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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Percentage of patients in clinical remission &#40;DAS28<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>2&#46;6&#41; or low disease activity &#40;DAS28<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>3&#46;2&#41; at 6 months of starting treatment with tocilizumab&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Rheumatoid arthritis &#40;RA&#41; is one of the most common chronic inflammatory diseases in Western countries&#46; The estimated prevalence of this disease in Spain is 0&#46;5&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Pharmacological treatment of RA focuses on reducing inflammatory activity and preventing the progression of joint damage and its consequences&#46; The consensus of experts from the Spanish Society of Rheumatology for RA management places full remission as therapeutic target of the disease and&#44; in the case of patients with longstanding RA&#44; achieving a low activity of the same&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Disease-modifying antirheumatic drugs &#40;DMARDs&#41; are the treatment of choice as soon as the RA diagnosis is confirmed&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Among the various DMARD&#44; Methotrexate&#39;s profile of efficacy and safety justifies its use as the drug of choice for initial treatment&#44; unless contraindicated&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> As a second step of treatment in patients with an insufficient response&#44; toxicity or intolerance to conventional DMARD&#44; biologic therapy treatment is recommended&#44; and antagonists of tumor necrosis factor &#40;anti-TNF&#41; are the most frequently used drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However&#44; between 30 and 40&#37; of patients have an unsatisfactory response to anti-TNF&#44; which has led to the search for new treatments for this disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#8211;7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Among them&#44; tocilizumab represents new therapeutic option&#46; It is a monoclonal antibody that binds to the soluble and membrane bound interleukin-6 receptors&#44; inhibiting the activity of this proinflammatory cytokine&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Different clinical trials have demonstrated the good efficacy and safety profile of tocilizumab in different populations of patients with RA&#44; as in the case of patients with inadequate response to conventional DMARDs or anti-TNF agents&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#8211;12</span></a> Despite the good results observed&#44; there are still open questions about the use of tocilizumab in routine clinical practice&#44; such as its use in less selected patients than those included in clinical trials or the need for a washout period of prior anti TNF employed before starting treatment with this antibody&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The objective of this national study was to evaluate the safety and efficacy of tocilizumab in RA patients with a profile closer to routine clinical practice&#44; including more comorbidities&#44; treatments combining DMARD or absence of washout of anti-TNF&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The high Spanish participation led us to make this subanalysis with the idea of specifically analyzing the behavior of the sample of Spanish patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and Methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">The open phase III b-ACT SURE clinical trial&#44; included patients from 25 different countries&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The results obtained in the patients from Spain are described in this paper&#46; The study was conducted in 28 Spanish centers&#46; The study was conducted according to the ethical principles of the Declaration of Helsinki and was approved by the Ethics Committee for Clinical Research of each unit&#46; All patients provided informed consent before undergoing any study procedures&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The study included patients of both genders&#44; aged 18 or over&#44; with moderate or high RA activity &#40;<span class="elsevierStyleItalic">Disease Activity Score</span> &#91;DAS&#93; 28<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>3&#46;2&#41; for 6 months or more&#44; who had been treated with conventional DMARDs or anti-TNF or both types of agents on stable doses for longer than 8 weeks&#46; Patients who were receiving glucocorticoids were receiving stable doses of &#8804;10<span class="elsevierStyleHsp" style=""></span>mg&#47;day of prednisone or equivalent&#46; Those patients who had been previously treated with abatacept&#44; anakinra or rituximab were excluded from the study&#46; After inclusion in the study&#44; patients received 8<span class="elsevierStyleHsp" style=""></span>mg&#47;kg of tocilizumab by intravenous infusion every 4 weeks during a period of 20 weeks &#40;6 infusions in total&#41;&#46; Patients could receive tocilizumab monotherapy or in combination with DMARDs&#44; at the discretion of the investigator&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Safety was evaluated in the population of patients who had received at least one dose of tocilizumab and had at least one post-baseline safety assessment&#46; In order to assess the need for an anti-TNF washout period before starting treatment with Tocilizumab&#44; a subgroup analysis was planned once the database was closed&#46; 3 groups of patients were considered&#58; patients who had not received prior treatment with anti-TNF &#40;anti-TNF na&#239;ve&#41;&#44; patients who had discontinued treatment with anti-TNF at least 2 months before the first infusion of tocilizumab &#40;anti-TNF with wash out&#41; and a third group consisted of patients who were treated with anti-TNF and where treatment with tocilizumab was started without a wash out &#40;anti-TNF without wash out&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Efficacy parameters proposed by the <span class="elsevierStyleItalic">American College of Rheumatology</span> &#40;ACR&#41; and DAS28 were measured at each study visit and at 4 weeks after the last infusion of tocilizumab&#46; The efficacy of treatment with tocilizumab was assessed as the percentage of patients who met ACR20&#47;50&#47;70 response criteria and the percentage of patients who met the criteria for remission and low disease activity d based on DAS28 &#40;DAS28<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>2&#44; 6 and DAS28<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>3&#46;2&#44; respectively&#41; after 6 months of starting treatment with tocilizumab&#46; Different parameters allowed the subsequent calculation of the <span class="elsevierStyleItalic">Simplified Disease Activity Index</span> &#40;SDAI&#41; and <span class="elsevierStyleItalic">Clinical Disease Activity Index</span> &#40;CDAI&#41; composite indexes&#46; Additionally&#44; the percentage of patients who met the European League Against Rheumatism &#40;EULAR&#41; criteria of good or moderate response <span class="elsevierStyleItalic">at 6 months after the first infusion of tocilizumab response was estimated&#46;</span> The disability associated with the disease was assessed using the <span class="elsevierStyleItalic">Health Assessment</span> Questionnaire <span class="elsevierStyleItalic">Disability Index</span> &#40;HAQ-DI&#41;&#46; The safety of treatment with tocilizumab was assessed by monitoring adverse events and analysis of hematological and biochemical parameters in each of the study visits&#46; Infusion reactions were considered adverse events if they occurred during the 24<span class="elsevierStyleHsp" style=""></span>h following the infusion of tocilizumab&#46; The intensity of adverse events and their relationship to the study medication were assessed by researchers&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The efficacy of treatment with tocilizumab was assessed as an intent to treat population&#44; which consisted of patients who had received one or more doses of tocilizumab&#46; Patients who discontinued the study prematurely were considered as non-responders in the efficacy analysis according to the ACR criteria&#46; The analysis of the other endpoints was performed on the number of patients with available data for each of the visits&#46; Descriptive statistics for all variables obtained were performed&#58; mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation &#40;SD&#41; for continuous variables and frequencies for categorical variables&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Demographic Characteristics and Disposition</span><p id="par0050" class="elsevierStylePara elsevierViewall">Of the 1681 patients included in the ACT-SURE international study&#44; 170 patients belonged to the Spanish hospitals participating&#46; The distribution of patients among the 3 groups was similar to that of the overall study&#58; 95 were anti-TNF na&#239;ve&#44; 36 had received anti-TNF and underwent a wash out period and 39 had received anti-TNF without wash out&#46; The clinical and demographic baseline characteristics for all patients and different groups were considered depending on the pretreatment with anti-TNF characteristics and are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Most patients in the study received tocilizumab with another DMARD&#59; only 19 &#40;11&#46;2&#37;&#41; patients received tocilizumab monotherapy&#44; similar to the overall study &#40;14&#37;&#41; figure&#46; 1&#46;8&#37; of patients received tocilizumab in combination with 2 DMARD&#44; significantly lower than the overall study &#40;19&#37;&#41;&#46; Methotrexate was the most commonly used DMARD &#40;62&#46;9&#37;&#41; at a mean dose<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD 15&#46;9 &#40;5&#46;0&#41; mg&#47;week&#46;15&#46;3&#37; of patients received leflunomide at a mean dose of 19&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46; 72&#46;4&#37; received concomitant corticosteroids&#46; Patients had a high baseline activity &#40;DAS28 6&#46;1&#41; and duration of RA&#44; almost 10 years&#44; similar to the overall study data&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">88&#46;8&#37; &#40;n&#61;151&#41; of patients completed the 6-month study&#44; similar to the overall study&#46; The reasons for study discontinuation were withdrawal of consent in 5 patients&#44; adverse event in 5 patients&#44; inadequate treatment response in 3 patients&#44; investigator&#39;s decision in 2 patients&#44; violation of any selection criteria in 2 patients and loss to follow in 2 patients&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Safety</span><p id="par0060" class="elsevierStylePara elsevierViewall">The main results of the safety study are presented in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; Overall&#44; adverse events were recorded in 118 patients&#46; Those who had previously been treated with anti-TNF&#44; and the had undergone a prior wash out&#44; showed a lower apparent numerical incidence of adverse events&#44; unlike the global study&#44; in which no safety differences were detected in terms of unwashed or washed out patients&#46; Infections were one of the most common adverse events&#44; 25&#46;9&#37; of patients had at least one infection during the study&#46; A single patient had an upper respiratory tract infection that was considered a serious adverse event &#40;1&#46;1 per 100 patient-years&#41;&#44; compared with 5&#46;1 per 100 patient-years in the overall study&#46; 15&#46;3&#37; of patients experienced infusion reactions&#44; defined as any adverse event occurring during or within the following 24<span class="elsevierStyleHsp" style=""></span>h infusion&#44; this figure was numerically lower in the group of washed out patients &#40;8&#44; 3&#37;&#41;&#46; No deaths were recorded during the study&#46; Non-infectious adverse events leading to withdrawal from the study were&#58; humerus fracture&#44; ulcerative keratitis&#44; laryngeal cancer and respiratory failure&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">14&#46;7&#37; of patients developed neutropenia during treatment with tocilizumab&#44; in no cases was the neutrophil count less than 500&#47;mm<span class="elsevierStyleSup">3</span>&#46; 16&#46;4&#37; of patients had elevated levels of alanine aminostransferase &#40;ALT&#41;&#44; this being more frequent in the anti-TNF na&#239;ve population&#59; only 1&#46;7&#37; of patients had elevated ALT between 3 and 5 times the upper limit of normal&#44; with no case exceeding this figure&#46; 3 8&#46;2&#37; of patients had elevations in total cholesterol&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Efficacy</span><p id="par0070" class="elsevierStylePara elsevierViewall">Efficacy data were in line with those of the overall study&#46; 71&#46;8&#37; &#40;n&#61;122&#41;&#44; 50&#37; &#40;n&#61;85&#41; and 30&#37; &#40;n&#61;51&#41; of patients respectively met ACR20&#44; ACR50 and ACR70 response criteria at 6 months after initiation of treatment with tocilizumab &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The high percentage of patients achieving ACR20 response after receiving the first infusion of tocilizumab &#40;44&#46;7&#37;&#41; is noteworthy&#46; This percentage increased progressively until week 16&#44; remaining roughly constant until the visit at 6 months &#40;data not shown&#41;&#46; The ACR20 response at 6 months in the na&#239;ve to anti-TNF group was higher than in the other two groups &#40;76&#46;8&#37; vs 63&#46;9&#37; in the anti-TNF group with prior wash out and 66&#46;7&#37; in the anti-TNF without wash out&#41;&#44; in accordance to what has been observed in other studies with tocilizumab&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;12</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">48 and 64&#46;9&#37; of patients had clinical remission and low disease activity&#44; respectively&#44; according to the DAS28 index after 6 months of treatment &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#46; These responses were also higher in patients na&#239;ve to anti-TNF &#40;76&#46;5&#37; vs 55&#46;2&#37; in the anti-TNF group with prior wash out and 44&#46;1&#37; in the anti-TNF group without wash out&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">DAS28 activity decreased progressively during treatment with tocilizumab &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#46; The mean DAS28 at 6 months of treatment was 2&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;3&#44; representing a mean improvement of 3&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;5 points in all patients&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a> shows the percentage of patients in clinical remission or low disease activity at 6 months of treatment as scored by the SDAI and CDAI criteria&#46; As can be seen&#44; the response to these 2 scores &#40;the only difference is that the CDAI does not include acute phase reactants&#41; were very similar in different subgroups of patients&#46; As to the EULAR response&#44; 84&#46;1&#37; of patients had a good or moderate response at 6 months &#40;86&#46;3&#37; of anti-TNF na&#239;ve patients&#44; 80&#46;5&#37; of the anti-TNF group with wash out and 82&#46;1&#37; of those receiving prior anti-TNF without wash out&#41;&#46; Additionally&#44; the majority of patients &#40;75&#46;5&#37;&#41; showed clinically significant improvement in disability questionnaire HAQ-DI &#40;reduction of 0&#46;22 points or more&#41; &#40;data not shown&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">This study included patients treated with tocilizumab&#44; both as monotherapy and in combination with DMARDs&#46; The ACR20&#44; 50 and 70 responses showed no significant differences between treatment groups &#40;data not shown&#41;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Discussion</span><p id="par0095" class="elsevierStylePara elsevierViewall">The added value of the ACT-SURE study lies in its design&#44; with a profile of RA patients similar to what is seen in routine clinical practice&#44; including populations with broader comorbidities&#44; patients with refractory to treatment &#40;failure to anti-TNF and DMARD&#41; and who could receive tocilizumab as monotherapy or in combination with different DMARD at doses near the maximum used&#44; including combinations thereof&#46; In addition&#44; it had the option to perform&#44; or not&#44; a washout period of anti-TNF before starting tocilizumab&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">This design is particularly important when analyzing safety data&#46; The overall results of ACT-SURE have confirmed the safety profile of tocilizumab observed in previous studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#8211;12</span></a> The incidence of adverse events in the subgroup of patients in Spain is similar to that reported in the overall study&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The main adverse effects detected were infections and altered laboratory parameters&#46; However&#44; some differences are observed between both studies&#46; It is noteworthy that in the Spanish subpopulation there was only one case of serious infection among 170 patients enrolled &#40;1&#46;1 per 100 patient-years&#41;&#44; compared to a rate of 5&#46;1 per 100 patient-years in the overall study&#46; Another safety related issue was that&#44; in the analysis of our population&#44; infusion reactions&#44; infections and transaminase elevations occurred less frequently in patients with anti-TNF wash out than in the rest&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The reasons for these discrepancies are unknown&#46; In principle&#44; it does not seem attributable to differences in the patient profile&#44; given that the distribution between the 3 subgroups&#44; and the time since onset of RA or the baseline activity were similar in the 2 analyses&#46; The lower frequency of patients treated with the combination of tocilizumab and 2 or more DMARDs in our population could be a differentiating factor&#44; but we do not know if this was associated with a higher rate of serious infections in the global analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The fact that the number of Spanish patients in the subgroup who underwent an anti-TNF wash out is only 36 &#40;21&#37;&#41; makes it likely to be only a random variation&#46; This is important because the overall analysis suggests that it is not necessary to perform a wash of anti-TNF before treatment with tocilizumab&#44; which has important practical implications&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In terms of efficiency&#44; our data confirm the general result of tocilizumab&#44; with a fast and consistent effect both in patients na&#239;ve to anti-TNF as in those with an inadequate response to these drugs&#46; As expected&#44; the response is better in the first group of patients than in the second&#46; This coincides with the results previously observed with tocilizumab&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#8211;12</span></a> Minor differences in tocilizumab efficacy after performing anti-TNF wash out are likely related to the limited number of patients with baseline differences in the activity and duration of illness&#46; The patients in whom prior wash out was not performed had a more severe and longer duration than patients in those whom this wash out was performed&#46; In the overall analysis of the data&#44; there were no differences in efficacy between these groups&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The highest percentage of responders according to the DAS28 index compared with the SDAI and CDAI can be explained by the significant effect tocilizumab has on acute phase reactants and the weight that the ESR has in the DAS28 formula&#46; However&#44; the fact that SDAI and CDAI responses &#40;2 indices which differ only in that CDAI does not include acute phase reactants&#41; are similar shows that the efficacy of tocilizumab is not primarily due to its effect on reactants&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">It is interesting to note that the efficacy of tocilizumab monotherapy in this analysis is similar to that of its combined use with DMARD&#46; While the fact that patients were not randomized based on this parameter limits the significance of this data&#44; other results support this idea&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> which makes tocilizumab a good choice for patients intolerant to or with contraindications to DMARD&#46; Furthermore&#44; a recent study has demonstrated the superiority of tocilizumab versus adalimumab monotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The main limitations of this analysis lie in the number of patients and duration of the 6-month follow-up&#46; Although the analysis of longer periods of treatment is essential to evaluate the safety of a drug&#44; our results are consistent with other studies of longer duration&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> In contrast&#44; the profile of less selected patients and&#44; therefore&#44; closer to actual clinical practice&#44; provides great value to this data&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">In conclusion&#44; the results of this study allow us to confirm the safety profile of tocilizumab in RA patients and failure to DMARD or anti-TNF&#46; Tocilizumab appears to be more effective in patients who do not respond satisfactorily to treatment with conventional DMARDs than those not responding to anti-TNF&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Ethical Responsibilities</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Protection of people and animals</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare that study procedures conformed to the ethical standards of the responsible committee on human experimentation and in accordance with the World Medical Association and the Declaration of Helsinki&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Data confidentiality</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their workplace regarding the publication of data from patients and that all patients included in the study have received sufficient information and have given their written informed consent to participate in the study&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Right to privacy and informed consent</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors have obtained informed consent from patients and&#47;or subjects referred to in the article&#46; This document is in the possession of the corresponding author&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of Interest</span><p id="par0150" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleGrantSponsor" id="gs0005">Roche Pharma</span> has been the ACT SURE study sponsor&#46; J&#46;M&#46; Alvaro-Gracia has received research support or honoraria for consultancy or presentations from <span class="elsevierStyleGrantSponsor" id="gs0010">Abbott</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0015">Aventis</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0020">Bristol Myers Squibb</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0025">Janssen-Cilag</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0030">MSD</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0035">Pfizer</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0040">Roche</span>&#44; and <span class="elsevierStyleGrantSponsor" id="gs0045">UCB Tigenix</span>&#59; FJ White has received research support or honoraria from <span class="elsevierStyleGrantSponsor" id="gs0050">Absciex</span>&#44; Abbott&#44; <span class="elsevierStyleGrantSponsor" id="gs0055">Ardea Bioscience</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0060">Bioiberica</span>&#44; Bristol Myers Squibb&#44; <span class="elsevierStyleGrantSponsor" id="gs0065">Celgene</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0070">Celltrion</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0075">Lilly</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0080">Merck</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0085">Novartis</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0090">Novo Nordisk</span>&#44; Pfizer&#44; Roche&#44; Sanofi Aventis&#44; and UCB Tigenix&#59; A&#46; Fern&#225;ndez-Nebro has received research support or honoraria for lectures from Abbott&#44; MSD&#44; Pfizer and Roche&#44; A&#46; Garcia-Lopez has received research support or honoraria from Abbott&#44; <span class="elsevierStyleGrantSponsor" id="gs0095">Amgen</span>&#44; Bristol Myers Squibb&#44; MSD&#44; Roche and UCB&#59; FJ Navarro has received research support or honoraria from Abbott&#44; Celltrion&#44; Roche and UCB&#59; S&#46; Bustabad has received research grants and honoraria from Roche&#44; MSD&#44; UCB&#44; Abbott and Bristol Myers Squibb&#59; Y&#46; Armendariz is employed by the Medical Department of Roche&#44; and JA Rom&#225;n-Ivorra has received research support or honoraria from Abbott&#44; Actelion&#44; Amgen&#44; Bristol Myers Squibb&#44; Merck&#44; Pfizer&#44; Roche and UCB&#46;</p></span></span>"
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            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Demographic Characteristics and Disposition"
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            1 => array:2 [
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              "titulo" => "Safety"
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              "identificador" => "sec0030"
              "titulo" => "Efficacy"
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          "titulo" => "Discussion"
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          "identificador" => "sec0040"
          "titulo" => "Ethical Responsibilities"
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            0 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Protection of people and animals"
            ]
            1 => array:2 [
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              "titulo" => "Data confidentiality"
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              "titulo" => "Right to privacy and informed consent"
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          "titulo" => "Conflict of Interest"
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        10 => array:2 [
          "identificador" => "xack77314"
          "titulo" => "Acknowledgements"
        ]
        11 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2013-02-06"
    "fechaAceptado" => "2013-07-03"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec307738"
          "palabras" => array:3 [
            0 => "Tocilizumab"
            1 => "Rheumatoid arthritis"
            2 => "Disease-modifying antirheumatic drugs"
          ]
        ]
      ]
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          "identificador" => "xpalclavsec307739"
          "palabras" => array:3 [
            0 => "Tocilizumab"
            1 => "Artritis reumatoide"
            2 => "F&#225;rmacos antirreum&#225;ticos modificadores de la enfermedad"
          ]
        ]
      ]
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To analyze the Spanish experience in an international study which evaluated tocilizumab in patients with rheumatoid arthritis &#40;RA&#41; and an inadequate response to conventional disease-modifying antirheumatic drugs &#40;DMARDs&#41; or tumor necrosis factor inhibitors &#40;TNFis&#41; in a clinical practice setting&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Subanalysis of 170 patients with RA from Spain who participated in a phase IIIb&#44; open-label&#44; international clinical trial&#46; Patients presented inadequate response to DMARDs or TNFis&#46; They received 8<span class="elsevierStyleHsp" style=""></span>mg&#47;kg of tocilizumab every 4 weeks in combination with a DMARD or as monotherapy during 20 weeks&#46; Safety and efficacy of tocilizumab were analyzed&#46; Special emphasis was placed on differences between failure to a DMARD or to a TNFi and the need to switch to tocilizumab with or without a washout period in patients who had previously received TNFi&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The most common adverse events were infections &#40;25&#37;&#41;&#44; increased total cholesterol &#40;38&#37;&#41; and transaminases &#40;15&#37;&#41;&#46; Five patients discontinued the study due to an adverse event&#46; After six months of tocilizumab treatment&#44; 71&#47;50&#47;30&#37; of patients had ACR 20&#47;50&#47;70 responses&#44; respectively&#46; A higher proportion of TNFi-naive patients presented an ACR20 response&#58; 76&#37; compared to 64&#37; in the TNFi group with previous washout and 66&#37; in the TNFi group without previous washout&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Safety results were consistent with previous results in patients with RA and an inadequate response to DMARDs or TNFis&#46; Tocilizumab is more effective in patients who did not respond to conventional DMARDs than in patients who did not respond to TNFis&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Analizar la experiencia espa&#241;ola en un estudio internacional para evaluar tocilizumab en pacientes con artritis reumatoide &#40;AR&#41; con respuesta insuficiente al tratamiento con f&#225;rmacos antirreum&#225;ticos modificadores de la enfermedad convencionales &#40;FAME&#41; o anti-TNF en condiciones cercanas a la pr&#225;ctica cl&#237;nica habitual&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Suban&#225;lisis de 170 pacientes con AR que participaron en Espa&#241;a en un ensayo cl&#237;nico&#44; internacional abierto de fase <span class="elsevierStyleSmallCaps">iii</span>b&#44; que presentaban una respuesta inadecuada al tratamiento con FAME o anti-TNF&#46; Los pacientes recibieron 8<span class="elsevierStyleHsp" style=""></span>mg&#47;kg de tocilizumab cada 4 semanas en combinaci&#243;n con FAME o en monoterapia durante un periodo de 20 semanas&#46; Se evaluaron la seguridad y la eficacia de tocilizumab distinguiendo entre pacientes con fallo a FAME o anti-TNF y&#44; dentro de estos&#44; entre los que hab&#237;an hecho o no periodo de lavado del anti-TNF&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Los acontecimientos adversos m&#225;s frecuentes fueron infecciones &#40;25&#37;&#41; y elevaci&#243;n de colesterol total &#40;38&#37;&#41; y transaminasas &#40;15&#37;&#41;&#46; Cinco pacientes abandonaron el estudio por un acontecimiento adverso&#46; El 71&#47;50&#47;30&#37; de los pacientes cumpl&#237;a criterios de respuesta ACR 20&#47;50&#47;70 a los 6 meses del inicio del tratamiento con tocilizumab&#46; Los pacientes na&#239;ve para anti-TNF presentaron una mayor respuesta ACR20&#58; el 76&#37; frente a un 64&#37; en el grupo anti-TNF con lavado previo y el 66&#37; en el grupo anti-TNF sin lavado previo&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se confirma el perfil de seguridad de tocilizumab en pacientes con AR y fallo a FAME o anti-TNF&#46; Tocilizumab es m&#225;s eficaz en pacientes que no responden de forma satisfactoria al tratamiento con FAME convencionales que con anti-TNF&#46;</p>"
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    "NotaPie" => array:2 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; &#193;lvaro-Gracia JM&#44; Fern&#225;ndez-Nebro A&#44; Garc&#237;a-L&#243;pez A&#44; Guzm&#225;n M&#44; Blanco FJ&#44; Navarro FJ&#44; et al&#46; Tocilizumab en pacientes con artritis reumatoide activa y respuesta inadecuada a f&#225;rmacos antirreum&#225;ticos modificadores de la enfermedad o antagonistas del factor de necrosis tumoral&#58; suban&#225;lisis de los datos espa&#241;oles de un estudio abierto cercano a la pr&#225;ctica cl&#237;nica habitual&#46; Reumatol Clin&#46; 2014&#59;10&#58;94&#8211;100&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">The names of the Spanish researchers participating in the ACT SURE study are listed in <a class="elsevierStyleCrossRef" href="#sec0065">Annex 1</a>&#46;</p>"
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            "apendice" => "<p id="par0160" class="elsevierStylePara elsevierViewall">Jose Luis Alvarez Vega</p> <p id="par0165" class="elsevierStylePara elsevierViewall">Jose Maria Alvaro-Gracia</p> <p id="par0170" class="elsevierStylePara elsevierViewall">Arboleya Luis Rodr&#237;guez</p> <p id="par0175" class="elsevierStylePara elsevierViewall">Joaqu&#237;n Belzunegui Otano</p> <p id="par0180" class="elsevierStylePara elsevierViewall">Francisco Blanco Garc&#237;a</p> <p id="par0185" class="elsevierStylePara elsevierViewall">M&#46; Sagrario Bustabad Reyes</p> <p id="par0190" class="elsevierStylePara elsevierViewall">Javier Calvo Catala</p> <p id="par0195" class="elsevierStylePara elsevierViewall">Cesar Diaz Torne</p> <p id="par0200" class="elsevierStylePara elsevierViewall">Antonio Domingo G&#243;mez Centeno</p> <p id="par0205" class="elsevierStylePara elsevierViewall">Escudero Alejandro Contreras</p> <p id="par0210" class="elsevierStylePara elsevierViewall">Luis Fern&#225;ndez Dom&#237;nguez</p> <p id="par0215" class="elsevierStylePara elsevierViewall">Antonio Fern&#225;ndez Nebro</p> <p id="par0220" class="elsevierStylePara elsevierViewall">Angel Aparicio Garc&#237;a</p> <p id="par0225" class="elsevierStylePara elsevierViewall">Sergio Garc&#237;a P&#233;rez</p> <p id="par0230" class="elsevierStylePara elsevierViewall">Alicia Garc&#237;a Testal</p> <p id="par0235" class="elsevierStylePara elsevierViewall">Jose Garcia Tor&#243;n</p> <p id="par0240" class="elsevierStylePara elsevierViewall">Eduardo Quesada Girona</p> <p id="par0245" class="elsevierStylePara elsevierViewall">Guzm&#225;n Manuel Ubeda</p> <p id="par0250" class="elsevierStylePara elsevierViewall">Ibero Isabel Diaz</p> <p id="par0255" class="elsevierStylePara elsevierViewall">Francisco Javier Ruiz Manero</p> <p id="par0260" class="elsevierStylePara elsevierViewall">Carlos Fernandez-Cid Marras</p> <p id="par0265" class="elsevierStylePara elsevierViewall">Sara Marsal Barrel</p> <p id="par0270" class="elsevierStylePara elsevierViewall">Francisco Javier Navarro Blasco</p> <p id="par0275" class="elsevierStylePara elsevierViewall">Francisco Javier Garc&#237;a Narv&#225;ez</p> <p id="par0280" class="elsevierStylePara elsevierViewall">Lucia Pantoja Zarza</p> <p id="par0285" class="elsevierStylePara elsevierViewall">Mar&#237;a Trinidad P&#233;rez Sandoval</p> <p id="par0290" class="elsevierStylePara elsevierViewall">Javier del Pino Montes</p> <p id="par0295" class="elsevierStylePara elsevierViewall">Paula Ramos Carmen Nunez</p> <p id="par0300" class="elsevierStylePara elsevierViewall">Elena Riera Alonso</p> <p id="par0305" class="elsevierStylePara elsevierViewall">Diaz Manuel Riesco</p> <p id="par0310" class="elsevierStylePara elsevierViewall">Jose Ramon Rodriguez Cros</p> <p id="par0315" class="elsevierStylePara elsevierViewall">Jose Manuel Rodriguez Heredia</p> <p id="par0320" class="elsevierStylePara elsevierViewall">Carlos Rodr&#237;guez Lozano</p> <p id="par0325" class="elsevierStylePara elsevierViewall">Jos&#233; Andr&#233;s Rom&#225;n Ivorra</p> <p id="par0330" class="elsevierStylePara elsevierViewall">Rosello Rosa Pardo</p> <p id="par0335" class="elsevierStylePara elsevierViewall">Jose Javier Salaberri Maestrojuan</p> <p id="par0340" class="elsevierStylePara elsevierViewall">Raimon Sanmarti Room</p> <p id="par0345" class="elsevierStylePara elsevierViewall">Manuel Utrilla Utrilla</p> <p id="par0350" class="elsevierStylePara elsevierViewall">Tom&#225;s V&#225;zquez Ram&#243;n Rodr&#237;guez</p> <p id="par0355" class="elsevierStylePara elsevierViewall">Paloma Vela Casasempere</p>"
            "etiqueta" => "Annex 1"
            "titulo" => "Spanish Researchers Participating in the ACT SURE Study"
            "identificador" => "sec0065"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">RA&#58; rheumatoid arthritis&#59; CDAI&#58; <span class="elsevierStyleItalic">Clinical Disease Activity Index</span>&#59; DAS28&#58; <span class="elsevierStyleItalic">Disease Activity Score</span> based on 28 joints&#59; SD&#58; standard deviation&#59; DMARD&#58; disease-modifying antirheumatic drugs&#59; NPJ&#58; number of painful joints&#59; NSJ&#58; number of swollen joints&#59; CRP&#58; C Reactive Protein&#59; SDAI&#58; <span class="elsevierStyleItalic">Simplified Disease Activity Index</span>&#59; ESR&#58; erythrocyte sedimentation rate&#46;</p>"
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                  \t\t\t\t"><span class="elsevierStyleItalic">Duration of RA &#40;years&#41;&#44; mean</span><span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Number of concomitant DMARDs&#44; n &#40;&#37;&#41;</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>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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9 &#40;9&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;8&#46;3&#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">7 &#40;17&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19 &#40;11&#46;2&#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>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">84 &#40;88&#46;4&#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">32 &#40;88&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32 &#40;82&#46;1&#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">148 &#40;87&#46;1&#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>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">2 &#40;2&#46;1&#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">1 &#40;2&#46;8&#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">-&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">3 &#40;1&#46;8&#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  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Patients taking leflunomide&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10 &#40;10&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;22&#46;2&#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">8 &#40;20&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26 &#40;15&#46;3&#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="elsevierStyleItalic">Patients treated with methotrexate&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63 &#40;66&#46;3&#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">23 &#40;63&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21 &#40;53&#46;8&#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">107 &#40;62&#46;9&#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="elsevierStyleItalic">Patients treated with corticosteroids&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59 &#40;62&#46;1&#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">34 &#40;94&#46;4&#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">30 &#40;76&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">123 &#40;72&#46;4&#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="elsevierStyleItalic">CRP &#40;mg&#47;dl&#41;&#44; mean</span><span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#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">2&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;4&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="elsevierStyleItalic">ESR &#40;mm&#47;h&#41;&#44; mean</span><span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>24&#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">48&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>30&#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">49&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>26&#46;6&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="elsevierStyleItalic">NPJ&#44; mean</span><span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&#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">19&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#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">22&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#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">20&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#46;5&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="elsevierStyleItalic">NSJ&#44; mean</span><span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;7&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="elsevierStyleItalic">DAS28&#44; mean</span><span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#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;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>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">6&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>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">6&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;1&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="elsevierStyleItalic">SDAI&#44; mean</span><span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">36&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#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">38&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">35&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">CDAI&#44; mean</span><span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD</span>&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">AE&#58; adverse events&#59; SAE&#58; serious adverse events&#44; ALT&#58; alanine aminotransferase&#44; ULN&#58; upper limit of normal&#46;</p>"
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                0 => """
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                  \t\t\t\t" style="border-bottom: 2px solid black">Patients&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Anti-TNF na&#239;ve &#40;No&#46;&#61;95&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Anti-TNF with prior wash out &#40;No&#46;&#61;36&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Anti-TNF with prior wash out &#40;No&#46;&#61;39&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Total &#40;No&#46;&#61;170&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">69 &#40;72&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">21 &#40;58&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">28 &#40;71&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">118 &#40;69&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">SAE&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">5 &#40;5&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2 &#40;5&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1 &#40;2&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">8 &#40;4&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Infections&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">28 &#40;29&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">6 &#40;16&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10 &#40;25&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">44 &#40;25&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Serious infections&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1 &#40;1&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0 &#40;0&#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="char" valign="\n
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                  \t\t\t\t">0 &#40;0&#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
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                  \t\t\t\t">1 &#40;0&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Infusion reactions&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">17 &#40;17&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;8&#46;3&#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">6 &#40;15&#46;4&#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
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                  \t\t\t\t">26 &#40;15&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">ALT elevation<span class="elsevierStyleHsp" style=""></span>&#60;1&#46;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>ULN&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">6 &#40;15&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">28 &#40;16&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Elevation cholesterol values<span class="elsevierStyleHsp" style=""></span>&#62;200<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \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 &#40;36&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 &#40;30&#46;8&#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">65 &#40;38&#46;2&#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">Neutrophil count<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>1500&#47;mm<span class="elsevierStyleSup">3</span>&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \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 &#40;16&#46;8&#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">4 &#40;11&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;12&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25 &#40;14&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Results Regarding Safety&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
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            0 => array:3 [
              "identificador" => "bib0005"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The prevalence of rheumatoid arthritis in the general population of Spain"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "L&#46; Carmona"
                            1 => "V&#46; Villaverde"
                            2 => "C&#46; Hernandez-Garcia"
                            3 => "J&#46; Ballina"
                            4 => "R&#46; Gabriel"
                            5 => "A&#46; Laffon"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Rheumatology &#40;Oxford&#41;"
                        "fecha" => "2002"
                        "volumen" => "41"
                        "paginaInicial" => "88"
                        "paginaFinal" => "95"
                      ]
                    ]
                  ]
                ]
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            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Actualizaci&#243;n de la Gu&#237;a de Pr&#225;ctica Cl&#237;nica para el Manejo de la Artritis Reumatoide en Espa&#241;a"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Sociedad Espa&#241;ola de Reumatolog&#237;a"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:1 [
                        "fecha" => "December 2011"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Current evidence for the management of rheumatoid arthritis with synthetic disease-modifying antirheumatic drugs&#58; a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
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