Methotrexate: New Therapeutic Approaches | Actas Dermo-Sifiliográficas

array:24 ["pii" => "S1578219014001462" "issn" => "15782190" "doi" => "10.1016/j.adengl.2014.05.011" "estado" => "S300" "fechaPublicacion" => "2014-07-01" "aid" => "785" "copyright" => "Elsevier España, S.L. and AEDV" "copyrightAnyo" => "2012" "documento" => "article" "crossmark" => 0 "subdocumento" => "ssu" "cita" => "Actas Dermosifiliogr. 2014;105:583-9" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 2126 "formatos" => array:3 [ "EPUB" => 46 "HTML" => 1538 "PDF" => 542 ] ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S0001731012005765" "issn" => "00017310" "doi" => "10.1016/j.ad.2012.11.017" "estado" => "S300" "fechaPublicacion" => "2014-07-01" "aid" => "785" "copyright" => "Elsevier España, S.L. and AEDV" "documento" => "article" "crossmark" => 0 "subdocumento" => "ssu" "cita" => "Actas Dermosifiliogr. 2014;105:583-9" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 9865 "formatos" => array:3 [ "EPUB" => 2 "HTML" => 1745 "PDF" => 8118 ] ] "es" => array:12 [ "idiomaDefecto" => true "cabecera" => "NOVEDADES EN DERMATOLOGÍA" "titulo" => "Metotrexato: novedades terapéuticas" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "583" "paginaFinal" => "589" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Methotrexate: New Therapeutic Approaches" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "L. Puig" "autores" => array:1 [ 0 => array:2 [ "nombre" => "L." "apellidos" => "Puig" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S1578219014001462" "doi" => "10.1016/j.adengl.2014.05.011" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219014001462?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731012005765?idApp=UINPBA000044" "url" => "/00017310/0000010500000006/v1_201406280127/S0001731012005765/v1_201406280127/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S1578219014001528" "issn" => "15782190" "doi" => "10.1016/j.adengl.2014.05.017" "estado" => "S300" "fechaPublicacion" => "2014-07-01" "aid" => "939" "copyright" => "Elsevier España, S.L. and AEDV" "documento" => "article" "crossmark" => 0 "subdocumento" => "fla" "cita" => "Actas Dermosifiliogr. 2014;105:590-6" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 1554 "formatos" => array:3 [ "EPUB" => 39 "HTML" => 1130 "PDF" => 385 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Original Article" "titulo" => "Allergic Contact Dermatitis due to Nickel: Descriptive Study in a Tertiary Hospital, 2000-2010" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "590" "paginaFinal" => "596" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Dermatitis alérgica de contacto a níquel. Estudio descriptivo en un hospital terciario en la década del 2000 al 2010" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1080 "Ancho" => 1447 "Tamanyo" => 244511 ] ] "descripcion" => array:1 [ "en" => "A-D. Metal objects causing nickel-induced allergic contact dermatitis. Note the positive result in the dimethylglyoxime spot test." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "A.E. García-Rabasco, V. Zaragozá-Ninet, R. García-Ruíz, J. de la Cuadra-Oyanguren" "autores" => array:4 [ 0 => array:2 [ "nombre" => "A.E." "apellidos" => "García-Rabasco" ] 1 => array:2 [ "nombre" => "V." "apellidos" => "Zaragozá-Ninet" ] 2 => array:2 [ "nombre" => "R." "apellidos" => "García-Ruíz" ] 3 => array:2 [ "nombre" => "J." "apellidos" => "de la Cuadra-Oyanguren" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0001731014000040" "doi" => "10.1016/j.ad.2013.12.003" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731014000040?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219014001528?idApp=UINPBA000044" "url" => "/15782190/0000010500000006/v1_201406280124/S1578219014001528/v1_201406280124/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1578219014001504" "issn" => "15782190" "doi" => "10.1016/j.adengl.2014.05.015" "estado" => "S300" "fechaPublicacion" => "2014-07-01" "aid" => "873" "copyright" => "Elsevier España, S.L. and AEDV" "documento" => "article" "crossmark" => 0 "subdocumento" => "ssu" "cita" => "Actas Dermosifiliogr. 2014;105:574-82" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 2618 "formatos" => array:3 [ "EPUB" => 40 "HTML" => 1911 "PDF" => 667 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Controversies in Dermatology" "titulo" => "Circumscribed Palmar or Plantar Hypokeratosis 10 Years After the First Description: What Is Known and the Issues Under Discussion" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "574" "paginaFinal" => "582" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Hipoqueratosis circunscrita palmar o plantar. Conocimientos y controversias tras 10 años de su descripción" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 695 "Ancho" => 981 "Tamanyo" => 92269 ] ] "descripcion" => array:1 [ "en" => "Circumscribed plantar hypokeratosis. A lesion with similar characteristics to those of Fig.1, but in a much less common site (source, Dr. Arno Rütten, with permission)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "F. Urbina, A. Pérez, L. Requena, A. Rütten" "autores" => array:4 [ 0 => array:2 [ "nombre" => "F." "apellidos" => "Urbina" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Pérez" ] 2 => array:2 [ "nombre" => "L." "apellidos" => "Requena" ] 3 => array:2 [ "nombre" => "A." "apellidos" => "Rütten" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0001731013002627" "doi" => "10.1016/j.ad.2013.05.011" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731013002627?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219014001504?idApp=UINPBA000044" "url" => "/15782190/0000010500000006/v1_201406280124/S1578219014001504/v1_201406280124/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Novelties in Dermatology" "titulo" => "Methotrexate: New Therapeutic Approaches" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "583" "paginaFinal" => "589" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "L. Puig" "autores" => array:1 [ 0 => array:3 [ "nombre" => "L." "apellidos" => "Puig" "email" => array:1 [ 0 => "lpuig@santpau.cat" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Metotrexato: novedades terapéuticas" ] ] "textoCompleto" => "IntroductionMethotrexate (MTX, 4-amino-4-deoxy-N10-methyl pteroylglutamic acid) is an analog of aminopterin (4-amino-pteroylglutamic acid), a folic acid antagonist that was introduced in 1948 to treat acute leukemia in children but later replaced by MTX as this had a more favorable toxicity profile. The first study of the efficacy of MTX in the treatment of psoriasis was published in 1958,<a class="elsevierStyleCrossRef" href="#bib0005">1</a> and the first guidelines on its use in dermatology appeared in 1972.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Until quite recently, however, there was relatively little evidence to support the use of MTX in the treatment of psoriasis.Among the advances that justify this review are new efficacy data that have led MTX to be considered the first-line therapy among the classic systemic treatments for psoriasis and new subcutaneous formulations that offer improved bioavailability and convenience of administration.PharmacokineticsMTX can be administered orally, subcutaneously, intramuscularly, or intravenously. In the case of psoriasis, the standard dose (7.5-25mg/wk) is nearly always administered orally or subcutaneously. The bioavailability of low-dose oral MTX is high (70%),<a class="elsevierStyleCrossRef" href="#bib0015">3</a> although it varies from patient to patient. At doses of more than 15mg/wk bioavailability drops to 30%, as the uptake of MTX by the gastrointestinal tract is mediated by a saturable transporter, reduced folate carrier 1 (RFC1).<a class="elsevierStyleCrossRef" href="#bib0015">3</a> The preferred route of administration in such cases is thus generally parenteral, which is also associated with better gastrointestinal tolerability,<a class="elsevierStyleCrossRef" href="#bib0020">4</a> although the use of split doses of oral MTX can improve bioavailability.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The absorption of oral MTX, which primarily occurs in the proximal jejunum, is not affected by food intake, but is decreased in cases of malabsorption or inflammatory bowel disease. The bioavailability of parenteral MTX is similar regardless of the administration route used.Once absorbed, 10% of MTX is converted in the liver to its partly inactive metabolite, 7-hydroxymethotrexate (7-OH-MTX), thereby reducing plasma MTX concentrations. The ability to convert MTX to 7-OH-MTX via aldehyde oxidase varies greatly—relative interindividual differences ranging from 1 to 14 have been described—and exhibits a bimodal distribution in the population. Rapid metabolizers have a poorer therapeutic response to MTX; additionally, folic acid (unlike folinic acid) blocks the production of 7-OH-MTX and could therefore contribute to higher levels of MTX in these patients.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> 7-OH-MTX competes with MTX for cellular uptake via RFCs, which also internalize reduced folates and folic acid, albeit with low affinity. Quantitative or qualitative alterations in RFCs, similarly to high levels of exogenous folates competing for the receptor, can result in transport-related resistance to the therapeutic action of MTX. A recent study described a single nucleotide polymorphism in the RCF1 gene that predicts therapeutic response to MTX in Japanese patients with rheumatoid arthritis,<a class="elsevierStyleCrossRef" href="#bib0035">7</a> illustrating the role that pharmacogenetics may come to play in improving treatment outcomes.MTX, like 7-OH-MTX, is metabolized intracellularly to produce monoglutamates and polyglutamates, which are the main inhibitors of a range of enzymes; the intracellular levels of these metabolites correlate with the therapeutic efficacy of MTX (which is actually a prodrug).<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Both the bioavailability of MTX and its intracellular conjugation are partly determined by the administration route. In one study of patients with rheumatoid arthritis, switching from oral to subcutaneous administration resulted in a 37% increase in the concentration of very long-chain polyglutamates and a 31% reduction in disease activity.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> Polyglutamates are released slowly from the interior of the cell by the action of active efflux carriers, which may contribute to prolonging the elimination of the drug and also reflect pharmacogenetic differences.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> While no studies have demonstrated that genetic variability in the enzymes involved in MTX metabolism is of clinical relevance in psoriasis,<a class="elsevierStyleCrossRef" href="#bib0050">10</a> variations in the genes involved in polyglutamate efflux transporters have been associated with differences in treatment efficacy and the risk of toxicity.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>Between 35% and 50% of circulating MTX binds to albumin (compared with 91%-95% of 7-OH-MTX) and peak concentrations are reached in the kidneys, liver, gallbladder, spleen, skin, and red blood cells (RBCs). RBC MTX levels may indicate possible hematologic toxicity and hepatic accumulation of the drug. MTX tends to accumulate in the extravascular compartment, and therefore extra caution should be exercised in patients with pleural effusion, ascites, or massive edema due to the risk of toxicity from reabsorption of extravascular fluid.Between 65% and 80% of MTX is eliminated unaltered by the kidneys (mainly in the first 12hours after administration) and 20% to 35% undergoes biliary secretion and is metabolized or transferred to other compartments. Glomerular filtration is the main pathway of renal elimination; tubular secretion and reabsorption are also involved but to a lesser extent. Biliary secretion is an important factor in patents with renal insufficiency, who have reduced drug clearance and an increased risk of toxicity. Hemodialysis and peritoneal dialysis result in limited and transient reductions in serum MTX levels due to the drug's low-to-medium protein binding and high tissue distribution.The terminal half-life of MTX in serum is approximately 7 to 10 hours, but it can be as long as 26 hours in some patients. RBC MTX concentrations remain stable for 9 days, while serum levels become undetectable after 52hours.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> Although individual MTX clearance rates can be established with just 2 tests (at 30 and 120minutes after administration), they have not been found to be useful for defining an optimal treatment regimen in rheumatoid arthritis.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> While many drugs interact with MTX, the use of various nonsteroidal anti-inflammatory drugs (NSAIDs) was not found to significantly alter MTX serum levels, as compared with levels in patients not treated with NSAIDs.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> Nevertheless, it is very important to remember that dose reductions are necessary in older patients (>65 years) and patients with renal insufficiency.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>Mechanisms of ActionVarious mechanisms of action have been proposed for MTX. The most relevant in the case of inflammatory diseases is the promotion of adenosine release with subsequent suppression of inflammation.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>MTX inhibits the proliferation of neoplastic cells, blocking the de novo synthesis of purines and pyrimidines by irreversibly inhibiting dihydrofolate reductase, which is responsible for the production of tetrahydrofolate. Although high doses of folic or folinic acid can reverse this effect, folic and folinic acid supplementation in inflammatory diseases is not used for this purpose but rather to prevent MTX toxicity without significantly reducing treatment efficacy.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>The most important mechanism of action of MTX in inflammatory diseases is probably related to the recently described anti-inflammatory activity of adenosine through specific receptors.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> In both animal models of inflammation and patients with rheumatoid arthritis, MTX induces the extracellular release of adenosine, which acts as an anti-inflammatory agent through specific type A2 receptors<a class="elsevierStyleCrossRef" href="#bib0090">18</a> that also participate in the pathogenesis of hepatic fibrosis.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>MTX, especially in its polyglutamate form—which accumulates in the interior of cells—inhibits AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) transformylase.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> This results in the intracellular accumulation of AICAR, which competitively inhibits adenosine monophosphate desaminase. The increased intracellular levels of AICAR would then induce the release of adenine nucleotides and their conversion to adenosine by ecto-5’-nucleotidase (CD73).<a class="elsevierStyleCrossRefs" href="#bib0105">21,22</a> Adenosine has a very short half-life (of just seconds) in peripheral blood and body fluids, and it is therefore extremely difficult to measure its levels. Most of the studies published have based their measurements on the inhibition of the biological effects of adenosine using drugs that inhibit the metabolism or receptors of MTX<a class="elsevierStyleCrossRefs" href="#bib0115">23,24</a> or on animal models such as the CD73-deficient mouse<a class="elsevierStyleCrossRef" href="#bib0105">21</a> and other mouse strains.<a class="elsevierStyleCrossRef" href="#bib0125">25</a>Caffeine, a nonselective adenosine receptor antagonist, blocks the anti-inflammatory effects of MTX in vitro and in animal models of arthritis<a class="elsevierStyleCrossRef" href="#bib0130">26</a>; it is therefore possible that coffee and other caffeine drinks interfere with the therapeutic (and perhaps toxic) activity of MTX. This hypothesis is supported by the findings of several studies<a class="elsevierStyleCrossRef" href="#bib0135">27</a> but was not corroborated in a retrospective study of patients with rheumatoid artritis.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> Moreover, no relationship was found between MTX at a maintenance dose and coffee consumption in patients with psoriasis or psoriatic arthritis.<a class="elsevierStyleCrossRef" href="#bib0145">29</a>Although the antiproliferative action of MTX explains stomatitis, anemia, leukopenia, and alopecia, the release of adenosine could help to explain other adverse effects of this drug. Adenosine binding to A1 and A2B receptors induces hepatic steatosis,<a class="elsevierStyleCrossRef" href="#bib0150">30</a> while binding to A2A receptors plays a role in the development of fibrosis<a class="elsevierStyleCrossRef" href="#bib0155">31</a> and hepatic cirrhosis.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> Some patients have reported marked asthenia on the day they take MTX. This may be related to the release of adenosine into the central nervous system<a class="elsevierStyleCrossRef" href="#bib0160">32</a> and could be improved with the administration of aminophylline.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>Another possible mechanism of action of MTX may involve its inhibitory effect on the proliferation of antigen-stimulated T cells, which has been reported both in vitro and in patients receiving MTX,<a class="elsevierStyleCrossRef" href="#bib0170">34</a> or the induction of apoptosis in activated T cells,<a class="elsevierStyleCrossRef" href="#bib0165">33</a> which may also be mediated by adenosine receptors.<a class="elsevierStyleCrossRef" href="#bib0175">35</a>Finally, the action of MTX in psoriasis could be mediated by the suppression of T-cell activation (through folate-dependent mechanisms) and the altered expression of adhesion molecules; adenosine would also have a role in this mechanism.<a class="elsevierStyleCrossRef" href="#bib0180">36</a>Efficacy in PsoriasisA number of clinical trials in recent years have explored the efficacy of MTX in psoriasis and compared it with other options.<a class="elsevierStyleCrossRefs" href="#bib0185">37–42</a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the findings.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Various regimens can produce a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) in up to 40% of patients by week 24, although in most cases PASI response at week 12 is a good indicator of whether treatment should be continued or not.<a class="elsevierStyleCrossRef" href="#bib0190">38</a>Experience with combination regimens of MTX and diverse biologics to treat moderate to severe psoriasis has shown improved patient responses and treatment adherence. The possible mechanisms underlying these effects include reduced clearance of the biologic agent and reduced production of antibodies against the agent.<a class="elsevierStyleCrossRef" href="#bib0215">43</a>The results of a clinical trial comparing etanercept monotherapy and etanercept plus MTX in 239 patients per arm were recently published.<a class="elsevierStyleCrossRef" href="#bib0220">44</a> Patients in the monotherapy arm received 50mg twice weekly for 12 weeks followed by 50mg weekly for 12 weeks, while those in the combination therapy group received 7.5mg weekly for the first 2 weeks, 10mg weekly for the next 2 weeks, and up to 15mg weekly up to week 24. Combination therapy with etanercept plus MTX was superior to etanercept alone, with PASI 75 responses observed in 70% of patients at week 12 (vs 54% in the monotherapy group) and in 77% of patients (vs 60%) at week 24. The corresponding rates of PASI 90 responses were 34% vs 23% and 54% vs 34%, respectively.Patterns of Use and Administration RoutesPatterns of MTX use by both rheumatologists and dermatologists have changed somewhat in recent years. One recent review concluded that the bioavailability of oral MTX decreases at doses above 17.5mg,<a class="elsevierStyleCrossRef" href="#bib0225">45</a> indicating that parenteral administration is preferable. In a clinical trial comparing the efficacy and safety of oral and subcutaneous MTX in patients with rheumatoid arthritis, 78% of patients treated with subcutaneous MTX and 70% of those treated with oral MTX achieved the treatment goal of a 20% improvement in the American College of Rheumatology criteria (ACR20) by week 48.<a class="elsevierStyleCrossRef" href="#bib0230">46</a> There were also differences in the frequency of adverse effects between the groups (66% vs 62%) but these were not statistically significant. Thirty percent of the patients who did not respond to oral MTX 15mg achieved an ACR20 response when they were switched to subcutaneous MTX. The study is the first to provide formal proof that subcutaneous MTX has superior clinical efficacy to oral MTX,<a class="elsevierStyleCrossRef" href="#bib0235">47</a> and one would expect these results to be extrapolated to the treatment of psoriasis, despite the current lack of scientific evidence in this setting. The main advantage of the subcutaneous route is the superior bioavailability of MTX. It has been demonstrated that the increased effectiveness seen in rheumatoid arthritis patients following a switch from oral to subcutaneous MTX without a change in dose is accompanied by an increase in RBC MTX polyglutamate concentrations, although it may take 6 months for the new steady-state concentrations to be reached.<a class="elsevierStyleCrossRef" href="#bib0240">48</a>Data on the superior clinical efficacy of subcutaneous MTX in the treatment of rheumatoid arthritis were used as the starting point for a pharmacoeconomic analysis conducted in Spain that concluded that the additional cost associated with the use of the subcutaneous route would be offset by improved effectivness.<a class="elsevierStyleCrossRef" href="#bib0245">49</a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the results of an incremental cost-effectiveness analysis of subcutaneous MTX and several alternatives based on data from comparative clinical trials. The results show that subcutaneous MTX has a higher incremental cost-effectiveness ratio to ciclosporin, adalimumab, and infliximab in the treatment of moderate to severe psoriasis. (We have omitted the sensitivity analysis and confidence intervals due to space constraints.)A study of MTX use among dermatologists and rheumatologists in Canada reported that most dermatologists (97%) and rheumatologists (80%) start treating psoriasis with oral MTX and that fewer dermatologists subsequently switch to parenteral MTX (49% vs 96% of rheumatologists); of the dermatologists that do switch 63% choose the subcutaneous route (vs 98% of the rheumatologists).<a class="elsevierStyleCrossRef" href="#bib0250">50</a>Considering that the usefulness of test doses of MTX in psoriasis is still being questioned (treatment is commonly initiated with a dose of 10 to 15mg in selected patients),<a class="elsevierStyleCrossRef" href="#bib0255">51</a> the advantages of subcutaneous MTX in rheumatoid arthritis (greater efficacy<a class="elsevierStyleCrossRef" href="#bib0225">45</a> and fewer gastrointestinal problems<a class="elsevierStyleCrossRef" href="#bib0260">52</a>) could probably be extrapolated to psoriasis, and it would appear reasonable to assume that subcutaneous MTX will be increasingly used in dermatology. Greater familiarity with subcutaneous injections among dermatology patients will undoubtedly contribute to this increased use, as will the introduction of higher-concentration formulations (50mg/mL) in prefilled syringes, as these offer greater tolerability and convenience<a class="elsevierStyleCrossRef" href="#bib0265">53</a> and are preferred to the 10-mg/mL formulations by the majority of patients treated with 20mg per week.<a class="elsevierStyleCrossRef" href="#bib0270">54</a> Single-dose formulations also have environmental and safety benefits as they eliminate the need to handle and discard unused portions of vials or syringes.<a class="elsevierStyleCrossRef" href="#bib0275">55</a>Ethical DisclosuresProtection of humans and animalsThe authors declare that no tests were carried out in humans or animals for the purpose of this study.Confidentiality of dataThe authors declare that they have followed their hospital's protocol on the publication of data concerning patients and that all patients included in the study have received sufficient information and have given their written informed consent to participate in the study.Right to privacy and informed consentThe authors declare that no private patient data appear in this article.Conflicts of InterestThe author has received speakers and/or consultancy and/or clinical trial investigator fees from Gebro Pharma and Pfizer; he has also received fees from Marge Medica Books for coordinating and co-authoring Methotraxate and psoriasis. Barcelona: Marge Medica Books; 2012, sponsored by Gebro Pharma." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:2 [ "identificador" => "xres349093" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec330760" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres349094" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec330759" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Pharmacokinetics" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Mechanisms of Action" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Efficacy in Psoriasis" ] ] ] 7 => array:2 [ "identificador" => "sec0025" "titulo" => "Patterns of Use and Administration Routes" ] 8 => array:3 [ "identificador" => "sec0030" "titulo" => "Ethical Disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Protection of humans and animals" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Right to privacy and informed consent" ] ] ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflicts of Interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-10-12" "fechaAceptado" => "2012-11-29" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec330760" "palabras" => array:6 [ 0 => "Psoriasis" 1 => "Methotrexate" 2 => "Clinical trials" 3 => "Pharmacokinetics" 4 => "Mechanism of action" 5 => "Cost-effectiveness" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec330759" "palabras" => array:6 [ 0 => "Psoriasis" 1 => "Metotrexato" 2 => "Ensayos clínicos" 3 => "Farmacocinética" 4 => "Mecanismo de acción" 5 => "Coste-eficacia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Although the first study on the efficacy of methotrexate in the treatment of psoriasis was reported in 1958, scientific evidence for this indication has been scant until quite recently. We now have new data on the pharmacokinetics and mechanism of action of methotrexate and new subcutaneous formulations that have improved the bioavailability, efficacy, and ease of administration of the drug. The results of recent clinical trials comparing methotrexate with several biologic agents have shown it to be the first-line therapy among the classic systemic treatments for psoriasis. Moreover, the incremental cost-effectiveness ratio for subcutaneous methotrexate has been shown to be superior to that of ciclosporin, adalimumab, and infliximab." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Pese a que el primer estudio sobre la eficacia de metotrexato en el tratamiento de la psoriasis se remonta a 1958, hasta no hace mucho ha sido escasa la evidencia científica disponible sobre su uso en esta indicación.Disponemos de nuevos datos acerca de la farmacocinética y el mecanismo de acción del metotrexato, así como de nuevas presentaciones por vía subcutánea que mejoran la biodisponibilidad, la eficacia y la conveniencia de la administración de este fármaco. La reciente publicación de ensayos clínicos comparativos con diversos biológicos permite considerar al metotrexato como el estándar terapéutico dentro de los tratamientos sistémicos clásicos de la psoriasis, con un cociente coste-eficacia incremental favorable al metotrexato subcutáneo si se compara con ciclosporina, adalimumab o infliximab." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Puig L. Metotrexato: novedades terapéuticas. Actas Dermosifiliogr. 2014;105:583–589." ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "Abbreviations: ALT, alanine aminotransferase; PASI, Psoriasis Area and Severity Index; PASI 50, ≥50% improvement in PASI score with respect to baseline; PASI 75, ≥75% improvement in PASI score with respect to baseline; PASI 90, ≥90% improvement in PASI score with respect to baseline; PGA, physician's global assessment." "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">MTX Regimen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Comparator \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">No. Treated (MTX) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">PASI 75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">ICER<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> PASI 75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">PASI 90 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Observations \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15mg/wk \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ciclosporin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60% wk 16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">691.52–390.88/0.71–0.60=€2733.09 in favor of subcutaneous MTX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40% wk 16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 patients had to stop taking MTX due to an increase in transanimase levels (max. ALT level, 198/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heydendael et al.<a class="elsevierStyleCrossRef" href="#bib0185">37</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.5mg/wk with gradual increments up to 15mg/wk in patients who did not achieve PASI 50. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ciclosporin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24% wk 12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">518.64–293.16/0.58–0.60=€633.18 in favor of subcutaneous MTX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11% wk 12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Flytström et al.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Initial dose of 7.5mg/wk, 10mg from wk 2, 15mg from wk 4. Increase to 20mg in patients who did not achieve PASI 50 by wk 8; increase to 25mg in patients who did not achieve PASI 50 by wk 12. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Adalimumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">110 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36% wk 16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6355.96–390.88/0.80–0.36=€13 557 in favor of subcutaneous MTX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14% wk 16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Treatment discontinuation recommended if no response by wk 12<a class="elsevierStyleCrossRef" href="#bib0195">39</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Saurat et al.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15mg/wk for first 6 wk; thereafter, dose increments up to 20mg/wk if PASI improvement was <25%. Patients who did not achieve PASI 50 or who did not tolerate treatment were able to change treatment arm at wk 16. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Infliximab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">215 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42% wk 1631% wk 26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8006.44–390.88/0.78–0.42=€21 154.33 in favor of subcutaneous MTX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19% wk 1615% wk 26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Barker et al.<a class="elsevierStyleCrossRef" href="#bib0205">41</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Initial dose of 5mg/wk, 10mg/wk for 1 wk, 15mg up to wk 9; 20mg after wk 10, and 25mg after wk 16 in patients who did not achieve PASI 75 or a PGA score of 0 or 1. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Briakinumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">163 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36% wk 1240% wk 2424% wk 52 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≈14% wk 12<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a>≈23% wk 24<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a>≈17% wk 52<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Reich et al.<a class="elsevierStyleCrossRef" href="#bib0210">42</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab521000.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "ICER, incremental cost-effectiveness ratio (cost of alternative−cost of subcutaneous MTX)/(efficacy alternative−efficacy subcutaneous MTX). Recommended retail prices as of October 2012. Metoject: €19.36€/wk (7.5mg); €24.43/wk (15mg) (based on maximum dose). Sandimmun Neoral 100mg/mL suspension: €128.62/50mL; €43.22/wk based on starting dose of 3mg/kg/d for a patient weighing 80kg. Remicade: 80kg, 4 vials of 100mg (€615.88) × 3.25 doses (16 wk)=€8006.44. Humira: €1127.57/2 × 9.5 doses (16 wk)=€5355.96." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Obtained by interpolation from graph." ] ] ] "descripcion" => array:1 [ "en" => "Summary of Comparative Clinical Trials of Methotrexate (MTX) in Psoriasis." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:55 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of psoriasis with folic acid antagonists" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "W.F. Edmundson" 1 => "W.B. Guy" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "AMA Arch Derm" "fecha" => "1958" "volumen" => "78" "paginaInicial" => "200" "paginaFinal" => "203" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/13558707" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Use of methotrexate in psoriasis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "H.H. Roenigk Jr." 1 => "H.I. Maibach" 2 => "G.D. Weinstein" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Dermatol" "fecha" => "1972" "volumen" => "105" "paginaInicial" => "363" "paginaFinal" => "365" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/5012144" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Understanding the mechanisms of action of methotrexate: implications for the treatment of rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H. Tian" 1 => "B.N. Cronstein" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Bull NYU Hosp Jt Dis" "fecha" => "2007" "volumen" => "65" "paginaInicial" => "168" "paginaFinal" => "173" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17922664" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Why intramuscular methotrexate works better than oral drug in patients with rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R.A. Hamilton" 1 => "J.M. Kremer" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Br J Rheumatol" "fecha" => "1997" "volumen" => "36" "paginaInicial" => "86" "paginaFinal" => "90" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9117183" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Splitting high-dose oral methotrexate improves bioavailability: a pharmacokinetic study in patients with rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M. Hoekstra" 1 => "C. Haagsma" 2 => "C. Neef" 3 => "J. Proost" 4 => "A. Knuif" 5 => "M. van de Laar" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "2006" "volumen" => "33" "paginaInicial" => "481" "paginaFinal" => "485" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16463431" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Methotrexate catabolism to 7-hydroxymethotrexate in rheumatoid arthritis alters drug efficacy and retention and is reduced by folic acid supplementation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.E. Baggott" 1 => "S.L. Morgan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.24685" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2009" "volumen" => "60" "paginaInicial" => "2257" "paginaFinal" => "2261" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19644884" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A single nucleotide polymorphism of reduced folate carrier 1 predicts methotrexate efficacy in Japanese patients with rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Hayashi" 1 => "Y. Tazoe" 2 => "S. Tsuboi" 3 => "M. Horino" 4 => "M. Morishita" 5 => "T. Arai" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Drug Metab Pharmacokinet" "fecha" => "2012" "volumen" => "11" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Red blood cell methotrexate polyglutamates emerge as a function of dosage intensity and route of administration during pulse methotrexate therapy in rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "T. Dervieux" 1 => "R. Zablocki" 2 => "J. Kremer" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2010" "volumen" => "49" "paginaInicial" => "2337" "paginaFinal" => "2345" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The pharmacogenetics of methotrexate" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "S.L. Hider" 1 => "I.N. Bruce" 2 => "W. Thomson" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2007" "volumen" => "46" "paginaInicial" => "1520" "paginaFinal" => "1524" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.B. Warren" 1 => "R.L. Smith" 2 => "E. Campalani" 3 => "S. Eyre" 4 => "C.H. Smith" 5 => "J.N. Barker" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2133.2008.08898.x" "Revista" => array:6 [ "tituloSerie" => "Br J Dermatol" "fecha" => "2009" "volumen" => "160" "paginaInicial" => "438" "paginaFinal" => "441" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19016697" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetic variation in efflux transporters influences outcome to methotrexate therapy in patients with psoriasis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.B. Warren" 1 => "R.L. Smith" 2 => "E. Campalani" 3 => "S. Eyre" 4 => "C.H. Smith" 5 => "J.N. Barker" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/jid.2008.16" "Revista" => array:6 [ "tituloSerie" => "J Invest Dermatol" "fecha" => "2008" "volumen" => "128" "paginaInicial" => "1925" "paginaFinal" => "1929" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18256692" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients. Association with hepatic folate deficiency and formation of polyglutamates" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "J.M. Kremer" 1 => "J. Galivan" 2 => "A. Streckfuss" 3 => "B. Kamen" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "1986" "volumen" => "29" "paginaInicial" => "832" "paginaFinal" => "835" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2427090" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lack of correlation between pharmacokinetics and efficacy of low dose methotrexate in patients with rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "P. Lafforgue" 1 => "S. Monjanel-Mouterde" 2 => "A. Durand" 3 => "J. Catalin" 4 => "P.C. Acquaviva" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "1995" "volumen" => "22" "paginaInicial" => "844" "paginaFinal" => "849" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8587070" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Monitoring methotrexate therapy in patients with rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A. Wiela-Hojenska" 1 => "K. Orzechowska-Juzwenko" 2 => "J. Swierkot" 3 => "P. Wiland" 4 => "M. Hurkacz" 5 => "J. Szechinski" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Int J Clin Pharmacol Ther" "fecha" => "2004" "volumen" => "42" "paginaInicial" => "434" "paginaFinal" => "441" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15366323" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Total and free methotrexate pharmacokinetics in elderly patients with rheumatoid arthritis. A comparison with young patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "F. Bressolle" 1 => "C. Bologna" 2 => "J.M. Kinowski" 3 => "B. Arcos" 4 => "J. Sany" 5 => "B. Combe" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "1997" "volumen" => "24" "paginaInicial" => "1903" "paginaFinal" => "1909" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9330930" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of folic or folinic acid supplementation on methotrexate-associated safety and efficacy in inflammatory disease: a systematic review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "S. Prey" 1 => "C. Paul" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2133.2008.08876.x" "Revista" => array:6 [ "tituloSerie" => "Br J Dermatol" "fecha" => "2009" "volumen" => "160" "paginaInicial" => "622" "paginaFinal" => "628" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18945303" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "How does methotrexate suppress inflammation?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "B. Cronstein" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Clin Exp Rheumatol" "fecha" => "2010" "volumen" => "28" "numero" => "5 Suppl 61" "paginaInicial" => "S21" "paginaFinal" => "S23" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21044428" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.C. Montesinos" 1 => "A. Desai" 2 => "D. Delano" 3 => "J.F. Chen" 4 => "J.S. Fink" 5 => "M.A. Jacobson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.10712" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2003" "volumen" => "48" "paginaInicial" => "240" "paginaFinal" => "247" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12528125" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.S. Chan" 1 => "M.C. Montesinos" 2 => "P. Fernandez" 3 => "A. Desai" 4 => "D.L. Delano" 5 => "H. Yee" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/sj.bjp.0706812" "Revista" => array:6 [ "tituloSerie" => "Br J Pharmacol" "fecha" => "2006" "volumen" => "148" "paginaInicial" => "1144" "paginaFinal" => "1155" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16783407" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Differences in methotrexate and 7-hydroxymethotrexate inhibition of folate-dependent enzymes of purine nucleotide biosynthesis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.E. Baggott" 1 => "S.L. Morgan" 2 => "W.H. Vaughn" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Biochem J" "fecha" => "1994" "volumen" => "300" "numero" => "Pt 3" "paginaInicial" => "627" "paginaFinal" => "629" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8010943" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "B.N. Cronstein" 1 => "D. Naime" 2 => "E. Ostad" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI116884" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "1993" "volumen" => "92" "paginaInicial" => "2675" "paginaFinal" => "2682" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8254024" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The antiinflammatory mechanism of methotrexate depends on extracellular conversion of adenine nucleotides to adenosine by ecto-5’-nucleotidase: findings in a study of ecto-5’-nucleotidase gene-deficient mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.C. Montesinos" 1 => "M. Takedachi" 2 => "L.F. Thompson" 3 => "T.F. Wilder" 4 => "P. Fernández" 5 => "B.N. Cronstein" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.22643" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2007" "volumen" => "56" "paginaInicial" => "1440" "paginaFinal" => "1445" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17469101" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5’-nucleotidase-mediated conversion of adenine nucleotides" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Morabito" 1 => "M.C. Montesinos" 2 => "D.M. Schreibman" 3 => "L. Balter" 4 => "L.F. Thompson" 5 => "R. Resta" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI1554" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "1998" "volumen" => "101" "paginaInicial" => "295" "paginaFinal" => "300" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9435300" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Methotrexate modulates the kinetics of adenosine in humans in vivo" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "N.P. Riksen" 1 => "P. Barrera" 2 => "P.H. van den Broek" 3 => "P.L. van Riel" 4 => "P. Smits" 5 => "G.A. Rongen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/ard.2005.048637" "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2006" "volumen" => "65" "paginaInicial" => "465" "paginaFinal" => "470" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16308339" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetically based resistance to the anti-inflammatory effects of methotrexate in the air-pouch model of acute inflammation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.L. Delano" 1 => "M.C. Montesinos" 2 => "A. Desai" 3 => "T. Wilder" 4 => "P. Fernandez" 5 => "P. d’Eustachio" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.21208" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2005" "volumen" => "52" "paginaInicial" => "2567" "paginaFinal" => "2575" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16059892" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Reversal of the antiinflammatory effects of methotrexate by the nonselective adenosine receptor antagonists theophylline and caffeine: evidence that the antiinflammatory effects of methotrexate are mediated via multiple adenosine receptors in rat adjuvant arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.C. Montesinos" 1 => "J.S. Yap" 2 => "A. Desai" 3 => "I. Posadas" 4 => "C.T. McCrary" 5 => "B.N. Cronstein" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/1529-0131(200003)43:3<656::AID-ANR23>3.0.CO;2-H" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2000" "volumen" => "43" "paginaInicial" => "656" "paginaFinal" => "663" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10728760" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of caffeine consumption on efficacy of methotrexate in rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "G. Nesher" 1 => "M. Mates" 2 => "S. Zevin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.10766" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2003" "volumen" => "48" "paginaInicial" => "571" "paginaFinal" => "572" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12571869" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dietary caffeine intake does not affect methotrexate efficacy in patients with rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Benito-Garcia" 1 => "J.E. Heller" 2 => "L.B. Chibnik" 3 => "N.E. Maher" 4 => "H.M. Matthews" 5 => "J.A. Bilics" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "2006" "volumen" => "33" "paginaInicial" => "1275" "paginaFinal" => "1281" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16821266" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Caffeine consumption and methotrexate dosing requirement in psoriasis and psoriatic arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "D.L. Swanson" 1 => "S.A. Barnes" 2 => "S.J. Mengden Koon" 3 => "R.A. el-Azhary" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-4632.2006.02954.x" "Revista" => array:6 [ "tituloSerie" => "Int J Dermatol" "fecha" => "2007" "volumen" => "46" "paginaInicial" => "157" "paginaFinal" => "159" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17269967" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adenosine signaling contributes to ethanol-induced fatty liver in mice" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Z. Peng" 1 => "P.A. Borea" 2 => "K. Varani" 3 => "T. Wilder" 4 => "H. Yee" 5 => "L. Chiriboga" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI37409" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "2009" "volumen" => "119" "paginaInicial" => "582" "paginaFinal" => "594" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19221436" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ecto-5’-nucleotidase (CD73) -mediated extracellular adenosine production plays a critical role in hepatic fibrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Z. Peng" 1 => "P. Fernandez" 2 => "T. Wilder" 3 => "H. Yee" 4 => "L. Chiriboga" 5 => "E.S. Chan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1096/fj.07-100685" "Revista" => array:6 [ "tituloSerie" => "FASEB J" "fecha" => "2008" "volumen" => "22" "paginaInicial" => "2263" "paginaFinal" => "2272" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18263696" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Neuroanatomy and neurochemistry of sleep" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "D. Stenberg" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00018-007-6530-3" "Revista" => array:6 [ "tituloSerie" => "Cell Mol Life Sci" "fecha" => "2007" "volumen" => "64" "paginaInicial" => "1187" "paginaFinal" => "1204" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17364141" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aminophylline for methotrexate-induced neurotoxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J.C. Bernini" 1 => "D.W. Fort" 2 => "J.C. Griener" 3 => "B.J. Kane" 4 => "W.B. Chappell" 5 => "B.A. Kamen" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "1995" "volumen" => "345" "paginaInicial" => "544" "paginaFinal" => "547" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7776773" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "L. Genestier" 1 => "R. Paillot" 2 => "S. Fournel" 3 => "C. Ferraro" 4 => "P. Miossec" 5 => "J.P. Revillard" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI2676" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "1998" "volumen" => "102" "paginaInicial" => "322" "paginaFinal" => "328" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9664073" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0175" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Expression of A2B adenosine receptors in human lymphocytes: their role in T cell activation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M. Mirabet" 1 => "C. Herrera" 2 => "O.J. Cordero" 3 => "J. Mallol" 4 => "C. Lluis" 5 => "R. Franco" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "J Cell Sci" "fecha" => "1999" "volumen" => "112" "numero" => "Pt 4" "paginaInicial" => "491" "paginaFinal" => "502" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9914161" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0180" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The effect of methotrexate on the expression of cell adhesion molecules and activation molecule CD69 in psoriasis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "B. Torres-Álvarez" 1 => "J.P. Castanedo-Cazares" 2 => "C. Fuentes-Ahumada" 3 => "B. Moncada" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1468-3083.2006.01916.x" "Revista" => array:6 [ "tituloSerie" => "J Eur Acad Dermatol Venereol" "fecha" => "2007" "volumen" => "21" "paginaInicial" => "334" "paginaFinal" => "339" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17309454" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "V.M. Heydendael" 1 => "P.I. Spuls" 2 => "B.C. Opmeer" 3 => "C.A. de Borgie" 4 => "J.B. Reitsma" 5 => "W.F. Goldschmidt" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa021359" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2003" "volumen" => "349" "paginaInicial" => "658" "paginaFinal" => "665" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12917302" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0190" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Methotrexate vs ciclosporin in psoriasis: effectiveness, quality of life and safety. A randomized controlled trial" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "I. Flytström" 1 => "B. Stenberg" 2 => "A. Svensson" 3 => "I.M. Bergbrant" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2133.2007.08284.x" "Revista" => array:6 [ "tituloSerie" => "Br J Dermatol" "fecha" => "2008" "volumen" => "158" "paginaInicial" => "116" "paginaFinal" => "121" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17986302" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0195" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Relationship between methotrexate dosing and clinical response in patients with moderate to severe psoriasis: subanalysis of the CHAMPION study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J.H. Saurat" 1 => "R.G. Langley" 2 => "K. Reich" 3 => "K. Unnebrink" 4 => "E.H. Sasso" 5 => "W. Kampman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2133.2011.10399.x" "Revista" => array:6 [ "tituloSerie" => "Br J Dermatol" "fecha" => "2011" "volumen" => "165" "paginaInicial" => "399" "paginaFinal" => "406" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21564071" "web" => "Medline" ] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0200" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CHAMPION Study Investigators. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs methotrexate vs placebo in patients with psoriasis (CHAMPION)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.H. Saurat" 1 => "G. Stingl" 2 => "L. Dubertret" 3 => "K. Papp" 4 => "R.G. Langley" 5 => "J.P. Ortonne" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2133.2007.08315.x" "Revista" => array:6 [ "tituloSerie" => "Br J Dermatol" "fecha" => "2008" "volumen" => "158" "paginaInicial" => "558" "paginaFinal" => "566" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18047523" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0205" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of infliximab vs methotrexate in patients with moderate-to-severe plaque psoriasis: results of an open-label, active-controlled, randomized trial (RESTORE1)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Barker" 1 => "M. Hoffmann" 2 => "G. Wozel" 3 => "J.P. Ortonne" 4 => "H. Zheng" 5 => "H. van Hoogstraten" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2133.2011.10615.x" "Revista" => array:6 [ "tituloSerie" => "Br J Dermatol" "fecha" => "2011" "volumen" => "165" "paginaInicial" => "1109" "paginaFinal" => "1117" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21910713" "web" => "Medline" ] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0210" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A 52-week trial comparing briakinumab with methotrexate in patients with psoriasis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Reich" 1 => "R.G. Langley" 2 => "K.A. Papp" 3 => "J.P. Ortonne" 4 => "K. Unnebrink" 5 => "M. Kaul" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1010858" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2011" "volumen" => "365" "paginaInicial" => "1586" "paginaFinal" => "1596" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22029980" "web" => "Medline" ] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0215" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metotrexato: guía de uso en psoriasis" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "Grupo de Psoriasis de la AEDV" "etal" => true "autores" => array:6 [ 0 => "G. Carretero" 1 => "L. Puig" 2 => "L. Dehesa" 3 => "J.M. Carrascosa" 4 => "M. Ribera" 5 => "M. Sánchez-Regaña" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Actas Dermosifiliogr" "fecha" => "2010" "volumen" => "101" "paginaInicial" => "600" "paginaFinal" => "613" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20858386" "web" => "Medline" ] ] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0220" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.B. Gottlieb" 1 => "R.G. Langley" 2 => "B.E. Strober" 3 => "K.A. Papp" 4 => "P. Klekotka" 5 => "K. Creamer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2133.2012.11015.x" "Revista" => array:6 [ "tituloSerie" => "Br J Dermatol" "fecha" => "2012" "volumen" => "167" "paginaInicial" => "649" "paginaFinal" => "657" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22533447" "web" => "Medline" ] ] ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0225" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Methotrexate bioavailability" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "E.N. Van Roon" 1 => "M.A. van de Laar" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Clin Exp Rheumatol" "fecha" => "2010" "volumen" => "28" "numero" => "5 Suppl 61" "paginaInicial" => "S27" "paginaFinal" => "S32" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20868567" "web" => "Medline" ] ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0230" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase iv trial" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "MC-MTX.6/RH Study Group" "etal" => true "autores" => array:6 [ 0 => "J. Braun" 1 => "P. Kästner" 2 => "P. Flaxenberg" 3 => "J. Währisch" 4 => "P. Hanke" 5 => "W. Demary" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.23144" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2008" "volumen" => "58" "paginaInicial" => "73" "paginaFinal" => "81" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18163521" "web" => "Medline" ] ] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0235" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Optimal administration and dosage of methotrexate" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J. Braun" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Clin Exp Rheumatol" "fecha" => "2010" "volumen" => "28" "numero" => "5 Suppl 61" "paginaInicial" => "S46" "paginaFinal" => "S51" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21122269" "web" => "Medline" ] ] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0240" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of changing from oral to subcutaneous methotrexate on red blood cell methotrexate polyglutamate concentrations and disease activity in patients with rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L.K. Stamp" 1 => "M.L. Barclay" 2 => "J.L. O’Donnell" 3 => "M. Zhang" 4 => "J. Drake" 5 => "C. Frampton" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3899/jrheum.110481" "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "2011" "volumen" => "38" "paginaInicial" => "2540" "paginaFinal" => "2547" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21965639" "web" => "Medline" ] ] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0245" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Análisis farmacoeconómico de Metoject® en el tratamiento de la artritis reumatoide en España" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Crespo" 1 => "M. Brosa" 2 => "J. Galván" 3 => "J. Carbonell" 4 => "J. Maymó" 5 => "J.L. Marenco" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.reuma.2009.11.001" "Revista" => array:6 [ "tituloSerie" => "Reumatol Clin" "fecha" => "2010" "volumen" => "6" "paginaInicial" => "203" "paginaFinal" => "211" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21794714" "web" => "Medline" ] ] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0250" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Differing patterns of methotrexate use for psoriatic disease amongst dermatologists and rheumatologists" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "E.C. Dupuis" 1 => "V.M. Bhole" 2 => "J.P. DFutz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2133.2012.10880.x" "Revista" => array:6 [ "tituloSerie" => "Br J Dermatol" "fecha" => "2012" "volumen" => "167" "paginaInicial" => "448" "paginaFinal" => "450" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22309601" "web" => "Medline" ] ] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib0255" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metotrexato en psoriasis: ¿es necesaria una dosis de prueba?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "G. Carretero-Hernández" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0001-7310(12)70001-7" "Revista" => array:6 [ "tituloSerie" => "Actas Dermosifiliogr" "fecha" => "2012" "volumen" => "103" "paginaInicial" => "1" "paginaFinal" => "4" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22364603" "web" => "Medline" ] ] ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib0260" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oral vs subcutaneous low-dose methotrexate treatment in reducing gastrointestinal side effects" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "L. Rutkowska-Sak" 1 => "M. Rell-Bakalarska" 2 => "B. Lisowska" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Reumatologia" "fecha" => "2009" "volumen" => "47" "paginaInicial" => "207" "paginaFinal" => "211" ] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib0265" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Preference, satisfaction and usability of subcutaneously administered methotrexate for rheumatoid arthritis or psoriatic arthritis: results of a postmarketing surveillance study with a high-concentration formulation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "F. Striesow" 1 => "A. Brandt" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Ther Adv Musculoeskel Dis" "fecha" => "2011" "volumen" => "4" "paginaInicial" => "3" "paginaFinal" => "9" ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib0270" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tolerability and patient/physician satisfaction with subcutaneously administered methotrexate provided in two formulations of different drug concentrations in patients with rheumatoid arthritis" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "MC-MTX.10/RH Study Group" "etal" => true "autores" => array:6 [ 0 => "U. Müller-Ladner" 1 => "K. Rockwitz" 2 => "J. Brandt-Jürgens" 3 => "R. Haux" 4 => "P. Kästner" 5 => "J. Braun" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2174/1874312901004010015" "Revista" => array:6 [ "tituloSerie" => "Open Rheumatol J" "fecha" => "2010" "volumen" => "4" "paginaInicial" => "15" "paginaFinal" => "22" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20461222" "web" => "Medline" ] ] ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib0275" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Protocolos de vigilancia sanitaria específica. Agentes citostáticos. Comisión de Salud Pública. Consejo Interterritorial del Sistema Nacional de Salud [accessed 24 February 2012]. Available at: <a id="intr0010" class="elsevierStyleInterRef" href="http://www.msc.es/ciudadanos/saludAmbLaboral/docs/Agentescitostaticos.pdf">http://www.msc.es/ciudadanos/saludAmbLaboral/docs/Agentescitostaticos.pdf</a>" ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/15782190/0000010500000006/v1_201406280124/S1578219014001462/v1_201406280124/en/main.assets" "Apartado" => array:4 [ "identificador" => "6170" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Novelties in Dermatology" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/15782190/0000010500000006/v1_201406280124/S1578219014001462/v1_201406280124/en/main.pdf?idApp=UINPBA000044&text.app=https://actasdermo.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219014001462?idApp=UINPBA000044"]

Statistics

Novelties in Dermatology

Methotrexate: New Therapeutic Approaches

Metotrexato: novedades terapéuticas

L. Puig

Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

Read

9345

Times
was read the article

3076

Total PDF

6269

Total HTML

Share statistics

 array:24 [
  "pii" => "S1578219014001462"
  "issn" => "15782190"
  "doi" => "10.1016/j.adengl.2014.05.011"
  "estado" => "S300"
  "fechaPublicacion" => "2014-07-01"
  "aid" => "785"
  "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46; and AEDV"
  "copyrightAnyo" => "2012"
  "documento" => "article"
  "crossmark" => 0
  "subdocumento" => "ssu"
  "cita" => "Actas Dermosifiliogr. 2014;105:583-9"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:2 [
    "total" => 2126
    "formatos" => array:3 [
      "EPUB" => 46
      "HTML" => 1538
      "PDF" => 542
    ]
  ]
  "Traduccion" => array:1 [
    "es" => array:19 [
      "pii" => "S0001731012005765"
      "issn" => "00017310"
      "doi" => "10.1016/j.ad.2012.11.017"
      "estado" => "S300"
      "fechaPublicacion" => "2014-07-01"
      "aid" => "785"
      "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46; and AEDV"
      "documento" => "article"
      "crossmark" => 0
      "subdocumento" => "ssu"
      "cita" => "Actas Dermosifiliogr. 2014;105:583-9"
      "abierto" => array:3 [
        "ES" => true
        "ES2" => true
        "LATM" => true
      ]
      "gratuito" => true
      "lecturas" => array:2 [
        "total" => 9865
        "formatos" => array:3 [
          "EPUB" => 2
          "HTML" => 1745
          "PDF" => 8118
        ]
      ]
      "es" => array:12 [
        "idiomaDefecto" => true
        "cabecera" => "<span class="elsevierStyleTextfn">NOVEDADES EN DERMATOLOG&#205;A</span>"
        "titulo" => "Metotrexato&#58; novedades terap&#233;uticas"
        "tienePdf" => "es"
        "tieneTextoCompleto" => "es"
        "tieneResumen" => array:2 [
          0 => "es"
          1 => "en"
        ]
        "paginas" => array:1 [
          0 => array:2 [
            "paginaInicial" => "583"
            "paginaFinal" => "589"
          ]
        ]
        "titulosAlternativos" => array:1 [
          "en" => array:1 [
            "titulo" => "Methotrexate&#58; New Therapeutic Approaches"
          ]
        ]
        "contieneResumen" => array:2 [
          "es" => true
          "en" => true
        ]
        "contieneTextoCompleto" => array:1 [
          "es" => true
        ]
        "contienePdf" => array:1 [
          "es" => true
        ]
        "autores" => array:1 [
          0 => array:2 [
            "autoresLista" => "L&#46; Puig"
            "autores" => array:1 [
              0 => array:2 [
                "nombre" => "L&#46;"
                "apellidos" => "Puig"
              ]
            ]
          ]
        ]
      ]
      "idiomaDefecto" => "es"
      "Traduccion" => array:1 [
        "en" => array:9 [
          "pii" => "S1578219014001462"
          "doi" => "10.1016/j.adengl.2014.05.011"
          "estado" => "S300"
          "subdocumento" => ""
          "abierto" => array:3 [
            "ES" => true
            "ES2" => true
            "LATM" => true
          ]
          "gratuito" => true
          "lecturas" => array:1 [
            "total" => 0
          ]
          "idiomaDefecto" => "en"
          "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219014001462?idApp=UINPBA000044"
        ]
      ]
      "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731012005765?idApp=UINPBA000044"
      "url" => "/00017310/0000010500000006/v1_201406280127/S0001731012005765/v1_201406280127/es/main.assets"
    ]
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S1578219014001528"
    "issn" => "15782190"
    "doi" => "10.1016/j.adengl.2014.05.017"
    "estado" => "S300"
    "fechaPublicacion" => "2014-07-01"
    "aid" => "939"
    "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46; and AEDV"
    "documento" => "article"
    "crossmark" => 0
    "subdocumento" => "fla"
    "cita" => "Actas Dermosifiliogr. 2014;105:590-6"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 1554
      "formatos" => array:3 [
        "EPUB" => 39
        "HTML" => 1130
        "PDF" => 385
      ]
    ]
    "en" => array:13 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>"
      "titulo" => "Allergic Contact Dermatitis due to Nickel&#58; Descriptive Study in a Tertiary Hospital&#44; 2000-2010"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "590"
          "paginaFinal" => "596"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Dermatitis al&#233;rgica de contacto a n&#237;quel&#46; Estudio descriptivo en un hospital terciario en la d&#233;cada del 2000 al 2010"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig0005"
          "etiqueta" => "Figure 1"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr1.jpeg"
              "Alto" => 1080
              "Ancho" => 1447
              "Tamanyo" => 244511
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">A-D&#46; Metal objects causing nickel-induced allergic contact dermatitis&#46; Note the positive result in the dimethylglyoxime spot test&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "A&#46;E&#46; Garc&#237;a-Rabasco, V&#46; Zaragoz&#225;-Ninet, R&#46; Garc&#237;a-Ru&#237;z, J&#46; de la Cuadra-Oyanguren"
          "autores" => array:4 [
            0 => array:2 [
              "nombre" => "A&#46;E&#46;"
              "apellidos" => "Garc&#237;a-Rabasco"
            ]
            1 => array:2 [
              "nombre" => "V&#46;"
              "apellidos" => "Zaragoz&#225;-Ninet"
            ]
            2 => array:2 [
              "nombre" => "R&#46;"
              "apellidos" => "Garc&#237;a-Ru&#237;z"
            ]
            3 => array:2 [
              "nombre" => "J&#46;"
              "apellidos" => "de la Cuadra-Oyanguren"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "S0001731014000040"
        "doi" => "10.1016/j.ad.2013.12.003"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => true
          "ES2" => true
          "LATM" => true
        ]
        "gratuito" => true
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "es"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731014000040?idApp=UINPBA000044"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219014001528?idApp=UINPBA000044"
    "url" => "/15782190/0000010500000006/v1_201406280124/S1578219014001528/v1_201406280124/en/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S1578219014001504"
    "issn" => "15782190"
    "doi" => "10.1016/j.adengl.2014.05.015"
    "estado" => "S300"
    "fechaPublicacion" => "2014-07-01"
    "aid" => "873"
    "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46; and AEDV"
    "documento" => "article"
    "crossmark" => 0
    "subdocumento" => "ssu"
    "cita" => "Actas Dermosifiliogr. 2014;105:574-82"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 2618
      "formatos" => array:3 [
        "EPUB" => 40
        "HTML" => 1911
        "PDF" => 667
      ]
    ]
    "en" => array:13 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Controversies in Dermatology</span>"
      "titulo" => "Circumscribed Palmar or Plantar Hypokeratosis 10 Years After the First Description&#58; What Is Known and the Issues Under Discussion"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "574"
          "paginaFinal" => "582"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Hipoqueratosis circunscrita palmar o plantar&#46; Conocimientos y controversias tras 10 a&#241;os de su descripci&#243;n"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig0010"
          "etiqueta" => "Figure 2"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr2.jpeg"
              "Alto" => 695
              "Ancho" => 981
              "Tamanyo" => 92269
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Circumscribed plantar hypokeratosis&#46; A lesion with similar characteristics to those of Fig&#46;<span class="elsevierStyleHsp" style=""></span>1&#44; but in a much less common site &#40;source&#44; Dr&#46; Arno R&#252;tten&#44; with permission&#41;&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "F&#46; Urbina, A&#46; P&#233;rez, L&#46; Requena, A&#46; R&#252;tten"
          "autores" => array:4 [
            0 => array:2 [
              "nombre" => "F&#46;"
              "apellidos" => "Urbina"
            ]
            1 => array:2 [
              "nombre" => "A&#46;"
              "apellidos" => "P&#233;rez"
            ]
            2 => array:2 [
              "nombre" => "L&#46;"
              "apellidos" => "Requena"
            ]
            3 => array:2 [
              "nombre" => "A&#46;"
              "apellidos" => "R&#252;tten"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "S0001731013002627"
        "doi" => "10.1016/j.ad.2013.05.011"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => true
          "ES2" => true
          "LATM" => true
        ]
        "gratuito" => true
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "es"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731013002627?idApp=UINPBA000044"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219014001504?idApp=UINPBA000044"
    "url" => "/15782190/0000010500000006/v1_201406280124/S1578219014001504/v1_201406280124/en/main.assets"
  ]
  "en" => array:19 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Novelties in Dermatology</span>"
    "titulo" => "Methotrexate&#58; New Therapeutic Approaches"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "583"
        "paginaFinal" => "589"
      ]
    ]
    "autores" => array:1 [
      0 => array:3 [
        "autoresLista" => "L&#46; Puig"
        "autores" => array:1 [
          0 => array:3 [
            "nombre" => "L&#46;"
            "apellidos" => "Puig"
            "email" => array:1 [
              0 => "lpuig&#64;santpau&#46;cat"
            ]
          ]
        ]
        "afiliaciones" => array:1 [
          0 => array:2 [
            "entidad" => "Servicio de Dermatolog&#237;a&#44; Hospital de la Santa Creu i Sant Pau&#44; Universitat Aut&#242;noma de Barcelona&#44; Barcelona&#44; Spain"
            "identificador" => "aff0005"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Metotrexato&#58; novedades terap&#233;uticas"
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Methotrexate &#40;MTX&#44; <span class="elsevierStyleItalic">4-amino-4-deoxy-N10</span>-methyl pteroylglutamic acid&#41; is an analog of aminopterin &#40;<span class="elsevierStyleItalic">4-amino</span>-pteroylglutamic acid&#41;&#44; a folic acid antagonist that was introduced in 1948 to treat acute leukemia in children but later replaced by MTX as this had a more favorable toxicity profile&#46; The first study of the efficacy of MTX in the treatment of psoriasis was published in 1958&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> and the first guidelines on its use in dermatology appeared in 1972&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Until quite recently&#44; however&#44; there was relatively little evidence to support the use of MTX in the treatment of psoriasis&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Among the advances that justify this review are new efficacy data that have led MTX to be considered the first-line therapy among the classic systemic treatments for psoriasis and new subcutaneous formulations that offer improved bioavailability and convenience of administration&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Pharmacokinetics</span><p id="par0015" class="elsevierStylePara elsevierViewall">MTX can be administered orally&#44; subcutaneously&#44; intramuscularly&#44; or intravenously&#46; In the case of psoriasis&#44; the standard dose &#40;7&#46;5-25<span class="elsevierStyleHsp" style=""></span>mg&#47;wk&#41; is nearly always administered orally or subcutaneously&#46; The bioavailability of low-dose oral MTX is high &#40;70&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> although it varies from patient to patient&#46; At doses of more than 15<span class="elsevierStyleHsp" style=""></span>mg&#47;wk bioavailability drops to 30&#37;&#44; as the uptake of MTX by the gastrointestinal tract is mediated by a saturable transporter&#44; reduced folate carrier 1 &#40;RFC1&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The preferred route of administration in such cases is thus generally parenteral&#44; which is also associated with better gastrointestinal tolerability&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> although the use of split doses of oral MTX can improve bioavailability&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The absorption of oral MTX&#44; which primarily occurs in the proximal jejunum&#44; is not affected by food intake&#44; but is decreased in cases of malabsorption or inflammatory bowel disease&#46; The bioavailability of parenteral MTX is similar regardless of the administration route used&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Once absorbed&#44; 10&#37; of MTX is converted in the liver to its partly inactive metabolite&#44; 7-hydroxymethotrexate &#40;7-OH-MTX&#41;&#44; thereby reducing plasma MTX concentrations&#46; The ability to convert MTX to 7-OH-MTX via aldehyde oxidase varies greatly&#8212;relative interindividual differences ranging from 1 to 14 have been described&#8212;and exhibits a bimodal distribution in the population&#46; Rapid metabolizers have a poorer therapeutic response to MTX&#59; additionally&#44; folic acid &#40;unlike folinic acid&#41; blocks the production of 7-OH-MTX and could therefore contribute to higher levels of MTX in these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> 7-OH-MTX competes with MTX for cellular uptake via RFCs&#44; which also internalize reduced folates and folic acid&#44; albeit with low affinity&#46; Quantitative or qualitative alterations in RFCs&#44; similarly to high levels of exogenous folates competing for the receptor&#44; can result in transport-related resistance to the therapeutic action of MTX&#46; A recent study described a single nucleotide polymorphism in the <span class="elsevierStyleItalic">RCF1</span> gene that predicts therapeutic response to MTX in Japanese patients with rheumatoid arthritis&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> illustrating the role that pharmacogenetics may come to play in improving treatment outcomes&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">MTX&#44; like 7-OH-MTX&#44; is metabolized intracellularly to produce monoglutamates and polyglutamates&#44; which are the main inhibitors of a range of enzymes&#59; the intracellular levels of these metabolites correlate with the therapeutic efficacy of MTX &#40;which is actually a prodrug&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Both the bioavailability of MTX and its intracellular conjugation are partly determined by the administration route&#46; In one study of patients with rheumatoid arthritis&#44; switching from oral to subcutaneous administration resulted in a 37&#37; increase in the concentration of very long-chain polyglutamates and a 31&#37; reduction in disease activity&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Polyglutamates are released slowly from the interior of the cell by the action of active efflux carriers&#44; which may contribute to prolonging the elimination of the drug and also reflect pharmacogenetic differences&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> While no studies have demonstrated that genetic variability in the enzymes involved in MTX metabolism is of clinical relevance in psoriasis&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> variations in the genes involved in polyglutamate efflux transporters have been associated with differences in treatment efficacy and the risk of toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Between 35&#37; and 50&#37; of circulating MTX binds to albumin &#40;compared with 91&#37;-95&#37; of 7-OH-MTX&#41; and peak concentrations are reached in the kidneys&#44; liver&#44; gallbladder&#44; spleen&#44; skin&#44; and red blood cells &#40;RBCs&#41;&#46; RBC MTX levels may indicate possible hematologic toxicity and hepatic accumulation of the drug&#46; MTX tends to accumulate in the extravascular compartment&#44; and therefore extra caution should be exercised in patients with pleural effusion&#44; ascites&#44; or massive edema due to the risk of toxicity from reabsorption of extravascular fluid&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Between 65&#37; and 80&#37; of MTX is eliminated unaltered by the kidneys &#40;mainly in the first 12<span class="elsevierStyleHsp" style=""></span>hours after administration&#41; and 20&#37; to 35&#37; undergoes biliary secretion and is metabolized or transferred to other compartments&#46; Glomerular filtration is the main pathway of renal elimination&#59; tubular secretion and reabsorption are also involved but to a lesser extent&#46; Biliary secretion is an important factor in patents with renal insufficiency&#44; who have reduced drug clearance and an increased risk of toxicity&#46; Hemodialysis and peritoneal dialysis result in limited and transient reductions in serum MTX levels due to the drug&#39;s low-to-medium protein binding and high tissue distribution&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The terminal half-life of MTX in serum is approximately 7 to 10 hours&#44; but it can be as long as 26 hours in some patients&#46; RBC MTX concentrations remain stable for 9 days&#44; while serum levels become undetectable after 52<span class="elsevierStyleHsp" style=""></span>hours&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Although individual MTX clearance rates can be established with just 2 tests &#40;at 30 and 120<span class="elsevierStyleHsp" style=""></span>minutes after administration&#41;&#44; they have not been found to be useful for defining an optimal treatment regimen in rheumatoid arthritis&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> While many drugs interact with MTX&#44; the use of various nonsteroidal anti-inflammatory drugs &#40;NSAIDs&#41; was not found to significantly alter MTX serum levels&#44; as compared with levels in patients not treated with NSAIDs&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Nevertheless&#44; it is very important to remember that dose reductions are necessary in older patients &#40;&#62;<span class="elsevierStyleHsp" style=""></span>65 years&#41; and patients with renal insufficiency&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Mechanisms of Action</span><p id="par0045" class="elsevierStylePara elsevierViewall">Various mechanisms of action have been proposed for MTX&#46; The most relevant in the case of inflammatory diseases is the promotion of adenosine release with subsequent suppression of inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">MTX inhibits the proliferation of neoplastic cells&#44; blocking the de novo synthesis of purines and pyrimidines by irreversibly inhibiting dihydrofolate reductase&#44; which is responsible for the production of tetrahydrofolate&#46; Although high doses of folic or folinic acid can reverse this effect&#44; folic and folinic acid supplementation in inflammatory diseases is not used for this purpose but rather to prevent MTX toxicity without significantly reducing treatment efficacy&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The most important mechanism of action of MTX in inflammatory diseases is probably related to the recently described anti-inflammatory activity of adenosine through specific receptors&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> In both animal models of inflammation and patients with rheumatoid arthritis&#44; MTX induces the extracellular release of adenosine&#44; which acts as an anti-inflammatory agent through specific type A<span class="elsevierStyleInf">2</span> receptors<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> that also participate in the pathogenesis of hepatic fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">MTX&#44; especially in its polyglutamate form&#8212;which accumulates in the interior of cells&#8212;inhibits AICAR &#40;5-aminoimidazole-4-carboxamide ribonucleotide&#41; transformylase&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> This results in the intracellular accumulation of AICAR&#44; which competitively inhibits adenosine monophosphate desaminase&#46; The increased intracellular levels of AICAR would then induce the release of adenine nucleotides and their conversion to adenosine by ecto-5&#8217;-nucleotidase &#40;CD73&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;22</span></a> Adenosine has a very short half-life &#40;of just seconds&#41; in peripheral blood and body fluids&#44; and it is therefore extremely difficult to measure its levels&#46; Most of the studies published have based their measurements on the inhibition of the biological effects of adenosine using drugs that inhibit the metabolism or receptors of MTX<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24</span></a> or on animal models such as the CD73-deficient mouse<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> and other mouse strains&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Caffeine&#44; a nonselective adenosine receptor antagonist&#44; blocks the anti-inflammatory effects of MTX in vitro and in animal models of arthritis<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&#59; it is therefore possible that coffee and other caffeine drinks interfere with the therapeutic &#40;and perhaps toxic&#41; activity of MTX&#46; This hypothesis is supported by the findings of several studies<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> but was not corroborated in a retrospective study of patients with rheumatoid artritis&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Moreover&#44; no relationship was found between MTX at a maintenance dose and coffee consumption in patients with psoriasis or psoriatic arthritis&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Although the antiproliferative action of MTX explains stomatitis&#44; anemia&#44; leukopenia&#44; and alopecia&#44; the release of adenosine could help to explain other adverse effects of this drug&#46; Adenosine binding to A<span class="elsevierStyleInf">1</span> and A<span class="elsevierStyleInf">2B</span> receptors induces hepatic steatosis&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> while binding to A<span class="elsevierStyleInf">2A</span> receptors plays a role in the development of fibrosis<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> and hepatic cirrhosis&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Some patients have reported marked asthenia on the day they take MTX&#46; This may be related to the release of adenosine into the central nervous system<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> and could be improved with the administration of aminophylline&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Another possible mechanism of action of MTX may involve its inhibitory effect on the proliferation of antigen-stimulated T cells&#44; which has been reported both in vitro and in patients receiving MTX&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> or the induction of apoptosis in activated T cells&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> which may also be mediated by adenosine receptors&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Finally&#44; the action of MTX in psoriasis could be mediated by the suppression of T-cell activation &#40;through folate-dependent mechanisms&#41; and the altered expression of adhesion molecules&#59; adenosine would also have a role in this mechanism&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Efficacy in Psoriasis</span><p id="par0085" class="elsevierStylePara elsevierViewall">A number of clinical trials in recent years have explored the efficacy of MTX in psoriasis and compared it with other options&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#8211;42</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the findings&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">Various regimens can produce a 75&#37; improvement in the Psoriasis Area and Severity Index &#40;PASI 75&#41; in up to 40&#37; of patients by week 24&#44; although in most cases PASI response at week 12 is a good indicator of whether treatment should be continued or not&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Experience with combination regimens of MTX and diverse biologics to treat moderate to severe psoriasis has shown improved patient responses and treatment adherence&#46; The possible mechanisms underlying these effects include reduced clearance of the biologic agent and reduced production of antibodies against the agent&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The results of a clinical trial comparing etanercept monotherapy and etanercept plus MTX in 239 patients per arm were recently published&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> Patients in the monotherapy arm received 50<span class="elsevierStyleHsp" style=""></span>mg twice weekly for 12 weeks followed by 50<span class="elsevierStyleHsp" style=""></span>mg weekly for 12 weeks&#44; while those in the combination therapy group received 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg weekly for the first 2 weeks&#44; 10<span class="elsevierStyleHsp" style=""></span>mg weekly for the next 2 weeks&#44; and up to 15<span class="elsevierStyleHsp" style=""></span>mg weekly up to week 24&#46; Combination therapy with etanercept plus MTX was superior to etanercept alone&#44; with PASI 75 responses observed in 70&#37; of patients at week 12 &#40;vs 54&#37; in the monotherapy group&#41; and in 77&#37; of patients &#40;vs 60&#37;&#41; at week 24&#46; The corresponding rates of PASI 90 responses were 34&#37; vs 23&#37; and 54&#37; vs 34&#37;&#44; respectively&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Patterns of Use and Administration Routes</span><p id="par0105" class="elsevierStylePara elsevierViewall">Patterns of MTX use by both rheumatologists and dermatologists have changed somewhat in recent years&#46; One recent review concluded that the bioavailability of oral MTX decreases at doses above 17&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> indicating that parenteral administration is preferable&#46; In a clinical trial comparing the efficacy and safety of oral and subcutaneous MTX in patients with rheumatoid arthritis&#44; 78&#37; of patients treated with subcutaneous MTX and 70&#37; of those treated with oral MTX achieved the treatment goal of a 20&#37; improvement in the American College of Rheumatology criteria &#40;ACR20&#41; by week 48&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> There were also differences in the frequency of adverse effects between the groups &#40;66&#37; vs 62&#37;&#41; but these were not statistically significant&#46; Thirty percent of the patients who did not respond to oral MTX 15<span class="elsevierStyleHsp" style=""></span>mg achieved an ACR20 response when they were switched to subcutaneous MTX&#46; The study is the first to provide formal proof that subcutaneous MTX has superior clinical efficacy to oral MTX&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> and one would expect these results to be extrapolated to the treatment of psoriasis&#44; despite the current lack of scientific evidence in this setting&#46; The main advantage of the subcutaneous route is the superior bioavailability of MTX&#46; It has been demonstrated that the increased effectiveness seen in rheumatoid arthritis patients following a switch from oral to subcutaneous MTX without a change in dose is accompanied by an increase in RBC MTX polyglutamate concentrations&#44; although it may take 6 months for the new steady-state concentrations to be reached&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Data on the superior clinical efficacy of subcutaneous MTX in the treatment of rheumatoid arthritis were used as the starting point for a pharmacoeconomic analysis conducted in Spain that concluded that the additional cost associated with the use of the subcutaneous route would be offset by improved effectivness&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the results of an incremental cost-effectiveness analysis of subcutaneous MTX and several alternatives based on data from comparative clinical trials&#46; The results show that subcutaneous MTX has a higher incremental cost-effectiveness ratio to ciclosporin&#44; adalimumab&#44; and infliximab in the treatment of moderate to severe psoriasis&#46; &#40;We have omitted the sensitivity analysis and confidence intervals due to space constraints&#46;&#41;</p><p id="par0115" class="elsevierStylePara elsevierViewall">A study of MTX use among dermatologists and rheumatologists in Canada reported that most dermatologists &#40;97&#37;&#41; and rheumatologists &#40;80&#37;&#41; start treating psoriasis with oral MTX and that fewer dermatologists subsequently switch to parenteral MTX &#40;49&#37; vs 96&#37; of rheumatologists&#41;&#59; of the dermatologists that do switch 63&#37; choose the subcutaneous route &#40;vs 98&#37; of the rheumatologists&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Considering that the usefulness of test doses of MTX in psoriasis is still being questioned &#40;treatment is commonly initiated with a dose of 10 to 15<span class="elsevierStyleHsp" style=""></span>mg in selected patients&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> the advantages of subcutaneous MTX in rheumatoid arthritis &#40;greater efficacy<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> and fewer gastrointestinal problems<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a>&#41; could probably be extrapolated to psoriasis&#44; and it would appear reasonable to assume that subcutaneous MTX will be increasingly used in dermatology&#46; Greater familiarity with subcutaneous injections among dermatology patients will undoubtedly contribute to this increased use&#44; as will the introduction of higher-concentration formulations &#40;50<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#41; in prefilled syringes&#44; as these offer greater tolerability and convenience<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> and are preferred to the 10-mg&#47;mL formulations by the majority of patients treated with 20<span class="elsevierStyleHsp" style=""></span>mg per week&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> Single-dose formulations also have environmental and safety benefits as they eliminate the need to handle and discard unused portions of vials or syringes&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Ethical Disclosures</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Protection of humans and animals</span><p id="par0125" class="elsevierStylePara elsevierViewall">The authors declare that no tests were carried out in humans or animals for the purpose of this study&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Confidentiality of data</span><p id="par0130" class="elsevierStylePara elsevierViewall">The authors declare that they have followed their hospital&#39;s protocol on the publication of data concerning patients and that all patients included in the study have received sufficient information and have given their written informed consent to participate in the study&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Right to privacy and informed consent</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare that no private patient data appear in this article&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of Interest</span><p id="par0140" class="elsevierStylePara elsevierViewall">The author has received speakers and&#47;or consultancy and&#47;or clinical trial investigator fees from Gebro Pharma and Pfizer&#59; he has also received fees from Marge Medica Books for coordinating and co-authoring <span class="elsevierStyleItalic">Methotraxate and psoriasis&#46; Barcelona&#58; Marge Medica Books&#59; 2012</span>&#44; sponsored by Gebro Pharma&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:11 [
        0 => array:2 [
          "identificador" => "xres349093"
          "titulo" => "Abstract"
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec330760"
          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "xres349094"
          "titulo" => "Resumen"
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec330759"
          "titulo" => "Palabras clave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Pharmacokinetics"
        ]
        6 => array:3 [
          "identificador" => "sec0015"
          "titulo" => "Mechanisms of Action"
          "secciones" => array:1 [
            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Efficacy in Psoriasis"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Patterns of Use and Administration Routes"
        ]
        8 => array:3 [
          "identificador" => "sec0030"
          "titulo" => "Ethical Disclosures"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Protection of humans and animals"
            ]
            1 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Confidentiality of data"
            ]
            2 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Right to privacy and informed consent"
            ]
          ]
        ]
        9 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Conflicts of Interest"
        ]
        10 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2012-10-12"
    "fechaAceptado" => "2012-11-29"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec330760"
          "palabras" => array:6 [
            0 => "Psoriasis"
            1 => "Methotrexate"
            2 => "Clinical trials"
            3 => "Pharmacokinetics"
            4 => "Mechanism of action"
            5 => "Cost-effectiveness"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec330759"
          "palabras" => array:6 [
            0 => "Psoriasis"
            1 => "Metotrexato"
            2 => "Ensayos cl&#237;nicos"
            3 => "Farmacocin&#233;tica"
            4 => "Mecanismo de acci&#243;n"
            5 => "Coste-eficacia"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Although the first study on the efficacy of methotrexate in the treatment of psoriasis was reported in 1958&#44; scientific evidence for this indication has been scant until quite recently&#46; We now have new data on the pharmacokinetics and mechanism of action of methotrexate and new subcutaneous formulations that have improved the bioavailability&#44; efficacy&#44; and ease of administration of the drug&#46; The results of recent clinical trials comparing methotrexate with several biologic agents have shown it to be the first-line therapy among the classic systemic treatments for psoriasis&#46; Moreover&#44; the incremental cost-effectiveness ratio for subcutaneous methotrexate has been shown to be superior to that of ciclosporin&#44; adalimumab&#44; and infliximab&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Pese a que el primer estudio sobre la eficacia de metotrexato en el tratamiento de la psoriasis se remonta a 1958&#44; hasta no hace mucho ha sido escasa la evidencia cient&#237;fica disponible sobre su uso en esta indicaci&#243;n&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Disponemos de nuevos datos acerca de la farmacocin&#233;tica y el mecanismo de acci&#243;n del metotrexato&#44; as&#237; como de nuevas presentaciones por v&#237;a subcut&#225;nea que mejoran la biodisponibilidad&#44; la eficacia y la conveniencia de la administraci&#243;n de este f&#225;rmaco&#46; La reciente publicaci&#243;n de ensayos cl&#237;nicos comparativos con diversos biol&#243;gicos permite considerar al metotrexato como el est&#225;ndar terap&#233;utico dentro de los tratamientos sist&#233;micos cl&#225;sicos de la psoriasis&#44; con un cociente coste-eficacia incremental favorable al metotrexato subcut&#225;neo si se compara con ciclosporina&#44; adalimumab o infliximab&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Puig L&#46; Metotrexato&#58; novedades terap&#233;uticas&#46; Actas Dermosifiliogr&#46; 2014&#59;105&#58;583&#8211;589&#46;</p>"
      ]
    ]
    "multimedia" => array:1 [
      0 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; ALT&#44; alanine aminotransferase&#59; PASI&#44; Psoriasis Area and Severity Index&#59; PASI 50&#44; &#8805;<span class="elsevierStyleHsp" style=""></span>50&#37; improvement in PASI score with respect to baseline&#59; PASI 75&#44; &#8805;<span class="elsevierStyleHsp" style=""></span>75&#37; improvement in PASI score with respect to baseline&#59; PASI 90&#44; &#8805;<span class="elsevierStyleHsp" style=""></span>90&#37; improvement in PASI score with respect to baseline&#59; PGA&#44; physician&#39;s global assessment&#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"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">MTX Regimen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Comparator&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">No&#46; Treated &#40;MTX&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">PASI 75&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">ICER<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> PASI 75&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">PASI 90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Observations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15<span class="elsevierStyleHsp" style=""></span>mg&#47;wk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ciclosporin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#37; wk 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">691&#46;52&#8211;390&#46;88&#47;0&#46;71&#8211;0&#46;60<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8364;2733&#46;09 in favor of subcutaneous MTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&#37; wk 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 patients had to stop taking MTX due to an increase in transanimase levels &#40;max&#46; ALT level&#44; 198&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heydendael et al&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;wk with gradual increments up to 15<span class="elsevierStyleHsp" style=""></span>mg&#47;wk in patients who did not achieve PASI 50&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ciclosporin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&#37; wk 12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">518&#46;64&#8211;293&#46;16&#47;0&#46;58&#8211;0&#46;60<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8364;633&#46;18 in favor of subcutaneous MTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#37; wk 12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Flytstr&#246;m et al&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Initial dose of 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;wk&#44; 10<span class="elsevierStyleHsp" style=""></span>mg from wk 2&#44; 15<span class="elsevierStyleHsp" style=""></span>mg from wk 4&#46; Increase to 20<span class="elsevierStyleHsp" style=""></span>mg in patients who did not achieve PASI 50 by wk 8&#59; increase to 25<span class="elsevierStyleHsp" style=""></span>mg in patients who did not achieve PASI 50 by wk 12&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Adalimumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">110&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36&#37; wk 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6355&#46;96&#8211;390&#46;88&#47;0&#46;80&#8211;0&#46;36<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8364;13&#160;557 in favor of subcutaneous MTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#37; wk 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Treatment discontinuation recommended if no response by wk 12<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Saurat et al&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15<span class="elsevierStyleHsp" style=""></span>mg&#47;wk for first 6 wk&#59; thereafter&#44; dose increments up to 20<span class="elsevierStyleHsp" style=""></span>mg&#47;wk if PASI improvement was &#60;<span class="elsevierStyleHsp" style=""></span>25&#37;&#46; Patients who did not achieve PASI 50 or who did not tolerate treatment were able to change treatment arm at wk 16&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Infliximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">215&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42&#37; wk 1631&#37; wk 26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8006&#46;44&#8211;390&#46;88&#47;0&#46;78&#8211;0&#46;42<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8364;21&#160;154&#46;33 in favor of subcutaneous MTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&#37; wk 1615&#37; wk 26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Barker et al&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Initial dose of 5<span class="elsevierStyleHsp" style=""></span>mg&#47;wk&#44; 10<span class="elsevierStyleHsp" style=""></span>mg&#47;wk for 1 wk&#44; 15<span class="elsevierStyleHsp" style=""></span>mg up to wk 9&#59; 20<span class="elsevierStyleHsp" style=""></span>mg after wk 10&#44; and 25<span class="elsevierStyleHsp" style=""></span>mg after wk 16 in patients who did not achieve PASI 75 or a PGA score of 0 or 1&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Briakinumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">163&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36&#37; wk 1240&#37; wk 2424&#37; wk 52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8776;<span class="elsevierStyleHsp" style=""></span>14&#37; wk 12<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&#8776;<span class="elsevierStyleHsp" style=""></span>23&#37; wk 24<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&#8776;<span class="elsevierStyleHsp" style=""></span>17&#37; wk 52<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Reich et al&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab521000.png"
              ]
            ]
          ]
          "notaPie" => array:2 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">ICER&#44; incremental cost-effectiveness ratio &#40;cost of alternative&#8722;cost of subcutaneous MTX&#41;&#47;&#40;efficacy alternative&#8722;efficacy subcutaneous MTX&#41;&#46; Recommended retail prices as of October 2012&#46; Metoject&#58; &#8364;19&#46;36<span class="elsevierStyleHsp" style=""></span>&#8364;&#47;wk &#40;7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#41;&#59; &#8364;24&#46;43&#47;wk &#40;15<span class="elsevierStyleHsp" style=""></span>mg&#41; &#40;based on maximum dose&#41;&#46; Sandimmun Neoral 100<span class="elsevierStyleHsp" style=""></span>mg&#47;mL suspension&#58; &#8364;128&#46;62&#47;50<span class="elsevierStyleHsp" style=""></span>mL&#59; &#8364;43&#46;22&#47;wk based on starting dose of 3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d for a patient weighing 80<span class="elsevierStyleHsp" style=""></span>kg&#46; Remicade&#58; 80<span class="elsevierStyleHsp" style=""></span>kg&#44; 4 vials of 100<span class="elsevierStyleHsp" style=""></span>mg &#40;&#8364;615&#46;88&#41; &#215; 3&#46;25 doses &#40;16 wk&#41;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8364;8006&#46;44&#46; Humira&#58; &#8364;1127&#46;57&#47;2 &#215; 9&#46;5 doses &#40;16 wk&#41;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8364;5355&#46;96&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Obtained by interpolation from graph&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Summary of Comparative Clinical Trials of Methotrexate &#40;MTX&#41; in Psoriasis&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:55 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Treatment of psoriasis with folic acid antagonists"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "W&#46;F&#46; Edmundson"
                            1 => "W&#46;B&#46; Guy"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "AMA Arch Derm"
                        "fecha" => "1958"
                        "volumen" => "78"
                        "paginaInicial" => "200"
                        "paginaFinal" => "203"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/13558707"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Use of methotrexate in psoriasis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "H&#46;H&#46; Roenigk Jr&#46;"
                            1 => "H&#46;I&#46; Maibach"
                            2 => "G&#46;D&#46; Weinstein"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Dermatol"
                        "fecha" => "1972"
                        "volumen" => "105"
                        "paginaInicial" => "363"
                        "paginaFinal" => "365"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/5012144"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Understanding the mechanisms of action of methotrexate&#58; implications for the treatment of rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "H&#46; Tian"
                            1 => "B&#46;N&#46; Cronstein"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Bull NYU Hosp Jt Dis"
                        "fecha" => "2007"
                        "volumen" => "65"
                        "paginaInicial" => "168"
                        "paginaFinal" => "173"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17922664"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Why intramuscular methotrexate works better than oral drug in patients with rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46;A&#46; Hamilton"
                            1 => "J&#46;M&#46; Kremer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Rheumatol"
                        "fecha" => "1997"
                        "volumen" => "36"
                        "paginaInicial" => "86"
                        "paginaFinal" => "90"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9117183"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Splitting high-dose oral methotrexate improves bioavailability&#58; a pharmacokinetic study in patients with rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46; Hoekstra"
                            1 => "C&#46; Haagsma"
                            2 => "C&#46; Neef"
                            3 => "J&#46; Proost"
                            4 => "A&#46; Knuif"
                            5 => "M&#46; van de Laar"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Rheumatol"
                        "fecha" => "2006"
                        "volumen" => "33"
                        "paginaInicial" => "481"
                        "paginaFinal" => "485"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16463431"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Methotrexate catabolism to 7-hydroxymethotrexate in rheumatoid arthritis alters drug efficacy and retention and is reduced by folic acid supplementation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46;E&#46; Baggott"
                            1 => "S&#46;L&#46; Morgan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.24685"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2009"
                        "volumen" => "60"
                        "paginaInicial" => "2257"
                        "paginaFinal" => "2261"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19644884"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A single nucleotide polymorphism of reduced folate carrier 1 predicts methotrexate efficacy in Japanese patients with rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46; Hayashi"
                            1 => "Y&#46; Tazoe"
                            2 => "S&#46; Tsuboi"
                            3 => "M&#46; Horino"
                            4 => "M&#46; Morishita"
                            5 => "T&#46; Arai"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Drug Metab Pharmacokinet"
                        "fecha" => "2012"
                        "volumen" => "11"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Red blood cell methotrexate polyglutamates emerge as a function of dosage intensity and route of administration during pulse methotrexate therapy in rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "T&#46; Dervieux"
                            1 => "R&#46; Zablocki"
                            2 => "J&#46; Kremer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Rheumatology &#40;Oxford&#41;"
                        "fecha" => "2010"
                        "volumen" => "49"
                        "paginaInicial" => "2337"
                        "paginaFinal" => "2345"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The pharmacogenetics of methotrexate"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "S&#46;L&#46; Hider"
                            1 => "I&#46;N&#46; Bruce"
                            2 => "W&#46; Thomson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Rheumatology &#40;Oxford&#41;"
                        "fecha" => "2007"
                        "volumen" => "46"
                        "paginaInicial" => "1520"
                        "paginaFinal" => "1524"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;B&#46; Warren"
                            1 => "R&#46;L&#46; Smith"
                            2 => "E&#46; Campalani"
                            3 => "S&#46; Eyre"
                            4 => "C&#46;H&#46; Smith"
                            5 => "J&#46;N&#46; Barker"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2133.2008.08898.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Dermatol"
                        "fecha" => "2009"
                        "volumen" => "160"
                        "paginaInicial" => "438"
                        "paginaFinal" => "441"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19016697"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetic variation in efflux transporters influences outcome to methotrexate therapy in patients with psoriasis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;B&#46; Warren"
                            1 => "R&#46;L&#46; Smith"
                            2 => "E&#46; Campalani"
                            3 => "S&#46; Eyre"
                            4 => "C&#46;H&#46; Smith"
                            5 => "J&#46;N&#46; Barker"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/jid.2008.16"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Invest Dermatol"
                        "fecha" => "2008"
                        "volumen" => "128"
                        "paginaInicial" => "1925"
                        "paginaFinal" => "1929"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18256692"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients&#46; Association with hepatic folate deficiency and formation of polyglutamates"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "J&#46;M&#46; Kremer"
                            1 => "J&#46; Galivan"
                            2 => "A&#46; Streckfuss"
                            3 => "B&#46; Kamen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "1986"
                        "volumen" => "29"
                        "paginaInicial" => "832"
                        "paginaFinal" => "835"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2427090"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Lack of correlation between pharmacokinetics and efficacy of low dose methotrexate in patients with rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "P&#46; Lafforgue"
                            1 => "S&#46; Monjanel-Mouterde"
                            2 => "A&#46; Durand"
                            3 => "J&#46; Catalin"
                            4 => "P&#46;C&#46; Acquaviva"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Rheumatol"
                        "fecha" => "1995"
                        "volumen" => "22"
                        "paginaInicial" => "844"
                        "paginaFinal" => "849"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8587070"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Monitoring methotrexate therapy in patients with rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46; Wiela-Hojenska"
                            1 => "K&#46; Orzechowska-Juzwenko"
                            2 => "J&#46; Swierkot"
                            3 => "P&#46; Wiland"
                            4 => "M&#46; Hurkacz"
                            5 => "J&#46; Szechinski"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Clin Pharmacol Ther"
                        "fecha" => "2004"
                        "volumen" => "42"
                        "paginaInicial" => "434"
                        "paginaFinal" => "441"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15366323"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0075"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Total and free methotrexate pharmacokinetics in elderly patients with rheumatoid arthritis&#46; A comparison with young patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "F&#46; Bressolle"
                            1 => "C&#46; Bologna"
                            2 => "J&#46;M&#46; Kinowski"
                            3 => "B&#46; Arcos"
                            4 => "J&#46; Sany"
                            5 => "B&#46; Combe"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Rheumatol"
                        "fecha" => "1997"
                        "volumen" => "24"
                        "paginaInicial" => "1903"
                        "paginaFinal" => "1909"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9330930"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0080"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of folic or folinic acid supplementation on methotrexate-associated safety and efficacy in inflammatory disease&#58; a systematic review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46; Prey"
                            1 => "C&#46; Paul"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2133.2008.08876.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Dermatol"
                        "fecha" => "2009"
                        "volumen" => "160"
                        "paginaInicial" => "622"
                        "paginaFinal" => "628"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18945303"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0085"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "How does methotrexate suppress inflammation&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "B&#46; Cronstein"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Clin Exp Rheumatol"
                        "fecha" => "2010"
                        "volumen" => "28"
                        "numero" => "5 Suppl 61"
                        "paginaInicial" => "S21"
                        "paginaFinal" => "S23"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21044428"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0090"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;C&#46; Montesinos"
                            1 => "A&#46; Desai"
                            2 => "D&#46; Delano"
                            3 => "J&#46;F&#46; Chen"
                            4 => "J&#46;S&#46; Fink"
                            5 => "M&#46;A&#46; Jacobson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.10712"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2003"
                        "volumen" => "48"
                        "paginaInicial" => "240"
                        "paginaFinal" => "247"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12528125"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0095"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Adenosine A&#40;2<span class="elsevierStyleHsp" style=""></span>A&#41; receptors play a role in the pathogenesis of hepatic cirrhosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;S&#46; Chan"
                            1 => "M&#46;C&#46; Montesinos"
                            2 => "P&#46; Fernandez"
                            3 => "A&#46; Desai"
                            4 => "D&#46;L&#46; Delano"
                            5 => "H&#46; Yee"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.bjp.0706812"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Pharmacol"
                        "fecha" => "2006"
                        "volumen" => "148"
                        "paginaInicial" => "1144"
                        "paginaFinal" => "1155"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16783407"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Differences in methotrexate and 7-hydroxymethotrexate inhibition of folate-dependent enzymes of purine nucleotide biosynthesis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46;E&#46; Baggott"
                            1 => "S&#46;L&#46; Morgan"
                            2 => "W&#46;H&#46; Vaughn"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Biochem J"
                        "fecha" => "1994"
                        "volumen" => "300"
                        "numero" => "Pt 3"
                        "paginaInicial" => "627"
                        "paginaFinal" => "629"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8010943"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The antiinflammatory mechanism of methotrexate&#46; Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "B&#46;N&#46; Cronstein"
                            1 => "D&#46; Naime"
                            2 => "E&#46; Ostad"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI116884"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "1993"
                        "volumen" => "92"
                        "paginaInicial" => "2675"
                        "paginaFinal" => "2682"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8254024"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The antiinflammatory mechanism of methotrexate depends on extracellular conversion of adenine nucleotides to adenosine by ecto-5&#8217;-nucleotidase&#58; findings in a study of ecto-5&#8217;-nucleotidase gene-deficient mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46;C&#46; Montesinos"
                            1 => "M&#46; Takedachi"
                            2 => "L&#46;F&#46; Thompson"
                            3 => "T&#46;F&#46; Wilder"
                            4 => "P&#46; Fern&#225;ndez"
                            5 => "B&#46;N&#46; Cronstein"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.22643"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2007"
                        "volumen" => "56"
                        "paginaInicial" => "1440"
                        "paginaFinal" => "1445"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17469101"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5&#8217;-nucleotidase-mediated conversion of adenine nucleotides"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Morabito"
                            1 => "M&#46;C&#46; Montesinos"
                            2 => "D&#46;M&#46; Schreibman"
                            3 => "L&#46; Balter"
                            4 => "L&#46;F&#46; Thompson"
                            5 => "R&#46; Resta"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI1554"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "1998"
                        "volumen" => "101"
                        "paginaInicial" => "295"
                        "paginaFinal" => "300"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9435300"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Methotrexate modulates the kinetics of adenosine in humans in vivo"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "N&#46;P&#46; Riksen"
                            1 => "P&#46; Barrera"
                            2 => "P&#46;H&#46; van den Broek"
                            3 => "P&#46;L&#46; van Riel"
                            4 => "P&#46; Smits"
                            5 => "G&#46;A&#46; Rongen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/ard.2005.048637"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2006"
                        "volumen" => "65"
                        "paginaInicial" => "465"
                        "paginaFinal" => "470"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16308339"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetically based resistance to the anti-inflammatory effects of methotrexate in the air-pouch model of acute inflammation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;L&#46; Delano"
                            1 => "M&#46;C&#46; Montesinos"
                            2 => "A&#46; Desai"
                            3 => "T&#46; Wilder"
                            4 => "P&#46; Fernandez"
                            5 => "P&#46; d&#8217;Eustachio"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.21208"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2005"
                        "volumen" => "52"
                        "paginaInicial" => "2567"
                        "paginaFinal" => "2575"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16059892"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Reversal of the antiinflammatory effects of methotrexate by the nonselective adenosine receptor antagonists theophylline and caffeine&#58; evidence that the antiinflammatory effects of methotrexate are mediated via multiple adenosine receptors in rat adjuvant arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46;C&#46; Montesinos"
                            1 => "J&#46;S&#46; Yap"
                            2 => "A&#46; Desai"
                            3 => "I&#46; Posadas"
                            4 => "C&#46;T&#46; McCrary"
                            5 => "B&#46;N&#46; Cronstein"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/1529-0131(200003)43:3<656::AID-ANR23>3.0.CO;2-H"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2000"
                        "volumen" => "43"
                        "paginaInicial" => "656"
                        "paginaFinal" => "663"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10728760"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of caffeine consumption on efficacy of methotrexate in rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "G&#46; Nesher"
                            1 => "M&#46; Mates"
                            2 => "S&#46; Zevin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.10766"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2003"
                        "volumen" => "48"
                        "paginaInicial" => "571"
                        "paginaFinal" => "572"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12571869"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dietary caffeine intake does not affect methotrexate efficacy in patients with rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Benito-Garcia"
                            1 => "J&#46;E&#46; Heller"
                            2 => "L&#46;B&#46; Chibnik"
                            3 => "N&#46;E&#46; Maher"
                            4 => "H&#46;M&#46; Matthews"
                            5 => "J&#46;A&#46; Bilics"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Rheumatol"
                        "fecha" => "2006"
                        "volumen" => "33"
                        "paginaInicial" => "1275"
                        "paginaFinal" => "1281"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16821266"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Caffeine consumption and methotrexate dosing requirement in psoriasis and psoriatic arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "D&#46;L&#46; Swanson"
                            1 => "S&#46;A&#46; Barnes"
                            2 => "S&#46;J&#46; Mengden Koon"
                            3 => "R&#46;A&#46; el-Azhary"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-4632.2006.02954.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Dermatol"
                        "fecha" => "2007"
                        "volumen" => "46"
                        "paginaInicial" => "157"
                        "paginaFinal" => "159"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17269967"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Adenosine signaling contributes to ethanol-induced fatty liver in mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Z&#46; Peng"
                            1 => "P&#46;A&#46; Borea"
                            2 => "K&#46; Varani"
                            3 => "T&#46; Wilder"
                            4 => "H&#46; Yee"
                            5 => "L&#46; Chiriboga"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI37409"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "2009"
                        "volumen" => "119"
                        "paginaInicial" => "582"
                        "paginaFinal" => "594"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19221436"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ecto-5&#8217;-nucleotidase &#40;CD73&#41; -mediated extracellular adenosine production plays a critical role in hepatic fibrosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Z&#46; Peng"
                            1 => "P&#46; Fernandez"
                            2 => "T&#46; Wilder"
                            3 => "H&#46; Yee"
                            4 => "L&#46; Chiriboga"
                            5 => "E&#46;S&#46; Chan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1096/fj.07-100685"
                      "Revista" => array:6 [
                        "tituloSerie" => "FASEB J"
                        "fecha" => "2008"
                        "volumen" => "22"
                        "paginaInicial" => "2263"
                        "paginaFinal" => "2272"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18263696"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neuroanatomy and neurochemistry of sleep"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "D&#46; Stenberg"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00018-007-6530-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cell Mol Life Sci"
                        "fecha" => "2007"
                        "volumen" => "64"
                        "paginaInicial" => "1187"
                        "paginaFinal" => "1204"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17364141"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aminophylline for methotrexate-induced neurotoxicity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "J&#46;C&#46; Bernini"
                            1 => "D&#46;W&#46; Fort"
                            2 => "J&#46;C&#46; Griener"
                            3 => "B&#46;J&#46; Kane"
                            4 => "W&#46;B&#46; Chappell"
                            5 => "B&#46;A&#46; Kamen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "1995"
                        "volumen" => "345"
                        "paginaInicial" => "544"
                        "paginaFinal" => "547"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7776773"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immunosuppressive properties of methotrexate&#58; apoptosis and clonal deletion of activated peripheral T cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "L&#46; Genestier"
                            1 => "R&#46; Paillot"
                            2 => "S&#46; Fournel"
                            3 => "C&#46; Ferraro"
                            4 => "P&#46; Miossec"
                            5 => "J&#46;P&#46; Revillard"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI2676"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "1998"
                        "volumen" => "102"
                        "paginaInicial" => "322"
                        "paginaFinal" => "328"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9664073"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Expression of A2B adenosine receptors in human lymphocytes&#58; their role in T cell activation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46; Mirabet"
                            1 => "C&#46; Herrera"
                            2 => "O&#46;J&#46; Cordero"
                            3 => "J&#46; Mallol"
                            4 => "C&#46; Lluis"
                            5 => "R&#46; Franco"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "J Cell Sci"
                        "fecha" => "1999"
                        "volumen" => "112"
                        "numero" => "Pt 4"
                        "paginaInicial" => "491"
                        "paginaFinal" => "502"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9914161"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The effect of methotrexate on the expression of cell adhesion molecules and activation molecule CD69 in psoriasis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "B&#46; Torres-&#193;lvarez"
                            1 => "J&#46;P&#46; Castanedo-Cazares"
                            2 => "C&#46; Fuentes-Ahumada"
                            3 => "B&#46; Moncada"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1468-3083.2006.01916.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Eur Acad Dermatol Venereol"
                        "fecha" => "2007"
                        "volumen" => "21"
                        "paginaInicial" => "334"
                        "paginaFinal" => "339"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17309454"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "V&#46;M&#46; Heydendael"
                            1 => "P&#46;I&#46; Spuls"
                            2 => "B&#46;C&#46; Opmeer"
                            3 => "C&#46;A&#46; de Borgie"
                            4 => "J&#46;B&#46; Reitsma"
                            5 => "W&#46;F&#46; Goldschmidt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa021359"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2003"
                        "volumen" => "349"
                        "paginaInicial" => "658"
                        "paginaFinal" => "665"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12917302"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Methotrexate vs ciclosporin in psoriasis&#58; effectiveness&#44; quality of life and safety&#46; A randomized controlled trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "I&#46; Flytstr&#246;m"
                            1 => "B&#46; Stenberg"
                            2 => "A&#46; Svensson"
                            3 => "I&#46;M&#46; Bergbrant"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2133.2007.08284.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Dermatol"
                        "fecha" => "2008"
                        "volumen" => "158"
                        "paginaInicial" => "116"
                        "paginaFinal" => "121"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17986302"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Relationship between methotrexate dosing and clinical response in patients with moderate to severe psoriasis&#58; subanalysis of the CHAMPION study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "J&#46;H&#46; Saurat"
                            1 => "R&#46;G&#46; Langley"
                            2 => "K&#46; Reich"
                            3 => "K&#46; Unnebrink"
                            4 => "E&#46;H&#46; Sasso"
                            5 => "W&#46; Kampman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2133.2011.10399.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Dermatol"
                        "fecha" => "2011"
                        "volumen" => "165"
                        "paginaInicial" => "399"
                        "paginaFinal" => "406"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21564071"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CHAMPION Study Investigators&#46; Efficacy and safety results from the randomized controlled comparative study of adalimumab vs methotrexate vs placebo in patients with psoriasis &#40;CHAMPION&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;H&#46; Saurat"
                            1 => "G&#46; Stingl"
                            2 => "L&#46; Dubertret"
                            3 => "K&#46; Papp"
                            4 => "R&#46;G&#46; Langley"
                            5 => "J&#46;P&#46; Ortonne"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2133.2007.08315.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Dermatol"
                        "fecha" => "2008"
                        "volumen" => "158"
                        "paginaInicial" => "558"
                        "paginaFinal" => "566"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18047523"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Efficacy and safety of infliximab vs methotrexate in patients with moderate-to-severe plaque psoriasis&#58; results of an open-label&#44; active-controlled&#44; randomized trial &#40;RESTORE1&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Barker"
                            1 => "M&#46; Hoffmann"
                            2 => "G&#46; Wozel"
                            3 => "J&#46;P&#46; Ortonne"
                            4 => "H&#46; Zheng"
                            5 => "H&#46; van Hoogstraten"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2133.2011.10615.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Dermatol"
                        "fecha" => "2011"
                        "volumen" => "165"
                        "paginaInicial" => "1109"
                        "paginaFinal" => "1117"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21910713"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A 52-week trial comparing briakinumab with methotrexate in patients with psoriasis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46; Reich"
                            1 => "R&#46;G&#46; Langley"
                            2 => "K&#46;A&#46; Papp"
                            3 => "J&#46;P&#46; Ortonne"
                            4 => "K&#46; Unnebrink"
                            5 => "M&#46; Kaul"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1010858"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2011"
                        "volumen" => "365"
                        "paginaInicial" => "1586"
                        "paginaFinal" => "1596"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22029980"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Metotrexato&#58; gu&#237;a de uso en psoriasis"
                      "autores" => array:1 [
                        0 => array:3 [
                          "colaboracion" => "Grupo de Psoriasis de la AEDV"
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Carretero"
                            1 => "L&#46; Puig"
                            2 => "L&#46; Dehesa"
                            3 => "J&#46;M&#46; Carrascosa"
                            4 => "M&#46; Ribera"
                            5 => "M&#46; S&#225;nchez-Rega&#241;a"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Actas Dermosifiliogr"
                        "fecha" => "2010"
                        "volumen" => "101"
                        "paginaInicial" => "600"
                        "paginaFinal" => "613"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20858386"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A randomized&#44; double-blind&#44; placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;B&#46; Gottlieb"
                            1 => "R&#46;G&#46; Langley"
                            2 => "B&#46;E&#46; Strober"
                            3 => "K&#46;A&#46; Papp"
                            4 => "P&#46; Klekotka"
                            5 => "K&#46; Creamer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2133.2012.11015.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Dermatol"
                        "fecha" => "2012"
                        "volumen" => "167"
                        "paginaInicial" => "649"
                        "paginaFinal" => "657"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22533447"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Methotrexate bioavailability"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "E&#46;N&#46; Van Roon"
                            1 => "M&#46;A&#46; van de Laar"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Clin Exp Rheumatol"
                        "fecha" => "2010"
                        "volumen" => "28"
                        "numero" => "5 Suppl 61"
                        "paginaInicial" => "S27"
                        "paginaFinal" => "S32"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20868567"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis&#58; results of a six-month&#44; multicenter&#44; randomized&#44; double-blind&#44; controlled&#44; phase <span class="elsevierStyleSmallCaps">iv</span> trial"
                      "autores" => array:1 [
                        0 => array:3 [
                          "colaboracion" => "MC-MTX&#46;6&#47;RH Study Group"
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Braun"
                            1 => "P&#46; K&#228;stner"
                            2 => "P&#46; Flaxenberg"
                            3 => "J&#46; W&#228;hrisch"
                            4 => "P&#46; Hanke"
                            5 => "W&#46; Demary"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.23144"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2008"
                        "volumen" => "58"
                        "paginaInicial" => "73"
                        "paginaFinal" => "81"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18163521"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Optimal administration and dosage of methotrexate"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "J&#46; Braun"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Clin Exp Rheumatol"
                        "fecha" => "2010"
                        "volumen" => "28"
                        "numero" => "5 Suppl 61"
                        "paginaInicial" => "S46"
                        "paginaFinal" => "S51"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21122269"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effects of changing from oral to subcutaneous methotrexate on red blood cell methotrexate polyglutamate concentrations and disease activity in patients with rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46;K&#46; Stamp"
                            1 => "M&#46;L&#46; Barclay"
                            2 => "J&#46;L&#46; O&#8217;Donnell"
                            3 => "M&#46; Zhang"
                            4 => "J&#46; Drake"
                            5 => "C&#46; Frampton"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3899/jrheum.110481"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Rheumatol"
                        "fecha" => "2011"
                        "volumen" => "38"
                        "paginaInicial" => "2540"
                        "paginaFinal" => "2547"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21965639"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An&#225;lisis farmacoecon&#243;mico de Metoject<span class="elsevierStyleSup">&#174;</span> en el tratamiento de la artritis reumatoide en Espa&#241;a"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Crespo"
                            1 => "M&#46; Brosa"
                            2 => "J&#46; Galv&#225;n"
                            3 => "J&#46; Carbonell"
                            4 => "J&#46; Maym&#243;"
                            5 => "J&#46;L&#46; Marenco"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.reuma.2009.11.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Reumatol Clin"
                        "fecha" => "2010"
                        "volumen" => "6"
                        "paginaInicial" => "203"
                        "paginaFinal" => "211"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21794714"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Differing patterns of methotrexate use for psoriatic disease amongst dermatologists and rheumatologists"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "E&#46;C&#46; Dupuis"
                            1 => "V&#46;M&#46; Bhole"
                            2 => "J&#46;P&#46; DFutz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2133.2012.10880.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Dermatol"
                        "fecha" => "2012"
                        "volumen" => "167"
                        "paginaInicial" => "448"
                        "paginaFinal" => "450"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22309601"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib0255"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Metotrexato en psoriasis&#58; &#191;es necesaria una dosis de prueba&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "G&#46; Carretero-Hern&#225;ndez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0001-7310(12)70001-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Actas Dermosifiliogr"
                        "fecha" => "2012"
                        "volumen" => "103"
                        "paginaInicial" => "1"
                        "paginaFinal" => "4"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22364603"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Oral vs subcutaneous low-dose methotrexate treatment in reducing gastrointestinal side effects"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "L&#46; Rutkowska-Sak"
                            1 => "M&#46; Rell-Bakalarska"
                            2 => "B&#46; Lisowska"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Reumatologia"
                        "fecha" => "2009"
                        "volumen" => "47"
                        "paginaInicial" => "207"
                        "paginaFinal" => "211"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Preference&#44; satisfaction and usability of subcutaneously administered methotrexate for rheumatoid arthritis or psoriatic arthritis&#58; results of a postmarketing surveillance study with a high-concentration formulation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "F&#46; Striesow"
                            1 => "A&#46; Brandt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Ther Adv Musculoeskel Dis"
                        "fecha" => "2011"
                        "volumen" => "4"
                        "paginaInicial" => "3"
                        "paginaFinal" => "9"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tolerability and patient&#47;physician satisfaction with subcutaneously administered methotrexate provided in two formulations of different drug concentrations in patients with rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:3 [
                          "colaboracion" => "MC-MTX&#46;10&#47;RH Study Group"
                          "etal" => true
                          "autores" => array:6 [
                            0 => "U&#46; M&#252;ller-Ladner"
                            1 => "K&#46; Rockwitz"
                            2 => "J&#46; Brandt-J&#252;rgens"
                            3 => "R&#46; Haux"
                            4 => "P&#46; K&#228;stner"
                            5 => "J&#46; Braun"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2174/1874312901004010015"
                      "Revista" => array:6 [
                        "tituloSerie" => "Open Rheumatol J"
                        "fecha" => "2010"
                        "volumen" => "4"
                        "paginaInicial" => "15"
                        "paginaFinal" => "22"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20461222"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib0275"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Protocolos de vigilancia sanitaria espec&#237;fica&#46; Agentes citost&#225;ticos&#46; Comisi&#243;n de Salud P&#250;blica&#46; Consejo Interterritorial del Sistema Nacional de Salud &#91;accessed 24 February 2012&#93;&#46; Available at&#58; <a id="intr0010" class="elsevierStyleInterRef" href="http://www.msc.es/ciudadanos/saludAmbLaboral/docs/Agentescitostaticos.pdf">http&#58;&#47;&#47;www&#46;msc&#46;es&#47;ciudadanos&#47;saludAmbLaboral&#47;docs&#47;Agentescitostaticos&#46;pdf</a>"
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/15782190/0000010500000006/v1_201406280124/S1578219014001462/v1_201406280124/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "6170"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Novelties in Dermatology"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/15782190/0000010500000006/v1_201406280124/S1578219014001462/v1_201406280124/en/main.pdf?idApp=UINPBA000044&text.app=https://actasdermo.org/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219014001462?idApp=UINPBA000044"
]

Article information

ISSN: 15782190
Original language: English

DOI:10.1016/j.adengl.2014.05.011

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	16	17	33
2024 October	104	49	153
2024 September	113	42	155
2024 August	132	62	194
2024 July	107	35	142
2024 June	142	55	197
2024 May	131	51	182
2024 April	119	39	158
2024 March	106	34	140
2024 February	91	52	143
2024 January	74	47	121
2023 December	90	33	123
2023 November	103	53	156
2023 October	123	48	171
2023 September	92	44	136
2023 August	79	16	95
2023 July	98	40	138
2023 June	103	31	134
2023 May	110	30	140
2023 April	107	41	148
2023 March	115	59	174
2023 February	69	35	104
2023 January	91	43	134
2022 December	68	60	128
2022 November	66	46	112
2022 October	41	43	84
2022 September	74	62	136
2022 August	54	49	103
2022 July	51	75	126
2022 June	47	43	90
2022 May	73	62	135
2022 April	114	60	174
2022 March	79	72	151
2022 February	85	30	115
2022 January	75	56	131
2021 December	86	52	138
2021 November	154	80	234
2021 October	79	84	163
2021 September	56	51	107
2021 August	57	29	86
2021 July	91	55	146
2021 June	73	62	135
2021 May	80	41	121
2021 April	135	87	222
2021 March	98	32	130
2021 February	83	41	124
2021 January	89	47	136
2020 December	55	24	79
2020 November	53	40	93
2020 October	60	26	86
2020 September	43	18	61
2020 August	52	20	72
2020 July	31	14	45
2020 June	50	25	75
2020 May	58	38	96
2020 April	54	23	77
2020 March	46	27	73
2020 February	7	7	14
2020 January	5	4	9
2019 December	8	4	12
2019 November	4	6	10
2019 October	0	1	1
2019 September	4	0	4
2019 August	4	3	7
2019 July	4	10	14
2019 June	6	21	27
2019 May	4	39	43
2019 April	2	14	16
2019 March	4	6	10
2019 February	1	12	13
2019 January	4	0	4
2018 December	2	7	9
2018 November	1	0	1
2018 October	6	0	6
2018 September	1	0	1
2018 March	2	0	2
2018 February	152	2	154
2018 January	118	5	123
2017 December	155	9	164
2017 November	73	6	79
2017 October	25	8	33
2017 September	34	6	40
2017 August	41	11	52
2017 July	31	6	37
2017 June	39	16	55
2017 May	27	12	39
2017 April	30	10	40
2017 March	22	23	45
2017 February	30	9	39
2017 January	19	7	26
2016 December	29	21	50
2016 November	36	27	63
2016 October	47	22	69
2016 September	46	14	60
2016 August	58	18	76
2016 July	46	14	60
2016 June	4	6	10
2016 May	5	17	22
2016 April	3	9	12
2016 March	9	11	20
2016 February	6	11	17
2016 January	26	10	36
2015 December	16	0	16
2015 November	9	2	11
2015 October	9	0	9
2015 September	7	7	14
2015 August	14	2	16
2015 July	44	5	49
2015 June	37	8	45
2015 May	40	11	51
2015 April	31	9	40
2015 March	39	5	44
2015 February	24	9	33
2015 January	31	5	36
2014 December	14	5	19
2014 November	16	6	22
2014 October	17	13	30
2014 September	5	4	9
2014 August	3	8	11
2014 July	8	3	11

Show all

Indexed in:

Follow us:

Statistics

Indexed in:

Follow us:

Statistics

Subscribe to our newsletter