Paradigm shift in monogenic autoinflammatory diseases and systemic vasculitis: The VEXAS syndrome

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Aróstegui" "autores" => array:3 [ 0 => array:4 [ "nombre" => "José" "apellidos" => "Hernández-Rodríguez" "email" => array:1 [ 0 => "jhernan@clinic.cat" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Anna" "apellidos" => "Mensa-Vilaró" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Juan I." "apellidos" => "Aróstegui" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidad Clínica de Enfermedades Autoinflamatorias y Grupo de Investigación en Vasculitis, Servicio de Enfermedades Autoinmunes, Hospital Clínic de Barcelona, Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Inmunología, Hospital Clínic de Barcelona, Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Cambio de paradigma en las enfermedades autoinflamatorias monogénicas y las vasculitis sistémicas: el síndrome VEXAS" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 440 "Ancho" => 1255 "Tamanyo" => 92169 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0150" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Right upper lobe (RUL) pulmonary infiltrate (arrowheads) in a patient with VEXAS syndrome: A) CT showing parenchymal infiltrate in RUL; B) PET/CT with FDG showing pathological uptake of the infiltrate, confirming its inflammatory nature (the patient did not receive antibiotic treatment)." ] ] ] "textoCompleto" => "IntroductionThe year 2022 marks the 25th anniversary of the start of a new era in medical and genetic research in the field of autoinflammation. In 1997, the teams of Dr Daniel Kastner at the National Institutes of Health (NIH), Bethesda, USA, and Dr Isabelle Touitou, Montpellier, France, identified for the first time a gene causing an autoinflammatory disease, namely the MEFV gene responsible for familial Mediterranean fever (FMF), the most common autoinflammatory disease<a class="elsevierStyleCrossRef" href="#bib0005">1</a>. In 1999, Dr. Kastner coined the term “autoinflammatory disease” to encompass those diseases of genetic origin with recurrent or persistent inflammatory manifestations driven by an alteration of innate immunity<a class="elsevierStyleCrossRef" href="#bib0005">1</a>. In 2002, the inflammasome was discovered as the cytoplasmic machinery that leads to uncontrolled production of interleukin 1-beta (IL-1β), the main inflammatory mediator of many monogenic autoinflammatory diseases, which later became known as inflammasomopathies. Among the best known are FMF itself, tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), hyper-IgD with periodic fever syndrome (HIDS) and cryopyrin-associated periodic syndrome (CAPS)<a class="elsevierStyleCrossRef" href="#bib0005">1</a>. A decade later, the number of genes causing new diseases and new autoinflammatory mechanisms increased exponentially thanks to the interest of researchers in detecting and studying autoinflammatory phenotypes of unknown cause and the development of new genetic analysis techniques, such as Next-Generation Sequencing (NGS). These advances contributed to the discovery of new patterns of inheritance, such as digenic inheritance, caused by mutations in 2 proteins that interact and generate a disease, and somatic or postzygotic mutations that cause disease, especially in adult patients<a class="elsevierStyleCrossRef" href="#bib0005">1</a>.In late 2020, the same NIH group described the VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) as a monogenic autoinflammatory disease occurring exclusively in adult patients<a class="elsevierStyleCrossRef" href="#bib0010">2</a>. The VEXAS acronym includes the terms: a) Vacuoles in the cytoplasm of myeloid and erythroid precursors in the bone marrow; b) initiator enzyme of the ubiquitination process E1; c) X chromosome-linked; d) Autoinflammatory disease; and e) Somatic mutations in the UBA1 gene.It is well known that some monogenic autoinflammatory diseases typical of paediatric age, such as FMF, TRAPS, CAPS, Blau syndrome, and adenosine deaminase 2 deficiency (DADA2), and other entities, can occasionally start in adulthood<a class="elsevierStyleCrossRefs" href="#bib0015">3–6</a>. Differences have been identified in the presentation of these diseases between children and adults<a class="elsevierStyleCrossRefs" href="#bib0015">3–6</a>. On the one hand, in the paediatric age group, they manifest more intensely or completely, are associated with the development of long-term complications, such as secondary amyloidosis, and are often caused by pathogenic variants. On the other hand, adult patients tend to have less specific and less severe symptoms, have a low risk of developing amyloidosis, and among the associated genetic variants, a higher frequency of variants of uncertain significance, variants with incomplete penetrance, non-confirmatory genotypes and postzygotic variants have been detected<a class="elsevierStyleCrossRefs" href="#bib0015">3–12</a>.Similar to VEXAS syndrome, there is evidence that postzygotic variants in autoinflammatory-related genes may be responsible for complete or severe presentations of autoinflammatory disease in adulthood. In this regard, there have been reports of adult patients with intermediate and severe forms of CAPS caused by postzygotic variants in the NLRP3 gene<a class="elsevierStyleCrossRefs" href="#bib0065">13–16</a>. These patients had symptom onset in their 40s and 50s and were diagnosed from the age of 60 onwards. They presented with fever, urticarial rash, and sensorineural deafness, and some cases developed ocular and central nervous system involvement, or secondary amyloidosis<a class="elsevierStyleCrossRefs" href="#bib0065">13–16</a>. Other autoinflammatory diseases caused by postzygotic variants that have been described in adults include TRAPS<a class="elsevierStyleCrossRefs" href="#bib0085">17,18</a>, Blau's syndrome<a class="elsevierStyleCrossRef" href="#bib0095">19</a> and autoinflammatory disease associated with NLRC4<a class="elsevierStyleCrossRef" href="#bib0100">20</a>.The discovery of VEXAS syndrome has been a paradigm shift in the approach to autoinflammatory syndromes of genetic cause, as until now these diseases were known to occur predominantly in the paediatric age group and, with a few exceptions, postzygotic variants were associated with milder clinical presentations than those caused by germline variants. As VEXAS syndrome manifests with different types of vasculitis, this paradigm shift has also had a major impact on systemic vasculitides since they are no longer considered primary or idiopathic in some patients due to the discovery of other forms of vasculitis associated with a genetic cause.Genetics and pathophysiologyVEXAS syndrome is caused by mosaicism of the gene UBA1located on the short arm of the X chromosome. The UBA1 gene encodes for the ubiquitin-activating enzyme (E1 ubiquitin-activating enzyme). Initially described as a X chromosome-linked disease exclusively affecting males, several females with VEXAS syndrome, usually carriers of an X chromosome monosomy, have now been reported<a class="elsevierStyleCrossRefs" href="#bib0105">21–23</a>.To date, six variants have been described that cause VEXAS syndrome, 4 of them in exon 3 (p.Met41Val, p.Met41Thr, p.Met41Leu, p.Ser56Phe) and 2 in intron 2 (c.118-1G>C and c.118-9_118-2del)<a class="elsevierStyleCrossRefs" href="#bib0010">2,24–27</a>. The most common variants are missense variants that affect the same methionine-41 residue (p.Met41) and are restricted to cells of the myeloid line, so in peripheral blood they are found in monocytes and neutrophils. One study identified the p.Met41Leu variant as associated with a better prognosis<a class="elsevierStyleCrossRef" href="#bib0120">24</a>. Updated information on the identified variants and their genotype-phenotype correlation can be obtained at the Infevers Registry (<a href="https://infevers.umai-montpellier.fr/web/search.php?n=46">https://infevers.umai-montpellier.fr/web/search.php?n=46</a>).The UBA1 protein is physiologically expressed as 2 isoforms: a) the nuclear isoform (UBA1a), which initiates translation in p.Met1; and b) the cytoplasmic isoform (UBA1b), which initiates it at position p.Met41. Mutations at position p.Met41 generate a new isoform (UBA1c), which initiates translation at position p.Met67, with cytoplasmic localisation and defective function<a class="elsevierStyleCrossRef" href="#bib0010">2</a>. Dysfunction of the E1 enzyme leads to a disruption in the start of the ubiquitination process, so that proteins are not properly ubiquitinated for subsequent degradation by the cytoplasmic proteasome complex. These alterations produce cellular stress and the activation of different pathophysiological mechanisms, including the NF-κB (nuclear factor-κB) transcription factor pathway<a class="elsevierStyleCrossRef" href="#bib0010">2</a>. Using transcriptomic techniques, a gene expression pattern of activation of multiple innate immune pathways, such as TNF, IL-6 and interferon gamma (IFNγ)<a class="elsevierStyleCrossRef" href="#bib0010">2</a> has been demonstrated in circulating monocytes and neutrophils of patients with VEXAS syndrome. These pathophysiological changes were absent in B and T cells<a class="elsevierStyleCrossRef" href="#bib0010">2</a>.Furthermore, a zebrafish model deficient for the UBA1 gene showed altered development and premature death of these fish compared to non-deficient fish and was associated with increased expression of pro-inflammatory genes<a class="elsevierStyleCrossRef" href="#bib0010">2</a>. These findings suggest that dysregulation and activation of these pathogenic pathways are responsible for alterations in mechanisms such as haematopoiesis and the immuno-inflammatory response leading to multisystemic involvement<a class="elsevierStyleCrossRef" href="#bib0010">2</a>. The redundancy of pathways and pathogenic mechanisms altered in VEXAS syndrome, not yet well understood, may contribute to the characteristic multi-treatment resistance in this disease.Clinical manifestationsAlthough new clinical phenotypes of VEXAS syndrome continue to be described, all 25 patients included in the original communication were male and onset of clinical manifestations was between the ages of 45 and 80<a class="elsevierStyleCrossRef" href="#bib0010">2</a>. Similar to this first publication, in subsequent retrospectively collected cases and series, patients had been frequently diagnosed with systemic diseases such as relapsing polychondritis, neutrophilic dermatoses, cutaneous or systemic vasculitis, and blood dyscrasias such as myelodysplastic syndrome (MDS), monoclonal gammopathy of uncertain significance and multiple myeloma, among others<a class="elsevierStyleCrossRefs" href="#bib0010">2,24,25,28–30</a>.<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the main clinical manifestations described in 4 series of patients with VEXAS syndrome<a class="elsevierStyleCrossRefs" href="#bib0010">2,24,25,28</a>. Persistent or periodic fever, constitutional symptoms with weight loss and arthralgias or arthritis are common systemic manifestations. Among the most common systemic manifestations are skin involvement in the form of cutaneous vasculitis, erythema nodosum, and various forms of neutrophilic dermatoses (such as Sweet's syndrome, pustulosis, and pyoderma gangrenosum) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Auricular and nasal chondritis, vasculitis lesions, with a wide spectrum of presentation, ranging from aortic to small vessels involvement (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>), spontaneous venous thrombosis and pulmonary parenchymal infiltrates (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>), are also common. Ocular inflammation (in the form of uveitis, scleritis, episcleritis and orbital tumour), renal involvement (due to vasculitis or interstitial nephritis), cardiac involvement (pericarditis or myocarditis), gastrointestinal tract (abdominal pain, diarrhoea, rectal bleeding, perforation/obstruction), central nervous system (due to vasculitis or cerebrovascular accidents), peripheral nervous system, testicular (orchitis), as well as lymphadenopathy, hepatomegaly and splenomegaly have also been described<a class="elsevierStyleCrossRefs" href="#bib0010">2,24,25,28–30</a>. About half of the patients develop some haematological abnormality, among which MDS stands out<a class="elsevierStyleCrossRefs" href="#bib0120">24,28</a>. Concomitant presentation of inflammatory manifestations and secondary amyloidosis with renal and cardiac involvement has been described in one patient<a class="elsevierStyleCrossRef" href="#bib0155">31</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia>VEXAS syndrome has a poor prognosis, with mortality ranging between 15.5 and 40%, depending on the series<a class="elsevierStyleCrossRefs" href="#bib0010">2,24,25,28</a>. Disease progression due to lack of response to immunosuppressive treatment and infections favoured by this prolonged immunosuppression are the most common causes of death in these patients<a class="elsevierStyleCrossRefs" href="#bib0010">2,24,25,28</a>.Supplementary testsLaboratory testsVEXAS syndrome is associated with a marked increase in acute phase reactants, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)<a class="elsevierStyleCrossRefs" href="#bib0010">2,24,25,28</a>. Serum amyloid A protein (SAA) has only been reported high in one patient who developed renal and cardiac amyloidosis<a class="elsevierStyleCrossRef" href="#bib0155">31</a>. In addition to the variable development of thrombocytopenia, leukopenia, and lymphopenia, the presence of macrocytic anaemia with a high mean corpuscular volume (MCV) and normal folic acid and vitamin B levels is characteristic in most patients<a class="elsevierStyleCrossRef" href="#bib0060">12</a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Detection of monoclonal components, usually classified as monoclonal gammopathy of undetermined significance, is also common<a class="elsevierStyleCrossRefs" href="#bib0010">2,24,25,28</a>. Positive autoantibody results, such as rheumatoid factor and lupus anticoagulant have been observed in some patients (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>)<a class="elsevierStyleCrossRefs" href="#bib0010">2,25</a>. VEXAS syndrome has also been associated with a prior diagnosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis<a class="elsevierStyleCrossRef" href="#bib0145">29</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>HistopathologyMyelogramIn addition to findings of myelodysplasia or multiple myeloma (if present), bone marrow aspirate from patients with VEXAS syndrome is usually hypercellular, with predominance of myeloid hyperplasia, and dysplastic elements and cytoplasmic vacuoles are typical in the bone marrow. myeloid and erythroid precursor cells (blasts, promyelocytes and proerythroblasts) (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>)<a class="elsevierStyleCrossRefs" href="#bib0010">2,32</a>. Although less frequently, vacuoles have also been observed in eosinophils, monocytes, plasma cells, and megakaryocytes<a class="elsevierStyleCrossRef" href="#bib0160">32</a>. The presence of these vacuoles in both cell series can be considered highly suggestive of VEXAS syndrome<a class="elsevierStyleCrossRefs" href="#bib0010">2,32</a>. In this sense, it is possible that in patients who do not have an underlying haematological disease and have not undergone myelotoxic treatments, the presence of these vacuoles in the myeloid and erythroid series may be considered a pathognomonic finding of this disease.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>Skin and other biopsiesIn the case of skin involvement, biopsy of the damaged skin can confirm the diagnosis of vasculitis, panniculitis, or neutrophilic dermatosis. The presence of vascular inflammation in the biopsy of other affected territories may provide the diagnosis of systemic vasculitis<a class="elsevierStyleCrossRefs" href="#bib0010">2,29</a>.RadiologyIn patients with VEXAS syndrome and inflammatory manifestations at the neurological, hepatic, renal, pulmonary, cardiac, gastrointestinal or arterial limb circulation level, computed tomography (CT) and magnetic resonance imaging (MRI) studies together with angiographic study (when necessary) can provide information on the inflammatory and/or vasculitic origin of the lesions and their extent. Cardiac MRI may also support the diagnosis of myocardial involvement due to secondary amyloidosis. The detection of pulmonary infiltrates, vasculitis changes, visceral infarcts, visceromegaly and lymphadenopathy will point to a systemic disease, the inflammatory nature of which can be confirmed by 18-fluorodeoxyglucose positron emission tomography (PET) combined with CT (PET/CT).Relapsing polychondritis, myelodysplastic syndrome, and VEXAS syndromeIn patients diagnosed with VEXAS syndrome, involvement as relapsing polychondritis is present in 36–64% of patients<a class="elsevierStyleCrossRefs" href="#bib0010">2,24,28</a>. Prior to the description of VEXAS syndrome, a 2016 study of 142 patients (61% women) diagnosed with relapsing polychondritis identified several factors associated with increased mortality<a class="elsevierStyleCrossRef" href="#bib0165">33</a>. These poor prognostic factors included male sex, presence of cardiac abnormalities, and concomitant development of MDS or other hematologic malignancy. According to clinical presentation, patients were divided into groups with different mortality. In patients with associated MDS, a mortality of 58% was observed, while those with tracheobronchial chondritis had a mortality of 13%. In cases with the absence of either of the 2 previous manifestations, mortality was 4%<a class="elsevierStyleCrossRef" href="#bib0165">33</a>. Therefore, the subgroup of patients with MDS and without tracheobronchial chondritis could possibly correspond to patients with VEXAS syndrome.After the discovery of the VEXAS syndrome, an international study with 92 patients with relapsing polychondritis detected postzygotic variants in the UBA1 gene in 7.6% of cases<a class="elsevierStyleCrossRef" href="#bib0125">25</a>. This same study identified some clinical manifestations that are significantly associated with VEXAS syndrome in patients with relapsing polychondritis. These included male gender, age of onset >45 years and the presence of fever, auricular chondritis, skin inflammation, deep vein thrombosis and pulmonary infiltrates<a class="elsevierStyleCrossRef" href="#bib0125">25</a>. In contrast, laryngeal, tracheobronchial, or costal chondritis does not manifest in VEXAS syndrome. Compared with isolated relapsing polychondritis, elevated acute-phase reactants and hematologic abnormalities, such as macrocytic anaemia, thrombocytopenia, and lymphopenia, are more common in VEXAS syndrome, as are prior diagnoses of MDS, gammopathy of uncertain significance, and multiple myeloma<a class="elsevierStyleCrossRef" href="#bib0125">25</a>.Proposal for a diagnostic algorithm in patients with relapsing polychondritisThe authors of the previous study also developed an algorithm for the diagnosis of VEXAS syndrome in those patients previously diagnosed with relapsing polychondritis<a class="elsevierStyleCrossRef" href="#bib0125">25</a>. Compliance with these 3 criteria a) Male gender; b) Mean corpuscular volume of red blood cells >100fL; and c) Platelet count <200,000/mm<a class="elsevierStyleCrossRef" href="#bib0015">3</a>, was associated with a sensitivity of 100% and a specificity of 96% for the identification of pathogenic variants in the UBA1 gene in patients with relapsing polychondritis<a class="elsevierStyleCrossRef" href="#bib0125">25</a>.Likewise, this diagnostic algorithm considers low platelet counts in patients with a previous diagnosis of relapsing polychondritis, so this parameter cannot yet be generalized or extrapolated to other common clinical situations, such as neutrophilic dermatoses, difficult-to-treat vasculitis, and probably myelodysplastic syndromes with more or less specific inflammatory manifestations. It is likely that in the near future diagnostic algorithms and criteria will be generated based on larger, well-characterised population-based studies, probably derived from national or international multicentre registries.Prognostic factors in VEXAS syndromeA French multicenter registry of 116 patients with VEXAS syndrome identified 3 groups with different 5-year survival. Although the overall mortality of the series was 15.5%, the group that had constitutional symptoms, higher CRP levels and less chondritis (37%) had a mortality of 10.4%. Patients with MDS (16%) had a worse prognosis, with a mortality of 49.5%. A mortality of 15.8% was observed in 47% of patients in the intermediate group<a class="elsevierStyleCrossRef" href="#bib0120">24</a>.Systemic vasculitides and VEXAS syndromeThe presence or prior diagnosis of systemic vasculitis has been reported in between 16% and 64% of patients with VEXAS syndrome<a class="elsevierStyleCrossRefs" href="#bib0010">2,24,28</a>. The most common have been cutaneous vasculitis, especially in the isolated form of leukocytoclastic vasculitis, and polyarteritis nodosa<a class="elsevierStyleCrossRefs" href="#bib0010">2,24,28,29</a>. Aortitis, central nervous system vasculitis, giant cell arteritis, Behçet's disease, cryoglobulinaemic vasculitis and ANCA-associated vasculitis have also been reported<a class="elsevierStyleCrossRefs" href="#bib0010">2,24,28,29</a>.In a study involving 147 patients seen in a vasculitis clinic, a diagnosis of VEXAS syndrome was suspected in 7 (5%) patients and could be confirmed by genetic testing in 3 (2%) cases<a class="elsevierStyleCrossRef" href="#bib0145">29</a>. The previous diagnoses of these patients were relapsing polychondritis, ANCA-associated vasculitis, and undifferentiated autoinflammatory disease. Five of the 7 (71.4%) patients were also diagnosed with MDS<a class="elsevierStyleCrossRef" href="#bib0145">29</a>.The discovery in 2014 of DADA2 and SAVI syndrome (STING1 [stimulator of interferon genes 1], STING-associated vasculopathy with onset in infancy) as 2 types of vasculitis/vasculopathy caused by genetic alterations<a class="elsevierStyleCrossRefs" href="#bib0170">34–36</a>, already represented a conceptual revolution in the field of primary systemic vasculitides. These forms of autoinflammatory vasculitis, although typical of early childhood, can also occur in adult patients<a class="elsevierStyleCrossRefs" href="#bib0180">36–38</a>. In addition to these previous descriptions, the description of VEXAS syndrome represents an even more significant advance in the understanding of the aetiopathogenesis of systemic vasculitides, especially those that occur exclusively in adulthood. For the time being, these findings already imply that genetic studies should be considered in the differential diagnosis of systemic vasculitides to confirm or rule out the presence of any of these autoinflammatory diseases (or vasculitides).Differential diagnosisA considerable number of patients with VEXAS syndrome had previously been diagnosed with systemic inflammatory or autoimmune diseases, chronic haematological disorders, or a combination of both<a class="elsevierStyleCrossRefs" href="#bib0010">2,24,25,28–30</a>. Therefore, the differential diagnosis with VEXAS syndrome should be considered in male adults with inflammatory and/or haematological manifestations, and multi-organ involvement resistant to different immunosuppressive treatments.The main diseases that should be considered in the differential diagnosis of VEXAS syndrome are: a) Systemic autoimmune diseases: Relapsing polychondritis, cutaneous leukocytoclastic vasculitis, and systemic vasculitides (such as polyarteritis nodosa, cutaneous arteritis, giant cell arteritis, Behçet’s disease, cryoglobulinaemic vasculitis, and ANCA-associated vasculitis), rheumatoid arthritis, and other undifferentiated arthritis; b) Diseases involving neutrophilic dermatoses or panniculitis: Sweet's syndrome, extrapulmonary sarcoidosis and autoinflammatory diseases with or without a known genetic basis; and c) Chronic haematological diseases: MDS, monoclonal gammopathy of uncertain significance, multiple myeloma, and some types of lymphomas.TreatmentAlthough evidence of therapeutic efficacy is limited, the experience with the drugs used so far in VEXAS syndrome is described below. As the information reported so far is from retrospective cases and series, the duration of treatment and its long-term effectiveness is unknown for most of the drugs where a positive or indeterminate effect has been obtained.Glucocorticoids and other conventional immunosuppressantsGlucocorticoids are the most widespread immunosuppressive therapy, and at high doses tend to control the inflammatory manifestations of VEXAS syndrome. This effect is usually transient, as in its tapering, prednisone doses lower than 10−20mg/day are usually not effective<a class="elsevierStyleCrossRefs" href="#bib0010">2,24,29,30</a>,<a class="elsevierStyleCrossRefs" href="#bib0195">39–41</a>. Other conventional glucocorticoid-sparing immunosuppressive drugs, such as azathioprine, methotrexate and mycophenolate mofetil, have also achieved insufficient or partial response in this disease<a class="elsevierStyleCrossRefs" href="#bib0010">2,24,28–30,39–41</a>. Partial responses have been described with cyclophosphamide and calcineurin inhibitors (cyclosporine and tacrolimus) in combination with glucocorticoids<a class="elsevierStyleCrossRefs" href="#bib0140">28,39</a>.Anti-inflammatory and immunomodulatory drugs such as hydroxychloroquine, dapsone and colchicine, as well as intravenous immunoglobulins, have also been tried without clinical benefit<a class="elsevierStyleCrossRefs" href="#bib0010">2,39–41</a>.Biologic drugsInterleukin-1 blockersBoth anakinra and canakinumab have been ineffective in most published cases concerning VEXAS syndrome<a class="elsevierStyleCrossRefs" href="#bib0010">2,28,29,39–41</a>, and have only been associated with disease control in isolated cases<a class="elsevierStyleCrossRefs" href="#bib0145">29,31,39</a>. In addition, the administration of anakinra has been associated with moderate or severe inflammatory reactions at injection sites in a high percentage of patients (8–62%)<a class="elsevierStyleCrossRefs" href="#bib0010">2,24,39</a>.Interleukin-6 and tumour necrosis factor blockersTocilizumab has been used in a number of cases and there are records of patients with VEXAS syndrome, with some positive effect<a class="elsevierStyleCrossRefs" href="#bib0195">39,42</a>, although most have reported a partial or unfavourable effect<a class="elsevierStyleCrossRefs" href="#bib0010">2,28,30,39</a>,<a class="elsevierStyleCrossRef" href="#bib0215">43</a>. In addition, some cases of intestinal perforation have been reported with its use<a class="elsevierStyleCrossRef" href="#bib0195">39</a>. Infliximab, adalimumab, etanercept, and golimumab have been used in several patients with VEXAS syndrome, with partial or ineffective response<a class="elsevierStyleCrossRefs" href="#bib0010">2,28–30,39,41</a>.Janus kinase inhibitorsNonselective Janus kinase (JAK) inhibitors, such as baricitinib (anti-JAK1/2)<a class="elsevierStyleCrossRef" href="#bib0010">2</a> and tofacitinib (anti-JAK1/3)<a class="elsevierStyleCrossRefs" href="#bib0010">2,28,30</a> have not had a beneficial effect in patients with VEXAS syndrome. Two patients with positive response have been described with ruxolitinib (anti-JAK1/2)<a class="elsevierStyleCrossRef" href="#bib0140">28</a>. The use of upadacitinib (anti-JAK1/3) has obtained a partial response together with glucocorticoid at medium-low doses in one patient<a class="elsevierStyleCrossRef" href="#bib0145">29</a>. Selective JAK inhibitors (anti-JAK1), such as abrocitinib and filgotinib, have been tried in these patients without good results<a class="elsevierStyleCrossRef" href="#bib0220">44</a>.Other biologic drugsSecukinumab (anti-IL-17 monoclonal antibody) has been used without benefit in one patient<a class="elsevierStyleCrossRef" href="#bib0010">2</a>, and in another patient, its administration together with intravenous immunoglobulins has been associated with a good response, which allowed the prednisone dose to be reduced to 20mg/day<a class="elsevierStyleCrossRef" href="#bib0225">45</a>. With ustekinumab (anti-IL-12/23 monoclonal antibody) no effective results have been reported<a class="elsevierStyleCrossRefs" href="#bib0010">2,41</a>. Following prednisone tapering, abatacept (fusion protein with the extracellular domain of CTLA-4 and the Fc portion of human IgG) was used subcutaneously in one patient with a partial and transient effect<a class="elsevierStyleCrossRef" href="#bib0230">46</a>. Except in a few isolated cases with an acceptable response<a class="elsevierStyleCrossRef" href="#bib0195">39</a>, rituximab (anti-CD20) has been shown to be ineffective in VEXAS syndrome<a class="elsevierStyleCrossRefs" href="#bib0010">2,28–30</a>. In a patient with VEXAS syndrome, who also had multiple myeloma, bortezomib (proteasome inhibitor) was used in combination with lenalidomide (anti-angiogenic and antineoplastic) without effect<a class="elsevierStyleCrossRef" href="#bib0150">30</a>. Lenalidomide had to be discontinued due to skin rash in one case<a class="elsevierStyleCrossRef" href="#bib0160">32</a>.Hypomethylating agentsIn low-risk MDS patients, hypomethylating agents, such as azacitidine and decitabine, have been associated with improved transfusion independence in 30% of patients without 5q deletion in whom erythropoietin treatment failed. In high-risk MDS patients, these drugs improve overall survival and delay transformation to acute myeloid leukemia<a class="elsevierStyleCrossRef" href="#bib0220">44</a>. Up to half of patients with VEXAS syndrome have a low-risk MDS in most cases, according to standard prognostic indices<a class="elsevierStyleCrossRef" href="#bib0235">47</a>.In some patients with VEXAS syndrome and MDS, azacitidine (administered at a dose of 75mg/m2/day in consecutive 7-day cycles every month subcutaneously or intravenously) has shown a positive effect on both glucocorticoid tapering and hemotherapy requirements<a class="elsevierStyleCrossRefs" href="#bib0140">28,40,41</a>. Azacitidine was used in 11 patients with MDS and VEXAS syndrome in a French registry<a class="elsevierStyleCrossRef" href="#bib0240">48</a>. Inflammatory manifestations were prevalent in 8 patients and MDS in 3 cases. After a median of 11 (range 2–35) cycles of azacitidine and a follow-up time of 32 (12–75) months, 5 (46%) patients had a good clinical response after 4–6 cycles of treatment, with a duration of response of 6–27 months. In responders to azacitidine, a significant reduction in CRP levels and prednisone dose was observed at 6 months, from a median (range) of 30 (20–70) to 10 (0–20) mg/day, which could be discontinued in one patient<a class="elsevierStyleCrossRef" href="#bib0240">48</a>.In a series of 3 patients with VEXAS syndrome and MDS, 2 of them also carried a mutation in the DNMT3A gene. In the 2 patients with mutations in this gene, positive effects were observed after 2–3 cycles, and although one of them had to be discontinued due to the development of diverticulitis, remission was maintained<a class="elsevierStyleCrossRef" href="#bib0200">40</a>. Azacitidine was ineffective in the patient without mutations in the DNMT3A gene<a class="elsevierStyleCrossRef" href="#bib0200">40</a>.Although it seems that azacitidine may have a superior effect on disease control in patients with VEXAS syndrome and MDS with mutations in their associated genes, this observation needs to be tested in a wider population.Allogeneic hematopoietic stem-cell transplantationA few isolated cases<a class="elsevierStyleCrossRef" href="#bib0245">49</a> and a retrospective series of six patients with VEXAS syndrome who underwent allogeneic haematopoietic stem cell transplantation have recently been published<a class="elsevierStyleCrossRef" href="#bib0250">50</a>. Five of them achieved a complete response, with follow-up periods greater than 2–3 years in 3 cases<a class="elsevierStyleCrossRef" href="#bib0250">50</a>.Although the age of patients with VEXAS syndrome may in itself be a limiting factor for allogeneic hematopoietic stem-cell transplantation eligibility, in order to define the subgroup of patients who will benefit most from this potentially curative procedure, there is currently a phase II clinical trial to study the safety of allogeneic haematopoietic stem-cell transplantation in VEXAS syndrome (ClinicalTrials.gov:NCT05027945).Future lines in VEXAS syndromeGiven the wide spectrum of presentation and the different specialties involved in the diagnosis and treatment of patients with VEXAS syndrome, a multidisciplinary approach is necessary to reach a rapid diagnosis that contributes to early targeted treatment. In addition, as for other minority diseases, it is important for VEXAS syndrome to implement international multicentre registries that contribute to increasing clinical, aetiopathogenic and evolutionary knowledge of this disease, helping to develop classificatory or diagnostic criteria, and that promote clinical trials to improve current therapeutic options<a class="elsevierStyleCrossRef" href="#bib0255">51</a>.ConclusionsVEXAS syndrome is a monogenic autoinflammatory disease caused by postzygotic variants in the UBA1 gene. It usually manifests in adult males with a systemic and varied presentation, including fever, arthritis or arthralgia, neutrophilic dermatosis and other skin lesions, auricular and nasal chondritis, pulmonary inflammation, venous thrombosis, and different types of vasculitis. An elevated acute phase response and cytopenias, most notably macrocytic anaemia, are typical in laboratory tests. Coexistence of MDS is common, and cytoplasmic vacuoles in myeloid and erythroid precursors in bone marrow are characteristic. It usually relies on medium to high doses of glucocorticoids, while all other immunosuppressive agents, both conventional and biological, show limited or no efficacy. Azacitidine, a hypomethylating agent, has shown beneficial effects, especially in patients with associated MDS. Allogeneic hematopoietic stem-cell transplantation appears to be the only curative alternative to date.The VEXAS syndrome has been a paradigm shift in the diagnosis and treatment of autoinflammatory diseases and systemic vasculitides, so that a targeted genetic approach could now identify new causative genes in systemic and complex diseases not diagnosed in adult patients. As in VEXAS syndrome, there would be a high probability that these pathogenic variants are postzygotic, developed in certain cell lines during the patient's lifetime, and would be the reason for the disease to manifest in old age. Therefore, as is already the case in adult forms of cancer and VEXAS syndrome, postzygotic mutations could be considered as the cause of new chronic and probably difficult-to-treat systemic diseases.FundingThis study has been funded by the Instituto de Salud Carlos III (ISCIII) through project PI21/01352 and co-financed by the European Union.Conflict of interestsThe authors approve the content of this manuscript and declare that they have no conflict of interest with regard to its publication." "textoCompletoSecciones" => array:1 [ "secciones" => array:17 [ 0 => array:3 [ "identificador" => "xres1839918" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1603401" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1839919" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1603400" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Genetics and pathophysiology" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Clinical manifestations" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "Supplementary tests" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Laboratory tests" ] 1 => array:3 [ "identificador" => "sec0030" "titulo" => "Histopathology" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Myelogram" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Skin and other biopsies" ] ] ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Radiology" ] ] ] 8 => array:3 [ "identificador" => "sec0050" "titulo" => "Relapsing polychondritis, myelodysplastic syndrome, and VEXAS syndrome" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Proposal for a diagnostic algorithm in patients with relapsing polychondritis" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Prognostic factors in VEXAS syndrome" ] ] ] 9 => array:2 [ "identificador" => "sec0065" "titulo" => "Systemic vasculitides and VEXAS syndrome" ] 10 => array:2 [ "identificador" => "sec0070" "titulo" => "Differential diagnosis" ] 11 => array:3 [ "identificador" => "sec0075" "titulo" => "Treatment" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0080" "titulo" => "Glucocorticoids and other conventional immunosuppressants" ] 1 => array:3 [ "identificador" => "sec0085" "titulo" => "Biologic drugs" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0090" "titulo" => "Interleukin-1 blockers" ] 1 => array:2 [ "identificador" => "sec0095" "titulo" => "Interleukin-6 and tumour necrosis factor blockers" ] 2 => array:2 [ "identificador" => "sec0100" "titulo" => "Janus kinase inhibitors" ] 3 => array:2 [ "identificador" => "sec0105" "titulo" => "Other biologic drugs" ] ] ] 2 => array:2 [ "identificador" => "sec0110" "titulo" => "Hypomethylating agents" ] 3 => array:2 [ "identificador" => "sec0115" "titulo" => "Allogeneic hematopoietic stem-cell transplantation" ] ] ] 12 => array:2 [ "identificador" => "sec0120" "titulo" => "Future lines in VEXAS syndrome" ] 13 => array:2 [ "identificador" => "sec0125" "titulo" => "Conclusions" ] 14 => array:2 [ "identificador" => "sec0130" "titulo" => "Funding" ] 15 => array:2 [ "identificador" => "sec0135" "titulo" => "Conflict of interests" ] 16 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-05-23" "fechaAceptado" => "2022-06-20" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1603401" "palabras" => array:5 [ 0 => "VEXAS syndrome" 1 => "Monogenic autoinflammatory diseases" 2 => "Autoinflammation" 3 => "Adult-onset" 4 => "Mosaicism" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1603400" "palabras" => array:5 [ 0 => "Síndrome VEXAS" 1 => "Enfermedades autoinflamatorias monogénicas" 2 => "Autoinflamación" 3 => "Inicio en la edad adulta" 4 => "Mosaicismo" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "VEXAS syndrome was described by the end of 2020 as an autoinflammatory disease caused by post-zygotic variants in the UBA1 gene. VEXAS syndrome occurs in adult males with recurrent fever, arthralgia/arthritis, ear/nose chondritis, neutrophilic dermatosis, lung inflammation, venous thrombosis, and different types of vasculitis. Common laboratory changes include raised acute phase reactants and macrocytic anemia. The coexistence of myelodysplasia is frequent, and bone marrow vacuolization of myeloid and erythroid precursors is characteristic. Glucocorticoids are effective at medium-high doses, but the remaining immunosuppressive drugs, either conventional or biological, have showed limited or absent efficacy. Azacitidine has been associated with a good response, especially in patients with accompanying myelodysplastic syndrome. Allogeneic hematopoietic stem cell transplantation appears to be the only curative therapy by now. VEXAS syndrome has become a paradigm shift in the diagnosis and treatment of autoinflammatory diseases and systemic vasculitis." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "A finales de 2020 se describió el síndrome VEXAS, como una enfermedad autoinflamatoria causada por variantes poscigóticas en el gen UBA1. Se presenta en varones adultos con fiebre recurrente, artralgias/artritis, condritis auricular/nasal, dermatosis neutrofílica, inflamación pulmonar, trombosis venosas y diferentes tipos de vasculitis. Los análisis muestran una respuesta de fase aguda elevada y anemia macrocítica. Es frecuente la coexistencia de mielodisplasia, y son características las vacuolas citoplasmáticas en precursores mieloides y eritroides en médula ósea. Los glucocorticoides a dosis medias-altas son eficaces, pero el resto de fármacos inmunodepresores, convencionales o biológicos, muestran una eficacia limitada o ausente. Azacitidina se ha asociado con una buena respuesta, sobre todo en pacientes con síndrome mielodisplásico acompañante. El trasplante alogénico de progenitores hematopoyéticos parece ser la única terapia curativa hasta el momento. El síndrome VEXAS ha supuesto un cambio de paradigma en el diagnóstico y tratamiento de las enfermedades autoinflamatorias y las vasculitis sistémicas." ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 608 "Ancho" => 1255 "Tamanyo" => 93975 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0145" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Skin lesions in VEXAS syndrome: A) Pustulosis in the form of folliculitis (arrows); B) Purpuric lesions caused by leukocytoclastic vasculitis; and C) Leg ulceration and distal ischaemia in the foot due to vasculitic involvement." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 440 "Ancho" => 1255 "Tamanyo" => 92169 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0150" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Right upper lobe (RUL) pulmonary infiltrate (arrowheads) in a patient with VEXAS syndrome: A) CT showing parenchymal infiltrate in RUL; B) PET/CT with FDG showing pathological uptake of the infiltrate, confirming its inflammatory nature (the patient did not receive antibiotic treatment)." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 629 "Ancho" => 755 "Tamanyo" => 82037 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0155" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Myelogram of a patient with VEXAS syndrome showing cytoplasmic vacuoles in the precursors of the myeloid (arrows) and erythroid (arrowheads) series." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0160" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "RA: rheumatoid arthritis; MGUS: monoclonal gammopathy of uncertain significance; ENT: ear, nose & throat; VEXA: vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic." "tablatextoimagen" => array:1 [ 0 => array:1 [ "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Characteristics \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Beck et al.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Bourbon et al. <a class="elsevierStyleCrossRef" href="#bib0140">28</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Ferrada et al.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Georgin-Lavialle et al.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No. (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No. (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No. (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No. (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Number of patients \t\t\t\t\t\t\n \t\t\t\t</td><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">25 \t\t\t\t\t\t\n \t\t\t\t</td><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">11 \t\t\t\t\t\t\n \t\t\t\t</td><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">13 \t\t\t\t\t\t\n \t\t\t\t</td><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">116 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Males \t\t\t\t\t\t\n \t\t\t\t</td><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">25 (100) \t\t\t\t\t\t\n \t\t\t\t</td><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">11 (100) \t\t\t\t\t\t\n \t\t\t\t</td><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">13 (100) \t\t\t\t\t\t\n \t\t\t\t</td><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">111 (95.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age at diagnosis (years); median (IQR or range) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">62 (48−71) \t\t\t\t\t\t\n \t\t\t\t</td><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">71 (66.76) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age of symptom onset (years); median (IQR) or (range) \t\t\t\t\t\t\n \t\t\t\t</td><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">64 (45−80) \t\t\t\t\t\t\n \t\t\t\t</td><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">66 (47−83) \t\t\t\t\t\t\n \t\t\t\t</td><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">56 (45−70) \t\t\t\t\t\t\n \t\t\t\t</td><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">67 (62.5−73) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">History \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Relapsing polychondritis \t\t\t\t\t\t\n \t\t\t\t</td><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">15 (60) \t\t\t\t\t\t\n \t\t\t\t</td><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">5 (46) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutrophilic dermatosis \t\t\t\t\t\t\n \t\t\t\t</td><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">8 (32) \t\t\t\t\t\t\n \t\t\t\t</td><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">5 (46) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vasculitis \t\t\t\t\t\t\n \t\t\t\t</td><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">4 (16) \t\t\t\t\t\t\n \t\t\t\t</td><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">7 (64) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Myelodysplastic syndrome \t\t\t\t\t\t\n \t\t\t\t</td><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">6 (24) \t\t\t\t\t\t\n \t\t\t\t</td><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">6 (55) \t\t\t\t\t\t\n \t\t\t\t</td><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">3 (23) \t\t\t\t\t\t\n \t\t\t\t</td><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">58 (50) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MGUS/multiple myeloma \t\t\t\t\t\t\n \t\t\t\t</td><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">5 (20) \t\t\t\t\t\t\n \t\t\t\t</td><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">1 (9) \t\t\t\t\t\t\n \t\t\t\t</td><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">2 (14) \t\t\t\t\t\t\n \t\t\t\t</td><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">12 (10.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RA/Still's disease in adults \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">2 (18) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mortality \t\t\t\t\t\t\n \t\t\t\t</td><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">10 (40) \t\t\t\t\t\t\n \t\t\t\t</td><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">3 (27) \t\t\t\t\t\t\n \t\t\t\t</td><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">3 (23) \t\t\t\t\t\t\n \t\t\t\t</td><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">18 (15.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Systemic manifestations \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Weight loss \t\t\t\t\t\t\n \t\t\t\t</td><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">14 (56) \t\t\t\t\t\t\n \t\t\t\t</td><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">6 (55) \t\t\t\t\t\t\n \t\t\t\t</td><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">4 (31) \t\t\t\t\t\t\n \t\t\t\t</td><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">62 (54.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fever \t\t\t\t\t\t\n \t\t\t\t</td><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">23 (92) \t\t\t\t\t\t\n \t\t\t\t</td><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">10 (91) \t\t\t\t\t\t\n \t\t\t\t</td><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">13 (100) \t\t\t\t\t\t\n \t\t\t\t</td><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">75 (64.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Arthritis/arthralgia \t\t\t\t\t\t\n \t\t\t\t</td><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">17 (68) \t\t\t\t\t\t\n \t\t\t\t</td><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">11 (100) \t\t\t\t\t\t\n \t\t\t\t</td><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">6 (46) \t\t\t\t\t\t\n \t\t\t\t</td><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">33 (28.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ENT manifestations \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chondritis \t\t\t\t\t\t\n \t\t\t\t</td><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">16 (64) \t\t\t\t\t\t\n \t\t\t\t</td><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">5 (46) \t\t\t\t\t\t\n \t\t\t\t</td><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">13 (100)<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><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">42 (36.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Auricular \t\t\t\t\t\t\n \t\t\t\t</td><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">16 (64) \t\t\t\t\t\t\n \t\t\t\t</td><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">5 (46) \t\t\t\t\t\t\n \t\t\t\t</td><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">13 (100) \t\t\t\t\t\t\n \t\t\t\t</td><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">37 (31.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nasal \t\t\t\t\t\t\n \t\t\t\t</td><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">12 (48) \t\t\t\t\t\t\n \t\t\t\t</td><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">1 (9) \t\t\t\t\t\t\n \t\t\t\t</td><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">12 (92) \t\t\t\t\t\t\n \t\t\t\t</td><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">18 (15.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sensorineural hearing loss \t\t\t\t\t\t\n \t\t\t\t</td><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">10/16 (63) \t\t\t\t\t\t\n \t\t\t\t</td><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">1 (9) \t\t\t\t\t\t\n \t\t\t\t</td><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">5 (50) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vestibular symptoms \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">3 (27) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Skin lesions \t\t\t\t\t\t\n \t\t\t\t</td><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">22 (88) \t\t\t\t\t\t\n \t\t\t\t</td><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">11 (100) \t\t\t\t\t\t\n \t\t\t\t</td><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">11 (85) \t\t\t\t\t\t\n \t\t\t\t</td><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">97 (83.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutrophilic dermatosis/plaques \t\t\t\t\t\t\n \t\t\t\t</td><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">9 (36) \t\t\t\t\t\t\n \t\t\t\t</td><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">7 (64) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">46 (39.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nodules/erythema nodosum \t\t\t\t\t\t\n \t\t\t\t</td><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">13 (52) \t\t\t\t\t\t\n \t\t\t\t</td><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">4 (36) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">15 (12.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hives/papular rash \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">35 (21.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vasculitis \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">6 (55) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">30 (25.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Periorbital oedema \t\t\t\t\t\t\n \t\t\t\t</td><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">4 (16) \t\t\t\t\t\t\n \t\t\t\t</td><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">1 (9) \t\t\t\t\t\t\n \t\t\t\t</td><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">4 (32) \t\t\t\t\t\t\n \t\t\t\t</td><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">10 (8.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gastrointestinal tract \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">16 (14.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Peripheral nervous system \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">1 (9) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">17 (14.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ocular (uveitis, scleritis, episcleritis, orbital mass) \t\t\t\t\t\t\n \t\t\t\t</td><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">7 (28) \t\t\t\t\t\t\n \t\t\t\t</td><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">6 (55) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">47 (40.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cardiac \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">13 (11.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pericarditis/pericardial effusion \t\t\t\t\t\t\n \t\t\t\t</td><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">1 (4) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">5 (4.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Myocarditis \t\t\t\t\t\t\n \t\t\t\t</td><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">1 (4) \t\t\t\t\t\t\n \t\t\t\t</td><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">2 (18) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">3 (2.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pulmonary \t\t\t\t\t\t\n \t\t\t\t</td><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">18 (72) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">57 (49.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pulmonary infiltrates \t\t\t\t\t\t\n \t\t\t\t</td><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">18 (72) \t\t\t\t\t\t\n \t\t\t\t</td><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">5 (46) \t\t\t\t\t\t\n \t\t\t\t</td><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">10 (77) \t\t\t\t\t\t\n \t\t\t\t</td><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">47 (40.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pleural effusion \t\t\t\t\t\t\n \t\t\t\t</td><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">8 (32) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">11 (9.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vascular \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td><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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Arterial (aortitis/aneurysms) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">1 (9) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">12 (10.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Spontaneous venous thrombosis \t\t\t\t\t\t\n \t\t\t\t</td><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">11 (44) \t\t\t\t\t\t\n \t\t\t\t</td><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">4 (46) \t\t\t\t\t\t\n \t\t\t\t</td><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">8 (62) \t\t\t\t\t\t\n \t\t\t\t</td><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">41 (35.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Renal \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">1 (9) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">11 (9.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lymphadenopathy \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">5 (46) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">40 (34.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Splenomegaly \t\t\t\t\t\t\n \t\t\t\t</td><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">9 (36) \t\t\t\t\t\t\n \t\t\t\t</td><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">3 (27) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">16 (13.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepatomegaly \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">2 (18) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">9 (7.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "All patients in the study had relapsing polychondritis prior to diagnosis of VEXAS syndrome." ] ] ] "descripcion" => array:1 [ "en" => "Main clinical manifestations in 4 series of patients diagnosed with VEXAS syndrome." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0165" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Laboratory parameters \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Beck et al.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Georgin-Lavialle et al.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Ferrada et al.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Median (IQR) or No. (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No.=25 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No.=116 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No.=13 \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Erythrocyte sedimentation rate; mm/1h \t\t\t\t\t\t\n \t\t\t\t</td><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">97 (64−124) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">66.5 (42−110) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C-reactive protein; g/dl \t\t\t\t\t\t\n \t\t\t\t</td><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">73 (18−128) \t\t\t\t\t\t\n \t\t\t\t</td><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">6.1 (3−12.8) \t\t\t\t\t\t\n \t\t\t\t</td><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">1.8 (1−10) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Haemoglobin; g/dl \t\t\t\t\t\t\n \t\t\t\t</td><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">9<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><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">10.1 (9−11.5) \t\t\t\t\t\t\n \t\t\t\t</td><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">10 (8−12) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean corpuscular volume; fl \t\t\t\t\t\t\n \t\t\t\t</td><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">110<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><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">101 (94.1−107) \t\t\t\t\t\t\n \t\t\t\t</td><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">105 (102−115) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Platelets; n/mm3 \t\t\t\t\t\t\n \t\t\t\t</td><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">110<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><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">204 (138,260) \t\t\t\t\t\t\n \t\t\t\t</td><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">145 (100−169) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WBC; n/mm3 \t\t\t\t\t\t\n \t\t\t\t</td><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">4.500<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><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">4400 (2972−6222) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutrophils; n/mm3 \t\t\t\t\t\t\n \t\t\t\t</td><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">2.500<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><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">2600 (1640−4185) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lymphocytes; n/mm3 \t\t\t\t\t\t\n \t\t\t\t</td><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">600<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">920 (500−1200) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rheumatoid factor; positive \t\t\t\t\t\t\n \t\t\t\t</td><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">5 (20) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">4 (31) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lupus anticoagulant; positive \t\t\t\t\t\t\n \t\t\t\t</td><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">12 (48) \t\t\t\t\t\t\n \t\t\t\t</td><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">— \t\t\t\t\t\t\n \t\t\t\t</td><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">7 (54) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "*" "nota" => "Approximate average value extracted from the chart in figure S3 of the original study." ] ] ] "descripcion" => array:1 [ "en" => "Main laboratory abnormalities in three series of patients diagnosed with VEXAS syndrome." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:51 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Editorial: autoinflammatory diseases: from genes to bedside" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "I. 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Paradigm shift in monogenic autoinflammatory diseases and systemic vasculitis: The VEXAS syndrome

Cambio de paradigma en las enfermedades autoinflamatorias monogénicas y las vasculitis sistémicas: el síndrome VEXAS

José Hernández-Rodrígueza,

Corresponding author

jhernan@clinic.cat

Corresponding author.

, Anna Mensa-Vilarób, Juan I. Arósteguib

a Unidad Clínica de Enfermedades Autoinflamatorias y Grupo de Investigación en Vasculitis, Servicio de Enfermedades Autoinmunes, Hospital Clínic de Barcelona, Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

b Servicio de Inmunología, Hospital Clínic de Barcelona, Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

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to encompass those diseases of genetic origin with recurrent or persistent inflammatory manifestations driven by an alteration of innate immunity<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46; In 2002&#44; the inflammasome was discovered as the cytoplasmic machinery that leads to uncontrolled production of interleukin 1-beta &#40;IL-1&#946;&#41;&#44; the main inflammatory mediator of many monogenic autoinflammatory diseases&#44; which later became known as inflammasomopathies&#46; Among the best known are FMF itself&#44; tumour necrosis factor &#40;TNF&#41; receptor-associated periodic syndrome &#40;TRAPS&#41;&#44; hyper-IgD with periodic fever syndrome &#40;HIDS&#41; and cryopyrin-associated periodic syndrome &#40;CAPS&#41;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46; A decade later&#44; the number of genes causing new diseases and new autoinflammatory mechanisms increased exponentially thanks to the interest of researchers in detecting and studying autoinflammatory phenotypes of unknown cause and the development of new genetic analysis techniques&#44; such as <span class="elsevierStyleItalic">Next-Generation Sequencing</span> &#40;NGS&#41;&#46; These advances contributed to the discovery of new patterns of inheritance&#44; such as digenic inheritance&#44; caused by mutations in 2 proteins that interact and generate a disease&#44; and somatic or postzygotic mutations that cause disease&#44; especially in adult patients<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">In late 2020&#44; the same NIH group described the VEXAS syndrome &#40;<span class="elsevierStyleItalic">Vacuoles&#44; E1 enzyme&#44;</span> X<span class="elsevierStyleItalic">-linked&#44; Autoinflammatory&#44; Somatic</span>&#41; as a monogenic autoinflammatory disease occurring exclusively in adult patients<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46; The VEXAS acronym includes the terms&#58; a&#41; <span class="elsevierStyleItalic">V</span>acuoles in the cytoplasm of myeloid and erythroid precursors in the bone marrow&#59; b&#41; initiator enzyme of the ubiquitination process <span class="elsevierStyleItalic">E1</span>&#59; c&#41; <span class="elsevierStyleItalic">X</span> chromosome-linked&#59; d&#41; <span class="elsevierStyleItalic">A</span>utoinflammatory disease&#59; and e&#41; <span class="elsevierStyleItalic">S</span>omatic mutations in the <span class="elsevierStyleItalic">UBA1</span> gene&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">It is well known that some monogenic autoinflammatory diseases typical of paediatric age&#44; such as FMF&#44; TRAPS&#44; CAPS&#44; Blau syndrome&#44; and adenosine deaminase 2 deficiency &#40;DADA2&#41;&#44; and other entities&#44; can occasionally start in adulthood<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;6</span></a>&#46; Differences have been identified in the presentation of these diseases between children and adults<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;6</span></a>&#46; On the one hand&#44; in the paediatric age group&#44; they manifest more intensely or completely&#44; are associated with the development of long-term complications&#44; such as secondary amyloidosis&#44; and are often caused by pathogenic variants&#46; On the other hand&#44; adult patients tend to have less specific and less severe symptoms&#44; have a low risk of developing amyloidosis&#44; and among the associated genetic variants&#44; a higher frequency of variants of uncertain significance&#44; variants with incomplete penetrance&#44; non-confirmatory genotypes and postzygotic variants have been detected<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;12</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Similar to VEXAS syndrome&#44; there is evidence that postzygotic variants in autoinflammatory-related genes may be responsible for complete or severe presentations of autoinflammatory disease in adulthood&#46; In this regard&#44; there have been reports of adult patients with intermediate and severe forms of CAPS caused by postzygotic variants in the <span class="elsevierStyleItalic">NLRP3 gene</span><a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#8211;16</span></a>&#46; These patients had symptom onset in their 40<span class="elsevierStyleHsp" style=""></span>s and 50<span class="elsevierStyleHsp" style=""></span>s and were diagnosed from the age of 60 onwards&#46; They presented with fever&#44; urticarial rash&#44; and sensorineural deafness&#44; and some cases developed ocular and central nervous system involvement&#44; or secondary amyloidosis<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#8211;16</span></a>&#46; Other autoinflammatory diseases caused by postzygotic variants that have been described in adults include TRAPS<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a>&#44; Blau&#39;s syndrome<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> and autoinflammatory disease associated with NLRC4<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The discovery of VEXAS syndrome has been a paradigm shift in the approach to autoinflammatory syndromes of genetic cause&#44; as until now these diseases were known to occur predominantly in the paediatric age group and&#44; with a few exceptions&#44; postzygotic variants were associated with milder clinical presentations than those caused by germline variants&#46; As VEXAS syndrome manifests with different types of vasculitis&#44; this paradigm shift has also had a major impact on systemic vasculitides since they are no longer considered primary or idiopathic in some patients due to the discovery of other forms of vasculitis associated with a genetic cause&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Genetics and pathophysiology</span><p id="par0030" class="elsevierStylePara elsevierViewall">VEXAS syndrome is caused by mosaicism of the gene <span class="elsevierStyleItalic">UBA1</span>located on the short arm of the X chromosome&#46; The <span class="elsevierStyleItalic">UBA1</span> gene encodes for the ubiquitin-activating enzyme <span class="elsevierStyleItalic">&#40;E1 ubiquitin-activating enzyme</span>&#41;&#46; Initially described as a X chromosome-linked disease exclusively affecting males&#44; several females with VEXAS syndrome&#44; usually carriers of an X chromosome monosomy&#44; have now been reported<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#8211;23</span></a>&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">To date&#44; six variants have been described that cause VEXAS syndrome&#44; 4 of them in exon 3 &#40;p&#46;Met41Val&#44; p&#46;Met41Thr&#44; p&#46;Met41Leu&#44; p&#46;Ser56Phe&#41; and 2 in intron 2 &#40;c&#46;118-1G<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>C and c&#46;118-9&#95;118-2del&#41;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#8211;27</span></a>&#46; The most common variants are <span class="elsevierStyleItalic">missense</span> variants that affect the same methionine-41 residue &#40;p&#46;Met41&#41; and are restricted to cells of the myeloid line&#44; so in peripheral blood they are found in monocytes and neutrophils&#46; One study identified the p&#46;Met41Leu variant as associated with a better prognosis<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>&#46; Updated information on the identified variants and their genotype-phenotype correlation can be obtained at the <span class="elsevierStyleItalic">Infevers Registry</span> &#40;<a href="https://infevers.umai-montpellier.fr/web/search.php?n=46">https&#58;&#47;&#47;infevers&#46;umai-montpellier&#46;fr&#47;web&#47;search&#46;php&#63;n&#61;46</a>&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The UBA1 protein is physiologically expressed as 2 isoforms&#58; a&#41; the nuclear isoform &#40;UBA1a&#41;&#44; which initiates translation in p&#46;Met1&#59; and b&#41; the cytoplasmic isoform &#40;UBA1b&#41;&#44; which initiates it at position p&#46;Met41&#46; Mutations at position p&#46;Met41 generate a new isoform &#40;UBA1c&#41;&#44; which initiates translation at position p&#46;Met67&#44; with cytoplasmic localisation and defective function<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46; Dysfunction of the E1 enzyme leads to a disruption in the start of the ubiquitination process&#44; so that proteins are not properly ubiquitinated for subsequent degradation by the cytoplasmic proteasome complex&#46; These alterations produce cellular stress and the activation of different pathophysiological mechanisms&#44; including the NF-&#954;B <span class="elsevierStyleItalic">&#40;nuclear factor-&#954;B&#41; transcription factor pathway</span><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46; Using transcriptomic techniques&#44; a gene expression pattern of activation of multiple innate immune pathways&#44; such as TNF&#44; IL-6 and interferon gamma &#40;IFN&#947;&#41;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> has been demonstrated in circulating monocytes and neutrophils of patients with VEXAS syndrome&#46; These pathophysiological changes were absent in B and T cells<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Furthermore&#44; a zebrafish model deficient for the <span class="elsevierStyleItalic">UBA1</span> gene showed altered development and premature death of these fish compared to non-deficient fish and was associated with increased expression of pro-inflammatory genes<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46; These findings suggest that dysregulation and activation of these pathogenic pathways are responsible for alterations in mechanisms such as haematopoiesis and the immuno-inflammatory response leading to multisystemic involvement<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46; The redundancy of pathways and pathogenic mechanisms altered in VEXAS syndrome&#44; not yet well understood&#44; may contribute to the characteristic multi-treatment resistance in this disease&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Clinical manifestations</span><p id="par0050" class="elsevierStylePara elsevierViewall">Although new clinical phenotypes of VEXAS syndrome continue to be described&#44; all 25 patients included in the original communication were male and onset of clinical manifestations was between the ages of 45 and 80<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46; Similar to this first publication&#44; in subsequent retrospectively collected cases and series&#44; patients had been frequently diagnosed with systemic diseases such as relapsing polychondritis&#44; neutrophilic dermatoses&#44; cutaneous or systemic vasculitis&#44; and blood dyscrasias such as myelodysplastic syndrome &#40;MDS&#41;&#44; monoclonal gammopathy of uncertain significance and multiple myeloma&#44; among others<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#44;25&#44;28&#8211;30</span></a>&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the main clinical manifestations described in 4 series of patients with VEXAS syndrome<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#44;25&#44;28</span></a>&#46; Persistent or periodic fever&#44; constitutional symptoms with weight loss and arthralgias or arthritis are common systemic manifestations&#46; Among the most common systemic manifestations are skin involvement in the form of cutaneous vasculitis&#44; erythema nodosum&#44; and various forms of neutrophilic dermatoses &#40;such as Sweet&#39;s syndrome&#44; pustulosis&#44; and pyoderma gangrenosum&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Auricular and nasal chondritis&#44; vasculitis lesions&#44; with a wide spectrum of presentation&#44; ranging from aortic to small vessels involvement &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#44; spontaneous venous thrombosis and pulmonary parenchymal infiltrates &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; are also common&#46; Ocular inflammation &#40;in the form of uveitis&#44; scleritis&#44; episcleritis and orbital tumour&#41;&#44; renal involvement &#40;due to vasculitis or interstitial nephritis&#41;&#44; cardiac involvement &#40;pericarditis or myocarditis&#41;&#44; gastrointestinal tract &#40;abdominal pain&#44; diarrhoea&#44; rectal bleeding&#44; perforation&#47;obstruction&#41;&#44; central nervous system &#40;due to vasculitis or cerebrovascular accidents&#41;&#44; peripheral nervous system&#44; testicular &#40;orchitis&#41;&#44; as well as lymphadenopathy&#44; hepatomegaly and splenomegaly have also been described<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#44;25&#44;28&#8211;30</span></a>&#46; About half of the patients develop some haematological abnormality&#44; among which MDS stands out<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;28</span></a>&#46; Concomitant presentation of inflammatory manifestations and secondary amyloidosis with renal and cardiac involvement has been described in one patient<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">VEXAS syndrome has a poor prognosis&#44; with mortality ranging between 15&#46;5 and 40&#37;&#44; depending on the series<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#44;25&#44;28</span></a>&#46; Disease progression due to lack of response to immunosuppressive treatment and infections favoured by this prolonged immunosuppression are the most common causes of death in these patients<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#44;25&#44;28</span></a>&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Supplementary tests</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Laboratory tests</span><p id="par0065" class="elsevierStylePara elsevierViewall">VEXAS syndrome is associated with a marked increase in acute phase reactants&#44; such as C-reactive protein &#40;CRP&#41; and erythrocyte sedimentation rate &#40;ESR&#41;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#44;25&#44;28</span></a>&#46; Serum amyloid A protein &#40;SAA&#41; has only been reported high in one patient who developed renal and cardiac amyloidosis<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a>&#46; In addition to the variable development of thrombocytopenia&#44; leukopenia&#44; and lymphopenia&#44; the presence of macrocytic anaemia with a high mean corpuscular volume &#40;MCV&#41; and normal folic acid and vitamin B levels is characteristic in most patients<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Detection of monoclonal components&#44; usually classified as monoclonal gammopathy of undetermined significance&#44; is also common<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#44;25&#44;28</span></a>&#46; Positive autoantibody results&#44; such as rheumatoid factor and lupus anticoagulant have been observed in some patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;25</span></a>&#46; VEXAS syndrome has also been associated with a prior diagnosis of antineutrophil cytoplasmic antibody &#40;ANCA&#41;-associated vasculitis<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Histopathology</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Myelogram</span><p id="par0070" class="elsevierStylePara elsevierViewall">In addition to findings of myelodysplasia or multiple myeloma &#40;if present&#41;&#44; bone marrow aspirate from patients with VEXAS syndrome is usually hypercellular&#44; with predominance of myeloid hyperplasia&#44; and dysplastic elements and cytoplasmic vacuoles are typical in the bone marrow&#46; myeloid and erythroid precursor cells &#40;blasts&#44; promyelocytes and proerythroblasts&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;32</span></a>&#46; Although less frequently&#44; vacuoles have also been observed in eosinophils&#44; monocytes&#44; plasma cells&#44; and megakaryocytes<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a>&#46; The presence of these vacuoles in both cell series can be considered highly suggestive of VEXAS syndrome<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;32</span></a>&#46; In this sense&#44; it is possible that in patients who do not have an underlying haematological disease and have not undergone myelotoxic treatments&#44; the presence of these vacuoles in the myeloid and erythroid series may be considered a pathognomonic finding of this disease&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Skin and other biopsies</span><p id="par0075" class="elsevierStylePara elsevierViewall">In the case of skin involvement&#44; biopsy of the damaged skin can confirm the diagnosis of vasculitis&#44; panniculitis&#44; or neutrophilic dermatosis&#46; The presence of vascular inflammation in the biopsy of other affected territories may provide the diagnosis of systemic vasculitis<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;29</span></a>&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Radiology</span><p id="par0080" class="elsevierStylePara elsevierViewall">In patients with VEXAS syndrome and inflammatory manifestations at the neurological&#44; hepatic&#44; renal&#44; pulmonary&#44; cardiac&#44; gastrointestinal or arterial limb circulation level&#44; computed tomography &#40;CT&#41; and magnetic resonance imaging &#40;MRI&#41; studies together with angiographic study &#40;when necessary&#41; can provide information on the inflammatory and&#47;or vasculitic origin of the lesions and their extent&#46; Cardiac MRI may also support the diagnosis of myocardial involvement due to secondary amyloidosis&#46; The detection of pulmonary infiltrates&#44; vasculitis changes&#44; visceral infarcts&#44; visceromegaly and lymphadenopathy will point to a systemic disease&#44; the inflammatory nature of which can be confirmed by 18-fluorodeoxyglucose positron emission tomography &#40;PET&#41; combined with CT &#40;PET&#47;CT&#41;&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Relapsing polychondritis&#44; myelodysplastic syndrome&#44; and VEXAS syndrome</span><p id="par0085" class="elsevierStylePara elsevierViewall">In patients diagnosed with VEXAS syndrome&#44; involvement as relapsing polychondritis is present in 36&#8211;64&#37; of patients<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#44;28</span></a>&#46; Prior to the description of VEXAS syndrome&#44; a 2016 study of 142 patients &#40;61&#37; women&#41; diagnosed with relapsing polychondritis identified several factors associated with increased mortality<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a>&#46; These poor prognostic factors included male sex&#44; presence of cardiac abnormalities&#44; and concomitant development of MDS or other hematologic malignancy&#46; According to clinical presentation&#44; patients were divided into groups with different mortality&#46; In patients with associated MDS&#44; a mortality of 58&#37; was observed&#44; while those with tracheobronchial chondritis had a mortality of 13&#37;&#46; In cases with the absence of either of the 2 previous manifestations&#44; mortality was 4&#37;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a>&#46; Therefore&#44; the subgroup of patients with MDS and without tracheobronchial chondritis could possibly correspond to patients with VEXAS syndrome&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">After the discovery of the VEXAS syndrome&#44; an international study with 92 patients with relapsing polychondritis detected postzygotic variants in the <span class="elsevierStyleItalic">UBA1</span> gene in 7&#46;6&#37; of cases<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&#46; This same study identified some clinical manifestations that are significantly associated with VEXAS syndrome in patients with relapsing polychondritis&#46; These included male gender&#44; age of onset &#62;45 years and the presence of fever&#44; auricular chondritis&#44; skin inflammation&#44; deep vein thrombosis and pulmonary infiltrates<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&#46; In contrast&#44; laryngeal&#44; tracheobronchial&#44; or costal chondritis does not manifest in VEXAS syndrome&#46; Compared with isolated relapsing polychondritis&#44; elevated acute-phase reactants and hematologic abnormalities&#44; such as macrocytic anaemia&#44; thrombocytopenia&#44; and lymphopenia&#44; are more common in VEXAS syndrome&#44; as are prior diagnoses of MDS&#44; gammopathy of uncertain significance&#44; and multiple myeloma<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&#46;</p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Proposal for a diagnostic algorithm in patients with relapsing polychondritis</span><p id="par0095" class="elsevierStylePara elsevierViewall">The authors of the previous study also developed an algorithm for the diagnosis of VEXAS syndrome in those patients previously diagnosed with relapsing polychondritis<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&#46; Compliance with these 3 criteria a&#41; Male gender&#59; b&#41; Mean corpuscular volume of red blood cells &#62;100<span class="elsevierStyleHsp" style=""></span>fL&#59; and c&#41; Platelet count &#60;200&#44;000&#47;mm<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#44; was associated with a sensitivity of 100&#37; and a specificity of 96&#37; for the identification of pathogenic variants in the <span class="elsevierStyleItalic">UBA1</span> gene in patients with relapsing polychondritis<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Likewise&#44; this diagnostic algorithm considers low platelet counts in patients with a previous diagnosis of relapsing polychondritis&#44; so this parameter cannot yet be generalized or extrapolated to other common clinical situations&#44; such as neutrophilic dermatoses&#44; difficult-to-treat vasculitis&#44; and probably myelodysplastic syndromes with more or less specific inflammatory manifestations&#46; It is likely that in the near future diagnostic algorithms and criteria will be generated based on larger&#44; well-characterised population-based studies&#44; probably derived from national or international multicentre registries&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Prognostic factors in VEXAS syndrome</span><p id="par0105" class="elsevierStylePara elsevierViewall">A French multicenter registry of 116 patients with VEXAS syndrome identified 3 groups with different 5-year survival&#46; Although the overall mortality of the series was 15&#46;5&#37;&#44; the group that had constitutional symptoms&#44; higher CRP levels and less chondritis &#40;37&#37;&#41; had a mortality of 10&#46;4&#37;&#46; Patients with MDS &#40;16&#37;&#41; had a worse prognosis&#44; with a mortality of 49&#46;5&#37;&#46; A mortality of 15&#46;8&#37; was observed in 47&#37; of patients in the intermediate group<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Systemic vasculitides and VEXAS syndrome</span><p id="par0110" class="elsevierStylePara elsevierViewall">The presence or prior diagnosis of systemic vasculitis has been reported in between 16&#37; and 64&#37; of patients with VEXAS syndrome<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#44;28</span></a>&#46; The most common have been cutaneous vasculitis&#44; especially in the isolated form of leukocytoclastic vasculitis&#44; and polyarteritis nodosa<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#44;28&#44;29</span></a>&#46; Aortitis&#44; central nervous system vasculitis&#44; giant cell arteritis&#44; Beh&#231;et&#39;s disease&#44; cryoglobulinaemic vasculitis and ANCA-associated vasculitis have also been reported<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#44;28&#44;29</span></a>&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In a study involving 147 patients seen in a vasculitis clinic&#44; a diagnosis of VEXAS syndrome was suspected in 7 &#40;5&#37;&#41; patients and could be confirmed by genetic testing in 3 &#40;2&#37;&#41; cases<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a>&#46; The previous diagnoses of these patients were relapsing polychondritis&#44; ANCA-associated vasculitis&#44; and undifferentiated autoinflammatory disease&#46; Five of the 7 &#40;71&#46;4&#37;&#41; patients were also diagnosed with MDS<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a>&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The discovery in 2014 of DADA2 and SAVI syndrome &#40;<span class="elsevierStyleItalic">STING1 &#91;stimulator of interferon genes 1&#93;&#44;</span> STING-associated vasculopathy with onset in infancy&#41; as 2 types of vasculitis&#47;vasculopathy caused by genetic alterations<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#8211;36</span></a>&#44; already represented a conceptual revolution in the field of primary systemic vasculitides&#46; These forms of autoinflammatory vasculitis&#44; although typical of early childhood&#44; can also occur in adult patients<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#8211;38</span></a>&#46; In addition to these previous descriptions&#44; the description of VEXAS syndrome represents an even more significant advance in the understanding of the aetiopathogenesis of systemic vasculitides&#44; especially those that occur exclusively in adulthood&#46; For the time being&#44; these findings already imply that genetic studies should be considered in the differential diagnosis of systemic vasculitides to confirm or rule out the presence of any of these autoinflammatory diseases &#40;or vasculitides&#41;&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Differential diagnosis</span><p id="par0125" class="elsevierStylePara elsevierViewall">A considerable number of patients with VEXAS syndrome had previously been diagnosed with systemic inflammatory or autoimmune diseases&#44; chronic haematological disorders&#44; or a combination of both<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#44;25&#44;28&#8211;30</span></a>&#46; Therefore&#44; the differential diagnosis with VEXAS syndrome should be considered in male adults with inflammatory and&#47;or haematological manifestations&#44; and multi-organ involvement resistant to different immunosuppressive treatments&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">The main diseases that should be considered in the differential diagnosis of VEXAS syndrome are&#58; a&#41; <span class="elsevierStyleItalic">Systemic autoimmune diseases&#58;</span> Relapsing polychondritis&#44; cutaneous leukocytoclastic vasculitis&#44; and systemic vasculitides &#40;such as polyarteritis nodosa&#44; cutaneous arteritis&#44; giant cell arteritis&#44; Beh&#231;et&#8217;s disease&#44; cryoglobulinaemic vasculitis&#44; and ANCA-associated vasculitis&#41;&#44; rheumatoid arthritis&#44; and other undifferentiated arthritis&#59; b&#41; <span class="elsevierStyleItalic">Diseases involving neutrophilic dermatoses or panniculitis</span>&#58; Sweet&#39;s syndrome&#44; extrapulmonary sarcoidosis and autoinflammatory diseases with or without a known genetic basis&#59; and c&#41; <span class="elsevierStyleItalic">Chronic haematological diseases</span>&#58; MDS&#44; monoclonal gammopathy of uncertain significance&#44; multiple myeloma&#44; and some types of lymphomas&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Treatment</span><p id="par0135" class="elsevierStylePara elsevierViewall">Although evidence of therapeutic efficacy is limited&#44; the experience with the drugs used so far in VEXAS syndrome is described below&#46; As the information reported so far is from retrospective cases and series&#44; the duration of treatment and its long-term effectiveness is unknown for most of the drugs where a positive or indeterminate effect has been obtained&#46;</p><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Glucocorticoids and other conventional immunosuppressants</span><p id="par0140" class="elsevierStylePara elsevierViewall">Glucocorticoids are the most widespread immunosuppressive therapy&#44; and at high doses tend to control the inflammatory manifestations of VEXAS syndrome&#46; This effect is usually transient&#44; as in its tapering&#44; prednisone doses lower than 10&#8722;20<span class="elsevierStyleHsp" style=""></span>mg&#47;day are usually not effective<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#44;29&#44;30</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#8211;41</span></a>&#46; Other conventional glucocorticoid-sparing immunosuppressive drugs&#44; such as azathioprine&#44; methotrexate and mycophenolate mofetil&#44; have also achieved insufficient or partial response in this disease<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#44;28&#8211;30&#44;39&#8211;41</span></a>&#46; Partial responses have been described with cyclophosphamide and calcineurin inhibitors &#40;cyclosporine and tacrolimus&#41; in combination with glucocorticoids<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;39</span></a>&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Anti-inflammatory and immunomodulatory drugs such as hydroxychloroquine&#44; dapsone and colchicine&#44; as well as intravenous immunoglobulins&#44; have also been tried without clinical benefit<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;39&#8211;41</span></a>&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Biologic drugs</span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Interleukin-1 blockers</span><p id="par0150" class="elsevierStylePara elsevierViewall">Both anakinra and canakinumab have been ineffective in most published cases concerning VEXAS syndrome<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;28&#44;29&#44;39&#8211;41</span></a>&#44; and have only been associated with disease control in isolated cases<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;31&#44;39</span></a>&#46; In addition&#44; the administration of anakinra has been associated with moderate or severe inflammatory reactions at injection sites in a high percentage of patients &#40;8&#8211;62&#37;&#41;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;24&#44;39</span></a>&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Interleukin-6 and tumour necrosis factor blockers</span><p id="par0155" class="elsevierStylePara elsevierViewall">Tocilizumab has been used in a number of cases and there are records of patients with VEXAS syndrome&#44; with some positive effect<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#44;42</span></a>&#44; although most have reported a partial or unfavourable effect<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;28&#44;30&#44;39</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a>&#46; In addition&#44; some cases of intestinal perforation have been reported with its use<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a>&#46; Infliximab&#44; adalimumab&#44; etanercept&#44; and golimumab have been used in several patients with VEXAS syndrome&#44; with partial or ineffective response<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;28&#8211;30&#44;39&#44;41</span></a>&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Janus kinase inhibitors</span><p id="par0160" class="elsevierStylePara elsevierViewall">Nonselective Janus kinase &#40;JAK&#41; inhibitors&#44; such as baricitinib &#40;anti-JAK1&#47;2&#41;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> and tofacitinib &#40;anti-JAK1&#47;3&#41;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;28&#44;30</span></a> have not had a beneficial effect in patients with VEXAS syndrome&#46; Two patients with positive response have been described with ruxolitinib &#40;anti-JAK1&#47;2&#41;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&#46; The use of upadacitinib &#40;anti-JAK1&#47;3&#41; has obtained a partial response together with glucocorticoid at medium-low doses in one patient<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a>&#46; Selective JAK inhibitors &#40;anti-JAK1&#41;&#44; such as abrocitinib and filgotinib&#44; have been tried in these patients without good results<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a>&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Other biologic drugs</span><p id="par0165" class="elsevierStylePara elsevierViewall">Secukinumab &#40;anti-IL-17 monoclonal antibody&#41; has been used without benefit in one patient<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#44; and in another patient&#44; its administration together with intravenous immunoglobulins has been associated with a good response&#44; which allowed the prednisone dose to be reduced to 20<span class="elsevierStyleHsp" style=""></span>mg&#47;day<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a>&#46; With ustekinumab &#40;anti-IL-12&#47;23 monoclonal antibody&#41; no effective results have been reported<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;41</span></a>&#46; Following prednisone tapering&#44; abatacept &#40;fusion protein with the extracellular domain of CTLA-4 and the Fc portion of human IgG&#41; was used subcutaneously in one patient with a partial and transient effect<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a>&#46; Except in a few isolated cases with an acceptable response<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a>&#44; rituximab &#40;anti-CD20&#41; has been shown to be ineffective in VEXAS syndrome<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;28&#8211;30</span></a>&#46; In a patient with VEXAS syndrome&#44; who also had multiple myeloma&#44; bortezomib &#40;proteasome inhibitor&#41; was used in combination with lenalidomide &#40;anti-angiogenic and antineoplastic&#41; without effect<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a>&#46; Lenalidomide had to be discontinued due to skin rash in one case<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a>&#46;</p></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Hypomethylating agents</span><p id="par0170" class="elsevierStylePara elsevierViewall">In low-risk MDS patients&#44; hypomethylating agents&#44; such as azacitidine and decitabine&#44; have been associated with improved transfusion independence in 30&#37; of patients without 5<span class="elsevierStyleHsp" style=""></span>q deletion in whom erythropoietin treatment failed&#46; In high-risk MDS patients&#44; these drugs improve overall survival and delay transformation to acute myeloid leukemia<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a>&#46; Up to half of patients with VEXAS syndrome have a low-risk MDS in most cases&#44; according to standard prognostic indices<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a>&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">In some patients with VEXAS syndrome and MDS&#44; azacitidine &#40;administered at a dose of 75<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;day in consecutive 7-day cycles every month subcutaneously or intravenously&#41; has shown a positive effect on both glucocorticoid tapering and hemotherapy requirements<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;40&#44;41</span></a>&#46; Azacitidine was used in 11 patients with MDS and VEXAS syndrome in a French registry<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a>&#46; Inflammatory manifestations were prevalent in 8 patients and MDS in 3 cases&#46; After a median of 11 &#40;range 2&#8211;35&#41; cycles of azacitidine and a follow-up time of 32 &#40;12&#8211;75&#41; months&#44; 5 &#40;46&#37;&#41; patients had a good clinical response after 4&#8211;6 cycles of treatment&#44; with a duration of response of 6&#8211;27 months&#46; In responders to azacitidine&#44; a significant reduction in CRP levels and prednisone dose was observed at 6 months&#44; from a median &#40;range&#41; of 30 &#40;20&#8211;70&#41; to 10 &#40;0&#8211;20&#41; mg&#47;day&#44; which could be discontinued in one patient<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a>&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">In a series of 3 patients with VEXAS syndrome and MDS&#44; 2 of them also carried a mutation in the <span class="elsevierStyleItalic">DNMT3A</span> gene&#46; In the 2 patients with mutations in this gene&#44; positive effects were observed after 2&#8211;3 cycles&#44; and although one of them had to be discontinued due to the development of diverticulitis&#44; remission was maintained<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>&#46; Azacitidine was ineffective in the patient without mutations in the <span class="elsevierStyleItalic">DNMT3A</span> gene<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Although it seems that azacitidine may have a superior effect on disease control in patients with VEXAS syndrome and MDS with mutations in their associated genes&#44; this observation needs to be tested in a wider population&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Allogeneic hematopoietic stem-cell transplantation</span><p id="par0190" class="elsevierStylePara elsevierViewall">A few isolated cases<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> and a retrospective series of six patients with VEXAS syndrome who underwent allogeneic haematopoietic stem cell transplantation have recently been published<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a>&#46; Five of them achieved a complete response&#44; with follow-up periods greater than 2&#8211;3 years in 3 cases<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a>&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Although the age of patients with VEXAS syndrome may in itself be a limiting factor for allogeneic hematopoietic stem-cell transplantation eligibility&#44; in order to define the subgroup of patients who will benefit most from this potentially curative procedure&#44; there is currently a phase II clinical trial to study the safety of allogeneic haematopoietic stem-cell transplantation in VEXAS syndrome &#40;ClinicalTrials&#46;gov&#58;NCT05027945&#41;&#46;</p></span></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Future lines in VEXAS syndrome</span><p id="par0200" class="elsevierStylePara elsevierViewall">Given the wide spectrum of presentation and the different specialties involved in the diagnosis and treatment of patients with VEXAS syndrome&#44; a multidisciplinary approach is necessary to reach a rapid diagnosis that contributes to early targeted treatment&#46; In addition&#44; as for other minority diseases&#44; it is important for VEXAS syndrome to implement international multicentre registries that contribute to increasing clinical&#44; aetiopathogenic and evolutionary knowledge of this disease&#44; helping to develop classificatory or diagnostic criteria&#44; and that promote clinical trials to improve current therapeutic options<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a>&#46;</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conclusions</span><p id="par0205" class="elsevierStylePara elsevierViewall">VEXAS syndrome is a monogenic autoinflammatory disease caused by postzygotic variants in the <span class="elsevierStyleItalic">UBA1</span> gene&#46; It usually manifests in adult males with a systemic and varied presentation&#44; including fever&#44; arthritis or arthralgia&#44; neutrophilic dermatosis and other skin lesions&#44; auricular and nasal chondritis&#44; pulmonary inflammation&#44; venous thrombosis&#44; and different types of vasculitis&#46; An elevated acute phase response and cytopenias&#44; most notably macrocytic anaemia&#44; are typical in laboratory tests&#46; Coexistence of MDS is common&#44; and cytoplasmic vacuoles in myeloid and erythroid precursors in bone marrow are characteristic&#46; It usually relies on medium to high doses of glucocorticoids&#44; while all other immunosuppressive agents&#44; both conventional and biological&#44; show limited or no efficacy&#46; Azacitidine&#44; a hypomethylating agent&#44; has shown beneficial effects&#44; especially in patients with associated MDS&#46; Allogeneic hematopoietic stem-cell transplantation appears to be the only curative alternative to date&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">The VEXAS syndrome has been a paradigm shift in the diagnosis and treatment of autoinflammatory diseases and systemic vasculitides&#44; so that a targeted genetic approach could now identify new causative genes in systemic and complex diseases not diagnosed in adult patients&#46; As in VEXAS syndrome&#44; there would be a high probability that these pathogenic variants are postzygotic&#44; developed in certain cell lines during the patient&#39;s lifetime&#44; and would be the reason for the disease to manifest in old age&#46; Therefore&#44; as is already the case in adult forms of cancer and VEXAS syndrome&#44; postzygotic mutations could be considered as the cause of new chronic and probably difficult-to-treat systemic diseases&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Funding</span><p id="par0215" class="elsevierStylePara elsevierViewall">This study has been funded by the <span class="elsevierStyleGrantSponsor" id="gs0005">Instituto de Salud Carlos III &#40;ISCIII&#41;</span> through project PI21&#47;01352 and co-financed by the <span class="elsevierStyleGrantSponsor" id="gs0010">European Union</span>&#46;</p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflict of interests</span><p id="par0220" class="elsevierStylePara elsevierViewall">The authors approve the content of this manuscript and declare that they have no conflict of interest with regard to its publication&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">VEXAS syndrome was described by the end of 2020 as an autoinflammatory disease caused by post-zygotic variants in the UBA1 gene&#46; VEXAS syndrome occurs in adult males with recurrent fever&#44; arthralgia&#47;arthritis&#44; ear&#47;nose chondritis&#44; neutrophilic dermatosis&#44; lung inflammation&#44; venous thrombosis&#44; and different types of vasculitis&#46; Common laboratory changes include raised acute phase reactants and macrocytic anemia&#46; The coexistence of myelodysplasia is frequent&#44; and bone marrow vacuolization of myeloid and erythroid precursors is characteristic&#46; Glucocorticoids are effective at medium-high doses&#44; but the remaining immunosuppressive drugs&#44; either conventional or biological&#44; have showed limited or absent efficacy&#46; Azacitidine has been associated with a good response&#44; especially in patients with accompanying myelodysplastic syndrome&#46; Allogeneic hematopoietic stem cell transplantation appears to be the only curative therapy by now&#46; VEXAS syndrome has become a paradigm shift in the diagnosis and treatment of autoinflammatory diseases and systemic vasculitis&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A finales de 2020 se describi&#243; el s&#237;ndrome VEXAS&#44; como una enfermedad autoinflamatoria causada por variantes poscig&#243;ticas en el gen UBA1&#46; Se presenta en varones adultos con fiebre recurrente&#44; artralgias&#47;artritis&#44; condritis auricular&#47;nasal&#44; dermatosis neutrof&#237;lica&#44; inflamaci&#243;n pulmonar&#44; trombosis venosas y diferentes tipos de vasculitis&#46; Los an&#225;lisis muestran una respuesta de fase aguda elevada y anemia macroc&#237;tica&#46; Es frecuente la coexistencia de mielodisplasia&#44; y son caracter&#237;sticas las vacuolas citoplasm&#225;ticas en precursores mieloides y eritroides en m&#233;dula &#243;sea&#46; Los glucocorticoides a dosis medias-altas son eficaces&#44; pero el resto de f&#225;rmacos inmunodepresores&#44; convencionales o biol&#243;gicos&#44; muestran una eficacia limitada o ausente&#46; Azacitidina se ha asociado con una buena respuesta&#44; sobre todo en pacientes con s&#237;ndrome mielodispl&#225;sico acompa&#241;ante&#46; El trasplante alog&#233;nico de progenitores hematopoy&#233;ticos parece ser la &#250;nica terapia curativa hasta el momento&#46; El s&#237;ndrome VEXAS ha supuesto un cambio de paradigma en el diagn&#243;stico y tratamiento de las enfermedades autoinflamatorias y las vasculitis sist&#233;micas&#46;</p></span>"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Right upper lobe &#40;RUL&#41; pulmonary infiltrate &#40;arrowheads&#41; in a patient with VEXAS syndrome&#58; A&#41; CT showing parenchymal infiltrate in RUL&#59; B&#41; PET&#47;CT with FDG showing pathological uptake of the infiltrate&#44; confirming its inflammatory nature &#40;the patient did not receive antibiotic treatment&#41;&#46;</p>"
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Beck et al&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Bourbon et al&#46; <a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Ferrada et al&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Georgin-Lavialle et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No&#46; &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No&#46; &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No&#46; &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No&#46; &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Number of patients</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">116&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Males</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">25 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">11 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">13 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">111 &#40;95&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Age at diagnosis &#40;years&#41;&#59;</span> median &#40;IQR or range&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&#8212;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&#8212;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">62 &#40;48&#8722;71&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">71 &#40;66&#46;76&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Age of symptom onset &#40;years&#41;&#59;</span> median &#40;IQR&#41; or &#40;range&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">64 &#40;45&#8722;80&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">66 &#40;47&#8722;83&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">56 &#40;45&#8722;70&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">67 &#40;62&#46;5&#8722;73&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">History</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Relapsing polychondritis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">15 &#40;60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">5 &#40;46&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&#8212;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&#8212;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Neutrophilic dermatosis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">8 &#40;32&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">5 &#40;46&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&#8212;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&#8212;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Vasculitis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">4 &#40;16&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">7 &#40;64&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&#8212;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&#8212;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Myelodysplastic syndrome</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">6 &#40;24&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">6 &#40;55&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">3 &#40;23&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">58 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">MGUS&#47;multiple myeloma</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">5 &#40;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">1 &#40;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">2 &#40;14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">12 &#40;10&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">RA&#47;Still&#39;s disease in adults</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&#8212;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">2 &#40;18&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&#8212;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Mortality</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">10 &#40;40&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">3 &#40;27&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Systemic manifestations</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Weight loss</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Arthritis&#47;arthralgia</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">6 &#40;46&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">13 &#40;100&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">42 &#40;36&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Auricular&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Nasal&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Sensorineural hearing loss</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Vestibular symptoms</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3 &#40;27&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Skin lesions</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">97 &#40;83&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Neutrophilic dermatosis&#47;plaques</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">9 &#40;36&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">7 &#40;64&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8212;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">46 &#40;39&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Nodules&#47;erythema nodosum</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">13 &#40;52&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">4 &#40;36&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8212;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">15 &#40;12&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hives&#47;papular rash</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8212;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Vasculitis</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Periorbital oedema</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Gastrointestinal tract</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Peripheral nervous system</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Ocular &#40;uveitis&#44; scleritis&#44; episcleritis&#44; orbital mass&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Cardiac</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Pericarditis&#47;pericardial effusion</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1 &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Myocarditis</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1 &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2 &#40;18&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3 &#40;2&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Pulmonary</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">18 &#40;72&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">57 &#40;49&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Pulmonary infiltrates</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">18 &#40;72&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">5 &#40;46&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">10 &#40;77&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">47 &#40;40&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Pleural effusion</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">8 &#40;32&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">11 &#40;9&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Vascular</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Arterial &#40;aortitis&#47;aneurysms&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&#8212;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1 &#40;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">12 &#40;10&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Spontaneous venous thrombosis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t" scope="col">Laboratory parameters&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">Ferrada et al&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>116&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>13&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">97 &#40;64&#8722;124&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8212;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">66&#46;5 &#40;42&#8722;110&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">C-reactive protein&#59; g&#47;dl&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">73 &#40;18&#8722;128&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">6&#46;1 &#40;3&#8722;12&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;8 &#40;1&#8722;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Haemoglobin&#59; g&#47;dl&nbsp;\t\t\t\t\t\t\n
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                  \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">9<a class="elsevierStyleCrossRef" href="#tblfn0010">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">10&#46;1 &#40;9&#8722;11&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">10 &#40;8&#8722;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Mean corpuscular volume&#59; fl&nbsp;\t\t\t\t\t\t\n
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                  \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">110<a class="elsevierStyleCrossRef" href="#tblfn0010">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">101 &#40;94&#46;1&#8722;107&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">105 &#40;102&#8722;115&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Platelets&#59; n&#47;mm<span class="elsevierStyleSup">3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">110<a class="elsevierStyleCrossRef" href="#tblfn0010">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">204 &#40;138&#44;260&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">145 &#40;100&#8722;169&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WBC&#59; n&#47;mm<span class="elsevierStyleSup">3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">4&#46;500<a class="elsevierStyleCrossRef" href="#tblfn0010">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">4400 &#40;2972&#8722;6222&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8212;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Neutrophils&#59; n&#47;mm<span class="elsevierStyleSup">3</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2&#46;500<a class="elsevierStyleCrossRef" href="#tblfn0010">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2600 &#40;1640&#8722;4185&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">&#8212;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lymphocytes&#59; n&#47;mm<span class="elsevierStyleSup">3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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