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array:22 [ "pii" => "S2387020624003693" "issn" => "23870206" "doi" => "10.1016/j.medcle.2024.01.041" "estado" => "S300" "fechaPublicacion" => "2024-09-13" "aid" => "6580" "copyrightAnyo" => "2024" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Med Clin. 2024;163:232-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:19 [ "pii" => "S238702062400367X" "issn" => "23870206" "doi" => "10.1016/j.medcle.2024.03.013" "estado" => "S300" "fechaPublicacion" => "2024-09-13" "aid" => "6660" "copyright" => "Elsevier España, S.L.U." 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Layla Diab, Jaime Pavón, Carlos Carpio, Rodolfo Álvarez-Sala, María Concepción Prados" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Ester" "apellidos" => "Zamarrón" ] 1 => array:2 [ "nombre" => "Layla" "apellidos" => "Diab" ] 2 => array:2 [ "nombre" => "Jaime" "apellidos" => "Pavón" ] 3 => array:2 [ "nombre" => "Carlos" "apellidos" => "Carpio" ] 4 => array:2 [ "nombre" => "Rodolfo" "apellidos" => "Álvarez-Sala" ] 5 => array:2 [ "nombre" => "María Concepción" "apellidos" => "Prados" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775324002720" "doi" => "10.1016/j.medcli.2024.03.010" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775324002720?idApp=UINPBA00004N" ] ] "EPUB" => 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=> "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "224" "paginaFinal" => "231" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Valor del biomarcador tirosina quinasa 1 soluble tipo fms (sFLT-1) en el diagnóstico y pronóstico de la sepsis: una revisión sistemática" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2440 "Ancho" => 1200 "Tamanyo" => 93102 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Flowchart of the study selection process according to the <span class="elsevierStyleItalic">Preferred Reporting Items for Systematic Reviews and Meta-analyses</span> (PRISMA) guidelines.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Miguel Javier Ugalde, Alberto Caballero, Marta Martín Fernández, Eduardo Tamayo, Olga de la Varga-Martínez" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Miguel Javier" "apellidos" => "Ugalde" ] 1 => array:2 [ "nombre" => "Alberto" "apellidos" => "Caballero" ] 2 => array:2 [ "nombre" => "Marta" "apellidos" => "Martín Fernández" ] 3 => array:2 [ "nombre" => "Eduardo" "apellidos" => "Tamayo" ] 4 => array:2 [ "nombre" => "Olga" "apellidos" => "de la Varga-Martínez" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775324002884" "doi" => "10.1016/j.medcli.2024.03.027" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775324002884?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020624003681?idApp=UINPBA00004N" "url" => "/23870206/0000016300000005/v1_202409110904/S2387020624003681/v1_202409110904/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Association between adipophilin expression and risk of dyslipidaemia in patients with granuloma annulare" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "232" "paginaFinal" => "237" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Javier Antoñanzas, Jorge María Núñez-Córdoba, Rafael Salido-Vallejo, Laura Álvarez-Gigli, Ramón Robledano, Agustín España" "autores" => array:6 [ 0 => array:3 [ "nombre" => "Javier" "apellidos" => "Antoñanzas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Jorge María" "apellidos" => "Núñez-Córdoba" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Rafael" "apellidos" => "Salido-Vallejo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Laura" "apellidos" => "Álvarez-Gigli" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "Ramón" "apellidos" => "Robledano" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 5 => array:4 [ "nombre" => "Agustín" "apellidos" => "España" "email" => array:1 [ 0 => "aespana@unav.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of Dermatology, University Clinic of Navarra, Pamplona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Research Support Service, Central Clinical Trials Unit, University Clinic of Navarra, Pamplona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Pathology, University Clinic of Navarra, Pamplona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Asociación entre la expresión de adipofilina y el riesgo de dislipidemia en pacientes con granuloma anular" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1127 "Ancho" => 1675 "Tamanyo" => 123292 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Risk of dyslipidaemia according to adipophilin expression in patients with GA. The risk for dyslipidaemia was clearly higher among the +ADPH staining group. These results showed statistical significance.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Granuloma annulare (GA) is characterized by a cutaneous reaction pattern of unknown origin, exhibiting a range of described disease associations and triggers, including infections, metabolic disorders, thyroid dysfunction, environmental antigens, and malignancy.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">1,2</span></a> Clinical manifestations present as erythematous circular papules or plaques, with a predominance of localized (LGA) lesions in 75% of cases, and less commonly, generalized (GGA) cutaneous involvement<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">3</span></a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Histologically, organized aggregates of histiocytes, frequently accompanied by mucin and exhibiting either a palisading or interstitial type of granulomatous inflammation, characterize GA.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">1,2</span></a> Numerous population-based cohort studies have established associations between GA and baseline type 2 diabetes, hyperlipidaemia, as well as both baseline and incident autoimmune conditions and hematologic malignant neoplasms.<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">4–7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">On the other hand, lipid droplets (LD) serve as intracellular storehouses of lipid esters, sequestered inside cells for subsequent use as metabolic fuel, membrane components, post-translational protein modifications, and cellular signalling. The PAT/perilipin family (Perilipin/perilipin-1, Adipophilin/perilipin-2, and TIP47/perilipin-3) comprises a group of proteins located on the surface phospholipid monolayer of the LD.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">8</span></a> The members of the mentioned PAT family exhibit distinct distribution patterns within the major metabolic tissues. Despite their sequence similarities, all PAT proteins share the capability to bind intracellular LD, either constitutively or in response to metabolic stimuli. Adipophilin, the most abundant LD-associated protein, is ubiquitously expressed across various cell types. Immunohistochemically, adipophilin appears as small LD in tissues under both physiological and pathological conditions,<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">9</span></a> typically not discernible by conventional light microscopy. It plays a crucial role in the formation and maintenance of intracellular LD, contributing to the regulation of physiological functions in the body.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">10</span></a> Additionally, positive adipophilin staining in tissues is recognized as a specific marker of lipid accumulation in diverse cell types and is considered a biomarker for metabolic dysregulation, irrespective of its underlying cause.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">12</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">While adipophilin has been detected in GA biopsies,<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">13</span></a> no studies have systematically analyzed adipophilin as a specific cutaneous marker of metabolic disorders in patients with GA. To fill this gap in knowledge, we conducted a clinical study to assess the relationship between the presence of adipophilin in GA biopsies and the risk of dyslipidaemia.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Data set source</span><p id="par0025" class="elsevierStylePara elsevierViewall">In this study, employing a combined cross-sectional and prospective design, we queried the database of the Department of Dermatology at a tertiary hospital to identify all cases of granuloma annulare (GA) diagnosed between January 1, 1990, and December 31, 2021. GA biopsies were obtained through searches in the Pathology Department database. The study received approval from the local Institutional Review Board, which waived the requirement for informed consent due to the utilization of only deidentified data.</p><p id="par0030" class="elsevierStylePara elsevierViewall">For each patient, the following information was collected: sex, age at diagnosis (≥18 years), GA type (LGA and GGA), disease progression, biopsy date, weight, height, body mass index (BMI), and blood lipid levels. The diagnoses of GA, LGA or GGA, and GA subtypes (palisaded GA [PGA] and interstitial GA [IGA]) were defined as reported elsewhere.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">1</span></a> Dyslipidemia was confirmed if one or more of the following criteria were met: elevated levels of cholesterol (>200<span class="elsevierStyleHsp" style=""></span>mg/dL), low-density lipoprotein cholesterol (LDL-C) (>130<span class="elsevierStyleHsp" style=""></span>mg/dL), triglycerides (>150<span class="elsevierStyleHsp" style=""></span>mg/dL), and/or reduced levels of high-density lipoprotein (HDL) (<40<span class="elsevierStyleHsp" style=""></span>mg/dL).<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">8</span></a> Only GA cases with complete information in the medical records, including GA lesion biopsies and clinical follow-up, were ultimately included in the analysis.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Immunohistochemical analysis</span><p id="par0035" class="elsevierStylePara elsevierViewall">The immunohistochemistry procedure was performed with a predilute polyclonal antibody to adipophilin (Cell Marque, Rocklin, CA).</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analysis</span><p id="par0040" class="elsevierStylePara elsevierViewall">We designated the date of GA biopsy as the reference date and assessed both cross-sectional and prospective associations between adipophilin and dyslipidemia in GA patients. For the cross-sectional analysis, we employed a logistic regression model to compute the odds ratio (OR) and the corresponding 95% confidence interval (95% CI). In the prospective assessment, person-months were calculated from the GA biopsy date to the date of incident dyslipidemia diagnosis or the last follow-up date, whichever occurred first. The relationship between adipophilin status and the risk of dyslipidemia was explored using the Kaplan–Meier method, and the log-rank test was applied. The Cox proportional hazards model was utilized to estimate the hazard ratio (HR) and the corresponding 95% CI over the entire follow-up period. All <span class="elsevierStyleItalic">p</span> values were two-sided, and values less than 0.05 were considered statistically significant. Stata version 14 (StataCorp LP, 2015, Stata Statistical Software: Release 14, College Station, Texas) was employed for all statistical analyses.</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Study cohort</span><p id="par0045" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> displays the baseline characteristics of the 107 patients included in the study, with 72% being women. The mean (SD) age was 50.4 (14.9) years. Patients had a mean (SD) BMI of 25.9 (4.6) kg/m<span class="elsevierStyleSup">2</span>. The median time from GA diagnosis was 5 months (<span class="elsevierStyleItalic">p</span>25: 2 months; <span class="elsevierStyleItalic">p</span>75: 12 months). The most prevalent clinical type was localized granuloma annulare (LGA), constituting 91.6% of cases (98 patients).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Histology and immunohistochemistry</span><p id="par0050" class="elsevierStylePara elsevierViewall">The histological results are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. The predominant histopathologic type was PGA, accounting for 75.7% of cases (81 patients). Positive adipophilin staining was observed in 72% of all patients. Demographic factors, BMI, and clinical findings exhibited similar distributions among patients with positive and negative adipophilin. However, the time from GA diagnosis was longer in patients with positive adipophilin (Median: 5 months; P25: 3 months; P75: 24 months) compared to those with negative adipophilin (Median: 3.5 months; P25: 2 months; P75: 12 months).</p><p id="par0055" class="elsevierStylePara elsevierViewall">The pattern of adipophilin expression varied based on the histologic subtype of GA. Adipophilin labelling in PGA was predominantly around granulomas, while a more diffuse pattern was observed in the interstitial variant. Notably, all cases exhibited both intracellular and extracellular staining of adipophilin (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><p id="par0060" class="elsevierStylePara elsevierViewall">The frequency of positive adipophilin in the interstitial and PGA subtypes was 50% and 79%, respectively. Patients with positive adipophilin staining were more likely to have PGA (83.1%) compared to patients with negative staining (56.7%) (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001). Additionally, positive adipophilin staining in LGA and GGA was 70% and 89%, respectively (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><p id="par0065" class="elsevierStylePara elsevierViewall">No statistically significant association was identified between the clinical form and the histological subtype.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Cross-sectional findings</span><p id="par0070" class="elsevierStylePara elsevierViewall">The cross-sectional study assessed the association between adipophilin status and the history of dyslipidemia. The prevalence of dyslipidemia in patients with positive adipophilin expression (62.3%) was significantly higher than in patients with negative adipophilin expression (13.3%). Relative to the dyslipidemia risk in patients with negative adipophilin labelling, the odds for study patients with positive adipophilin were increased 10-fold (OR: 10.8; 95% CI: 3.4; 33.9; <span class="elsevierStyleItalic">p</span>-value<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>; <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Prospective findings</span><p id="par0075" class="elsevierStylePara elsevierViewall">For the prospective study, we monitored 54 patients with no history of dyslipidaemia at the date of the GA biopsy. We identified 23 incident cases of dyslipidaemia over a median follow-up period of 91 months (totalling 4831 person-months). The overall incidence rate was 4.8 cases per 1000 person-months. Kaplan–Meier curves based on adipophilin status (positive or negative) are presented in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>. Adipophilin status was significantly associated with the risk of developing dyslipidaemia in patients with GA (log-rank test: <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001). Patients with positive adipophilin expression exhibited a higher risk of developing dyslipidaemia (HR: 8.9; 95% CI: 2.6, 30.0; <span class="elsevierStyleItalic">p</span>-value<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001) compared to the group with negative adipophilin staining (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">Previous observations have described an association between GA and metabolic dysfunction, primarily type 2 diabetes and dyslipidemia.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">1–4</span></a> Furthermore, adipophilin deposits have been identified as a specific biomarker for metabolic disorders.<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">10,11</span></a> However, recent findings indicate that adipophilin is strongly expressed not only in metabolic conditions but also in lipid-laden macrophages associated with atherosclerosis, cardiomyopathies, kidney diseases, hepatocyte steatosis, colon ischaemia, and organ infarcts.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">9</span></a> Consequently, elevated levels of adipophilin in the bloodstream are proposed to serve as a biomarker of inflammation.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">17</span></a> Hence, we postulated a potential correlation between the presence of adipophilin in GA biopsies and metabolic imbalance, specifically investigating its association with dyslipidaemia—a hypothesis not previously explored.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Traditionally, the identification of LD in tissue has been an indicator in the diagnoses of GA. Dabski and Winkelmann<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">3</span></a> initially reported this histological observation, noting the presence of LD in LGA and GGA in up to 45% and 37% of cases, respectively. This description employed Oil Red staining on frozen sections, as paraffin inclusion typically alters sample integrity. The authors observed bright red staining localized in fine, scattered droplets within histiocytes, not extending beyond the cellular aggregates of a granuloma. An alternative method for investigating lipid presence in tissue is adipophilin staining, which targets the most abundant protein of the surface phospholipid monolayer of LD and may preserve during processing. Schulman and LeBoit<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">13,14</span></a> documented adipophilin expression in GA, analysing 19 patients and reporting a frequency of approximately 80% of positivity, with adipophilin deposits both inside and outside of cellular aggregates. In our study, with a larger sample size, positive adipophilin staining was observed also both inside and outside, and the positivity rate was 72% of all the GA biopsies (70% in LGA and 89% in GGA). Although the significance of this double expression (intra- and extracellular) remains to be clarified, we suggest that the release of adipophilin to the extracellular space could contribute to amplifying the inflammatory response observed in GA. Furthermore, patients with positive adipophilin biopsies were more likely to have PGA (83.1%), compared with adipophilin negative patients (56.7%) (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.006), what could be related with the staining being more frequently observed when the granuloma is completely formed. Curiously, regarding its association with dyslipidaemia our findings revealed that those patients whose GA biopsy was positive for adipophilin, had a higher risk (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001). These results were observed consistently in both cross-sectional and longitudinal analyses. In GA formation, a delayed-type hypersensitivity reaction to an unknown antigen has been postulated as the precipitating event, with a Th1 inflammation reaction, TNF-α production, and elevation in both IFN-γ-producing and IL-2R-positive lymphocytes.<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">16-19</span></a> These lymphocytes may release several cytokines, such as macrophage inhibitory factor, with monocytes to accumulate within the dermis degrading connective tissue by releasing lysosomal enzymes. Interestingly, adipophilin promotes inflammation by increasing several pro-inflammatory cytokines (TNF-α, IL-6, monocyte chemoattractant protein 1)<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">20</span></a> and is correlated with the activated inflammatory state of monocytes in subjects with a low HDL-C,<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">21</span></a> a fact observed in patients with dyslipidaemia. Therefore, it is tentative to hypothesize that adipophilin might be involved in the amplification of the inflammatory response, in the pathogenesis of GA and in the appearance of metabolic imbalance.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">19</span></a> Straub et al.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">12</span></a> found that the numbers of adipophilin-positive LD are also increased in several clinical disorders, such as ischaemia, metabolic syndrome, and genetic diseases (glycogenosis), and concluded that up-regulation of adipophilin might be found in general conditions of metabolic dysregulation, irrespective of the specific cause.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">17</span></a> Furthermore, macrophages from adipophilin deficient mice displayed a reduced ability to become foam cells, and these mice were protected against atherosclerosis at the aortic sinus.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">22</span></a> Therefore, an attractive objective for the future might be to assess long term patients with positive adipophilin GA and evaluating their risk of developing cardiovascular disorders, atherosclerosis, or dysfunction in lipid storage in tissue, especially at the liver.<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">23,24</span></a> Thus, our results could support the staining for adipophilin in all GA biopsies to detect those patients with the highest risk for both basal and incident dyslipidaemia and potential to develop cardiovascular disease.</p><p id="par0090" class="elsevierStylePara elsevierViewall">The limitations of the study include the possibility of misclassification bias. This bias cannot be completely excluded despite the efforts to follow patients and confirm their dyslipidaemia diagnosis.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conclusions</span><p id="par0095" class="elsevierStylePara elsevierViewall">In summary, our findings show that patients with a positive adipophilin GA biopsy have a higher risk for both basal and incident dyslipidaemia. According to these results, the recommendation of screening and/or follow-up control for dyslipidaemia in GA patients with positive adipophilin could be justified. These findings may also inspire future investigations on the role of adipophilin in GA as a potential biomarker for other metabolic disorders.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Ethics disclosures</span><p id="par0100" class="elsevierStylePara elsevierViewall">The study received approval from the local Institutional Review Board, which waived the requirement for informed consent due to the utilization of only deidentified data.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Funding statement</span><p id="par0105" class="elsevierStylePara elsevierViewall">There is no funding to declare.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflict of interest</span><p id="par0110" class="elsevierStylePara elsevierViewall">All authors involved in this manuscript declare no conflicts of interest including financial interests, activities, relationships and relevant affiliations.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres2239486" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1873943" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2239485" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1873942" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Data set source" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Immunohistochemical analysis" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Study cohort" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Histology and immunohistochemistry" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Cross-sectional findings" ] 3 => array:2 [ "identificador" => "sec0050" "titulo" => "Prospective findings" ] ] ] 7 => array:2 [ "identificador" => "sec0055" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0060" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0065" "titulo" => "Ethics disclosures" ] 10 => array:2 [ "identificador" => "sec0070" "titulo" => "Funding statement" ] 11 => array:2 [ "identificador" => "sec0075" "titulo" => "Conflict of interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-10-04" "fechaAceptado" => "2024-01-22" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1873943" "palabras" => array:4 [ 0 => "Granuloma annulare" 1 => "Dyslipidemia" 2 => "Biomarker" 3 => "Metabolic disease" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1873942" "palabras" => array:4 [ 0 => "Granuloma anular" 1 => "Dislipemia" 2 => "Biomarcador" 3 => "Enfermedad metabólica" ] ] ] ] "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">An association between granuloma annulare (GA) and dyslipidaemia has been reported. Adipophilin expression may play a plausible role as a cutaneous biomarker for dyslipidaemia in patients with GA; however, this potential link remains to be explored.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Patients with GA were identified at our hospital between January 1, 1990, and December 31, 2021, with a thorough review of their clinical and histological characteristics. Adipophilin staining was assessed in biopsies of GA lesions.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of 107 patients with GA were included. The prevalence of dyslipidaemia in patients with positive adipophilin staining was clearly higher than in those with negative labelling (62.3% vs 13.3%). Relative to the dyslipidaemia risk for patients with negative adipophilin expression, the odds for patients with positive adipophilin expression were increased 10-fold (OR: 10.8; <span class="elsevierStyleItalic">p</span>-value<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.01). We identified 23 incident cases of dyslipidaemia over a median follow-up period of 91 months among 54 patients with no history of dyslipidaemia. The patients with positive adipophilin expression showed a higher risk of developing dyslipidaemia (HR: 8.9; <span class="elsevierStyleItalic">p</span>-value<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.01).</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Patients with positive adipophilin staining in their GA biopsies were found to be associated with a higher risk for both baseline and incident dyslipidaemia.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Se ha descrito una asociación entre el granuloma anular (GA) y la dislipidemia. La expresión de adipofilina en las biopsias de GA podría desempeñar un papel como biomarcador de riesgo de dislipidemia; sin embargo, este posible vínculo aún no ha sido explorado.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se identificaron pacientes con GA en nuestro hospital entre el 1 de enero de 1990 y el 31 de diciembre de 2021, mediante una revisión exhaustiva de sus características clínicas e histológicas. Se evaluó la tinción de adipofilina en las biopsias de lesiones de GA.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron un total de 107 pacientes con GA. La prevalencia de dislipidemia en pacientes con tinción positiva de adipofilina fue notablemente mayor que en aquellos con tinción negativa (62,3% vs. 13,3%). En comparación con el riesgo de dislipidemia en pacientes con expresión negativa de adipofilina, las probabilidades para pacientes con expresión positiva de adipofilina aumentaron 10 veces (OR: 10,8; valor de p <<span class="elsevierStyleHsp" style=""></span>0,01). Identificamos 23 casos incidentes de dislipidemia durante un período de seguimiento medio de 91 meses entre 54 pacientes sin antecedentes de dislipidemia. Los pacientes con expresión positiva de adipofilina mostraron un mayor riesgo de desarrollar dislipidemia (HR: 8,9; valor de p <<span class="elsevierStyleHsp" style=""></span>0,01).</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se encontró que los pacientes con tinción positiva de adipofilina en sus biopsias de GA estaban asociados con un mayor riesgo tanto de dislipidemia basal como incidente.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2476 "Ancho" => 2175 "Tamanyo" => 911359 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Clinical, histological and immunohistochemical findings in GA biopsies. (a, b) Clinical forms of GA. Fine arrows indicating the lesions. (a) Localized and (b) generalized GA forms respectively. (c–e) Palisading GA. Graphical elements, circles and rectangles, emphasizing regions with a denser inflammatory infiltrate, and consequently enhancing the visibility of positive staining with adipophilin. (c) Palisading GA, with lymphohistiocytic inflammation surrounding central altered collagen with palisading histiocytes (haematoxylin–eosin stain; original magnification ×40). (d) Adipophilin staining showing labelling around of granulomatous lesions (original magnification ×40). (e) Close-up, with adipophilin labelling inside and outside of cells (original magnification ×100). (f–h) Interstitial GA. Graphical elements, circles and rectangles, emphasizing regions with a denser inflammatory infiltrate, and consequently enhancing the visibility of positive staining with adipophilin. (f) Histiocytes intercalate between the collagen bundles singularly or in small aggregates. Mucin is present (haematoxylin–eosin stain; original magnification ×40). (g) Diffuse adipophilin staining (original magnification ×60). (h) Close-up, showing both, inside and outside cells adipophilin labelling between collagen fibres (original magnification ×100).</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1127 "Ancho" => 1675 "Tamanyo" => 123292 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Risk of dyslipidaemia according to adipophilin expression in patients with GA. The risk for dyslipidaemia was clearly higher among the +ADPH staining group. These results showed statistical significance.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1015 "Ancho" => 1500 "Tamanyo" => 99598 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Kaplan–Meier curves according to adipophilin expression in patients with GA. Patients with +ADPH were diagnosed with incident dyslipidaemia much more frequently than the −ADPH group. This result also showed statistical significance.</p>" ] ] 3 => 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="spar0065" class="elsevierStyleSimplePara elsevierViewall">BMI, body mass index. GA, granuloma annulare. <span class="elsevierStyleItalic">p</span>25: 25th percentile. <span class="elsevierStyleItalic">p</span>75: 75th percentile. SD: standard deviation.</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-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Characteristic \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Participants with GA, no. (%)</th><th 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" scope="col"><span class="elsevierStyleItalic">p</span>-Value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th 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" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Total \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Negative adipophilin \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Positive adipophilin \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">N</span> \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">107 (100) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30 (28) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">77 (72) \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Age, mean (SD), y</span> \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50.4 (14.9) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">47.7 (18.7) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51.4 (13.1) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.328 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Women</span> \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">77 (72) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21 (70) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56 (73) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.813 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">BMI (SD), kg/m</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">2</span></span> \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25.9 (4.6) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25.5 (5.3) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26.1 (4.3) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.277 \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 " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Clinical presentation of GA</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Localized \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">98 (91.6) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29 (96.7) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">69 (89.6) \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 " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.440</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Generalized \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 (8.4) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (3.3) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (10.4) \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 " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Histopathologic type of GA</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Interstitial \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26 (24.3) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 (43.3) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 (16.9) \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 " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.006</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Palisading \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">81 (75.7) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17 (56.7) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 (83.1) \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 " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Time from GA diagnosis, median (p25; p75), months</span> \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (2; 12) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.5 (2; 12) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (3; 24) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.024 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3649981.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Baseline characteristics of patients with granuloma annulare.</p>" ] ] 4 => 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="spar0075" class="elsevierStyleSimplePara elsevierViewall">95% CI: 95% confidence interval. HR, hazard ratio. OR, odds ratio.</p>" "tablatextoimagen" => array:2 [ 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="\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" scope="col" style="border-bottom: 2px solid black">Cross-sectional analysis \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Prevalent cases of dyslipidaemia, no. (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Prevalent cases of dyslipidaemia in negative adipophilin patients with GA, no. (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Prevalent cases of dyslipidaemia in positive adipophilin patients with GA, no. (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">OR (95% CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-Value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></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="" 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">107 \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">52 (48.6) \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 (13.3) \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">48 (62.3) \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">10.8 (3.4; 33.9) \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"><span class="elsevierStyleBold"><0.001</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3649979.png" ] ] 1 => 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="\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" scope="col" style="border-bottom: 2px solid black">Prospective analysis \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Incident cases of dyslipidaemia, no. (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Incident cases of dyslipidaemia in negative adipophilin patients with GA, no. (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Incident cases of dyslipidaemia in positive adipophilin patients with GA, no. (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">HR (95% CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-Value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></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="" 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">54 \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">23 (42.6) \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">3 (12) \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">20 (69) \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">8.9 (2.6; 30.0) \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"><span class="elsevierStyleBold"><0.001</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3649980.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Association between adipophilin and dyslipidaemia in patients with granuloma annulare.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:24 [ 0 => array:3 [ "identificador" => "bib0125" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Granuloma annulare: clinical and histologic variants, epidemiology, and genetics" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "E.W. 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