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Background:ALPS is a rare disorder due to a defective apoptotic mechanism leading to abnormal lymphoproliferation and autoimmunity. The disease is difficult to identify in the early phase when it may be misdiagnosed. Elevated TCR alpha-beta CD4-CD8- lymphocytes (double negative T lymphocytes DNT) together with hyperIgG, high levels of IL10, Il18, vitamin B12 and soluble Fas ligand have been suggested as the main ALPS hallmarks (1). Therefore, a specific flow cytometry panel (DNT cells, ratio of CD25+CD3+ to HLA−DR+CD3+ cells, increased B220+ T-cells, and decreased CD27+ memory B cells) has been proposed to serve as a diagnostic screen for ALPS (2).Objectives:To evaluate the usefulness of a specific lymphocyte flow cytometry panel in the early identification of ALPS/ALPS-like disorders in a cohort of patients with undefined autoinflammatory or autoimmune disorders.Methods:The clinical data of patients referred to the pediatric Rheumatology Unit of the Istituto Giannina Gaslini Hospital for a suspicion of autoimmune or autoinflammatory condition from October 2015 to April 2018, were retrospectively analyzed. Data on clinical manifestations, laboratory workup, genetic analysis and treatment were collected. Flow cytometry was included among the screening panel: DNT, CD25+CD3+, HLA−DR+CD3+ cells, B220+ T-cells, and CD27+ memory B cells were included. A statistical analysis was performed: data were analyzed with an univariate logistic regression analysis, to identify the most significant variables associated with ALPS. These variables were then included in a multivariate analysis to select a set of clinical and laboratory parameters, each of them associated with a significant probability to be associated with ALPS independently from other variables.Results:475 patients were retrospectively analized. 211 patients not fulfilling the inclusion criteria were excluded. The patients were classified as follows: i) Autoimmune disease 26 pts (10 SLE; 3 MCTD; 6 jDM; 5 Behçet; 1 SjS; 1 Kawasaki) ii) Juvenile Idiopathic Arthritis 35 pts iii) Monogenic systemic autoinflammatory disease (MSAID) 27 pts (17 FMF; 3 MKD; 1 TRAPS; 4 DADA2; 2 SAVI) iv) PFAPA 100 pts v) Systemic Undefined Recurrent Fever 45 pts vi) Undetermined-SAID 15 pts vii) ALPS/ ALPS probable 16 pts. The flow cytometry panel showed, as expected, an elevation of DNT in all ALPS patients. Among the other parameters, CD3CD25+/CD3HLADR+, and B220+ T cells, were significatively altered in 75% of ALPS patients. Conversely, B CD27+ did not differentiate ALPS from the other subgroups. The multivariate analysis revealed 5 clinical/laboratory parameters that showed the higher independent association to ALPS in the cohort of patients. Splenomegaly, female gender, elevated DNT, arthralgia and elevated alfabeta+B220+ lymphocytes were positively and significantly associated to ALPS.Conclusion:The use of the specific flow cytometry panel, comprehensive of DNT, B220+, HLA-DR and CD25, in patients with undefined autoinflammatory or autoimmune disorders may identify a subgroup of patients with ALPS.References:[1]Joao B. Oliveira et al. Blood 2010; 116 (14): e35–e40.[2]Lenardo MJ et al.Immunity. 2010;32(3):291–295.Disclosure of Interests:Caterina Matucci Cerinic: None declared, Leonardo Oliveira Mendonca: None declared, maurizio miano: None declared, paola terrnaova: None declared, federica casabona: None declared, Marta Bustaffa: None declared, Francesca Bovis: None declared, Roberta Caorsi: None declared, Stefano Volpi: None declared, Angelo Ravelli: None declared, Carlo Dufour: None declared, Marco Gattorno Consultant of: Sobi, Novartis, Speakers bureau: Sobi, Novartis

Background: Rituximab (RTX) in combination with methotrexate (MTX) has been licensed since 2006 for the management of severe active rheumatoid arthritis (RA) in patients who have failed at least one anti-tumour necrosis factor (anti-TNF) therapy. Published clinical trials have demonstrated the efficacy of RTX in improving both clinical symptoms and patients' physical function. This study aimed to assess the effectiveness of RTX in RA patients treated in routine clinical practice by examining clinical and patient reported outcomes six months after receiving a first course of RTX. Methods: The analysis involved 550 RA patients registered with the BSRBR, who were starting RTX and were followed up for at least 6 months. Change in Disease Activity Score (DAS28) and European League Against Rheumatism (EULAR) response were used to assess the clinical response while change in Health Assessment Questionnaire (HAQ) score was used to assess the physical function of the patients 6 months after starting RTX. The change in DAS28 and HAQ was compared between seronegative and seropositive patients and anti-TNF naïve patients versus anti-TNF failures. The response was also compared between patients receiving RTX in combination with MTX, other non-biologic disease modifying anti-rheumatic drugs (nbDMARDs) or no nbDMARDs. Results: The mean (s.d.) age of the cohort was 59 (12) years and 78% of the patients were females. The patients had a mean (s.d.) of 15 (10) years of disease duration. 16% were biologic naïve while 84% were anti-TNF failures. 32% of the patients were seronegative and 68% were seropositive. The mean (95% CI) DAS28 at baseline was 6.2 (6.1, 6.3) which decreased to 4.8 (4.7, 4.9) at 6 months of follow up. 16% were EULAR good responders, 43% were moderate responders and 41% were non responders. The mean (95% CI) change in HAQ was −0.1 (−0.2, −0.1) (Table 1). The mean change in DAS28 was similar in seropositive and seronegative patients (p = 0.18) while the anti-TNF naïve patients showed a greater reduction in DAS28 scores than anti-TNF failures (p = 0.05). Patients receiving RTX in combination with MTX showed similar changes in DAS28 and HAQ compared to patients receiving RTX alone or with other nbDMARDs. Conclusions: RTX has proven to be effective in the routine clinical practice. Anti-TNF naïve patients seem to benefit more from RTX treatment than anti-TNF failures. Disclosure statement: The authors have declared no conflicts of interest

**Background:** Cryopyrin-associated periodic syndromes (CAPS) is a group of rare autoinflammatory diseases. Little is known about the burden of disease, patients’ views on treatment, and adverse events (AEs) with current therapy. **Objectives:** The main study objective was to quantify the patients’ burden of disease in terms of flares and resource use and to characterize patient symptomatology and tolerability of treatment with anakinra. A secondary objective included comparing chart review and patient recall of symptoms and AEs. **Methods:** A retrospective medical chart review and concurrent online patient survey was conducted in four European countries. Data 12 months prior to initiation of/during anakinra treatment were entered into web-based case report forms by study groups. **Results:** Forty-two patients received/were receiving anakinra as primary treatment for at least 12 months. Patients experienced a 79.5% reduction in flares after commencing anakinra treatment. During the past 12 months on anakinra, four of five (80%) patients who recalled experiencing flares reported cancelling social activities and staying home as the most common courses of action. Most common AEs were injection site pain upon treatment initiation and weight gain. According to patient recall, 12 of 21 patients (57.1%) discontinued anakinra to enter another clinical trial; of the 12, eight (38%) specifically discontinued anakinra only for that reason, and four patients cited entering a clinical trial as one of many reasons for discontinuing anakinra. **Conclusions:** To our knowledge, this is the most comprehensive survey of patient experience with CAPS. Although improved, CAPS treatment remains suboptimal and a significant burden is placed upon patients, caregivers, and the healthcare system. With new agents available, it will be important to compare outcomes in patients using all therapeutic options.

Cryopyrin associated periodic syndrome (CAPS) can be represented by various clinical variants of disease course with different severity of clinical manifestations — from mild to severe (FCAS, MWS, NOMID/CINCA). They are caused by mutations of NLRP3 gene, encoding cryopyrin. Mutations of cryopyrin gene in humans lead to excessive and accelerated production of interleukin 1b. The key role of cryopyrin in massive secretion of active form of interleukin 1b suggested the possibility of treatment aimed against this cytokine.

BD is rarely encountered in children where the disease is very difficult to recognize. The outcome ofpatients with few symptoms is currently unknown

Osteolytic lesions are the hallmark of a number of inherited (DIRA and Majeed syndrome) and multifactorial (CRMO and SAPHO) autoinflammatory diseases.

Recurrent pericarditis represents an important complication of acute pericarditis. Therapeutic approach during recurrences consists of NSAID (non-steroidal anti-inflammatory drugs) administration. However steroid is often necessary to control disease flares. IL-1 inhibitors efficacy has been anecdotally described as effective in the control of the disease in steroid-dependent and colchicine-resistant patients.

Results Monocytes isolated from PAPA patients tent to secrete higher levels of IL-1b but this was not consistent in all the patients (p = 0.144). Variability in IL-1b release occurred even in the presence of the same PSTPIP1 variant and it did not parallel disease activity when the whole cohort was taken in consideration. However, IL-1b levels varied according to the clinical picture (p = 0.0197), and it was significantly higher (P < 0.05) in patients displaying articular manifestations (N = 3) compared to those affected by cutaneous (N =6 ) or combined (N = 2) lesions. In the former, IL-1b secretion was increased in the presence of acute phase reactants elevation and active joint lesions, and treatment with Anakinra resulted in acute phase reactans normalization and symptom-free period. Silencing of of NLRP3 activity consistently inhibited LPS-induced IL-1b release in both PAPA and HD monocytes. Conclusion IL-1b secretion is higher in PAPA patients displaying prevalent articular manifestations. In these patients, IL-1b release correlates with disease activity and it is mediated by NLRP3.

Recurrent pericarditis represents an important complication of acute pericarditis. Therapeutic approach during recurrences consists of NSAID administration. However steroid is often necessary to control disease flares. IL-1 inhibitors efficacy has been anecdotally described as effective in the control of the disease in steroid-dependent and Colchicine-resistant patients.

The autoinflammatory diseases (AID) include monogenic and polygenic disorders characterized by primary dysfunction of the innate immune system.

Background Periodic fever syndromes (PFS) are a group of rare auto-inflammatory conditions, which includes, among others, cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD), TNF-receptor associated periodic syndrome (TRAPS). Canakinumab (CAN), a fully human, highly specific anti-IL-1β neutralising monoclonal antibody, is effective in CAPS.1 IL-1β has been shown to be involved in the pathogenesis of FMF, HIDS/MKD and TRAPS, for whom no approved treatment exists. A series of small open label studies suggested efficacy of CAN in colchicine resistant/intolerant FMF (crFMF), HIDS/MKD and TRAPS.2,3 We report the efficacy and safety of CAN from the randomised treatment epoch of a phase III trial in patients (pts) with crFMF, HIDS/MKD or TRAPS. Objectives Primary objective of this phase III pivotal trial was to demonstrate that CAN 150 mg (or 2 mg/kg for pts ≤40 kg) sc q4w is superior to placebo (PBO) in achieving a clinically meaningful response defined as resolution of the index flare at Day 15 and no new disease flares over 16 wks of treatment. Secondary objectives were: % pts who achieved a physician global assessment of disease activity (PGA) Methods The trial (NCT02059291) consists of 3 disease cohorts (crFMF, HIDS/MKD and TRAPS) and 4 study epochs (E1–4): a screening epoch (E1) of up to 12 wks, a randomised treatment epoch (E2) of 16 wks, a randomised withdrawal epoch (E3) of 24 wks and an open-label treatment epoch (E4) of 72 wks. Pts (age ≥2 years) with crFMF, HIDS/MKD or TRAPS with a flare during E1 were randomised (1:1) in E2 to receive CAN or PBO. Safety assessments included adverse events (AEs). Results Of 181 pts (crFMF, n=63; HIDS/MKD, n=72; TRAPS, n=46) randomised in E2, 6 pts discontinued (5 PBO; 1 CAN). In all 3 disease cohorts, the proportion of pts who were responders for the primary outcome at Wk 16 was significantly higher with CAN vs PBO (Table). At Wk 16, a significantly higher proportion of pts achieved PGA score Conclusions These results demonstrated superior efficacy of canakinumab at dose level of 150 mg q4w after a 16 weeks treatment period compared to placebo. The overall safety profile was not distinct from previous controlled studies and expectations in an auto-inflammatory patient population. Disclosure of Interest F. De Benedetti Grant/research support from: Pfizer, Abbvie, Roche, Novartis, Novimmune, BMS, J. Anton Grant/research support from: Novartis, Pfizer, Abbvie, Roche, SOBI, Consultant for: Novartis, M. Gattorno Grant/research support from: Novartis, SOBI, Consultant for: Novartis, SOBI, Speakers bureau: Novartis, SOBI, H. Lachmann Consultant for: Novartis, SOBI, Takeda, GSK, Speakers bureau: Novartis, SOBI, I. Kone-Paut Grant/research support from: SOBI, Roche, Novartis, Consultant for: Novartis, SOBI, Pfizer, Abbvie, Chugai, S. Ozen Consultant for: Novartis, Speakers bureau: SOBI, J. Frenkel Grant/research support from: Novartis, SOBI, A. Simon Grant/research support from: CSL Behring, Novartis, Xoma/Servier, A. Zeft: None declared, E. Ben-Chetrit Consultant for: Novartis, H. Hoffman Grant/research support from: BMS, Consultant for: Novartis, SOBI, Regeneron, Speakers bureau: Novartis, Y. Joubert Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, A. Speziale Employee of: Novartis, G. Junge Employee of: Novartis

Patients showed recurrent flares of pericarditis with malaise, precordial pain, tachyorthopnoea, sometimes fever. 2/3 developed a life-threatening cardiac tamponade needing pericardiotomy. None of them presented signs or symptoms consistent with a chronic rheumatic disease: antinuclear, anti-coxsackie and anti adenovirus antibodies were negative. Genetic analysis ruled out Familial Mediterranean Fever. Mean disease duration was 2 years and mean rate of recurrences was 4 yearly. Pericarditis seemed steroid dependent and poorly responsive to colchicine.

Mutations of CERC1 have been recently reported as causative of an inflammatory condition characterized by polyarteritis, cerebral stroke and immunodeficiency; the response to immunosuppressors and biological drugs is not univocal.

Methods We collected blood samples from a cohort of pediatric rheumatologic patients and scored them according to a qPCR based IFN gene signature assay. Expression of 6 type I IFN-related genes (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1) was quantified by standard RTPCR techniques. An IFN score was calculated for each patient using the median fold change of gene expression related to a healthy control. Patients were selected based on the presence of the following features: i) atypical or incomplete SLE-like symptoms occurring in infancy or in preprepubertal age; ii) vasculopathy (skin ulcers, chilblains, strokes) iii) panniculitis with or without lypodystrophy iv) interstitial lung disease in the context of systemic inflammation.

Results The girl, first born from healthy, not relatives parents, at the age of 8 months started to present erythematosusinfiltrated skin lesions with pustular evolution and finally hesitating in scars in 15-20 days. From the age of three years chilblains and severe nail dystrophy appeared. A CT scan performed at the age of 8 years revealed the presence of diffuse interstitial thickening with ground-glass appearance. A restrictive framework was detected at spirometry (FVC 51%). The autoantibodies detection revealed positive ANA (1: 160), ANCA (1:80) and Coombs test. The skin biopsy revealed a predominantly granulomatous nodular dermatitis, with folliculitis and secondary fibrosis. The lung biopsy revealed focal hemorrhage, edema and predominantly lymphocytic inflammatory aggregates in the peribronchial interstitial areas with aspects of capillaritis and contiguous focal subatelettasia with alveolar cavity filled of macrophages. Steroidal treatment (prednisone 1 mg/kg/day) was started with improvement of clinical manifestation, anemia and normalization of inflammatory markers. However attempts to reduce such therapy were followed by an exacerbation of the clinical picture. Treatment with both immunosuppressive (azathioprine) and biologic (etanercept) drugs was tempted, without clear improvement. Unsatisfactory growth was also detected. In the following months the child started to present a mild renal involvement with microscopic hematuria and hypertension, requiring anti-hypertensive treatment. Given the evocative framework, interferon gene signature was performed, revealing a significant activation; the molecular analysis of TMEM173 gene showed the presence of the de novo Val155Met mutation, already described as causative of SAVI syndrome. The child continued to present persistent severe microcytic anemia, requiring erythrocytes’ transfusions, despite high levels of erythropoietin. Bone marrow aspiration revealed dysmaturative signs in the in erythroid progenitors. Treatment with jak1/2 inhibitor (Ruxolitinib, 5 mg day) was just started at the time of abstract presentation.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a more frequent cause of recurrent fever in children. The exact etiology of this pediatric disorder is still unknown. Palatine tonsils are sites where innate immunity leads to the onset of adaptive immunity, mediated by B and T lymphocytes.

Background ADA2 deficiency, a recently described disease, is characterized by systemic vasculopathy and episodes of strokes. The defect is due to a loss of function mutation of CECR1 gene, codifying for Adenosine Deaminase 2 protein. This protein regulates the catabolism of extracellular adenosine, which we have recently shown is an important regulator of Class Switch Recombination in B lymphocytes. Accordingly DADA2 patients can present hypogammaglobulinemia. Objectives The aim of the project is to characterize peripheral B-cell compartment of two patients to directly address if ADA2 mutation affects B-cell function. Methods Two brothers (15 and 7 years old) carrying mutations in CECR1 were followed up from the age of two. They showed similar clinical history with livedo reticularis, fever, vasculitis and neurological symptoms caused by haemorragic strokes. Both presented early hypogammaglobulinemia requiring intravenous immunoglobulin replacement therapy. Remarkably after etanercept treatment serum Igs slowly increased to a normal level. We analyzed peripheral B-cell phenotype by flow cytometry, in vitro B-cell proliferation and differentiation to plasmacells in response to CpG, BCR and T cell help. Results Flow cytometer analysis showed a significative reduction of total B cells compared with age matched controls. Intriguingly a defect in the memory B-cell compartment (CD19 + CD27 + ) was observed. We found that the rate of proliferation and differentiation to Igs secreting cells is lower as compared to normal controls and it is not supported by autologous T cells. Conclusions Our findings suggest that ADA2 defect could lead to a reduced formation of T cell dependent memory B cells. References Zhou Q. et al., N Engl J Med. 2014 Mar 6;370(10):911-20 Navon Elkan et al. P. N Engl J Med. 2014 Mar 6;370(10):921-31 Garg N. et al. Eur J Pediatr. 2014 Jun;173(6):827-30 Schena F. et al. Cell Rep. 2013 Jun 27;3(6):1824-31 Hasko G. et al. Trends Mol Med. 2013 Jun;19(6):355-67 Antonioli L. et al. Nat Rev Cancer. 2013 Dec;13(12):842-57 Eltzschig HK et al. N Engl J Med. 2012 Dec 13;367(24):2322-33. Disclosure of Interest None declared

Background Mutations of CECR1 have been recently reported as causative of an inflammatory condition characterized by polyarteritis nodosa, cerebral stroke and immunodeficiency; the clinical manifestations of the disease are heterogeneous with a wide range of severity. Objectives To analyze the prevalence of CECR1 mutations in pediatric patients with polyarteritis nodosa, livedo reticularis and/or stroke. Methods Pediatric patients of Caucasian Italian origin with the following diseases/manifestations were included in the study: i) histologically confirmed polyartiritis nodosa (PAN) or cutaneous polyartiritis nodosa (cPAN), ii) persistent livedo reticularis with elevation of acute phase reactants, iii) ischemic or hemorrhagic strokes with systemic inflammation. Direct sequencing of CECR1 gene (exons 1-9) was performed with Sanger analysis. Results Up to January 2015, 27 patients from 25 families were included in the study. Homozygous or compound heterozygous CECR1 mutations with deleterious effects (G47R, G47A, P251L, R312X, E328D, T360A) were detected in 6 patients. A heterozygous causative mutation (G47V) was observed in 2 affected brothers, their father and the unaffected brother. So far a second mutation has not been detected; loss of heterozygosity could not be demonstrated and the mother is being investigated for a possible interstitial deletion. In the remaining patients common polymorphisms (L46L, N53N, H335R, Y453Y) were detected. The mean age of onset of the disease in genetically confirmed patients was 24 months (range 6 months – 5 years); all of them presented fever, elevation of acute phase reactants, livedo reticularis and a skin biopsy suggestive for vasculitis; two of them presented subcutaneous nodules while one of them presented ulcerations at extremities. Hypertension was detected in four patients, while one presented miocarditis. 3 patients presented one or more cerebral stroke during their disease course, while in 3 patients peripheral neuropathy was detected. 4 patients presented intestinal involvement (ranging from recurrent abdominal pain to intestinal perforation) and 2 patients presented growth delay, independent from steroidal treatment. Low immunoglobulin levels were detected in two patients. The clinical characteristics of the two heterozygous patients were similar: fever, livedo reticularis, increased acute phase reactants and hypogammaglobulinemia were detected in both; cerebral stroke occurred in one of them. Conclusions CECR1mutations are present in the Italian population and associated with severe cases of ADA2 deficiency. A clinical heterogeneity has been detected in genetically confirmed patients. In a few patients a typical phenotype was associated to incomplete or negative genotype, thus supporting the hypothesis of a genetic heterogeneity of this condition. Disclosure of Interest None declared

Background SAVI syndrome is a recently identified condition associated to mutations of TMEM173. Up to know only few cases of this disease have been described. Objectives To describe the clinical manifestation of an Italian patient affected by SAVI syndrome Results The girl, first born from healthy, not relatives parents, at the age of 8 months started to present erythematosus-infiltrated skin lesions with pustular evolution and finally hesitating in scars in 15-20 days. From the age of three years chilblains and severe nail dystrophy appeared. At the age of 8 years the girl presented a severe pneumonia, requiring prolonged antibiotic therapy. The chest CT performed showed, in addition to the lung infiltrate, the presence of diffuse interstitial thickening with ground-glass appearance. A restrictive framework was detected at spirometry (FVC 51%). The autoantibodies detection revealed positive ANA (1: 160), ANCA (1:80) and Coombs test; rheumatoid factor was slightly increased. Anti-DNA and ENA were negative. The skin biopsy revealed a predominantly granulomatous nodular dermatitis, with aspects of deep granulomatous folliculitis and secondary fibrosis. The lung biopsy revealed focal hemorrhage, edema and predominantly lymphocytic inflammatory aggregates in the peribronchial interstitial areas with aspects of capillaritis and contiguous focal subatelettasia with alveolar cavity filled of macrophages. In the following months, in light of the progression of the disease, steroidal treatment (prednisone 1 mg/kg/day) was started with improvement of clinical manifestation, anemia and normalization of inflammatory markers. However attempts to reduce such therapy were followed by an exacerbation of the clinical picture. In the attempt to reduce steroidal treatment, the child was treated wit both immunosuppressive (azathioprine) and biologic (etanercept) drugs, without clear improvement. Unsatisfactory growth was also detected. In the following months the child started to present a mild renal involvement with microscopic hematuria and hypertension, requiring anti-hypertensive treatment. Given the evocative framework, interferon gene signature was performed, revealing a significant activation; the molecular analysis of TMEM173 gene showed the presence of the de novo Val155Met mutation, already described as causative of SAVI syndrome. The child continued to present persistent severe microcytic anemia, requiring erythrocytes9 transfusions, despite high levels of erythropoietin. Bone marrow aspiration was therefore performed, that revealed dysmaturative signs in the in erythroid progenitors. Conclusions This report of the first Italian patient with SAVI syndrome confirms the presence of the previously described clinical manifestations. Persistent hematuria and hypertension are reasonably signs of an underlying renal involvement, not previously described in this condition. Thus a renal biopsy is needed for confirmation. The origin of severe anemia is still unclear. Thus a possible deregulatory effect of mutated STING protein on bone marrow progenitors has to be investigated and is actually under study in our patient. Disclosure of Interest None declared

Background Positional differences of Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) mutations may trigger opposite clinical outcomes in Pyogenic sterile Arthritis Pyoderma gangrenosum and Acne (PAPA) syndorme. The typical triad may not be fully displayed, and clinical picture often vary along the disease history in the same individual. PSTPIP1-ASC-pyrin interaction may lead to caspase-1 dependent Interleukin (IL)1β secretion. However, the involvement of NLRP3 and IL1β signaling itself in PAPA were explored mostly in in vitro or in vivo systems. Furthermore, due to disease rarity, anti-IL1 effectiveness was unveiled or refuted based on brief clinical reports with significant variability in response to treatment. Differences in experimental conditions and assessments being performed in possibly differing stage of patients9 diseases activity may give reason of the discrepancies observed. Thus, to date univocal insights concerning the actual role of IL1β signaling, its extent and the underlying regulatory molecular mechanisms in PAPA remain undefined, thus challenging an evidence-based application of anti-IL1 regimen. Objectives To define whether IL1β secretion in PAPA syndrome (1) is enhanced, (2) requires NLRP3, and (3) correlates with different PSTPIP1 mutations, disease activity and/or clinical picture. Methods A clinically well characterized cohort including 13 genetically confirmed PAPA subjects (E250Q+ N =10, E250K+ N =1, E256G+ N =2) and 1 patient wild-type (WT) for the common PSTPIP1 mutations were evaluated and compared with 35 healthy donors (HD). Peripheral blood monocytes were purified and studied at baseline and following in vitro TLR4 activation. Secretion pattern of IL1β, IL1α, IL1Ra, IL6, IL18 and Tumor Necrosis Factor (TNF)α was assessed in supernatants by ELISA and correlated to genotype, disease activity, ongoing therapies and clinical picture. Requirement of NLRP3 for IL1β secretion was investigated by silencing NLRP3 in monocytes purified from patients and HD. Results Increased IL1β release was found in the overall PAPA cohort (P=0.254), and silencing of NLRP3 prevented it. Patients with active disease displayed higher IL1β oversecretion (P Conclusions Variable IL1 β secretion was obserbed in PAPA cohort according to disease activity and clinical phenotype. The availability of a relevant number of patients and the chance to clinically and experimentally evaluate them in different phases of their disease history, allowed us to better define the actual behavior of IL1β secretion in this condition. Even if other mechanisms related to the complex PSTPISP1 protein networking might play additional roles, these results are in agreement with preliminary anecdotal reports on anti-IL1 regimen in PAPA and support the use of IL1 blockade as a potential effective therapeutic strategy in the clinical management of this condition. Disclosure of Interest None declared

Background PAPA syndrome (Pyogenic Arthritis, Pyoderma gangrenosum, and Acne) is an ultra-rare autosomal dominant, auto-inflammatory disease associated to mutations in the PSTPIP1 / CD2BP1 gene. The therapeutic approach during recurrences consists of steroids, while no agreement exists on the chronic management. Evidences on the use of biologics are anecdotal and variable results have been reported. Objectives To evaluate the long-term response to treatment with IL1 antagonist in six patients affected by PAPA syndrome. Methods Six patients (M:F=3:3; 4 pediatric, 1 young adult and 1 adult, mean age 18 years, range 3-50) affected by PAPA syndrome were enrolled and treated with IL1 blockers (5 patients Anakinra, 1 patient Anakinra followed by Canakinumab). Three patients were already treated with anti-TNFα monoclonal antibodies without benefit. Data were collected retrospectively (mean follow-up 26 months, range 4-38). The frequency of articular and cutaneous flares in the 24 months before starting therapy where compared to those occurred during anti-IL1 regimen. Acute phase reactants (ESR, CRP, SAA) were assessed at the last visit before the study enrolment and at last follow-up. Results All the patients displayed a significant decrease in frequency of disease flares (Table) and normalization of acute phase reactants. Three patients were asymptomatic during whole follow-up. Patient#4, with a severe and persistent pyoderma gangrenosum, displayed a partial response to Anakinra partially due to a poor compliance to daily s.c. administration. The shift to Canakinumab lead to a fast and complete resolution of the skin manifestations. Conclusions The long-term use of IL1 blockers is associated to satisfactory and persistent control of clinical manifestations and laboratory findings in PAPA syndrome. Disclosure of Interest M. Finetti: None declared, R. Caorsi: None declared, D. Marotto: None declared, A. Buoncompagni: None declared, A. Omenetti: None declared, B. Lattanzi: None declared, F. Minoia: None declared, P. Picco: None declared, M. Jorini: None declared, A. Martini Grant/research support from: Unrestricted grants from SOBI and Novartis, Speakers bureau: Speaker9s fees, M. Gattorno Grant/research support from: Unrestricted grants from SOBI and Novartis, Speakers bureau: Speaker9s fees

Background CAPS are autoinflammatory diseases characterized by recurrent episodes of fever and systemic inflammation. Three nosological entities representing different phenotypes, from the milder to the most severe (FCAS, MWS, CINCA). Cryopyrin, renamed NLRP3, is part of the intracellular multiprotein complex inflammasome that mediates IL-1 processing and secretion through caspase-1 activation. NLRP3 mutations in CAPS are gain-of-function, as they enhance inflammasome activity. The result is hypersecretion of IL-1, responsible for the inflammatory clinical manifestations. Objectives –To increase the knowledge on the pathologic consequences of NLRP3 mutations in CAPS patients; –To understand the underlying molecular and regulatory mechanisms of CAPS disease; –To identify novel molecular targets for the treatment of cryopyrin/NLRP3 related disorders. Methods We have generated a KI mouse carrying the N475K mutation into the murine NLRP3 gene. This mutation corresponds to the N477K human mutation, associated to a severe CINCA phenotype with neurological complications; Phenotypical and immunological characterization of NLRP3 Knock In (KI) mice has been performed by flow cytometry; The IL1β secretion from bone marrow derived dendritic cells (BMDCs) and peritoneal macrophages (PMs) of NLRP3 Knock In Mice has been evaluated by ELISA. Results The NLRP3 KI mice that we have obtained show hair loss, presence of skin rash and reduced survival time when compared to wild type (WT). Autopsy of KI mice, prematurely dead, revealed splenomegaly and a relevant inflammatory status. We compared the IL-1 secretion of inflammatory cells from WT and KI mice. PMs and BMDCs from mutant mice did not secrete mature IL-1β spontaneously. When stimulated with 100 ng/ml of LPS KI cells secreted higher levels of IL-1b than WT cells. The kinetics of IL-1β secretion was much faster in KI cells, reaching the plateau at 3h from exposure to LPS, thus reproducing the results obtained from monocytes of CAPS patients. As in CAPS monocytes, brief exposure to ATP strongly induced the secretion of IL-1β by LPS-activated WT cells while failed to stimulate further IL-1β secretion by inflammatory cells of KI mice. Finally, PMs and BMDCs from KI are more responsive to agonists of TLRs when compared to WT cells: LPS at 0.01 ng/ml triggered high levels of IL-1β secretion (comparable to 100 ng/ml of LPS) in inflammatory cells from KI indicating that the presence of the mutation lowers the threshold of activation. The neurological studies by MRI are in progress Conclusions The NLRP3 KI mice recapitulates phenotype and functional characteristics of CAPS patients. Thus, this model will hopefully provide elucidations in the mechanisms underlying CAPS as well as other inflammasomepathies. References Brydges SD et al., Immunity. 2009. Meng et al., Immunity 2009. Gattorno M. et al., Arthritis Rheum. 2013. Disclosure of Interest None declared

Background Familial Mediterranean fever (FMF) and pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome are inherited autoinflammatory diseases. FMF patients have mutations in pyrin, a protein that has been suggested to play a role in the regulation of the inflammasome, PAPA patients have mutations in PSTPIP1, which interacts with pyrin. In both diseases, extraordinarily elevated serum levels of MRP8/14 were detected. Recently, we have identified two novel autosomal dominant mutations in the PSTPIP1 gene, p.E250K or p.E257K substitution, as genetic cause for a novel, more severe autoinflammatory entity: PAMI syndrome (PSTPIP1-associated myeloid-related-proteinaemia inflammatory syndrome). PAMI patients present with even higher levels of MRP8/14. MRP8 and MRP14 belong to the family of proinflammatory Damage Associated Molecular Pattern (DAMP) proteins, are mostly expressed in phagocytes and activate innate immune cells via TLR4 (Fassl et al. J. Immunol. 2015) after released via a so-called alternative pathway. However, the mechanism of secretion of MRP8/14 is still unknown. Objectives We investigated if pyrin and PSTPIP1 play a role in the secretion of MRP8/14. Methods MRP8/14 serum concentrations of patients were determined by ELISA. PSTPIP1 gene sequencing was performed in 14 patients with PAMI syndrome. Monocytes from patients were isolated and MRP8/14 levels were measured in culture supernatants prior and after activation. PSTPIP1-Pyrin-MRP8/14 interactions were investigated by immunoprecipitations and structural analysis. Results Monocytes from patients with PSTPIP1 mutations release significantly higher amounts of MRP8/14 than control cells. Immunoprecipitation studies demonstrated that p.E250K-PSTPIP1 is hyperphsphorylated and binds stronger to pyrin compared to wildtype protein. Furthermore, we could prove a direct interaction of both PSTPIP1 and pyrin with MRP8/14. By using deletion constructs of PSTPIP1 we could demonstrate that the MRP8/14 binding motif is mutated in PAMI syndrome. Conclusions Phagocytes seem to be the responsible cell type for the high serum concentration of MRP8/14 in PAMI syndrome. The DAMP proteins MRP8 and MRP14 interact directly with PSTPIP1 and mutations found in all patients are apparently located inside the PSTPIP1-MRP8/14 binding region. Moreover, the PSTPIP1 mutations influence the interaction with pyrin. Overall, our data indicate that hypersecretion of MRP8/14 is a relevant pathomechanism in PSTPIP1- and pyrin-associated diseases. Disclosure of Interest None declared

Background Autosomal dominant gain of function mutations in caspase recruitment domain family member 14 (CARD14) were found to cause plaque psoriasis in two families and severe generalized pustular psoriasis as a monogenic form of childhood (CARD14-mediated pustular psoriasis, CAMPS) [1]. CARD14 mutations have also been implicated in plaque-type psoriasis and pityriasis rubra pilaris [2]. Objectives Describing a family with an unusual clinical phenotype characterized by some members with childhood-onset erytrodermic psoriasis first localized and then diffuse over all the skin surface; in some family members is also reported psoriatic arthritis. Methods We assessed for the first time the family in december 2013, because of their skin lesions and family recurrence for erytrodermic psoriasis associated to arthritis in some cases. There are three pairs of twins, five of them presenting psoriasis and two of them presenting psoriatic arthritis. The children presented poor clinical response to topic and systemic therapy with antihistamine, steroid, retinoids, cyclosporine and etanercept. The whole pedigree is depicted in the figure with the grey symbols indicating the affected members and an asterisk pointing out members for whom we got a biological sample (Figure). After exclusion of the most common genes associated to autoinflammatory diseases (IL36RN, IL1RN, MVK, TNFRSF1A, NLRP3, NLRP12, MEFV, IL1RN, NOD2, PSMB8, PSTPIP1, LPIN2). Successively, we approached the new gene search by subjecting to Whole Exome Sequencing (WES) analysis five members of the family, namely those indicated by an arrow. Samples were processed in outsourcing and raw data were transferred to our lab for the bio-informatic analysis. Results Among variants shared by the four affected individuals and not present in the unaffected subject, a missense mutation of the CARD14 gene resulted worth of further investigation. In particular, it was the case of an exon4 heterozygous nucleotide change, c.446T>G, leading to the missense amino acid substitution p.L149R. The presence of this variant was validated by Sanger sequencing not only in the affected members undergone WES, but also assessed in all the rest of the available family members. This allowed us to confirm the expected segregation of the CARD14 mutation with the disease phenotype. Conclusions CARD14 gain of function mutations can give rise to unusual clinical phenotype like diffuse erytrodermic psoriasis and psoriatic arthritis. WES appears to be a powerful, suitable and proper approach to identify new SAID genes, thus also disclosing new molecular pathogenic mechanisms. References Jordan CT, Cao L, Roberson ED, Pierson KC, Yang CF, Joyce CE, et al. PSORS2 is due to mutations in CARD14. American journal of human genetics. 2012; 90(5):784–95. Epub 2012/04/24. Fuchs-Telem D, Sarig O, van Steensel MA, Isakov O, Israeli S, Nousbeck J, et al. Familial pityriasis rubra pilaris is caused by mutations in CARD14. American journal of human genetics.n 2012; 91(1):163–70. Epub 2012/06/19. Disclosure of Interest None declared

TNF receptor-associated periodic syndrome (TRAPS) is an autoinflammatory disease causing unprovoked fevers, myalgia, abdominal pain, rash, headaches, and, in severe cases, AA amyloidosis. It is an autosomal dominant condition resulting from variants in the TNF super family receptor 1A (TNFRSF1A) gene [1]. A hallmark of TRAPS is a huge activation of the inflammatory response in the absence of autoantibodies or antigen-specific T-cells [1]. Canakinumab (CAN) is a high-affinity, fully human, selective, anti-IL-1β monoclonal antibody, developed for the treatment of autoinflammatory diseases [2].

Autoinflammatory diseases are rare disorders secondary to mutation of genes involved in the regulation of innate immunity. The main limitation to a better knowledge of Autoinflammatory diseases is related to the extreme fragmentation of the diagnosed cases that are spread over different centers and countries. The general aim of the Eurofever Project was to build an international registry on Autoinflammatory diseases. A web-based registry collecting baseline and cross-sectional clinical information on Autoinflammatory diseases is available in the member area of the PRINTO web-site (www.printo.it). The registry is open to all pediatric and adult Centers with a specific interest in Autoinflammatory diseases. The following monogenic autoinflammatory diseases were considered: Familial Mediterranean Fever (FMF), Cryopyrin-associated periodic syndromes (CAPS), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), Blau syndrome, pyogenic arthritis, pioderma and acne (PAPA) syndrome, deficiency of IL-1 receptor antagonist (DIRA), NLRP12-mediated periodic fever. Information on CRMO, Behcet9s disease, PFAPA and undefined periodic fevers were also collected. 2916 patients, from 95 centers in 53 countries, have been enrolled in the registry during the first 36 months. Baseline demographic data (country of residence, disease onset, disease duration, mutations, family history ect) from all patients are now available. In 2275 (81%) complete information on clinical manifestations and responses to treatments is also available. The disease distribution of enrolled patients is: FMF 787 (621 with complete clinical data); TRAPS 237 (211 with complete clinical data); CAPS 207 (186 with complete clinical data); MKD 153 (133 with complete clinical data); Blau syndrome 62 (21 with complete clinical data); PAPA 19 (18 with complete clinical data); NLRP-12 mediated periodic fever 8 (6 with complete clinical data); DIRA and Majeed 3 and 2 patients, respectively (all with complete clinical data). Among multifactorial autoinflammatory diseases: PFAPA 564 (402 with complete clinical data); CRMO 392 (370 with complete clinical data); pediatric Behcet disease 84 (68 with complete clinical data) and 205 patients with undefined periodic fever (174 with complete clinical data). So far 8 papers involving 56 different authors and 32 centers have been published in high-rank international journals and other papers are in preparation. A large registry of patients with Autoinflammatory diseases is available and, despite the expiring of the initial grant, the enrolment is still ongoing with an increasing number of centers involved. Eurofever represents a good example of how a disease-oriented registry can provide relevant scientific answers to many unknown clinical aspects of ultra-rare diseases. This aspects was the main reason of the relevant success of the enrolment we have observed. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.6310

Background TNF receptor-associated periodic syndrome (TRAPS) is an autoinflammatory disease causing unprovoked fevers, myalgia, abdominal pain, rash, headaches, and, in severe cases, AA amyloidosis. It is an autosomal dominant condition resulting from variants in the TNF super family receptor 1A ( TNFRSF1A ) gene. 1 A hallmark of TRAPS is a huge activation of the inflammatory response in the absence of autoantibodies or antigen-specific T-cells. 1 Canakinumab (CAN) is a high-affinity, fully human, selective, anti-IL-1β monoclonal antibody, developed for the treatment of autoinflammatory diseases. 2 Objectives To determine whether gene expression in whole blood can support a molecular mechanism for the activity of CAN in TRAPS patients (pts). Methods Twenty pts with active TRAPS received open-label CAN 150mg sc/month for 4 months in an efficacy and safety study. These pts were assessed at Day 15 for response by physician global assessment (PGA) disease activity scale. Whole blood was collected at baseline, Day 15 and Day 113 from 19 of these pts and 1 sample each from 19 untreated age-matched healthy volunteers for analysis of gene expression levels by microarrays. Results All 20 pts showed improvements in PGA score (Figure 1-left). Gene expression profiles of these pts were altered by treatment with CAN. Forty-six differentially expressed genes showed a >2-fold change after treatment with expression levels that shifted towards that of healthy volunteers. The disease-causing gene ( TNFRSF1A , Figure 1-right), drug target gene ( IL-1β ), and other inflammation related genes (e.g., MAPK14 ) were downregulated after treatment and several inflammation related pathways were evident among the differentially expressed genes. Many of the high confidence differentially expressed genes had expression levels that correlated with neutrophil count, however, neutrophil count alone could not account for the expression differences observed. Conclusions Altogether, the gene expression data support a model in which CAN increases neutrophil apoptosis and reduces pro-inflammatory signals through its inhibition of IL-1β. CAN is able to reverse the overexpression of several genes associated with inflammatory response, including IL-1. Interestingly, IL-1 blockade normalized the overexpression of the disease-causing gene, TNFRSF1A , at the RNA level, suggesting a direct impact on its main pathogenic mechanism. References McDermott MF, et al. Cell 1999; 97(1):133–44. 2. Lachmann HJ, et al. J Exp Med.2009; 206(5):1029–36. Disclosure of Interest : N. Nirmala Employee of: Novartis Institutes of Biomedical Research, R. Torene Employee of: Novartis Institutes of Biomedical Research, H. Lachmann Grant/research support: Novartis, Celtic, L. Obici Consultant for: Consultation fees from Pfizer Pharmaceuticals, A. Meini: None declared, V. Tormey: None declared, R. Caorsi: None declared, L. Baeriswyl Employee of: Novartis Institutes of Biomedical Research, U. Affentranger Employee of: Novartis Institutes of Biomedical Research, S. Starck-Schwertz Employee of: Novartis Institutes of Biomedical Research, M. Letzkus Employee of: Novartis Institutes of Biomedical Research, N. Hartmann Employee of: Novartis Institutes of Biomedical Research, K. Abrams Shareholder of: Novartis, Employee of: Novartis Pharmaceutical corporation, M. Gattorno Grant/research support: Novartis, SOBI, Speakers bureau: Novartis, SOBI DOI 10.1136/annrheumdis-2014-eular.1503

Background Acute pericarditis is defined as at least 2 of the following: typical chest pain (sharp and pleuritic, improved by sitting up and leaning forward), pericardial friction rub, suggestive EKG changes (widespread ST elevation or PR depression), new or worsening pericardial effusion. Pericarditis may recur in 15-30% of cases; these children are frequently followed by pediatric Rheumatologists. At present the largest case series described 15 children affected by recurrent pericarditis. Objectives This is a multicenter, retrospective cohort study including all consecutive cases of recurrent pericarditis with at least 2 recurrences in pediatric patients seen in 7 referral centers in Italy. Methods We analyzed 107 children; the mean age at the time of the first attack was 11,1 years; 67 were males and 40 females. Results The mean recurrence number was 4.8 (2-25); pericarditis was idiopathic in the majority of cases (88%), post-pericardiotomic in 10%, related to Familiar Mediterranean fever in 2%. Most children had fever and CRP elevation at disease onset (77% fever, 93% CRP elevation), and so was pericardial effusion (76%: typically mild, with cardiac tamponade in 13%, only at disease onset), while pericardial rub and EKG changes were detected in a smaller number of patients (28% and 45% respectively). After a mean follow-up of 73 months, none of the patients with idiopathic RP developed a systemic autoimmune disease (even if ANA was positive in 19%) or was found as having an infectious disease. 80% children were treated with NSAIDs, 64% with steroids and 63% with colchicine. Refractory cases were treated with immunosuppressant drugs (AZA: 4, MTX: 2, IVIG: 1, Antimalarials: 5, CSA: 1), and 11 with Anakinra. Children treated with corticosteroids experienced more recurrences (5,9 vs 2,6, p Conclusions This is the largest ever published case-series on pediatric recurrent pericarditis. Because of lack of standardized treatment guidelines, we believe that our data will help clinicians in manage these children, typically treated with rheumatological drugs. Corticosteroids should be used with extreme caution and NSAIDs remain the mainstay of the therapy. Anti-IL1 may be useful in very selected cases. The long term outcome is good. References Imazio M, et al. A randomized trial of colchicines for acute pericarditis. New Engl J Med 2013; 369:1522-8. Gaspari S. et al. New insights in the pathogenesis and therapy of idiopathic recurrent pericarditis in children. Clin Exp Rheumatol 2013;31:788-94. Raatikka M et al. Recurrent pericarditis in children and adolescents. Report of 15 cases. J Am Coll Cardiol 2003;42:759-64. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1952

AA amyloidosis is the most severe complication of hereditary autoinflammatory diseases. In TRAPS it has been reported to occur in approximately 25% of patients in the absence of an effective treatment. However, susceptibility to AA is difficult to predict. Identification of key risk factors affecting the development of AA would improve the clinical management of TRAPS patients, by allowing a more tailored treatment approach.

PAPA syndrome is a very rare autoinflammatory condition. Few data are nowadays available about the clinical characteristic, the response to treatment and the outcome of this disease.

TNF-receptor associated periodic syndrome (TRAPS) is a rare, dominantly inherited periodic fever syndrome due to mutations of the TNFRSF1A gene. The IL-1 receptor antagonist anakinra has been reported to be an efficacious daily treatment. Canakinumab (CAN) is a fully human monoclonal selective anti-IL-1β antibody with a T1/2 of ~4 wks. Interim clinical and PK data of CAN treatment in patients with active TRAPS are presented.

Autosomal Recessive Osteopetrosis (ARO) is a severe bone disease characterized by increased bone density due to impairment in osteoclast bone resorptive function (osteoclast-rich forms) or differentiation (osteoclast-poor forms). The latter form carries mutations in Tnfsf11 gene, which codifies for the receptor activator of NF-κB ligand (RANKL), an essential cytokine expressed in stromal cells. It contributes (with M-CSF) to the differentiation and activation of specialized osteoclasts from monocyte precursors in bone marrow niche. These patients, differently from other forms, do not benefit from HSC transplantation, demonstrating a pathogenetic role of stromal cells in unbalanced bone remodeling.

Background Familial Mediterranean fever (FMF) and Pyogenic Arthritis, Pyoderma gangrenosum and Acne (PAPA) syndrome are autoinflammatory disorders that are thought to share similar pathoetiology. While FMF is due to mutations of MEFV gene encoding for Pyrin, PAPA syndrome is caused by genetic variants of CD2 binding protein 1 (CD2BP1). Since Pyrin is able to bind CD2BP1 in a newly identified inflammasome called Pyroptosome, FMF and PAPA have been recently recognized as disorders of the same pathway, probably involving caspase-1 mediated interleukin (IL)-1β secretion, as suggested by the response to anti IL-1 treatment. However, a clear involvement of IL-1β is still controversial, especially because most of the data derive from studies applying not homogeneous experimental approaches. Objectives To investigate in our cohorts of FMF and PAPA patients whether 1) MEFV/CD2BP1 mutated monocytes displayed enhancedredox-stress and IL1β secretion, 2) IL1β pathway activationcorrelated with type of mutation and 3) pyroptosome-related IL1β secretion was mediated by NLRP3 inflammasome. Methods Thirteen genetically confirmed FMF pediatric patients (7 with 2 high penetrance and 6 with 1 high penetrance and 1 low penetrance or 2 low penetrance mutation) and 10 asymptomatic parents (healthy carriers, HC) were evaluated. Four PAPA (2 children and 2 adults) patients carrying different CD2BP1 mutations (E250Q, E250K and E256G) were also analyzed and compared to 25 healthy donors (HD). Peripheral blood primary human monocytes were freshly isolated and studied at baseline and after 3-6-18 hours (h) of TLR s in vitro activation. Intracellular reactive oxygen species (ROS) were examined by biochemical assay. Monocyte pattern of secretion of IL-1β, IL-18 and IL-1Ra was assessed by ELISA. The involvement of NLRP3 inflammasome was investigated by in vitro silencing. Results FMF patients carrying high penetrance MEFV mutations displayed higher ROS levels than HD at baseline. The same pattern was observed for PAPA patients carrying the E250Q and E256G mutations. Overall FMF and PAPA monocytes displayed enhanced but not anticipated IL1β and IL18 secretion, in the presence of IL1Ra levels comparable to HD. Increased IL-1β pathway activation was greater in the presence of more severe MEFV mutations and in pediatric E250Q(+) and E256G(+) PAPA patients. Silencing of NLRP3 in representative cases inhibited IL-1β secretion in both FMF (N=1), FMF HC (N=3), PAPA (N=2) and HD (N=6). Conclusions MEFV and CD2BP1 mutated monocytes are under sustained oxidative stress. This parallels an enhanced pattern of secretion of the pro-inflammatory IL1β, with greater effect in the presence of high-penetrance mutations in FMF and E249Q or E256G mutation in PAPA patients. Results from in vitro silencing experiments in freshly isolated monocytes suggest that NLRP3 inflammasome may be involved. Disclosure of Interest None Declared

Background TNF receptor associated periodic syndrome (TRAPS) is an autoinflammatory syndrome. Diagnosis relies on genetic testing. More than 70 TNFRSF1A pathogenic sequence variants (PSV) have been reported but it is not known if there are phenotype genotype correlations and interpretation of the significance of R92Q, a common variant of unknown significance (VUS), is often problematic. Objectives To analyse the presenting clinical features of patients with TNFRSF1A PSV and of those with inflammatory symptoms and the R92Q VUS. Methods Anonymised data derived from patient recall and case records were entered by specialist physicians to a web-based registry (www.printo.it). Results 46 TNFRSF1A PSV were identified in 86 patients; 11 (13%) carried the T50M PSV and in 40 (47%) a cysteine residue was affected; 61% patients reported a family history of similar symptoms; 52% were male; 94% were Caucasian and the mean age at symptom onset was 7.6 yrs (range: neonatal to 49 yrs). In 9% symptoms onset after aged 30 yrs. Median attack duration was 10 days and the median number of symptomatic days/yr was 51.5 (range: 8 – 365). Patients with the R92Q VUS were 98% Caucasian, 46% male and 17% reported a family history. Symptoms onset at a median of 10 yrs (range: neonatal to 52.6 yrs). Median attack duration was 6.5 days and the median number of symptomatic days/yr was 57. Clinical features seen in attacks are summarised in the table. Patients with the R92Q VUS were significantly less likely to have rash and more likely to have attacks features of headache, cervical adenopathy, headache and/or pharyngitis than patients with TNFRSF1A PSV. AA amyloidosis complicated 16 cases (19%) including 7 cysteine PSV (17.5%), 2 (18%) T50M and no patients with R92Q. Among patients with clear TNFRSF1A PSV no phenotype genotype correlations were identified. Conclusions The phenotype of PSV confirmed TRAPS is very variable with no pathognomonic pattern and no increased severity with cysteine or the T50M PSVs; musculoskeletal pain, fever, gastrointestinal symptoms and constitutional upset are most frequent. Even though there may have been a bias to entering patients with severe R92Q associated disease into the registry there are significant differences compared to patients with PSVs with a later presentation and more upper respiratory tract type symptoms reminiscent of those seen in PFAPA. Disclosure of Interest None Declared

Background Anti-IL1 drugs have been shown to be an effective treatment for the control of disease activity in patients with CAPS. Anakinra has been used for several years and his long-term efficacy and safety has been demonstrated; Canakinumab has been recently described as an effective treatment in CAPS, even if by this time few follow-up data are available. Objectives To compare the efficacy and the impact on the quality of life in CAPS patients receiving the two IL1-blockers during their disease course. Methods 11 patients (F:M =6:5, 8 children and 3 adults) with a clinical diagnosis of CINCA (7 pts), Muckle-Wells syndrome (MWS, 2 pts), MWS overlapping CINCA (2 pts) were analyzed. All patients, who received a previous treatment with Anakinra, were enrolled in the CACZ885D2306 trial(1) and then treated in compassionate use for the following 12 months. Disease activity, laboratory parameters, doses of IL-1 inhibitors and health related quality of life were analyzed at the time of the last administration of Anakinra and after 12 months of compassionate use with Canakinumab. Health related quality of life was assessed with the Child Health Questionnaire (CHQ-PF 50). Results At the last administration of Anakinra the patients were treated with a mean dose of 1,38 mg/kg/day (range 0,66-2). Six patients (3 CINCA, 1 MWS/CINCA and 2 MWS) displayed a complete response while a partial response was observed in 5 patients (4 CINCA, 1 MWS/CINCA patients), due to a slight increase of acute phase reactants. At the last follow-up during Canakinumab treatment 4 patients (2 MWS, 1 MWS/CINCA and 1 CINCA patients) were treated with a stable dose of 2 mg/kg (or 150 mg if weight was higher than 40 kg) every 8 weeks, all of them displaying a complete response. Two CINCA patients were treated with the dose of 2 mg/kg (or 150 mg) every 7 and 6 weeks respectively, with a complete response. Four patients (3 CINCA and 1 MWS/CINCA patients) were treated with the dosage of 300 mg with a frequency of 7, 6, 5 and 4 weeks. All of them displayed a partial response. One CINCA patient discontinued the treatment due to persistent relapse and poor compliance. The evaluation of the quality of life with the CHQ-PF50 questionnaire did not reveal a significant difference of the impact of the two drugs on physical concepts (Phs 51.88 during Anakinra, 51.55 during Canakinumab), while Canakinumab determined a significant amelioration of psychosocial concepts (PsS 47.03 during Anakinra, 54.01 during Canakinumab; p Conclusions This study shows that both Anakinra and Canakinumab are able to completely control the clinical manifestations associated to CAPS. In general Anakinra was able to better control the elevation of acute phase reactants. In the other hand, while both drugs were able to normalize many aspect of health related quality of life, Canakinumab showed a better impact on the psychosocial concepts. References Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes. Kummerle-Dechner et al, ARD 2011. Disclosure of Interest R. Caorsi: None Declared, L. Lepore: None Declared, F. Zulian: None Declared, M. Alessio: None Declared, A. Stabile: None Declared, M. Finetti: None Declared, C. Bibalo: None Declared, A. Martini: None Declared, M. Gattorno Grant/Research support from: Novartis, Consultant for: Novarits, Speakers Bureau: Sobi

Background The main limitation to a better knowledge of Autoinflammatory diseases is related to the extreme fragmentation of the diagnosed cases that are spread over different centers and countries. The general aim of the Eurofever Project (agreement n 2007332, EAHC) is to build an international registry on Autoinflammatory diseases. Objectives To evaluate the number of patients enrolled in the Registry in the first 24 months after starting the enrolment. Methods A web-based registry collecting baseline and clinical information on Autoinflammatory diseases is available in the member area of the PRINTO web-site. The following monogenic autoinflammatory diseases were considered: FMF, CAPS, TRAPS, mevalonate kinase deficiency (MKD), Blau’s syndrome, PAPA, DIRA, NLRP12-mediated periodic fever. Information on CRMO, Behcet’s disease, PFAPA and undefined periodic fevers were also collected. Results During the first 24 months from the beginning of the enrolment 2293 patients from 51 centers in 38 countries have been entered in the registry. At present baseline demographic information from 2293 (M:F=1121:1172) patients are available. In 1797 (78%) complete information on clinical manifestations form disease onset to diagnosis and response to treatment is also available. For each disease the number of enrolled patients is: FMF 694 pts (493 with complete clinical data); TRAPS 215 pts (180 with with complete clinical data); CAPS 180 pts (155 with complete clinical data); MKD 129 pts (107 with complete clinical data); Blau’s disease 30 pts (18 with complete clinical data); PAPA 8 pts (all with complete clinical data); NLRP-12 mediated periodic fever 6 pts – 4 with complete clinical data); DIRA 3 pts (all with complete clinical data). In total 19 new mutations have been reported in 22 pts. Among multifactorial autoinflammatory diseases: PFAPA 405 pts (264 with complete clinical data); CRMO 372 pts (334 with complete clinical data); pediatric Bechet disease 79 pts (64 with complete clinical data) and 173 patients with undefined periodic fever (167 with complete clinical data). Conclusions A common registry for collection of patients with Autoinflammatory disease is available and the enrolment is ongoing. The analysis of data on the clinical presentation, outcome and response to treatment of Autoinflammatory diseases and comparative studies among different Autoinflammatory conditions are ongoing. Disclosure of Interest None Declared

Background BD is rarely encountered in children where the disease is very difficult to recognize. The outcome of patients with few symptoms is currently unknown Objectives To define the outcome of paediatric patients with at least two symptoms of BD, and to obtain an appropriate definition of BD in patients Methods An international expert committee has defined the criteria of inclusion. New patients or patients followed for a maximum of 3 years, who presented at least 2 symptoms of BD (among a list), and gave their informed consent were included, reviewed yearly. Results 223 patients (SR: 1), from 22 centres of 12 countries, were included since 2008, median age of 13,3y (2.3-21y). Median age at first symptom was 8y (9m-18y). Family history of BD was present in 50 (22.4%) and consanguinity in 10 (4.5%). Median disease duration at inclusion was 4.7y (0-16,5y) and from the first symptom to last visit was 5.5y (1m-19.4y). Inclusion criteria plus oral aphtosis (mandatory) were (%): genital aphtosis 51.1, necrotic folliculitis 31.4, uveitis 28.7, familial history 22%, pathergy test positive 18.8, erythema nodosum 14.3, vascular 10 and retinal vasculitis 7.2. Mean number of symptoms: 1 plus family history (41%), 2 (33%), more than 3 (26%). Patient had a median of 1.0 follow-up visit (0-4). 217 patients had a first visit: where symptoms were as follows (%): genital aphtosis 49, skin lesions 49, joints and fever 41, eyes lesions 35, neurological 34.5, gastrointestinal 30.5 and vascular16.5. HLAB51 was present in 48% and A26 in 4%. Male patients had significantly more uveitis. 138 patients had a 1-y visit (mean BD duration: 5.6y). 81 patients had 2-y (6.3y), 44 a 3-y (7.2y) and 18 a 4-y visit (7.4y). Between 1 st -4 th visit: 62% had no new symptom, 23% had one, and 8% had 2 and 7 had more than 3. The expert committee has reviewed 196 files at a median disease duration of 6,7y (0.9-19y), and classified 118 patients as definite, 21 as probable and 3 as not BD. 54 charts were reviewed but did not reached consensus. 45 files have been reviewed more than once. Although good concordance (Kappa coefficient = 0.72), International criteria and expert classification showed significant differences: 60.2% (118/196) patients were classified as definite BD by experts, whereas only 45.9% of these patients met the international criteria (P Conclusions The expert committee has classified the majority of patients in the BD group although they did not fulfil the international BD classification criteria (for adults) Disclosure of Interest None Declared

Under the term of monogenic autoinflammatory syndromes are gathered a number of different conditions secondary to mutations of genes coding for proteins that play a pivotal role in the regulation of the inflammatory response. Some of them are characterized by recurrent flares of systemic inflammation presenting as sudden fever episodes associated with a dramatic elevation of acute phase reactants and with a number of clinical manifestations, such as rash, serositis (peritonitis, pleuritis), lymphadenopathy, arthritis. Familial Mediterranean Fever (FMF), Mevalonate-kinase deficiency (MKD), and Tumour necrosis factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS) are the three monogenic disorders gathered under the term of hereditary recurrent fevers. In other disorders, systemic inflammation is dominated by a characteristic urticarial rash that may be associated with a number of other clinical manifestations. Familiar Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS) and Chronic Infantile Neurological Cutaneous and Articular Syndrome (CINCA) represent the clinical spectrum associated to gain-of-function mutations of a gene named NLRP3 coding for a protein called Cryopyrin. Cryopyrin is crucial for the activation and secretion of the active form of one of the most potent pro-inflammatory cytokines, interleukin (IL)-1b. A clinical phenotype similar to that observed in Familiar Cold Autoinflammatory Syndrome (FCAS2) has been observed also in patients carrying mutation of NLRP12 gene. Blau’s syndrome, includes noncaseating granulomatous inflammation affecting the joint, skin, and uveal tract and is associated with mutations of the NACHT domain of the gene CARD15 (or NOD2). Finally, other very rare disorders are dominated by the presence of sterile pyogen abscesses prevalently affecting skin, joints and bones (pyogenic disorders). This include the Pyogenic Sterile Arthritis, Pyoderma Gangrenosum and Acne (PAPA) syndrome associated to mutations of the CD2-binding protein 1 (CD2BP1) gene. Deficiency of the interleukin-1–receptor antagonist (DIRA) is the more recently identified autosomal recessive autoinflammatory syndrome. It is characterized by very severe systemic inflammation that begins around birth with multifocal osteomyelitis, periostitis, and pustulosis. Disclosure of Interest M. Gattorno Grant/Research support from: Novartis for Eurofever, Consultant for: Novartis, Sobi, Speakers Bureau: Novartis, Sobi

Background Pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is a rare autosomal dominant autoinflammatory disorder due to mutations in the CD2 binding protein 1 (CD2BP1) gene. This syndrome is featured by pyoderma gangrenosum, cystic acne and recurrent pyogenic sterile arthritis, with increased serological acute phase reactants during active disease. However, the clinical presentation and response to treatment display significant individual variability. The therapeutic approach during recurrences consists of steroids, while no agreement exists on the chronic management. Recent evidence suggests the possible use of anti-TNFα monoclonal antibodies (Punaro et al.), while the efficacy of Adalimumab (IgG1 humanized monoclonal anti-TNFα antibody) has been described only in a few cases and not yet proven. Objectives To evaluate the response to treatment with Adalimumab (IgG1 humanized monoclonal anti-TNFα antibody) in 3 PAPA patients followed in a single Center. Methods Three patients (M:F=2:1, mean age 13 years, range 5-22 years) with a molecular diagnosis of PAPA syndrome (mutations E256G, E250K, E250Q) were enrolled and treated with Adalimumab (patients#1-2: 40 mg/15 days, patient#3: 20 mg/15 days). Results Clinical outcomes evaluated were the frequency of articular and cutaneous flares in the 12 months before starting therapy compared to those occurred during Adalimumab regimen, whereas laboratory tests (ESR, PCR) were assessed at the last visit before the study enrolment and at end of treatment. Patient#1 (F, E256G+) presented both articular and cutaneous involvement. During the 25 months of treatment, she had only mild decrease in the frequency of articular recurrences (3 episodes/year before vs 1 episode/year after treatment) and pyoderma gangrenosum episodes (12 episodes/year before vs 4 episodes/year after treatment); however, a worsening size of the cutaneous lesions occurred, requiring surgical removal in one occasion. Patient#2 (M, E250K+) displayed only cutaneous involvement in the 12 months before starting Adalimumab administration, with persistent pyoderma gangrenosum on the left arms. Following the treatment period (3 months), he showed the persistence of the lesion, without clinical improvement. Reactivation of the articular symptoms was not observed. Patient#3 (M, E250Q+) was affected by recurrent arthritis localized to left elbow, ankles and knees, without cutaneous involvement. During the 9 months of treatment, he didn’t show any clinical improvement, with no significant changes in the frequency of articular episodes (10 episodes/year before vs 8 episodes/year after treatment). No difference in the levels of acute phase reactants were observed for all three patients before and after Adalimumab treatment. Conclusions Taken together, these findings suggest that our cohort of PAPA patients didn’t gain any benefit from Adalimumab administration, nor at clinical or serological level. Thus, further research is needed in order to explore novel therapeutic approaches. Disclosure of Interest None Declared

Background TNF-receptor associated periodic syndrome (TRAPS) is a rare dominantly inherited periodic fever syndrome involving a genetic mutation of the TNF Super Family Receptor 1A gene. Usually presenting in childhood, it is characterized by recurrent fever attacks associated with rash, musculoskeletal and abdominal pain, conjunctivitis, and periorbital edema and ∼10% develop renal AA amyloidosis. Case reports suggest successful treatment with the IL-1 receptor antagonist anakinra. Canakinumab is a fully human monoclonal selective anti-IL-1β antibody with a half-life of ∼4 wks. Here we report 4-month interim data of canakinumab treatment in patients with active TRAPS. Objectives To assess the efficacy and safety of canakinumab patients with active TRAPS. Methods Twenty pts with a median age of 18 years (7 to 78 yrs) and active TRAPS entered a 3-part trial comprising of 4 months of open-label 150mg (or 300mg) sc canakinumab injection every 4 weeks followed by 5 months follow-up (treatment withdrawal), and then 24 months open-label treatment. Pts were evaluated clinically by a 5-point physician’s global assessment (PGA) disease activity scale and serologically by CRP and SAA levels. The primary endpoint was complete or almost complete response at Day 15. Complete response was defined as clinical remission (PGA of 0 or 1 [absent or minimal]) and normal CRP and/or SAA. Almost complete response was clinical remission and elevated but ≥70% reduction of baseline CRP and/or SAA. Those who without response by Day 8 were eligible to receive another 150mg sc injection that day and remain at the 300mg dose thereafter. Results On Day 8, 16 (80%) achieved complete/almost complete response and 18 (90%) achieved clinical remission.The 2 pts without clinical remission were dose up-titrated to 300mg. The primary endpoint was met. At Day 15, 19/20 (95%) achieved complete/almost complete response, including all 4 who did not achieve it at Day 8. Clinical remission was maintained for all from Day 15 onwards in the 4-month treatment period except for 1 patient with a relapse at Day 85 that responded to the scheduled canakinumab dose. Median time to clinical remission was 4 days (95% CI:3,8). Median baseline CRP (125 mg/L) and SAA (207 mg/mL) normalized to 4mg/L from Day 15 onwards. 95% of patients reported at least 1 adverse event (AE). Infection, mostly upper respiratory tract infections (URI), was the most common (n=13, 65%) category of AE reported. One serious AE, a URI, was reported. All patients continued into the 5 months follow-up and entered the 24-month final open-label treatment period. Conclusions In this on-going study, canakinumab produced a rapid and highly effective clinical and serological benefit which was maintained with monthly dosing in patients with TRAPS. Canakinumab demonstrated an acceptable safety and tolerability profile in this small study. Data confirm that IL-1β plays a pivotal role in TRAPS and further study is needed to better define canakinumab treatment. Disclosure of Interest M. Gattorno Grant/Research support from: Novartis, Consultant for: Novartis, Speakers Bureau: Novartis, L. Obici Consultant for: Novartis, A. Meini Consultant for: Novartis, V. Tormey: None Declared, K. Abrams Shareholder of: Novartis, Employee of: Novartis, N. Davis Employee of: Novartis, C. Andrews Shareholder of: Novartis, Employee of: Novartis, H. Lachmann Consultant for: Novartis

Background BD is rarely encountered in patients before 16y where the disease is very difficult to recognize. In addition to the diagnostic challenge, the outcome of patients with few symptoms is currently unknown. Objectives PED-BD is an international database aimed to define the outcome of either paediatric BD patients or patients with at least two symptoms of the disease, in order to propose paediatric criteria for BD. Methods An international expert committee has defined criteria for eligibility in the study. New patients or patients followed for a maximum of 3 years, who presented at least 2 symptoms of BD (among a list), were selected for retrospective and prospective analyses. An eCRF was built and inserted into a secured database (CLeanWeb). Patients included are reviewed yearly and judged as definite, probable or not BD, by an expert committee. Results 206 patients (SR:1), from 22 centres of 12 countries, have been included since 2008, median age 13,5y (2,3-21y). Median age at onset was 8y (9m-18y), family history was 22,3% and consanguinity 4.4%. At inclusion, median disease duration from onset to last visit was 5.5y (1m-19y). The criteria of inclusion in addition to oral aphtosis (mandatory): genital aphtosis 52%, necrotic folliculitis 30%, uveitis 29%, familial history 22%, pathergy positive 19%, erythema nodosum 14,5%, skin ulceration 11%, vascular 8,7% and retinal vasculitis 7%. Number of symptoms: 1 plus family history (42,7%), 2 (30,6%), more than 3 (26,7%). Patient had a median of 1 follow-up visit (0-4). 200 patients had a first visit, symptoms as follows: Skin lesions 58%, joints and fever 41%, eyes lesions 36%, neurological 34%, gastrointestinal 29% and vascular (12%). 84% received treatment: colchicine 59%, steroids 29%, azathioprine 12% and MTX 9%. Male patients had significantly more uveitis. 135 patients underwent first year visit. 62 had no new symptom, 43 had one, and 15 had 2 and 15 had 3. 73 patients had a 2y, 37 a 3y and 17 a 4y visit. The expert committee has reviewed 114 files at a median disease duration of 6,2y (0-18y), and classified 72 patients has definite, 44 as probable and 2 as not BD. Among patients classified as BD: 57 met the international criteria. Symptoms associated with classification as definite were skin (74% of the definite had this symptom), genital aphtosis (67%), eyes (51%) and pathergy (26%). None of the symptoms were observed in patients not classified as definite. The Kappa concordance coefficient between the 2 classifications reached 0.73 with a 95% CI= [0.62-0.86]. Conclusions The PED-BD cohort is characterized by an equal sex ratio, a high rate of familial aggregation, and marked phenotypic differences by gender. In this large series of patients with few symptoms, the expert committee judgments gave higher number of patients classified as BD than the classification by the international classification criteria. Disclosure of Interest None Declared

Results 158 TRAPS pts were enrolled from November 2009 to June 2012. analyzed. The majority of pts were adults (105, 67%). The median age at disease onset and at disease diagnosis were 4.1 (range 0.2-63 years) and 25.9 (0-77) years, respectively. The median delay of diagnosis was 10.3 years, with a rate of delay 10 times higher in adult patients. Patients were enrolled by 18 centers in 11 countries, with 18 different countries of origin. 145 (91%) were European Caucasians, 4 Arabs, 3 black Africans, 2 Asiatics, 2 Ashkenazi Jewish, 2 had a mixed origin. 58 pts (36.7%) carried high-penetrant mutations (T50M or involving cysteine residues), 30 pts (19%) other missense mutations previously associated to TRAPS phenotype. Low-penetrant or hypomorphic variants, such as R92Q and P46L, were found in 53 and 5 pts, respectively. 12 pts carried mutations with uncertain association with TRAPS phenotype. High penetrant mutations were observed in 50/123 (40%) pts with pediatric onset and in 8/35 pts (22.9%) with an adult onset (p < 0.001). The prevalence of patients carrying low-penetrant or hypomorphyc mutations were two time higher in the adult onset (48%) compared with pediatric onset (25.2%) (p < 0.001). Mean duration of fever episodes was 10.6 days with mean number of 6.6 episodes/year. In one third of the cohort a mean duration of fever episodes was shorter than 1 week. The most frequent symptoms accompanying attacks were fever, limb pain (arthalgia, myalgia), abdominal pain and a variety of skin rashes. The prevalence of a number of clinical manifestations significantly differ among the age of onset. Pediatric patients displayed an increased prevalence of enlarged cervical lymph nodes abdominal pain and periorbital edema in respect to patients with an adult onset. Adult onset was characterized by an higher prevalence of respiratory symptoms (chest pain, persistent cough), serositis and polyarthritis. The most common long term complication was amyloidosis, that was observed in 16 (10%) adult patients. The mean age at onset of amyloidosis was 43 years (range 20-77). Patients who developed AA amyloidosis had significantly longer disease duration than those who have not (39 years versus 19.4 years; p=0.001).

Osteolytic lesions are the hallmark of a number of inherited (DIRA and Majeed syndrome) and multifactorial (CRMO and SAPHO) autoinflammatory diseases. We report a clinical case in which bone lesions are part of the clinical picture of an additional inherited AID.

Pyogenic sterile Arthritis Pyoderma gangrenosum and Acne (PAPA) syndrome is a rare autosomal dominant inherited autoinflammatory disease caused by mutations in Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1). In childhood, the syndrome is featured by recurrent sterile, erosive arthritis, potentially leading to joint destruction. By puberty, cutaneous symptoms become predominant, with recurrent onset of pathergy, abscesses, severe cystic acne, and pyoderma gangrenosum. Typically, both articular and cutaneous outcomes occur following a minor trauma. PSTPIP1 may interact with NLRP3 and caspase-1 but a clear involvement of IL-1β is still controversial. While anti-IL1 treatment seems to be effective on joint manifestations, IL inhibition does not display the same effectiveness in the management of skin lesions.

The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever disease in young children. The etiology of this disorder is still unknown. Palatine tonsils are sites where innate immunity leads to onset of the adaptive immunity, mediated by B and T lymphocytes. Three families of pathogen sensors mediate the recognition of microbes: Toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs). The interplay of these receptors ensures the efficient coordination of innate immune responses.

Familial Mediterranean Fever (FMF) is the most common of the hereditary autoinflammatory disorders. FMF is caused by mutations of MEFV gene which encodes for pyrin. It has been recently reported that frequency of FMF-like symptoms decreases from patients carrying two high penetrance mutations towards patients with a single low penetrance mutation. The effectiveness of interleukin (IL)-1b blockers has suggested that IL-1b may play a role in the pathophysiology of the disease. However, evidence of dysregulated IL-1b secretion in FMF patients is so far missing. Moreover, the role of NLRP3 has never been directly examined in FMF patients.

ADA2 deficiency, a recently described disease, is characterized by systemic vasculopathy and episodes of strokes. The defect is due to a loss of function mutation of CECR1 gene, codifying for Adenosine Deaminase 2 protein. This protein regulates the catabolism of extracellular adenosine, which we have recently shown is an important regulator of Class Switch Recombination in B lymphocytes. Accordingly DADA2 patients can present hypogammaglobulinemia.

Mevalonate kinase deficiency (MKD) is a rare autoinflammatory disease, caused by mutations in the isoprenoid pathway that lead to fever episodes. Approximately 300 MKD patients are known.