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
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Departamento de Dermatología, Hospital Infantil Universitario Niño Jesús, Madrid, España
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"apellidos" => "Hernández-Martín" "email" => array:1 [ 0 => "ahernandez@aedv.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Departamento de Dermatología, Hospital Infantil Universitario Niño Jesús, Madrid, España" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Estudio retrospectivo del tratamiento sistémico de la dermatitis atópica grave con azatioprina. Eficacia y tolerancia en 11 pacientes pediátricos" ] ] "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. Some children have severe disease that is refractory to conventional treatment with topical corticosteroids, thus necessitating immunosuppressive therapy to achieve control.<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. 6-Mercaptopurine is subsequently metabolized in the liver and gastrointestinal tract by 3 main enzymes: hypoxanthine-guanine phosphoribosyltransferase, xanthine oxidase, and thiopurine methyltransferase. Azathioprine antagonizes purine metabolism and thus inhibits the synthesis of DNA, RNA, and proteins, as well as cell mitosis.<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, including (off-label) atopic dermatitis and nummular eczema.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">3–5</span></a> Its most common adverse effects are myelosuppression, liver toxicity, gastrointestinal symptoms, hypersensitivity reactions, and pancreatitis. Measurement of the activity of the enzyme thiopurine methyltransferase in serum, which varies depending on specific gene polymorphisms,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">1</span></a> helps to prevent some of these adverse effects, mainly myelosuppression. Given that the agent is not authorized for infantile atopic dermatitis, it is reserved for specific cases where topical treatments or other types of systemic treatment are not effective.</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.</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 Niño Jesús, Madrid, Spain between January 2007 and May 2017. The local ethics committee approved the study. Patients were identified using computerized and imaging databases. Atopic dermatitis was defined using the Investigator Global Assessment scale, which defined the disease as the presence of intense, dark erythema with induration, excoriated papules, exudation, and crusting.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">6,7</span></a> Before receiving azathioprine, all patients had had a poor response to standard treatment with moderate-potency topical corticosteroids (class 3) applied twice daily or once daily with wet-wrap dressing techniques and/or topical immunomodulators. No patients received oral azathioprine as their first line of immunosuppressive therapy: 10 had previously received ciclosporin A, and 1 had received methotrexate. Patients were allowed to apply moderate-potency topical corticosteroids during treatment with azathioprine. In all cases, levels of thiopurine methyltransferase were assessed before starting treatment, and the dose of azathioprine was adjusted according to outcome (< 5.1<span class="elsevierStyleHsp" style=""></span>U/mL red cells, not administered; 5.1-13.7<span class="elsevierStyleHsp" style=""></span>U/mL, 0.5<span class="elsevierStyleHsp" style=""></span>mg/kg/d; 13.8-18.0<span class="elsevierStyleHsp" style=""></span>U/mL, 1.5<span class="elsevierStyleHsp" style=""></span>mg/kg/d; 18.1-26.0<span class="elsevierStyleHsp" style=""></span>U/mL, 2.5<span class="elsevierStyleHsp" style=""></span>mg/kg/d; and 26.1-40<span class="elsevierStyleHsp" style=""></span>U/mL, 3.0<span class="elsevierStyleHsp" style=""></span>mg/kg/d).</p><p id="par0020" class="elsevierStylePara elsevierViewall">The demographic data recorded included sex, age at onset of atopic dermatitis, age at initiation of treatment, history of asthma and/or sensitization to food (defined as specific immunoglobulin [Ig] E levels for food greater than 95% of the positive predictive value), total IgE levels, and eosinophilia in blood (defined as peripheral eosinophilia<span class="elsevierStyleHsp" style=""></span>> 500/μL). Drug-related variables included the initial dose of azathioprine, dose increases (yes/no), and duration of treatment. Outcome was assessed based on the clinical response after 4 weeks of treatment, after 3-4 months of treatment, and at<span class="elsevierStyleHsp" style=""></span>>6 months of treatment and on long-term efficacy (time to relapse and disease-free period after withdrawal of azathioprine). Given that the Investigator Global Assessment scale is difficult to evaluate in a retrospective study, evaluation was based on the clinical notes of the attending dermatologist, with outcome classified as complete or near-complete clearance (improvement<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>90%), marked improvement (50%-89%), slight improvement (<<span class="elsevierStyleHsp" style=""></span>50%), and failure (no improvement). In the case of good to excellent outcome (complete clearance, near-complete clearance, or marked clearance), the disease was considered to be in remission when the patient's condition had resolved and could be managed with topical therapy (moderate-potency corticosteroids/topical immunomodulators) and to be recurrent when flares made it advisable to administer another systemic immunosuppressive drug.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Laboratory monitoring consisted of a complete blood count and biochemistry before initiation of treatment, 15 days after initiation, 4 weeks after initiation, and every 3 months thereafter. Clinical follow-up was at least at the same intervals. The assessment of adverse effects included symptoms (eg, asthenia), gastrointestinal adverse effects (eg, nausea, vomiting, and abdominal pain), physical examination, complete blood count, serum urea, creatinine, and serum liver enzymes. Any complaint that could be considered a clinical adverse effect of azathioprine was also reported.</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 (SD) or median (range) in the case of nonnormally distributed values. Differences between means were assessed using the <span class="elsevierStyleItalic">t</span> test or Mann-Whitney test in the case of nonnormally distributed variables. The χ<span class="elsevierStyleSup">2</span> test or Fisher exact test was used to determine the association between qualitative variables. All of the analyses were performed using Wizard for Mac, version 1.9.9.</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 (6 boys, 5 girls) with a mean age of 13 years (range, 8-18 years). Mean age at initiation of treatment was 10.9 (2.2) years (95% CI, 8.6-13.1 years). The mean initial dose was 1.8 (0.2) mg/kg/d. We evaluated the response to treatment at 4 weeks, between weeks 12 and 16, and from 6 months onward. One patient remains in follow-up.</p><p id="par0040" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows demographic data and drug-related variables. Two patients had to suspend therapy with azathioprine because of adverse effects, one during the first month and the other at the fourth month after starting treatment. In the group of patients who completed treatment with azathioprine, the mean duration of therapy was 10.8 (5.7) months (95% CI, 5.0-16.6). After 1 month of treatment, no patients had a complete or near-complete response. Between 12 and 16 weeks, clearance was near-complete in 4 of 9 patients, a marked improvement was observed in 3 patients, and a slight improvement in 2. 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. Therefore, of the 9 patients whose treatment was extended for a minimum of 6 months, clearance was almost complete in 6 at this point.</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, history of asthma, eosinophilia, and IgE levels.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The mean dose of azathioprine used in the present study was 1.8 (0.2) mg/kg/d (95% CI, 1.5-2.1). The mean follow-up time was 33.1 (12.0) months. One patient was still taking azathioprine at the end of the study. After suspension of treatment, 2 patients with complete clearance required new systemic therapy at 8 and 20 months, respectively. The remaining cases were managed with topical corticosteroids, immunomodulators, or both.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Adverse effects were recorded in 3 patients (27%). One patient experienced nausea and epigastric pain, one experienced a mild increase in transaminases, and a third patient experienced a mild transitory increase in transaminases that resolved spontaneously. In the case of the 2 patients with epigastric pain, treatment was suspended owing to the intensity of the pain. No patients had a severe intercurrent infection or complained of effects other than those already commented upon.</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, 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.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">4,8–10</span></a> Both our results and those of previous studies<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">1,10</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. Thus, in our study, clearance was complete or near-complete in 7 of 9 patients; this figure is slightly higher than that reported elsewhere.<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. The main disadvantage of azathioprine is not its efficacy, which is similar to that of other immunosuppressants (eg, ciclosporin and methotrexate),<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">11,12</span></a> but the time to response, since it does not take effect for at least 3 months.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">10</span></a> In fact, consistent with the view of other European specialists,<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">13,14</span></a> this interval and the adverse effects profile meant that azathioprine was not our first choice for any of the patients. We also agree with other authors that the adverse effects we observed were mainly mild gastrointestinal adverse effects, which led to suspension of treatment in only 2 cases.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">5,10</span></a> It is noteworthy that in both cases, these effects appeared during the first month of treatment and resolved once medication was suspended.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Our study is subject to a series of limitations, mainly its small sample size. In addition, it was a retrospective study, and adverse events may have been underestimated if patients were not actively asked about them. For the same reason, it is difficult to evaluate the Investigator Global Assessment scale. Finally, the limited follow-up period prevents us from drawing definitive conclusions about the duration of remission and long-term safety of treatment with azathioprine.</p><p id="par0070" class="elsevierStylePara elsevierViewall">In conclusion, our data confirm the efficacy and tolerability of azathioprine in the treatment of moderate to severe atopic dermatitis in children; therefore, we should include it as part of our systemic treatment options in these patients. While azathioprine does not seem to have serious adverse effects on children in the short term, strict monitoring is mandatory in this age group.</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.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1174042" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Patients and methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1097960" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1174041" "titulo" => "Resumen" "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 métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1097961" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Objectives" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Material and methods" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Statistical analysis" ] ] ] 7 => array:2 [ "identificador" => "sec0025" "titulo" => "Results" ] 8 => array:2 [ "identificador" => "sec0030" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflicts of Interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-01-09" "fechaAceptado" => "2018-06-03" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1097960" "palabras" => array:5 [ 0 => "Azathioprine" 1 => "Atopic dermatitis" 2 => "Atopic eczema" 3 => "Immunosuppressants" 4 => "Children" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1097961" "palabras" => array:5 [ 0 => "Azatioprina" 1 => "Dermatitis atópica" 2 => "Eccema atópico" 3 => "Inmunosupresores" 4 => "Niños" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Atopic dermatitis (AD) is a chronic inflammatory skin disease that typically affects children. Severe forms may have a profound effect on patients’ quality of life. Some forms are resistant to conventional treatment and require the use of systemic immunosuppressants such as azathioprine (AZA) to adequately manage the disease.</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.</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.</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 (6 boys and 5 girls) with a mean age of 13 years (range, 8-18 years). The mean (SD) age at start of treatment was 10.9 (2.2) years (95% CI 8.6-13.1). The mean initial dosage of AZA was 1.8 (0.2) mg/kg/d. We evaluated treatment response after 4 weeks, 12 to 16 weeks, and 6 months. Mean treatment duration was 10.8 (5.7) months. Treatment had to be suspended in 2 patients because of adverse effects. Seven of the 9 remaining patients presented complete or almost complete clearance of the AD after 6 months of treatment.</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusion</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">In our experience, AZA is well tolerated and may be considered as a treatment option in children with severe AD resistant to conventional treatment.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Patients and methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La dermatitis atópica (DA) es una enfermedad inflamatoria crónica de la piel típicamente infantil cuyas formas graves pueden afectar intensamente la calidad de vida del paciente. Existen formas refractarias al tratamiento convencional en las que es preciso emplear inmunosupresores sistémicos como la azatioprina (AZA) para alcanzar un buen control de la enfermedad.</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 niños con DA grave.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pacientes y métodos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se realizó una revisión retrospectiva de niños con DA grave tratados con AZA entre enero de 2007 y mayo de 2017.</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 (6 varones, 5 mujeres) con una edad promedio de 13 años (rango 8-18 años). La edad media<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>DE al inicio del tratamiento fue de 10,9<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2,2 años (IC 95% 8,6-13,1). La media de la dosis inicial de AZA fue de 1,8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0,2<span class="elsevierStyleHsp" style=""></span>mg/kg/d. Evaluamos la respuesta al tratamiento de nuestros pacientes a las 4 semanas, entre la semana 12 y la 16, y a partir de los 6 meses. La media del tratamiento fue de 10,8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5,7 meses. Dos pacientes tuvieron que suspender el tratamiento por efectos adversos. Siete de los 9 pacientes restantes presentaron un aclaramiento completo o casi completo de la DA a los 6 meses de tratamiento.</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusión</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">En nuestra experiencia, la AZA es bien tolerada y puede ser considerada como una opción terapéutica en los niños con DA grave refractaria a tratamientos convencionales.</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 métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusión" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Noguera-Morel L, Knöpfel N, Torrelo A, Hernández-Martín A. Estudio retrospectivo del tratamiento sistémico de la dermatitis atópica grave con azatioprina. Eficacia y tolerancia en 11 pacientes pediátricos. Actas Dermosifiliogr. 2019;110:227–231.</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: AD, atopic dermatitis; AZA, azathioprine; TPMT, thiopurine methyltransferase.</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"> \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, No. (%) \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> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 (100) \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> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Male/female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 (55)/5 (45) \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, mo</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Median (range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 (0-60) \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, cells/μL</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>500/<<span class="elsevierStyleHsp" style=""></span>500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 (91)/1 (9) \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> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>No/yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 (36)/7 (64) \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> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>No/yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 (55)/5 (45) \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, y</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mean (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.9 (2.2) \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, IU/mL</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mean (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19.8 (2.3) \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, mo</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mean (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.8 (5.7) \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, mg/kg/d</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mean (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.8 (0.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2003838.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Demographic Data and Drug-Related Variables.</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" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Abbreviations: AE, adverse effect; NA, not available; PCP, primary care physician; PDN, prednisolone; TPMT, thiopurine methyltransferase.</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"> \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> \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> \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.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">10</span></a> \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 \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 \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 \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 \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 \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 \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. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">82 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 \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, y \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0-12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2-18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8.6 (mean) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8-18 \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, mg/kg/d \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2-3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.4 (normal TPMT)<br>1.5 (low TPMT) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.8 \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 \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 \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mean (SD), 10 (5.7) mo \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 wk \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2, 4, 8, 12 wk and every 2 mo thereafter \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12-16 wk \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Excellent 28/48 \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 11/12, mean (SD), 27.7 (8.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Complete or near-complete clearance in 7/9 \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">33.1 mo \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 \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 1/48. Resolved with suspension of therapy<br><br>Mild elevation of transaminases in 5/48 (treatment suspended by PCP in 1 case)<br><br>Nausea and vomiting in 1/48<br>Treatment suspended in 2/48 because of AEs \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 2/12<br><br>Mild elevation of transaminases in 1/12 (improved when the dose was reduced)<br><br>No patients interrupted treatment because of AEs \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 33/82 (24 in the complete blood count and 11 with increased transaminases)<br><br>Treatment was interrupted owing to AEs in 6/82 cases (2 with abnormal complete blood count and 4 with increased transaminases) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AEs in 3/11: epigastric pain in 2/11 and increased transaminases in 1/11<br><br>Treatment interrupted because of AEs (epigastric pain) in 2/11 \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Monitoring of TPMT activity throughout treatment \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. Treatment was suspended briefly in cases of laboratory abnormalities and restarted after further laboratory testing \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2003837.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Summary of Data From Studies on Atopic Dermatitis Treated With Azathioprine in Children.</p>" ] ] ] "bibliografia" => array:2 [ "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, 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. 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| 2021 Noviembre | 65 | 58 | 123 |
| 2021 Octubre | 52 | 52 | 104 |
| 2021 Septiembre | 51 | 37 | 88 |
| 2021 Agosto | 53 | 32 | 85 |
| 2021 Julio | 44 | 18 | 62 |
| 2021 Junio | 30 | 25 | 55 |
| 2021 Mayo | 41 | 41 | 82 |
| 2021 Abril | 99 | 89 | 188 |
| 2021 Marzo | 68 | 32 | 100 |
| 2021 Febrero | 49 | 20 | 69 |
| 2021 Enero | 42 | 6 | 48 |
| 2020 Diciembre | 29 | 15 | 44 |
| 2020 Noviembre | 16 | 16 | 32 |
| 2020 Octubre | 29 | 12 | 41 |
| 2020 Septiembre | 29 | 11 | 40 |
| 2020 Agosto | 24 | 19 | 43 |
| 2020 Julio | 16 | 11 | 27 |
| 2020 Junio | 22 | 14 | 36 |
| 2020 Mayo | 25 | 15 | 40 |
| 2020 Abril | 28 | 18 | 46 |
| 2020 Marzo | 13 | 9 | 22 |
| 2020 Febrero | 4 | 0 | 4 |
| 2019 Mayo | 4 | 1 | 5 |
| 2019 Abril | 1 | 1 | 2 |
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