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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may result in a severe pneumonia associated with elevation of blood inflammatory parameters, reminiscent of cytokine storm syndrome. Steroidal anti-inflammatory therapies have shown efficacy in reducing mortality in critically ill patients; however, the mechanisms by which SARS-CoV-2 triggers such an extensive inflammation remain unexplained.To dissect the mechanisms underlying SARS-CoV-2-associated inflammation in patients with severe coronavirus disease 2019 (COVID-19), we studied the role of IL-1β, a pivotal cytokine driving inflammatory phenotypes, whose maturation and secretion are regulated by inflammasomes.We analyzed nod-like receptor protein 3 pathway activation by means of confocal microscopy, plasma cytokine measurement, cytokine secretion following in vitro stimulation of blood circulating monocytes, and whole-blood RNA sequencing. The role of open reading frame 3a SARS-CoV-2 protein was assessed by confocal microscopy analysis following nucleofection of a monocytic cell line.We found that circulating monocytes from patients with COVID-19 display ASC (adaptor molecule apoptotic speck like protein-containing a CARD) specks that colocalize with nod-like receptor protein 3 inflammasome and spontaneously secrete IL-1β in vitro. This spontaneous activation reverts following patient's treatment with the IL-1 receptor antagonist anakinra. Transfection of a monocytic cell line with cDNA coding for the ORF3a SARS-CoV-2 protein resulted in ASC speck formation.These results provide further evidence that IL-1β targeting could represent an effective strategy in this disease and suggest a mechanistic explanation for the strong inflammatory manifestations associated with COVID-19.

Background Recurrent pericarditis (RP) is a complication (15–30%) of acute pericarditis with an unknown etiology. Treatment regimen consists of a combination of non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine, with the addition of corticosteroids in resistant or intolerant cases. In the last decade anakinra was shown as an effective treatment in patients with colchicine resistant and steroid-dependent RP, initially in anecdotal reports in children and more recently in a randomized trial. Canakinumab is a monoclonal antibody selectively blocking IL-1β and its use is only anecdotally reported to treat pericarditis. We report two pediatric patients with refractory recurrent pericarditis, who presented an optimal response to anakinra treatment but prompt relapse after switch to canakinumab. Case presentation The first patient is a girl with Recurrent Pericarditis started in April 2015, after heart surgery. NSAIDs and oral steroids were started, with prompt relapse after steroid suspension. The child showed a steroid-dependent RP; anakinra was therefore started with excellent response, but discontinued after 2 weeks for local reactions. In July 2016 therapy with canakinumab was started. She experienced four relapses during canakinumab therapy despite dosage increase and steroid treatment. In January 2018 a procedure of desensitization from anakinra was performed, successfully. Anakinra as monotherapy is currently ongoing, without any sign of flare. The second patient is a girl with an idiopathic RP, who showed an initial benefit from NSAIDs and colchicine. However, 10 days after the first episode a relapse occurred and therapy with anakinra was established. Two months later, while being in complete remission, anakinra was replaced with canakinumab due to patient’s poor compliance to daily injections. She experienced a relapse requiring steroids 10 days after the first canakinumab injection. Anakinra was subsequently re-started with complete remission, persisting after 24 months follow-up. Conclusions We describe two cases of failure of the treatment with anti-IL-1β monoclonal antibodies in steroid- dependent idiopathic RP. This anecdotal and preliminary observation suggests a different efficacy of the two IL-1 blockers in the management of RP and support a possible pivotal role of IL-1α in the pathogenesis of this condition.

INTRODUCTION: New Eurofever/PRINTO classification criteria (EPCC) for Familial Mediterranean Fever (FMF) and other recurrent fevers have been recently developed, together with the classification of the pathogenicity of MEFV variants. OBJECTIVES: To evaluate the impact in real life of both the EPCC and INSAID pathogenicity classification of MEFV variants in the large international Eurofever FMF cohort. METHODS: Baseline demographic, genetic and clinical data of FMF patients included in the Eurofever registry were evaluated. The EPCC and the 2018 INSAID classification for MEFV variants were applied in all eligible FMF patients. RESULTS: Since November 2009, clinical information was available for 1012 FMF (532 males/480 females, 827 children/185 adults) from 119 centres. Complete data were available for 887 patients in whom 623 (70.2%) satisfied EPCC (EPCC+), while 264 (29.8%) did not (EPCC-). The majority of the EPCC- patients (172, 65.1%) displayed negative or non-informative genetics (monoallelic or biallelic benign variants, monoallelic variant of unknown significance). At baseline, colchicine was used in most of EPCC+ patients (88%) and in a lower percentage of EPCC- patients (69%, p

To describe a homogeneous group of patients with undifferentiated recurrent fevers followed-up in a tertiary referral center for systemic autoinflammatory diseases (SAIDs).Patients with undifferentiated recurrent fevers seen at our Center from 2008 to 2021 and followed-up for at least one year were included in a retrospective study. Monogenic recurrent fevers, patients carrying variants of unknown origin and PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) syndrome were excluded.Fifty patients (34 male, 16 female) were included in the study. The median age at onset was 3 years, and the median follow-up was 3.3 years. At baseline, arthralgia (70%) and abdominal pain (65%) were the most frequent manifestations. NSAIDs or steroids on demand had a variable and transient effect. Tonsillectomy was ineffective in the 10 patients (20%) that underwent surgery. Forty-eight patients (96%) were treated with colchicine. A complete response (absence of fever) was achieved in 31 patients (64.6%). Nine patients (18%) showed a partial response, with a median reduction of fever episodes per year of 72%. Nine patients (16.7%) were considered resistant to colchicine. The presence of generalized lymphadenopathy and, to a lesser extent, exudative tonsillitis was associated with a lack of response to colchicine.We describe the largest series of patients with syndrome of undifferentiated recurrent fever (SURF) reported in the literature so far. SURF should be considered as a distinct clinical entity in the context of multifactorial autoinflammatory diseases.

Background Interleukin-1 plays a pivotal role in the inflammatory response during cytokine storm syndromes. Objective To analyse the efficacy and safety of early anti-inflammatory treatment (AIT) with i.v anakinra with or without glucocorticoids (GC) in COVID19 pneumonia. Methods We performed a retrospective single-centre cohort study on patients admitted for COVID19 pneumonia from February 26th to April 29th, 2020 to assess the efficacy of early AIT with i.v. Anakinra (100mg every 8 hours for 3 days, with tapering) alone or in combination with GC (i.v. methylprednisolone, 1-2 mg/kg daily, with tapering). Standard of care (SOC) treatment was: hydroxychloroquine and/or azithromycin with or without antivirals and anticoagulants. Late rescue AIT with anakinra or tocilizumab was also evaluated. Treatment effect on Overall Survival (OS) was assessed by a Propensity Score adjusted Cox model. Results 128 patients were analyzed; 63 received early AIT (30 anakinra, 33 anakinra and CG) at admission; 65 patients (44 with SOC, 21 SOC plus late rescue AIT) did not and were used as controls. After adjusting for all the unbalanced baseline covariates, early AIT reduced the hazard of mortality by 74% (adjusted HR=0.26, p, Graphical abstract, Capsule summary: This study provide evidence that the early use of Anakinra alone or with glucocorticoids allows a prompt amelioration of the inflammatory and respiratory parameters, reducing the mortality rate in patients with severe COVID-19 pneumonia.

Familial Mediterranean fever (FMF) is characterized by self limited episodes of fever and polyserositis.1 MEFV gene en codes for a protein named Pyrin, which plays a pivotal role in the activation and secretion of IL-1.2 Daily colchicine is highly effective in preventing attacks in this disorder in a dose-related fashion.3 Many definitions of colchicine resistance are available in the literature. The European League Against Rheumatism (EULAR) guidelines defined resistance as one or more attacks per month in compliant patients who had been receiving the maxi mally tolerated dose for at least 6 months.4 A similar definition was confirmed by a recent consensus among experts.5 In the present national multicentric longitudinal study, we analyze the impact of colchicine treatment on disease activity and quality of life in real life in pediatric and adult patients with FMF.

Background:Colchicine is the standard treatment for Familiar Mediterranean Fever (FMF), however about 5% of patients experience colchicine resistance. There is no standard definition of colchicine resistance. Recently a panel of experts elaborated a new definition based on a Delphi consensus approach.Objectives:We aim to describe main features of the disease and clinical outcome of a cohort of FMF patients with particular interest on the colchicine resistance and tolerability according to the definitions proposed by the recent consensus.Methods:Since November 2009, 425 Italian pediatric and adult FMF patients (pts) from 13 centers were enrolled in a national longitudinal cohort study, using the international EUROFEVER registry. Demographic, genetic and clinical data, including response to treatment, were analyzed. Supplementary information on health related quality of life and treatment adherence was also collected by a specific questionnaire.Results:Complete information were available in 341 pts (189 M and 152 F, 211 children and 120 adults). The median age at disease onset was 5.0 years (1 m-59 y); the mean diagnostic delay was 8.7 y (range 0-61 y). The median age at enrollment was 12.1 y (range 3 m - 82 y). The MEFV genotype was the following: 103 (30.2%) pts carried biallelic pathogenic variants; 59 (17.3%) one pathogenic variants and one VOUS /LB variant; 27 (7.9%) had biallelic VOUS/LB variants; 97 (28.45%) were heterozygous for pathogenic variants; 30 (8.8%) were heterozygous for VOUS/LB, 25 (7.33%) were genetically negative.Colchicine treatment was used in 280 pts; during treatment, biologic treatment (anti-IL1) in 22 pts. 61 pts received NSAID or steroid on demand.We analyzed the behavior of the pts treated with colchicine according to the statements on colchicine resistance/intolerance defined by Ozen et al (1) (Table 1).Table 1.Adherence62% displayed a total adherence (> 90% of prescription); 10.8% a good adherence (50-89% of prescriptions); 1.9% poor adherence (< 50% of prescriptions); 0.9% no adherenceDose adjustment criteria/ Recommended maximum colchicine doseMean colchicine dose:Pts 5-10 year: 0.77mg/die (std. dev. 0.23)10-18 years: 1.1mg/die (std. dev. 0.39)Adults: 1.16 mg/die (std. dev. 0.37)Pts with a dose inferior to the minimum recommended dose5-10 years: 2.5%10-18 years: 15%Adults: 4%Resistance to ColchicineResistance was be defined as persistence of fever attacks, despite optimal treatment. 41.6% pts had a complete disease control32.8% Pts had < 1 episode/month for 3 months25.5% had ≥1 episode/month for 3 monthsInclusion of secondary amyloidosis in the definition of colchicine resistance5 adult pts (1.5%) displayed amyloidosisColchicine intolerance11 pts (3.2%) withdraw colchicine because of drug intolerancePatient quality of life and patient-reported outcomes20.7% of pts experience fatigue or chronic pain, 16.9% limitations in daily activities, and 16.9% have lost school/work days.Conclusion:Almost 58% of FMF pts display disease activity despite colchicine treatment. The treatment is generally under-dosed, especially in children. The adherence and the compliance to the treatment is generally good.References:[1]Ozen S et all. Recommendation on colchicine dosing and definition of colchicine resistance/intolerance in the management of FMF. Pediatric Rheumatology, 2019.Acknowledgments:This research was financial supported by Novartis AGDisclosure of Interests:Romina Gallizzi: None declared, Marta Bustaffa: None declared, Francesca Mazza: None declared, Diana Sutera: None declared, Giovanna Fabio: None declared, Laura Obici: None declared, Maria Alessio: None declared, Donato Rigante: None declared, Luca Cantarini: None declared, Antonella Insalaco: None declared, Marco Cattalini: None declared, Maria Cristina Maggio: None declared, Gabriele Simonini: None declared, Alma Nunzia Olivieri: None declared, Serena Pastore: None declared, Maddalena Lancieri: None declared, Nicolino Ruperto Grant/research support from: Bristol-Myers Squibb, Eli Lily, F Hoffmann-La Roche, GlaxoSmithKline, Janssen, Novartis, Pfizer, Sobi (paid to institution), Consultant of: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Speakers bureau: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Marco Gattorno Consultant of: Sobi, Novartis, Speakers bureau: Sobi, Novartis

Background Vaccine-preventable diseases are again emerging in our population after anti-vaccine campaign has started. In autoinflammatory diseases (AID), vaccine triggered-disease is a well known phenomenon for Hyper-IgD/Mevalonate-Kinase Deficiency (MKD). In CAPS, severe flares have been experienced after pneumococcus vaccine, while PFAPA patients did not achieve sufficient and protective levels of antibodies. This evidence has raised doubts in physicians and families about the safety of vaccines. Objectives To evaluate, in a cohort of italian AID, the vaccination coverage of the Italian Vaccination Schedule and the prevalence of adverse reactions and disease flares induced by vaccinations. Methods An anamnestic questionnaire was applied to AID patients refering to the AID Unit of the Istituto Giannina Gaslini from August 2017 to August 2018. Acquired data were revised for quality of information. Data about disease triggers in AID were obtained from the EUROFEVER registry for statistical reference. Results Triggers in AID Eurofever Registry: In august 2018 a total of 3783 patients were enrolled in the EUROFEVER registry (1908 female, 50,43%). The mean age of symptoms at disease onset was 7.04 +/- 9,48 SD yrs, (minimal 0 - maximum 75,92 yrs). The distribution among the periodic hereditary fevers was: 28,75% FMF (n=1081); 17,66% PFAPA (n=666); 9% Undefined inflammatory disease (UND n = 347); 7,85% CAPS (n=297); 7,16% TRAPS (n=271) and 5,39% MKD (n=204). Vaccines triggered the disease in 70% of the MKD, while PFAPA, TRAPS and UND had a rate of reactions of 20%. This was also found in 12.34% of CAPS, whereas FMF and inflammatory bone disorders had a rate of 6% and 3%, respectively. Excluding other causes of reactions, and isolating just vaccines as a cause, MKD had a higher percentage of reactions (7,14%), while PFAPA and UND had 1% and CAPS, TRAPS, FMF and inflammatory bone disorders had less than 1%. Triggers in IGG cohort: 150 questionnaires were distributed with 70% rate of response. Quality of data was 100% for coverage and adverse reactions. 105 patients were identified: PFAPA (n=26); CAPS (n=5); TRAPS (n=6); FMF (n=14); MKD (n=8); Inflammatory Bone Disorders (CRMO and PAPA, n=4) and UND (n=41). Rate of coverage was lower than 90% for Hib3 (83,11%), MMR/MMRV (88,9%) and for Rota C (1,85%). For DTP3, Hep3, PCV3 and IPV the rate of coverage was higher than 90% for all vaccines. 11 moderate/severe reactions were observed as following: 5 after DTPA+IPV (1 PFAPA; 2 TRAPS, 1 MKD and 1 UND); 1 after Hib (PFAPA); 1 after P10/13 (PFAPA); 4 after MPR (1 PFAPA, 1 TRAPS, 1 MKD and 1 UND). The general rate of severe reactions/shot was 6,36 for 1000 shots and no severe infection, death, persistent or significant disability or life-threatening condition was observed. Just one MKD patient had a severe disease flare requiring hospitalization following pneumococcal vaccine. Conclusion Data show that in AID patients vaccines may more frequently trigger the disease. Therefore, vaccination in AID may be cosidered a peculiar public health problem. Specific recommendations for vaccination in AID are warranted as well as further investigations for immunologic protection. References [1] Ter Haar, et al. The phenotype and genotype of mevalonate kinase deficiency.Arthritis Rheumatol. 2016 Nov;68(11):2795-2805. [2] Walker A, et al. Severe inflammation following vaccination against Streptococcus Pneumoniae in patients with cryopyrin-associated periodic syndrome.Arthritis Rheumatol. 2016 Nov;68(2):516-520. Disclosure of Interests Sara Signa: None declared, Caterina Matucci Cerinic: None declared, enrica toniolo: None declared, Marta Bustaffa: None declared, Matteo D’Alessandro: None declared, Stefano Volpi: None declared, Roberta Caorsi: None declared, Leonardo Oliveira Mendonca: None declared, Marco Gattorno Grant/research support from: MG has received unrestricted grants from Sobi and Novartis

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

The aim of this study was to investigate the possible effects of environmental factors such as temperature, rainfall, and light conditions on hair cortisol concentrations in foals during the perinatal period. The study, performed during three consecutive foaling seasons from January to July, enrolled 219 foals from one farm. Hair samples were collected from each foal immediately after birth and at 30 days of age, and the samples were analyzed by radioimmunoassay to measure the cortisol concentrations. The mean cortisol concentration of hair collected at 30 days of age was significantly (P < .01) lower than that found at birth, but none of the evaluated environmental factors (temperature, rainfall, or day length) influenced the hair cortisol concentrations.