0090" class="elsevierStylePara elsevierViewall">In week 14, 61% of the patients reached CR (58.5% PRO, 63.9% CLN) and 80.5% at least PR (80.5% PRO, 80.6% CLN). In the disease analysis (CD and UC) the results were also similar in both groups, as shown in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">Of the 9 patients with PR at week 14 in the PRO group, 4 (44.4%) had dose-escalation due to subtherapeutic levels and maintained the response after one year.</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Without primary response</span><p id="par0100" class="elsevierStylePara elsevierViewall">In the PRO group, of the 7 patients (17.1%) with no primary response, 4 (57.1%) had subtherapeutic levels at week 14 and underwent dose-escalation, and in 3 (42.9%) the biologic drug was changed with another therapeutic target (patients with >3<span class="elsevierStyleHsp" style=""></span>μg/dl), 2 of them with good response. No patient presented anti-IFX antibodies at that time. Of the patients undergoing dose-escalation, 50% obtained CR, which was maintained at week 54.</p><p id="par0105" class="elsevierStylePara elsevierViewall">Two of the 5 patients (13.9%) in the CLN group without primary response underwent dose-escalation, 2 had a change to another biologic agent and one patient required surgical intervention. Of the 2 patients undergoing dose-escalation, one achieved CR and maintained it at week 54.</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Long-term efficacy (week 54)</span><p id="par0110" class="elsevierStylePara elsevierViewall">At one year of follow-up, at week 54, 68.8% of patients remained in CR (61% PRO, 77.8% CLN; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.11) and 76.6% had at least PR (73.2% PRO, 80.6% CLN, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.44). There were also no statistically significant differences in the subgroup analysis according to CD or UC (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).</p><p id="par0115" class="elsevierStylePara elsevierViewall">A total of 27 patients (66%) in the PRO group required dose-escalation, and of these, 7 (26%) required dose re-escalation.</p><p id="par0120" class="elsevierStylePara elsevierViewall">In addition, over the weeks until reaching one year of follow-up, 2 patients in each group required dose-escalation (empirical in the CLN group and level-guided in the PRO group) due to loss of response, with 50% (one patient) responding to each group.</p><p id="par0125" class="elsevierStylePara elsevierViewall">The drug was withdrawn due to loss of secondary response in 3 patients in the PRO group (pharmacodynamic failure) and 2 in the CLN group.</p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Analysis of patients in remission at week 14</span><p id="par0130" class="elsevierStylePara elsevierViewall">In the CLN group, 23 patients were in post-induction CR. In the PRO group, 24 patients were in remission, 13 of them with subtherapeutic levels, who underwent dose-escalation. No patient in the PRO group lost the response, while one patient in the CLN required dose-escalation at week 38. When analysing loss of secondary response at week 54 in those patients in CR after induction, no statistically significant differences were observed between the 2 groups (PRO 0.0%, CLN 2, 8.7%; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.22). No patient experienced loss of response due to the occurrence of anti-IFX antibodies.</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Adverse effects and drug discontinuation</span><p id="par0135" class="elsevierStylePara elsevierViewall">Seven patients (17.1%) in the PRO group and 6 (16.7%) in the CLN suffered an adverse effect: 6 infusion reactions, 4 dermatological reactions (3 of them psoriasiform), 2 severe infections and a delayed hypersensitivity. There were no differences between groups in the distribution of complications. The drug was discontinued in 6 patients (5 PRO, 1 CLN; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.109).</p><p id="par0140" class="elsevierStylePara elsevierViewall">Overall, treatment was withdrawn in 29.3% of patients in the PRO group and in 22.9% in the CLN group. The reason was for primary non-response in 9 (4 PRO, 5 CLN), for loss of secondary response in 5 (3 PRO, 2 CLN) and for adverse effect in 6.</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><p id="par0145" class="elsevierStylePara elsevierViewall">Reactive monitoring consists of measuring IFX levels (supplemented with anti-IFX antibodies in case of low-level detection) in patients with active IBD (without primary response or, especially, with loss of response). It helps us in therapeutic decision-making, since it allows us to classify failure as immunological, pharmacodynamic or pharmacokinetic.<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">11,20,21</span></a> The first consists of the appearance of antibodies that favour the drug's immune clearance, with the addition of an immunomodulator as an alternative, especially in case of low antibody titre; another alternative would be to change the biologic drug, either for another anti-TNF (<span class="elsevierStyleItalic">switch</span>) or for another drug with a different mechanism of action (<span class="elsevierStyleItalic">swap</span>), especially in case of high titres. Pharmacokinetic failure is characterized by a low level of the drug without antibodies, as a consequence of an increase in the non-immune clearance of the drug and, therefore, dose-escalation would be recommended. Pharmacodynamic failure, characterized by a normal or high drug level, occurs when the pathway of inflammation does not mainly depend on TNF, in which case a drug <span class="elsevierStyleItalic">swap would be recommended.</span></p><p id="par0150" class="elsevierStylePara elsevierViewall">Proactive monitoring involves evaluating drug and antibody levels as part of patient follow-up, regardless of clinical status. The fact that it could prevent loss of response has been suggested, however, the supporting evidence is currently limited. In the largest clinical trial to date, the <span class="elsevierStyleItalic">Trough level Adapted infliXImab Treatment</span> (TAXIT),<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a> compared the level-based IFX dosage versus the clinical symptom and C-reactive protein-based dosage in patients who had previously responded to IFX. Initially there was a dose optimization phase in all patients, in which levels were measured and escalated or de-escalated according to a therapeutic window. In this phase, in patients with CD and subtherapeutic levels, this dose-escalation represented a significant increase in the proportion of those who achieved CR, a difference that was not observed in patients with UC. However, the main objective of improving both clinical and biochemical remission after one year, with proactive monitoring after this optimization phase, was not achieved, although fewer exacerbations requiring steroids were observed in the proactive group (7 vs. 17% at 1-year; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.018). However, our clinical scenario is far from TAXIT, since our patients were evaluated from the start of treatment, while TAXIT patients were evaluated during maintenance, and the mean between the first dose of IFX and trial screening was 4.5 years.</p><p id="par0155" class="elsevierStylePara elsevierViewall">The next question to answer focused on the role of this proactive monitoring from the start of maintenance, right after induction. In this scenario we find the recently published trial <span class="elsevierStyleItalic">Tailored Treatment with Infliximab for Active Luminal Crohn's Disease</span> (TAILORIX),<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">22</span></a> in which patients were monitored for 3 dose-escalation strategies based simply on biomarkers and clinical data versus the addition of level monitoring. They found no additional benefit in either the steroid-free CR primary endpoint or in endoscopic remission.</p><p id="par0160" class="elsevierStylePara elsevierViewall">By systematically measuring CT-P13 levels at week 14, we can find patients who achieve remission with subtherapeutic levels. In our series of 24 patients who achieved remission in the PRO group, 13 (54.1%) showed levels <3<span class="elsevierStyleHsp" style=""></span>μg/dl. The decision to dose-escalate these patients is controversial, given the results of TAILORIX. However, an observational retrospective study found a lower probability of treatment failure, hospital admission, surgery, development of anti-drug antibodies, or severe infusion reactions with a proactive monitoring strategy.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">23</span></a> Therefore, despite the fact that TAXIT and TAILORIX, the only clinical trials carried out to date, have failed to demonstrate their primary <span class="elsevierStyleItalic">endpoint</span>, data from retrospective studies show real utility of proactive level-based monitoring. Our initial hypothesis was that a patient who begins the maintenance phase with low drug levels is more at risk of losing the response throughout the follow-up, a fact that generally occurs often, up to 13% at 1-year.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">24</span></a> For this reason, we decided to dose-escalate these patients, with the intention of avoiding loss of response. In a review sponsored by the Australian Gastroenterology Society,<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a> CR just after the induction phase is considered as the time when measuring drug levels should be carried out. In their algorithm, they consider dose-escalation adequate in asymptomatic patients with low IFX levels.</p><p id="par0165" class="elsevierStylePara elsevierViewall">The results obtained in our study, as in the TAXIT and TAILORIX trials, were not initially expected, as we did not find significant differences at week 54 in the rates of clinical response or loss of secondary response. It could be that there were differences but, for various reasons, we did not find them. The first reason could be related to a limited sample size in each group. The second is the follow-up time (one year), which could be too short to assess response losses. In this sense, Vaughn et al.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">25</span></a> found that patients with proactive IFX monitoring were significantly more likely to stay on the same drug at 5 years (86 vs. 52%; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.3). If we look at the graphs of this study, we will see that it is from week 75 approximately, and not before, when the differences begin to be more noticeable.</p><p id="par0170" class="elsevierStylePara elsevierViewall">Another noteworthy aspect is that we have extrapolated the optimal IFX levels at week 14, using those of the studies during maintenance treatment. Furthermore, while some studies have shown that lower concentrations of IFX were associated with a lower response<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">26</span></a> that detection of detectable levels of IFX predicted CR, endoscopic improvement and lower risk of colectomy compared to undetectable levels,<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">27</span></a> later studies have shown that a large percentage of patients with “subtherapeutic” levels do achieve a response. Our study demonstrated that 54.2% of the patients in post-induction remission had subtherapeutic levels. This percentage is slightly higher than that observed in the medical literature, which ranges between 95 and 43%,<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a> with 30% being the most common.</p><p id="par0175" class="elsevierStylePara elsevierViewall">The main strength of our study is that the level monitoring strategy is evaluated prospectively from maintenance initiation in routine clinical practice, in a context where data is very scarce. Furthermore, it evaluates the role of early dose-escalation in patients with subtherapeutic post-induction levels despite achieving a response, something controversial which had not been analyzed up to now.</p><p id="par0180" class="elsevierStylePara elsevierViewall">Despite not having reached the primary <span class="elsevierStyleItalic">endpoint</span>, some of our results would support therapeutic drug level monitoring. Mainly, we refer to patients with pharmacodynamic failure, in whom, if we had not obtained a clinical response, we would have implemented dose-escalation if we had not performed level monitoring, but having done so has allowed an earlier change to another molecule with a different mechanism of action. On the other hand, we have also saved dose-escalation in patients with PR but correct levels, in whom the approach was conservative thanks to level monitoring, seeing the progression and repeating level monitoring in subsequent infusions.</p><p id="par0185" class="elsevierStylePara elsevierViewall">Our study has limitations, in addition to those already mentioned. Firstly, since this was an observational study in real clinical practice, the endoscopic response was not evaluated systematically, but through clinical indices, which may not accurately reflect intestinal activity.<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">28,29</span></a> Although, <span class="elsevierStyleItalic">a priori,</span> we expected to have very similar populations as these were cohorts of reference IBD hospitals, the PRO group had certain patients associated with greater severity, such as a higher percentage of surgeries as a result of a greater number of patients with B2 or B3 patterns. This could decrease the efficacy of CT-P13 in the proactive group, but it is also true that combined treatment with immunosuppressants was used more often in this group, which has been associated with a better response and higher levels of anti-TNF.</p><p id="par0190" class="elsevierStylePara elsevierViewall">Another relevant limitation is the absence of therapeutic drug level monitoring in the exclusively clinical approach group. As of today, this type of monitoring is not available in all hospitals in Spain and many IBD units are based on clinical and biochemical parameters. Therefore, due to the design of the study, only 2 approach strategies could be compared from the start of treatment (clinical versus proactive) and not an analysis of a group with subtherapeutic levels in which dose-escalation in applied versus another group without dose-escalation.</p><p id="par0195" class="elsevierStylePara elsevierViewall">Subsequent studies could analyze the levels during induction and its progression so that an earlier optimization could be carried out and avoid arriving with subtherapeutic or undetectable levels at the start of maintenance. Taking into account the emergence of new biologic drugs, cost-effectiveness studies will be necessary.</p><p id="par0200" class="elsevierStylePara elsevierViewall">In summary, our study reflects that proactive management of IFX treatment after induction did not improve their CR or PR rates at one year compared to a purely clinical approach. IFX dose-escalation in patients who have achieved CR but have subtherapeutic levels at week 14 does not appear to significantly prevent loss of subsequent secondary response, at least in the first year of follow-up.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflict of interests</span><p id="par0205" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1351367" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1242776" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1351366" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1242777" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Patients and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Study design and patients" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Method" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Baseline characteristics and indication of CT-P13" ] 1 => array:3 [ "identificador" => "sec0040" "titulo" => "Initial efficacy (week 14)" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Without primary response" ] ] ] 2 => array:3 [ "identificador" => "sec0050" "titulo" => "Long-term efficacy (week 54)" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Analysis of patients in remission at week 14" ] ] ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Adverse effects and drug discontinuation" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflict of interests" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-03-10" "fechaAceptado" => "2019-07-31" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1242776" "palabras" => array:4 [ 0 => "Drug monitoring" 1 => "Infliximab" 2 => "CT-P13" 3 => "Inflammatory bowel disease" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1242777" "palabras" => array:4 [ 0 => "Monitorización de niveles de fármaco" 1 => "Infliximab" 2 => "CT-P13" 3 => "Enfermedad inflamatoria intestinal" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">CT-P13 is a biosimilar drug of infliximab (IFX), effective in patients with inflammatory bowel disease (IBD). The monitoring of levels of IFX and anti-IFX antibodies is now considered part of the integral management.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To compare the clinical response according to a strictly clinical (CLN) or proactive (PRO) approach based on the monitoring of levels in week 14, in clinical practice.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We conducted a prospective study in IBD patients starting CT-P13. In the PRO group, levels of IFX and post-induction antibodies were systematically measured (week 14) and those with infraterapeutic levels (<3<span class="elsevierStyleHsp" style=""></span>μg/ml) were intensified, irrespective of the clinical response.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">We included 77 patients (23 ulcerative colitis and 54 Crohn's disease). Both PRO (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>41) and CLN (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>36) groups showed initial and long-term efficacy without significant differences. At week 14, 61% clinical remission (CR) (58.5% PRO, 63.9% CLN) and 80.5% at least partial response (PR) (80.5% PRO, 80.6% CLN). In week 54, 68.8% CR (61% PRO, 77.8% CLN) and 76.6% at least PR (73.2% PRO, 80.6% CLN). Of the patients in CR in week 14 (24 PRO, 23 CLN), 13 of the PRO group were intensified due to infra-therapeutic levels. In this subgroup no significant differences were observed in secondary loss of response (PRO 0%, CLN 8.7%).</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusion</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Proactive management does not improve response or remission rates in the first year. The intensification of clinical remission patients with post-induction infratherapeutic levels does not seem to significantly prevent secondary loss of response in the first year.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introducción</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">CT-P13 es un fármaco biosimilar de infliximab (IFX), efectivo en pacientes con enfermedad inflamatoria intestinal (EII). La medición de niveles de IFX y anticuerpos anti-IFX forma parte del tratamiento integral de dicha enfermedad.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivo</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Comparar la respuesta clínica en función de un abordaje estrictamente clínico (CLN) o proactivo (PRO) basado en la medición de niveles en la semana 14, en la práctica clínica.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Métodos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Estudio prospectivo en pacientes que inician CT-P13 por EII. En el grupo PRO se midieron sistemáticamente los niveles de IFX y de anticuerpos postinducción (semana 14) y se intensificaron aquellos con niveles infraterapéuticos (<<span class="elsevierStyleHsp" style=""></span>3<span class="elsevierStyleHsp" style=""></span>μg/ml), independientemente de la respuesta clínica.</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 77 pacientes (23 colitis ulcerosa y 54 enfermedad de Crohn). Ambos grupos, PRO (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>41) y CLN (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>36) presentaron una eficacia inicial y a largo plazo sin diferencias significativas. En la semana 14 hubo un 61% de remisión clínica (RC) (58,5% PRO, 63,9% CLN) y un 80,5% de al menos respuesta parcial (RP) (80,5% PRO, 80,6% CLN). En la semana 54 hubo un 68,8% de RC (61% PRO, 77,8% CLN) y un 76,6% de al menos RP (73,2% PRO, 80,6% CLN). De los pacientes en RC en la semana 14 (24 PRO, 23 CLN), 13 del grupo PRO fueron intensificados por niveles infraterapéuticos. En este subgrupo no se observaron diferencias significativas en la pérdida de respuesta secundaria (PRO 0%, CLN 8,7%).</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusión</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Un manejo proactivo no mejoró las tasas de respuesta ni la remisión en el primer año. La intensificación de pacientes en RC y niveles infraterapéuticos postinducción no parece prevenir de forma significativa la pérdida de respuesta secundaria en el primer año.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusión" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Elosua González A, Sanz Segura P, Oyón Lara D, López García S, Arroyo Villarino MT, Alcalá Escriche MJ, et al. Utilidad clínica de la determinación de niveles de CT-P13, biosimilar de infliximab, en el control de la enfermedad inflamatoria intestinal. Med Clin (Barc). 2020;154:475–480.</p>" ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "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"><th 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" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Proactive group (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>41) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Clinical group (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>36) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Sex (male), n (%)</span> \t\t\t\t\t\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">26 (63.4) \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">18 (50) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Age, mean (IQR)</span> \t\t\t\t\t\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">45.9 (18–81) \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">46.4 (18–80) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">BMI, average (IQR)</span> \t\t\t\t\t\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">23.6 (15–40) \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">24.5 (20–29) \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 " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Diagnosis, n (%)</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>CD \t\t\t\t\t\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">31 (75.6) \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">23 (63.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>UC \t\t\t\t\t\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 (24.4) \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">13 (36.1) \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="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">UC extension, n (%)</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>E2 \t\t\t\t\t\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 (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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (38.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>E3 \t\t\t\t\t\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">9 (90) \t\t\t\t\t\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">8 (61.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Mayo clinical baseline</span> \t\t\t\t\t\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">6.3 (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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.8 (5–8) \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="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">CD extension, n (%)</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>L1 \t\t\t\t\t\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 (48.4) \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">12 (54.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>L2 \t\t\t\t\t\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 (22.5) \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">4 (18.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>L3 \t\t\t\t\t\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">9 (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">6 (27.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>In addition L4 \t\t\t\t\t\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 (12.9) \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 \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="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">CD pattern, n (%)</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>B1 \t\t\t\t\t\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">12 (38.7) \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">14 (60.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>B2 \t\t\t\t\t\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 (35.5) \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 (26.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>B3 \t\t\t\t\t\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">8 (25.8) \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">3 (13) \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="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Harvey-Bradshaw Index, mean (IQR)</span> \t\t\t\t\t\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">7.4 (0–15) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.7 (1–14) \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="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Previous treatment, n (%)</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Steroids \t\t\t\t\t\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 (80.5) \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">36 (100) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Immunomodulator \t\t\t\t\t\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">35 (85.4) \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">26 (72.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17 (41.5) \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">10 (27.8) \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="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Previous surgeries (CD), n (%)</span> \t\t\t\t\t\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">12 (38.7) \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">2 (8.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Perianal surgery, n (%)</span> \t\t\t\t\t\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 (12.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (12.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2319296.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Demographic characteristics.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "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"><th 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" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Proactive group \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Clinical group \t\t\t\t\t\t\n \t\t\t\t\t\t</th></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="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">CT-P13 indication, n (%)</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Corticosteroid dependence \t\t\t\t\t\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 (2.4) \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 (16.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Corticosteroid-refractory \t\t\t\t\t\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 (12.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 (16.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Failure to immunomodulators \t\t\t\t\t\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">21 (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">22 (61.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Failure to 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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 (36.6) \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">8 (22.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Treatment of postsurgical recurrence \t\t\t\t\t\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">9 (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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (6.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Top-down</span> strategy \t\t\t\t\t\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 (7.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0) \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="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Concomitant treatment, n (%)</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Steroids \t\t\t\t\t\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 (14.6) \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">8 (22.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Immunomodulator \t\t\t\t\t\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">28 (68.3) \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">15 (41.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2319297.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Indication and concomitant treatments.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "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"><th 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" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Week 14</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Week 54</th></tr><tr title="table-row"><th 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" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">CLN (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">PRO (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">CLN (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">PRO (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Total</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No 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">19.5 \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">19.4 \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">26.8 \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">19.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Remission \t\t\t\t\t\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">58.5 \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">63.9 \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">61 \t\t\t\t\t\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">77.8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Partial 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">80.5 \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">80.6 \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">73.2 \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">80.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">CD</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No 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">16.1 \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">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22.6 \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">13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Remission \t\t\t\t\t\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">61.3 \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">73.9 \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">61.3 \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">87 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Partial 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">83.9 \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">87 \t\t\t\t\t\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">77.4 \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">87 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">UC</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No 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">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30.8 \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">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">30.8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Remission \t\t\t\t\t\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">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">46.2 \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">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">61.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Partial 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">70 \t\t\t\t\t\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">69.2 \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">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">69.2 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2319295.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Response Results at Weeks 14 and 54.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib0150" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. 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