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            "etiqueta" => "g"
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            "entidad" => "Servicio de Reumatolog&#237;a&#44; Hospital Universitario de Gran Canaria Doctor Negr&#237;n&#44; Las Palmas de Gran Canaria&#44; Spain"
            "etiqueta" => "h"
            "identificador" => "aff0040"
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            "entidad" => "Secci&#243;n Reumatolog&#237;a&#44; Cl&#237;nica HLA Vistahermosa&#44; Alicante&#44; Spain"
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            "entidad" => "Servicio de Reumatolog&#237;a&#44; Hospital Universitari Cl&#237;nic&#44; Barcelona&#44; Spain"
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        "titulo" => "Eficacia y seguridad de la terapia combinada con f&#225;rmacos modificadores de la enfermedad sint&#233;ticos en la artritis reumatoide&#58; revisi&#243;n sistem&#225;tica de la literatura"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flow diagram of studies&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The management of rheumatoid arthritis &#40;RA&#41; has changed enormously in recent years&#46; New drugs and treatment strategies have completely changed the prognosis of these patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">1&#8211;4</span></a> Synthetic disease-modifying anti-rheumatic drugs &#40;DMARDs&#41; like methotrexate &#40;MTX&#41; or leflunomide &#40;LEF&#41; have been and continue to be essential therapies for the management of these patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">5&#8211;7</span></a> However&#44; with new findings in the disease pathogenesis and the appearance of biologic therapies recommendations on their use has changed&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">8&#8211;10</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">For example&#44; in the latest updating of the EULAR consensus document on RA management &#40;2016&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a> albeit with great controversy&#44; one recommendation from the 2013 issue was finally excluded&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a> which suggested in DMARD naive RA&#44; regardless of the use of combined corticosteroids&#44; conventional synthetic DMARD should be used as monotherapy or in combination therapy&#46; There are different reasons for definitively excluding combined therapy in initial treatment&#44; from the higher effect when combined with biologics compared to the combination of the DMARD themselves to the higher number of adverse events compared with monotherapy&#46; In the same document and&#44; regarding refractory patients or those with toxicity to initial treatment&#44; if no bad prognostic factors present&#44; therapy combined with MTX&#44; LEF or salazopyrin &#40;SSZ&#41; is a recommended option and they show that the combination of the 3 is the most common therapy used&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">However&#44; even with this present&#44; unresolved questions remain&#46; For example&#44; relating to the use of combined therapy with synthetic DMARD&#44; although arguments against this are cited&#44; are they really sufficient so as to exclude this model of treatment in early RA&#63; Also&#44; in the case of established RA which are refractory to initial treatment and where there are no poor prognostic factors&#44; which combined therapy would be the most appropriate&#63;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The NEXUS Project is an annual activity where&#44; based on the best evidence and experience possible&#44; an attempt is made to respond to issues in RA which are&#46; As a result&#44; and bearing in mind everything commented above&#44; in the context of this project&#44; the aim of this systematic literature review &#40;SLR&#41; was to evaluate some aspects on efficacy and safety of combined therapy with synthetic DMARD in RA and subsequently issue a series of practical recommendations to serve as guidelines for clinicians in their daily practice&#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">NEXUS Project</span><p id="par0025" class="elsevierStylePara elsevierViewall">This publication forms part of the NEXUS Project&#46; This is led by 2 national coordinators &#40;rheumatologist experts&#41; and comprises 8 work groups&#44; each with a regional coordinator and 2 or 3 reviewers &#40;depending on the group&#41;&#44; for a total of 22 reviewers&#46; Every year different subjects of interest in the field of RA are analysed&#46; In the 2017&#8211;2018 issue this was the use of corticosteroids and combined therapy with synthetic DMARD in RA&#46; In this publication we describe the SLR referring to the question on combined therapy in RA&#46; The Spanish Society of Rheumatology guarantees that the methodology used is appropriate&#44; but does not endorse the conclusions because the Spanish Society of Rheumatology has official policies in this regard&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Review protocol</span><p id="par0030" class="elsevierStylePara elsevierViewall">Initially&#44; one of the national coordinators put forward the following questions which were responded to through an SLR&#58;&#8221;In early RA patients&#44; is combined therapy with synthetic DMARD better than sequential therapy with synthetic DMARD&#63; In established RA patients who are refractory to standard first line therapy &#40;synthetic DMARD&#41;&#44; is the combination of MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LEF or triple synthetic DMARD therapy effective and safe&#63;&#8221; The SLR protocol was defined with these questions&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">PICO and study selection criteria</span><p id="par0035" class="elsevierStylePara elsevierViewall">The 2 clinical questions were transformed into the PICO with which the inclusion and exclusion criteria were defined&#46; For the first questions we selected studies which included patients with RA &#40;international criteria or clinical judgement&#41;&#44; early RA &#40;&#8804;2 years onset&#41; adults &#40;&#8805;18 years&#41;&#44; DMARD naive&#59; being treated with combined therapy &#40;double or triple&#41; with synthetic DMARD with or without corticosteroids or other adjuvant drugs&#46; Comparative studies had to have synthetic DMARD in sequential therapy &#40;monotherapies or DMARD therapy with add-on drugs&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">For the second question we selected studies which included patients with RA &#40;international criteria or clinical judgement&#41;&#44; adults &#40;&#8805;18 years&#41;&#44; established RA &#40;&#62; 2 years onset&#41;&#44; refractory to standard first line treatment &#40;synthetic DMARD&#41;&#59; being treated with combined MTX and LEF therapy or triple therapy with synthetic DMARD&#44; with or without corticosteroids or other adjuvant drugs&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In both questions articles were sought whose outcomes analysed efficacy and safety variables regularly used in the study of RA&#46; Finally&#44; only those studies with the following designs were included&#58; met analysis&#44; systematic reviews and randomised clinical trials &#40;RCT&#41;&#46; Studies on animals and basic science were excluded&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Search strategy</span><p id="par0050" class="elsevierStylePara elsevierViewall">Aided by an expert documentalist search strategies were created for the different databases&#46; For this they used the MeSH terms and terms in free text&#46; Only articles on humans&#44; in English or Spanish were included in the search&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">For this review the following bibliographic data bases were screened&#58; Medline&#44; Embase and Cochrane Library &#40;all from their initiation up until July 2017&#41;&#46; Due to the volume of bibliographic references recovered&#44; we decided not to review the grey literature of the main national and international rheumatology conferences&#46; A manual search was subsequently performed secondary to the bibliography of the articles finally included&#46; The <a class="elsevierStyleCrossRef" href="#sec0090">supplementary material</a> shows the search strategy used&#44; together with the number of references collected&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">All the references resulting from the searches were inserted into the EndNote programme for easier management&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Article selection</span><p id="par0065" class="elsevierStylePara elsevierViewall">Following this&#44; 2 reviewers created the first selection of articles resulting from the search strategy by reading the title and abstract&#44; complying with the inclusion and exclusion criteria&#44; each independently&#46; Whenever a discrepancy arose&#44; a third reviewer was taken on board to make a decision&#46; After this&#44; 11 reviewers made a second article selection through independent detailed reading and applying the same inclusion and exclusion criteria&#46; To do this&#44; the number of references collected was equally distributed among the 11 reviewers&#46; Whenever a discrepancy arose&#44; the other reviewer of the previous phase resolved the problem&#46; In <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> we show the flow diagram of the selection process of the articles&#44; and in the <a class="elsevierStyleCrossRef" href="#sec0090">supplementary material</a>&#44; the characteristics of the studies included and excluded&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Data collection and assessment of the study quality</span><p id="par0070" class="elsevierStylePara elsevierViewall">The 11 reviewers and one of the reviewers from the first selection stage&#44; collected the study data included using specifically pre-designed templates&#41;&#46; The Jadad<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">12</span></a> scale was used to assess the methodological quality of the studies included&#46; Again&#44; where discrepancies arose the other reviewer from the previous stage resolved the problem&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Data analysis and presentation</span><p id="par0075" class="elsevierStylePara elsevierViewall">Tables of evidence and outcomes were created&#44; where the main characteristics and outcomes of the included studies were described&#46; Some of these were expressed as numbers and percentages &#40;&#37;&#41;&#44; mean and standard deviation&#44; mean and interquartile range &#40;p25&#8211;p75&#41;&#44; others as odds ratios&#44; relative risk or hazard ratios and their 95&#37; confidence intervals &#40;CI&#41;&#46; The possibility of performing meta-analysis was only assessed where there was homogeneity&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Nominal group meeting and drawing up of recommendations</span><p id="par0080" class="elsevierStylePara elsevierViewall">During a 2-day nominal group meeting which all NEXUS Project members attended&#44; the outcomes of the SLR were presented and discussed&#46; A series of recommendations were agreed to&#46; Each of the recommendations&#44; with guidance from the methodologist&#44; was assigned a level of evidence and a level of recommendation&#44; in keeping with the recommendations for evidence-based medicine from the Centre for Evidence-based Medicine in Oxford&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">13</span></a></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Results</span><p id="par0085" class="elsevierStylePara elsevierViewall">Out of the 2603 references collected after the initial selection process 83 were assessed in depth and a further 3 through a secondary search&#46; Finally&#44; after an in-depth reading&#44; no RCT were found which directly responded to the 2 questions &#40;see excluded studies in the <a class="elsevierStyleCrossRef" href="#sec0090">supplementary material</a>&#41;&#46; Below are comments on some of the studies excluded in this SLR which did not meet with the criteria to be included&#44; but provide relevant data and ideas in relation to the 2 research questions&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> outlines the main conclusions and recommendations&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Question 1&#46; In patients with early RA is combined therapy with synthetic DMARD better than sequential therapy with synthetic DMARD&#63;</span><p id="par0090" class="elsevierStylePara elsevierViewall">The BeSt study was a study designed to analyse&#44; the effect of different treatment strategies in early RA&#46; Patients were assigned to one of the 4 groups and if there was no response a therapeutic decision was quickly taken&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">14&#8211;26</span></a> Patients therefore changed therapy &#40;within their group&#41; and even passed from one treatment branch to another&#46; These groups were as follows&#58; group 1 sequential monotherapy&#44; group 2 combined sequential therapy &#40;staged&#44; i&#46;e&#46; monotherapy initiated and if response was insufficient another drug was added on&#41;&#44; group 3 combined therapy with MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>prednisone &#40;high doses with fast dose reduction&#41; and group 4 combined therapy MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>infliximab &#40;IFX&#41;&#46; Data of up to 10 years follow-up was available&#44; where the RA activity was evaluated&#44; in addition to function&#44; structure damage&#44; quality of life and safety&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">In the BeSt study&#44; after one year&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">17</span></a> the groups treated with MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>prednisone and MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IFX&#44; demonstrated better control of the activity&#44; function&#44; radiographic damage progression than the other groups although they also presented with more adverse events &#40;AE&#41;&#44; with no differences being observed in bone mineral density&#46; Progressively&#44; in years 2&#8211;5&#44;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">16&#44;19&#44;20&#44;26</span></a> these differences between the groups practically disappeared and specifically after 5 years&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a> 48&#37; of the patients were in clinical remission &#40;DAS28<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>1&#46;6&#41; and 14&#37; in drug-free remission&#44; regardless of the initial treatment group&#46; After 5 years it was published that radiographic damage was lower in those patients who had started treatment in one of the combination groups&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a> After 10 years a subanalysis of ACPA-negative patients was performed reporting that the early use of MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>prednisone and MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IFX was more effective compared with MTX as monotherapy&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Question 2&#46; In patients with established RA who are refractory to standard first line treatment &#40;synthetic DMARD&#41;&#44; is the combination of MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LEF or the triple therapy of synthetic DMARD effective and safe&#63;</span><p id="par0100" class="elsevierStylePara elsevierViewall">Three good quality RCT<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">27&#8211;29</span></a> were found &#40;one is really data added onto the other 2 studies&#41;&#46; They include almost 1000 patients with RA&#44; mostly established RA &#40;mean duration from 5 to 18 years&#41; and refractory to standard synthetic DMARD&#44; especially to MTX &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; MTX was prescribed at a dose of 10&#8211;20 milligrams &#40;mg&#41;&#47;week and LEF between 10 and 20<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46; MTX in monotherapy was compared with MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>etanercept &#40;ETN&#41;&#44; MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>hydroxychloroquine &#40;HCQ&#41; and rituximab &#40;RTX&#41;&#46; All the patients included could take prednisone &#40;up to 10<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&#46; These RCTs analysed the efficacy &#40;activity&#44; function&#44; quality of life&#41; and safety of this combination up to 24 weeks&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">The combination of MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LEF was statistically superior to MTX in monotherapy in ACR 20&#44; 50 and 70&#44; HAQ and SF-36 after 24 weeks of treatment in one of the RCT&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a> However&#44; another 16-week study found that&#44; although all of the combinations analysed improved the activity and function of the patients&#44; the combination of MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ETN was higher than MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LEF in many of the variables which evaluated the activity of RA &#40;ACR 20&#44; 50&#44; 70&#44; DAS28&#44; CDAI&#41; and the function&#46; Furthermore&#44; in this study it was not possible to show the superiority of MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LEF compared with MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ or MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ in these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">27</span></a> In the third study included&#44; the combination of MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LEF was similar to MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RTX &#40;at intravenous doses of 500<span class="elsevierStyleHsp" style=""></span>mg in 2 doses&#41; to improve the activity &#40;evaluated among others with the DAS28 and the EULAR response&#41;&#44; in changes in the acute phase reactants and depending on the patients at 24 weeks&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Regarding safety&#44; the expected AE were reported with the use of these DMARD&#44; such as nausea&#44; diarrhoea or elevated transaminases&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">27&#8211;29</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">With regards to efficacy and safety of the triple therapy in established and refractory RA&#44; the SLR included 3 good quality RCT&#44;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">30&#8211;33</span></a> which analysed the triple therapy with synthetic DMARD in patients with RA&#44; most of which were established &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; The duration of the RCT was from 1 to 2 years&#44; and included over 400 patients with RA of 6&#8211;10 years onset&#44; active &#40;DAS28 mean of 6&#41;&#44; refractory to synthetic DMARD&#46; In all cases the triple therapy consisted of MTX at a dose of 20<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#44; SSZ 1&#8211;2<span class="elsevierStyleHsp" style=""></span>g&#47;day and HCQ 400<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46; The comparators in these RCT were MTX as monotherapy&#44; MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ and ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#46; All patients included could take stable corticosteroid doses &#40;&#8804;10<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41; and triggers evaluated were the RA activity &#40;clinical and analytical&#41;&#44; overall patient assessment &#40;OPA&#41;&#44; structural damage and safety&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">In the first RCT&#44;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">32</span></a> published in 1996&#44; triple therapy was significantly superior to MTX as monotherapy for improving the number of swollen joints&#44; the OPA score and the physician global assessment &#40;PGA&#41;&#46; Equally&#44; the combination of SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ improved the number of swollen&#44; painful joints and the PGA&#44; from medium to long term &#40;2 years&#41;&#46; Notwithstanding there were no differences in the ESR and duration of morning stiffness&#46; Neither were there any differences in terms of safety&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The RACAT study was a RCT of non inferiority&#44; in which the triple therapy&#40;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ&#41; was compared with the combination of MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ETN&#46; After 24 weeks of treatment&#44; MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ETN was statistically superior to the triple therapies in the percentage of patients who achieved low activity DAS28 &#40;24&#46;8&#37; vs 34&#46;8&#37; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;050&#41;&#44; remission-DAS28 &#40;12&#46;7&#37; vs 21&#46;7&#37; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;030&#41; and ACR70 &#40;5&#37; vs 16&#37; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; with no differences in the other variables&#44; including the reduction mean of the DAS28 which was the mean of the main trigger&#46; However&#44; after 48 weeks &#40;where the patients could be assigned to the other branch if response was insufficient&#41;&#44; there were no statistically significant differences between groups relating to RA activity &#40;DAS28&#44; CDAI&#44; ACR response 20&#44; 50&#44; 70&#41;&#44; the HAQ and radiographic progression &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; In open extension at 72 weeks&#44;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">30</span></a> adherence to treatment at one year was higher in the ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX group than in the triple therapy group&#44; 78&#37; vs 63&#37;&#44; and changes of regimen were higher from triple therapy to ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX than the inverse &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;005&#41;&#46; The DAS28 continued to improve with no statistically significant differences between the groups&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Regarding safety&#44; the expected AE were reported for the use of these DMARDs&#44; including infections and gastrointestinal disorders&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">30&#8211;32</span></a></p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discussion</span><p id="par0135" class="elsevierStylePara elsevierViewall">In this SLR we have tried to analyse some aspects relating to combined therapy with synthetic DMARD in RA patients&#46; One of the questions relates to their use in early RA &#40;this possibility is currently not included in the latest EULAR<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a> recommendations&#41;&#46; The other question was raised to analyse the combination of MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LEF and the triple therapy of MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ&#44; in established RA patient&#39;s refractory to standard treatment with synthetic DMARD&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Notwithstanding&#44; after the selection processes of the SLR&#44; no article was included which met all inclusion criteria and the questions raised could not be directly answered&#46; Despite this&#44; with analysis of the RCT excluded in the same&#44; we could extract a series of conclusions and recommendations relating to the questions&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Firstly&#44; relating to the use of the combined synthetic DMARD in early RA&#44; we exposed the results of the BeSt study&#46; After its ten years existence&#44;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">14&#8211;22&#44;24&#8211;26</span></a> we may conclude that what is really important is to begin early treatment and take decisions if the expected response is not obtained&#46; Thus many studies in RA have demonstrated that an early diagnosis and treatment following a treat-to-target strategy clearly improves the prognosis of these patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">3&#44;4&#44;34</span></a> Although it is difficult to analyse&#44; it has also been suggested that&#44; although in the end the effect of the 4 groups is very similar&#44; of the patients who began in some of the combined therapy groups&#44; one included two synthetics DMARD&#58; MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ but also in combination with high dose glucocorticoids&#41; and had a faster response &#40;although including high dose corticosteroids in one group and biologic therapy in the other may have had a great impact on outcomes&#41; and a lower radiographic progression &#40;possibly conditioned by the previous point&#41;&#46; Later&#44; relating to the question for the patients with established RA refractory to synthetic DMARDs&#44; the combination of MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LEF&#44; and of MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ&#44; as put forward by EULAR&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a> may be therapeutic options to assess in this patient profile&#44; despite the low or nil accumulated scientific evidence&#46; Specific high quality studies are required in this regard&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Nevertheless&#44; this SLR has several limitations&#46; The first and most important was the difficulty in finding studies that fitted in with the PICO of the research questions&#44; and the review inclusion criteria&#46; This was so to such an extent that it was not possible to find any studies which could directly provide an answer to this&#46; Also&#44; even with the RCT which we have commented upon being available&#44; some of them have very small sample sizes which limit outcome generality and others require more long-term data to conclude with greater assurance&#46; For example&#44; in the BeSt study&#44; respondents were able to change treatment within their group change group &#40;there were 4&#41;&#46; In this study&#44; similarly to others&#44; the DMARD doses could be changed&#46; All of this complicates statistics and its interpretation&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">To conclude&#44; although it has not been possible to answer all the questions raised directly in this SLR&#44; we are convinced that the outcomes&#44; conclusions and recommendations in this document may make a positive contribution to better knowledge of the use of synthetic DMARD in RA&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Financing</span><p id="par0160" class="elsevierStylePara elsevierViewall">The NEXUS Project was financed by <span class="elsevierStyleGrantSponsor" id="gs1">Roche</span> which did not participate in the choice of subjects&#44; or development of review&#44; conclusions or recommendations&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflict of interests</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors have no conflict of interests to declare&#46;</p></span></span>"
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              "titulo" => "Question 1&#46; In patients with early RA is combined therapy with synthetic DMARD better than sequential therapy with synthetic DMARD&#63;"
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            1 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Question 2&#46; In patients with established RA who are refractory to standard first line treatment &#40;synthetic DMARD&#41;&#44; is the combination of MTX &#43; LEF or the triple therapy of synthetic DMARD effective and safe&#63;"
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    "fechaRecibido" => "2018-04-11"
    "fechaAceptado" => "2018-07-19"
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          "clase" => "keyword"
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          "identificador" => "xpalclavsec1262801"
          "palabras" => array:4 [
            0 => "Rheumatoid arthritis"
            1 => "Disease-modifying antirheumatic drugs"
            2 => "Combined therapy"
            3 => "Systematic literature review"
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            0 => "Artritis reumatoide"
            1 => "F&#225;rmacos modificadores de la enfermedad"
            2 => "Terapia combinada"
            3 => "Revisi&#243;n sistem&#225;tica de la literatura"
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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">&#40;1&#41; To systematically and critically review the evidence of combined therapy with synthetic disease-modifying antirheumatic drugs &#40;DMARDs&#41; in rheumatoid arthritis &#40;RA&#41; and &#40;2&#41; to design practical recommendations on their use&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A systematic literature review &#40;SLR&#41; was performed with a sensitive bibliographic search strategy in Medline&#44; EMBASE and Cochrane Library&#46; We selected randomised clinical trials that analysed the efficacy and&#47;or safety of &#40;1&#41; combined therapy of synthetic compared with sequential therapy of synthetic DMARD in early RA and &#40;2&#41; combination of methotrexate<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>leflunomide or triple therapy with synthetic DMARD in established RA refractory to synthetic DMARD&#46; Two reviewers made the first selection by title and abstract and 11 performed the selection after detailed review of the articles and data collection&#46; The quality of the studies was evaluated with the Jadad scale&#46; Based on the results&#44; related recommendations were agreed upon in a nominal group meeting&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Ultimately&#44; no articles were included in the SLR&#46; The analysis of the reviewed articles demonstrated the effectiveness of the treatment with synthetic DMARD following a &#8220;treat to target&#8221; strategy in early RA patients&#44; and of combination therapy of synthetic DMARD in established RA refractory to synthetic DMARD&#46; This resulted in 6 recommendations concerning combination therapy with synthetic DMARD&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">These recommendations aim to facilitate decision-making with the use of combined therapy with DMARD in RA&#46;</p></span>"
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          0 => array:2 [
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">1&#41; Revisar sistem&#225;tica y cr&#237;ticamente la evidencia sobre eficacia y seguridad de la terapia combinada con f&#225;rmacos modificadores de la enfermedad &#40;FAME&#41; sint&#233;ticos en la artritis reumatoide &#40;AR&#41;&#59; 2&#41; Emitir recomendaciones pr&#225;cticas sobre su uso&#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 realiz&#243; una revisi&#243;n sistem&#225;tica de la literatura con una estrategia de b&#250;squeda bibliogr&#225;fica sensible en Medline&#44; Embase y Cochrane Library&#46; Se seleccionaron ensayos cl&#237;nicos aleatorizados que analizasen la eficacia y&#47;o seguridad de 1&#41; la terapia combinada con FAME sint&#233;ticos comparada con la terapia secuencial con FAME sint&#233;tico en la AR de inicio&#59; y 2&#41; la combinaci&#243;n metotrexato<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>leflunomida o la triple terapia de FAME sint&#233;ticos en la AR establecida refractaria a FAME sint&#233;ticos&#46; Dos revisores realizaron la primera selecci&#243;n por t&#237;tulo y abstract y 11 la selecci&#243;n tras lectura en detalle y la recogida de datos&#46; La calidad se evalu&#243; con la escala de Jadad&#46; En una reuni&#243;n de grupo nominal en base sus resultados se consensuaron una serie de recomendaciones&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Finalmente no se incluy&#243; ning&#250;n art&#237;culo en la RSL&#46; Del an&#225;lisis de los art&#237;culos revisados se encontr&#243; la eficacia en las AR de inicio del tratamiento precoz con FAME sint&#233;ticos siguiendo una estrategia &#171;<span class="elsevierStyleItalic">treat to target</span>&#187; y en AR establecidas refractarias a FAME sint&#233;ticos la de la terapia combinada con FAME sint&#233;ticos&#46; Con ello se generaron 5 recomendaciones sobre la terapia combinada con FAME sint&#233;ticos&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Estas recomendaciones pretenden facilitar la toma de decisiones con el uso de la terapia combinada con FAME sint&#233;ticos en la AR&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Calvo Al&#233;n J&#44; P&#233;rez T&#44; Romero Yuste S&#44; Ferraz-Amaro I&#44; Alegre Sancho JJ&#44; Pinto Tasende JA&#44; et al&#46; Eficacia y seguridad de la terapia combinada con f&#225;rmacos modificadores de la enfermedad sint&#233;ticos en la artritis reumatoide&#58; revisi&#243;n sistem&#225;tica de la literatura&#46; Reumatol Clin&#46; 2020&#59;16&#58;324&#8211;332&#46;</p>"
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            "apendice" => "<p id="par0180" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">AE&#58; adverse events&#59; ACR&#58; <span class="elsevierStyleItalic">American College of Rheumatology</span>&#59; RA&#58; rheumatoid arthritis&#59; ETN&#58; etanercept&#59; DMARD&#58; disease-modifying anti-rheumatic drugs&#59; GR&#58; grade of recommendation&#59; HCQ&#58; hydroxychloroquine&#59; iv&#58; intravenous&#59; LEF&#58; leflunomide&#59; mg&#58; milligram&#59; MTX&#58; methotrexate&#59; LE&#58; level of evidence&#59; SSZ&#58; salazopyrin&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Conclusions&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">In early onset RA&#8230;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">An early treatment with a treat-to-target strategy improves the activity&#44; damage&#44; function and quality of life parameters in the short and medium term and maintains them long term &#40;LE 1<span class="elsevierStyleHsp" style=""></span>b&#59; GR B&#41;&nbsp;\t\t\t\t\t\t\n
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                  \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">The addition of LEF is better than MTX as monotherapy for improving activity&#44; function and quality of life in the short to medium term&#44; with no clear differences in AE &#40;number of and severe AE&#41; &#40;LE 1<span class="elsevierStyleHsp" style=""></span>b&#59; GR B&#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">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">The combination of MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ETN appears to be superior to the combination of synthetic DMARD in optimising activity and function in the short term&#44; particularly when the best outcomes are analysed &#40;remission&#44; ACR70&#41; &#40;LE 1<span class="elsevierStyleHsp" style=""></span>b&#59; GR B&#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">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">The superiority of MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LEF compared with MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ o MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ cannot be demonstrated in patients with established RA refractory to MTX&#44; in the short term &#40;LE 1<span class="elsevierStyleHsp" style=""></span>b&#59; GR B&#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">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">The combination of synthetic DMARD is similar to MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RTX &#40;at doses of 500<span class="elsevierStyleHsp" style=""></span>mg iv 2 doses&#41; to improve activity and function in the short to medium term&#44; with no clear differences relating to AE &#40;number of and severe AE&#41; &#40;LE 1<span class="elsevierStyleHsp" style=""></span>b&#59; GR B&#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">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">Triple therapy with MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ improves parameters of activity and radiographic damage &#40;LE 1<span class="elsevierStyleHsp" style=""></span>b&#59; GR B&#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">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">The efficacy of triple therapy with synthetic DMARDs is comparable with the combination of ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX &#40;LE 1<span class="elsevierStyleHsp" style=""></span>b&#59; GR B&#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">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">The AE of triple therapy with MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ are those expected from the use of this type of drug &#40;LE 1<span class="elsevierStyleHsp" style=""></span>b&#59; GR B&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Recommendations</span>&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">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 early RA a treat-to-target strategy is recommended&#44; aimed at achieving remission as soon as possible &#40;LE 1<span class="elsevierStyleHsp" style=""></span>b&#59; GA A&#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">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 established RA refractory to first line treatment with synthetic DMARD the option of using the combination of MTX y LEF is recommended&#44; depending on the clinical context and the clinician&#39;s opinion &#40;LE 1<span class="elsevierStyleHsp" style=""></span>b&#59; GR B&#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">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">If the combination of MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LEF &#40;LE 5&#59; GR D&#41; is prescribed we recommend following the standard risk management guidelines&#46;&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">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">In patients with established RA refractory to first line treatment with synthetic DMARD we recommend bearing in mind the option of using the triple therapy with MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ&#44; depending on the clinical context and clinician&#39;s opinion &#40;LE 1<span class="elsevierStyleHsp" style=""></span>b&#59; GR B&#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">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">Strict risk management is recommended in patients with RA who have been prescribed the triple therapy with MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ &#40;LE 5&#59; GR D&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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></tbody></table>
                  """
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Main conclusions and recommendations of the review&#46;</p>"
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        "etiqueta" => "Table 2"
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Yrs&#46;&#58; years&#59; AE&#58; adverse events&#59; ACR&#58; American College of Rheumatology&#59; RA&#58; rheumatoid arthritis&#59; CDAI&#58; Clinical Disease Activity Index&#59; DAS&#58; Disease Activity Score&#59; durat&#46;&#58; duration&#59; RCT&#58; randomised clinical trial&#59; ETN&#58; etanercept&#59; RF&#58; rheumatoid factor&#59; HAQ&#58; Health Assessment Questionnaire&#59; HCQ&#58; hydroxychloroquine&#59; AMI&#58; acute myocardial infarction&#59; iv&#58; intravenous&#59; LEF&#58; leflunomide&#59; ULN&#58; upper limit of normality&#59; max&#46;&#58; maximum&#59; mg&#58; milligram&#59; MTX&#58; methotrexate&#59; NAD&#58; number of painful joints&#59; ns&#58; not significant&#59; PBO&#58; placebo&#59; CRP&#58; C-reactive protein&#59; RTX&#58; rituximab&#59; week&#46;&#58; week&#59; SF&#58; Short Form&#59; SSZ&#58; salazopyrin&#59; sup&#58; superior&#59; op&#58; oral pathway&#59; ESR&#58; erythrocyte sedimentation rate&#46;</p>"
          "tablatextoimagen" => array:1 [
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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">Study&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">Population&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">Intervention&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">Efficacy&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">Safety&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">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">Fleischmann&#95;2014 &#40;aggregated data APPEAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Latin RA&#41;&#44; durat&#46; 16 week&#46;&#44; Jadad 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">-Group ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>478&#41;&#58; 89&#37; women&#44; mean age 48 yrs&#46;&#44; DAS28 mean 6&#46;4&#44; durat&#46; RA 7 yrs&#46;-Group HCQ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>81&#41;&#58; 86&#37; women&#44; mean age 49 yrs&#46;&#44; DAS28 mean 6&#46;6&#44; durat&#46; RA 8 yrs&#46;-Group SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>95&#41;&#58; 91&#37; women&#44; mean age 47 yrs&#46;&#44; DAS28 mean 6&#46;6&#44; durat&#46; RA 7 yrs&#46;-Group LEF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>69&#41;&#58; 89&#37; women&#44; mean age 49 yrs&#46;&#44; DAS28 mean 6&#46;2&#44; durat&#46; RA 8 yrs&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Group ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX-Group HCQ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX-Group SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX-Group LEF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&#37; patients with ACR20Group ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>82&#37;Group HCQ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>59&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>54&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group LEF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>62&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;-&#37; patients with ACR50Group ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>56&#37;Group HCQ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>31&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group LEF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>38&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;-&#37; patients with ACR70Group ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24&#37;Group HCQ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>12&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;01 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group LEF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;-&#37; patients with low activity DAS28Group ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>39&#37;Group HCQ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;01 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>14&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;01 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group LEF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;01 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;-&#37; patients with remission DAS28Group ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>18&#37;Group HCQ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;01 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group LEF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#37; &#40;<span class="elsevierStyleItalic">P</span> not shown&#41;-&#37; patients with low activity CDAIGroup ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>54&#37;Group HCQ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>30&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;01 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05 vs SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>18&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group LEF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>42&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;-&#37; patients with remission CDAIGroup ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#37;Group HCQ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#37;Group SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#37;Group LEF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#37; &#40;<span class="elsevierStyleItalic">P</span> not shown&#41;-&#916; DAS28&#58;Group ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;2&#46;7Group HCQ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;2&#46;0 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;1&#46;5 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group LEF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;1&#46;8 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;-&#916; CDAI&#58;Group ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;26&#46;7Group HCQ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;21&#46;1 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;17&#46;4 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group LEF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;17&#46;7 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;-&#916; HAQ&#58;Group ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;&#46;77Group HCQ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;&#46;47 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;&#46;48 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#41;Group LEF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;&#46;58 &#40;<span class="elsevierStyleItalic">P</span> not shown&#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">-Not analysed&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">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">Kremer&#95;2002&#44; RCT double blind&#44; active control&#44; durat&#46; 24 week&#46;&#44; multicentre&#44; international&#44; Jadad 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">-Group LFN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>130&#41;&#58; 76&#37; women&#44; mean age 55 yrs&#46;&#44; durat&#46; RA 10 yrs&#46;-Group MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PBO &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>133&#41;&#58; 76&#37; women&#44; mean age 55 yrs&#46;&#44; durat&#46; RA 10 yrs&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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 &#40;15&#8211;20<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#46; or 10&#8211;15<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#46;&#44; if max&#46; dose tolerated&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB-MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LFN 100<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; 2 days &#8594; LFN 10<span class="elsevierStyleHsp" style=""></span>mg&#47;day &#40;if activity&#44; &#8593; dose to 20<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;-Prednisone 10<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&#37; patients with ACR20MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LFN 46&#46;2&#37; vs MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB 19&#46;5&#37;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001-&#37; patients with ACR50MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LFN 26&#46;2&#37; vs MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB 6&#37;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001-&#37; patients with ACR70MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LFN 10&#37; vs MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PBO 2&#46;3&#37;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;015-&#916; HAQMTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LFN &#8722;&#46;42 vs MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB &#8722;&#46;09&#44; difference<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;&#46;33 &#40;95&#37; CI &#8722;&#46;44&#44; &#8722;&#46;21&#41;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001-&#916; SF-36 Physical componentMTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LFN 6&#46;8 vs MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB &#46;3&#44; difference<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#46;5 &#40;95&#37; CI 3&#46;9&#44; 8&#46;7&#41;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001-&#916; SF-36 mental componentMTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LFN<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;0 vs MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB 1&#46;2 &#40;ns&#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">-DiarrhoeaMTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LFN<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25&#46;4&#37;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>13&#46;5&#37;-Upper respira&#46; tract infect&#46;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LFN<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>22&#46;3&#37;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24&#46;1&#37;-NauseaMTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LFN<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16&#46;2&#37;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>11&#46;3&#37;-HeadacheMTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LFN<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#46;0&#37;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#46;3&#37;-RashMTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LFN<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#46;7&#37;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#46;3&#37;-DizzinessMTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LFN<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#46;7&#37;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#46;3&#37;-InfectionsMTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LFN<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>40&#46;8&#37;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>51&#46;9&#37;-ALT<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>3 ULNLFN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX 3&#46;8&#37;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB &#46;8&#37;-AST<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>3 ULNLFN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX 1&#46;5&#37;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB &#46;8&#37;&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">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">Wijesinghe&#95;2017&#44; RCT&#44; double blind&#44; active control&#44; durat&#46; 24 week&#46;&#44; multicentre&#44; national&#44; Jadad 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">-RTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#41;&#58; 80&#37; women&#44; mean age 44 yrs&#46;&#44; DAS28 mean 6&#46;88&#44; durat&#46; RA 5 yrs&#46;-LFN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>19&#41;&#58; 95&#37; women&#44; mean age 48 yrs&#46;&#44; DAS28 mean 6&#46;43&#44; durat&#46; RA 18 yrs&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-RTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#58;RTX 500<span class="elsevierStyleHsp" style=""></span>mg iv days 0 and 14 months<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX-LEF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#58; LFN 10<span class="elsevierStyleHsp" style=""></span>mg&#47;day op &#40;up to 20<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX-All corticosteroids-NSAID and analgesics permitted&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-RTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX vs LFN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTXACR20&#58; 85&#37; vs 84&#37; &#40;ns&#41;ACR50&#58; 60&#37; vs 64&#37; &#40;ns&#41;ACR70&#58; 35&#37; vs 32&#37; &#40;ns&#41;No response ACR&#58; 15&#37; vs 16&#37; &#40;ns&#41;DAS28&#58; 3&#46;26 vs 3&#46;25 &#40;ns&#41;DAS remission &#40;&#60;2&#46;6&#41;&#58; 20&#37; vs 26&#37; &#40;ns&#41;DAS low activity &#40;&#60;3&#46;2&#41;&#58; 40&#37; vs 42&#37; &#40;ns&#41;DAS moderate activity &#40;3&#46;2&#8211;51&#41;&#58; 60&#37; vs 58&#37; &#40;ns&#41;DAS high activity &#40;&#62;5&#46;1&#41;&#58; 0&#37; vs 0&#37;Moderate EULAR response 60&#37; vs 58&#37; &#40;ns&#41;Good EULAR response&#58; 40&#37; vs 42&#37; &#40;ns&#41;NAD&#58; 1&#46;8 vs 1&#46;16 &#40;ns&#41;CRP&#58; 6 vs 3 &#40;ns&#41;ESR&#58; 28&#46;05 vs 30&#46;42 &#40;ns&#41;RF&#58; 84 vs 60 &#40;ns&#41;HAQ&#58; 2&#46;872 vs 2&#46;132 &#40;ns&#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">-RTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTXSevere AE <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5Infections <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4Unstable angina <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1Deaths <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0-LFN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTXSevere AE <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3Infections <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1Cardiac events <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2Death <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Main characteristics and outcomes of the studies included with combined therapy of MTX and LEF&#46;</p>"
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        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Yrs&#46;&#58; years&#59; AE&#58; adverse events&#59; ACR&#58; American College of Rheumatology&#59; NSAID&#58; non steroidal anti-inflammatory drugs&#59; RA&#58; rheumatoid arthritis&#59; IC&#58; inclusion criteria&#59; CDAI&#58; Clinical Disease Activity Index&#59; Durat&#46;&#58; duration&#59; DAS&#58; Disease Activity Score&#59; durat&#46;&#58; duration&#59; DAS&#58; Disease Activity Score&#59; RCT&#58; randomised clinical trial&#59; ETN&#58; etanercept&#59; g&#58; gram&#59; gastroint&#58; gastrointestinal&#59; HAQ&#58; Health Assessment Questionnaire&#59; HCQ&#58; hydroxychloroquine&#59; ULN&#58; upper limit of normality&#59; mg&#58; milligram&#59; min&#58; minutes&#44; MTX&#58; methotrexate&#59; NAD&#58; number of painful joints&#59; NSJ&#59; number of swollen joints&#59; ns&#58; not significant&#59; week&#46;&#58; week&#59; MS&#58; morning stiffness&#59; SSZ&#58; salazopyrin&#59; ESR&#58; erythrocyte sedimentation rate&#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="" 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">Study&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">Population&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">Intervention&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">Efficacy&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">Safety&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">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">O&#8217;Dell&#95;1996&#44; RCT&#44; double blind&#44; durat&#46; 2 yrs&#46;&#44; multicentre national&#44; Jadad 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">-MTX &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>36&#41;&#44; 58&#37; women&#44; mean age 50 yrs&#46;&#44; durat&#46; mean RA 10 yrs&#46;&#44; mean 1&#46;6 previous DMARD-SZZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>35&#41;&#44; 72&#37; women&#44; mean age 49 yrs&#46;&#44; durat&#46; mean RA 6 yrs&#46;-MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>31&#41;&#44; 65&#37; women&#44; mean age 50 yrs&#46;&#44; durat&#46; mean RA 10 yrs&#46;&#44; mean 16 previous DMARD-CI&#58; MTX 15&#8211;25<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#46; &#8805;12 week&#46; Previous and DAS28 &#8805;4&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-MTX 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#46;-SSZ 500<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ 400<span class="elsevierStyleHsp" style=""></span>mg&#47;day-MTX MTX 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#46;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ 500<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ 400<span class="elsevierStyleHsp" style=""></span>mg&#47;day-If no remission at 3 months &#8593; MTX 12&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#46; &#8594; if no remission at 6 months &#8593; MTX a 17&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#46;-Prednisone stable &#40;&#8804;10<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41; and permitted NSAIDs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-ESRMTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16 &#40;ns vs triple therapy&#41;SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ 16 &#40;ns vs triple therapy&#41;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ 10-NPJMTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7 &#40;ns vs triple therapy&#41;SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;016 vs triple therapy&#41;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3-NSJMTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;006 vs triple therapy&#41;SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs triple therapy&#41;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2-MS &#40;min&#41;MTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>63 &#40;ns vs triple therapy&#41;SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50 &#40;ns vs triple therapy&#41;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>38-OPAMTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;020 vs triple therapy&#41;SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3 &#40;ns vs triple therapy&#41;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2-PGAMTX<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;002 vs triple therapy&#41;SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 vs triple therapy&#41;MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-no major differences between groups-MTX <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7 discontinuations &#40;2 pneumonia&#44; 1 stomatitis&#44; 1 diarrhoea&#44; 1 nauseas&#44; 1 vertigo&#44; 1 sepsis-death&#41;-SZS<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3 discontinuations &#40;1 pneumonia&#44; 1 diarrhoea&#44;1 Crohn&#41;-MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3 discontinuations &#40;1 nausea&#44; 1 cervical cancer&#44; 1 weight gain&#41;-<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0 &#8593; GOT &#8805;2 ULN&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">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">O&#8217;Dell&#95;2013&#44; RCT&#44; no inferiority&#44; double blind&#44; durat&#46; 48 week&#46;&#44; multicentre national &#40;RACAT study&#41;&#44; Jadad 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">-MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>178&#41;&#44; 77&#37; women&#44; mean age 58 yrs&#46;&#44; durat&#46; mean RA 5 yrs&#46;&#44; DAS28 mean 5&#46;8-ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>175&#41;&#44; 85&#37; women&#44; mean age 56 yrs&#46;&#44; durat&#46; mean RA 4 yrs&#46;&#44; DAS28 mean 5&#46;9&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">-MTX &#40;their regular dose&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ 1<span class="elsevierStyleHsp" style=""></span>g&#47;day 6 week&#46;<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>g&#47;day<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ 400<span class="elsevierStyleHsp" style=""></span>mg&#47;day-ETN 50<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#46;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX &#40;their regular dose&#41;-If DAS28<span class="elsevierStyleHsp" style=""></span>&#8595;<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>1&#46;2 to 24 week&#46; change to different regimen-SZZ could &#8595; to 1<span class="elsevierStyleHsp" style=""></span>g&#47;day if AE-Prednisone stable &#40;&#8804;10<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41; and permitted NSAIDs&nbsp;\t\t\t\t\t\t\n
                  \t\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">-MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX &#40;48 week&#46;&#41;&#916; DAS28 &#8722;2&#46;12 vs &#8722;2&#46;29 &#40;ns&#41;&#916; HAQ &#8722;&#46;46 vs &#8722;&#46;64 &#40;ns&#41;&#916; Modified Sharp score &#46;54 vs 29 &#40;ns&#41;&#916; CDAI &#8722;20&#46;93 vs &#8722;21&#46;56 &#40;ns&#41;DAS28 &#8804;3&#46;2 37&#37; vs 41&#46;9&#37; &#40;ns&#41;DAS28 &#8804;2&#46;6 20&#46;8&#37; vs 25&#46;2&#37; &#40;ns&#41;ACR20 57&#46;4&#37; vs 65&#46;8&#37; &#40;ns&#41;ACR50 35&#46;5&#37; vs 42&#46;6&#37; &#40;ns&#41;ACR70 18&#46;1&#37; vs 26&#46;5&#37; &#40;ns&#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">-MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ76&#46;6&#37; any AE11&#46;3&#37; severe AE29&#46;7&#37; gastroint disorder25&#46;2&#37; infections-ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX75&#46;3&#37; any AE11&#46;9&#37; severe AE21&#46;5&#37; gastroint disorder37&#46;4&#37; infections&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">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
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                  \t\t\t\t">Peper&#95;2017&#44; open extension of the RACAT study&#44; durat&#46; 72 weeks&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\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">-MTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>145&#41;&#44; 39&#37; women&#44; mean age 59 yrs&#46;&#44; durat&#46; mean RA 6 yrs&#46;&#44; DAS28 mean 3&#46;8-ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>144&#41;&#44; 47&#37; women&#44; mean age 56 yrs&#46;&#44; durat&#46; mean RA 5 yrs&#46;&#44; DAS28 mean 3&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">-MTX &#40;their regular dose&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ 1<span class="elsevierStyleHsp" style=""></span>g&#47;day 6 week&#46;<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>g&#47;day<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ 400<span class="elsevierStyleHsp" style=""></span>mg&#47;day-ETN 50<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#46;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX &#40;their regular dose&#41;-Si DAS28 &#8595; &#60;1&#46;2 to 24 weeks&#46; Change to another regimen-SZZ could &#8595; to 1<span class="elsevierStyleHsp" style=""></span>g&#47;day if AE-Prednisone stable &#40;&#8804;10<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41; and permitted NSAIDs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ vs ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX&#916; DAS28 &#8722;3&#46;03 &#40;ns&#41;NPJ&#44; NSJ&#44; OPA&#44; ESR &#40;ns&#41;Adherence at one year 63&#37; vs 78&#37;Regimen changes greater from triple therapy to ETN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;005&#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">-Not assessed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                      "titulo" => "EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs&#58; 2016 update"
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                          "etal" => true
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                            3 => "P&#46;M&#46; Ten Klooster"
                            4 => "A&#46;E&#46; van der Bijl"
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                            3 => "D&#46; Viecceli"
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