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"documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Med Clin. 2015;145:545-50" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Diagnosis and treatment</span>" "titulo" => "Update of treatment in chronic heart failure" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "545" "paginaFinal" => "550" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Actualización en las estrategias terapéuticas de la insuficiencia cardiaca crónica" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Jesús Casado Cerrada, Vicente Gómez del Olmo, Luis Manzano" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Jesús" "apellidos" => "Casado Cerrada" ] 1 => array:2 [ "nombre" => "Vicente" "apellidos" => "Gómez del Olmo" ] 2 => array:2 [ "nombre" => "Luis" "apellidos" => "Manzano" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775315003590" "doi" => "10.1016/j.medcli.2015.06.009" "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/S0025775315003590?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020616300468?idApp=UINPBA00004N" "url" => "/23870206/0000014500000012/v1_201605120032/S2387020616300468/v1_201605120032/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2387020616300444" "issn" => "23870206" "doi" => "10.1016/j.medcle.2016.04.022" "estado" => "S300" "fechaPublicacion" => "2015-12-21" "aid" => "3328" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Med Clin. 2015;145:535-8" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Special article</span>" "titulo" => "Knowledge of health outcomes generated by drugs in the real world: Temporary fashion or real need?" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "535" "paginaFinal" => "538" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Conocimiento de los resultados en salud generados por los medicamentos en el mundo real: ¿moda pasajera o necesidad real?" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Javier Soto Álvarez" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Javier" "apellidos" => "Soto Álvarez" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775315002973" "doi" => "10.1016/j.medcli.2015.04.027" "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/S0025775315002973?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020616300444?idApp=UINPBA00004N" "url" => "/23870206/0000014500000012/v1_201605120032/S2387020616300444/v1_201605120032/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "IgG4-related disease" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "539" "paginaFinal" => "544" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Juan González-Moreno, Inés Losada López, Norberto Ortego Centeno" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Juan" "apellidos" => "González-Moreno" "email" => array:1 [ 0 => "juan.glzmr@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Inés" "apellidos" => "Losada López" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Norberto" "apellidos" => "Ortego Centeno" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Son Llàtzer, Palma de Mallorca, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Unidad de Enfermedades Autoinmunes Sistémicas, Hospital Clínico San Cecilio, Granada, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Enfermedad relacionada con IgG4" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">IgG4-related disease (IgG4-RD) is a clinicopathological entity recently described with a wide spectrum of clinical manifestations.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">1</span></a> The presence of high serum IgG4 levels was associated with many IgG4-positive lymphoplasmacytic cells in samples from patients with autoimmune pancreatitis (AIP)<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">2</span></a> in 2001. Since then, there is growing interest in the participation of this molecule in various autoimmune/inflammatory disease. A Japanese group first suggested the IgG4-RD as a new clinicopathological entity with systemic involvement when they observed 8 AIP patients with the same histopathological pattern in other organs such as bile ducts, gastric mucosa, salivary glands or lymph nodes.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">3</span></a> In recent years the number of publications related to the disease has been growing exponentially. Although several names have been used (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), the nomenclature most widely accepted is IgG4-RD.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">4</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Involvement of virtually any organ has been reported,<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">5</span></a> being involvement of healthy tissue by swollen masses characteristic and they can often be confused with malignant processes.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The purpose of this review is to approach the clinician to the fundamental concepts of the etiopathogenesis and histopathology of the IgG4-RD and describe the clinical features and treatment strategies.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Etiopathogenesis</span><p id="par0020" class="elsevierStylePara elsevierViewall">The etiopathogenesis of IgG4-RD remains poorly elucidated, and one of the great unknowns is the role of the immunoglobulin associated with the disease. IgG4 is the rarest immunoglobulin G subtype, comprising 1–4% and its role is poorly understood. Its capability to activate the classical complement pathway is poor, and thus effective inflammatory response is low.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">6</span></a> The potential anti-inflammatory role of IgG4 suggests that its presence is a response to an unknown inflammatory stimulus, although its potential to generate an inflammatory response has not been ruled out.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">1</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Although it has not been fully proven, the hypothesis that IgG4-RD is induced by autoimmune phenomena appears to be the most accepted. Autoreactivity of IgG4 molecule against the epithelial tissue of pancreatic, bile and salivary gland ducts in patients with AIP has been reported, as well as several autoantibodies against several targets (carbonic anhydrase, lactoferrin, trypsinogens)<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">7,8</span></a> in AIP patients, with uncertain meaning in the pathophysiology of the disease.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The immunological mechanism involved in the pathogenesis of IgG4-RD appears to be mediated by a Th2 lymphocyte response. Cytokines released by these cells have increased in tissues involved, including interleukins 4, 5, 10 and 13.<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">9</span></a> The presence of eosinophilia and elevated serum IgE levels, present in up to 40% of patients with IgG4-RD, is also mediated by Th2 cytokines.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Another immunological feature in IgG4-RD is activation of regulatory T cells<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">9</span></a> unlike other autoimmune diseases in which the activity of these cells is decreased.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">10</span></a> These cells have been associated with increased expression of transforming growth factor β which might play a core role in causing fibrosis in IgG4-RD.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Histopathology</span><p id="par0040" class="elsevierStylePara elsevierViewall">Histopathology represents the cornerstone for the diagnosis of IgG4-RD and has played a key role in the recognition of IgG4-RD as a systemic disease. There are 3 major morphological features (dense lymphoplasmacytic infiltrate, storiform pattern fibrosis and obliterative phlebitis), which sometimes can be accompanied by a mild or moderate eosinophilic infiltrate and non-obliterative phlebitis.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">12</span></a> The inflammatory infiltrate consists predominantly of T lymphocytes, although there are also B lymphocytes, occasionally organized in germinal centers.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">12</span></a> The presence of plasma cells is characteristic and sometimes they can be predominant.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">12</span></a> Two extraordinary findings virtually rule out IgG4-RD: the presence of granulomas and the presence of neutrophilic infiltrate.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">12</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Histological analysis must be accompanied by an immunohistochemical confirmation. Since in other processes cells positive to IgG4 immunostaining<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">12</span></a> have been reported (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>), it is important to perform a quantitative analysis of these cells. The number of IgG4-positive cells found in tissues with IgG4-RD ranges from >10 and >200 cells per field and depends on the tissue analyzed.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">12</span></a> Another tool that has been suggested for diagnosing the disease is the IgG4 positive plasma cell/IgG positive plasma cell ratio. A ratio >40% would be suggestive of IgG4-RD.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">13</span></a> During the International Symposium on IgG4-RD in Boston in 2011 a consensus was reached on the histopathology of the disease and the histopathological terminology for IgG4-RD<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">12</span></a> was proposed, as summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical manifestations</span><p id="par0050" class="elsevierStylePara elsevierViewall">The type patient with IgG4-RD is a middle-aged and elderly male with, either simultaneous or progressive systemic involvement.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">1</span></a> Clinical presentation is subacute, and constitutional symptoms such as fever or weight loss are rare. Many patients report a history of rhinitis, asthma, nasal polyps or atopy<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">1</span></a> and involvement of virtually every organ has been reported<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">5,14</span></a> (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Pancreatic involvement was first described, considering today type 1 autoimmune pancreatitis the prototype disease.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">2</span></a> It occurs in 41% IgG4-RD patients.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">5</span></a> The symptoms most frequently reported are jaundice, abdominal pain, pruritus, steatorrhea and diabetes.<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">15</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Involvement of salivary glands is also frequent.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">5</span></a> Both forms of presentation are those previously known as Mikulicz disease and Küttner tumor. The first form has been reported as painless, idiopathic, bilateral and symmetrical inflammation of lacrimal, parotid and submandibular glands.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">16</span></a> The second presentation form is chronic sclerosing sialadenitis affecting submandibular glands.<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">17</span></a> The most common clinical manifestations are dry syndrome and gland inflammation.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Ocular involvement is mainly divided into two entities: chronic sclerosing dacryoadenitis and idiopathic orbital inflammation.<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">18,19</span></a> The latter has been described as idiopathic masses, which can affect lacrimal glands, extraocular muscles, intraocular uvea, optic nerve, superior orbital fissure, cavernous sinus and orbital fat.<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">20</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The presence of systemic or localized lymphadenopathies adjacent to the specific organ involved is frequent.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">5</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">As for the involvement of the bile duct it should be noted that 83% patients with sclerosing cholangitis also have AIP.<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">21,22</span></a> The most common clinical manifestations are obstructive jaundice, weight loss and mild abdominal discomfort.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">23</span></a> Gallbladder involvement has also been reported, generally as asymptomatic cholecystitis.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">5</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Clinical manifestations of liver disease are similar to those of autoimmune hepatitis.<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">24</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The most common manifestation of thyroid is hypothyroidism<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">25</span></a> in the form of Riedel's or Hashimoto's thyroiditis.<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">26</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The most common forms of renal involvement are proteinuria, hematuria or kidney damage<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">27</span></a> by kidney pseudotumors<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">28</span></a> with anatomical pathology consistent with tubulointerstitial nephritis with or without glomerular involvement in the form of membranous nephritis.<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">29</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">More than half of patients formerly diagnosed with idiopathic retroperitoneal fibrosis (Ormond fibrosis) can be classified today as IgG4-RD patients.<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">30</span></a> The most frequent clinical manifestations are lumbar pain and edema of lower limbs.<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">30</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">There are several pulmonary manifestations, and they can occur as pulmonary nodules, ground-glass infiltrates, interstitial alveolar injury or bronchovascular thickening. Most patients are asymptomatic, but the disease can cause cough, dyspnea, hemoptysis, or chest pain.<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">31</span></a> The pleura might also be affected in patients with pulmonary manifestations, mainly as pleural effusion or nodular pleural thickening.<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">15</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The aortic involvement is the most frequent vascular involvement. It can occur as an incidental finding on imaging tests or as aortic dissection and sudden death from rupture.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">32</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Skin manifestations are rare. They have been described in the form of erythematous plaques and subcutaneous nodules mainly affecting head and neck.<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">33</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Neurological involvement is rare, preferably by meninges and cranial nerves in the form of pachymeningitis. The most common clinical manifestations are headache, cranial nerve palsies, impaired vision, motor weakness, hearing loss, dizziness and cognitive deficits.<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">34</span></a> Cases of hypophysitis related to IgG4-RD and secondary hypopituitarism have also been reported.<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">35</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Other rare manifestations reported have been prostate,<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">36</span></a> testicular,<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">37</span></a> mammary,<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">38</span></a> mediastinal<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">39</span></a> or pericardial manifestations.<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">40,41</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Diagnosis and differential diagnosis</span><p id="par0125" class="elsevierStylePara elsevierViewall">IgG4-RD diagnosis is mainly based on the histopathological findings described above (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>), accompanied by a compatible clinical context. Other diagnostic tools that can be useful are serum IgG4, radiological images or response to medical treatment.</p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Serum IgG4 levels</span><p id="par0130" class="elsevierStylePara elsevierViewall">One of the most discussed topics in the medical literature is the role of serum IgG4 levels in the diagnosis and monitoring of IgG4-RD. These levels are usually high in the disease. However, there is a variable frequency of individuals (up to 30%) with IgG4 normal levels confirmed by histology. Its role has been studied mainly in the AIP, where said role has been focused primarily on differentiation from pancreatic cancer. In a Japanese study it was seen that serum IgG4<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>135<span class="elsevierStyleHsp" style=""></span>mg/dl had a sensitivity and specificity of 95% and 97% to differentiate AIP from pancreatic cancer.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">2</span></a> In the cohort of the Mayo Clinic, where a cutoff point used for serum IgG4 is 140<span class="elsevierStyleHsp" style=""></span>mg/dl, specificity to differentiate AIP from pancreatic cancer and from controls was similar (90% and 93%, respectively). However, sensitivity was lower (76%).<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">43</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">More and more authors study the role of serum immunoglobulin measurement in other clinical manifestations of AIP. In a study recently published the authors found that the sensitivity (90%) and negative predictive value (96%) of serum IgG4 were high. However, their specificity (60%) and positive predictive value (34%) were insufficient.<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">44</span></a> Multiplying by two the cutoff of serum IgG4 or using the IgG4/IgG ratio in serum improved the overall characteristics of the test. Current evidence does not yield definitive conclusions about the role of serum IgG4 for diagnosis. However, their use in an appropriate clinical context, and particularly if the normal maximum value in serum is multiplied by two, can be useful.</p><p id="par0140" class="elsevierStylePara elsevierViewall">Another possible purpose of measuring IgG4 serum levels is to monitor disease activity and response to treatment. In this regard some studies have found conflicting results. For example, in some studies with few patients it was observed that serum IgG4 decreased to normal levels during the treatment with steroids.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">3</span></a> Khosroshahi et al.<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">45</span></a> found that serum IgG4 levels decreased after treatment with rituximab (RTX) in 10 IgG4-RD patients, and the 2 relapses recorded during follow-up were consistent with increased serum IgG4, showing their role in the etiopathogenesis and prognosis. However, in a Japanese multicenter study,<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">46</span></a> glucocorticoids only normalized serum IgG4 levels in 67 patients (36.8%) and clinical relapses were also observed in up to 10% patients with persistently normal IgG4 levels. Similar results were reported in the cohort of the Mayo Clinic where IgG4 levels were determined in 19 patients during steroid treatment, and in 11 of them (57.9%) these levels were normalized.<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">42</span></a> Therefore, to date, there is no sufficient evidence to justify the use of IgG4 levels in monitoring the disease.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Imaging studies</span><p id="par0145" class="elsevierStylePara elsevierViewall">Radiological images in IgG4-RD are non-specific and vary according to the organ involved. The characteristic behavior of infiltrative inflammatory disease in the form of swollen masses often makes it difficult to distinguish it from neoplastic processes through imaging. Other forms of manifestation can occur in lung, kidney or blood vessels. In lung, radiologic images may vary from solid nodular lesions to bronchovascular or interstitial alveolar patterns (with the presence of honeycomb and/or ground-glass images).<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">47</span></a> Kidneys may show hypodense nodular lesions, predominantly cortical, or diffuse patchy involvement.<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">48</span></a> Finally, vascular involvement in IgG4-RD mainly occurs in the aorta (both in thoracic and abdominal portion) and its main branches, where the characteristic image is the homogeneous thickening of the vascular wall.<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">49</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Response to treatment</span><p id="par0150" class="elsevierStylePara elsevierViewall">The response to steroid treatment is characteristic of AIP. Therefore, it is considered a diagnostic criterion in both Mayo Clinic criteria and Kim criteria (Korea).<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">50</span></a> In general, it seems that the extrapancreatic manifestations of IgG4-RD respond satisfactorily to treatment with glucocorticoids.<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">51</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Diagnostic criteria</span><p id="par0155" class="elsevierStylePara elsevierViewall">Currently there are no validated diagnostic criteria for IgG4-RD. While histopathologic criteria of the disease (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>) were agreed in 2011, many researchers have worked to develop diagnostic criteria that eliminate the need for histological study in all patients, particularly in organs of difficult access to biopsy (such as the aorta). For example, Okazaki et al. have proposed diagnostic criteria in which in addition to the major histopathological features of the disease, 2 other non-histological criteria have been added: the presence of diffuse or focal swelling in one or more organs and high IgG4 serum levels (>135<span class="elsevierStyleHsp" style=""></span>mg/dl).<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">52</span></a> Some similar criteria have been proposed by Carruthers et al., in order to homogenize patients to be included in clinical trials. They have also included a radiological criterion (typical radiological image of IgG4-RD), and have specified that serum IgG4 concentrations must be 1.5 times over the upper normal limit.<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">53</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">The differential diagnosis of IgG4-RD is large (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>), and will depend on the organ involved.<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">54</span></a></p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Treatment</span><p id="par0165" class="elsevierStylePara elsevierViewall">Treatment for IgG4-RD depends mainly on the symptomatology because, given the nature of the disease and its usual subacute and indolent features, in many cases the diagnosis will be a chance finding without significant organ impact. Occasionally, symptomatology may improve with no treatment.<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">55</span></a> Experience in the IgG4-RD treatment is extrapolated from studies focused mainly on AIP. In addition, the available evidence is based on observational retrospective studies, as there are no randomized controlled prospective studies published.</p><p id="par0170" class="elsevierStylePara elsevierViewall">Glucocorticoids represent the cornerstone of treatment for IgG4-RD.<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">51</span></a> These have been proven effective in AIP, obtaining better rates of clinical remission, reducing the time to remission and improving pancreatic exocrine function.<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">56</span></a> It has also been seen that maintaining low doses of glucocorticoids in AIP can prevent recurrence.<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">46</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">The most accepted glucocorticoid treatment schedule has been published in a Japanese consensus on AIP treatment.<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">57</span></a> Initial dose of prednisone 0.6<span class="elsevierStyleHsp" style=""></span>mg/kg/day, maintained from 2 to 4 weeks, is recommended to then gradually decrease 5<span class="elsevierStyleHsp" style=""></span>mg every 1–2 weeks and reach, after 2–3 months, a 2–5<span class="elsevierStyleHsp" style=""></span>mg maintenance dose.<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">57</span></a> This dosage can be maintained for years depending on the clinical evolution.<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">57</span></a> At these doses relapse rate published is approximately 25%, despite maintenance treatment.<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">46</span></a> A similar initial treatment schedule but shorter (11 weeks) has been proposed by the Mayo Clinic group.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">23</span></a> However, with this regimen, the relapse rate is up to 50% after completion of steroid treatment.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">23</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Despite the initial response to steroid treatment, the clinical relapse rates published range from 26%<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">56</span></a> to 92%,<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">46</span></a> risk of recurrence increasing with time,<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">46</span></a> especially if glucocorticoids are discontinued.<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">56</span></a> These rates of relapse, along with the adverse effects of glucocorticoids, particularly in elderly population, require the search for new therapeutic approaches using other immunosuppressive drugs. However, to date, due to the rarity of the disease, there is little evidence to support the use of these drugs, and recommendations are based primarily on published experience in clinical cases or retrospective series.</p><p id="par0185" class="elsevierStylePara elsevierViewall">The use of azathioprine (AZA) or mycophenolate mofetil (MMF) is extrapolated from the experience in other autoimmune diseases such as autoimmune hepatitis. In the experience of the Mayo Clinic, the 6 patients who relapsed after withdrawal of glucocorticoids and were treated with these drugs in monotherapy (4 with AZA, 2 with MMF), remained in remission during the follow-up period (average of 6 months).<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">23</span></a> In a multicenter study recently published, AZA was used in 68 patients with relapsed AIP after the withdrawal of glucocorticoids, being effective in inducing remission in 56 patients (85%).<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">14</span></a> In this same study MMF was used in 8 patients and cyclosporine in 3, with an overall response rate of 86%.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">14</span></a> However, in another study published by Hart et al.,<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">58</span></a> remission rates in patients with relapsed AIP were 23% and 27% in patients treated with AZA (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>31) and MMF (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>11), respectively.</p><p id="par0190" class="elsevierStylePara elsevierViewall">RTX is postulated as a promising drug in IgG4-RD due to the results obtained with this chimeric monoclonal antibody. Khosroshahi et al.<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">45</span></a> have published their experience with the use of RTX in 10 IgG4-RD patients. 90% patients showed clinical response after the first month of treatment. In addition, these 10 patients could discontinue prednisone and the associated immunosuppressive therapy.<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">45</span></a> In this paper it was also noted that the RTX helped decrease IgG4 levels to normal values in 80% patients, a decline that did not happen in other subclasses of IgG. The 2 patients who did not normalize serum IgG4 had clinical relapse and increased immunoglobulin.<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">45</span></a> Currently, there is an ongoing clinical trial intended to deepen the understanding of the efficacy and safety of RTX in IgG4-RD (ClinicalTrials.gov: <a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01584388">NCT01584388</a>).</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conclusions</span><p id="par0195" class="elsevierStylePara elsevierViewall">IgG4-RD is a multisystemic inflammatory disease, etiology still unclarified, whose clinical spectrum includes multiple syndromes previously considered as idiopathic and organ-specific. Its prevalence and incidence are poorly known, and probably underestimated, since it is a disease recently reported. However, in recent years, there has been growing interest in its study. Its most characteristic manifestation is inflammatory tumors in various organs, frequently associated with high serum IgG4 levels, which share a common characteristic histology. Treatment is based mainly on glucocorticoids. However, the use of other drugs, particularly RTX, is increasing.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflict of interests</span><p id="par0200" class="elsevierStylePara elsevierViewall">The authors report no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres635248" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec647760" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres635249" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec647759" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Etiopathogenesis" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Histopathology" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Clinical manifestations" ] 8 => array:3 [ "identificador" => "sec0025" "titulo" => "Diagnosis and differential diagnosis" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Serum IgG4 levels" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Imaging studies" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Response to treatment" ] 3 => array:2 [ "identificador" => "sec0045" "titulo" => "Diagnostic criteria" ] ] ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Treatment" ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusions" ] 11 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflict of interests" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-10-28" "fechaAceptado" => "2014-12-19" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec647760" "palabras" => array:2 [ 0 => "IgG4-related disease" 1 => "Autoimmune pancreatitis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec647759" "palabras" => array:2 [ 0 => "Enfermedad relacionada con IgG4" 1 => "Pancreatitis autoinmune" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">IgG4-related disease is a recently described clinicopathological entity showing a wide spectrum of clinical manifestations that share a common pathology. Its most characteristic feature is the formation of inflammatory tumors in different organs, which makes differentiation mainly with neoplastic diseases fundamental. The inflammatory process is typically comprised of IgG4 lymphoplasmacytic cells. The pathophysiological role of the immunoglobulin is not clear. The treatment of choice is corticosteroids. This article aims to summarize the main features of the disease.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La enfermedad relacionada con IgG4 es una entidad clínico-patológica descrita recientemente con un amplio espectro de manifestaciones clínicas que comparten una histopatología en común. Su manifestación más característica es la formación de tumores inflamatorios en diferentes órganos, lo que hace fundamental la diferenciación principalmente de enfermedades neoplásicas. Este fenómeno inflamatorio está compuesto característicamente por linfoplasmocitos productores de IgG4. El papel fisiopatogénico de la inmunoglobulina no está aclarado. El tratamiento de elección son los glucocorticoides. Este trabajo pretende resumir las principales características de la enfermedad.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Please cite this article as: González-Moreno J, Losada López I, Ortego Centeno N. Enfermedad relacionada con IgG4. Med Clin (Barc). 2015;145:539–544.</p>" ] ] "multimedia" => array:5 [ 0 => array:9 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "<span class="elsevierStyleItalic">Source</span>: Modified from Stone et al.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">4</span></a>" "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "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-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IgG4-related systemic disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IgG4-related sclerosing disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IgG4-related disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IgG4 syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IgG4-related systemic sclerosing disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IgG4-related autoimmune disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hyper-IgG4 disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Systemic IgG4-related plasmacytic syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IgG4 positive multiorgan lymphoproliferative syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1042203.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Different nomenclature used for IgG4 related disease.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">ANCA: antineutrophil cytoplasmic antibodies.</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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Inflammatory diseases</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Primary sclerosing cholangitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>ANCA-associated vasculitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Rheumatoid arthritis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Inflammatory bowel disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Autoimmune atrophic gastritis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Lymphomas</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mainly from low-grade B cells \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Other neoplasms</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pancreatobiliary \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Oral cavity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Genitourinary \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Colon \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1042202.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Other pathologies with presence of IgG4-positive plasma cells.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "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-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">High suspicion of IgG4-RD (must meet each one of the 3 criteria) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(1) ≥2 of the major histopathological criteria<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dense lymphoplasmacytic infiltrate \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Storiform fibrosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Obliterative phlebitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="2" align="left" valign="top">(2) Quantification of IgG4 cells: 10–200 cells per field depending on tissue<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a></td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="2" align="left" valign="top">(3) IgG4/IgG cell ratio<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>40%<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Probable IgG4-RD<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a> (either 3 situations) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="2" align="left" valign="top">(a) A major histological criterion and consistent immunohistochemistry</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="2" align="left" valign="top">(b) Those biopsies with fine needle</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="2" align="left" valign="top">(c) Meningeal and cutaneous disease (little data published)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Insufficient evidence of IgG4-RD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="2" align="left" valign="top">Cases not included in the above groups</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1042205.png" ] ] ] "notaPie" => array:4 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Except in lacrimal gland where only one finding is required because there is usually no fibrosis and no obliterative phlebitis.</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">>10 in meninges, pancreas (biopsy), bile ducts (biopsy), liver (biopsy) and kidney (biopsy); >20 in lung (biopsy); >30 in kidney (surgical specimen) and retroperitoneum; >50 in lung (surgical specimen), pleura, pancreas (surgical specimen), bile ducts (surgical specimen), liver (surgical specimen), aorta; >100 in salivary and lacrimal glands and lymph nodes; >200 in skin.</p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Except in aorta where ratio is considered as >50%.</p>" ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Data such as serum IgG4<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>135<span class="elsevierStyleHsp" style=""></span>mg/dl or involvement of any other organ (through radiological technique or physical examination) would support the diagnosis.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Terminology recommended to describe the histopathological patterns of IgG4-related disease (IgG4-RD).</p>" ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Organ/tissue involved (% patients<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">a</span></a>) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Nomenclature accepted<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pancreas (41) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Type 1 autoimmune pancreatitis or IgG4-related pancreatitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Salivary glands (40) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related dacryoadenitis; IgG4-related mumps; IgG4-related sialadenitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Eye (29) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related ocular disease; IgG4-related Dacryoadenitis; IgG4-related orbital inflammation (or orbital inflammatory pseudotumor associated with IgG4); IgG4-related orbital myositis; IgG4-related pan-orbital inflammation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lymph nodes (26) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related lymphadenopathy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bile duct (19.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related sclerosing cholangitis; IgG4-related cholecystitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Thyroid (19) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related thyroiditis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kidney (13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related kidney disease; tubulointerstitial nephritis secondary to IgG4-related disease; membranous glomerulonephritis secondary to IgG4-related disease; IgG4-related pielitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Retroperitoneum (13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related retroperitoneal fibrosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lung (12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related lung disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Aorta (9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related aortitis/periaortitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Liver (<5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related liver disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pleura (<5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related pleuritis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Prostate (<5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related prostatitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Breast (<5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related mastitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Skin (<5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related skin disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mediastinium (<5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related mediastinitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Meninges (<5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related pachymeningitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypophysis (<5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related hypophysitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pericardium (<5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG4-related pericarditis \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1042206.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Percentages according to the cases reported in the literature, and obtained from Brito-Zerón et al.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">5</span></a></p>" ] 1 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Nomenclature accepted during the international symposium on IgG4-related disease in 2011 (Stone et al.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">4</span></a>).</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Organs and tissues involved in IgG4-related disease and nomenclature accepted.</p>" ] ] 4 => array:8 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at5" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">ANCA, antineutrophil cytoplasmic antibodies; CMV, cytomegalovirus; EBV, Epstein–Barr virus; MALT, mucosa-associated lymphoid tissue; HBV, hepatitis B virus; HCV, hepatitis C; HIV, human immunodeficiency virus.</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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Neoplastic diseases</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lymphomas (including MALT lymphomas) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Other solid neoplasms (depending on the organ involved) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Infectious diseases</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Viruses (HIV, CMV, EBV, HCV, HBV, etc.) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Bacteria (<span class="elsevierStyleItalic">Treponema pallidum</span>, <span class="elsevierStyleItalic">Coxiella</span>, etc.) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mycobacteria (<span class="elsevierStyleItalic">Mycobacterium tuberculosis</span>, nontuberculous mycobacteria) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Other (parasites, fungi) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Autoimmune/inflammatory diseases</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Sarcoidosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Large vessel vasculitis (Takayasu arteritis and giant cell arteritis) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Vasculitis ANCA+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Behçet's disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Systemic lupus erythematosus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Autoimmune hepatitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Primary biliary cirrhosis \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1042204.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Differential diagnosis of IgG4-related disease.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:58 [ 0 => array:3 [ "identificador" => "bib0295" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "IgG4-related disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.H. 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