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Review
IgG4-related disease
Enfermedad relacionada con IgG4
Juan González-Morenoa,
Corresponding author
juan.glzmr@gmail.com

Corresponding author.
, Inés Losada Lópeza, Norberto Ortego Centenob
a Servicio de Medicina Interna, Hospital Son Llàtzer, Palma de Mallorca, Spain
b Unidad de Enfermedades Autoinmunes Sistémicas, Hospital Clínico San Cecilio, Granada, Spain
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    "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 &#40;IgG4-RD&#41; is a clinicopathological entity recently described with a wide spectrum of clinical manifestations&#46;<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 &#40;AIP&#41;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">2</span></a> in 2001&#46; Since then&#44; there is growing interest in the participation of this molecule in various autoimmune&#47;inflammatory disease&#46; 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&#44; gastric mucosa&#44; salivary glands or lymph nodes&#46;<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&#46; Although several names have been used &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; the nomenclature most widely accepted is IgG4-RD&#46;<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&#44;<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&#46;</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&#46;</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&#44; and one of the great unknowns is the role of the immunoglobulin associated with the disease&#46; IgG4 is the rarest immunoglobulin G subtype&#44; comprising 1&#8211;4&#37; and its role is poorly understood&#46; Its capability to activate the classical complement pathway is poor&#44; and thus effective inflammatory response is low&#46;<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&#44; although its potential to generate an inflammatory response has not been ruled out&#46;<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&#44; the hypothesis that IgG4-RD is induced by autoimmune phenomena appears to be the most accepted&#46; Autoreactivity of IgG4 molecule against the epithelial tissue of pancreatic&#44; bile and salivary gland ducts in patients with AIP has been reported&#44; as well as several autoantibodies against several targets &#40;carbonic anhydrase&#44; lactoferrin&#44; trypsinogens&#41;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">7&#44;8</span></a> in AIP patients&#44; with uncertain meaning in the pathophysiology of the disease&#46;</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&#46; Cytokines released by these cells have increased in tissues involved&#44; including interleukins 4&#44; 5&#44; 10 and 13&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">9</span></a> The presence of eosinophilia and elevated serum IgE levels&#44; present in up to 40&#37; of patients with IgG4-RD&#44; is also mediated by Th2 cytokines&#46;</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&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">10</span></a> These cells have been associated with increased expression of transforming growth factor &#946; which might play a core role in causing fibrosis in IgG4-RD&#46;<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&#46; There are 3 major morphological features &#40;dense lymphoplasmacytic infiltrate&#44; storiform pattern fibrosis and obliterative phlebitis&#41;&#44; which sometimes can be accompanied by a mild or moderate eosinophilic infiltrate and non-obliterative phlebitis&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">12</span></a> The inflammatory infiltrate consists predominantly of T lymphocytes&#44; although there are also B lymphocytes&#44; occasionally organized in germinal centers&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">12</span></a> The presence of plasma cells is characteristic and sometimes they can be predominant&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">12</span></a> Two extraordinary findings virtually rule out IgG4-RD&#58; the presence of granulomas and the presence of neutrophilic infiltrate&#46;<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&#46; Since in other processes cells positive to IgG4 immunostaining<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">12</span></a> have been reported &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; it is important to perform a quantitative analysis of these cells&#46; The number of IgG4-positive cells found in tissues with IgG4-RD ranges from &#62;10 and &#62;200 cells per field and depends on the tissue analyzed&#46;<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&#47;IgG positive plasma cell ratio&#46; A ratio &#62;40&#37; would be suggestive of IgG4-RD&#46;<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&#44; as summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46;</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&#44; either simultaneous or progressive systemic involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">1</span></a> Clinical presentation is subacute&#44; and constitutional symptoms such as fever or weight loss are rare&#46; Many patients report a history of rhinitis&#44; asthma&#44; 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&#44;14</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Pancreatic involvement was first described&#44; considering today type 1 autoimmune pancreatitis the prototype disease&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">2</span></a> It occurs in 41&#37; IgG4-RD patients&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">5</span></a> The symptoms most frequently reported are jaundice&#44; abdominal pain&#44; pruritus&#44; steatorrhea and diabetes&#46;<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&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">5</span></a> Both forms of presentation are those previously known as Mikulicz disease and K&#252;ttner tumor&#46; The first form has been reported as painless&#44; idiopathic&#44; bilateral and symmetrical inflammation of lacrimal&#44; parotid and submandibular glands&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">16</span></a> The second presentation form is chronic sclerosing sialadenitis affecting submandibular glands&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">17</span></a> The most common clinical manifestations are dry syndrome and gland inflammation&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Ocular involvement is mainly divided into two entities&#58; chronic sclerosing dacryoadenitis and idiopathic orbital inflammation&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">18&#44;19</span></a> The latter has been described as idiopathic masses&#44; which can affect lacrimal glands&#44; extraocular muscles&#44; intraocular uvea&#44; optic nerve&#44; superior orbital fissure&#44; cavernous sinus and orbital fat&#46;<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&#46;<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&#37; patients with sclerosing cholangitis also have AIP&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">21&#44;22</span></a> The most common clinical manifestations are obstructive jaundice&#44; weight loss and mild abdominal discomfort&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">23</span></a> Gallbladder involvement has also been reported&#44; generally as asymptomatic cholecystitis&#46;<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&#46;<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&#39;s or Hashimoto&#39;s thyroiditis&#46;<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&#44; 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&#46;<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 &#40;Ormond fibrosis&#41; can be classified today as IgG4-RD patients&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">30</span></a> The most frequent clinical manifestations are lumbar pain and edema of lower limbs&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">30</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">There are several pulmonary manifestations&#44; and they can occur as pulmonary nodules&#44; ground-glass infiltrates&#44; interstitial alveolar injury or bronchovascular thickening&#46; Most patients are asymptomatic&#44; but the disease can cause cough&#44; dyspnea&#44; hemoptysis&#44; or chest pain&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">31</span></a> The pleura might also be affected in patients with pulmonary manifestations&#44; mainly as pleural effusion or nodular pleural thickening&#46;<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&#46; It can occur as an incidental finding on imaging tests or as aortic dissection and sudden death from rupture&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">32</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Skin manifestations are rare&#46; They have been described in the form of erythematous plaques and subcutaneous nodules mainly affecting head and neck&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">33</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Neurological involvement is rare&#44; preferably by meninges and cranial nerves in the form of pachymeningitis&#46; The most common clinical manifestations are headache&#44; cranial nerve palsies&#44; impaired vision&#44; motor weakness&#44; hearing loss&#44; dizziness and cognitive deficits&#46;<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&#46;<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&#44;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">36</span></a> testicular&#44;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">37</span></a> mammary&#44;<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&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">40&#44;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 &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#44; accompanied by a compatible clinical context&#46; Other diagnostic tools that can be useful are serum IgG4&#44; radiological images or response to medical treatment&#46;</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&#46; These levels are usually high in the disease&#46; However&#44; there is a variable frequency of individuals &#40;up to 30&#37;&#41; with IgG4 normal levels confirmed by histology&#46; Its role has been studied mainly in the AIP&#44; where said role has been focused primarily on differentiation from pancreatic cancer&#46; In a Japanese study it was seen that serum IgG4<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>135<span class="elsevierStyleHsp" style=""></span>mg&#47;dl had a sensitivity and specificity of 95&#37; and 97&#37; to differentiate AIP from pancreatic cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">2</span></a> In the cohort of the Mayo Clinic&#44; where a cutoff point used for serum IgG4 is 140<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#44; specificity to differentiate AIP from pancreatic cancer and from controls was similar &#40;90&#37; and 93&#37;&#44; respectively&#41;&#46; However&#44; sensitivity was lower &#40;76&#37;&#41;&#46;<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&#46; In a study recently published the authors found that the sensitivity &#40;90&#37;&#41; and negative predictive value &#40;96&#37;&#41; of serum IgG4 were high&#46; However&#44; their specificity &#40;60&#37;&#41; and positive predictive value &#40;34&#37;&#41; were insufficient&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">44</span></a> Multiplying by two the cutoff of serum IgG4 or using the IgG4&#47;IgG ratio in serum improved the overall characteristics of the test&#46; Current evidence does not yield definitive conclusions about the role of serum IgG4 for diagnosis&#46; However&#44; their use in an appropriate clinical context&#44; and particularly if the normal maximum value in serum is multiplied by two&#44; can be useful&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Another possible purpose of measuring IgG4 serum levels is to monitor disease activity and response to treatment&#46; In this regard some studies have found conflicting results&#46; For example&#44; in some studies with few patients it was observed that serum IgG4 decreased to normal levels during the treatment with steroids&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">3</span></a> Khosroshahi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">45</span></a> found that serum IgG4 levels decreased after treatment with rituximab &#40;RTX&#41; in 10 IgG4-RD patients&#44; and the 2 relapses recorded during follow-up were consistent with increased serum IgG4&#44; showing their role in the etiopathogenesis and prognosis&#46; However&#44; in a Japanese multicenter study&#44;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">46</span></a> glucocorticoids only normalized serum IgG4 levels in 67 patients &#40;36&#46;8&#37;&#41; and clinical relapses were also observed in up to 10&#37; patients with persistently normal IgG4 levels&#46; Similar results were reported in the cohort of the Mayo Clinic where IgG4 levels were determined in 19 patients during steroid treatment&#44; and in 11 of them &#40;57&#46;9&#37;&#41; these levels were normalized&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">42</span></a> Therefore&#44; to date&#44; there is no sufficient evidence to justify the use of IgG4 levels in monitoring the disease&#46;</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&#46; 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&#46; Other forms of manifestation can occur in lung&#44; kidney or blood vessels&#46; In lung&#44; radiologic images may vary from solid nodular lesions to bronchovascular or interstitial alveolar patterns &#40;with the presence of honeycomb and&#47;or ground-glass images&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">47</span></a> Kidneys may show hypodense nodular lesions&#44; predominantly cortical&#44; or diffuse patchy involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">48</span></a> Finally&#44; vascular involvement in IgG4-RD mainly occurs in the aorta &#40;both in thoracic and abdominal portion&#41; and its main branches&#44; where the characteristic image is the homogeneous thickening of the vascular wall&#46;<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&#46; Therefore&#44; it is considered a diagnostic criterion in both Mayo Clinic criteria and Kim criteria &#40;Korea&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">50</span></a> In general&#44; it seems that the extrapancreatic manifestations of IgG4-RD respond satisfactorily to treatment with glucocorticoids&#46;<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&#46; While histopathologic criteria of the disease &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41; were agreed in 2011&#44; many researchers have worked to develop diagnostic criteria that eliminate the need for histological study in all patients&#44; particularly in organs of difficult access to biopsy &#40;such as the aorta&#41;&#46; For example&#44; Okazaki et al&#46; have proposed diagnostic criteria in which in addition to the major histopathological features of the disease&#44; 2 other non-histological criteria have been added&#58; the presence of diffuse or focal swelling in one or more organs and high IgG4 serum levels &#40;&#62;135<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">52</span></a> Some similar criteria have been proposed by Carruthers et al&#46;&#44; in order to homogenize patients to be included in clinical trials&#46; They have also included a radiological criterion &#40;typical radiological image of IgG4-RD&#41;&#44; and have specified that serum IgG4 concentrations must be 1&#46;5 times over the upper normal limit&#46;<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 &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#44; and will depend on the organ involved&#46;<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&#44; given the nature of the disease and its usual subacute and indolent features&#44; in many cases the diagnosis will be a chance finding without significant organ impact&#46; Occasionally&#44; symptomatology may improve with no treatment&#46;<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&#46; In addition&#44; the available evidence is based on observational retrospective studies&#44; as there are no randomized controlled prospective studies published&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Glucocorticoids represent the cornerstone of treatment for IgG4-RD&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">51</span></a> These have been proven effective in AIP&#44; obtaining better rates of clinical remission&#44; reducing the time to remission and improving pancreatic exocrine function&#46;<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&#46;<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&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">57</span></a> Initial dose of prednisone 0&#46;6<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#44; maintained from 2 to 4 weeks&#44; is recommended to then gradually decrease 5<span class="elsevierStyleHsp" style=""></span>mg every 1&#8211;2 weeks and reach&#44; after 2&#8211;3 months&#44; a 2&#8211;5<span class="elsevierStyleHsp" style=""></span>mg maintenance dose&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">57</span></a> This dosage can be maintained for years depending on the clinical evolution&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">57</span></a> At these doses relapse rate published is approximately 25&#37;&#44; despite maintenance treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">46</span></a> A similar initial treatment schedule but shorter &#40;11 weeks&#41; has been proposed by the Mayo Clinic group&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">23</span></a> However&#44; with this regimen&#44; the relapse rate is up to 50&#37; after completion of steroid treatment&#46;<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&#44; the clinical relapse rates published range from 26&#37;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">56</span></a> to 92&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">46</span></a> risk of recurrence increasing with time&#44;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">46</span></a> especially if glucocorticoids are discontinued&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">56</span></a> These rates of relapse&#44; along with the adverse effects of glucocorticoids&#44; particularly in elderly population&#44; require the search for new therapeutic approaches using other immunosuppressive drugs&#46; However&#44; to date&#44; due to the rarity of the disease&#44; there is little evidence to support the use of these drugs&#44; and recommendations are based primarily on published experience in clinical cases or retrospective series&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">The use of azathioprine &#40;AZA&#41; or mycophenolate mofetil &#40;MMF&#41; is extrapolated from the experience in other autoimmune diseases such as autoimmune hepatitis&#46; In the experience of the Mayo Clinic&#44; the 6 patients who relapsed after withdrawal of glucocorticoids and were treated with these drugs in monotherapy &#40;4 with AZA&#44; 2 with MMF&#41;&#44; remained in remission during the follow-up period &#40;average of 6 months&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">23</span></a> In a multicenter study recently published&#44; AZA was used in 68 patients with relapsed AIP after the withdrawal of glucocorticoids&#44; being effective in inducing remission in 56 patients &#40;85&#37;&#41;&#46;<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&#44; with an overall response rate of 86&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">14</span></a> However&#44; in another study published by Hart et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">58</span></a> remission rates in patients with relapsed AIP were 23&#37; and 27&#37; in patients treated with AZA &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>31&#41; and MMF &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>11&#41;&#44; respectively&#46;</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&#46; Khosroshahi et al&#46;<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&#46; 90&#37; patients showed clinical response after the first month of treatment&#46; In addition&#44; these 10 patients could discontinue prednisone and the associated immunosuppressive therapy&#46;<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&#37; patients&#44; a decline that did not happen in other subclasses of IgG&#46; The 2 patients who did not normalize serum IgG4 had clinical relapse and increased immunoglobulin&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">45</span></a> Currently&#44; there is an ongoing clinical trial intended to deepen the understanding of the efficacy and safety of RTX in IgG4-RD &#40;ClinicalTrials&#46;gov&#58; <a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01584388">NCT01584388</a>&#41;&#46;</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&#44; etiology still unclarified&#44; whose clinical spectrum includes multiple syndromes previously considered as idiopathic and organ-specific&#46; Its prevalence and incidence are poorly known&#44; and probably underestimated&#44; since it is a disease recently reported&#46; However&#44; in recent years&#44; there has been growing interest in its study&#46; Its most characteristic manifestation is inflammatory tumors in various organs&#44; frequently associated with high serum IgG4 levels&#44; which share a common characteristic histology&#46; Treatment is based mainly on glucocorticoids&#46; However&#44; the use of other drugs&#44; particularly RTX&#44; is increasing&#46;</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&#46;</p></span></span>"
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            0 => "IgG4-related disease"
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        "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&#46; Its most characteristic feature is the formation of inflammatory tumors in different organs&#44; which makes differentiation mainly with neoplastic diseases fundamental&#46; The inflammatory process is typically comprised of IgG4 lymphoplasmacytic cells&#46; The pathophysiological role of the immunoglobulin is not clear&#46; The treatment of choice is corticosteroids&#46; This article aims to summarize the main features of the disease&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La enfermedad relacionada con IgG4 es una entidad cl&#237;nico-patol&#243;gica descrita recientemente con un amplio espectro de manifestaciones cl&#237;nicas que comparten una histopatolog&#237;a en com&#250;n&#46; Su manifestaci&#243;n m&#225;s caracter&#237;stica es la formaci&#243;n de tumores inflamatorios en diferentes &#243;rganos&#44; lo que hace fundamental la diferenciaci&#243;n principalmente de enfermedades neopl&#225;sicas&#46; Este fen&#243;meno inflamatorio est&#225; compuesto caracter&#237;sticamente por linfoplasmocitos productores de IgG4&#46; El papel fisiopatog&#233;nico de la inmunoglobulina no est&#225; aclarado&#46; El tratamiento de elecci&#243;n son los glucocorticoides&#46; Este trabajo pretende resumir las principales caracter&#237;sticas de la enfermedad&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Please cite this article as&#58; Gonz&#225;lez-Moreno J&#44; Losada L&#243;pez I&#44; Ortego Centeno N&#46; Enfermedad relacionada con IgG4&#46; Med Clin &#40;Barc&#41;&#46; 2015&#59;145&#58;539&#8211;544&#46;</p>"
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                  <table border="0" frame="\n
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                  \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&nbsp;\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&nbsp;\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&nbsp;\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&nbsp;\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&nbsp;\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&nbsp;\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&nbsp;\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&nbsp;\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1042203.png"
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Different nomenclature used for IgG4 related disease&#46;</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"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">ANCA&#58; antineutrophil cytoplasmic antibodies&#46;</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>&nbsp;\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&nbsp;\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&nbsp;\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&nbsp;\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&nbsp;\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&nbsp;\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>&nbsp;\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&nbsp;\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>&nbsp;\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&nbsp;\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&nbsp;\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&nbsp;\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1042202.png"
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Other pathologies with presence of IgG4-positive plasma cells&#46;</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 &#40;must meet each one of the 3 criteria&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;1&#41; &#8805;2 of the major histopathological criteria<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\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&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Storiform fibrosis&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Obliterative phlebitis&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">&#40;2&#41; Quantification of IgG4 cells&#58; 10&#8211;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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">&#40;3&#41; IgG4&#47;IgG cell ratio<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>40&#37;<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> &#40;either 3 situations&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">&#40;a&#41; A major histological criterion and consistent immunohistochemistry</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">&#40;b&#41; Those biopsies with fine needle</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">&#40;c&#41; Meningeal and cutaneous disease &#40;little data published&#41;</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&nbsp;\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>
                  """
              ]
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                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&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">&#62;10 in meninges&#44; pancreas &#40;biopsy&#41;&#44; bile ducts &#40;biopsy&#41;&#44; liver &#40;biopsy&#41; and kidney &#40;biopsy&#41;&#59; &#62;20 in lung &#40;biopsy&#41;&#59; &#62;30 in kidney &#40;surgical specimen&#41; and retroperitoneum&#59; &#62;50 in lung &#40;surgical specimen&#41;&#44; pleura&#44; pancreas &#40;surgical specimen&#41;&#44; bile ducts &#40;surgical specimen&#41;&#44; liver &#40;surgical specimen&#41;&#44; aorta&#59; &#62;100 in salivary and lacrimal glands and lymph nodes&#59; &#62;200 in skin&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Except in aorta where ratio is considered as &#62;50&#37;&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Data such as serum IgG4<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>135<span class="elsevierStyleHsp" style=""></span>mg&#47;dl or involvement of any other organ &#40;through radiological technique or physical examination&#41; would support the diagnosis&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Terminology recommended to describe the histopathological patterns of IgG4-related disease &#40;IgG4-RD&#41;&#46;</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&#47;tissue involved &#40;&#37; patients<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">a</span></a>&#41;&nbsp;\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>&nbsp;\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 &#40;41&#41;&nbsp;\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&nbsp;\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;40&#41;&nbsp;\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&#59; IgG4-related mumps&#59; IgG4-related sialadenitis&nbsp;\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 &#40;29&#41;&nbsp;\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&#59; IgG4-related Dacryoadenitis&#59; IgG4-related orbital inflammation &#40;or orbital inflammatory pseudotumor associated with IgG4&#41;&#59; IgG4-related orbital myositis&#59; IgG4-related pan-orbital inflammation&nbsp;\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 &#40;26&#41;&nbsp;\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&nbsp;\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 &#40;19&#46;5&#41;&nbsp;\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&#59; IgG4-related cholecystitis&nbsp;\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 &#40;19&#41;&nbsp;\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&nbsp;\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 &#40;13&#41;&nbsp;\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&#59; tubulointerstitial nephritis secondary to IgG4-related disease&#59; membranous glomerulonephritis secondary to IgG4-related disease&#59; IgG4-related pielitis&nbsp;\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 &#40;13&#41;&nbsp;\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&nbsp;\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 &#40;12&#41;&nbsp;\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&nbsp;\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 &#40;9&#41;&nbsp;\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&#47;periaortitis&nbsp;\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 &#40;&#60;5&#41;&nbsp;\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&nbsp;\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 &#40;&#60;5&#41;&nbsp;\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&nbsp;\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 &#40;&#60;5&#41;&nbsp;\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&nbsp;\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 &#40;&#60;5&#41;&nbsp;\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&nbsp;\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 &#40;&#60;5&#41;&nbsp;\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&nbsp;\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 &#40;&#60;5&#41;&nbsp;\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&nbsp;\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 &#40;&#60;5&#41;&nbsp;\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&nbsp;\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 &#40;&#60;5&#41;&nbsp;\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&nbsp;\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 &#40;&#60;5&#41;&nbsp;\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1042206.png"
              ]
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          "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&#44; and obtained from Brito-Zer&#243;n et al&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">5</span></a></p>"
            ]
            1 => array:3 [
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Original language: English
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

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Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos