Original Article
Efficacy and safety of azathioprine and dapsone as an adjuvant in the treatment of bullous pemphigoid
A. Tirado-Sánchez
, V. Díaz-Molina, R.M. Ponce-Olivera
Corresponding author
Servicio de Dermatología, Hospital General de México, Mexico City, Mexico
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Activation of basophils by lysine-aspirin was demonstrated in aspirin sensitivity patients. (A) Negative control: basophils were detected in 0.7% of all leukocytes. (B) There were 3.8% of spontaneous activated basophils (anti-CD203c +ve/anti-IgE highly +ve cells) at baseline. (C) Basophil population in sample incubated with lysine-aspirin. (D) 38.7% of basophils were activated after stimulated with lysine-aspirin in this patient with aspirin sensitivity.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "P. Wismol, P. Putivoranat, S. Buranapraditkun, P. Pinnobphun, K. Ruxrungtham, J. Klaewsongkram" "autores" => array:6 [ 0 => array:2 [ "nombre" => "P." "apellidos" => "Wismol" ] 1 => array:2 [ "nombre" => "P." "apellidos" => "Putivoranat" ] 2 => array:2 [ "nombre" => "S." "apellidos" => "Buranapraditkun" ] 3 => array:2 [ "nombre" => "P." "apellidos" => "Pinnobphun" ] 4 => array:2 [ "nombre" => "K." "apellidos" => "Ruxrungtham" ] 5 => array:2 [ "nombre" => "J." "apellidos" => "Klaewsongkram" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054611001170?idApp=UINPBA00004N" "url" => "/03010546/0000004000000003/v1_201304101107/S0301054611001170/v1_201304101107/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S0301054611001522" "issn" => "03010546" "doi" => "10.1016/j.aller.2011.03.005" "estado" => "S300" "fechaPublicacion" => "2012-05-01" "aid" => "285" "copyright" => "SEICAP" "documento" => "article" "crossmark" => 0 "subdocumento" => "fla" "cita" => "Allergol Immunopathol (Madr). 2012;40:144-51" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 2974 "formatos" => array:3 [ "EPUB" => 8 "HTML" => 2479 "PDF" => 487 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Seasonal population of <span class="elsevierStyleItalic">Acarus siro</span> mites and effects of their faeces on allergenic immunological disorder modulated by garlic in albino rat" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "144" "paginaFinal" => "151" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 830 "Ancho" => 1624 "Tamanyo" => 106203 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Acarofauna composition found in five visited flour mills samples collected from El-Minia governorate through one year (from February 2009 to January 2010).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Bahaa K.A. Abdel-Salam" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Bahaa K.A." "apellidos" => "Abdel-Salam" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054611001522?idApp=UINPBA00004N" "url" => "/03010546/0000004000000003/v1_201304101107/S0301054611001522/v1_201304101107/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>" "titulo" => "Efficacy and safety of azathioprine and dapsone as an adjuvant in the treatment of bullous pemphigoid" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "152" "paginaFinal" => "155" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "A. Tirado-Sánchez, V. Díaz-Molina, R.M. Ponce-Olivera" "autores" => array:3 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "Tirado-Sánchez" "email" => array:1 [ 0 => "atsdermahgm@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "V." "apellidos" => "Díaz-Molina" ] 2 => array:2 [ "nombre" => "R.M." "apellidos" => "Ponce-Olivera" ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Servicio de Dermatología, Hospital General de México, Mexico City, Mexico" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1257 "Ancho" => 1615 "Tamanyo" => 96696 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Percentage of reepithelialisation of the lesions in the patients studied.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Bullous pemphigoid (BP) is an autoimmune disease, characterised by subepidermal blistering. The disease usually presents in elderly patients. Bullous pemphigoid rarely affects the mucous membranes and is associated with substantial morbidity. The disease express autoantibodies directed against cutaneous autoantigens, BP230 and BP180, called antigen 1 and 2 of BP respectively, both located in the hemidesmosome and anchoring filaments.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The treatment of choice are systemic steroids, like prednisone, at the dose of 0.5–0.75<span class="elsevierStyleHsp" style=""></span>mg/kg/day,<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> however, class I topical steroids are preferred in localised forms.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Systemic steroids improve patients’ survival in BP, but also increase the risk of death and life-threatening adverse events.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Other immunosupresant drugs, called adjuvants, have been widely used to treat autoimmune diseases (e.g. Pemphigus vulgaris) to achieve a corticosteroid-sparing effect.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> The most frequently used agent is azathioprine, while dapsone is another effective option. Therefore we decided to conduct a retrospective study to evaluate the effectiveness and safety of azathioprine and dapsone in BP.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Material and methods</span><p id="par0015" class="elsevierStylePara elsevierViewall">We selected the records of the patients with BP, diagnosed by clinical (lesions suggestive of BP), histological (subepidermal blister) and/or immunological criteria (linear deposition of IgG and/or C3 at the dermoepidermal junction), admitted at the Department of Dermatology, General Hospital of Mexico, in the period from January 2006 to January 2010. All patients had received prednisone 0.5–0.75<span class="elsevierStyleHsp" style=""></span>mg/kg/day in combination with either azathioprine (group 1, 2–3<span class="elsevierStyleHsp" style=""></span>mg/kg/day) or dapsone (group 2, 100<span class="elsevierStyleHsp" style=""></span>mg/day).</p><p id="par0020" class="elsevierStylePara elsevierViewall">The primary outcome measure was the complete remission, defined as the complete reepithelialisation of all lesions. The secondary outcome measure was the inhibition of disease progression, defined as the time where no new lesions appear, and the control of pruritus.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Results from routine laboratory tests performed each week were obtained (complete blood count, liver function tests), as well as the daily records of blood pressure, heart and respiratory rates. The extent and location of the blisters were recorded. Drugs adverse events were classified as mild, moderate or severe and those that could endanger life.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Statistical analysis</span><p id="par0030" class="elsevierStylePara elsevierViewall">We perform a Wilcoxon test to evaluate the primary outcome measure. Dichotomous and ordered categorical data were analysed with the Fisher exact and the Mann Whitney test respectively. The analysis was conducted using the statistical program SPSS (version 12 for Windows, Chicago, Ill., USA).</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Baseline</span><p id="par0035" class="elsevierStylePara elsevierViewall">We selected 15 records of patients with BP, eight (53%) with azathioprine and seven (47%) with dapsone (demographic and clinical data of the sample are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). All patients represented newly diagnosis BP cases. The mean age was 65.36<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.69 years. The approximate body surface affected (BSA) was 26.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.85% (the calculation was made based on the rule of nine). In group 1 (azathioprine), the mean age was 66.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.83 years, with BSA of 24.65<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.13%, while in the dapsone group, the average age was 64.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5.38 years and 28.22<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.64% of BSA.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Monitoring</span><p id="par0040" class="elsevierStylePara elsevierViewall">The complete remission (reepithelialisation of all lesions) was achieved by six weeks of both treatment groups (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). However, disease progression was inhibited firstly in azathioprine group by around week two, and week three in dapsone group (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.083). Pruritus was controlled at week four in both treatments. No deaths were reported in the eight weeks of follow up.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Adverse events reported were: for azathioprine, vertigo (2/5, 40%), gastric intolerance (1/5, 20%), while for the group with dapsone, they were abnormal liver function tests (3/5, 60%). In one patient (dapsone group), it was necessary to discontinue the immunosuppressant medication dose and begin treatment with systemic steroid as monotherapy. Adverse events did not require additional treatment.</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0050" class="elsevierStylePara elsevierViewall">Bullous pemphigoid is a chronic, autoimmune, bullous disease, most commonly seen in the elderly.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,6</span></a> The incidence does not vary among male and female.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Bullous pemphigoid represents one of the most common subepidermal autoimmune blistering diseases. Patients generally exhibit disseminated lesions consisting in tense blisters, variable in number and size, accompanied by moderate to severe pruritus, often with erythematous or urticarial lesions that may precede the blister, and subsequently accompanied by erosions and pigmented lesions. It rarely affects the mucous membranes.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> The disease results from autoantibodies directed against cutaneous autoantigens at the dermoepidermal junction (BP180 and BP230). The antigen–antibody complex activates the complement cascade, resulting in the recruitment of eosinophils and neutrophils.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Thus, on histology, there is a subepidermal blister with mixed inflammatory infiltrate rich in eosinophils. Direct immunofluorescence shows linear deposits of IgG and C3 along the basement membrane, while indirect immunofluorescence showed circulating antibodies (salt-split pattern). Bullous pemphigoid is potentially associated with substantial morbidity and even mortality. The mortality ranges from 25 to 40% during the first year. Risk factors of mortality identified are: elderly, female gender, concomitant diseases (cardiovascular disease, liver disorders, chronic lung disease, neuropsychiatric disorders, and diabetes mellitus, and malignancy, urological and endocrine disorders) and low Karnofsky (≤40).<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The selection of treatment options is based more on clinical experience than in controlled studies,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> and includes many drugs. The treatments of choice are topical/systemic corticosteroids; however, systemic antibiotics (like tetracycline) and systemic immunosuppressant are needed. Systemic corticosteroids have been considered the standard and the best-validated treatment,<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,8</span></a> and have been used alone or combined. The recommended dose of systemic corticosteroid (prednisone) is 0.75<span class="elsevierStyleHsp" style=""></span>mg/kg/day (with ranges 0.3–1.25<span class="elsevierStyleHsp" style=""></span>mg/kg/day)<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> until disease control and then reduce and keeping the adjuvant. Since complications related to the use of oral corticosteroids may contribute to the prognosis of patients with BP, more studies, which evaluate other treatment options are needed. Topical high-potency steroid like clobetasol propionate has also been studied, and is found to be useful in the control of localised and disseminated BP without increasing mortality, but it should be noted that the use of topical corticosteroids over large areas of body surface area (≥40<span class="elsevierStyleHsp" style=""></span>g/dia) can lead to epidermal atrophy and also determines drug absorption, and inducing systemic effects of the drug.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Numerous studies suggest that the adjuvant use of immunosuppressant shows some steroid-sparing effect, thereby helping to reduce the total dose of systemic corticosteroid that the patient needs in order to control the disease. These drugs are azathioprine and dapsone, commonly used in our practice for this purpose. Azathioprine is an antimetabolite, a synthetic analogue of purine derivative of 6-mercaptopurine, used in the treatment of several skin diseases.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,10</span></a> It is the most frequently used adjuvant in the treatment of BP, at doses ranging from 1 to 3<span class="elsevierStyleHsp" style=""></span>mg/kg.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,9,11</span></a> The steroid-sparing effect of azathioprine has been reported.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> It is generally well tolerated; the most common side effect is myelosuppression, other adverse effects are gastrointestinal disturbances (nausea, diarrhoea), dizziness, alopecia, hepatotoxicity, increased incidence of malignancy in patients after kidney transplantation, and opportunistic infections.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9–11</span></a> The optimal therapeutic response occurs between 6 and 8 weeks; if no response were observed by week 12–16, the drug should be changed for another immunosuppressant.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Dapsone is a drug used primarily in the treatment of leprosy, pneumonia by Pneumocystis jiroveci and malaria, but has also been used in autoimmune bullous diseases for its steroid-sparing effect. In BP, it is reported an efficacy rate close to 84%, either alone or in combined therapy with systemic corticosteroids or another immunosuppressant. The most common adverse events of dapsone are haemolysis and secondary anaemia.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Other adverse events reported are metahaemoglobinaemia, nausea, vomiting, peripheral neuropathy, elevated transaminases, and cutaneous drug reactions.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">In our study, we found no difference in the effectiveness in the inhibition of disease progression (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.083), and in achieve disease control.</p><p id="par0075" class="elsevierStylePara elsevierViewall">In accordance with the literature reviewed, the disease was more common in older adults. The most frequently observed adverse event was dizziness for azathioprine (40%) and impaired liver function test for dapsone (60%), whereas in the literature, haematological disorders are the most frequently reported for both drugs. Our patients responded well to treatment in both groups and no deaths were reported up to eight weeks.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Azathioprine is the most studied adjuvant and is used successfully in the treatment of autoimmune blistering diseases, being particularly important in the treatment of bullous pemphigoid. In addition, dapsone is a promising agent, useful in treating patients with bullous diseases of autoimmune aetiology, including BP. Adverse events of dapsone are dose dependent and usually reversible.</p><p id="par0085" class="elsevierStylePara elsevierViewall">We recommend the use of an immunosuppressive agent at the beginning of the treatment. Both immunosuppressants are equally effective to inhibit disease progression and to induce reepithelialisation of all lesions at eight weeks of follow up. Both have an acceptable safety profile at eight weeks of treatment. More studies to evaluate these two drugs at longer term treatments are needed.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:2 [ "identificador" => "xres86105" "titulo" => array:5 [ 0 => "Summary" 1 => "Background" 2 => "Methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec74269" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:2 [ "identificador" => "sec0010" "titulo" => "Material and methods" ] 4 => array:2 [ "identificador" => "sec0015" "titulo" => "Statistical analysis" ] 5 => array:3 [ "identificador" => "sec0020" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Baseline" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Monitoring" ] ] ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflicts of interest" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2010-10-12" "fechaAceptado" => "2010-12-23" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec74269" "palabras" => array:5 [ 0 => "Adjuvant" 1 => "Azathioprine" 2 => "Bullous pemphigoid" 3 => "Dapsone" 4 => "Treatment" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Summary" "resumen" => "<span class="elsevierStyleSectionTitle">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Bullous pemphigoid is a chronic, blistering and autoimmune disease, common in old age. The treatment usually includes systemic steroids, however, these cause high morbidity rates, and then different products that function as adjuvants have been tried. At present, there are no studies to determine which adjuvant offers a better efficacy and safety profile.</p> <span class="elsevierStyleSectionTitle">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We performed a retrospective study which included the records of patients with bullous pemphigoid, treated either with azathioprine or dapsone. We evaluated the time to achieve complete remission, the time to inhibit disease progression, and the control of pruritus.</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Fifteen records of patients were selected, eight (53%) treated with azathioprine and seven (47%) with dapsone. Complete remission was achieved at week six in both groups. We found no difference in the inhibition of disease progression (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.083). Pruritus was controlled at four weeks of treatment in both treatments.</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Both products are effective as adjuvant in the treatment of bullous pemphigoid, with an acceptable safety profile.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1257 "Ancho" => 1615 "Tamanyo" => 96696 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Percentage of reepithelialisation of the lesions in the patients studied.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">BSA<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>Body surface affected.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Variable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Group (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>15)</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Azathioprine (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Dapsone (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>7) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age (years)<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65.36<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.69</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">66.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5.38 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gender (Male) (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (62) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (57) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BSA<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.85</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24.65<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28.22<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.64 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Duration of the disease (months)<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.86<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.35 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab165468.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Demographic and clinical data of the sample.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:12 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune bullous dermatoses: a review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "P. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 10 | 3 | 13 |
| 2024 October | 83 | 33 | 116 |
| 2024 September | 92 | 33 | 125 |
| 2024 August | 105 | 28 | 133 |
| 2024 July | 68 | 18 | 86 |
| 2024 June | 75 | 14 | 89 |
| 2024 May | 73 | 20 | 93 |
| 2024 April | 66 | 12 | 78 |
| 2024 March | 98 | 22 | 120 |
| 2024 February | 126 | 19 | 145 |
| 2024 January | 97 | 21 | 118 |
| 2023 December | 71 | 18 | 89 |
| 2023 November | 114 | 16 | 130 |
| 2023 October | 142 | 42 | 184 |
| 2023 September | 98 | 11 | 109 |
| 2023 August | 84 | 11 | 95 |
| 2023 July | 94 | 32 | 126 |
| 2023 June | 107 | 30 | 137 |
| 2023 May | 144 | 54 | 198 |
| 2023 April | 130 | 25 | 155 |
| 2023 March | 101 | 7 | 108 |
| 2023 February | 72 | 3 | 75 |
| 2023 January | 97 | 23 | 120 |
| 2022 December | 58 | 19 | 77 |
| 2022 November | 61 | 21 | 82 |
| 2022 October | 77 | 20 | 97 |
| 2022 September | 67 | 23 | 90 |
| 2022 August | 85 | 27 | 112 |
| 2022 July | 72 | 16 | 88 |
| 2022 June | 58 | 16 | 74 |
| 2022 May | 69 | 14 | 83 |
| 2022 April | 83 | 11 | 94 |
| 2022 March | 88 | 21 | 109 |
| 2022 February | 102 | 20 | 122 |
| 2022 January | 98 | 21 | 119 |
| 2021 December | 63 | 46 | 109 |
| 2021 November | 55 | 23 | 78 |
| 2021 October | 63 | 64 | 127 |
| 2021 September | 58 | 40 | 98 |
| 2021 August | 48 | 31 | 79 |
| 2021 July | 42 | 29 | 71 |
| 2021 June | 36 | 26 | 62 |
| 2021 May | 48 | 23 | 71 |
| 2021 April | 67 | 56 | 123 |
| 2021 March | 77 | 19 | 96 |
| 2021 February | 28 | 20 | 48 |
| 2021 January | 30 | 20 | 50 |
| 2020 December | 1 | 7 | 8 |
| 2020 November | 0 | 8 | 8 |
| 2020 October | 0 | 8 | 8 |
| 2020 September | 0 | 4 | 4 |
| 2020 August | 0 | 6 | 6 |
| 2020 July | 0 | 8 | 8 |
| 2020 June | 0 | 3 | 3 |
| 2020 May | 0 | 12 | 12 |
| 2020 April | 0 | 5 | 5 |
| 2020 March | 0 | 13 | 13 |
| 2020 February | 0 | 12 | 12 |
| 2020 January | 0 | 3 | 3 |
| 2019 December | 0 | 10 | 10 |
| 2019 November | 0 | 16 | 16 |
| 2019 October | 0 | 3 | 3 |
| 2019 September | 0 | 10 | 10 |
| 2019 August | 0 | 7 | 7 |
| 2019 July | 0 | 21 | 21 |
| 2019 June | 0 | 26 | 26 |
| 2019 May | 0 | 30 | 30 |
| 2019 April | 0 | 21 | 21 |
| 2019 March | 0 | 5 | 5 |
| 2019 February | 0 | 7 | 7 |
| 2018 December | 0 | 9 | 9 |
| 2018 February | 5 | 1 | 6 |
| 2018 January | 4 | 3 | 7 |
| 2017 December | 6 | 1 | 7 |
| 2017 November | 4 | 6 | 10 |
| 2017 October | 9 | 4 | 13 |
| 2017 September | 11 | 4 | 15 |
| 2017 August | 17 | 10 | 27 |
| 2017 July | 15 | 0 | 15 |
| 2017 June | 12 | 12 | 24 |
| 2017 May | 12 | 5 | 17 |
| 2017 April | 18 | 6 | 24 |
| 2017 March | 17 | 21 | 38 |
| 2017 February | 37 | 2 | 39 |
| 2017 January | 14 | 1 | 15 |
| 2016 December | 14 | 8 | 22 |
| 2016 November | 21 | 4 | 25 |
| 2016 October | 26 | 6 | 32 |
| 2016 September | 10 | 10 | 20 |
| 2016 August | 14 | 4 | 18 |
| 2016 July | 9 | 1 | 10 |
| 2016 June | 14 | 12 | 26 |
| 2016 May | 15 | 15 | 30 |
| 2016 April | 19 | 16 | 35 |
| 2016 March | 19 | 16 | 35 |
| 2016 February | 11 | 13 | 24 |
| 2016 January | 19 | 18 | 37 |
| 2015 December | 16 | 8 | 24 |
| 2015 November | 13 | 5 | 18 |
| 2015 October | 28 | 4 | 32 |
| 2015 September | 12 | 3 | 15 |
| 2015 August | 16 | 5 | 21 |
| 2015 July | 11 | 5 | 16 |
| 2015 June | 3 | 0 | 3 |
| 2015 May | 7 | 5 | 12 |
| 2015 April | 14 | 10 | 24 |
| 2015 March | 11 | 3 | 14 |
| 2015 February | 7 | 3 | 10 |
| 2015 January | 16 | 6 | 22 |
| 2014 December | 20 | 6 | 26 |
| 2014 November | 7 | 4 | 11 |
| 2014 October | 9 | 8 | 17 |
| 2014 September | 21 | 4 | 25 |
| 2014 August | 15 | 3 | 18 |
| 2014 July | 14 | 2 | 16 |
| 2014 June | 17 | 1 | 18 |
| 2014 May | 14 | 3 | 17 |
| 2014 April | 9 | 1 | 10 |
| 2014 March | 56 | 7 | 63 |
| 2014 February | 44 | 9 | 53 |
| 2014 January | 45 | 12 | 57 |
| 2013 December | 38 | 10 | 48 |
| 2013 November | 33 | 9 | 42 |
| 2013 October | 44 | 10 | 54 |
| 2013 September | 37 | 8 | 45 |
| 2013 August | 40 | 7 | 47 |
| 2013 July | 48 | 14 | 62 |
| 2013 June | 21 | 2 | 23 |
| 2013 May | 21 | 6 | 27 |
| 2013 April | 20 | 8 | 28 |
| 2013 March | 22 | 8 | 30 |
| 2013 February | 9 | 7 | 16 |
| 2013 January | 8 | 1 | 9 |
| 2012 December | 8 | 4 | 12 |
| 2012 November | 4 | 5 | 9 |
| 2012 October | 2 | 3 | 5 |
| 2012 September | 3 | 3 | 6 |
| 2012 April | 383 | 0 | 383 |
Show all
