Recommendations for the use of methotrexate in patients with juvenile idiopathic arthritis

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Calvo, J. Antón, J.C. López Robledillo, J. de Inocencio, M.L. Gamir, R. Merino, L. Lacruz, M. Camacho, M.J. Rua, S. Bustabad, G. Díaz Cordovés-Rego" "autores" => array:11 [ 0 => array:4 [ "nombre" => "I." "apellidos" => "Calvo" "email" => array:2 [ 0 => "calvo_inm@gva.es" 1 => "inmaculadacalvopenades@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "J." "apellidos" => "Antón" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "J.C." "apellidos" => "López Robledillo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "J." "apellidos" => "de Inocencio" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 4 => array:3 [ "nombre" => "M.L." 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"apellidos" => "Díaz Cordovés-Rego" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "k" "identificador" => "aff0055" ] ] ] ] "afiliaciones" => array:11 [ 0 => array:3 [ "entidad" => "Hospital Universitario y Politécnico La Fe, Valencia, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues de Llobregat, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Hospital Infantil Universitario Niño Jesús, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Hospital Universitario 12 de Octubre, Madrid, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Hospital Universitario Ramón y Cajal, Madrid, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Hospital Universitario La Paz, Madrid, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Hospital Son Espases, Palma de Mallorca, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "Hospital Universitario Virgen del Rocío, Sevilla, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] 8 => array:3 [ "entidad" => "Hospital Universitario Cruces, San Vicente de Barakaldo, Spain" "etiqueta" => "i" "identificador" => "aff0045" ] 9 => array:3 [ "entidad" => "Hospital Universitario de Canarias, San Cristóbal de La Laguna , Santa Cruz de Tenerife, Spain" "etiqueta" => "j" "identificador" => "aff0050" ] 10 => array:3 [ "entidad" => "Hospital Materno Infantil del Hospital Regional Universitario de Málaga, Málaga, Spain" "etiqueta" => "k" "identificador" => "aff0055" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Recomendaciones para el uso de metotrexato en pacientes con artritis idiopática juvenil" ] ] "textoCompleto" => "IntroductionJuvenile idiopathic arthritis (JIA) is an inflammatory arthropathy that comprehends 7 subtypes based on the classification of the International League of Association for Rheumatology (ILAR).<a class="elsevierStyleCrossRef" href="#bib0205">1</a> These subtypes differ in their pathophysiology, clinical features, and treatment.Juvenile idiopathic arthritis is a chronic disease that impairs the functional capacity and quality of life of affected individuals, and thus it is important that it be diagnosed and treated early.The pharmacological treatment of JIA depends on the subtype and severity of the disease, with frequent use of disease-modifying antirheumatic drugs (DMARDs) as monotherapy or in combination with oral and intra-articular non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids (GCs). Early introduction of DMARDs—methotrexate (MTX) being one of them—may help prevent disease progression.The use of MTX in patients with JIA is recommended due to its proven efficacy and safety profile.<a class="elsevierStyleCrossRef" href="#bib0210">2</a> However, despite being the DMARD most frequently used for JIA<a class="elsevierStyleCrossRef" href="#bib0215">3</a> and having been available for many years, certain points pertaining to its management in clinical practice are still in question. Thus, the aim of this study was to establish consensus-based clinical and therapeutic recommendations for the management of MTX in patients with JIA.MethodsWe set up a guideline-developing group (GDG) consisting of three coordinators and eight specialists in paediatric rheumatology, all members of the Sociedad Española de Reumatología Pediátrica (Spanish Society of Paediatric Rheumatology [SERPE]). The GDG formulated the clinical questions pertaining to MTX management applying the PICO framework (patient, intervention, control and outcome).Strategy for literature search and selectionWe carried out a systematic search in Medline and the Cochrane Library for human studies published in English or Spanish in the past 15 years for which an abstract was available. The keywords used in the search were “idiopathic juvenile arthritis”, “methotrexate”, “routes of administration”, “dosage”, “tapering”, “discontinuation” and other, more specific terms based on each particular clinical question. Finally, we completed the search with articles provided directly by the GDG and the summaries of product characteristics for methotrexate.Of the resulting list of publications, we selected review articles, consensus documents, guidelines by scientific associations and articles that explicitly addressed specific aspects of the proposed questions, and proceeded to summarise the evidence.Consensus processWe used the nominal group technique. The experts discussed the contents of the evidence summary in a structured fashion during a work session. Based on the conclusions reached at the session, we drafted a document with the agreed-on recommendations and determined the level of evidence (LE) and grade of recommendation (GR) for each of them, either adhering to the system employed in the source (if any had been used) or applying the grading system of the Scottish Intercollegiate Guidelines Network (SIGN).<a class="elsevierStyleCrossRef" href="#bib0220">4</a> Lastly, the resulting document was presented to the group of experts for a final review.ResultsLiterature searchWe obtained 344 references in the literature search. Through a subsequent screening, we selected 67 articles, 6 clinical practice guidelines and 9 summaries of product characteristics for critical reading. After evaluation by the GDG members and the implementation of the structured and participatory consensus methodology, we validated sixteen recommendations (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Initiation of methotrexate treatmentEfficacy of methotrexate in juvenile idiopathic arthritisMost clinical trials and prospective cohort studies demonstrate that MTX is efficacious for the treatment of active JIA.<a class="elsevierStyleCrossRefs" href="#bib0240">8–13</a>Several studies have demonstrated the impact of MTX on the quality of life of patients with JIA, regardless of the dose used. Depending on the form and severity of the disease, MTX treatment is administered in combination with local and/or systemic NSAIDs and GCs or even with biologics.<a class="elsevierStyleCrossRefs" href="#bib0245">9,12–14</a> Given the extensive experience with the use of MTX for JIA, MTX is considered the first-line DMARD and is the mainstay of long-term therapy in these patients.<a class="elsevierStyleCrossRef" href="#bib0210">2</a><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">•Recommendation 1: MTX is recommended as the first-line treatment for remission induction in JIA due to its proven efficacy and safety profile<a class="elsevierStyleCrossRef" href="#bib0210">2</a> (IA; Feldman<a class="elsevierStyleCrossRef" href="#bib0225">5</a>).</li></ul>Indication for methotrexateSeveral international publications have established recommendations for the use of MTX,<a class="elsevierStyleCrossRefs" href="#bib0205">1,7,8</a> based on which we developed our own recommendations. We found variability in the criteria applied to certain aspects, consistent with the variability that exists in everyday clinical practice. Thus, we agreed on a set of minimum criteria that would allow for a uniform decision-making process as pertains to the indication of MTX (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010">•Recommendation 2: MTX will be indicated based on the clinical classification of JIA as presented in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> (4D√; SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a>).</li></ul><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Evaluation of the patient prior to receiving methotrexateIf MTX is indicated, the clinical evaluation of patients with JIA must include at least certain diagnostic tests and other parameters depending on the risk factors.<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0015">•Recommendation 3: prior to initiation of treatment with MTX, performance of a complete blood count, differential blood count, liver enzyme level and serum creatinine<a class="elsevierStyleCrossRef" href="#bib0235">7</a> tests is recommended (D; Oxford<a class="elsevierStyleCrossRef" href="#bib0230">6</a>).</li><li class="elsevierStyleListItem" id="lsti0020">•Recommendation 4: depending on the existing risk factors, the patient's condition and previous diagnostic tests, testing for acute phase reactants (ESR-CRP) and hepatitis B and C serology (HBV and HCV) will be considered. In female adolescents, a potential pregnancy should be ruled out by means of an appropriate test. Confirmation of a negative Mantoux skin test in the past six months is recommended (4D√; SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a>).</li></ul>Initial dose and maximum doseA study by Giannini et al.<a class="elsevierStyleCrossRef" href="#bib0280">16</a> showed that an initial MTX dose of 5mg/m2 is no more efficient than placebo. A study conducted by PRINTO<a class="elsevierStyleCrossRef" href="#bib0250">10</a> showed that patients with polyarticular JIA responded to MTX within nine months of starting treatment at standard doses of 8–12.5mg/m2 (administered by the oral, subcutaneous and intramuscular routes). Thus, we have determined the following:<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0025">•Recommendation 5: the following doses are recommended<a class="elsevierStyleCrossRef" href="#bib0240">8</a>: initial dose, 10–15mg/m2/week; maximum total dose: 25mg/week (IA; Niehues<a class="elsevierStyleCrossRef" href="#bib0240">8</a>).</li></ul>While additional randomised controlled trials are needed, several studies suggest that MTX is useful for the treatment of chronic uveitis in patients with JIA, preventing its onset,<a class="elsevierStyleCrossRef" href="#bib0285">17</a> and improving disease activity in a significant percentage of patients.<a class="elsevierStyleCrossRef" href="#bib0290">18</a> Thus, we agreed on the following initial dose:<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0030">•Recommendation 6: in patients with uveitis or polyarthritis, an initial dose of 15mg/m2/week is recommended (4D; SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a>).</li></ul>Route of administrationThe study of Niehues et al.<a class="elsevierStyleCrossRef" href="#bib0240">8</a> reviews several studies<a class="elsevierStyleCrossRefs" href="#bib0295">19–22</a> on the bioavailability of MTX. The conclusion is that for doses of up to 15mg/m2/week, the bioavailability after parenteral and oral administration is similar; at higher doses (≥15mg/m2/week) parenteral administration is recommended for its higher bioavailability and tolerability.<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0035">•Recommendation 7: for doses ≥15mg/m2/week, parenteral administration is recommended due to a higher bioavailability and tolerability<a class="elsevierStyleCrossRef" href="#bib0240">8</a> (IIIC; Niehues<a class="elsevierStyleCrossRef" href="#bib0240">8</a>).</li></ul>The criteria for making decisions regarding the initial dose and route of administration are variable and subject to the preferences of the patient and/or family members and the required doses.<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0040">•Recommendation 8: for initial doses of 10mg/m2/week, a choice will be made between oral or subcutaneous administration, deciding on whichever is most suitable based on the circumstances of the patient (4D√; SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a>).</li></ul>Tapering and discontinuation of methotrexateWe did not find sufficient evidence to make a recommendation. However, the data of a clinical trial<a class="elsevierStyleCrossRef" href="#bib0315">23</a> show similar results whether MTX is discontinued six or twelve months after achieving remission. Thus, in principle, MTX could be discontinued six months after achieving remission.The panel of experts found a wide variability in the tapering off and discontinuation of MTX doses in everyday clinical practice: from withdrawal of treatment to tapering down in steps of 2.5mg in each visit (every 6–8 weeks). Other strategies consisted of increasing the interval between doses without changing the dose itself; that is, for example, giving the same dose every 15 days as opposed to every week, and so on, until discontinuation.In gradual tapering schemes, it is acceptable to choose to switch to oral administration once a dose of 10mg is reached, applying the previously noted criteria regarding the route of administration.Safety of methotrexateBased on the review of the summaries of product characteristics, the most significant adverse effects of MTX involve the suppression of the haematopoietic system and gastrointestinal disorders. Specifically, the most frequent adverse reactions (≥1/10) are gastrointestinal (stomatitis, dyspepsia, nausea and loss of appetite) and hepatobiliary (elevated transaminases); with less frequent effects (≥1/100, <1/10) including involvement of the gastrointestinal tract (mouth ulcers and diarrhoea), cutaneous and subcutaneous tissues (exanthema, erythema and pruritus), nervous system (headache, fatigue and sleepiness), respiratory system, thorax and mediastinum (pneumonia and interstitial alveolitis/pneumonitis, often associated with eosinophilia) and the blood and lymphatic system (leukopenia, anaemia and thrombocytopenia). Hair loss, while being rare (≥1/1000, <1/100), is usually a source of concern for the families.<a class="elsevierStyleCrossRef" href="#bib0320">24</a>The development and degree of severity of adverse reactions depend on the dose and frequency of administration. Since severe adverse reactions may occur even at the lowest doses, it is imperative that physicians monitor these patients at regular intervals (every 3–4 months).We recommend the subcutaneous administration of MTX, as it is well tolerated at the site of injection. Only mild local skin reactions have been observed, and these diminish over the course of treatment. Intramuscular administration has led to reports of local adverse reactions (burning feeling) or lesions (formation of sterile abscesses or destruction of fatty tissues) at the site of administration.<a class="elsevierStyleCrossRef" href="#bib0320">24</a>The contraindications for MTX need also be considered<a class="elsevierStyleCrossRef" href="#bib0320">24</a>: hypersensitivity to MTX or any of the excipients; liver failure, alcohol abuse, or kidney failure; pre-existing blood dyscrasias such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anaemia; severe acute or chronic infection, such as tuberculosis or HIV infection; mouth ulcers or known active gastrointestinal ulcerative disease; pregnancy and breastfeeding; and concurrent vaccination with live or live-attenuated vaccines, although the evidence-based recommendations of a panel of experts of the EULAR<a class="elsevierStyleCrossRef" href="#bib0325">25</a> recommend the live-attenuated vaccine if the dose used is less than 15mg/m2.Followup and monitoring of patients undergoing treatment with methotrexateA study by Ortiz-Álvarez et al.<a class="elsevierStyleCrossRef" href="#bib0330">26</a> assessed the utility of the ACR guidelines for monitoring patients with JIA, and estimated a probability of 11% for having significantly abnormal blood tests at three months, compared to 10% probability of having an abnormal test by chance alone. Consequently, they deemed that periodical routine blood tests were unnecessary. The conclusions of a different study<a class="elsevierStyleCrossRef" href="#bib0335">27</a> suggested that the adult standard of surveillance laboratory testing every four to eight weeks might not be necessary in children treated with MTX, especially if certain risk factors are absent. Other studies suggest the need to monitor for potential and usually reversible liver function test abnormalities, especially if the dose needs to be increased or large doses of MTX are required.<a class="elsevierStyleCrossRef" href="#bib0340">28</a> There seems to be no question that testing should be performed to confirm normal levels one month after initiation of MTX treatment.<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0045">•Recommendation 9: it is recommended that laboratory testing of baseline parameters is repeated one month after initiating MTX or one to two months after any dose increases (2+D√; SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a>).</li><li class="elsevierStyleListItem" id="lsti0050">•Recommendation 10: in patients receiving stable doses and with no previous test abnormalities, surveillance laboratory testing is recommended every 3–4 months (4D; SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a>).</li></ul>Hashkes et al.<a class="elsevierStyleCrossRef" href="#bib0345">29</a> analysed the relationship between hepatotoxic risk factors and liver histology in patients with JIA treated with MTX. They found that biochemical abnormalities were associated with liver damage based on the Roenigk classification and the presence of liver fibrosis, which concurred with studies of patients with rheumatoid arthritis (RA). This suggests that the guidelines for monitoring MTX hepatotoxicity in AR may be applicable to JIA. These data along with further evidence extrapolated from adults with RA<a class="elsevierStyleCrossRefs" href="#bib0335">27–30</a> justified the recommendations of the ACR<a class="elsevierStyleCrossRef" href="#bib0235">7</a>:<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0055">•Recommendation 11: in response to liver enzyme elevation between 1 and 2 times the upper limit of normal, either no specific action or rechecking liver enzymes at a shorter interval until the levels normalise is recommended<a class="elsevierStyleCrossRef" href="#bib0235">7</a> (C; Oxford<a class="elsevierStyleCrossRef" href="#bib0230">6</a>).</li><li class="elsevierStyleListItem" id="lsti0060">•Recommendation 12: in response to liver enzyme elevation more than twice the upper limit of normal, decreasing the dose of methotrexate or temporarily withholding methotrexate administration is recommended<a class="elsevierStyleCrossRef" href="#bib0235">7</a> (C; Oxford<a class="elsevierStyleCrossRef" href="#bib0230">6</a>).</li><li class="elsevierStyleListItem" id="lsti0065">•Recommendation 13: if liver enzymes remain at levels more than 3 times the upper limit of normal following a decrease in the methotrexate dose, discontinuation of methotrexate is recommended<a class="elsevierStyleCrossRef" href="#bib0235">7</a> (C; Oxford<a class="elsevierStyleCrossRef" href="#bib0230">6</a>).</li></ul>Other possible causes of elevated liver enzymes unrelated to the administration of MTX must be investigated, and tapering off can be considered if these levels are abnormal or elevated.Combination therapyMore evidence is needed to establish the indications for combination therapy with MTX, be it with conventional or biologic DMARDs, in order to simplify decision-making.The recommendations of the ACR<a class="elsevierStyleCrossRef" href="#bib0235">7</a> propose the addition of a TNFα inhibitor for patients receiving MTX as monotherapy and with persistent JIA activity, recommending that treatment with MTX be continued or not depending on the patient's previous response to it. Other authors recommend exhausting the time frame to observe the response to MTX therapy and achieve the maximum effective doses of MTX by the parenteral route before considering initiation of combination therapies.<a class="elsevierStyleCrossRefs" href="#bib0355">31,32</a>In recent years, several studies have demonstrated that in some patients clinical worsening and a diminished response to treatment with certain TNF inhibitors is associated with the development of anti-drug antibodies.<a class="elsevierStyleCrossRefs" href="#bib0365">33,34</a> On the other hand, other studies have shown how the concomitant use of MTX reduces the immunogenicity of these drugs.<a class="elsevierStyleCrossRefs" href="#bib0375">35,36</a> For all of the above, we recommend considering the use of MTX in patients treated with biologic agents to improve the response and/or reduce the development of antibodies to certain biologics.<ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0070">•Recommendation 14: we recommend considering the use of MTX in patients treated with biologic agents to improve the response and/or reduce the development of antibodies to certain biologics (4D; SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a>).</li></ul>Supplementary use of folic or folinic acidMethotrexate reduces inflammation by a mechanism related to the metabolism of folic acid. The prescription of folic or folinic acid can improve the tolerability and safety of MTX (mouth ulcers, gastrointestinal complaints, diarrhoea, haematologic changes, elevation of transaminases, etc.). Folic or folinic acid is given at least one day apart from the administration of MTX.<a class="elsevierStyleCrossRefs" href="#bib0240">8,12</a>Some expert-consensus guidelines state the need of supplementing MTX treatment with folic acid.<a class="elsevierStyleCrossRef" href="#bib0385">37</a><ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0075">•Recommendation 15: to prevent side effects such as dyspepsia and nausea, the use of either folic or folinic acid is recommended as an adjuvant to MTX therapy. Folic or folinic acid will be given in tablet form in doses of 5mg/week at least one day apart from the administration of MTX or, alternatively, in doses of 1mg/day, skipping the day that MTX is administered (LE, 4; GR, D; SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a>).</li></ul>DiscussionThere have been advances in the knowledge of JIA in recent years, both in criteria regarding its classification, clinical improvement, remission and inactive disease, and in tools used to measure disease activity (JADAS)<a class="elsevierStyleCrossRef" href="#bib0390">38</a> and quality of life (JAMAR<a class="elsevierStyleCrossRef" href="#bib0395">39</a> and CHAQ<a class="elsevierStyleCrossRef" href="#bib0400">40</a>). This has made the follow-up of patients with JIA easier.Although at present MTX is considered the most effective nonbiologic agent for induction remission in patients with JIA, there is great variability in the management of this drug in clinical practice. This called for the development of a consensus by a group of experts in paediatric rheumatology involved in the management of patients with JIA treated with MTX. Their contributions have resulted in a set of recommendations that will make it possible to improve the pattern of use of MTX for the treatment of children and adolescents with JIA by the integration of scientific evidence and clinical experience. These consensus-based recommendations aim at optimising the health and quality of life of patients with a JIA diagnosis, regardless of the stage and course of the disease.Based on the clinical aspects that were deemed essential, we found scientific evidence pertaining to the selection and indication of MTX,<a class="elsevierStyleCrossRefs" href="#bib0205">1,7,8</a> the choice of dosage<a class="elsevierStyleCrossRefs" href="#bib0240">8,10,16</a> and route of administration,<a class="elsevierStyleCrossRef" href="#bib0240">8</a> criteria for dose reduction and discontinuation,<a class="elsevierStyleCrossRef" href="#bib0315">23</a>, safety,<a class="elsevierStyleCrossRef" href="#bib0320">24</a> monitoring,<a class="elsevierStyleCrossRefs" href="#bib0235">7,26–30</a> combined therapy<a class="elsevierStyleCrossRefs" href="#bib0235">7,31,32</a> and adjuvant use of folic acid.<a class="elsevierStyleCrossRefs" href="#bib0240">8,12</a>The set of recommendations presented here addresses issues such as the use of MTX based on the clinical classification of JIA, the initiation of MTX at full doses to achieve remission quickly and subsequent tapering off, the importance of the subcutaneous route of administration, especially in cases of polyarticular disease or associated with uveitis, and the ongoing adjustment of MTX therapy to patient-related factors and clinical status. The panel of experts highlighted the importance of regular laboratory testing in the follow-up of patients treated with MTX and ongoing monitoring for adverse events and adherence to treatment, which requires increased watchfulness by the parents or guardians of the patient. On the other hand, the wide variability of clinical criteria for the discontinuation of MTX (with or without tapering off) sparked debates that did not ultimately lead to specific recommendations.In conclusion, we found evidence of a marked variability in the therapeutic management of JIA with MTX. We believe that these recommendations for the management of MTX in patients with JIA will facilitate decision-making and promote a more uniform follow-up of these patients.FundingThis project has received funding from Laboratorios Gebro Pharma, S.A.Conflict of interestsJ. Antón has received honoraria for conferences organised by Gebro Pharma. The remaining authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres609006" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec622533" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres609005" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec622534" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Strategy for literature search and selection" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Consensus process" ] ] ] 6 => array:3 [ "identificador" => "sec0025" "titulo" => "Results" "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Literature search" ] 1 => array:3 [ "identificador" => "sec0035" "titulo" => "Initiation of methotrexate treatment" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Efficacy of methotrexate in juvenile idiopathic arthritis" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Indication for methotrexate" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Evaluation of the patient prior to receiving methotrexate" ] ] ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Initial dose and maximum dose" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Route of administration" ] 4 => array:2 [ "identificador" => "sec0065" "titulo" => "Tapering and discontinuation of methotrexate" ] 5 => array:2 [ "identificador" => "sec0070" "titulo" => "Safety of methotrexate" ] 6 => array:2 [ "identificador" => "sec0075" "titulo" => "Followup and monitoring of patients undergoing treatment with methotrexate" ] 7 => array:2 [ "identificador" => "sec0080" "titulo" => "Combination therapy" ] 8 => array:2 [ "identificador" => "sec0085" "titulo" => "Supplementary use of folic or folinic acid" ] ] ] 7 => array:2 [ "identificador" => "sec0090" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0095" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0100" "titulo" => "Conflict of interests" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-03-02" "fechaAceptado" => "2015-05-05" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec622533" "palabras" => array:3 [ 0 => "Methotrexate" 1 => "Juvenile idiopathic arthritis" 2 => "Consensus" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec622534" "palabras" => array:3 [ 0 => "Metotrexato" 1 => "Artritis idiópatica juvenil" 2 => "Consenso" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectivesTo develop a consensus document of recommendations for the use of methotrexate (MTX) in patients with juvenile idiopathic arthritis (JIA). Material and methodA group of eleven experts proposed several clinical questions on the use of MTX in patients with JIA. A systematic review was conducted and the evidence and recommendations for each question were extracted. The results were discussed and validated by the experts in a work session to establish the final recommendations. ResultsMTX is recommended as the first drug for inducing remission in JIA, and its indication should be made according to the clinical category of the patient. Prior to treatment, it is recommended to perform a complete blood count, including white cells, levels of liver enzymes, serum creatinine, and other analytical parameters according to specific risk factors. Treatment should be initiated with a dose of 10–15mg/m2/week. In cases of uveitis or polyarthritis, an initial dose of 15mg/m2/week should be considered. For a better bioavailability and tolerability, it is preferable to administer MTX parenterally if the dose is ≥15mg/m2/week. It is necessary to periodically perform an analytical monitoring of the patient and to assess possible alterations in liver enzymes to make changes if necessary. Combinations with biological agents may be necessary, as well as the concomitant addition of folic or folinic acid. ConclusionsThis document describes the main recommendations for the appropriate use of MTX in JIA patients, according to scientific evidence and clinical experience." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "ObjetivosElaborar un documento de recomendaciones consensuadas para el uso de metotrexato (MTX) en pacientes con artritis idiopática juvenil (AIJ). Material y métodoUn grupo de 11 expertos planteó diversos interrogantes clínicos en el uso de MTX en pacientes con AIJ. Se realizó una revisión sistemática y se extrajeron las evidencias y recomendaciones para cada pregunta. Los resultados fueron valorados y consensuados por los expertos en una sesión presencial para establecer las recomendaciones finales. ResultadosSe recomienda el MTX como primer fármaco inductor de remisión en AIJ, cuya indicación se realizará según la categoría clínica del paciente. Previo al tratamiento se recomienda evaluar un hemograma que incluya recuento leucocitario, niveles de enzimas hepáticas y creatinina sérica, así como otros parámetros analíticos conforme a factores de riesgo específicos. El tratamiento se iniciará con dosis de 10–15mg/m2/semana. En casos de uveítis o poliartritis se valorará una dosis inicial de 15mg/m2/semana. Para una mejor biodisponibilidad y tolerabilidad, se administrará preferentemente por vía parenteral si la dosis es≥15mg/m2/semana. Se deberá realizar un seguimiento analítico del paciente periódicamente y evaluar posibles alteraciones en enzimas hepáticas para realizar cambios si fuera preciso. La combinación con biológicos puede ser necesaria, además del uso concomitante de ácido fólico o folínico. ConclusionesEste documento recoge las principales recomendaciones para el empleo adecuado de MTX en pacientes con AIJ, de acuerdo a la evidencia científica y a la experiencia clínica." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Calvo I, Antón J, López Robledillo JC, de Inocencio J, Gamir ML, Merino R, et al. Recomendaciones para el uso de metotrexato en pacientes con artritis idiopática juvenil. An Pediatr (Barc). 2016;84:177." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "This study was presented at the X Congreso de la Sociedad Española de Reumatología Pediátrica; November 14, 2013; Granada, Spain." ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "GR, grade of recommendation; NA, not available; LE, level of evidence; Ref, source reference." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"># \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Recommendation \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LE \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">GR \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Grading system \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Ref. \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MTX is recommended as the first-line treatment for remission induction in JIA, due to its demonstrated efficacy and safety profile \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Feldman<a class="elsevierStyleCrossRef" href="#bib0225">5</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dueckers et al.<a class="elsevierStyleCrossRef" href="#bib0210">2</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MTX will be indicated based on the clinical classification of JIA as presented in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">D√ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Prior to initiation of treatment with MTX, performance of a complete blood count, differential blood count, liver enzymes and serum creatinine tests is recommended for all patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">D \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oxford<a class="elsevierStyleCrossRef" href="#bib0230">6</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Beukelman et al.<a class="elsevierStyleCrossRef" href="#bib0235">7</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Based on the existing risk factors, the patient's condition and previous diagnostic tests, testing for acute phase reactants (ESR-CRP) and hepatitis B and C serology (HBV and HCV) will be considered. In female adolescents, a potential pregnancy should be ruled out by means of an appropriate test. Confirmation of a negative Mantoux skin test in the past six months is recommended. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">D√ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The following doses are recommended<a class="elsevierStyleCrossRef" href="#bib0240">8</a>:Initial dose, 10–15mg/m2/weekMaximum total dose: 25mg/week \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Niehues<a class="elsevierStyleCrossRef" href="#bib0240">8</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Niehues et al.<a class="elsevierStyleCrossRef" href="#bib0240">8</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">In patients with uveitis or polyarthritis, an initial dose of 15mg/m2/week is recommended \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">D \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">For doses ≥15mg/m2/week, parenteral administration is recommended due to a higher bioavailability and tolerability \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Niehues<a class="elsevierStyleCrossRef" href="#bib0240">8</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Niehues et al.<a class="elsevierStyleCrossRef" href="#bib0240">8</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">For initial doses of 10mg/m2/week, a choice will be made between oral or subcutaneous administration, deciding on whichever is most suitable based on the circumstances of the patient \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">D√ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">It is recommended that laboratory testing of baseline parameters is repeated 1 month after initiating MTX or 1–2 months after any dose increases \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">D√ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">In patients receiving stable doses and with no previous test abnormalities, surveillance laboratory testing is recommended every 3–4 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">D \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">In response to liver enzyme elevation between 1 and 2 times the upper limit of normal, no specific action will be taken, or liver enzymes will be rechecked at a shorter interval until the levels normalise \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oxford<a class="elsevierStyleCrossRef" href="#bib0230">6</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Beukelman et al.<a class="elsevierStyleCrossRef" href="#bib0235">7</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">In response to liver enzyme elevation more than twice the upper limit of normal, decreasing the dose of methotrexate or temporarily withholding methotrexate administration is recommended \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oxford<a class="elsevierStyleCrossRef" href="#bib0230">6</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Beukelman et al.<a class="elsevierStyleCrossRef" href="#bib0235">7</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">If liver enzymes remain at levels more than 3 times the upper limit of normal following a decrease in the methotrexate dose, discontinuation of methotrexate is recommended \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oxford<a class="elsevierStyleCrossRef" href="#bib0230">6</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Beukelman et al.<a class="elsevierStyleCrossRef" href="#bib0235">7</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">We recommend considering the use of MTX in patients treated with biologic agents to improve the response and/or reduce the development of antibodies to certain biologics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">D \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">To prevent side effects such as dyspepsia and nausea, the use of either folic or folinic acid is recommended as an adjuvant to MTX therapy. Folic or folinic acid will be given in tablet form in doses of 5mg/week at least one day apart from the administration of MTX or, alternatively, in doses of 1mg/day skipping the day that MTX is administered \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">D \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220">4</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab996952.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Recommendations for the use of methotrexate (MTX) in patients with juvenile idiopathic arthritis (JIA)." ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "NSAID, nonsteoridal anti-inflammatory drug; RF, rheumatoid factor; GC, glucocorticoid; MTX, methotrexate." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Category \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Criteria for indication of MTX \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Exceptions \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oligoarticular \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MTX recommended as first-line treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Monoarticular presentations that are easy to manage and assess and respond well to intra-articular GCs \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Polyarticular (RF[+] and [–]) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MTX recommended for all cases alone or combined with other medication such as NSAIDs or oral or intra-articular GCs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Psoriatic arthritis</td><td class="td" title="table-entry " align="left" valign="top">Oligoarticular: MTX recommended as first-line treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Monoarticular presentations that are easy to manage and assess and respond well to intra-articular GCs.</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Polyarticular: we recommend the use of MTX in all cases, combined with oral and/or intra-articular GCs and with or without NSAID therapy. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Enthesitis-related arthritis (ERA)</td><td class="td" title="table-entry " align="left" valign="top">Peripheral: we recommend the use of MTX or sulfasalazine combined with oral and/or intra-articular GCs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Axial: a therapeutic trial with MTX or sulfasalazine is recommended when initial treatment with full-dose NSAID has failed after 4 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Systemic arthritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The use of MTX may be considered in patients with active joint involvement and no systemic component \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Presence of uveitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MTX is recommended in cases of uveitis associated with JIA that do not respond to first-line topical treatment<a class="elsevierStyleCrossRef" href="#bib0275">15</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab996951.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Indication of MTX based on the clinical classification of JIA." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:40 [ 0 => array:3 [ "identificador" => "bib0205" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.E. 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Recommendations for the use of methotrexate in patients with juvenile idiopathic arthritis

Recomendaciones para el uso de metotrexato en pacientes con artritis idiopática juvenil

I. Calvoa,

Corresponding author

calvo_inm@gva.es
inmaculadacalvopenades@gmail.com

Corresponding author.

, J. Antónb, J.C. López Robledilloc, J. de Inocenciod, M.L. Gamire, R. Merinof, L. Lacruzg, M. Camachoh, M.J. Ruai, S. Bustabadj, G. Díaz Cordovés-Regok

a Hospital Universitario y Politécnico La Fe, Valencia, Spain

b Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues de Llobregat, Barcelona, Spain

c Hospital Infantil Universitario Niño Jesús, Madrid, Spain

d Hospital Universitario 12 de Octubre, Madrid, Spain

e Hospital Universitario Ramón y Cajal, Madrid, Spain

f Hospital Universitario La Paz, Madrid, Spain

g Hospital Son Espases, Palma de Mallorca, Spain

h Hospital Universitario Virgen del Rocío, Sevilla, Spain

i Hospital Universitario Cruces, San Vicente de Barakaldo, Spain

j Hospital Universitario de Canarias, San Cristóbal de La Laguna , Santa Cruz de Tenerife, Spain

k Hospital Materno Infantil del Hospital Regional Universitario de Málaga, Málaga, Spain

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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">Juvenile idiopathic arthritis &#40;JIA&#41; is an inflammatory arthropathy that comprehends 7 subtypes based on the classification of the International League of Association for Rheumatology &#40;ILAR&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">1</span></a> These subtypes differ in their pathophysiology&#44; clinical features&#44; and treatment&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Juvenile idiopathic arthritis is a chronic disease that impairs the functional capacity and quality of life of affected individuals&#44; and thus it is important that it be diagnosed and treated early&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The pharmacological treatment of JIA depends on the subtype and severity of the disease&#44; with frequent use of disease-modifying antirheumatic drugs &#40;DMARDs&#41; as monotherapy or in combination with oral and intra-articular non-steroidal anti-inflammatory drugs &#40;NSAIDs&#41; and glucocorticoids &#40;GCs&#41;&#46; Early introduction of DMARDs&#8212;methotrexate &#40;MTX&#41; being one of them&#8212;may help prevent disease progression&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The use of MTX in patients with JIA is recommended due to its proven efficacy and safety profile&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a> However&#44; despite being the DMARD most frequently used for JIA<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">3</span></a> and having been available for many years&#44; certain points pertaining to its management in clinical practice are still in question&#46; Thus&#44; the aim of this study was to establish consensus-based clinical and therapeutic recommendations for the management of MTX in patients with JIA&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">We set up a guideline-developing group &#40;GDG&#41; consisting of three coordinators and eight specialists in paediatric rheumatology&#44; all members of the Sociedad Espa&#241;ola de Reumatolog&#237;a Pedi&#225;trica &#40;Spanish Society of Paediatric Rheumatology &#91;SERPE&#93;&#41;&#46; The GDG formulated the clinical questions pertaining to MTX management applying the PICO framework &#40;patient&#44; intervention&#44; control and outcome&#41;&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Strategy for literature search and selection</span><p id="par0030" class="elsevierStylePara elsevierViewall">We carried out a systematic search in Medline and the Cochrane Library for human studies published in English or Spanish in the past 15 years for which an abstract was available&#46; The keywords used in the search were &#8220;idiopathic juvenile arthritis&#8221;&#44; &#8220;methotrexate&#8221;&#44; &#8220;routes of administration&#8221;&#44; &#8220;dosage&#8221;&#44; &#8220;tapering&#8221;&#44; &#8220;discontinuation&#8221; and other&#44; more specific terms based on each particular clinical question&#46; Finally&#44; we completed the search with articles provided directly by the GDG and the summaries of product characteristics for methotrexate&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Of the resulting list of publications&#44; we selected review articles&#44; consensus documents&#44; guidelines by scientific associations and articles that explicitly addressed specific aspects of the proposed questions&#44; and proceeded to summarise the evidence&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Consensus process</span><p id="par0040" class="elsevierStylePara elsevierViewall">We used the nominal group technique&#46; The experts discussed the contents of the evidence summary in a structured fashion during a work session&#46; Based on the conclusions reached at the session&#44; we drafted a document with the agreed-on recommendations and determined the level of evidence &#40;LE&#41; and grade of recommendation &#40;GR&#41; for each of them&#44; either adhering to the system employed in the source &#40;if any had been used&#41; or applying the grading system of the Scottish Intercollegiate Guidelines Network &#40;SIGN&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a> Lastly&#44; the resulting document was presented to the group of experts for a final review&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Literature search</span><p id="par0045" class="elsevierStylePara elsevierViewall">We obtained 344 references in the literature search&#46; Through a subsequent screening&#44; we selected 67 articles&#44; 6 clinical practice guidelines and 9 summaries of product characteristics for critical reading&#46; After evaluation by the GDG members and the implementation of the structured and participatory consensus methodology&#44; we validated sixteen recommendations &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Initiation of methotrexate treatment</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Efficacy of methotrexate in juvenile idiopathic arthritis</span><p id="par0050" class="elsevierStylePara elsevierViewall">Most clinical trials and prospective cohort studies demonstrate that MTX is efficacious for the treatment of active JIA&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">8&#8211;13</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Several studies have demonstrated the impact of MTX on the quality of life of patients with JIA&#44; regardless of the dose used&#46; Depending on the form and severity of the disease&#44; MTX treatment is administered in combination with local and&#47;or systemic NSAIDs and GCs or even with biologics&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">9&#44;12&#8211;14</span></a> Given the extensive experience with the use of MTX for JIA&#44; MTX is considered the first-line DMARD and is the mainstay of long-term therapy in these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0060" class="elsevierStylePara elsevierViewall">Recommendation 1&#58; MTX is recommended as the first-line treatment for remission induction in JIA due to its proven efficacy and safety profile<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a> &#40;IA&#59; Feldman<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">5</span></a>&#41;&#46;</p></li></ul></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Indication for methotrexate</span><p id="par0065" class="elsevierStylePara elsevierViewall">Several international publications have established recommendations for the use of MTX&#44;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">1&#44;7&#44;8</span></a> based on which we developed our own recommendations&#46; We found variability in the criteria applied to certain aspects&#44; consistent with the variability that exists in everyday clinical practice&#46; Thus&#44; we agreed on a set of minimum criteria that would allow for a uniform decision-making process as pertains to the indication of MTX &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0070" class="elsevierStylePara elsevierViewall">Recommendation 2&#58; MTX will be indicated based on the clinical classification of JIA as presented in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> &#40;4D&#8730;&#59; SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&#41;&#46;</p></li></ul></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Evaluation of the patient prior to receiving methotrexate</span><p id="par0075" class="elsevierStylePara elsevierViewall">If MTX is indicated&#44; the clinical evaluation of patients with JIA must include at least certain diagnostic tests and other parameters depending on the risk factors&#46;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Recommendation 3&#58; prior to initiation of treatment with MTX&#44; performance of a complete blood count&#44; differential blood count&#44; liver enzyme level and serum creatinine<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a> tests is recommended &#40;D&#59; Oxford<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0085" class="elsevierStylePara elsevierViewall">Recommendation 4&#58; depending on the existing risk factors&#44; the patient&#39;s condition and previous diagnostic tests&#44; testing for acute phase reactants &#40;ESR-CRP&#41; and hepatitis B and C serology &#40;HBV and HCV&#41; will be considered&#46; In female adolescents&#44; a potential pregnancy should be ruled out by means of an appropriate test&#46; Confirmation of a negative Mantoux skin test in the past six months is recommended &#40;4D&#8730;&#59; SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&#41;&#46;</p></li></ul></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Initial dose and maximum dose</span><p id="par0090" class="elsevierStylePara elsevierViewall">A study by Giannini et al&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a> showed that an initial MTX dose of 5<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> is no more efficient than placebo&#46; A study conducted by PRINTO<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">10</span></a> showed that patients with polyarticular JIA responded to MTX within nine months of starting treatment at standard doses of 8&#8211;12&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> &#40;administered by the oral&#44; subcutaneous and intramuscular routes&#41;&#46; Thus&#44; we have determined the following&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0095" class="elsevierStylePara elsevierViewall">Recommendation 5&#58; the following doses are recommended<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a>&#58; initial dose&#44; 10&#8211;15<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week&#59; maximum total dose&#58; 25<span class="elsevierStyleHsp" style=""></span>mg&#47;week &#40;IA&#59; Niehues<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a>&#41;&#46;</p></li></ul></p><p id="par0100" class="elsevierStylePara elsevierViewall">While additional randomised controlled trials are needed&#44; several studies suggest that MTX is useful for the treatment of chronic uveitis in patients with JIA&#44; preventing its onset&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">17</span></a> and improving disease activity in a significant percentage of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">18</span></a> Thus&#44; we agreed on the following initial dose&#58;<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0105" class="elsevierStylePara elsevierViewall">Recommendation 6&#58; in patients with uveitis or polyarthritis&#44; an initial dose of 15<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week is recommended &#40;4D&#59; SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&#41;&#46;</p></li></ul></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Route of administration</span><p id="par0110" class="elsevierStylePara elsevierViewall">The study of Niehues et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a> reviews several studies<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">19&#8211;22</span></a> on the bioavailability of MTX&#46; The conclusion is that for doses of up to 15<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week&#44; the bioavailability after parenteral and oral administration is similar&#59; at higher doses &#40;&#8805;15<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week&#41; parenteral administration is recommended for its higher bioavailability and tolerability&#46;<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0115" class="elsevierStylePara elsevierViewall">Recommendation 7&#58; for doses &#8805;15<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week&#44; parenteral administration is recommended due to a higher bioavailability and tolerability<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a> &#40;IIIC&#59; Niehues<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a>&#41;&#46;</p></li></ul></p><p id="par0120" class="elsevierStylePara elsevierViewall">The criteria for making decisions regarding the initial dose and route of administration are variable and subject to the preferences of the patient and&#47;or family members and the required doses&#46;<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8226;</span><p id="par0125" class="elsevierStylePara elsevierViewall">Recommendation 8&#58; for initial doses of 10<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week&#44; a choice will be made between oral or subcutaneous administration&#44; deciding on whichever is most suitable based on the circumstances of the patient &#40;4D&#8730;&#59; SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&#41;&#46;</p></li></ul></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Tapering and discontinuation of methotrexate</span><p id="par0130" class="elsevierStylePara elsevierViewall">We did not find sufficient evidence to make a recommendation&#46; However&#44; the data of a clinical trial<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">23</span></a> show similar results whether MTX is discontinued six or twelve months after achieving remission&#46; Thus&#44; in principle&#44; MTX could be discontinued six months after achieving remission&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The panel of experts found a wide variability in the tapering off and discontinuation of MTX doses in everyday clinical practice&#58; from withdrawal of treatment to tapering down in steps of 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg in each visit &#40;every 6&#8211;8 weeks&#41;&#46; Other strategies consisted of increasing the interval between doses without changing the dose itself&#59; that is&#44; for example&#44; giving the same dose every 15 days as opposed to every week&#44; and so on&#44; until discontinuation&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">In gradual tapering schemes&#44; it is acceptable to choose to switch to oral administration once a dose of 10<span class="elsevierStyleHsp" style=""></span>mg is reached&#44; applying the previously noted criteria regarding the route of administration&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Safety of methotrexate</span><p id="par0145" class="elsevierStylePara elsevierViewall">Based on the review of the summaries of product characteristics&#44; the most significant adverse effects of MTX involve the suppression of the haematopoietic system and gastrointestinal disorders&#46; Specifically&#44; the most frequent adverse reactions &#40;&#8805;1&#47;10&#41; are gastrointestinal &#40;stomatitis&#44; dyspepsia&#44; nausea and loss of appetite&#41; and hepatobiliary &#40;elevated transaminases&#41;&#59; with less frequent effects &#40;&#8805;1&#47;100&#44; &#60;1&#47;10&#41; including involvement of the gastrointestinal tract &#40;mouth ulcers and diarrhoea&#41;&#44; cutaneous and subcutaneous tissues &#40;exanthema&#44; erythema and pruritus&#41;&#44; nervous system &#40;headache&#44; fatigue and sleepiness&#41;&#44; respiratory system&#44; thorax and mediastinum &#40;pneumonia and interstitial alveolitis&#47;pneumonitis&#44; often associated with eosinophilia&#41; and the blood and lymphatic system &#40;leukopenia&#44; anaemia and thrombocytopenia&#41;&#46; Hair loss&#44; while being rare &#40;&#8805;1&#47;1000&#44; &#60;1&#47;100&#41;&#44; is usually a source of concern for the families&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">24</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The development and degree of severity of adverse reactions depend on the dose and frequency of administration&#46; Since severe adverse reactions may occur even at the lowest doses&#44; it is imperative that physicians monitor these patients at regular intervals &#40;every 3&#8211;4 months&#41;&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">We recommend the subcutaneous administration of MTX&#44; as it is well tolerated at the site of injection&#46; Only mild local skin reactions have been observed&#44; and these diminish over the course of treatment&#46; Intramuscular administration has led to reports of local adverse reactions &#40;burning feeling&#41; or lesions &#40;formation of sterile abscesses or destruction of fatty tissues&#41; at the site of administration&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">24</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">The contraindications for MTX need also be considered<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">24</span></a>&#58; hypersensitivity to MTX or any of the excipients&#59; liver failure&#44; alcohol abuse&#44; or kidney failure&#59; pre-existing blood dyscrasias such as bone marrow hypoplasia&#44; leukopenia&#44; thrombocytopenia or significant anaemia&#59; severe acute or chronic infection&#44; such as tuberculosis or HIV infection&#59; mouth ulcers or known active gastrointestinal ulcerative disease&#59; pregnancy and breastfeeding&#59; and concurrent vaccination with live or live-attenuated vaccines&#44; although the evidence-based recommendations of a panel of experts of the EULAR<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">25</span></a> recommend the live-attenuated vaccine if the dose used is less than 15<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Followup and monitoring of patients undergoing treatment with methotrexate</span><p id="par0165" class="elsevierStylePara elsevierViewall">A study by Ortiz-&#193;lvarez et al&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">26</span></a> assessed the utility of the ACR guidelines for monitoring patients with JIA&#44; and estimated a probability of 11&#37; for having significantly abnormal blood tests at three months&#44; compared to 10&#37; probability of having an abnormal test by chance alone&#46; Consequently&#44; they deemed that periodical routine blood tests were unnecessary&#46; The conclusions of a different study<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">27</span></a> suggested that the adult standard of surveillance laboratory testing every four to eight weeks might not be necessary in children treated with MTX&#44; especially if certain risk factors are absent&#46; Other studies suggest the need to monitor for potential and usually reversible liver function test abnormalities&#44; especially if the dose needs to be increased or large doses of MTX are required&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">28</span></a> There seems to be no question that testing should be performed to confirm normal levels one month after initiation of MTX treatment&#46;<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8226;</span><p id="par0170" class="elsevierStylePara elsevierViewall">Recommendation 9&#58; it is recommended that laboratory testing of baseline parameters is repeated one month after initiating MTX or one to two months after any dose increases &#40;2<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>D&#8730;&#59; SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8226;</span><p id="par0175" class="elsevierStylePara elsevierViewall">Recommendation 10&#58; in patients receiving stable doses and with no previous test abnormalities&#44; surveillance laboratory testing is recommended every 3&#8211;4 months &#40;4D&#59; SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&#41;&#46;</p></li></ul></p><p id="par0180" class="elsevierStylePara elsevierViewall">Hashkes et al&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">29</span></a> analysed the relationship between hepatotoxic risk factors and liver histology in patients with JIA treated with MTX&#46; They found that biochemical abnormalities were associated with liver damage based on the Roenigk classification and the presence of liver fibrosis&#44; which concurred with studies of patients with rheumatoid arthritis &#40;RA&#41;&#46; This suggests that the guidelines for monitoring MTX hepatotoxicity in AR may be applicable to JIA&#46; These data along with further evidence extrapolated from adults with RA<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">27&#8211;30</span></a> justified the recommendations of the ACR<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a>&#58;<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8226;</span><p id="par0185" class="elsevierStylePara elsevierViewall">Recommendation 11&#58; in response to liver enzyme elevation between 1 and 2 times the upper limit of normal&#44; either no specific action or rechecking liver enzymes at a shorter interval until the levels normalise is recommended<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a> &#40;C&#59; Oxford<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#8226;</span><p id="par0190" class="elsevierStylePara elsevierViewall">Recommendation 12&#58; in response to liver enzyme elevation more than twice the upper limit of normal&#44; decreasing the dose of methotrexate or temporarily withholding methotrexate administration is recommended<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a> &#40;C&#59; Oxford<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8226;</span><p id="par0195" class="elsevierStylePara elsevierViewall">Recommendation 13&#58; if liver enzymes remain at levels more than 3 times the upper limit of normal following a decrease in the methotrexate dose&#44; discontinuation of methotrexate is recommended<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a> &#40;C&#59; Oxford<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a>&#41;&#46;</p></li></ul></p><p id="par0200" class="elsevierStylePara elsevierViewall">Other possible causes of elevated liver enzymes unrelated to the administration of MTX must be investigated&#44; and tapering off can be considered if these levels are abnormal or elevated&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Combination therapy</span><p id="par0205" class="elsevierStylePara elsevierViewall">More evidence is needed to establish the indications for combination therapy with MTX&#44; be it with conventional or biologic DMARDs&#44; in order to simplify decision-making&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">The recommendations of the ACR<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a> propose the addition of a TNF&#945; inhibitor for patients receiving MTX as monotherapy and with persistent JIA activity&#44; recommending that treatment with MTX be continued or not depending on the patient&#39;s previous response to it&#46; Other authors recommend exhausting the time frame to observe the response to MTX therapy and achieve the maximum effective doses of MTX by the parenteral route before considering initiation of combination therapies&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">31&#44;32</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">In recent years&#44; several studies have demonstrated that in some patients clinical worsening and a diminished response to treatment with certain TNF inhibitors is associated with the development of anti-drug antibodies&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">33&#44;34</span></a> On the other hand&#44; other studies have shown how the concomitant use of MTX reduces the immunogenicity of these drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">35&#44;36</span></a> For all of the above&#44; we recommend considering the use of MTX in patients treated with biologic agents to improve the response and&#47;or reduce the development of antibodies to certain biologics&#46;<ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8226;</span><p id="par0220" class="elsevierStylePara elsevierViewall">Recommendation 14&#58; we recommend considering the use of MTX in patients treated with biologic agents to improve the response and&#47;or reduce the development of antibodies to certain biologics &#40;4D&#59; SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&#41;&#46;</p></li></ul></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Supplementary use of folic or folinic acid</span><p id="par0225" class="elsevierStylePara elsevierViewall">Methotrexate reduces inflammation by a mechanism related to the metabolism of folic acid&#46; The prescription of folic or folinic acid can improve the tolerability and safety of MTX &#40;mouth ulcers&#44; gastrointestinal complaints&#44; diarrhoea&#44; haematologic changes&#44; elevation of transaminases&#44; etc&#46;&#41;&#46; Folic or folinic acid is given at least one day apart from the administration of MTX&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">8&#44;12</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">Some expert-consensus guidelines state the need of supplementing MTX treatment with folic acid&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">37</span></a><ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8226;</span><p id="par0235" class="elsevierStylePara elsevierViewall">Recommendation 15&#58; to prevent side effects such as dyspepsia and nausea&#44; the use of either folic or folinic acid is recommended as an adjuvant to MTX therapy&#46; Folic or folinic acid will be given in tablet form in doses of 5<span class="elsevierStyleHsp" style=""></span>mg&#47;week at least one day apart from the administration of MTX or&#44; alternatively&#44; in doses of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; skipping the day that MTX is administered &#40;LE&#44; 4&#59; GR&#44; D&#59; SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&#41;&#46;</p></li></ul></p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Discussion</span><p id="par0240" class="elsevierStylePara elsevierViewall">There have been advances in the knowledge of JIA in recent years&#44; both in criteria regarding its classification&#44; clinical improvement&#44; remission and inactive disease&#44; and in tools used to measure disease activity &#40;JADAS&#41;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">38</span></a> and quality of life &#40;JAMAR<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">39</span></a> and CHAQ<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">40</span></a>&#41;&#46; This has made the follow-up of patients with JIA easier&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">Although at present MTX is considered the most effective nonbiologic agent for induction remission in patients with JIA&#44; there is great variability in the management of this drug in clinical practice&#46; This called for the development of a consensus by a group of experts in paediatric rheumatology involved in the management of patients with JIA treated with MTX&#46; Their contributions have resulted in a set of recommendations that will make it possible to improve the pattern of use of MTX for the treatment of children and adolescents with JIA by the integration of scientific evidence and clinical experience&#46; These consensus-based recommendations aim at optimising the health and quality of life of patients with a JIA diagnosis&#44; regardless of the stage and course of the disease&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Based on the clinical aspects that were deemed essential&#44; we found scientific evidence pertaining to the selection and indication of MTX&#44;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">1&#44;7&#44;8</span></a> the choice of dosage<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">8&#44;10&#44;16</span></a> and route of administration&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a> criteria for dose reduction and discontinuation&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">23</span></a>&#44; safety&#44;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">24</span></a> monitoring&#44;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">7&#44;26&#8211;30</span></a> combined therapy<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">7&#44;31&#44;32</span></a> and adjuvant use of folic acid&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">8&#44;12</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">The set of recommendations presented here addresses issues such as the use of MTX based on the clinical classification of JIA&#44; the initiation of MTX at full doses to achieve remission quickly and subsequent tapering off&#44; the importance of the subcutaneous route of administration&#44; especially in cases of polyarticular disease or associated with uveitis&#44; and the ongoing adjustment of MTX therapy to patient-related factors and clinical status&#46; The panel of experts highlighted the importance of regular laboratory testing in the follow-up of patients treated with MTX and ongoing monitoring for adverse events and adherence to treatment&#44; which requires increased watchfulness by the parents or guardians of the patient&#46; On the other hand&#44; the wide variability of clinical criteria for the discontinuation of MTX &#40;with or without tapering off&#41; sparked debates that did not ultimately lead to specific recommendations&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">In conclusion&#44; we found evidence of a marked variability in the therapeutic management of JIA with MTX&#46; We believe that these recommendations for the management of MTX in patients with JIA will facilitate decision-making and promote a more uniform follow-up of these patients&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Funding</span><p id="par0265" class="elsevierStylePara elsevierViewall">This project has received funding from <span class="elsevierStyleGrantSponsor" id="gs1">Laboratorios Gebro Pharma&#44; S&#46;A</span>&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Conflict of interests</span><p id="par0270" class="elsevierStylePara elsevierViewall">J&#46; Ant&#243;n has received honoraria for conferences organised by Gebro Pharma&#46; The remaining authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "titulo" => "Resumen"
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              "titulo" => "Objetivos"
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              "titulo" => "Material y m&#233;todo"
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          "titulo" => "Introduction"
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          "titulo" => "Methods"
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            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Strategy for literature search and selection"
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                  "titulo" => "Efficacy of methotrexate in juvenile idiopathic arthritis"
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                  "titulo" => "Indication for methotrexate"
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                  "titulo" => "Evaluation of the patient prior to receiving methotrexate"
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              "titulo" => "Initial dose and maximum dose"
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              "identificador" => "sec0065"
              "titulo" => "Tapering and discontinuation of methotrexate"
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              "titulo" => "Safety of methotrexate"
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              "titulo" => "Followup and monitoring of patients undergoing treatment with methotrexate"
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              "titulo" => "Combination therapy"
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          "titulo" => "Conflict of interests"
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    "fechaRecibido" => "2015-03-02"
    "fechaAceptado" => "2015-05-05"
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            0 => "Methotrexate"
            1 => "Juvenile idiopathic arthritis"
            2 => "Consensus"
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            0 => "Metotrexato"
            1 => "Artritis idi&#243;patica juvenil"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To develop a consensus document of recommendations for the use of methotrexate &#40;MTX&#41; in patients with juvenile idiopathic arthritis &#40;JIA&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and method</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A group of eleven experts proposed several clinical questions on the use of MTX in patients with JIA&#46; A systematic review was conducted and the evidence and recommendations for each question were extracted&#46; The results were discussed and validated by the experts in a work session to establish the final recommendations&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">MTX is recommended as the first drug for inducing remission in JIA&#44; and its indication should be made according to the clinical category of the patient&#46; Prior to treatment&#44; it is recommended to perform a complete blood count&#44; including white cells&#44; levels of liver enzymes&#44; serum creatinine&#44; and other analytical parameters according to specific risk factors&#46; Treatment should be initiated with a dose of 10&#8211;15<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week&#46; In cases of uveitis or polyarthritis&#44; an initial dose of 15<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week should be considered&#46; For a better bioavailability and tolerability&#44; it is preferable to administer MTX parenterally if the dose is &#8805;15<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week&#46; It is necessary to periodically perform an analytical monitoring of the patient and to assess possible alterations in liver enzymes to make changes if necessary&#46; Combinations with biological agents may be necessary&#44; as well as the concomitant addition of folic or folinic acid&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This document describes the main recommendations for the appropriate use of MTX in JIA patients&#44; according to scientific evidence and clinical experience&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Objectives"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Material and method"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusions"
          ]
        ]
      ]
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Elaborar un documento de recomendaciones consensuadas para el uso de metotrexato &#40;MTX&#41; en pacientes con artritis idiop&#225;tica juvenil &#40;AIJ&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todo</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Un grupo de 11 expertos plante&#243; diversos interrogantes cl&#237;nicos en el uso de MTX en pacientes con AIJ&#46; Se realiz&#243; una revisi&#243;n sistem&#225;tica y se extrajeron las evidencias y recomendaciones para cada pregunta&#46; Los resultados fueron valorados y consensuados por los expertos en una sesi&#243;n presencial para establecer las recomendaciones finales&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se recomienda el MTX como primer f&#225;rmaco inductor de remisi&#243;n en AIJ&#44; cuya indicaci&#243;n se realizar&#225; seg&#250;n la categor&#237;a cl&#237;nica del paciente&#46; Previo al tratamiento se recomienda evaluar un hemograma que incluya recuento leucocitario&#44; niveles de enzimas hep&#225;ticas y creatinina s&#233;rica&#44; as&#237; como otros par&#225;metros anal&#237;ticos conforme a factores de riesgo espec&#237;ficos&#46; El tratamiento se iniciar&#225; con dosis de 10&#8211;15<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;semana&#46; En casos de uve&#237;tis o poliartritis se valorar&#225; una dosis inicial de 15<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;semana&#46; Para una mejor biodisponibilidad y tolerabilidad&#44; se administrar&#225; preferentemente por v&#237;a parenteral si la dosis es<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>15<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;semana&#46; Se deber&#225; realizar un seguimiento anal&#237;tico del paciente peri&#243;dicamente y evaluar posibles alteraciones en enzimas hep&#225;ticas para realizar cambios si fuera preciso&#46; La combinaci&#243;n con biol&#243;gicos puede ser necesaria&#44; adem&#225;s del uso concomitante de &#225;cido f&#243;lico o fol&#237;nico&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Este documento recoge las principales recomendaciones para el empleo adecuado de MTX en pacientes con AIJ&#44; de acuerdo a la evidencia cient&#237;fica y a la experiencia cl&#237;nica&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Objetivos"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Material y m&#233;todo"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
    ]
    "NotaPie" => array:2 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Calvo I&#44; Ant&#243;n J&#44; L&#243;pez Robledillo JC&#44; de Inocencio J&#44; Gamir ML&#44; Merino R&#44; et al&#46; Recomendaciones para el uso de metotrexato en pacientes con artritis idiop&#225;tica juvenil&#46; An Pediatr &#40;Barc&#41;&#46; 2016&#59;84&#58;177&#46;</p>"
      ]
      1 => array:2 [
        "etiqueta" => "&#9734;&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">This study was presented at the X Congreso de la Sociedad Espa&#241;ola de Reumatolog&#237;a Pedi&#225;trica&#59; November 14&#44; 2013&#59; Granada&#44; Spain&#46;</p>"
      ]
    ]
    "multimedia" => array:2 [
      0 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">GR&#44; grade of recommendation&#59; NA&#44; not available&#59; LE&#44; level of evidence&#59; Ref&#44; source reference&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&#35;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Recommendation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">GR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Grading system&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MTX is recommended as the first-line treatment for remission induction in JIA&#44; due to its demonstrated efficacy and safety profile&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">I</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Feldman<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">5</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dueckers et al&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MTX will be indicated based on the clinical classification of JIA as presented in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">D&#8730;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Prior to initiation of treatment with MTX&#44; performance of a complete blood count&#44; differential blood count&#44; liver enzymes and serum creatinine tests is recommended for all patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oxford<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Beukelman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Based on the existing risk factors&#44; the patient&#39;s condition and previous diagnostic tests&#44; testing for acute phase reactants &#40;ESR-CRP&#41; and hepatitis B and C serology &#40;HBV and HCV&#41; will be considered&#46; In female adolescents&#44; a potential pregnancy should be ruled out by means of an appropriate test&#46; Confirmation of a negative Mantoux skin test in the past six months is recommended&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">D&#8730;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The following doses are recommended<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a>&#58;Initial dose&#44; 10&#8211;15<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;weekMaximum total dose&#58; 25<span class="elsevierStyleHsp" style=""></span>mg&#47;week&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Niehues<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Niehues et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">In patients with uveitis or polyarthritis&#44; an initial dose of 15<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week is recommended&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">For doses &#8805;15<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week&#44; parenteral administration is recommended due to a higher bioavailability and tolerability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Niehues<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Niehues et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">For initial doses of 10<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week&#44; a choice will be made between oral or subcutaneous administration&#44; deciding on whichever is most suitable based on the circumstances of the patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">D&#8730;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">It is recommended that laboratory testing of baseline parameters is repeated 1 month after initiating MTX or 1&#8211;2 months after any dose increases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">D&#8730;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">In patients receiving stable doses and with no previous test abnormalities&#44; surveillance laboratory testing is recommended every 3&#8211;4 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">In response to liver enzyme elevation between 1 and 2 times the upper limit of normal&#44; no specific action will be taken&#44; or liver enzymes will be rechecked at a shorter interval until the levels normalise&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oxford<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Beukelman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">In response to liver enzyme elevation more than twice the upper limit of normal&#44; decreasing the dose of methotrexate or temporarily withholding methotrexate administration is recommended&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oxford<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Beukelman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">If liver enzymes remain at levels more than 3 times the upper limit of normal following a decrease in the methotrexate dose&#44; discontinuation of methotrexate is recommended&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oxford<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Beukelman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">We recommend considering the use of MTX in patients treated with biologic agents to improve the response and&#47;or reduce the development of antibodies to certain biologics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">To prevent side effects such as dyspepsia and nausea&#44; the use of either folic or folinic acid is recommended as an adjuvant to MTX therapy&#46; Folic or folinic acid will be given in tablet form in doses of 5<span class="elsevierStyleHsp" style=""></span>mg&#47;week at least one day apart from the administration of MTX or&#44; alternatively&#44; in doses of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;day skipping the day that MTX is administered&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIGN<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Recommendations for the use of methotrexate &#40;MTX&#41; in patients with juvenile idiopathic arthritis &#40;JIA&#41;&#46;</p>"
        ]
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        "etiqueta" => "Table 2"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">NSAID&#44; nonsteoridal anti-inflammatory drug&#59; RF&#44; rheumatoid factor&#59; GC&#44; glucocorticoid&#59; MTX&#44; methotrexate&#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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Category&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Criteria for indication of MTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Exceptions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oligoarticular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MTX recommended as first-line treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Monoarticular presentations that are easy to manage and assess and respond well to intra-articular GCs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Polyarticular &#40;RF&#91;&#43;&#93; and &#91;&#8211;&#93;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MTX recommended for all cases alone or combined with other medication such as NSAIDs or oral or intra-articular GCs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Psoriatic arthritis</td><td class="td" title="table-entry  " align="left" valign="top">Oligoarticular&#58; MTX recommended as first-line treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Monoarticular presentations that are easy to manage and assess and respond well to intra-articular GCs&#46;</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Polyarticular&#58; we recommend the use of MTX in all cases&#44; combined with oral and&#47;or intra-articular GCs and with or without NSAID therapy&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Enthesitis-related arthritis &#40;ERA&#41;</td><td class="td" title="table-entry  " align="left" valign="top">Peripheral&#58; we recommend the use of MTX or sulfasalazine combined with oral and&#47;or intra-articular GCs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Axial&#58; a therapeutic trial with MTX or sulfasalazine is recommended when initial treatment with full-dose NSAID has failed after 4 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Systemic arthritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The use of MTX may be considered in patients with active joint involvement and no systemic component&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Presence of uveitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MTX is recommended in cases of uveitis associated with JIA that do not respond to first-line topical treatment<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">15</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Indication of MTX based on the clinical classification of JIA&#46;</p>"
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                  "host" => array:1 [
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                        0 => array:2 [
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Article information

ISSN: 23412879
Original language: English

DOI:10.1016/j.anpede.2015.05.022

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Year/Month	Html	Pdf	Total

2024 November	18	10	28
2024 October	122	61	183
2024 September	111	58	169
2024 August	118	87	205
2024 July	126	54	180
2024 June	127	53	180
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2024 April	88	52	140
2024 March	93	40	133
2024 February	101	24	125
2024 January	85	36	121
2023 December	78	22	100
2023 November	67	19	86
2023 October	89	24	113
2023 September	83	27	110
2023 August	85	30	115
2023 July	101	25	126
2023 June	96	27	123
2023 May	123	23	146
2023 April	72	17	89
2023 March	121	28	149
2023 February	96	25	121
2023 January	133	20	153
2022 December	104	47	151
2022 November	89	59	148
2022 October	102	45	147
2022 September	78	46	124
2022 August	103	51	154
2022 July	80	41	121
2022 June	73	46	119
2022 May	88	40	128
2022 April	86	45	131
2022 March	104	57	161
2022 February	106	31	137
2022 January	102	36	138
2021 December	67	46	113
2021 November	63	57	120
2021 October	90	64	154
2021 September	62	49	111
2021 August	59	42	101
2021 July	60	36	96
2021 June	60	36	96
2021 May	53	30	83
2021 April	221	97	318
2021 March	120	52	172
2021 February	111	20	131
2021 January	115	33	148
2020 December	94	25	119
2020 November	86	25	111
2020 October	69	21	90
2020 September	90	26	116
2020 August	129	11	140
2020 July	103	26	129
2020 June	133	17	150
2020 May	199	17	216
2020 April	102	18	120
2020 March	88	33	121
2020 February	73	19	92
2020 January	74	16	90
2019 December	252	27	279
2019 November	70	18	88
2019 October	82	18	100
2019 September	74	37	111
2019 August	52	31	83
2019 July	51	58	109
2019 June	58	40	98
2019 May	83	30	113
2019 April	62	60	122
2019 March	80	34	114
2019 February	54	33	87
2019 January	59	48	107
2018 December	59	43	102
2018 November	108	59	167
2018 October	72	40	112
2018 September	45	25	70
2018 August	3	0	3
2018 July	13	0	13
2018 June	7	0	7
2018 May	10	0	10
2018 April	35	0	35
2018 March	40	0	40
2018 February	8	0	8
2018 January	37	0	37
2017 December	18	0	18
2017 November	38	0	38
2017 October	42	0	42
2017 September	27	0	27
2017 August	24	0	24
2017 July	41	1	42
2017 June	36	13	49
2017 May	44	11	55
2017 April	39	24	63
2017 March	21	5	26
2017 February	26	11	37
2017 January	35	2	37
2016 December	24	5	29
2016 November	51	8	59
2016 October	30	14	44
2016 September	44	8	52
2016 August	42	17	59
2016 July	33	7	40
2016 May	1	0	1
2016 April	1	0	1
2016 March	2	0	2

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