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These questions include&#44; for example&#44; what are the optimal doses and route of administration of MTX at the start of the combination therapy&#44; or the tapering strategy in patients that have achieved the therapeutic target&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Bearing in mind all previous considerations&#44; the aim of this project was to provide specific and practice guide regarding the use of MTX combination therapy with bDMARDs o tsDMARDs&#44; based on the best evidence and experts opinion&#46; We are confident that these recommendations will help health professionals involved in the management of RA patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study design and panel selection</span><p id="par0025" class="elsevierStylePara elsevierViewall">The consensus statement has been developed using nominal group and Delphi techniques&#44; along with a systematic literature review &#40;SLR&#41;&#46; The project was carried out following the Declaration of Helsinki ethical principles for medical research involving human subjects&#44; and in accordance with the Good Clinical Practice regulations&#46; First&#44; a group of 11rheumatologists &#40;2 of them the coordinators&#41; with interest and demonstrated experience in the management of RA were designated &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Systematic literature review</span><p id="par0030" class="elsevierStylePara elsevierViewall">The coordinators defined 13 questions &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; connected to the use of MTX in combination with b- or tsDMARDs&#44; that included the indication of the combination therapy&#44; MTX dose&#44; route of administration&#44; dose adjustments&#44; etc&#46; A comprehensive SLR was performed to address these questions&#46; The following PICO queries and inclusion criteria were defined&#58; &#40;1&#41; Adult RA patients &#40;population&#41;&#59; &#40;2&#41; on&#44; or considering the start of combined therapy with MTX and b-or tsDMARDs approved for RA including 5 tumor necrosis factor &#40;TNF&#41; inhibitors &#40;infliximab&#44; adalimumab&#44; etanercept&#44; golimumab&#44; certolizumab pegol&#41;&#44; abatacept &#40;ABT&#41;&#44; rituximab &#40;RTX&#41;&#44; interleukin 6 &#40;IL-6&#41; inhibitors tocilizumab and sarilumab&#44; biosimilars&#44; and Janus kinase inhibitors &#40;JAKs&#41; tofacitinib and baricitinib &#40;intervention&#41;&#59; &#40;3&#41; compared with placebo or an active drug &#40;comparator&#41;&#59; reporting efficacy and&#47;or safety variables like composite activity indexes&#44; radiographic progression&#44; serious adverse events&#44; etc&#46; &#40;outcomes&#41;&#59; &#40;4&#41; searches were restricted to SLR and meta-analysis based on randomized controlled trials &#40;RCTs&#41; &#40;study design&#41;&#44; humans&#44; and articles written in English and&#47;or Spanish&#46; The publications were identified by sensitive search strategies in the main bibliographic databases&#46; For this purpose&#44; an expert librarian designed the search strategies&#44; using Mesh and text word terms&#46; The following bibliographic databases were screened up to January 2019&#58; Medline&#44; Embase and the Cochrane Library&#46; The abstracts of the two previous &#40;2017 and 2018&#41; annual scientific meetings of the American College of Rheumatology &#40;ACR&#41; and EULAR were also examined along with national and international consensus and guidelines&#46; Two reviewers selected the articles and collected data&#44; independently&#46; Subsequently&#44; a manual search of the bibliography of the articles that were finally included was performed&#46; The quality was evaluated with the Oxford Center for Evidence Based Medicine recommendations&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">5</span></a> Subsequently&#44; the coordinators proposed a set of preliminary recommendations based on the SLR results&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Nominal group meeting</span><p id="par0035" class="elsevierStylePara elsevierViewall">The experts held a nominal meeting in which objectives&#44; scope and users were defined&#46; Then&#44; through guided discussions&#44; the results of the SLR and the preliminary recommendations were analyzed&#46; Afterwards&#44; definitive recommendations were generated&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Delphi</span><p id="par0040" class="elsevierStylePara elsevierViewall">Recommendations were submitted to a Delphi process&#46; All experts voted &#8216;yes&#8217; or &#8216;no&#8217; for every recommendation&#46; Agreement was defined when at least 80&#37; of experts voted &#8216;yes&#8217;&#46; This high cut-off was established because the coordinators wanted to achieve a maximum level of agreement among the experts &#40;when possible&#41;&#46; Recommendations with a grade of agreement &#40;GA&#41; inferior to 80&#37; were reassessed and&#44; if appropriate&#44; re-edited and voted on in a second round&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Final consensus document</span><p id="par0045" class="elsevierStylePara elsevierViewall">After the Delphi&#44; and along with the results of the SLR&#44; the final document was written&#46; For each recommendation&#44; the level of evidence &#40;LE&#41; and grade of recommendation &#40;GR&#41; were assigned according to the recommendations of the Oxford Center for Evidence Based Medicine recommendations&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">5</span></a></p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Systematic literature review</span><p id="par0050" class="elsevierStylePara elsevierViewall">The SLR retrieved 530 articles &#40;see <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; After the selection processes and the hand search 61 studies were finally included&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Recommendations&#44; evidence and expert&#39;s considerations</p><p id="par0060" class="elsevierStylePara elsevierViewall">A total of 9 preliminary recommendations were proposed&#58; 2 were not voted and were explained in the main text of the document and 3 new ones were generated&#46; Finally&#44; 10 recommendations were voted and accepted&#46; The level of agreement was very high in all of them and was achieved in the first Delphi round&#46; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> depicts the recommendations with their respective LE&#44; GR and GA&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">R 1&#46; In patients with active RA and inadequate response to MTX&#44; this drug should be continued when starting a TNF inhibitor &#40;LE 1a&#59; GR A&#59; GA 100&#37;&#41;&#44; ABT &#40;LE 2a&#59; GR B&#59; GA 100&#37;&#41;&#44; or RTX &#40;LE 1b-2a&#59; GR B&#59; GA 100&#37;&#41;</span><p id="par0065" class="elsevierStylePara elsevierViewall">In patients with established RA &#40;but also in early RA&#41; and inadequate response to MTX&#44; different SLR and meta-analyses have shown<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">6&#44;7</span></a> that the addition of TNF inhibitors to MTX was superior to the biologics monotherapy in terms of disease activity &#40;ACR20&#44; 50&#44; 70 response&#41;&#44; function evaluated with the Health Assessment Questionnaire &#40;HAQ&#41;&#44; pain control&#44; patient global assessment or radiographic progression&#46; Although less evaluated &#40;at least in RCTs&#41;&#44; the combination of ABT or RTX plus MTX&#44; compared with ABT or RTX monotherapy seems to be more effective as well&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">8&#8211;10</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">R 2&#46;MTX should not be discontinued in patients with active RA and inadequate response to MTX who start IL-6 inhibitors &#40;LE 1a&#59; GR A&#59; GA 91&#37;&#41;</span><p id="par0070" class="elsevierStylePara elsevierViewall">RCTs and observational studies have compared TCZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX combination therapy with TCZ monotherapy in patients with inadequate response to MTX&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">11&#44;12</span></a> Most of them have revealed no statistical differences between groups in outcomes such as pain&#44; function&#44; ACR response or Clinical Disease Activity Index and Simple Disease Activity Index remission rates&#44; especially in the short term&#46; However&#44; in other trials&#44; combined therapy was significantly superior in the ACR&#47;EULAR Boolean remission rate or radiographic progression in the medium&#47;long term&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">12&#8211;14</span></a> Similar results have been observed with other IL-6 inhibitors&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">15</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The panel weighed up this heterogeneity and established that&#44; in general&#44; MTX &#40;excluding contraindications&#41; should not be discontinued because there is evidence that supports combination efficacy&#44; especially in the long term&#46; However&#44; there might be cases in which IL-6 inhibitor monotherapy might be a good option &#40;e&#46;g&#46; in case of MTX intolerance&#41;&#44; but these cases should be carefully individualized&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">R 3&#46; MTX should not be discontinued in patients with active RA and inadequate response to MTX who start JAKs inhibitors &#40;LE 1b&#59; GR A&#59; GA 91&#37;&#41;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Although data from RCTs have shown no efficacy differences between tofacitinib &#40;TFC&#41; monotherapy and combination therapy with MTX&#44; a network meta-analysis depicted greater ACR20&#47;50&#47;70 responses with the drugs combination&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">6</span></a> However&#44; due to the study design&#44; these results should be considered cautiously&#46; Moreover&#44; it has been estimated that in absolute terms&#44; 6 &#40;0&#8211;12&#41; extra patients out of 100 patients treated with TFC will achieve the ACR50 goal due to concomitant MTX therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">7</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Other SLRs and RCTs have revealed that the ACR response rates are similar when comparing patients on baricitinib &#40;BARI&#41; and MTX combination therapy with BARI monotherapy&#46; However&#44; in patients with no or limited prior DMARD treatment&#44; the change in total Sharp score was significantly higher than MTX monotherapy only when BARI was combined with MTX&#44; not for BARI monotherapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">11&#44;16</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">As in the case of IL-6 inhibitors&#44; with the evidence collected so far&#44; the panel doesn&#8217;t recommend MTX cessation when considering the combination with tsDMARDs&#44; especially with BARI&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">R 4&#46; When starting a combined therapy with MTX and bDMARDs in MTX-inadequate responders RA patients&#44; it is recommended to continue with the same MTX doses &#40;LE 1b&#59; GR A&#59; GA 100&#37;&#41;</span><p id="par0095" class="elsevierStylePara elsevierViewall">A SLR that addressed MTX doses in biologic trials &#40;most of them in MTX-inadequate responders&#41;&#44; as well as other RCTs&#44;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">17&#44;18</span></a> have showed that the maximal MTX doses at the start of the bDMARDs combination were 25<span class="elsevierStyleHsp" style=""></span>mg&#47;week for oral and 15<span class="elsevierStyleHsp" style=""></span>mg&#47;week for parenteral routes&#44; respectively&#46; However&#44; mean MTX doses were frequently around 12&#46;5-15<span class="elsevierStyleHsp" style=""></span>mg&#47;week in these trials&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">18</span></a> In the same way&#44; observational studies have described that maximum MTX doses when combined with bDMARDs are variable and reach up to 25&#8211;30<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#44; but mean doses are quite similar to the reported in the RCTs&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">19</span></a> In a randomized controlled trial &#40;MUSICA&#41; analyzing the efficacy of two doses of MTX &#40;7&#46;5<span class="elsevierStyleHsp" style=""></span>mg vs 20<span class="elsevierStyleHsp" style=""></span>mg&#44; orally and&#47;or injectable&#41; in patients with established RA with an insufficient response to MTX &#40;&#62;15<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#41; who started adalimumab&#44; the non-inferiority of the low dose was not met&#44; although some clinical and ultrasound parameters do not reach statistical significance&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">19</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The panel also kept in mind current guidelines in the management of RA&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">1&#8211;4</span></a> They recommend maximization of treatment effects that includes reaching an optimal MTX dose within a few weeks and maintaining the maximal dose &#40;25&#8211;30<span class="elsevierStyleHsp" style=""></span>mg weekly&#41; for at least 8 weeks if tolerated&#46; The panel supports these recommendations and therefore assumes that in patients with inadequate response to MTX in whom a bDMARD is considered&#44; the maximum tolerated dose should have already been achieved irrespectively of the route of administration&#46; This is the dose and route of administration that should be continued&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">R 5&#46; When combining MTX with TNF inhibitors&#44; the dose of MTX should be of at least 10<span class="elsevierStyleHsp" style=""></span>mg&#47;week &#40;LE 1b&#59; GR A&#59; GA 100&#37;&#41;</span><p id="par0105" class="elsevierStylePara elsevierViewall">It has been stated that in established RA patients with inadequate response to MTX&#44; MTX at 10<span class="elsevierStyleHsp" style=""></span>mg&#47;week provides additional efficacy to TNF inhibitors &#40;including the reduction of the incidence of antidrug antibodies&#41;&#44; while intolerance leading to discontinuation at these low doses was very rare&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">20</span></a> In the randomized trial CONCERTO in MTX na&#239;ve RA patients who started adalimumab&#44; efficacy of 10 and 20<span class="elsevierStyleHsp" style=""></span>mg&#47;week MTX appeared equivalent&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">20</span></a> As exposed in the recommendation 4&#44; it is possible that a bDMARD or tsDMARDs is indicated in a patient on MTX below 10<span class="elsevierStyleHsp" style=""></span>mg&#47;week due to toxicity&#47;tolerability&#46; In this cases the previous doses should be continued&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">R 6&#46; When starting a combined therapy with MTX and JAKs inhibitors in MTX- inadequate responders RA patients&#44; it is recommended to continue with the same MTX doses &#40;LE 1b&#59; GR A&#59; GA 100&#37;&#41;</span><p id="par0110" class="elsevierStylePara elsevierViewall">MTX doses when adding TFC in MTX inadequate responders are different among RCTs&#44; from7&#46;5 to 25<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">21&#44;22</span></a> In the ORAL Standard trial&#44; patients were receiving weekly 7&#46;5&#8211;25<span class="elsevierStyleHsp" style=""></span>mg MTX&#44;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">23</span></a> in the ORAL Sync mean MTX dose was 14<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#44;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">21</span></a> and in the ORAL Scan doses ranged between 15 and 25<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">22</span></a> Recent real world evidence have shown that in daily practice MTX doses combined with TFC are close to those reported in the RCTs&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">24</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">MTX doses in combination with BARI in the published RCTs are also variable&#44;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">25</span></a> mainly from 10 to 25<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#46; Mean doses are quite similar to those in TFC trials&#44; like in the RA-Beam study &#40;15<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">25</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">The same considerations exposed for bDMARDs are applicable for tsDMARDs&#46; A post hoc analysis based on pooled data from 2 RCTs in Japanese patients&#44; showed that tofacitinib efficacy may be unaffected by background MTX dose&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">26</span></a> At month 3&#44; ACR20&#47;50&#47;70 response rates&#44; mean DAS28-4 &#40;ESR&#41; CFB and HAQ-DI CFB were similar across different MTX doses&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">R 7&#46; In RA patients who have achieved and sustained the treatment goal&#44; the panel recommends&#44; as treatment strategy&#44; to give priority to the de-escalation of the bDMARDs&#44; which does not exclude MTX dose adjustments or even MTX withdrawal in some intolerant patients on IL-6 inhibitors &#40;LE 5&#59; GR D&#59; GA 100&#37;&#41;</span><p id="par0125" class="elsevierStylePara elsevierViewall">The panel agreed that in patients who have achieved and sustained the treatment goal&#44; the de-escalation of the bDMARDs &#40;irrespectively of the type&#41; should be considered&#46; The term &#8216;sustained&#8217; is still not defined precisely&#44; but at least 6 months was delimited as a minimal time frame&#46; However&#44; on the other hand&#44; this does not exclude MTX dose adjustments &#40;along with the de-escalation of the bDMARDs&#41; or even MTX withdrawal in some intolerant patients on IL-6 inhibitors&#46; Moreover&#44; in some cases&#44; the adjustment of MTX doses could even be the first step &#40;before the de-escalation of the bDMARDs&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">In this context&#44; the TNF inhibitor tapering after attainment of remission in early and established RA allows excellent outcomes to be maintained&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">27&#8211;29</span></a> The PRESERVE study&#44; a RCT comparing the safety and efficacy of once-weekly ETN 50<span class="elsevierStyleHsp" style=""></span>mg&#44; ETN 25<span class="elsevierStyleHsp" style=""></span>mg&#44; and placebo in combination with MTX&#44; analyzed radiological progression between groups of patients continuing full-dose ETN with patients switching to half-dose or stopping of ETN&#46; There were no differences in the changes of the modified total Sharp score between these groups&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">27</span></a> Recently&#44; in a RCT designed to evaluate the effectiveness of two tapering strategies after achieving controlled disease in patients with RA receiving combination therapy with TNF inhibitors and csDMARDs&#44; for up to 9 months&#44; flare rates when tapering csDMARDs or TNF inhibitors were similar&#46; Moreover&#44; after 1 year&#44; anon-significant difference was found between them&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">30</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">On the other hand&#44; in a non-inferiority RCT&#44; RA patients on TCZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX and good&#47;moderate EULAR response were randomized to tapering MTX or continuing stable doses of MTX for 24 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">31</span></a> Although the study stopped early due to low recruitment&#44; the predetermined non-inferiority criteria were still met&#46; Therefore&#44; tapering MTX in patients with RA receiving TCZ was non-inferior to continuing stable MTX in maintaining a good&#47;moderate EULAR response&#46; In another double-blind RCT in biologic-na&#239;ve RA patients with a disease activity score 28 &#40;DAS28&#41;<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>3&#46;2 despite oral MTX&#44; treatment with TCZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX was prescribed for an initial 16 weeks period&#46; Patients who achieved low disease activity &#40;DAS28 &#8804;3&#46;2&#41; were randomised to continue with TCZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX or switch to TCZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo for an additional 12 weeks&#46; In both treatment groups&#44; the percentage of patients in clinical remission from 16 to 28 weeks was similar&#44; as were the improvements in disease activity&#44; functional disability and quality of life&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">32</span></a> However&#44; as the authors comment&#44; the short period of 12 weeks on TCZ monotherapy after randomisation in JUST-ACT does not allow for a long term evaluation of response maintenance&#44; which may theoretically influence our results&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The SMART study was an open-label non-inferiority study in patients with an inadequate response to TNF inhibitors in which all patients on RTX 1000<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX and a moderate or good EULAR response were randomized to RTX 1&#44;000<span class="elsevierStyleHsp" style=""></span>mg for 1 or 2 doses&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">33</span></a> Over 104 weeks&#44; the adjusted mean difference in DAS28 area under the curve was 51&#46;4 &#40;95&#37; CI &#8722;131&#46;2 to &#8722;234&#41;&#44; indicating non-inferiority &#40;as it was pre-defined&#41; between the two doses&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Dose reduction of ABA to half-dose &#40;plus other DMARDs mainly MTX&#41; in patients with early RA was evaluated in a sub-study of the AGREE trial&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">34</span></a> At 1 year&#44; 34&#37; &#40;half-dose&#41; and 31&#37; &#40;full-dose&#41; of patients experienced a flare&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Regarding to the JAKs inhibitors&#44; we need more studies to make robust recommendations&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">As previously suggested in the Spanish REDOSER project&#44; the panel considered that rheumatologists should individualize every case and consider tapering in clinical situations in which down titration will likely be successful&#44; related primarily to early RA&#44; depth of improvement and duration of remission&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">35</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">R 8&#46; bDMARDs should be combined with MTX as the first csDMARD choice&#44; although other csDMARDs could be considered in case of MTX intolerance&#47;contraindication &#40;LE 1b&#59; GR A&#59; GA 100&#37;&#41;</span><p id="par0160" class="elsevierStylePara elsevierViewall">TNF inhibitors efficacy and safety in combination with MTX or leflunomide &#40;LEF&#41; was analyzed in the RABBIT biologics registry&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">36</span></a> EULAR response rates after 24 months ranged from 74&#37; to 81&#37; for combinations with MTX and 72&#37; to 81&#37; for LEF &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;050&#41;&#46; The safety profile was the expected when using these drugs&#46; Regarding ABT&#44; a post-hoc exploratory analysis from 3 interventional trials and 1 real-world study&#44; showed the efficacy and safety data extracted from RA studies in which ABT combination with csDMARDs other than MTX was permitted&#46; At 6 months and 2 years&#44; the efficacy &#40;DAS28 and HAQ&#41; was similar for combinations of ABA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX and ABA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>other csDMARDs like LEF&#44; hydroxychloroquine&#44; SZZ or azathioprine&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">37</span></a> The CERERRA Collaboration &#40;10 European biologics registries&#41; found that significantly more patients achieved a EULAR good response at 6 months when treated with RTX plus mean LEF doses of 20<span class="elsevierStyleHsp" style=""></span>mg&#47;day &#40;29&#46;1&#37;&#41; compared with RTX plus mean MTX doses of 14&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;week &#40;21&#46;1&#37;&#41;&#46; Similar results were observed at 12 months&#46; Adverse events &#40;AE&#41; occurred in 10&#46;2&#37; and 13&#46;2&#37; of patients&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">10</span></a> There are also RCTs of IL6 inhibitors that included patients in combined therapy with different csDMARDs but no comparative data were shown&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">13</span></a> A small observational study did not find efficacy or safety differences between TCZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX and TCZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LEF&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">38</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">On the other hand&#44; MTX in combination with TNF inhibitors has largely demonstrated to increase this group of biologics survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">39&#44;40</span></a> However&#44; connected to ABT&#44; RTX and IL6 inhibitors&#44; so far MTX has not clearly been associated with longer survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">41&#44;42</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Some bDMARDs are associated with immunogenicity &#40;and impact on clinical efficacy and safety&#41; that might be attenuated with the concomitant use of MTX&#46;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">43&#8211;45</span></a> The positivity of anti-drug antibodies to TNF inhibitors occurs in about 13&#37; of patients but varies greatly&#44; depending on the specific TNF inhibitors&#44; with the highest rates observed with IFX and ADA&#44; and the lowest with ETN&#46;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">43&#8211;45</span></a> Several studies have confirmed that in patients treated with IFX&#44; ADA&#44; CZP or GOL&#44; the combination with MTX decreases the rate of anti-drug antibodies&#46;<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">45&#44;46</span></a> Data related to ABT&#44; RTX and IL-6 inhibitors suggest that these drugs are clearly less immunogenic&#46;<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">45&#44;47</span></a> However&#44; it should be taken into account that immunogenicity of individual agents has been analyzed using different study designs&#44; treatment duration&#44; RA characteristics&#44; as well as a great immunoassay heterogeneity&#46; Therefore&#44; data interpretation is challenging and should be carefully considered&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">48</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Finally&#44; regarding the use of parenteral MTX&#44; although more data is still needed&#44; observational studies have shown that its efficacy and safety when combined with bDMARDs are similar to those with oral MTX&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">2&#44;49&#44;50</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">R 9&#46; JAKs inhibitors should be combined with MTX as the first csDMARD choice&#44; although other csDMARDs could be considered in case of MTX intolerance&#47;contraindication &#40;LE 1b&#59; GR A&#59; GA 100&#37;&#41;</span><p id="par0180" class="elsevierStylePara elsevierViewall">Up to 86&#37; of patients from TFC&#8217; RCTs on combined therapy use MTX&#44;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">51</span></a> although there are also some patients taking other DMARDs like LFN&#44; antimalarials&#44; SZZ&#44; sodium aurothiomalate or D-penicillamine&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">51</span></a> However&#44; comparative analyses are not available&#46; BARI RCTs have reported the same data&#46; In terms of survival&#44; a pooled analysis of TFC studies found that up to week 72&#44; the discontinuation rate when receiving combination therapy with a csDMARD &#40;86&#46;2&#37; MTX&#41; was 50&#46;7&#37; vs 45&#46;2&#37; of patients receiving TFC monotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">52</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Nevertheless&#44; so far TFC and BARI are not immunogenic drugs&#44; and more studies are necessary to assess the role of parenteral MTX in patients with JAK inhibitors&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">R 10&#46; Combination therapy of MTX with bDMARDs and tsDMARDs does not imply a different management of the standard of care for routine patient safety monitoring &#40;LE 5&#59; GR D&#59; GA 100&#37;&#41;</span><p id="par0190" class="elsevierStylePara elsevierViewall">Pooled data from RCTs have depicted that MTX and bDMARD combination therapy is not significantly associated with an increased risk of serious AE&#44; serious infections or death when compared with bDMARD monotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">53</span></a> However&#44; an increase risk of gastrointestinal AE&#40;including hepatic AE&#41; has been reported with the combined therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">7</span></a> Observational studies including biologic registries have also found no increased risk in other relevant AE like cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">54</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">As a result of all data exposed above&#44; the panel considered that risk management when combining MTX with b- or tsDMARDs should be the same as for their individual components&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">55</span></a></p></span></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Discussion</span><p id="par0200" class="elsevierStylePara elsevierViewall">In RA&#44; MTX continues to be the anchor &#40;&#8216;first&#8217;&#41; drug both as monotherapy as well as in combination with other drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">2&#44;56</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">It has been estimated that&#44; in MTX <span class="elsevierStyleItalic">na&#239;ve</span> patients&#44; MTX monotherapy achieves satisfactory disease control in approximate one-third of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">57</span></a> Therefore&#44; an important rate of RA population &#40;with an inadequate response to MTX&#41; will need intensification of therapy which may include addition of a bDMARD or tsDMARD&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">1&#8211;4</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">We have proposed practical and specific recommendations when using MTX combined therapy with b- or tsDMARDs that provide complementary advice to those from EULAR recommendations and similar documents&#46; These recommendations were based on the best evidence available and achieved high level of agreement among experts&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">The first question addressed the need to continue or discontinue MTX in patients with inadequate response to MTX when initiating a bDMARD or tsDMARD&#46; As described in the main text&#44; all bDMARDs have superior efficacy when combined with MTX compared to monotherapy&#44;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">6&#8211;10</span></a> even for IL-6 and JAKs inhibitors in many aspects&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">11&#44;12&#44;14&#44;16</span></a> However&#44; the panel also considered that&#44; in reference to RA signs and symptoms or physical function&#44; most of IL-6 and JAKs inhibitors RCTs have shown no differences between biologic monotherapy and combined therapy&#46; This led the experts to definitely recommend the continuation of MTX &#40;if no contraindications are present&#41; with TNF inhibitors&#44; ABT and RTX&#44; and not to discontinue MTX with IL-6 and JAKs inhibitors&#44; in line with EULAR recommendations&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">1</span></a> This proposal is in line with Spanish national and EULAR recommendations<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">1&#8211;3</span></a> but differ from ACR guidelines that allow the option of bDMARDs monotherapy&#44; even when TNF inhibitors&#44; ABT and RTX are selected&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">4</span></a> For IL-6 and JAK inhibitors&#44; the panel pointed out that in some cases biologic monotherapy could be considered as treatment option&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Next&#44; for patients who start a combination of a csDMARD with b- or tsDMRDs&#44; the panel proposed MTX as first choice&#46; There is plenty of evidence regarding its efficacy&#44; safety profile&#44; and role in biologics immunogenicity and survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">10&#44;37&#44;39&#8211;43&#44;45&#8211;48</span></a> However&#44; the evidence also supports the use of other csDMARDs&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">13&#44;37&#44;38</span></a> Concerning MTX optimal doses&#44; the panel stated that this should be the maximum tolerated as recommended in EULAR and similar consensus documents&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">1&#8211;4</span></a> This is a key requirement in daily practice to support the cost-effectiveness of adding a b- or tsCDMARDs&#44; since it has been argued that many RCT let the recruitment of &#8220;inadequate&#8221; MTX responders with unusual low doses of MTX&#46; In the case of MTX route of administration&#44; when combined with b- or tsDMARDs&#44; oral and parenteral should be considered as previously recommended&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">2&#44;49&#44;50</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">Another challenge in daily practice is the treatment strategy in patients that have achieved the treatment goal&#46; In fact&#44; for the panel it is crucial that the target-state should be achieved and sustained&#46; Although the panel fully agreed on prioritizing the b- or tsDMARD de-escalation&#44; especially considering MTX tolerability in RA patients&#44; other scenarios were also accepted&#46; For example&#44; in patients who are not experiencing a proper tolerance to MTX&#44; MTX dose adjustments could be considered along with the de-escalation &#40;even as a first step&#41;&#44; or MTX withdrawal in patients on IL-6 and JAK inhibitors&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Finally&#44; safety issues were discussed and analyzed&#46; It could be expected that the combination therapy might increase the frequency of AE&#46; Nevertheless&#44; according to evidence&#44; MTX and b- or tsDMARD combination therapy is not significantly associated with an increased risk of serious AE compared with bDMARD or MTX monotherapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">7&#44;53&#44;54</span></a> Therefore&#44; risk management when combining MTX with b- or tsDMARDs should be the already recommended monitorization&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">1&#44;55</span></a> And this is why we just generated one general recommendation&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">On the other hand we should comment some limitations of the present project&#46; As described&#44; this was a very ambitious project&#44; with a wide scope&#46; We have tried to answer multiple questions about all available drugs in RA&#46; As a consequence&#44; we decided to perform a SLR based basically on previous SLRs&#46; This means that a single SLR can fall short in obtaining the information necessary to answer all the proposed questions&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">In summary&#44; this document provides a series of practical recommendations on the use of MTX in combination with bDMARDs or tsDMARDs&#46; We hope that the current recommendations will find their way into the clinic for a better care of the RA patients in the real-world setting&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Financing</span><p id="par0245" class="elsevierStylePara elsevierViewall">This Project was financed by <span class="elsevierStyleGrantSponsor" id="gs1">Gebro Pharma</span>&#44; Barcelona&#44; Spain&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Conflict of interest</span><p id="par0250" class="elsevierStylePara elsevierViewall">JTM has received honoraria from Gebro&#44; Lilly&#44; Pfizer&#44; Roche&#44; Fresenius&#46; The rest of the authors report having no conflicts of interest&#46;</p></span></span>"
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        4 => array:2 [
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          "titulo" => "Introduction"
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        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Methods"
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            0 => array:2 [
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              "titulo" => "Study design and panel selection"
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              "titulo" => "Systematic literature review"
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            2 => array:2 [
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              "titulo" => "Systematic literature review"
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              "titulo" => "R 1&#46; In patients with active RA and inadequate response to MTX&#44; this drug should be continued when starting a TNF inhibitor &#40;LE 1a&#59; GR A&#59; GA 100&#37;&#41;&#44; ABT &#40;LE 2a&#59; GR B&#59; GA 100&#37;&#41;&#44; or RTX &#40;LE 1b-2a&#59; GR B&#59; GA 100&#37;&#41;"
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              "identificador" => "sec0055"
              "titulo" => "R 2&#46;MTX should not be discontinued in patients with active RA and inadequate response to MTX who start IL-6 inhibitors &#40;LE 1a&#59; GR A&#59; GA 91&#37;&#41;"
            ]
            3 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "R 3&#46; MTX should not be discontinued in patients with active RA and inadequate response to MTX who start JAKs inhibitors &#40;LE 1b&#59; GR A&#59; GA 91&#37;&#41;"
            ]
            4 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "R 4&#46; When starting a combined therapy with MTX and bDMARDs in MTX-inadequate responders RA patients&#44; it is recommended to continue with the same MTX doses &#40;LE 1b&#59; GR A&#59; GA 100&#37;&#41;"
            ]
            5 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "R 5&#46; When combining MTX with TNF inhibitors&#44; the dose of MTX should be of at least 10 mg&#47;week &#40;LE 1b&#59; GR A&#59; GA 100&#37;&#41;"
            ]
            6 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "R 6&#46; When starting a combined therapy with MTX and JAKs inhibitors in MTX- inadequate responders RA patients&#44; it is recommended to continue with the same MTX doses &#40;LE 1b&#59; GR A&#59; GA 100&#37;&#41;"
            ]
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              "identificador" => "sec0080"
              "titulo" => "R 7&#46; In RA patients who have achieved and sustained the treatment goal&#44; the panel recommends&#44; as treatment strategy&#44; to give priority to the de-escalation of the bDMARDs&#44; which does not exclude MTX dose adjustments or even MTX withdrawal in some intolerant patients on IL-6 inhibitors &#40;LE 5&#59; GR D&#59; GA 100&#37;&#41;"
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              "identificador" => "sec0085"
              "titulo" => "R 8&#46; bDMARDs should be combined with MTX as the first csDMARD choice&#44; although other csDMARDs could be considered in case of MTX intolerance&#47;contraindication &#40;LE 1b&#59; GR A&#59; GA 100&#37;&#41;"
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              "identificador" => "sec0090"
              "titulo" => "R 9&#46; JAKs inhibitors should be combined with MTX as the first csDMARD choice&#44; although other csDMARDs could be considered in case of MTX intolerance&#47;contraindication &#40;LE 1b&#59; GR A&#59; GA 100&#37;&#41;"
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              "identificador" => "sec0095"
              "titulo" => "R 10&#46; Combination therapy of MTX with bDMARDs and tsDMARDs does not imply a different management of the standard of care for routine patient safety monitoring &#40;LE 5&#59; GR D&#59; GA 100&#37;&#41;"
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    "fechaRecibido" => "2020-05-06"
    "fechaAceptado" => "2020-08-20"
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          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Methotrexate"
            1 => "Rheumatoid arthritis"
            2 => "Disease modifying anti-rheumatic drugs"
            3 => "Combined therapy"
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          "palabras" => array:4 [
            0 => "Metotrexato"
            1 => "Artritis reumatoide"
            2 => "F&#225;rmacos modificadores de la enfermedad"
            3 => "Terapia combinada"
          ]
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    "resumen" => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">We aimed to develop recommendations for the management of methotrexate &#40;MTX&#41; when considering the combination with biological &#40;b&#41; or targeted synthetic &#40;ts&#41; disease modifying drugs &#40;DMARDs&#41; in rheumatoid arthritis &#40;RA&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Eleven experts on RA were selected&#46; Two coordinators formulated 13 questions about the combination therapy of MTX with bDMARDs or tsDMARDs&#46; A systematic review was conducted to answer the questions&#46; Inclusion and exclusion criteria were established as well as the search strategies &#40;Medline&#44; Embase and the Cochrane Library were searched up to January 2019&#41;&#46; Two reviewers selected the articles and collected data&#46; Simultaneously&#44; EULAR and ACR meeting abstracts were evaluated&#46; Based on this evidence&#44; the coordinators proposed preliminary recommendations that the experts discussed and voted in a nominal group meeting&#46; The level of evidence and grade of recommendation was established using the Oxford Center for Evidence Based Medicine and the level of agreement with a <span class="elsevierStyleItalic">Delphi</span>&#46; Agreement was established if at least 80&#37; of the experts voted &#8216;yes&#8217; &#40;yes&#47;no&#41;&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The systematic review retrieved 513 citations of which 61 were finally included&#46; A total of 10 recommendations were generated&#44; voted and accepted&#46; The level of agreement was very high in all of them and it was achieved in the first Delphi round&#46; Final recommendations cover aspects such as the optimal MTX dosage&#44; tapering strategy or patients&#8217; risk management&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This document is intended to help clinicians solve usual clinical questions and facilitate decision making when treating RA patients with MTX in combination with bDMARDs or tsDMARDs&#46;</p></span>"
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      "es" => array:3 [
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Desarrollar recomendaciones sobre el uso de metotrexato &#40;MTX&#41; en combinaci&#243;n con medicamentos modificadores de la enfermedad &#40;DMARD&#41; biol&#243;gicos &#40;b&#41; o sint&#233;ticos espec&#237;ficos &#40;ts&#41; en la artritis reumatoide &#40;AR&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se seleccionaron 11 expertos en AR&#46; Dos coordinadores formularon 13 preguntas sobre la terapia combinada de MTX con bDMARD o tsDMARD&#46; Se realiz&#243; una revisi&#243;n sistem&#225;tica para responder las preguntas&#46; Se establecieron criterios de inclusi&#243;n y exclusi&#243;n&#44; as&#237; como las estrategias de b&#250;squeda &#40;se realizaron b&#250;squedas en Medline&#44; Embase y la Biblioteca Cochrane hasta enero de 2019&#41;&#46; Dos revisores seleccionaron los art&#237;culos y recopilaron datos&#46; Simult&#225;neamente&#44; se evaluaron los res&#250;menes de las reuniones EULAR y ACR&#46; Con base en esta evidencia&#44; los coordinadores propusieron recomendaciones preliminares que los expertos discutieron y votaron en una reuni&#243;n de grupo nominal&#46; El nivel de evidencia y el grado de recomendaci&#243;n se establecieron utilizando el Centro de Oxford para Medicina Basada en Evidencia y el nivel de acuerdo con un Delphi&#46; El acuerdo se estableci&#243; si al menos el 80&#37; de los expertos votaron &#171;s&#237;&#187; &#40;s&#237;&#47;no&#41;&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La revisi&#243;n sistem&#225;tica recuper&#243; 513 citas&#44; de las cuales finalmente se incluyeron 61&#46; Se generaron&#44; votaron y aceptaron un total de 10 recomendaciones&#46; El nivel de acuerdo fue muy alto en todas ellas y se logr&#243; en la primera ronda de Delphi&#46; Las recomendaciones finales cubren aspectos como la dosis &#243;ptima de MTX&#44; la estrategia de reducci&#243;n o la gesti&#243;n del riesgo de los pacientes&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Este documento est&#225; destinado a ayudar a los m&#233;dicos a resolver preguntas cl&#237;nicas habituales y facilitar la toma de decisiones al tratar a pacientes con AR con MTX&#44; en combinaci&#243;n con bDMARD o tsDMARD&#46;</p></span>"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>methotrexate&#59; RA<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>rheumatoid arthritis&#59; JAKs<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>Januskinases&#59; bDMARDs<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>biological disease modifying drugs&#59; csDMARDs<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>conventional synthetic disease modifying drugs&#59; bDMARDs<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>biological disease modifying drugs&#46;</p>"
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                  <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">&#35;&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">Questions&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" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">In patients with active RA and inadequate response to MTX&#44; when adding a bDMARD&#44; is it better to continue or to stop MTX&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">In patients with active RA and inadequate response to MTX&#44; when adding a JAK inhibitor&#44; is it better to continue or to stop MTX&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Which is the optimal MTX dose when combined with bDMARD&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Which is the optimal MTX dose when combined with JAKs inhibitors&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">In patients who have achieved and maintained the treatment goal&#58; is it better to taper MTX or the bDMARD&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">In patients who have achieved and maintained the treatment goal&#58; is it better to taper MTX or the JAK-inhibitor&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Is MTX the csDMARD of choice to combine with bDMARDs &#40;regarding efficacy&#44; safety and survival&#41;&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Is MTX the csDMARD of choice to combine with JAK-inhibitors &#40;regarding efficacy&#44; safety and survival&#41;&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Does MTX in combination with bDMADRS&#47;JAKs inhibitors increase these drugs survival&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Which is MTX influence on bDMADRS&#47;JAKs inhibitors immunogenicity when combined&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Which is parenteral MTX role when combined with bDMADRS&#47;JAKs inhibitors&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Is the combination of MTX with bDMADRS&#47;JAKs inhibitors safe&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Is risk management of MTX different when combined with bDMARDS&#47;Jak inhbitors&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>methotrexate&#59; RA<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>rheumatoid arthritis&#59; TNF<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>tumour necrosis factor&#59; ABT<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>abatacept&#59; RTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>rituximab&#59; mg<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>milligram&#59; IL-6<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>interleukin 6&#59; JAKs<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>Januskinases&#59; bDMARDs<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>biological disease modifying drugs&#59; tsDMARDs<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>targeted synthetic disease modifying drugs &#40;DMARDs&#41;&#46;</p>"
          "tablatextoimagen" => array:1 [
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                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">&#35;&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">Recommendation&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">LE&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">GR&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">GA&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" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">In patients with active RA and inadequate response to MTX&#44; this drug should be continued when starting a TNF inhibitor &#40;LE 1a&#59; GR A&#41;&#44; ABT &#40;LE 2a&#59; GR B&#41;&#44; RTX &#40;LE 1b-2a&#59; GR B&#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">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MTX should not be discontinued in patients with active RA and inadequate response to MTX who start IL-6 inhibitors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">91&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MTX should not be discontinued in patients with active RA and inadequate response to MTX who start JAKs inhibitors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">91&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">When starting a combined therapy with MTX and bDMARDs in MTX-inadequate responders RA patients&#44; it is recommended to continue with the same MTX doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">When combining MTX with TNF inhibitors&#44; the dose of MTX should be at least 10<span class="elsevierStyleHsp" style=""></span>mg&#47;week&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">When starting a combined therapy with MTX and JAKs inhibitorsin MTX inadequate responders RA patients&#44; it is recommended to continue with the same MTX doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">In RA patients who have achieved and sustained the treatment goal&#44; the panel recommends&#44; as treatment strategy&#44; to give priority to the de-escalation of the bDMARDs&#44; which does not exclude MTX dose adjustments or even MTX withdrawal in some intolerant patients on IL-6 inhibitors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">bDMARDs should be combined with MTX as the first csDMARD choice&#44; although other csDMARDs could be considered in case of MTX intolerance&#47;contraindication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAKs inhibitors should be combined with MTX as the first csDMARD choice&#44; although other csDMARDs could be considered in case of MTX intolerance&#47;contraindication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Combined therapy of MTX with bDMARDs and tsDMARDs does not imply a different management of the standard of care for routine patient safety monitoring&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab2801211.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Recommendations with their level of evidence &#40;LE&#41;&#44; grade of recommendation &#40;GR&#41; and grade ofagreement &#40;GA&#41;&#46;</p>"
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      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:57 [
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                            1 => "K&#46;G&#46; Saag"
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                            4 => "R&#46;R&#46; Bannuru"
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                  ]
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            4 => array:3 [
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            ]
            5 => array:3 [
              "identificador" => "bib0315"
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                          "autores" => array:5 [
                            0 => "F&#46; Buckley"
                            1 => "A&#46; Finckh"
                            2 => "T&#46;W&#46; Huizinga"
                            3 => "F&#46; Dejonckheere"
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            ]
            6 => array:3 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Added value of combining methotrexate with a biological agent compared to biological monotherapy in rheumatoid arthritis patients&#58; a systematic review and meta-analysis of randomised trials"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Tarp"
                            1 => "T&#46;S&#46; Jorgensen"
                            2 => "D&#46;E&#46; Furst"
                            3 => "A&#46; Dossing"
                            4 => "P&#46;C&#46; Taylor"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                        0 => array:2 [
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                            0 => "T&#46; Pascart"
                            1 => "P&#46; Philippe"
                            2 => "E&#46; Drumez"
                            3 => "X&#46; Deprez"
                            4 => "B&#46; Cortet"
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                  ]
                  "host" => array:1 [
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