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
Corresponding author
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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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 9 | 12 | 21 |
| 2024 October | 65 | 57 | 122 |
| 2024 September | 81 | 42 | 123 |
| 2024 August | 135 | 70 | 205 |
| 2024 July | 95 | 46 | 141 |
| 2024 June | 85 | 44 | 129 |
| 2024 May | 54 | 46 | 100 |
| 2024 April | 72 | 40 | 112 |
| 2024 March | 76 | 38 | 114 |
| 2024 February | 70 | 46 | 116 |
| 2024 January | 64 | 47 | 111 |
| 2023 December | 64 | 29 | 93 |
| 2023 November | 99 | 37 | 136 |
| 2023 October | 89 | 49 | 138 |
| 2023 September | 78 | 46 | 124 |
| 2023 August | 59 | 33 | 92 |
| 2023 July | 66 | 42 | 108 |
| 2023 June | 64 | 26 | 90 |
| 2023 May | 84 | 24 | 108 |
| 2023 April | 48 | 38 | 86 |
| 2023 March | 63 | 34 | 97 |
| 2023 February | 71 | 29 | 100 |
| 2023 January | 68 | 32 | 100 |
| 2022 December | 73 | 43 | 116 |
| 2022 November | 41 | 31 | 72 |
| 2022 October | 35 | 34 | 69 |
| 2022 September | 31 | 43 | 74 |
| 2022 August | 28 | 55 | 83 |
| 2022 July | 29 | 53 | 82 |
| 2022 June | 28 | 32 | 60 |
| 2022 May | 50 | 55 | 105 |
| 2022 April | 59 | 44 | 103 |
| 2022 March | 63 | 58 | 121 |
| 2022 February | 46 | 28 | 74 |
| 2022 January | 45 | 48 | 93 |
| 2021 December | 41 | 44 | 85 |
| 2021 November | 43 | 61 | 104 |
| 2021 October | 40 | 65 | 105 |
| 2021 September | 38 | 56 | 94 |
| 2021 August | 55 | 55 | 110 |
| 2021 July | 26 | 49 | 75 |
| 2021 June | 33 | 41 | 74 |
| 2021 May | 40 | 52 | 92 |
| 2021 April | 95 | 57 | 152 |
| 2021 March | 77 | 32 | 109 |
| 2021 February | 50 | 24 | 74 |
| 2021 January | 27 | 20 | 47 |
| 2020 December | 33 | 22 | 55 |
| 2020 November | 28 | 20 | 48 |
| 2020 October | 32 | 12 | 44 |
| 2020 September | 29 | 7 | 36 |
| 2020 August | 13 | 21 | 34 |
| 2020 July | 26 | 18 | 44 |
| 2020 June | 34 | 17 | 51 |
| 2020 May | 17 | 17 | 34 |
| 2020 April | 28 | 17 | 45 |
| 2020 March | 50 | 21 | 71 |
| 2020 February | 8 | 5 | 13 |
| 2020 January | 4 | 4 | 8 |
| 2019 December | 8 | 4 | 12 |
| 2019 November | 4 | 9 | 13 |
| 2019 September | 8 | 8 | 16 |
| 2019 August | 4 | 3 | 7 |
| 2019 July | 2 | 4 | 6 |
| 2019 June | 6 | 4 | 10 |
| 2019 May | 1 | 31 | 32 |
| 2019 April | 1 | 12 | 13 |
| 2019 March | 2 | 8 | 10 |
| 2019 February | 0 | 3 | 3 |
| 2019 January | 4 | 0 | 4 |
| 2018 December | 2 | 0 | 2 |
| 2018 November | 1 | 0 | 1 |
| 2018 October | 3 | 0 | 3 |
| 2018 September | 4 | 0 | 4 |
| 2018 May | 0 | 4 | 4 |
| 2018 March | 4 | 0 | 4 |
| 2018 February | 42 | 6 | 48 |
| 2018 January | 37 | 8 | 45 |
| 2017 December | 51 | 9 | 60 |
| 2017 November | 26 | 11 | 37 |
| 2017 October | 32 | 14 | 46 |
| 2017 September | 39 | 11 | 50 |
| 2017 August | 57 | 24 | 81 |
| 2017 July | 48 | 7 | 55 |
| 2017 June | 72 | 43 | 115 |
| 2017 May | 46 | 12 | 58 |
| 2017 April | 63 | 15 | 78 |
| 2017 March | 44 | 17 | 61 |
| 2017 February | 36 | 9 | 45 |
| 2017 January | 46 | 8 | 54 |
| 2016 December | 45 | 16 | 61 |
| 2016 November | 81 | 13 | 94 |
| 2016 October | 73 | 15 | 88 |
| 2016 September | 134 | 16 | 150 |
| 2016 August | 67 | 16 | 83 |
| 2016 July | 39 | 6 | 45 |
| 2016 June | 8 | 9 | 17 |
| 2016 May | 5 | 10 | 15 |
| 2016 April | 6 | 10 | 16 |
| 2016 March | 2 | 1 | 3 |
| 2016 February | 6 | 1 | 7 |
| 2016 January | 11 | 19 | 30 |
| 2015 December | 7 | 2 | 9 |
| 2015 November | 14 | 7 | 21 |
| 2015 October | 13 | 3 | 16 |
| 2015 September | 12 | 0 | 12 |
| 2015 August | 15 | 1 | 16 |
| 2015 July | 92 | 117 | 209 |
| 2015 June | 72 | 14 | 86 |
| 2015 May | 108 | 30 | 138 |
| 2015 April | 38 | 6 | 44 |
| 2015 March | 33 | 6 | 39 |
| 2015 February | 44 | 6 | 50 |
| 2015 January | 36 | 5 | 41 |
| 2014 December | 36 | 6 | 42 |
| 2014 November | 31 | 9 | 40 |
| 2014 October | 52 | 2 | 54 |
| 2014 September | 36 | 3 | 39 |
| 2014 August | 44 | 8 | 52 |
| 2014 July | 27 | 6 | 33 |
| 2014 June | 53 | 9 | 62 |
| 2014 May | 61 | 13 | 74 |
| 2014 April | 44 | 7 | 51 |
| 2014 March | 59 | 11 | 70 |
| 2014 February | 51 | 14 | 65 |
| 2014 January | 44 | 16 | 60 |
| 2013 December | 49 | 14 | 63 |
| 2013 November | 45 | 8 | 53 |
| 2013 October | 36 | 9 | 45 |
| 2013 September | 36 | 6 | 42 |
| 2013 August | 24 | 5 | 29 |
| 2013 July | 19 | 6 | 25 |
| 2013 June | 11 | 10 | 21 |
| 2013 May | 8 | 8 | 16 |
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