Novelties in dermatology
Advances in the Diagnosis and Treatment of Tumor Necrosis Factor Receptor–Associated Periodic Syndrome
Novedades en el diagnóstico y tratamiento del síndrome periódico asociado al receptor del factor de necrosis tumoral
L. Aguado-Gil
, I. Irarrazaval-Armendáriz, M. Pretel-Irazabal
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Departamento de Dermatología, Clínica Universidad de Navarra, Pamplona, Spain
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Aguado-Gil, I. Irarrazaval-Armendáriz, M. Pretel-Irazabal" "autores" => array:3 [ 0 => array:4 [ "nombre" => "L." "apellidos" => "Aguado-Gil" "email" => array:1 [ 0 => "laguado@unav.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "I." "apellidos" => "Irarrazaval-Armendáriz" ] 2 => array:2 [ "nombre" => "M." "apellidos" => "Pretel-Irazabal" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Departamento de Dermatología, Clínica Universidad de Navarra, Pamplona, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding Author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Novedades en el diagnóstico y tratamiento del síndrome periódico asociado al receptor del factor de necrosis tumoral" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Concept</span><p id="par0005" class="elsevierStylePara elsevierViewall">Autoinflammatory syndromes are a group of disorders characterized by recurrent fever, localized inflammation, an absence of autoantibodies, and a tendency toward familial aggregation.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Autoinflammatory diseases cause several different types of febrile episodes, including fever of unknown origin, periodic fever, and recurrent fever. Differential diagnosis of febrile episodes should therefore include autoinflammatory diseases once infections, malignancies, and autoimmune diseases have been ruled out.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Cytokines are secreted by macrophages and other cells of the immune system in response to pathogens, against which they mount and inflammatory response. In autoinflammatory diseases cytokines are secreted in the absence of pathogenic stimuli.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">There are several systemic autoinflammatory diseases with a Mendelian pattern of inheritance for which the causative gene has been identified. This group of diseases is divided into several subgroups (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Hereditary periodic fever syndromes constitute the most important subgroup of systemic autoinflammatory diseases. This subgroup comprises 2 diseases with a recessive pattern of inheritance (familial Mediterranean fever [FMF], and hyperimmunoglobulinemia D and periodic fever syndrome [HIDS]) and 1 dominantly-inherited condition (tumor necrosis factor [TNF] receptor-associated periodic syndrome [TRAPS]).</p><p id="par0025" class="elsevierStylePara elsevierViewall">In recent years there has been an exponential increase in interest in autoinflammatory diseases by doctors of different specialties, and in the study of these diseases.</p><p id="par0030" class="elsevierStylePara elsevierViewall">In this review we summarize and discuss new data relating to TRAPS that has been published in the last 5 years. To gather this data, we searched the PubMed database using the search term <span class="elsevierStyleItalic">TRAPS</span>. We retrieved 8221 articles, some of which did not pertain to TRAPS. The search term <span class="elsevierStyleItalic">TRAPS TNF receptor</span> returned 179 articles. We selected articles that were published within the last 5 years (78 articles in total). We also reviewed the most important references cited in the selected articles.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Clinical Manifestations</span><p id="par0035" class="elsevierStylePara elsevierViewall">A 1982 study described members of a family of Scandinavian origin who presented episodes of prolonged fever, abdominal pain, myalgia, erythema, conjunctivitis, and/or periorbital edema.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> This condition was termed Hibernian fever, as distinct from Mediterranean fever.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In 1999, 6 missense mutations (i.e., mutations that result in amino acid changes) were discovered in the gene encoding tumor necrosis factor receptor 1 (<span class="elsevierStyleItalic">TNFR1</span>), located on chromosome 12p, in individuals affected by this condition.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Following this discovery the acronym TRAPS (TNF-receptor-associated periodic syndrome) was coined.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Although the first cases were described in Irish and Central European populations, TRAPS has been reported in countries throughout the world, including Spain.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> The sex distribution is approximately 1:1. The main clinical characteristics of TRAPS are summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">The symptoms of TRAPS generally appear around 3 years of age (preschool age). Attacks are usually prolonged (lasting up to 3 weeks) and recur with variable frequency.</p><p id="par0055" class="elsevierStylePara elsevierViewall">However, some patients present persistent symptoms that increase and decrease in intensity without clear asymptomatic intervals. Some patients have reported that certain factors or situations can trigger the episodes (physical or psychological stress, ovulation, or menstruation) and in some cases patients experience prodromal symptoms (periorbital edema, general malaise, headache).<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Patients have described prodromal symptoms such as deep muscle pain that increases progressively to reach maximum intensity after 2 to 3 days and subsequently subsides.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Fever is always present in children but may be absent in adults. The most notable differentiating symptom of TRAPS is myalgia, which normally affects only 1 region of the body and varies in intensity throughout the duration of the attack.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Myalgia is caused by chronic inflammatory fasciitis, not myositis, and thus serum concentrations of creatine and aldolase are usually normal.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">In addition to myalgia, patients usually present a migratory erythematous rash (centrifugal spread), which is frequently maculopapular. This rash often takes the form of a bullseye as the inflammatory episode evolves.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Joint pain is very common, while arthritis, whether monoarticular and oligoarticular, occurs less frequently.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Ocular manifestations are very common (over 80% of cases) and include conjunctivitis, edema, and/or periorbital pain (unilateral or bilateral). Periorbital edema can occur as a prodromal symptom.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Digestive symptoms are present in a large proportion (up to 92%) of patients with TRAPS and often manifest as abdominal pain, which may be secondary to inflammatory peritonitis or inflammation of the muscles of the abdominal wall.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,8</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Vomiting and constipation also occur in many patients, some of whom require surgical intervention for acute abdomen, usually caused by sterile inflammatory peritonitis.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Other less common manifestations include lymphadenopathy, chest pain (with pleural or intercostal muscle involvement), and testicular pain and swelling.</p><p id="par0105" class="elsevierStylePara elsevierViewall">Many patients with TRAPS report that they do not feel completely well between episodes. Quillinan and coworkers<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> demonstrated that subclinical fasciitis and arthritis persist between febrile attacks.</p><p id="par0110" class="elsevierStylePara elsevierViewall">The most serious complication of TRAPS is the development of secondary amyloidosis due to recurrent inflammatory processes over several years. TRAPS patients with mutations that affect cysteine amino acids have a higher risk of developing amyloidosis than those carrying noncysteine mutations (24% versus 2%, respectively). The kidney is usually the first organ affected by amyloidosis, and proteinuria is the earliest indicator.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,12</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pathogenesis</span><p id="par0115" class="elsevierStylePara elsevierViewall">Studies of the pathogenesis of TRAPS have demonstrated defective TNF-dependent cellular signaling, an unexpected finding given the hyperinflammatory phenotype of the disease. Several studies have found that the majority of mutated TNF receptors never reach the cell surface and remain trapped in the endoplasmic reticulum, where they elicit an intracellular inflammatory response resulting in the constitutive expression of proinflammatory cytokines.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,14</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Elevated levels of IL-22 expression have been reported in a patient with TRAPS. This T cell-derived cytokine induces inflammation of the liver, pancreas, intestine, and skin. Elevated IL-22 levels have also been described in patients with psoriasis or pityriasis rosea.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Diagnosis</span><p id="par0125" class="elsevierStylePara elsevierViewall">With the exception of genetic analysis, there are no specific laboratory tests for TRAPS. During episodes an intense acute reaction occurs, involving neutrophilia, left shift, thrombocytosis, anemia, and increases in the erythrocyte sedimentation rate and in the levels of C-reactive and serum amyloid proteins. A polyclonal increase in immunoglobulins may occur, and no autoantibodies are detected. These alterations tend to attenuate during asymptomatic periods.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,8</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Although TRAPS usually begins in early childhood, this disease has also been diagnosed in adult patients. It is thus inadvisable to rule out the presence of this syndrome based solely on the age of patient.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Eighty-six <span class="elsevierStyleItalic">TNFRSF1A</span> mutations (109 sequence variants) able to induce the development of this disease have been described.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">The relationship between mutations and the disease phenotype is unclear, due to the large degree of heterogeneity between different mutations and between patients with the same mutation.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">However, certain mutations are associated with milder forms of the disease. For example, the R92Q substitution generally causes a much milder disease course than that seen in patients with a structural mutation in the <span class="elsevierStyleItalic">TNFRSF1A</span> gene.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18,19</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">It is likely that many <span class="elsevierStyleItalic">TNFRSF1A</span> mutations have yet to be described. Many patients display all the clinical characteristics of TRAPS but carry none of the associated mutations described to date.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20,21</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">A recent review summarized all skin manifestations in TRAPS,<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> which included migratory plaques, rashes, urticaria, erysipelas-like erythema, edematous plaques, periorbital edema, and/or conjunctivitis. Skin lesions were usually described as painful due to underlying myalgia, and were histologically nonspecific. The most characteristic finding was a dermal infiltrate of lymphocytes and monocytes. Immunohistochemistry revealed that the infiltrate consisted of CD3<span class="elsevierStyleSup">+</span>, CD4<span class="elsevierStyleSup">+</span>, CD8<span class="elsevierStyleSup">+</span>, CD68<span class="elsevierStyleSup">+</span>, CD79a<span class="elsevierStyleSup">−</span>, and CD20<span class="elsevierStyleSup">−</span> cells. None of the biopsies indicated leukocytoclastic or granulomatous vasculitis, or multinucleated macrophages.</p><p id="par0160" class="elsevierStylePara elsevierViewall">It is clear that patients who present the main symptoms of this syndrome should undergo genetic testing. However, problems arise with patients who present only some of the possible symptoms of TRAPS. For example, cases of TRAPS patients whose only manifestation is recurrent pericarditis have been reported.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">A study of 131 patients with acute recurrent pericarditis found that TRAPS was the cause of this condition in only 6% of the cases studied.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> The authors concluded that patients with recurrent acute pericarditis in whom TRAPS is suspected (and hence who require genetic testing) are those with a family history of pericarditis or periodic fever syndromes, a poor response to colchicine, and who experience recurrences within 1 year of diagnosis or during colchicine treatment,<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> as well as patients who require immunosuppressive agents to control the disease.</p><p id="par0170" class="elsevierStylePara elsevierViewall">A V20A mutation that causes regular gastrointestinal symptoms (nausea, vomiting, diarrhea, and extreme fatigue) without other manifestations of TRAPS (fever, arthralgia, or skin lesions) has also been described.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Association of TRAPS With Other Diseases</span><p id="par0175" class="elsevierStylePara elsevierViewall">TNF signaling is implicated in the pathophysiology of multiple sclerosis. The R92Q mutation in the <span class="elsevierStyleItalic">TNFR1</span> gene is a genetic risk factor for the development of multiple sclerosis. Cases of multiple sclerosis patients who carry the R92Q mutation and also present symptoms of TRAPS have been reported. This mutation appears to be a genetic risk factor for both diseases. An alteration in TNF-TNFR signaling could induce an increase in proinflammatory signaling, while the final clinical phenotype may be determined by other as-yet-unknown genetic or environmental factors.<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27–29</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">A previously unknown <span class="elsevierStyleItalic">TNFR1</span> mutation that causes symptoms of TRAPS and HIDS was recently discovered in a child.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">The case of a patient carrying a mutation in the <span class="elsevierStyleItalic">TRAPS</span> gene and another in the gene that causes FMF has been reported; the patient's phenotype was a mixture of the 2 pathological processes.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Treatment</span><p id="par0190" class="elsevierStylePara elsevierViewall">The complexity of the pathogenesis of TRAPS is evidenced by the number of different treatments that have been used in this condition, with varying degrees of success.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">Colchicine can potentiate the effect of corticosteroids in controlling attacks, and its use during asymptomatic periods can decrease the risk of amyloidosis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to attenuate symptoms.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,32</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Corticosteroids at doses of over 20<span class="elsevierStyleHsp" style=""></span>mg/d can provide short-term control of TRAPS. However, coadministration of NSAIDS may be required due to the development of corticosteroid tolerance and dependence over time.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">Etanercept, administered subcutaneously at a dose of 25<span class="elsevierStyleHsp" style=""></span>mg twice a week, has been shown to reduce both the duration and frequency of attacks, allowing a reduction in corticosteroid dose.<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34–36</span></a> However, the benefits of etanercept treatment are variable and in some cases are not sustained.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> This treatment has been shown to reverse nephrotic syndrome induced by amyloidosis in a patient with TRAPS, but failed to decrease the amount of amyloid deposited.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Patients with TRAPS should not be treated with the anti-TNF monoclonal antibody infliximab, as this can induce paradoxical inflammatory reactions.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39,40</span></a> Adalimumab also appears to induce paradoxical inflammatory reactions.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> However, some patients with TRAPS respond well to infliximab treatment.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> It is postulated that the response to infliximab and the development of paradoxical inflammatory reactions may depend on the type of mutation carried by the patient.</p><p id="par0215" class="elsevierStylePara elsevierViewall">Anakinra, a recombinant antagonist of the IL-1 receptor, has shown promising results in the treatment of TRAPS,<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42–44</span></a> particularly in patients who do not respond to etanercept.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> However, a more recent study demonstrated a lack of response to anakinra by TRAPS patients carrying the T50<span class="elsevierStyleHsp" style=""></span>M mutation (who had previously failed to respond to etanercept).<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Treatment of a TRAPS patient with tocilizumab, a humanized monoclonal antibody that binds to the IL-6 cellular receptor, was found to abort an acute episode and prevent further episodes, although levels of IL-1a and IL8 remained elevated in this patient.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">An improvement was reported in a patient with TRAPS who was treated with moxifloxacin, although this effect was not observed in 3 other patients who received the same treatment.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> It is not known whether the beneficial effects of moxifloxacin were due to the elimination of bacterial antigens or its anti-inflammatory action.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusions</span><p id="par0230" class="elsevierStylePara elsevierViewall">Given the risk of amyloidosis it is essential to diagnose patients with TRAPS.</p><p id="par0235" class="elsevierStylePara elsevierViewall">Dermatologists should be familiar with this syndrome, as a large proportion of patients can be diagnosed by their skin symptoms.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Ethical Responsibilities</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Protection of persons and animals</span><p id="par0240" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals during the course of this study.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Data confidentiality</span><p id="par0245" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their place of work pertaining to the publication of patient data and that all patients included in the study were appropriately informed and provided written informed consent to participate in the study.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Right to privacy and informed consent</span><p id="par0250" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article.</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflict of Interest</span><p id="par0255" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:2 [ "identificador" => "xres261463" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec246072" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres261464" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec246071" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Concept" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Clinical Manifestations" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Pathogenesis" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Diagnosis" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Association of TRAPS With Other Diseases" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Treatment" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusions" ] 11 => array:3 [ "identificador" => "sec0040" "titulo" => "Ethical Responsibilities" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Protection of persons and animals" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Data confidentiality" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Right to privacy and informed consent" ] ] ] 12 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflict of Interest" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-06-18" "fechaAceptado" => "2012-11-17" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec246072" "palabras" => array:4 [ 0 => "Autoinflammatory diseases" 1 => "Tumor necrosis factor receptor" 2 => "Syndrome" 3 => "Tumor necrosis factor receptor-associated periodic syndrome" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec246071" "palabras" => array:4 [ 0 => "Enfermedades autoinflamatorias" 1 => "Receptor del factor de necrosis tumoral" 2 => "Síndrome" 3 => "Síndrome periódico asociado al receptor del factor de necrosis tumoral" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Tumor necrosis factor receptor–associated periodic syndrome (TRAPS) is a rare autosomal dominant disease included in the group of autoinflammatory syndromes. It is characterized by recurrent episodes of fever and inflammation in different regions of the body. The main clinical manifestations are myalgia, migratory erythematous rash, periorbital edema, and abdominal pain. The diagnosis is reached using gene analysis and prognosis depends on the appearance of amyloidosis secondary to the recurrent episodes of inflammation. Tumor necrosis factor inhibitors and corticosteroids are the most widely used treatments. In recent years, significant advances have been made in the diagnosis and treatment of TRAPS, thanks to a better understanding of its pathogenesis. Dermatologists must be aware that the skin manifestations of TRAPS are particularly important, as they are often diagnostic.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El síndrome periódico asociado al receptor del factor de necrosis tumoral (TRAPS) es una rara enfermedad autosómica dominante que forma parte de los síndromes autoinflamatorios. Se caracteriza por episodios recurrentes de fiebre e inflamación en distintos sitios del organismo, siendo sus principales manifestaciones: las mialgias, el exantema eritematoso migratorio, el edema periorbitario y el dolor abdominal. El diagnóstico se realiza mediante el análisis genético y su pronóstico está determinado por el desarrollo de amiloidosis, secundaria a los episodios inflamatorios repetidos. Los tratamientos más utilizados son los corticoides y los inhibidores del TNF. Durante los últimos años, gracias a un mayor conocimiento de su patogénesis, se han logrado importantes avances en su diagnóstico y tratamiento. Como dermatólogos es importante tener en cuenta que las manifestaciones cutáneas son particularmente importantes en el TRAPS, ya que muchas veces guían al clínico hacia su correcto diagnóstico.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Aguado-Gil L, et al. Novedades en el diagnóstico y tratamiento del síndrome periódico asociado al receptor del factor de necrosis tumoral. Actas Dermosifiliogr. 2013;104:617–22.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Abbreviations: CINCA, chronic infantile neurological, cutaneous, and articular syndrome; CRMO, chronic recurrent multifocal osteomyelitis; FCAS, familial cold-induced autoinflammatory syndrome; NOMID, neonatal-onset multisystemic inflammatory disease; PAPA, pyogenic sterile arthritis, pyoderma gangrenosum and acne syndrome.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Hereditary periodic fever syndromes</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Familial Mediterranean fever \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hyperimmunoglobulinemia D syndrome with periodic fever (HIDS) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>TNF receptor-associated periodic syndrome (TRAPS) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Cryopyrin-associated periodic syndromes</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>FCAS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Muckle-Wells syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>CINCA-NOMID syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Pediatric systemic granulomatosis</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Blau syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Early onset sarcoidosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Other hereditary systemic autoinflammatory diseases</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>PAPA syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>CRMO \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab367510.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Classification of Hereditary Systemic Autoinflammatory Diseases.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">It is not necessary for patients to meet all criteria nor is there a minimum number of criteria required to suspect this syndrome.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Recurrent episodes of inflammatory symptoms</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Fever \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Abdominal pain \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Myalgia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Migratory macular erythema \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Eyelid edema or conjunctivitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Chest pain \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Arthralgia or monoarticular synovitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Episodes lasting more than 5 days and occurring every 2 to 9 months</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Respond to corticosteroids but not to colchicine</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Affected family members (not in all cases)</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Any ethnic group can be affected</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab367511.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Diagnostic Criteria 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 12 | 8 | 20 |
| 2024 Octubre | 86 | 45 | 131 |
| 2024 Septiembre | 91 | 36 | 127 |
| 2024 Agosto | 131 | 63 | 194 |
| 2024 Julio | 100 | 39 | 139 |
| 2024 Junio | 137 | 36 | 173 |
| 2024 Mayo | 134 | 41 | 175 |
| 2024 Abril | 88 | 34 | 122 |
| 2024 Marzo | 109 | 30 | 139 |
| 2024 Febrero | 60 | 27 | 87 |
| 2024 Enero | 58 | 38 | 96 |
| 2023 Diciembre | 66 | 17 | 83 |
| 2023 Noviembre | 79 | 37 | 116 |
| 2023 Octubre | 61 | 34 | 95 |
| 2023 Septiembre | 75 | 35 | 110 |
| 2023 Agosto | 41 | 19 | 60 |
| 2023 Julio | 47 | 43 | 90 |
| 2023 Junio | 62 | 25 | 87 |
| 2023 Mayo | 58 | 32 | 90 |
| 2023 Abril | 40 | 27 | 67 |
| 2023 Marzo | 61 | 40 | 101 |
| 2023 Febrero | 84 | 23 | 107 |
| 2023 Enero | 47 | 46 | 93 |
| 2022 Diciembre | 75 | 56 | 131 |
| 2022 Noviembre | 38 | 28 | 66 |
| 2022 Octubre | 30 | 23 | 53 |
| 2022 Septiembre | 22 | 25 | 47 |
| 2022 Agosto | 26 | 32 | 58 |
| 2022 Julio | 34 | 57 | 91 |
| 2022 Junio | 27 | 30 | 57 |
| 2022 Mayo | 43 | 30 | 73 |
| 2022 Abril | 39 | 41 | 80 |
| 2022 Marzo | 59 | 50 | 109 |
| 2022 Febrero | 45 | 31 | 76 |
| 2022 Enero | 44 | 51 | 95 |
| 2021 Diciembre | 49 | 37 | 86 |
| 2021 Noviembre | 45 | 41 | 86 |
| 2021 Octubre | 55 | 62 | 117 |
| 2021 Septiembre | 37 | 43 | 80 |
| 2021 Agosto | 41 | 45 | 86 |
| 2021 Julio | 28 | 31 | 59 |
| 2021 Junio | 34 | 34 | 68 |
| 2021 Mayo | 49 | 48 | 97 |
| 2021 Abril | 79 | 71 | 150 |
| 2021 Marzo | 74 | 48 | 122 |
| 2021 Febrero | 94 | 38 | 132 |
| 2021 Enero | 48 | 29 | 77 |
| 2020 Diciembre | 36 | 22 | 58 |
| 2020 Noviembre | 40 | 30 | 70 |
| 2020 Octubre | 24 | 18 | 42 |
| 2020 Septiembre | 47 | 22 | 69 |
| 2020 Agosto | 31 | 23 | 54 |
| 2020 Julio | 26 | 15 | 41 |
| 2020 Junio | 39 | 39 | 78 |
| 2020 Mayo | 24 | 15 | 39 |
| 2020 Abril | 49 | 33 | 82 |
| 2020 Marzo | 41 | 30 | 71 |
| 2020 Febrero | 6 | 12 | 18 |
| 2020 Enero | 6 | 10 | 16 |
| 2019 Diciembre | 8 | 4 | 12 |
| 2019 Noviembre | 4 | 0 | 4 |
| 2019 Octubre | 2 | 2 | 4 |
| 2019 Septiembre | 6 | 5 | 11 |
| 2019 Agosto | 6 | 10 | 16 |
| 2019 Julio | 4 | 7 | 11 |
| 2019 Junio | 6 | 17 | 23 |
| 2019 Mayo | 5 | 11 | 16 |
| 2019 Abril | 2 | 14 | 16 |
| 2019 Marzo | 4 | 12 | 16 |
| 2019 Febrero | 1 | 4 | 5 |
| 2019 Enero | 2 | 2 | 4 |
| 2018 Diciembre | 4 | 6 | 10 |
| 2018 Noviembre | 0 | 3 | 3 |
| 2018 Octubre | 6 | 0 | 6 |
| 2018 Septiembre | 6 | 0 | 6 |
| 2018 Marzo | 1 | 0 | 1 |
| 2018 Febrero | 53 | 4 | 57 |
| 2018 Enero | 39 | 9 | 48 |
| 2017 Diciembre | 68 | 8 | 76 |
| 2017 Noviembre | 51 | 10 | 61 |
| 2017 Octubre | 36 | 12 | 48 |
| 2017 Septiembre | 45 | 7 | 52 |
| 2017 Agosto | 75 | 7 | 82 |
| 2017 Julio | 53 | 4 | 57 |
| 2017 Junio | 83 | 13 | 96 |
| 2017 Mayo | 87 | 11 | 98 |
| 2017 Abril | 53 | 16 | 69 |
| 2017 Marzo | 53 | 5 | 58 |
| 2017 Febrero | 47 | 7 | 54 |
| 2017 Enero | 24 | 18 | 42 |
| 2016 Diciembre | 46 | 13 | 59 |
| 2016 Noviembre | 68 | 13 | 81 |
| 2016 Octubre | 71 | 21 | 92 |
| 2016 Septiembre | 59 | 17 | 76 |
| 2016 Agosto | 61 | 7 | 68 |
| 2016 Julio | 48 | 9 | 57 |
| 2016 Junio | 14 | 12 | 26 |
| 2016 Mayo | 8 | 9 | 17 |
| 2016 Abril | 3 | 1 | 4 |
| 2016 Marzo | 5 | 9 | 14 |
| 2016 Febrero | 9 | 4 | 13 |
| 2016 Enero | 6 | 2 | 8 |
| 2015 Diciembre | 16 | 0 | 16 |
| 2015 Noviembre | 13 | 2 | 15 |
| 2015 Octubre | 5 | 9 | 14 |
| 2015 Septiembre | 6 | 5 | 11 |
| 2015 Agosto | 7 | 5 | 12 |
| 2015 Julio | 31 | 1 | 32 |
| 2015 Junio | 30 | 9 | 39 |
| 2015 Mayo | 51 | 19 | 70 |
| 2015 Abril | 26 | 9 | 35 |
| 2015 Marzo | 43 | 12 | 55 |
| 2015 Febrero | 24 | 14 | 38 |
| 2015 Enero | 20 | 11 | 31 |
| 2014 Diciembre | 24 | 12 | 36 |
| 2014 Noviembre | 18 | 11 | 29 |
| 2014 Octubre | 59 | 18 | 77 |
| 2014 Septiembre | 29 | 10 | 39 |
| 2014 Agosto | 35 | 20 | 55 |
| 2014 Julio | 35 | 7 | 42 |
| 2014 Junio | 42 | 9 | 51 |
| 2014 Mayo | 52 | 15 | 67 |
| 2014 Abril | 37 | 4 | 41 |
| 2014 Marzo | 40 | 15 | 55 |
| 2014 Febrero | 22 | 7 | 29 |
| 2014 Enero | 22 | 11 | 33 |
| 2013 Diciembre | 15 | 4 | 19 |
| 2013 Noviembre | 24 | 12 | 36 |
| 2013 Octubre | 25 | 6 | 31 |
| 2013 Septiembre | 28 | 10 | 38 |
| 2013 Agosto | 4 | 3 | 7 |
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