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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introducci&#243;n</span><p id="par0005" class="elsevierStylePara elsevierViewall">El metotrexato &#40;MTX&#41; sigue siendo una piedra angular del tratamiento de la artritis reumatoide &#40;AR&#41;&#44; y las principales gu&#237;as para el manejo de la enfermedad lo recomiendan como terapia de inicio y como soporte clave del tratamiento con terapias biol&#243;gicas<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">1&#8211;3</span></a>&#46; No es de extra&#241;ar que en un estudio observacional internacional reciente&#44; COMORA &#40;Comorbidities in RA&#41;&#44; hasta el 89&#37; de los pacientes reciben tratamiento con MTX o lo han recibido a lo largo de su enfermedad<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a>&#46; En Espa&#241;a los estudios EMECAR &#40;Estudio de Morbilidad y Expresi&#243;n Cl&#237;nica de la Artritis Reumatoide&#41; o emARII&#44; realizados en los &#250;ltimos 10 a&#241;os&#44; revelan que MTX fue el f&#225;rmaco inicial de elecci&#243;n en el 55&#37; de los casos&#44; y entre el 60&#37; y el 64&#37; recib&#237;a este f&#225;rmaco modificador de la enfermedad&#44; bien en monoterapia o en combinaci&#243;n<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">5&#44;6</span></a>&#46; A pesar de su amplio uso y una extensa investigaci&#243;n sobre este f&#225;rmaco&#44; el mecanismo de acci&#243;n del MTX en la AR no est&#225; perfectamente establecido&#46; Aunque el f&#225;rmaco inhibe diferentes v&#237;as metab&#243;licas relacionadas con el &#225;cido f&#243;lico &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#44; los datos disponibles sugieren que los suplementos con &#225;cido f&#243;lico repercuten m&#225;s en la toxicidad del MTX que en su eficacia<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a>&#46; As&#237;&#44; se ha comprobado una gran susceptibilidad individual tanto en su efecto inmunomodulador como en su toxicidad&#44; que obliga a la suspensi&#243;n del tratamiento hasta en una cuarta parte de los pacientes<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a>&#46; Esto lleva a que&#44; aun siendo el f&#225;rmaco modificador de la enfermedad sint&#233;tico con mayor supervivencia&#44; menos del 55&#37; de los pacientes lo mantienen m&#225;s all&#225; de 8 a&#241;os<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Dado que el tratamiento precoz en AR ha demostrado ser b&#225;sico en la consecuci&#243;n de un &#243;ptimo control de la enfermedad&#44; ser&#237;a de gran utilidad disponer de biomarcadores que permitieran predecir qu&#233; individuos van a presentar toxicidad que impida alcanzar dosis terap&#233;uticas plenas de MTX&#46; El estudio de variantes gen&#233;ticas en enzimas de las rutas metab&#243;licas en las que participa el &#225;cido f&#243;lico ha sido un tema de inter&#233;s que ha llevado a la realizaci&#243;n de m&#250;ltiples estudios para tratar de predecir la respuesta o toxicidad a MTX&#44; aunque la informaci&#243;n obtenida hasta ahora&#44; en pacientes con enfermedad reum&#225;tica inflamatoria&#44; no es concluyente<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a>&#46; El objetivo de este estudio es analizar el efecto de variantes gen&#233;ticas en la metilen-tetrahidrofolatorreductasa &#40;MTHFR&#59; rs1801131 y rs1801133&#41;&#44; el transportador de membrana que une ATP B1 &#40;ABCB1&#59; rs1045642&#41;&#44; la aicartransformilasa&#47;IMP ciclohidrolasa &#40;ATIC&#59;rs2372536&#41; y la folilpoliglutamatosintetasa &#40;FPGS&#59; rs1544105&#41;&#44; cuya funci&#243;n se ilustra en el esquema de la <a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a>&#44; en la toxicidad relacionada con el f&#225;rmaco en pacientes con artritis de reciente comienzo &#40;ARC&#41; expuestos a MTX&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">ABCB1 pertenece a la s&#250;per-familia ATP-<span class="elsevierStyleItalic">binding cassette</span> que se encarga del transporte hacia el exterior de la membrana citoplasm&#225;tica de m&#250;ltiples mol&#233;culas&#44; entre ellas los citot&#243;xicos&#46; En concreto&#44; el SNP rs1045642 consiste en un cambio de una C por T en el ex&#243;n 26 del gen del trasportador ABCB1<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a>&#46; Esta sustituci&#243;n provoca inestabilidad del mARN y se ha asociado a una disminuci&#243;n de la expresi&#243;n y&#44; por tanto&#44; de la funci&#243;n de ABCB1&#44; acompa&#241;&#225;ndose de mayores niveles tisulares de diversos f&#225;rmacos<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a>&#46; En el caso de MTHFR&#44; el SNP rs1801133 supone un cambio de una C por T en el ex&#243;n 4&#44; que conlleva el cambio de una alanina por valina en la posici&#243;n 222 de la prote&#237;na&#44; mientras que el SNP rs1801131 supone el cambio de A por C en el ex&#243;n 7&#44; provocando el cambio de un glut&#225;mico por alanina en la posici&#243;n 429 de la prote&#237;na&#46; En ambos casos esto supone una mayor termolabilidad de la enzima y menor actividad funcional&#46; Respecto a rs1544105 es un cambio de G por A en la regi&#243;n promotora del gen de FPGS que se ha relacionado con menores niveles de mARN de esta enzima<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a>&#46; El SNP rs2372536 en ATIC supone un cambio de C por G en el ex&#243;n 5&#44; que conlleva el cambio de una treonina por serina en la posici&#243;n 116 de la prote&#237;na<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a>&#46; Esta informaci&#243;n previa sobre la repercusi&#243;n funcional de estas variantes gen&#233;ticas llev&#243; a su selecci&#243;n para el presente estudio que se planific&#243; en 2008&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Pacientes y m&#233;todos</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Pacientes</span><p id="par0020" class="elsevierStylePara elsevierViewall">Se han utilizado los datos del estudio P<span class="elsevierStyleItalic">rincesa</span> E<span class="elsevierStyleItalic">arly</span> A<span class="elsevierStyleItalic">rthritis</span> R<span class="elsevierStyleItalic">egister</span> L<span class="elsevierStyleItalic">ongitudinal Study</span> &#40;PEARL&#41;&#44; en el que se reclutan pacientes que presentan una o m&#225;s articulaciones inflamadas durante al menos 4 semanas y una evoluci&#243;n menor de un a&#241;o&#46; El registro comenz&#243; en septiembre de 2001 y contin&#250;a en la actualidad&#46; El protocolo del estudio fue revisado y aprobado por el Comit&#233; de &#201;tica de la Investigaci&#243;n Cl&#237;nica del Hospital Universitario La Princesa&#44; y todos los pacientes participantes firman un consentimiento informado en el momento de su inclusi&#243;n en el registro&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">De todos los individuos incluidos en la base de datos se han utilizado aquellos que&#44; a los 2 a&#241;os de seguimiento&#44; cumplen criterios de AR ACR 1987<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a>&#44; y aquellos considerados artritis indiferenciada &#40;AI&#41;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> tras excluirse otras causas de artropat&#237;a inflamatoria&#44; como artritis microcristalinas&#44; artritis s&#233;pticas&#44; espondiloartritis y otras enfermedades del tejido conectivo&#46; La fecha de corte para el an&#225;lisis de los datos fue septiembre de 2014&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">M&#233;todos</span><p id="par0030" class="elsevierStylePara elsevierViewall">En PEARL se recogen de forma protocolizada datos demogr&#225;ficos y cl&#237;nicos que incluyen el recuento de 28 articulaciones dolorosas y tumefactas&#44; la valoraci&#243;n global de la enfermedad por parte del m&#233;dico y del paciente mediante escala anal&#243;gica visual y la versi&#243;n espa&#241;ola del cuestionario HAQ para la evaluaci&#243;n del estado de salud<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a>&#46; Tambi&#233;n se recogen datos anal&#237;ticos como las cifras de leucocitos&#44; hemoglobina &#40;Hb&#41;&#44; plaquetas y de la transaminasa glut&#225;mico-pir&#250;vica &#40;GPT&#41;&#44; realizados seg&#250;n la t&#233;cnica habitual en los servicios de hematolog&#237;a y bioqu&#237;mica de nuestro centro&#44; la velocidad de sedimentaci&#243;n glomerular &#40;determinada por m&#233;todo de Westergren&#41;&#44; la prote&#237;na C reactiva &#40;&#91;PCR&#93; determinada por nefelometr&#237;a&#41;&#44; el factor reumatoide &#40;determinado por nefelometr&#237;a&#44; positivo si &#62;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>U&#47;ml&#41;&#44; los anticuerpos antip&#233;ptido c&#237;clico citrulinado &#40;determinado por ELISA&#44; Euro-Diagnostica Immunoscan RA&#59; positivo &#62;<span class="elsevierStyleHsp" style=""></span>50<span class="elsevierStyleHsp" style=""></span>IU&#47;ml&#41;&#44; as&#237; como el tratamiento recibido en cada visita &#40;<a class="elsevierStyleCrossRef" href="#sec0110">tabla 1 del anexo 1 &#91;disponible on line&#93;</a>&#41;&#46; La actividad de la enfermedad se estima mediante el DAS28<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a>&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">La extracci&#243;n de ADN se realiz&#243;&#44; en todos los pacientes del estudio&#44; mediante procedimientos est&#225;ndar &#40;QIAamp DNA Blood Mini Kit&#44; Qiagen&#41;&#46; Se estudiaron los SNPs rs1801131 y rs1801133 de la MTHFR&#44; rs1045642 del transportador de membrana ABCB1&#44; rs2372536 de la ATIC y rs1544105 de la FPGS&#44; mediante los kits de sondas TaqMan C&#95;&#95;&#95;1202883&#95;20&#44; C&#95;&#95;&#95;&#95;850486&#95;20&#44; C&#95;&#95;&#95;7586657&#95;20&#44; C&#95;&#95;16218146&#95;10 y C&#95;&#95;&#95;8342611&#95;10 respectivamente &#40;Applied Biosystems&#44; Foster City&#44; California&#44; EE&#46; UU&#46;&#41;&#46; Las muestras se genotiparon mediante PCR en tiempo real en un termociclador StepOne Plus Real-Time PCR &#40;Applied Biosystems&#41; siguiendo las instrucciones del fabricante&#46; La asignaci&#243;n del genotipo se realiz&#243; con el software SDS &#40;version 2&#46;3&#44; Applied Biosystems&#41;&#46; Se incluyeron muestras duplicadas y controles negativos para comprobar la precisi&#243;n del genotipado&#46; Se estim&#243; una precisi&#243;n mayor del 99&#37;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">An&#225;lisis estad&#237;stico</span><p id="par0040" class="elsevierStylePara elsevierViewall">Con el fin de excluir consideraciones subjetivas&#44; tanto del m&#233;dico como del paciente&#44; se restringi&#243; el estudio de la toxicidad de MTX a su efecto sobre variables anal&#237;ticas que se usan rutinariamente para evaluar la toxicidad hep&#225;tica y medular de MTX&#58; GPT&#44; leucocitos&#44; plaquetas y Hb&#46; Para cada una de ellas se estudi&#243; la asociaci&#243;n con diferentes variables sociodemogr&#225;ficas&#44; cl&#237;nicas&#44; de la enfermedad y gen&#233;ticas&#46; Posteriormente&#44; para cada una de las 4 variables dependientes se llev&#243; a cabo un an&#225;lisis multivariable mediante modelos lineales generalizados usando el comando &#171;glm&#187; de Stata12 &#40;StataCorp&#44; College Station&#44; TX&#44; EE&#46; UU&#46;&#41; en las visitas en las que los pacientes estaban tomando MTX&#46; Es decir&#44; que se analiz&#243; qu&#233; ocurr&#237;a en cada una de las visitas en las que el paciente hab&#237;a recibido MTX&#46; De promedio se analizaron 2&#44;8 visitas por paciente&#46; El ajuste de los modelos multivariables se realiz&#243; incluyendo inicialmente todas aquellas variables con niveles de significaci&#243;n p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;15 en el an&#225;lisis bivariable y&#44; posteriormente&#44; se fueron excluyendo todas aquellas variables con p<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#44;15 o&#44; en el caso de las variables categ&#243;ricas&#44; aquellas en las que todas sus categor&#237;as tuviesen p<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#44;15&#46; Una vez establecido el mejor modelo multivariable para cada variable de desenlace de toxicidad&#44; con las visitas en las que los pacientes recibieron MTX&#44; ese mismo modelo se repiti&#243; en las visitas sin MTX&#46; Dado que se han realizado comparaciones m&#250;ltiples &#40;GPT&#44; Hb&#44; leucocitos y plaquetas&#41; se ajust&#243; la significaci&#243;n estad&#237;stica mediante el m&#233;todo de Bonferroni&#44; estableci&#233;ndose en p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0125&#46; Se realiz&#243; un an&#225;lisis de sensibilidad usando modelos lineales generalizados anidados por paciente y visita con el comando <span class="elsevierStyleItalic">xtgee</span> de Stata&#44; que proporcion&#243; resultados muy similares &#40;datos no mostrados&#41;&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Por otra parte&#44; se realiz&#243; un an&#225;lisis multivariable para determinar las variables que se asociaron con la dosis de MTX recibida en cada visita del seguimiento&#44; usando el comando <span class="elsevierStyleItalic">xtgee</span> de Stata&#46; El modelo se ajust&#243; con la opci&#243;n de correlaci&#243;n autorregresiva de primer nivel&#44; de forma que solo se considerasen aquellas visitas de pacientes en los que se hab&#237;a recibido MTX durante al menos un a&#241;o &#40;2 visitas consecutivas&#41;&#44; de forma que se hubiese podido alcanzar la m&#225;xima dosis tolerable&#46; En este caso se estudiaron un promedio de 3&#44;2 visitas por paciente&#46; La obtenci&#243;n del modelo m&#225;s ajustado se realiz&#243; como se ha descrito previamente&#46; Adem&#225;s&#44; una vez determinadas qu&#233; variantes gen&#233;ticas eran relevantes en el an&#225;lisis&#44; se opt&#243; por un modelo aditivo de las mismas por ser el que mejor explicaba su contribuci&#243;n a las dosis de MTX utilizadas&#46; En este an&#225;lisis se estableci&#243; el nivel de significaci&#243;n en p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Resultados</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Pacientes</span><p id="par0050" class="elsevierStylePara elsevierViewall">Se estudiaron un total de 350 pacientes&#58; 248 con el diagn&#243;stico de AR y 102 con el de AI&#46; Los datos descriptivos basales se muestran en la <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#46; Los pacientes que cumplieron criterios de AR presentaron de forma significativa mayor frecuencia de FR y anti-PCC&#44; mayor nivel de DAS28 y HAQ&#44; mayor n&#250;mero de plaquetas y mayores cifras de PCR&#44; en comparaci&#243;n con aquellos diagnosticados de AI &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;&#46; Respecto al tratamiento 223 pacientes recibieron MTX en el grupo de AR &#40;89&#37;&#41; y 43 en el grupo de AI &#40;43&#37;&#41;&#44; con un total de 732 visitas en las que los pacientes recibieron este f&#225;rmaco &#40;<a class="elsevierStyleCrossRef" href="#sec0110">tabla 1 del anexo 1 &#91;disponible on line&#93;</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Toxicidad hep&#225;tica</span><p id="par0055" class="elsevierStylePara elsevierViewall">En el an&#225;lisis multivariable se observ&#243; que en las visitas en las que los pacientes recib&#237;an MTX&#44; la edad&#44; el sexo&#44; el estado civil soltero y el &#237;ndice de masa corporal mostraron una tendencia a menores niveles de GPT en las 2 primeras variables y a mayores niveles en las 2 restantes &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>&#41;&#46; Ajustando por estas variables de confusi&#243;n&#44; se comprob&#243; que los pacientes homocigotos para el alelo C de la variante rs1045642 del transportador ABCB1 presentaban significativamente mayores niveles de GPT que aquellos portadores de&#44; al menos&#44; un alelo T &#40;genotipos TT o CT &#91;<a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>&#93;&#41;&#46; Adem&#225;s se observ&#243; una tendencia&#44; que no alcanz&#243; la significaci&#243;n estad&#237;stica&#44; hacia que los pacientes portadores de&#44; al menos&#44; un alelo T del SNP rs1801133 de la MTHFR tuvieran mayores niveles de GPT &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>&#41;&#46; El resto de variantes gen&#233;ticas no influyeron de forma significativa&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">En las visitas en las que los pacientes no recib&#237;an MTX solo el estado civil soltero y el &#237;ndice de masa corporal mostraron una tendencia a mayores niveles de GPT &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Toxicidad hematol&#243;gica</span><p id="par0065" class="elsevierStylePara elsevierViewall">Como variables dependientes para el estudio de la toxicidad hematol&#243;gica se utilizaron la hemoglobina&#44; los leucocitos y la cifra de plaquetas&#46;</p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Leucocitos</span><p id="par0070" class="elsevierStylePara elsevierViewall">Tanto en el an&#225;lisis de las visitas en las que los pacientes recibieron MTX &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a>&#41;&#44; como en el realizado con las visitas en las que los pacientes no recib&#237;an MTX &#40;<a class="elsevierStyleCrossRef" href="#sec0110">tabla 2 del anexo 1 &#91;disponible on line&#93;</a>&#41;&#44; se observ&#243; que los fumadores activos&#44; los varones&#44; los pacientes de edad avanzada y el tratamiento con glucocorticoides se asociaron de forma significativa a mayores cifras de leucocitos&#46; Ajustando por estas variables&#44; en las visitas en las que los pacientes recib&#237;an tratamiento con MTX&#44; se observ&#243; que ser portador de&#44; al menos&#44; un alelo G del SNP rs1544105 de la FPGS se asoci&#243; con una tendencia no significativa a cifras menores de leucocitos &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a>&#41;&#44; mientras que esta tendencia desaparec&#237;a en el an&#225;lisis de las visitas sin MTX &#40;<a class="elsevierStyleCrossRef" href="#sec0110">tabla 2 del anexo 1 &#91;disponible on line&#93;</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Hemoglobina</span><p id="par0075" class="elsevierStylePara elsevierViewall">Los varones&#44; fumadores activos y pacientes con menor estado de actividad de la artritis&#44; presentaban niveles significativamente mayores de Hb&#44; tanto en el an&#225;lisis de visitas en las que los pacientes recib&#237;an MTX &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a>&#41;&#44; como en aquellas en las que no lo tomaban &#40;<a class="elsevierStyleCrossRef" href="#sec0110">tabla 2 del anexo 1 &#91;disponible on line&#93;</a>&#41;&#46; Ajustando por estas variables&#44; de nuevo se observ&#243; que los portadores de&#44; al menos&#44; un alelo G del SNP rs1544105 de la FPGS presentaron cifras significativamente menores de Hb &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a>&#41;&#46; Adem&#225;s&#44; aquellos individuos portadores de un alelo A de la MTHFR rs1801131 o uno T de la rs1801133&#44; presentaron una tendencia que no alcanza la significaci&#243;n estad&#237;stica hacia tener menores niveles de Hb &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a>&#41;&#46; En los 3 SNP la asociaci&#243;n solo se detect&#243; en las visitas en las que los pacientes tomaban MTX&#44; mientras que no se encontr&#243; asociaci&#243;n significativa entre las diferentes variables gen&#233;ticas y los niveles de Hb en las visitas en las que no tomaban MTX &#40;<a class="elsevierStyleCrossRef" href="#sec0110">tabla 2 del anexo 1 &#91;disponible on line&#93;</a>&#41;&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Plaquetas</span><p id="par0080" class="elsevierStylePara elsevierViewall">Los pacientes con mayor actividad y de g&#233;nero femenino presentaron cifras m&#225;s elevadas de plaquetas&#44; aunque estas variables solo alcanzaron significaci&#243;n estad&#237;stica en las visitas en las que los enfermos no recib&#237;an MTX &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a>&#41;&#46; Ajustando por estas variables&#44; la presencia del alelo G de la FPGS se asoci&#243; de forma significativa con un menor n&#250;mero de plaquetas tanto en las visitas con MTX como sin MTX &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a>&#41;&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Factores que influyen en las dosis de metotrexato</span><p id="par0085" class="elsevierStylePara elsevierViewall">Dado que el efecto observado de las variantes gen&#233;ticas de la MTHFR&#44; el ABCB1 y la FPGS no fue de una magnitud elevada&#44; nos planteamos si esta situaci&#243;n podr&#237;a estar relacionada con una modulaci&#243;n de la dosis de MTX por parte de los m&#233;dicos prescriptores ante la presencia factores de riesgo ya reconocidos de toxicidad por MTX&#44; o la constataci&#243;n de datos de toxicidad en visitas intermedias no recogidas en el registro&#46; Por ello se realiz&#243; un an&#225;lisis multivariable en el cual se estudi&#243; la influencia de las variables gen&#233;ticas de estas enzimas en la dosis empleada de MTX en cada visita&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Como era de esperar&#44; los mayores de 65 a&#241;os recibieron significativamente menores dosis de MTX&#44; mientras que la presencia de anticuerpos antip&#233;ptido c&#237;clico citrulinado y el sexo femenino se asociaron a una tendencia al uso de dosis m&#225;s elevadas &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">tabla 4</a>&#41;&#46; Ajustando por estas variables de confusi&#243;n se observ&#243; que existe una interacci&#243;n del efecto de las variantes rs1801133 de la MTHFR y de la rs1544105 de la FPGS sobre la dosis prescrita de f&#225;rmaco&#46; As&#237;&#44; comparando con ser homocigotos de los alelos comunes de dichas variantes&#44; se observ&#243; que la dosis de MTX disminu&#237;a de forma progresiva cuantos m&#225;s alelos menores de dichas prote&#237;nas portaba el paciente &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">tabla 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discusi&#243;n</span><p id="par0095" class="elsevierStylePara elsevierViewall">Nuestros datos sugieren que variantes gen&#233;ticas funcionales de las prote&#237;nas ABCB1&#44; FPGS y MTHFR se asocian a la presencia de mayor toxicidad y uso de menores dosis de MTX en pacientes con ARC&#46; Estos datos son congruentes con la literatura previa&#44; especialmente en el caso de la MTHFR&#44; donde se dispone de mayor evidencia en el campo de la reumatolog&#237;a<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">18&#44;19</span></a>&#44; incluida la poblaci&#243;n espa&#241;ola<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">20&#8211;22</span></a>&#46; En pacientes con enfermedades inflamatorias reumatol&#243;gicas el papel de ABCB1 y la FPGS ha sido menos estudiado&#44; y se han enfocado principalmente a la eficacia de MTX y menos a la toxicidad<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a>&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Un aspecto llamativo de nuestros resultados es el efecto diferencial en las variantes gen&#233;ticas estudiadas&#44; afectando principalmente a la toxicidad hep&#225;tica los SNP rs1045642 del trasportador ABCB1 y rs1801133 de MTHFR&#44; mientras que el SNPrs1544105 de la FPGS se ha asociado con la toxicidad hematol&#243;gica&#46; No hay estudios previos que investiguen la toxicidad diferencial de estas variantes gen&#233;ticas en el campo de la reumatolog&#237;a&#44; pues la mayor&#237;a de los estudios citados se han basado en variables dicot&#243;micas de suspensi&#243;n del f&#225;rmaco por toxicidad&#44; sin especificar la causa<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">18&#8211;22</span></a>&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">En el caso de ABCB1&#44; las c&#233;lulas de los pacientes portadores del alelo menor de rs1045642 tendr&#237;an dificultad para eliminar el MTX y&#44; consecuentemente&#44; una mayor biodisponibilidad que podr&#237;a explicar la mayor toxicidad observada&#46; Es m&#225;s&#44; nuestros datos confirman el estudio de Gregers et al&#46;&#44; que describieron una mayor toxicidad hep&#225;tica en ni&#241;os con leucemia linfobl&#225;stica aguda tratados con MTX cuando eran portadores homocigotos del genotipo CC de rs1045642 en ABCB1 frente a los portadores de los genotipos CT o TT<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a>&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">En el caso del SNP rs1801133 de MTHFR&#44; la presencia del alelo infrecuente T se asocia con menor actividad funcional&#44; que se estima en un 30&#37; para los homocigotos TT y un 70&#37; para los heterocigotos CT<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a>&#46; Adem&#225;s&#44; esta variante gen&#233;tica se ha asociado a un aumento de los niveles de homociste&#237;na y el correspondiente aumento del riesgo cardiovascular<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a>&#46; El aumento de homociste&#237;na en pacientes con niveles bajos de actividad de la MTHFR se debe a que para que se catalice el paso de homociste&#237;na a metionina se precisa 5-CH3-THF&#44; que es generado a partir del 5-10-CH2-THF por la MTHFR &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#46; La relaci&#243;n con la toxicidad hep&#225;tica vendr&#237;a dada porque estos pacientes tendr&#237;an una menor producci&#243;n de metionina y tambi&#233;n de S-adenosil-metionina &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#44; que es de gran importancia en el metabolismo hep&#225;tico<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a>&#46; Aunque nuestros datos solo han mostrado una tendencia a mayores niveles de GPT en los portadores de los genotipos CT y TT de rs1801133&#44; estos datos est&#225;n en concordancia con estudios previos que asocian esos genotipos con elevaci&#243;n de transaminasas<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">27&#44;28</span></a>&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">En lo que respecta a FGPS&#44; como ya se ha mencionado&#44; el alelo infrecuente A de rs1544105 se ha asociado a menores niveles de la enzima<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> y diferencias en la eficacia de MTX&#44; tanto en leucemias como en AR<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a>&#46; En relaci&#243;n con nuestros datos&#44; la presencia del alelo ancestral G es la que se asocia con mayor toxicidad hematol&#243;gica y requerimientos de menor dosis de MTX&#46; Probablemente se relacione con una mayor eficacia en la poliglutamaci&#243;n del MTX y una mayor actividad de este sobre las v&#237;as de s&#237;ntesis de purinas y pirimidinas &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#44; y por ello mayor toxicidad en las 3 series hematol&#243;gicas&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">La principal limitaci&#243;n de este estudio reside en que se ha realizado en una sola poblaci&#243;n de pacientes con ARC&#44; y las pr&#225;cticas locales en el uso de MTX pueden haber sesgado los resultados&#46; As&#237;&#44; el m&#233;dico prescriptor podr&#237;a decidir no iniciar el f&#225;rmaco en pacientes con un perfil que les predisponga a presentar toxicidad <span class="elsevierStyleItalic">a priori</span>&#44; como son ancianos o pacientes con alcoholismo o hepatopat&#237;a previa&#44; lo que podr&#237;a infravalorar el efecto observado&#46; Sin embargo&#44; el hecho de que se hayan reproducido factores asociados a mayor toxicidad de MTX&#44; como la obesidad para toxicidad hep&#225;tica<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a>&#44; o que la asociaci&#243;n de los factores gen&#233;ticos con alteraciones en las cifras de GPT&#44; Hb&#44; leucocitos o plaquetas aparezcan en las visitas en las que reciben los pacientes MTX&#44; pero no en aquellas en las que no lo est&#225;n tomando&#44; confiere credibilidad al acercamiento propuesto en nuestro art&#237;culo&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Tambi&#233;n como limitaci&#243;n&#44; resulta intrigante desconocer la raz&#243;n por la que variantes gen&#233;ticas de prote&#237;nas como ABCB1 y FPGS&#44; que act&#250;an en niveles comunes del manejo de MTX y &#225;cido f&#243;lico&#44; presentan repercusi&#243;n diferente en cuanto a la toxicidad de MTX&#44; hep&#225;tica en la primera y hematol&#243;gica en la segunda&#46; Finalmente&#44; debido a la organizaci&#243;n en la recogida de muestras de PEARL&#44; no se han podido determinar niveles de poliglutamatos de MTX intraeritrocitarios que podr&#237;an haber contribuido a un mejor conocimiento del efecto del SNP estudiado en FPGS&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Por &#250;ltimo&#44; la relevancia cl&#237;nica del efecto observado puede ser menor del deseado&#44; pues las variantes de ABCB1 y FPGS&#44; que hemos observado asociadas a toxicidad de MTX&#44; tambi&#233;n se han relacionado con una mayor eficacia del f&#225;rmaco<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a>&#46; No obstante&#44; la combinaci&#243;n de genotipos que m&#225;s podr&#237;a limitar la dosis usada de MTX seg&#250;n nuestro estudio&#44; ser homocigoto G de rs1544105 en FPGS y genotipos CT o TT de rs1801133 en MTHFR&#44; ocurre en un 22&#37; de los pacientes de nuestra poblaci&#243;n&#46; En definitiva&#44; el porcentaje de poblaci&#243;n que comparte los SNP que hemos estudiado no es desde&#241;able&#44; y es posible que la determinaci&#243;n de variantes gen&#233;ticas en ABCB1&#44; MTHFR y FPGS pudieran ser de ayuda para determinar en qu&#233; pacientes con ARC deber&#237;a usarse una dosis menor de MTX o sustituirlo por otros f&#225;rmacos modificadores de la enfermedad&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Responsabilidades &#233;ticas</span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Protecci&#243;n de personas y animales</span><p id="par0135" class="elsevierStylePara elsevierViewall">Los autores declaran que los procedimientos seguidos se conformaron a las normas &#233;ticas del comit&#233; de experimentaci&#243;n humana responsable y de acuerdo con la Asociaci&#243;n M&#233;dica Mundial y la Declaraci&#243;n de Helsinki&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Confidencialidad de los datos</span><p id="par0140" class="elsevierStylePara elsevierViewall">Los autores declaran que han seguido los protocolos de su centro de trabajo sobre la publicaci&#243;n de datos de pacientes&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Derecho a la privacidad y consentimiento informado</span><p id="par0145" class="elsevierStylePara elsevierViewall">Los autores han obtenido el consentimiento informado de los pacientes y&#47;o sujetos referidos en el art&#237;culo&#46; Este documento obra en poder del autor de correspondencia&#46;</p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Financiaci&#243;n</span><p id="par0150" class="elsevierStylePara elsevierViewall">Este estudio ha sido realizado gracias a fondos de los proyectos RD12&#47;0009&#47;0017&#44; PI11&#47;00551&#44; PI14&#47;00442 y PIE13&#47;00041 del Ministerio de Econom&#237;a y Competitividad &#40;Instituto de Salud Carlos <span class="elsevierStyleSmallCaps">III</span>&#41;&#44; cofinanciados por el Fondo Europeo de Desarrollo Regional &#40;FEDER&#41;&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Conflicto de intereses</span><p id="par0155" class="elsevierStylePara elsevierViewall">IG-A ha recibido en los &#250;ltimos 5 a&#241;os financiaci&#243;n para proyectos de investigaci&#243;n de BMS&#44; Roche y UCB&#44; as&#237; como pagos por asesor&#237;a y presentaciones cient&#237;ficas por parte de Abbvie&#44; BMS&#44; Lilly&#44; Pfizer&#44; Roche y UCB&#46; IG-A y AMO son coinventores de la patente <span class="elsevierStyleItalic">Prognostic method for autoimmune disorders through genotyping vasoactive intestinal peptide variants</span> c&#243;digo PCT&#47;ES2015&#47;070182&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">LS&#44; AL&#44; EG-L y PM-F declaran no tener conflicto de intereses en relaci&#243;n con este trabajo&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objetivo</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Analizar el efecto de polimorfismos de nucle&#243;tido &#250;nico &#40;SNPs&#41; de la metilen-tetrahidrofolatorreductasa &#40;MTHFR&#59; rs1801131 y rs1801133&#41;&#44; el transportador de membrana que une ATP B1 &#40;ABCB1&#59; rs1045642&#41;&#44; la aicartransformilasa&#47;IMP ciclohidrolasa &#40;ATIC&#59; rs2372536&#41; y la folilpoliglutamatosintetasa &#40;FPGS&#59; rs1544105&#41; en la toxicidad hep&#225;tica y medular de metotrexato &#40;MTX&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Pacientes y m&#233;todos</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se analizaron 1&#46;415 visitas &#40;732 con MTX&#44; 683 sin MTX&#41; de 350 pacientes del <span class="elsevierStyleItalic">Princesa Early Arthritis Register Longytudinal study</span>&#46; El genotipo de los diferentes SNP se determin&#243; mediante sondas TaqMan &#40;Applied Biosystems&#41;&#46; Se realizaron an&#225;lisis multivariables mediante modelos lineales generalizados en los que las variables dependientes fueron los niveles s&#233;ricos de transaminasa glut&#225;mico-pir&#250;vica &#40;toxicidad hep&#225;tica&#41;&#44; leucocitos&#44; plaquetas o hemoglobina &#40;toxicidad hematol&#243;gica&#41; y se ajustaron por variables cl&#237;nicas &#40;actividad de la enfermedad&#44; etc&#46;&#41;&#44; anal&#237;ticas &#40;funci&#243;n renal&#44; etc&#46;&#41;&#44; sociodemogr&#225;ficas &#40;edad&#44; sexo&#44; etc&#46;&#41; y las variantes gen&#233;ticas de MTHFR&#44; ABCB1&#44; ATIC y FPGS&#46; Tambi&#233;n se analizaron las variables que influyeron en las dosis de MTX administradas a lo largo del seguimiento&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Cuando recib&#237;an MTX los portadores del genotipo <span class="elsevierStyleSmallCaps">CC</span> del SNP rs1045642 de ABCB1 presentaron niveles significativamente mayores de GPT &#40;7&#44;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;0<span class="elsevierStyleHsp" style=""></span>U&#47;l&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; Los portadores de al menos un alelo G de rs1544105 en FPGS presentaron niveles significativamente menores de leucocitos &#40;&#8722;0&#44;67<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;32&#59; 0&#44;038&#41;&#44; hemoglobina &#40;&#8722;0&#44;34<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;11<span class="elsevierStyleHsp" style=""></span>g&#47;dl&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;002&#41; y de plaquetas &#40;&#8722;11&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#44;7&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;012&#41;&#46; La presencia del alelo G de rs1544105 &#40;FPGS&#41; y T de rs1801133 &#40;MTHFR&#41; se asoci&#243;&#44; de forma aditiva y significativa&#44; al uso de menores dosis de MTX&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Discusi&#243;n</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Nuestros datos sugieren que variantes gen&#233;ticas de las enzimas FGPS y MTHFR&#44; y del transportador ABCB1&#44; podr&#237;an ayudar a detectar pacientes con mayor riesgo de toxicidad por MTX&#46;</p></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objective</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">To analyze the effect of single nucleotide polymorphisms &#40;SNPs&#41; with well-known functional impact of methylenetetrahydrofolatereductase &#40;MTHFR&#59; rs1801131 and rs1801133&#41;&#44; the membrane transporter ABCB1 &#40;rs1045642&#41;&#44; the AICAR transformylase&#47;IMP cyclohydrolase &#40;ATIC&#59; rs2372536&#41; and folyl-polyglutamatesynthetase &#40;FPGS&#59; rs1544105&#41;&#44; on liver and bone marrow toxicity of methotrexate &#40;MTX&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Patients and methods</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">We analyzed 1415 visits from 350 patients of the PEARL &#40;Princesa Early Arthritis Register Longitudinal&#41; study&#58; &#40;732 with MTX&#44; 683 without MTX&#41;&#46; The different SNPs were genotyped using specific TaqMan probes &#40;Applied Biosystems&#41;&#46; Multivariate analyzes were performed using generalized linear models in which the dependent variables were the levels of serum alanine aminotransferase &#40;liver toxicity&#41;&#44; leukocytes&#44; platelets or hemoglobin &#40;hematologic toxicity&#41; and adjusted for clinical variables &#40;disease activity&#44; etc&#46;&#41;&#44; analytical &#40;renal function&#44; etc&#46;&#41;&#44; sociodemographic &#40;age&#44; sex&#44; etc&#46;&#41; and genetic variants of MTHFR&#44; ABCB1&#44; ATIC and FPGS&#46; The effect of these variables on the MTX doses prescribed throughout follow-up was also analyzed through multivariate analysis nested by visit and patient&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">When taking MTX&#44; those patients carrying the CC genotype of rs1045642 in ABCB1 showed significantly higher GPT levels &#40;7&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;0 U&#47;L&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; Carrying at least one G allele of rs1544105 in FPGS was associated with lower leukocyte &#40;&#8722;0&#46;67<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;32&#59; 0&#46;038&#41;&#44; hemoglobin &#40;&#8722;0&#46;34<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;11<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#59; <span class="elsevierStyleItalic">P<span class="elsevierStyleHsp" style=""></span></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;002&#41;&#44; and platelet &#40;&#8722;11&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;7&#59; <span class="elsevierStyleItalic">P<span class="elsevierStyleHsp" style=""></span></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;012&#41; levels&#46; The presence of the G allele of rs1544105 in FPGS&#44; and the T allele of rs1801133 in MTHFR&#44; was significantly associated with the use of lower doses of MTX&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Discussion</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Our data suggest that genotyping functional variants in FGPS and MTHFR enzymes and the transporter ABCB1 could help to identify patients with increased risk of MTX toxicity&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Objective"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Patients and methods"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Discussion"
          ]
        ]
      ]
    ]
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          0 => array:4 [
            "apendice" => "<p id="par0175" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Anexo A"
            "titulo" => "Material suplementario"
            "identificador" => "sec0110"
          ]
        ]
      ]
    ]
    "multimedia" => array:6 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figura 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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        "descripcion" => array:1 [
          "es" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Esquema de las v&#237;as metab&#243;licas en las que est&#225; implicado el &#225;cido f&#243;lico y enzimas sobre las que act&#250;a metotrexato&#46;</p> <p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Los &#243;valos de color azul oscuro indican las enzimas que han sido estudiadas&#46; Las enzimas a las que llegan las l&#237;neas rojas se refieren a las que son inhibidas por los poliglutamatos de metotrexato&#46;</p> <p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">ABCB1&#58; transportador que une ATP B1&#59; ADA&#58; deaminasa de adenosina&#59; ADP&#58; bifosfato de adenosina&#59; AMP&#58; monofosfato de adenosina&#59; ATIC&#58; AICAR transformilasa&#47;IMP ciclohidrolasa&#59; ATP&#58; trifosfato de adenosina&#59; DHFR&#58; dihidrofolato reductasa&#59; FPGS&#58; folilpoliglutamato sintetasa&#59; GGH&#58; gamma glutamil hidrolasa&#59; IMP&#58; monofosfato de inositol&#59; MTHFD1&#58; 5-10-metilentetrahidrofolato deshidrogenasa 1&#59; MTHFR&#58; metilentetrahidrofolato reductasa&#59; MTR&#58; metionina reductasa&#59; MTX&#58; metotrexato&#59; MTXPG&#58; poliglutamatos de metotrexato&#59; RFC&#58; transportador de folato reducido&#59; SAM&#58; <span class="elsevierStyleItalic">s-</span>adenosil-l-metionina&#59; TYMS&#58; timidilato sintetasa&#46;</p>"
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        "etiqueta" => "Tabla 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
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            "identificador" => "at1"
            "detalle" => "Tabla "
            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">ABCB1&#58; ATP-<span class="elsevierStyleItalic">binding cassette</span> B1&#59; ACPA&#58; anticuerpos anti p&#233;ptido citrulinado&#59; AI&#58; artritis indiferenciada&#59; AR&#58; artritis reumatoide&#59; ATIC&#58; aicar transformilasa&#47;IMP ciclohidrolasa&#46;FPGS&#58; folilpoliglutamato sintetasa&#59; FR&#58; factor reumatoide&#59; GPT&#58; transaminasa glut&#225;mico-pir&#250;vica&#59; HAQ&#58; <span class="elsevierStyleItalic">Health Assesment Questionnaire</span>&#59; MTHFR&#58; metil&#233;n-tetrahidrofolatorreductasa&#59; PCR&#58; prote&#237;na C reactiva&#46;</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">&#42;</span>Se consider&#243; significaci&#243;n estad&#237;stica si p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#46;</p>"
          "tablatextoimagen" => array:1 [
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AR<br>n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>248&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AI<br>n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>102&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total<br>n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>350&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p<span class="elsevierStyleSup">&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sexo femenino n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">201 &#40;81&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">76 &#40;74&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">277 &#40;79&#44;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;174&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Edad al inicio de la enfermedad &#40;a&#241;os&#59; mediana &#91;p25-p75&#93;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">54 &#40;45-68&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">54 &#40;39-66&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">54 &#40;43-67&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;351&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FR positivo n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">164 &#40;66&#44;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17 &#40;16&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">181 &#40;51&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ACPA positivo n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">152 &#40;61&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15 &#40;14&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">167 &#40;47&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">DAS 28 &#40;mediana &#91;p25-p75&#93;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#44;8 &#40;3&#44;6-5&#44;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44;9 &#40;3&#44;0-4&#44;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#44;5 &#40;3&#44;4-5&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PCR &#40;mediana &#91;p25-p75&#93;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;8 &#40;0&#44;3-1&#44;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5 &#40;0&#44;2-1&#44;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;7 &#40;0&#44;2-1&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HAQ &#40;mediana &#91;p25-p75&#93;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;125 &#40;0&#44;5-1&#44;75&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;75 &#40;0&#44;375-1&#44;375&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;0&#44;5-1&#44;625&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;003&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Leucocitos&#47;mm<span class="elsevierStyleSup">3</span> &#40;mediana &#91;p25-p75&#93;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#46;400 &#40;6&#46;220-9&#46;090&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#46;460 &#40;6&#46;030-9&#46;480&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#46;420 &#40;6&#46;200-9&#46;160&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;899&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GPT &#40;U&#47;ml&#41; &#40;mediana &#91;p25-p75&#93;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="center" valign="middle">17 &#40;13-23&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="center" valign="middle">19 &#40;14-25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="center" valign="middle">17 &#40;13-23&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;038&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Plaquetas<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>1&#46;000&#47;mm<span class="elsevierStyleSup">3</span> &#40;mediana &#91;p25-p75&#93;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="center" valign="middle">281 &#40;241-344&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="center" valign="middle">260 &#40;203-301&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="center" valign="middle">275 &#40;229-329&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Creatinina &#40;mediana &#91;p25-p75&#93;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;80 &#40;0&#44;70&#8211;0&#44;95&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;80 &#40;0&#44;70-0&#44;91&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;80 &#40;0&#44;70-0&#44;95&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;949&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">MTHFR &#40;rs1801131&#41;<br>CC&#47;CA&#47;AA &#40;&#37; pacientes&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&#44;3&#47;35&#44;9&#47;55&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#44;2&#47;43&#44;3&#47;50&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#44;7&#47;38&#44;5&#47;54&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;422&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">MTHFR &#40;rs1801133&#41;<br>CC&#47;CT&#47;TT &#40;&#37; pacientes&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">39&#44;7&#47;45&#44;6&#47;14&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32&#44;6&#47;43&#44;9&#47;23&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">37&#44;6&#47;45&#44;1&#47;17&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;137&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ABCB1 &#40;rs1045642&#41;<br>TT&#47;TC&#47;CC &#40;&#37; pacientes&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19&#44;7&#47;46&#44;5&#47;33&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#44;2&#47;55&#44;1&#47;34&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17&#44;0&#47;50&#44;0&#47;34&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;090&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ATIC &#40;rs2372536&#41;<br>CC&#47;CG&#47;GG &#40;&#37; pacientes&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">39&#44;9&#47;48&#44;5&#47;11&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">49&#44;5&#47;35&#44;0&#47;15&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">42&#44;7&#47;44&#44;6&#47;12&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;080&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FPGS &#40;rs1544105&#41;<br>GG&#47;GA&#47;AA &#40;&#37; pacientes&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">37&#44;2&#47;43&#44;4&#47;19&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35&#44;7&#47;44&#44;9&#47;19&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">36&#44;7&#47;43&#44;8&#47;19&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;962&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">ABCB1&#58; ATP-<span class="elsevierStyleItalic">binding cassette</span> B1&#59; ATIC&#58; aicar transformilasa&#47;IMP ciclohidrolasa&#59; DAS28&#58; <span class="elsevierStyleItalic">Disease activity score</span> de 28 articulaciones&#59; FPGS&#58; folilpoliglutamato sintetasa&#59; GPT&#58; transaminasa glut&#225;mico-pir&#250;vica&#59; IMC&#58; &#237;ndice de masa corporal&#59; MTHFR&#58; metil&#233;n-tetrahidrofolatorreductasa&#59; MTX&#58; metotrexato&#59; N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&#58; no incluido&#59; n&#46;s&#46;&#58; no significativo&#59; Ref&#46;&#58; referencia&#46;</p><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">&#42;</span>Se consider&#243; significaci&#243;n estad&#237;stica si p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0125 &#40;v&#233;ase la secci&#243;n de <span class="elsevierStyleItalic">Estad&#237;stica</span> para justificaci&#243;n&#41;&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Variables</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Visitas con MTX &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>607&#41;</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Visitas sin MTX &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>551&#41;</th></tr><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Coef&#46;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>e&#46;e&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Coef&#46;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>e&#46;e&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p<span class="elsevierStyleSup">&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Edad &#40;a&#241;os&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>45-65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;413&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;087&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;7&#44;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;2&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;187&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Sexo</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hombre&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mujer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;4&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;064&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;1&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;244&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">E&#46; civil</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Casado&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Separado&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#44;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;173&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;054&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Soltero&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;018&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;537&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Viudo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;314&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;0&#44;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;812&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">IMC &#40;kg&#47;m</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">2</span></span><span class="elsevierStyleItalic">&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;023&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;25<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;072&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">MTHFR &#40;rs1801131&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CC&#47;CA&#47;AA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">MTHFR &#40;rs1801133&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CT&#47;TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;108&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;0&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;818&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">ABCB1 &#40;rs1045642&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>TT&#47;TC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#44;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;0&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;845&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">ATIC &#40;rs2372536&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CC&#47;CG&#47;GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">FPGS &#40;rs1544105&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>GG&#47;GA&#47;AA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "es" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">An&#225;lisis multivariable del efecto de diferentes variables sobre los niveles de la transaminasa glut&#225;mico-pir&#250;vica en pacientes con artritis de inicio</p>"
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          "leyenda" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">ABCB1&#58; ATP-<span class="elsevierStyleItalic">binding cassette</span> B1&#59; ATIC&#58; aicar transformilasa&#47;IMP ciclohidrolasa&#59; DAS28&#58; <span class="elsevierStyleItalic">Disease activity score</span> de 28 articulaciones&#59; FPGS&#58; folilpoliglutamato sintetasa&#59; GPT&#58; transaminasa glut&#225;mico-pir&#250;vica&#59; IMC&#58; &#237;ndice de masa corporal&#59; MTHFR&#58; metil&#233;n-tetrahidrofolatorreductasa&#59; MTX&#58; metotrexato&#59; N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&#58; no incluido&#59; n&#46;s&#46;&#58; no significativo&#59; Ref&#46;&#58; referencia&#46;&#59;</p><p id="spar0100" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">&#42;</span>Se consider&#243; significaci&#243;n estad&#237;stica si p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0125 &#40;v&#233;ase la secci&#243;n de <span class="elsevierStyleItalic">Estad&#237;stica</span> para justificaci&#243;n&#41;&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col">Leucocitos &#40;&#215;<span class="elsevierStyleHsp" style=""></span>1&#46;000&#47;mm<span class="elsevierStyleSup">3</span>&#41;</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col">Hemoglobina &#40;g&#47;dl&#41;</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col">Plaquetas &#40;&#215;<span class="elsevierStyleHsp" style=""></span>1&#46;000&#47;mm<span class="elsevierStyleSup">3</span>&#41;</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>673 visitas</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>588 visitas</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>659 visitas</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Coef&#46;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>e&#46;e&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Coef&#46;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>e&#46;e&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Coef&#46;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>e&#46;e&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p<span class="elsevierStyleSup">&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Edad &#40;a&#241;os&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>45-65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;641&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;26<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;2&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;609&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;79<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;0&#44;01<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;922&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;19&#44;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Sexo</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Masculino&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Femenino&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;1&#44;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;1&#44;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17&#44;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Tabaco</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Nunca&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Ex-fumador&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;29<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;390&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;34<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;003&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Actual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;06<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;42<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">DAS28</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;0&#44;28<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#44;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Corticoides &#40;mg&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;21<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">MTHFR &#40;rs1801131&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CA&#47;AA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;0&#44;32<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;063&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">MTHFR &#40;rs1801133&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CT&#47;TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;0&#44;20<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;043&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">ABCB1 &#40;rs1045642&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>TT&#47;TC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">ATIC &#40;rs2372536&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CC&#47;CG&#47;GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">N&#46;<span class="elsevierStyleSmallCaps">I&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">FPGS &#40;rs1544105&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>AA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>GG&#47;GA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;0&#44;67<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;&#8242;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;038&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;0&#44;34<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;11&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "es" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">An&#225;lisis multivariable del efecto de diferentes factores sobre los niveles variables hematol&#243;gicos en las visitas en las que pacientes con artritis de inicio se encuentran en tratamiento con metotrexato</p>"
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          "leyenda" => "<p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">ACPA&#58; anticuerpos anti-prote&#237;nas citrulinadas&#59; Coef&#58; coeficiente&#59; e&#46;e&#46;&#58; error est&#225;ndar&#59; MTX&#58; metotrexato&#59; n&#58; n&#250;mero de pacientes&#59; n&#46;s&#46;&#58; no significativo&#59; Ref&#46;&#58; referencia&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col">Dosis MTX &#40;mg&#47;sem&#41;</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>636 visitas</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Coef&#46;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>e&#46;e&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p<span class="elsevierStyleSup">&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Edad &#40;a&#241;os&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>45-65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;0&#44;17<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;753&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;2&#44;05<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Sexo</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Masculino&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Femenino&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;17<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;051&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">ACPA</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Negativo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Positivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;86<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;060&nbsp;\t\t\t\t\t\t\n
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                    0 => array:2 [
                      "titulo" => "EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs&#58; 2013 update"
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                            2 => "F&#46;C&#46; Breedveld"
                            3 => "M&#46; Buch"
                            4 => "G&#46; Burmester"
                            5 => "M&#46; Dougados"
                          ]
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                      "doi" => "10.1136/annrheumdis-2013-204573"
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                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2014"
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                        "paginaInicial" => "492"
                        "paginaFinal" => "509"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24161836"
                            "web" => "Medline"
                          ]
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                  ]
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              "identificador" => "bib0160"
              "etiqueta" => "2"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "2014 update of the Consensus Statement of the Spanish Society of Rheumatology on the use of biological therapies in rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "S&#46; Garcia-Rodriguez"
                            2 => "J&#46;M&#46; Alvaro-Gracia"
                            3 => "J&#46;L&#46; Andreu"
                            4 => "A&#46; Balsa"
                            5 => "R&#46; Caliz"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.reuma.2015.05.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Reumatol Clin"
                        "fecha" => "2015"
                        "volumen" => "11"
                        "paginaInicial" => "279"
                        "paginaFinal" => "294"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26051464"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "3"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis"
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                          "etal" => true
                          "autores" => array:6 [
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                            2 => "S&#46;L&#46; Bridges Jr&#46;"
                            3 => "E&#46;A&#46; Akl"
                            4 => "R&#46;R&#46; Bannuru"
                            5 => "M&#46;C&#46; Sullivan"
                          ]
                        ]
                      ]
                    ]
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                    0 => array:2 [
                      "doi" => "10.1002/art.39977"
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                        "tituloSerie" => "Arthritis Rheumatol"
                        "fecha" => "2016"
                        "volumen" => "68"
                        "paginaInicial" => "1"
                        "paginaFinal" => "26"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27870508"
                            "web" => "Medline"
                          ]
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                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0170"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring&#58; Results of an international&#44; cross-sectional study &#40;COMORA&#41;"
                      "autores" => array:1 [
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                            1 => "M&#46; Soubrier"
                            2 => "A&#46; Antunez"
                            3 => "P&#46; Balint"
                            4 => "A&#46; Balsa"
                            5 => "M&#46;H&#46; Buch"
                          ]
                        ]
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                    ]
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                    0 => array:2 [
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                        "link" => array:1 [
                          0 => array:2 [
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              "etiqueta" => "5"
              "referencia" => array:1 [
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                    0 => array:2 [
                      "titulo" => "Trends towards an improved disease state in rheumatoid arthritis over time&#58; Influence of new therapies and changes in management approach&#58; Analysis of the EMECAR cohort"
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                        0 => array:2 [
                          "etal" => false
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                    0 => array:2 [
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                        "tituloSerie" => "Arthritis Res Ther"
                        "fecha" => "2008"
                        "volumen" => "10"
                        "paginaInicial" => "R138"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19036152"
                            "web" => "Medline"
                          ]
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                      ]
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                  ]
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              "identificador" => "bib0180"
              "etiqueta" => "6"
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                0 => array:1 [
                  "referenciaCompleta" => "Sociedad Espa&#241;ola de Reumatolog&#237;a&#46; Proyecto EMAR II&#46; Variabilidad en el manejo de la Artritis reumatoide y las espondiloartritis en Espa&#241;a&#46; Informe de resultados&#46; Madrid&#58; SER&#59; 2011 &#91;actualizado Feb 2011&#59; consultado 5 Sept 2013&#93;&#46; Disponible en&#58; <a href="http://www.ser.es/ArchivosDESCARGABLES/Proyectos/Emar/EMAR_Informe.pdf">http&#58;&#47;&#47;www&#46;ser&#46;es&#47;ArchivosDESCARGABLES&#47;Proyectos&#47;Emar&#47;EMAR&#95;Informe&#46;pdf</a>"
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              "etiqueta" => "7"
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                      "titulo" => "Folate supplementation during methotrexate therapy for rheumatoid arthritis"
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                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46;L&#46; Morgan"
                            1 => "J&#46;E&#46; Baggott"
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                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Rheumatol"
                        "fecha" => "2010"
                        "volumen" => "28"
                        "paginaInicial" => "S102"
                        "paginaFinal" => "S109"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20868587"
                            "web" => "Medline"
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                      "titulo" => "Patterns of disease modifying antirheumatic drug use in a Spanish cohort of patients with rheumatoid arthritis"
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                          "etal" => false
                          "autores" => array:6 [
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                            4 => "M&#46;A&#46; Belmonte"
                            5 => "X&#46; Tena"
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                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Rheumatol"
                        "fecha" => "2003"
                        "volumen" => "30"
                        "paginaInicial" => "697"
                        "paginaFinal" => "704"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12672186"
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                      "titulo" => "Adverse reactions to disease-modifying anti-rheumatic drugs in clinical practice"
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                          "autores" => array:4 [
                            0 => "M&#46;L&#46; Grove"
                            1 => "A&#46;B&#46; Hassell"
                            2 => "E&#46;M&#46; Hay"
                            3 => "M&#46;F&#46; Shadforth"
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                        "fecha" => "2001"
                        "volumen" => "94"
                        "paginaInicial" => "309"
                        "paginaFinal" => "319"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11391029"
                            "web" => "Medline"
                          ]
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                  ]
                ]
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                          "autores" => array:4 [
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                            2 => "A&#46; Monsivais-Urenda"
                            3 => "R&#46; Gonzalez-Amaro"
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                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Pharm Des"
                        "fecha" => "2015"
                        "volumen" => "21"
                        "paginaInicial" => "202"
                        "paginaFinal" => "211"
                        "link" => array:1 [
                          0 => array:2 [
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                      "titulo" => "Functional polymorphisms of the human multidrug-resistance gene&#58; Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo"
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                            4 => "J&#46; Brockmoller"
                            5 => "A&#46; Johne"
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                    0 => array:2 [
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                        "tituloSerie" => "Proc Natl Acad Sci U S A"
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                        "volumen" => "97"
                        "paginaInicial" => "3473"
                        "paginaFinal" => "3478"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10716719"
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                    0 => array:2 [
                      "titulo" => "Identification and characterization of genetic variation in the folylpolyglutamate synthase gene"
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                      "doi" => "10.1158/0008-5472.CAN-07-0156"
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                        "paginaFinal" => "8782"
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                          0 => array:2 [
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                      "titulo" => "Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier&#44; aminoimidazole carboxamide ribonucleotide transformylase&#44; and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Dervieux"
                            1 => "D&#46; Furst"
                            2 => "D&#46;O&#46; Lein"
                            3 => "R&#46; Capps"
                            4 => "K&#46; Smith"
                            5 => "M&#46; Walsh"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.20460"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2004"
                        "volumen" => "50"
                        "paginaInicial" => "2766"
                        "paginaFinal" => "2774"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15457444"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46;C&#46; Arnett"
                            1 => "S&#46;M&#46; Edworthy"
                            2 => "D&#46;A&#46; Bloch"
                            3 => "D&#46;J&#46; McShane"
                            4 => "J&#46;F&#46; Fries"
                            5 => "N&#46;S&#46; Cooper"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "1988"
                        "volumen" => "31"
                        "paginaInicial" => "315"
                        "paginaFinal" => "324"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3358796"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Undifferentiated arthritis--disease course assessed in several inception cohorts"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "K&#46;N&#46; Verpoort"
                            1 => "H&#46; van Dongen"
                            2 => "C&#46;F&#46; Allaart"
                            3 => "R&#46;E&#46; Toes"
                            4 => "F&#46;C&#46; Breedveld"
                            5 => "T&#46;W&#46; Huizinga"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Rheumatol"
                        "fecha" => "2004"
                        "volumen" => "22"
                        "paginaInicial" => "S12"
                        "paginaFinal" => "S17"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15552509"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Spanish version of the Health Assessment Questionnaire&#58; Reliability&#44; validity and transcultural equivalency&#46; Grupo para la adaptaci&#243;n del HAQ a la poblaci&#243;n espa&#241;ola"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46; Esteve-Vives"
                            1 => "E&#46; Batlle-Gualda"
                            2 => "A&#46; Reig"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Rheumatol"
                        "fecha" => "1993"
                        "volumen" => "20"
                        "paginaInicial" => "2116"
                        "paginaFinal" => "2122"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8014941"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Modified disease activity scores that include twenty-eight-joint counts&#46; Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46;L&#46; Prevoo"
                            1 => "M&#46;A&#46; van&#8217;t Hof"
                            2 => "H&#46;H&#46; Kuper"
                            3 => "M&#46;A&#46; van Leeuwen"
                            4 => "L&#46;B&#46; van de Putte"
                            5 => "P&#46;L&#46; van Riel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "1995"
                        "volumen" => "38"
                        "paginaInicial" => "44"
                        "paginaFinal" => "48"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7818570"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Methylene tetrahydrofolate reductase gene polymorphisms and their association with methotrexate toxicity&#58; A meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "K&#46;P&#46; Spyridopoulou"
                            1 => "N&#46;L&#46; Dimou"
                            2 => "S&#46;J&#46; Hamodrakas"
                            3 => "P&#46;G&#46; Bagos"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/FPC.0b013e32834ded2a"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pharmacogenet Genomics"
                        "fecha" => "2012"
                        "volumen" => "22"
                        "paginaInicial" => "117"
                        "paginaFinal" => "133"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22143415"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of the MTHFR C677<span class="elsevierStyleHsp" style=""></span>T and A1298<span class="elsevierStyleHsp" style=""></span>C polymorphisms with methotrexate toxicity in rheumatoid arthritis&#58; A meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "G&#46;G&#46; Song"
                            1 => "S&#46;C&#46; Bae"
                            2 => "Y&#46;H&#46; Lee"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10067-014-2645-8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Rheumatol"
                        "fecha" => "2014"
                        "volumen" => "33"
                        "paginaInicial" => "1715"
                        "paginaFinal" => "1724"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24794492"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The C677<span class="elsevierStyleHsp" style=""></span>T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46; Caliz"
                            1 => "J&#46; del Amo"
                            2 => "A&#46; Balsa"
                            3 => "F&#46; Blanco"
                            4 => "L&#46; Silva"
                            5 => "R&#46; Sanmarti"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3109/03009742.2011.617312"
                      "Revista" => array:6 [
                        "tituloSerie" => "Scand J Rheumatol"
                        "fecha" => "2012"
                        "volumen" => "41"
                        "paginaInicial" => "10"
                        "paginaFinal" => "14"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22044028"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0255"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacogenetic polymorphisms contributing to toxicity induced by methotrexate in the southern Spanish population with rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;C&#46; Plaza-Plaza"
                            1 => "M&#46; Aguilera"
                            2 => "M&#46; Canadas-Garre"
                            3 => "C&#46; Chemello"
                            4 => "A&#46; Gonzalez-Utrilla"
                            5 => "M&#46;J&#46; Faus Dader"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1089/omi.2011.0142"
                      "Revista" => array:6 [
                        "tituloSerie" => "OMICS"
                        "fecha" => "2012"
                        "volumen" => "16"
                        "paginaInicial" => "589"
                        "paginaFinal" => "595"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23095111"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Influence of MTHFR C677<span class="elsevierStyleHsp" style=""></span>T polymorphism on methotrexate monotherapy discontinuation in rheumatoid arthritis patients&#58; Results from the GAPAID European project"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Uribarri"
                            1 => "O&#46; Ruiz-Larranaga"
                            2 => "D&#46; Arteta"
                            3 => "L&#46; Hernandez"
                            4 => "M&#46;C&#46; Alcaro"
                            5 => "A&#46; Martinez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Rheumatol"
                        "fecha" => "2015"
                        "volumen" => "33"
                        "paginaInicial" => "699"
                        "paginaFinal" => "705"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26314492"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Gregers"
                            1 => "H&#46; Green"
                            2 => "I&#46;J&#46; Christensen"
                            3 => "K&#46; Dalhoff"
                            4 => "H&#46; Schroeder"
                            5 => "N&#46; Carlsen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/tpj.2014.81"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pharmacogenomics J"
                        "fecha" => "2015"
                        "volumen" => "15"
                        "paginaInicial" => "372"
                        "paginaFinal" => "379"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25582575"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Molecular genetics of methylenetetrahydrofolate reductase deficiency"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "R&#46; Rozen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Inherit Metab Dis"
                        "fecha" => "1996"
                        "volumen" => "19"
                        "paginaInicial" => "589"
                        "paginaFinal" => "594"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8892013"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0275"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A candidate genetic risk factor for vascular disease&#58; A common mutation in methylenetetrahydrofolate reductase"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Frosst"
                            1 => "H&#46;J&#46; Blom"
                            2 => "R&#46; Milos"
                            3 => "P&#46; Goyette"
                            4 => "C&#46;A&#46; Sheppard"
                            5 => "R&#46;G&#46; Matthews"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/ng0595-111"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Genet"
                        "fecha" => "1995"
                        "volumen" => "10"
                        "paginaInicial" => "111"
                        "paginaFinal" => "113"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7647779"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mechanisms and consequences of the impaired trans-sulphuration pathway in liver disease&#58; Part II&#46; Clinical consequences and potential for pharmacological intervention in cirrhosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "E&#46; Pisi"
                            1 => "G&#46; Marchesini"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:8 [
                        "tituloSerie" => "Drugs"
                        "fecha" => "1990"
                        "volumen" => "40"
                        "numero" => "Suppl 3"
                        "paginaInicial" => "65"
                        "paginaFinal" => "72"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2092972"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0163445316302158"
                          "estado" => "S300"
                          "issn" => "01634453"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0285"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphisms C677<span class="elsevierStyleHsp" style=""></span>T and A1298<span class="elsevierStyleHsp" style=""></span>C in the MTHFR gene in Mexican patients with rheumatoid arthritis treated with methotrexate&#58; Implication with elevation of transaminases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;P&#46; Mena"
                            1 => "M&#46; Salazar-Paramo"
                            2 => "L&#46; Gonzalez-Lopez"
                            3 => "J&#46;I&#46; Gamez-Nava"
                            4 => "L&#46; Sandoval-Ramirez"
                            5 => "J&#46;D&#46; Sanchez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/tpj.2010.32"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pharmacogenomics J"
                        "fecha" => "2011"
                        "volumen" => "11"
                        "paginaInicial" => "287"
                        "paginaFinal" => "291"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20514079"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0290"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The C677<span class="elsevierStyleHsp" style=""></span>T mutation in the methylenetetrahydrofolate reductase gene&#58; A genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;E&#46; van Ede"
                            1 => "R&#46;F&#46; Laan"
                            2 => "H&#46;J&#46; Blom"
                            3 => "T&#46;W&#46; Huizinga"
                            4 => "C&#46;J&#46; Haagsma"
                            5 => "B&#46;A&#46; Giesendorf"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2001"
                        "volumen" => "44"
                        "paginaInicial" => "2525"
                        "paginaFinal" => "2530"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11710708"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0295"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Purine biosynthetic pathway genes and methotrexate response in rheumatoid arthritis patients among north Indians"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Sharma"
                            1 => "M&#46; Das"
                            2 => "A&#46; Kumar"
                            3 => "V&#46; Marwaha"
                            4 => "S&#46; Shankar"
                            5 => "P&#46; Singh"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Pharmacogenet Genomics"
                        "fecha" => "2009"
                        "volumen" => "19"
                        "paginaInicial" => "823"
                        "paginaFinal" => "828"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19902562"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0300"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Identification of risk factors for elevated transaminases in methotrexate users through an electronic health record"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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