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Explanted heart in a transplanted patient.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Rebeca Lorca, José Rozado, María Martín" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Rebeca" "apellidos" => "Lorca" ] 1 => array:2 [ "nombre" => "José" "apellidos" => "Rozado" ] 2 => array:2 [ "nombre" => "María" "apellidos" => "Martín" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775317308205" "doi" => "10.1016/j.medcli.2017.09.026" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775317308205?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020618300901?idApp=UINPBA00004N" "url" => "/23870206/0000015000000009/v1_201805200428/S2387020618300901/v1_201805200428/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2387020618300895" "issn" => "23870206" "doi" => "10.1016/j.medcle.2017.10.035" "estado" => "S300" "fechaPublicacion" => "2018-05-11" "aid" => "4319" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Med Clin. 2018;150:345-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial article</span>" "titulo" => "Is it time to discuss on low-intervention clinical trials without participants’ informed consent?" 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Other frequent manifestations are odynophagia, myalgias, hepatic involvement (elevation of liver tests with or without hepatomegaly), and the presence of lymphadenopathy and/or splenomegaly.<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">1–9</span></a> From a lab-results point of view, the existence of a significant leukocytosis with neutrophilia and an elevation of serum ferritin levels is characteristic.<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">1–9</span></a> None of these data is pathognomonic, so the diagnosis of certainty of the disease is always one of exclusion and, in some cases, difficult. To complicate it further, there is increasing evidence that AOSD is a very heterogeneous entity in terms of clinical presentation, severity and progression. Therefore, it is important to know the latest advances and other less known aspects of this entity to avoid diagnostic delays and wrong treatments (antibiotics, antihistamines, etc.), as well as to try to establish the phenotype of the disease early and to establish a prognosis that can help decide the most appropriate treatment.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Clinical manifestations</span><p id="par0010" class="elsevierStylePara elsevierViewall">One of the clinical signs that classically supports the diagnosis of AOSD is rash. In typical cases, it is a maculopapular salmon-coloured rash, sometimes pruritic, that appears on the trunk, proximal parts of the limbs and pressure areas, usually during febrile episodes. It tends to develop with dermatographism. Histologically, it is characterized by an inflammatory perivascular superficial infiltrate at the expense of lymphocytes and neutrophils.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">10</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In addition to the evanescent rash characteristic of the disease, we now know that AOSD can also develop atypical skin rashes, mainly persistent pruritic papules or plaques (PPP) and urticarial rashes (<a class="elsevierStyleCrossRefs" href="#fig0005">Figs. 1 and 2</a>).<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">11–13</span></a> The prevalence of these atypical skin lesions is 14%.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">11</span></a> Although they can appear at any time during the course of the disease, they most often appear at the beginning or during a flare of activity, coinciding or not with the typical evanescent rash. It is important to keep in mind that in 43% of cases they are the only cutaneous manifestation of AOSD so that, when they occur in the beginning of the disease, it is common that they are mistakenly attributed to a non-steroidal anti-inflammatories-induced drug allergic reaction prescribed to treat fever or joint manifestations with the consequent diagnostic delay.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">11</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">The PPP usually have an erythematous, violaceous or brownish colouration, they may develop desquamation or scabs, and are usually located on the trunk (especially on the neck and back) and extension surface of the limbs, usually presenting a linear configuration simulating a flagellate rash. However, they can also adopt other morphological patterns such as urticariform or lichenoid papules, or lesions similar to those of prurigo pigmentosa, dermatomyositis or lichen amyloidosis.<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">11–13</span></a> Histologically, PPPs have a characteristic pattern defined by the presence of necrotic and dyskeratotic keratinocytes in the upper layers of the epidermis together with a perivascular inflammatory infiltrate in the dermis, and the presence of dermal mucin deposits is also common. Therefore, biopsy of these lesions is recommended since the finding of their distinctive histopathological features may help to reaffirm AOSD suspicion.<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">11,12</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The occurrence of atypical skin lesions also has a prognostic value since, generally speaking, they appear in persistent and severe forms of the disease with frequent (23%) occurrence of visceral complications and macrophage activation syndrome (MAS).<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">4</span></a> Thus, the detection of cutaneous lesions other than the classic evanescent rash that can also occur in AOSD is crucial to avoid a diagnostic delay in these cases of atypical presentation and also predicts a persistent and serious disease, anticipating the need for more intensive immunosuppressant treatment.</p><p id="par0030" class="elsevierStylePara elsevierViewall">In addition to the clinical manifestations previously mentioned, less frequent or exceptional manifestations have also been described in AOSD, which should be kept in mind especially in the evaluation and follow-up of patients with the systemic form of the disease. These include haematological complications, serositis (pleuritis and pericarditis, which can be complicated by cardiac tamponade), abdominal pain, pulmonary complications (the most frequent being acute respiratory distress syndrome and interstitial lung disease, almost always with a non-specific pattern of interstitial pneumonia, although cases of diffuse alveolar haemorrhage have also been reported), cardiac complications (myocarditis and primary pulmonary hypertension), neurological complications (especially aseptic meningitis, cerebral ischaemic attacks and cranial nerve palsies), kidney disease (tubulo-interstitial nephritis, different types of glomerulonephritis and renal amyloidosis), acute hepatic failure (sometimes fulminating), and the systemic inflammatory response syndrome (shock, acute respiratory distress syndrome, acute renal failure and disseminated intravascular coagulation).<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">1–9,14–22</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Among the most serious haematological complications (in addition to thrombotic thrombocytopenic purpura, disseminated intravascular coagulation and pure red cell aplasia), we must highlight MAS, also called hemophagocytic reactive syndrome, which appears in up to 10–15% of patients.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">22</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the main clinical and analytical data that should alert the clinician to suspect a MAS.<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">22–24</span></a> In 2016 consensus criteria was established for the diagnosis of this complication in the systemic forms of juvenile idiopathic arthritis, endorsed by the <span class="elsevierStyleItalic">European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organization Collaborative Initiative</span> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">25</span></a> They have not yet been validated in AOSD although they seem to be useful.<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">26</span></a> Obtaining histopathological confirmation of hemophagocytic activity is recommended (it is usually demonstrated in the myelogram obtained by aspiration or bone marrow biopsy, a lymph node, liver or spleen biopsy is not necessary), but this should never delay the treatment that is always urgent, given the fatal progression of this complication, with a current mortality of 10–20%.<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">22–24</span></a> The most standardized treatment is glucocorticoid boluses (500<span class="elsevierStyleHsp" style=""></span>mg of methylprednisolone for 3 days) followed by 1<span class="elsevierStyleHsp" style=""></span>mg/kg/day of prednisone, intravenous immunoglobulins (400<span class="elsevierStyleHsp" style=""></span>mg/kg/day for 5 days or 1<span class="elsevierStyleHsp" style=""></span>g/kg/day for 2 days) and cyclosporine A.<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">22,24</span></a> With respect to biological treatments, anakinra at high doses (200<span class="elsevierStyleHsp" style=""></span>mg/day) has shown efficacy in cases refractory to standard treatment, although the experience is limited to clinical cases and series of cases.<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">27–29</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">It is important to note that neither interleukin (IL)-1 receptor antagonists (anakinra and canakinumab) nor tocilizumab (IL-6 receptor antagonist) have been shown to prevent the development of MAS.<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">29</span></a> Therefore, this complication should also be considered in the follow-up of patients treated with biological agents, especially in the case of any intercurrent infection (especially viral) that often acts as a triggering factor. Note that in patients treated with tocilizumab, the action of the drug may mask the presentation of MAS, delaying its diagnosis if there is no high index of suspicion.<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">30</span></a> Preliminary data indicate that interferon blockade γ) could be a good therapeutic target to prevent the development of this complication.<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Diagnosis</span><p id="par0045" class="elsevierStylePara elsevierViewall">The diagnosis of AOSD in a patient with compatible clinical symptoms, is usually done by ruling out infections, neoplasms (haematological and some solid tumours), systemic autoimmune diseases (systemic lupus erythematosus, dermatomyositis, panarteritis nodosa), Castleman's disease, autoinflammatory syndromes and reaction to drugs/DRESS syndrome.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">1</span></a> Different diagnostic criteria of AOSD have been proposed, the most common being those of Yamaguchi et al.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">31</span></a> and those of Fautrel et al.<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">32</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The criteria of Yamaguchi et al. include 4 major criteria (fever<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>39<span class="elsevierStyleHsp" style=""></span>°<span class="elsevierStyleSmallCaps">C</span><span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>week of duration, arthralgias/arthritis for 2 or more weeks, typical evanescent rash and leukocytosis<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>10,000/mm<span class="elsevierStyleSup">3</span> with<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>80% polymorphonuclear) and 5 minor (odynophagia, lymphadenopathy, splenomegaly, impaired liver function tests and negativity of rheumatoid factor and antinuclear antibodies). The simultaneous presence of 5 or more of these criteria, of which at least 2 have to be major, would establish the diagnosis of the disease as long as infections, neoplasms and other systemic diseases that can simulate AOSD have been ruled out, just as expressly mentioned in the original article.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">31</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Fautrel et al. criteria also include major criteria (fever peaks<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>39<span class="elsevierStyleHsp" style=""></span>°C, arthralgia, transient cutaneous rash, odynophagia, a percentage of polymorphonuclear leukocytes >80% and glycosylated ferritin ≤20%) and minor criteria (maculopapular rash and leukocytosis >10,000/mm<span class="elsevierStyleSup">3</span>). For the diagnosis, 4 or more major or 3 major +2 minor criteria are needed. The application of the Fautrel criteria does not depend as much on the exclusion of other systemic processes as on the Yamaguchi criteria, but has the disadvantage that the determination of glycosylated ferritin is a relatively restricted access test.</p><p id="par0060" class="elsevierStylePara elsevierViewall">The Yamaguchi criteria are the most widespread in clinical practice, presenting a sensitivity of 96.2% and a specificity of 92.1%<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">31</span></a> (while the Fautrel have a sensitivity of 80.6% and a specificity of 98.5%). Although its diagnostic validity is not bad, in recent years an increasing number of cases have been reported with paraneoplastic AOSD.<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">13,33</span></a> Thus, up to December 2016, 47 patients initially diagnosed with AOSD have been described, fulfilling the Yamaguchi criteria, in whom a hematologic malignancy (50%) was detected months later (median of 9 months), almost always a lymphoma, or a solid tumour. The most frequent cancers were breast and lung; 67% of these patients had metastasis at the time of diagnosis of the tumour, which suggests that the cancer was already present when AOSD was diagnosed.<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">33</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The typical symptoms of Still's disease were resolved completely or partially after the treatment of the underlying neoplasm in 71% of these patients.<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">13,33</span></a> As warning symptoms that should make us suspect a possible paraneoplastic AOSD, the onset of the clinical symptoms after the age of 50, the appearance of atypical skin lesions, the elevation of the enzyme lactate dehydrogenase, the presence of atypical cells in peripheral blood, and very high levels of the soluble α-receptor of IL-2.<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">33</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">As an alternative or complement to the diagnostic criteria, biomarkers have been sought for some time now, so as to increase the diagnostic accuracy of the disease. So far, the combination that has shown the highest precision is a serum ferritin >1000<span class="elsevierStyleHsp" style=""></span>μg/l or values 5 times above the upper limit of normal, together with a fraction of glycosylated ferritin <20%.<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">34</span></a> Its sensitivity and specificity are 70.5 and 92.9%, respectively.<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">34</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">In addition to having an important role as a regulator of immunity and as a mediator of inflammation and microcirculatory dysfunction, ferritin is a protein that intervenes in the metabolism of iron, regulated by a hepatic synthesis hormone, hepcidin.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">35</span></a> Elevated ferritin levels, when associated with an increase in hepcidin, show inflammation and anaemia secondary to chronic disorder, due to decreased intestinal iron absorption and deposition in macrophages.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">35</span></a> This biochemical pattern is common to all hyperferritinemic syndromes, including AOSD, MAS, septic shock, and the catastrophic antiphospholipid syndrome. On the other hand, when hyperferritinemia is related to an iron overload, as for example in hemochromatosis, hepcidin levels are low.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">35</span></a> Currently, commercial kits are available for the determination of hepcidin, with which we can perform a differential diagnosis of hyperferritinemia and distinguish between iron overload and inflammatory anaemia in cases where this doubt is raised.</p><p id="par0080" class="elsevierStylePara elsevierViewall">The possible diagnostic utility of the different cytokines involved in the pathogenesis of the disease has also been evaluated (IL-1β, IL-6, IL-18, IL-8, tumour necrosis factor α, interferon α).<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">36</span></a> Of all of them, the only one that has shown utility in the differential diagnosis of AOSD with infectious diseases is IL-18.<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">36–39</span></a> The levels of this cytokine are substantially higher in AOSD than in infections.<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">37–39</span></a> When a cut/off point ≥366.1<span class="elsevierStyleHsp" style=""></span>pg/ml is established, its sensitivity and specificity reach 91.7 and 99.1%, respectively.<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">39</span></a> The usefulness of calprotectin in this scenario could not be confirmed in the only study in which it was analyzed.<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">40</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Other possible diagnostic biomarkers currently under evaluation (because their levels are significantly higher in patients with AOSD than in the healthy population) are the S100A12 protein (calgranulin), advanced glycation products, CXXL10 and CXCL13 chemokines, and proteins S100A8 and S100A9.<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">36</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Prognosis</span><p id="par0090" class="elsevierStylePara elsevierViewall">The progression of AOSD is unpredictable and its prognosis is very variable. Although in the most recent series it has improved significantly due to early diagnosis and a more effective treatment, mortality at 5 years reaches 10%. Different prognostic factors have been identified, both clinical and biomarkers. The main clinical factors predictive of poor prognosis are the occurrence of atypical skin lesions, involvement of hips and shoulders at the onset of the disease, development of pulmonary complications, persistence of fever after 3 days of treatment with glucocorticoids, and a prolonged need for glucocorticoids (>2 years).<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">1–9,11,14,41</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">A specific prognostic index for AOSD has also been developed, with the objective of stratifying patients into risk categories: <span class="elsevierStyleItalic">Systemic Score System</span>, proposed by Pouchot et al.<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">6</span></a> This index assigns a point to the following 12 items if they are present at the time of diagnosis: fever, typical evanescent rash, pleuritis, pneumonitis, pericarditis, alteration of liver tests or hepatomegaly, splenomegaly, lymphadenopathy, leukocytosis >15,000/mm<span class="elsevierStyleSup">3</span>, odynophagia, myalgias and abdominal pain (score range: 0–12 points). With the aim of improving its prognostic value, Rau et al.<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">40</span></a> proposed replacing the criteria “splenomegaly” and “abdominal pain” with “serum ferritin ≥3000<span class="elsevierStyleHsp" style=""></span>μg/l” and “arthritis”. The predictive prognostic value of this index has been confirmed recently, showing that a score ≥7 identifies those patients with higher risk of death from complications of the disease.<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">42</span></a> Since today AOSD is considered a heterogeneous entity halfway between autoinflammatory syndromes and systemic autoimmune diseases,<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">1</span></a> the use of the <span class="elsevierStyleItalic">Auto-Inflammatory Diseases Activity Index</span><a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">43</span></a> has also being suggested. In this sense, an increased activity of the NLRP3 inflammasome activity has been demonstrated in patients with AOSD, which correlates with the activity of the disease.<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">44</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">As biological markers, in addition to persistent hyperferritinemia, the role of cytokine levels that correlate with disease activity such as IL-18, IL-1ß, IL-6 and calprotectin has been studied.<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">1,36</span></a> Of these, only the persistently elevated levels of IL-18 have been shown to be a predictor of poor prognosis.<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">29,35,45–48</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Tissue ferritin is composed of 24 subunits of 2 different types of chains: L<span class="elsevierStyleItalic">(Light)</span> chains and H<span class="elsevierStyleItalic">(heavy) chains.</span> Recently, an increase in the expression of H-ferritin in skin biopsies of PPPs and in the bone marrow and liver tissue of patients with MAS has been described, so the finding of an increase in tissue H-ferritin has been correlated with a greater severity of the disease (frequent development of visceral complications and MAS) and a higher mortality.<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">49,50</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Historically, 3 well-differentiated patterns were accepted in the progression of AOSD: (1) monophasic, characterized by a self-limited flare, which usually resolves spontaneously in several weeks or months; (2) systemic intermittent, with episodes or recurrent flares, with or without joint symptoms, symptoms disappearing in the intercritical periods and (3) chronic articular, with progressive polyarticular involvement, usually destructive, which in the long run causes significant disability.<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">1,2,51</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">However, based on new knowledge about the pathogenesis of the disease and the increasingly widespread use of biological treatments, most opinion leaders in this disease have opted to simplify these 3 categories into 2 patterns: (1) systemic form and (2) predominantly articular form.<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">35,45,52–57</span></a> In patients with the systemic form, although they have joint symptoms, the general manifestations are clinically prominent (fever, rash, etc.) and they can end up developing serious complications, both visceral as well as a MAS. They may have a monophasic, intermittent systemic or, more rarely, chronic course. As predictive factors of progression to the systemic form, the following have been identified: high fever (>39<span class="elsevierStyleHsp" style=""></span>°C), alteration of liver tests (elevation of transaminases), thrombocytopenia, persistent hyperferritinemia and elevation of C-reactive protein.<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">45</span></a><span class="elsevierStyleSup">.</span><a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">46</span></a><span class="elsevierStyleSup">.</span><a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">52–54</span></a><span class="elsevierStyleSup">.</span><a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">56</span></a> In patients with the articular form, although they may have systemic manifestations at the onset of the disease, arthritis takes almost all the clinical role and is quite frequent to end up having a chronic course, developing erosive arthritis in a third of cases. As predictive factors of progression to the articular form, the female sex, involvement of the hips and shoulders at the beginning of the disease and the prolonged need for glucocorticoids have been reported.<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">45</span></a><span class="elsevierStyleSup">.</span><a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">46</span></a><span class="elsevierStyleSup">.</span><a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">52–54</span></a><span class="elsevierStyleSup">.</span><a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">56</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">In addition to the differences in the clinical phenotype, this distinction in 2 categories is also based on differences in the cytokine profile. Thus, systemic forms have much higher levels of IL-18 and IL-1β that the predominantly articular forms; in these, the levels of these 2 cytokines are lower, presenting, instead, higher levels of IL-6.<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">36,46,52–57</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Treatment</span><p id="par0125" class="elsevierStylePara elsevierViewall">This simplification in 2 categories has a practical utility when deciding which is the most appropriate biological treatment in those patients who need it. The current indications of biological treatment at AOSD are: (1) insufficient response after 3 months of standard treatment with glucocorticoids<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>≥1 disease modifying drug (including methotrexate); (2) development of adverse effects or contraindication to standard treatment, and (3) occurrence at any time of the progression of the disease of potentially fatal serious complications.<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">28,58</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Although IL-1 and IL-6 antagonists have been shown to be effective both for systemic and articular forms, based on the differences in the cytokine profile, in the systemic forms, the most advisable first-line biological treatment would be IL-1 antagonists (anakinra or canakinumab), while in the predominantly articular forms it would be tocilizumab (or other anti-IL6 such as sarilumab or sirukumab, which will soon be marketed).<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">36,46,52–57</span></a> In case of refractory therapy or adverse effects after the first biological agent, a target change between anti-IL1 and anti-IL6 can be made. The fact that TNF inhibitors are also effective in articular forms<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">28,51</span></a> should be highlighted. For more detailed information on the diagnosis and treatment of AOSD, the reader can consult the review carried out by Castañeda et al. recently published in this magazine.<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">51</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">As a new therapeutic target in AOSD, the blockade of IL-18 is being tested with <span class="elsevierStyleItalic">Tadekining Alfa (recombinant human IL-18 binding protein)</span>, having completed a phase <span class="elsevierStyleSmallCaps">II</span> multicentre trial of 12 weeks of which the results have not yet been published<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">59</span></a> and, as a promising avenue of research, there is great hope in interferon activity blockadeγ.<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="par0140" class="elsevierStylePara elsevierViewall">AOSD is very heterogeneous in terms of clinical presentation, progression and severity.</p><p id="par0145" class="elsevierStylePara elsevierViewall">Although its pathogenesis is complex and is still far from being understood in its entirety, recent advances in the knowledge of its pathophysiology have opened the way to the search for new diagnostic biomarkers, to a better evaluation of its prognosis, and to the increasingly widespread use of biological treatments in patients with severe or refractory forms of the disease.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conflict of interests</span><p id="par0150" class="elsevierStylePara elsevierViewall">The author declares no conflicts of interest in relation to this publication.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1027757" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec985234" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1027758" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec985233" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Clinical manifestations" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Diagnosis" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Prognosis" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Treatment" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflict of interests" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-07-11" "fechaAceptado" => "2017-10-25" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec985234" "palabras" => array:4 [ 0 => "Adult onset Still's disease" 1 => "Update" 2 => "Prognostic" 3 => "Treatment" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec985233" "palabras" => array:4 [ 0 => "Enfermedad de Still del adulto" 1 => "Actualización" 2 => "Pronóstico" 3 => "Tratamiento" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Adult onset Still's disease is a rare systemic condition at the crossroads between auto-inflammatory syndromes and autoimmune diseases, with considerable heterogeneity in terms of clinical presentation, evolution and severity. This article reviews the main advances and lesser known aspects of this entity related to its clinical spectrum (atypical cutaneous lesions, unusual manifestations, macrophage activation syndrome, disease phenotypes), the emerging controversy around its association with delayed malignancy, the search for new biomarkers for its diagnosis, evaluation of prognosis (clinical factors, prognostic indexes and biomarkers to identify patients at risk of severe organ failure or life-threatening complications), and the determinants in the choice of biological treatment.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La enfermedad de Still del adulto es una entidad infrecuente a medio camino entre los síndromes autoinflamatorios y las enfermedades autoinmunes, con una gran heterogeneidad en su presentación clínica, gravedad y evolución. En este artículo se revisan las novedades y aspectos menos conocidos de esta enfermedad referidos a su espectro clínico (lesiones cutáneas atípicas, complicaciones distintas de las manifestaciones clásicas, síndrome de activación macrofágica, fenotipos de la enfermedad), a la controversia existente acerca de su posible asociación con neoplasias, la búsqueda de biomarcadores para su diagnóstico, la evaluación del pronóstico (factores clínicos, índices pronósticos y biomarcadores) y los factores determinantes en la elección del tratamiento biológico.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Narváez J. Enfermedad de Still del adulto. Med Clin (Barc). 2018;150:348–353.</p>" ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1199 "Ancho" => 950 "Tamanyo" => 161706 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Persistent urticarial rash as the only skin lesion in the onset of the disease.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1952 "Ancho" => 941 "Tamanyo" => 273741 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Persistent pruritic plaques, adopting in B a distribution similar to a flagellate rash.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">EEG: electroencephalogram; IL-2: interleukin 2; CNS: central nervous system; ESR: erythrocyte sedimentation rate.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Clinical manifestations</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Severe compromise of the general condition and high fever non-remitting high fever</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Atypical skin lesions (persistent pruritic papules or plaques or urticarial rash</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Somnolence/CNS dysfunction (EEG: slow base activity)</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Occurrence of haemorrhages (gingival haemorrhage, melena, purpura)</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Polyadenopathy</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hepatosplenomegaly</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Laboratory</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Normal ESR</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Pancytopenia</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Alteration of liver tests (especially elevation of transaminases and bilirubin)</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Coagulation dysfunction</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hypofibrinogenemia</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hypoalbuminemia</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Increase in triglycerides</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hyperferritinemia (>684</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ng/ml)</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Other data</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Decreased cytotoxic activity of natural killer cells</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Elevated values of the soluble IL-2 alpha receptor (sCD25) and soluble CD163</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Histology (bone marrow aspirate/biopsy)</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Hemophagocytosis of macrophages in bone marrow \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Inflammatory infiltrate CD68 that expresses H-ferritin in bone marrow \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1748595.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Symptoms and warning signs of macrophage activation syndrome.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">AST: aspartate aminotransferase; MAS: macrophage activation 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-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient with fever and systemic onset juvenile idiopathic arthritis (suspicion or confirmed diagnosis) \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">The diagnosis of MAS is established if <span class="elsevierStyleItalic">serum ferritin</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">684</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ng/ml</span> and presents 2 or more of the following criteria:<br><br>Platelets<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>181<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>/l<br>AST<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>48<span class="elsevierStyleHsp" style=""></span>U/l<br>Triglycerides<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>156<span class="elsevierStyleHsp" style=""></span>mg/dl<br>Fibrinogen<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>360<span class="elsevierStyleHsp" style=""></span>mg/dl \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1748594.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Diagnostic criteria of the macrophage activation syndrome (or reactive hemophagocytic syndrome) in the systemic forms of juvenile idiopathic arthritis proposed in 2016 by the <span class="elsevierStyleItalic">European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organization Collaborative Initiative</span>.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:59 [ 0 => array:3 [ "identificador" => "bib0300" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adult-onset Still's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. 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Review
Adult onset Still's disease
Enfermedad de Still del adulto
Javier Narváez
Servicio de Reumatología, Hospital Universitario de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain