Case Report
Sulfasalazine-Induced Linear Immunoglobulin A Bullous Dermatosis with DRESS
Dermatosis ampollosa inducida por inmunoglobulina A lineal con clínica de síndrome DRESS por sulfasalazina
N. Hernández
, L. Borrego, E. Soler, J. Hernández
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Servicio de Dermatología, Complejo Hospitalario Universitario Insular Materno Infantil de Gran Canaria, Las Palmas, Spain
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Hernández, L. Borrego, E. Soler, J. Hernández" "autores" => array:4 [ 0 => array:4 [ "nombre" => "N." "apellidos" => "Hernández" "email" => array:1 [ 0 => "noheh@hotmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "L." "apellidos" => "Borrego" ] 2 => array:2 [ "nombre" => "E." "apellidos" => "Soler" ] 3 => array:2 [ "nombre" => "J." "apellidos" => "Hernández" ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Servicio de Dermatología, Complejo Hospitalario Universitario Insular Materno Infantil de Gran Canaria, Las Palmas, Spain" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Dermatosis ampollosa inducida por inmunoglobulina A lineal con clínica de síndrome DRESS por sulfasalazina" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1575 "Ancho" => 1583 "Tamanyo" => 306436 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Linear deposit of IgA along the basement membrane (direct immunofluorescence, original magnification ×10).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Sulfasalazine is a sulfonamide-derived drug with anti-inflammatory properties that is used in the treatment of rheumatoid arthritis and inflammatory bowel disease. Although a maculopapular rash is the most common cutaneous reaction caused by this treatment,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> other potential reactions should not be ignored.</p><p id="par0010" class="elsevierStylePara elsevierViewall">We treated a case of linear IgA dermatosis (LAD) secondary to sulfasalazine treatment which presented as drug-rash with eosinophilia and systemic symptoms (DRESS) in a patient with rheumatoid arthritis.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Case Description</span><p id="par0015" class="elsevierStylePara elsevierViewall">The patient was a 60-year-old woman with a history of rheumatoid arthritis, systemic hypertension, and dyslipidemia, who was receiving treatment with deflazacort (18 mg/d), diclofenac (50 mg/d), omeprazole (20 mg/d), and a combination of hydrochlorothiazide and valsartan (150/12.5 mg). She was prescribed treatment with sulfasalazine (2<span class="elsevierStyleHsp" style=""></span>g/d) for joint pain. Three weeks later the patient presented to the emergency department with fever and skin lesions on the trunk and limbs that had appeared 2 weeks previously. Physical examination revealed general malaise, fever, hypotension, and tachycardia. Confluent erythematous macules and papules that formed moderately infiltrated plaques with poorly defined borders affected 70% of the body surface area. Tense blisters filled with a clear fluid were present on both legs and the dorsum of the hands (<a class="elsevierStyleCrossRefs" href="#fig0005">Figures 1 and 2</a>), but the Nikolsky sign was negative. No mucosal lesions or lymphadenopathy were detected. Blood tests revealed a white blood cell count of 15 700/μL (normal range, 4500-11 000/μL) (54.5% neutrophils [normal range, 40.0%-70.0%] and 8.4% eosinophils [normal range, 0.00%-5.00%]) and eosinophilia of 1320/μL; erythrocyte sedimentation rate, 42<span class="elsevierStyleHsp" style=""></span>mm/h; alanine aminotransferase, 44.5 U/L (normal range, 7-40 U/L); γ-glutamyltransferase, 452.3 U/L (normal range, 12-54 U/L); lactate dehydrogenase, 716.1 U/L (normal range, 230-460 U/L); and C-reactive protein, 9.88<span class="elsevierStyleHsp" style=""></span>mg/dl. Serology for Epstein-Barr virus (EBV) was positive (IgM and IgG) and abdominal ultrasound showed no abnormal findings. Skin biopsy revealed a blister caused by dermoepidermal detachment with a neutrophil-rich infiltrate (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>) and on direct immunofluorescence there were linear deposits of IgA but not IgG or complement along the basement membrane (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).Treatment was initiated with a tapering dose of prednisone, starting at 60<span class="elsevierStyleHsp" style=""></span>mg/d, in conjunction with topical corticosteroids, with a good response. The sulfasalazine treatment was discontinued at the same time and the existing lesions improved and no new lesions were detected. The patient responded favorably with an improvement in her general health and normalization of laboratory parameters. The skin lesions disappeared completely within 2 months. After 3 years of follow-up, the patient is asymptomatic and receiving no treatment.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0020" class="elsevierStylePara elsevierViewall">We report the case of a woman with LAD and DRESS syndrome secondary to sulfasalazine administration. No other changes had been made to the patient's treatment regimen; the initiation of sulfasalazine treatment 3 weeks before the onset of symptoms and the linear deposits of IgA but not of IgG or complement suggest that this drug was the most likely cause. Moreover, fever, hypertension, tachycardia, elevated transaminase levels, and eosinophilia are inclusion criteria for the diagnosis of DRESS in hospitalized patients.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">LAD is an immune-mediated blistering disease, characterized by the presence of linear IgA deposits along the basement membrane. This condition is often idiopathic and is occasionally associated with drug treatment,<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> inflammatory bowel disease,<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> or lymphoid tumors.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The association of LAD with gluten-sensitive enteropathy<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and rheumatoid arthritis<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> has also been described in isolated cases.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Drug-induced LAD can be indistinguishable from the clinical features of classical LAD, as it is characterized by the development of an erythematous plaque surrounded by vesicles or blisters, giving the appearance of a “string of pearls”. However, the skin lesions are generally more polymorphic, and cases of erythema multiforme and toxic epidermal necrolysis with dissemination of bullous lesions and mucosal involvement have been described.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,9</span></a> The lesions can be asymptomatic or pruritic and are most commonly found on the trunk, limbs, and acral areas. The symptoms usually appear between 24<span class="elsevierStyleHsp" style=""></span>hours and 15 days after starting treatment with the causative drug, and the formation of new lesions ceases 24 to 72<span class="elsevierStyleHsp" style=""></span>hours after discontinuation of the treatment. Resolution of the lesions occurs on average within 2 months. Mucosal involvement has been reported in approximately 40% of cases, as compared with 80% of cases of classical LAD.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Direct immunofluorescence in classical LAD reveals linear deposits of IgA along the basement membrane, accompanied by IgG deposits in over 30% of cases. In drug-induced DAL, only linear IgA deposits are observed in the basement membrane, accompanied by complement (C3) in 20% of cases.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> There are no clinical or immunofluorescence patterns to differentiate with certainty between classical and drug-induced LAD.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Vancomycin is the drug most commonly associated with LAD secondary to drug administration.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4,10,11</span></a> Other causative antibiotics include second generation cephalosporins, penicillin derivatives, and trimetoprim-sulfametoxazole (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,11</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">In the present case, the patient was receiving chronic treatment with diclofenac/misoprostol, deflazacort, omeprazole, and a combination of hydrochlorothiazide and valsartan; this regimen was maintained after the remission of symptoms.</p><p id="par0045" class="elsevierStylePara elsevierViewall">NSAID-induced LAD has only been described in isolated cases among patients treated with diclofenac<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> or piroxicam.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Although we cannot rule out a link between LAD and the other treatments administered to our patient, sulfasalazine seems the most likely causative drug, based on the chronology of events.</p><p id="par0050" class="elsevierStylePara elsevierViewall">A review of the literature revealed no cases of sulfasalazine-induced LAD, although a link has been reported between LAD and trimetoprim-sulfametoxazole,<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a> another sulfonamide-derived molecule.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Sulfasalazine is a sulfonamide derivative that inhibits the synthesis of dihydrofolic acid by the intestinal flora. In the digestive tract, sulfasalazine is broken down into 2 metabolites: 5-aminosalacyclic acid and sulfapyridine. Sulfapyridine is rapidly absorbed and is hydroxylated and acetylated in the liver, with subsequent excretion in the urine. The rate of acetylation in the liver is genetically determined and slow acetylators are at increased risk of adverse reactions, such as hypersensitivity syndrome.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">DRESS is characterized by skin rash, fever, lymphadenopathy, and systemic involvement. The REGISCAR group has suggested several inclusion criteria for hospitalized patients, including skin rash and at least 3 of 4 systemic symptoms (fever, lymphadenopathy, internal organ involvement, and abnormal complete blood count).<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Reactivation of human herpesvirus type-6 and Epstein-Barr virus has also been associated with DRESS.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,15</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">It is not known whether rheumatoid arthritis alone can be associated with LAD. Hayakawa et al.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> described the case of a 65-year-old woman with a 6-year history of rheumatoid arthritis who developed LAD, but did not state which drugs were prescribed to treat the patient's arthritis. The authors suggest that the overproduction and increase action of cytokines in arthritis could give rise to immune dysregulation that triggers this condition, but they conclude that this association cannot be confirmed and may have been an incidental finding.</p><p id="par0070" class="elsevierStylePara elsevierViewall">To the best of our knowledge this is the first case reported in the literature of sulfasalazine-induced LAD with clinical features of DRESS. We believe it is important to recognize this association and to include sulfasalazine in the list of drugs that can cause drug-induced LAD.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict 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:9 [ 0 => array:2 [ "identificador" => "xres104059" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec91624" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres104060" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec91623" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Case Description" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflict of Interest" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec91624" "palabras" => array:4 [ 0 => "Sulfasalazine" 1 => "Rheumatoid arthritis" 2 => "Bullous dermatosis" 3 => "Adverse skin reaction" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec91623" "palabras" => array:4 [ 0 => "Sulfasalazina" 1 => "Artritis reumatoide" 2 => "Dermatosis ampollosa" 3 => "Reacción adversa cutánea" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Linear immunoglobulin (Ig) A dermatosis is an immune-mediated bullous disease characterized by linear deposits of IgA along the basal membrane. While usually idiopathic, it can occasionally be induced by drug exposure. We report the case of a 60-year-old woman with rheumatoid arthritis being treated with sulfasalazine who developed linear IgA dermatosis and drug rash with eosinophilia and systemic symptoms (DRESS). The dermatosis and associated symptoms resolved following withdrawal of the drug and treatment with systemic corticosteroids for 2 months. This is the first report of sulfasalazine-induced linear IgA dermatosis in association with DRESS and we believe that sulfasalazine should be added to the list of drugs that can cause linear IgA dermatosis.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La dermatosis IgA lineal es una enfermedad ampollosa mediada inmunológicamente que se define por presentar un depósito lineal de IgA a lo largo de la membrana basal. Habitualmente es idiopática y ocasionalmente se asocia con algunos fármacos. Describimos el caso de una mujer de 60 años con artritis reumatoide en tratamiento con sulfasalazina, que desarrolló un cuadro de dermatosis IgA lineal con clínica de DRESS (drug-rash with eosinophilia and systemic symptoms) el cual respondió al suspender el fármaco causal más tratamiento con corticoides sistémicos durante dos meses. Este es el primer caso descrito de dermatosis IgA lineal con clínica de DRESS relacionado con la sulfasalazina. Creemos que es importante tener en cuenta esta asociación para poder incluir a la sulfasalazina en el listado de fármacos que pueden producir dermatosis IgA lineal por fármacos.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Hernández N, et al. Dermatosis ampollosa inducida por inmunoglobulina A lineal con clínica de síndrome DRESS por sulfasalazina. Actas Dermosifiliogr. 2013;104:343–6.</p>" ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2133 "Ancho" => 1583 "Tamanyo" => 340997 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Erythematous papules coalesced to form firm plaques on the lower limbs, accompanied by blisters filled with clear fluid.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1187 "Ancho" => 1583 "Tamanyo" => 236281 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Tense blisters filled with clear fluid on the dorsum of the hands.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2115 "Ancho" => 1583 "Tamanyo" => 427735 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Dermoepidermal detachment with a neutrophil-rich inflammatory infiltrate. Hematoxylin-eosin, original magnification ×10.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1575 "Ancho" => 1583 "Tamanyo" => 306436 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Linear deposit of IgA along the basement membrane (direct immunofluorescence, original magnification ×10).</p>" ] ] 4 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "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=""><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">Vanomycin \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">Trimetoprim-sulfametoxazole \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">Amiodarone \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">Captopril \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">Cefamandole \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">Diclofenac \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">Furosemide \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">Glibenclamide \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">Lithium \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">Penicillin \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">Phenytoin \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">Piroxicam \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">Somatostatin \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">Vigabatrin \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab185601.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Drugs Associated with LAD.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adverse cutaneous reaction to sulfasalazine" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "C. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 9 | 12 | 21 |
| 2024 Octubre | 65 | 57 | 122 |
| 2024 Septiembre | 81 | 42 | 123 |
| 2024 Agosto | 135 | 70 | 205 |
| 2024 Julio | 95 | 46 | 141 |
| 2024 Junio | 85 | 44 | 129 |
| 2024 Mayo | 54 | 46 | 100 |
| 2024 Abril | 72 | 40 | 112 |
| 2024 Marzo | 76 | 38 | 114 |
| 2024 Febrero | 70 | 46 | 116 |
| 2024 Enero | 64 | 47 | 111 |
| 2023 Diciembre | 64 | 29 | 93 |
| 2023 Noviembre | 99 | 37 | 136 |
| 2023 Octubre | 89 | 49 | 138 |
| 2023 Septiembre | 78 | 46 | 124 |
| 2023 Agosto | 59 | 33 | 92 |
| 2023 Julio | 66 | 42 | 108 |
| 2023 Junio | 64 | 26 | 90 |
| 2023 Mayo | 84 | 24 | 108 |
| 2023 Abril | 48 | 38 | 86 |
| 2023 Marzo | 63 | 34 | 97 |
| 2023 Febrero | 71 | 29 | 100 |
| 2023 Enero | 68 | 32 | 100 |
| 2022 Diciembre | 73 | 43 | 116 |
| 2022 Noviembre | 41 | 31 | 72 |
| 2022 Octubre | 35 | 34 | 69 |
| 2022 Septiembre | 31 | 43 | 74 |
| 2022 Agosto | 28 | 55 | 83 |
| 2022 Julio | 29 | 53 | 82 |
| 2022 Junio | 28 | 32 | 60 |
| 2022 Mayo | 50 | 55 | 105 |
| 2022 Abril | 59 | 44 | 103 |
| 2022 Marzo | 63 | 58 | 121 |
| 2022 Febrero | 46 | 28 | 74 |
| 2022 Enero | 45 | 48 | 93 |
| 2021 Diciembre | 41 | 44 | 85 |
| 2021 Noviembre | 43 | 61 | 104 |
| 2021 Octubre | 40 | 65 | 105 |
| 2021 Septiembre | 38 | 56 | 94 |
| 2021 Agosto | 55 | 55 | 110 |
| 2021 Julio | 26 | 49 | 75 |
| 2021 Junio | 33 | 41 | 74 |
| 2021 Mayo | 40 | 52 | 92 |
| 2021 Abril | 95 | 57 | 152 |
| 2021 Marzo | 77 | 32 | 109 |
| 2021 Febrero | 50 | 24 | 74 |
| 2021 Enero | 27 | 20 | 47 |
| 2020 Diciembre | 33 | 22 | 55 |
| 2020 Noviembre | 28 | 20 | 48 |
| 2020 Octubre | 32 | 12 | 44 |
| 2020 Septiembre | 29 | 7 | 36 |
| 2020 Agosto | 13 | 21 | 34 |
| 2020 Julio | 26 | 18 | 44 |
| 2020 Junio | 34 | 17 | 51 |
| 2020 Mayo | 17 | 17 | 34 |
| 2020 Abril | 28 | 17 | 45 |
| 2020 Marzo | 50 | 21 | 71 |
| 2020 Febrero | 8 | 5 | 13 |
| 2020 Enero | 4 | 4 | 8 |
| 2019 Diciembre | 8 | 4 | 12 |
| 2019 Noviembre | 4 | 9 | 13 |
| 2019 Septiembre | 8 | 8 | 16 |
| 2019 Agosto | 4 | 3 | 7 |
| 2019 Julio | 2 | 4 | 6 |
| 2019 Junio | 6 | 4 | 10 |
| 2019 Mayo | 1 | 31 | 32 |
| 2019 Abril | 1 | 12 | 13 |
| 2019 Marzo | 2 | 8 | 10 |
| 2019 Febrero | 0 | 3 | 3 |
| 2019 Enero | 4 | 0 | 4 |
| 2018 Diciembre | 2 | 0 | 2 |
| 2018 Noviembre | 1 | 0 | 1 |
| 2018 Octubre | 3 | 0 | 3 |
| 2018 Septiembre | 4 | 0 | 4 |
| 2018 Mayo | 0 | 4 | 4 |
| 2018 Marzo | 4 | 0 | 4 |
| 2018 Febrero | 42 | 6 | 48 |
| 2018 Enero | 37 | 8 | 45 |
| 2017 Diciembre | 51 | 9 | 60 |
| 2017 Noviembre | 26 | 11 | 37 |
| 2017 Octubre | 32 | 14 | 46 |
| 2017 Septiembre | 39 | 11 | 50 |
| 2017 Agosto | 57 | 24 | 81 |
| 2017 Julio | 48 | 7 | 55 |
| 2017 Junio | 72 | 43 | 115 |
| 2017 Mayo | 46 | 12 | 58 |
| 2017 Abril | 63 | 15 | 78 |
| 2017 Marzo | 44 | 17 | 61 |
| 2017 Febrero | 36 | 9 | 45 |
| 2017 Enero | 46 | 8 | 54 |
| 2016 Diciembre | 45 | 16 | 61 |
| 2016 Noviembre | 81 | 13 | 94 |
| 2016 Octubre | 73 | 15 | 88 |
| 2016 Septiembre | 134 | 16 | 150 |
| 2016 Agosto | 67 | 16 | 83 |
| 2016 Julio | 39 | 6 | 45 |
| 2016 Junio | 8 | 9 | 17 |
| 2016 Mayo | 5 | 10 | 15 |
| 2016 Abril | 6 | 10 | 16 |
| 2016 Marzo | 2 | 1 | 3 |
| 2016 Febrero | 6 | 1 | 7 |
| 2016 Enero | 11 | 19 | 30 |
| 2015 Diciembre | 7 | 2 | 9 |
| 2015 Noviembre | 14 | 7 | 21 |
| 2015 Octubre | 13 | 3 | 16 |
| 2015 Septiembre | 12 | 0 | 12 |
| 2015 Agosto | 15 | 1 | 16 |
| 2015 Julio | 92 | 117 | 209 |
| 2015 Junio | 72 | 14 | 86 |
| 2015 Mayo | 108 | 30 | 138 |
| 2015 Abril | 38 | 6 | 44 |
| 2015 Marzo | 33 | 6 | 39 |
| 2015 Febrero | 44 | 6 | 50 |
| 2015 Enero | 36 | 5 | 41 |
| 2014 Diciembre | 36 | 6 | 42 |
| 2014 Noviembre | 31 | 9 | 40 |
| 2014 Octubre | 52 | 2 | 54 |
| 2014 Septiembre | 36 | 3 | 39 |
| 2014 Agosto | 44 | 8 | 52 |
| 2014 Julio | 27 | 6 | 33 |
| 2014 Junio | 53 | 9 | 62 |
| 2014 Mayo | 61 | 13 | 74 |
| 2014 Abril | 44 | 7 | 51 |
| 2014 Marzo | 59 | 11 | 70 |
| 2014 Febrero | 51 | 14 | 65 |
| 2014 Enero | 44 | 16 | 60 |
| 2013 Diciembre | 49 | 14 | 63 |
| 2013 Noviembre | 45 | 8 | 53 |
| 2013 Octubre | 36 | 9 | 45 |
| 2013 Septiembre | 36 | 6 | 42 |
| 2013 Agosto | 24 | 5 | 29 |
| 2013 Julio | 19 | 6 | 25 |
| 2013 Junio | 11 | 10 | 21 |
| 2013 Mayo | 8 | 8 | 16 |
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