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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In patients with rheumatoid arthritis &#40;RA&#41; treated with anti-TNF drugs &#40;anti-TNF&#41;&#46; A correlation has been found between drug levels and clinical response<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46; For example&#44; in infliximab-treated patients&#44; the presence of anti-drug antibodies &#40;ADA&#41; provoke loss of response&#44; ifuional reactions and increased treatment withdrawal<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46; These data are not exclusive to RA and have also been described in spondyloarhritis &#40;SpA&#41;&#44; where anti-infliximab and anti-adalimumab antibodies are found in non-responders and in the case of infliximab&#44; they are also related to infusional reactions&#44; motivating a switch to another drug<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Various drug level measurement techniques are available with different standardisation<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#44; creating uncertainty as to the value of measuring drug levels&#46; A consensus article has recently been published with the aim of reducing this uncertainty in the Spanish setting<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The aims of this study were to compare anti-TNF levels in RA patients vs&#46; SpA&#44; in patients in remission&#47;low disease activity &#40;LDA&#41; vs&#46; non-remission&#47;non-LDA according to rheumatic disease&#44; and to determine the influence of the use of conventional synthetic disease-modifying drugs &#40;DMARDs&#41; on these levels&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Material and methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">A total of 474 patients were being treated with anti-TNF drugs at our centre&#44; including 51 patients with infliximab&#44; 198 patients with adlmumab&#44; and 225 patients with etanercept&#46; A retrospective&#44; observational study was conducted to measure anti-TNF levels and the presence of ADA in a group of consecutively selected patients who attended consultations at the rheumatology department of the Miguel Servet University Hospital&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Inclusion criteria</span><p id="par0025" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0030" class="elsevierStylePara elsevierViewall">Adult patients on anti-TNF treatment&#46;</p></li></ul></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Exclusion criteria</span><p id="par0035" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0040" class="elsevierStylePara elsevierViewall">Patients who declined to participate in the study</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0045" class="elsevierStylePara elsevierViewall">Patients under follow-up in other hospitals</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0050" class="elsevierStylePara elsevierViewall">Diagnoses other than RA or SpA</p></li></ul></p><p id="par0055" class="elsevierStylePara elsevierViewall">The most commonly used methods for measuring levels are the sandwich ELISA and the indirect ELISA<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#46; In our study&#44; the sample was obtained on the day the drug was due to be administered &#40;trough level&#41;&#44; using the Promonitor&#174; test from Laboratorios Grifols &#40;sandwich ELISA&#41;&#44; and according to the methodology described by Chen DY et al&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46; In cases with undetectable anti-TNF levels&#44; Acaf was measured using the Promonitor&#174; test from Laboratorios Grifols &#40;bridge-type ELISA&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The following data were collected from the patients&#8217; clinical history&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Time of evolution of the disease</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0070" class="elsevierStylePara elsevierViewall">Type and schedule of biologic treatment and DMARDs</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0075" class="elsevierStylePara elsevierViewall">Adherence&#58; percentage of the prescribed dosage of the drug that the patient withdraws from the hospital pharmacy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8226;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Disease activity&#58; considering remission&#47;low activity in patients with RA when they had a DAS28 &#40;CRP&#41;&#8239;&#8804;&#8239;3&#46;2 and in patients with SpA a BASDAI&#8239;&#8804;&#8239;4 and ASDAS &#40;CRP&#41;&#8239;&#8804;&#8239;2&#46;1&#46; The activity indices were obtained from the consultation prior to the measurement of the levels&#46;</p></li></ul></p><p id="par0085" class="elsevierStylePara elsevierViewall">With these data&#44; a group of patients with RA and SpA was obtained and in each&#44; subgroups with drug dosages according to the technical data sheet &#40;standard dose&#41; and others with dosages lower than those recommended &#40;suboptimal dose&#41;&#44; as well as patients with&#47;without treatment with DMARDs&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Ethical aspects</span><p id="par0090" class="elsevierStylePara elsevierViewall">All patients signed an informed consent form for this study and for the use of biological samples for biomedical research&#46; This study was approved by the Research Ethics Committee of the Autonomous Community of Aragon&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Statistical method</span><p id="par0095" class="elsevierStylePara elsevierViewall">Quantitative variables&#58; distribution was determined with the Kolmogorov-Smirnov statistic &#40;Lilliefors correction&#41;&#59; in variables with N&#8239;&#60;&#8239;50&#44; the Shapiro&#8211;Wilk statistic was applied&#59; if the distribution was normal&#44; the mean and standard deviation &#40;SD&#41; were determined&#59; in variables with non-parametric distribution&#44; the median and interquartile range &#40;IQR&#41; were determined&#46; For differences between means and between medians&#58; Student&#8217;s t test and Mann&#8211;Whitney U test were used&#44; respectively&#46; For qualitative variables&#58; 2&#8239;&#215;&#8239;2 contingency tables with Pearson&#8217;s Chi-square test&#46; Statistical procedures were performed with the R statistical programme and calculated with a 95&#37; confidence interval&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Results</span><p id="par0100" class="elsevierStylePara elsevierViewall">A total of 53&#44; 73&#44; and 78 patients on treatment with infliximab&#44; adalimumab&#44; and etanercept&#44; respectively&#44; were studied&#46; In all cases&#44; a single sample extraction was performed&#46; Eleven patients were excluded due to AFA and absence of drug levels&#58; 3 &#40;5&#46;6&#37;&#41; treated with infliximab&#44; all with SpA&#44; none treated with DMARDs&#59; 8 &#40;11&#37;&#41; treated with adalimumab&#44; 2 with RA on leflunomide&#44; 6 patients with SpA&#44; one treated with leflunomide&#44; the remaining 5 without DMARDs&#46; No anti-etanercept antibodies were detected&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">No differences were found in drug levels according to disease type and disease activity&#46; Patients with RA had a median DAS28&#58; 2&#46;79 &#40;RI&#58; 2&#46;27&#8722;3&#46;62&#41; and those with SpA had a BASDAI of 3&#46;47 &#40;SD&#58; 2&#46;2&#41; and an ASDAS of 1&#46;70 &#40;1&#46;40&#8722;2&#46;27&#41;&#46; The variables studied are displayed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">The percentage of remission&#47;LDA in cases with RA and SpA was 74&#46;3&#37; and 77&#46;8&#37;&#44; respectively&#46; The time of disease progression was 12&#46;9 years &#40;RI&#58; 7&#46;49&#8722;22&#46;5&#41;&#44; with no differences between diseases &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#59; adherence was &#8805;80&#37; in 88&#46;6&#37; of cases&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Drug levels in patients on standard-dose anti-TNF were 2&#46;2&#8239;g&#47;mL &#40;1&#46;4&#8211;5&#46;2&#41;&#44; 4&#46;9&#8239;g&#47;mL &#40;0&#46;8&#8722;8&#46;9&#41;&#44; and 3&#46;1&#8239;g&#47;mL &#40;2&#46;3&#8722;4&#46;4&#41; for infliximab&#44; adalimumab and etanercept&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>A&#41;&#44; with no differences according to rheumatic disease &#40;data not shown&#41;&#46; We also found no differences in the group of cases with standard drug dosages&#44; segmented by disease type and activity &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>B&#41;&#46; When dividing patients with standard drug dosages according to treatment with&#47;without DMARDs&#44; we obtained significant differences in serum levels of infliximab and etanercept&#59; adalimumab levels were similar in both groups &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>C&#41;&#44; and subdividing these cases according to rheumatic disease&#44; only etanercept levels exhibited differences in patients with SpA &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>C1&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">The drug level achieved after the standard treatment regimen may differ from one patient to another&#59; however&#44; the drug level required to achieve remission may not differ&#44; hence the importance of evidence to support monitoring of anti-TNF6 levels&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The patients studied were fairly homogeneous&#44; even between those in remission and non-remission&#59; for instance&#44; RA patients had generally low activity indices&#44; which may have contributed to differences in drug levels not being conspicuous when comparing patient subgroups&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">With respect to infliximab&#44; the study by Jurado T et al&#46; found that most RA patients in remission at week 54 after perfusion displayed levels of 4&#46;4&#8239;g&#47;mL at week<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> whereas in our study at week 12&#44; we logically found lower levels of infliximab&#44; with no differences in the remission&#47;LDA vs&#46; non-remission&#47;non-LDA groups&#46; Our results show no difference between infliximab levels between RA and SpA&#59; nevertheless&#44; Padilla-Mart&#237;nez EM et al&#46; detected different infliximab trough levels between the 2 diseases<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&#44; but did not exclude cases with ADA from the analysis&#59; similarly&#44; they had a smaller sample size&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Sanmarti R et al&#46; found adalimumab levels of 6&#46;9&#8239;g&#47;mL in patients with RA in remission<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46; Pouw MF et al&#46; suggest that they should have levels of between 5&#8722;8&#8239;g&#47;mL<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#44; similar to what was found in our study in patients in remission&#46; Finally&#44; Kneepkens EL et al&#46; obtained an etanercept level of 3&#46;8&#8239;g&#47;mL &#40;2&#46;5&#8211;5&#46;2&#41; in SpA patients with ASDAS&#8239;&#60;&#8239;2&#46;1<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> and Sanmarti R et al&#46; obtained etanercept levels of 2&#46;3&#8239;g&#47;mL in RA patients in remission<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46; Our results were similar in both diseases excluding patients with suboptimal doses&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Anti-TNF levels can be affected by different factors such as comorbidity&#44; route of drug administration&#44; ADA formation&#44; or the use of cSFs<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>&#46; In our study&#44; we detected differences in drug levels between patients with&#47;without cAMP for infliximab and etanercept&#59; nonetheless&#44; we found no differences for adalimumab levels&#46; However&#44; Vogelzang EH et al&#46; found higher levels of adalimumab in patients with RA or psoriatic arthritis treated with methotrexate<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">In general&#44; we did not find differences in drug levels according to disease activity&#44; perhaps because of the homogeneity of the sample in this aspect&#44; but if we add a cSF-MEF&#44; then differences do emerge&#44; mainly in SpA&#46; Does this suggest the need to always use cSF-MEFs in association with anti-TNFs&#63; Probably not routinely&#44; albeit this opinion might be different if we assessed other biomarkers&#44; such as the CXCL12 genotype or HLA-DQA1&#42;05<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a>&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">One of the limitations of our study is that as it is observational&#44; retrospective&#44; and conducted in clinical practice&#46; As such&#44; we do not aways have the results for all the variables studied&#46; In addition&#44; when the sample was subdivided&#44; it was reduced&#44; in some cases losing representativeness of the population under study&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">In summary&#44; we purport that anti-TNF drug levels will be modified by treatment with cAMP&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Funding</span><p id="par0160" class="elsevierStylePara elsevierViewall">This research has not received any specific public or private funding&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of interest</span><p id="par0165" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
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          "titulo" => "Material and methods"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2020-09-07"
    "fechaAceptado" => "2021-06-03"
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          "clase" => "keyword"
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            0 => "Anti-TNF&#945; levels"
            1 => "Rheumatoid arthritis"
            2 => "Spondyloarthritis"
          ]
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          "palabras" => array:3 [
            0 => "Niveles de anti-TNF&#945;"
            1 => "Artritis reumatoide"
            2 => "Espondiloartritis"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objectives</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Knowledge of the levels of anti-TNFa drugs can modify treatment in patients with rheumatoid arthritis &#40;RA&#41; and spondyloarthritis &#40;SpA&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objectives</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">To compare the levels of anti-TNFa in patients with RA vs SpA&#44; in different clinical situations&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Materials and methods</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A retrospective&#44; observational study was conducted&#46; Levels of anti-TNFa and the presence of anti-drug antibodies were measured in consecutively selected patients&#44; using the ELISA technique&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Fifty-three&#44; 73 and 78 patients treated with infliximab&#44; adalimumab and etanercept were studied&#44; respectively&#46; The median drug levels in patients using standard doses were infliximab 2&#46;2&#8239;&#181;g&#47;mL &#40;1&#46;4&#8211;5&#46;2&#41;&#44; adalimumab 4&#46;9&#8239;&#181;g&#47;mL &#40;0&#46;8&#8722;8&#46;9&#41; and etanercept 3&#46;1&#8239;&#181;g&#47;mL &#40;2&#46;3&#8722;4&#46;4&#41;&#46; There were no differences in drug levels according to disease activity but we found differences in etanercept and infliximab levels according to DMARD use&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Levels of anti-TNFa drugs will change with DMARD treatment&#46;</p></span>"
        "secciones" => array:5 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background and objectives"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Objectives"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Materials and methods"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Results"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes y objetivos</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">El conocimiento de los niveles de f&#225;rmacos anti-TNF&#945; puede modificar el tratamiento en pacientes con artritis reumatoide &#40;AR&#41; y espondiloartritis &#40;EspA&#41;&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivos</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Comparar los niveles de anti-TNF&#945; en pacientes con AR vs EspA&#44; en diferentes situaciones cl&#237;nicas&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Materiales y m&#233;todos</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Se realiz&#243; un estudio retrospectivo&#44; observacional donde se midieron los niveles de anti-TNF&#945; y la presencia de anticuerpos antif&#225;rmacos en pacientes seleccionados consecutivamente&#44; utilizando la t&#233;cnica de ELISA&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Se estudiaron 53&#44; 73 y 78 pacientes en tratamiento con infliximab&#44; adalimumab y etanercept&#44; respectivamente&#46; Los niveles medios de f&#225;rmaco en pacientes con dosis est&#225;ndar fueron&#58; infliximab 2&#44;2&#8239;&#956;g&#47;mL &#40;1&#44;4&#8211;5&#44;2&#41;&#44; adalimumab 4&#44;9&#8239;&#956;g&#47;mL &#40;0&#44;8&#8722;8&#44;9&#41; y etanercept 3&#44;1&#8239;&#956;g&#47;mL &#40;2&#44;3&#8211;4&#44;4&#41;&#46; No se encontraron diferencias en los niveles f&#225;rmacos seg&#250;n la actividad de la enfermedad&#44; sin embargo&#44; hubo diferencias en los niveles de etanercept e infliximab seg&#250;n el uso de f&#225;rmacos modificadores de la enfermedad sint&#233;ticos &#40;FAMEsc&#41;&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusiones</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Los niveles de f&#225;rmacos anti-TNF&#945; se ver&#225;n modificados por el tratamiento con FAMEsc&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Meri&#241;o-Ibarra E&#44; Manero Ru&#237;z FJ&#46; Niveles de f&#225;rmacos anti-TNF&#945; en pacientes con artritis reumatoide y espondiloartritis&#46; Reumatol Cl&#237;n&#46; 2022&#59;18&#58;475&#8211;479&#46;</p>"
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          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">ASDAS&#58; Ankylosing Spondylitis Disease Activity Score&#59; BASDAI&#58; Bath Ankylosing Spondylitis Disease Activity Index&#59; BMI&#58; Body Mass Index&#59; CRP&#58; C-reactive protein&#59; DAS28&#58; Disease Activity Score 28-joint counts&#59; DMARDs&#58; synthetic disease-modifying drugs&#46;</p>"
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                  \t\t\t\t" scope="col">Variable&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">Rheumatoid arthritis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">N&#8239;&#61;&#8239;74&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">N&#8239;&#61;&#8239;119&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">N&#8239;&#61;&#8239;193&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Age &#40;years&#41;</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">59&#46;8 &#40;12&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">54&#46;7 &#40;14&#46;0&#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"><span class="elsevierStyleItalic">Infliximab &#40;g&#47;mL&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Adalimumab &#40;g&#47;mL&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Etanercept &#40;g&#47;mL&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Biological therapy&#44; N</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Infliximab<span class="elsevierStyleItalic">&#44; N &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Adalimumab<span class="elsevierStyleItalic">&#44; N &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">65 &#40;33&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Etanercept<span class="elsevierStyleItalic">&#44; N &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">39 &#40;52&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">39 &#40;32&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">78 &#40;40&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Time to disease progression&#44; &#40;years&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#46;877&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Time on biologic therapy&#44; &#40;years&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#46;386&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">BMI&#44; &#40;kg&#47;m<span class="elsevierStyleSup">2</span>&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#46;325&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">CRP&#44; &#40;mg&#47;dl&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&#46;27 &#40;&#46;13&#8722;&#46;70&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#46;555&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">DAS28&#44; &#40;CRP&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8212;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#44;79 &#40;2&#44;27&#8722;3&#44;62&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\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
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                  \t\t\t\t"><span class="elsevierStyleItalic">BASDAIa</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8212;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;47 &#40;2&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">3&#46;47 &#40;2&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">ASDAS&#44; &#40;CRP&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8212;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#46;70 &#40;1&#46;40&#8722;2&#46;27&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#46;70 &#40;1&#46;40&#8722;2&#46;27&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\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">DMARDs&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50 &#40;67&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27 &#40;22&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">77 &#40;39&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;000&nbsp;\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>Methotrexate&#44; N &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33 &#40;44&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19 &#40;15&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52 &#40;26&#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="left" 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></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>Leflunomide&#44; N &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16 &#40;21&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;4&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21 &#40;10&#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="left" 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></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>Sulphasalazine&#44; N &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;1&#46;63&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;2&#46;53&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#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="left" 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></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">Cases with suboptimal dose of anti-TNF&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26 &#40;35&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39 &#40;32&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">65 &#40;33&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;735&nbsp;\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>Infliximab&#44; N &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;6&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9 &#40;7&#46;56&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14 &#40;7&#46;25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\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>Adalimumab&#44; N &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;6&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14 &#40;11&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19 &#40;9&#46;84&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\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>Etanercept&#44; N &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16 &#40;21&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16 &#40;13&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32 &#40;16&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\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">Remission&#47;low activity&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">55 &#40;74&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88 &#40;77&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">143 &#40;76&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;575&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                  \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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">A</span>&nbsp;\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">anti-TNF&#945; levels &#40;&#956;g&#47;mL&#41;&#44; N&#8239;&#61;&#8239;128&nbsp;\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">Infliximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;2 &#40;1&#46;4&#8722;5&#46;25&#41;&nbsp;\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">Adalimumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;9 &#40;&#46;8&#8722;8&#46;9&#41;&nbsp;\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">Etanercept&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;1 &#40;2&#46;3&#8722;4&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
            1 => array:1 [
              "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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col"><span class="elsevierStyleBold">B</span>&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Remission&#47;LDA vs&#46; no remission&#47;no LDA</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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><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">&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Rheumatoid arthritis N&#8239;&#61;&#8239;48</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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><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">&nbsp;\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">Remission&#47;LDA N&#8239;&#61;&#8239;33&nbsp;\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">No remission&#47;no LDA N&#8239;&#61;&#8239;15&nbsp;\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"><span class="elsevierStyleItalic">P</span> value&nbsp;\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">Infliximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;0 &#40;1&#46;5&#8722;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;4 &#40;3&#46;4&#8722;3&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;427&nbsp;\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">Adalimumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;4 &#40;2&#46;8&#8722;8&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;0 &#40;0&#46;23&#8722;3&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;128&nbsp;\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">Etanercept&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;7 &#40;2&#46;3&#8722;4&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;0 &#40;3&#46;1&#8722;4&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;366&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
            2 => array:1 [
              "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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Spondyloarthritis N&#8239;&#61;&#8239;80</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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><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">&nbsp;\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">Remission&#47;LDA N&#8239;&#61;&#8239;55&nbsp;\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">No remission&#47;no LDA N&#8239;&#61;&#8239;25&nbsp;\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"><span class="elsevierStyleItalic">P</span> value&nbsp;\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">Infliximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;4 &#40;1&#46;4&#8722;7&#46;55&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;4&#40;1&#46;0&#8722;6&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;563&nbsp;\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">Adalimumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;6 &#40;0&#46;45&#8722;9&#46;95&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;2 &#40;1&#46;85&#8722;8&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;999&nbsp;\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">Etanercept&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;8 &#40;2&#46;4&#8722;3&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;2 &#40;2&#46;35&#8722;6&#46;65&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;219&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
            3 => array:1 [
              "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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">C</span>&nbsp;\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">DMARDs N&#8239;&#61;&#8239;52&nbsp;\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">No DMARDs N&#8239;&#61;&#8239;76&nbsp;\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"><span class="elsevierStyleItalic">P</span> value&nbsp;\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">Infliximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;0 &#40;2&#46;2&#8722;6&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;8 &#40;1&#46;0&#8722;2&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;035&nbsp;\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">Adalimumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;2 &#40;&#46;7&#8722;8&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;9 &#40;1&#46;2&#8722;9&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;607&nbsp;\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">Etanercept&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;4 &#40;2&#46;6&#8722;4&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;5 &#40;1&#46;8&#8722;3&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;039&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
            4 => array:1 [
              "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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col"><span class="elsevierStyleBold">C1</span>&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Rheumatoid arthritis N&#8239;&#61;&#8239;48</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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><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">&nbsp;\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">DMARDs N&#8239;&#61;&#8239;32&nbsp;\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">No DMARDs N&#8239;&#61;&#8239;16&nbsp;\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
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span> value&nbsp;\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">Infliximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;2 &#40;1&#46;8&#8722;5&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;0 &#40;1&#46;55&#8722;2&#46;75&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;520&nbsp;\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">Adalimumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;9 &#40;0&#46;7&#8722;7&#46;45&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;9 &#40;3&#46;55&#8722;4&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;539&nbsp;\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">Etanercept&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;2 &#40;2&#46;6&#8722;4&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;2 &#40;1&#46;95&#8722;4&#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="left" valign="\n
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                  \t\t\t\t">&#46;833&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Infliximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;4 &#40;3&#46;4&#8722;7&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;1 &#40;0&#46;95&#8722;6&#46;65&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;223&nbsp;\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">Adalimumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#46;3 &#40;6&#46;6&#8722;10&#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="left" valign="\n
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                  \t\t\t\t">6&#46;3 &#40;0&#46;55&#8722;9&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&#46;607&nbsp;\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
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                  \t\t\t\t">Etanercept&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">4&#46;4 &#40;3&#46;3&#8722;6&#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="left" valign="\n
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                  \t\t\t\t">2&#46;5 &#40;1&#46;95&#8722;3&#46;25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Anti-TNF drug levels in standard-dose patients&#46; A&#58; Overall results&#46; B&#58; Anti-TNF drug levels according to rheumatic disease and according to remission&#47;low disease activity vs&#46; no remission&#47;no low disease activity&#46; C&#58; Drug levels according to treatment with DMARDs and C1 according to rheumatic disease&#46;</p>"
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                      "titulo" => "Significant associations of antidrug antibody levels with serum drug trough levels and therapeutic response of adalimumab and etanercept treatment in rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;Y&#46; Chen"
                            1 => "Y&#46;M&#46; Chen"
                            2 => "W&#46;C&#46; Tsai"
                            3 => "J&#46;C&#46; Tseng"
                            4 => "Y&#46;H&#46; Chen"
                            5 => "C&#46;W&#46; Hsieh"
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                    0 => array:2 [
                      "doi" => "10.1136/annrheumdis-2013-203893"
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                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2015"
                        "volumen" => "74"
                        "paginaInicial" => "1"
                        "paginaFinal" => "10"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25477133"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46; Pascual-Salcedo"
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                            3 => "L&#46; Nu&#241;o"
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                        "tituloSerie" => "Rheumatology &#40;Oxford&#41;"
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                        "paginaFinal" => "1452"
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                      "titulo" => "Influence of immunogenicity on the efficacy of long-term treatment with TNF &#945; blockers in rheumatoid arthritis and spondyloarthritis patients"
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                            3 => "A&#46; Venalis"
                            4 => "G&#46; Shi"
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                  ]
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                    0 => array:2 [
                      "doi" => "10.1155/2015/604872"
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                            3 => "V&#46; Navarro-Comp&#225;n"
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Brief Report
Anti-TNFα drug levels in patients with rheumatoid arthritis and spondyloarthritis
Niveles de fármacos anti-TNFα en pacientes con artritis reumatoide y espondiloartritis
Erardo Meriño-Ibarra
Corresponding author
eemerinnoi@salud.aragon.es

Corresponding author.
, Francisco Javier Manero Ruíz
Servicio de Reumatología, Hospital Universitario Miguel Servet, Zaragoza, Spain
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    "titulo" => "Anti-TNF&#945; drug levels in patients with rheumatoid arthritis and spondyloarthritis"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In patients with rheumatoid arthritis &#40;RA&#41; treated with anti-TNF drugs &#40;anti-TNF&#41;&#46; A correlation has been found between drug levels and clinical response<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46; For example&#44; in infliximab-treated patients&#44; the presence of anti-drug antibodies &#40;ADA&#41; provoke loss of response&#44; ifuional reactions and increased treatment withdrawal<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46; These data are not exclusive to RA and have also been described in spondyloarhritis &#40;SpA&#41;&#44; where anti-infliximab and anti-adalimumab antibodies are found in non-responders and in the case of infliximab&#44; they are also related to infusional reactions&#44; motivating a switch to another drug<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Various drug level measurement techniques are available with different standardisation<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#44; creating uncertainty as to the value of measuring drug levels&#46; A consensus article has recently been published with the aim of reducing this uncertainty in the Spanish setting<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The aims of this study were to compare anti-TNF levels in RA patients vs&#46; SpA&#44; in patients in remission&#47;low disease activity &#40;LDA&#41; vs&#46; non-remission&#47;non-LDA according to rheumatic disease&#44; and to determine the influence of the use of conventional synthetic disease-modifying drugs &#40;DMARDs&#41; on these levels&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Material and methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">A total of 474 patients were being treated with anti-TNF drugs at our centre&#44; including 51 patients with infliximab&#44; 198 patients with adlmumab&#44; and 225 patients with etanercept&#46; A retrospective&#44; observational study was conducted to measure anti-TNF levels and the presence of ADA in a group of consecutively selected patients who attended consultations at the rheumatology department of the Miguel Servet University Hospital&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Inclusion criteria</span><p id="par0025" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0030" class="elsevierStylePara elsevierViewall">Adult patients on anti-TNF treatment&#46;</p></li></ul></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Exclusion criteria</span><p id="par0035" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0040" class="elsevierStylePara elsevierViewall">Patients who declined to participate in the study</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0045" class="elsevierStylePara elsevierViewall">Patients under follow-up in other hospitals</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0050" class="elsevierStylePara elsevierViewall">Diagnoses other than RA or SpA</p></li></ul></p><p id="par0055" class="elsevierStylePara elsevierViewall">The most commonly used methods for measuring levels are the sandwich ELISA and the indirect ELISA<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#46; In our study&#44; the sample was obtained on the day the drug was due to be administered &#40;trough level&#41;&#44; using the Promonitor&#174; test from Laboratorios Grifols &#40;sandwich ELISA&#41;&#44; and according to the methodology described by Chen DY et al&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46; In cases with undetectable anti-TNF levels&#44; Acaf was measured using the Promonitor&#174; test from Laboratorios Grifols &#40;bridge-type ELISA&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The following data were collected from the patients&#8217; clinical history&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Time of evolution of the disease</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0070" class="elsevierStylePara elsevierViewall">Type and schedule of biologic treatment and DMARDs</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0075" class="elsevierStylePara elsevierViewall">Adherence&#58; percentage of the prescribed dosage of the drug that the patient withdraws from the hospital pharmacy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8226;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Disease activity&#58; considering remission&#47;low activity in patients with RA when they had a DAS28 &#40;CRP&#41;&#8239;&#8804;&#8239;3&#46;2 and in patients with SpA a BASDAI&#8239;&#8804;&#8239;4 and ASDAS &#40;CRP&#41;&#8239;&#8804;&#8239;2&#46;1&#46; The activity indices were obtained from the consultation prior to the measurement of the levels&#46;</p></li></ul></p><p id="par0085" class="elsevierStylePara elsevierViewall">With these data&#44; a group of patients with RA and SpA was obtained and in each&#44; subgroups with drug dosages according to the technical data sheet &#40;standard dose&#41; and others with dosages lower than those recommended &#40;suboptimal dose&#41;&#44; as well as patients with&#47;without treatment with DMARDs&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Ethical aspects</span><p id="par0090" class="elsevierStylePara elsevierViewall">All patients signed an informed consent form for this study and for the use of biological samples for biomedical research&#46; This study was approved by the Research Ethics Committee of the Autonomous Community of Aragon&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Statistical method</span><p id="par0095" class="elsevierStylePara elsevierViewall">Quantitative variables&#58; distribution was determined with the Kolmogorov-Smirnov statistic &#40;Lilliefors correction&#41;&#59; in variables with N&#8239;&#60;&#8239;50&#44; the Shapiro&#8211;Wilk statistic was applied&#59; if the distribution was normal&#44; the mean and standard deviation &#40;SD&#41; were determined&#59; in variables with non-parametric distribution&#44; the median and interquartile range &#40;IQR&#41; were determined&#46; For differences between means and between medians&#58; Student&#8217;s t test and Mann&#8211;Whitney U test were used&#44; respectively&#46; For qualitative variables&#58; 2&#8239;&#215;&#8239;2 contingency tables with Pearson&#8217;s Chi-square test&#46; Statistical procedures were performed with the R statistical programme and calculated with a 95&#37; confidence interval&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Results</span><p id="par0100" class="elsevierStylePara elsevierViewall">A total of 53&#44; 73&#44; and 78 patients on treatment with infliximab&#44; adalimumab&#44; and etanercept&#44; respectively&#44; were studied&#46; In all cases&#44; a single sample extraction was performed&#46; Eleven patients were excluded due to AFA and absence of drug levels&#58; 3 &#40;5&#46;6&#37;&#41; treated with infliximab&#44; all with SpA&#44; none treated with DMARDs&#59; 8 &#40;11&#37;&#41; treated with adalimumab&#44; 2 with RA on leflunomide&#44; 6 patients with SpA&#44; one treated with leflunomide&#44; the remaining 5 without DMARDs&#46; No anti-etanercept antibodies were detected&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">No differences were found in drug levels according to disease type and disease activity&#46; Patients with RA had a median DAS28&#58; 2&#46;79 &#40;RI&#58; 2&#46;27&#8722;3&#46;62&#41; and those with SpA had a BASDAI of 3&#46;47 &#40;SD&#58; 2&#46;2&#41; and an ASDAS of 1&#46;70 &#40;1&#46;40&#8722;2&#46;27&#41;&#46; The variables studied are displayed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">The percentage of remission&#47;LDA in cases with RA and SpA was 74&#46;3&#37; and 77&#46;8&#37;&#44; respectively&#46; The time of disease progression was 12&#46;9 years &#40;RI&#58; 7&#46;49&#8722;22&#46;5&#41;&#44; with no differences between diseases &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#59; adherence was &#8805;80&#37; in 88&#46;6&#37; of cases&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Drug levels in patients on standard-dose anti-TNF were 2&#46;2&#8239;g&#47;mL &#40;1&#46;4&#8211;5&#46;2&#41;&#44; 4&#46;9&#8239;g&#47;mL &#40;0&#46;8&#8722;8&#46;9&#41;&#44; and 3&#46;1&#8239;g&#47;mL &#40;2&#46;3&#8722;4&#46;4&#41; for infliximab&#44; adalimumab and etanercept&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>A&#41;&#44; with no differences according to rheumatic disease &#40;data not shown&#41;&#46; We also found no differences in the group of cases with standard drug dosages&#44; segmented by disease type and activity &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>B&#41;&#46; When dividing patients with standard drug dosages according to treatment with&#47;without DMARDs&#44; we obtained significant differences in serum levels of infliximab and etanercept&#59; adalimumab levels were similar in both groups &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>C&#41;&#44; and subdividing these cases according to rheumatic disease&#44; only etanercept levels exhibited differences in patients with SpA &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>C1&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">The drug level achieved after the standard treatment regimen may differ from one patient to another&#59; however&#44; the drug level required to achieve remission may not differ&#44; hence the importance of evidence to support monitoring of anti-TNF6 levels&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The patients studied were fairly homogeneous&#44; even between those in remission and non-remission&#59; for instance&#44; RA patients had generally low activity indices&#44; which may have contributed to differences in drug levels not being conspicuous when comparing patient subgroups&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">With respect to infliximab&#44; the study by Jurado T et al&#46; found that most RA patients in remission at week 54 after perfusion displayed levels of 4&#46;4&#8239;g&#47;mL at week<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> whereas in our study at week 12&#44; we logically found lower levels of infliximab&#44; with no differences in the remission&#47;LDA vs&#46; non-remission&#47;non-LDA groups&#46; Our results show no difference between infliximab levels between RA and SpA&#59; nevertheless&#44; Padilla-Mart&#237;nez EM et al&#46; detected different infliximab trough levels between the 2 diseases<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&#44; but did not exclude cases with ADA from the analysis&#59; similarly&#44; they had a smaller sample size&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Sanmarti R et al&#46; found adalimumab levels of 6&#46;9&#8239;g&#47;mL in patients with RA in remission<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46; Pouw MF et al&#46; suggest that they should have levels of between 5&#8722;8&#8239;g&#47;mL<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#44; similar to what was found in our study in patients in remission&#46; Finally&#44; Kneepkens EL et al&#46; obtained an etanercept level of 3&#46;8&#8239;g&#47;mL &#40;2&#46;5&#8211;5&#46;2&#41; in SpA patients with ASDAS&#8239;&#60;&#8239;2&#46;1<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> and Sanmarti R et al&#46; obtained etanercept levels of 2&#46;3&#8239;g&#47;mL in RA patients in remission<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46; Our results were similar in both diseases excluding patients with suboptimal doses&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Anti-TNF levels can be affected by different factors such as comorbidity&#44; route of drug administration&#44; ADA formation&#44; or the use of cSFs<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>&#46; In our study&#44; we detected differences in drug levels between patients with&#47;without cAMP for infliximab and etanercept&#59; nonetheless&#44; we found no differences for adalimumab levels&#46; However&#44; Vogelzang EH et al&#46; found higher levels of adalimumab in patients with RA or psoriatic arthritis treated with methotrexate<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">In general&#44; we did not find differences in drug levels according to disease activity&#44; perhaps because of the homogeneity of the sample in this aspect&#44; but if we add a cSF-MEF&#44; then differences do emerge&#44; mainly in SpA&#46; Does this suggest the need to always use cSF-MEFs in association with anti-TNFs&#63; Probably not routinely&#44; albeit this opinion might be different if we assessed other biomarkers&#44; such as the CXCL12 genotype or HLA-DQA1&#42;05<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a>&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">One of the limitations of our study is that as it is observational&#44; retrospective&#44; and conducted in clinical practice&#46; As such&#44; we do not aways have the results for all the variables studied&#46; In addition&#44; when the sample was subdivided&#44; it was reduced&#44; in some cases losing representativeness of the population under study&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">In summary&#44; we purport that anti-TNF drug levels will be modified by treatment with cAMP&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Funding</span><p id="par0160" class="elsevierStylePara elsevierViewall">This research has not received any specific public or private funding&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of interest</span><p id="par0165" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objectives</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Knowledge of the levels of anti-TNFa drugs can modify treatment in patients with rheumatoid arthritis &#40;RA&#41; and spondyloarthritis &#40;SpA&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objectives</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">To compare the levels of anti-TNFa in patients with RA vs SpA&#44; in different clinical situations&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Materials and methods</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A retrospective&#44; observational study was conducted&#46; Levels of anti-TNFa and the presence of anti-drug antibodies were measured in consecutively selected patients&#44; using the ELISA technique&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Fifty-three&#44; 73 and 78 patients treated with infliximab&#44; adalimumab and etanercept were studied&#44; respectively&#46; The median drug levels in patients using standard doses were infliximab 2&#46;2&#8239;&#181;g&#47;mL &#40;1&#46;4&#8211;5&#46;2&#41;&#44; adalimumab 4&#46;9&#8239;&#181;g&#47;mL &#40;0&#46;8&#8722;8&#46;9&#41; and etanercept 3&#46;1&#8239;&#181;g&#47;mL &#40;2&#46;3&#8722;4&#46;4&#41;&#46; There were no differences in drug levels according to disease activity but we found differences in etanercept and infliximab levels according to DMARD use&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Levels of anti-TNFa drugs will change with DMARD treatment&#46;</p></span>"
        "secciones" => array:5 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background and objectives"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Objectives"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Materials and methods"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Results"
          ]
          4 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Conclusions"
          ]
        ]
      ]
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes y objetivos</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">El conocimiento de los niveles de f&#225;rmacos anti-TNF&#945; puede modificar el tratamiento en pacientes con artritis reumatoide &#40;AR&#41; y espondiloartritis &#40;EspA&#41;&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivos</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Comparar los niveles de anti-TNF&#945; en pacientes con AR vs EspA&#44; en diferentes situaciones cl&#237;nicas&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Materiales y m&#233;todos</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Se realiz&#243; un estudio retrospectivo&#44; observacional donde se midieron los niveles de anti-TNF&#945; y la presencia de anticuerpos antif&#225;rmacos en pacientes seleccionados consecutivamente&#44; utilizando la t&#233;cnica de ELISA&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Se estudiaron 53&#44; 73 y 78 pacientes en tratamiento con infliximab&#44; adalimumab y etanercept&#44; respectivamente&#46; Los niveles medios de f&#225;rmaco en pacientes con dosis est&#225;ndar fueron&#58; infliximab 2&#44;2&#8239;&#956;g&#47;mL &#40;1&#44;4&#8211;5&#44;2&#41;&#44; adalimumab 4&#44;9&#8239;&#956;g&#47;mL &#40;0&#44;8&#8722;8&#44;9&#41; y etanercept 3&#44;1&#8239;&#956;g&#47;mL &#40;2&#44;3&#8211;4&#44;4&#41;&#46; No se encontraron diferencias en los niveles f&#225;rmacos seg&#250;n la actividad de la enfermedad&#44; sin embargo&#44; hubo diferencias en los niveles de etanercept e infliximab seg&#250;n el uso de f&#225;rmacos modificadores de la enfermedad sint&#233;ticos &#40;FAMEsc&#41;&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusiones</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Los niveles de f&#225;rmacos anti-TNF&#945; se ver&#225;n modificados por el tratamiento con FAMEsc&#46;</p></span>"
        "secciones" => array:5 [
          0 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Antecedentes y objetivos"
          ]
          1 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Objetivos"
          ]
          2 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Materiales y m&#233;todos"
          ]
          3 => array:2 [
            "identificador" => "abst0045"
            "titulo" => "Resultados"
          ]
          4 => array:2 [
            "identificador" => "abst0050"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Meri&#241;o-Ibarra E&#44; Manero Ru&#237;z FJ&#46; Niveles de f&#225;rmacos anti-TNF&#945; en pacientes con artritis reumatoide y espondiloartritis&#46; Reumatol Cl&#237;n&#46; 2022&#59;18&#58;475&#8211;479&#46;</p>"
      ]
    ]
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      0 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0005"
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">ASDAS&#58; Ankylosing Spondylitis Disease Activity Score&#59; BASDAI&#58; Bath Ankylosing Spondylitis Disease Activity Index&#59; BMI&#58; Body Mass Index&#59; CRP&#58; C-reactive protein&#59; DAS28&#58; Disease Activity Score 28-joint counts&#59; DMARDs&#58; synthetic disease-modifying drugs&#46;</p>"
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t" scope="col">Variable&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">Rheumatoid arthritis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">N&#8239;&#61;&#8239;74&nbsp;\t\t\t\t\t\t\n
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                  \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
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">N&#8239;&#61;&#8239;193&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">59&#46;8 &#40;12&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">56&#46;7 &#40;13&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&#46;011&nbsp;\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
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                  \t\t\t\t"><span class="elsevierStyleItalic">Women&#44; N &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">57 &#40;77&#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">44 &#40;36&#46;9&#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">101 &#40;52&#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
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Infliximab &#40;g&#47;mL&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">2&#46;9 &#40;0&#46;85&#8722;6&#46;50&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">2&#46;3 &#40;1&#46;0&#8722;5&#46;80&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Adalimumab &#40;g&#47;mL&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">3&#46;80 &#40;1&#46;80&#8722;8&#46;60&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Etanercept &#40;g&#47;mL&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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