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BACKGROUND Familial Mediterranean fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by recurrent fever flares. METHODS We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution of flare and no flare until week 16). In the subsequent phase up to week 40, patients who had a complete response underwent a second randomization to receive canakinumab or placebo every 8 weeks. Patients who underwent a second randomization and had a subsequent flare and all other patients received open-label canakinumab. RESULTS At week 16, significantly more patients receiving canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with colchicine-resistant familial Mediterranean fever (PcO.OOl), 35% versus 6% of those with mevalonate kinase deficiency (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006). The inclusion of patients whose dose was increased to 300 mg every 4 weeks yielded a complete response in 71% of those with colchicine-resistant familial Mediterranean fever, 57% of those with mevalonate kinase deficiency, and 73% of those with TRAPS. After week 16, an extended dosing regimen (every 8 weeks) maintained disease control in 46% of patients with colchicine-resistant familial Mediterranean fever, 23% of those with mevalonate kinase deficiency, and 53% of those with TRAPS. Among patients who received canakinumab, the most frequently reported adverse events were infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean fever, those with mevalonate kinase deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years). CONCLUSIONS In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS. [ABSTRACT FROM AUTHOR]

Recurrent fever can be the sole or leading manifestation of a variety of diseases including malignancies, autoimmune diseases and infections. Because the differential diagnoses are manifold, no formal guidelines for the approach of patients with recurrent fever exists. The newly recognized group of autoinflammatory diseases are often accompanied by repetitive fever attacks. As these episodes are frequently associated by a variety of divergent presentations, the differentiation of other causes for febrile illnesses can be difficult. In this article, we first review disease entities, which frequently present with the symptom of recurrent fever. In a next step, we summarize their characteristic pattern of disease presentation. Finally, we analyse key features of autoinflammatory diseases, which are helpful to distinguish this group of diseases from the other causes of recurrent fever. Recognizing these symptom patterns can provide the crucial clues and, thus, lead to the initiation of targeted specific diagnostic tests and therapies. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Hereditary periodic fever syndromes (HPFs) develop as a result of uncontrolled activation of the inflammatory response, with a substantial contribution from interleukin-1beta or tumor necrosis factor alpha (TNFalpha). The HPFs include familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), TNF receptor-associated syndrome (TRAPS), and cryopyrinopathies, which are attributable to mutations of the MEFV, MVK, TNFRSF1A, and CIAS1 genes, respectively. However, in many patients, the mutated gene has not been determined; therefore, the condition in these patients with an HPF-like clinical picture is referred to as idiopathic periodic fever (IPF). The aim of this study was to assess involvement of X-linked inhibitor of apoptosis (XIAP), which plays a role in caspase inhibition and NF-kappaB signaling, both of which are processes that influence the development of inflammatory cells. METHODS: The XIAP gene (X-linked) was sequenced in 87 patients with IPF, 46 patients with HPF (13 with HIDS, 17 with TRAPS, and 16 with FMF), and 182 healthy control subjects. The expression of different alleles was evaluated by sequencing XIAP-specific complementary DNA mini-libraries and by real-time polymerase chain reaction and Western blot analyses. The functional effect of XIAP on caspase 9 activity was assessed by a fluorimetric assay, and cytokine secretion was evaluated by enzyme-linked immunosorbent assay. RESULTS: Sequencing disclosed a 1268A>C variation that caused a Q423P amino acid substitution. The frequency of 423Q-homozygous female patients and 423Q-hemizygous male patients was significantly higher in the IPF group than in the control group (69% versus 51%; odds ratio 2.17, 95% confidence interval 1.23-3.87, P = 0.007), whereas no significant difference was detected in the HPF group (59%) compared with controls. In primary lymphocytes and transfected cell lines, 423Q, as compared with 423P, was associated with higher XIAP protein and messenger RNA expression and lower caspase 9 activation. In lipopolysaccharide-activated monocytes, 423Q was associated with higher secretion of TNFalpha. CONCLUSION: These results suggest that 423Q is a predisposing factor for IPF development, possibly through its influence on monocyte function. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To identify a set of clinical parameters that can predict the probability of carrying mutations in one of the genes associated with hereditary autoinflammatory syndromes. METHODS: A total of 228 consecutive patients with a clinical history of periodic fever were screened for mutations in the MVK, TNFRSF1A, and MEFV genes, and detailed clinical information was collected. A diagnostic score was formulated based on univariate and multivariate analyses in genetically positive and negative patients (training set). The diagnostic score was validated in an independent set of 77 patients (validation set). RESULTS: Young age at onset (odds ratio [OR] 0.94, P = 0.003), positive family history of periodic fever (OR 4.1, P = 0.039), thoracic pain (OR 4.6, P = 0.05), abdominal pain (OR 33.1, P < 0.001), diarrhea (OR 3.3, P = 0.028), and oral aphthosis (OR 0.2, P = 0.007) were found to be independently correlated with a positive genetic test result. These variables were combined in a linear score whose ability to predict a positive result on genetic testing was validated in an independent data set. In this latter set, the diagnostic score revealed high sensitivity (82%) and specificity (72%) for discriminating patients who were genetically positive from those who were negative. In patients with a high probability of having a positive result on genetic testing, a regression tree analysis provided the most reasonable order in which the genes should be screened. CONCLUSION: The proposed approach in patients with periodic fever will increase the probability of obtaining positive results on genetic testing, with good specificity and sensitivity. Our results further help to optimize the molecular analysis by suggesting the order in which the genes should be screened. [ABSTRACT FROM AUTHOR]

The article details a study which analyzed the efficacy and safety of treatment with the interleukin-1 receptor antagonist anakinra in patients diagnosed with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) requiring high cumulative doses of steroids. The study included four children and one adult, who were treated with anakinra. All patients had prompt response to anakinra, showing symptoms disappearance and normalization of acute phase reactant levels.

OBJECTIVE: To examine the synthesis, processing, and secretion of interleukin-1beta (IL-1beta), as well as the clinical and biologic effects of IL-1 blockade, in patients with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome and Muckle-Wells syndrome (MWS), in an effort to understand the molecular mechanisms linking mutations of the CIAS1 gene and IL-1beta hypersecretion, and the underlying response to IL-1 receptor antagonist (IL-1Ra). METHODS: Six patients with CINCA syndrome or MWS were treated with IL-1Ra and followed up longitudinally. Monocytes obtained from the patients and from 24 healthy donors were activated with lipopolysaccharide (LPS) for 3 hours, and intracellular and secreted IL-1beta levels were determined by Western blotting and enzyme-linked immunosorbent assay before and after exposure to exogenous ATP. RESULTS: LPS-induced IL-1beta secretion was markedly increased in monocytes from patients with CIAS1 mutations. However, unlike in healthy subjects, secretion of IL-1beta was not induced by exogenous ATP. Treatment with IL-1Ra resulted in a dramatic clinical improvement, which was paralleled by an early and strong down-regulation of LPS-induced IL-1beta secretion by the patients' cells in vitro. CONCLUSION: Our results showed that the requirements of ATP stimulation for IL-1beta release observed in healthy individuals are bypassed in patients bearing CIAS1 mutations. This indicates that cryopyrin is the direct target of ATP and that the mutations release the protein from the requirement of ATP for activation. In addition, the dramatic amelioration induced by IL-1Ra treatment is at least partly due to the strong decrease in IL-1beta secretion that follows the first injections of the antagonist. These findings may have implications for other chronic inflammatory conditions characterized by increased IL-1beta. [ABSTRACT FROM AUTHOR]

The objective of this paper is to investigate the long-term outcome of primary antiphospholipid syndrome (APS) in the paediatric age. The features of unselected patients with primary APS who had disease onset before the age of 16 years were retrospectively analysed in three Italian referral centres. Clinical and laboratory manifestations were assessed to establish whether, at the end of follow-up, the final diagnosis was still primary APS or whether they had developed definite SLE or lupus-like syndrome. Fourteen patients, nine boys and five-girls, who had the presenting clinical manifestation of APS between three and 13 years of age (median nine years) and were followed for two to 16 years (median six years). Six patients presented with deep vein thrombosis, five with cerebral stroke, two with peripheral artery occlusion and one with myocardial infarction. During follow-up, four patients had one or more recurrences of vascular thrombosis. At last observation, 10 patients could still be classified as having primary APS, two had developed SLE, one lupus-like syndrome and one Hodgkin's lymphoma. In conclusion; our analysis suggests that some children who present with the features of primary APS may progress to develop SLE or lupus-like syndrome. [ABSTRACT FROM AUTHOR]

We report a series of 22 children with idiopathic, drug unrelated erythema nodosum (EN) admitted to our Department. In 5 of them an history of streptococcal pharyngitis was referred; the remaining patients came to us with a diagnosis of "EN of unknown origin". Acute phase reactants, immunoglobulins, stool α1 antitrypsin, ANA, anti dsDNA antibodies and ANCA assay, chest roentgenogram, tuberculin test, and ophthalmologic assessment were performed in all patients. Etiologic diagnosis was made in 16 patients: Streptococcal pharyngitis (5 cases), chronic inflammatory bowel disease, IBD (3 cases), Behçet syndrome (2 cases), Yersinia enteritis (2 cases), infectious mononucleosis, atypical mycobacterial infection, immunodeficiency related infection, and SLE-like syndrome due to C4 deficiency (1 case each). We found oral/scrotal aphthae in 3 cases, gastrointestinal symptoms in 5 cases, arthritis in 3 cases. Acute phase reactants were positive in 16 patients without correlation to the underlying disease. Conversely, the increased α1 antitrypsin stool excretion and IgA serum concentration seemed to represent helpful indicators of IBD and Behçet syndrome, respectively. Proinflammatory cytokine pattern showed increased IL6 serum concentrations both in infectious and in non infectious disease-related EN, whereas a minor involvement of TNF was found in these patients. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the patterns of cytokine production by T cell clones raised from in vivo activated synovial fluid (SF) mononuclear cells (MNC) of five patients with oligoarticular juvenile arthritis (JA). Freshly isolated SF T cells were cultured in vitro with low dose recombinant IL-2 and subsequently cloned by limiting dilution. Sixty-four clones were obtained from the five patients studied. Fifty-nine clones were TCR α/β+ either CD4+ (n = 43) or CD8+ (n = 15). The remaining five clones were TCR γ/δ+, CD4-, CD8-. Clone immunophenotypes differed in the individual patients. Forty-four T cell clones were stimulated with phytohaemagglutinin (PHA) and phorbol myristate acetate (PMA) and supernatants tested for the presence of IL-2, IL-4, IL-5 and interferon-gamma (IFN-γ) by ELISA or bioassays. Cytokine mRNA accumulation was tested by reverse transcriptase-polymerase chain reaction (RT-PCR). Most of 44 clones tested released large amounts of IFN-7 irrespective of the immunophenotype. Of these, 27 were classified as Th1-type and 17 as Th0-type based upon the IFN-γ/IL-4 ratio in culture supernatants. Finally, when 10 representative T cell clones were tested for pro- and anti inflammatory cytokines, gene expression by RT-PCR, all of them were found to express the granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor-alpha (TNF-α), IL-10 and transforming growth factor-beta I (TGF-β1) genes, and half of them IL-6 and IL-8 mRNA. In conclusion, T cell clones, that represent the progeny of in vivo activated SF T cells from oligoarticular JA patients, display heterogeneous immunophenotypes, but all share the ability to produce large amounts of IFN-γ, with a predominant Th1/Th0 pattern. The expression of pro- and anti-inflammatory cytokine genes in these clones suggests that in vivo activated SFT cells modulate joint inflammation in a complex fashion. [ABSTRACT FROM AUTHOR]

Background: Among the various numbers of different autoinflammatory diseases (AIDs), the absolute majority of them remains rare, with a single representative in large populations. This project, endorsed by PRES, supported by the EMERGE fellowship program, and performed in line with the Metadata registry for the ERN RITA (MeRITA), has the objective of performing a data synchronization attempt of the most relevant research questions regarding clinical features, diagnostic strategies, and optimal management of autoinflammatory diseases. Results: An analysis of three large European registries: Eurofever, JIR-cohort and AID-Net, with a total coverage of 7825 patients from 278 participating centers from different countries, was performed in the context of epidemiological and clinical data merging. The data collected and evaluated in the registries does not cover only pediatric patients, but also adults with newly diagnosed AIDs. General aspects of the existing epidemiological data have been discussed in the context of patient global distribution, potential diagnostic delays, access to genetic testing, and the availability of the treatment. Conclusions: In general, the results indicate a great potential for upcoming collaborative work using existing data in cohorts that enhance the quality of medical care performed for patients with autoinflammatory diseases. [ABSTRACT FROM AUTHOR]

Details the case of a newborn baby girl with vasculitic rash, stunted growth, and hepatosplenomegaly. Examination and test results; Diagnosis of lysinuric protein intolerance confirmed by molecular analysis of the SLC747 gene; Treatment of LPI, an autosomal recessive disease resulting from a defect in the membrane transport of the cationic aminoacids lysine, arginine, and ornithine; Signs and symptoms, including aversion to protein-rich food and failure to thrive; Differential diagnosis of neonatal lupus.

Describes the cases of a brother and sister with different forms of vasculitis. Sister diagnosed with Henoch-Schonlein purpura (HSP); Brother diagnosed with acute hemorrhagic edema of childhood (AHE); Spontaneous disappearance of the conditions; Details about AHE, or Finkelstein's disease; Debate over the relation between the two conditions; Siblings showing a common immunopathological response.

Le lupus érythémateux systémique est une maladie très hétérogène associée habituellement à une activation de la voie des interférons de type I et à la présence d'auto-anticorps ciblant des auto-antigènes nucléaires. L'existence de formes familiales y compris chez des jumeaux monozygotes suggèrent une composante héréditaire majeure, concordante avec la description de quelques formes monogéniques. Les Toll-like récepteurs (TLRs) sont une famille de récepteurs immunitaires qui reconnaissent des motifs microbiens conservés et entraînent une réponse immunitaire innée et adaptative. Parmi les TLRs, TLR7, qui reconnaît les acides nucléiques viraux mais aussi du soi, a été particulièrement impliqué dans la physiopathologie du lupus. En effet, la surexpression de TLR7 suffit à entraîner une maladie lupique dans des modèles murins. De plus, des mutations hétérozygotes gain de fonction (GOF) du gène TLR7 (situé sur le chromosome X) ont été décrites récemment comme une cause de lupus monogénique chez l'homme. Nous décrivons dans ce travail deux nouvelles mutations de TLR7 qui élargissent le spectre clinique du phénotype. Le cas index de la première famille (F1.P1) était une fille qui a développé à 4 ans un tableau de lupus avec une fièvre, un rash malaire, une anémie, une lymphopénie et une glomérulonéphrite classe III/IV associées à des anticorps antinucléaires (AAN) avec présence d'anti-ADN, d'anticorps anti-phospholipides et une hypocomplémentémie C3/C4. Elle a, de manière plus atypique, présenté un tableau de vascularite cérébrale avec ischémies cérébrales et calcifications cérébrales diffuses. Malgré de nombreux traitements immunosuppresseurs, elle est décédée à l'âge de 17 ans d'un infarctus du myocarde. Le frère de F1.P1 a présenté à l'âge de 2 jours une épilepsie réfractaire révélant des calcifications des noyaux gris centraux. Une fièvre associée à des poussées d'éruptions cutanées et une lymphopénie sont ensuite apparues et ont bien répondu à un traitement immunosuppresseur comprenant du ruxolitinib. Le bilan auto-immun était négatif. La mère des deux enfants a développé à 12 ans un rash malaire avec AAN positifs puis a présenté à 24 ans un épisode de purpura thrombopénique immunologique (PTI), et une thrombose artérielle étendue du membre inférieur droit à 44 ans (malgré l'absence d'anticorps anti-phospholipides). Les trois membres de la famille étaient porteurs de la mutation F507S (c.1520 T>C) dans le gène TLR7. La deuxième famille était composée d'une seule fille (F2.P1) qui a développé à l'âge de 1 an un PTI et une anémie hémolytique auto-immune (syndrome d'Evans). Une IRM cérébrale, réalisée à l'âge de 8 ans devant un retard de développement, retrouvait de nombreux hypersignaux corticaux et sous corticaux. À 10 ans, du fait du caractère réfractaire de l'anémie et de la thrombopénie malgré de nombreux traitements immunosuppresseurs, elle a reçu une allogreffe de moelle osseuse d'un donneur phéno-identique. L'évolution hématologique a été favorable au décours de la greffe mais la leuco-encéphalopathie a continué à progresser sur les IRM. La patiente était porteuse de la substitution L528I (c.1582C>A) survenue de manière de novo dans le gène TLR7. Les analyses fonctionnelles réalisées dans un modèle cellulaire ont montré un mécanisme gain de fonction pour les deux variants (F507S et L528I) au même niveau qu'un mutant GOF TLR7 déjà publié (F507L). La modélisation de la structure protéique de TLR7 a montré que tous les variants étaient situés au niveau de l'interface d'homo-dimérisation de TLR7, et que l'effet du variant L528I était prédit comme le plus élevé sur la capacité de dimérisation de TLR7. Etant donné que l'homo-dimérisation de TLR7 est nécessaire pour l'activation de son signal, il est probable que la perturbation de cette interface entraîne l'effet GOF que nous observons. Nous rapportons ici deux nouvelles mutations de TLR7 encore jamais décrites. Bien que les mutations de TLR7 soient principalement associées à des phénotypes de lupus, nous décrivons ici un spectre clinique plus élargi, avec atteinte neuro-inflammatoire atypique pour des lupus et la possible absence d'auto-immunité lupique. De plus, nous décrivons pour la première fois la possibilité que des hommes hémizygotes soient atteints. Enfin, ce travail souligne l'importance de l'homo-dimérisation de TLR7 pour la régulation de son activité. [ABSTRACT FROM AUTHOR]

Analysing the two distinct periods, we found an incidence of 5080 MIS-C every 100,000 patients with COVID in the period April 2020-November 2021, while in the period December 2021-March 2022 the incidence was reduced to 1439 MIS-C every 100,000 accesses ( I p i < 0.0001, I i SP 2 sp Test). Analysing the incidence of MIS-C in patients who have had fever >=38°C for at least 24 h during the period April 2020-November 2021, the incidence was 380 MIS-C every 100,000 febrile patients whereas in the period December 2021-March 2022 we found an incidence of 491 MIS-C every 100,000 febrile patients ( I p i = 0.0002, I i SP 2 sp Test). In this period of times, total admissions were 50,413, of which 8017 (15.9%) patients had fever >=38°C lasting at least 24 h; 1197 (2.37%) patients had Sars-CoV-2 infection. [Extracted from the article]

Background Pyoderma gangrenosum ( PG) is a rare skin disease characterized clinically by ulcers with undermined borders, and histologically by neutrophil-rich infiltrates. PG may occur alone, in syndromic forms or associated with systemic diseases, such as inflammatory bowel disease and haematological or rheumatological disorders. Objectives To determine a specific genetic background related to autoinflammation for PG. Methods We assessed autoinflammation by evaluating the cytokine profile and genes involved in classic autoinflammatory diseases in 13 patients with PG and in seven patients with the syndromic form, known as PASH (pyoderma gangrenosum, acne and suppurative hidradenitis). Results In skin samples, the expression of interleukin ( IL)-1β and its receptors, IL-17 and its receptor, and tumour necrosis factor-α and its receptors were significantly higher in both PG ( P = 0·001) and in PASH ( P < 0·001) than in controls. The chemokines IL-8; chemokine (C-X-C motif) ligand 1/2/3; chemokine (C-X-C motif) ligand 16; and RANTES (regulated on activation, normal T-cell-expressed and secreted) were also overexpressed. Cases of PG and PASH showed mutations in the autoinflammatory genes MEFV, NLRP3, NLRP12, NOD2, LPIN2 and PSTPIP1. Conclusions Overexpression of cytokines/chemokines, along with genetic changes, supports the hypothesis that PG and its syndromic form, PASH, are a spectrum of polygenic autoinflammatory conditions. [ABSTRACT FROM AUTHOR]

An abstract of the conference paper "B cell subsets phenotype in autoimmunity with immunodeficiency: analysis of a cohort of patients with APECED syndrome," by A. Magnani and colleagues is presented.

Urticarial skin reactions are one of the most frequent problems seen by allergists and clinical immunologists in daily practice. The most common reason for recurrent wheals is spontaneous urticaria. There are, however, several less common diseases that present with urticarial rash, such as urticarial vasculitis and autoinflammatory disorders. The latter include cryopyrin-associated periodic syndrome and Schnitzler's syndrome, both rare and disabling conditions mediated by increased interleukin-1 secretion. Apart from the urticarial rash, patients are suffering from a variety of systemic symptoms including recurrent fever attacks, arthralgia or arthritis and fatigue. Autoinflammatory diseases are often associated with a diagnostic delay of many years and do not respond to antihistamines and other treatments of urticaria. Also, the chronic inflammation may lead to long-term complications such as amyloidosis. It is therefore important not to miss these diseases when diagnosing and treating patients with chronic recurrent urticarial rash. Here, we present clinical clues and tips that can help to identify autoinflammatory disorders in patients presenting with chronic urticarial rash and discuss their clinical picture and management. [ABSTRACT FROM AUTHOR]

Human glycolytic enzyme α-enolase was associated with human diseases and with inflammation. An ELISA test was developed to measure anti-α-enolase AAE IgG and AAE IgA in the serum from patients affected by inflammatory diseases with the purpose to evaluate it as a novel diagnostic marker. 80 healthy blood donors and 194 paediatric patients affected by Juvenile idiopathic arthritis (JIA), celiac disease (CD), Crohn's Disease (CrD), hereditary periodic fever (HPF), and PFAPA syndrome were included in the study. HPF patients showed high levels of AAE antibodies, whereas JIA, CD, and CrD presented only partial results. Benign fevers such as PFAPA were almost negative for AAE Abs. These findings suggested that the genetic dysfunction of inflammasome associated with HPF could lead to the formation of AAE Abs that could be used for an early and easy diagnosis. [ABSTRACT FROM AUTHOR]

Recurrent pericarditis occurs in association with various medical conditions, but in most cases the condition appears to be idiopathic. Although high-dose steroid treatment is often effective, it may have serious side effects. Herein we describe 3 children with recurrent pericarditis who were treated at our hospital, during flares, with the interleukin-1beta receptor antagonist anakinra, with immediate response. Pericarditis recurred when anakinra treatment was discontinued, and no further episodes occurred after it was resumed. Idiopathic recurrent pericarditis shares several features with autoinflammatory diseases, and anakinra has been efficacious in the treatment of the latter diseases. The findings in these patients suggest that idiopathic recurrent pericarditis may be a previously unrecognized autoinflammatory disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Synovial inflammation is a major determinant of juvenile idiopathic arthritis (JIA) pathogenesis and is mediated by local chemokine secretion. Monocytic cells are an important source of chemokines. The purpose of this study was to investigate expression of CCL20, a macrophage inflammatory protein, in synovial fluid (SF) and SF-derived monocytic cells from JIA patients and its regulation by hypoxia, a common feature of the inflamed synovial environment. METHODS: Mononuclear cells and monocytic cells were isolated from paired SF and peripheral blood (PB) samples from JIA patients and were maintained in a hypoxic environment or subjected to reoxygenation. CCL20 concentrations in SF, PB, and culture supernatants were measured by enzyme-linked immunosorbent assay. CCL20 expression was assessed in both freshly purified and cultured cells by reverse transcriptase-polymerase chain reaction and immunocytochemistry. Hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha were detected in the synovial tissue and cells of JIA patients by immunohistochemistry and Western blotting. RESULTS: CCL20 concentrations were significantly higher in SF compared with PB samples (P < 0.0001). SF mononuclear cells, but not matched PB mononuclear cells, constitutively expressed CCL20 messenger RNA. The SF monocytic cell fraction produced higher amounts of CCL20 than did SF lymphocytes, and CCL20 expression was associated with HIF positivity. Reoxygenation abrogated HIF and CCL20 expression, which was maintained in SF monocytic cells exposed to prolonged hypoxia. CONCLUSION: CCL20 is released into the SF of JIA patients, and SF monocytic cells are a major source of this chemokine. The hypoxic synovial microenvironment may directly contribute to the persistent inflammation associated with JIA by increasing CCL20 production by SF monocytic cells, thus representing a potential therapeutic target. [ABSTRACT FROM AUTHOR]

OBJECTIVE. To explore tumor necrosis factor (TNF)-induced apoptosis in neutrophils from patients with TNF receptor-associated periodic syndrome (TRAPS) and to correlate the results with the different kinds of TNFRSF1A mutations. METHODS: Two hundred sixty-five patients with clinically suspected inherited autoinflammatory syndrome were screened for mutations of the TNFRSF1A gene. Neutrophils were isolated from heparinized blood by dextran sedimentation and incubated with and without cycloheximide (CHX) and TNFalpha. Cell apoptosis was assessed by human annexin V binding, and caspase 8 activation was assessed by flow cytometry. RESULTS: Twenty-one patients were found to carry a variant of the TNFRSF1A gene: 13 patients had an R92Q substitution, and 8 patients presented other missense substitutions, 1 splicing mutation, and 1 in-frame interstitial deletion. Neutrophil stimulation with TNF and CHX was associated with induction of apoptosis in 12 normal controls and in 10 subjects with the R92Q mutation. Conversely, neutrophils from 8 TRAPS patients with mutations of cysteine or threonine residues or interstitial deletion did not show any induction of apoptosis after stimulation. The incidence of the R92Q mutation among patients with recurrent autoinflammatory syndromes was similar to that observed in the normal population. CONCLUSION: Resistance to TNF-mediated apoptosis is a feature in TRAPS patients who have mutations of cysteine residues or interstitial deletion, and may play a pathogenic role. The R92Q mutation does not appear to be significantly associated with TRAPS. [ABSTRACT FROM AUTHOR]

Unlabelled: Antiphospholipid antibodies (aPL) are frequently associated with thrombotic disorders in the so-called antiphospholipid syndrome. Together with anticardiolipin antibodies (aCL), lupus anticoagulant (LA) is the main diagnostic tool for aPL detection. Since LA determination is based on the finding of prolonged clotting time in vitro, concomitant anticoagulant therapy may significantly interfere with its detection. We report a case of a boy in whom recurrent aPL-related thrombosis heralded for several months the onset of systemic lupus erythematosus (SLE). Abnormally increased in vitro clotting times at the time of the second thrombotic event led to the suspicion of the presence of LA activity. However, this latter finding was difficult to interpret since the patient was already on heparin treatment at the time of our first observation. Thus, LA was assayed using a commercial kit in which a heparin neutralizer is included (Staclot LA). Two consecutive samples from the patient were compared with eight patients on anticoagulant therapy for non-aPL-related thrombotic events and 20 healthy controls. The study showed that, taking into account the concomitant anticoagulant treatment, Staclot LA was positive only in the propositus, raising the suspicion of a possible aPL-related origin of the thrombotic event. This issue was definitively confirmed in a subsequent follow-up.Conclusion: The present report shows that aPL-related deep vein thrombosis can be the earliest clinical manifestation of pediatric SLE, and that Staclot LA may have a role in LA detection during the course of anticoagulant treatment. [ABSTRACT FROM AUTHOR]

The presence of large granular lymphocytes has been reported in patients with ADA2 deficiency and T-LGL leukemia. Here we describe two siblings with novel ADA2 variants, expanding the mutational spectrum of ADA2 deficiency. We show that lymphoproliferation, persistence of large granular lymphocytes, T-cell perturbations, and activation of PI3K pathway, measured by means of phosphorylation levels of S6, are detectable in DADA2 patients without T-LGL leukemia. [ABSTRACT FROM AUTHOR]

Background: Autosomal dominant gain of function mutations in caspase recruitment domain family member 14 (CARD14) is a rare condition associated with plaque-type psoriasis, generalized pustular psoriasis, palmoplantar pustular psoriasis and pityriasis rubra pilaris. Recently, a new CARD14 –associated phenotype defined as CAPE (CARD14-associated papulosquamous eruption) with clinical features of both psoriasis and pityriasis rubra pilaris was reported. We describe a family carrying a novel heterozygous mutation in CARD14 gene, with childhood-onset erythrodermic psoriasis requiring an unusual extremely high dose (up to 2 mg/kg every 8 weeks) of ustekinumab to achieve disease remission. Case presentation: We describe a large family with three pairs of twins presenting a clinical phenotype characterized by childhood-onset erythrodermic psoriasis; in some family members is also reported psoriatic arthritis. The two probands presented poor clinical response to topic and systemic therapy with antihistamine, steroid, retinoids, cyclosporine and etanercept. After exclusion of the most common genes associated to autoinflammatory diseases (IL36RN, IL1RN, MVK, TNFRSF1A, NLRP3, NLRP12, MEFV, NOD2, PSMB8, PSTPIP1, LPIN2) we approached a new gene search by subjecting to Whole Exome Sequencing (WES) analysis five members of the family. A novel heterozygous mutation (c.446 T > G, leading to the missense amino acid substitution p.L149R) in the exon 4 of the CARD14 gene was identified in all affected members. Increasing dosages (up to 2 mg/kg every 8 weeks) of ustekinumab, a human monoclonal antibody targeting interleukin-12 (IL-12) and interleukin-23 (IL-23), allowed the complete control of the clinical manifestations, with an evident reduction of circulating Th17 and Th22 CD4+ T cell subsets. Conclusions: We describe the association of mutations of the CARD14 gene with an erythrodermic psoriasis pedigree, underlying the necessity to investigate CARD14 mutations in childhood-onset psoriasis cases and confirming the presence of CARD14 causative mutations also in erythrodermic psoriasis form, as recently reported. Also in pediatric age, ustekinumab represents a powerful therapeutic option for this rare condition, that is usually refractory to other treatments. In young children, high and frequent dosages allowed a complete control of the clinical manifestations without any severe side effects, with a long-term follow-up. [ABSTRACT FROM AUTHOR]

An abstract of the conference paper "Dosing patterns of canakinumab in patients with Cryopyrin-Associated Periodic Syndromes (CAPS): A comparative analysis of a study in Western versus Japanese patients," by P. Hachulla and colleagues is presented.

An abstract of the conference paper "Significance of I313V mutation of NLPR3 gene in two pediatric patients," by A. Omenetti and colleagues is presented.

An abstract of the conference paper "Canakinumab in the routinary clinical practice in cryopyrin-associated periodic syndromes (CAPS): one year of follow-up," by A. Martini, and colleagues, is presented.

An abstract of the conference paper "National CAPS (Cryopyrin-Associated Periodic Syndrome) Registry," by C. Bibalo and colleagues is presented.

An abstract of the conference paper "A novel mutatioin in the PSTPIP1 gene is associated with an autoinflammatory disease distinct from classical PAPA syndrome," by D. Holzinger and colleagues is presented.

An abstract of the conference paper "Characterization of tonsil infiltration and gene expression profile of innate sensors in PFAPA patients," by S. Chiesa and colleagues is presented.

An abstract of the conference paper "International cohort study for pediatric Behçet's Disease: Update 2011," by M. Darce Bello and colleagues is presented.

OBJECTIVES: The purpose of this study was to obtain data on the association of antiphospholipid antibodies with clinical manifestations in childhood and to enable future studies to determine the impact of treatment and long-term outcome of pediatric antiphospholipid syndrome. PATIENTS AND METHODS: A European registry extended internationally of pediatric patients with antiphospholipid syndrome was established as a collaborative project of the European Antiphospholipid Antibodies Forum and Lupus Working Group of the Pediatric Rheumatology European Society. To be eligible for enrollment the patient must meet the preliminary criteria for the classification of pediatric antiphospholipid syndrome and the onset of antiphospholipid syndrome must have occurred before the patient's 18th birthday. RESULTS: As of December 1, 2007, there were 121 confirmed antiphospholipid syndrome cases registered from 14 countries. Fifty-six patients were male, and 65 were female, with a mean age at the onset of antiphospholipid syndrome of 10.7 years. Sixty (49.5%) patients had underlying autoimmune disease. Venous thrombosis occurred in 72 (60%), arterial thrombosis in 39 (32%), small-vessel thrombosis in 7 (6%), and mixed arterial and venous thrombosis in 3 (2%). Associated nonthrombotic clinical manifestations included hematologic manifestations (38%), skin disorders (18%), and nonthrombotic neurologic manifestations (16%). Laboratory investigations revealed positive anticardiolipin antibodies in 81% of the patients, anti-beta(2)-glycoprotein I antibodies in 67%, and lupus anticoagulant in 72%. Comparisons between different subgroups revealed that patients with primary antiphospholipid syndrome were younger and had a higher frequency of arterial thrombotic events, whereas patients with antiphospholipid syndrome associated with underlying autoimmune disease were older and had a higher frequency of venous thrombotic events associated with hematologic and skin manifestations. CONCLUSIONS: Clinical and laboratory characterization of patients with pediatric antiphospholipid syndrome implies some important differences between antiphospholipid syndrome in pediatric and adult populations. Comparisons between children with primary antiphospholipid syndrome and antiphospholipid syndrome associated with autoimmune disease have revealed certain differences that suggest 2 distinct subgroups. [ABSTRACT FROM AUTHOR]