Autoinflammatory diseases in adults. Clinical characteristics and prognostic implications

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Clinical characteristics and prognostic implications" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "108" "paginaFinal" => "116" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "A. González García, J.L. Patier de la Peña, N. Ortego Centeno" "autores" => array:3 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "González García" "email" => array:1 [ 0 => "andres_gonzalez_garcia@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "J.L." "apellidos" => "Patier de la Peña" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "N." 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Características clínicas e implicaciones pronósticas" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2195 "Ancho" => 2503 "Tamanyo" => 247070 ] ] "descripcion" => array:1 [ "en" => "Two-step literature search strategy." ] ] ] "textoCompleto" => "BackgroundAutoinflammatory diseases (ADs) are characterized by systemic, recurrent or persistent inflammatory episodes that are produced in the absence of infection, neoplasia or concomitant autoimmune disease. These diseases are considered acquired or hereditary disorders of the innate immune response.<a class="elsevierStyleCrossRef" href="#bib0425">1</a> Most of these diseases occur in childhood; however, although infrequent, some patients have late-onset manifestations in adulthood. This late onset could be due to the fact that the disease is expressed symptomatically in later ages or due to diagnostic delays during the initial stages in which the presence of the disease was not recognized. There is scarce literature on this subject, and given the low prevalence of these diseases, the ADs that appear or are diagnosed in adults pose numerous questions.In recent years, new classifications have been proposed for several of the conditions reviewed below. In a number of cases, genetic disorders in adults have been reported at a rate higher than expected based on the information currently available.<a class="elsevierStyleCrossRef" href="#bib0430">2</a>The objective of this review is to describe the phenotype of ADs in adults. More specifically, we review the most relevant clinical aspects for each of the diseases in adulthood, both for those diseases that start during this period and for those that were previously diagnosed in childhood and continue into adulthood.MethodsLiterature searchWe conducted a 2-step literature search in the MEDLINE database for all publications, English and Spanish, from January 1990 to April 2016. The initial search was conducted with the following keywords: “autoinflammatory disease” or “periodic fever syndromes” along with “adult-onset” or “adult”. The search was also emphasized with the commands (“clinical profile”, “clinical features” OR “clinical characteri*). We then conducted an individual search for each of the ADs using the keywords for each disease along with “adult-onset” or “adult” and the command (“clinical profile”, “clinical features” OR “clinical characteri*). All relevant articles were reviewed, as well as the additional references included in these manuscripts.We also conducted a search in the Web of Science (WOS) platform of the books of abstracts of the main congresses of the American College of Rheumatology (ACR), European League Against Rheumatism, European Academy of Allergy and Clinical Immunology Congress, Society for Investigative Dermatology and Paediatric Rheumatology International Trials Organization.Article inclusion and exclusion criteriaWe excluded exclusively pediatric AD-related articles and molecular studies without an associated clinical description. The literature search did not include articles on patients with a previous diagnosis of Behçet's disease, adult-onset Still's disease, inflammatory bowel disease or other diseases considered polygenic such as microcrystalline arthropathy.We excluded articles that were considered duplicates due to similar content, as well as strictly experimental studies and those whose information was irrelevant or incomplete, in the opinion of the authors of this review.Selection of referencesAfter employing the search strategy, we selected those literature references that contained descriptions of aspects regarding the clinical presentation of AD in adults. We also included descriptions of individual cases that, due to their exceptional nature, represented an important contribution to the understanding of the pathophysiology or other aspects of AD. Given the low prevalence of AD, there are few randomized and controlled studies regarding the clinical expression or treatment. We therefore included those clinical trials in which an age greater than 18 years was not an exclusion criterion.Using the initial search strategy, we obtained 584 literature references from MEDLINE and 15 abstracts from the WOS platform. From the review of the previous articles, we obtained 6 additional references. With the specific searches for each of the ADs, we identified a total of 119 articles. Ultimately, 274 articles were selected (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Implementation and discussionADs were first reported in 1999 by Kastner et al., who also discovered the genetic defects associated with familial Mediterranean fever (FMF) and with tumor necrosis factor (TNF) 1 receptor-associated periodic syndrome (TRAPS).<a class="elsevierStyleCrossRef" href="#bib0435">3</a> Since then, vast scientific literature has been generated, which has led to the description of new syndromes and monogenic and polygenic autoinflammatory-based diseases. These diseases have a low prevalence, and therefore many of them are included in the rare disease group.The clinical presentation of AD in adults is poorly known, and there are a number of differences that need to be considered between adult-onset ADs and those that progress from childhood to later ages.Classification of autoinflammatory diseasesOverviewThe main ADs are listed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Despite the phenotypic variability and diversity of affected genes, there is the belief that all these diseases share a common pathophysiological denominator. At the beginning of 2000, when research was underway on the function of mutated cryopyrin in cryopyrin-associated periodic syndromes (CAPS), the concept of “inflammasome” was proposed.<a class="elsevierStyleCrossRef" href="#bib0440">4</a> The inflammasome would be a complex formed by a multitude of proteins that intervene in the inflammatory cascade and the members of the family of nod-like receptors (NLR). Inflammasome hyperactivity, as well as the various families of NLRs and their different tissue response, would explain the various phenotypes of AD.<a class="elsevierStyleCrossRef" href="#bib0445">5</a> In any case, most of these conditions have common manifestations, including recurrent fever, polyserositis, skin disorder in the form of dermatitis and rash, muscle-skeletal disorder and increased levels of acute-phase reactants during acute episodes.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The clinical presentation of this collection of diseases usually occurs in childhood. Diagnostic delay is not uncommon, given the nonspecific nature of the symptoms. Many of these diseases progress with asymptomatic periods between crises, which can further delay an early diagnosis. Diagnostic confirmation is usually performed with sophisticated genetic tests found in specialized centers. This, coupled with the benign nature of the symptoms in some of these ADs, makes them a real diagnostic challenge.In cases in which these diseases go unnoticed in childhood and are manifested in adulthood, the diagnosis is even more difficult. It is therefore essential to maintain a high index of suspicion. If the possibility of an AD is considered in the differential diagnosis of any process, appropriate genetic tests should be performed to confirm or rule out this possibility. Nevertheless, given the scarcity of data from the adult population, a number of researchers have suggested the implementation, prior to the genetic study, of a clinical “score” for increasing the performance of these tests.<a class="elsevierStyleCrossRef" href="#bib0450">6</a>A number of treatments with a modulator effect, such as colchicine, have helped improve the prognosis and symptom control in a number of these diseases, such as FMF.<a class="elsevierStyleCrossRef" href="#bib0455">7</a> Other drugs with anti-inflammatory effect, such as corticosteroids and nonsteroidal anti-inflammatory drugs, can be useful in controlling the clinical expression but usually have limitations, which range from significant adverse effects to suboptimal control of the inflammatory burden over the course of the disease progression.<a class="elsevierStyleCrossRef" href="#bib0460">8</a>In recent years and based on the description of ADs with metabolic pathway defects in which the interleukin-1 (IL-1) receptor was involved, studies have observed that the use of blockers of these cytokines produced a significant improvement in the degree of control of the inflammatory condition.<a class="elsevierStyleCrossRef" href="#bib0465">9</a> This finding encouraged the use of biological therapy focused on the IL-1 pathway as a fundamental tool for controlling ADs refractory to first-line treatments.<a class="elsevierStyleCrossRefs" href="#bib0470">10,11</a> There is experience with a number of other biological drugs, such as tocilizumab (an antibody against interleukin-6),<a class="elsevierStyleCrossRef" href="#bib0480">12</a> with highly promising results in advanced disease and for preventing the development of amyloidosis. Biological therapy against TNF alpha, in contrast, offers mixed results. Although its efficacy has been demonstrated in isolated cases of FMF<a class="elsevierStyleCrossRef" href="#bib0485">13</a> and pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA),<a class="elsevierStyleCrossRef" href="#bib0490">14</a> there are also cases refractory to these treatments. The main therapeutic failures with anti-TNF therapy occur in patients with TRAPS,<a class="elsevierStyleCrossRefs" href="#bib0495">15,16</a> with higher response rates for etanercept than for infliximab<a class="elsevierStyleCrossRef" href="#bib0505">17</a> or adalimumab.<a class="elsevierStyleCrossRef" href="#bib0500">16</a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> lists the studies that support the various drugs being used for ADs in adult patients.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Familial Mediterranean feverThe late onset of FMF, a rarity, is the most common form among ADs. A number of series have reported an adult onset of the disease in up to 14% of the patients.<a class="elsevierStyleCrossRef" href="#bib0510">18</a> The case with the most advanced age was that of a 75-year-old woman with overlap syndrome, diagnosed with systemic lupus erythematosus and rheumatoid arthritis, who presented a clinical condition of polyserositis in which the E148Q mutation of exon 2 of the MEFV gene in heterozygosity was found.<a class="elsevierStyleCrossRef" href="#bib0515">19</a> FMF frequently presents in more advanced ages in patients of oriental ethnicity.<a class="elsevierStyleCrossRef" href="#bib0520">20</a> Nevertheless, cases have also been reported in Western Europe of initial presentation in advanced ages,<a class="elsevierStyleCrossRef" href="#bib0525">21</a> and its presentation in intermediate ages is not uncommon.In general, the clinical presentation resembles that of the pediatric forms. Several studies have observed that the adult forms are usually milder and that their response rates to treatment with colchicine are better than in childhood.<a class="elsevierStyleCrossRefs" href="#bib0430">2,22,23</a> It is believed that the adult variants are due to low-penetration mutations, which produce more indolent forms and, characteristically, lower joint and skin involvement.<a class="elsevierStyleCrossRef" href="#bib0510">18</a>The presence of various causal mutations in FMF translates into variability in its presentation,<a class="elsevierStyleCrossRef" href="#bib0540">24</a> which has prognostic implications, especially if there are homozygous mutations.<a class="elsevierStyleCrossRef" href="#bib0545">25</a> Most of the reviewed studies on adult patient cohorts with FMF report heterozygous mutations or genetic disorders considered as polymorphisms, which are also present in a high percentage of healthy individuals. In general, polymorphisms and heterozygous mutations usually associate with mild forms of the disease and perhaps could explain the benign nature of their presentation.Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)This condition progresses with periodic fever and is characterized by acute inflammatory episodes of extended duration, spaced over time, and in general, with a pediatric onset.<a class="elsevierStyleCrossRef" href="#bib0435">3</a> In recent years, however, cases of TRAPS have been reported in the adult population. A series of 158 cases from the European registry Eurofever/EUROTRAPS revealed that 9.1% of the patients were older than 30 years at the time of the diagnosis.<a class="elsevierStyleCrossRef" href="#bib0550">26</a> These patients also presented low-penetration genotype variants compared with those with childhood-onset TRAPS.<a class="elsevierStyleCrossRef" href="#bib0555">27</a> Characteristically, respiratory symptoms and cases of pericarditis<a class="elsevierStyleCrossRefs" href="#bib0560">28,29</a> are more frequently observed among adults, whereas abdominal and skin symptoms are observed in children.<a class="elsevierStyleCrossRef" href="#bib0550">26</a>Although this disease usually presents with symptoms that affect various organs and systems, there have been recent reports of TRAPS-related mutations in adult patients with recurrent idiopathic pericarditis but no other associated manifestations, who respond well to anti-IL-1 therapy.<a class="elsevierStyleCrossRef" href="#bib0570">30</a> These patients usually are carriers of low-penetration mutations in the TNF superfamily gene, with a less torpid clinical course and fewer long-term complications such as amyloidosis, unlike patients with structural mutations and more complicated clinical conditions.<a class="elsevierStyleCrossRef" href="#bib0560">28</a>Despite the high suspicion of TRAPS in a patient with compatible symptoms, genetic studies sometimes have low cost-effectiveness due to the heterogeneity of the found mutations.<a class="elsevierStyleCrossRef" href="#bib0575">31</a>Mevalonate kinase deficiency or hyper-IgD syndromeThis is an uncommon condition of which approximately 200 cases have been reported. The condition belongs to a group of disorders encompassed within human mevalonate kinase deficiency, which includes mevalonic aciduria, the most severe form of the disease.<a class="elsevierStyleCrossRef" href="#bib0580">32</a> The syndrome progresses clinically with fever, joint impairment, skin rash, adenomegaly and hepatosplenomegaly, along with increased levels of acute-phase reactants (such as C-reactive protein) and an increase in immunoglobulin D concentrations. There is usually a moderate increase in mevalonic acid levels in urine only during episodes of acute inflammation, which return to normal during the intervals between these episodes. The diagnosis is usually performed in adulthood because the condition frequently goes unnoticed during childhood.<a class="elsevierStyleCrossRef" href="#bib0585">33</a> The episodes usually respond to steroidal or biological treatment. However, the patients’ quality of life is significantly affected despite the fact that the treatment adapted to the crisis achieves a reduction in its frequency.<a class="elsevierStyleCrossRef" href="#bib0590">34</a>Cryopyrinopathy or cryopyrin-associated periodic syndromes (CAPS)This term, which includes the term familial urticaria syndromes, refers to several entities that make up a spectrum of disorders from milder forms such as familial cold autoinflammatory syndrome (FCAS) to more severe forms such as Muckle–Wells syndrome (MW) and chronic infantile neurological, cutaneous and articular syndrome. There are no epidemiological studies on these diseases, but their prevalence is estimated at 1–10 cases per million inhabitants in various countries.<a class="elsevierStyleCrossRef" href="#bib0595">35</a> These diseases are generally diagnosed in childhood. When they are detected in an adult patient, there is usually a diagnostic delay of years, given that the symptoms usually start in the first 7 years of life.<a class="elsevierStyleCrossRef" href="#bib0600">36</a> However, cases have been reported in adult patients caused by low-penetration mutations, which reproduce FCAS symptoms when exposed to cold conditions.<a class="elsevierStyleCrossRefs" href="#bib0605">37,38</a> There was a reported case of a 50-year-old patient with a diagnosis of CAPS, consisting of neurological impairment (deafness and meningitis), skin disorder and fever, who responded well to anti IL-1 therapy.<a class="elsevierStyleCrossRef" href="#bib0615">39</a> It is especially interesting that somatic mutations could explain the onset of this group of disorders in adults. In fact, there was a report on a series of 7 patients, one of whom had findings of somatic mosaicism and a diagnosis of MW at the age of 18 years, characterized by joint and skin symptoms.<a class="elsevierStyleCrossRef" href="#bib0620">40</a>PAPAThe abbreviation PAPA (pyogenic arthritis, pyoderma gangrenosum and acne syndrome) was coined in 1997 to describe a family with members from several generations affected by this syndrome.<a class="elsevierStyleCrossRef" href="#bib0625">41</a> The condition is characterized by the early onset of joint symptoms, consisting of intermittent migrating arthritis flares, which can affect both large and small joints and that can even require repeated surgical lavages given the similarity with septic arthritis. Subsequently, the onset is usually accompanied by skin manifestations, such as extensive acne with poor response to standard topical treatment, as well as phenomena of pathergy and pyoderma gangrenosum.<a class="elsevierStyleCrossRef" href="#bib0630">42</a> The entire constellation of symptoms tends to occur in adults, although with significant heterogeneity in the expression of the disease.<a class="elsevierStyleCrossRef" href="#bib0635">43</a> Several types of mutations have been reported in this syndrome, most frequently in the gene that encodes the proline–serine–threonine phosphatase-interacting protein 1, located in chromosome 15.<a class="elsevierStyleCrossRef" href="#bib0640">44</a> Despite the correct identification of the gene and of other genetic abnormalities, cases of PAPA have been diagnosed without finding mutations in the genetic study.<a class="elsevierStyleCrossRef" href="#bib0645">45</a>PFAPAPFAPA syndrome (an abbreviation for periodic fever, aphthous stomatitis, pharyngitis and adenitis) was first reported in 1987 in 12 children with periodic fever, oral aphthosis and pharyngotonsillitis, with adenopathies that resemble cyclic neutropenia.<a class="elsevierStyleCrossRef" href="#bib0650">46</a> Treatment with oral prednisone rapidly shortens the duration of the conditions, constituting one of the diagnostic criteria of the syndrome also known as Marshall syndrome.<a class="elsevierStyleCrossRef" href="#bib0655">47</a> The first case in adults was reported in 2008.<a class="elsevierStyleCrossRef" href="#bib0660">48</a> Since then, an increasing number of cases have been reported. One of the theories as to why this syndrome also occurs in adulthood is related to a hypothetical immaturity of the immune system, which facilitates episodes of PFAPA. The clinical presentation, in general, is usually similar to that of the pediatric syndrome. The response to steroid therapy is usually good, but adenoidectomy only produces partial responses. Exceptional cases have been reported with renal immunological manifestations in the form of glomerulonephritis.<a class="elsevierStyleCrossRef" href="#bib0665">49</a> Isolated cases of response to cimetidine have been reported.<a class="elsevierStyleCrossRefs" href="#bib0670">50,51</a>Schnitzler syndromeSchnitzler syndrome was first reported in 1972 and is characterized by symptoms of chronic urticaria, periodic fever, joint pain, monoclonal gammopathy (commonly IgM-к) and increased levels of acute-phase reactants. The syndrome's pathogenesis is unknown, although it is believed that it has a significant connection with ADs, given that mutations in the NLR family pyrin domain containing 3 (NLRP3) gene have been observed in a number of patients.<a class="elsevierStyleCrossRef" href="#bib0680">52</a> The disease is rare; however, it is important to suspect it given that some cases can progress to blood dyscrasia.<a class="elsevierStyleCrossRefs" href="#bib0685">53,54</a> The response to IL-1 inhibitors is satisfactory,<a class="elsevierStyleCrossRefs" href="#bib0695">55–57</a> and overall survival is good, although extended treatment needs to be maintained, given that recurrence is the rule.<a class="elsevierStyleCrossRef" href="#bib0710">58</a>Blau syndromeBlau syndrome (BS) and early-onset sarcoidosis share a common etiopathogenic mechanism related to the nucleotide-binding oligomerization domain-containing 2 (NOD2) protein, which is why variants of the same disease are considered, with the difference in the sporadic presentation in early-onset sarcoidosis and the familial presentation in BS. The NOD2 protein is a member of the NLR family of receptors of the innate immune system.<a class="elsevierStyleCrossRef" href="#bib0715">59</a> The mutations related to this gene produce an overactive protein, which results in an increase in the signal transduced by the nuclear transcription factor kappaB.<a class="elsevierStyleCrossRef" href="#bib0720">60</a>Clinically, BS is characterized by a persistent inflammatory condition with periodic episodes of exacerbation over the course of the disease's progression. The disease usually starts before the age of 4 years, typically with skin and joint symptoms. The other manifestations, mainly ocular, progressively appear with age. Cases of BS have been reported in a family in which the onset of the disease in the father was later. The genetic study revealed that the father had a somatic mutation in gene NOD2 (p.Arg334Gln), unlike the children, whose mutation was germinal.<a class="elsevierStyleCrossRef" href="#bib0725">61</a> This finding leads to the conclusion that the mosaicisms favor the onset of the disease in later ages and cause conditions with milder manifestations.ConclusionsADs occur infrequently in adulthood; when they do occur, they are mostly due to diagnostic delays. However, they can also occur due to adult onset, in which case the symptoms are generally milder and atypical.Monogenic ADs that appear in adulthood are usually associated with low-penetration mutations and milder symptoms. Sporadic ADs (Schnitzler syndrome) usually present almost exclusively in adulthood. Only PFAPA syndrome, which is characteristic of childhood, presents with similar characteristics in the few cases of adult onset.It is important to maintain a high diagnostic suspicion for the proper identification of these diseases, given that treatment with biological therapies is usually accompanied by a good response or a better control of the disease.Conflicts of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres806052" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec804153" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres806051" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec804152" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Literature search" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Article inclusion and exclusion criteria" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Selection of references" ] ] ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "Implementation and discussion" "secciones" => array:7 [ 0 => array:3 [ "identificador" => "sec0035" "titulo" => "Classification of autoinflammatory diseases" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Overview" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Familial Mediterranean fever" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)" ] ] ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Mevalonate kinase deficiency or hyper-IgD syndrome" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Cryopyrinopathy or cryopyrin-associated periodic syndromes (CAPS)" ] 3 => array:2 [ "identificador" => "sec0065" "titulo" => "PAPA" ] 4 => array:2 [ "identificador" => "sec0070" "titulo" => "PFAPA" ] 5 => array:2 [ "identificador" => "sec0075" "titulo" => "Schnitzler syndrome" ] 6 => array:2 [ "identificador" => "sec0080" "titulo" => "Blau syndrome" ] ] ] 7 => array:2 [ "identificador" => "sec0085" "titulo" => "Conclusions" ] 8 => array:2 [ "identificador" => "sec0090" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec804153" "palabras" => array:6 [ 0 => "Hereditary autoinflammatory diseases" 1 => "Adults" 2 => "Periodic fever" 3 => "Inflammasome" 4 => "Nod-like receptor" 5 => "TNF" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec804152" "palabras" => array:6 [ 0 => "Enfermedades autoinflamatorias hereditarias" 1 => "Adulto" 2 => "Fiebre periódica" 3 => "Inflamasoma" 4 => "Nod-like receptor" 5 => "TNF" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Autoinflammatory diseases are clinical conditions with inflammatory manifestations that present in a periodic or persistent manner and are caused by acquired or hereditary disorders of the innate immune response. In general, these diseases are more common in childhood, but cases have been reported in adults and are therefore important for all specialists. There are few references on these diseases in adults due to their low prevalence and underdiagnosis. The aim of this study is to review the scientific literature on these disorders to systematize their clinical, prognostic and treatment response characteristics in adults." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Las enfermedades autoinflamatorias son cuadros clínicos con manifestaciones inflamatorias que se presentan de forma periódica o persistente, producidas por alteraciones adquiridas o hereditarias de la respuesta inmune innata. En general, son más frecuentes en la edad pediátrica, pero se han descrito casos en adultos, por lo que son de interés para cualquier especialista. Existen pocas referencias de estas enfermedades en el adulto por su baja prevalencia e infradiagnóstico. El objetivo de este trabajo es revisar la literatura científica sobre estos trastornos para sistematizar sus características clínicas, pronósticas y la respuesta al tratamiento en el adulto." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: González García A, Patier de la Peña JL, Ortego Centeno N. Enfermedades autoinflamatorias en el adulto. Características clínicas e implicaciones pronósticas. Rev Clin Esp. 2017;217:108–116." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2195 "Ancho" => 2503 "Tamanyo" => 247070 ] ] "descripcion" => array:1 [ "en" => "Two-step literature search strategy." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: FMF, familial Mediterranean fever; TRAPS, tumor necrosis factor receptor-associated periodic syndrome; Hyper IgD-MVK, hyper IgD syndrome/mevalonate-kinase deficiency; CAPS, cryopyrinopathy or cryopyrin-associated periodic syndromes; FCAS, familial cold autoinflammatory syndrome; MW, Muckle–Wells disease; CINCA, chronic infantile neurological, cutaneous and articular syndrome, previously known as neonatal onset multisystem inflammatory disease; BS, Blau syndrome; PAPA, pyogenic arthritis, pyoderma gangrenosum and acne syndrome; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome." "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">Autosomal recessive inheritance \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Autosomal dominant inheritance</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Other (acquired, polygenic) \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">Periodic fever \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Periodic fever \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Persistent autoinflammatory disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PFAPA \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">FMF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TRAPS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CAPS: FCAS, MW, CINCA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Schnitzler 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">Hyper IgD-MVK \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">BS \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></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">PAPA \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></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1352701.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Spectrum of autoinflammatory diseases." ] ] 2 => 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" => "Abbreviations: FMF, familial Mediterranean fever; TRAPS, tumor necrosis factor receptor-associated periodic syndrome; Hyper IgD-MVK, hyper IgD syndrome/mevalonate-kinase deficiency; CAPS, cryopyrinopathy or cryopyrin-associated periodic syndromes; BS, Blau syndrome; PAPA, pyogenic arthritis, pyoderma gangrenosum and acne syndrome; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome." "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">Drug \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">Autoinflammatory disease \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">Level of evidence \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="7" align="left" valign="top">Anakinra</td><td class="td" title="table-entry " align="left" valign="top">CAPS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRefs" href="#bib0730">62,63</a> \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">TRAPS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRefs" href="#bib0740">64,65</a> \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">FMF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0750">66</a> \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 IgD syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0755">67</a> \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">PAPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRefs" href="#bib0630">42,68–70</a> \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">Schnitzler syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0710">58</a> \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">PFAPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0775">71</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Rilonacept</td><td class="td" title="table-entry " align="left" valign="top">CAPS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Randomized and controlled study<a class="elsevierStyleCrossRef" href="#bib0780">72</a> \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">FMF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Randomized and controlled study<a class="elsevierStyleCrossRef" href="#bib0785">73</a> \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">Schnitzler syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Quasi-experimental study<a class="elsevierStyleCrossRef" href="#bib0695">55</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="6" align="left" valign="top">Canakimumab</td><td class="td" title="table-entry " align="left" valign="top">CAPS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Open study<a class="elsevierStyleCrossRef" href="#bib0790">74</a> Real-life study<a class="elsevierStyleCrossRef" href="#bib0795">75</a> \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">TRAPS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0800">76</a> \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 IgD syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0705">57</a> \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">FMF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRefs" href="#bib0485">13,57</a> \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">PAPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0805">77</a> \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">Schnitzler syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Controlled study without randomization<a class="elsevierStyleCrossRefs" href="#bib0700">56,78</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Adalimumab</td><td class="td" title="table-entry " align="left" valign="top">FMF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0485">13</a> \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">PAPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRefs" href="#bib0490">14,42</a> \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">SB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0815">79</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Infliximab</td><td class="td" title="table-entry " align="left" valign="top">FMF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0485">13</a> \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">SB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0820">80</a> \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">PAPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0630">42</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Etanercept</td><td class="td" title="table-entry " align="left" valign="top">FMF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0485">13</a> \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">TRAPS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Open study<a class="elsevierStyleCrossRefs" href="#bib0495">15,81</a> \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 IgD syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0590">34</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Tocilizumab</td><td class="td" title="table-entry " align="left" valign="top">TRAPS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRefs" href="#bib0830">82,83</a> \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 IgD syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0840">84</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1352702.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Indications and levels of evidence for biological drugs in autoinflammatory diseases in adult patients." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:84 [ 0 => array:3 [ "identificador" => "bib0425" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoinflammatory diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "G. 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Autoinflammatory diseases in adults. Clinical characteristics and prognostic implications

Enfermedades autoinflamatorias en el adulto. Características clínicas e implicaciones pronósticas

A. González Garcíaa,

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andres_gonzalez_garcia@hotmail.com

Corresponding author.

, J.L. Patier de la Peñaa, N. Ortego Centenob

a Servicio de Medicina Interna, Hospital Universitario Ramón y Cajal , Madrid, Spain

b Unidad de Enfermedades Autoinmunes Sistémicas, Complejo Hospitalario Universitario Granada, Granada, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Autoinflammatory diseases &#40;ADs&#41; are characterized by systemic&#44; recurrent or persistent inflammatory episodes that are produced in the absence of infection&#44; neoplasia or concomitant autoimmune disease&#46; These diseases are considered acquired or hereditary disorders of the innate immune response&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">1</span></a> Most of these diseases occur in childhood&#59; however&#44; although infrequent&#44; some patients have late-onset manifestations in adulthood&#46; This late onset could be due to the fact that the disease is expressed symptomatically in later ages or due to diagnostic delays during the initial stages in which the presence of the disease was not recognized&#46; There is scarce literature on this subject&#44; and given the low prevalence of these diseases&#44; the ADs that appear or are diagnosed in adults pose numerous questions&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">In recent years&#44; new classifications have been proposed for several of the conditions reviewed below&#46; In a number of cases&#44; genetic disorders in adults have been reported at a rate higher than expected based on the information currently available&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The objective of this review is to describe the phenotype of ADs in adults&#46; More specifically&#44; we review the most relevant clinical aspects for each of the diseases in adulthood&#44; both for those diseases that start during this period and for those that were previously diagnosed in childhood and continue into adulthood&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Literature search</span><p id="par0020" class="elsevierStylePara elsevierViewall">We conducted a 2-step literature search in the MEDLINE database for all publications&#44; English and Spanish&#44; from January 1990 to April 2016&#46; The initial search was conducted with the following keywords&#58; &#8220;autoinflammatory disease&#8221; or &#8220;periodic fever syndromes&#8221; along with &#8220;adult-onset&#8221; or &#8220;adult&#8221;&#46; The search was also emphasized with the commands &#40;&#8220;clinical profile&#8221;&#44; &#8220;clinical features&#8221; OR &#8220;clinical characteri&#42;&#41;&#46; We then conducted an individual search for each of the ADs using the keywords for each disease along with &#8220;adult-onset&#8221; or &#8220;adult&#8221; and the command &#40;&#8220;clinical profile&#8221;&#44; &#8220;clinical features&#8221; OR &#8220;clinical characteri&#42;&#41;&#46; All relevant articles were reviewed&#44; as well as the additional references included in these manuscripts&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">We also conducted a search in the Web of Science &#40;WOS&#41; platform of the books of abstracts of the main congresses of the American College of Rheumatology &#40;ACR&#41;&#44; European League Against Rheumatism&#44; European Academy of Allergy and Clinical Immunology Congress&#44; Society for Investigative Dermatology and Paediatric Rheumatology International Trials Organization&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Article inclusion and exclusion criteria</span><p id="par0030" class="elsevierStylePara elsevierViewall">We excluded exclusively pediatric AD-related articles and molecular studies without an associated clinical description&#46; The literature search did not include articles on patients with a previous diagnosis of Beh&#231;et&#39;s disease&#44; adult-onset Still&#39;s disease&#44; inflammatory bowel disease or other diseases considered polygenic such as microcrystalline arthropathy&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">We excluded articles that were considered duplicates due to similar content&#44; as well as strictly experimental studies and those whose information was irrelevant or incomplete&#44; in the opinion of the authors of this review&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Selection of references</span><p id="par0040" class="elsevierStylePara elsevierViewall">After employing the search strategy&#44; we selected those literature references that contained descriptions of aspects regarding the clinical presentation of AD in adults&#46; We also included descriptions of individual cases that&#44; due to their exceptional nature&#44; represented an important contribution to the understanding of the pathophysiology or other aspects of AD&#46; Given the low prevalence of AD&#44; there are few randomized and controlled studies regarding the clinical expression or treatment&#46; We therefore included those clinical trials in which an age greater than 18 years was not an exclusion criterion&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Using the initial search strategy&#44; we obtained 584 literature references from MEDLINE and 15 abstracts from the WOS platform&#46; From the review of the previous articles&#44; we obtained 6 additional references&#46; With the specific searches for each of the ADs&#44; we identified a total of 119 articles&#46; Ultimately&#44; 274 articles were selected &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Implementation and discussion</span><p id="par0050" class="elsevierStylePara elsevierViewall">ADs were first reported in 1999 by Kastner et al&#46;&#44; who also discovered the genetic defects associated with familial Mediterranean fever &#40;FMF&#41; and with tumor necrosis factor &#40;TNF&#41; 1 receptor-associated periodic syndrome &#40;TRAPS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">3</span></a> Since then&#44; vast scientific literature has been generated&#44; which has led to the description of new syndromes and monogenic and polygenic autoinflammatory-based diseases&#46; These diseases have a low prevalence&#44; and therefore many of them are included in the rare disease group&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The clinical presentation of AD in adults is poorly known&#44; and there are a number of differences that need to be considered between adult-onset ADs and those that progress from childhood to later ages&#46;</p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Classification of autoinflammatory diseases</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Overview</span><p id="par0060" class="elsevierStylePara elsevierViewall">The main ADs are listed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Despite the phenotypic variability and diversity of affected genes&#44; there is the belief that all these diseases share a common pathophysiological denominator&#46; At the beginning of 2000&#44; when research was underway on the function of mutated cryopyrin in cryopyrin-associated periodic syndromes &#40;CAPS&#41;&#44; the concept of &#8220;inflammasome&#8221; was proposed&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">4</span></a> The inflammasome would be a complex formed by a multitude of proteins that intervene in the inflammatory cascade and the members of the family of nod-like receptors &#40;NLR&#41;&#46; Inflammasome hyperactivity&#44; as well as the various families of NLRs and their different tissue response&#44; would explain the various phenotypes of AD&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">5</span></a> In any case&#44; most of these conditions have common manifestations&#44; including recurrent fever&#44; polyserositis&#44; skin disorder in the form of dermatitis and rash&#44; muscle-skeletal disorder and increased levels of acute-phase reactants during acute episodes&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">The clinical presentation of this collection of diseases usually occurs in childhood&#46; Diagnostic delay is not uncommon&#44; given the nonspecific nature of the symptoms&#46; Many of these diseases progress with asymptomatic periods between crises&#44; which can further delay an early diagnosis&#46; Diagnostic confirmation is usually performed with sophisticated genetic tests found in specialized centers&#46; This&#44; coupled with the benign nature of the symptoms in some of these ADs&#44; makes them a real diagnostic challenge&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In cases in which these diseases go unnoticed in childhood and are manifested in adulthood&#44; the diagnosis is even more difficult&#46; It is therefore essential to maintain a high index of suspicion&#46; If the possibility of an AD is considered in the differential diagnosis of any process&#44; appropriate genetic tests should be performed to confirm or rule out this possibility&#46; Nevertheless&#44; given the scarcity of data from the adult population&#44; a number of researchers have suggested the implementation&#44; prior to the genetic study&#44; of a clinical &#8220;score&#8221; for increasing the performance of these tests&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">6</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">A number of treatments with a modulator effect&#44; such as colchicine&#44; have helped improve the prognosis and symptom control in a number of these diseases&#44; such as FMF&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">7</span></a> Other drugs with anti-inflammatory effect&#44; such as corticosteroids and nonsteroidal anti-inflammatory drugs&#44; can be useful in controlling the clinical expression but usually have limitations&#44; which range from significant adverse effects to suboptimal control of the inflammatory burden over the course of the disease progression&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">8</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In recent years and based on the description of ADs with metabolic pathway defects in which the interleukin-1 &#40;IL-1&#41; receptor was involved&#44; studies have observed that the use of blockers of these cytokines produced a significant improvement in the degree of control of the inflammatory condition&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">9</span></a> This finding encouraged the use of biological therapy focused on the IL-1 pathway as a fundamental tool for controlling ADs refractory to first-line treatments&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">10&#44;11</span></a> There is experience with a number of other biological drugs&#44; such as tocilizumab &#40;an antibody against interleukin-6&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">12</span></a> with highly promising results in advanced disease and for preventing the development of amyloidosis&#46; Biological therapy against TNF alpha&#44; in contrast&#44; offers mixed results&#46; Although its efficacy has been demonstrated in isolated cases of FMF<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">13</span></a> and pyogenic arthritis&#44; pyoderma gangrenosum and acne syndrome &#40;PAPA&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">14</span></a> there are also cases refractory to these treatments&#46; The main therapeutic failures with anti-TNF therapy occur in patients with TRAPS&#44;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">15&#44;16</span></a> with higher response rates for etanercept than for infliximab<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">17</span></a> or adalimumab&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">16</span></a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> lists the studies that support the various drugs being used for ADs in adult patients&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Familial Mediterranean fever</span><p id="par0085" class="elsevierStylePara elsevierViewall">The late onset of FMF&#44; a rarity&#44; is the most common form among ADs&#46; A number of series have reported an adult onset of the disease in up to 14&#37; of the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">18</span></a> The case with the most advanced age was that of a 75-year-old woman with overlap syndrome&#44; diagnosed with systemic lupus erythematosus and rheumatoid arthritis&#44; who presented a clinical condition of polyserositis in which the E148Q mutation of exon 2 of the MEFV gene in heterozygosity was found&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">19</span></a> FMF frequently presents in more advanced ages in patients of oriental ethnicity&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">20</span></a> Nevertheless&#44; cases have also been reported in Western Europe of initial presentation in advanced ages&#44;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">21</span></a> and its presentation in intermediate ages is not uncommon&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In general&#44; the clinical presentation resembles that of the pediatric forms&#46; Several studies have observed that the adult forms are usually milder and that their response rates to treatment with colchicine are better than in childhood&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">2&#44;22&#44;23</span></a> It is believed that the adult variants are due to low-penetration mutations&#44; which produce more indolent forms and&#44; characteristically&#44; lower joint and skin involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">18</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">The presence of various causal mutations in FMF translates into variability in its presentation&#44;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">24</span></a> which has prognostic implications&#44; especially if there are homozygous mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">25</span></a> Most of the reviewed studies on adult patient cohorts with FMF report heterozygous mutations or genetic disorders considered as polymorphisms&#44; which are also present in a high percentage of healthy individuals&#46; In general&#44; polymorphisms and heterozygous mutations usually associate with mild forms of the disease and perhaps could explain the benign nature of their presentation&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Tumor necrosis factor receptor-associated periodic syndrome &#40;TRAPS&#41;</span><p id="par0100" class="elsevierStylePara elsevierViewall">This condition progresses with periodic fever and is characterized by acute inflammatory episodes of extended duration&#44; spaced over time&#44; and in general&#44; with a pediatric onset&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">3</span></a> In recent years&#44; however&#44; cases of TRAPS have been reported in the adult population&#46; A series of 158 cases from the European registry Eurofever&#47;EUROTRAPS revealed that 9&#46;1&#37; of the patients were older than 30 years at the time of the diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">26</span></a> These patients also presented low-penetration genotype variants compared with those with childhood-onset TRAPS&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">27</span></a> Characteristically&#44; respiratory symptoms and cases of pericarditis<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">28&#44;29</span></a> are more frequently observed among adults&#44; whereas abdominal and skin symptoms are observed in children&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">26</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Although this disease usually presents with symptoms that affect various organs and systems&#44; there have been recent reports of TRAPS-related mutations in adult patients with recurrent idiopathic pericarditis but no other associated manifestations&#44; who respond well to anti-IL-1 therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">30</span></a> These patients usually are carriers of low-penetration mutations in the TNF superfamily gene&#44; with a less torpid clinical course and fewer long-term complications such as amyloidosis&#44; unlike patients with structural mutations and more complicated clinical conditions&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">28</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Despite the high suspicion of TRAPS in a patient with compatible symptoms&#44; genetic studies sometimes have low cost-effectiveness due to the heterogeneity of the found mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">31</span></a></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Mevalonate kinase deficiency or hyper-IgD syndrome</span><p id="par0115" class="elsevierStylePara elsevierViewall">This is an uncommon condition of which approximately 200 cases have been reported&#46; The condition belongs to a group of disorders encompassed within human mevalonate kinase deficiency&#44; which includes mevalonic aciduria&#44; the most severe form of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">32</span></a> The syndrome progresses clinically with fever&#44; joint impairment&#44; skin rash&#44; adenomegaly and hepatosplenomegaly&#44; along with increased levels of acute-phase reactants &#40;such as C-reactive protein&#41; and an increase in immunoglobulin D concentrations&#46; There is usually a moderate increase in mevalonic acid levels in urine only during episodes of acute inflammation&#44; which return to normal during the intervals between these episodes&#46; The diagnosis is usually performed in adulthood because the condition frequently goes unnoticed during childhood&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">33</span></a> The episodes usually respond to steroidal or biological treatment&#46; However&#44; the patients&#8217; quality of life is significantly affected despite the fact that the treatment adapted to the crisis achieves a reduction in its frequency&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Cryopyrinopathy or cryopyrin-associated periodic syndromes &#40;CAPS&#41;</span><p id="par0120" class="elsevierStylePara elsevierViewall">This term&#44; which includes the term familial urticaria syndromes&#44; refers to several entities that make up a spectrum of disorders from milder forms such as familial cold autoinflammatory syndrome &#40;FCAS&#41; to more severe forms such as Muckle&#8211;Wells syndrome &#40;MW&#41; and chronic infantile neurological&#44; cutaneous and articular syndrome&#46; There are no epidemiological studies on these diseases&#44; but their prevalence is estimated at 1&#8211;10 cases per million inhabitants in various countries&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">35</span></a> These diseases are generally diagnosed in childhood&#46; When they are detected in an adult patient&#44; there is usually a diagnostic delay of years&#44; given that the symptoms usually start in the first 7 years of life&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">36</span></a> However&#44; cases have been reported in adult patients caused by low-penetration mutations&#44; which reproduce FCAS symptoms when exposed to cold conditions&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">37&#44;38</span></a> There was a reported case of a 50-year-old patient with a diagnosis of CAPS&#44; consisting of neurological impairment &#40;deafness and meningitis&#41;&#44; skin disorder and fever&#44; who responded well to anti IL-1 therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">39</span></a> It is especially interesting that somatic mutations could explain the onset of this group of disorders in adults&#46; In fact&#44; there was a report on a series of 7 patients&#44; one of whom had findings of somatic mosaicism and a diagnosis of MW at the age of 18 years&#44; characterized by joint and skin symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">40</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">PAPA</span><p id="par0125" class="elsevierStylePara elsevierViewall">The abbreviation PAPA &#40;pyogenic arthritis&#44; pyoderma gangrenosum and acne syndrome&#41; was coined in 1997 to describe a family with members from several generations affected by this syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">41</span></a> The condition is characterized by the early onset of joint symptoms&#44; consisting of intermittent migrating arthritis flares&#44; which can affect both large and small joints and that can even require repeated surgical lavages given the similarity with septic arthritis&#46; Subsequently&#44; the onset is usually accompanied by skin manifestations&#44; such as extensive acne with poor response to standard topical treatment&#44; as well as phenomena of pathergy and pyoderma gangrenosum&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">42</span></a> The entire constellation of symptoms tends to occur in adults&#44; although with significant heterogeneity in the expression of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">43</span></a> Several types of mutations have been reported in this syndrome&#44; most frequently in the gene that encodes the proline&#8211;serine&#8211;threonine phosphatase-interacting protein 1&#44; located in chromosome 15&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">44</span></a> Despite the correct identification of the gene and of other genetic abnormalities&#44; cases of PAPA have been diagnosed without finding mutations in the genetic study&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">45</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">PFAPA</span><p id="par0130" class="elsevierStylePara elsevierViewall">PFAPA syndrome &#40;an abbreviation for periodic fever&#44; aphthous stomatitis&#44; pharyngitis and adenitis&#41; was first reported in 1987 in 12 children with periodic fever&#44; oral aphthosis and pharyngotonsillitis&#44; with adenopathies that resemble cyclic neutropenia&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">46</span></a> Treatment with oral prednisone rapidly shortens the duration of the conditions&#44; constituting one of the diagnostic criteria of the syndrome also known as Marshall syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">47</span></a> The first case in adults was reported in 2008&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">48</span></a> Since then&#44; an increasing number of cases have been reported&#46; One of the theories as to why this syndrome also occurs in adulthood is related to a hypothetical immaturity of the immune system&#44; which facilitates episodes of PFAPA&#46; The clinical presentation&#44; in general&#44; is usually similar to that of the pediatric syndrome&#46; The response to steroid therapy is usually good&#44; but adenoidectomy only produces partial responses&#46; Exceptional cases have been reported with renal immunological manifestations in the form of glomerulonephritis&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">49</span></a> Isolated cases of response to cimetidine have been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0670"><span class="elsevierStyleSup">50&#44;51</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Schnitzler syndrome</span><p id="par0135" class="elsevierStylePara elsevierViewall">Schnitzler syndrome was first reported in 1972 and is characterized by symptoms of chronic urticaria&#44; periodic fever&#44; joint pain&#44; monoclonal gammopathy &#40;commonly IgM-&#1082;&#41; and increased levels of acute-phase reactants&#46; The syndrome&#39;s pathogenesis is unknown&#44; although it is believed that it has a significant connection with ADs&#44; given that mutations in the NLR family pyrin domain containing 3 &#40;NLRP3&#41; gene have been observed in a number of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">52</span></a> The disease is rare&#59; however&#44; it is important to suspect it given that some cases can progress to blood dyscrasia&#46;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">53&#44;54</span></a> The response to IL-1 inhibitors is satisfactory&#44;<a class="elsevierStyleCrossRefs" href="#bib0695"><span class="elsevierStyleSup">55&#8211;57</span></a> and overall survival is good&#44; although extended treatment needs to be maintained&#44; given that recurrence is the rule&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">58</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Blau syndrome</span><p id="par0140" class="elsevierStylePara elsevierViewall">Blau syndrome &#40;BS&#41; and early-onset sarcoidosis share a common etiopathogenic mechanism related to the nucleotide-binding oligomerization domain-containing 2 &#40;NOD2&#41; protein&#44; which is why variants of the same disease are considered&#44; with the difference in the sporadic presentation in early-onset sarcoidosis and the familial presentation in BS&#46; The NOD2 protein is a member of the NLR family of receptors of the innate immune system&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">59</span></a> The mutations related to this gene produce an overactive protein&#44; which results in an increase in the signal transduced by the nuclear transcription factor kappaB&#46;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">60</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Clinically&#44; BS is characterized by a persistent inflammatory condition with periodic episodes of exacerbation over the course of the disease&#39;s progression&#46; The disease usually starts before the age of 4 years&#44; typically with skin and joint symptoms&#46; The other manifestations&#44; mainly ocular&#44; progressively appear with age&#46; Cases of BS have been reported in a family in which the onset of the disease in the father was later&#46; The genetic study revealed that the father had a somatic mutation in gene NOD2 &#40;p&#46;Arg334Gln&#41;&#44; unlike the children&#44; whose mutation was germinal&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">61</span></a> This finding leads to the conclusion that the mosaicisms favor the onset of the disease in later ages and cause conditions with milder manifestations&#46;</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conclusions</span><p id="par0150" class="elsevierStylePara elsevierViewall">ADs occur infrequently in adulthood&#59; when they do occur&#44; they are mostly due to diagnostic delays&#46; However&#44; they can also occur due to adult onset&#44; in which case the symptoms are generally milder and atypical&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Monogenic ADs that appear in adulthood are usually associated with low-penetration mutations and milder symptoms&#46; Sporadic ADs &#40;Schnitzler syndrome&#41; usually present almost exclusively in adulthood&#46; Only PFAPA syndrome&#44; which is characteristic of childhood&#44; presents with similar characteristics in the few cases of adult onset&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">It is important to maintain a high diagnostic suspicion for the proper identification of these diseases&#44; given that treatment with biological therapies is usually accompanied by a good response or a better control of the disease&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflicts of interest</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Abstract"
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              "identificador" => "abst0005"
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          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Background"
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        5 => array:3 [
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          "titulo" => "Methods"
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            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Literature search"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Article inclusion and exclusion criteria"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Selection of references"
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          "identificador" => "sec0030"
          "titulo" => "Implementation and discussion"
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              "identificador" => "sec0035"
              "titulo" => "Classification of autoinflammatory diseases"
              "secciones" => array:3 [
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                  "identificador" => "sec0040"
                  "titulo" => "Overview"
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                1 => array:2 [
                  "identificador" => "sec0045"
                  "titulo" => "Familial Mediterranean fever"
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                2 => array:2 [
                  "identificador" => "sec0050"
                  "titulo" => "Tumor necrosis factor receptor-associated periodic syndrome &#40;TRAPS&#41;"
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            1 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Mevalonate kinase deficiency or hyper-IgD syndrome"
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              "identificador" => "sec0060"
              "titulo" => "Cryopyrinopathy or cryopyrin-associated periodic syndromes &#40;CAPS&#41;"
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              "identificador" => "sec0065"
              "titulo" => "PAPA"
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              "titulo" => "PFAPA"
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              "identificador" => "sec0075"
              "titulo" => "Schnitzler syndrome"
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              "identificador" => "sec0080"
              "titulo" => "Blau syndrome"
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          "titulo" => "Conclusions"
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          "titulo" => "Conflicts of interest"
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            0 => "Hereditary autoinflammatory diseases"
            1 => "Adults"
            2 => "Periodic fever"
            3 => "Inflammasome"
            4 => "Nod-like receptor"
            5 => "TNF"
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            0 => "Enfermedades autoinflamatorias hereditarias"
            1 => "Adulto"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Autoinflammatory diseases are clinical conditions with inflammatory manifestations that present in a periodic or persistent manner and are caused by acquired or hereditary disorders of the innate immune response&#46; In general&#44; these diseases are more common in childhood&#44; but cases have been reported in adults and are therefore important for all specialists&#46; There are few references on these diseases in adults due to their low prevalence and underdiagnosis&#46; The aim of this study is to review the scientific literature on these disorders to systematize their clinical&#44; prognostic and treatment response characteristics in adults&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Las enfermedades autoinflamatorias son cuadros cl&#237;nicos con manifestaciones inflamatorias que se presentan de forma peri&#243;dica o persistente&#44; producidas por alteraciones adquiridas o hereditarias de la respuesta inmune innata&#46; En general&#44; son m&#225;s frecuentes en la edad pedi&#225;trica&#44; pero se han descrito casos en adultos&#44; por lo que son de inter&#233;s para cualquier especialista&#46; Existen pocas referencias de estas enfermedades en el adulto por su baja prevalencia e infradiagn&#243;stico&#46; El objetivo de este trabajo es revisar la literatura cient&#237;fica sobre estos trastornos para sistematizar sus caracter&#237;sticas cl&#237;nicas&#44; pron&#243;sticas y la respuesta al tratamiento en el adulto&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Gonz&#225;lez Garc&#237;a A&#44; Patier de la Pe&#241;a JL&#44; Ortego Centeno N&#46; Enfermedades autoinflamatorias en el adulto&#46; Caracter&#237;sticas cl&#237;nicas e implicaciones pron&#243;sticas&#46; Rev Clin Esp&#46; 2017&#59;217&#58;108&#8211;116&#46;</p>"
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; FMF&#44; familial Mediterranean fever&#59; TRAPS&#44; tumor necrosis factor receptor-associated periodic syndrome&#59; Hyper IgD-MVK&#44; hyper IgD syndrome&#47;mevalonate-kinase deficiency&#59; CAPS&#44; cryopyrinopathy or cryopyrin-associated periodic syndromes&#59; FCAS&#44; familial cold autoinflammatory syndrome&#59; MW&#44; Muckle&#8211;Wells disease&#59; CINCA&#44; chronic infantile neurological&#44; cutaneous and articular syndrome&#44; previously known as neonatal onset multisystem inflammatory disease&#59; BS&#44; Blau syndrome&#59; PAPA&#44; pyogenic arthritis&#44; pyoderma gangrenosum and acne syndrome&#59; PFAPA&#44; periodic fever&#44; aphthous stomatitis&#44; pharyngitis&#44; adenitis syndrome&#46;</p>"
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                  \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">Autosomal recessive inheritance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Autosomal dominant inheritance</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Other &#40;acquired&#44; polygenic&#41;&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">Periodic fever&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Periodic fever&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Persistent autoinflammatory disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PFAPA&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">FMF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TRAPS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CAPS&#58; FCAS&#44; MW&#44; CINCA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Schnitzler 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">Hyper IgD-MVK&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BS&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></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">PAPA&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
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; FMF&#44; familial Mediterranean fever&#59; TRAPS&#44; tumor necrosis factor receptor-associated periodic syndrome&#59; Hyper IgD-MVK&#44; hyper IgD syndrome&#47;mevalonate-kinase deficiency&#59; CAPS&#44; cryopyrinopathy or cryopyrin-associated periodic syndromes&#59; BS&#44; Blau syndrome&#59; PAPA&#44; pyogenic arthritis&#44; pyoderma gangrenosum and acne syndrome&#59; PFAPA&#44; periodic fever&#44; aphthous stomatitis&#44; pharyngitis&#44; adenitis syndrome&#46;</p>"
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                  \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">Drug&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">Autoinflammatory disease&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">Level of evidence&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" title="table-entry  " rowspan="7" align="left" valign="top">Anakinra</td><td class="td" title="table-entry  " align="left" valign="top">CAPS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRefs" href="#bib0730"><span class="elsevierStyleSup">62&#44;63</span></a>&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">TRAPS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRefs" href="#bib0740"><span class="elsevierStyleSup">64&#44;65</span></a>&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">FMF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">66</span></a>&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 IgD syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">67</span></a>&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">PAPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">42&#44;68&#8211;70</span></a>&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">Schnitzler syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">58</span></a>&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">PFAPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">71</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Rilonacept</td><td class="td" title="table-entry  " align="left" valign="top">CAPS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Randomized and controlled study<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">72</span></a>&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">FMF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Randomized and controlled study<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">73</span></a>&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">Schnitzler syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Quasi-experimental study<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">55</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="6" align="left" valign="top">Canakimumab</td><td class="td" title="table-entry  " align="left" valign="top">CAPS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Open study<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">74</span></a><br>Real-life study<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">75</span></a>&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">TRAPS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">76</span></a>&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 IgD syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">57</span></a>&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">FMF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">13&#44;57</span></a>&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">PAPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0805"><span class="elsevierStyleSup">77</span></a>&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">Schnitzler syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Controlled study without randomization<a class="elsevierStyleCrossRefs" href="#bib0700"><span class="elsevierStyleSup">56&#44;78</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Adalimumab</td><td class="td" title="table-entry  " align="left" valign="top">FMF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">13</span></a>&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">PAPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">14&#44;42</span></a>&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">SB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">79</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Infliximab</td><td class="td" title="table-entry  " align="left" valign="top">FMF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">13</span></a>&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">SB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0820"><span class="elsevierStyleSup">80</span></a>&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">PAPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">42</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Etanercept</td><td class="td" title="table-entry  " align="left" valign="top">FMF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">13</span></a>&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">TRAPS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Open study<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">15&#44;81</span></a>&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 IgD syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">34</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Tocilizumab</td><td class="td" title="table-entry  " align="left" valign="top">TRAPS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">82&#44;83</span></a>&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 IgD syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">84</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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      "titulo" => "References"
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        0 => array:2 [
          "identificador" => "bibs0005"
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                          "etal" => false
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                      "autores" => array:1 [
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                            1 => "E&#46; Ruiz-Ortiz"
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                            0 => "F&#46; Martinon"
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                      "titulo" => "Lights and shadows in autoinflammatory syndromes from the childhood and adulthood perspective"
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                            0 => "D&#46; Rigante"
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                  "contribucion" => array:1 [
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                          "etal" => true
                          "autores" => array:6 [
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                            2 => "F&#46; Iacoponi"
                            3 => "R&#46; Cimaz"
                            4 => "G&#46; Simonini"
                            5 => "D&#46; Rigante"
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                        "fecha" => "2010"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoinflammatory conditions&#58; when to suspect&#63; How to treat"
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                          "etal" => false
                          "autores" => array:2 [
                            0 => "G&#46; Grateau"
                            1 => "M&#46;T&#46; Duruoz"
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                  "host" => array:1 [
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                      "doi" => "10.1016/j.berh.2009.12.009"
                      "Revista" => array:6 [
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                        "fecha" => "2010"
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2016.10.001

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