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RNA&#44; and proteins&#44; as well as cell mitosis&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">2</span></a> It is used in dermatology as a corticosteroid-sparing agent in a wide variety of inflammatory and autoimmune diseases&#44; including &#40;off-label&#41; atopic dermatitis and nummular eczema&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">3&#8211;5</span></a> Its most common adverse effects are myelosuppression&#44; liver toxicity&#44; gastrointestinal symptoms&#44; hypersensitivity reactions&#44; and pancreatitis&#46; Measurement of the activity of the enzyme thiopurine methyltransferase in serum&#44; which varies depending on specific gene polymorphisms&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">1</span></a> helps to prevent some of these adverse effects&#44; mainly myelosuppression&#46; Given that the agent is not authorized for infantile atopic dermatitis&#44; it is reserved for specific cases where topical treatments or other types of systemic treatment are not effective&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Objectives</span><p id="par0010" class="elsevierStylePara elsevierViewall">To evaluate the efficacy and tolerance of azathioprine in children with severe atopic dermatitis that is refractory to conventional approaches&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Material and methods</span><p id="par0015" class="elsevierStylePara elsevierViewall">We performed a single-center retrospective observational cohort study of 11 patients with severe atopic dermatitis treated with azathioprine at Hospital Infantil Universitario Ni&#241;o Jes&#250;s&#44; Madrid&#44; Spain between January 2007 and May 2017&#46; The local ethics committee approved the study&#46; Patients were identified using computerized and imaging databases&#46; 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total IgE levels&#44; and eosinophilia in blood &#40;defined as peripheral eosinophilia<span class="elsevierStyleHsp" style=""></span>&#62; 500&#47;&#956;L&#41;&#46; Drug-related variables included the initial dose of azathioprine&#44; dose increases &#40;yes&#47;no&#41;&#44; and duration of treatment&#46; Outcome was assessed based on the clinical response after 4 weeks of treatment&#44; after 3-4 months of treatment&#44; and at<span class="elsevierStyleHsp" style=""></span>&#62;6 months of treatment and on long-term efficacy &#40;time to relapse and disease-free period after withdrawal of azathioprine&#41;&#46; Given that the Investigator Global Assessment scale is difficult to evaluate in a retrospective study&#44; evaluation was based on the clinical notes of the attending dermatologist&#44; with outcome classified as complete or near-complete clearance &#40;improvement<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>90&#37;&#41;&#44; marked improvement &#40;50&#37;-89&#37;&#41;&#44; slight improvement &#40;&#60;<span class="elsevierStyleHsp" style=""></span>50&#37;&#41;&#44; and failure &#40;no improvement&#41;&#46; In the case of good to excellent outcome &#40;complete clearance&#44; near-complete clearance&#44; or marked clearance&#41;&#44; the disease was considered to be in remission when the patient&#39;s condition had resolved and could be managed with topical therapy &#40;moderate-potency corticosteroids&#47;topical immunomodulators&#41; and to be recurrent when flares made it advisable to administer another systemic immunosuppressive drug&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Laboratory monitoring consisted of a complete blood count and biochemistry before initiation of treatment&#44; 15 days after initiation&#44; 4 weeks after initiation&#44; and every 3 months thereafter&#46; Clinical follow-up was at least at the same intervals&#46; The assessment of adverse effects included symptoms &#40;eg&#44; asthenia&#41;&#44; gastrointestinal adverse effects &#40;eg&#44; nausea&#44; vomiting&#44; and abdominal pain&#41;&#44; physical examination&#44; complete blood count&#44; serum urea&#44; creatinine&#44; and serum liver enzymes&#46; Any complaint that could be considered a clinical adverse effect of azathioprine was also reported&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Statistical analysis</span><p id="par0030" class="elsevierStylePara elsevierViewall">Data are expressed as mean &#40;SD&#41; or median &#40;range&#41; in the case of nonnormally distributed values&#46; Differences between means were assessed using the <span class="elsevierStyleItalic">t</span> test or Mann-Whitney test in the case of nonnormally distributed variables&#46; The &#967;<span class="elsevierStyleSup">2</span> test or Fisher exact test was used to determine the association between qualitative variables&#46; All of the analyses were performed using Wizard for Mac&#44; version 1&#46;9&#46;9&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><p id="par0035" class="elsevierStylePara elsevierViewall">We reviewed 11 patients &#40;6 boys&#44; 5 girls&#41; with a mean age of 13 years &#40;range&#44; 8-18 years&#41;&#46; Mean age at initiation of treatment was 10&#46;9 &#40;2&#46;2&#41; years &#40;95&#37; CI&#44; 8&#46;6-13&#46;1 years&#41;&#46; The mean initial dose was 1&#46;8 &#40;0&#46;2&#41; mg&#47;kg&#47;d&#46; We evaluated the response to treatment at 4 weeks&#44; between weeks 12 and 16&#44; and from 6 months onward&#46; One patient remains in follow-up&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows demographic data and drug-related variables&#46; Two patients had to suspend therapy with azathioprine because of adverse effects&#44; one during the first month and the other at the fourth month after starting treatment&#46; In the group of patients who completed treatment with azathioprine&#44; the mean duration of therapy was 10&#46;8 &#40;5&#46;7&#41; months &#40;95&#37; CI&#44; 5&#46;0-16&#46;6&#41;&#46; After 1 month of treatment&#44; no patients had a complete or near-complete response&#46; Between 12 and 16 weeks&#44; clearance was near-complete in 4 of 9 patients&#44; a marked improvement was observed in 3 patients&#44; and a slight improvement in 2&#46; Two of the 3 patients who had improved at the fourth month continued to improve until near-complete clearance was observed at the sixth month of treatment&#46; Therefore&#44; of the 9 patients whose treatment was extended for a minimum of 6 months&#44; clearance was almost complete in 6 at this point&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">We found no statistically significant association between response to treatment and a history of allergic sensitization&#44; history of asthma&#44; eosinophilia&#44; and IgE levels&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The mean dose of azathioprine used in the present study was 1&#46;8 &#40;0&#46;2&#41; mg&#47;kg&#47;d &#40;95&#37; CI&#44; 1&#46;5-2&#46;1&#41;&#46; The mean follow-up time was 33&#46;1 &#40;12&#46;0&#41; months&#46; One patient was still taking azathioprine at the end of the study&#46; After suspension of treatment&#44; 2 patients with complete clearance required new systemic therapy at 8 and 20 months&#44; respectively&#46; The remaining cases were managed with topical corticosteroids&#44; immunomodulators&#44; or both&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Adverse effects were recorded in 3 patients &#40;27&#37;&#41;&#46; One patient experienced nausea and epigastric pain&#44; one experienced a mild increase in transaminases&#44; and a third patient experienced a mild transitory increase in transaminases that resolved spontaneously&#46; In the case of the 2 patients with epigastric pain&#44; treatment was suspended owing to the intensity of the pain&#46; No patients had a severe intercurrent infection or complained of effects other than those already commented upon&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0060" class="elsevierStylePara elsevierViewall">Although azathioprine is not authorized by the United Stated Food and Drug Administration or the European Medicines Agency for the treatment of atopic dermatitis in children&#44; it has proven beneficial in 2 randomized placebo-controlled trials in adults with atopic dermatitis treated with azathioprine for 12 weeks and in several retrospective pediatric case series&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">4&#44;8&#8211;10</span></a> Both our results and those of previous studies<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">1&#44;10</span></a> that evaluated the efficacy and tolerability of azathioprine in children with severe atopic dermatitis indicate that most patients have a good or very good response at 12-16 weeks after starting treatment&#46; Thus&#44; in our study&#44; clearance was complete or near-complete in 7 of 9 patients&#59; this figure is slightly higher than that reported elsewhere&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">9</span></a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows studies that analyzed treatment with azathioprine in pediatric patients with atopic dermatitis&#46; The main disadvantage of azathioprine is not its efficacy&#44; which is similar to that of other immunosuppressants &#40;eg&#44; ciclosporin and methotrexate&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">11&#44;12</span></a> but the time to response&#44; since it does not take effect for at least 3 months&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">10</span></a> In fact&#44; consistent with the view of other European specialists&#44;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">13&#44;14</span></a> this interval and the adverse effects profile meant that azathioprine was not our first choice for any of the patients&#46; We also agree with other authors that the adverse effects we observed were mainly mild gastrointestinal adverse effects&#44; which led to suspension of treatment in only 2 cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">5&#44;10</span></a> It is noteworthy that in both cases&#44; these effects appeared during the first month of treatment and resolved once medication was suspended&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Our study is subject to a series of limitations&#44; mainly its small sample size&#46; In addition&#44; it was a retrospective study&#44; and adverse events may have been underestimated if patients were not actively asked about them&#46; For the same reason&#44; it is difficult to evaluate the Investigator Global Assessment scale&#46; Finally&#44; the limited follow-up period prevents us from drawing definitive conclusions about the duration of remission and long-term safety of treatment with azathioprine&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In conclusion&#44; our data confirm the efficacy and tolerability of azathioprine in the treatment of moderate to severe atopic dermatitis in children&#59; therefore&#44; we should include it as part of our systemic treatment options in these patients&#46; While azathioprine does not seem to have serious adverse effects on children in the short term&#44; strict monitoring is mandatory in this age group&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflicts of Interest</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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            1 => "Atopic dermatitis"
            2 => "Atopic eczema"
            3 => "Immunosuppressants"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Atopic dermatitis &#40;AD&#41; is a chronic inflammatory skin disease that typically affects children&#46; Severe forms may have a profound effect on patients&#8217; quality of life&#46; Some forms are resistant to conventional treatment and require the use of systemic immunosuppressants such as azathioprine &#40;AZA&#41; to adequately manage the disease&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To evaluate the effectiveness and tolerance of AZA in children with severe AD&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Patients and methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We performed a retrospective study of children with severe AD treated with AZA between January 2007 and May 2017&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">We reviewed the cases of 11 patients &#40;6 boys and 5 girls&#41; with a mean age of 13 years &#40;range&#44; 8-18 years&#41;&#46; The mean &#40;SD&#41; age at start of treatment was 10&#46;9 &#40;2&#46;2&#41; years &#40;95&#37; CI 8&#46;6-13&#46;1&#41;&#46; The mean initial dosage of AZA was 1&#46;8 &#40;0&#46;2&#41; mg&#47;kg&#47;d&#46; We evaluated treatment response after 4 weeks&#44; 12 to 16 weeks&#44; and 6 months&#46; Mean treatment duration was 10&#46;8 &#40;5&#46;7&#41; months&#46; Treatment had to be suspended in 2 patients because of adverse effects&#46; Seven of the 9 remaining patients presented complete or almost complete clearance of the AD after 6 months of treatment&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusion</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">In our experience&#44; AZA is well tolerated and may be considered as a treatment option in children with severe AD resistant to conventional treatment&#46;</p></span>"
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        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La dermatitis at&#243;pica &#40;DA&#41; es una enfermedad inflamatoria cr&#243;nica de la piel t&#237;picamente infantil cuyas formas graves pueden afectar intensamente la calidad de vida del paciente&#46; Existen formas refractarias al tratamiento convencional en las que es preciso emplear inmunosupresores sist&#233;micos como la azatioprina &#40;AZA&#41; para alcanzar un buen control de la enfermedad&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivo</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Evaluar la eficacia y la tolerancia de la AZA en ni&#241;os con DA grave&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pacientes y m&#233;todos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se realiz&#243; una revisi&#243;n retrospectiva de ni&#241;os con DA grave tratados con AZA entre enero de 2007 y mayo de 2017&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Se revisaron 11 pacientes &#40;6 varones&#44; 5 mujeres&#41; con una edad promedio de 13 a&#241;os &#40;rango 8-18 a&#241;os&#41;&#46; La edad media<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>DE al inicio del tratamiento fue de 10&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;2 a&#241;os &#40;IC 95&#37; 8&#44;6-13&#44;1&#41;&#46; La media de la dosis inicial de AZA fue de 1&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#46; Evaluamos la respuesta al tratamiento de nuestros pacientes a las 4 semanas&#44; entre la semana 12 y la 16&#44; y a partir de los 6 meses&#46; La media del tratamiento fue de 10&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#44;7 meses&#46; Dos pacientes tuvieron que suspender el tratamiento por efectos adversos&#46; Siete de los 9 pacientes restantes presentaron un aclaramiento completo o casi completo de la DA a los 6 meses de tratamiento&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusi&#243;n</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">En nuestra experiencia&#44; la AZA es bien tolerada y puede ser considerada como una opci&#243;n terap&#233;utica en los ni&#241;os con DA grave refractaria a tratamientos convencionales&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Noguera-Morel L&#44; Kn&#246;pfel N&#44; Torrelo A&#44; Hern&#225;ndez-Mart&#237;n A&#46; Estudio retrospectivo del tratamiento sist&#233;mico de la dermatitis at&#243;pica grave con azatioprina&#46; Eficacia y tolerancia en 11 pacientes pedi&#225;tricos&#46; Actas Dermosifiliogr&#46; 2019&#59;110&#58;227&#8211;231&#46;</p>"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; AD&#44; atopic dermatitis&#59; AZA&#44; azathioprine&#59; TPMT&#44; thiopurine methyltransferase&#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" 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">Total&#44; No&#46; &#40;&#37;&#41;&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"><span class="elsevierStyleItalic">Patients</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Sex</span>&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>Male&#47;female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 &#40;55&#41;&#47;5 &#40;45&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Age at onset of AD&#44; mo</span>&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>Median &#40;range&#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 &#40;0-60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Blood eosinophil count&#44; cells&#47;&#956;L</span>&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>&#62;<span class="elsevierStyleHsp" style=""></span>500&#47;&#60;<span class="elsevierStyleHsp" style=""></span>500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;91&#41;&#47;1 &#40;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Sensitization to food</span>&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>No&#47;yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 &#40;36&#41;&#47;7 &#40;64&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Asthma</span>&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>No&#47;yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 &#40;55&#41;&#47;5 &#40;45&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Age at initiation of AZA&#44; y</span>&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>Mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#46;9 &#40;2&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Levels of TPMT&#44; IU&#47;mL</span>&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>Mean &#40;SD&#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&#46;8 &#40;2&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Duration of treatment&#44; mo</span>&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>Mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#46;8 &#40;5&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Initial dose&#44; mg&#47;kg&#47;d</span>&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>Mean &#40;SD&#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&#46;8 &#40;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Demographic Data and Drug-Related Variables&#46;</p>"
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; AE&#44; adverse effect&#59; NA&#44; not available&#59; PCP&#44; primary care physician&#59; PDN&#44; prednisolone&#59; TPMT&#44; thiopurine methyltransferase&#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  " align="left" valign="top" scope="col">Murphy and Atherton<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">1</span></a>&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">Caufield and Tom<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">8</span></a>&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">Fuggle et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">10</span></a>&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">Present series&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of Study&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">Retrospective&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">Prospective&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">Prospective&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">Retrospective&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">No&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">82&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&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">Age&#44; y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0-12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2-18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&#46;6 &#40;mean&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8-18&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">Dose&#44; mg&#47;kg&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2-3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;4 &#40;normal TPMT&#41;<br>1&#46;5 &#40;low TPMT&#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&#46;8&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">Duration of treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Up to 2 y in responders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6-12 mo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mean &#40;SD&#41;&#44; 10 &#40;5&#46;7&#41; mo&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">Time to evaluate efficacy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 wk&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; 4&#44; 8&#44; 12 wk and every 2 mo thereafter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12-16 wk&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">Outcome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Excellent 28&#47;48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduced SCORAD in 11&#47;12&#44; mean &#40;SD&#41;&#44; 27&#46;7 &#40;8&#46;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">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete or near-complete clearance in 7&#47;9&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">Mean follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">33&#46;1 mo&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">Adverse effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypersensitivity reaction in 1&#47;48&#46; Resolved with suspension of therapy<br><br>Mild elevation of transaminases in 5&#47;48 &#40;treatment suspended by PCP in 1 case&#41;<br><br>Nausea and vomiting in 1&#47;48<br>Treatment suspended in 2&#47;48 because of AEs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mild gastrointestinal discomfort in 2&#47;12<br><br>Mild elevation of transaminases in 1&#47;12 &#40;improved when the dose was reduced&#41;<br><br>No patients interrupted treatment because of AEs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Laboratory abnormalities in 33&#47;82 &#40;24 in the complete blood count and 11 with increased transaminases&#41;<br><br>Treatment was interrupted owing to AEs in 6&#47;82 cases &#40;2 with abnormal complete blood count and 4 with increased transaminases&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AEs in 3&#47;11&#58; epigastric pain in 2&#47;11 and increased transaminases in 1&#47;11<br><br>Treatment interrupted because of AEs &#40;epigastric pain&#41; in 2&#47;11&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">Remarks&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">Monitoring of TPMT activity throughout treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral PDN was administered in all cases during the first 4-6 weeks&#46; Treatment was suspended briefly in cases of laboratory abnormalities and restarted after further laboratory testing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Summary of Data From Studies on Atopic Dermatitis Treated With Azathioprine in Children&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:14 [
            0 => array:3 [
              "identificador" => "bib0075"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A retrospective evaluation of azathioprine in severe childhood atopic eczema&#44; using thiopurine methyltransferase levels to exclude patients at high risk of myelosuppression"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "L&#46; Murphy"
                            1 => "D&#46; Atherton"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Dermatol"
                        "fecha" => "2002"
                        "volumen" => "147"
                        "paginaInicial" => "308"
                        "paginaFinal" => "315"
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              "identificador" => "bib0080"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Azathioprine&#58; Drug information&#46; Lexicomp C&#44; S BNU&#44; Infatabs D&#44; Infatabs P&#46; 2014&#59;15-20&#46;"
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              ]
            ]
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              "identificador" => "bib0085"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Review of systemic treatment options for adult atopic dermatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Gooderham"
                            1 => "C&#46;W&#46; Lynde"
                            2 => "K&#46; Papp"
                            3 => "M&#46; Bourcier"
                            4 => "L&#46; Guenther"
                            5 => "W&#46; Gulliver"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/1203475416670364"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Cutan Med Surg&#46;"
                        "fecha" => "2017"
                        "volumen" => "21"
                        "paginaInicial" => "31"
                        "paginaFinal" => "39"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27635033"
                            "web" => "Medline"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Off-label use of azathioprine in dermatology"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46; Schram"
                            1 => "R&#46; Borgmonjen"
                            2 => "M&#46; Bik"
                            3 => "J&#46; van der Schroeff"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Arch Dermatol&#46;"
                        "fecha" => "2011"
                        "volumen" => "147"
                        "paginaInicial" => "474"
                        "paginaFinal" => "488"
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                  ]
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              "identificador" => "bib0095"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "British Association of Dermatologists&#8217; guidelines for the safe and effective prescribing of azathioprine 2011"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46;J&#46; Meggitt"
                            1 => "A&#46;V&#46; Anstey"
                            2 => "M&#46;F&#46; Mohd Mustapa"
                            3 => "N&#46;J&#46; Reynolds"
                            4 => "S&#46; Wakelin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Br J Dermatol&#46;"
                        "fecha" => "2011"
                        "volumen" => "165"
                        "paginaInicial" => "711"
                        "paginaFinal" => "734"
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              "identificador" => "bib0100"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A systematic review of Investigator Global Assessment &#40;IGA&#41; in atopic dermatitis &#40;AD&#41; trials&#58; Many options&#44; no standards"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46; Futamura"
                            1 => "Y&#46;A&#46; Leshem"
                            2 => "K&#46;S&#46; Thomas"
                            3 => "H&#46; Nankervis"
                            4 => "H&#46;C&#46; Williams"
                            5 => "E&#46;L&#46; Simpson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2016"
                        "volumen" => "74"
                        "paginaInicial" => "288"
                        "paginaFinal" => "294"
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              "identificador" => "bib0105"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Guidelines of care for the management of atopic dermatitis&#58; Section 1&#46; Diagnosis and assessment of atopic dermatitis"
                      "autores" => array:1 [
                        0 => array:2 [
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Original Article
A Retrospective Study of Systemic Treatment of Severe Atopic Dermatitis With Azathioprine: Effectiveness and Tolerance in 11 Pediatric Patients
Estudio retrospectivo del tratamiento sistémico de la dermatitis atópica grave con azatioprina. Eficacia y tolerancia en 11 pacientes pediátricos
L. Noguera-Morel, N. Knöpfel, A. Torrelo, A. Hernández-Martín
Corresponding author
ahernandez@aedv.es

Corresponding author.
Departamento de Dermatología, Hospital Infantil Universitario Niño Jesús, Madrid, España
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    "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>"
    "titulo" => "A Retrospective Study of Systemic Treatment of Severe Atopic Dermatitis With Azathioprine&#58; Effectiveness and Tolerance in 11 Pediatric Patients"
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        "titulo" => "Estudio retrospectivo del tratamiento sist&#233;mico de la dermatitis at&#243;pica grave con azatioprina&#46; Eficacia y tolerancia en 11 pacientes pedi&#225;tricos"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Atopic dermatitis is a chronic inflammatory disease of childhood that is characterized by recurrent outbreaks of very pruriginous lesions&#46; Some children have severe disease that is refractory to conventional treatment with topical corticosteroids&#44; thus necessitating immunosuppressive therapy to achieve control&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">1</span></a> Azathioprine is a prodrug that is converted into 6-mercaptopurine after absorption in the intestine&#46; 6-Mercaptopurine is subsequently metabolized in the liver and gastrointestinal tract by 3 main enzymes&#58; hypoxanthine-guanine phosphoribosyltransferase&#44; xanthine oxidase&#44; and thiopurine methyltransferase&#46; Azathioprine antagonizes purine metabolism and thus inhibits the synthesis of DNA&#44; RNA&#44; and proteins&#44; as well as cell mitosis&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">2</span></a> It is used in dermatology as a corticosteroid-sparing agent in a wide variety of inflammatory and autoimmune diseases&#44; including &#40;off-label&#41; atopic dermatitis and nummular eczema&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">3&#8211;5</span></a> Its most common adverse effects are myelosuppression&#44; liver toxicity&#44; gastrointestinal symptoms&#44; hypersensitivity reactions&#44; and pancreatitis&#46; Measurement of the activity of the enzyme thiopurine methyltransferase in serum&#44; which varies depending on specific gene polymorphisms&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">1</span></a> helps to prevent some of these adverse effects&#44; mainly myelosuppression&#46; Given that the agent is not authorized for infantile atopic dermatitis&#44; it is reserved for specific cases where topical treatments or other types of systemic treatment are not effective&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Objectives</span><p id="par0010" class="elsevierStylePara elsevierViewall">To evaluate the efficacy and tolerance of azathioprine in children with severe atopic dermatitis that is refractory to conventional approaches&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Material and methods</span><p id="par0015" class="elsevierStylePara elsevierViewall">We performed a single-center retrospective observational cohort study of 11 patients with severe atopic dermatitis treated with azathioprine at Hospital Infantil Universitario Ni&#241;o Jes&#250;s&#44; Madrid&#44; Spain between January 2007 and May 2017&#46; The local ethics committee approved the study&#46; Patients were identified using computerized and imaging databases&#46; Atopic dermatitis was defined using the Investigator Global Assessment scale&#44; which defined the disease as the presence of intense&#44; dark erythema with induration&#44; excoriated papules&#44; exudation&#44; and crusting&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">6&#44;7</span></a> Before receiving azathioprine&#44; all patients had had a poor response to standard treatment with moderate-potency topical corticosteroids &#40;class 3&#41; applied twice daily or once daily with wet-wrap dressing techniques and&#47;or topical immunomodulators&#46; No patients received oral azathioprine as their first line of immunosuppressive therapy&#58; 10 had previously received ciclosporin A&#44; and 1 had received methotrexate&#46; Patients were allowed to apply moderate-potency topical corticosteroids during treatment with azathioprine&#46; In all cases&#44; levels of thiopurine methyltransferase were assessed before starting treatment&#44; and the dose of azathioprine was adjusted according to outcome &#40;&#60;&#160;5&#46;1<span class="elsevierStyleHsp" style=""></span>U&#47;mL red cells&#44; not administered&#59; 5&#46;1-13&#46;7<span class="elsevierStyleHsp" style=""></span>U&#47;mL&#44; 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#59; 13&#46;8-18&#46;0<span class="elsevierStyleHsp" style=""></span>U&#47;mL&#44; 1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#59; 18&#46;1-26&#46;0<span class="elsevierStyleHsp" style=""></span>U&#47;mL&#44; 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#59; and 26&#46;1-40<span class="elsevierStyleHsp" style=""></span>U&#47;mL&#44; 3&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#41;&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The demographic data recorded included sex&#44; age at onset of atopic dermatitis&#44; age at initiation of treatment&#44; history of asthma and&#47;or sensitization to food &#40;defined as specific immunoglobulin &#91;Ig&#93; E levels for food greater than 95&#37; of the positive predictive value&#41;&#44; total IgE levels&#44; and eosinophilia in blood &#40;defined as peripheral eosinophilia<span class="elsevierStyleHsp" style=""></span>&#62; 500&#47;&#956;L&#41;&#46; Drug-related variables included the initial dose of azathioprine&#44; dose increases &#40;yes&#47;no&#41;&#44; and duration of treatment&#46; Outcome was assessed based on the clinical response after 4 weeks of treatment&#44; after 3-4 months of treatment&#44; and at<span class="elsevierStyleHsp" style=""></span>&#62;6 months of treatment and on long-term efficacy &#40;time to relapse and disease-free period after withdrawal of azathioprine&#41;&#46; Given that the Investigator Global Assessment scale is difficult to evaluate in a retrospective study&#44; evaluation was based on the clinical notes of the attending dermatologist&#44; with outcome classified as complete or near-complete clearance &#40;improvement<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>90&#37;&#41;&#44; marked improvement &#40;50&#37;-89&#37;&#41;&#44; slight improvement &#40;&#60;<span class="elsevierStyleHsp" style=""></span>50&#37;&#41;&#44; and failure &#40;no improvement&#41;&#46; In the case of good to excellent outcome &#40;complete clearance&#44; near-complete clearance&#44; or marked clearance&#41;&#44; the disease was considered to be in remission when the patient&#39;s condition had resolved and could be managed with topical therapy &#40;moderate-potency corticosteroids&#47;topical immunomodulators&#41; and to be recurrent when flares made it advisable to administer another systemic immunosuppressive drug&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Laboratory monitoring consisted of a complete blood count and biochemistry before initiation of treatment&#44; 15 days after initiation&#44; 4 weeks after initiation&#44; and every 3 months thereafter&#46; Clinical follow-up was at least at the same intervals&#46; The assessment of adverse effects included symptoms &#40;eg&#44; asthenia&#41;&#44; gastrointestinal adverse effects &#40;eg&#44; nausea&#44; vomiting&#44; and abdominal pain&#41;&#44; physical examination&#44; complete blood count&#44; serum urea&#44; creatinine&#44; and serum liver enzymes&#46; Any complaint that could be considered a clinical adverse effect of azathioprine was also reported&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Statistical analysis</span><p id="par0030" class="elsevierStylePara elsevierViewall">Data are expressed as mean &#40;SD&#41; or median &#40;range&#41; in the case of nonnormally distributed values&#46; Differences between means were assessed using the <span class="elsevierStyleItalic">t</span> test or Mann-Whitney test in the case of nonnormally distributed variables&#46; The &#967;<span class="elsevierStyleSup">2</span> test or Fisher exact test was used to determine the association between qualitative variables&#46; All of the analyses were performed using Wizard for Mac&#44; version 1&#46;9&#46;9&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><p id="par0035" class="elsevierStylePara elsevierViewall">We reviewed 11 patients &#40;6 boys&#44; 5 girls&#41; with a mean age of 13 years &#40;range&#44; 8-18 years&#41;&#46; Mean age at initiation of treatment was 10&#46;9 &#40;2&#46;2&#41; years &#40;95&#37; CI&#44; 8&#46;6-13&#46;1 years&#41;&#46; The mean initial dose was 1&#46;8 &#40;0&#46;2&#41; mg&#47;kg&#47;d&#46; We evaluated the response to treatment at 4 weeks&#44; between weeks 12 and 16&#44; and from 6 months onward&#46; One patient remains in follow-up&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows demographic data and drug-related variables&#46; Two patients had to suspend therapy with azathioprine because of adverse effects&#44; one during the first month and the other at the fourth month after starting treatment&#46; In the group of patients who completed treatment with azathioprine&#44; the mean duration of therapy was 10&#46;8 &#40;5&#46;7&#41; months &#40;95&#37; CI&#44; 5&#46;0-16&#46;6&#41;&#46; After 1 month of treatment&#44; no patients had a complete or near-complete response&#46; Between 12 and 16 weeks&#44; clearance was near-complete in 4 of 9 patients&#44; a marked improvement was observed in 3 patients&#44; and a slight improvement in 2&#46; Two of the 3 patients who had improved at the fourth month continued to improve until near-complete clearance was observed at the sixth month of treatment&#46; Therefore&#44; of the 9 patients whose treatment was extended for a minimum of 6 months&#44; clearance was almost complete in 6 at this point&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">We found no statistically significant association between response to treatment and a history of allergic sensitization&#44; history of asthma&#44; eosinophilia&#44; and IgE levels&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The mean dose of azathioprine used in the present study was 1&#46;8 &#40;0&#46;2&#41; mg&#47;kg&#47;d &#40;95&#37; CI&#44; 1&#46;5-2&#46;1&#41;&#46; The mean follow-up time was 33&#46;1 &#40;12&#46;0&#41; months&#46; One patient was still taking azathioprine at the end of the study&#46; After suspension of treatment&#44; 2 patients with complete clearance required new systemic therapy at 8 and 20 months&#44; respectively&#46; The remaining cases were managed with topical corticosteroids&#44; immunomodulators&#44; or both&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Adverse effects were recorded in 3 patients &#40;27&#37;&#41;&#46; One patient experienced nausea and epigastric pain&#44; one experienced a mild increase in transaminases&#44; and a third patient experienced a mild transitory increase in transaminases that resolved spontaneously&#46; In the case of the 2 patients with epigastric pain&#44; treatment was suspended owing to the intensity of the pain&#46; No patients had a severe intercurrent infection or complained of effects other than those already commented upon&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0060" class="elsevierStylePara elsevierViewall">Although azathioprine is not authorized by the United Stated Food and Drug Administration or the European Medicines Agency for the treatment of atopic dermatitis in children&#44; it has proven beneficial in 2 randomized placebo-controlled trials in adults with atopic dermatitis treated with azathioprine for 12 weeks and in several retrospective pediatric case series&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">4&#44;8&#8211;10</span></a> Both our results and those of previous studies<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">1&#44;10</span></a> that evaluated the efficacy and tolerability of azathioprine in children with severe atopic dermatitis indicate that most patients have a good or very good response at 12-16 weeks after starting treatment&#46; Thus&#44; in our study&#44; clearance was complete or near-complete in 7 of 9 patients&#59; this figure is slightly higher than that reported elsewhere&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">9</span></a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows studies that analyzed treatment with azathioprine in pediatric patients with atopic dermatitis&#46; The main disadvantage of azathioprine is not its efficacy&#44; which is similar to that of other immunosuppressants &#40;eg&#44; ciclosporin and methotrexate&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">11&#44;12</span></a> but the time to response&#44; since it does not take effect for at least 3 months&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">10</span></a> In fact&#44; consistent with the view of other European specialists&#44;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">13&#44;14</span></a> this interval and the adverse effects profile meant that azathioprine was not our first choice for any of the patients&#46; We also agree with other authors that the adverse effects we observed were mainly mild gastrointestinal adverse effects&#44; which led to suspension of treatment in only 2 cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">5&#44;10</span></a> It is noteworthy that in both cases&#44; these effects appeared during the first month of treatment and resolved once medication was suspended&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Our study is subject to a series of limitations&#44; mainly its small sample size&#46; In addition&#44; it was a retrospective study&#44; and adverse events may have been underestimated if patients were not actively asked about them&#46; For the same reason&#44; it is difficult to evaluate the Investigator Global Assessment scale&#46; Finally&#44; the limited follow-up period prevents us from drawing definitive conclusions about the duration of remission and long-term safety of treatment with azathioprine&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In conclusion&#44; our data confirm the efficacy and tolerability of azathioprine in the treatment of moderate to severe atopic dermatitis in children&#59; therefore&#44; we should include it as part of our systemic treatment options in these patients&#46; While azathioprine does not seem to have serious adverse effects on children in the short term&#44; strict monitoring is mandatory in this age group&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflicts of Interest</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Atopic dermatitis &#40;AD&#41; is a chronic inflammatory skin disease that typically affects children&#46; Severe forms may have a profound effect on patients&#8217; quality of life&#46; Some forms are resistant to conventional treatment and require the use of systemic immunosuppressants such as azathioprine &#40;AZA&#41; to adequately manage the disease&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To evaluate the effectiveness and tolerance of AZA in children with severe AD&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Patients and methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We performed a retrospective study of children with severe AD treated with AZA between January 2007 and May 2017&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">We reviewed the cases of 11 patients &#40;6 boys and 5 girls&#41; with a mean age of 13 years &#40;range&#44; 8-18 years&#41;&#46; The mean &#40;SD&#41; age at start of treatment was 10&#46;9 &#40;2&#46;2&#41; years &#40;95&#37; CI 8&#46;6-13&#46;1&#41;&#46; The mean initial dosage of AZA was 1&#46;8 &#40;0&#46;2&#41; mg&#47;kg&#47;d&#46; We evaluated treatment response after 4 weeks&#44; 12 to 16 weeks&#44; and 6 months&#46; Mean treatment duration was 10&#46;8 &#40;5&#46;7&#41; months&#46; Treatment had to be suspended in 2 patients because of adverse effects&#46; Seven of the 9 remaining patients presented complete or almost complete clearance of the AD after 6 months of treatment&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusion</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">In our experience&#44; AZA is well tolerated and may be considered as a treatment option in children with severe AD resistant to conventional treatment&#46;</p></span>"
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        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La dermatitis at&#243;pica &#40;DA&#41; es una enfermedad inflamatoria cr&#243;nica de la piel t&#237;picamente infantil cuyas formas graves pueden afectar intensamente la calidad de vida del paciente&#46; Existen formas refractarias al tratamiento convencional en las que es preciso emplear inmunosupresores sist&#233;micos como la azatioprina &#40;AZA&#41; para alcanzar un buen control de la enfermedad&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivo</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Evaluar la eficacia y la tolerancia de la AZA en ni&#241;os con DA grave&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pacientes y m&#233;todos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se realiz&#243; una revisi&#243;n retrospectiva de ni&#241;os con DA grave tratados con AZA entre enero de 2007 y mayo de 2017&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Se revisaron 11 pacientes &#40;6 varones&#44; 5 mujeres&#41; con una edad promedio de 13 a&#241;os &#40;rango 8-18 a&#241;os&#41;&#46; La edad media<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>DE al inicio del tratamiento fue de 10&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;2 a&#241;os &#40;IC 95&#37; 8&#44;6-13&#44;1&#41;&#46; La media de la dosis inicial de AZA fue de 1&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#46; Evaluamos la respuesta al tratamiento de nuestros pacientes a las 4 semanas&#44; entre la semana 12 y la 16&#44; y a partir de los 6 meses&#46; La media del tratamiento fue de 10&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#44;7 meses&#46; Dos pacientes tuvieron que suspender el tratamiento por efectos adversos&#46; Siete de los 9 pacientes restantes presentaron un aclaramiento completo o casi completo de la DA a los 6 meses de tratamiento&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusi&#243;n</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">En nuestra experiencia&#44; la AZA es bien tolerada y puede ser considerada como una opci&#243;n terap&#233;utica en los ni&#241;os con DA grave refractaria a tratamientos convencionales&#46;</p></span>"
        "secciones" => array:5 [
          0 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Antecedentes"
          ]
          1 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Objetivo"
          ]
          2 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Pacientes y m&#233;todos"
          ]
          3 => array:2 [
            "identificador" => "abst0045"
            "titulo" => "Resultados"
          ]
          4 => array:2 [
            "identificador" => "abst0050"
            "titulo" => "Conclusi&#243;n"
          ]
        ]
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Noguera-Morel L&#44; Kn&#246;pfel N&#44; Torrelo A&#44; Hern&#225;ndez-Mart&#237;n A&#46; Estudio retrospectivo del tratamiento sist&#233;mico de la dermatitis at&#243;pica grave con azatioprina&#46; Eficacia y tolerancia en 11 pacientes pedi&#225;tricos&#46; Actas Dermosifiliogr&#46; 2019&#59;110&#58;227&#8211;231&#46;</p>"
      ]
    ]
    "multimedia" => array:2 [
      0 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; AD&#44; atopic dermatitis&#59; AZA&#44; azathioprine&#59; TPMT&#44; thiopurine methyltransferase&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" 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">Total&#44; No&#46; &#40;&#37;&#41;&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"><span class="elsevierStyleItalic">Patients</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Sex</span>&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>Male&#47;female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 &#40;55&#41;&#47;5 &#40;45&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Age at onset of AD&#44; mo</span>&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>Median &#40;range&#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 &#40;0-60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Blood eosinophil count&#44; cells&#47;&#956;L</span>&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>&#62;<span class="elsevierStyleHsp" style=""></span>500&#47;&#60;<span class="elsevierStyleHsp" style=""></span>500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;91&#41;&#47;1 &#40;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Sensitization to food</span>&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>No&#47;yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 &#40;36&#41;&#47;7 &#40;64&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Asthma</span>&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>No&#47;yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 &#40;55&#41;&#47;5 &#40;45&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Age at initiation of AZA&#44; y</span>&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>Mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#46;9 &#40;2&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Levels of TPMT&#44; IU&#47;mL</span>&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>Mean &#40;SD&#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&#46;8 &#40;2&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Duration of treatment&#44; mo</span>&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>Mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#46;8 &#40;5&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Initial dose&#44; mg&#47;kg&#47;d</span>&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>Mean &#40;SD&#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&#46;8 &#40;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2003838.png"
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Demographic Data and Drug-Related Variables&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; AE&#44; adverse effect&#59; NA&#44; not available&#59; PCP&#44; primary care physician&#59; PDN&#44; prednisolone&#59; TPMT&#44; thiopurine methyltransferase&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&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">Murphy and Atherton<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">1</span></a>&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">Caufield and Tom<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">8</span></a>&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">Fuggle et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">10</span></a>&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">Present series&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of Study&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">Retrospective&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">Prospective&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">Prospective&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">Retrospective&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">No&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">82&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&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">Age&#44; y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0-12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2-18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&#46;6 &#40;mean&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8-18&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">Dose&#44; mg&#47;kg&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2-3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;4 &#40;normal TPMT&#41;<br>1&#46;5 &#40;low TPMT&#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&#46;8&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">Duration of treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Up to 2 y in responders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6-12 mo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mean &#40;SD&#41;&#44; 10 &#40;5&#46;7&#41; mo&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">Time to evaluate efficacy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 wk&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; 4&#44; 8&#44; 12 wk and every 2 mo thereafter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12-16 wk&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">Outcome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Excellent 28&#47;48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduced SCORAD in 11&#47;12&#44; mean &#40;SD&#41;&#44; 27&#46;7 &#40;8&#46;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">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete or near-complete clearance in 7&#47;9&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">Mean follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">33&#46;1 mo&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">Adverse effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypersensitivity reaction in 1&#47;48&#46; Resolved with suspension of therapy<br><br>Mild elevation of transaminases in 5&#47;48 &#40;treatment suspended by PCP in 1 case&#41;<br><br>Nausea and vomiting in 1&#47;48<br>Treatment suspended in 2&#47;48 because of AEs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mild gastrointestinal discomfort in 2&#47;12<br><br>Mild elevation of transaminases in 1&#47;12 &#40;improved when the dose was reduced&#41;<br><br>No patients interrupted treatment because of AEs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Laboratory abnormalities in 33&#47;82 &#40;24 in the complete blood count and 11 with increased transaminases&#41;<br><br>Treatment was interrupted owing to AEs in 6&#47;82 cases &#40;2 with abnormal complete blood count and 4 with increased transaminases&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AEs in 3&#47;11&#58; epigastric pain in 2&#47;11 and increased transaminases in 1&#47;11<br><br>Treatment interrupted because of AEs &#40;epigastric pain&#41; in 2&#47;11&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">Remarks&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">Monitoring of TPMT activity throughout treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral PDN was administered in all cases during the first 4-6 weeks&#46; Treatment was suspended briefly in cases of laboratory abnormalities and restarted after further laboratory testing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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