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Abstracts from the ISSAID 2021 Periodic Congress

Abstracts from the ISSAID 2021 Periodic Congress Pediatric Rheumatology (2022) 20:2 https://doi.org/10.1186/s12969-021-00659-2 MEETING ABSTRACTS Open Access Abstracts from the ISSAID 2021 Periodic Congress Virtual. May - Dec 2021 Conclusion: The results showed that miR-30e-3p has an anti- Oral presentations inflammatory effect by regulating IL-1β expression, which is a key protein in inflammatory pathways. O01 The possible effect of miR-30e-3p which targets IL-1Β in the Acknowledgments pathogenesis of systemic autoinflammatory diseases 1 1 2 2 3 This project has been funded by the ERARE3 project (INSAID,003037603) and T. H. Akbaba , Y. Akkaya-Ulum , E. Batu , E. Sönmez , M. V. Gijn ,D. 4 5 2 1 The Technical and Scientific Research Council of Turkey, 315S096. Foell , M. Gattorno , S. Ozen , B. Balci-Peynircioglu 1 2 Medical Biology; Pediatric Rheumatology Unit, Hacettepe University, Disclosure of Interest Ankara, Turkey; University Medical Center, Utrecht, Netherlands; None Declared Department for Pediatric Rheumatology & Immunology, Muenster, Germany; Giannina Gaslini Institute (IRCCS), Genoa, Italy Correspondence: T. H. Akbaba O02 Pediatric Rheumatology 2021, 20(Suppl 1):O01 Number of episodes can be used as a disease activity measure in familial mediterranean fever Introduction: Systemic Auto Inflammatory Diseases(SAID) is a group 1 2 3 4 5 1 D. Piskin , Z. Arici , D. Konukbay , M. Romano , S. Ozen , K. Speechley ,E. of rare hereditary fever syndromes. Phenotypic heterogeneity among Demirkaya SAID patients is quite common, and epigenetic factors can be a 1 2 University of Western Ontario, London, Canada; Pediatric cause of these variable clinical profiles. MiRNAs take an active role in Rheumatology, Sanliurfa Research and Training Hospital, Sanliurfa; the regulation of inflammation. 3 4 University of Health Sciences, Ankara, Turkey; Pediatric Rheumatology, Objectives: This study aims to investigate the potential impact of University of Western Ontario, London, Canada; Pediatric miRNAs in autoinflammation. Rheumatology, Hacettepe University, Ankara, Turkey Methods: Expression levels of miRNAs in blood samples of 6 severe FMF Correspondence: D. Piskin and 7 mild FMF, 6 other rare SAIDs, and healthy controls were analyzed by Pediatric Rheumatology 2021, 20(Suppl 1):O02 miRNA array, bioinformatics tools and pathway analyzes related to inflam- matory pathways. The candidate miRNAs were functionally studied for ex- Introduction: Monitoring disease activity in Familial Mediterranean pression levels of inflammatory genes, caspase I activation, apoptosis, cell Fever (FMF) is essential to define disease effects on the general migration assays in SW982 cells. Then, 3'UTR luciferase activity experiments health and quality of life (QoL) of patients, to determine treatment were carried out to determine the target gene. Then, target gene expres- response, optimize disease follow-up and prevent complications. The sion studies were performed at both RNA and protein levels. Also, miR-30e- importance of monitoring disease activity and doing regularly are 3p was analyzed in a group (total of 44 patients) of European patients highlighted in the international recommendations for the manage- (Germany, Italy, and the Netherland). ment of autoinflammatory diseases. It is necessary to assess disease Results: The expression levels of miRNAs by miRNA array were activity easily in research and clinical practice. confirmed by qRT-PCR. miR-30e-3p was significantly reduced Objectives: To assess the validity of number of episodes as a feasible among patient groups. After pre-miR transfection of miR-30e-3p; stand-alone measure of disease activity in these patients, we developed expression levels of inflammatory genes (IL1β, IL18, TNFα,TGFβ) apriori predictions of expected associations that number of episodes in and apoptosis rates decreased, caspase I activation and cell mi- a year would have with particular PROMS based on the evidence in the gration rate decreased significantly (p <0.05). As a result of func- literature regarding observed associations with level of disease activity tional analysis, target gene studies were performed with miR-30e, in patients with FMF. Specifically, we predicted the following associa- which has an anti-inflammatory effect in all experimental systems. tions in children with FMF: functional status, quality of life, level of de- It has been shown that miR-30e is the direct target of the IL-1β pressive symptoms and perceived level of pain would be negatively gene. Expression of the IL-1β gene at RNA and protein levels de- associated with number of episodes in the past year. creased in pre-miR-30e-3p transfected cells. Also, miR-30e-3p was Methods: In this cross-sectional study, patients were recruited from decreased in a group of European SAID patients (Germany, Italy, the seven tertiary hospitals in Turkey. Demographic data, main and the Netherland). © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Pediatric Rheumatology (2022) 20:2 Page 2 of 39 clinical symptoms of the episodes, treatment modalities, and genetic admission period and all follow/up visits. For the purpose of this study, mutations were recorded. The patients were grouped as: no episodes we analyzed all patients with at least 3months of follow/up mainly fo- (Group 1), 1-4 episodes (Group 2), more than 4 episodes (Group 3) cusing on heart involvement. according to number of episodes in the past 12 months. The four- Results: Fifty-three patients who received MIS-C diagnosis between item Morisky Medication Adherence Scale (MMAS-4), Pediatric Qual- February 1st and May 31st 2020 were included in our study. The me- ity Life Inventory (PedsQL), Children's Depression Inventory (CDI) and dian age at diagnosis was 7 years (IQR 4,5-11). Forty-one patients Wong-Baker FACES pain rating scale (FACES) scores were compared showed cardiac involvement during the course of the disease. Treat- between groups. ment with IVIG was reported in 66% of patients at diagnosis and glu- Results: A total of 239 patients (male 44.4%, female 55.6%) were in- cocorticoids in 56,6%. Four patients received treatment with IL-1 cluded. There were 74 patients (31%) in Group 1, 99 patients (41.4%) in receptor antagonist (anakinra) and one with hydroxychloroquine. Use Group 2 and 66 patients (27.6%) in Group 3. Age at diagnosis, gender, of vasoactive agents was reported in 20,8% of patients. No case of consanguinity, family history and history of amyloidosis were not differ- death was reported in our population. ent among the groups (p>0.05). The main clinical symptoms were similar Data on cardiac outcome were available for 33 patients after a me- among the groups and also the groups were compared according to the dian time of follow-up of 6 months (IQR 7.2- 4.08). Twenty-eight out each item on the AIDAI symptom scale and there were no statistically sig- of 33 patients presented a cardiac involvement during hospitalization nificant differences among groups (p>0.05). Most of the patients (232 of for MIS-C: 17 had myocarditis, 5 had pericarditis, 3 coronary artery 239 patients, 97.1%) were treated with colchicine. Groups were similar in abnormalities, 8 heart failure, 9 valvular insufficiency, 11 shock or terms of M694V, and V726A allele frequency (p=0.843, p=0.46). For par- hypotension. For each patient cardiac outcome was assessed by ent and child PedsQL scale scores, patients in no episode group (Group heart ultrasonography. At the end of our follow-up period only four 1) had higher scores that means better HRQoL than Group 2, and Group patients still had heart abnormalities: all of them presented mild 2 had higher scores (better HRQoL) than Group 3. Both parent and child valvular insufficiency and 2 patients still had ultrasonographic signs MMAS scores were not different among the groups. In Group 3, patients of hypokinesia. None of them was on medication. have higher parent CDI scores than no episode (Group 1) group (p< Conclusion: MIS-C is an emerging inflammatory condition that spreads 0.001). Child CDI scores were significantly lower in Group 1 than Group 2 among the pediatric population in parallel to SARS-CoV2 pandemic. The (p=0.01), and in Group 2 than Group 3 (p=0.03). Both parent and child disease is frequently complicated by cardiological involvement but, dif- FACES scores were significantly lower in no episode group than Group 2, ferently to Kawasaki disease, myocarditis and shock are the most com- and patients in Group 2 lower than Group 3. mon complications. As we reported in our previous study, short-term Conclusion: In a homogeneous patient population in terms of demo- outcome is usually good in children with MIS- C and heart involvement. graphic features, mutation types, clinical symptoms, and treatment, With this study we also provide a long-term cardiac follow-up and we increasing number of episodes was associated with worst PedsQL, showed that only a minority of patients with previous cardiac involve- CDI, and FACES scores. We conclude that number of episodes is the ment presented minor heart abnormalities. Furthermore, no patients key element of disease activity in patients with FMF and can be used developed new heart disease during follow-up. as a single measure to assess disease activity. Acknowledgments Disclosure of Interest Francesca Biscaro: UOC Pediatria, Ospedale Ca’ Foncello, Treviso. Andrea None Declared Campana: Bambino Gesù Children’s Hospital, Rome, Italy. Rosa Maria Dellepiane: Pediatric Intermediate Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy. Angela Mauro: Department of O03 Paediatrics, Emergency Department, Santobono-Pausilipon Children’s Long-term cardiac outcome in patients with multisystem Hospital, Naples, Italy. Alesssandra Meneghel: Department of Woman’s and inflammatory syndrome in children (MIS-C) Child’sHealth, University of Padova, 2 Padua, Italy. Alma Olivieri: Dipartimento 1 2 3 4 5 S. Della Paolera , F. Zunica , D. Montin , G. Zuccotti , F. La Torre ,S. della donna, del bambino e di chirurgia generale e specialistica, Università 6 7 1,8 2 Mannarino , M. Fabi , A. Taddio , M. Cattalini della Campania, “L Vanvitelli, Napoli. Rita Sottile: Department of Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste; Paediatrics, Santobono-Pausilipon Children’s Hospital, Naples, Italy. Sara Pediatrics Clinic, ASST Spedali Civili di Brescia, University of Brescia , Stucchi and Barbara Teruzzi : Maternal and Child Health, Division of Brescia; Department of Pediatrics and Public Health, University of Turin, Paediatrics, ASST Grande Ospedale Metropolitano Niguarda, Milano, Turin; Department of Pediatrics, University of Milan, Children’s Hospital Italy. Tatiana Utytatnikova: Dipartimento Materno-Infantile, Pediatria, ASST V Buzzi, Milan; Pediatric Rheumatology Center, Pediatric Unit, “Giovanni Bergamo-EST, Seriate, Bergamo. Gianluca Vergine: UOC Pediatria, Ospedale XXIII” Pediatric Hospital, Bari; Division of Cardiology, Children's Hospital degli Infermi di Rimini, Rimini, Italy. V Buzzi, ASST FBF Sacco, Milan; Department of Pediatrics, University of Bologna, IRCCS Sant’Orsola-Malpighi Hospital, Bologna; University of Disclosure of Interest Trieste, Trieste, Italy None Declared Correspondence: A. Taddio Pediatric Rheumatology 2021, 20(Suppl 1):O03 O04 Introduction: Multisystem Inflammatory Syndrome in children (MIS- SARS-CoV2 ORF3a protein drives inflammation in COVID-19 C) was initially described during the first phase of COVID-19 pan- through NLRP3 inflammasome activation 1 1 1,2 1 1 1 demic as a severe clinical condition with systemic inflammation and A. Bertoni , F. Penco , H. Mollica , P. Bocca , I. Prigione , A. Corcione , 1 3 1 4 4 1,2 multi-organ involvement. Many patients show features of Kawasaki D. Cangelosi , A. Amaro , N. Paladino , E. Pontali , M. Feasi , S. Signa , 1 1 5,6 3 1,7 1 Disease. Cardiac involvement, from myocarditis to coronary abnor- M. Bustaffa , R. Caorsi , R. De Palma , U. Pfeffer , P. Uva , A. Rubartelli , 1 1,2 malities, is a key feature of the syndrome, but there are still little data M. Gattorno , S. Volpi on behalf of UOSD Centro per le Malattie concerning the long-term outcome in these patients. Autoinfiammatorie e Immunodeficienze 1 2 3 Objectives: The aim of our study was to evaluate long-term cardiac IRCCS Istituto Giannina Gaslini; DINOGMI, University of Genova; IRCCS outcome in patients diagnosed with MIS-C during the first phase of Ospedale Policlinico San Martino; Ente Ospedaliero Ospedale Galliera; 5 6 COVID-19 pandemic in Italy. IRCCS IST-Ospedale San Martino; Internal Medicine, University of Methods: We previously published the results of the Italian multicenter Genova; Italian Institute of Technology, Genova, Italy survey of MIS-C, launched by the Rheumatology Study Group of Italian Correspondence: S. Volpi Pediatric Society during the first wave of COVID-19 pandemic. For each Pediatric Rheumatology 2021, 20(Suppl 1):O04 patient who received MIS-C diagnosis, we collected demographic, clin- ical, laboratory data, imaging findings, and treatment information in an Introduction: COVID-19 severe pneumonia has been associated to sys- online anonymized database (RedCAP). Data collection included all the temic inflammation and elevation of blood parameters and reminiscent Pediatric Rheumatology (2022) 20:2 Page 3 of 39 of cytokine storm syndrome. Stimulation of PBMC from patients with phenotypes, to allow for earlier detection and therapeutic intervention. severe COVID-19 have shown a high secretion of IL-1β, a pivotal cyto- We also sought to determine the variant distribution amongst VEXAS kine driving inflammatory phenotypes, which maturation and secretion patients and compare with disease course to establish if a specific mu- is regulated by NLRP3 inflammasome. Steroidal anti-inflammatory ther- tation can be a biomarker of disease severity. apies have shown efficacy in reducing mortality in critically ill patients, Methods: To identify key phenotypic presentations of VEXAS that war- however the mechanisms by which SARS-CoV2 virus triggers such an rant genetic testing we compared the clinical characteristics of our first extensive inflammation remain unexplained. reported 25 patients and our newly identified additional 43 patients. Objectives: The overall objective of this study was to investigate if We performed Sanger sequencing and digital droplet PCR (ddPCR) to SARS-CoV2 drives inflammation in COVID-19 patients through NLRP3 detect and quantify mutation levels in our referred patients. inflammasome activation and IL-1β secretion. Results: After the initially reported clinical manifestations of VEXAS Methods: Samples from SARS-CoV2 infected patients, were collected (25 patients last year), 80 patients have been referred to our clinic at day 0 and at 3 and 7 following treatment with anakinra. Fresh based on clinical similarities to our first report. 43 new patients have monocytes, purified through adherence, were cultured for 3, 6, 18 h been identified with somatic mutations in UBA1, making our current in the presence or absence of LPS (100 ng/ml) and MCC950 (10μM). diagnostic rate 54%. The clinical characteristics of newly diagnosed Release of IL-1β, IL-1Ra, IL-6, TNF-α, IL-18 was quantified by ELISA kit. patients are highly consistent with the reported manifestations of Relative gene expression analysis of ORF3a gene was performed by the initial VEXAS cohort with some expanded phenotypes including RT-qPCR. THP-1 cells were transfected with a plasmid containing renal, neurologic and hematologic manifestations. We determined ORF3a sequence by nucleofection. NLRP3 inflammasome and ASC that patients with history of chondritis and MDS have a higher posi- speck formation were detected by confocal microscopy and/or by tivity rate than those with general systemic inflammation. Variant dis- FACS analysis. tribution in our expanded cohort is consistent with our initial report, Results: In the present study we show that circulating monocytes with threonine being the most common p.Met41 variant (56%) from COVID-19 patients display ASC specks, index of NLRP3 activa- followed by valine and leucine (26% and 18% respectively). 35% of tion, and spontaneously secrete IL-1β in vitro. This spontaneous acti- patients with the valine variant are deceased as compared to 16% vation reverts following patient’s treatment with the IL-1 receptor for other mutations, indicating that p.Met41Val may confer a more antagonist anakinra. Transfection of a monocytic cell line with cDNA severe phenotype. coding for the ORF3a SARS-CoV2 protein, resulted in NLRP3- Conclusion: Our 54% positivity rate indicates that the initially re- dependent ASC speck formation. The involvement of ORF3a in ported clinical manifestations are effectively identifying additional inflammasome activation was further supported by the detection by VEXAS patients. Through analyzing the symptoms of our larger co- RT-PCR of ORF3a in monocytes from COVID-19 patients. hort, we have further characterized the phenotype of this novel syn- Conclusion: In summary, these results provide a mechanistic explan- drome. Additionally, identifying the p.Met41Val variant as a marker ation for the strong inflammatory manifestations associated to of severe disease may offer more accurate prognosis and the possi- COVID-19 and further evidence that NLRP3 and IL-1β targeting could bility for earlier intervention. Together, this work provides further in- represent an effective strategy in this disease. sights into VEXAS syndrome with the goal of increasing diagnosis and improving management Acknowledgments We thank the patients and their families for their willingness to participate in Acknowledgments our study, the service of Immunohematology and transfusion medicine of We would like to sincerely thank all the patients and their families involved Gaslini Institute for the collection of biological samples and the Laboratory in our continued studies for their incredible contributions. Core Facility of Gaslini Institute for support for confocal analysis. SV received financial support from AMRI, “associazione malattie reumatiche infantili”. IRCC Disclosure of Interest S G Gaslini is members of the European Reference Network for Rare None Declared Immunodeficiency, Autoinflammatory and Autoimmune Diseases -Project ID No 739543. This work was developed within the framework of the DINOGMI Department of Excellence of MIUR 2018-2022 O06 Adult-onset autoinflammation caused by somatic mutations in Disclosure of Interest UBA1: a Dutch case series of VEXAS patients None Declared This abstract has not been included here as it has been previously published O05 O07 Defining clinical and genetic hallmarks of VEXAS syndrome 1 1 2 1 Short-term follow-up results of children with familial D. Ospina Cardona , L. L. Wilson , M. A. Ferrada , A. K. Ombrello ,P.C. 2 1 1 1 mediterranean fever after cessation of canakinumab Grayson , I. Aksentijevich , D. B. Beck , D. L. Kastner 1 2 1 2 3 4 5 6 B. Sözeri , H. E. Sönmez , S. Karadağ , E. Baglan , K. Öztürk , M. Çakan ,F. National Human Genome Research Institute; National Institute of 1 7 4 8 Demir , G. Otar Yener , S. Özdel , N. Ayaz Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, Department of Peditarics, Division of Rheumatology, Umraniye Research United States and Training Hospital, Istanbul; Department of Peditarics, Division of Correspondence: D. Ospina Cardona Rheumatology, Kocaeli University, Kocaeli; Department of Peditarics, Pediatric Rheumatology 2021, 20(Suppl 1):O05 Division of Rheumatology, Sadi Konuk Research and Training Hospital, Istanbul; Department of Peditarics, Division of Rheumatology, Sami Ulus Introduction: VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflamma- Research and Training Hospital, Ankara; Department of Peditarics, tory, Somatic) syndrome is a late-onset, autoinflammatory disorder Division of Rheumatology, Istanbul Medeniyet University Göztepe discovered last year through shared genetic variants as opposed to Research and Training Hospital; Department of Peditarics, Division of shared clinical descriptions. VEXAS is caused by hematopoietic, som- Rheumatology, University of Health Science, Zeynep Kamil Maternity atic mutations in the X-chromosomal UBA1 (ubiquitin activating en- and Children’s Diseases Research and Training Hospital, Istanbul; zyme 1) gene encoding the primary E1 enzyme of the essential Department of Peditarics, Division of Rheumatology, Şanlıurfa Research ubiquitylation pathway. VEXAS patients share variants in the UBA1 and Training Hospital, Şanlıurfa; Department of Peditarics, Division of gene while displaying broad clinical heterogeneity in disease severity Rheumatology, Istanbul University, Istanbul, Turkey and onset. Correspondence: H. E. Sönmez Objectives: We aimed to further elucidate the clinical features that are Pediatric Rheumatology 2021, 20(Suppl 1):O07 predictive of VEXAS syndrome through analyzing new patient Pediatric Rheumatology (2022) 20:2 Page 4 of 39 Introduction: Familial Mediterranean fever (FMF) is a systemic autoin- O08 flammatory disease manifesting with recurrent attacks of serositis ac- Traditional laboratory parameters and new biomarkers in companied by fever, usually lasting 12-72 hours. Although colchicine Macrophage Activation Syndrome (MAS) and Secondary has dramatically improved the quality of life in majority of the pa- Hemophagocytic Lymphohistiocytosis (SHLH) 1 1 1 1 1 tients by resolving attacks, unfortunately, it is ineffective in 5–10% of A. De Matteis , D. Pires Marafon , I. Caiello , M. Pardeo , G. Marucci ,E. 1 2 3 4 5 6 patients with FMF. Sacco , F. Minoia , F. Licciardi , A. Miniaci , I. Maccora , M. C. Maggio ,G. 1 1 1 Objectives: The aim of this study was to investigate the efficacy and Prencipe , F. De Benedetti , C. Bracaglia safety o canakinumab (CAN) in patients with colchicine-resistant (cr) Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, FMF and to report our experience on cessation of CAN in crFMF Roma; Pediatric Rheumatology, Fondazione IRCCS Ca’ Grande Ospedale patients. Maggiore Policlinico, Milano; Department of Pediatrics and Infectious Methods: This is an observational retrospective cohort study includ- Diseases, School of Medicine, University of Turin, Regina Margherita ing crFMF patients treated with CAN for at least 6 months. Data of Children’s Hospital, Torino; Department of Pediatrics, University of st rd th th th 5 the patients were recorded at treatment onset, 1 ,3 ,6 ,12 ,18 , Bologna, S. Orsola-Malpighi Hospital, Bologna; Pediatric Rheumatology th 6 and 24 months. Unit, Meyer Children's University Hospital, Firenze; University Results: A total of 114 patients followed up 2736 person-months Department Pro.Sa.M.I. “G. D’Alessandro”, University of Palermo, Palermo, were included in the study. During the 24-month follow-up, drug Italy interval was not changed in 44 patients. Injection intervals were ex- Correspondence: A. De Matteis tended in 58 patients within a median of 6 (3-18) months. Of these Pediatric Rheumatology 2021, 20(Suppl 1):O08 58 patients, 4 patients had a new attack after the prolongation of th dose interval. CAN was ceased in 12 patients (5 at 12 month, 7 at Introduction: Macrophage Activation Syndrome (MAS) and Second- th 18 month), two of whom experienced a new attack within 3 ary Hemophagocytic Lymphohistiocytosis (sHLH) are hyperinflamma- months. CAN was restarted and applied every 8 weeks. The tory conditions caused by a cytokine storm, in which IFNγ plays a th remaining 10 patients did not report any symptom at the 24 pivotal role. Prompt recognition and early treatment are essential to month. The median attack-free period under CAN treatment was 669 improve the high disease mortality. (95% confidence interval: 644-696) days (Table 1). Methods: Routine laboratory parameters of disease activity and se- Conclusion: Cessation of CAN or extended drug intervals may be verity were collected from a cohort of 103 patients, 41 sHLH, 40 MAS feasible in crFMF. The real life experience may provide clinicians to in the context of sJIA, and 22 sJIA without MAS, from 6 Italian cen- create standardized treatment approaches for these patients. ters. The samples were collected at three different time points: active disease (T0), 7-10 days from starting therapy (T1) and in clinical in- Acknowledgments active disease on medication (from 1 to 3 months from onset) (T2). None Serum levels of the IFN-γ related biomarkers (CXCL9, CXCL10, Neop- terin) and IL-18 were measured at each time points by ELISA. Disclosure of Interest Results: 367 samples were collected from the three groups of pa- None Declared tients in the three different time points. Thirty-eight patients with sHLH (92.7%) met the HLH-2004 diagnostic criteria while 34 patients with MAS (85.0%) met the 2016 classification criteria for MAS. Fever was present in the majority of patients (96%), while hepato- megaly and/or splenomegaly were observed more frequently in MAS Table 1 (abstract O07). Assessment of drug response in the patients and sHLH patients (76.9% and 82.9% respectively) compared to sJIA with colchicine resistant familial Mediterranean fever (36.8%). Laboratory characteristics at T0 are detailed in table 1. Using the st rd th th th th Baseline 1 month 3 month 6 month 12 month 18 24 month 2016 classification criteria for MAS, in our cohort we can confirm that (n=114) (n=114) (n=114) (n=114) (n=114) month (n=114) (n=114) platelet count is a specific parameter, only 4 patients with sJIA had a PGA* 8 (5-10) 1 (0-10) 0 (0-5) 0 (0-5) 0 (0-3) 0 (0-5) 0 (0-3) value <181x10 /liter; while ferritin is a sensitive parameter, 94.2% of CRP* 16.2 (11- 0.65 (0.02- 0.2 (0-15.8) 0.7 (0-68) 0.5 (0-24.9) 0.3 (0-41) 0.3 (0.16.1) patients with MAS had ferritin >684 mg/ml. Moreover, we have 31) 58.6) found that lactate dehydrogenase (LDH) values were statistically SAA* 89 (2.9- 3.9 (0-17) 4 (0-23) 3.3 (0-70) 3.6 (0-152) 3 (0-42) 3 (0-24) higher in MAS and sHLH groups compared to sJIA. ROC curve of LDH 1870) values in MAS group showed a statistically significant area under the Dose interval of CAN 4 (4-8) 4 (4-8) 4 (4-8) 6 (4-8) 6 (4-8) 8 (4-12) 8 (4-12) (weeks) 4 weeks 4 weeks in 4 weeks in 4 weeks in 66 4 weeks in 50 4 weeks in 4 weeks in 39 curve (AUC= 0.78, p-value <0.0001). A cut-off of 681 U/L had a sensi- in 94 94 94 6 weeks in 21 6 weeks in 21 45 6 weeks in 25 8 weeks 8 weeks in 8 weeks in 8 weeks in 27 8 weeks in 41 6 weeks in 8 weeks in 38 tivity of 72.6% and a specificity of 69.2%. in 20 20 20 12 weeks in 2 21 No drug in 12 8 weeks in CXCL9, CXCL10, neopterin and IL-18 values in T0 were significantly higher in MAS and sHLH patients compared to sJIA. Furthermore IL- 12 weeks in 18 in MAS was significantly high than in sHLH group (p<0.0001). The No drug in ROC curves performed for each biomarker showed a statistically sig- Dosage of CAN (mg/kg) 2-4 mg/ 2-4 mg/kg 2-4 mg/kg 2-4 mg/kg 2-4 mg/kg 2-4 mg/kg 2-4 mg/kg nificant AUCs (p<0.01), except for IL-18 in sHLH group. We have iden- kg tified a cut off value for each biomarker in MAS (CXCL9 900 pg/ml, Number of patients NA 0 2 1 5 4 2 CXCL10 280 pg/ml, Neopterin 6.0 ng/ml, IL-18 78,000 pg/ml) and experienced attacks sHLH (CXCL9 1,900 pg/ml, CXCL10 270 pg/ml, Neopterin 8.0 ng/ml). Number of patients NA 0 2 0 2 (recurrent 4 (recurrent 2 (recurrent requiring higher dose or (recurrent attacks) attacks) attacks, CAN CXCL9, CXCL10, neopterin and IL-18 levels lowered progressively at shortening drug interval attacks) (shortened was restarted) from 8 to T1 with a normalization in T2. CXCL9 decreased faster compared to 6 weeks neopterin, similarly to the decrease of routine laboratory parameters. Number of patients NA 0 7 patients 16 patients 5 patients 6 patients NA Conclusion: Our results confirm that platelet count and ferritin are whose prolonged drug (prolonged (prolonged (prolonged (prolonged interval from 4 to 8 from 4 to 8 from 4 to 8 from 4 to 8 two relevant laboratory parameters, with high specificity and sensitiv- weeks) weeks) weeks) weeks) 21 patients 2 patients 1 patient ity, respectively, to diagnose MAS in the context of sJIA. Even if LDH (prolonged (prolonged (prolonged from 4 to 6 from 8 to 12 from 8 to 12 is not included in 2016 classification criteria for MAS in sJIA, we have weeks) weeks) weeks) found that this parameter could help to discriminate MAS in sJIA, in Number of patients 0 0 0 0 5 patients 7 patients 0 addition to the others. Moreover, our results confirm that the IFN-γ discontinued CAN related biomarkers and IL-18 are significantly high in patients with Number of infections NA 1 1 (upper 0 0 0 2 (upper (pneumonia) respiratory respiratory MAS and sHLH and might be useful for diagnosis in addition to the tract tract infection) infection) traditional laboratory parameters. As already reported, IL-18 could be Number of adverse event NA 0 0 0 0 0 0 also useful to distinguish sHLH from MAS. Moreover, these Pediatric Rheumatology (2022) 20:2 Page 5 of 39 biomarkers seem to be helpful to monitor clinical evolution and extracellular Adenosine, inducing TNFα secretion from Macrophages treatment response. stimulated by NETs, has been implicated in the pathogenesis of DADA2. Objectives: The aim of the project is to dissect NETosis directly in Disclosure of Interest neutrophils isolated from DADA2 patients and healthy controls (HDs), A. De Matteis: None Declared, D. Pires Marafon: None Declared, I. Caiello: and to quantify suicidal and vital NETosis induced by several stimuli None Declared, M. Pardeo: None Declared, G. Marucci: None Declared, E. (PMA, Adenosine, LPS) using a multispectral Imaging Flow Sacco: None Declared, F. Minoia: None Declared, F. Licciardi: None Declared, Cytometry. To determine if NET epitopes can change depending A. Miniaci: None Declared, I. Maccora: None Declared, M. C. Maggio: None from the inflammatory microenvironment and if protein composition Declared, G. Prencipe: None Declared, F. De Benedetti Consultant for: Abbvie, of NETs is disease specific, we used quantitative proteomics SOBI, Novimmune, Novartis, Roche, Pfizer, Employee of: SOBI, C. Bracaglia approach to characterize NET proteins, released from neutrophils Consultant for: SOBI and Novartis after different stimuli in DADA2 patients, HDs and nongenetic Table 1 (abstract O08). Laboratory parameters in T0. Values are shown vasculitis. Moreover we investigated the mechanisms of NETs as median (IQR); p-value: Mann-Whitney U test removal, quantifying DNAse in the plasma samples. Methods: We analyzed and quantified NETosis by Imaging Flow Citometry (IFC): neutrophils isolated from peripheral blood were MAS sHLH sJIA MAS MAS sHLH stimulated in vitro to induce NETosis and were analyzed in the (N=52) (N=48) (N=40) vs vs vs sJIA ImageStreamXMark II IFC equipped with a MultiMag system. We sHLH sJIA evaluated also NETs remnants and DNAse in the plasma samples by Ferritin (ng/ 4,593 (1,770- 4,098 728 (335- 0.72 < < ELISA assay. LC-MS/MS analyses were conducted on Orbitrap Fusion ml) 10,842) (2,075- 2,786) 0.0001 0.0001 Tribrid mass spectrometer and NET protein quantification was carried 16,867) out using Label-Free Quantification method. Platelet 200 (114- 97 (47- 449 (275- 0.0003 < < Results: Neutrophils from DADA2 show a significant increased count 310) 184) 559) 0.0001 0.0001 suicidal NETosis, identified as nuclear decondensation and (x10^9/l) Myeloperoxidase (MPO) colocalization with DNA, following PMA AST (U/L) 86 (51-149) 150 (51- 33 (23-46) 0.07 < < stimulation and we observed an increase also with LPS and 340) 0.0001 0.0001 Adenosine. Then we analyzed vital NETosis, identified as elongated shape of cells, nuclei polarized within the cell and not colocalized Triglycerides 188 (148- 226 (166- 108 (78- 0.11 < < with MPO and we found an increased vital NETosis in DADA2 (mg/dl) 286) 381) 140) 0.0001 0.0001 neutrophils. Accordingly, plasmatic levels of circulating nucleosomes Fibrinogen 330 (225- 228 (137- 565 (441- 0.0018 < < (NET remnants) were elevated in patients, whereas DNAse levels (mg/dl) 437) 331) 691) 0.0001 0.0001 were normal. We set up experimental conditions for proteomic LDH (U/L) 975 (666- 1,255 (701- 599 (407- 0.11 < < analysis of NETs, induced by PMA, Adenosine and TNFα, testing two 1,446) 2,748) 724) 0.0001 0.0001 patients, HDs and patients with nongenetic vasculitis: in total we identified 1770 proteins among which a hundred of proteins were CXCL9 (pg/ 1,728 (798- 4,159 300 (300- 0.15 0.0010 < significantly up or down-modulated in DADA2 NETs compared to ml) 1,1507) (1,880- 1,989) 0.0001 10,016) controls NETs. Conclusion: Our findings demonstrate that neutrophils of DADA2 CXCL10 (pg/ 905 (229- 729 (235- 150 (150- 0.82 < < patients are prone to undergo NETosis and that inflammation ml) 2,646) 3,042) 452) 0.0001 0.0001 mediators such as Adenosine or TNFa in this disease can modify this Neopterin 9.4 (4.9-16.0) 20.3 (9.6- 4.3 (3.0- 0.0023 < < pathogenic process. (ng/ml) 35.0) 7.4) 0.0001 0.0001 Disclosure of Interest IL-18 (pg/ml) 159,833 13,640 36,764 < < 0.16 (50,000- (2230- (8,958- 0.0001 0.0001 None Declared 250,000) 83,909) 82,714) O10 O09 Next generation sequencing based multiplex long-range PCR for Dissecting netosis in adenosine deaminase 2 Deficiency (DADA2) routine genotyping of autoinflammatory disorders patients 1 2 3 4 4 This abstract has not been included here as it has been previously F. Schena , S. Signa , G. Del Zotto , M. Bartolucci , A. Petretto ,R. 5 6 1,7 published Bertelli , R. Caorsi , M. Gattorno Centre for Autoinflammatory Diseases and Immunodeficiencies, IRCCS 2 3 Giannina Gaslini Institute; DINOGMI , University of Genoa; Core O11 Facilities Flow Cytometry and Cell imaging Lab; Core Facilities-Clinical 5 6 Gene therapy for IL-1-mediated systemic autoinflammatory Proteomics and Metabolomics; Laboratory of Human Genetics; Second diseases Pediatric Division and Centro Malattie Autoinfiammatorie e 1,2 1 1 1,3 M. Colantuoni , R. Jofra Hernandez , E. Pettinato , M. Zoccolilllo ,L. Immunodeficienze; Second Pediatric Division, IRCCS Giannina Gaslini 2 1 1 1 1,2 Magnani , L. Basso-Ricci , S. Scala , L. Sergi Sergi , A. Kajaste-Rudnitski , Institute, Genoa, Italy 1,2 1,2,4 1 L. Naldini , A. Aiuti , A. Mortellaro Correspondence: F. Schena San Raffaele Telethon Institute for Gene Therapy (SR TIGET), IRCCS San Pediatric Rheumatology 2021, 20(Suppl 1):O09 Raffaele Scientific Institute; Vita-Salute San Raffaele University; 3 4 Department of Medicine and Surgery, Tor Vergata University; Pediatric Introduction: Deficiency of Adenosine deaminase 2 is a monogenic Immunohematology and Bone Marrow Transplantation Unit, IRCCS San autoinflammatory disorder presenting a broad spectrum of clinical Raffaele Scientific Institute, Milan, Italy manifestations, including vasculitis, immunodeficiency and hematologic Correspondence: M. Colantuoni disease. The genetic mutations in ADA2 gene have been associated to an Pediatric Rheumatology 2021, 20(Suppl 1):O11 insufficient ADA2 activity leading to reduction in deamination of adenosine to deoxyadenosine, and a consequent accumulation of extracellular Introduction: Systemic autoinflammatory diseases (SAIDs) delineate a adenosine. The pathogenic mechanisms investigated so far have elucidated group of clinical entities caused by an anomaly of the innate a skewed polarization from the M2 macrophage subtype to the immune response that includes rare periodic fever syndromes proinflammatory M1 subtype with an increased production of characterized by uncontrolled production of the proinflammatory inflammatory cytokines (TNF-α, Interferon IFN). More recently a chronic cytokine interleukin-1 (IL-1). Patients suffering from these conditions neutrophil activation and a dysregulation of NETosis, as process induced by Pediatric Rheumatology (2022) 20:2 Page 6 of 39 experience severe and recurrent inflammation ranging from fevers to O14 gradual hearing loss, blindness, and organ failure due to amyloid ac- Systemic juvenile idiopathic arthritis associated lung disease in cumulation. Conventional therapy includes anakinra, the recombin- Europe 1 2 ant form of the IL-1 receptor antagonist (IL-1RA), but it has a short C. Bracaglia on behalf of MAS/sJIA Working Party of PReS, F. Minoia ,C. 3 4 1 1 5 6 half-life, poor tissue distribution, and some patients respond poorly. Kessel , S. Vastert , M. Pardeo , A. Arduini , O. Basaran , N. Kiper ,M. 7 8 9 10 11 Besides being a lifelong therapy, this treatment is no definitive cure Kostik , M. Glerup , S. Fingerhutova , R. Caorsi , A. Horne ,G. 2 3 12 13 14 for these patients. Filocamo , H. Wittkowski , M. Jelusic , J. Anton , S. Khaldi-Plassart ,A. 14 9 15 5 1 Objectives: Here, we propose a gene therapy approach based on Belot , P. Dolezalova , A. Ravelli , S. Ozen , F. De Benedetti on behalf autologous hematopoietic stem cells transduced with a lentiviral of MAS/sJIA Working Party of PReS vector expressing IL-1RA. Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Methods: Mouse HSPCs were transduced either with a purified Roma; Fondazione IRCCS Ca' Grande Ospedale Maggiore Policlinico, human IL-1RA or GFP (control) lentiviral vectors (LV). The transduc- Milano, Italy; Department of Pediatric Rheumatology & Immunology, tion efficiency, IL-1RA production, clonogenic potential, and growth WWU Medical Center (UKM), Muenster, Germany; Pediatric rate of HSPCs were analysed and compared after the transduction. Rheumatology & Immunology, University Medical Center Utrecht, Bone marrow (BM) chimeric mice were generated by transplanting Utrecht, Netherlands; Department of Pediatrics, Division of Pediatric transduced (IL-1RA-LV or GFP-LV) C57BL/6 Ly5.1 lineage-negative Rheumatology, Hacettepe University; Department of Pediatrics, Division cells into congenic C57BL/6 Ly5.2 mice. Engraftment level and im- of Pediatric Pulmonology, Hacettepe University, Ankara, Turkey; Saint- mune cell reconstitution were assessed by flow cytometry. IL-1RA Petersburg State Pediatric Medical University, Saint-Petersburg, Russian and GFP chimeras were injected intraperitoneally with MSU crystals Federation; Department of Pediatrics, Aarhus University Hospital, to induce IL-1 mediated inflammation. After 6 hours, peritoneal cells Aarhus, Denmark; Paediatric Rheumatology and Autoinflammatory were collected, and the percentage of neutrophils (CD11b+Ly6G+ Diseases Unit, General University Hospital, Prague, Czech Republic; cells) was determined by flow cytometry. BM-derived mouse den- Department of Pediatrics and Rheumatology, IRRCS Istituto G. Gaslini, dritic cells (BMDCs) and human monocyte cell line THP1 were trans- Genova, Italy; Department of Pediatric Rheumathology Karolinska duced with IL-1RA LV, untransduced cells were used as control. University Hospital and Department of pediatrics, Karolinska Institute, Inflammasome mediated-cytokines production was measured by Stockholm, Sweden; Department of Paediatrics, University of Zagreb qRT-PCR and by ELISA. School of Medicine, Zagreb, Croatia; Pediatric Rheumatology, Hospital Results: LV-mediated IL-1RA gene transfer in mouse HSPCs did Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain; Pediatric not alter progenitor cells’ clonogenic capacity as IL-1RA trans- Nephrology, Rheumatology, Dermatology Unit, Hôpital Femme Mère duced HSPCs proliferated and differentiated similarly to GFP Enfant, Hospices Civils de Lyon, Lyon, France; IRRCS Istituto Giannina transduced HSPCs in vitro. There was a direct correlation between Gaslini and Università degli Studi di Genova, Genova, Italy vector-dose and IL-1RA levels in HPSC-derived supernatants. In IL- Correspondence: C. Bracaglia 1RA chimeras, HSPC transduction with IL-1RA-LV led to robust Pediatric Rheumatology 2021, 20(Suppl 1):O14 and sustained IL-1RA levels in plasma. Supraphysiological expres- sion of IL-1RA did not impact the engraftment and the clono- Introduction: Chronic parenchymal lung disease (LD) is a new genic potential of HSPCs in vivo. Full immune reconstitution of emerging severe life-threatening complication of sJIA. The number of lineage-committed cells was achieved in mice that received IL- sJIA patients with LD is apparently increasing and interestingly it is 1RA-transduced HSPCs. LV-derived IL-1RA production efficiently reported more frequently in North America. Data regarding fre- suppressed neutrophilic infiltration in a mouse model of IL-1- quency and features of sJIA-LD in Europe are not available. mediated peritonitis. Additionally, in vitro IL-1RA transduction of Objectives: To evaluate the burden of sJIA-LD in Europe. BMDCs and THP1 resulted in a reduced production of inflamma- Methods: Patients with diagnosis of sJIA with LD, including tory cytokines compared to control cells. pulmonary alveolar proteinosis (PAP), interstitial lung disease (ILD) Conclusion: We have successfully generated an LV delivering and as pulmonary arterial hypertension (PAH), followed in European steady IL-1RA release in mouse HSPCs in vitro and in vivo.Gene paediatric rheumatology centres were identified through a survey transfer of IL-1RA in mouse HSPCs resulted in long-term sent to the members of the MAS/SJIA Working Party. hematopoietic reconstitution and decreased IL-1-mediated inflam- Results: Data from 28 sJIA-LD patients, diagnosed in 12 European mation in an acute peritonitis mouse model, suggesting that this paediatric rheumatology centres between 2005 and 2020, were col- approach is safe and well tolerated. On-going studies investigate lected. Twenty-seven patients were Caucasian and 1 African- whether IL-1RA-LV HSPC gene therapy transduction suppresses American, 16 were female, the median age at sJIA onset was 6 years the exaggerated IL-1 activity in cells from patients and a mouse and LD onset occurred after a median time of 2.8 years. Sixteen pa- model recapitulating SAIDs phenotype. tients had a chronic persistent sJIA disease course, 11 had a polycyc- lic course and only 1 patient had a monocyclic course; 25 (89%) had Disclosure of Interest active sJIA at time of LD diagnosis. During the disease course, 22 None Declared (78%) patients developed MAS, 10 (35%) of whom had MAS at sJIA onset and 15 (54%) had full-blown MAS at time of LD diagnosis; 17 (77%) patients had >1 MAS episode. Twenty-two (78%) patients were O12 treated with at least one IL-1 or IL-6 inhibitor before LD diagnosis: 18 Application of systems biology-based in silico tools to optimize with anakinra, 13 with canakinumab and 10 with tocilizumab. Eleven treatment strategy in Still’s disease (39%) patients experienced drug adverse reaction to a cytokine in- This abstract has not been included here as it has been previously hibitor: 8 to tocilizumab and 3 to anakinra. Twenty-one (75%) pa- published tients developed ILD, 5 (18%) PAP and 3 (11%) PAH. 13 (46%) patients presented acute digital clubbing; 11 (39%) patients devel- oped hypoxia and 6 (21%) developed pulmonary hypertension. A O13 chest CT scan was performed in all patients with evidence of septal Disease flares in CANDLE/PRAAS with dose reductions of thickening and peri-bronchovascular thickening in the majority of pa- baricitinib tients (22 and 15 respectively). In 14 patients a bronchoalveolar lav- This abstract has not been included here as it has been previously age was performed and 11 underwent a lung biopsy. The published histopathological pattern was alveolar proteinosis in 4 patients, Pediatric Rheumatology (2022) 20:2 Page 7 of 39 endogenous lipoid pneumonia in 3, vasculitis in 1 and fibrosis in 1. Conclusion: TCZ improved fever and inflammatory response in Most of the patients (93%) were treated with glucocorticoids (GCs) at VEXAS-RP and allowed steroid reduction. Future studies are needed time of diagnosis, and 24 (86%) received IL-1 or IL-6 inhibitor after to verify its safety with long-term use and its effects on the diagnosis (18 anakinra, 12 canakinumab, 14 tocilizumab). Twelve hematological abnormalities and structural changes in chondritis. (43%) patients required ICU admission and 4 (14%) died. Conclusion: Lung involvement is an emerging life-threatening com- Disclosure of Interest plication of sJIA in Europe, particularly in patients with a history of None Declared MAS, and a prompt recognition is crucial. New strategies are needed Table 1 (abstract O15). Clinical features of the VEXAS syndrome to reduce the risk and improve outcome of this complication. patients with RP using TCZ Disclosure of Interest Patient ID RP13 RP15 RP16 C. Bracaglia Consultant for: SOBI, Novartis, F. Minoia Consultant for: SOBI, C. Age at 66.3 73.5 66.6 Kessel Consultant for: SOBI, Novartis, S. Vastert Consultant for: SOBI, Novartis, diagnosis M. Pardeo: None Declared, A. Arduini: None Declared, O. Basaran: None (years) Declared, N. Kiper: None Declared, M. Kostik: None Declared, M. Glerup: None UBA1 variants c.122T>C: p.Met41Thr c.122T>C: c.121A>C: p.Met41Leu Declared, S. Fingerhutova: None Declared, R. Caorsi Consultant for: Novartis, p.Met41 p.Met41Thr Lilly, A. Horne: None Declared, G. Filocamo Consultant for: SOBI, H. Wittkowski: None Declared, M. Jelusic : None Declared, J. Anton Grant Clinical High-grade fever, skin High-grade High-grade fever, skin /Research support from: Sobi, Novimmune, Novartis, abbvie, Pfizer, GSK, findings at rash, RP, scleritis, fever, skin rash, rash, GCA, RP, MDS, Roche, Amgen, Lilly, BMS, Sanofi, Consultant for: Sobi, Novimmune, Novartis, diagnosis peritonitis, pericarditis, RP, macrocytic DVT, scleritis, airway meningitis anemia involvement Pfizer, GSK, Speaker bureau of: Sobi, Novimmune, Novartis, GSK, Pfizer, S. Khaldi-Plassart: None Declared, A. Belot: None Declared, P. Dolezalova: None Treatments PSL PSL, MTX PSL, AZP, colchicine Declared, A. Ravelli Consultant for: AbbVie, Novartis, Pfizer, Angelini, Reckitt before TCZ Benkiser, S. Ozen Consultant for: SOBI, Novartis, Pfizer, F. De Benedetti Symptoms High-grade fever, Low-grade High-grade fever, skin Employee of: SOBI, Novimmune, Novartis, Roche, Pfizer existed at TCZ myalgia, headache fever rash, RBC and PLT induction* transfusion- dependence PSL dose 9 mg 22.5 mg 30 mg O15 before TCZ Tocilizumab for VEXAS syndrome with relapsing polychondritis: administration extension study Y. Kunishita, Y. Kirino, N. Tsuchida, A. Maeda, L. Hirahara, H. Nakajima PSL dose at 1 mg 12.5 mg 12.5 mg Department of Stem Cell and Immune Regulation, Yokohama City last visit University Graduate School of Medicine, Yokohama, Japan Duration of 12.0 months 6.3 months 7.1 months Correspondence: Y. Kunishita TCZ Pediatric Rheumatology 2021, 20(Suppl 1):O15 administration at last visit Introduction: Recently, VEXAS syndrome, a severe autoinflammatory Symptoms None None RBC transfusion- disease in adults caused by UBA1 somatic mutations, has been existed after 6 dependence, mild skin reported. In addition to systemic inflammatory pathology, VEXAS months rash syndrome is associated with hematological abnormalities such as RP; relapsing chondritis, GCA; giant-cell arteritis, Hb; hemoglobin, DVT, deep myelodysplastic syndrome, making it difficult to treat in clinical vein thrombosis; MDS, myelodysplastic syndrome; PSL, prednisolone; MTX; practice and forcing patients to continue moderate or higher doses methotrexate, AZP, azathioprine; TCZ, tocilizumab, RBC; red blood cells, PLT: of steroids. Therefore, there is an unmet need to develop therapies platelets, * symptoms existed during the past 1 month before TCZ induction that can reduce steroids and improve prognosis in VEXAS syndrome. Objectives: To identify promising therapeutic targets and therapies O16 for VEXAS syndrome. Genetic and immunologic characterization of male and female Methods: Patients with clinically diagnosed relapsing polychondritis patients with nemo-deleted exon 5 autoinflammatory syndrome (RP) in our department and known UBA1 mutations identified by 1 1 2 1 1 1 A. A. de Jesus , B. Lin , E. Karlins , D. Kahle , A. Rastegar , J. Mitchell ,S. Sanger sequencing (VEXAS-RP), who had been introduced to 1 1 1 1 1 Torreggiani , F. Bhuyan , S. Alehashemi , K. Cetin Gedik , K. Uss , C.-C. tocilizumab (TCZ), an IL-6 receptor antibody, were included in the 3 4 4 4 5 6 Lee , H. Kuehn , S. Rosenzweig , K. Calvo , M. Walkiewicz , J. Lack ,E. study. Clinical information and laboratory findings were collected retro- 7 8 9 10 11 11 Hanson , A. Khojah ,E.Wu , C. Scott , T. R. Leahy , E. MacDermott ,O. spectively from electronic medical records to validate the efficacy of 11 12 13 14 15 Kileen , T. Arkachaisri , Z. Gucev , K. Cook , V. Mamadova ,G. TCZ. Fractional abundance of UBA1 variant in peripheral blood was de- 15 16 17 18 19 Nasrullayeva , M. Marques , S. Canna , S. Ozen , D. Kuhns ,C. tected using dd-PCR. Serum cytokine levels before and after TCZ ad- 20 9 2 1 Dalgard , T. Moran , A. Oler , R. Goldbach-Mansky ministration were measured using a cytometer bead array. 1 2 Translational Autoinflammatory Diseases Section; BCBB, NIAID, NIH; Results: Three patients with VEXAS-RP, all male, were receiving 3 4 5 6 7 NCI, NIH; DLM, NIH; CSI; NCBR, NIAID, NIH, Bethesda; Indiana TCZ in our department. All patients were still receiving TCZ at University School of Medicine, Indianapolis; Lurie Children’s Hospital, their last visit and could continue for more than six months. Chicago; University of North Carolina School of Medicine, Chapel Hill, After the initiation of TCZ, fever was relieved in all patients, United States; University of Cape Town, Cape Town, South Africa; and blood tests showed a decrease in CRP levels and an in- 11 12 Children’s Health Ireland (CHI) at Crumlin, Dublin, Ireland; KK crease in albumin levels, which was thought to be the effect of Women's and Children's Hospital, Kallang, Singapore; University blocking the IL-6 pathway to reduce systemic inflammation. As Children's Hospital, Skopje, Republic of North Macedonia; Akron a result, allpatientswereableto reducesteroid useafter Children’s Hospital, Akron , United States; Azerbaijan Medical starting TCZ. In the patient with severe anemia and 16 17 University, Baku, Azerbaijan; NIAMS, NIH, Bethesda; The Children’s thrombocytopenia (RP16 on Table 1), the frequency of receiving Hospital of Philadelphia, Philadelphia, United States; Hacettepe red blood cell transfusions decreased after TCZ administration, University Faculty of Medicine, Ankara, Turkey; Frederick National and his platelet counts had improved to over 100,000/μl. How- Laboratory for Cancer Research, Frederick; The American Genome ever, macrocytic changes in erythrocytes were still observed in Center, Bethesda, United States all patients after TCZ administration, suggesting that the effect Correspondence: A. A. de Jesus of IL-6 blockade on hematological abnormalities was partial. Pediatric Rheumatology 2021, 20(Suppl 1):O16 Pediatric Rheumatology (2022) 20:2 Page 8 of 39 Introduction: Splice site variants in IKBKG that lead to exon 5 O17 deletion cause NEMO-deleted exon 5 autoinflammatory syndrome Existing transition practices for autoinflammatory diseases across (NEMO-NDAS). NEMO-NDAS clinically mimics the interferonopathy Europe 1 1 2 3 4 5 chronic atypical neutrophilic dermatosis with lipodystrophy and M. Israni , B. Nicholson , N. Mahlaoui , L. Obici , L. Rossi , H. Lachmann , 6 7 8 9 10 elevated temperature (CANDLE) but genetic diagnosis is challen- G. Hayward , M. Zajc Avramovič , A. Guffroy , V. Dalm , R. Rimmer ,L. 11 12 13 14 11 ging and treatment with JAK inhibitors provides only partial Solis , C. Villar , A. R. Gennery , S. Skeffington , J. Nordin ,K. 15 8 16 17 18 benefit. Warnatz , A. S. Korganow , J. Antón , M. Cattalini , E. Morrison ,T. 19 20 21 22 23 24 Objectives: To characterize the immunodysregulation present in Amin , P. Wekell , S. Berg , P. Soler-Palacín , S. Burns , M. Campbell NEMO-NDAS patients (pts) and to validate a bioinformatics approach on behalf of RITA-ERN Transition Working Group Consortium to diagnose these pts. Department of Immunology, Royal Free Hospital, London, United Methods: A bioinformatics pipeline to mask the IKBKG Kingdom; Pediatric Immuno-Haematology and Rheumatology Unit, pseudogene was refined using splice prediction tools (SpliceAi, Necker Enfants Malades University Hospital, Assistance Publique- TraP, MaxEntScan and Human Splicing Finder). Screening of IKBKG Hôpitaux de Paris (AP-HP), Paris, France; Fondazione IRCCS Policlinico exon 5 ± 30bp was validated in 701 samples from subjects San Matteo, Centro per lo Studio e la Cura delle Amiloidosi Sistemiche, enrolled in an IRB-approved protocol, and in internal (n=2655, Pavia, Italy; Unité Policlinique pédiatrique, Hôpital Bicêtre, Assistance whole exome sequencing (WES)) and public (n=2498, whole gen- Publique-Hôpitaux de Paris (AP-HP), Paris, France; Division of Medicine, ome sequencing (WGS)) databases. The variants detected were National Amyloidosis Centre , University College London, London; validated by Sanger or amplicon deep sequencing (seq) and Paediatric and Adult Rheumatology, Leeds Teaching Hospital Trust, spliced product was confirmed by Western blot, cDNA seq and Leeds, United Kingdom; University Children's Hospital Ljubljana, RNA-seq. Nanostring gene expression, PBMC stimulation and cyto- Ljubljana, Slovenia; Department of Clinical Immunology and Internal kine assays were performed. CRISPR generated U937 cell line Medicine, National Reference Center for Systemic Autoimmune Diseases clones were functionally assessed. (CNR RESO), Tertiary Center for Primary Immunodeficiency, Hôpitaux Results: 13 pts (9 females and 4 males), had 9 different de novo Universitaires de Strasbourg, Strasbourg, France; Department of splice site variants in IKBKG. cDNA seq (13/13) or Western blot (5/ Immunology, Erasmus University Medical Center, Rotterdam, 5) confirmed the splice product in all pts tested. RNA-seq (n=12) Netherlands; Rare Autoinflammatory Conditions Community – UK showed a high frequency of exon 5 skipping (median 55% (35- (RACC – UK), England and Wales; IPOPI, Downderry, United Kingdom; 12 13 80%)). IKBKG exon 5 splice site variants were screened in internal Barcelona PID Foundation, Barcelona, Spain; Paediatric and public WES/WGS databases (n=5149) and 11 variants in 22 Haematopoietic Stem Cell Transplant Unit, Great North Children's subjects passed filters. Sanger seq confirmed 1 of the 11 variants Hospital (GNCH), Royal Victoria Infirmary, Newcastle upon Tyne, United 14 15 (9%); amplicon deep seq is pending. The most common clinical Kingdom; Irish Vasculitis Organisation, Ireland, Ireland; Department of features in NEMO-NDAS pts were panniculitis with systemic in- Immunology, Universitätsklinikum Freiburg, Freiburg, Germany; flammation (100%), ectodermal dysplasia (83%), hepatosplenome- Department of Pediatric Rheumatology , Sant Joan de Déu Hospital, galy (77%) and B-cell lymphopenia (80%). Compared to CANDLE Barcelona, Spain; Pediatrics Clinic, University of Brescia and ASST pts (n=5), NEMO-NDAS pts’ skin biopsies (n=7) showed histiocytic Spedali Civili di Brescia, Brescia, Italy; Department of Rheumatology, panniculitis, vacuolar interface changes and dyskeratosis. Liver bi- Southern General Hospital, Glasgow; Children's Rheumatology, The opsies (n=3) showed granulomatous hepatitis; 2 other pts had Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom; NU- portal hypertension. All pts were steroid-dependent with partial sjukvården - Barn- och ungdomskliniken , Uddevalla; Department of responses to anti-TNF (n=9) or JAK inhibition (n=9). Nanostring Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy, IFN and NF-κB scores were elevated in all 13 pts. Pts with NEMO- University of Gothenburg, Gothenburg, Sweden; Pediatric Infectious NDAS had higher serum levels of IFN-γ, IL-12p40, IL-17 and IL-23 Diseases and Immunodeficiencies Unit, Hospital Universitari Vall than seen in CANDLE pts (p<0.0001 for all). Stimulated M1 and d’Hebron. Universitat Autonoma de Barcelona, Barcelona, Spain; M2 macrophages from NEMO-NDAS pts (n=3) produced higher Immunity and Transplantation, University College London; levels of CCL3/4 (MIP1-α/β) than healthy control (HC) cells (n= Department of Immunology, Royal Free London NHS Foundation 7)(p<0.05). NEMO-NDAS pts (n=2) had normal T and B cell prolif- Trust, London, United Kingdom eration, and Fas-induced T cell death was comparable to HC. Correspondence: M. Israni U937 cell line clones lacking exon 5 normally degraded IκBα Pediatric Rheumatology 2021, 20(Suppl 1):O17 upon LPS stimulation and mutant U937 clones showed enhanced TNF induced cell death compared to wildtype and PSMB8-/- Introduction: Substantial improvements in the diagnosis and clones. management of Autoinflammatory Diseases (AID) have translated Conclusion: Our bioinformatics pipeline masking IKBKG into longer life expectancies among patients, thus prompting a need pseudogene provides a sensitive diagnostic tool for the early for defined transition protocols for long-term follow-up in adult care. recognition of NEMO-NDAS pts. The role of cytokine dysregula- Presently, there are limited data on existing transition programs for tion and TNF induced cell death in the specific pathogenesis of these disorders and their efficacy. NEMO-NDAS is being evaluated to improve therapeutic options. Objectives: This study aimed to examine the prevalence of transition programs and existing practices for the transition of young people Acknowledgments with AID to adult services across European health centres. The results This work was supported by the NIH Intramural Research Program (IRP) of from this survey will be used to develop best practice guidelines for NIAID the transition of patients with AID. Methods: A survey examining existing transition practices was Disclosure of Interest developed by the European Reference Network on Rare None Declared Immunodeficiency, Autoinflammatory and Autoimmune Diseases Pediatric Rheumatology (2022) 20:2 Page 9 of 39 O18 Transition Working group and electronically circulated to paediatric COVID-19 infection and vaccination in patients with AID centres across Europe. autoinflammatory diseases on biologics Results: The survey generated 32 responses from AID centres spread 1,2 1 1 1 C. J. Peet , C. Papdopoulou , B. R. Sombrito , M. Wood ,H.J. across 29 cities in 13 countries. Majority of the respondents Lachmann transitioned young patients to specialist AID services (24/31) or Adult CAPS and Autoinflammatory Diseases Treatment Service, National Rheumatologists (10/31). However, approximately 10% (3/31) of the Amyloidosis Centre, Royal Free London NHS Foundation Trust & Division centres reported experiencing difficulties with identifying specialist of Medicine University College London; Department of Medical and adult centres for onwards referral - with 19% (6/31) of paediatric AID Molecular Genetics, King's College London, London, United Kingdom services transitioning patients to non-specialist Adult Internal Medi- Correspondence: C. J. Peet cine Physicians. Pediatric Rheumatology 2021, 20(Suppl 1):O18 Most AID centres started the transition process in early adolescence - with 55% (17/31) of the services beginning Introduction: Inflammatory cytokines are central to the pathogenesis transition between the ages of 10 and 16. 61% (19/31) of the of the systemic autoinflammatory diseases (SAID) and agents AID centres tended to end transition and transfer care to adult targeting these pathways have transformed the management of services after the age of 18. SAID. These same pathways are involved in the balance between Whilst 77% (24/31) of the services had an internal process for viral clearance and hyperinflammation during infection and have transition, only 20% (6/30) reported having access to national therefore been areas of active research interest into COVID-19. As a guidelines for transition. 68% (21/31) of the services offered patients result, among patients with SAID on biologics, there are legitimate joint appointments with multidisciplinary healthcare professionals concerns regarding the risk of COVID-19 infection and safety of vac- from paediatric and adult services prior to transfer, and 73% (22/30) cination, which are exacerbated by the scarcity of published data on of the services described complete integration of medical records the outcomes of COVID-19 infection and vaccination in these across centres. patients. Only 29% (9/31) of the paediatric services referred patients to Objectives: This study establishes the prevalence and outcomes of adult centres with dedicated ‘young adult clinics' - with even COVID-19 infection and early outcomes of vaccination among a co- fewer services transitioning patients to adolescent centres prior hort of 248 patients with SAID on biologics. to adult care (16% or 5/31). Only 29% (9/31) of the AID centres Methods: Data were collected from the electronic medical records of reported transition-specific research programs at their site. 248 patients with SAID on biologics at a national centre up to 26/7/ Conclusion: Whilst most paediatric AID centres followed an 21. Patients were also surveyed using a web-based survey completed internal, integrated transition protocol, defined national and in clinic or remotely between 4/3/21 and 26/7/21. international guidelines are required to support successful Results: No deaths were recorded in this cohort of 248 patients transition of young patients to adult centres. Transition programs between 29/1/20 and 26/7/21. In line with national guidance, all must be adapted to provide adolescent-friendly care that pre- patients in this cohort were advised that the diagnosis of SAID pares young patients for transfer to adult care. Finally, the devel- managed with single-line biologic therapy was not an indication for opment of more transition-specific research programs is shielding and that they should continue their biologic therapy unless warranted to determine the predictors of successful transition otherwise instructed by a medical professional. Survey responses and design effective transition interventions. were received from 195 patients (195/248, 78.6%). Biologic therapy Keywords: transition, primary immunodeficiencies, autoinflammatory was as follows: anakinra (129/195, 66.2%), canakinumab (55/195, diseases, network. 28.2%), tocilizumab (8/195, 4.1%), etanercept (3/195, 1.5%), adalimu- mab (co-prescribed with anakinra) (1/195, 0.5%). Among survey re- Disclosure of Interest spondents, 32 cases of suspected COVID-19 infection were reported, M. Israni: None Declared, B. Nicholson: None Declared, N. Mahlaoui: of which 15 were confirmed on testing (15/195, 7.7%). Two patients None Declared, L. Obici: None Declared, L. Rossi: None Declared, H. on anakinra were hospitalised due to dehydration. No patient re- Lachmann: None Declared, G. Hayward: None Declared, M. Zajc quired supplemental oxygen, mechanical ventilation or intensive care Avramovič: None Declared, A. Guffroy Grant /Research support from: CSL admission. Biologic therapy continued uninterrupted in all patients Behring and Takeda, V. Dalm: None Declared, R. Rimmer: None Declared, managed in the outpatient setting and was temporailty discontinued L. Solis: None Declared, C. Villar: None Declared, A. R. Gennery Grant in the two hospitalised patients by the admitting team. Three pa- /Research support from: Mallinckrodt and JAZZ Pharmaceuticals, S. tients with suspected or confirmed COVID-19 infection reported new Skeffington: None Declared, J. Nordin: None Declared, K. Warnatz: None symptoms that persisted for more than twelve weeks. 164/195 Declared, A. S. Korganow Grant /Research support from: CSL Behring and (84.1%) respondents had received the first vaccine dose and 79/195 Takeda, J. Antón Grant /Research support from: European Union, Insituto (40.5%) had received two doses. 162/164 (98.8%) patients continued Carlos III, Fundación Daniel Bravo, Novartis, Sobi, Novimmune, Roche, biologic therapy uninterrupted around the time of vaccination. Of Pfizer, Lilly, AbbVie and Amgen, Conflict with: Received personal fees or the 243 vaccine doses administered, 138 (56.8%) were the Oxford travel expenses from Novartis, Sobi, Roche, Pfizer, Lilly, AbbVie and Astra-Zeneca vaccine and 105 (43.2%) were the Pfizer-BioNTech vac- Gebro, M. Cattalini Speaker bureau of: Novartis Farma, Abbvie, Sobi, and cine. Following vaccination, no serious adverse events were reported Pfizer , E. Morrison: None Declared, T. Amin: None Declared, P. Wekell: and no patient required hospital admission. Side effects were re- None Declared, S. Berg: None Declared, P. Soler-Palacín Grant /Research ported following 130/243 (53.5%) doses and symptoms reported by support from: European Union, Instituto Carlos III, Grifols and CSL patients to be in keeping with a flare of the underlying SAID were re- Behring, Conflict with: Received personal fees or travel expenses from ported following 40/243 (16.5%). Side effects had fully resolved by 72 CSL Behring, Takeda and Grifols , S. Burns Grant /Research support from: hours following 92.2% of doses (224/243). No cases of COVID-19 European Union, National Institute of Health Research, UCLH and GOSH/ were reported following administration of both vaccine doses and ICH Biomedical Research Centers and CSL Behring, Conflict with: only one early case was reported after the first dose, with symptom Received personal fees or travel expenses from Immunodeficiency onset within five days of vaccine administration. Median follow up Canada/IAACI, CSL Behring, Baxalta US Inc and Biotest, M. Campbell following vaccination was 10.5 weeks following the first dose and 6.0 Grant /Research support from: National Institute of Health Research, weeks following the second. PIDUK, CSL Behring and the Royal Free Charity, Conflict with: Received Conclusion: This study shows COVID-19 infection rates broadly in line personal fees or travel expenses from Biotest, BPL, CSL Behring, Grifols, with that of the UK general population among patients with SAID on HAEUK, Shire and Takeda Pediatric Rheumatology (2022) 20:2 Page 10 of 39 biologics and demonstrates no significant concerns regarding out- predicting patients with cr-FMF (Table 1). Scores were assigned ac- comes of infection in these patients. We also present the largest cording to β coefficients in the final model. The cut-off value of pre- series of patients with SAID or on IL-1/6 biologics to have received dictor score as 4.5 was 88% sensitive and 82% specific to foresee the an adenoviral vector or mRNA vaccine and observe no significant risk of colchicine resistance in the ROC. early safety concerns. Whilst longer follow-up is needed to establish The predictive score was applied to 374 patients (colchicine resistant the efficacy of vaccination in these patients, these findings will sup- = 75, colchicine responsive = 299) which were registered to PeRA-RG port patients and their clinicians to make informed decisions around database up to December 2020. Sixty-five (86.6%) cr-FMF patients continuation of biologic therapy and vaccination during the ongoing and 3 (1%) colchicine responsive patients had a total score of more COVID-19 pandemic. than 4.5. The cut-off value of the score as 4.5 was 86.6% sensitive and 99% specific to identify the risk of colchicine resistance in the Acknowledgments ROC. CJP is funded by a British Heart Foundation Clinical Research Training Conclusion: In advance of the previous studies, we intended to Fellowship. design a composite predictive scoring system to foresee unresponsive patients. By constructing this novel reliable predictor Disclosure of Interest tool, we enunciate that physicians will be capable of anticipating C. J. Peet: None Declared, C. Papdopoulou: None Declared, B. R. Sombrito: drug resistance in children with FMF at the initiation of the disease None Declared, M. Wood: None Declared, H. J. Lachmann Consultant for: and, thereby have a chance to interfere timely before the emergence Novartis and Sobi of complications during the disease course. Key Words: Familial Mediterranean fever, predictive score, colchicine resistance Abstracts accepted for publication only REFERENCES P01 1. Ozen S, Kone-Paut I, Gül A. Colchicine resistance and intolerance in famil- In pursuit of colchicine resistance prediction in familial ial mediterranean fever: Definition, causes, and alternative treatments. mediterranean fever: exploring a novel scoring model and Seminars in arthritis and rheumatism. 2017;47(1):115-20. simultaneous validation 2. Babaoglu H, Armagan B, Bodakci E, Satis H, Atas N, Sari A, et al. Predictors 1 1 2 2 1 N. Aktay Ayaz , F. G. Demirkan , T. Coskuner , F. Demir , A. Tanatar ,M. of persistent inflammation in familial Mediterranean fever and association 3 4 5 6 7 2 Çakan , S. G. Karadag , G. Otar Yener , S. Caglayan ,K.Ulu , B. Sozeri ,H. with damage. Rheumatology (Oxford, England). 2021;60(1):333-9. E. Sonmez 3. Betul Sozeri HES, Ferhat Demir, Mustafa Çakan, Kübra Öztürk, Semanur Pediatric Rheumatology, Istanbul University, Istanbul Faculty of Özdel, Gulcin Otar Yener, Şerife Gül Karadağ, Nuray Aktay Ayaz. Time to Medicine; Pediatric Rheumatology, University of Health Sciences, collaborate: Objectives, Design, and Methodology of PeRA-Research Umraniye Research and Training Hospital; Pediatric Rheumatology, Group. The North Clinics of Istanbul. 2020. University of Health Sciences, Zeynep Kamil Women and Children's 4. Özçakar ZB, Elhan AH, Yalçınkaya F. Can colchicine response be predicted Diseases Training and Research Hospital; Pediatric Rheumatology, in familial Mediterranean fever patients? Rheumatology (Oxford, University of Health Sciences, Bakırkoy Dr. Sadi Konuk Training and England). 2014;53(10):1767-72. Research Hospital, Istanbul; Pediatric Rheumatology, Sanlıurfa Training and Research Hospital, Sanlıurfa, Sanlıurfa; Pediatric Rheuamtology, Disclosure of Interest University of Health Sciences, Umraniye Research and Training Hospital; None Declared Pediatric Rheumatology, University of Health Sciences, Umraniye Table 1 (abstract P01). Multivariate logistic regression analysis of Research and Training Hospital, Istanbul, Istanbul; Pediatric prediction of colchicine resistance and scoring system Rheumatology, Kocaeli University, Kocaeli School of Medicine, Kocaeli, Kocaeli, Turkey Predictors Odds Ratio (95% P Score Correspondence: N. Aktay Ayaz CI) value assigned Pediatric Rheumatology 2021, 20(Suppl 1):P01 Recurrent arthritis 2.6 (0.99-7.02) 0.03 2 Introduction: Over the years, definition and prediction of colchicine Protracted febrile myalgia 6.8 (1.43-32.34) 0.01 6 resistance have been the most intriguing issues of researches 1,2 Erysipelas-like erythema 2.3 (0.92-6.21) 0.02 2 concerning familial Mediterranean fever (FMF). Objectives: The aim of this study is to develop a novel scoring Anemia 3.4 (1.26-9.65 0.02 3 system based on the initial clinical features and laboratory findings Elevated SAA in the attack free 0.95 (0.91-1.01) 0.04 1 via synchronous validation of it in an independent group for period predicting colchicine resistance in children with FMF. Methods: The medical records of the cases with FMF who applied to SAA, Serum amyloid A the pediatric rheumatology outpatient clinic were evaluated retrospectively. To define the predictive factors for colchicine P02 resistance, baseline clinical and laboratory findings prior to initiation of Diagnostic delay in a rare autoinflammatory syndrome 1 1 2 1 2 colchicine were evaluated. After generating a predictive score in the F. Annunziata , M. L. Pennacchio , M. Tardi , F. Paciello , R. Borrelli ,R. 1 1 2 2 initial cohort, it was applied to an independent cohort in the database Naddei , M. Alessio , L. Martemucci , F. Orlando of Pediatric Rheumatology Academy (PeRA)-research group (RG) Department of Translational Medical Sciences, Section of Pediatrics, 3 2 established in 2019 , for external validation of effectiveness and University of Naples Federico II; Pediatrics, AORN Santobono Pausilipon, reliability. Naples, Italy Results: A total of 327 patients with FMF were included in the study. Correspondence: F. Annunziata Among them, 78 (23.9%) (Group I) were colchicine resistant (cr)-FMF Pediatric Rheumatology 2021, 20(Suppl 1):P02 patients and 249 (76.1%) (Group II) were colchicine responsive. Erysipelas-like erythema (ELE), myalgia, arthritis, chronic arthritis, pro- Introduction: TRNT1 is a nuclear gene encoding a ubiquitous tracted febrile myalgia, amyloidosis, vasculitis, anemia, and protein- enzyme (CCA-adding tRNA nucleotidyltransferase enzyme) necessary uria were more common in patients who were in group I than those for aminoacylation of both mitochondrial and cytosolic tRNA. in group II. A logistic regression model was used to estimate a model Mutations of that gene lead to heterogeneous phenotypes and to predict the colchicine resistance in FMF patients. According to the systemic involvement of variable severity and progression. regression analysis, recurrent arthritis, protracted febrile myalgia, pres- Objectives: To consider mutations of TRNT1 as an important ence of ELE, chronic anemia and elevated serum amyloid A levels in the differential diagnosis in patients with overlap of immunodeficiency attack-free period were determined as the scoring parameters for and autoinflammatory features to avoid diagnostic delay. Pediatric Rheumatology (2022) 20:2 Page 11 of 39 Methods: A 10-year-old female admitted to our rheumatology patients have been successfully treated with the interleukin-1β in- pediatric unit of Santobono Children's Hospital of Naples for febrile hibitor canakinumab. Canakinumab has been approved and applied illness associated with vomit and diarrhoea, evolved in shock. She for the treatment of TRAPS patients since 2017. was treated in intensive care with broad spectrum antibiotics and Objectives: The present study explores the long-term efficacy and cardiovascular support. safety of canakinumab under routine clinical practice conditions Results: The anamnesis revealed recurrent fever accompanied by vomit, in pediatric (age ≥2 years) and adult TRAPS patients. metabolic acidosis, dyselectrolytemia and increase of inflammatory markers, Methods: RELIANCE is a prospective, non-interventional, multi-center, without evidence of infective causes, since second month of life. Even in observational study based in Germany with a 3-year follow-up the absence of evidence of infective origins, these febrile episodes were period. Patients with clinically confirmed diagnoses of TRAPS who often treated with systemic antibiotic therapy with poor clinical response. routinely receive canakinumab are enrolled in order to evaluate effi- However, it was observed resolution of symptoms after steroids therapy. cacy and safety of canakinumab under standard clinical practice con- She presented to our attention with following clinical conditions: microcytic ditions. Inflammatory markers, disease activity and remission by anaemia (requiring blood transfusion),bilateral cataract, hypotonia, physician assessment, disease activity and fatigue by patient assess- intellectual disability andhypogammaglobulinemia. Physical examination ment, were assessed at baseline and at 6-monthly intervals. documented occurrence of facial dysmorphisms,brittle hair and intellectual Results: disability. At the admission, laboratory assessment showed: white blood cell The interim analysis of TRAPS patients enrolled by December 2020 4920/ul (n.v. 5-19), Haemoglobin 9.4 g/dl (n.v. 10.18), MCV 60.9 fL (85-120), includes baseline (N=16, including 1 patient with atypical TRAPS) and RDW 43 fL (n.v. 38.7-45.1), Platlets 119000/ul (n.v. 140-440), Neutrophiles preliminary 18-month data. Mean age in this cohort was 23 years (3- 3870/uL (n.v. 1300-8500), Lymphocytes 619/uL (n.v.1300-8500), Eosino- 43 years) and the median duration of prior CAN treatment was 1.0 philes50/uL (n.v. 0-80), C Reactive Protein 324 mg/l (n.v. 0.5), Procalcitonin year (0-4 years). All patients already were on canakinumab when be- 610 ng/ml (n.v. <0.5), Ferritin 2071 ng/ml (n.v. 6-67), lactic dehydrogenase ing enrolled. Prior treatments were colchicin (N=2), anakinra (N=10) 1198 U/l (n.v. 230-500). Immunological screening was performed, showing and tocilizumab (N=1). hypogammaglobulinemia, with IgA <0.22 g/l (n.v 0.5-3) and IgG 6,3 g/dl Physician assessment indicated 60-80% remission and laboratory (n.v. 7-15), and low levels of T total (TCD3 49%, n.v.55-78%) and T helper parameters were within normal range. Disease control by patient lymphocites (TCD4 29%, n.v. 27-53%). No infective causes were found. Be- assessment showed no major changes regarding the analyzed pa- cause of the history characterized by recurrent fever, immunological alter- rameters (table 1). Of the three serious adverse events reported ations and dismorphic appearance, TRNT1 mutation associated disease was none was classified as drug-related. suspected. Genetic analysis was done, confirming our suspicion.Based on Conclusion: Preliminary analysis of 18-month interim data of TRAPS case reports available in literature, after the molecular diagnosisshe started patients treated with CAN available from the RELIANCE study indicate onanti-TNF alfa (Etanercept) therapy. stable efficacy and safety of CAN long-term treatment. Conclusion: The presence of recurrent fever associated with elevation of inflammatory indexes, without evidence of infections, Disclosure of Interest led to consider TRNT1 mutation related disease as an N. Blank Grant /Research support from: Novartis, Sobi, Consultant for: autoinflammatory syndrome. Currently, 49 case are reported in Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer- literature. This condition was firstly associated to congenital Ingelheim, Roche, J. Henes Grant /Research support from: Novartis, Roche, sideroblastic anaemia with immunodeficiency, fevers, and Consultant for: Novartis, AbbVie, Sobi, Roche, Janssen, Boehringer-Ingelheim, developmental delay (SIFD) but over the years phenotypic T. Kallinich Grant /Research support from: Novartis, Consultant for: Sobi, heterogeneity was described. Due to the rarity of that syndrome, Novartis, Roche, P. T. Oommen Grant /Research support from: Novartis, C. dignostic delay is observed, as in our patient. Early diagnosis of this Schuetz: None Declared, M. Borte: None Declared, J. Weber-Arden Employee condition would enable patients to promptly access to therapies. of: Novartis, J. Kuemmerle-Deschner: None Declared Symptomatic treatments, including red blood cells transfusions, immunoglobulin replacement therapy and steroids, are the most used; however, mortality is high. Etanercept has been recently Table 1 (abstract P03). Baseline characteristics and interim analysis described as effective treatment. TNFa inhibitors can lead to a data of patients with TRAPS significative response for those patients who can benefit early in life. Our patient started that treatment but we are still waiting to define the clinical benefits of this therapy. Baseline 6 12 18 months months months Disclosure of Interest Number of patients, N 16 13 10 6 None Declared Females (%) 11 (69) 9 (69) 7 (70) 3 (50) Median duration of prior CAN therapy at 1.0 (0; 4) 1.0 (0; 1.0 (0; 1.5 (0; P03 baseline, years (min; max) 4) 4) 2) Long-term efficacy and safety of canakinumab in patients with Number (%*) of patients in disease 9 (60.0) 9 (81.8) 7 (77.8) 4 (80.0) traps (tumor necrosis factor receptor-associated periodic remission (physician assessment) syndrome) - interim analysis of the reliance registry 1 2 3 4 5 6 Physician Global Assessment, percentage 40 / 53 / 82 / 9 / 44 / 44 80 / 20 N. Blank , J. Henes , T. Kallinich , P. T. Oommen , C. Schuetz , M. Borte , 7 2 of absent/mild-moderate/severe rating 0 0 /11 /0 J. Weber-Arden , J. Kuemmerle-Deschner 1 2 3 University Hospital, Heidelberg; University Hospital, Tuebingen; Charité Patient assessment of current disease 1.5 (0; 5) 1.0 (0; 1.0 (0; 0.0 (0; University Medicine, Berlin; University Hospital, Duesseldorf; activity; 0–10, median (min; max) 4) 6) 3) 5 6 Medizinische Fakultaet Carl Gustav Carus, Dresden; Hospital St. Georg Patient assessment of current fatigue; 0– 2.0 (0; 8) 1.0 (0; 2,5 (0; 4.0 (0; gGmbH, Leipzig; NOVARTIS PHARMA, Nürnberg, Germany 10, median (min; max) 7) 8) 7) Correspondence: N. Blank Number (%*) of patients without 4 (50) 5 (63) 2 (33) 3 (60) Pediatric Rheumatology 2021, 20(Suppl 1):P03 impairment of social life by the disease Introduction: Tumor necrosis factor receptor-associated periodic syn- CRP, SAA median (mg/dl) 0.1/0.5 0.1/0.4 0.1/0.4) 0.0/0.3 drome (TRAPS) is a rare autoinflammatory condition characterized by *not reported for all patients severe systemic and organ inflammation. In clinical trials TRAPS CRP, c-reactive protein; SAA, serum amyloid A Pediatric Rheumatology (2022) 20:2 Page 12 of 39 P04 mutation, coding for a protein at Y861, a dephosphorylation site in the Evaluation of E148Q and concomitant AA amyloidosis secondary leucine-rich repeat (LRR) domain of NLRP3. Phosphorylation/dephosphoryla- to familial mediterranean fever after adjusted clinical-demographic tion of NLRP3 at key sites, as Y861, has been shown to be an essential step characteristics for the regulation of the NLRP3 inflammasome, with Y861c mutation lead- This abstract has not been included here as it has been previously ing to spontaneous inflammasome activation and interleukin-1β published hyperproduction. The mitochondrial VOUS m.12236G>A is associated with non- syndromic SND, MELAS syndrome (mitochondrial encephalomyopathy, P05 lactic acidosis, and stroke-like episodes) and respiratory chain defi- Non-urticarial Muckle-Wells syndrome and mitochondrial ciency (affecting complexes I, III and IV). Both patients did not fulfil cytopathy – hand-in-hand in the NLRP3 inflammasome diagnostic criteria for MELAS syndrome (Hirano et al. (1992) or Yat- 1 1,2 3 2,4 A. Lamas , D. G Oliveira , M. Rodrigues , R. Faria suga et al. (2012)), an insufficient hypothesis to explain all the clinical 1 2 Medicine, Centro Hospitalar e Universitário do Porto; UMIB, ICBAS - manifestations. Mitochondrial dysfunction with increased production Universidade do Porto, Porto; Neurology Department, Hospital de of reactive oxygen species and oxidized mitochondrial DNA (mtDNA) Braga, Braga; Consulta de Sindromas Autoinflamatórios, Unidade de may act synergically in NLRP3 activation, autoinflammation and Imunologia Clínica, Centro Hospitalar e Universitário do Porto, Porto, “inflammaging”. This case illustrates the intricacies of NLRP3 inflam- Portugal masome hyperactivation through a rare mutation in exon 6, resulting Correspondence: D. G Oliveira in a distinct clinical phenotype. It also underlines the complex inter- Pediatric Rheumatology 2021, 20(Suppl 1):P05 play between mitochondria and NLRP3 activation, and its potential role in the modulation/definition of clinical phenotypes. Introduction: Muckle-Wells syndrome (MWS) is a rare inherited cryopyrin-associated periodic syndrome (CAPS) with NLRP3 gain-of- Disclosure of Interest function mutations. Although urticaria is a prominent clinical feature, None Declared cases have been reported with systemic and neurological involve- ment without cutaneous manifestations. Inflammasome activation is a complex process and there is mounting evidence of the key role P06 played by mitochondria. Long-term safety and effectiveness of canakinumab in patients Objectives: To describe the clinical phenotype of two adult sisters with familial mediterranean fever (FMF) interim analysis of the harbouring a heterozygous NLRP3 mutation (c.2582A>G p.(Tyr861Cys) reliance registry 1 2 3 4 and a homoplasmic MT-TS2 mitochondrial variant of uncertain signifi- J. Henes , J. Kümmerle-Deschner , T. Kallinich , F. Dressler , F. Weller- 5 6 7 8 9 cance (VOUS) (m.12236G>A). Heinemann , B. Kortus-Goetze , I. Foeldvari , G. Horneff , M. Hufnagel ,F. 10 11 12 Results: The patients described are siblings from a sibship of 5 (1 male Meier , J. Weber-Arden , N. Blank 1 2 and 4 females), in a family with a history of sensorineural deafness University Hospital, Tuebingen, Germany; Pediatric Department, (SND) (at least 3 generations affected, onset during adolescence). A University Hospital, Tuebingen; Charité University Medicine, Berlin; 4 5 niece was diagnosed with MWS without mitochondrial mutation at Hannover Medical School, Hannover; Prof. Hess Kinderklinik, Bremen; 6 7 another centre. University Hospital, Marburg; Centre for Pediatric and Adolescence Patient 1: a 52-year-old woman with a history of SND and chronic Rheumatology Hamburg, Hamburg; Asklepios Clinic , Sankt Augustin; 9 10 headaches (onset at age 10), associated with nausea, vomiting and University Hospital, Freiburg; University Hospital, Frankfurt; 11 12 fever (mostly concomitant with headaches), recurrent aseptic menin- NOVARTIS PHARMA, Nürnberg; University Hospital, Heidelberg, gitis and stroke-like episodes. Other features included recurrent con- Germany junctivitis, polyarthritis, inflammatory/iron deficiency anaemia and Correspondence: J. Henes accelerated atherosclerosis (myocardial infarction at age 43). There Pediatric Rheumatology 2021, 20(Suppl 1):P06 was no history of cutaneous involvement. Patient 2: a 46-year-old woman with a history of SND (onset at age 18), presented with Introduction: Familial Mediterranean Fever (FMF) is characterized by chronic recurrent headaches (onset at age 15), with concomitant recurrent attacks of fever and serositis as well as elevated nausea, vomiting and fever, with documentation of aseptic meningi- inflammatory markers. FMF treatment goals according to EULAR are tis, and stroke-like episodes. Polyarthritis, synovitis and enthesopathy to control acute attacks and subclinical inflammation and to improve were more severe, and clinodactyly was present. There was no his- patients´ quality of life. tory of cutaneous involvement. Other features included recurrent Objectives: The present study explores the long-term efficacy and conjunctivitis and inflammatory/iron deficiency anaemia. safety of canakinumab (CAN) in routine clinical practice in pediatric Both presented with markedly elevated serum amyloid A, (age ≥2 years) and adult FMF patients. erythrocyte sedimentation rate and C-reactive protein. Serum lactate Methods: RELIANCE is a prospective, non-interventional, multi-center, levels were normal. Cerebrospinal fluid analysis revealed elevated observational study based in Germany for patients with clinically protein levels, with associated pleocytosis. Electromyography was confirmed FMF who routinely receive CAN. Disease activity parame- normal and muscle biopsy showed no evidence of mitochondrial my- ters by physicians´ and patients’ assessment were recorded at base- opathy. Abdominal fat biopsy showed no evidence of amyloid line and were assessed at 6-monthly intervals. deposition. Results: This interim analysis of FMF patients (N=54) enrolled by PCR and Sanger sequencing detected a homoplasmic mitochondrial December 2020 includes baseline as well as 6-, 12- and 18-month VOUS in MT-TS2 gene (m.12236G>A) and a heterozygous missense data. Mean age in this cohort was 25 years (4-56 years) and the pro- NLRP3 mutation (c.2582A>G p.Tyr861Cys, Y861c or previously known portion of female patients was 46 % (N=25). At baseline, median dur- as Y859c – in mice). Extensive genetic studies for the exclusion of ation of prior CAN treatment was 2.0 years (0-6 years). 34 patients other mitochondrial cytopathies were performed. (63%) were concomitantly treated with colchicine. A diagnosis of MWS syndrome was assumed and treatment started While physician ratings report around 62% of patients in disease with IL-1 receptor antagonist (anakinra), with significant clinical im- remission, 52% with absent and 34% with mild-moderate disease ac- provement (headaches, fever, arthritis) and inflammatory marker tivity, patient-reported disease activity decreased during the observa- remission. tion period, especially in patients without prior CAN therapy (table Conclusion: The clinical features fulfil diagnostic criteria for CAPS, as 1). A total of 11 serious adverse events was reported, of which one proposed by Kuemmerle-Deschner et al. (2016). They are also compatible case of tonsillectomy in a 6-year-old patient was classified as drug- with the phenotype previously described for this exon 6 missense related. Pediatric Rheumatology (2022) 20:2 Page 13 of 39 Conclusion: Interim data of FMF patients from the RELIANCE study Introduction: The CDC42 (Cell Division Cycle 42) gene product, CDC42, confirm efficacy and safety of long-term CAN treatment. is a member of the family of small Rho GTPases, which are implicated in a broad spectrum of physiological functions in cell cycle regulation. Disclosure of Interest Missense variants in CDC42 underlie a clinically heterogeneous group J. Henes Grant /Research support from: Novartis, Roche, Consultant for: of phenotypes characterized by variable neurodevelopmental, growth, Novartis, AbbVie, Sobi, Roche, Janssen, Boehringer-Ingelheim, J. Kümmerle- hematological, and immunological disorders. Deschner Grant /Research support from: Novartis, AbbVie, Sobi, Consultant Objectives: Here, we report a family of 4 affected members with a for: Novartis, AbbVie, Sobi, T. Kallinich: None Declared, F. Dressler Grant dominant missense mutation in the CDC42 gene and analyze the /Research support from: Novartis, Consultant for: Abbvie, Mylan, Novartis, pathophysiological mechanisms explaining a large part of the Pfizer, F. Weller-Heinemann: None Declared, B. Kortus-Goetze Consultant for: phenotype Novartis, I. Foeldvari Consultant for: Novartis, G. Horneff Grant /Research Methods: The family (a mother with 3 of her children) was referred support from: AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, to our reference center for a suspected tumor necrosis factor Speaker bureau of: AbbVie, Bayer, Chugai, Merck Sharp & Dohme, Novartis, receptor-associated periodic syndrome. No pathogenic variant was Pfizer, Roche, M. Hufnagel Grant /Research support from: Novartis, F. Meier identified in 8 autoinflammation-related genes including TNFRSF1A, Speaker bureau of: Novartis, J. Weber-Arden Employee of: Novartis, N. Blank NLRP3 and MVK. Affected members presented with recurrent fevers Grant /Research support from: Novartis, Sobi, Consultant for: Novartis, Sobi, lasting several weeks, severe arthromyalgias, arthritis and splenomeg- Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche aly. Two children had in addition labio-palatine cleft and one devel- opmental delay. All the affected members presented with other slight dysmorphic signs: hypertelorism, wide nasal bridge and mouth with widely spaced teeth. Inflammatory manifestations responded re- Table 1 (abstarct P06). Baseline characteristics and third interim markably well to IL-1beta inhibition. Patients were included to the analysis data of patients with FMF France Genomique research program allowing us to perform whole genome sequencing in trio and investigate the pathophysiological Baseline 6 months 18 months mechanisms. All patients All Patients All patients Patients All patients Patients Results: A novel heterozygous p.Thr43Ile mutation in the CDC42 | Patients patients without without without gene was identified in all affected family members. In silico without prior CAN prior CAN prior CAN prior CAN modelisation predicted no structural change of CDC42, but a therapy probable impaired interaction with DOCK proteins, a family of Number of 54 11 35 7 16 3 proteins involved in intracellular signaling networks. Fibroblasts as patients, N well as Peripheral Blood Mononuclear cells (PBMC) from the patients Number (%*) 18 (48.6) 1 (20.0) 19 (73.1) 3 8 (61.5) 1 (100.0) showed an inflammatory signature with an increased expression of of patients (75.0) in disease IL-1β, IL-6, TNFα, IL-8 and IL-18 on a basal state in the untreated pa- remission tient and after stimulation in treated ones. In respect to PBMC con- (physician assessment) trols, patients showed an over-activation of both pyrine and NLRP3 inflammasomes using both agonist triggers and specific inibitors Patient 3.0 7.0 (0; 2.5 (0; 2.0 2.0 0.5 assessment (0; 10) 10) 7) (0; 5) (0; 6) (0; 1) (NLRP3 inflammasome inhibitor MCC 112 and pro-caspase-1 inhibitor of current Z-VAD).The spontaneous increased ASC/Speck aggregation in mu- disease activity; 0– tated PBMCs confirms this observation strongly. 10, median These observations allow us to hypothesize that the inflammatory (min; max) profile of the CDC42 mutations, passes through abnormal activation Patient 5.0 5.0 (0; 3.5 3.0 3.0 0.5 assessment (0; 10) 9) (0; 10) (1; 6) (0; 7) (0; 1) of the pyrin and probably the NLRP3 inflammasome thus linking the of current CDC42 abnormalities to the same inflammatory pathways than fatigue; 0– 10, median familial Mediterranean fever and mevalonate kinase deficiency. (min; max) Conclusion: We describe in four affected members of the same Number (%*) 19 3 18 3 5 2 family a novel heterozygous dominant p.Thr43Ile mutation in the of patients (46.3) (37.5) (66.7) (75.0) (55.6) (66.7) CDC42 gene. CDC42 encodes a small GTPase of the Rho subfamily, without impairment playing a pivotal role in cell cycle regulation. In the family studied, of social life diverse clinical manifestations compose a syndromic phenotype with by the disease autoinflammation, facial dysmorphism and neurodevelopmental delay. The pathophysiological assessment showed that the CRP/SAA, 0.2/0.7 1.1/6.8 0.2/0.8 0.1/0.4 0.1/0.6 0.5/0.7 median inflammatory profile of the p.Thr43Ile CDC42 mutation is linked to (mg/dl) the pyrin and to a lesser extend to the NLRP3 inflammasome, *not reported for all patients unravelling a heretofore-unrecognized connection between seem- CRP, c-reactive protein; SAA, serum amyloid A ingly unrelated autoinflammatory diseases. CDC42 mutations should be searched for USAID patients with splenomegaly, recurrent arthral- gia and a clinical response to IL1 blockers, sporadic or dominant P07 transmission. A family with an autosomal dominant CDC42-mutation covering the full clinical spectrum from developmental defects to Disclosure of Interest autoinflammation None Declared 1 2 2 3 4 V. Hentgen , B. Bekhouche , A. Terre-Becker , J. Cherfils , M. Andre ,S. 5 6 2 Georgin-Lavialle , G. Boursier , A. Smahi Reference Center for AutoInflammatory diseases and amyloidosis, P08 Versailles Hospital, Le Chesnay; INSERM U1163, Imagine Institute, Paris; Evaluation of fatigue level and sleep quality in patients with Laboratoire d’Enzymologie et Biochimie Structurales, CNRS, Gif-sur- familial mediterranean fever Yvette; Service de médecine interne, Montpied Hospital, Clermont- 1 2 2 2 2 Ç. İncesu , G. Kavrul Kayaalp , F. G. Demirkan , O. Köker , F. Çakmak ,Ö. Ferrand; Reference Center for AutoInflammatory diseases and 2 2 2 Akgün , N. Aktay Ayaz , R. Eker Ömeroğlu amyloidosis, Tenon Hospital, Paris; Laboratory of Rare and 1 2 Pediatrics; Pediatric Rheumatology, Istanbul University, Faculty of Autoinflammatory Genetic Diseases, CHRU Montpellier, Montpellier, Medicine, İstanbul, Turkey France Correspondence: G. Kavrul Kayaalp Correspondence: V. Hentgen Pediatric Rheumatology 2021, 20(Suppl 1):P08 Pediatric Rheumatology 2021, 20(Suppl 1):P07 Pediatric Rheumatology (2022) 20:2 Page 14 of 39 Introduction: Familial Mediterranean fever (FMF) is the most laboratory grounds is difficult due to non-specific clinical presenta- prevalent hereditary autoinflammatory disease. It is characterized by tion. Besides monogenic autoinflammatory conditions periodic fevers recurrent inflammatory episodes of fever and serositis. Its lifelong may be a component of other primary immunodeficiency syndrome and inflammatory nature can cause detrimental effects on all aspects (PIDs), rheumatic diseases or cancer. of patients' quality of life. Sleep quality and fatigue are essential Objectives: To evaluate benefits of next generation sequencing factors affecting quality of life, which may be impaired in FMF (NGS) in patients with periodic or persistent fevers and no evidence patients due to recurrent episodes or ongoing subclinical of infectious disease. inflammation. Methods: 55 patients with suspected autoinflammatory PFS were Objectives: In this study, it is aimed to evaluate whether sleep tested for genetic mutations in 344 PID-associated genes using tar- quality and fatigue level are affected in children with FMF compared geted NGS. to healthy children and to assess the parameters that may affect Results: Out of 55 patients, 53% (n=29) presented periodic fevers sleep quality and fatigue status in FMF patients. (recurrent rises of body temperature over 38.0°C), 44% (n=24) had Methods: 225 children aged 7- 18 years who are followed up with the persistent fevers (i.e. lasting rises of body temperature over 38.0°C diagnosis of FMF in Istanbul University Faculty of Medicine Pediatric for at least 3 weeks). Two patients had clinical and laboratory signs Rheumatology Clinic were included in the study. 182 age matched of autoinflammatory disease but no fever. Other symptoms included: healthy peers were included as control group. Demographic features, local or generalized lymphadenopathy (n = 23; 42%), rash (n=29; family history, MEFV gene mutations, medications and The International 53%), arthritis (n=36; 65%), vasculitis (n=17; 31%), serositis (n=17; Severity Score for FMF (ISSF) scores of the patients were recorded. The 31%). We noticed a rise of inflammatory laboratory markers such as PedsQL Multidimensional Fatigue Scale module which consists of three ESR, CRP, leukocyte numbers in all the patients. parts as general fatigue, sleep/rest-related fatigue and cognitive fatigue Based on the results of targeted NGS, we divided the patients into 3 was used to assess fatigue. Five answer options were offered and raw groups: scores were extrapolated to a scale of 0 to 100 reversely (0 converted Group I (n = 25) included patients with mutations associated with to 100, 1 to 75, 2 to 50, 3 to 25 and 4 to 0). Pittsburgh Sleep Quality autoinflammatory diseases. These included mutations in MEFV (n= Index (PSQI) was used to assess sleep quality. The scores ranged 0 to 10), TNFRSF1A (n=6), NLRP12 (n=5), TNFAIP3 (n=2), MVK (n=1), NOD2 21were calculated according to the calculation sheet. A total score of 5 (n=1). and above was considered as poor sleep quality. Group II (n=5) included patients with mutations in the genes Results: Gender distribution was 59.3% female and 40.7% male in associated with other PIDS: WAS, NFKB2 (n=2), CTLA4 and a MBL2. the patient group and 51.6% female, 48.4% male in the control Group III included patients (n = 25) with no mutation identified. This group. The mean age was 12.2 ± 2.4 years, and 12.1 ± 3.3 years in group included patients with a systemic juvenile idiopathic arthritis, the patient and control groups respectively. Mean ISSF score was 2.2 undifferentiated systemic vasculitis and systemic connective tissue ± 1.1 points. Medications of the patients were 88.4% colchicine, diseases. 11.6% colchicine and anti IL-1 treatment (canakinumab or anakinra). We compared clinical and laboratory findings in patients of groups II The MEFV mutations were homozygous in 25.8%, heterozygous in and III with those of group I. No significant difference in age of 38.2%, compound heterozygous in 28% of the patients group. In the onset, clinical manifestation or laboratory activity was found. last year 13.3% of the patients didn’t have any attack, 86.7% had at Conclusion: Usage of NGS makes it possible to find causative least 1 attack. The median PSQI score was significantly higher in the mutations - in those cases where they are detected it is easier to find patient group (5.1±2.3 in the patient group, 3.2±1,3 in the control better therapeutic options. group; p <0.05) and the median PEDsQL score was significantly higher in the control group (66.0±17.3 in the patient group, 70.4± Acknowledgments 15.9 in the control group; p <0.05). A significant positive correlation This work was supported by the Russian Foundation for Basic Research was observed between the number of attacks in the last 1 year and (grant № 18-515-57001). the PSQI score (r=0.721, p <0.05). There was no significant difference in terms of ISSF score, PSQI score, PEDsQL score, general fatigue Disclosure of Interest score, sleep/rest fatigue score, and thought fatigue score between None Declared homozygous, heterozygous and compound heterozygous groups. Conclusion: This study demonstrates that children with FMF have lower sleep quality and higher fatigue levels compared to their P10 healthy peers. The disease activity also effects the sleep quality and Long-term efficacy and safety of canakinumab in Cryopyrin- fatigue status of FMF patients. Maintaining low disease activity in the Associated Periodic Syndromes (CAPS) – 30-month data from the of the patients with FMF and evaluation of sleep quality in the reliance registry routine follow-ups can improve the quality of life of the patients. This abstract has not been included here as it has been previously published Disclosure of Interest None Declared P11 Autoimmunity within autoinflammatory diseases: not so far, not so P09 rare Next generation sequencing in diagnosis of periodic fevers: one J. R. Marques Soares on behalf of Autonflammatory Diseases Unit - 2 3 center experience Hospital Vall Hebron, M. Martinez Gallo , M. Antolin Mate , S. Bujan 1,2 2 2 2 3 1 Z. Korobova , I. Svitina , K. Belozerov , A. Tumakova , A. Romanko ,E. Rivas on behalf of Autoinflammatory Diseases Unit - Hospital Vall 2,3 2,4 Suspitsyn , M. Kostik Hebron 1 2 1 2 3 Saint Petersburg Pasteur Institiute; Saint Petersburg State Pediatric Internal Medicine; Immunology; Genetics, Hospital Vall D´Hebron Medical University; N.N. Petrov National Medical Research Center of (Barcelona) Spain, Barcelona, Spain Oncology; Almazov National Medical Research Centre, Saint-Petersburg, Correspondence: J. R. Marques Soares Russian Federation Pediatric Rheumatology 2021, 20(Suppl 1):P11 Correspondence: Z. Korobova Pediatric Rheumatology 2021, 20(Suppl 1):P09 Introduction: Autoinflammation and autoimmunity are two sides of the immune system. Altought phisiopathological mechanism are Introduction: Periodic fever syndromes (PFS) is a group of disorders supposed to be clearly different, some autoimmune features have characterized by recurrent attacks of systemic and organ-specific in- been identified as signifcative parts of new entities like SAVI, DADA2 flammation. Establishing a reliable diagnosis on clinical and or COPA syndrome. In some cases, the clinical and antibody profile Pediatric Rheumatology (2022) 20:2 Page 15 of 39 in some autoinflammatory diseases can remind autoimmune gene have been reported as part of NLRC4-related familial cold auto- conditions. inflammatory syndrome and periodic fever-infantile enterocolitis Objectives: To evaluate the presence of sera autoantibodies and autoinflammatory syndrome. We report a case of a 15-year old male organ-specific / systemic autoimmune diseases according to the with an enterocolitis autoinflammatory syndrome phenotype with a international clasification criteria among a cohort of autoinflamma- not previously reported mutation in NRLC4. tory adult patients followed at a reference unit of autoinflammatory Objectives: To establish a molecular diagnosis in a patient with diseases froma thir-care centre. unreported family history of neonatal-onset enterocolitis, periodic Methods: Retrospective review of clinical and laboratory reports of a fever and arthritis, well controlled with Anakinra. cohort of 75 adult patients followed at the Autoinflammatory Diseases Methods: We report the case of a 15-year-old male patient who has Unit from Hospital Vall Hebron (Barcelona, Spain). Demographic, clinical been followed up in the pediatric rheumatology unit since the neo- and immunological laboratory data were collected. natal period. Born to non-consanguineous parents of Catalan origin, Results: The mean age of the cohort was 46 y with a female/male he had no family history of immune-mediated disorders. He required ratio 0.875. All but one patient were caucasian. admission at 3 days old due to fever, salmon-coloured macular trun- The SAIs of the cohort were as follow: FMF 33 (44%), TRAPS 9 (12%), cal rash and gastroenterological and neurological signs suggesting MKD 2 (2.6%), CAPS 10 (13.3%), PFAPA 8 (10.6%), indeterminate SAI both enterocolitis and meningitis. At an analytical level, the elevation 6 (8%) and others 7 (9.3%) including 2 Blau syndrome, 2 Schnitzler of acute phase reactants with ESR> 120 mm/h and CRP> 10 mg/dl syndrome, 1 DADA2, 1 SAVI and 1 DITRA. stood out. All microbiological tests were negative. A Sanger study The allelic variants found among the cohort were mainly monoallelic was requested for CIAS1 which was negative. Given the suspicion of in 48 (64%) cases, biallelic in 2 (2.6%) cases, double monoallelic in 9 autoinflammatory syndrome, without being able to identify the exact (12%) cases while no variant was found in 16 /21% cases (PFAPA, cause, treatment with corticosteroids was started with clinical im- Schnitzler syndrome and indeterminate SAI patients). provement. At 2 years of age, he was admitted due to arthritis in Among the 75 patients, 10 (20.1%) presented any autoimmune both hips requiring new corticosteroid treatment that could not be systemic / organ-specific autoimmune disease: 2 spondyloarthritis, 2 withdrawn due to persistent local inflammation. Finally, at 11-years- autoimmune thyroiditis, and 1 case each of ANCA-associated vascu- old, treatment with Ankinra at 100 mg/day was started with good litis, autoimmune thrombopenia, rheumathoid arthritis, AIJ, urticaria- clinical control. vasculitis and PLA2R-associated glomerulonephritis. The most preva- At 13-years-old, new DNA samples were obtained from the patient lent associated SAI was FMF (7 , 70%). and his parents and the genetic autoinflammatory disease study was Among the autoantibodies profile, 17 (22%) patients showed any widen by capturing and sequencing the flanking exonic and intronic autoantibody with 4 cases with >1 autoantiboy isolated. Antinuclear areas of the following 17 genes: MEFV, MVK, TNFRSF1A, NOD2, NLRP3, antibodies were detected in 8 patients at a titer ≥ 1/160. ANCA NLRC4, NLRP12, IL1RN, IL6RN, PLCG2, PSTPIP1, CARD14, TMEM173, antibodies and rheumatoid factor were found in 3 cases each. Anti- PSSMB8, LPIN2, CECR1 and TNFAIP3. slim muscle and anti-thyroid antibodies were found in 2 cases each The study was conducted using the SeqCap EZ HyperCap while anti-Ro52, anti-PLA2R, anti-gastric parietal cell antibodies, anti- (NimbleGen) methodology on a Illumina's MiSeq platform. CCP and direct Coombs were identified in 1 case each. The most Bioinformatic analysis was performed with the sequences obtained: prevalent SAI among autoantibody carrier patients was also FMF (6 alignment against the hg38 genome with BWA-MEM, detection of cases, 35%). changes with GATK and annotation with ANNOVAR. Changes with a No autoantibody was found in 4 out of 10 patients with diagnosis of variant/reading ratio> 0.2 wereconsidered variants. Variants identified any autoimmune condition. On the opposite point of view, 6/17 as pathogenic or probably pathogenic, as well as areas with coverage patients with autoantibodies had an autoimmune disease. <20x, were studied by capillary sequencing. The nomenclature used Conclusion: Autoimmune diseases are not so unfrequent among is the one recommended by HGVS. adult patients diagnosed with SAI of our cohort, mainly in FMF Results: The c.1015C>G p.(Leu339Val) missense variant was detected in patients, as expected for the most prevalent SAI. heterozygosis in NLRC4 NM_0212209.4, a gene intolerant to missense Positivity for any autoantibody were present among >20% of the variation (z-score=0.977). Moreover, this variant which was not found in cohort patients but the presence of autoantibodies was linked to an population database (gnomAD), was located in the NLRC4_HUMAN domain autoimmune disease in only 1/3 of cases. 'NACHT', where most of the missense variants were previously described as The coexistence on the same patient of autoimmune and pathogenic, and a change in the same aminoacid,p.(Leu339Pro), has been autoinflammatory conditions is unfrequent but not mutually recently reported in a symptomatic individual with an autoinflammation excluding. On the other hand, positivity for autoantibodies have with infantile enterocolitis (AIFEC) phenotype. Additional studies in proved in this cohort a limited value as a clue for the identification the progenitors of our patient demonstrated that it was a de novo variant. of an underlying autoimmune diesase. Taking into account all this findings and according to the classification proposed by the American College of Medical Genetics and Genomics Disclosure of Interest (ACMG) the c.1015C>G p.(Leu339Val) missense variant should be considered None Declared as a likely pathogenic variant. Conclusion: We describe a de novo mutation in NLRC4 gene encoding a Leu339Val substitution, which confirms the clinical P12 diagnosis of autoinflammation with infantile enterocolitis (AIFEC). A new autoinflammatory variation in the human domain of NLRC4 gene associated with infantile enterocolitis Disclosure of Interest 1 1 1 L. Martinez Mitjana , M. Lopez Corbeto , E. Moreno Ruzafa , E. García- None Declared 2 2 2 Arumí , E. Tizziano , M. Antolín Pediatric Rheumatology, Hospital Universitario Vall d'Hebron; Department of Clinical and Molecular Genetics, Hospital Universitario P13 Vall d’Hebron, Barcelona, Spain Recurrent fever diagnosis: a case disguised as PFAPA syndrome 1 2 1 Correspondence: L. Martinez Mitjana C. Naharro-Fernández , N. Palmou-Fontana , A. E. López- Lundh ,S. 1 3 3 Pediatric Rheumatology 2021, 20(Suppl 1):P12 Armesto Alonso , B. Jimenez-Montero , C. Alvarez-Alvarez , M. J. Cabero- Perez 1 2 Introduction: NLR family CARD domain-containing protein 4 (NLRC4) Dermatology; Rheumatology, Universitary Hospital Marques De is a key component of inflammasomes that indirectly senses specific Valdecilla; Paediatrician, Hospital Universitario Marquez De Valdecilla, proteins from pathogenic bacteria and fungi and responds by assem- Santander, Spain bling an inflammasome complex that promotes caspase-1 activation, Correspondence: C. Naharro-Fernández cytokine production and macrophage pyroptosis. Mutations in this Pediatric Rheumatology 2021, 20(Suppl 1):P13 Pediatric Rheumatology (2022) 20:2 Page 16 of 39 Introduction: Fever is a very common symptom in childhood. In the mutation in MEFV gene has been detected. We should not forget that FMF first years of life, a healthy child could have annually up to twelve could have a PFAPA-like presentation in order not to misdiagnose this en- fever episodes, especially during the cold season. In most cases, tity. Genetic test in selected patients could allow us to make the correct these episodes correspond to viral infections. However, in other diagnosis in order to improve prognosis of our patients and families. circumstances, infectious etiology is not responsible,and diagnosis becomes a challenge for the pediatrician. Disclosure of Interest Differential diagnosis of recurrent feverencompassesneoplastic None Declared processes, autoinflammatory diseases and immunodeficiencies. Keywords: Recurrent fever; Aphthae; Aphthous stomatitis PFAPA syndrome; Familiar Mediterranean Fever; FMF; MEVF P14 Abbreviations: FMF: Familiar Mediterranean Fever; MEVF: Familiar A patient diagnosed with sifd syndrome (Sideroblastic anemia with Mediterranean Fever Gene; PFAPA: Periodic Fever; Aphthous immunodeficiency, fevers, and developmental delay) Stomatitis; Pharyngitis; Adenitis A. Paç Kisaarslan, S. Ozdemir Cicek, N. Şahin, H. Poyrazoglu Objectives: Recurrent fever is common in childhood. Differential Pediatric Rheumatology, Erciyes University School of Medicine, Kayseri, diagnosis should be conducted in some patients. Autoinflammatory Turkey diseases could be responsible in some circumstances but diagnosis is Correspondence: A. Paç Kisaarslan not easy, as different syndromes could appear overlapped. We Pediatric Rheumatology 2021, 20(Suppl 1):P14 present a clinical case of a boy with recurrent fever, aphthous stomatitisand growing delay. Introduction: Immunodeficiencies with autoinflammatory diseases Methods: We present the case of a 10-year-old boy with recurrent are increasingly being defined.Clinical findings are described wide fever and aphthous stomatitis. range of system. It takes time to diagnose these syndromes. Fever He was asthmatic and he received treatment with inhaled and high acute phase reactants that cannot be explained by corticosteroids. The child had short stature with a delay in bone age infection in immunocompromised patients should suggest of nearly three years. Parents referred previous episodes of fever autoinflammatory diseases. andaphthae. Objectives: Here we present a patient with SIFD syndrome At the age of nine, he was admitted at the hospital with fever, (Sideroblastic anemia with immunodeficiency, fevers, and erosive lesion in mouth developmental delay) with hypogammaglobulinemia, anemia, and decreased intake that started three days before. growth retardation, developmental delay and autoinflammatory Physical examination highlighted multiple aphthae on oral mucosa, findings. hard palate and soft palate and cervical bilateral lymphadenopathies. Methods: Twenty Seven-month-old girl suffered from diarrhea and Blood count revealed leukocytosis and RCP of 2,9 mg/dl with a fever with high acute phase reactants for 4-month-old. Hypogamma- maximum during the hospital admission of 8,3 mg/dl.Chest globulinemia and microcytic anemia were detected at 7-month-old. radiograph showed a left lower lobe infiltrate suggesting pneumonia. Intravenous immunoglobulin (IVIG) treatment was administered, but He received amoxicillin-clavulanic acid and azithromycin.After 72 fever and diarrhea attacks were not resolved. Her colonoscopic and hours fever disappeared and oral lesion improved. biopsy findings were normal. She had growth and developmental re- Serology for herpes simplex virus and bacteria were negative. tardations at 18-month-old. Her attacks were resolved by steroid Mycoplasma pneumoniae IgM and IgG were positives. treatment. But, IL-1 blockade (anakinra) did not effect the attacks. The patient was discharged with diagnosis of mucositis cause by Her autoinflammatory panel did not show any mutations. Parents de- Mycoplasma pneumoniae. nied a further investigation. The patient was administered monthly Results: The patient continued to present additional episodes of IVIG, and low dose steroid treatment for one year. The patient was fever and oral lesions. A rheumatology study was conducted, admitted to our rheumatology department at 27-mounth old. On the showing negative immunodeficiency and autoimmunity. Despite the physical examination, height SDS:-5.26, weight SDS: -5,27 , mental fact that the patient fulfilled the diagnosis criteria for PFAPA, a and motor retardation, microcytic anemia( not sideroblastic anemia) genetic study was requested and the potentially pathogenic were detected. Her whole exon sequencing (WES) showed mutation p.Lys695Arg was detected in the gene MEFV. g.3188201_3188201 del NM_182916.2: c.679delA p.(I233fs*10) on We finally made the diagnosis of FMF in our case. Colchicina was exon 6, and K416E on exon 8 heterozygous mutations. After etaner- prescribed and the boy became asymptomatic in a few weeks. cept treatment, fever and diarrhea attacks resolved, she gained Conclusion: weight and started sitting. However, our genetical study revealed a heterozygous MEFV Results: Sideroblastic anemia with immunodeficiency, fevers, and mutations affecting to exon 10 showing that Familial Mediterranean developmental delay (SIFD syndrome:OMIM 616084) is developed fever should be considered in differential diagnosis of PFAPA. In due to mutation of the tRNA nucleotidyltransferase 1 gene. The some patients, genetic screening could help to make diagnosis of syndrome is characterized by fever, microcytic or sideroblastic autoinflammatory disease with a PFAPA-like presentation. In this hy- anemia, B cell deficiency, HLH, growth and developmental delay, pothesis underlying MEFV gene mutations possibly lead to PFAPA- cerebral atrophy, deafness and blindness, arthritis, panniculitis, oral like clinical presentation in FMF patients. ulcers, subcutaneous nodules. IL-1 and TNF blockade, IVIG, and HSCT Advances in genetic testing enable to identify genetic diseases with higher are recommended treatment of SIFD syndrome. sensibility. Clinical presentation of autoinflammatory syndromes are often Conclusion: Immune deficiencies with autoinflammatory findings are overlapped, especially in PFAFA syndrome, where an important rate of defined increasing rate. Genetic analysis is a significant diagnostic mutation in MEFV gene has been detected. We should not forget that FMF methot of these diseases. The importance of WES analysis increases could have a PFAPA-like presentation in order not to misdiagnose this en- in autoinflammatory patients who cannot be diagnosed, especially in tity. Genetic test in selected patients could allow us to make the correct the presence of accompanying signs of immunodeficiency. diagnosis in order to improve prognosis of our patients and families. Advances in genetic testing enable to identify genetic diseases with higher sensibility. Clinical presentation of autoinflammatory syndromes are often Disclosure of Interest overlapped, especially in PFAFA syndrome, where an important rate of None Declared Pediatric Rheumatology (2022) 20:2 Page 17 of 39 P15 patient (and seemingly the previously described patient carrying the Safety of anakinra in patients with Cryopyrin Associated Periodic c.2626del/p.(Ile876Leufs*15) mutation) had milder phenotype than Syndromes (CAPS) using a graduated pre-filled syringe did the other five. So far, at 7 years old, she does not present more This abstract has not been included here as it has been previously than a systemic autoinflammatory phenotype with panniculitis. published Conclusion: SAMD9L associated autoinflammatory disease is a new entity whose clinical feature overlaps with CANDLE. It is worth to be separated from CANDLE as it may predispose to early and severe complications that P16 need to be prevented. Indeed, early and severe ILD or cytopenia may A patient with candle-like phenotype and de novo frameshift justify eligibility to hematopoietic stem cell transplantation. As a treatment mutation in the SAMD9L gene concern, patients with SAAD may respond to JAK inhibiting therapies 1,2 3,4 5 5 6 A. Remy , C. Borocco , G. Sarrabay , G. Boursier , S. Fraitag ,B. despite their interferon signature may be only moderately elevated(4). The 2,7 2,8 3,9 Catteau , H. Reumaux , I. Koné-Paut functional consequences of SAMD9L gene mutations need to be clarified to Pediatric Emergency, Infectious Diseases and Rheumatology optimize targeted therapy. Department, CHU Lille; Faculté de médecine, University of Lille, Lille; (1) Torrelo A. CANDLE Syndrome As a Paradigm of Proteasome- Pediatric Rheumatology Department, CHU Bicêtre, AP-HP, Le Kremlin- Related Autoinflammation. Front Immunol 2017;8:927. 4 5 Bicêtre; University of Paris Saclay, Paris; Laboratory of Rare and (2) Insalaco A, Prencipe G, Pardeo M, et al. Involvement of the IFN- Autoinflammatory Genetic Diseases, CHU Montpellier, Montpellier; gamma pathway in a patient with candle syndrome carrying a novel Pathology Department, CHU Necker-Enfants Malades, AP-HP, Paris; variant of PSMB8 gene. Pediatr Rheumatol Online J 2014;12:P249. 7 8 9 Dermatology Department; CHU Lille, Lille; Faculté de médecine, (3) de Jesus AA, Hou Y, Brooks S, et al. Distinct interferon signatures University of Paris Saclay, Paris, France and cytokine patterns define additional systemic autoinflammatory Correspondence: A. Remy diseases. J Clin Invest 2020;130:1669–82. Pediatric Rheumatology 2021, 20(Suppl 1):P16 (4) Sanchez GAM, Reinhardt A, Ramsey S, et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Introduction: Chronic Atypical Neutrophilic Dermatosis with Clin Invest 2018;128:3041–52. Lipodystrophy and Elevated Temperature syndrome (CANDLE) syndrome belongs to a group of rare monogenic systemic Disclosure of Interest autoinflammatory diseases (SAID) also called interferonopathies. They None Declared originate in aberrant IFN production and signaling. Prototypic CANDLE syndrome is linked to recessive mutations in immunoproteasome subunits genes, e.g. subunit beta type 8 (PSMB8), affecting the P17 clearance of damaged proteins via the proteasome (1). Antiinflammatory, antioxidant and anti-atherosclerotic effects of a Objectives: To underline the interest of pursuing the investigations combination of natural supplements on patients with FMF related when both the phenotype and the genotype of a patient does not AA amyloidosis: a non-randomized 24 weeks open label come strictly within the framework of what has been previously interventional study known. This abstract has not been included here as it has been previously Methods: We report a case of a child with prominent inflammatory published and cutaneous phenotype that appeared at birth. Despite initial next generation sequencing (NGS) of a small panel of autoinflammatory genes showed an heterozygous mutation in PSMB8 gene, the patient P18 did not present typical features of CANDLE. Further genetical The effect of M694V homozygosity on the carotid intima-media investigations rescued diagnosis. thickness and flow mediated dilatation in patients with fmf related Results: The girl was born to unrelated Caucasian parents. From amyloidosis birth, she presented with urticaria that covered her face and limbs, This abstract has not been included here as it has been previously became ecchymotic, and extended to palms and soles. Since the age published of 3 months old, she developed unexplained recurrent fever (2 days long, twice a month) and painful edema of extremities without true arthritis. Blood work-up showed continuous and moderate inflamma- P19 tion during and in-between outbreaks. A diagnostic of SAID was sug- From mild to severe distinct faces of adenosine deaminase 2 gested. The patient received anakinra with partial efficacy. Skin deficiency in the single pediatric rheumatology center study biopsy showed inflammatory infiltrate in the whole dermis that was B. Sozeri, F. Demir, S. Caglayan, K. Ulu, T. Coskuner compatible with the diagnosis of CANDLE. NGS of an auto- Pediatric Rheumatology, University of Health Sciences , Istanbul, inflammatory genes panel did not find any variant with a putative Umraniye Training and Research Hospital,, Istanbul, Turkey pathogenic role notably in the NLRP3-associated autoinflammatory Correspondence: B. Sozeri syndrome and mevalonate kinase deficiency. However, it showed Pediatric Rheumatology 2021, 20(Suppl 1):P19 one heterozygous p.(Thr74Ser) variant in the PMSB8 gene (2). Despite the fact that our patient had prominent inflammatory and cutaneous Introduction: Deficiency of adenosine deaminase 2 (DADA2) is an phenotype, the constellation of criteria was incomplete and atypical autosomal recessive disorder characterized by poliarteritis nodosa- for CANDLE syndrome. First, her skin examination by an experienced like symptoms, fever, livedoid racemose, early-onset stroke and mild dermatologist did not show lipodystrophy. Then, other marked differ- immunodeficiency. The loss-of-function mutations in CECR1 gene ences were the absence of hepatomegaly, of cytopenia, and the which encodes the enzymatic protein adenosine deaminase 2 mildly elevated interferon signature. There was more than met the (ADA2) associated with the DADA2. eyes. Genetic analysis was pursued with whole exome sequencing re- DADA2 is present with a spectrum of vascular and inflammatory vealing a de novo frameshift variant p.(Ile876Leufs*15) in the Sterile phenotypes with highly varied clinical expression. The patients Alpha Motif Domain–containing protein 9-Like (SAMD9L) gene. Treat- can present with isolated constitutional symptoms, arthralgia, ment switch with JAK inhibitor (baricitinib) finally enabled a clear myalgia, and/or livedoid rash. The severe phenotype of the skin improvement. disease is emerge as early-onset stroke, bone morrow suppres- In a recent study, SAMD9L mutations were identified in six patients sion, neutropenia, liver failure and/or neurologic disorders It is among twelve with CANDLE-like phenotype (3). The overall pheno- currently not well understood what cause the variability in the type of patients is very severe as two out of six patients are deceased severity of clinical phenotype. at an early age and two other patients underwent bone marrow Objectives: We aim to describe the clinical characteristics, genotype transplantation for severe cytopenia or interstitial lung disease. Our and treatment of patients diagnosed with DADA2 in our clinic. Pediatric Rheumatology (2022) 20:2 Page 18 of 39 Methods: All the patients diagnosed and followed up in Department 390, 30.4%), persistence of disease activity frequent attacks (n= of Pediatric Rheumatology, Umraniye Training and Research Hospital, 44, 47.3% and n=1,023, 79.9%) and/or uncontrolled inflammatory Istanbul, Turkey, between 2016 and 2020. All symptomatic patients syndrome (n=46, 49.5% and n=398, 31.1%), and worsening in pa- suspected with DADA2 were analyze by genetic test and ADA-2 en- tients' quality of life (n=36, 38.7% and n=100, 7,8%). No rea- zyme activity, also relatives of index cases were also screened. ADA-2 sons were specified for 12 (16.4%) JIR cohort patients and 154 enzyme activity was evaluated at Duke University Medical Center. (12%) patients in the literature. Results: We diagnosed 10 patients with DADA2, 5 of them had mild Conclusion: In the absence of standardized indications for IL1 phenotype or asymptomatic, or they were relatives of index cases, and inhibitors in crFMF, MKD and TRAPS, these results could serve as a 5 of the patients had severe phenotype. Three of the patients were basis for developing a standardized composite score that would help girls and seven were boysThe age of the patients at diagnosis was in clinicians to assess the activity and severity of HRF at a specific time the range of 2–28 years. The age of the patients at disease onset was point in order to evaluate the need of a therapeutic escalation with also in the range of 2 months–14 years. Six of the patients were index IL-1 inhibitors. cases and the other four were their relatives. Homozygous mutations in CECR1 were shown in all subjects.The frequency of phenotypic Acknowledgments manifestations of the patients were seen as follow respectively; fever 80%, livedoid rash 70%, digital ulsers and/or amputations 20%, keywords : hereditary recurrent fevers, indications, interleukin-1 neurologic involvement 50%, gastrointestinal involvement 20%, blocking agents, anakinra, canakinumab hematological involvement 40%, and immunodeficiency 30%.The initial diagnosis of index cases were as follows; two classic PAN, one cutaneos Disclosure of Interest PAN, one Behçet’s disease and two Diamond Blackfan syndrome. The None Declared activity of ADA2 was evaluated and clearly diminished in all patients (0- 12.1 mU/g protein). 6 of the 10 patients were treated with anti-tumor necrosis factor therapy.Two patients were awaiting bone marrow P21 transplantation. Dysregulation of MIR-505-5P which targets CYP3A4 in colchicine- Conclusion: The clinical manifestations of DADA2 vary from mild skin resistant familial mediterranean fever patients 1 1 1 2 3 involvement to severe multisystemic vasculitis. It is suggesting that T. H. H. Akbaba , B. S. Ozdemir , Y. Z. Akkaya-Ulum , P. Mutlu , S. Ozen , both residual ADA2 activity levels and gene mutation are important B. Balci-Peynircioglu 1 2 in clinical phenotype. Medical Biology, Hacettepe University, Middle East Technical University, Hacettepe University, Ankara, Turkey Disclosure of Interest Correspondence: T. H. H. Akbaba None Declared Pediatric Rheumatology 2021, 20(Suppl 1):P21 Introduction: Familial Mediterranean Fever (FMF) is an autosomal P20 recessive inherited autoinflammatory disease. The well-known treat- Real-life indications of interleukin-1 blocking agents in hereditary ment of the disease is daily colchicine uptake. However, approxi- recurrent fevers: data from the jircohort and a literature review mately 5% of patients do not respond to colchicine treatment 1 2 3 4 C. Vinit , S. Georgin-Lavialle , A. Theodoropoulou , S. Atmane ,C. despite using the highest tolerable colchicine. In addition to colchi- 5 6 3 3 7 8 Barbier , A. Belot , F. Hofer , M. Mejbri , P. Pillet , J. Pachlopnik ,S. cine treatment, these patients receive anakinra, canakinumab, and 9 7 10 4 1 Poignant , C. Rebelle , A. Woerner , I. Kone-Paut , V. Hentgen similar drugs to prevent inflammation. 1 2 3 Versailles hospital, Versailles; Tenon hospital, Paris, France; Lausanne Objectives: This study aims to investigate the potential impact of University Hospital, Geneva, Switzerland; Bicetre University hospital, miRNAs on drug resistance observed in FMF patients. 5 6 Kremlin Bicetre, Grenoble Hospital, Grenoble; Lyon University hospital, Methods: Microarray data obtained in our previous studies was re- 7 8 Lyon; Bordeaux University hospital, Bordeaux, France; Kinderspital, evaluated for colchicine-resistant patients with severe phenotype 9 10 Zurich, Switzerland; Nantes University hospital, Nantes, France; UKBB and candidate miRNAs that are involved in drug metabolism were Hospital, Bâle, Switzerland determined by performing bioinformatics analysis. miRNA-target Correspondence: C. Vinit gene studies were performed and miRNAs which have a role in the Pediatric Rheumatology 2021, 20(Suppl 1):P20 mechanism of drug resistance in FMF were determined. Then, 3'UTR luciferase activity experiments were carried out to determine the tar- Introduction: Interleukin (IL)-1 inhibitors represent the main get gene. Then, target gene expression studies were performed. treatment in patients with familial Mediterranean fever (and Results: As a result of miRNA array analysis, miR-186-3p, miR-548a- colchicine resistance or intolerance, crFMF), mevalonate kinase 3p, miR-7-5p were decreased, miR-505-5p and miR-4482-3p were in- deficiency (MKD) and periodic tumor necrosis factor receptor-related creased in colchicine-resistant familial Mediterranean fever patients. syndrome (TRAPS). However, the reasons for use of IL-1 inhibitors in miR-505-5p was found as a regulator of drug metabolism and drug these diseases are still unclear. resistance-related genes by bioinformatical tools and validated by Objectives: Identify real life situations that led to use anakinra or qRT-PCR. Target gene studies performed in HEPG2 cell (hepatocellu- canakinumab in hereditary recurrent fevers (HRF), combining data lar carcinoma cell line) showed that miR-505-5p regulates CYP3A4 ex- from an international registry, the JIR cohort, and an up-to-date lit- pression at the RNA level. MiR-505-5p – CYP3A4 interaction was erature review. shown by 3’UTR luciferase assay. Methods: We extracted data from a web-based registry: the JIRco- Conclusion: Functional analyzes related to colchicine metabolism are hort, in which clinical information (demographic data, treatment, dis- underway. A possibly explanation about drug resistance observed in ease activity and quality of life) on patients with FMF, MKD and complex FMF patients through miRNAs will allow the development TRAPS was collected retrospectively. A literature search was con- of new drug targets for these patients in the future. ducted using Medline and EMBASE. Results: We analyzed complete data of 93 patients with HRF Acknowledgments (53.8% FMF, 31.2% MKD and 15.1% TRAPS). Data from both the This project has been funded by The Technical and Scientific Research registry and the literature review confirmed that the main Council of Turkey, 218S522. reasons for use of IL-1 blockers were: failure of previous treat- ment (n=57, 61.3% and n=964, 75.3% respectively), severe disease Disclosure of Interest complication or associated comorbidities (n=38, 40.9% and n= None Declared Pediatric Rheumatology (2022) 20:2 Page 19 of 39 P22 increasing interactions between the NLRP3 and NEK7 proteins, An atypical periodic fever syndrome due to a mutation in the thereby lowering the threshold required for NLRP3 inflammasome leucine rich repeat domain of NLRP3 activation. 1 1 1,2,3 1 E. A. Caseley , J. Topping , S. Savic , M. F. McDermott Leeds Institute of Rheumatic and Musculoskeletal Medicine, St James's References University Hospital; Department of Clinical Immunology and Allergy, St 1. Nakanishi H, Kawashima Y, Kurima K, Muskett JA, Kim HJ, Brewer CC, James’s University Hospital; National Institute for Health Research–Leeds et al. Gradual symmetric progression of DFNA34 hearing loss caused by Biomedical Research Centre, Chapel Allerton Hospital, Leeds, United an NLRP3 mutation and cochlear autoinflammation. Otology & Kingdom neurotology: official publication of the American Otological Society, Correspondence: E. A. Caseley American Neurotology Society [and] European Academy of Otology and Pediatric Rheumatology 2021, 20(Suppl 1):P22 Neurotology. 2018;39(3):e181. 2. Meng G, Zhang F, Fuss I, Kitani A, Strober W. A mutation in the Nlrp3 Introduction: Gain-of-function mutations in the NLRP3 inflamma- gene causing inflammasome hyperactivation potentiates Th17 cell- some cause NLRP3-associated autoinflammatory diseases (NLRP3- dominant immune responses. Immunity. 2009;30(6):860-74. AIDs); these mutations are rarely located in the leucine rich repeat 3. Medvedeva IV, Stokes ME, Eisinger D, LaBrie ST, Ai J, Trotter MW, et al. (LRR) domain. Here we present a patient with a c.2753 G>A variant Large-scale analyses of disease biomarkers and apremilast pharmacody- in NLRP3 exon 7, resulting in the Arg918Gln (R918Q) mutation in the namic effects. Scientific reports. 2020;10(1):1-11. LRR domain of NLRP3(1), causing oral ulcers and hearing loss; she 4. He Y, Zeng MY, Yang D, Motro B, Núñez G. NEK7 is an essential mediator was significantly less responsive to anakinra treatment compared to of NLRP3 activation downstream of potassium efflux. Nature. previously reported cases of this mutation but has responded well to 2016;530(7590):354-7. apremilast, a phosphodiesterase 4 inhibitor. Objectives: We aimed to identify molecular mechanisms contributing Acknowledgments to this patient’s unusual disease presentation and response to This project has received funding from the European Union’s Horizon 2020 treatment, in addition to characterising changes in protein-protein in- research and innovation programme under the grant agreement No: 779295 teractions caused by the R918Q mutation. Methods: We isolated CD14+ monocytes from the patient or three Disclosure of Interest healthy controls (HCs) and analysed cell responses after NLRP3 None Declared stimulation using RT-PCR, ELISA or flow cytometry. Monocytes were also differentiated into M0, M1 or M2 macrophages, from which RNA was isolated and used for RNA sequencing (RNA-seq). Interactions P23 between NLRP3 and NIMA-related kinase 7 (NEK7) were analysed in SAA1 Polymorphisms contribute more than mefv mutations in silico using PDBePISA and PyMOL, combined with immunoprecipita- renal AA-amyloidosis -preliminary results 1 2 tion and subsequent immunoblotting studies in HEK293T cells trans- D. Ait-Idir , B. Djerdjouri fected with NLRP3 and NEK7. Biology, Faculty of sciences, University M'hamed Bougara, Boumerdes; Results: Elevated IL-1β release was seen in patient’s monocytes when Faculty of Biological Sciences, University of Sciences and Technology unstimulated or stimulated with a priming stimulus alone compared Houari Boumediene, Algiers, Algeria to the HCs, a hallmark of NLRP3-AIDs. This was accompanied by a sig- Correspondence: D. Ait-Idir nificant increase in IL-18 release in response to NLRP3 stimulation in Pediatric Rheumatology 2021, 20(Suppl 1):P23 the patient’s cells and elevated IL-6 in patient serum. Extracellular ASC specks, pivotal components of the NLRP3 inflammasome, were Introduction: Renal AA amyloidosis can develop with a high also more readily released by the patient’s monocytes. Transcrip- prevalence in untreated patients with familial Mediterranean fever tomic profiling of NLRP3-R918Q macrophages showed similar M1 (FMF, OMIM 249100). The MEFV and SAA1 genotypes are the two and M2 macrophage genotypes in patient’s cells compared to HCs, genetic risk factors that have been associated with the development suggesting impaired mucosal tissue healing by M2 macrophages, of this serious complication. which may contribute to the patient’s persistent oral ulcers. KEGG en- Objectives: This study aimed to evaluate the involvement of each richment analysis further showed significant enrichment of inflamma- genetic factor in the occurrence of renal AAamyloidosis. tory pathways, particularly the IL-17 and NF-kB signalling pathways. Methods: Sixty-two unrelated Algerian FMF patients were included Upregulation of IL-17 indicates a skewing of T-helper responses to- in this study. Among them, 41 (19 men, 22 women; mean age: 36.26 wards a Th17 phenotype, as previously observed in NLRP3-AIDs(2), in ± 14.43 years) with biopsy-confirmed AA amyloidosis were recruited addition to IL17A and NF-kB being a biomarker for apremilast effi- from the nephrology departments, and 21 (9 men, 12 women; 33, 80 cacy(3), partly explaining this patient’s unusual response to therapy. ± 14, 71 years) without renal complications came from the internal Molecular characterisation of the R918Q mutation was also carried medicine departments. out, using the recently determined cryo-electron microscopy struc- Sixty-two unrelated Algerian FMF patients were included in this ture of NLRP3 in complex with its endogenous regulator, NEK7(4). study. Among them, 41 (19 men, 22 women;mean age: 36.26 ± 14.43 The R918Q mutation was shown in silico to increase the electrostatic years) with biopsy-confirmed AA amyloidosis were recruited from the complementarity between the NLRP3 LRR domain and the interact- nephrology departments,and 21 (9 men, 12 women; 33, 80 ± 14, 71 ing interface of NEK7. This was confirmed by co-immunoprecipitation years) without renal complications came from the internal experiments; cells transfected with the mutant NLRP3-R918Q showed medicinedepartments. increased binding to NEK7 compared to WT NLRP3. Results: Screening of the MEFV gene revealed a significant Conclusion: Here we show that the NLRP3-R918Q mutation causes correlation between the M694I/M694I genotype and renal an atypical periodic fever syndrome with significant mucosal amyloidosis. The genotypes of the SAA1 locus were differentially involvement. The involvement of factors such as a Th17 phenotype, distributed between the two groups of patients. A significant in addition to increased NLRP3 inflammasome activity, go some way predominance of SAA1.1/1.1 genotype was found in patients with to explaining the lack of efficacy of anakinra treatment. We propose amyloidosis, compared to those without this complication (p=0.001), that the R918Q mutation enhances NLRP3 inflammasome activity by while the SAA1.5/1.5 genotype was exclusively associated with Pediatric Rheumatology (2022) 20:2 Page 20 of 39 P25 patients without amyloidosis. Logistic regression analysis for the risk Patient Engaged Genomic Understanding and Interpretation of development of amyloidosis revealed a 4.3times increase in risk in (PENGUIN): a case study in patients with Familial Mediterranean the M694I/M694I genotype (95% CI 1,35 – 14). However, this risk Fever (FMF) increases eight times in presence of the SAA1.1/1.1 genotype (OR 1 1 1 1 2 3 K. A. Maloney , M. Giglio , H. Zhang , L. Jeng , D. Sewell , N. Ambulos , 8.7; 95% CI 2.25 – 33). 1 1 1 1 4 A. Beitelshees , E. Streeten , D. Loesch , N. Sampaio Moura , N. Dueker , Conclusion: Our preliminary results based on a small cohort of FMF 1 5 6 1 7 1 K. Palmer , R. Gore , S. Kittner , T. O'Connor , J. Jagger , T. Pollin ,S. patients suggest that genotypes at the SAA1 locus may predispose Riley more than genotypes at the MEFV locus to the occurrence of renal 1 2 3 Medicine; Translational Genomics Laboratory; Microbiology and AA amyloidosis. Immunology, University of Maryland School of Medicine, Baltimore; 4 5 University of Miami Miller School of Medicine, Miami; Pediatrics; Acknowledgments Neurology, University of Maryland School of Medicine, Baltimore; We thank the physicians for their contribution in patients recruitment. Familial Mediterranean Fever Foundation, Barboursville, United States Correspondence: K. A. Maloney Disclosure of Interest Pediatric Rheumatology 2021, 20(Suppl 1):P25 None Declared Introduction: Many patients with FMF are motivated to seek genomic information not available through their medical providers. P24 We explored a novel solution providing patients with direct access to Is interferonopathy caused nasal perforation in a patient with their genomic data while mitigating adverse consequences of nijmegen breakage syndrome ? misinformation arising from some direct-to-consumer genetic testing. S. S. Kilic Objectives: To meet patients’ objectives for informed access to Pediatric Rheumatology, Uludag University Medical Faculty, Bursa, Turkey genomic data by providing them with their own exome sequence in Pediatric Rheumatology 2021, 20(Suppl 1):P24 the setting of a professionally administered genomics educational workshop. Introduction: Nijmegen breakage syndrome (NBS) is a rare Methods: Thirty-two adults, residing in the U.S. or Canada were re- autosomal recessive disorder of chromosomal instability. It is cruited via email from the FMF Foundation. All provided medical characterized by short stature, microcephaly, a typical facial documentation of clinical and/or molecular diagnosis of FMF. Follow- appearance, immunodeficiency, radiation sensitivity, and a strong ing informed consent, saliva samples underwent clinical exome se- predisposition to lymphoid malignancy. NBS is caused by a mutation quencing and data were filtered to analyze variants in 30 auto- in the NBS1 gene, located at human chromosome 8q21. inflammatory (AI) genes and 59 clinically significant genes (“second- Objectives: We present a case with NBS suspected having ary findings”) deemed actionable by the American College of Medical interferonopathy Genetics and Genomics (ACMG). Participants were informed of Methods: A 14 years old girl was first admitted to our pathogenic and likely pathogenic variants in AI and ACMG genes, outpatient clinic with the complaint of perforated nasal septum, and variants of unknown significance (VUS) in AI genes. They also re- chronic otitis externa and persistent skin lesions. There was a ceived their raw exome data files. An educational workshop featured parental consanguinity. Nasal septum perforation occurred at 10 eight sessions on general genetics, personal data exploration using years of age. Physical examination revealed; weight: 38 kg (< GenomeBrowse, pharmacogenomics, and AI diseases. Participants 3P), height: 136 cm (<3P), microcephaly, crepitation in both completed surveys before and two weeks after the workshop (e.g., lung bases, ulcerated lesion below the right eye and from right FMF disease severity, health numeracy, genomics knowledge, health upper lip extending to the nasal septum which was perforated. literacy, self-efficacy). While total blood count, erythrocyte sedimentation rate, IgG, Results: The PENGUIN workshop was held virtually on November 20- IgG1, IgG3, IgA, IgE, NBT were normal, serum IgM <16,9 mg/dl 21, 2020, utilizing Zoom and Slack. Participants’ ages were from 24- (88-322 mg/dl) and IgG2: 183 mg/dl (236-605 mg/dl) levels 74, 63% were female, and 84% had university degrees. They had were low. Lymphocyte subsets were normal except for slight high numeracy and genomic literacy. Twenty-two (69%) participants low CD8 (16.3%, 489/mm ). Antibody responses (anti HBS and had prior MEFV genetic testing, including one who had research- tetanus IgG) were negative. HLA ABC expression by flow based exome sequencing. PENGUIN testing detected all previously cytometry was 99 % (MFI:13669). Histologic analysis of a nasal reported disease-associated MEFV variants; however, three variants septum biopsy was unhelpful, revealing only a nonspecific were reclassified as VUS. Molecular diagnosis was newly confirmed in polymorphic inflammatory infiltrate without perivascular six individuals with a prior clinical diagnosis of FMF. Eighteen partici- distribution and an absence of vasculitis or granulomatosis. PPD pants harbored 28 VUS in 14 AI genes; some of these may be risk was15x17mm, quantiferon measurement test and sputum variants as part of a complex etiology. Only VUS were found in five culture were negative. Tests for leishmaniasis ere negative. participants. Two individuals had secondary findings. Immediate Thorax CT showed bronchiectasis in the middle lobe of right feedback from the workshop was extremely positive, with partici- lung. A homozygous JL2494 – NBN exon 3 mutation was found pants expressing strong appreciation for the opportunity to receive by kindly Anne Puel's lab. Nijmegen breakage syndrome was comprehensive genetic results, understand and explore their gen- diagnosed. The patient commenced on IVIG treatment. Stem omic data, and interact with FMF patients, scientists and clinicians in cell transplantation has been planned. a collegial manner. Conclusion: It has been showed that type I and III IFN signatures Conclusion: The genetic findings across the AI spectrum confirmed were elevated in patients with AT, Artemis deficiency, and SAVI. FMF patients’ perceptions of the paucity of genetic information Although cutaneous granulomas have been reported in patients with through their medical providers, validating their incentive to seek NBS but interferonopathy has not been reported. We believe that, genetic testing outside of the medical system. As the cost of more information is needed on this issue. genomic sequencing decreases, the PENGUIN model of patient engagement may be a valuable method for meeting FMF and other Disclosure of Interest rare genetic disease patients’ legitimate quest for access to None Declared Pediatric Rheumatology (2022) 20:2 Page 21 of 39 comprehensive genomic data and knowledge. This inaugural group c.1991T>C (p.Met662Thr). No NLRP3 mutation was detected in the of FMF patients was engaged and capable, and future studies will patient’s parents. The mutation had previously been described in need to assess the wider uptake and success of such a program. two cases of severe NLRP3-AID. Canakinumab was started at a dose of 150 mg every 2 months, but neurologic deterioration prompted a Acknowledgments switch to anakinra 100 mg daily after a few months. The latter We would like to thank the participants of the PENGUIN workshop and allowed clinical stabilization as well as normalization of cerebrospinal funding from the University of Maryland Dean's Challenge Grant. fluid analysis and inflammatory markers. The proband displayed unique manifestations of NLRP3-AID, namely the absence of an Disclosure of Interest urticaria-like rash and peripheral eosinophilia with organ infiltration, None Declared as well as prominent serositis. Conclusion: In summary, we hereby report a case of severe NLRP3- AID with peripheral and tissue eosinophilia and prominent serositis, P26 but lacking urticaria. As a result, the absence of an urticarial rash An atypical presentation of NLRP3-associated autoinflammatory should not curtail a diagnosis of NLRP3-AID in patients with other disease compatible manifestations. Furthermore, the association of autoin- 1 2 3 L. Marois , S. Ducharme-Bénard , H. Chapdelaine flammatory features and eosinophilia should raise suspicion for this 1 2 Institut de recherches cliniques de Montréal, Internal Medicine, Hopital diagnosis. du Sacré-Coeur de Montréal, Immunologie, Institut de recherches cliniques de Montréal, Montréal, Canada Disclosure of Interest Correspondence: L. Marois None Declared Pediatric Rheumatology 2021, 20(Suppl 1):P26 Introduction: NLRP3-associated autoinflammatory diseases (NLRP3- P27 AID) are rare genetic autoinflammatory diseases associated with Unravelling clinical and genetic spectrum of Mevalonate Kinase gain-of-function mutations in NLRP3 coding for cryopyrin. We hereby Deficiency (MVKD) in Libya 1 1,2 report a case with unique manifestations of NLRP3-AID. A. A. Abushhaiwia , Y. Yusra AElfawires Results: A 36-year-old French Canadian male presented with a 3- Paediatric Rheumatology, faculty of Medicine, Tripoli university ,Tripoli week history of left knee arthritis and systemic inflammation (neutro- children's hospital; paediatric Rheumatology , faculty of Medicine, philia, microcytic anemia, thrombocytosis, elevated C-reactive protein Tripoli university, Tripoli children's hospital , Tripoli , Libya (208 mg/L), and erythrocyte sedimentation (94 mm/h). Joint aspir- Correspondence: Y. Yusra AElfawires ation revealed 161 500 white blood cells/ml with 91% neutrophils, Pediatric Rheumatology 2021, 20(Suppl 1):P27 low glucose level, elevated lactate, and negative gram stain. Despite treatment with cefazolin then meropenem and repeated arthroscopic Introduction: Hyper-IgD syndrome (HIDS, MIM #260920 and MIM joint drainages for suspicion of septic arthritis, no improvement was #610377) is a rare spectral autosomal recessive autoinflammatory dis- noted after one week. Synovial fluid and blood cultures returned order caused by mutations in the mevalonate kinase (MVK) gene. negatives. At that point, an underlying inflammatory disorder was HIDS share similar phenotype to the others hereditary periodic fever suspected. Antibiotics were discontinued and oral prednisone was in- syndromes (HPFS), which include: recurrent fever, lymphadenopathy, troduced, with prompt improvement in inflammatory markers and hepatomegaly, rash, arthritis, abdominal pain. Specifically increased knee swelling. Work-up for autoimmune diseases revealed negative levels of biomarkers related to acute inflammation like serum amyl- anti-nuclear antibodies and anti-cyclic citrullinated peptide anti- oid A (SAA), C-Reactive Protein (CRP) is also a common finding to all bodies, normal complement levels, positive rheumatoid factor, and HPFS. Serum levels of immunoglobulin D (IgD) is not a specific find- HLA B27 antigen. Screening for viral hepatitis, human immunodefi- ing as it can also be present in other syndromes as PFAPA. A ciency virus, tuberculosis, streptococcal infection, and Lyme disease more specific feature, the aciduria mevalonica, can be found in the was negative. Radiographs of axial and peripheral joints were unre- severe spectrum of patients with the deficiency of mevalonate kin- markable, apart from a right knee effusion that also responded to ase. The clinical presentation largely depends on the residual activity steroid therapy. One week later, the patient complained of chest of mevalonate kinase ranging from virtually undetectable to a range pain, with a concomitant increase in inflammatory markers. Imaging of unfunctional but detectable levels. Due to decreased level of revealed a right loculated pleural effusion. Pleural liquid revealed low mevalonate kinase, RhoA remains unprenylated and increases the se- pH, elevated proteins, elevated LDH, and undetectable glucose level, cretion of pro-inflammatory cytokines such as IL-1β that results in despite a surprisingly low white blood cell count and negative gram the development of the cardinal autoinflammatory symptoms. Rarity stain. Antibiotics were resumed for suspected complicated parapneu- of the disease and lack of genetic testing for confirmation makes monic effusion, and the dose of prednisone was halved. Pleural bac- diagnosis challenging in Libya and in other middle-income coun- terial, fungal, and mycobacterial cultures eventually came back tries. Interestingly colchicines do not prevent attacks, anti-TNF has a negative. Antibiotics were nevertheless continued for a total of 4 variable effect and only anti-IL1 is effective. weeks. Prednisone was also continued at 20 mg daily. Upon dis- Objectives: To report for the first time the clinical and genetic charge, knee synovitis and pleural effusion had resolved, and C- findings in two patients from Libya. reactive protein had decreased to 105 mg/L. Methods: We retrieved clinical data from patient’s records. Genomic Family history was unremarkable, with no consanguinity. On the DNA was isolated from peripheral blood and a target gene panel other hand, the patient had a personal history of aseptic meningitis with all the 5 genes already known to be related to the HPFS was at 2 years, sensorineural deafness, seronegative juvenile idiopathic performed. arthritis (history of recurrent fevers with flares of arthritis and high Results: Case report inflammatory markers), pericarditis requiring drainage at 6 years, as An 11-year-old Arab Libyan girl, born of un-consanguineous parents. well as a global developmental delay whose investigation by She has been evaluated, managed and admitted several times since cerebral CT scan revealed diffuse atrophy and pseudopapilloedema. the age of 50 days, without reaching a specific diagnosis. She pre- Also, the investigation of failure to thrive has demonstrated sented to our Rheumatology clinic in January 2013, at age of 2 years eosinophilic enteropathy. and has been followed since. Presenting with recurrent attacks of In light of the long-standing history of sensorineural hearing loss, fever (reaching 40.3°C), lasting 3-5 days, every 2–8 weeks accompan- physical and mental developmental delay, intermittent serositis, and ied by oral aphthae, abdominal pain and diarrhea. Associated with elevated inflammatory markers, NLRP3-AID was suspected. DNA ana- headache, abdominal pain, nausea, and vomiting frequently. Cervical lysis by next-generation sequencing (NGS) revealed a heterozygous LAP was almost always present in attacks. Leukocytosis (15,000mm3- mutation in exon 3 encoding the NACHT domain of the NLRP3 gene, 26, 000mm3), increased ESR and CRP (50 100mg/L), the remaining Pediatric Rheumatology (2022) 20:2 Page 22 of 39 variables were normal.IgD levels were normal (37mg/dL), negative Leu27Pro) were associated with severe clinical phenotypes com- urine movalenate kinase and elevated SAA (initially 2mg/L, later 199 pared with mutations with decreased or unchanged protein mg\L and currently 5mg/L). Initially, attacks were occurring every 3 expression. weeks, but frequency decreased as the child grew. Last year one at- Objectives: we report for the first time DITRA in a Libyan child. We tack occurred every 2-3 months. The diagnosis of FMF or HIgD syn- also briefly discuss potential provisional therapeutical interventions drome was entertained initially and she was put on colchicines. for the treatment of this rare disorder in middle income countries However, she continued to have recurrent attacks despite high doses where neither anti-IL1 nor anti-IL12/23 are available. (1.5 mg) of daily colchicines. Methods: We retrieved clinical data from patient’s records. Genomic Her 5-year-old sister (P2) had similar symptoms since the age of 2 DNA was obtained from peripheral blood. A direct sequencing of the years clinically characterized by recurrent attacks of fever that coding exons and the flanking splice signals of the IL36RN gene was reached as high as 40.3°C associated with oral ulceration, joint pain performed using standard procedures. and enlarged cervical lymph nodes. Headache, abdominal pain, nau- Results: Case Report sea, and vomiting, similar to P1, were also present in some of the at- A 4 year-old Arab Libyan boy, born from non-consanguineous par- tacks. The initial attacks were occurring as frequently as every 3 ents came to our attention due to a suspicion of a systemic autoin- weeks. Laboratory investigation during attacks revealed mild anemia. flammatory condition. Of note, the index patient had two (Haemoglobin as low as 10.3 g/l) during the attacks with platelets healthy brothers and an uncle diagnosed with psoriatic arthritis. At were within normal limits, white blood cells count were as high as the age of 2 years recurrent and severe episodes of generalized 24,400 always with fluctuant levels of acute reactant markers as pustular psoriases requiring many hospital admissions started. Ini- erythrocyte sedimentation rate (ranged from 40 to 80 mm/h). She tially, he was managed as of pustular psoriasis after a 6-month his- was put on colchicines but it did not achieve clinical control. Familial tory of appearance. Skin lesions were characterized by diffuse pedigree reconstruction allowed the suspicion of a recessive disorder pustules involving cheeks, perioral area associated with mouth ul- and due to a suspicion of an inborn error of immunity a target gene cers. A rapidly progression of his condition could be observed char- panel was performed (MEFV, NRLP3, MVK, TNERS1A). Curiously a het- acterized by worsening of general condition and generalization of erozygous mutation in exon 11 of the mevalonate kinase (MVK) gene the rash over different body parts. Other clinical pictures fre- variant c.1129GA and a premature stop codon c.2T>A, p.met1?. quently observed was fever; psoriatic nail changes (e.g. Pitting and Therefore the clinical and diagnosis of MVK was established for the 2 onychomadesis) and ichthyosis altogether with joint involvement children. We surrogated that the other mutation was missed in P1 limiting his activity. Rash became severe with discharging pus- and genetic sequencing in P1 is ongoing to confirm the other variant tules and failure to thrive could be observed. At his admission, wide- found in P2. spread presence of scaly erythematous plaques with pinhead Conclusion: Here we report for the first time HIDS in Libya and we pustules involving the scalp, face, extremities, torso, and buttocks. highlight red flags for the suspicion of such a specific disorder in The palms and soles were also affected. Nail pitting and onycho- children with recurrent fever. We also demonstrate the importance madesis. Marked hypertrichosis was also noted. At his admission of genetic analysis for the final diagnosis as well as the right genetic a complete blood count demonstrated anemia HGB 8.1 g\dl and evaluation in such a complex clinical scenario. Besides, the leukocytosis.However, during febrile episodes the patient’swhite prevalence of hereditary autoinflammatory diseases remains blood cell count increased to 17,000/ll with neutrophilia of 92%, unknown in Libya. ESR 50mm\h, and elevated CRP 20mg\dl level. No other condition, such as infection, could be observed over the time. A skin biopsy Acknowledgments demonstrated parakeratosis, spongiosis, and psoriasiform acantho- I would like to extend my appreciation and thanks to Dr Leonardo Oliveira sis, We could also observe an elevated level of vitamin B12 757.90 Mendonca to revising this manuscript pg\ml(reference range). Due to a suspicion of a systemic autoin- flammatory condition, a genetic sequencing was requested. A Disclosure of Interest homozygous already described mutation in the IL36RN was None Declared found (c.80T>C; .pLeu27Pro), thus confirming the diagnosis of DITRA.Once neither anti-IL1 (anakinra) neither anti-Il12/23 (secuki- numab) is available in Libya , high doses of systemic steroids was P28 initiated and could achieve clinical control. In order to avoid pro- Deficiency of Interleukin-36 Receptor Antagonist deficiency longed use of steroids, the patient’s dose was gradually tap- (DITRA) with C.80T>C (P. LEU27PRO) mutation: report of the first pered. However, cutaneous exacerbation could be observed and an Libyan child steroid spared agent, methotrexate, at a dose of 7.5 mg once per 1 2 3 A. A. Abushhaiwia , Y. AElfawires , N. Alhouni week was therefore added. Under this treatment, the patient pro- Paediatrics Department, Faculty of Medicine, Univeristy of Tripoli,Tripoli gressed towards a good general condition. However, there Children Hospital; Paediatrics Department, Faculty of Medicine, wasn’t complete improvement of his skin rash neither control of University of Tripoli, Tripoli Children Hospital; Dermatology Department, the febrile episodes. Tripoli Central Hospital, Tripoli, Libya Conclusion: DITRA is a rare disease that has to be considered in GPP Correspondence: A. A. Abushhaiwia with systemic inflammation and fever. Increased awareness of this Pediatric Rheumatology 2021, 20(Suppl 1):P28 distinct type of GPP caused by mutations in IL36RN is of major importance for future potential therapy directed at the IL36RA protein. Introduction: Loss-of-function mutations along the IL36RN gene defines a recently described recessively inherited autoinflamma- Acknowledgments: tory syndrome named deficiency of IL-36 receptor antagonist Disclosure of Interest (DITRA). This genetically determined deficiency was first described None Declared in a subgroup of patients with generalized pustular psoriasis. It is a life-threatening condition characterized by recurrent episodes of severe skin inflammation, with pustule development, associated P29 with fever, malaise, extracutaneous involvement, neutrophilia and An early onset of skin rash: a case of 4-month-old infant 1 2 1 1 1 a marked acute phase response. Recently there was a possible A. Mauro , O. Francesca , G. Antonietta , M. Rosa , A. Sabrina ,A. 1 1 1 1 1 genotype and phenotype correlation regarding disease severity. It Francesca , D. Carolina , M. Stefania , S. Esposito , V. Tipo 1 2 was surrogated whether the presence of mutations that Emergency Department; Pediatrics, Aorn Santobono-Pausilipon, Naples, accounted for critical protein expression could be associated to Italy severe DIRA phenotypes observed. At least, 10 null mutations Correspondence: A. Mauro with complete absence of the IL36RN antagonist (eg, c.80T>C/p. Pediatric Rheumatology 2021, 20(Suppl 1):P29 Pediatric Rheumatology (2022) 20:2 Page 23 of 39 Introduction: Dermatological diseases are a challenge for then, 2 weeks later, by low-grade evening fever (up to 37.5 °C). The pediatricians. The skin is often involved in monogenic rash was mildly pruritic. Since the second day after rash onset, she autoinflammatory syndrome with a wide range of cutaneous lesions. had been treated with oral antihistamines and betamethasone (0,03 Objectives: We describe a weird case of an early onset mg/kg/day) for 2 weeks, followed by oral methylprednisolone for 4 hyperkeratosis and maculo-papular rash. days (0,2 mg/kg/day) with only partial improvement of skin lesions. Methods: A 4-month-old male was admitted to our Paediatric Emer- The day after glucocorticoid withdrawal, she presented fever (up to gency Unit due to history of rash since the age of one month. He 39.5°C) and rash worsening, thus she was admitted to our Unit. Her was born to non consanguineous parents, at 39 weeks of gestational past medical history was unremarkable, except for adenotonsillect- age following an uncomplicated pregnancy and delivery with normal omy performed at the age of 7 due to sleep apneas. Her father was neonatal phenomena. He had a good growth with no feeding diffi- affected with psoriasis and, since adulthood, episodic hidradenitis. At culties and without any comorbidity. presentation, she presented papular wheals at trunk and face and At the beginning, suspecting atopic dermatitis, he was treated with coxalgia at passive flexion. Laboratory investigations showed marked topical corticosteroid, emollients, and oral antihistamine. Because of elevation of acute phase reactants (C-reactive protein, CRP, 120,9 the lack of improvement of the eruption and no relief of the itch, the mg/L with normal values <5 mg/L and erythrocyte sedimentation family paediatrician assumed a cow's milk proteins allergy, so the rate, ESR, 79 mm/h) and slight neutrophilic leucocytosis (neutrophils baby started feeding with a hydrolysed milk. Even this treatment had 9290 cells/mmc). Fibrinogen was elevated (681 mg/dl) while procalci- no success. tonin was negative. No evidence of infection was detected at a thor- On examination, the child was apyretic, alert but too irritable. He ough serological and microbiological screening. Antinuclear presented whole body extended rash characterized by red papules, antibody, rheumatoid factor and complement were normal. Abdo- excoriation, and hyperkeratotic whitish crusts with crackings on the men ultrasound showed slight hepatosplenomegaly. Autoimmune palmo-plantar surfaces. thyroiditis with normal thyroid function was detected. Bone marrow Due to the early age of the onset of rash and the lack of rash aspiration revealed no signs of hemophagocytosis or cellular atypia. improvement with previous treatment, the hypothesis of Skin biopsy showed dermal neutrophils and lymphocytes infiltrate. autoinflammatory disease was made, such as DITRA Syndrome. During the hospitalization, lasted two weeks, the patient presented Results: Routine blood tests revealed a leukocyte count of 44,60 × spontaneous progressive clinical amelioration with fever and arthral- 9 3 10 cells/L with a very high eosinophil count of 20,39× 10 cells/L. gias disappearance few days after admission and progressive reduc- Inflammatory markers (C-reactive protein , Erythrocyte sedimentation tion of inflammatory indexes. At discharge, CRP was 6,6 mg/L, ESR rate , Serum Amyloid A ) were within normal range . The infant was 30 mm/h and a mild elevation of Serum amyloid A (SAA) was screening for immunodeficiency, differential count, T-cell and B-cell detected (60,1 mg/L, normal values <3,47 mg/L). One month later, subsets, quantitative immuno-globulins, and HIV test were all normal. CRP, ESR and SAA were normalized. Spontaneous sporadic episodes In consideration of absence of fever ad normal level of inflammatory of short-duration (less than 24 hours) urticarial rash persisted over markers, we decided to postpone genetic tests and we performed an the following three months and then disappeared. She presented accurate anamnesis and we evaluated the patient clinically again overall well-being for the following two years. At the age of 15, she During the baby examination our physicians noticed on the baby newly developed persistent spontaneous urticarial rash without fever mother’s arms an erythematous papular and excoriated eruption or arthralgias. Skin lesions appeared mainly during evening, were with scratching. For this reason we performed an accurate anamnesis pruritic, localized at face, thighs and back of the hands and steroid- and a dermatoscopic examination of skin scrapings revealing dependent. Inflammatory markers were newly elevated: CRP was 20 numerous scabies mites and eggs. mg/L, ESR 40 mm/h and SAA 166 mg/L. Due to elevation of inflam- Conclusion: A diagnosis of crusted or Norwegian scabies was made matory markers in association with rash reappearance, next gener- and he was treated with oral antihistamine, overnight application of ation sequencing (NGS) analysis for SAIDs was performed and topical 5% permethrin. The patient was discharged from the hospital showed the heterozygotic variant c.362G>A, p.(Arg121Gln) of TNFR after three days of treatment with complete resolution of cutaneous SF1A gene, consistent with TRAPS. Therefore, about six months after lesions and normalization of the blood tests. The aim of this case chronic urticaria reappearance, the patient started subcutaneous ana- report is underlying the importance of an accurate anamnesis and kinra (100 mg/day) with prompt resolution of skin rash. At one- clinical examination, also of the parents, to avoid delayed diagnosis month follow-up after anakinra starting, the patient did not experi- ence any urticaria relapse and inflammatory markers were normal. Disclosure of Interest Conclusion: In this 16-year-old female, TRAPS was diagnosed due to None Declared spontaneous chronic urticaria, associated with inflammatory markers increase. She presented fever and arthralgias only at the onset, oc- curred at the age of 13. This case showed that chronic urticaria can P30 characterize the clinical course of TRAPS, even though fever and Tumor Necrosis Factor Receptor-associated Periodic Syndrome other systemic signs may not be present. Elevation of inflammatory (TRAPS) masquerading as chronic urticaria in a teenage girl indices should give rise to the suspicion of SAID in patients with R. Naddei, R. Alfani, F. Mozzillo, T. Lastella, M. Amico, M. C. Carrella, M. chronic urticaria, also in case of a late onset. Anakinra was effective Tripodi, M. Alessio in skin rash resolution in our patient. Written informed parental con- Pediatric Rheumatology Unit, Mother and Child Department, University sent for publication was given. of Naples Federico II, Naples, Italy Correspondence: R. Naddei Disclosure of Interest Pediatric Rheumatology 2021, 20(Suppl 1):P30 None Declared Introduction: Skin manifestations are frequent in systemic auto- inflammatory diseases (SAIDs). Skin rash frequently accompanies sys- P31 temic symptoms such as fever, malaise and joint involvement during Chronic recurrent multifocal osteomyelitis: a first case report from recurrent autoinflammatory episodes. Libya 1 2 3 Objectives: To describe clinical presentation of a young girl A. A. Abushhaiwia , Y. AElfawires , A. Ateeq diagnosed with Tumor Necrosis Factor receptor-associated periodic paediatric Rheumatology, faculty of Medicine,Tripoli university, Tripoli syndrome (TRAPS) at the age of 16 due to chronic urticaria. children's hospital; paediatric Rheumatology , Faculty of Medicine, Methods: Case report. Tripoli university , Tripoli children's hospital; paediatric Rheumatology , Results: A 13-year-old girl referred to our Unit for an urticarial rash, Tripoli children's hospital , Tripoli , Libya started one month earlier. Single skin lesions lasted up to 24 hours, Correspondence: A. A. Abushhaiwia were localized at trunk and limbs and followed by arthralgias and Pediatric Rheumatology 2021, 20(Suppl 1):P31 Pediatric Rheumatology (2022) 20:2 Page 24 of 39 Introduction: Chronic recurrent multifocal osteomyelitis (CRMO) is a laboratory, laboratoristic and radiological findings and bone bi- rare idiopathic inflammatory disease that affects mainly children and opsy CRMO was diagnosed. Patient started anti-inflammatory young adults. The clinical signs and symptoms are nonspecific, treatment (naproxen) for 3 months and his conditions im- hindering and delaying diagnosis. Radiological and histopathological proved. NSAID treatment has been suspended. tests are essential for its definition .To our knowledge, there are no Conclusion: CRMO should be considered in any a child with chronic reports of CRMO in Libya, this is the first case report, which was bone pain to perform a correct diagnosis and start an adequate initially misdiagnosed and treated by multiple courses of different treatment. Timely diagnosis of these disorders is crucial to avoid types of antibiotics is presented. We describe the clinical and potential complications laboratory features and treatment of it Objectives: To present a case of CRMO to demonstrate the Disclosure of Interest diagnostic importance of clinical, laboratory, mainly, imaging tests, None Declared and avoids misdiagnoses or late diagnoses. Methods: The diagnosis of CRMO was based on evidence of recurrent osteomyelitis with radiographic evidence of chronic P32 osteomyelitis involving at least two sites in the absence of infectious Emotional distress as a trigger for PFAPA attacks 1 2 1 1 1 1 cause in a child less than 14 years old Y. Levinsky , Y. A. Butbul , T. Tal , M. Natour , K. Kedar , N. Dagan ,G. 1 3 Results: A 14-year-old Libyan boy, born of non-consanguineous Amarilyo , L. Harel 1 2 healthy parents, Was referred to our Department of Paediatric Schneider Children's medical center of Israel, Petah tikva; Rambam Rheumatology in December 2020 with a history of episodes of Health Care Campus, Haifa; Schneider children's Medicalcenter of Israel, bone pain in different sites sometimes associated swelling and Petah Tikva, Israel hotness but no redness, Symptoms had been started since at the Correspondence: Y. Levinsky age 10 years, he was evaluated several times without a specific Pediatric Rheumatology 2021, 20(Suppl 1):P32 diagnosis being made and he had received various antibiotics and several admissions as a case of acute or chronic osteomyli- Introduction: There is scarce information regarding potential triggers ties and bone biopsy had been taken from different site (left for PFAPA attacks. tibia, left and right ulna) revealed chronic osteomylities and no Objectives: To examine whether an emotional stress serves as a bacterial growth in the different hospitals in Libya and outside trigger for these attacks. Libya without specific diagnosis, in 2016 the patient sought Methods: Active PFAPA Patients aged 3-12 years from two Israeli medical care because of aching pain over the right anterior as- centers were enrolled. Patients parents were reached via phone call pect of leg associated with swelling, hotness but no redness, the and asked about the occurrence of PFAPA attacks in the preceding 2 pain not radiated, was worse with rest, The patient was otherwise weeks of a "stressful period" which was assumed to be (and later val- healthy with no history of fevers, chills, or weight loss. He had idated by an emotional distress scale questionnaire) within two neither history of previous surgeries nor a family history of bone weeks of returning to school after the first Israeli COVID-19 lockdown. or joint abnormalities, including tumors. He underwent MRI left Each patient served as its own control and parents were re-reached leg, which revealed acute osteomylities, the patient’swhite blood two weeks during summer break where COVID-19 outbreak was in count (WBC) was normal, erythrocyte sedimentation rate (ESR) remission (i.e. un-stressful period). The difference between occur- was normal 5mm/hr (0–20 mm/hr), and C-reactive protein (CRP) rences of attacks during these 2 periods was recorded was normal at <5mg/L (<5 mg/L). He received oral antibiotic, an Results: One hundred and six pediatric patient were enrolled in the open bone biopsy was performed on right tibia in Italy and re- study. Mean age was 7.37± 2.9. The mean emotional distress vealed no bacterial growth, no specific pathological finding seen questionnaire was higher in the first period compared to the second in sub matted materials treated with broad spectrum antibiotics period (35.6± 8.1 versus 32.1± 7.7, respectively, P = 0.047). In the without improvement but he had spontaneous remission for one "Stressful period" 41 (38.7%) reported at least 1 attack during the year. In 2018 he had another episode of bone pain but over the preceding 2 weeks compared to 24 (22.6%) in the "unstresfull extensor aspect of right forearm associated with swelling and period" (p = 0.017). hotness, MRI right forearm that showed proximal ulna metaphysis Conclusion: Here we provide first evidence that emotional stress periosteal with evidence of intra medullar small fluid collection of may induce PFAPA attack. high signal intensity on T2 image, low signal intensity on T1 image surrounded by bone marrow edema on STIR image con- Disclosure of Interest cluded proximal acute osteomyelitis, in order to exclude malig- None Declared nancy CTscan right forearm with 3D post processing was normal, received also antibiotics , sought medical advice in Jordan for more diagnostic workup due Radiologist suggested the lesion P34 could be due to tumoral involvement like Ewing’s sarcoma, or Efficacy of jak-inhibitor in treatment of a patient with ADA2 oesteomylities or eosinophilic granuloma , MRI right forearm deficiency (DADA2) 1 1 2 2 1 with IV contrast in Jordan was revealed diffuse and significant V. I. Burlakov , A. Kozlova , E. Raykina , M. Kurnikova , N. Kan ,Z. 1 3 3 1 bone infiltration and bone marrow edema involving the proximal Nesterenko , S. J. Kelly , M. S. Hershfield , A. Shcherbina 1 2 third of ulna associated with periosteal edema.CTscan right fore- Immunology, Laboratory of Molecular Biology, Federal Research and arm without contract showed suspicious infiltrative bone disease Clinical Center of Pediatric Hematology, Oncology and Immunology, in proximal two third of ulna with periosteal reaction and eleva- Moscow, Russia, Moscow, Russian Federation, Duke University School of tion. According to the radiographic findings, the patient was can- Medicine, Durham, United States didate for open 2nd time bone biopsy from right ulna showed Correspondence: A. Kozlova chronic osteomylities no bacterial growth, received oral antibiotics Pediatric Rheumatology 2021, 20(Suppl 1):P34 and NSAID (ibuprofen syrup) for 3 weeks. His symptoms disap- peared for 2 years. In June 2020 he had pain in left forearm, Introduction: DADA2 is a rare disease caused by bi-allelic mutations rd 3 biopsy performed MRI of the left forearm was hypointense in in the ADA2 gene. It is characterized by a variable phenotype that in- T1 and hyperintense in T2 and STIR, suggesting an inflammatory cludes systemic inflammation, vasculitis and polyarteritis nodosa with process. He assumed NSAID for a week. 6 months later, the pa- strokes, humoral immunodeficiency and bone marrow failure. Recent tient came to our Department because of pain and swelling in studies demonstrated increased interferon signature in DADA2, pla- left forearm. Based on his clinical history, physical examination, cing this disease in the group of type I interferonopathies. Pediatric Rheumatology (2022) 20:2 Page 25 of 39 Objectives: To assess effectiveness of ruxolitinib in treatment of a P35 patient with DADA2. Safety and effectiveness of biosimilar of adalimumab ABP501 in Methods: DADA2 diagnosis was confirmed by detection of the treatment of juvenile idiopathic arthritis: pera research group homozygous c.39C>A, p.C13* ADA2 mutation using targeted next experience 1 2 3 4 5 generation sequencing panel and confirmed by Sanger sequencing. F. G. Demirkan ,K.Ulu , K. Öztürk , S. G. Karadağ , S. Özdel ,H. E. 6 1 2 2 1 Plasma ADA2 enzymatic activity was measured in extracts of the Sönmez , F. Çakmak , F. Demir , B. Sözeri , N. Aktay Ayaz dried plasma spots using the high-performance liquid chromatog- Pediatric Rheumatology, Istanbul University/Faculty of Medicine; raphy method. Pediatric Rheumatology, University of Health Sciences, Ümraniye Results: A boy with DADA2 born to nonconsanguineous parents of Research and Training Hospital; Pediatric Rheumatology, Istanbul the Crimean Tatar descent was referred to our Center at the age of Medeniyet University, School of Medicine, Goztepe Research and 11 years. His symptoms included: Training Hospital; Pediatric Rheumatology, University of Health Sciences, -Anemia, which presented in the first months of life, progressed over Bakırköy Dr. SadiKonuk Training and Research Hospital, istanbul; time with the need of monthly erythrocyte transfusions despite the Pediatric Rheumatology, University of Health Sciences, Dr. Sami Ulus treatment with steroids up to 2 mg/kg. Bone marrow smear showed Obstetrics and Gynecology, Pediatric Health and Disease Training and isolated red cell hypoplasia. Research Hospital, Ankara; Pediatric Rheumatology, Kocaeli University, -Livedo vasculitis since 5 years of age. Kocaeli School of Medicine, Kocaeli, kocaeli, Turkey -Recurrent fevers. Correspondence: F. G. Demirkan -Periventricular ischemic lesions on the MRI brain scans at the age of Pediatric Rheumatology 2021, 20(Suppl 1):P35 9 years. Laboratory tests at admission showed also mild inflammatory Introduction: Over the past twenty years, biologic products and activity, lymphopenia (Table 1) with decrease in all lymphocyte subsequently biosimilars, have dramatically enhanced the treatment populations: CD3+CD4+ 0,196 cells/μl, CD3+CD8+ 0,139 cells/μl, of several chronic pediatric inflammatory conditions particularly CD19+ 0,009 cells/μl. juvenile idiopathic arthritis (JIA). The patient was deficient in plasma ADA2 enzymatic activity 4,3 mU/ Objectives: We aimed to review the real-life data regarding adalimu- g vs 75,9 mU/g for a healthy control sample (lab reference ranges for mab biosimilar treatment in children with JIA and make a contribu- controls and carriers are 130 ± 53 U/g and 55 ± 22 U/g, respectively). tion to the literature about its efficacy and safety. The patient was started on etanercept 0,8 mg/kg weekly with Methods: This retrospective, multi-centric study included children with gradual discontinuation of steroids and vasculitis’ resolution, yet a rheumatic disease who were followed-up by tertiary pediatric he developed multi-lineage cytopenia with positive Coombs test rheumatology centers across Turkey. Patients were followed for at (Table 1), that was treated with steroids at 1 mg/kg for 3 months least 24-weeks from the initiation of adalimumab biosimilar treat- and a course of rituximab 4 x 375 mg/m with partial response. ment with prescription indications, clinical responses, disease activ- He developed severe Cushing syndrome. ity scores, and adverse events reported. He was then started on ruxolitinib 10 mg/m daily with gradual Results: The study included 43 pediatric patients with a median steroid discontinuation. age of 15.4±2.6 (5-18) years; 60 % of them were male. The diagnoses of At the 12 months follow-up the patient was clinically asymptomatic, the group were as follows: JIA in 41 patients (95%); uveitis secondary to had no fever flares or signs of vasculitis. Laboratory tests showed sarcoidosis in 1 patient (2%) and iridocyclitis in 1 patient (2%). marked increase of platelet and lymphocyte counts and normalization JIA categories were oligoarticular (n=12, 27%), enthesitis-related (n=20, of all other parameters. He had no severe infections or signs of treat- 46%), psoriatic (n=6, 14%), and polyarticular (n=3, 7%). Seven patients ment toxicity. with JIA developed uveitis during the disease course. Conclusion: DADA2 is a complex and diverse life-threatening disease, The first treatment option of the experts was adalimumab biosimilar often with poor response to various modes of treatment. In our pa- (ADL) in 33, etanercept in 9, and secukinumab in 1 patient. A tient, ruxolitinib was well tolerated and effective in acquiring and standard dose of ADL biosimilar 40 mg once-in-2-week was started maintaining remission of vasculitis and cytopenia. This experience to the patients. Etanercept was switched to adalimumab biosimi- deserves further investigation in a larger cohort of patients. lar due to allergic reactions (n=2), development/activation of uveitis (n=3), psoriasis activation (n=1), and arthritis (n=2). In one patient Disclosure of Interest with psoriatic arthritis, as the arthritis was not responsive to secuki- None Declared numab, ADL biosimilar switching was made. rd In the 3 month of follow-up, uveitis was in remission in 5 pa- tients. Clinical remission and response status were evaluated with Ju- venile Arthritis Disease Activity Score 27 score. A significant decrease Table 1 (abstract P34). Treatment modalities and outcomes in patient in the scores determined the clinical effectiveness of ADL biosimilar with DADA2 in JIA patients (p=0.001). One patient at the third month of therapy had compliance problems with the biosimilar, so a switch to the ori- ginal ADL molecule was rendered. Treatment Clinical symptoms Laboratory tests Of the 41 patients who received ADL biosimilar; 34 patients had no Vasculitis Hepato- Fever Hb, PLT, WBC, NEU, LYM, CRP, splenomegaly g/l 10 / cells/ cells/ cells/ mg/ active complaints during follow-up. No adverse events were l μl μl μl l observed. Before treatment +++ +++ +++ 59 n/a n/a n/a n/a n/a Conclusion: In rheumatology, the majority of previous reports of Steroids, + - +/- 133 109 3740 2403 760 16,4 biosimilars were concerning adults, yet data with reference to the 0,1-30 mg/kg effectiveness and safety of biosimilars in pediatric rheumatic diseases Etanercept, - - - 52 49 610 200 270 4,62 is scarce. Real-life data on drug safety and efficacy need to be col- 0,8 mg/kg lected to increase evidence base data and in this context, this report Etanercept 0,8 mg/kg + - - - 144 62 3898 2447 535 1,6 reflects the prescription patterns and treatment strategies for a fre- steroids 1 mg/kg quently preferred biosimilar drug in pediatric rheumatology with Ruxolitinib, - - - 154 91 5890 4317 967 1,4 2,3 2 real-life experience for the first time. ABP-501 is a suitable and 10 mg/m cost-effective treatment option for patients with the chronic rheum- Hb – hemoglobin, PLT – platelet count, WBC – white blood cell count, NEU – neutrophil count, LYM – atic disease when adalimumab use is indicated. lymphocyte count, CRP – C-reactive protein. Laboratory test results show median values for the observation time Keywords: adalimumab, biosimilar, amjevita, juvenile idiopathic arthritis Pediatric Rheumatology (2022) 20:2 Page 26 of 39 Disclosure of Interest P37 None Declared Fetal exposure to canakinumab: a report of three pregnancies 1 2 3 4 U. Ilgen , S. Eyüpoğlu , E. Yayla , O. Küçükşahin 1 2 3 Rheumatology, Trakya University, Edirne; Nephrology; Rheumatology, P36 Ankara University; Rheumatology, Ankara Yıldırım Beyazıt Univeristy, Anakinra and canakinumab for patients with R92Q-associated Ankara, Turkey autoinflammatory syndrome: a multicentre observational study Correspondence: U. Ilgen from the AIDA Network Pediatric Rheumatology 2021, 20(Suppl 1):P37 1 2 3 1 1 C. Gaggiano , D. Rigante , J. Hernández-Rodríguez , A. Vitale , M. Tarsia , 4 5 6 7 8 A. Soriano , G. Lopalco , M. A. Jaber , R. Giacomelli ,E.Więsik-Szewczyk , Introduction: Interleukin-1 (IL-1) blockade during pregnancy is 9 9 10 11 9 10 M. Cattalini , M. Frassi , M. Piga , G. Ragab , F. Zunica , A. Floris ,V. well tolerated but safety data is limited particularly for canakinu- 12 11 3 3 1 Sabato , M. T. Hegazy , O. Araújo , L. Pelegrín , B. Frediani ,A. mab, under which a total of only ten pregnancies were reported 1 1 1 1 Fabbiani , A. Renieri , S. Grosso , L. Cantarini to date. 1 2 University of Siena, Siena; Fondazione Policlinico Universitario A. Objectives: To provide additional safety data of canaknumab Gemelli IRCCS and Università Cattolica Sacro Cuore, Rome, Italy; based on three pregnancies of two cases, one with familial Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Mediterranean fever (FMF) and the other with Muckle-Wells syn- 4 5 Spain; Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia; University drome (MWS). 6 7 of Bari, Bari; Santa Chiara Hospital, Trento; University of L'Aquila, Methods: A data sheet consisting of general disease characteristics L'Aquila, Italy; Central Clinical Hospital of the Ministry of National and a detailed pregnancy and postpartum follow-up information Defense, Military Institute of Medicine, Warsaw, Poland; University of consisting of the age and disease activity at conception, timing of Brescia and Spedali Civili of Brescia, Brescia; University and AOU of the last canakinumab dose with respect to pregnancy week, disease 11 12 Cagliari, Cagliari, Italy; Cairo University, Cairo, Egypt; University of activity and canakinumab use during and after pregnancy, type and Antwerp and Antwerp University Hospital, Antwerpen, Belgium timing of delivery and feeding, status of the baby during intrauterine, Correspondence: C. Gaggiano neonatal, and infancy period, was completed for each pregnancy. Pediatric Rheumatology 2021, 20(Suppl 1):P36 Results: The patients were 29- and 31-year-old women with MWS and FMF, respectively. The first had two pregnancies under canakinu- Introduction: The gold standard treatment of TNF receptor- mab. Both were complicated by renal amyloidosis but were attack- associated periodic syndrome (TRAPS) is the inhibition of IL-1, the free with normal acute phase reactants and stable proteinuria (240 final effector of the stress-response mechanisms activated by the mg/day and 550 mg/day, respectively) for years before conception deregulated cellular homeostasis in TRAPS patients. Given the uncer- and both were under monotherapy with canakinumab. Pregnancy tainty about the molecular mechanism and pathogenic significance outcomes were provided in the Table. The first patient with a mid- of the R92Q variant, the therapeutic response to IL-1 inhibitors in pa- trimester miscarriage held canakinumab 14 weeks before the follow- tients with recurrent inflammatory attacks due to the presence of ing conception until the 31st week of gestation. During this period this specific mutation is worth an extensive investigation. she had attacks partially responsive to low-to-moderate dose steroids Objectives: This study aims at describing the therapeutic outcome of and on-demand anakinra but proteinuria progressed to 2600 mg/day patients carrying the R92Q variant in the TNFRSF1A gene treated with persistent elevation in acute phase reactants, for which canaki- with anakinra (ANA) or canakinumab (CAN) and identifying any numab was resumed at the 31st week of gestation. Both patients factors predictive of complete response to IL-1 inhibition. were under canakinumab over the entire course of breastfeeding. No Methods: This is an observational study involving 13 international significant infections were reported in the infants. Anti-hepatitis B centres from the AIDA Network. Demographic, clinical, laboratory, surface antigen titers were 218 and 470 IU/L in the sixth month and clinimetric and therapeutic data of patients treated with ANA or CAN 402 and 620 IU/L in the second year of age (Three doses of hepatitis for recurrent inflammatory attacks due to the presence of the R92Q B vaccine in the 0, 1, and 6 months were administered according to variant were retrospectively collected and analysed. the national immunization program). Results: Data about 20 treatment courses with IL-1 inhibitors (16 with Conclusion: Considering all 13 reported cases of pregnancy under ANA and 4 with CAN) from 19 patients were collected. Mean age at canakinumab, two resulted in miscarriage, one in the first and one in disease onset was 20.2±14.8 years. In 5 cases (26%) the R92Q variant the second trimester. Underlying disease was active in the one with was found in a family member affected by recurrent fever. The thera- the first trimester miscarriage. All fetuses were exposed to peutic response was complete in 13(68%) and partial in 2 patients canakinumab during embryogenesis with no reported anomalies. (11%); treatment failure was observed in 4 cases (21%). Median AIDAI Most cases continued canakinumab throughout pregnancy with no decreased from 10(IQR 28) to 0(IQR 1) at the 12-month follow-up visit preterm labor or severe infection in the infant. Hepatitis B (p<0.001). Mean ESR and median PCR dropped respectively from vaccination in the infant was shown to be successful in two cases. 40.8±24.8 to 9.1±4.5 mm/h (p<0.001) and from 3.0 (IQR 1.9) to 0.3 (IQR 0.3) mg/dl (p<0.001) after 12 months of treatment. A steroid- Disclosure of Interest sparing effect was observed from the third month of treatment (p< None Declared 0.01). Thirteen patients (65%) were still on treatment at the last follow-up visit (median duration of treatment 17 (IQR 38) months). The presence of R92Q mutation in a symptomatic relative (p=0.022), Table 1 (abstract P37). Pregnancy outcomes under canakinumab the relapsing remitting disease course (p<0.001) and the presence of migratory erythematous skin rashes during fever attacks (p=0.005) Age at Last cana Doses and Date and Birth APGAR Fetoplacental Feeding Current pregnancy dose before duration of cana type of weight score anomaly, IUGR, or age of were associated with complete efficacy of IL-1 inhibitors. conception after conception delivery developmental the delay child Conclusion: R92Q patients showed a favourable response to ANA 1* 25 years 150 mg, 2 150 mg at 6 and 16 week, - - No phenotypic or -- and CAN, particularly when the mutation segregated in a family weeks 14 weeks miscarriage chromosomal member and when a relapsing-remitting disease course or TRAPS anomaly typical skin rash were observed. In the subgroup of patients not tak- 2* 26 years 150 mg, 14 150 mg at 31 37 week, 2.9 kg 8,9,10 No anomaly, IUGR, Breastfed 2.5 years weeks weeks and 4-to- C/S or delay 16 ing advantage of IL-1 blockage different molecular mechanisms 6-weekly months thereafter underlying the autoinflammatory picture are likely to exist. 3 28 years 150 mg, 4 150 mg 8-weekly 39 week, 3.4 kg 9,10,10 No anomaly, IUGR, Breastfed 2 years weeks throughout C/S or delay 8 months Disclosure of Interest pregnancy None Declared cana, canakinumab; C/S, Caesarean section; IUGR, intrauterine growth retardation. * the same patient Pediatric Rheumatology (2022) 20:2 Page 27 of 39 P38 P39 The comparison of vaccination rates of children with rheumatic Willingness to get the COVID-19 vaccine among children with diseases and their healthy peers rheumatic diseases: a survey study to parents 1 1 1 2 2 Ö. Akgün , F. G. Demirkan , F. Çakmak , M. Erdemir , G. Keskindemirci , Ö. Akgün, F. G. Demirkan, F. Ataman Çakmak, G. Kavrul Kayaalp, O. Köker 1 3 1 2 G. Kavrul Kayaalp , N. Akay , R. Eker Ömeroğlu , E. G. Gökçay , N. Aktay Turan, A. Tanatar, N. Aktay Ayaz Ayaz Pediatric Rheumatologist, Istanbul Faculty of Medicine, Istanbul, Turkey 1 2 3 Pediatric Rheumatology; Social Pediatrics; Pediatrics, Istanbul Faculty Correspondence: Ö. Akgün of Medicine, Istanbul, Turkey Pediatric Rheumatology 2021, 20(Suppl 1):P39 Correspondence: Ö. Akgün Pediatric Rheumatology 2021, 20(Suppl 1):P38 Introduction: Severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19), first re- Introduction: Patients who are followed-up in the pediatric rheuma- ported from the Wuhan city of China in December 2019, affected all the tology outpatient clinic are at risk due to immune dysfunction world in a few months and became a global health emergency of primary caused by both their primary disease and by the drugs they use. As international concern and was announced a pandemic by the World Health they are more prone to infection, these patients should be protected Organisation. Although the disease is showing a milder course in children, carefully from vaccine-preventable diseases. vaccination of this age group may be important due to increased number Objectives: Our aim is to find out the vaccination rates in patients of the multisystem inflammatory syndrome (MIS-C) and vaccines role in diagnosed with a pediatric rheumatologic disease (PedRD) and to prevention of the spread of infection in children who have had asymptom- assess their vaccination status comparing with their healthy peers. atic disease. As vaccine refusal and hesitancy are increasing around the Another objective of the study is to evaluate factors that may lead to world, a new problem has emerged for children with pediatric rheumatic incomplete vaccination in patients with PedRD. diseases who are already prone to infection. Methods: The electronic healthcare recording system data of Objectives: This study aimed to investigate the parental acceptance patients with PedRD who were followed in the pediatric of COVID-19 vaccination for children with chronic rheumatic diseases rheumatology out-patient clinic in Istanbul University Faculty of when the vaccine is approved in childhood and to evaluate the back- Medicine between October 2019 and October 2020 were reviewed ground characteristics of willingness to get COVID-19 vaccine. and 102 patients (aged 0-18) whose vaccination records were avail- Methods: The study included an analysis of a cross-sectional online able are included in the study. One hundred two age-matched peers questionnaire to the parents of the patients diagnosed with a without any chronic disease and whose vaccination data were avail- chronic rheumatic disease at the Pediatric Rheumatology Outpatient able through electronic healthcare recording system were included Clinic of Istanbul Faculty of Medicine. A message containing a link to as the control group. Incomplete vaccination status and missing vac- the actual questionnaire was sent to their phones simultaneously cines were identified according to the national vaccination schedule which covers their view for the SARS CoV-2 infection, sociodemo- individualized by age. Fifty- one patients (50%) have the diagnosis of graphic data, thoughts about the vaccine, their child's behavior dur- juvenile idiopathic arthritis (JIA), 38 patients (37.2%) have the diagno- ing the pandemic related to the disease, and completed by self- sis of periodic fever syndromes and 13 patients (12.74%) have the response method. Clinical information was accessed from the med- diagnosis of connective tissue diseases. ical records of the patients. Results: The proportion of the females was 67% in the patient Results: The prevalence of parents’ acceptance of COVID-19 vaccin- group (n=68) and 57% in the control group (n=58). The median ation for their children was 39.5% (30/76). The proportion of parents age of the patient group was 8.1(1.9-15.5) and the mean age who were hesitant about the vaccination of their children was 47.4%. control group was 7.5(±3.4) years. There was no difference Whereas, the rates of acceptance of the vaccine by mothers and fa- between the patient and the control group in terms of age and thers themselves were 48.7% and 52.6%, respectively. Factors for vac- gender. The median age at diagnosis was 3.3(0.3-11.4) years. cine referral were side effects (47.4%), limited information about the Incomplete vaccination rate was 35.3 % in the patient group and vaccine (45.2%) and possible ineteraction of the vaccines with the 6.9 % in the control group (P<0.0001). The most common medications of the patients (40.2%). Parents were able to give mul- neglected vaccine was the first dose of oral poliovirus vaccine tiple answers to this question. There was no significant relationship (OPV) (n=19, 18.6%), followed by the second dose of OPV (n=18, between the parents' educational status and their acceptance of the 15.7%) and the first dose of measles, rubella, mumps vaccine (n= vaccine (respectively p=0.09, p=0.10) 13, 12.7%). Patients were divided into four groups according to Conclusion: Children can serve as a reservoir that will undermine the immunosuppressive antirheumatic treatments they received: efforts to end the pandemic. While the vaccines have yet no nonbiologic disease modifying antirheumatic drugs (DMARDs), approval for children <18 years, vaccinating children against the biological DMARDs, nonbiological + biological DMARDs and COVID-19 virus will contribute to the pandemic control, and the re- others (colchicine, non-steroidal anti-inflammatory drugs, hydroxy- covery of the global economy. The preliminary results of this survey chloroquine). Although the patients who received biologic ther- targeting parents may be guide for physicians while promoting vac- apy had the highest rate of missing vaccine at 43%, no cination in the near future. significant difference was detected between the treatment key words: Covid-19, vaccine, survey. pediatric rheumatic disease groups. Conclusion: : It is important to determine the vaccination status of Disclosure of Interest patients followed by PedRD and to take measures against vaccine- None Declared preventable diseases by increasing the awareness of physicians and patients in this regard. As a result, questioning the status of the vac- cine and to plan a catch-up immunization schedule for patients with P40 incomplete vaccines should be a part of the routine rheumatologic Live attenuated MMR booster vaccine in children with rheumatic examinations. Electronic registration systems can fill an important disease: a single center study 1 1 1 1 1 gap in solving this problem by giving warnings in case of vaccine de- F. Çakmak , Ö. Akgün , F. G. Demirkan , A. Tanatar , G. Kavrul Kayaalp ,G. 2 1 2 1 ficiency which can be convenient in busy outpatient clinics. Keskindemirci , R. Eker Ömeroğlu , E. G. Gökçay , N. Aktay Ayaz 1 2 Key Words: Vaccination, Pediatric rheumatic disease, biologic therapy Pediatric Rheumatology; Social Pediatrics, Istanbul Faculty of Medicine, Istanbul, Turkey Disclosure of Interest Correspondence: F. Çakmak None Declared Pediatric Rheumatology 2021, 20(Suppl 1):P40 Pediatric Rheumatology (2022) 20:2 Page 28 of 39 Introduction: Juvenile Idiopathic Arthritis (JIA) is a heterogeneous, Objectives: To identify modifying factors explaining the reduced chronic inflammatory disease of unknown cause which begins before penetrance and the variable expressivity. 16 years of age. Vaccination is the most effective way to prevent Methods: We compared two groups of patients with CTLA4 infectious diseases. In May 2017, European League Against mutations: 1) affected mutation carriers; 2) unaffected mutation Rheumatism-Paediatric Rheumatology European Society (EULAR- carriers. We analyzed the exome sequence, the HLA type, the PReS) Task Force for Vaccination, based on small case series and ex- microbial stool content, the infection history, and epigenetic pert opinion updated the recommendations for live vaccines in signatures. In addition, we looked for somatic mutations in CTLA4 children. and pathway-related genes. Objectives: In this study, it is aimed to collect the data of patients Results: When analyzing the WES data of mutation carriers, we did with JIA and other rheumatic diseases who received live attenuated not identify additional genes which were only mutated in affected booster measles-mumps-rubella (MMR) vaccine during treatment but not in the unaffected mutation carriers, or vice versa. Moreover, with biological therapy and present if any disease flares or adverse during our studies, we became aware of a monozygotic twin pair reactions occured after vaccinations. with a discordant phenotype, additionally arguing for somatic or Methods: The files of the patients followed-up in İstanbul University environmental modifying factors. In >50 patients tested, we did not Istanbul Faculty of Medicine with the diagnosis of JIA or other identify any additional somatic mutation in candidate genes. The rheumatic diseases who received biological treatment were analyzed HLA type, however, may add an additional susceptibility factor, as we retrospectively. According to the current national vaccination sched- observed that the haplotype HLA-DRB1 *15:01 and -DQB1 *06:02 in ule, the MMR vaccine booster dose is administered in the first year of CTLA-4-insufficient patients might be associated with a severe im- primary school, so we evaluated from electronic vaccination records mune dysregulation phenotype. Interestingly, the microbial compos- whether any of our patients had received live attenuated booster ition in stool was different in affected CTLA4 mutation carriers when vaccinations for MMR while being treated with biologics. Demo- compared to unaffected mutation carriers. Details will be reported at graphic data and information on disease subtypes, disease activity at the meeting. The infection history was not revealing, as for all infec- the time of the booster vaccination, and adverse reactions after vac- tious agents investigated, there were infected and not-infected muta- cinations (disease flare or vaccine-related event) were collected from tion carriers in both groups. The analysis of the epigenetic signatures the files of the patients retrospectively. is pending and will be presented at the meeting. Results: Among 72 patients under biologic therapy, 14 patients (7 Conclusion: According to our current assessment, the HLA-type and girls and 7 boys) had received live attenuated booster measles- the microbiome are the most promising determinants of disease ac- mumps-rubella (MMR) during treatment with biologics. The mean tivity in patients with CTLA4-insufficiency. age of diagnosis was 43,7 (9-73) months and the mean age of booster vaccination was 76,2 (70-84) months. The mean follow-up Disclosure of Interest time was 54 months (23-84) and the mean time to initiate biologics None Declared before vaccination was 14 months (4-45). Seven of these patients had oligoarticular juvenile idiopathic arthritis (JIA), 3 had systemic on- set JIA, 2 had enthesitis related arthritis, 1 had psoriatic arthritis and P42 1 had colchicine resistant familial Mediterranean fever. Eight patients High prevalence of autoinflammatory diseases in autosomal received booster MMR while on biologic treatment only and 6 were dominant NFΚB1 insufficiency under both methotrexate and biologic therapy. During vaccination, 4 B. Grimbacher, K. Thoma, on behalf of AG Grimbacher, M. Fliegauf (%30) patients had low and 3 had moderate (%23) disease activity, Institute for Immunodeficiency, Universital Hospital Freiburg, Freiburg, and 7 (%50) patients were in remission on medication. Germany Out of 14 patients who had MMR booster, only 1 patient with the Correspondence: B. Grimbacher diagnosis of systemic onset JIA under methotrexate and tocilizumab Pediatric Rheumatology 2021, 20(Suppl 1):P42 therapy had a maculopapular rash after vaccination. None of the patients reproted any disease flare. Introduction: NF-κB1 (haplo)insufficiency due to heterozygous dam- Conclusion: In the literature, data regarding live attenuated aging variants in NFKB1 has been recognized as an inborn error of vaccination of patients under biological therapy is limited. At the immunity with immune dysregulation. NFKB1 encodes the transcrip- evaluation of our cohort from electronic vaccination records and tion factor precursor p105, which undergoes processing to produce patient files, it was noticed that the live attenuated booster MMR the mature p50. vaccine was seemingly safe for children with rheumatic diseases who Objectives: Due to the highly heterogeneous immunological were receiving biologic therapy. However, to conclude that live phenotypes, including incomplete penetrance (70%) and age- vaccination is effective and safe, this data should be supported by dependent disease severity, attempts to establish clear genotype- multicentric and larger cohorts. phenotype correlations have been unsuccessful so far. Therefore, we set out to better describe the phenotype of patients with variants in Disclosure of Interest NFKB1. Moreover, functional evaluation of each identified NFKB1 se- None Declared quence variation was attempted to demonstrate causality. Methods: We use a standard cell culture model, based on transient overexpression of mutant NF-κB1 proteins in HEK293T cells, to test P41 the expression, subcellular localization, precursor processing, DNA Towards the Identification of disease-modifying factors in CTLA4 binding and promoter activation. In addition, we test protein interac- insufficiency tions, cytoplasmic retention/nuclear translocation and DNA-binding B. Grimbacher, N. Mitsuiki, M. Krausz, L. Gámez-Díaz, C. Schwab, F. competition, following experimentally simulated pathway activation. Emmerich, N. Camacho Ordonez, S. Posadas-Cantera, H. Hengel, M. Results: Autoinflammatory symptoms in NFKB1 insufficiency include Proietti, A. Caballero-Garcia-de-Oteyza oral and genital aphthous ulcerations (18.5%), non-infectious epi- Institute for Immunodeficiency, Universital Hospital Freiburg, Freiburg, sodes of fever and systemic inflammation (12%) as well as vasculitis Germany (4.6%). Multi-organ autoinflammatory diseases (29.6%), including Correspondence: B. Grimbacher Behçet's disease (5.6%), are among most frequent clinical complica- Pediatric Rheumatology 2021, 20(Suppl 1):P41 tions in affected mutation carriers besides hypogammaglobulinemia (88.9%), respiratory infections (83%) and reduced switched memory Introduction: Heterozygous mutations in CTLA4 lead to an inborn error B cells (60.3%). The clinical spectrum further comprises autoimmunity of immunity characterized by immunodeficiency and multi-organ auto- (57.4%), lymphoproliferation (52.4%), non-infectious enteropathy immunity. Interestingly, the penetrance of these deleterious mutations (23.1%), opportunistic (15.7%) and gastrointestinal (28.6%) infections, is only about 70%, and their expressivity is highly variable. and malignancy (16.8%). Pediatric Rheumatology (2022) 20:2 Page 29 of 39 Data regarding the prevalence of autoinflammatory complications in increasing evidence that the expression of the NLRP3 inflammasome patients with mutations in NFKB1 are currently being updated and is dysregulated in many cancers. At the same time, some studies will be presented at the meeting. The disease-causing mechanism demonstrate that TIF1 might influence tumors via NLRP3 signaling. presumably originates from imbalanced ratios of NF-κB signaling This could explain both clinical manifestations of our patient and components, and altered NF-κB signaling dynamics. TIF1 expression. Conclusion: Due to the high frequency of autoinflammation associated with NF-κB1 insufficiency, mutational and functional ana- Disclosure of Interest lyses of NFKB1 mutations should be considered, particularly when None Declared autosomal-dominant autoinflammatory diseases are evaluated. Disclosure of Interest P44 None Declared Unilateral proptosis in a child with Behçet’s disease 1 1 1 1 2 F. G. Demirkan , O. Akgun , G. Kavrul Kayaalp , F. Cakmak ,M. A.Kılıc ,E. 2 3 4 1 P. Yıldız , S. Sencer , A. Unuvar , N. Aktay Ayaz 1 2 3 P43 Pediatric Rheumatology; Pediatric Neurology; Neuroradiology; Unraveling the mysteries of an unusual monogenic Pediatric Hematology, Istanbul University/Faculty of Medicine, Istanbul, autoinflammatory disease presenting as an idiopathic Turkey inflammatory myopathy Correspondence: F. G. Demirkan J. Álvarez Troncoso Pediatric Rheumatology 2021, 20(Suppl 1):P44 Internal Medicine, Hospital Universitario La Paz, Madrid, Spain Pediatric Rheumatology 2021, 20(Suppl 1):P43 Introduction: Central nervous system (CNS) involvement is a rare complication of Behçet's disease (BD) in children and may present in Introduction: We present the case of a 49-year-old woman from the the form of parenchymal changes or as damage to the vascular United States of America with a previous diagnosis of urticaria- structures in its nonparenchymal form. vasculitis since adolescence with the need for high-dose steroids and Objectives: A teenager having BD complicated with recurrent episodes of unclassified arthritis. cerebral venous thrombosis is presented. Objectives: To describe an atypical case of a 49-year-old woman di- Methods: A-14 year-old boy followed up in dermatology and oph- agnosed with an idiopathic inflammatory myopathy with positivity thalmology clinics for eight years with BD, was referred to the for anti-TIF1 antibodies that was actually a monogenic autoinflamma- pediatric rheumatology clinic with complaints of headache, periorbi- tory disease. tal pain, diplopia, and blurred vision. His pathergy test was posi- Results: In 2015, she was diagnosed with adenocarcinoma of the tive. He had a history of recurrent and unremitting oral ulcers. He cervix treated with radical hysterectomy and right adnexectomy was under daily colchicine therapy. without the need for chemotherapy or radiotherapy. Results: On his physical examination, he was afebrile and ill- In the subsequent follow-up she presented absence of recurrence on appearing. He had multiple painful aphthosis in his buccal mucosa, PET-CT (at 1, 2 and 5 years). However, due to the persistence of arth- an averagely 1 cm in diameter, but no genital ulcer. Bilateral conjunc- ritis, an immunological study was performed with only weak positiv- tival bulbar hyperemia was present. He had also painful eye move- ity for anti-TIF1 antibodies. On EMG she had mild myopathic ments due to the bulging of the right eye anteriorly out of the orbita changes. Muscle biopsy was anodyne (without HLA-I or inflammatory defined as proptosis. The rest of the neurologic and systematic infiltrates), muscle MRI and the rest of the study was normal, includ- examination was otherwise unremarkable. Ophthalmologic examin- ing repeatedly normal CPK. However, in the presence of arthritis and ation revealed bilateral optic disc swelling with established disc skin lesions of urticarial vasculitis, treatment with methotrexate (MTX) oedema and proptosis of the right eye. and steroids was started with incomplete clinical improvement. The patient’s white blood count was 7.6 10 /μl with normal In July 2020, she attended first time to our consultation for the differential; red cell count was 10.9 g/dL; hematocrit, 31.9%, and follow-up of myopathy due to anti-TIF1. The history was notable for platelets were 579 10 /μl. C-reactive protein was 89.5 mg/L and D- the appearance of cold-induced urticaria / bruising, low grade fever dimer level was 640 μg/L. and worsening of the arthritis during the last years. This ‘’cold intoler- CNS imaging by magnetic resonance imaging (MRI) and magnetic ance” forced her to move to another city. She also mentioned that resonance venography (MRV) reported left transverse sinus her teenage daughter had started 2 years ago with unstudied cold- thrombosis including left sigmoid sinus and internal jugular vein. induced urticaria. Given these data, a skin biopsy of urticaria and a Thrombophilia screening tests for identifying a hypercoagulable study of systemic autoinflammatory diseases (SAID) directed at state showed no abnormality and no additional hereditary or NLRP3 (but including the complete usual panel of SAID) was per- acquired thrombosis risk factors were detected. He was treated formed. The skin biopsy showed periecrine and perivascular neutro- with intravenous methylprednisolone pulse therapy (30 mg/m / phils in the middle and deep dermis with no edema, compatible day) for 3 days. He was anti-coagulated with low molecular with CAPS. weight heparin. Acetazolamide and topiramate were initiated due Treatment with daily subcutaneous anakinra 100 mg was started to the optic disc oedema. At discharge, immunosuppressive ther- with complete resolution of all skin lesions and arthritis, allowing the apy with azathioprine and anticoagulant therapy with enoxaparin withdrawal of steroids and initiating a decrease in MTX. The genetic was prescribed. study of mother and daughter is pending at the time of case Control MRV after 2 months revealed significant regression in the presentation. thrombus. The patient had no complaints during the following 5 Conclusion: CAPS or cryopirinopathies comprise three autosomal months and proptosis was recovered. D-dimer level was 200 μg/L. dominant conditions with different disease severity (FCAS, MWS, Acetazolamide and topiramate were stopped when ophthalmologic CINCA/NOMID). All CAPS are caused by mutations in the NLRP3 evaluation showed significant regression regarding disc oedema. gene, which encodes NLRP3 protein or cryopyrin and lead to After 5 months, he presented with severe headache and tinnitus. On constitutive activation of NLRP3 inflammasome and IL-1β overpro- eye examination, optic disc swelling and oedema were progressed in duction. CAPS skin biopsies are neutrophilic urticarial dermatosis with the left eye. In MRV, a new thrombus image was reported at the no or mild dermal edema and neutrophilic epitheliotropism (neutro- same anatomical localization as 5 months ago which affected the left phils around or within eccrine glands or ducts, or inside the epider- transverse sinus and sigmoid sinus. The D-dimer level was 190 μg/L mis). NLRP12-AD and NLRC4-AD are SAID with similar cutaneous and and there was no significant abnormality in remaining laboratory ex- clinical characteristics but different cutaneous histopathology. aminations. Anticoagulant therapy was continued with enoxaparin. TIF1 is an E3 ubiquitin-ligase reported to be involved in DNA repair, Methylprednisolone bolus was given and cyclophosphamide was ini- dermatomyositis and cancer among others. Besides, there is tiated as immunosuppressive treatment. Pediatric Rheumatology (2022) 20:2 Page 30 of 39 Eventually, he is asymptomatic and has developed no new serum immunoglobulin G, A and M were found to be low for his age. symptoms related to the disease. Eye examinations are performed Low immunoglobulin levels and the history of frequent viral RTIs and periodically and there is no progression in fundus examination. His microatelectasis in lungs were found consistent with humoral control cranial MRV revealed significant regression in the thrombosis. immunodeficiency, and intravenous immunoglobulin treatment was Ultimate D-dimer level is 190 μg/L. Monthly six doses of cyclophos- commenced once a month. phamide is planned in the treatment. Conclusion: In this case, severe arthropathy was prominent with Conclusion: CNS involvement in children is a rarely reported systemic inflammation. The absence of serious infections other than manifestation of BD and this report has a distinct clinical view of a RTI, later onset of low immunoglobulin levels, and the absence of teenage boy presenting with proptosis and recurrent thrombosis. signs of intestinal inflammation were the distinct features of the Key words: Behçet's disease, cerebral venous sinus thrombosis, patient. This case emphasizes that the diagnosis of RIPK1 deficiency proptosis should be considered in treatment-resistant arthropathies in child- hood, especially in the presence of signs of inflammation, and the Disclosure of Interest importance of genetic consultation in resistant cases. None Declared Disclosure of Interest None Declared P45 RIPK1 deficiency in a patient with severe arthritis 1 1 2 2 3 G. Kavrul Kayaalp , F. Çakmak ,G.Yeşil Sayın , A. D. Aslanger , E. Yücel , P46 N. Aktay Ayaz Complex genetic diagnosis of DADA2 in a patient with an ADA2 1 2 3 Pediatric Rheumatology; Medical Genetics; Pediatric Immunology and single allele mutation: the long and winding road 1 1 1 Allergy, Istanbul University, Faculty of Medicine, İstanbul, Turkey J. R. Marques Soares , S. Buján Rivas , R. Solans Laqué , J. I. Aróstegui Correspondence: G. Kavrul Kayaalp Gorospe Pediatric Rheumatology 2021, 20(Suppl 1):P45 Internal Medicine, Hospital Vall D´Hebron (Barcelona) SPAIN; Immunology, Hospital Clínic i Provincial - Idibaps, Barcelona, Spain Introduction: Receptor Interacting Protein Kinase 1 (RIPK1) is a widely Correspondence: J. R. Marques Soares expressed cytosolic protein kinase found in protein complexes that Pediatric Rheumatology 2021, 20(Suppl 1):P46 mediate signal transduction from cell surface receptors. It has an essential role in controlling signaling pathways related to inflammation, apoptosis Introduction: Deficiency of adenosine deaminase 2 (DADA2) (ORPHA: and necroptosis. RIPK1 deficiency causes impaired mitogen activated 404553) is a rare monogenic autoinflammatory disease with an autosomal protein kinase signals and irregular cytokine production. Immunodeficiency, recessive inheritance, deriving from biallelic loss-of-function mutations in intestinal inflammation, and progressive polyarthritis have been reported in the ADA2 gene, which encodes for the homonym protein. Its patients with RIPK1 mutations, however the current knowledge about the heterogeneous clinical phenotype can range from multisystemic vascular clinical aspects of the disease is still scarce. inflammation, often mimicking polyarteritis nodosa (PAN), to hematological Objectives: Here we report a novel RIPK1 mutation in a patient with involvement (including cytopenias and bone marrow failure) and mild severe arthritis and some distinct clinical features. humoral immunodeficiency in the form of hypogammaglobulinemia and B Methods: Clinical and laboratory features of the patient were cell lymphopenia. Because it was first described in 2014, prior cases were described. often diagnosed as PAN. Results: Case presentation: An 18 months-old male has presented Objectives: To expand the knowledge about genetic basis of DADA2 with recurrent febrile episodes and arthralgia in his multiple joints. with special attention to high suspicion cases with unconclusive His family reported febrile episodes in which he was diagnosed with genetic results, specially when the ADA2 activity test are unavailable. respiratory tract infection (RTI) since three months of age. At the Methods: Review of clinical charts, biochemistry and autoimmunity ages of 8 months and 16 months, febrile attacks were accompanied profiles and genetic tests of the proband and his 4 alive siblings by severe arthralgia for 3 days with elevation of acute phase reac- pedigree. Genetic analysis of DNA samples obtained frompatients tants. Family history revealed the diagnosis of familial Mediterranean under informed consent, according to the Helsinki declaration. fever (FMF) in his grandparent, uncles and cousins and rheumatoid Results: In the case hereby presented, after numerous tests, a first arthritis in his great-uncle. diagnosis of PAN-like disease was established in a 30-year-old male His physical examination was unremarkable. Blood count, acute with no relevant familial history and a personal history of Raynaud’s phase reactants, liver and kidney function tests, urinalysis and serum phenomenon, livedo reticularis, digital ischemia, early-onset strokes, immunoglobulin examinations were within normal limits for age. optic and peripheral neuropathy, cardiomyopathy, mesenteric and MEFV gene analysis was performed which revealed a heterozygous renal aneurysms, hypertension, vertigo, and multiple other systemic mutation in V726A. The patient was commenced on colchicine inflammation manifestations. Given the clinical history, atypical onset, considering the diagnosis of FMF. After the colchicine treatment, his the presence of hypogammaglobulinemia and disease progression family reported a decrease in the number of febrile episodes, despite several cyclophosphamide (CP) bolus and high-dose cortico- however at the age of two, joint swelling was accompanied to febrile steroid therapy, DADA2 diagnosis was considered. attacks. Autoinflammatory genetics panel was negative. There were At the age of 37 years a first genetic testing was performed arthritis and limited range of motion in both knees, elbows and small through direct sequencing of ADA2 via Sanger analysis using joints of hands and feet. The patient was diagnosed with DNA extracted from peripheral blood. One of the most common polyarticular juvenile idiopathic arthritis (JIA) due to persistent pathogenic ADA2 variants - p.G47R - was identified in a simple arthritis and intravenous pulse methylprednisolone treatment was heterozygous genotype. These results led to hypothesize the given for 3 days which was switched to oral methylprednisolone and presence of a structural gene variant in this locus that could tapered. Methotrexate was initiated subcutaneously once a week. justify the range of the previously mentioned clinical features. A After the treatment, his arthralgia was subsided and a significant whole genome sequencing (WGS) was executed without solid improvement was observed in his ability to walk, however joint bioinformatic analysis results. Therefore, multiplex ligation- swelling did not improve. The patient underwent to whole exome dependent probe amplification (MLPA) of the ADA2 gene was sequencing and a homozygous missense mutation in RIPK1 at performed, revealing a heterozygous genomic deletion that en- c.1849C>G [p.(His617Asp)] was detected, which was not previously compass exon 7 and flanking intronic boundaries. The Sanger reported in the literature and the databases. Whole body MR exon 2 and exon 7 analyses of the 4 siblings identified an het- imaging revealed microatelectasis in both lungs, arthritis in bilateral erozygous p.G47R variant on proband's mother while the exon 7 glenohumoral and coxofemoral joints, edema and inflammation in avaluation concluded a trans inheritance pattern. The ADA2 activ- adjacent soft tissues, and trochanteric bursitis. Control levels of ity was finally performed 11 years after the first diagnosis of Pediatric Rheumatology (2022) 20:2 Page 31 of 39 PAN. As expected, the proband p.G47R variant / exon 7 deletion Ursodeoxycholic acid (UDCA) was started. Transaminases persisted slightly in trans manner produced an almost complete lack of activity. elevated the following months, although CMV-IgM and urine CMV-DNA ADA2 activity for her mother, was reduced at 50%. normalization. Eight months later, UDCA was discontinued but liver en- In the reported case, disease remission was achieved after initiation zymes increased (SGOT 198 U/L ALAT 271 U/L), thus UDCA was resumed of anti-tumor necrosis factor (anti-TNF) therapy with Adalimumab. with progressive laboratory normalization. An extensive diagnostic work-up Conclusion: DADA2 is a monogenic autoinflammatory disease with a ruled out metabolic and autoimmune diseases. MRCP was normal. Array- wide clinical spectrum mimcicking PAN. Despite the lack of familar CGH, karyotype and a NGS for genetic cholestatic liver diseases resulted history, complex genetic changes can drive to a refractory PAN-like negative. At the age of 8, UDCA was discontinued without any following al- clinical picture. In this enviroment, the seric ADA2 activity is a useful teration of liver function. screening tool with limited availability. Genetic diagnostic test with a During early infancy, developmental delay was noted in association more specific approach using WGS and/or MLPA can be the key for with spastic paraplegia and microcephaly. Brain MRI, performed at the final diagnosis. the age of 1 and 9, showed radiated crowns and semioval centers hyperintensity, lateral ventricles slight dilation and two symmetrical Acknowledgments hyperintense areas at pontine tegmentum. She also presented IgA Special acknowledge for dr. Solans, first physician who suspected the deficiency, mild psoriasis and dysmorphic elements (broad forehead, disease, and all the laboratory crews of the Immunology Department of very high and external eyelids, long eyelashes, fetal pads, protruding Hospital Clínic i Provincial - IDIBAPS, and the Biochemistry Section of the auricles and supernumerary teeth). Hospital Vall Hebron. At the age of 10, whole-exome sequencing showed the de novo vari- ation c.2159G>A, p.(Arg720Gln) in the IFIH1 gene, consistent with Disclosure of Interest AGS. Therefore, blood IFN signature was investigated, resulting mark- None Declared edly elevated. She underwent a thorough autoimmune screening, which was unremarkable. Brain MRI was repeated, resulting stable compared to the previous ones, as well as neurologic evaluation. P47 Conclusion: AGS syndrome should be suspected in infants with Clinical course of aicardi-goutières syndrome in a girl with idiopathic cholestatic liver disease, in particular when a history of cholestatic liver disease and global neurological impairment unexplained neonatal thrombocytopenia is present, even before the 1 1 1 1 1 A. Diana , R. Naddei , A. Di Stazio , F. Di Dato , G. Cappuccio ,G. neurological impairment onset. In this regard, IFN signature may be 1 1 2 1 1 Terrone , N. Brunetti-Pierri , S. Volpi , R. Iorio , M. Alessio useful in the diagnostic work-up. Given the disease prognosis and Department of Translational Medical Sciences, Section of Pediatrics, the lack of approved therapeutic options, we are going to start an University of Naples Federico II, Naples; Center for Autoinflammatory off-label treatment with a JAK/STAT inhibitor in this patient, although Diseases and Immunodeficiency, IRCCS Istituto Giannina Gaslini, Genoa, some issues are unsolved, such as the risk of liver toxicity associated Italy to JAK/STAT inhibitors, the real effectiveness to treat a long-course Correspondence: R. Naddei brain disease and the difficulty in monitoring treatment efficacy. Pediatric Rheumatology 2021, 20(Suppl 1):P47 Written informed parental consent for publication was given. Introduction: Aicardi-Goutières Syndrome (AGS) is an autoinflamma- Disclosure of Interest tory leukodystrophy characterized by global neurologic dysfunction, None Declared associated to an increased expression of type I interferon (IFN)-stimu- lated genes (the so-called IFN signature). Objectives: To describe the clinical course of a 10-year-old girl diag- P48 nosed with AGS. Myositis as an unusual presentation of ADA2 deficiency 1 1 1 1 2 1 Methods: Case report. M. Rossano , F. Baldo , S. Torreggiani , L. Baselli , S. Giliani , S. Lanni ,A. 1 1 1 Results: The girl was born at 37 weeks of gestation to non- Petaccia , G. Filocamo , F. Minoia consanguineous parents by urgent caesarean section due to fetal dis- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan; tress. Her mother suffered from congenital hearing loss and intellectual ASST Spedali Civili di Brescia , Brescia, Italy disability. Birth weight was 2150 g (small for gestational age). Since the Correspondence: M. Rossano first days of life, she presented hypotonia, thrombocytopenia (platelets Pediatric Rheumatology 2021, 20(Suppl 1):P48 [PLT]: 29400/mmc) and splenomegaly, so she was admitted to a Neo- natal Intensive Care Unit (NICU) where she remained for four weeks. Introduction: ADA2 deficiency (DADA2) is a complex monogenic Suspecting neonatal sepsis, she underwent intravenous antibiotic treat- autoinflammatory condition characterized by protean manifestations, ment, soon after discontinued due to negative blood, urine and cere- including haematological, cutaneous, articular and vascular involvement. brospinal fluid (CSF) cultures. TORCH showed positivity for rubella- and Diagnosis is often difficult, due to the highly variable clinical phenotypes CMV-IgG, as well as maternal TORCH all over the pregnancy. Urine, and the indolent course of the disease, often becoming overt when a plasma and CSF CMV-DNA was negative. Few days later, she presented major event occurs. fever and severe anemia requiring red blood cells transfusion in associ- Objectives: To describe an unusual case of ADA2 deficiency ation with Staphylococcus Hominis sepsis, treated with intravenous an- presenting with myositis, due to compound heterozygosity for a tibiotics. At one-month follow-up, PLT were normalized and have missense mutation and a novel deletion in ADA2. remained normal since then. Echocardiography revealed anomalous Methods: A 7-year old boy came to our attention for intermittent bi- pulmonary venous return, that required, at 8 months of life, coil lateral leg pain. Clinical evaluation was unremarkable, with normal embolization. Cerebral ultrasound showed lenticulostriate vasculopathy. strength. Blood tests revealed elevated inflammatory markers and During her stay in NICU, the patient also started a protein hydrolysate normal lactic dehydrogenase (LDH) and creatinkinase (CK). Moderate formula due to repeated episodes of vomiting. At the age of 4 years, lymphopenia was observed with low count of both CD19+ and NK cow’s milk proteins were reintroduced. cells, elevated CD3+HLA-DR+ cells, and low levels of IgM; double At the age of 4 months, she presented vomit and lethargy. She was negative αβ T lymphocytes were normal (Table 1). Magnetic reson- admitted to a local hospital where anicteric cholestatic hepatitis (SGOT ance (MRI) showed bilateral signs of polymyositis of the lower limbs. 1321 U/L, ALAT 1834 U/L, GGT 231 U/L), acidosis and hyperammonemia He subsequently developed nocturnal fever, multiple inguinal and were found. She was treated by providing a glucose-based solution with axillary lymphadenopathy and splenomegaly. An infectious workup pH and ammonium normalization and then she was transferred to our De- was negative, as well as an autoimmunity panel including myositis partment, due to persistence of transaminases and GGT elevation. Abdo- specific and associated autoantibodies, and serum markers of malig- men ultrasound was normal. IgG and IgM for CMV resulted positive, as well nancies. PET-scan showed multiple tracer uptake in axillary, inguinal as urine CMV-DNA, therefore CMV-related hepatitis was suspected. and abdominal lymph nodes (SUV max 2.2). A myogenic pattern of Pediatric Rheumatology (2022) 20:2 Page 32 of 39 active denervation was confirmed by electromyography. Muscle bi- specific diagnosis, either because their clinical phenotype is not diagnostic opsy revealed non-specific signs of inflammation with scarce macro- or genetic tests are negative. phagic infiltration; no alteration of muscle fibres nor perifascicular Objectives: To report an unsolved case of uSAID with successful anti- atrophy or clear signs of vasculitis were reported. Bone marrow and IL-1 treatment. lymph node biopsy with flow cytometry were negative for Methods: A twelve years old male with recurrent fever associated malignancy. with fatigue, myalgia and oral aphthosis. Due to the extremely painful musculoskeletal involvement associated Results: Since the age of 11 years the patient had recurrent to the development of recurrent infiltrative burning nodular skin febrile episodes, with high fever (maximum temperature 40°C) of lesions of both hands and feet, a symptomatic treatment with variable duration (range 3-10 days), monthly, associated with fa- indomethacin was started with dramatic and prompt relief, but tigue, myalgia, periorbital oedema and sometimes oral aphthosis. persistence of elevated acute phase reactants. There was no rash and no history of genital aphthosis. The boy Genetic sequencing of ADA2 revealed compound heterozygosity for was born full term from physiological pregnancy and unrelated a novel frameshift deletion in the catalytic domain, parents. Family history revealed mother with history of similar c.1100_1113del:p.I367Tfs*41, inherited from the father, and a symptoms. At the admission, during a febrile episode, laboratory maternally inherited missense variant, c.1148G>A:p.G383D , assessment showed low white blood cells count (3540/uL, n.v. previously described in compound heterozygosity in a patient with 5000-19000), raised C reactive protein (CRP) (100,84 mg/l, n.v < DADA2. ADA2 functional analysis confirmed pathological low activity 5), raised erythrocyte sedimentation rate (ESR)(101 mm/h, n.v. 0- of the enzyme. Brain angio-MRI was unremarkable. Etanercept treat- 13) and anemia (hemoglobin 8.9 gr/dl, n.v. 10-18). Covering the ment was started with rapid response of muscoloskeletal and skin in- possibility of a bacterial infection, the patient was treated with volvement, normalization of inflammatory markers and regression of broad spectrum antibiotics. Infections were excluded. Fecal cal- lymphoproliferation. protectin showed not pathological values. Chest x-ray, echocar- Results: diogram and electrocardiogram were normal. Abdominal Conclusion: We report an unusual case of DADA2 presenting with ultrasound showed a liver and spleen increased volume. Bone myositis, which is seen in less than 1% of ADA2 deficiencies, due to marrow aspirate resulted negative. Because of the persistence of a novel ADA2 deletion leading to premature protein truncation, in fever, he started on Indomethacin therapy with response. a whole compound heterozygosity with the recently described c.1148G>A body MRI STIR sequences was performed showing symmetrical mutation. The pathogenic role of the latter, so far reported in only signal hyperintensity of the cancellous bone of the distal femur, two siblings in compound heterozygosity, is supported by our data. tibia and radius. On the basis of clinical history and imaging a DADA2 phenotype spectrum is constantly increasing and description chronic recurrent multifocal osteomyelitis (CRMO) was suspected. of peculiar cases could improve genotype/phenotype correlation and Because of the worsening of symptoms and laboratory parame- lead to significant progress in diagnosis, management and prognosis ters, even with maximum dosage of the drug, , after few months of these patients. Written informed parental consent for publication he switched to Colchicine therapy. He showed clinical and labora- was given. tory wellness associated with resolution of lesions to MRI study, but also in that case, after few months symptoms recurred and Disclosure of Interest the initial dosage of drug was gradually increased, without bene- None Declared fits. Genetic tests for autoinflammatory diseases were performed, resulting negative. In the last hospitalization MRI STIR was re- peated, confirming previous findings. He also underwent to bone biopsy, that excluded malignancy. In consideration of persistence of fever, associated with fatigue and myalgia and increased in- Table 1 (abstract P48). See text for description flammatory markers (CRP 111,3 mg/L, ESR 49 mm/h), Anakinra (anti IL-1) was introduced (2 mg/kg/die), with ready significant Weeks from 4 6 14 16 21 43 46 56 61 clinical and laboratory response. disease onset Conclusion: The spectrum of autoinflammatory diseases is rapidly Therapy Indomethacin Etanercept expanding owing to recent developments in molecular sciences and start start genetics. However, for some autoinflammatory disorders no genetic CRP (mg/dl) 2,64 3,19 5,13 2,08 0,9 2,53 0,05 0,05 0,05 alteration can be found. These cases are defined uSAID and Anakinra ESR (mm/h) 52 63 52 40 35 44 13 4 2 seems to be a feasible treatment option. Our patients presents features of different autoinflammatory disorders (recurrent fever, oral Hb (g/dl) 11,1 9,9 9,9 9,4 10,2 9,5 10,3 11,3 12 aphthosis, peri orbital oedema, symmetrical hyperintensity STIR WBC (cell/ 5400 6100 7050 4990 5060 5540 4650 3260 4020 lesions at MRI, leukopenia in acute phase, elevation of inflammatory mm3) indexes) but no mutations of associated genes were found. We N (cell/mm3) 3760 4270 4760 2840 2910 3320 2210 1050 1890 expect to perform whole exome sequencing. L (cell/mm3) 850 750 1390 1380 1310 1470 1790 1570 1440 Disclosure of Interest None Declared P49 A case of undifferentiated systemic autoinflammatory disorder 1 2 2 2 1 P50 M. Tardi , F. Annunziata , M. L. Pennacchio , F. Paciello , B. Raffaele ,R. 1 1 1 Early-onset recurrent neuroinflammation and arthritis: a diagnostic Sottile , L. Martemucci , F. Orlando and therapeutic challenge Rheumatology Unit, Department of Pediatrics, Santobono-Pausilipon 1 1,2 1 1 1 S. Torreggiani , M. Pozzato , G. Filocamo , S. Lanni , S. Guez ,F. M. Children Hospital; Department of Translational Medical Sciences, 1 3 3 3 4 Triulzi , A. Tozzo , F. Andreetta , P. Cavalcante , M. Iascone ,C. Section of Pediatrics, University of Naples Federico II, Naples, Italy 1,2 1,2 1,2 1,2 Agostoni , N. Bresolin , S. Barbieri , F. Martinelli Boneschi ,F. Correspondence: M. Tardi 1 1 Minoia , R. Dilena Pediatric Rheumatology 2021, 20(Suppl 1):P49 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; 2 3 Università degli Studi di Milano; IRCCS Istituto Neurologico C. Besta, Introduction: Autoinflammatory diseases are a group of diseases related Milan; ASST Papa Giovanni XXIII, Bergamo, Italy to dysfunction or dysregulation of innate immunity and can cause serious Correspondence: S. Torreggiani morbidity and mortality by affecting multiple organ systems. Patients with Pediatric Rheumatology 2021, 20(Suppl 1):P50 symptoms commonly found in autoinflammatory disorders may not fit a Pediatric Rheumatology (2022) 20:2 Page 33 of 39 Introduction: Neuroinflammation is increasingly identified in Introduction: Actinopathies are a growing group of monogenic pediatric patients, as an isolated finding or in the context of immune attributed diseases related to the defects in remodeling autoimmune and autoinflammatory conditions. Due to marked pathways of actin cytoskeleton. clinical heterogeneity and phenotypic overlap, diagnosis is often Objectives: To confirm the significance of Immuno-Actinopathies role challenging. in the pathogensis of an expanding group of autoinflammatory dis- Objectives: To describe an unusual case of early-onset recurrent cen- eases and primary immunodeficiencies. tral nervous system (CNS) inflammation and demyelination associ- Methods: Two patients referred with a history of chronic ated with arthritis. mucocutaneous lesions and selected laboratory immune phenotype Methods: Whole exome sequencing (WES) was performed, followed abnormalities. 1 st by targeted reanalysis of neuroinflammation related genes. First, A 3 years old female patient of 1 cousin consanginous parents Results: A previously healthy 13-month-old girl was admitted to our presented with spontaneous vascuilitic cutaneous ulcerations in the hospital due to hyporeactivity and asymmetric tetraparesis with dys- inguinal flexure& the thighs (Biopsy confirmed) and multiple vulval tonic posturing, a week after an upper respiratory infection. Brain abscesses.She had a serial history starting at the age of 2 months MRI showed symmetric talamic lesions, with involvement of the sur- with bleeding per rectum & eczema diagnosed as cow milk protein rounding white matter and the right optic tract. CSF studies includ- intolerance, an althrough sequences of recurrent infections (bilateral ing PCR for HSV1-2, VZV, CMV and anti-MOG antibodies were normal. purulent otitis media(P.aeruginosa) , skin abscesses &Staphylococcal She was diagnosed with acute disseminated encephalomyelitis pneumonia) and multiple confirmed food allergies during weaning st (ADEM) and treated with high dose intravenous methylprednisolone trials. Second, A 5 years old male patient of 1 cousin consanginous and 2 g/kg IVIG. Due to the age at onset and the basal ganglia invo- parents,presented with multiple spontaneous cutaneous sterile lement, a Biotin-Thiamine-Responsive Basal Ganglia Disease was ex- ulcerations,punched out lesions, necrotic demal lesions & paperous cluded by sequencing of the SLC19A3 gene. Further metabolic shiny skin in both upper& lower limbs together with acquired mild investigations including mitochondrial DNA analysis were also nega- microstomia (a result of recurrent attacks of stomatitis), fissured lips, tive. Three months later her neurologic exam was unremarkable with distorted tongue mucosal lining and decayed teeth. He had a the exception of mild right lower limb dystonia; her brain MRI chronic history of attacks of periodic fever . rd showed an almost complete resolution of previous abnormalities. Results: On physical examination, first patient was below 3 centiles At 19 months of age, 17 days after the anti measles, mumps, and for weight & height, coarse facies& no organomegaly or rubella vaccine, the patient presented with acute onset of lymphadenopathy.Significant lab studies was in the form of chronic strabismus, vertical nystagmus and ataxia. Brain and spinal cord MRI fluctuating thrombocytopenia(3- 36 X 10³μL) with small platelet showed new lesions in the supra- and infratentorial white matter and volume(<7fl), high IgA (679mg/dl)&significantly high IgE(3600-7500 IU/ in the optic nerves, and a longitudinally-extensive transverse myelitis L).Patient responded markedly to repeated sessions of pulse steroid (LTEM) lesion at C2-C4 level. As in the first episode, inflammatory theray (Methylprednisolone; 30mg/kg x 5 days) paired with IVIG markers were negative. CSF studies were normal, with oligoclonal followed by oral steroids and was referred for HSCT(Hematopoietic bands, anti-aquaporin and anti-MOG antibodies negative both on stem cell transplantation).Genetic studies revealed ARPC1B deficiency. th serum and CSF. Complement function was normal and blood IFN sig- On physical examination, second patient was on 25 centiles for nature was negative. A transient positivity for ANA (1:640) and for p- weight&height, IQ 75, facies(frontal bossing, wide nostrils& long ANCA was observed but not confirmed in further testing. HLA-B51 dense eye lashes) and no organomegaly or lymphadenopathy. was detected. WES was not contributive, despite a reanalysis of > Significant lab studies was in the form of high inflammatory markers 250 neuroinflammation related genes . She again required high dose (Neutrophilia,high ESR&CRP), low seum IgG(440 mg/dl) and high intravenous methylprednisolone and was started on periodic 2 g/kg seum IgA(270 mg/dl).Patient responded partially to pulse steroid IVIG for 12 months. Despite almost complete regression of neuro- theray(Methylprednisolone; 30mg/kg x 5 days) and IVIG. Marked logic signs, MRI lesions improved but persisted. improvement was noted post an add–on Subcutaneous weekly Nine months after the last neurological event, the patient Methotrexate injections with oral steroids. Genetic studies revealed a developed arthritis involving the temporomandibular joint, the right Homozygous WDR1mutation. knee and ankle, requiring treatment with intra-articular steroid Conclusion: Refractory mucodermal disintegrity in pediatrics can clue to injections. Based on the joint involvement and the positivity of HLA- serious rare immunorelated disorders.Actinopathies paves the complexity B51, she was also started on methotrexate and colchicine. At the age of merging autoinflammatory states and immunodeficiencies.HSCT is a of 38 months, she is neurologically stable with fluctuant right lower fundemental curative therapeutic line. Written informed parental consent limb dystonia, despite incomplete regression of right ankle arthritis. for publication was given. Conclusion: We described a case of early-onset recurrent neuroin- flammation presenting with features of ADEM, MOG Associated Dis- Disclosure of Interest ease (MOGAD) and Neuromyelitis optica spectrum disorder (NMOSD), None Declared associated with arthritis. Clarifying the immunologic process under- lying this phenotype will help guide treatment. 1. McCreary D, Omoyinmi E, Hong Y, et al. Development and Validation P52 of a Targeted Next-Generation Sequencing Gene Panel for Children A novel presentation of a hereditary periodic syndrome: which With Neuroinflammation. JAMA Netw Open. 2019;2(10):e1914274. variant is responsible? S. Al-Mayouf, L. Akbar Disclosure of Interest Pediatric Rheumatology- King Faisal Specialist Hospital and Research None Declared Center, Riyadh, Saudi Arabia Correspondence: L. Akbar Pediatric Rheumatology 2021, 20(Suppl 1):P52 P51 chronic mucocutaneous lesions revealed underlying rare Introduction: Recently, plasminogen, its activators, and its receptors have actinopathies-related disorders (Two case reports) gained more attention in inflammation regulatory processes, including H. M. Abd El-Lateef release proinflammatory signaling molecules, and thus its role has Pediatric Rheumatology Immunology department, Ain Shams University, implications for a wide spectrum of clinical manifestations. Cairo, Egypt Objectives: Heres’ we presented a case of homozygous Pediatric Rheumatology 2021, 20(Suppl 1):P51 plasminogen variant managed initially as periodic fever syndrome. Pediatric Rheumatology (2022) 20:2 Page 34 of 39 Methods: Case report chondritis, and vasculitis. Patients fulfilled clinical criteria for inflam- A 9-year-old boy presented at the age of 18-months with peri- matory (relapsing polychondritis, Sweet syndrome, polyarteritis odic fevers and vomiting every 3 weeks, lasting for 48-72 hours. nodosa, giant cell arteritis) and hematologic (myelodysplastic syn- Heterozygous variant of MEFV gene was detected drome or multiple myeloma) conditions. We have named this disease (c.442G>C; p.E148Q). Over a period of 7 years he developed re- VEXAS (Vacuoles, E1 ubiquitin activating enzyme, X-linked, Autoin- current headaches, abdominal pain, dysphagia, failure to thrive, flammatory, Somatic) syndrome. Mutations at p.Met41 resulted in eosinophilic esophagitis, recurrent otitis media, pneumonias, bron- loss of the cytoplasmic isoform of UBA1 and decreased ubiquitylation chial asthma like exacerbations, eye redness, tearing, delayed and, unexpectedly, the expression of a novel, catalytically inactive, wound healing, periodontitis, and loss of teeth. Also, he was toxic isoform, in mutant, but not wildtype, lineages. We have further found to have Pseudotumor cerebri. Immunological and infectious identified a genotype-phenotype correlation, suggesting specific risk work-up were inconclusive. Colchicine and short courses of ste- factors for severe disease progression. Mutant peripheral blood cells, roids were initiated. However, anakinra was added with a partial and depletion of UBA1 in vitro, exhibited activated innate immune response. It is worth mentioning that his parents are first-de- pathways and evidence for unfolded protein response (UPR). Knock- gree cousins; he has a twin sister with severe cyclic GI manifesta- out of the zebrafish UBA1 cytoplasmic isoform homologue caused tions, with remarkable response to anakinra. Other siblings had systemic inflammation. sickle cell disease suffered from similar complaints as the index Conclusion: By querying exomes for mutations in ubiquitylation case with varying degrees in severity. With the constellation of genes, we have defined a novel disorder, VEXAS) syndrome, which findings and the inadequate response to therapies, whole-exome connects seemingly unrelated adult-onset inflammatory syndromes sequencing was obtained revealing homozygous variant in plas- and hematologic diseases and establishes a precedent for a new mo- minogen gene; coding for plasminogen. However, his twin was lecular taxonomy of rheumatic diseases. Our work also reveals som- found to have heterozygous plasminogen variant. atic mutations as an underrecognized cause of adult-onset rheumatic Conclusion: Our case had a constellation of diseases. findings cannot fully be explained by one classified autoinflammatory disease. Although we have no Disclosure of Interest definite diagnosis; we believe that plasminogen gene variant, with None Declared the coexistence of MEFV gene variant might contribute to the clinical manifestations. Further studies needed to confirm this finding and allow more definitive conclusion. Written informed P54 parental consent for publication was given. Sharpenia, a novel autoinflammatory disorder caused by dysregulation in TNF-mediated cell death 1 1 1 2 1 1 Disclosure of Interest H. Oda , K. Manthiram , H. Kuehn , A. Rao , D. Beck , M. Nehrebecky ,A. 1 1 1 1 1 None Declared Ombrello , T. Romeo , J. J. Chae , I. Aksentijevich , D. Kastner 1 2 NIH, Bethesda, United States; Manipal Hospital, Bangalore, India Correspondence: H. Oda P53 Pediatric Rheumatology 2021, 20(Suppl 1):P54 Identification and characterization of vexas syndrome caused by somatic mutations in UBA1 Introduction: The linear ubiquitin chain assembly complex (LUBAC) D. Beck, M. Ferrada, K. Sikora, A. Ombrello, D. Ospina Cardona, L. Wilson, consists of HOIP, HOIL1, and SHARPIN and is essential for linear P. Hoffman, K. Manthiram, I. Aksentijevich, P. Grayson, D. Kastner ubiquitination of NF-κB and other immune pathways. Patients with National Institutes of Health, Bethesda, United States HOIP and HOIL1 deficiencies present with severe immunodeficiency, Correspondence: D. Beck autoinflammation, and excessive glycogen storage. The role of cell Pediatric Rheumatology 2021, 20(Suppl 1):P53 death pathways in LUBAC deficiencies has not been investi- gated. Sharpin-deficient mice exhibit severe TNF-dependent skin in- Introduction: Identifying the causes of adult-onset rheumatic dis- flammation due to enhanced apoptosis and necroptosis in the eases remains a challenge, and limits diagnosis, prognosis, and tar- keratinocytes; however the role of SHARPIN in human disease is geted treatment. We hypothesized that mutations in genes unknown. regulating the post-translational modification ubiquitin, previously Objectives: We aimed to investigate a 14 year-old boy from a con- implicated in autoinflammatory diseases, may define new rheumatic sanguineous family in India who presented with childhood-onset disorders. polyarthritis, parotitis, colitis and hepatic glycogen deposition. No Objectives: This study aimed to identify novel genetic causes of skin inflammation or immunodeficiency was noted. autoinflammation using a "genotype" first approach. Methods: We utilized whole exome sequencing in the proband and Methods: We analyzed peripheral blood exome sequence data from his unaffected parents to identify a genetic cause of the disease. 2,560 individuals with inflammation-related diagnoses for deleterious Results: We identified a homozygous frameshift mutation c.220dupC mutations in >800 ubiquitin-related genes. Sanger sequencing, in SHARPIN in the proband. Patient cells revealed no detectable digital droplet PCR, immunoblotting, immunohistochemistry, flow cy- SHARPIN protein and markedly reduced expression of HOIP and tometry, and transcriptome/cytokine profiling were performed. HOIL1, suggesting destabilization of the entire LUBAC. Besides, CRISPR/Cas9 knockout zebrafish provided an in vivo model to assess mutant cells displayed a reduced activity of the canonical NF-κB UBA1 gene function. pathway. We then study the role of apoptosis in the Sharpenia Results: Sixty adult males with autoinflammation and hematologic proband and other patients with LUBAC deficiency. We observed disease were identified with somatic mutations in UBA1, an X-linked dysregulated apoptosis ex vivo, in vitro, and in vivo in all three gene, encoding the major E1 enzyme that initiates cytoplasmic ubi- LUBAC-deficient samples. Of note, the extent of apoptosis correlated quitylation. Mutations were primarily identified at methionine 41, a with the severity of the disease. We identified a stark difference of in- highly conserved residue, and these mutations were not observed in flammatory signatures between blood and synovial fluid samples in exome sequences from over 80,000 healthy controls. Among affected the Sharpenia patient, suggesting tissue-specific inflammation as the individuals, mutations were found in more than half of cause of this disease.Anti-TNF therapy achieved the complete reso- hematopoietic stem cells, exclusively in peripheral blood myeloid lution of inflammation, which further corroborates the role of TNF- cells, and not in lymphocytes or other non-hematopoeitic tissues. Pa- mediated cell death in the pathogenesis of autoinflammation. Intri- tients developed an often-fatal, treatment-refractory inflammatory guingly, despite the absence of clinical immunodeficiency, the aden- syndrome in late adulthood, with fevers, cytopenias, characteristic oids of the SHARPIN deficiency patient showed a remarkably vacuoles in myeloid and erythroid precursors cells, dysplastic bone diminished germinal center formation, which was also notable in marrow, neutrophilic cutaneous and pulmonary inflammation, HOIP and HOIL1 deficiency patients. Pediatric Rheumatology (2022) 20:2 Page 35 of 39 Conclusion: We identified the first case of human SHARPIN episodes and duration /intensity of the pain of arthritis, no further deficiency in a patient with autoinflammation and subclinical skin rash and steroids have been tapered to low dose. immunodeficiency. We re-define human LUBAC deficiency as an Conclusion: We report a new autoinflammatory disease that might autoinflammatory disease caused by dysregulation in cell death be caused by a hypomorphic pathogenic variant in TBK1. Further pathways. studies are necessary to confirm the clinical significance of this finding. Written informed parental consent for publication was given. Disclosure of Interest None Declared Disclosure of Interest None Declared P55 New monogenic autoinflammatory disease due to homozygous P56 loss of function mutation in tank binding kinase 1 Nailfold capillaroscopy: a sensitive method for evaluating 1 1 2 2 P. Pimpale Chavan , I. Aksentijevich , D. Bogunovic , J. Taft ,S. microvascular involvement in children with SARS-COV-2 infection 3 4 1 2 3 4 2 Khubchandani , R. Khubchandani F. Çakmak , A. Demirbuga , D. Demirkol , S. Gümüş , S. Hançerli Torun , 1 2 1 1 2 4 4 NHGRI, National Institutes of Health, Bethesda; Icahn School of G. Kavrul Kayaalp , R. Eker Ömeroğlu , A. Somer , M. Uysalol ,R. Yıldız , 3 1 Medicine at Mount Sinai, New York, United States; Section of N. Aktay Ayaz 4 1 2 3 Histopathology; Section of Pediatric Rheumatology, NH SRCC Children's Pediatric Rheumatology; Pediatric Infectious Diseases; Pediatric Hospital, Mumbai, India Intensive Care Unit; Pediatric Emergency Unit, Istanbul Faculty of Correspondence: P. Pimpale Chavan Medicine, istanbul, Turkey Pediatric Rheumatology 2021, 20(Suppl 1):P55 Correspondence: F. Çakmak Pediatric Rheumatology 2021, 20(Suppl 1):P56 Introduction: TANK binding kinase 1 (TBK1) is a protein kinase with an important role in innate immunity by regulating IFN-I and NF-κB Introduction: The coronavirus (SARS-CoV-2) pandemic, known as signaling, and TNF-induced RIPK1-dependent cell death. To date, COVID-19 has spread all over the world in a short period of time and only 3 cases (one sibship and the index patient) have been identified caused the death of more than 2 million people to date. Although in to have disease-causing variants in the TBK1 gene. severe cases, it mainly progresses as a serious lung disease such as Objectives: We describe the first case report of an Indian patient of pneumonia or acute respiratory distress syndrome (ARDS), numerous Hindu ancestry with a homozygous predicted deleterious missense extrapulmonary manifestations due to systemic hyperinflammation mutation in the TBK1 gene. associated with COVID-19 have been described. The hyperinflamma- Methods: A 8 year old male born of third degree consanguineous tory state and the viral invasion may result in endothelial dysfunction marriage was first seen at 4 years 7 months of age with a history of and capillaroscopic examination of the nailfold may be a feasible onset at 18 months. He presented with irregularly spaced episodic method for monitoring the microvascular circulation in SARS-CoV-2 large and small joint arthritis lasting for few hours to 2-3 days, poly- infection. morphic skin rash described by his previous physician notes as ul- Objectives: With this study, we aimed to investigate the cerative, nodular, urticarial, and one episode of seizures and status microvascular circulation in patients diagnosed with COVID-19 and epilepticus. multisystem inflammatory syndrome in children (MIS-C) by nailfold th Results: His weight (11.5kg) and height (93cm) were below 5 videocapillaroscopy (NVC). centile for age, and he was developmentally normal. There was no Methods: Thirty-one patients with SARS-CoV-2 infection, 26 of whom lymphadenopathy or organomegaly and he had a 2 cms café au lait were diagnosed with COVID-19 and 6 with MIS-C, and 58 healthy spot on the posterior aspect of the left knee. Laboratory peers were included in the study. All fingers except the thumbs were investigations revealed hemoglobin of 7.9 -11.8 g/dL, white blood examined paying greater attention to the ring finger of the non- 3 3 cells 8600-23700/mm , platelets 3,00,000-7,19,000/mm , ESR 7- dominant hand for the presence of any abnormality bilaterally and 90mm/Hr, CRP 13-69mg/dL, and Immunoglobulin profile were nor- two images from eight fingers were obtained from both the study mal for age and gender. Anemia, neutrophilic leukocytosis, thrombo- and control groups. Sixteen images were examined for the morph- cytosis, and raised acute phase reactants normalized between the ology of capillaries, presence of pericapillary edema, microhemor- episodes. Bone scan, MRI, and CT brain were normal. rhage, avascular area, and neoangiogenesis. These parameters were Suspecting a systemic autoinflammatory disease (SAID), a next- assessed as present or absent, and the presence of signs in at least generation sequencing SAID gene panel (53 genes) was utilized but two fingers was recorded as capillary abnormality in both groups. Ca- was not contributory. Meanwhile, he was started on colchicine which pillary length, capillary width, apical loop, arterial and venous width, had to be discontinued after the family reported an increase in the fre- and intercapillary distance were measured from three consecutive ca- quency of rash. His episodes responded well to p.r.n paracetamol or na- pillaries from the ring finger of the non-dominant hand. proxen and the family was reluctant to add treatment without a Results: COVID-19 patients showed significantly more capillary ramifi- definitive diagnosis. At age 7 years 9 months, he developed periorbital cation (p<0.001), capillary meandering (p=0.04), microhemorrhage swelling, anasarca, and nephrotic range proteinuria and was started on (p<0.001), neoangiogenesis (p<0.001), capillary tortuosity (p=0.003). prednisolone @2mg/kg by a nephrologist with a diagnosis of nephrotic Capillary density (p=0.002) and capillary length (p=0.002) were sig- syndrome. A kidney biopsy was performed when he was on steroid nificantly lower in the patient group while intercapillary distance (p= treatment, which revealed minimally involved glomeruli with no signs 0.01) was significantly longer compared with healthy volunteers. of chronicity or amyloid deposits and immunofluorescence was nega- Morphologically, patients with MIS-C had a higher frequency of capil- tive while electron microscopy revealed flattening of the foot pro- lary ramification and neoangiogenesis compared with COVID-19 pa- cesses. The proteinuria responded well to steroids. Whole exome tients (p=0.04). Patients with capillary abnormalities had significantly sequencing was performed in the proband and his unaffected parent higher levels of C-reactive protein (CRP) and D-dimer (CRP; and identified a homozygous missense mutation in the kinase domain 16.4 vs 2.2, p=0.04 and D-dimer; 900 vs 340, p=0.04). of the TBK1 gene, c.634T>G (p.Y212D). Both the parents and elder fe- Conclusion: Children diagnosed with COVID-19 and MIS-C present male sib are healthy carriers for this variant. This missense substitution with several microvascular abnormalities on NVC examination. MIS-C is classified as Likely Pathogenic by ACMG classification criteria with a is an emergency phenomenon in which evidence suggests activation CADD score of 24.9. Preliminary functional experiments support the of ECs as the key determinant in the pathogenesis of the disease, pathogenicity of this variant. and NVC may be a useful non-invasive, valid method for assessing The patient has been started on Infliximab biosimilar molecule since the microcirculatory status of children with MIS-C. As a preliminary 3 months to which he has responded well with the decrease in one, our study may take attention to the use of NVC for follow-up of Pediatric Rheumatology (2022) 20:2 Page 36 of 39 patients with SARS-CoV-2 infection during clinical course and Table 1 (abstract P57). Clinical and laboratory data of the study management. population Key Words: COVID-19, Nailfold Videocapillaroscopy, microcirculation, endotheliitis Clinical data (n = Clinical data (n = Laboratory n= Laboratory n = 27 Laboratory n=27 27) 27) Data 27 Data Data Gender, n (%) Symptoms at SARS-CoV2 Hemoglobin 12.2 g/dL ALT 24 U/L Disclosure of Interest presentation, n serologic (9.4 – 15.5) (8 – (%) status, n (%) 115) None Declared Male 14 Fever 26 IgG+ / IgM- 24 Platelet 197 10 /μL LDH 540 U/ (52) (96.3) (88.9) count (62 – 513) L (317 – 1014) P57 Female 13 Abdominal 16 IgG+ / IgM+ 2 (7.4) CRP 112.3 mg/L Albumin 3.4 g/ Early recognition of multisystem inflammatory syndrome (48) pain (59.2) (9.15 – dL 420.8) (2.1 – temporally associated to COVID-19 in the emergency department: 4.5) a single tertiary care centre experience Age, yrs 7.1 Diarrhea 14 IgG- / IgM+ 1 (3.7) PCT 2.38 ng/mL Triglycerides 193mg/ 1 1 2 1 1 A. Mauro , M. Maglione , F. Orlando , A. Giannattasio , R. Margherita ,T. (0.8- (51.8) (0.16 – dL 1 1 1 1 1 1 12.3) 188) (70 - Gagliardo , L. Zenzeri , S. Lenta , S. Muzzica , C. D'Anna , C. Di Lillo ,R. 850) 1 1 Mancusi , V. Tipo History of SARS- Vomit 12 Blood tests Fibrinogen 598 mg/dL Creatinin 0.43 1 2 CoV2 (44.4) (223 – mg/dL Emergency Department; Pediatrics, Aorn Santobono-Pausilipon, Naples, infection/contact, 1109) (0.15 – n (%) 1.63) Italy Correspondence: A. Mauro Previous 5 Conjunctivitis 13 WBC count 11.74 D-dimer 1016 ng/ CK 80 U/L infection (18.5) (48.1) 10 / ml (8.8 - (16 - Pediatric Rheumatology 2021, 20(Suppl 1):P57 μL 14776) 5930) (4.16 28.72) Introduction: Multisystem Inflammatory Syndrome in Children (MIS- Close contact 9 Skin rash 11 Neutrophil 9.41 Ferritin 635.8 μg/L BNP 199.5 C) is a new and life-threatening disease temporally associated to with SARS- (33.3) (40.7) count 10 / (31.3 – pg/mL Covid-19. CoV2+ subject μL 8115) (5 - (3.29 5000) Objectives: The aim of the study is to analyze the clinical, 24.64) laboratoristic and instrumental features of patients with diagnosis of Both 8 Other 0 (0) Lymphocyte 1.29 AST 31 U/L Troponin 25.2 MIS-C at the onset in order to early recognize the disease. (29.6) count 10 / (13 – 245) ng/L μL (0.02 - Methods: We retrospectively reviewed clinical records of children (0.36 1523) admitted to our Emergency Department between April 2020 and – 15.93) March 2021, who were ultimately diagnosed with MIS-C associated Abbreviations: WBC, white blood cells ; CRP, C-reactive protein; PCT, procalcitonin; AST, aspartate aminotransferase; ALT, alanine with SARS-CoV2. Data collected included all clinical and laboratory aminotransferase; LDH, lactate dehydrogenase; CK, creatin kinase; BNP, brain natriuretic peptide parameters at presentation to the Emergency Department. We also recorded data regarding the duration of fever and hospitalization and the presence of abnormalities at chest X-ray, abdominal and car- P58 diac ultrasound. Multisystem inflammatory syndrome in children: clinical Results: Clinical and laboratory data of the twenty-seven children characteristics, diagnostic findings and therapeutic interventions at retrospectively enrolled, including symptoms at presentation to the a tertiary care center in South of Italy Emergency Department, are summarized in Table 1. Median duration 1 2 3 2 4 F. Orlando , A. Giannattasio , F. Paciello , A. Mauro , M. Tardi ,S. of fever was 4 days (range 1.5 – 7). With the exception of fever, ab- 2 2 2 2 4 4 Muzzica , C. D'Anna , M. Rosa , M. Maglione , R. Sottile , L. Martemucci , dominal pain and diarrhea were the most frequent complaints at V. Tipo presentation. No significant differences were found between labora- Department of Pediatrics, AORN Santobono Pausilipon, Napoli; tory parameters in children with or without abdominal pain, diarrhea, 2 3 Pediatric Emergency Unit, AORN Santobono Pausilipon; Department of vomit, conjunctivitis or rash. Translational Medical Sciences, Section of Pediatrics, University of Naples Heartultrasoundshowedno abnormalitiesin11out of 27 Federico II; Department of Pediatrics, AORN Santobono Pausilipon, children (41%). Findings in other children were mainly Naples, Italy represented by mild pericardial effusion (29.6%) and mild mitral Correspondence: F. Orlando valve insufficiency (25.9%). Minor abnormalities in the Pediatric Rheumatology 2021, 20(Suppl 1):P58 interventricular septal dynamics were detected in 3 subjects (11.1%). Abdominal ultrasound was unremarkable in 5 out of 27 Introduction: Multisystem inflammatory syndrome in children (MIS- patients (18.5%). Most children (51.8%) had mild-to-moderate C), also known as paediatric inflammatory multisystem syndrome peritoneal effusion, which was often associated with ileal loops temporally associated with COVID-19 (PIMS-TS), is a condition charac- wall thickening (29.6%). The thickened segments were mostly lo- terised by persistent fever, elevation of inflammatory indexes and cated in proximity of the ileo-cecal valve or of the appendix. evidence of organs involvement or shock. Mesenteric lymphadenitis was found in eleven children (40.7%). Objectives: To describe clinical characteristics, diagnostic findings No significant differences were found in clinical or laboratory and therapeutic interventions of monocentric cohort of MIS-C. parameters between children with abnormal heart or abdominal Methods: Diagnosis of MIS-C was done following CDC criteria. Pa- ultrasounds and those without pathologic findings at these exams. tients were hospitalised at Santobono-Pausilipon Children’s Hospital Chest X ray at presentation showed no significant abnormalities in in Naples, Italy, from November 2020 to March 2021. most patients, and only the child who died one day after admission Results: MIS-C was diagnosed in 29 patients, 14 males (48.3%). Mean showed bilateral basal opacities. age at diagnosis was 7,2 years old (range 4 months-12,9 years). Con- Conclusion: The collected data allow to identify clinical and tact with SARS-CoV-2–positive patient emerged in 18/29 patients laboratoristic tic elements of patients admitted to Emergency care (62%) while 5/29 patients (17,2%) reported symptomatic COVID-19 in unit to provide early recognition of the MIS-C .The study included a the weeks before. SARS-CoV-2 serologic assayrevealed IgG +/IgM- in modest sample size and for this reason the generalizability of results 100% of the patients. No one presented concurrent conditions but is limited. A national multicentre study is ongoing. obesity in 6/29 (20,7%). Mucocutaneous involvement was evidenced in 21/29 patients (72%), gastrointestinal symptoms 22/29 (75.9%), Disclosure of Interest cardiac involvement in 27/29 (93,1%). The most frequent symptoms None Declared Pediatric Rheumatology (2022) 20:2 Page 37 of 39 were fever (100%), conjunctivitis (65.5%), abdominal pain (62%), diar- 35, 74%), the fingers (n=5, 10%) or on both sites (n=7, 15%). SARS- rhoea (48,2%), rash (44,9%), vomiting (31%) and cheilitis (31%). La- CoV-2 RNA detection resulted negative except for 2 patients. Further- boratory findings are summarised in table 1. Troponin resulted more, ten patients observed during the first wave showed a recur- elevated in 16/29 (55,1%), associated elevation of BNP was evidenced rence during the second (F:6), which developed 1-4 weeks after the in 12/29 (62%). Electrocardiography showed alterations in 25/29 second COVID-19 peak; the clinical features were comparable to (86,2%) while echocardiography in 21/29 (72%). Concerning therapy, those of the previous episode. Five of them (50%) reported non- 27/29 (93%) patients underwent parenteral antibiotics at the admis- specific systemic symptoms before onset and/or close contact with sion. Intravenous immunoglobulin (IVIG) was performed in 25/29 SARS-CoV2 positive subject. Repeated SARS-CoV-2 specific IgG/IgA (86,2%) of patients. Due to cardiac involvement 13/29 patients tests were negative for all patients except for three cases (two of (44,8%) received bolus of steroids. 4/29 patients (13,8%) presented them with positive swabs). Neither common virus serology nor co- worsening of clinical and laboratoristic parameters during treatment agulation studies revealed significative results. Two patients pre- with steroids, requiring Anakinra. One patient died due to cardio- sented positive ANA and anti β2 glycoprotein, respectively. A genic shock at the admission. positive IFN signature was detected in 12/ 33 patients (36%).Among Conclusion: Mucocutaneous, gastrointestinal and cardiac the 35 patients tested, the cytokine array showed high levels of IP10 involvement are the most common manifestations in our cohort, as (n= 35, range 12.4-739 pg/ml, n.v. 0.0-0.2 pg/ml) and a mild increase also reported in literature. Biologic treatment was necessary in of IL-6 (n=21, range 2.4-401 pg/ml, n.v. 0.5-2.2pg/ml), without alter- minority of patients. MIS-C is a new emerging condition and repre- ations of CXCL9, IL-1β and TNFa. The detection of SARS-CoV2 specific sent a challenge to paediatricians due to the severity of presentation. lymphocytes showed the presence of SARS-CoV2 specific lympho- More data are needed to better define incidence and prognosis of cytes in 9/17 (52%) patients tested (validated with positive and nega- that condition. tive controls), only one of them with a positive serological test. Conclusion: Albeit the pathogenetic mechanism of ACBLL remains to Disclosure of Interest be elucidated, our preliminary results showed a significant increase None Declared in serum IP10 levels, not frankly associated with a peripheral blood IFN signature, which is instead a characteristic of pernio-related chil- blains. We also proved the presence of a T-specific memory against P59 in 50% of the tested patients, despite the negativity of coltures and COVID-19 pandemic - related chilblains: clinical and immunological serological tests, strengthening the link between SARS-CoV2 infection characterization of an Italian cohort and this peculiar clinical manifestation. 1,2 3 3 1 1 1 S. Signa , F. Manunza , C. Pastorino , P. Bocca , A. Corcione , F. Penco , 1 4 3 4 5 5 A. Bertoni , I. Airoldi , G. Viglizzo , F. Morandi , S. Rosina , S. Viola ,C. Disclosure of Interest 3 6 4 5 2 Occella , M. Acquila , M. Podestà , A. Ravelli , E. Castagnola ,M. None Declared 1 1 Gattorno , S. Volpi 1 2 UOSD Centro Malattie Autoinfiammatorie e Immunodeficienze; UO 3 4 Malattie Infettive; UO Dermatologia; Laboratorio Cellule Staminali post P60 5 6 natali e Terapie Cellulari; UOC Clinica Pediatrica e Reumatologia; UO Diagnostic utility of genetic testing in autoinflammatory diseases - Laboratorio Analisi, IRCCS G. Gaslini, Genoa, Italy current situation in Belgium 1 1 2 Correspondence: S. Signa A. Le Goueff , F. Vandergheynst , G. Smits 1 2 Pediatric Rheumatology 2021, 20(Suppl 1):P59 Internal Medicine Department; Genetic Laboratory, Hôpital Erasme, Brussels, Belgium Introduction: During COVID-19 pandemic, acute acral chilblain-like Correspondence: A. Le Goueff lesions (ACBLL), reminiscent of lupus pernio, were observed during Pediatric Rheumatology 2021, 20(Suppl 1):P60 both first and second COVID-19 peak among patients with highly suspected (but mostly unconfirmed) infection with SARS-CoV-2.The Introduction: Autoinflammatory diseases (AID) are a group of rare aetiology of this phenomenon has not been elucidated yet and monogenic illnesses, leading to uncontrolled activation of the pathogenetic mechanism remains unknown. Several studies have in- innate immune system and presenting with recurrent flares of vestigated cytokine and chemokine profile in patients with COVID-19 systemic and localized inflammation. Diagnosis is confirmed by but an accurate characterization of ACBLL patients is lacking. the detection of a mutation in an AID-related gene and improve- Objectives: We aimed to describe the clinical, laboratory and ments in sequencing techniques have enabled the discovery of immunological features of children presenting with ACBLL referred new entities. to our Institute during the COVID-19 pandemic spread. Objectives: The aim of our study is to explore the impact of evolving Methods: We prospectively collected data of children referred to our genetic testing methods for AID in Belgium and to determine st th Institute from April 1 2020 to February 28 2021. We investigate whether increasing gene panels generate a higher diagnostic rate. the presence of SARS-CoV2 infection through RT-PCR from nasophar- Methods: Retrospective study of 2620 patients that underwent ingeal swabs and three different serologic kit.. All patients underwent sequencing for a clinical suspicion of AID in Belgium, between a laboratory work-up including coagulation, viral serology and auto- January 2015 and December 2020. Sequencing was performed antibodies panel. Finally, we analysed peripheral blood IFN signa- through a 10-gene panel between 2015 and 2017, a 25-gene panel ture, a panel of inflammatory biomarkers in serum/plasma by a flow between 2018 and 2020 and mendeliome technology with a 66- and cytometry bead array (CXCL10, CXCL9, IL-6, IL-1β,TNFα) and the pres- a 502- in silico gene panel in 2020. ence of SARS-CoV2 T specific lymphocytes. Results: Diagnostic rate increased along with the expansion of the Results: We examined 36 children during the first peak, and 11 gene panel with a diagnostic yield of 16% with 10 genes, 18% with children during the second COVID-19 peak (F: 28; median age 12 y), 25 genes and 23% with 502 genes. Factors that raised the diagnostic at a median delay of 26 days after symptoms onset (2-73 days). Fif- rate were Mediterranean ethnicity, abdominal and cardiorespiratory teen patients (31%) presented non-specific systemic symptoms pre- symptoms and absence of mucocutaneous, musculoskeletal, ceding ACBLL onset. Nine patients (19%) reported a possible ophthalmologic or ENT symptoms. contagion from a close contact. All patients presented stereotypical Conclusion: Our study is the first nationwide study for features resembling classical chilblains with acral erythematous- autoinflammatory genetic testing and the first use of mendeliome edematous violaceous plaques and nodules localized on the toes (n= technology for AID diagnosis. Although we confirmed that the Pediatric Rheumatology (2022) 20:2 Page 38 of 39 -31 -28 bigger the gene panel, the higher the diagnostic rate, this expected (P values 7.1 x10 and 2.5 x10 , respectively). Unexpect- technology generated inevitably a higher financial and human cost edly, differences were also observed in frequencies of abdominal -6 although the majority of diagnoses remained amongst the four pain (P=9.6 x 10 ) and of transfusion in absence of macrophage acti- -4 original hereditary recurrent fevers (HRFs). vation syndrome (MAS) or bleeding (P= 1.9x10 ). MAS during treat- -16 ment occurred almost exclusively in DRESS cases (P= 6.2 x 10 ). Acknowledgments HLA-DRB1*15 alleles were strikingly associated with DRESS, but did We thank the whole team from the ULB Centre of Human Genetics for their not distinguish DRESS cases with versus without diffuse lung disease help and their support and especially Mélanie Delaunoy. (DLD) developing during anti-IL-1/IL-6, MAS or comorbid conditions. We also thank the statisticians, Jazon Bouziotis and Mélina Houinsou Hans Preliminary data on outcome after careful drug removal include im- for their work. provement or resolution of lung disease in 11 cases stopping drug with ≥3mos of follow up. Disclosure of Interest Conclusion: A number of clinical features characterize serious DRESS None Declared to IL-1/IL-6 inhibitors in Still’s disease patients. These features are shared by subjects with (~80%) and without the HLA risk allele. For the former, HLA testing allows pre-prescription risk determin- P61 ation. DRESS to IL-1/IL-6 inhibitors in Still’s may be enriched in those Characteristics of hla linked dress reactions to inhibitors of IL-1 with younger onset age, co-occurring cardiopulmonary disease, pre- AND IL-6 in still's disease maturity, or Trisomy 21. Patient outcome with drug removal, as indi- 1 2 3 4 5 6 V. Saper , S. Prahalad , S. Canna , M. Ombrello , M. Kostik , A. Ravelli ,E. cated for DRESS, will be important to evaluate. 7 8 9 10 11 5 Cassidy , S. Bhattad , O. Kasapcopur , T. Hahn , O. Phadke , E. Isupova , 6 12 13 13 13 14 J. Tibaldi , C. Stingl , A. Casey , H. Wobma , T. Klouda , M. Alvarez , Disclosure of Interest 14 15 15 4 G. Espada , K. Torok , A. Robinson , M. Corriea Marques ,J. None Declared 16 1 1 1 Hollenbach , M. Fernandez Vina , L. Tian , E. Mellins on behalf of the Table 1 (abstract P61). See text for description Drug Hypersensitivity consortium 1 2 Stanford University, Stanford; Emory University, Children's Healthcare of DRESS cases Institutional P OR Atlanta , Atlanta; Children's Hospital of Philadelphia, Philadelphia; controls value (95CI) 4 5 NIAMS, Bethesda, United States; Saint-Petersburg State Pediatric Still’s onset age < 2.5 43% (29/67) 19% (19/100) 8.9 x 3.2 (1.6- Medical University, Saint-Petersburg, Russian Federation; IRCCS Istituto -4 years 10 6.5) Giannina Gaslini, Genova, Italy; Geisinger Medical Center, Danville, 8 9 Abdominal pain 24% (16/67) 2% (2/100) 9.6 x 15.4 (3.4- United States; Aster CMI Hospital, Bangalore , India; Istanbul University- -6 10 70) Cerrahpasa, Istanbul, Turkey; Penn State Health Children's Hospital, Hershey; Emory University School of Medicine and Children’s Transfusion (no MAS or 13% (9/67) 0% (0/100) 1.9 x Infinite 12 -4 bleeding) 10 Healthcare of Atlanta, Atlanta; Spectrum Health, Grand Rapids; 13 14 Boston Children's Hospital, Boston, United States; Hospital de Niños Atypical non-evanescent 90% (60/67) 5% (5/100) 2.5 x 98.6 (34- -28 Dr RIcardo Gutierrez, Buenos Aires, Argentina; UPMC Children's rash 10 286) Hospital of Pittsburgh, Pittsburgh; University of San Francisco, San Absolute eosinophils 79% (53/67) 0% (0/100) 7.1 x infinite Francisco, United States -31 >700/ul 10 Correspondence: V. Saper DRESS cases Drug-tolerant Pediatric Rheumatology 2021, 20(Suppl 1):P61 controls Introduction: A subset of Still's patients receiving treatment with IL-1 HLA-DRB1*15:XX (all 79% (56/71) 7% (2/30) not applicable and IL-6 inhibitors developed features (e.g., eosinophilia, atypical ancestries) across ancestries rash) that raised the possibility of drug reaction with eosinophilia HLA-DRB1*15:01 (White) 79% (38/48) 0% (0/19) 8.2 x infinite and systemic symptoms (DRESS). -10 Objectives: To identify features of DRESS that distinguish it from Anti-IL-1 exposure 96% (68/71) 86% (26/30) NS active disease in Still's patients. (0.19) Methods: We organized a multi-center (48 institutions, 11 countries), retrospective case/control study of Still's patients treated with ana- Tocilizumab exposure 27% (19/71) 40% (12/30) NS (0.24) kinra, canakinumab, or tocilizumab (anti-IL-1/IL-6). Inclusion as a case required physician suspicion of a drug reaction during anti-IL-1/IL-6 Elevated AST/ALT 75% (53/71) 13% (4/30) 1.1 x 19 (5.9- -8 treatment. Drug-exposed controls from the same sites (institutional 10 62) controls) were randomly selected Still’s subjects not satisfying the DRESS DRESS with DLD case definition. Each subject was scored for DRESS using the vali- without DLD dated scoring system, RegiSCAR for DRESS, which specifies that fea- HLA-DRB1*15:XX 68% (15/22) 84% (41/49) not applicable tures may be asynchronous and discontinuous. Demographic and across ancestries clinical features of cases and controls were compared; frequencies of some features were compared to population frequencies. HLA allelic MAS during drug 59% (12/22) 71% (34/49) NS frequencies were compared in 71 DRESS cases and 30 drug-tolerant (0.29) controls. Results: Still’s onset age was enriched for <2.5 years in cases vs P62 institutional controls; no significant differences were found in Actinopathies that can be mistaken as hyper ige autosomal frequency of onset age >10 years, adult (>16y) onset of Still's, sex, or recessive ARPC1B deficiency is an actinopathy, this pathology is MAS occurrence pre-treatment. Interestingly, ten cases reported ser- similar way to Hyper IgE syndrome with recurrent infections, ious comorbidities: four with severe congenital heart disease eczema, IgE elevation and vasculitis (CHD),~40X expected live birth rate for CHD, pre-term birth (3) result- 1 1 N. Gomez Hernandez , M. Ortega Cisneros , M. A. Yamasaki ing in bronchopulmonary dysplasia (BPD) in 2 (~30X expected live 2 1 1 Nakashimada , A. Delgado Bañuelos , R. Benitez Serrano on behalf of birth rate), congenital lung disease (1), severe neonatal pneumonia Institute National Pediatric Mexico , City (1), and 2 with CHD and 1 with BPD were among four with Trisomy 1 2 Instituto Mexicano Del Seguro Social, Guadalajara; IInstituto Nacional 21 (~50X expected live birth rate). Comorbid conditions were mostly Pediatria, Ciudad de Mexico, Mexico (7/10) among those with Still’s onset age <2.5 years. Eosinophilia and Correspondence: N. Gomez Hernandez atypical rash were markedly enriched in cases vs controls, as Pediatric Rheumatology 2021, 20(Suppl 1):P62 Pediatric Rheumatology (2022) 20:2 Page 39 of 39 Introduction: Actinopathies that can be mistaken as Hyper IgE None Declared Introduction : Autosomal recessive ARPC1B deficiency is an actinopathy. Defective actin polymerization affects hematopoietic cells, impairing their P63 migration and immunological synapse , characterized by leukocytosis, Allergic reactions of COVID-19 vaccine in a teaching hospital 1 2 eosinophilia, platelet abnormalities and hypergammaglobulinemia; and P.-C. Chen , K.-H. Yang 1 2 clinically, by eczema and food allergy ,infections caused by bacteria, Taipei City Hospital, Taipei, Taiwan, Province of China; Pharmacy, Taipei fungi and viruses, vasculitis, and bleeding diathesis. city hospital, Taipei, Taiwan, Province of China Objectives: Case Report Correspondence: P.-C. Chen 28-year-old male, originally from Michoacan Mexico, his parents are Pediatric Rheumatology 2021, 20(Suppl 1):P63 first cousins. The patient began a three-month-old developed an ab- scess with an anorectal fistula that required surgery at 10 months he Introduction: Because of the epidemic, countries have begun to was hospitalized for an infectious gastroenteritis and a few weeks administer the COVID-19 vaccine. The adverse reactions (ADRs) fol- later once again for a urinary tract infection. This patient presents ec- lowing the vaccine can be divided into three categories. Categories zema and recurrent abscesses from one year of age, multiple epi- are allergic reactions including anaphylaxis, vasovagal reaction in- sodes of otitis media and sinusitis,. cluding vasovagal syncope and vaccine side effects including local At the age of 8 years he was admitted to the National Institute of and systemic. Allergic reactions occurring within 5-30 minutes are Pediatrics of Mexico City with a one-month history of cough and considered as autoimmune problems, and the problems caused are fever, as well as two months of painful erythematous subcutaneous usually unpredictable and may be serious. nodules on both legs. Physical examination revealed a keloid scar on Objectives: For further analysis of the types of allergic reactions, the abdomen after Nissen fundoplication, a normal BCG scar, diffuse medical professionals could remind the patient, prepare the crackles throughout both lung fields, and nodular erythematous le- responder as soon as possible, and as a reference for diagnosis and sions on both legs. Laboratory tests showed Hb 9.8 g / dl, leukocytes related treatment. 15,200 / μl, neutrophils 73%, lymphocytes 17%, eosinophils 5% , Methods: This study is a cross-sectional study that analyzes the noti- 317,000 / μl platelets. IgE 2000 IU / ml, IgG 1870 mg / dl , IgM 420 fication data of adverse drug reaction cases in a regional hospital mg / dl and IgA 968 mg / dl . He also had a negative ANCA and low from March 30 to July 31, 2021, including the AstraZeneca® (AZ) positive ANA, while tuberculin and yeast tests were negative. Sputum brand and the Moderna® brand. And analyze whether the discomfort cultures and gastric aspirates for fungal and bacterial organisms were immediately after vaccination is Allergic reactions, vasovagal reaction also negative. The CT scan of nasal and pulmonary sinuses revealed or vaccine side effects. pansinusitis and saccular bronchiectasis located in the right lung. Results: The total number of COVID-19 vaccines administered under Skin Biopsy of the leg lesions showed septal and lobular paniculitis the AZ® brand was 27,131, and Moderna® had a total of 9,203 with predominant infiltration of lymphocytes and histiocytes. people. A total of 80 adverse events were received. The AZ ® brand Initially, a diagnosis of HIES with erythema nodosum was made: the had 75 and the Moderna® brand had 5 ADRs. Among the ADRs of patient's NIH scoring system was 39, with a positive result diagnosis AZ®, there are 17 allergic reactions (22.67%), 1 vasovagal reaction re- for scores greater than 20 action, and 57 vaccine side effects. Among the ADRs of Moderna®, Treatment with amoxicillin, thalidomide, and prednisone was started there are 3 allergic reactions (60.00%), 0 vasovagal reaction reactions, with improvement of respiratory symptoms and resolution of skin and 2 vaccine side effects. lesions. At age 9 he had multiple flat warts involving the trunk. The skin Out of a total of 20 Allergic reactions, 20 cases require additional biopsy revealed a human papillomavirus infection. The patient was processing to deal with side effects. These side effects include treated with topical retinoids leading to a gradual resolution of the problems related to the injection site (redness at the injection site*2, warts, and thalidomide and corticosteroids were discontinued. In itching at the injection site*5, rash at the injection site*3, soreness at January 2003 he developed thrombocytopenia (63,000 / μl). At age 10, the injection site, pain at the injection site, swollen left upper arm*2, a lung biopsy was performed due to persistent cough and wheezing red upper left arm, lower arm Itchy rash on the other side of the despite taking inhaled steroids and prophylactic antibiotics: results armpit*2), skin-related problems (red rash on the chest with oxygen, revealed obliterative bronchiolitis organizing pneumonia. Mesenteric hives*2, itchy rash on the face and neck*2, skin rash*4), other prob- vasculitis was detected, initiating management with oral cyclosporine lems (wheezing, vomiting*3, red and swollen eyes, chest tightness, and continued with MMF 1 g / day and monthly intravenous gamma dizziness). Among them, one case was reported as a "serious adverse globulin at a replacement dose in the Institute Mexican Secure Social . event", who died eight hours after vaccination. Immunosuppressive treatment was suspended because, at the age of Conclusion: In the ADR of AZ®, 22.67% of allergic reactions is allergic 21 he developed a disseminated molluscum contagiosum on the reactions, which is 0.63 ‰ of the number of people who were trunk, which is why weekly subcutaneous application of interferon administered. Although the proportion is not high, the adverse alpha is indicated with total resolution of his lesions. He has a reactions caused by autoimmunity are likely to become very serious. sequencing study for variants STAT 3, ERBB21P, CARD 11, DOCL8 Medical professionals should pay more attention to these IL6ST, PGM3, SPINK 5 with negative result. It is finally documented information before administering the vaccine. ARPC1B. Conclusion: ARPC1B deficiency phenotype the clinical defect appears Acknowledgments to be characterized by recurrent bacterial and viral infections, Taipei City Hospital extensive eczema, allergies, thrombocytopenia, and skin vasculitis This phenotype is expressed in a similar way to Hyper IgE syndrome Disclosure of Interest with recurrent infections, eczema, IgE elevation and vasculitis .This None Declared particular case made us think about the importance of having a genetic diagnosis. Written informed patient consent for publication was given. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims Disclosure of Interest in published maps and institutional affiliations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Pediatric Rheumatology Springer Journals

Abstracts from the ISSAID 2021 Periodic Congress

Pediatric Rheumatology , Volume 20 (Suppl 1) – Jan 10, 2022

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10.1186/s12969-021-00659-2
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Pediatric Rheumatology (2022) 20:2 https://doi.org/10.1186/s12969-021-00659-2 MEETING ABSTRACTS Open Access Abstracts from the ISSAID 2021 Periodic Congress Virtual. May - Dec 2021 Conclusion: The results showed that miR-30e-3p has an anti- Oral presentations inflammatory effect by regulating IL-1β expression, which is a key protein in inflammatory pathways. O01 The possible effect of miR-30e-3p which targets IL-1Β in the Acknowledgments pathogenesis of systemic autoinflammatory diseases 1 1 2 2 3 This project has been funded by the ERARE3 project (INSAID,003037603) and T. H. Akbaba , Y. Akkaya-Ulum , E. Batu , E. Sönmez , M. V. Gijn ,D. 4 5 2 1 The Technical and Scientific Research Council of Turkey, 315S096. Foell , M. Gattorno , S. Ozen , B. Balci-Peynircioglu 1 2 Medical Biology; Pediatric Rheumatology Unit, Hacettepe University, Disclosure of Interest Ankara, Turkey; University Medical Center, Utrecht, Netherlands; None Declared Department for Pediatric Rheumatology & Immunology, Muenster, Germany; Giannina Gaslini Institute (IRCCS), Genoa, Italy Correspondence: T. H. Akbaba O02 Pediatric Rheumatology 2021, 20(Suppl 1):O01 Number of episodes can be used as a disease activity measure in familial mediterranean fever Introduction: Systemic Auto Inflammatory Diseases(SAID) is a group 1 2 3 4 5 1 D. Piskin , Z. Arici , D. Konukbay , M. Romano , S. Ozen , K. Speechley ,E. of rare hereditary fever syndromes. Phenotypic heterogeneity among Demirkaya SAID patients is quite common, and epigenetic factors can be a 1 2 University of Western Ontario, London, Canada; Pediatric cause of these variable clinical profiles. MiRNAs take an active role in Rheumatology, Sanliurfa Research and Training Hospital, Sanliurfa; the regulation of inflammation. 3 4 University of Health Sciences, Ankara, Turkey; Pediatric Rheumatology, Objectives: This study aims to investigate the potential impact of University of Western Ontario, London, Canada; Pediatric miRNAs in autoinflammation. Rheumatology, Hacettepe University, Ankara, Turkey Methods: Expression levels of miRNAs in blood samples of 6 severe FMF Correspondence: D. Piskin and 7 mild FMF, 6 other rare SAIDs, and healthy controls were analyzed by Pediatric Rheumatology 2021, 20(Suppl 1):O02 miRNA array, bioinformatics tools and pathway analyzes related to inflam- matory pathways. The candidate miRNAs were functionally studied for ex- Introduction: Monitoring disease activity in Familial Mediterranean pression levels of inflammatory genes, caspase I activation, apoptosis, cell Fever (FMF) is essential to define disease effects on the general migration assays in SW982 cells. Then, 3'UTR luciferase activity experiments health and quality of life (QoL) of patients, to determine treatment were carried out to determine the target gene. Then, target gene expres- response, optimize disease follow-up and prevent complications. The sion studies were performed at both RNA and protein levels. Also, miR-30e- importance of monitoring disease activity and doing regularly are 3p was analyzed in a group (total of 44 patients) of European patients highlighted in the international recommendations for the manage- (Germany, Italy, and the Netherland). ment of autoinflammatory diseases. It is necessary to assess disease Results: The expression levels of miRNAs by miRNA array were activity easily in research and clinical practice. confirmed by qRT-PCR. miR-30e-3p was significantly reduced Objectives: To assess the validity of number of episodes as a feasible among patient groups. After pre-miR transfection of miR-30e-3p; stand-alone measure of disease activity in these patients, we developed expression levels of inflammatory genes (IL1β, IL18, TNFα,TGFβ) apriori predictions of expected associations that number of episodes in and apoptosis rates decreased, caspase I activation and cell mi- a year would have with particular PROMS based on the evidence in the gration rate decreased significantly (p <0.05). As a result of func- literature regarding observed associations with level of disease activity tional analysis, target gene studies were performed with miR-30e, in patients with FMF. Specifically, we predicted the following associa- which has an anti-inflammatory effect in all experimental systems. tions in children with FMF: functional status, quality of life, level of de- It has been shown that miR-30e is the direct target of the IL-1β pressive symptoms and perceived level of pain would be negatively gene. Expression of the IL-1β gene at RNA and protein levels de- associated with number of episodes in the past year. creased in pre-miR-30e-3p transfected cells. Also, miR-30e-3p was Methods: In this cross-sectional study, patients were recruited from decreased in a group of European SAID patients (Germany, Italy, the seven tertiary hospitals in Turkey. Demographic data, main and the Netherland). © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Pediatric Rheumatology (2022) 20:2 Page 2 of 39 clinical symptoms of the episodes, treatment modalities, and genetic admission period and all follow/up visits. For the purpose of this study, mutations were recorded. The patients were grouped as: no episodes we analyzed all patients with at least 3months of follow/up mainly fo- (Group 1), 1-4 episodes (Group 2), more than 4 episodes (Group 3) cusing on heart involvement. according to number of episodes in the past 12 months. The four- Results: Fifty-three patients who received MIS-C diagnosis between item Morisky Medication Adherence Scale (MMAS-4), Pediatric Qual- February 1st and May 31st 2020 were included in our study. The me- ity Life Inventory (PedsQL), Children's Depression Inventory (CDI) and dian age at diagnosis was 7 years (IQR 4,5-11). Forty-one patients Wong-Baker FACES pain rating scale (FACES) scores were compared showed cardiac involvement during the course of the disease. Treat- between groups. ment with IVIG was reported in 66% of patients at diagnosis and glu- Results: A total of 239 patients (male 44.4%, female 55.6%) were in- cocorticoids in 56,6%. Four patients received treatment with IL-1 cluded. There were 74 patients (31%) in Group 1, 99 patients (41.4%) in receptor antagonist (anakinra) and one with hydroxychloroquine. Use Group 2 and 66 patients (27.6%) in Group 3. Age at diagnosis, gender, of vasoactive agents was reported in 20,8% of patients. No case of consanguinity, family history and history of amyloidosis were not differ- death was reported in our population. ent among the groups (p>0.05). The main clinical symptoms were similar Data on cardiac outcome were available for 33 patients after a me- among the groups and also the groups were compared according to the dian time of follow-up of 6 months (IQR 7.2- 4.08). Twenty-eight out each item on the AIDAI symptom scale and there were no statistically sig- of 33 patients presented a cardiac involvement during hospitalization nificant differences among groups (p>0.05). Most of the patients (232 of for MIS-C: 17 had myocarditis, 5 had pericarditis, 3 coronary artery 239 patients, 97.1%) were treated with colchicine. Groups were similar in abnormalities, 8 heart failure, 9 valvular insufficiency, 11 shock or terms of M694V, and V726A allele frequency (p=0.843, p=0.46). For par- hypotension. For each patient cardiac outcome was assessed by ent and child PedsQL scale scores, patients in no episode group (Group heart ultrasonography. At the end of our follow-up period only four 1) had higher scores that means better HRQoL than Group 2, and Group patients still had heart abnormalities: all of them presented mild 2 had higher scores (better HRQoL) than Group 3. Both parent and child valvular insufficiency and 2 patients still had ultrasonographic signs MMAS scores were not different among the groups. In Group 3, patients of hypokinesia. None of them was on medication. have higher parent CDI scores than no episode (Group 1) group (p< Conclusion: MIS-C is an emerging inflammatory condition that spreads 0.001). Child CDI scores were significantly lower in Group 1 than Group 2 among the pediatric population in parallel to SARS-CoV2 pandemic. The (p=0.01), and in Group 2 than Group 3 (p=0.03). Both parent and child disease is frequently complicated by cardiological involvement but, dif- FACES scores were significantly lower in no episode group than Group 2, ferently to Kawasaki disease, myocarditis and shock are the most com- and patients in Group 2 lower than Group 3. mon complications. As we reported in our previous study, short-term Conclusion: In a homogeneous patient population in terms of demo- outcome is usually good in children with MIS- C and heart involvement. graphic features, mutation types, clinical symptoms, and treatment, With this study we also provide a long-term cardiac follow-up and we increasing number of episodes was associated with worst PedsQL, showed that only a minority of patients with previous cardiac involve- CDI, and FACES scores. We conclude that number of episodes is the ment presented minor heart abnormalities. Furthermore, no patients key element of disease activity in patients with FMF and can be used developed new heart disease during follow-up. as a single measure to assess disease activity. Acknowledgments Disclosure of Interest Francesca Biscaro: UOC Pediatria, Ospedale Ca’ Foncello, Treviso. Andrea None Declared Campana: Bambino Gesù Children’s Hospital, Rome, Italy. Rosa Maria Dellepiane: Pediatric Intermediate Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy. Angela Mauro: Department of O03 Paediatrics, Emergency Department, Santobono-Pausilipon Children’s Long-term cardiac outcome in patients with multisystem Hospital, Naples, Italy. Alesssandra Meneghel: Department of Woman’s and inflammatory syndrome in children (MIS-C) Child’sHealth, University of Padova, 2 Padua, Italy. Alma Olivieri: Dipartimento 1 2 3 4 5 S. Della Paolera , F. Zunica , D. Montin , G. Zuccotti , F. La Torre ,S. della donna, del bambino e di chirurgia generale e specialistica, Università 6 7 1,8 2 Mannarino , M. Fabi , A. Taddio , M. Cattalini della Campania, “L Vanvitelli, Napoli. Rita Sottile: Department of Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste; Paediatrics, Santobono-Pausilipon Children’s Hospital, Naples, Italy. Sara Pediatrics Clinic, ASST Spedali Civili di Brescia, University of Brescia , Stucchi and Barbara Teruzzi : Maternal and Child Health, Division of Brescia; Department of Pediatrics and Public Health, University of Turin, Paediatrics, ASST Grande Ospedale Metropolitano Niguarda, Milano, Turin; Department of Pediatrics, University of Milan, Children’s Hospital Italy. Tatiana Utytatnikova: Dipartimento Materno-Infantile, Pediatria, ASST V Buzzi, Milan; Pediatric Rheumatology Center, Pediatric Unit, “Giovanni Bergamo-EST, Seriate, Bergamo. Gianluca Vergine: UOC Pediatria, Ospedale XXIII” Pediatric Hospital, Bari; Division of Cardiology, Children's Hospital degli Infermi di Rimini, Rimini, Italy. V Buzzi, ASST FBF Sacco, Milan; Department of Pediatrics, University of Bologna, IRCCS Sant’Orsola-Malpighi Hospital, Bologna; University of Disclosure of Interest Trieste, Trieste, Italy None Declared Correspondence: A. Taddio Pediatric Rheumatology 2021, 20(Suppl 1):O03 O04 Introduction: Multisystem Inflammatory Syndrome in children (MIS- SARS-CoV2 ORF3a protein drives inflammation in COVID-19 C) was initially described during the first phase of COVID-19 pan- through NLRP3 inflammasome activation 1 1 1,2 1 1 1 demic as a severe clinical condition with systemic inflammation and A. Bertoni , F. Penco , H. Mollica , P. Bocca , I. Prigione , A. Corcione , 1 3 1 4 4 1,2 multi-organ involvement. Many patients show features of Kawasaki D. Cangelosi , A. Amaro , N. Paladino , E. Pontali , M. Feasi , S. Signa , 1 1 5,6 3 1,7 1 Disease. Cardiac involvement, from myocarditis to coronary abnor- M. Bustaffa , R. Caorsi , R. De Palma , U. Pfeffer , P. Uva , A. Rubartelli , 1 1,2 malities, is a key feature of the syndrome, but there are still little data M. Gattorno , S. Volpi on behalf of UOSD Centro per le Malattie concerning the long-term outcome in these patients. Autoinfiammatorie e Immunodeficienze 1 2 3 Objectives: The aim of our study was to evaluate long-term cardiac IRCCS Istituto Giannina Gaslini; DINOGMI, University of Genova; IRCCS outcome in patients diagnosed with MIS-C during the first phase of Ospedale Policlinico San Martino; Ente Ospedaliero Ospedale Galliera; 5 6 COVID-19 pandemic in Italy. IRCCS IST-Ospedale San Martino; Internal Medicine, University of Methods: We previously published the results of the Italian multicenter Genova; Italian Institute of Technology, Genova, Italy survey of MIS-C, launched by the Rheumatology Study Group of Italian Correspondence: S. Volpi Pediatric Society during the first wave of COVID-19 pandemic. For each Pediatric Rheumatology 2021, 20(Suppl 1):O04 patient who received MIS-C diagnosis, we collected demographic, clin- ical, laboratory data, imaging findings, and treatment information in an Introduction: COVID-19 severe pneumonia has been associated to sys- online anonymized database (RedCAP). Data collection included all the temic inflammation and elevation of blood parameters and reminiscent Pediatric Rheumatology (2022) 20:2 Page 3 of 39 of cytokine storm syndrome. Stimulation of PBMC from patients with phenotypes, to allow for earlier detection and therapeutic intervention. severe COVID-19 have shown a high secretion of IL-1β, a pivotal cyto- We also sought to determine the variant distribution amongst VEXAS kine driving inflammatory phenotypes, which maturation and secretion patients and compare with disease course to establish if a specific mu- is regulated by NLRP3 inflammasome. Steroidal anti-inflammatory ther- tation can be a biomarker of disease severity. apies have shown efficacy in reducing mortality in critically ill patients, Methods: To identify key phenotypic presentations of VEXAS that war- however the mechanisms by which SARS-CoV2 virus triggers such an rant genetic testing we compared the clinical characteristics of our first extensive inflammation remain unexplained. reported 25 patients and our newly identified additional 43 patients. Objectives: The overall objective of this study was to investigate if We performed Sanger sequencing and digital droplet PCR (ddPCR) to SARS-CoV2 drives inflammation in COVID-19 patients through NLRP3 detect and quantify mutation levels in our referred patients. inflammasome activation and IL-1β secretion. Results: After the initially reported clinical manifestations of VEXAS Methods: Samples from SARS-CoV2 infected patients, were collected (25 patients last year), 80 patients have been referred to our clinic at day 0 and at 3 and 7 following treatment with anakinra. Fresh based on clinical similarities to our first report. 43 new patients have monocytes, purified through adherence, were cultured for 3, 6, 18 h been identified with somatic mutations in UBA1, making our current in the presence or absence of LPS (100 ng/ml) and MCC950 (10μM). diagnostic rate 54%. The clinical characteristics of newly diagnosed Release of IL-1β, IL-1Ra, IL-6, TNF-α, IL-18 was quantified by ELISA kit. patients are highly consistent with the reported manifestations of Relative gene expression analysis of ORF3a gene was performed by the initial VEXAS cohort with some expanded phenotypes including RT-qPCR. THP-1 cells were transfected with a plasmid containing renal, neurologic and hematologic manifestations. We determined ORF3a sequence by nucleofection. NLRP3 inflammasome and ASC that patients with history of chondritis and MDS have a higher posi- speck formation were detected by confocal microscopy and/or by tivity rate than those with general systemic inflammation. Variant dis- FACS analysis. tribution in our expanded cohort is consistent with our initial report, Results: In the present study we show that circulating monocytes with threonine being the most common p.Met41 variant (56%) from COVID-19 patients display ASC specks, index of NLRP3 activa- followed by valine and leucine (26% and 18% respectively). 35% of tion, and spontaneously secrete IL-1β in vitro. This spontaneous acti- patients with the valine variant are deceased as compared to 16% vation reverts following patient’s treatment with the IL-1 receptor for other mutations, indicating that p.Met41Val may confer a more antagonist anakinra. Transfection of a monocytic cell line with cDNA severe phenotype. coding for the ORF3a SARS-CoV2 protein, resulted in NLRP3- Conclusion: Our 54% positivity rate indicates that the initially re- dependent ASC speck formation. The involvement of ORF3a in ported clinical manifestations are effectively identifying additional inflammasome activation was further supported by the detection by VEXAS patients. Through analyzing the symptoms of our larger co- RT-PCR of ORF3a in monocytes from COVID-19 patients. hort, we have further characterized the phenotype of this novel syn- Conclusion: In summary, these results provide a mechanistic explan- drome. Additionally, identifying the p.Met41Val variant as a marker ation for the strong inflammatory manifestations associated to of severe disease may offer more accurate prognosis and the possi- COVID-19 and further evidence that NLRP3 and IL-1β targeting could bility for earlier intervention. Together, this work provides further in- represent an effective strategy in this disease. sights into VEXAS syndrome with the goal of increasing diagnosis and improving management Acknowledgments We thank the patients and their families for their willingness to participate in Acknowledgments our study, the service of Immunohematology and transfusion medicine of We would like to sincerely thank all the patients and their families involved Gaslini Institute for the collection of biological samples and the Laboratory in our continued studies for their incredible contributions. Core Facility of Gaslini Institute for support for confocal analysis. SV received financial support from AMRI, “associazione malattie reumatiche infantili”. IRCC Disclosure of Interest S G Gaslini is members of the European Reference Network for Rare None Declared Immunodeficiency, Autoinflammatory and Autoimmune Diseases -Project ID No 739543. This work was developed within the framework of the DINOGMI Department of Excellence of MIUR 2018-2022 O06 Adult-onset autoinflammation caused by somatic mutations in Disclosure of Interest UBA1: a Dutch case series of VEXAS patients None Declared This abstract has not been included here as it has been previously published O05 O07 Defining clinical and genetic hallmarks of VEXAS syndrome 1 1 2 1 Short-term follow-up results of children with familial D. Ospina Cardona , L. L. Wilson , M. A. Ferrada , A. K. Ombrello ,P.C. 2 1 1 1 mediterranean fever after cessation of canakinumab Grayson , I. Aksentijevich , D. B. Beck , D. L. Kastner 1 2 1 2 3 4 5 6 B. Sözeri , H. E. Sönmez , S. Karadağ , E. Baglan , K. Öztürk , M. Çakan ,F. National Human Genome Research Institute; National Institute of 1 7 4 8 Demir , G. Otar Yener , S. Özdel , N. Ayaz Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, Department of Peditarics, Division of Rheumatology, Umraniye Research United States and Training Hospital, Istanbul; Department of Peditarics, Division of Correspondence: D. Ospina Cardona Rheumatology, Kocaeli University, Kocaeli; Department of Peditarics, Pediatric Rheumatology 2021, 20(Suppl 1):O05 Division of Rheumatology, Sadi Konuk Research and Training Hospital, Istanbul; Department of Peditarics, Division of Rheumatology, Sami Ulus Introduction: VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflamma- Research and Training Hospital, Ankara; Department of Peditarics, tory, Somatic) syndrome is a late-onset, autoinflammatory disorder Division of Rheumatology, Istanbul Medeniyet University Göztepe discovered last year through shared genetic variants as opposed to Research and Training Hospital; Department of Peditarics, Division of shared clinical descriptions. VEXAS is caused by hematopoietic, som- Rheumatology, University of Health Science, Zeynep Kamil Maternity atic mutations in the X-chromosomal UBA1 (ubiquitin activating en- and Children’s Diseases Research and Training Hospital, Istanbul; zyme 1) gene encoding the primary E1 enzyme of the essential Department of Peditarics, Division of Rheumatology, Şanlıurfa Research ubiquitylation pathway. VEXAS patients share variants in the UBA1 and Training Hospital, Şanlıurfa; Department of Peditarics, Division of gene while displaying broad clinical heterogeneity in disease severity Rheumatology, Istanbul University, Istanbul, Turkey and onset. Correspondence: H. E. Sönmez Objectives: We aimed to further elucidate the clinical features that are Pediatric Rheumatology 2021, 20(Suppl 1):O07 predictive of VEXAS syndrome through analyzing new patient Pediatric Rheumatology (2022) 20:2 Page 4 of 39 Introduction: Familial Mediterranean fever (FMF) is a systemic autoin- O08 flammatory disease manifesting with recurrent attacks of serositis ac- Traditional laboratory parameters and new biomarkers in companied by fever, usually lasting 12-72 hours. Although colchicine Macrophage Activation Syndrome (MAS) and Secondary has dramatically improved the quality of life in majority of the pa- Hemophagocytic Lymphohistiocytosis (SHLH) 1 1 1 1 1 tients by resolving attacks, unfortunately, it is ineffective in 5–10% of A. De Matteis , D. Pires Marafon , I. Caiello , M. Pardeo , G. Marucci ,E. 1 2 3 4 5 6 patients with FMF. Sacco , F. Minoia , F. Licciardi , A. Miniaci , I. Maccora , M. C. Maggio ,G. 1 1 1 Objectives: The aim of this study was to investigate the efficacy and Prencipe , F. De Benedetti , C. Bracaglia safety o canakinumab (CAN) in patients with colchicine-resistant (cr) Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, FMF and to report our experience on cessation of CAN in crFMF Roma; Pediatric Rheumatology, Fondazione IRCCS Ca’ Grande Ospedale patients. Maggiore Policlinico, Milano; Department of Pediatrics and Infectious Methods: This is an observational retrospective cohort study includ- Diseases, School of Medicine, University of Turin, Regina Margherita ing crFMF patients treated with CAN for at least 6 months. Data of Children’s Hospital, Torino; Department of Pediatrics, University of st rd th th th 5 the patients were recorded at treatment onset, 1 ,3 ,6 ,12 ,18 , Bologna, S. Orsola-Malpighi Hospital, Bologna; Pediatric Rheumatology th 6 and 24 months. Unit, Meyer Children's University Hospital, Firenze; University Results: A total of 114 patients followed up 2736 person-months Department Pro.Sa.M.I. “G. D’Alessandro”, University of Palermo, Palermo, were included in the study. During the 24-month follow-up, drug Italy interval was not changed in 44 patients. Injection intervals were ex- Correspondence: A. De Matteis tended in 58 patients within a median of 6 (3-18) months. Of these Pediatric Rheumatology 2021, 20(Suppl 1):O08 58 patients, 4 patients had a new attack after the prolongation of th dose interval. CAN was ceased in 12 patients (5 at 12 month, 7 at Introduction: Macrophage Activation Syndrome (MAS) and Second- th 18 month), two of whom experienced a new attack within 3 ary Hemophagocytic Lymphohistiocytosis (sHLH) are hyperinflamma- months. CAN was restarted and applied every 8 weeks. The tory conditions caused by a cytokine storm, in which IFNγ plays a th remaining 10 patients did not report any symptom at the 24 pivotal role. Prompt recognition and early treatment are essential to month. The median attack-free period under CAN treatment was 669 improve the high disease mortality. (95% confidence interval: 644-696) days (Table 1). Methods: Routine laboratory parameters of disease activity and se- Conclusion: Cessation of CAN or extended drug intervals may be verity were collected from a cohort of 103 patients, 41 sHLH, 40 MAS feasible in crFMF. The real life experience may provide clinicians to in the context of sJIA, and 22 sJIA without MAS, from 6 Italian cen- create standardized treatment approaches for these patients. ters. The samples were collected at three different time points: active disease (T0), 7-10 days from starting therapy (T1) and in clinical in- Acknowledgments active disease on medication (from 1 to 3 months from onset) (T2). None Serum levels of the IFN-γ related biomarkers (CXCL9, CXCL10, Neop- terin) and IL-18 were measured at each time points by ELISA. Disclosure of Interest Results: 367 samples were collected from the three groups of pa- None Declared tients in the three different time points. Thirty-eight patients with sHLH (92.7%) met the HLH-2004 diagnostic criteria while 34 patients with MAS (85.0%) met the 2016 classification criteria for MAS. Fever was present in the majority of patients (96%), while hepato- megaly and/or splenomegaly were observed more frequently in MAS Table 1 (abstract O07). Assessment of drug response in the patients and sHLH patients (76.9% and 82.9% respectively) compared to sJIA with colchicine resistant familial Mediterranean fever (36.8%). Laboratory characteristics at T0 are detailed in table 1. Using the st rd th th th th Baseline 1 month 3 month 6 month 12 month 18 24 month 2016 classification criteria for MAS, in our cohort we can confirm that (n=114) (n=114) (n=114) (n=114) (n=114) month (n=114) (n=114) platelet count is a specific parameter, only 4 patients with sJIA had a PGA* 8 (5-10) 1 (0-10) 0 (0-5) 0 (0-5) 0 (0-3) 0 (0-5) 0 (0-3) value <181x10 /liter; while ferritin is a sensitive parameter, 94.2% of CRP* 16.2 (11- 0.65 (0.02- 0.2 (0-15.8) 0.7 (0-68) 0.5 (0-24.9) 0.3 (0-41) 0.3 (0.16.1) patients with MAS had ferritin >684 mg/ml. Moreover, we have 31) 58.6) found that lactate dehydrogenase (LDH) values were statistically SAA* 89 (2.9- 3.9 (0-17) 4 (0-23) 3.3 (0-70) 3.6 (0-152) 3 (0-42) 3 (0-24) higher in MAS and sHLH groups compared to sJIA. ROC curve of LDH 1870) values in MAS group showed a statistically significant area under the Dose interval of CAN 4 (4-8) 4 (4-8) 4 (4-8) 6 (4-8) 6 (4-8) 8 (4-12) 8 (4-12) (weeks) 4 weeks 4 weeks in 4 weeks in 4 weeks in 66 4 weeks in 50 4 weeks in 4 weeks in 39 curve (AUC= 0.78, p-value <0.0001). A cut-off of 681 U/L had a sensi- in 94 94 94 6 weeks in 21 6 weeks in 21 45 6 weeks in 25 8 weeks 8 weeks in 8 weeks in 8 weeks in 27 8 weeks in 41 6 weeks in 8 weeks in 38 tivity of 72.6% and a specificity of 69.2%. in 20 20 20 12 weeks in 2 21 No drug in 12 8 weeks in CXCL9, CXCL10, neopterin and IL-18 values in T0 were significantly higher in MAS and sHLH patients compared to sJIA. Furthermore IL- 12 weeks in 18 in MAS was significantly high than in sHLH group (p<0.0001). The No drug in ROC curves performed for each biomarker showed a statistically sig- Dosage of CAN (mg/kg) 2-4 mg/ 2-4 mg/kg 2-4 mg/kg 2-4 mg/kg 2-4 mg/kg 2-4 mg/kg 2-4 mg/kg nificant AUCs (p<0.01), except for IL-18 in sHLH group. We have iden- kg tified a cut off value for each biomarker in MAS (CXCL9 900 pg/ml, Number of patients NA 0 2 1 5 4 2 CXCL10 280 pg/ml, Neopterin 6.0 ng/ml, IL-18 78,000 pg/ml) and experienced attacks sHLH (CXCL9 1,900 pg/ml, CXCL10 270 pg/ml, Neopterin 8.0 ng/ml). Number of patients NA 0 2 0 2 (recurrent 4 (recurrent 2 (recurrent requiring higher dose or (recurrent attacks) attacks) attacks, CAN CXCL9, CXCL10, neopterin and IL-18 levels lowered progressively at shortening drug interval attacks) (shortened was restarted) from 8 to T1 with a normalization in T2. CXCL9 decreased faster compared to 6 weeks neopterin, similarly to the decrease of routine laboratory parameters. Number of patients NA 0 7 patients 16 patients 5 patients 6 patients NA Conclusion: Our results confirm that platelet count and ferritin are whose prolonged drug (prolonged (prolonged (prolonged (prolonged interval from 4 to 8 from 4 to 8 from 4 to 8 from 4 to 8 two relevant laboratory parameters, with high specificity and sensitiv- weeks) weeks) weeks) weeks) 21 patients 2 patients 1 patient ity, respectively, to diagnose MAS in the context of sJIA. Even if LDH (prolonged (prolonged (prolonged from 4 to 6 from 8 to 12 from 8 to 12 is not included in 2016 classification criteria for MAS in sJIA, we have weeks) weeks) weeks) found that this parameter could help to discriminate MAS in sJIA, in Number of patients 0 0 0 0 5 patients 7 patients 0 addition to the others. Moreover, our results confirm that the IFN-γ discontinued CAN related biomarkers and IL-18 are significantly high in patients with Number of infections NA 1 1 (upper 0 0 0 2 (upper (pneumonia) respiratory respiratory MAS and sHLH and might be useful for diagnosis in addition to the tract tract infection) infection) traditional laboratory parameters. As already reported, IL-18 could be Number of adverse event NA 0 0 0 0 0 0 also useful to distinguish sHLH from MAS. Moreover, these Pediatric Rheumatology (2022) 20:2 Page 5 of 39 biomarkers seem to be helpful to monitor clinical evolution and extracellular Adenosine, inducing TNFα secretion from Macrophages treatment response. stimulated by NETs, has been implicated in the pathogenesis of DADA2. Objectives: The aim of the project is to dissect NETosis directly in Disclosure of Interest neutrophils isolated from DADA2 patients and healthy controls (HDs), A. De Matteis: None Declared, D. Pires Marafon: None Declared, I. Caiello: and to quantify suicidal and vital NETosis induced by several stimuli None Declared, M. Pardeo: None Declared, G. Marucci: None Declared, E. (PMA, Adenosine, LPS) using a multispectral Imaging Flow Sacco: None Declared, F. Minoia: None Declared, F. Licciardi: None Declared, Cytometry. To determine if NET epitopes can change depending A. Miniaci: None Declared, I. Maccora: None Declared, M. C. Maggio: None from the inflammatory microenvironment and if protein composition Declared, G. Prencipe: None Declared, F. De Benedetti Consultant for: Abbvie, of NETs is disease specific, we used quantitative proteomics SOBI, Novimmune, Novartis, Roche, Pfizer, Employee of: SOBI, C. Bracaglia approach to characterize NET proteins, released from neutrophils Consultant for: SOBI and Novartis after different stimuli in DADA2 patients, HDs and nongenetic Table 1 (abstract O08). Laboratory parameters in T0. Values are shown vasculitis. Moreover we investigated the mechanisms of NETs as median (IQR); p-value: Mann-Whitney U test removal, quantifying DNAse in the plasma samples. Methods: We analyzed and quantified NETosis by Imaging Flow Citometry (IFC): neutrophils isolated from peripheral blood were MAS sHLH sJIA MAS MAS sHLH stimulated in vitro to induce NETosis and were analyzed in the (N=52) (N=48) (N=40) vs vs vs sJIA ImageStreamXMark II IFC equipped with a MultiMag system. We sHLH sJIA evaluated also NETs remnants and DNAse in the plasma samples by Ferritin (ng/ 4,593 (1,770- 4,098 728 (335- 0.72 < < ELISA assay. LC-MS/MS analyses were conducted on Orbitrap Fusion ml) 10,842) (2,075- 2,786) 0.0001 0.0001 Tribrid mass spectrometer and NET protein quantification was carried 16,867) out using Label-Free Quantification method. Platelet 200 (114- 97 (47- 449 (275- 0.0003 < < Results: Neutrophils from DADA2 show a significant increased count 310) 184) 559) 0.0001 0.0001 suicidal NETosis, identified as nuclear decondensation and (x10^9/l) Myeloperoxidase (MPO) colocalization with DNA, following PMA AST (U/L) 86 (51-149) 150 (51- 33 (23-46) 0.07 < < stimulation and we observed an increase also with LPS and 340) 0.0001 0.0001 Adenosine. Then we analyzed vital NETosis, identified as elongated shape of cells, nuclei polarized within the cell and not colocalized Triglycerides 188 (148- 226 (166- 108 (78- 0.11 < < with MPO and we found an increased vital NETosis in DADA2 (mg/dl) 286) 381) 140) 0.0001 0.0001 neutrophils. Accordingly, plasmatic levels of circulating nucleosomes Fibrinogen 330 (225- 228 (137- 565 (441- 0.0018 < < (NET remnants) were elevated in patients, whereas DNAse levels (mg/dl) 437) 331) 691) 0.0001 0.0001 were normal. We set up experimental conditions for proteomic LDH (U/L) 975 (666- 1,255 (701- 599 (407- 0.11 < < analysis of NETs, induced by PMA, Adenosine and TNFα, testing two 1,446) 2,748) 724) 0.0001 0.0001 patients, HDs and patients with nongenetic vasculitis: in total we identified 1770 proteins among which a hundred of proteins were CXCL9 (pg/ 1,728 (798- 4,159 300 (300- 0.15 0.0010 < significantly up or down-modulated in DADA2 NETs compared to ml) 1,1507) (1,880- 1,989) 0.0001 10,016) controls NETs. Conclusion: Our findings demonstrate that neutrophils of DADA2 CXCL10 (pg/ 905 (229- 729 (235- 150 (150- 0.82 < < patients are prone to undergo NETosis and that inflammation ml) 2,646) 3,042) 452) 0.0001 0.0001 mediators such as Adenosine or TNFa in this disease can modify this Neopterin 9.4 (4.9-16.0) 20.3 (9.6- 4.3 (3.0- 0.0023 < < pathogenic process. (ng/ml) 35.0) 7.4) 0.0001 0.0001 Disclosure of Interest IL-18 (pg/ml) 159,833 13,640 36,764 < < 0.16 (50,000- (2230- (8,958- 0.0001 0.0001 None Declared 250,000) 83,909) 82,714) O10 O09 Next generation sequencing based multiplex long-range PCR for Dissecting netosis in adenosine deaminase 2 Deficiency (DADA2) routine genotyping of autoinflammatory disorders patients 1 2 3 4 4 This abstract has not been included here as it has been previously F. Schena , S. Signa , G. Del Zotto , M. Bartolucci , A. Petretto ,R. 5 6 1,7 published Bertelli , R. Caorsi , M. Gattorno Centre for Autoinflammatory Diseases and Immunodeficiencies, IRCCS 2 3 Giannina Gaslini Institute; DINOGMI , University of Genoa; Core O11 Facilities Flow Cytometry and Cell imaging Lab; Core Facilities-Clinical 5 6 Gene therapy for IL-1-mediated systemic autoinflammatory Proteomics and Metabolomics; Laboratory of Human Genetics; Second diseases Pediatric Division and Centro Malattie Autoinfiammatorie e 1,2 1 1 1,3 M. Colantuoni , R. Jofra Hernandez , E. Pettinato , M. Zoccolilllo ,L. Immunodeficienze; Second Pediatric Division, IRCCS Giannina Gaslini 2 1 1 1 1,2 Magnani , L. Basso-Ricci , S. Scala , L. Sergi Sergi , A. Kajaste-Rudnitski , Institute, Genoa, Italy 1,2 1,2,4 1 L. Naldini , A. Aiuti , A. Mortellaro Correspondence: F. Schena San Raffaele Telethon Institute for Gene Therapy (SR TIGET), IRCCS San Pediatric Rheumatology 2021, 20(Suppl 1):O09 Raffaele Scientific Institute; Vita-Salute San Raffaele University; 3 4 Department of Medicine and Surgery, Tor Vergata University; Pediatric Introduction: Deficiency of Adenosine deaminase 2 is a monogenic Immunohematology and Bone Marrow Transplantation Unit, IRCCS San autoinflammatory disorder presenting a broad spectrum of clinical Raffaele Scientific Institute, Milan, Italy manifestations, including vasculitis, immunodeficiency and hematologic Correspondence: M. Colantuoni disease. The genetic mutations in ADA2 gene have been associated to an Pediatric Rheumatology 2021, 20(Suppl 1):O11 insufficient ADA2 activity leading to reduction in deamination of adenosine to deoxyadenosine, and a consequent accumulation of extracellular Introduction: Systemic autoinflammatory diseases (SAIDs) delineate a adenosine. The pathogenic mechanisms investigated so far have elucidated group of clinical entities caused by an anomaly of the innate a skewed polarization from the M2 macrophage subtype to the immune response that includes rare periodic fever syndromes proinflammatory M1 subtype with an increased production of characterized by uncontrolled production of the proinflammatory inflammatory cytokines (TNF-α, Interferon IFN). More recently a chronic cytokine interleukin-1 (IL-1). Patients suffering from these conditions neutrophil activation and a dysregulation of NETosis, as process induced by Pediatric Rheumatology (2022) 20:2 Page 6 of 39 experience severe and recurrent inflammation ranging from fevers to O14 gradual hearing loss, blindness, and organ failure due to amyloid ac- Systemic juvenile idiopathic arthritis associated lung disease in cumulation. Conventional therapy includes anakinra, the recombin- Europe 1 2 ant form of the IL-1 receptor antagonist (IL-1RA), but it has a short C. Bracaglia on behalf of MAS/sJIA Working Party of PReS, F. Minoia ,C. 3 4 1 1 5 6 half-life, poor tissue distribution, and some patients respond poorly. Kessel , S. Vastert , M. Pardeo , A. Arduini , O. Basaran , N. Kiper ,M. 7 8 9 10 11 Besides being a lifelong therapy, this treatment is no definitive cure Kostik , M. Glerup , S. Fingerhutova , R. Caorsi , A. Horne ,G. 2 3 12 13 14 for these patients. Filocamo , H. Wittkowski , M. Jelusic , J. Anton , S. Khaldi-Plassart ,A. 14 9 15 5 1 Objectives: Here, we propose a gene therapy approach based on Belot , P. Dolezalova , A. Ravelli , S. Ozen , F. De Benedetti on behalf autologous hematopoietic stem cells transduced with a lentiviral of MAS/sJIA Working Party of PReS vector expressing IL-1RA. Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Methods: Mouse HSPCs were transduced either with a purified Roma; Fondazione IRCCS Ca' Grande Ospedale Maggiore Policlinico, human IL-1RA or GFP (control) lentiviral vectors (LV). The transduc- Milano, Italy; Department of Pediatric Rheumatology & Immunology, tion efficiency, IL-1RA production, clonogenic potential, and growth WWU Medical Center (UKM), Muenster, Germany; Pediatric rate of HSPCs were analysed and compared after the transduction. Rheumatology & Immunology, University Medical Center Utrecht, Bone marrow (BM) chimeric mice were generated by transplanting Utrecht, Netherlands; Department of Pediatrics, Division of Pediatric transduced (IL-1RA-LV or GFP-LV) C57BL/6 Ly5.1 lineage-negative Rheumatology, Hacettepe University; Department of Pediatrics, Division cells into congenic C57BL/6 Ly5.2 mice. Engraftment level and im- of Pediatric Pulmonology, Hacettepe University, Ankara, Turkey; Saint- mune cell reconstitution were assessed by flow cytometry. IL-1RA Petersburg State Pediatric Medical University, Saint-Petersburg, Russian and GFP chimeras were injected intraperitoneally with MSU crystals Federation; Department of Pediatrics, Aarhus University Hospital, to induce IL-1 mediated inflammation. After 6 hours, peritoneal cells Aarhus, Denmark; Paediatric Rheumatology and Autoinflammatory were collected, and the percentage of neutrophils (CD11b+Ly6G+ Diseases Unit, General University Hospital, Prague, Czech Republic; cells) was determined by flow cytometry. BM-derived mouse den- Department of Pediatrics and Rheumatology, IRRCS Istituto G. Gaslini, dritic cells (BMDCs) and human monocyte cell line THP1 were trans- Genova, Italy; Department of Pediatric Rheumathology Karolinska duced with IL-1RA LV, untransduced cells were used as control. University Hospital and Department of pediatrics, Karolinska Institute, Inflammasome mediated-cytokines production was measured by Stockholm, Sweden; Department of Paediatrics, University of Zagreb qRT-PCR and by ELISA. School of Medicine, Zagreb, Croatia; Pediatric Rheumatology, Hospital Results: LV-mediated IL-1RA gene transfer in mouse HSPCs did Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain; Pediatric not alter progenitor cells’ clonogenic capacity as IL-1RA trans- Nephrology, Rheumatology, Dermatology Unit, Hôpital Femme Mère duced HSPCs proliferated and differentiated similarly to GFP Enfant, Hospices Civils de Lyon, Lyon, France; IRRCS Istituto Giannina transduced HSPCs in vitro. There was a direct correlation between Gaslini and Università degli Studi di Genova, Genova, Italy vector-dose and IL-1RA levels in HPSC-derived supernatants. In IL- Correspondence: C. Bracaglia 1RA chimeras, HSPC transduction with IL-1RA-LV led to robust Pediatric Rheumatology 2021, 20(Suppl 1):O14 and sustained IL-1RA levels in plasma. Supraphysiological expres- sion of IL-1RA did not impact the engraftment and the clono- Introduction: Chronic parenchymal lung disease (LD) is a new genic potential of HSPCs in vivo. Full immune reconstitution of emerging severe life-threatening complication of sJIA. The number of lineage-committed cells was achieved in mice that received IL- sJIA patients with LD is apparently increasing and interestingly it is 1RA-transduced HSPCs. LV-derived IL-1RA production efficiently reported more frequently in North America. Data regarding fre- suppressed neutrophilic infiltration in a mouse model of IL-1- quency and features of sJIA-LD in Europe are not available. mediated peritonitis. Additionally, in vitro IL-1RA transduction of Objectives: To evaluate the burden of sJIA-LD in Europe. BMDCs and THP1 resulted in a reduced production of inflamma- Methods: Patients with diagnosis of sJIA with LD, including tory cytokines compared to control cells. pulmonary alveolar proteinosis (PAP), interstitial lung disease (ILD) Conclusion: We have successfully generated an LV delivering and as pulmonary arterial hypertension (PAH), followed in European steady IL-1RA release in mouse HSPCs in vitro and in vivo.Gene paediatric rheumatology centres were identified through a survey transfer of IL-1RA in mouse HSPCs resulted in long-term sent to the members of the MAS/SJIA Working Party. hematopoietic reconstitution and decreased IL-1-mediated inflam- Results: Data from 28 sJIA-LD patients, diagnosed in 12 European mation in an acute peritonitis mouse model, suggesting that this paediatric rheumatology centres between 2005 and 2020, were col- approach is safe and well tolerated. On-going studies investigate lected. Twenty-seven patients were Caucasian and 1 African- whether IL-1RA-LV HSPC gene therapy transduction suppresses American, 16 were female, the median age at sJIA onset was 6 years the exaggerated IL-1 activity in cells from patients and a mouse and LD onset occurred after a median time of 2.8 years. Sixteen pa- model recapitulating SAIDs phenotype. tients had a chronic persistent sJIA disease course, 11 had a polycyc- lic course and only 1 patient had a monocyclic course; 25 (89%) had Disclosure of Interest active sJIA at time of LD diagnosis. During the disease course, 22 None Declared (78%) patients developed MAS, 10 (35%) of whom had MAS at sJIA onset and 15 (54%) had full-blown MAS at time of LD diagnosis; 17 (77%) patients had >1 MAS episode. Twenty-two (78%) patients were O12 treated with at least one IL-1 or IL-6 inhibitor before LD diagnosis: 18 Application of systems biology-based in silico tools to optimize with anakinra, 13 with canakinumab and 10 with tocilizumab. Eleven treatment strategy in Still’s disease (39%) patients experienced drug adverse reaction to a cytokine in- This abstract has not been included here as it has been previously hibitor: 8 to tocilizumab and 3 to anakinra. Twenty-one (75%) pa- published tients developed ILD, 5 (18%) PAP and 3 (11%) PAH. 13 (46%) patients presented acute digital clubbing; 11 (39%) patients devel- oped hypoxia and 6 (21%) developed pulmonary hypertension. A O13 chest CT scan was performed in all patients with evidence of septal Disease flares in CANDLE/PRAAS with dose reductions of thickening and peri-bronchovascular thickening in the majority of pa- baricitinib tients (22 and 15 respectively). In 14 patients a bronchoalveolar lav- This abstract has not been included here as it has been previously age was performed and 11 underwent a lung biopsy. The published histopathological pattern was alveolar proteinosis in 4 patients, Pediatric Rheumatology (2022) 20:2 Page 7 of 39 endogenous lipoid pneumonia in 3, vasculitis in 1 and fibrosis in 1. Conclusion: TCZ improved fever and inflammatory response in Most of the patients (93%) were treated with glucocorticoids (GCs) at VEXAS-RP and allowed steroid reduction. Future studies are needed time of diagnosis, and 24 (86%) received IL-1 or IL-6 inhibitor after to verify its safety with long-term use and its effects on the diagnosis (18 anakinra, 12 canakinumab, 14 tocilizumab). Twelve hematological abnormalities and structural changes in chondritis. (43%) patients required ICU admission and 4 (14%) died. Conclusion: Lung involvement is an emerging life-threatening com- Disclosure of Interest plication of sJIA in Europe, particularly in patients with a history of None Declared MAS, and a prompt recognition is crucial. New strategies are needed Table 1 (abstract O15). Clinical features of the VEXAS syndrome to reduce the risk and improve outcome of this complication. patients with RP using TCZ Disclosure of Interest Patient ID RP13 RP15 RP16 C. Bracaglia Consultant for: SOBI, Novartis, F. Minoia Consultant for: SOBI, C. Age at 66.3 73.5 66.6 Kessel Consultant for: SOBI, Novartis, S. Vastert Consultant for: SOBI, Novartis, diagnosis M. Pardeo: None Declared, A. Arduini: None Declared, O. Basaran: None (years) Declared, N. Kiper: None Declared, M. Kostik: None Declared, M. Glerup: None UBA1 variants c.122T>C: p.Met41Thr c.122T>C: c.121A>C: p.Met41Leu Declared, S. Fingerhutova: None Declared, R. Caorsi Consultant for: Novartis, p.Met41 p.Met41Thr Lilly, A. Horne: None Declared, G. Filocamo Consultant for: SOBI, H. Wittkowski: None Declared, M. Jelusic : None Declared, J. Anton Grant Clinical High-grade fever, skin High-grade High-grade fever, skin /Research support from: Sobi, Novimmune, Novartis, abbvie, Pfizer, GSK, findings at rash, RP, scleritis, fever, skin rash, rash, GCA, RP, MDS, Roche, Amgen, Lilly, BMS, Sanofi, Consultant for: Sobi, Novimmune, Novartis, diagnosis peritonitis, pericarditis, RP, macrocytic DVT, scleritis, airway meningitis anemia involvement Pfizer, GSK, Speaker bureau of: Sobi, Novimmune, Novartis, GSK, Pfizer, S. Khaldi-Plassart: None Declared, A. Belot: None Declared, P. Dolezalova: None Treatments PSL PSL, MTX PSL, AZP, colchicine Declared, A. Ravelli Consultant for: AbbVie, Novartis, Pfizer, Angelini, Reckitt before TCZ Benkiser, S. Ozen Consultant for: SOBI, Novartis, Pfizer, F. De Benedetti Symptoms High-grade fever, Low-grade High-grade fever, skin Employee of: SOBI, Novimmune, Novartis, Roche, Pfizer existed at TCZ myalgia, headache fever rash, RBC and PLT induction* transfusion- dependence PSL dose 9 mg 22.5 mg 30 mg O15 before TCZ Tocilizumab for VEXAS syndrome with relapsing polychondritis: administration extension study Y. Kunishita, Y. Kirino, N. Tsuchida, A. Maeda, L. Hirahara, H. Nakajima PSL dose at 1 mg 12.5 mg 12.5 mg Department of Stem Cell and Immune Regulation, Yokohama City last visit University Graduate School of Medicine, Yokohama, Japan Duration of 12.0 months 6.3 months 7.1 months Correspondence: Y. Kunishita TCZ Pediatric Rheumatology 2021, 20(Suppl 1):O15 administration at last visit Introduction: Recently, VEXAS syndrome, a severe autoinflammatory Symptoms None None RBC transfusion- disease in adults caused by UBA1 somatic mutations, has been existed after 6 dependence, mild skin reported. In addition to systemic inflammatory pathology, VEXAS months rash syndrome is associated with hematological abnormalities such as RP; relapsing chondritis, GCA; giant-cell arteritis, Hb; hemoglobin, DVT, deep myelodysplastic syndrome, making it difficult to treat in clinical vein thrombosis; MDS, myelodysplastic syndrome; PSL, prednisolone; MTX; practice and forcing patients to continue moderate or higher doses methotrexate, AZP, azathioprine; TCZ, tocilizumab, RBC; red blood cells, PLT: of steroids. Therefore, there is an unmet need to develop therapies platelets, * symptoms existed during the past 1 month before TCZ induction that can reduce steroids and improve prognosis in VEXAS syndrome. Objectives: To identify promising therapeutic targets and therapies O16 for VEXAS syndrome. Genetic and immunologic characterization of male and female Methods: Patients with clinically diagnosed relapsing polychondritis patients with nemo-deleted exon 5 autoinflammatory syndrome (RP) in our department and known UBA1 mutations identified by 1 1 2 1 1 1 A. A. de Jesus , B. Lin , E. Karlins , D. Kahle , A. Rastegar , J. Mitchell ,S. Sanger sequencing (VEXAS-RP), who had been introduced to 1 1 1 1 1 Torreggiani , F. Bhuyan , S. Alehashemi , K. Cetin Gedik , K. Uss , C.-C. tocilizumab (TCZ), an IL-6 receptor antibody, were included in the 3 4 4 4 5 6 Lee , H. Kuehn , S. Rosenzweig , K. Calvo , M. Walkiewicz , J. Lack ,E. study. Clinical information and laboratory findings were collected retro- 7 8 9 10 11 11 Hanson , A. Khojah ,E.Wu , C. Scott , T. R. Leahy , E. MacDermott ,O. spectively from electronic medical records to validate the efficacy of 11 12 13 14 15 Kileen , T. Arkachaisri , Z. Gucev , K. Cook , V. Mamadova ,G. TCZ. Fractional abundance of UBA1 variant in peripheral blood was de- 15 16 17 18 19 Nasrullayeva , M. Marques , S. Canna , S. Ozen , D. Kuhns ,C. tected using dd-PCR. Serum cytokine levels before and after TCZ ad- 20 9 2 1 Dalgard , T. Moran , A. Oler , R. Goldbach-Mansky ministration were measured using a cytometer bead array. 1 2 Translational Autoinflammatory Diseases Section; BCBB, NIAID, NIH; Results: Three patients with VEXAS-RP, all male, were receiving 3 4 5 6 7 NCI, NIH; DLM, NIH; CSI; NCBR, NIAID, NIH, Bethesda; Indiana TCZ in our department. All patients were still receiving TCZ at University School of Medicine, Indianapolis; Lurie Children’s Hospital, their last visit and could continue for more than six months. Chicago; University of North Carolina School of Medicine, Chapel Hill, After the initiation of TCZ, fever was relieved in all patients, United States; University of Cape Town, Cape Town, South Africa; and blood tests showed a decrease in CRP levels and an in- 11 12 Children’s Health Ireland (CHI) at Crumlin, Dublin, Ireland; KK crease in albumin levels, which was thought to be the effect of Women's and Children's Hospital, Kallang, Singapore; University blocking the IL-6 pathway to reduce systemic inflammation. As Children's Hospital, Skopje, Republic of North Macedonia; Akron a result, allpatientswereableto reducesteroid useafter Children’s Hospital, Akron , United States; Azerbaijan Medical starting TCZ. In the patient with severe anemia and 16 17 University, Baku, Azerbaijan; NIAMS, NIH, Bethesda; The Children’s thrombocytopenia (RP16 on Table 1), the frequency of receiving Hospital of Philadelphia, Philadelphia, United States; Hacettepe red blood cell transfusions decreased after TCZ administration, University Faculty of Medicine, Ankara, Turkey; Frederick National and his platelet counts had improved to over 100,000/μl. How- Laboratory for Cancer Research, Frederick; The American Genome ever, macrocytic changes in erythrocytes were still observed in Center, Bethesda, United States all patients after TCZ administration, suggesting that the effect Correspondence: A. A. de Jesus of IL-6 blockade on hematological abnormalities was partial. Pediatric Rheumatology 2021, 20(Suppl 1):O16 Pediatric Rheumatology (2022) 20:2 Page 8 of 39 Introduction: Splice site variants in IKBKG that lead to exon 5 O17 deletion cause NEMO-deleted exon 5 autoinflammatory syndrome Existing transition practices for autoinflammatory diseases across (NEMO-NDAS). NEMO-NDAS clinically mimics the interferonopathy Europe 1 1 2 3 4 5 chronic atypical neutrophilic dermatosis with lipodystrophy and M. Israni , B. Nicholson , N. Mahlaoui , L. Obici , L. Rossi , H. Lachmann , 6 7 8 9 10 elevated temperature (CANDLE) but genetic diagnosis is challen- G. Hayward , M. Zajc Avramovič , A. Guffroy , V. Dalm , R. Rimmer ,L. 11 12 13 14 11 ging and treatment with JAK inhibitors provides only partial Solis , C. Villar , A. R. Gennery , S. Skeffington , J. Nordin ,K. 15 8 16 17 18 benefit. Warnatz , A. S. Korganow , J. Antón , M. Cattalini , E. Morrison ,T. 19 20 21 22 23 24 Objectives: To characterize the immunodysregulation present in Amin , P. Wekell , S. Berg , P. Soler-Palacín , S. Burns , M. Campbell NEMO-NDAS patients (pts) and to validate a bioinformatics approach on behalf of RITA-ERN Transition Working Group Consortium to diagnose these pts. Department of Immunology, Royal Free Hospital, London, United Methods: A bioinformatics pipeline to mask the IKBKG Kingdom; Pediatric Immuno-Haematology and Rheumatology Unit, pseudogene was refined using splice prediction tools (SpliceAi, Necker Enfants Malades University Hospital, Assistance Publique- TraP, MaxEntScan and Human Splicing Finder). Screening of IKBKG Hôpitaux de Paris (AP-HP), Paris, France; Fondazione IRCCS Policlinico exon 5 ± 30bp was validated in 701 samples from subjects San Matteo, Centro per lo Studio e la Cura delle Amiloidosi Sistemiche, enrolled in an IRB-approved protocol, and in internal (n=2655, Pavia, Italy; Unité Policlinique pédiatrique, Hôpital Bicêtre, Assistance whole exome sequencing (WES)) and public (n=2498, whole gen- Publique-Hôpitaux de Paris (AP-HP), Paris, France; Division of Medicine, ome sequencing (WGS)) databases. The variants detected were National Amyloidosis Centre , University College London, London; validated by Sanger or amplicon deep sequencing (seq) and Paediatric and Adult Rheumatology, Leeds Teaching Hospital Trust, spliced product was confirmed by Western blot, cDNA seq and Leeds, United Kingdom; University Children's Hospital Ljubljana, RNA-seq. Nanostring gene expression, PBMC stimulation and cyto- Ljubljana, Slovenia; Department of Clinical Immunology and Internal kine assays were performed. CRISPR generated U937 cell line Medicine, National Reference Center for Systemic Autoimmune Diseases clones were functionally assessed. (CNR RESO), Tertiary Center for Primary Immunodeficiency, Hôpitaux Results: 13 pts (9 females and 4 males), had 9 different de novo Universitaires de Strasbourg, Strasbourg, France; Department of splice site variants in IKBKG. cDNA seq (13/13) or Western blot (5/ Immunology, Erasmus University Medical Center, Rotterdam, 5) confirmed the splice product in all pts tested. RNA-seq (n=12) Netherlands; Rare Autoinflammatory Conditions Community – UK showed a high frequency of exon 5 skipping (median 55% (35- (RACC – UK), England and Wales; IPOPI, Downderry, United Kingdom; 12 13 80%)). IKBKG exon 5 splice site variants were screened in internal Barcelona PID Foundation, Barcelona, Spain; Paediatric and public WES/WGS databases (n=5149) and 11 variants in 22 Haematopoietic Stem Cell Transplant Unit, Great North Children's subjects passed filters. Sanger seq confirmed 1 of the 11 variants Hospital (GNCH), Royal Victoria Infirmary, Newcastle upon Tyne, United 14 15 (9%); amplicon deep seq is pending. The most common clinical Kingdom; Irish Vasculitis Organisation, Ireland, Ireland; Department of features in NEMO-NDAS pts were panniculitis with systemic in- Immunology, Universitätsklinikum Freiburg, Freiburg, Germany; flammation (100%), ectodermal dysplasia (83%), hepatosplenome- Department of Pediatric Rheumatology , Sant Joan de Déu Hospital, galy (77%) and B-cell lymphopenia (80%). Compared to CANDLE Barcelona, Spain; Pediatrics Clinic, University of Brescia and ASST pts (n=5), NEMO-NDAS pts’ skin biopsies (n=7) showed histiocytic Spedali Civili di Brescia, Brescia, Italy; Department of Rheumatology, panniculitis, vacuolar interface changes and dyskeratosis. Liver bi- Southern General Hospital, Glasgow; Children's Rheumatology, The opsies (n=3) showed granulomatous hepatitis; 2 other pts had Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom; NU- portal hypertension. All pts were steroid-dependent with partial sjukvården - Barn- och ungdomskliniken , Uddevalla; Department of responses to anti-TNF (n=9) or JAK inhibition (n=9). Nanostring Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy, IFN and NF-κB scores were elevated in all 13 pts. Pts with NEMO- University of Gothenburg, Gothenburg, Sweden; Pediatric Infectious NDAS had higher serum levels of IFN-γ, IL-12p40, IL-17 and IL-23 Diseases and Immunodeficiencies Unit, Hospital Universitari Vall than seen in CANDLE pts (p<0.0001 for all). Stimulated M1 and d’Hebron. Universitat Autonoma de Barcelona, Barcelona, Spain; M2 macrophages from NEMO-NDAS pts (n=3) produced higher Immunity and Transplantation, University College London; levels of CCL3/4 (MIP1-α/β) than healthy control (HC) cells (n= Department of Immunology, Royal Free London NHS Foundation 7)(p<0.05). NEMO-NDAS pts (n=2) had normal T and B cell prolif- Trust, London, United Kingdom eration, and Fas-induced T cell death was comparable to HC. Correspondence: M. Israni U937 cell line clones lacking exon 5 normally degraded IκBα Pediatric Rheumatology 2021, 20(Suppl 1):O17 upon LPS stimulation and mutant U937 clones showed enhanced TNF induced cell death compared to wildtype and PSMB8-/- Introduction: Substantial improvements in the diagnosis and clones. management of Autoinflammatory Diseases (AID) have translated Conclusion: Our bioinformatics pipeline masking IKBKG into longer life expectancies among patients, thus prompting a need pseudogene provides a sensitive diagnostic tool for the early for defined transition protocols for long-term follow-up in adult care. recognition of NEMO-NDAS pts. The role of cytokine dysregula- Presently, there are limited data on existing transition programs for tion and TNF induced cell death in the specific pathogenesis of these disorders and their efficacy. NEMO-NDAS is being evaluated to improve therapeutic options. Objectives: This study aimed to examine the prevalence of transition programs and existing practices for the transition of young people Acknowledgments with AID to adult services across European health centres. The results This work was supported by the NIH Intramural Research Program (IRP) of from this survey will be used to develop best practice guidelines for NIAID the transition of patients with AID. Methods: A survey examining existing transition practices was Disclosure of Interest developed by the European Reference Network on Rare None Declared Immunodeficiency, Autoinflammatory and Autoimmune Diseases Pediatric Rheumatology (2022) 20:2 Page 9 of 39 O18 Transition Working group and electronically circulated to paediatric COVID-19 infection and vaccination in patients with AID centres across Europe. autoinflammatory diseases on biologics Results: The survey generated 32 responses from AID centres spread 1,2 1 1 1 C. J. Peet , C. Papdopoulou , B. R. Sombrito , M. Wood ,H.J. across 29 cities in 13 countries. Majority of the respondents Lachmann transitioned young patients to specialist AID services (24/31) or Adult CAPS and Autoinflammatory Diseases Treatment Service, National Rheumatologists (10/31). However, approximately 10% (3/31) of the Amyloidosis Centre, Royal Free London NHS Foundation Trust & Division centres reported experiencing difficulties with identifying specialist of Medicine University College London; Department of Medical and adult centres for onwards referral - with 19% (6/31) of paediatric AID Molecular Genetics, King's College London, London, United Kingdom services transitioning patients to non-specialist Adult Internal Medi- Correspondence: C. J. Peet cine Physicians. Pediatric Rheumatology 2021, 20(Suppl 1):O18 Most AID centres started the transition process in early adolescence - with 55% (17/31) of the services beginning Introduction: Inflammatory cytokines are central to the pathogenesis transition between the ages of 10 and 16. 61% (19/31) of the of the systemic autoinflammatory diseases (SAID) and agents AID centres tended to end transition and transfer care to adult targeting these pathways have transformed the management of services after the age of 18. SAID. These same pathways are involved in the balance between Whilst 77% (24/31) of the services had an internal process for viral clearance and hyperinflammation during infection and have transition, only 20% (6/30) reported having access to national therefore been areas of active research interest into COVID-19. As a guidelines for transition. 68% (21/31) of the services offered patients result, among patients with SAID on biologics, there are legitimate joint appointments with multidisciplinary healthcare professionals concerns regarding the risk of COVID-19 infection and safety of vac- from paediatric and adult services prior to transfer, and 73% (22/30) cination, which are exacerbated by the scarcity of published data on of the services described complete integration of medical records the outcomes of COVID-19 infection and vaccination in these across centres. patients. Only 29% (9/31) of the paediatric services referred patients to Objectives: This study establishes the prevalence and outcomes of adult centres with dedicated ‘young adult clinics' - with even COVID-19 infection and early outcomes of vaccination among a co- fewer services transitioning patients to adolescent centres prior hort of 248 patients with SAID on biologics. to adult care (16% or 5/31). Only 29% (9/31) of the AID centres Methods: Data were collected from the electronic medical records of reported transition-specific research programs at their site. 248 patients with SAID on biologics at a national centre up to 26/7/ Conclusion: Whilst most paediatric AID centres followed an 21. Patients were also surveyed using a web-based survey completed internal, integrated transition protocol, defined national and in clinic or remotely between 4/3/21 and 26/7/21. international guidelines are required to support successful Results: No deaths were recorded in this cohort of 248 patients transition of young patients to adult centres. Transition programs between 29/1/20 and 26/7/21. In line with national guidance, all must be adapted to provide adolescent-friendly care that pre- patients in this cohort were advised that the diagnosis of SAID pares young patients for transfer to adult care. Finally, the devel- managed with single-line biologic therapy was not an indication for opment of more transition-specific research programs is shielding and that they should continue their biologic therapy unless warranted to determine the predictors of successful transition otherwise instructed by a medical professional. Survey responses and design effective transition interventions. were received from 195 patients (195/248, 78.6%). Biologic therapy Keywords: transition, primary immunodeficiencies, autoinflammatory was as follows: anakinra (129/195, 66.2%), canakinumab (55/195, diseases, network. 28.2%), tocilizumab (8/195, 4.1%), etanercept (3/195, 1.5%), adalimu- mab (co-prescribed with anakinra) (1/195, 0.5%). Among survey re- Disclosure of Interest spondents, 32 cases of suspected COVID-19 infection were reported, M. Israni: None Declared, B. Nicholson: None Declared, N. Mahlaoui: of which 15 were confirmed on testing (15/195, 7.7%). Two patients None Declared, L. Obici: None Declared, L. Rossi: None Declared, H. on anakinra were hospitalised due to dehydration. No patient re- Lachmann: None Declared, G. Hayward: None Declared, M. Zajc quired supplemental oxygen, mechanical ventilation or intensive care Avramovič: None Declared, A. Guffroy Grant /Research support from: CSL admission. Biologic therapy continued uninterrupted in all patients Behring and Takeda, V. Dalm: None Declared, R. Rimmer: None Declared, managed in the outpatient setting and was temporailty discontinued L. Solis: None Declared, C. Villar: None Declared, A. R. Gennery Grant in the two hospitalised patients by the admitting team. Three pa- /Research support from: Mallinckrodt and JAZZ Pharmaceuticals, S. tients with suspected or confirmed COVID-19 infection reported new Skeffington: None Declared, J. Nordin: None Declared, K. Warnatz: None symptoms that persisted for more than twelve weeks. 164/195 Declared, A. S. Korganow Grant /Research support from: CSL Behring and (84.1%) respondents had received the first vaccine dose and 79/195 Takeda, J. Antón Grant /Research support from: European Union, Insituto (40.5%) had received two doses. 162/164 (98.8%) patients continued Carlos III, Fundación Daniel Bravo, Novartis, Sobi, Novimmune, Roche, biologic therapy uninterrupted around the time of vaccination. Of Pfizer, Lilly, AbbVie and Amgen, Conflict with: Received personal fees or the 243 vaccine doses administered, 138 (56.8%) were the Oxford travel expenses from Novartis, Sobi, Roche, Pfizer, Lilly, AbbVie and Astra-Zeneca vaccine and 105 (43.2%) were the Pfizer-BioNTech vac- Gebro, M. Cattalini Speaker bureau of: Novartis Farma, Abbvie, Sobi, and cine. Following vaccination, no serious adverse events were reported Pfizer , E. Morrison: None Declared, T. Amin: None Declared, P. Wekell: and no patient required hospital admission. Side effects were re- None Declared, S. Berg: None Declared, P. Soler-Palacín Grant /Research ported following 130/243 (53.5%) doses and symptoms reported by support from: European Union, Instituto Carlos III, Grifols and CSL patients to be in keeping with a flare of the underlying SAID were re- Behring, Conflict with: Received personal fees or travel expenses from ported following 40/243 (16.5%). Side effects had fully resolved by 72 CSL Behring, Takeda and Grifols , S. Burns Grant /Research support from: hours following 92.2% of doses (224/243). No cases of COVID-19 European Union, National Institute of Health Research, UCLH and GOSH/ were reported following administration of both vaccine doses and ICH Biomedical Research Centers and CSL Behring, Conflict with: only one early case was reported after the first dose, with symptom Received personal fees or travel expenses from Immunodeficiency onset within five days of vaccine administration. Median follow up Canada/IAACI, CSL Behring, Baxalta US Inc and Biotest, M. Campbell following vaccination was 10.5 weeks following the first dose and 6.0 Grant /Research support from: National Institute of Health Research, weeks following the second. PIDUK, CSL Behring and the Royal Free Charity, Conflict with: Received Conclusion: This study shows COVID-19 infection rates broadly in line personal fees or travel expenses from Biotest, BPL, CSL Behring, Grifols, with that of the UK general population among patients with SAID on HAEUK, Shire and Takeda Pediatric Rheumatology (2022) 20:2 Page 10 of 39 biologics and demonstrates no significant concerns regarding out- predicting patients with cr-FMF (Table 1). Scores were assigned ac- comes of infection in these patients. We also present the largest cording to β coefficients in the final model. The cut-off value of pre- series of patients with SAID or on IL-1/6 biologics to have received dictor score as 4.5 was 88% sensitive and 82% specific to foresee the an adenoviral vector or mRNA vaccine and observe no significant risk of colchicine resistance in the ROC. early safety concerns. Whilst longer follow-up is needed to establish The predictive score was applied to 374 patients (colchicine resistant the efficacy of vaccination in these patients, these findings will sup- = 75, colchicine responsive = 299) which were registered to PeRA-RG port patients and their clinicians to make informed decisions around database up to December 2020. Sixty-five (86.6%) cr-FMF patients continuation of biologic therapy and vaccination during the ongoing and 3 (1%) colchicine responsive patients had a total score of more COVID-19 pandemic. than 4.5. The cut-off value of the score as 4.5 was 86.6% sensitive and 99% specific to identify the risk of colchicine resistance in the Acknowledgments ROC. CJP is funded by a British Heart Foundation Clinical Research Training Conclusion: In advance of the previous studies, we intended to Fellowship. design a composite predictive scoring system to foresee unresponsive patients. By constructing this novel reliable predictor Disclosure of Interest tool, we enunciate that physicians will be capable of anticipating C. J. Peet: None Declared, C. Papdopoulou: None Declared, B. R. Sombrito: drug resistance in children with FMF at the initiation of the disease None Declared, M. Wood: None Declared, H. J. Lachmann Consultant for: and, thereby have a chance to interfere timely before the emergence Novartis and Sobi of complications during the disease course. Key Words: Familial Mediterranean fever, predictive score, colchicine resistance Abstracts accepted for publication only REFERENCES P01 1. Ozen S, Kone-Paut I, Gül A. Colchicine resistance and intolerance in famil- In pursuit of colchicine resistance prediction in familial ial mediterranean fever: Definition, causes, and alternative treatments. mediterranean fever: exploring a novel scoring model and Seminars in arthritis and rheumatism. 2017;47(1):115-20. simultaneous validation 2. Babaoglu H, Armagan B, Bodakci E, Satis H, Atas N, Sari A, et al. Predictors 1 1 2 2 1 N. Aktay Ayaz , F. G. Demirkan , T. Coskuner , F. Demir , A. Tanatar ,M. of persistent inflammation in familial Mediterranean fever and association 3 4 5 6 7 2 Çakan , S. G. Karadag , G. Otar Yener , S. Caglayan ,K.Ulu , B. Sozeri ,H. with damage. Rheumatology (Oxford, England). 2021;60(1):333-9. E. Sonmez 3. Betul Sozeri HES, Ferhat Demir, Mustafa Çakan, Kübra Öztürk, Semanur Pediatric Rheumatology, Istanbul University, Istanbul Faculty of Özdel, Gulcin Otar Yener, Şerife Gül Karadağ, Nuray Aktay Ayaz. Time to Medicine; Pediatric Rheumatology, University of Health Sciences, collaborate: Objectives, Design, and Methodology of PeRA-Research Umraniye Research and Training Hospital; Pediatric Rheumatology, Group. The North Clinics of Istanbul. 2020. University of Health Sciences, Zeynep Kamil Women and Children's 4. Özçakar ZB, Elhan AH, Yalçınkaya F. Can colchicine response be predicted Diseases Training and Research Hospital; Pediatric Rheumatology, in familial Mediterranean fever patients? Rheumatology (Oxford, University of Health Sciences, Bakırkoy Dr. Sadi Konuk Training and England). 2014;53(10):1767-72. Research Hospital, Istanbul; Pediatric Rheumatology, Sanlıurfa Training and Research Hospital, Sanlıurfa, Sanlıurfa; Pediatric Rheuamtology, Disclosure of Interest University of Health Sciences, Umraniye Research and Training Hospital; None Declared Pediatric Rheumatology, University of Health Sciences, Umraniye Table 1 (abstract P01). Multivariate logistic regression analysis of Research and Training Hospital, Istanbul, Istanbul; Pediatric prediction of colchicine resistance and scoring system Rheumatology, Kocaeli University, Kocaeli School of Medicine, Kocaeli, Kocaeli, Turkey Predictors Odds Ratio (95% P Score Correspondence: N. Aktay Ayaz CI) value assigned Pediatric Rheumatology 2021, 20(Suppl 1):P01 Recurrent arthritis 2.6 (0.99-7.02) 0.03 2 Introduction: Over the years, definition and prediction of colchicine Protracted febrile myalgia 6.8 (1.43-32.34) 0.01 6 resistance have been the most intriguing issues of researches 1,2 Erysipelas-like erythema 2.3 (0.92-6.21) 0.02 2 concerning familial Mediterranean fever (FMF). Objectives: The aim of this study is to develop a novel scoring Anemia 3.4 (1.26-9.65 0.02 3 system based on the initial clinical features and laboratory findings Elevated SAA in the attack free 0.95 (0.91-1.01) 0.04 1 via synchronous validation of it in an independent group for period predicting colchicine resistance in children with FMF. Methods: The medical records of the cases with FMF who applied to SAA, Serum amyloid A the pediatric rheumatology outpatient clinic were evaluated retrospectively. To define the predictive factors for colchicine P02 resistance, baseline clinical and laboratory findings prior to initiation of Diagnostic delay in a rare autoinflammatory syndrome 1 1 2 1 2 colchicine were evaluated. After generating a predictive score in the F. Annunziata , M. L. Pennacchio , M. Tardi , F. Paciello , R. Borrelli ,R. 1 1 2 2 initial cohort, it was applied to an independent cohort in the database Naddei , M. Alessio , L. Martemucci , F. Orlando of Pediatric Rheumatology Academy (PeRA)-research group (RG) Department of Translational Medical Sciences, Section of Pediatrics, 3 2 established in 2019 , for external validation of effectiveness and University of Naples Federico II; Pediatrics, AORN Santobono Pausilipon, reliability. Naples, Italy Results: A total of 327 patients with FMF were included in the study. Correspondence: F. Annunziata Among them, 78 (23.9%) (Group I) were colchicine resistant (cr)-FMF Pediatric Rheumatology 2021, 20(Suppl 1):P02 patients and 249 (76.1%) (Group II) were colchicine responsive. Erysipelas-like erythema (ELE), myalgia, arthritis, chronic arthritis, pro- Introduction: TRNT1 is a nuclear gene encoding a ubiquitous tracted febrile myalgia, amyloidosis, vasculitis, anemia, and protein- enzyme (CCA-adding tRNA nucleotidyltransferase enzyme) necessary uria were more common in patients who were in group I than those for aminoacylation of both mitochondrial and cytosolic tRNA. in group II. A logistic regression model was used to estimate a model Mutations of that gene lead to heterogeneous phenotypes and to predict the colchicine resistance in FMF patients. According to the systemic involvement of variable severity and progression. regression analysis, recurrent arthritis, protracted febrile myalgia, pres- Objectives: To consider mutations of TRNT1 as an important ence of ELE, chronic anemia and elevated serum amyloid A levels in the differential diagnosis in patients with overlap of immunodeficiency attack-free period were determined as the scoring parameters for and autoinflammatory features to avoid diagnostic delay. Pediatric Rheumatology (2022) 20:2 Page 11 of 39 Methods: A 10-year-old female admitted to our rheumatology patients have been successfully treated with the interleukin-1β in- pediatric unit of Santobono Children's Hospital of Naples for febrile hibitor canakinumab. Canakinumab has been approved and applied illness associated with vomit and diarrhoea, evolved in shock. She for the treatment of TRAPS patients since 2017. was treated in intensive care with broad spectrum antibiotics and Objectives: The present study explores the long-term efficacy and cardiovascular support. safety of canakinumab under routine clinical practice conditions Results: The anamnesis revealed recurrent fever accompanied by vomit, in pediatric (age ≥2 years) and adult TRAPS patients. metabolic acidosis, dyselectrolytemia and increase of inflammatory markers, Methods: RELIANCE is a prospective, non-interventional, multi-center, without evidence of infective causes, since second month of life. Even in observational study based in Germany with a 3-year follow-up the absence of evidence of infective origins, these febrile episodes were period. Patients with clinically confirmed diagnoses of TRAPS who often treated with systemic antibiotic therapy with poor clinical response. routinely receive canakinumab are enrolled in order to evaluate effi- However, it was observed resolution of symptoms after steroids therapy. cacy and safety of canakinumab under standard clinical practice con- She presented to our attention with following clinical conditions: microcytic ditions. Inflammatory markers, disease activity and remission by anaemia (requiring blood transfusion),bilateral cataract, hypotonia, physician assessment, disease activity and fatigue by patient assess- intellectual disability andhypogammaglobulinemia. Physical examination ment, were assessed at baseline and at 6-monthly intervals. documented occurrence of facial dysmorphisms,brittle hair and intellectual Results: disability. At the admission, laboratory assessment showed: white blood cell The interim analysis of TRAPS patients enrolled by December 2020 4920/ul (n.v. 5-19), Haemoglobin 9.4 g/dl (n.v. 10.18), MCV 60.9 fL (85-120), includes baseline (N=16, including 1 patient with atypical TRAPS) and RDW 43 fL (n.v. 38.7-45.1), Platlets 119000/ul (n.v. 140-440), Neutrophiles preliminary 18-month data. Mean age in this cohort was 23 years (3- 3870/uL (n.v. 1300-8500), Lymphocytes 619/uL (n.v.1300-8500), Eosino- 43 years) and the median duration of prior CAN treatment was 1.0 philes50/uL (n.v. 0-80), C Reactive Protein 324 mg/l (n.v. 0.5), Procalcitonin year (0-4 years). All patients already were on canakinumab when be- 610 ng/ml (n.v. <0.5), Ferritin 2071 ng/ml (n.v. 6-67), lactic dehydrogenase ing enrolled. Prior treatments were colchicin (N=2), anakinra (N=10) 1198 U/l (n.v. 230-500). Immunological screening was performed, showing and tocilizumab (N=1). hypogammaglobulinemia, with IgA <0.22 g/l (n.v 0.5-3) and IgG 6,3 g/dl Physician assessment indicated 60-80% remission and laboratory (n.v. 7-15), and low levels of T total (TCD3 49%, n.v.55-78%) and T helper parameters were within normal range. Disease control by patient lymphocites (TCD4 29%, n.v. 27-53%). No infective causes were found. Be- assessment showed no major changes regarding the analyzed pa- cause of the history characterized by recurrent fever, immunological alter- rameters (table 1). Of the three serious adverse events reported ations and dismorphic appearance, TRNT1 mutation associated disease was none was classified as drug-related. suspected. Genetic analysis was done, confirming our suspicion.Based on Conclusion: Preliminary analysis of 18-month interim data of TRAPS case reports available in literature, after the molecular diagnosisshe started patients treated with CAN available from the RELIANCE study indicate onanti-TNF alfa (Etanercept) therapy. stable efficacy and safety of CAN long-term treatment. Conclusion: The presence of recurrent fever associated with elevation of inflammatory indexes, without evidence of infections, Disclosure of Interest led to consider TRNT1 mutation related disease as an N. Blank Grant /Research support from: Novartis, Sobi, Consultant for: autoinflammatory syndrome. Currently, 49 case are reported in Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer- literature. This condition was firstly associated to congenital Ingelheim, Roche, J. Henes Grant /Research support from: Novartis, Roche, sideroblastic anaemia with immunodeficiency, fevers, and Consultant for: Novartis, AbbVie, Sobi, Roche, Janssen, Boehringer-Ingelheim, developmental delay (SIFD) but over the years phenotypic T. Kallinich Grant /Research support from: Novartis, Consultant for: Sobi, heterogeneity was described. Due to the rarity of that syndrome, Novartis, Roche, P. T. Oommen Grant /Research support from: Novartis, C. dignostic delay is observed, as in our patient. Early diagnosis of this Schuetz: None Declared, M. Borte: None Declared, J. Weber-Arden Employee condition would enable patients to promptly access to therapies. of: Novartis, J. Kuemmerle-Deschner: None Declared Symptomatic treatments, including red blood cells transfusions, immunoglobulin replacement therapy and steroids, are the most used; however, mortality is high. Etanercept has been recently Table 1 (abstract P03). Baseline characteristics and interim analysis described as effective treatment. TNFa inhibitors can lead to a data of patients with TRAPS significative response for those patients who can benefit early in life. Our patient started that treatment but we are still waiting to define the clinical benefits of this therapy. Baseline 6 12 18 months months months Disclosure of Interest Number of patients, N 16 13 10 6 None Declared Females (%) 11 (69) 9 (69) 7 (70) 3 (50) Median duration of prior CAN therapy at 1.0 (0; 4) 1.0 (0; 1.0 (0; 1.5 (0; P03 baseline, years (min; max) 4) 4) 2) Long-term efficacy and safety of canakinumab in patients with Number (%*) of patients in disease 9 (60.0) 9 (81.8) 7 (77.8) 4 (80.0) traps (tumor necrosis factor receptor-associated periodic remission (physician assessment) syndrome) - interim analysis of the reliance registry 1 2 3 4 5 6 Physician Global Assessment, percentage 40 / 53 / 82 / 9 / 44 / 44 80 / 20 N. Blank , J. Henes , T. Kallinich , P. T. Oommen , C. Schuetz , M. Borte , 7 2 of absent/mild-moderate/severe rating 0 0 /11 /0 J. Weber-Arden , J. Kuemmerle-Deschner 1 2 3 University Hospital, Heidelberg; University Hospital, Tuebingen; Charité Patient assessment of current disease 1.5 (0; 5) 1.0 (0; 1.0 (0; 0.0 (0; University Medicine, Berlin; University Hospital, Duesseldorf; activity; 0–10, median (min; max) 4) 6) 3) 5 6 Medizinische Fakultaet Carl Gustav Carus, Dresden; Hospital St. Georg Patient assessment of current fatigue; 0– 2.0 (0; 8) 1.0 (0; 2,5 (0; 4.0 (0; gGmbH, Leipzig; NOVARTIS PHARMA, Nürnberg, Germany 10, median (min; max) 7) 8) 7) Correspondence: N. Blank Number (%*) of patients without 4 (50) 5 (63) 2 (33) 3 (60) Pediatric Rheumatology 2021, 20(Suppl 1):P03 impairment of social life by the disease Introduction: Tumor necrosis factor receptor-associated periodic syn- CRP, SAA median (mg/dl) 0.1/0.5 0.1/0.4 0.1/0.4) 0.0/0.3 drome (TRAPS) is a rare autoinflammatory condition characterized by *not reported for all patients severe systemic and organ inflammation. In clinical trials TRAPS CRP, c-reactive protein; SAA, serum amyloid A Pediatric Rheumatology (2022) 20:2 Page 12 of 39 P04 mutation, coding for a protein at Y861, a dephosphorylation site in the Evaluation of E148Q and concomitant AA amyloidosis secondary leucine-rich repeat (LRR) domain of NLRP3. Phosphorylation/dephosphoryla- to familial mediterranean fever after adjusted clinical-demographic tion of NLRP3 at key sites, as Y861, has been shown to be an essential step characteristics for the regulation of the NLRP3 inflammasome, with Y861c mutation lead- This abstract has not been included here as it has been previously ing to spontaneous inflammasome activation and interleukin-1β published hyperproduction. The mitochondrial VOUS m.12236G>A is associated with non- syndromic SND, MELAS syndrome (mitochondrial encephalomyopathy, P05 lactic acidosis, and stroke-like episodes) and respiratory chain defi- Non-urticarial Muckle-Wells syndrome and mitochondrial ciency (affecting complexes I, III and IV). Both patients did not fulfil cytopathy – hand-in-hand in the NLRP3 inflammasome diagnostic criteria for MELAS syndrome (Hirano et al. (1992) or Yat- 1 1,2 3 2,4 A. Lamas , D. G Oliveira , M. Rodrigues , R. Faria suga et al. (2012)), an insufficient hypothesis to explain all the clinical 1 2 Medicine, Centro Hospitalar e Universitário do Porto; UMIB, ICBAS - manifestations. Mitochondrial dysfunction with increased production Universidade do Porto, Porto; Neurology Department, Hospital de of reactive oxygen species and oxidized mitochondrial DNA (mtDNA) Braga, Braga; Consulta de Sindromas Autoinflamatórios, Unidade de may act synergically in NLRP3 activation, autoinflammation and Imunologia Clínica, Centro Hospitalar e Universitário do Porto, Porto, “inflammaging”. This case illustrates the intricacies of NLRP3 inflam- Portugal masome hyperactivation through a rare mutation in exon 6, resulting Correspondence: D. G Oliveira in a distinct clinical phenotype. It also underlines the complex inter- Pediatric Rheumatology 2021, 20(Suppl 1):P05 play between mitochondria and NLRP3 activation, and its potential role in the modulation/definition of clinical phenotypes. Introduction: Muckle-Wells syndrome (MWS) is a rare inherited cryopyrin-associated periodic syndrome (CAPS) with NLRP3 gain-of- Disclosure of Interest function mutations. Although urticaria is a prominent clinical feature, None Declared cases have been reported with systemic and neurological involve- ment without cutaneous manifestations. Inflammasome activation is a complex process and there is mounting evidence of the key role P06 played by mitochondria. Long-term safety and effectiveness of canakinumab in patients Objectives: To describe the clinical phenotype of two adult sisters with familial mediterranean fever (FMF) interim analysis of the harbouring a heterozygous NLRP3 mutation (c.2582A>G p.(Tyr861Cys) reliance registry 1 2 3 4 and a homoplasmic MT-TS2 mitochondrial variant of uncertain signifi- J. Henes , J. Kümmerle-Deschner , T. Kallinich , F. Dressler , F. Weller- 5 6 7 8 9 cance (VOUS) (m.12236G>A). Heinemann , B. Kortus-Goetze , I. Foeldvari , G. Horneff , M. Hufnagel ,F. 10 11 12 Results: The patients described are siblings from a sibship of 5 (1 male Meier , J. Weber-Arden , N. Blank 1 2 and 4 females), in a family with a history of sensorineural deafness University Hospital, Tuebingen, Germany; Pediatric Department, (SND) (at least 3 generations affected, onset during adolescence). A University Hospital, Tuebingen; Charité University Medicine, Berlin; 4 5 niece was diagnosed with MWS without mitochondrial mutation at Hannover Medical School, Hannover; Prof. Hess Kinderklinik, Bremen; 6 7 another centre. University Hospital, Marburg; Centre for Pediatric and Adolescence Patient 1: a 52-year-old woman with a history of SND and chronic Rheumatology Hamburg, Hamburg; Asklepios Clinic , Sankt Augustin; 9 10 headaches (onset at age 10), associated with nausea, vomiting and University Hospital, Freiburg; University Hospital, Frankfurt; 11 12 fever (mostly concomitant with headaches), recurrent aseptic menin- NOVARTIS PHARMA, Nürnberg; University Hospital, Heidelberg, gitis and stroke-like episodes. Other features included recurrent con- Germany junctivitis, polyarthritis, inflammatory/iron deficiency anaemia and Correspondence: J. Henes accelerated atherosclerosis (myocardial infarction at age 43). There Pediatric Rheumatology 2021, 20(Suppl 1):P06 was no history of cutaneous involvement. Patient 2: a 46-year-old woman with a history of SND (onset at age 18), presented with Introduction: Familial Mediterranean Fever (FMF) is characterized by chronic recurrent headaches (onset at age 15), with concomitant recurrent attacks of fever and serositis as well as elevated nausea, vomiting and fever, with documentation of aseptic meningi- inflammatory markers. FMF treatment goals according to EULAR are tis, and stroke-like episodes. Polyarthritis, synovitis and enthesopathy to control acute attacks and subclinical inflammation and to improve were more severe, and clinodactyly was present. There was no his- patients´ quality of life. tory of cutaneous involvement. Other features included recurrent Objectives: The present study explores the long-term efficacy and conjunctivitis and inflammatory/iron deficiency anaemia. safety of canakinumab (CAN) in routine clinical practice in pediatric Both presented with markedly elevated serum amyloid A, (age ≥2 years) and adult FMF patients. erythrocyte sedimentation rate and C-reactive protein. Serum lactate Methods: RELIANCE is a prospective, non-interventional, multi-center, levels were normal. Cerebrospinal fluid analysis revealed elevated observational study based in Germany for patients with clinically protein levels, with associated pleocytosis. Electromyography was confirmed FMF who routinely receive CAN. Disease activity parame- normal and muscle biopsy showed no evidence of mitochondrial my- ters by physicians´ and patients’ assessment were recorded at base- opathy. Abdominal fat biopsy showed no evidence of amyloid line and were assessed at 6-monthly intervals. deposition. Results: This interim analysis of FMF patients (N=54) enrolled by PCR and Sanger sequencing detected a homoplasmic mitochondrial December 2020 includes baseline as well as 6-, 12- and 18-month VOUS in MT-TS2 gene (m.12236G>A) and a heterozygous missense data. Mean age in this cohort was 25 years (4-56 years) and the pro- NLRP3 mutation (c.2582A>G p.Tyr861Cys, Y861c or previously known portion of female patients was 46 % (N=25). At baseline, median dur- as Y859c – in mice). Extensive genetic studies for the exclusion of ation of prior CAN treatment was 2.0 years (0-6 years). 34 patients other mitochondrial cytopathies were performed. (63%) were concomitantly treated with colchicine. A diagnosis of MWS syndrome was assumed and treatment started While physician ratings report around 62% of patients in disease with IL-1 receptor antagonist (anakinra), with significant clinical im- remission, 52% with absent and 34% with mild-moderate disease ac- provement (headaches, fever, arthritis) and inflammatory marker tivity, patient-reported disease activity decreased during the observa- remission. tion period, especially in patients without prior CAN therapy (table Conclusion: The clinical features fulfil diagnostic criteria for CAPS, as 1). A total of 11 serious adverse events was reported, of which one proposed by Kuemmerle-Deschner et al. (2016). They are also compatible case of tonsillectomy in a 6-year-old patient was classified as drug- with the phenotype previously described for this exon 6 missense related. Pediatric Rheumatology (2022) 20:2 Page 13 of 39 Conclusion: Interim data of FMF patients from the RELIANCE study Introduction: The CDC42 (Cell Division Cycle 42) gene product, CDC42, confirm efficacy and safety of long-term CAN treatment. is a member of the family of small Rho GTPases, which are implicated in a broad spectrum of physiological functions in cell cycle regulation. Disclosure of Interest Missense variants in CDC42 underlie a clinically heterogeneous group J. Henes Grant /Research support from: Novartis, Roche, Consultant for: of phenotypes characterized by variable neurodevelopmental, growth, Novartis, AbbVie, Sobi, Roche, Janssen, Boehringer-Ingelheim, J. Kümmerle- hematological, and immunological disorders. Deschner Grant /Research support from: Novartis, AbbVie, Sobi, Consultant Objectives: Here, we report a family of 4 affected members with a for: Novartis, AbbVie, Sobi, T. Kallinich: None Declared, F. Dressler Grant dominant missense mutation in the CDC42 gene and analyze the /Research support from: Novartis, Consultant for: Abbvie, Mylan, Novartis, pathophysiological mechanisms explaining a large part of the Pfizer, F. Weller-Heinemann: None Declared, B. Kortus-Goetze Consultant for: phenotype Novartis, I. Foeldvari Consultant for: Novartis, G. Horneff Grant /Research Methods: The family (a mother with 3 of her children) was referred support from: AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, to our reference center for a suspected tumor necrosis factor Speaker bureau of: AbbVie, Bayer, Chugai, Merck Sharp & Dohme, Novartis, receptor-associated periodic syndrome. No pathogenic variant was Pfizer, Roche, M. Hufnagel Grant /Research support from: Novartis, F. Meier identified in 8 autoinflammation-related genes including TNFRSF1A, Speaker bureau of: Novartis, J. Weber-Arden Employee of: Novartis, N. Blank NLRP3 and MVK. Affected members presented with recurrent fevers Grant /Research support from: Novartis, Sobi, Consultant for: Novartis, Sobi, lasting several weeks, severe arthromyalgias, arthritis and splenomeg- Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche aly. Two children had in addition labio-palatine cleft and one devel- opmental delay. All the affected members presented with other slight dysmorphic signs: hypertelorism, wide nasal bridge and mouth with widely spaced teeth. Inflammatory manifestations responded re- Table 1 (abstarct P06). Baseline characteristics and third interim markably well to IL-1beta inhibition. Patients were included to the analysis data of patients with FMF France Genomique research program allowing us to perform whole genome sequencing in trio and investigate the pathophysiological Baseline 6 months 18 months mechanisms. All patients All Patients All patients Patients All patients Patients Results: A novel heterozygous p.Thr43Ile mutation in the CDC42 | Patients patients without without without gene was identified in all affected family members. In silico without prior CAN prior CAN prior CAN prior CAN modelisation predicted no structural change of CDC42, but a therapy probable impaired interaction with DOCK proteins, a family of Number of 54 11 35 7 16 3 proteins involved in intracellular signaling networks. Fibroblasts as patients, N well as Peripheral Blood Mononuclear cells (PBMC) from the patients Number (%*) 18 (48.6) 1 (20.0) 19 (73.1) 3 8 (61.5) 1 (100.0) showed an inflammatory signature with an increased expression of of patients (75.0) in disease IL-1β, IL-6, TNFα, IL-8 and IL-18 on a basal state in the untreated pa- remission tient and after stimulation in treated ones. In respect to PBMC con- (physician assessment) trols, patients showed an over-activation of both pyrine and NLRP3 inflammasomes using both agonist triggers and specific inibitors Patient 3.0 7.0 (0; 2.5 (0; 2.0 2.0 0.5 assessment (0; 10) 10) 7) (0; 5) (0; 6) (0; 1) (NLRP3 inflammasome inhibitor MCC 112 and pro-caspase-1 inhibitor of current Z-VAD).The spontaneous increased ASC/Speck aggregation in mu- disease activity; 0– tated PBMCs confirms this observation strongly. 10, median These observations allow us to hypothesize that the inflammatory (min; max) profile of the CDC42 mutations, passes through abnormal activation Patient 5.0 5.0 (0; 3.5 3.0 3.0 0.5 assessment (0; 10) 9) (0; 10) (1; 6) (0; 7) (0; 1) of the pyrin and probably the NLRP3 inflammasome thus linking the of current CDC42 abnormalities to the same inflammatory pathways than fatigue; 0– 10, median familial Mediterranean fever and mevalonate kinase deficiency. (min; max) Conclusion: We describe in four affected members of the same Number (%*) 19 3 18 3 5 2 family a novel heterozygous dominant p.Thr43Ile mutation in the of patients (46.3) (37.5) (66.7) (75.0) (55.6) (66.7) CDC42 gene. CDC42 encodes a small GTPase of the Rho subfamily, without impairment playing a pivotal role in cell cycle regulation. In the family studied, of social life diverse clinical manifestations compose a syndromic phenotype with by the disease autoinflammation, facial dysmorphism and neurodevelopmental delay. The pathophysiological assessment showed that the CRP/SAA, 0.2/0.7 1.1/6.8 0.2/0.8 0.1/0.4 0.1/0.6 0.5/0.7 median inflammatory profile of the p.Thr43Ile CDC42 mutation is linked to (mg/dl) the pyrin and to a lesser extend to the NLRP3 inflammasome, *not reported for all patients unravelling a heretofore-unrecognized connection between seem- CRP, c-reactive protein; SAA, serum amyloid A ingly unrelated autoinflammatory diseases. CDC42 mutations should be searched for USAID patients with splenomegaly, recurrent arthral- gia and a clinical response to IL1 blockers, sporadic or dominant P07 transmission. A family with an autosomal dominant CDC42-mutation covering the full clinical spectrum from developmental defects to Disclosure of Interest autoinflammation None Declared 1 2 2 3 4 V. Hentgen , B. Bekhouche , A. Terre-Becker , J. Cherfils , M. Andre ,S. 5 6 2 Georgin-Lavialle , G. Boursier , A. Smahi Reference Center for AutoInflammatory diseases and amyloidosis, P08 Versailles Hospital, Le Chesnay; INSERM U1163, Imagine Institute, Paris; Evaluation of fatigue level and sleep quality in patients with Laboratoire d’Enzymologie et Biochimie Structurales, CNRS, Gif-sur- familial mediterranean fever Yvette; Service de médecine interne, Montpied Hospital, Clermont- 1 2 2 2 2 Ç. İncesu , G. Kavrul Kayaalp , F. G. Demirkan , O. Köker , F. Çakmak ,Ö. Ferrand; Reference Center for AutoInflammatory diseases and 2 2 2 Akgün , N. Aktay Ayaz , R. Eker Ömeroğlu amyloidosis, Tenon Hospital, Paris; Laboratory of Rare and 1 2 Pediatrics; Pediatric Rheumatology, Istanbul University, Faculty of Autoinflammatory Genetic Diseases, CHRU Montpellier, Montpellier, Medicine, İstanbul, Turkey France Correspondence: G. Kavrul Kayaalp Correspondence: V. Hentgen Pediatric Rheumatology 2021, 20(Suppl 1):P08 Pediatric Rheumatology 2021, 20(Suppl 1):P07 Pediatric Rheumatology (2022) 20:2 Page 14 of 39 Introduction: Familial Mediterranean fever (FMF) is the most laboratory grounds is difficult due to non-specific clinical presenta- prevalent hereditary autoinflammatory disease. It is characterized by tion. Besides monogenic autoinflammatory conditions periodic fevers recurrent inflammatory episodes of fever and serositis. Its lifelong may be a component of other primary immunodeficiency syndrome and inflammatory nature can cause detrimental effects on all aspects (PIDs), rheumatic diseases or cancer. of patients' quality of life. Sleep quality and fatigue are essential Objectives: To evaluate benefits of next generation sequencing factors affecting quality of life, which may be impaired in FMF (NGS) in patients with periodic or persistent fevers and no evidence patients due to recurrent episodes or ongoing subclinical of infectious disease. inflammation. Methods: 55 patients with suspected autoinflammatory PFS were Objectives: In this study, it is aimed to evaluate whether sleep tested for genetic mutations in 344 PID-associated genes using tar- quality and fatigue level are affected in children with FMF compared geted NGS. to healthy children and to assess the parameters that may affect Results: Out of 55 patients, 53% (n=29) presented periodic fevers sleep quality and fatigue status in FMF patients. (recurrent rises of body temperature over 38.0°C), 44% (n=24) had Methods: 225 children aged 7- 18 years who are followed up with the persistent fevers (i.e. lasting rises of body temperature over 38.0°C diagnosis of FMF in Istanbul University Faculty of Medicine Pediatric for at least 3 weeks). Two patients had clinical and laboratory signs Rheumatology Clinic were included in the study. 182 age matched of autoinflammatory disease but no fever. Other symptoms included: healthy peers were included as control group. Demographic features, local or generalized lymphadenopathy (n = 23; 42%), rash (n=29; family history, MEFV gene mutations, medications and The International 53%), arthritis (n=36; 65%), vasculitis (n=17; 31%), serositis (n=17; Severity Score for FMF (ISSF) scores of the patients were recorded. The 31%). We noticed a rise of inflammatory laboratory markers such as PedsQL Multidimensional Fatigue Scale module which consists of three ESR, CRP, leukocyte numbers in all the patients. parts as general fatigue, sleep/rest-related fatigue and cognitive fatigue Based on the results of targeted NGS, we divided the patients into 3 was used to assess fatigue. Five answer options were offered and raw groups: scores were extrapolated to a scale of 0 to 100 reversely (0 converted Group I (n = 25) included patients with mutations associated with to 100, 1 to 75, 2 to 50, 3 to 25 and 4 to 0). Pittsburgh Sleep Quality autoinflammatory diseases. These included mutations in MEFV (n= Index (PSQI) was used to assess sleep quality. The scores ranged 0 to 10), TNFRSF1A (n=6), NLRP12 (n=5), TNFAIP3 (n=2), MVK (n=1), NOD2 21were calculated according to the calculation sheet. A total score of 5 (n=1). and above was considered as poor sleep quality. Group II (n=5) included patients with mutations in the genes Results: Gender distribution was 59.3% female and 40.7% male in associated with other PIDS: WAS, NFKB2 (n=2), CTLA4 and a MBL2. the patient group and 51.6% female, 48.4% male in the control Group III included patients (n = 25) with no mutation identified. This group. The mean age was 12.2 ± 2.4 years, and 12.1 ± 3.3 years in group included patients with a systemic juvenile idiopathic arthritis, the patient and control groups respectively. Mean ISSF score was 2.2 undifferentiated systemic vasculitis and systemic connective tissue ± 1.1 points. Medications of the patients were 88.4% colchicine, diseases. 11.6% colchicine and anti IL-1 treatment (canakinumab or anakinra). We compared clinical and laboratory findings in patients of groups II The MEFV mutations were homozygous in 25.8%, heterozygous in and III with those of group I. No significant difference in age of 38.2%, compound heterozygous in 28% of the patients group. In the onset, clinical manifestation or laboratory activity was found. last year 13.3% of the patients didn’t have any attack, 86.7% had at Conclusion: Usage of NGS makes it possible to find causative least 1 attack. The median PSQI score was significantly higher in the mutations - in those cases where they are detected it is easier to find patient group (5.1±2.3 in the patient group, 3.2±1,3 in the control better therapeutic options. group; p <0.05) and the median PEDsQL score was significantly higher in the control group (66.0±17.3 in the patient group, 70.4± Acknowledgments 15.9 in the control group; p <0.05). A significant positive correlation This work was supported by the Russian Foundation for Basic Research was observed between the number of attacks in the last 1 year and (grant № 18-515-57001). the PSQI score (r=0.721, p <0.05). There was no significant difference in terms of ISSF score, PSQI score, PEDsQL score, general fatigue Disclosure of Interest score, sleep/rest fatigue score, and thought fatigue score between None Declared homozygous, heterozygous and compound heterozygous groups. Conclusion: This study demonstrates that children with FMF have lower sleep quality and higher fatigue levels compared to their P10 healthy peers. The disease activity also effects the sleep quality and Long-term efficacy and safety of canakinumab in Cryopyrin- fatigue status of FMF patients. Maintaining low disease activity in the Associated Periodic Syndromes (CAPS) – 30-month data from the of the patients with FMF and evaluation of sleep quality in the reliance registry routine follow-ups can improve the quality of life of the patients. This abstract has not been included here as it has been previously published Disclosure of Interest None Declared P11 Autoimmunity within autoinflammatory diseases: not so far, not so P09 rare Next generation sequencing in diagnosis of periodic fevers: one J. R. Marques Soares on behalf of Autonflammatory Diseases Unit - 2 3 center experience Hospital Vall Hebron, M. Martinez Gallo , M. Antolin Mate , S. Bujan 1,2 2 2 2 3 1 Z. Korobova , I. Svitina , K. Belozerov , A. Tumakova , A. Romanko ,E. Rivas on behalf of Autoinflammatory Diseases Unit - Hospital Vall 2,3 2,4 Suspitsyn , M. Kostik Hebron 1 2 1 2 3 Saint Petersburg Pasteur Institiute; Saint Petersburg State Pediatric Internal Medicine; Immunology; Genetics, Hospital Vall D´Hebron Medical University; N.N. Petrov National Medical Research Center of (Barcelona) Spain, Barcelona, Spain Oncology; Almazov National Medical Research Centre, Saint-Petersburg, Correspondence: J. R. Marques Soares Russian Federation Pediatric Rheumatology 2021, 20(Suppl 1):P11 Correspondence: Z. Korobova Pediatric Rheumatology 2021, 20(Suppl 1):P09 Introduction: Autoinflammation and autoimmunity are two sides of the immune system. Altought phisiopathological mechanism are Introduction: Periodic fever syndromes (PFS) is a group of disorders supposed to be clearly different, some autoimmune features have characterized by recurrent attacks of systemic and organ-specific in- been identified as signifcative parts of new entities like SAVI, DADA2 flammation. Establishing a reliable diagnosis on clinical and or COPA syndrome. In some cases, the clinical and antibody profile Pediatric Rheumatology (2022) 20:2 Page 15 of 39 in some autoinflammatory diseases can remind autoimmune gene have been reported as part of NLRC4-related familial cold auto- conditions. inflammatory syndrome and periodic fever-infantile enterocolitis Objectives: To evaluate the presence of sera autoantibodies and autoinflammatory syndrome. We report a case of a 15-year old male organ-specific / systemic autoimmune diseases according to the with an enterocolitis autoinflammatory syndrome phenotype with a international clasification criteria among a cohort of autoinflamma- not previously reported mutation in NRLC4. tory adult patients followed at a reference unit of autoinflammatory Objectives: To establish a molecular diagnosis in a patient with diseases froma thir-care centre. unreported family history of neonatal-onset enterocolitis, periodic Methods: Retrospective review of clinical and laboratory reports of a fever and arthritis, well controlled with Anakinra. cohort of 75 adult patients followed at the Autoinflammatory Diseases Methods: We report the case of a 15-year-old male patient who has Unit from Hospital Vall Hebron (Barcelona, Spain). Demographic, clinical been followed up in the pediatric rheumatology unit since the neo- and immunological laboratory data were collected. natal period. Born to non-consanguineous parents of Catalan origin, Results: The mean age of the cohort was 46 y with a female/male he had no family history of immune-mediated disorders. He required ratio 0.875. All but one patient were caucasian. admission at 3 days old due to fever, salmon-coloured macular trun- The SAIs of the cohort were as follow: FMF 33 (44%), TRAPS 9 (12%), cal rash and gastroenterological and neurological signs suggesting MKD 2 (2.6%), CAPS 10 (13.3%), PFAPA 8 (10.6%), indeterminate SAI both enterocolitis and meningitis. At an analytical level, the elevation 6 (8%) and others 7 (9.3%) including 2 Blau syndrome, 2 Schnitzler of acute phase reactants with ESR> 120 mm/h and CRP> 10 mg/dl syndrome, 1 DADA2, 1 SAVI and 1 DITRA. stood out. All microbiological tests were negative. A Sanger study The allelic variants found among the cohort were mainly monoallelic was requested for CIAS1 which was negative. Given the suspicion of in 48 (64%) cases, biallelic in 2 (2.6%) cases, double monoallelic in 9 autoinflammatory syndrome, without being able to identify the exact (12%) cases while no variant was found in 16 /21% cases (PFAPA, cause, treatment with corticosteroids was started with clinical im- Schnitzler syndrome and indeterminate SAI patients). provement. At 2 years of age, he was admitted due to arthritis in Among the 75 patients, 10 (20.1%) presented any autoimmune both hips requiring new corticosteroid treatment that could not be systemic / organ-specific autoimmune disease: 2 spondyloarthritis, 2 withdrawn due to persistent local inflammation. Finally, at 11-years- autoimmune thyroiditis, and 1 case each of ANCA-associated vascu- old, treatment with Ankinra at 100 mg/day was started with good litis, autoimmune thrombopenia, rheumathoid arthritis, AIJ, urticaria- clinical control. vasculitis and PLA2R-associated glomerulonephritis. The most preva- At 13-years-old, new DNA samples were obtained from the patient lent associated SAI was FMF (7 , 70%). and his parents and the genetic autoinflammatory disease study was Among the autoantibodies profile, 17 (22%) patients showed any widen by capturing and sequencing the flanking exonic and intronic autoantibody with 4 cases with >1 autoantiboy isolated. Antinuclear areas of the following 17 genes: MEFV, MVK, TNFRSF1A, NOD2, NLRP3, antibodies were detected in 8 patients at a titer ≥ 1/160. ANCA NLRC4, NLRP12, IL1RN, IL6RN, PLCG2, PSTPIP1, CARD14, TMEM173, antibodies and rheumatoid factor were found in 3 cases each. Anti- PSSMB8, LPIN2, CECR1 and TNFAIP3. slim muscle and anti-thyroid antibodies were found in 2 cases each The study was conducted using the SeqCap EZ HyperCap while anti-Ro52, anti-PLA2R, anti-gastric parietal cell antibodies, anti- (NimbleGen) methodology on a Illumina's MiSeq platform. CCP and direct Coombs were identified in 1 case each. The most Bioinformatic analysis was performed with the sequences obtained: prevalent SAI among autoantibody carrier patients was also FMF (6 alignment against the hg38 genome with BWA-MEM, detection of cases, 35%). changes with GATK and annotation with ANNOVAR. Changes with a No autoantibody was found in 4 out of 10 patients with diagnosis of variant/reading ratio> 0.2 wereconsidered variants. Variants identified any autoimmune condition. On the opposite point of view, 6/17 as pathogenic or probably pathogenic, as well as areas with coverage patients with autoantibodies had an autoimmune disease. <20x, were studied by capillary sequencing. The nomenclature used Conclusion: Autoimmune diseases are not so unfrequent among is the one recommended by HGVS. adult patients diagnosed with SAI of our cohort, mainly in FMF Results: The c.1015C>G p.(Leu339Val) missense variant was detected in patients, as expected for the most prevalent SAI. heterozygosis in NLRC4 NM_0212209.4, a gene intolerant to missense Positivity for any autoantibody were present among >20% of the variation (z-score=0.977). Moreover, this variant which was not found in cohort patients but the presence of autoantibodies was linked to an population database (gnomAD), was located in the NLRC4_HUMAN domain autoimmune disease in only 1/3 of cases. 'NACHT', where most of the missense variants were previously described as The coexistence on the same patient of autoimmune and pathogenic, and a change in the same aminoacid,p.(Leu339Pro), has been autoinflammatory conditions is unfrequent but not mutually recently reported in a symptomatic individual with an autoinflammation excluding. On the other hand, positivity for autoantibodies have with infantile enterocolitis (AIFEC) phenotype. Additional studies in proved in this cohort a limited value as a clue for the identification the progenitors of our patient demonstrated that it was a de novo variant. of an underlying autoimmune diesase. Taking into account all this findings and according to the classification proposed by the American College of Medical Genetics and Genomics Disclosure of Interest (ACMG) the c.1015C>G p.(Leu339Val) missense variant should be considered None Declared as a likely pathogenic variant. Conclusion: We describe a de novo mutation in NLRC4 gene encoding a Leu339Val substitution, which confirms the clinical P12 diagnosis of autoinflammation with infantile enterocolitis (AIFEC). A new autoinflammatory variation in the human domain of NLRC4 gene associated with infantile enterocolitis Disclosure of Interest 1 1 1 L. Martinez Mitjana , M. Lopez Corbeto , E. Moreno Ruzafa , E. García- None Declared 2 2 2 Arumí , E. Tizziano , M. Antolín Pediatric Rheumatology, Hospital Universitario Vall d'Hebron; Department of Clinical and Molecular Genetics, Hospital Universitario P13 Vall d’Hebron, Barcelona, Spain Recurrent fever diagnosis: a case disguised as PFAPA syndrome 1 2 1 Correspondence: L. Martinez Mitjana C. Naharro-Fernández , N. Palmou-Fontana , A. E. López- Lundh ,S. 1 3 3 Pediatric Rheumatology 2021, 20(Suppl 1):P12 Armesto Alonso , B. Jimenez-Montero , C. Alvarez-Alvarez , M. J. Cabero- Perez 1 2 Introduction: NLR family CARD domain-containing protein 4 (NLRC4) Dermatology; Rheumatology, Universitary Hospital Marques De is a key component of inflammasomes that indirectly senses specific Valdecilla; Paediatrician, Hospital Universitario Marquez De Valdecilla, proteins from pathogenic bacteria and fungi and responds by assem- Santander, Spain bling an inflammasome complex that promotes caspase-1 activation, Correspondence: C. Naharro-Fernández cytokine production and macrophage pyroptosis. Mutations in this Pediatric Rheumatology 2021, 20(Suppl 1):P13 Pediatric Rheumatology (2022) 20:2 Page 16 of 39 Introduction: Fever is a very common symptom in childhood. In the mutation in MEFV gene has been detected. We should not forget that FMF first years of life, a healthy child could have annually up to twelve could have a PFAPA-like presentation in order not to misdiagnose this en- fever episodes, especially during the cold season. In most cases, tity. Genetic test in selected patients could allow us to make the correct these episodes correspond to viral infections. However, in other diagnosis in order to improve prognosis of our patients and families. circumstances, infectious etiology is not responsible,and diagnosis becomes a challenge for the pediatrician. Disclosure of Interest Differential diagnosis of recurrent feverencompassesneoplastic None Declared processes, autoinflammatory diseases and immunodeficiencies. Keywords: Recurrent fever; Aphthae; Aphthous stomatitis PFAPA syndrome; Familiar Mediterranean Fever; FMF; MEVF P14 Abbreviations: FMF: Familiar Mediterranean Fever; MEVF: Familiar A patient diagnosed with sifd syndrome (Sideroblastic anemia with Mediterranean Fever Gene; PFAPA: Periodic Fever; Aphthous immunodeficiency, fevers, and developmental delay) Stomatitis; Pharyngitis; Adenitis A. Paç Kisaarslan, S. Ozdemir Cicek, N. Şahin, H. Poyrazoglu Objectives: Recurrent fever is common in childhood. Differential Pediatric Rheumatology, Erciyes University School of Medicine, Kayseri, diagnosis should be conducted in some patients. Autoinflammatory Turkey diseases could be responsible in some circumstances but diagnosis is Correspondence: A. Paç Kisaarslan not easy, as different syndromes could appear overlapped. We Pediatric Rheumatology 2021, 20(Suppl 1):P14 present a clinical case of a boy with recurrent fever, aphthous stomatitisand growing delay. Introduction: Immunodeficiencies with autoinflammatory diseases Methods: We present the case of a 10-year-old boy with recurrent are increasingly being defined.Clinical findings are described wide fever and aphthous stomatitis. range of system. It takes time to diagnose these syndromes. Fever He was asthmatic and he received treatment with inhaled and high acute phase reactants that cannot be explained by corticosteroids. The child had short stature with a delay in bone age infection in immunocompromised patients should suggest of nearly three years. Parents referred previous episodes of fever autoinflammatory diseases. andaphthae. Objectives: Here we present a patient with SIFD syndrome At the age of nine, he was admitted at the hospital with fever, (Sideroblastic anemia with immunodeficiency, fevers, and erosive lesion in mouth developmental delay) with hypogammaglobulinemia, anemia, and decreased intake that started three days before. growth retardation, developmental delay and autoinflammatory Physical examination highlighted multiple aphthae on oral mucosa, findings. hard palate and soft palate and cervical bilateral lymphadenopathies. Methods: Twenty Seven-month-old girl suffered from diarrhea and Blood count revealed leukocytosis and RCP of 2,9 mg/dl with a fever with high acute phase reactants for 4-month-old. Hypogamma- maximum during the hospital admission of 8,3 mg/dl.Chest globulinemia and microcytic anemia were detected at 7-month-old. radiograph showed a left lower lobe infiltrate suggesting pneumonia. Intravenous immunoglobulin (IVIG) treatment was administered, but He received amoxicillin-clavulanic acid and azithromycin.After 72 fever and diarrhea attacks were not resolved. Her colonoscopic and hours fever disappeared and oral lesion improved. biopsy findings were normal. She had growth and developmental re- Serology for herpes simplex virus and bacteria were negative. tardations at 18-month-old. Her attacks were resolved by steroid Mycoplasma pneumoniae IgM and IgG were positives. treatment. But, IL-1 blockade (anakinra) did not effect the attacks. The patient was discharged with diagnosis of mucositis cause by Her autoinflammatory panel did not show any mutations. Parents de- Mycoplasma pneumoniae. nied a further investigation. The patient was administered monthly Results: The patient continued to present additional episodes of IVIG, and low dose steroid treatment for one year. The patient was fever and oral lesions. A rheumatology study was conducted, admitted to our rheumatology department at 27-mounth old. On the showing negative immunodeficiency and autoimmunity. Despite the physical examination, height SDS:-5.26, weight SDS: -5,27 , mental fact that the patient fulfilled the diagnosis criteria for PFAPA, a and motor retardation, microcytic anemia( not sideroblastic anemia) genetic study was requested and the potentially pathogenic were detected. Her whole exon sequencing (WES) showed mutation p.Lys695Arg was detected in the gene MEFV. g.3188201_3188201 del NM_182916.2: c.679delA p.(I233fs*10) on We finally made the diagnosis of FMF in our case. Colchicina was exon 6, and K416E on exon 8 heterozygous mutations. After etaner- prescribed and the boy became asymptomatic in a few weeks. cept treatment, fever and diarrhea attacks resolved, she gained Conclusion: weight and started sitting. However, our genetical study revealed a heterozygous MEFV Results: Sideroblastic anemia with immunodeficiency, fevers, and mutations affecting to exon 10 showing that Familial Mediterranean developmental delay (SIFD syndrome:OMIM 616084) is developed fever should be considered in differential diagnosis of PFAPA. In due to mutation of the tRNA nucleotidyltransferase 1 gene. The some patients, genetic screening could help to make diagnosis of syndrome is characterized by fever, microcytic or sideroblastic autoinflammatory disease with a PFAPA-like presentation. In this hy- anemia, B cell deficiency, HLH, growth and developmental delay, pothesis underlying MEFV gene mutations possibly lead to PFAPA- cerebral atrophy, deafness and blindness, arthritis, panniculitis, oral like clinical presentation in FMF patients. ulcers, subcutaneous nodules. IL-1 and TNF blockade, IVIG, and HSCT Advances in genetic testing enable to identify genetic diseases with higher are recommended treatment of SIFD syndrome. sensibility. Clinical presentation of autoinflammatory syndromes are often Conclusion: Immune deficiencies with autoinflammatory findings are overlapped, especially in PFAFA syndrome, where an important rate of defined increasing rate. Genetic analysis is a significant diagnostic mutation in MEFV gene has been detected. We should not forget that FMF methot of these diseases. The importance of WES analysis increases could have a PFAPA-like presentation in order not to misdiagnose this en- in autoinflammatory patients who cannot be diagnosed, especially in tity. Genetic test in selected patients could allow us to make the correct the presence of accompanying signs of immunodeficiency. diagnosis in order to improve prognosis of our patients and families. Advances in genetic testing enable to identify genetic diseases with higher sensibility. Clinical presentation of autoinflammatory syndromes are often Disclosure of Interest overlapped, especially in PFAFA syndrome, where an important rate of None Declared Pediatric Rheumatology (2022) 20:2 Page 17 of 39 P15 patient (and seemingly the previously described patient carrying the Safety of anakinra in patients with Cryopyrin Associated Periodic c.2626del/p.(Ile876Leufs*15) mutation) had milder phenotype than Syndromes (CAPS) using a graduated pre-filled syringe did the other five. So far, at 7 years old, she does not present more This abstract has not been included here as it has been previously than a systemic autoinflammatory phenotype with panniculitis. published Conclusion: SAMD9L associated autoinflammatory disease is a new entity whose clinical feature overlaps with CANDLE. It is worth to be separated from CANDLE as it may predispose to early and severe complications that P16 need to be prevented. Indeed, early and severe ILD or cytopenia may A patient with candle-like phenotype and de novo frameshift justify eligibility to hematopoietic stem cell transplantation. As a treatment mutation in the SAMD9L gene concern, patients with SAAD may respond to JAK inhibiting therapies 1,2 3,4 5 5 6 A. Remy , C. Borocco , G. Sarrabay , G. Boursier , S. Fraitag ,B. despite their interferon signature may be only moderately elevated(4). The 2,7 2,8 3,9 Catteau , H. Reumaux , I. Koné-Paut functional consequences of SAMD9L gene mutations need to be clarified to Pediatric Emergency, Infectious Diseases and Rheumatology optimize targeted therapy. Department, CHU Lille; Faculté de médecine, University of Lille, Lille; (1) Torrelo A. CANDLE Syndrome As a Paradigm of Proteasome- Pediatric Rheumatology Department, CHU Bicêtre, AP-HP, Le Kremlin- Related Autoinflammation. Front Immunol 2017;8:927. 4 5 Bicêtre; University of Paris Saclay, Paris; Laboratory of Rare and (2) Insalaco A, Prencipe G, Pardeo M, et al. Involvement of the IFN- Autoinflammatory Genetic Diseases, CHU Montpellier, Montpellier; gamma pathway in a patient with candle syndrome carrying a novel Pathology Department, CHU Necker-Enfants Malades, AP-HP, Paris; variant of PSMB8 gene. Pediatr Rheumatol Online J 2014;12:P249. 7 8 9 Dermatology Department; CHU Lille, Lille; Faculté de médecine, (3) de Jesus AA, Hou Y, Brooks S, et al. Distinct interferon signatures University of Paris Saclay, Paris, France and cytokine patterns define additional systemic autoinflammatory Correspondence: A. Remy diseases. J Clin Invest 2020;130:1669–82. Pediatric Rheumatology 2021, 20(Suppl 1):P16 (4) Sanchez GAM, Reinhardt A, Ramsey S, et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Introduction: Chronic Atypical Neutrophilic Dermatosis with Clin Invest 2018;128:3041–52. Lipodystrophy and Elevated Temperature syndrome (CANDLE) syndrome belongs to a group of rare monogenic systemic Disclosure of Interest autoinflammatory diseases (SAID) also called interferonopathies. They None Declared originate in aberrant IFN production and signaling. Prototypic CANDLE syndrome is linked to recessive mutations in immunoproteasome subunits genes, e.g. subunit beta type 8 (PSMB8), affecting the P17 clearance of damaged proteins via the proteasome (1). Antiinflammatory, antioxidant and anti-atherosclerotic effects of a Objectives: To underline the interest of pursuing the investigations combination of natural supplements on patients with FMF related when both the phenotype and the genotype of a patient does not AA amyloidosis: a non-randomized 24 weeks open label come strictly within the framework of what has been previously interventional study known. This abstract has not been included here as it has been previously Methods: We report a case of a child with prominent inflammatory published and cutaneous phenotype that appeared at birth. Despite initial next generation sequencing (NGS) of a small panel of autoinflammatory genes showed an heterozygous mutation in PSMB8 gene, the patient P18 did not present typical features of CANDLE. Further genetical The effect of M694V homozygosity on the carotid intima-media investigations rescued diagnosis. thickness and flow mediated dilatation in patients with fmf related Results: The girl was born to unrelated Caucasian parents. From amyloidosis birth, she presented with urticaria that covered her face and limbs, This abstract has not been included here as it has been previously became ecchymotic, and extended to palms and soles. Since the age published of 3 months old, she developed unexplained recurrent fever (2 days long, twice a month) and painful edema of extremities without true arthritis. Blood work-up showed continuous and moderate inflamma- P19 tion during and in-between outbreaks. A diagnostic of SAID was sug- From mild to severe distinct faces of adenosine deaminase 2 gested. The patient received anakinra with partial efficacy. Skin deficiency in the single pediatric rheumatology center study biopsy showed inflammatory infiltrate in the whole dermis that was B. Sozeri, F. Demir, S. Caglayan, K. Ulu, T. Coskuner compatible with the diagnosis of CANDLE. NGS of an auto- Pediatric Rheumatology, University of Health Sciences , Istanbul, inflammatory genes panel did not find any variant with a putative Umraniye Training and Research Hospital,, Istanbul, Turkey pathogenic role notably in the NLRP3-associated autoinflammatory Correspondence: B. Sozeri syndrome and mevalonate kinase deficiency. However, it showed Pediatric Rheumatology 2021, 20(Suppl 1):P19 one heterozygous p.(Thr74Ser) variant in the PMSB8 gene (2). Despite the fact that our patient had prominent inflammatory and cutaneous Introduction: Deficiency of adenosine deaminase 2 (DADA2) is an phenotype, the constellation of criteria was incomplete and atypical autosomal recessive disorder characterized by poliarteritis nodosa- for CANDLE syndrome. First, her skin examination by an experienced like symptoms, fever, livedoid racemose, early-onset stroke and mild dermatologist did not show lipodystrophy. Then, other marked differ- immunodeficiency. The loss-of-function mutations in CECR1 gene ences were the absence of hepatomegaly, of cytopenia, and the which encodes the enzymatic protein adenosine deaminase 2 mildly elevated interferon signature. There was more than met the (ADA2) associated with the DADA2. eyes. Genetic analysis was pursued with whole exome sequencing re- DADA2 is present with a spectrum of vascular and inflammatory vealing a de novo frameshift variant p.(Ile876Leufs*15) in the Sterile phenotypes with highly varied clinical expression. The patients Alpha Motif Domain–containing protein 9-Like (SAMD9L) gene. Treat- can present with isolated constitutional symptoms, arthralgia, ment switch with JAK inhibitor (baricitinib) finally enabled a clear myalgia, and/or livedoid rash. The severe phenotype of the skin improvement. disease is emerge as early-onset stroke, bone morrow suppres- In a recent study, SAMD9L mutations were identified in six patients sion, neutropenia, liver failure and/or neurologic disorders It is among twelve with CANDLE-like phenotype (3). The overall pheno- currently not well understood what cause the variability in the type of patients is very severe as two out of six patients are deceased severity of clinical phenotype. at an early age and two other patients underwent bone marrow Objectives: We aim to describe the clinical characteristics, genotype transplantation for severe cytopenia or interstitial lung disease. Our and treatment of patients diagnosed with DADA2 in our clinic. Pediatric Rheumatology (2022) 20:2 Page 18 of 39 Methods: All the patients diagnosed and followed up in Department 390, 30.4%), persistence of disease activity frequent attacks (n= of Pediatric Rheumatology, Umraniye Training and Research Hospital, 44, 47.3% and n=1,023, 79.9%) and/or uncontrolled inflammatory Istanbul, Turkey, between 2016 and 2020. All symptomatic patients syndrome (n=46, 49.5% and n=398, 31.1%), and worsening in pa- suspected with DADA2 were analyze by genetic test and ADA-2 en- tients' quality of life (n=36, 38.7% and n=100, 7,8%). No rea- zyme activity, also relatives of index cases were also screened. ADA-2 sons were specified for 12 (16.4%) JIR cohort patients and 154 enzyme activity was evaluated at Duke University Medical Center. (12%) patients in the literature. Results: We diagnosed 10 patients with DADA2, 5 of them had mild Conclusion: In the absence of standardized indications for IL1 phenotype or asymptomatic, or they were relatives of index cases, and inhibitors in crFMF, MKD and TRAPS, these results could serve as a 5 of the patients had severe phenotype. Three of the patients were basis for developing a standardized composite score that would help girls and seven were boysThe age of the patients at diagnosis was in clinicians to assess the activity and severity of HRF at a specific time the range of 2–28 years. The age of the patients at disease onset was point in order to evaluate the need of a therapeutic escalation with also in the range of 2 months–14 years. Six of the patients were index IL-1 inhibitors. cases and the other four were their relatives. Homozygous mutations in CECR1 were shown in all subjects.The frequency of phenotypic Acknowledgments manifestations of the patients were seen as follow respectively; fever 80%, livedoid rash 70%, digital ulsers and/or amputations 20%, keywords : hereditary recurrent fevers, indications, interleukin-1 neurologic involvement 50%, gastrointestinal involvement 20%, blocking agents, anakinra, canakinumab hematological involvement 40%, and immunodeficiency 30%.The initial diagnosis of index cases were as follows; two classic PAN, one cutaneos Disclosure of Interest PAN, one Behçet’s disease and two Diamond Blackfan syndrome. The None Declared activity of ADA2 was evaluated and clearly diminished in all patients (0- 12.1 mU/g protein). 6 of the 10 patients were treated with anti-tumor necrosis factor therapy.Two patients were awaiting bone marrow P21 transplantation. Dysregulation of MIR-505-5P which targets CYP3A4 in colchicine- Conclusion: The clinical manifestations of DADA2 vary from mild skin resistant familial mediterranean fever patients 1 1 1 2 3 involvement to severe multisystemic vasculitis. It is suggesting that T. H. H. Akbaba , B. S. Ozdemir , Y. Z. Akkaya-Ulum , P. Mutlu , S. Ozen , both residual ADA2 activity levels and gene mutation are important B. Balci-Peynircioglu 1 2 in clinical phenotype. Medical Biology, Hacettepe University, Middle East Technical University, Hacettepe University, Ankara, Turkey Disclosure of Interest Correspondence: T. H. H. Akbaba None Declared Pediatric Rheumatology 2021, 20(Suppl 1):P21 Introduction: Familial Mediterranean Fever (FMF) is an autosomal P20 recessive inherited autoinflammatory disease. The well-known treat- Real-life indications of interleukin-1 blocking agents in hereditary ment of the disease is daily colchicine uptake. However, approxi- recurrent fevers: data from the jircohort and a literature review mately 5% of patients do not respond to colchicine treatment 1 2 3 4 C. Vinit , S. Georgin-Lavialle , A. Theodoropoulou , S. Atmane ,C. despite using the highest tolerable colchicine. In addition to colchi- 5 6 3 3 7 8 Barbier , A. Belot , F. Hofer , M. Mejbri , P. Pillet , J. Pachlopnik ,S. cine treatment, these patients receive anakinra, canakinumab, and 9 7 10 4 1 Poignant , C. Rebelle , A. Woerner , I. Kone-Paut , V. Hentgen similar drugs to prevent inflammation. 1 2 3 Versailles hospital, Versailles; Tenon hospital, Paris, France; Lausanne Objectives: This study aims to investigate the potential impact of University Hospital, Geneva, Switzerland; Bicetre University hospital, miRNAs on drug resistance observed in FMF patients. 5 6 Kremlin Bicetre, Grenoble Hospital, Grenoble; Lyon University hospital, Methods: Microarray data obtained in our previous studies was re- 7 8 Lyon; Bordeaux University hospital, Bordeaux, France; Kinderspital, evaluated for colchicine-resistant patients with severe phenotype 9 10 Zurich, Switzerland; Nantes University hospital, Nantes, France; UKBB and candidate miRNAs that are involved in drug metabolism were Hospital, Bâle, Switzerland determined by performing bioinformatics analysis. miRNA-target Correspondence: C. Vinit gene studies were performed and miRNAs which have a role in the Pediatric Rheumatology 2021, 20(Suppl 1):P20 mechanism of drug resistance in FMF were determined. Then, 3'UTR luciferase activity experiments were carried out to determine the tar- Introduction: Interleukin (IL)-1 inhibitors represent the main get gene. Then, target gene expression studies were performed. treatment in patients with familial Mediterranean fever (and Results: As a result of miRNA array analysis, miR-186-3p, miR-548a- colchicine resistance or intolerance, crFMF), mevalonate kinase 3p, miR-7-5p were decreased, miR-505-5p and miR-4482-3p were in- deficiency (MKD) and periodic tumor necrosis factor receptor-related creased in colchicine-resistant familial Mediterranean fever patients. syndrome (TRAPS). However, the reasons for use of IL-1 inhibitors in miR-505-5p was found as a regulator of drug metabolism and drug these diseases are still unclear. resistance-related genes by bioinformatical tools and validated by Objectives: Identify real life situations that led to use anakinra or qRT-PCR. Target gene studies performed in HEPG2 cell (hepatocellu- canakinumab in hereditary recurrent fevers (HRF), combining data lar carcinoma cell line) showed that miR-505-5p regulates CYP3A4 ex- from an international registry, the JIR cohort, and an up-to-date lit- pression at the RNA level. MiR-505-5p – CYP3A4 interaction was erature review. shown by 3’UTR luciferase assay. Methods: We extracted data from a web-based registry: the JIRco- Conclusion: Functional analyzes related to colchicine metabolism are hort, in which clinical information (demographic data, treatment, dis- underway. A possibly explanation about drug resistance observed in ease activity and quality of life) on patients with FMF, MKD and complex FMF patients through miRNAs will allow the development TRAPS was collected retrospectively. A literature search was con- of new drug targets for these patients in the future. ducted using Medline and EMBASE. Results: We analyzed complete data of 93 patients with HRF Acknowledgments (53.8% FMF, 31.2% MKD and 15.1% TRAPS). Data from both the This project has been funded by The Technical and Scientific Research registry and the literature review confirmed that the main Council of Turkey, 218S522. reasons for use of IL-1 blockers were: failure of previous treat- ment (n=57, 61.3% and n=964, 75.3% respectively), severe disease Disclosure of Interest complication or associated comorbidities (n=38, 40.9% and n= None Declared Pediatric Rheumatology (2022) 20:2 Page 19 of 39 P22 increasing interactions between the NLRP3 and NEK7 proteins, An atypical periodic fever syndrome due to a mutation in the thereby lowering the threshold required for NLRP3 inflammasome leucine rich repeat domain of NLRP3 activation. 1 1 1,2,3 1 E. A. Caseley , J. Topping , S. Savic , M. F. McDermott Leeds Institute of Rheumatic and Musculoskeletal Medicine, St James's References University Hospital; Department of Clinical Immunology and Allergy, St 1. Nakanishi H, Kawashima Y, Kurima K, Muskett JA, Kim HJ, Brewer CC, James’s University Hospital; National Institute for Health Research–Leeds et al. Gradual symmetric progression of DFNA34 hearing loss caused by Biomedical Research Centre, Chapel Allerton Hospital, Leeds, United an NLRP3 mutation and cochlear autoinflammation. Otology & Kingdom neurotology: official publication of the American Otological Society, Correspondence: E. A. Caseley American Neurotology Society [and] European Academy of Otology and Pediatric Rheumatology 2021, 20(Suppl 1):P22 Neurotology. 2018;39(3):e181. 2. Meng G, Zhang F, Fuss I, Kitani A, Strober W. A mutation in the Nlrp3 Introduction: Gain-of-function mutations in the NLRP3 inflamma- gene causing inflammasome hyperactivation potentiates Th17 cell- some cause NLRP3-associated autoinflammatory diseases (NLRP3- dominant immune responses. Immunity. 2009;30(6):860-74. AIDs); these mutations are rarely located in the leucine rich repeat 3. Medvedeva IV, Stokes ME, Eisinger D, LaBrie ST, Ai J, Trotter MW, et al. (LRR) domain. Here we present a patient with a c.2753 G>A variant Large-scale analyses of disease biomarkers and apremilast pharmacody- in NLRP3 exon 7, resulting in the Arg918Gln (R918Q) mutation in the namic effects. Scientific reports. 2020;10(1):1-11. LRR domain of NLRP3(1), causing oral ulcers and hearing loss; she 4. He Y, Zeng MY, Yang D, Motro B, Núñez G. NEK7 is an essential mediator was significantly less responsive to anakinra treatment compared to of NLRP3 activation downstream of potassium efflux. Nature. previously reported cases of this mutation but has responded well to 2016;530(7590):354-7. apremilast, a phosphodiesterase 4 inhibitor. Objectives: We aimed to identify molecular mechanisms contributing Acknowledgments to this patient’s unusual disease presentation and response to This project has received funding from the European Union’s Horizon 2020 treatment, in addition to characterising changes in protein-protein in- research and innovation programme under the grant agreement No: 779295 teractions caused by the R918Q mutation. Methods: We isolated CD14+ monocytes from the patient or three Disclosure of Interest healthy controls (HCs) and analysed cell responses after NLRP3 None Declared stimulation using RT-PCR, ELISA or flow cytometry. Monocytes were also differentiated into M0, M1 or M2 macrophages, from which RNA was isolated and used for RNA sequencing (RNA-seq). Interactions P23 between NLRP3 and NIMA-related kinase 7 (NEK7) were analysed in SAA1 Polymorphisms contribute more than mefv mutations in silico using PDBePISA and PyMOL, combined with immunoprecipita- renal AA-amyloidosis -preliminary results 1 2 tion and subsequent immunoblotting studies in HEK293T cells trans- D. Ait-Idir , B. Djerdjouri fected with NLRP3 and NEK7. Biology, Faculty of sciences, University M'hamed Bougara, Boumerdes; Results: Elevated IL-1β release was seen in patient’s monocytes when Faculty of Biological Sciences, University of Sciences and Technology unstimulated or stimulated with a priming stimulus alone compared Houari Boumediene, Algiers, Algeria to the HCs, a hallmark of NLRP3-AIDs. This was accompanied by a sig- Correspondence: D. Ait-Idir nificant increase in IL-18 release in response to NLRP3 stimulation in Pediatric Rheumatology 2021, 20(Suppl 1):P23 the patient’s cells and elevated IL-6 in patient serum. Extracellular ASC specks, pivotal components of the NLRP3 inflammasome, were Introduction: Renal AA amyloidosis can develop with a high also more readily released by the patient’s monocytes. Transcrip- prevalence in untreated patients with familial Mediterranean fever tomic profiling of NLRP3-R918Q macrophages showed similar M1 (FMF, OMIM 249100). The MEFV and SAA1 genotypes are the two and M2 macrophage genotypes in patient’s cells compared to HCs, genetic risk factors that have been associated with the development suggesting impaired mucosal tissue healing by M2 macrophages, of this serious complication. which may contribute to the patient’s persistent oral ulcers. KEGG en- Objectives: This study aimed to evaluate the involvement of each richment analysis further showed significant enrichment of inflamma- genetic factor in the occurrence of renal AAamyloidosis. tory pathways, particularly the IL-17 and NF-kB signalling pathways. Methods: Sixty-two unrelated Algerian FMF patients were included Upregulation of IL-17 indicates a skewing of T-helper responses to- in this study. Among them, 41 (19 men, 22 women; mean age: 36.26 wards a Th17 phenotype, as previously observed in NLRP3-AIDs(2), in ± 14.43 years) with biopsy-confirmed AA amyloidosis were recruited addition to IL17A and NF-kB being a biomarker for apremilast effi- from the nephrology departments, and 21 (9 men, 12 women; 33, 80 cacy(3), partly explaining this patient’s unusual response to therapy. ± 14, 71 years) without renal complications came from the internal Molecular characterisation of the R918Q mutation was also carried medicine departments. out, using the recently determined cryo-electron microscopy struc- Sixty-two unrelated Algerian FMF patients were included in this ture of NLRP3 in complex with its endogenous regulator, NEK7(4). study. Among them, 41 (19 men, 22 women;mean age: 36.26 ± 14.43 The R918Q mutation was shown in silico to increase the electrostatic years) with biopsy-confirmed AA amyloidosis were recruited from the complementarity between the NLRP3 LRR domain and the interact- nephrology departments,and 21 (9 men, 12 women; 33, 80 ± 14, 71 ing interface of NEK7. This was confirmed by co-immunoprecipitation years) without renal complications came from the internal experiments; cells transfected with the mutant NLRP3-R918Q showed medicinedepartments. increased binding to NEK7 compared to WT NLRP3. Results: Screening of the MEFV gene revealed a significant Conclusion: Here we show that the NLRP3-R918Q mutation causes correlation between the M694I/M694I genotype and renal an atypical periodic fever syndrome with significant mucosal amyloidosis. The genotypes of the SAA1 locus were differentially involvement. The involvement of factors such as a Th17 phenotype, distributed between the two groups of patients. A significant in addition to increased NLRP3 inflammasome activity, go some way predominance of SAA1.1/1.1 genotype was found in patients with to explaining the lack of efficacy of anakinra treatment. We propose amyloidosis, compared to those without this complication (p=0.001), that the R918Q mutation enhances NLRP3 inflammasome activity by while the SAA1.5/1.5 genotype was exclusively associated with Pediatric Rheumatology (2022) 20:2 Page 20 of 39 P25 patients without amyloidosis. Logistic regression analysis for the risk Patient Engaged Genomic Understanding and Interpretation of development of amyloidosis revealed a 4.3times increase in risk in (PENGUIN): a case study in patients with Familial Mediterranean the M694I/M694I genotype (95% CI 1,35 – 14). However, this risk Fever (FMF) increases eight times in presence of the SAA1.1/1.1 genotype (OR 1 1 1 1 2 3 K. A. Maloney , M. Giglio , H. Zhang , L. Jeng , D. Sewell , N. Ambulos , 8.7; 95% CI 2.25 – 33). 1 1 1 1 4 A. Beitelshees , E. Streeten , D. Loesch , N. Sampaio Moura , N. Dueker , Conclusion: Our preliminary results based on a small cohort of FMF 1 5 6 1 7 1 K. Palmer , R. Gore , S. Kittner , T. O'Connor , J. Jagger , T. Pollin ,S. patients suggest that genotypes at the SAA1 locus may predispose Riley more than genotypes at the MEFV locus to the occurrence of renal 1 2 3 Medicine; Translational Genomics Laboratory; Microbiology and AA amyloidosis. Immunology, University of Maryland School of Medicine, Baltimore; 4 5 University of Miami Miller School of Medicine, Miami; Pediatrics; Acknowledgments Neurology, University of Maryland School of Medicine, Baltimore; We thank the physicians for their contribution in patients recruitment. Familial Mediterranean Fever Foundation, Barboursville, United States Correspondence: K. A. Maloney Disclosure of Interest Pediatric Rheumatology 2021, 20(Suppl 1):P25 None Declared Introduction: Many patients with FMF are motivated to seek genomic information not available through their medical providers. P24 We explored a novel solution providing patients with direct access to Is interferonopathy caused nasal perforation in a patient with their genomic data while mitigating adverse consequences of nijmegen breakage syndrome ? misinformation arising from some direct-to-consumer genetic testing. S. S. Kilic Objectives: To meet patients’ objectives for informed access to Pediatric Rheumatology, Uludag University Medical Faculty, Bursa, Turkey genomic data by providing them with their own exome sequence in Pediatric Rheumatology 2021, 20(Suppl 1):P24 the setting of a professionally administered genomics educational workshop. Introduction: Nijmegen breakage syndrome (NBS) is a rare Methods: Thirty-two adults, residing in the U.S. or Canada were re- autosomal recessive disorder of chromosomal instability. It is cruited via email from the FMF Foundation. All provided medical characterized by short stature, microcephaly, a typical facial documentation of clinical and/or molecular diagnosis of FMF. Follow- appearance, immunodeficiency, radiation sensitivity, and a strong ing informed consent, saliva samples underwent clinical exome se- predisposition to lymphoid malignancy. NBS is caused by a mutation quencing and data were filtered to analyze variants in 30 auto- in the NBS1 gene, located at human chromosome 8q21. inflammatory (AI) genes and 59 clinically significant genes (“second- Objectives: We present a case with NBS suspected having ary findings”) deemed actionable by the American College of Medical interferonopathy Genetics and Genomics (ACMG). Participants were informed of Methods: A 14 years old girl was first admitted to our pathogenic and likely pathogenic variants in AI and ACMG genes, outpatient clinic with the complaint of perforated nasal septum, and variants of unknown significance (VUS) in AI genes. They also re- chronic otitis externa and persistent skin lesions. There was a ceived their raw exome data files. An educational workshop featured parental consanguinity. Nasal septum perforation occurred at 10 eight sessions on general genetics, personal data exploration using years of age. Physical examination revealed; weight: 38 kg (< GenomeBrowse, pharmacogenomics, and AI diseases. Participants 3P), height: 136 cm (<3P), microcephaly, crepitation in both completed surveys before and two weeks after the workshop (e.g., lung bases, ulcerated lesion below the right eye and from right FMF disease severity, health numeracy, genomics knowledge, health upper lip extending to the nasal septum which was perforated. literacy, self-efficacy). While total blood count, erythrocyte sedimentation rate, IgG, Results: The PENGUIN workshop was held virtually on November 20- IgG1, IgG3, IgA, IgE, NBT were normal, serum IgM <16,9 mg/dl 21, 2020, utilizing Zoom and Slack. Participants’ ages were from 24- (88-322 mg/dl) and IgG2: 183 mg/dl (236-605 mg/dl) levels 74, 63% were female, and 84% had university degrees. They had were low. Lymphocyte subsets were normal except for slight high numeracy and genomic literacy. Twenty-two (69%) participants low CD8 (16.3%, 489/mm ). Antibody responses (anti HBS and had prior MEFV genetic testing, including one who had research- tetanus IgG) were negative. HLA ABC expression by flow based exome sequencing. PENGUIN testing detected all previously cytometry was 99 % (MFI:13669). Histologic analysis of a nasal reported disease-associated MEFV variants; however, three variants septum biopsy was unhelpful, revealing only a nonspecific were reclassified as VUS. Molecular diagnosis was newly confirmed in polymorphic inflammatory infiltrate without perivascular six individuals with a prior clinical diagnosis of FMF. Eighteen partici- distribution and an absence of vasculitis or granulomatosis. PPD pants harbored 28 VUS in 14 AI genes; some of these may be risk was15x17mm, quantiferon measurement test and sputum variants as part of a complex etiology. Only VUS were found in five culture were negative. Tests for leishmaniasis ere negative. participants. Two individuals had secondary findings. Immediate Thorax CT showed bronchiectasis in the middle lobe of right feedback from the workshop was extremely positive, with partici- lung. A homozygous JL2494 – NBN exon 3 mutation was found pants expressing strong appreciation for the opportunity to receive by kindly Anne Puel's lab. Nijmegen breakage syndrome was comprehensive genetic results, understand and explore their gen- diagnosed. The patient commenced on IVIG treatment. Stem omic data, and interact with FMF patients, scientists and clinicians in cell transplantation has been planned. a collegial manner. Conclusion: It has been showed that type I and III IFN signatures Conclusion: The genetic findings across the AI spectrum confirmed were elevated in patients with AT, Artemis deficiency, and SAVI. FMF patients’ perceptions of the paucity of genetic information Although cutaneous granulomas have been reported in patients with through their medical providers, validating their incentive to seek NBS but interferonopathy has not been reported. We believe that, genetic testing outside of the medical system. As the cost of more information is needed on this issue. genomic sequencing decreases, the PENGUIN model of patient engagement may be a valuable method for meeting FMF and other Disclosure of Interest rare genetic disease patients’ legitimate quest for access to None Declared Pediatric Rheumatology (2022) 20:2 Page 21 of 39 comprehensive genomic data and knowledge. This inaugural group c.1991T>C (p.Met662Thr). No NLRP3 mutation was detected in the of FMF patients was engaged and capable, and future studies will patient’s parents. The mutation had previously been described in need to assess the wider uptake and success of such a program. two cases of severe NLRP3-AID. Canakinumab was started at a dose of 150 mg every 2 months, but neurologic deterioration prompted a Acknowledgments switch to anakinra 100 mg daily after a few months. The latter We would like to thank the participants of the PENGUIN workshop and allowed clinical stabilization as well as normalization of cerebrospinal funding from the University of Maryland Dean's Challenge Grant. fluid analysis and inflammatory markers. The proband displayed unique manifestations of NLRP3-AID, namely the absence of an Disclosure of Interest urticaria-like rash and peripheral eosinophilia with organ infiltration, None Declared as well as prominent serositis. Conclusion: In summary, we hereby report a case of severe NLRP3- AID with peripheral and tissue eosinophilia and prominent serositis, P26 but lacking urticaria. As a result, the absence of an urticarial rash An atypical presentation of NLRP3-associated autoinflammatory should not curtail a diagnosis of NLRP3-AID in patients with other disease compatible manifestations. Furthermore, the association of autoin- 1 2 3 L. Marois , S. Ducharme-Bénard , H. Chapdelaine flammatory features and eosinophilia should raise suspicion for this 1 2 Institut de recherches cliniques de Montréal, Internal Medicine, Hopital diagnosis. du Sacré-Coeur de Montréal, Immunologie, Institut de recherches cliniques de Montréal, Montréal, Canada Disclosure of Interest Correspondence: L. Marois None Declared Pediatric Rheumatology 2021, 20(Suppl 1):P26 Introduction: NLRP3-associated autoinflammatory diseases (NLRP3- P27 AID) are rare genetic autoinflammatory diseases associated with Unravelling clinical and genetic spectrum of Mevalonate Kinase gain-of-function mutations in NLRP3 coding for cryopyrin. We hereby Deficiency (MVKD) in Libya 1 1,2 report a case with unique manifestations of NLRP3-AID. A. A. Abushhaiwia , Y. Yusra AElfawires Results: A 36-year-old French Canadian male presented with a 3- Paediatric Rheumatology, faculty of Medicine, Tripoli university ,Tripoli week history of left knee arthritis and systemic inflammation (neutro- children's hospital; paediatric Rheumatology , faculty of Medicine, philia, microcytic anemia, thrombocytosis, elevated C-reactive protein Tripoli university, Tripoli children's hospital , Tripoli , Libya (208 mg/L), and erythrocyte sedimentation (94 mm/h). Joint aspir- Correspondence: Y. Yusra AElfawires ation revealed 161 500 white blood cells/ml with 91% neutrophils, Pediatric Rheumatology 2021, 20(Suppl 1):P27 low glucose level, elevated lactate, and negative gram stain. Despite treatment with cefazolin then meropenem and repeated arthroscopic Introduction: Hyper-IgD syndrome (HIDS, MIM #260920 and MIM joint drainages for suspicion of septic arthritis, no improvement was #610377) is a rare spectral autosomal recessive autoinflammatory dis- noted after one week. Synovial fluid and blood cultures returned order caused by mutations in the mevalonate kinase (MVK) gene. negatives. At that point, an underlying inflammatory disorder was HIDS share similar phenotype to the others hereditary periodic fever suspected. Antibiotics were discontinued and oral prednisone was in- syndromes (HPFS), which include: recurrent fever, lymphadenopathy, troduced, with prompt improvement in inflammatory markers and hepatomegaly, rash, arthritis, abdominal pain. Specifically increased knee swelling. Work-up for autoimmune diseases revealed negative levels of biomarkers related to acute inflammation like serum amyl- anti-nuclear antibodies and anti-cyclic citrullinated peptide anti- oid A (SAA), C-Reactive Protein (CRP) is also a common finding to all bodies, normal complement levels, positive rheumatoid factor, and HPFS. Serum levels of immunoglobulin D (IgD) is not a specific find- HLA B27 antigen. Screening for viral hepatitis, human immunodefi- ing as it can also be present in other syndromes as PFAPA. A ciency virus, tuberculosis, streptococcal infection, and Lyme disease more specific feature, the aciduria mevalonica, can be found in the was negative. Radiographs of axial and peripheral joints were unre- severe spectrum of patients with the deficiency of mevalonate kin- markable, apart from a right knee effusion that also responded to ase. The clinical presentation largely depends on the residual activity steroid therapy. One week later, the patient complained of chest of mevalonate kinase ranging from virtually undetectable to a range pain, with a concomitant increase in inflammatory markers. Imaging of unfunctional but detectable levels. Due to decreased level of revealed a right loculated pleural effusion. Pleural liquid revealed low mevalonate kinase, RhoA remains unprenylated and increases the se- pH, elevated proteins, elevated LDH, and undetectable glucose level, cretion of pro-inflammatory cytokines such as IL-1β that results in despite a surprisingly low white blood cell count and negative gram the development of the cardinal autoinflammatory symptoms. Rarity stain. Antibiotics were resumed for suspected complicated parapneu- of the disease and lack of genetic testing for confirmation makes monic effusion, and the dose of prednisone was halved. Pleural bac- diagnosis challenging in Libya and in other middle-income coun- terial, fungal, and mycobacterial cultures eventually came back tries. Interestingly colchicines do not prevent attacks, anti-TNF has a negative. Antibiotics were nevertheless continued for a total of 4 variable effect and only anti-IL1 is effective. weeks. Prednisone was also continued at 20 mg daily. Upon dis- Objectives: To report for the first time the clinical and genetic charge, knee synovitis and pleural effusion had resolved, and C- findings in two patients from Libya. reactive protein had decreased to 105 mg/L. Methods: We retrieved clinical data from patient’s records. Genomic Family history was unremarkable, with no consanguinity. On the DNA was isolated from peripheral blood and a target gene panel other hand, the patient had a personal history of aseptic meningitis with all the 5 genes already known to be related to the HPFS was at 2 years, sensorineural deafness, seronegative juvenile idiopathic performed. arthritis (history of recurrent fevers with flares of arthritis and high Results: Case report inflammatory markers), pericarditis requiring drainage at 6 years, as An 11-year-old Arab Libyan girl, born of un-consanguineous parents. well as a global developmental delay whose investigation by She has been evaluated, managed and admitted several times since cerebral CT scan revealed diffuse atrophy and pseudopapilloedema. the age of 50 days, without reaching a specific diagnosis. She pre- Also, the investigation of failure to thrive has demonstrated sented to our Rheumatology clinic in January 2013, at age of 2 years eosinophilic enteropathy. and has been followed since. Presenting with recurrent attacks of In light of the long-standing history of sensorineural hearing loss, fever (reaching 40.3°C), lasting 3-5 days, every 2–8 weeks accompan- physical and mental developmental delay, intermittent serositis, and ied by oral aphthae, abdominal pain and diarrhea. Associated with elevated inflammatory markers, NLRP3-AID was suspected. DNA ana- headache, abdominal pain, nausea, and vomiting frequently. Cervical lysis by next-generation sequencing (NGS) revealed a heterozygous LAP was almost always present in attacks. Leukocytosis (15,000mm3- mutation in exon 3 encoding the NACHT domain of the NLRP3 gene, 26, 000mm3), increased ESR and CRP (50 100mg/L), the remaining Pediatric Rheumatology (2022) 20:2 Page 22 of 39 variables were normal.IgD levels were normal (37mg/dL), negative Leu27Pro) were associated with severe clinical phenotypes com- urine movalenate kinase and elevated SAA (initially 2mg/L, later 199 pared with mutations with decreased or unchanged protein mg\L and currently 5mg/L). Initially, attacks were occurring every 3 expression. weeks, but frequency decreased as the child grew. Last year one at- Objectives: we report for the first time DITRA in a Libyan child. We tack occurred every 2-3 months. The diagnosis of FMF or HIgD syn- also briefly discuss potential provisional therapeutical interventions drome was entertained initially and she was put on colchicines. for the treatment of this rare disorder in middle income countries However, she continued to have recurrent attacks despite high doses where neither anti-IL1 nor anti-IL12/23 are available. (1.5 mg) of daily colchicines. Methods: We retrieved clinical data from patient’s records. Genomic Her 5-year-old sister (P2) had similar symptoms since the age of 2 DNA was obtained from peripheral blood. A direct sequencing of the years clinically characterized by recurrent attacks of fever that coding exons and the flanking splice signals of the IL36RN gene was reached as high as 40.3°C associated with oral ulceration, joint pain performed using standard procedures. and enlarged cervical lymph nodes. Headache, abdominal pain, nau- Results: Case Report sea, and vomiting, similar to P1, were also present in some of the at- A 4 year-old Arab Libyan boy, born from non-consanguineous par- tacks. The initial attacks were occurring as frequently as every 3 ents came to our attention due to a suspicion of a systemic autoin- weeks. Laboratory investigation during attacks revealed mild anemia. flammatory condition. Of note, the index patient had two (Haemoglobin as low as 10.3 g/l) during the attacks with platelets healthy brothers and an uncle diagnosed with psoriatic arthritis. At were within normal limits, white blood cells count were as high as the age of 2 years recurrent and severe episodes of generalized 24,400 always with fluctuant levels of acute reactant markers as pustular psoriases requiring many hospital admissions started. Ini- erythrocyte sedimentation rate (ranged from 40 to 80 mm/h). She tially, he was managed as of pustular psoriasis after a 6-month his- was put on colchicines but it did not achieve clinical control. Familial tory of appearance. Skin lesions were characterized by diffuse pedigree reconstruction allowed the suspicion of a recessive disorder pustules involving cheeks, perioral area associated with mouth ul- and due to a suspicion of an inborn error of immunity a target gene cers. A rapidly progression of his condition could be observed char- panel was performed (MEFV, NRLP3, MVK, TNERS1A). Curiously a het- acterized by worsening of general condition and generalization of erozygous mutation in exon 11 of the mevalonate kinase (MVK) gene the rash over different body parts. Other clinical pictures fre- variant c.1129GA and a premature stop codon c.2T>A, p.met1?. quently observed was fever; psoriatic nail changes (e.g. Pitting and Therefore the clinical and diagnosis of MVK was established for the 2 onychomadesis) and ichthyosis altogether with joint involvement children. We surrogated that the other mutation was missed in P1 limiting his activity. Rash became severe with discharging pus- and genetic sequencing in P1 is ongoing to confirm the other variant tules and failure to thrive could be observed. At his admission, wide- found in P2. spread presence of scaly erythematous plaques with pinhead Conclusion: Here we report for the first time HIDS in Libya and we pustules involving the scalp, face, extremities, torso, and buttocks. highlight red flags for the suspicion of such a specific disorder in The palms and soles were also affected. Nail pitting and onycho- children with recurrent fever. We also demonstrate the importance madesis. Marked hypertrichosis was also noted. At his admission of genetic analysis for the final diagnosis as well as the right genetic a complete blood count demonstrated anemia HGB 8.1 g\dl and evaluation in such a complex clinical scenario. Besides, the leukocytosis.However, during febrile episodes the patient’swhite prevalence of hereditary autoinflammatory diseases remains blood cell count increased to 17,000/ll with neutrophilia of 92%, unknown in Libya. ESR 50mm\h, and elevated CRP 20mg\dl level. No other condition, such as infection, could be observed over the time. A skin biopsy Acknowledgments demonstrated parakeratosis, spongiosis, and psoriasiform acantho- I would like to extend my appreciation and thanks to Dr Leonardo Oliveira sis, We could also observe an elevated level of vitamin B12 757.90 Mendonca to revising this manuscript pg\ml(reference range). Due to a suspicion of a systemic autoin- flammatory condition, a genetic sequencing was requested. A Disclosure of Interest homozygous already described mutation in the IL36RN was None Declared found (c.80T>C; .pLeu27Pro), thus confirming the diagnosis of DITRA.Once neither anti-IL1 (anakinra) neither anti-Il12/23 (secuki- numab) is available in Libya , high doses of systemic steroids was P28 initiated and could achieve clinical control. In order to avoid pro- Deficiency of Interleukin-36 Receptor Antagonist deficiency longed use of steroids, the patient’s dose was gradually tap- (DITRA) with C.80T>C (P. LEU27PRO) mutation: report of the first pered. However, cutaneous exacerbation could be observed and an Libyan child steroid spared agent, methotrexate, at a dose of 7.5 mg once per 1 2 3 A. A. Abushhaiwia , Y. AElfawires , N. Alhouni week was therefore added. Under this treatment, the patient pro- Paediatrics Department, Faculty of Medicine, Univeristy of Tripoli,Tripoli gressed towards a good general condition. However, there Children Hospital; Paediatrics Department, Faculty of Medicine, wasn’t complete improvement of his skin rash neither control of University of Tripoli, Tripoli Children Hospital; Dermatology Department, the febrile episodes. Tripoli Central Hospital, Tripoli, Libya Conclusion: DITRA is a rare disease that has to be considered in GPP Correspondence: A. A. Abushhaiwia with systemic inflammation and fever. Increased awareness of this Pediatric Rheumatology 2021, 20(Suppl 1):P28 distinct type of GPP caused by mutations in IL36RN is of major importance for future potential therapy directed at the IL36RA protein. Introduction: Loss-of-function mutations along the IL36RN gene defines a recently described recessively inherited autoinflamma- Acknowledgments: tory syndrome named deficiency of IL-36 receptor antagonist Disclosure of Interest (DITRA). This genetically determined deficiency was first described None Declared in a subgroup of patients with generalized pustular psoriasis. It is a life-threatening condition characterized by recurrent episodes of severe skin inflammation, with pustule development, associated P29 with fever, malaise, extracutaneous involvement, neutrophilia and An early onset of skin rash: a case of 4-month-old infant 1 2 1 1 1 a marked acute phase response. Recently there was a possible A. Mauro , O. Francesca , G. Antonietta , M. Rosa , A. Sabrina ,A. 1 1 1 1 1 genotype and phenotype correlation regarding disease severity. It Francesca , D. Carolina , M. Stefania , S. Esposito , V. Tipo 1 2 was surrogated whether the presence of mutations that Emergency Department; Pediatrics, Aorn Santobono-Pausilipon, Naples, accounted for critical protein expression could be associated to Italy severe DIRA phenotypes observed. At least, 10 null mutations Correspondence: A. Mauro with complete absence of the IL36RN antagonist (eg, c.80T>C/p. Pediatric Rheumatology 2021, 20(Suppl 1):P29 Pediatric Rheumatology (2022) 20:2 Page 23 of 39 Introduction: Dermatological diseases are a challenge for then, 2 weeks later, by low-grade evening fever (up to 37.5 °C). The pediatricians. The skin is often involved in monogenic rash was mildly pruritic. Since the second day after rash onset, she autoinflammatory syndrome with a wide range of cutaneous lesions. had been treated with oral antihistamines and betamethasone (0,03 Objectives: We describe a weird case of an early onset mg/kg/day) for 2 weeks, followed by oral methylprednisolone for 4 hyperkeratosis and maculo-papular rash. days (0,2 mg/kg/day) with only partial improvement of skin lesions. Methods: A 4-month-old male was admitted to our Paediatric Emer- The day after glucocorticoid withdrawal, she presented fever (up to gency Unit due to history of rash since the age of one month. He 39.5°C) and rash worsening, thus she was admitted to our Unit. Her was born to non consanguineous parents, at 39 weeks of gestational past medical history was unremarkable, except for adenotonsillect- age following an uncomplicated pregnancy and delivery with normal omy performed at the age of 7 due to sleep apneas. Her father was neonatal phenomena. He had a good growth with no feeding diffi- affected with psoriasis and, since adulthood, episodic hidradenitis. At culties and without any comorbidity. presentation, she presented papular wheals at trunk and face and At the beginning, suspecting atopic dermatitis, he was treated with coxalgia at passive flexion. Laboratory investigations showed marked topical corticosteroid, emollients, and oral antihistamine. Because of elevation of acute phase reactants (C-reactive protein, CRP, 120,9 the lack of improvement of the eruption and no relief of the itch, the mg/L with normal values <5 mg/L and erythrocyte sedimentation family paediatrician assumed a cow's milk proteins allergy, so the rate, ESR, 79 mm/h) and slight neutrophilic leucocytosis (neutrophils baby started feeding with a hydrolysed milk. Even this treatment had 9290 cells/mmc). Fibrinogen was elevated (681 mg/dl) while procalci- no success. tonin was negative. No evidence of infection was detected at a thor- On examination, the child was apyretic, alert but too irritable. He ough serological and microbiological screening. Antinuclear presented whole body extended rash characterized by red papules, antibody, rheumatoid factor and complement were normal. Abdo- excoriation, and hyperkeratotic whitish crusts with crackings on the men ultrasound showed slight hepatosplenomegaly. Autoimmune palmo-plantar surfaces. thyroiditis with normal thyroid function was detected. Bone marrow Due to the early age of the onset of rash and the lack of rash aspiration revealed no signs of hemophagocytosis or cellular atypia. improvement with previous treatment, the hypothesis of Skin biopsy showed dermal neutrophils and lymphocytes infiltrate. autoinflammatory disease was made, such as DITRA Syndrome. During the hospitalization, lasted two weeks, the patient presented Results: Routine blood tests revealed a leukocyte count of 44,60 × spontaneous progressive clinical amelioration with fever and arthral- 9 3 10 cells/L with a very high eosinophil count of 20,39× 10 cells/L. gias disappearance few days after admission and progressive reduc- Inflammatory markers (C-reactive protein , Erythrocyte sedimentation tion of inflammatory indexes. At discharge, CRP was 6,6 mg/L, ESR rate , Serum Amyloid A ) were within normal range . The infant was 30 mm/h and a mild elevation of Serum amyloid A (SAA) was screening for immunodeficiency, differential count, T-cell and B-cell detected (60,1 mg/L, normal values <3,47 mg/L). One month later, subsets, quantitative immuno-globulins, and HIV test were all normal. CRP, ESR and SAA were normalized. Spontaneous sporadic episodes In consideration of absence of fever ad normal level of inflammatory of short-duration (less than 24 hours) urticarial rash persisted over markers, we decided to postpone genetic tests and we performed an the following three months and then disappeared. She presented accurate anamnesis and we evaluated the patient clinically again overall well-being for the following two years. At the age of 15, she During the baby examination our physicians noticed on the baby newly developed persistent spontaneous urticarial rash without fever mother’s arms an erythematous papular and excoriated eruption or arthralgias. Skin lesions appeared mainly during evening, were with scratching. For this reason we performed an accurate anamnesis pruritic, localized at face, thighs and back of the hands and steroid- and a dermatoscopic examination of skin scrapings revealing dependent. Inflammatory markers were newly elevated: CRP was 20 numerous scabies mites and eggs. mg/L, ESR 40 mm/h and SAA 166 mg/L. Due to elevation of inflam- Conclusion: A diagnosis of crusted or Norwegian scabies was made matory markers in association with rash reappearance, next gener- and he was treated with oral antihistamine, overnight application of ation sequencing (NGS) analysis for SAIDs was performed and topical 5% permethrin. The patient was discharged from the hospital showed the heterozygotic variant c.362G>A, p.(Arg121Gln) of TNFR after three days of treatment with complete resolution of cutaneous SF1A gene, consistent with TRAPS. Therefore, about six months after lesions and normalization of the blood tests. The aim of this case chronic urticaria reappearance, the patient started subcutaneous ana- report is underlying the importance of an accurate anamnesis and kinra (100 mg/day) with prompt resolution of skin rash. At one- clinical examination, also of the parents, to avoid delayed diagnosis month follow-up after anakinra starting, the patient did not experi- ence any urticaria relapse and inflammatory markers were normal. Disclosure of Interest Conclusion: In this 16-year-old female, TRAPS was diagnosed due to None Declared spontaneous chronic urticaria, associated with inflammatory markers increase. She presented fever and arthralgias only at the onset, oc- curred at the age of 13. This case showed that chronic urticaria can P30 characterize the clinical course of TRAPS, even though fever and Tumor Necrosis Factor Receptor-associated Periodic Syndrome other systemic signs may not be present. Elevation of inflammatory (TRAPS) masquerading as chronic urticaria in a teenage girl indices should give rise to the suspicion of SAID in patients with R. Naddei, R. Alfani, F. Mozzillo, T. Lastella, M. Amico, M. C. Carrella, M. chronic urticaria, also in case of a late onset. Anakinra was effective Tripodi, M. Alessio in skin rash resolution in our patient. Written informed parental con- Pediatric Rheumatology Unit, Mother and Child Department, University sent for publication was given. of Naples Federico II, Naples, Italy Correspondence: R. Naddei Disclosure of Interest Pediatric Rheumatology 2021, 20(Suppl 1):P30 None Declared Introduction: Skin manifestations are frequent in systemic auto- inflammatory diseases (SAIDs). Skin rash frequently accompanies sys- P31 temic symptoms such as fever, malaise and joint involvement during Chronic recurrent multifocal osteomyelitis: a first case report from recurrent autoinflammatory episodes. Libya 1 2 3 Objectives: To describe clinical presentation of a young girl A. A. Abushhaiwia , Y. AElfawires , A. Ateeq diagnosed with Tumor Necrosis Factor receptor-associated periodic paediatric Rheumatology, faculty of Medicine,Tripoli university, Tripoli syndrome (TRAPS) at the age of 16 due to chronic urticaria. children's hospital; paediatric Rheumatology , Faculty of Medicine, Methods: Case report. Tripoli university , Tripoli children's hospital; paediatric Rheumatology , Results: A 13-year-old girl referred to our Unit for an urticarial rash, Tripoli children's hospital , Tripoli , Libya started one month earlier. Single skin lesions lasted up to 24 hours, Correspondence: A. A. Abushhaiwia were localized at trunk and limbs and followed by arthralgias and Pediatric Rheumatology 2021, 20(Suppl 1):P31 Pediatric Rheumatology (2022) 20:2 Page 24 of 39 Introduction: Chronic recurrent multifocal osteomyelitis (CRMO) is a laboratory, laboratoristic and radiological findings and bone bi- rare idiopathic inflammatory disease that affects mainly children and opsy CRMO was diagnosed. Patient started anti-inflammatory young adults. The clinical signs and symptoms are nonspecific, treatment (naproxen) for 3 months and his conditions im- hindering and delaying diagnosis. Radiological and histopathological proved. NSAID treatment has been suspended. tests are essential for its definition .To our knowledge, there are no Conclusion: CRMO should be considered in any a child with chronic reports of CRMO in Libya, this is the first case report, which was bone pain to perform a correct diagnosis and start an adequate initially misdiagnosed and treated by multiple courses of different treatment. Timely diagnosis of these disorders is crucial to avoid types of antibiotics is presented. We describe the clinical and potential complications laboratory features and treatment of it Objectives: To present a case of CRMO to demonstrate the Disclosure of Interest diagnostic importance of clinical, laboratory, mainly, imaging tests, None Declared and avoids misdiagnoses or late diagnoses. Methods: The diagnosis of CRMO was based on evidence of recurrent osteomyelitis with radiographic evidence of chronic P32 osteomyelitis involving at least two sites in the absence of infectious Emotional distress as a trigger for PFAPA attacks 1 2 1 1 1 1 cause in a child less than 14 years old Y. Levinsky , Y. A. Butbul , T. Tal , M. Natour , K. Kedar , N. Dagan ,G. 1 3 Results: A 14-year-old Libyan boy, born of non-consanguineous Amarilyo , L. Harel 1 2 healthy parents, Was referred to our Department of Paediatric Schneider Children's medical center of Israel, Petah tikva; Rambam Rheumatology in December 2020 with a history of episodes of Health Care Campus, Haifa; Schneider children's Medicalcenter of Israel, bone pain in different sites sometimes associated swelling and Petah Tikva, Israel hotness but no redness, Symptoms had been started since at the Correspondence: Y. Levinsky age 10 years, he was evaluated several times without a specific Pediatric Rheumatology 2021, 20(Suppl 1):P32 diagnosis being made and he had received various antibiotics and several admissions as a case of acute or chronic osteomyli- Introduction: There is scarce information regarding potential triggers ties and bone biopsy had been taken from different site (left for PFAPA attacks. tibia, left and right ulna) revealed chronic osteomylities and no Objectives: To examine whether an emotional stress serves as a bacterial growth in the different hospitals in Libya and outside trigger for these attacks. Libya without specific diagnosis, in 2016 the patient sought Methods: Active PFAPA Patients aged 3-12 years from two Israeli medical care because of aching pain over the right anterior as- centers were enrolled. Patients parents were reached via phone call pect of leg associated with swelling, hotness but no redness, the and asked about the occurrence of PFAPA attacks in the preceding 2 pain not radiated, was worse with rest, The patient was otherwise weeks of a "stressful period" which was assumed to be (and later val- healthy with no history of fevers, chills, or weight loss. He had idated by an emotional distress scale questionnaire) within two neither history of previous surgeries nor a family history of bone weeks of returning to school after the first Israeli COVID-19 lockdown. or joint abnormalities, including tumors. He underwent MRI left Each patient served as its own control and parents were re-reached leg, which revealed acute osteomylities, the patient’swhite blood two weeks during summer break where COVID-19 outbreak was in count (WBC) was normal, erythrocyte sedimentation rate (ESR) remission (i.e. un-stressful period). The difference between occur- was normal 5mm/hr (0–20 mm/hr), and C-reactive protein (CRP) rences of attacks during these 2 periods was recorded was normal at <5mg/L (<5 mg/L). He received oral antibiotic, an Results: One hundred and six pediatric patient were enrolled in the open bone biopsy was performed on right tibia in Italy and re- study. Mean age was 7.37± 2.9. The mean emotional distress vealed no bacterial growth, no specific pathological finding seen questionnaire was higher in the first period compared to the second in sub matted materials treated with broad spectrum antibiotics period (35.6± 8.1 versus 32.1± 7.7, respectively, P = 0.047). In the without improvement but he had spontaneous remission for one "Stressful period" 41 (38.7%) reported at least 1 attack during the year. In 2018 he had another episode of bone pain but over the preceding 2 weeks compared to 24 (22.6%) in the "unstresfull extensor aspect of right forearm associated with swelling and period" (p = 0.017). hotness, MRI right forearm that showed proximal ulna metaphysis Conclusion: Here we provide first evidence that emotional stress periosteal with evidence of intra medullar small fluid collection of may induce PFAPA attack. high signal intensity on T2 image, low signal intensity on T1 image surrounded by bone marrow edema on STIR image con- Disclosure of Interest cluded proximal acute osteomyelitis, in order to exclude malig- None Declared nancy CTscan right forearm with 3D post processing was normal, received also antibiotics , sought medical advice in Jordan for more diagnostic workup due Radiologist suggested the lesion P34 could be due to tumoral involvement like Ewing’s sarcoma, or Efficacy of jak-inhibitor in treatment of a patient with ADA2 oesteomylities or eosinophilic granuloma , MRI right forearm deficiency (DADA2) 1 1 2 2 1 with IV contrast in Jordan was revealed diffuse and significant V. I. Burlakov , A. Kozlova , E. Raykina , M. Kurnikova , N. Kan ,Z. 1 3 3 1 bone infiltration and bone marrow edema involving the proximal Nesterenko , S. J. Kelly , M. S. Hershfield , A. Shcherbina 1 2 third of ulna associated with periosteal edema.CTscan right fore- Immunology, Laboratory of Molecular Biology, Federal Research and arm without contract showed suspicious infiltrative bone disease Clinical Center of Pediatric Hematology, Oncology and Immunology, in proximal two third of ulna with periosteal reaction and eleva- Moscow, Russia, Moscow, Russian Federation, Duke University School of tion. According to the radiographic findings, the patient was can- Medicine, Durham, United States didate for open 2nd time bone biopsy from right ulna showed Correspondence: A. Kozlova chronic osteomylities no bacterial growth, received oral antibiotics Pediatric Rheumatology 2021, 20(Suppl 1):P34 and NSAID (ibuprofen syrup) for 3 weeks. His symptoms disap- peared for 2 years. In June 2020 he had pain in left forearm, Introduction: DADA2 is a rare disease caused by bi-allelic mutations rd 3 biopsy performed MRI of the left forearm was hypointense in in the ADA2 gene. It is characterized by a variable phenotype that in- T1 and hyperintense in T2 and STIR, suggesting an inflammatory cludes systemic inflammation, vasculitis and polyarteritis nodosa with process. He assumed NSAID for a week. 6 months later, the pa- strokes, humoral immunodeficiency and bone marrow failure. Recent tient came to our Department because of pain and swelling in studies demonstrated increased interferon signature in DADA2, pla- left forearm. Based on his clinical history, physical examination, cing this disease in the group of type I interferonopathies. Pediatric Rheumatology (2022) 20:2 Page 25 of 39 Objectives: To assess effectiveness of ruxolitinib in treatment of a P35 patient with DADA2. Safety and effectiveness of biosimilar of adalimumab ABP501 in Methods: DADA2 diagnosis was confirmed by detection of the treatment of juvenile idiopathic arthritis: pera research group homozygous c.39C>A, p.C13* ADA2 mutation using targeted next experience 1 2 3 4 5 generation sequencing panel and confirmed by Sanger sequencing. F. G. Demirkan ,K.Ulu , K. Öztürk , S. G. Karadağ , S. Özdel ,H. E. 6 1 2 2 1 Plasma ADA2 enzymatic activity was measured in extracts of the Sönmez , F. Çakmak , F. Demir , B. Sözeri , N. Aktay Ayaz dried plasma spots using the high-performance liquid chromatog- Pediatric Rheumatology, Istanbul University/Faculty of Medicine; raphy method. Pediatric Rheumatology, University of Health Sciences, Ümraniye Results: A boy with DADA2 born to nonconsanguineous parents of Research and Training Hospital; Pediatric Rheumatology, Istanbul the Crimean Tatar descent was referred to our Center at the age of Medeniyet University, School of Medicine, Goztepe Research and 11 years. His symptoms included: Training Hospital; Pediatric Rheumatology, University of Health Sciences, -Anemia, which presented in the first months of life, progressed over Bakırköy Dr. SadiKonuk Training and Research Hospital, istanbul; time with the need of monthly erythrocyte transfusions despite the Pediatric Rheumatology, University of Health Sciences, Dr. Sami Ulus treatment with steroids up to 2 mg/kg. Bone marrow smear showed Obstetrics and Gynecology, Pediatric Health and Disease Training and isolated red cell hypoplasia. Research Hospital, Ankara; Pediatric Rheumatology, Kocaeli University, -Livedo vasculitis since 5 years of age. Kocaeli School of Medicine, Kocaeli, kocaeli, Turkey -Recurrent fevers. Correspondence: F. G. Demirkan -Periventricular ischemic lesions on the MRI brain scans at the age of Pediatric Rheumatology 2021, 20(Suppl 1):P35 9 years. Laboratory tests at admission showed also mild inflammatory Introduction: Over the past twenty years, biologic products and activity, lymphopenia (Table 1) with decrease in all lymphocyte subsequently biosimilars, have dramatically enhanced the treatment populations: CD3+CD4+ 0,196 cells/μl, CD3+CD8+ 0,139 cells/μl, of several chronic pediatric inflammatory conditions particularly CD19+ 0,009 cells/μl. juvenile idiopathic arthritis (JIA). The patient was deficient in plasma ADA2 enzymatic activity 4,3 mU/ Objectives: We aimed to review the real-life data regarding adalimu- g vs 75,9 mU/g for a healthy control sample (lab reference ranges for mab biosimilar treatment in children with JIA and make a contribu- controls and carriers are 130 ± 53 U/g and 55 ± 22 U/g, respectively). tion to the literature about its efficacy and safety. The patient was started on etanercept 0,8 mg/kg weekly with Methods: This retrospective, multi-centric study included children with gradual discontinuation of steroids and vasculitis’ resolution, yet a rheumatic disease who were followed-up by tertiary pediatric he developed multi-lineage cytopenia with positive Coombs test rheumatology centers across Turkey. Patients were followed for at (Table 1), that was treated with steroids at 1 mg/kg for 3 months least 24-weeks from the initiation of adalimumab biosimilar treat- and a course of rituximab 4 x 375 mg/m with partial response. ment with prescription indications, clinical responses, disease activ- He developed severe Cushing syndrome. ity scores, and adverse events reported. He was then started on ruxolitinib 10 mg/m daily with gradual Results: The study included 43 pediatric patients with a median steroid discontinuation. age of 15.4±2.6 (5-18) years; 60 % of them were male. The diagnoses of At the 12 months follow-up the patient was clinically asymptomatic, the group were as follows: JIA in 41 patients (95%); uveitis secondary to had no fever flares or signs of vasculitis. Laboratory tests showed sarcoidosis in 1 patient (2%) and iridocyclitis in 1 patient (2%). marked increase of platelet and lymphocyte counts and normalization JIA categories were oligoarticular (n=12, 27%), enthesitis-related (n=20, of all other parameters. He had no severe infections or signs of treat- 46%), psoriatic (n=6, 14%), and polyarticular (n=3, 7%). Seven patients ment toxicity. with JIA developed uveitis during the disease course. Conclusion: DADA2 is a complex and diverse life-threatening disease, The first treatment option of the experts was adalimumab biosimilar often with poor response to various modes of treatment. In our pa- (ADL) in 33, etanercept in 9, and secukinumab in 1 patient. A tient, ruxolitinib was well tolerated and effective in acquiring and standard dose of ADL biosimilar 40 mg once-in-2-week was started maintaining remission of vasculitis and cytopenia. This experience to the patients. Etanercept was switched to adalimumab biosimi- deserves further investigation in a larger cohort of patients. lar due to allergic reactions (n=2), development/activation of uveitis (n=3), psoriasis activation (n=1), and arthritis (n=2). In one patient Disclosure of Interest with psoriatic arthritis, as the arthritis was not responsive to secuki- None Declared numab, ADL biosimilar switching was made. rd In the 3 month of follow-up, uveitis was in remission in 5 pa- tients. Clinical remission and response status were evaluated with Ju- venile Arthritis Disease Activity Score 27 score. A significant decrease Table 1 (abstract P34). Treatment modalities and outcomes in patient in the scores determined the clinical effectiveness of ADL biosimilar with DADA2 in JIA patients (p=0.001). One patient at the third month of therapy had compliance problems with the biosimilar, so a switch to the ori- ginal ADL molecule was rendered. Treatment Clinical symptoms Laboratory tests Of the 41 patients who received ADL biosimilar; 34 patients had no Vasculitis Hepato- Fever Hb, PLT, WBC, NEU, LYM, CRP, splenomegaly g/l 10 / cells/ cells/ cells/ mg/ active complaints during follow-up. No adverse events were l μl μl μl l observed. Before treatment +++ +++ +++ 59 n/a n/a n/a n/a n/a Conclusion: In rheumatology, the majority of previous reports of Steroids, + - +/- 133 109 3740 2403 760 16,4 biosimilars were concerning adults, yet data with reference to the 0,1-30 mg/kg effectiveness and safety of biosimilars in pediatric rheumatic diseases Etanercept, - - - 52 49 610 200 270 4,62 is scarce. Real-life data on drug safety and efficacy need to be col- 0,8 mg/kg lected to increase evidence base data and in this context, this report Etanercept 0,8 mg/kg + - - - 144 62 3898 2447 535 1,6 reflects the prescription patterns and treatment strategies for a fre- steroids 1 mg/kg quently preferred biosimilar drug in pediatric rheumatology with Ruxolitinib, - - - 154 91 5890 4317 967 1,4 2,3 2 real-life experience for the first time. ABP-501 is a suitable and 10 mg/m cost-effective treatment option for patients with the chronic rheum- Hb – hemoglobin, PLT – platelet count, WBC – white blood cell count, NEU – neutrophil count, LYM – atic disease when adalimumab use is indicated. lymphocyte count, CRP – C-reactive protein. Laboratory test results show median values for the observation time Keywords: adalimumab, biosimilar, amjevita, juvenile idiopathic arthritis Pediatric Rheumatology (2022) 20:2 Page 26 of 39 Disclosure of Interest P37 None Declared Fetal exposure to canakinumab: a report of three pregnancies 1 2 3 4 U. Ilgen , S. Eyüpoğlu , E. Yayla , O. Küçükşahin 1 2 3 Rheumatology, Trakya University, Edirne; Nephrology; Rheumatology, P36 Ankara University; Rheumatology, Ankara Yıldırım Beyazıt Univeristy, Anakinra and canakinumab for patients with R92Q-associated Ankara, Turkey autoinflammatory syndrome: a multicentre observational study Correspondence: U. Ilgen from the AIDA Network Pediatric Rheumatology 2021, 20(Suppl 1):P37 1 2 3 1 1 C. Gaggiano , D. Rigante , J. Hernández-Rodríguez , A. Vitale , M. Tarsia , 4 5 6 7 8 A. Soriano , G. Lopalco , M. A. Jaber , R. Giacomelli ,E.Więsik-Szewczyk , Introduction: Interleukin-1 (IL-1) blockade during pregnancy is 9 9 10 11 9 10 M. Cattalini , M. Frassi , M. Piga , G. Ragab , F. Zunica , A. Floris ,V. well tolerated but safety data is limited particularly for canakinu- 12 11 3 3 1 Sabato , M. T. Hegazy , O. Araújo , L. Pelegrín , B. Frediani ,A. mab, under which a total of only ten pregnancies were reported 1 1 1 1 Fabbiani , A. Renieri , S. Grosso , L. Cantarini to date. 1 2 University of Siena, Siena; Fondazione Policlinico Universitario A. Objectives: To provide additional safety data of canaknumab Gemelli IRCCS and Università Cattolica Sacro Cuore, Rome, Italy; based on three pregnancies of two cases, one with familial Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Mediterranean fever (FMF) and the other with Muckle-Wells syn- 4 5 Spain; Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia; University drome (MWS). 6 7 of Bari, Bari; Santa Chiara Hospital, Trento; University of L'Aquila, Methods: A data sheet consisting of general disease characteristics L'Aquila, Italy; Central Clinical Hospital of the Ministry of National and a detailed pregnancy and postpartum follow-up information Defense, Military Institute of Medicine, Warsaw, Poland; University of consisting of the age and disease activity at conception, timing of Brescia and Spedali Civili of Brescia, Brescia; University and AOU of the last canakinumab dose with respect to pregnancy week, disease 11 12 Cagliari, Cagliari, Italy; Cairo University, Cairo, Egypt; University of activity and canakinumab use during and after pregnancy, type and Antwerp and Antwerp University Hospital, Antwerpen, Belgium timing of delivery and feeding, status of the baby during intrauterine, Correspondence: C. Gaggiano neonatal, and infancy period, was completed for each pregnancy. Pediatric Rheumatology 2021, 20(Suppl 1):P36 Results: The patients were 29- and 31-year-old women with MWS and FMF, respectively. The first had two pregnancies under canakinu- Introduction: The gold standard treatment of TNF receptor- mab. Both were complicated by renal amyloidosis but were attack- associated periodic syndrome (TRAPS) is the inhibition of IL-1, the free with normal acute phase reactants and stable proteinuria (240 final effector of the stress-response mechanisms activated by the mg/day and 550 mg/day, respectively) for years before conception deregulated cellular homeostasis in TRAPS patients. Given the uncer- and both were under monotherapy with canakinumab. Pregnancy tainty about the molecular mechanism and pathogenic significance outcomes were provided in the Table. The first patient with a mid- of the R92Q variant, the therapeutic response to IL-1 inhibitors in pa- trimester miscarriage held canakinumab 14 weeks before the follow- tients with recurrent inflammatory attacks due to the presence of ing conception until the 31st week of gestation. During this period this specific mutation is worth an extensive investigation. she had attacks partially responsive to low-to-moderate dose steroids Objectives: This study aims at describing the therapeutic outcome of and on-demand anakinra but proteinuria progressed to 2600 mg/day patients carrying the R92Q variant in the TNFRSF1A gene treated with persistent elevation in acute phase reactants, for which canaki- with anakinra (ANA) or canakinumab (CAN) and identifying any numab was resumed at the 31st week of gestation. Both patients factors predictive of complete response to IL-1 inhibition. were under canakinumab over the entire course of breastfeeding. No Methods: This is an observational study involving 13 international significant infections were reported in the infants. Anti-hepatitis B centres from the AIDA Network. Demographic, clinical, laboratory, surface antigen titers were 218 and 470 IU/L in the sixth month and clinimetric and therapeutic data of patients treated with ANA or CAN 402 and 620 IU/L in the second year of age (Three doses of hepatitis for recurrent inflammatory attacks due to the presence of the R92Q B vaccine in the 0, 1, and 6 months were administered according to variant were retrospectively collected and analysed. the national immunization program). Results: Data about 20 treatment courses with IL-1 inhibitors (16 with Conclusion: Considering all 13 reported cases of pregnancy under ANA and 4 with CAN) from 19 patients were collected. Mean age at canakinumab, two resulted in miscarriage, one in the first and one in disease onset was 20.2±14.8 years. In 5 cases (26%) the R92Q variant the second trimester. Underlying disease was active in the one with was found in a family member affected by recurrent fever. The thera- the first trimester miscarriage. All fetuses were exposed to peutic response was complete in 13(68%) and partial in 2 patients canakinumab during embryogenesis with no reported anomalies. (11%); treatment failure was observed in 4 cases (21%). Median AIDAI Most cases continued canakinumab throughout pregnancy with no decreased from 10(IQR 28) to 0(IQR 1) at the 12-month follow-up visit preterm labor or severe infection in the infant. Hepatitis B (p<0.001). Mean ESR and median PCR dropped respectively from vaccination in the infant was shown to be successful in two cases. 40.8±24.8 to 9.1±4.5 mm/h (p<0.001) and from 3.0 (IQR 1.9) to 0.3 (IQR 0.3) mg/dl (p<0.001) after 12 months of treatment. A steroid- Disclosure of Interest sparing effect was observed from the third month of treatment (p< None Declared 0.01). Thirteen patients (65%) were still on treatment at the last follow-up visit (median duration of treatment 17 (IQR 38) months). The presence of R92Q mutation in a symptomatic relative (p=0.022), Table 1 (abstract P37). Pregnancy outcomes under canakinumab the relapsing remitting disease course (p<0.001) and the presence of migratory erythematous skin rashes during fever attacks (p=0.005) Age at Last cana Doses and Date and Birth APGAR Fetoplacental Feeding Current pregnancy dose before duration of cana type of weight score anomaly, IUGR, or age of were associated with complete efficacy of IL-1 inhibitors. conception after conception delivery developmental the delay child Conclusion: R92Q patients showed a favourable response to ANA 1* 25 years 150 mg, 2 150 mg at 6 and 16 week, - - No phenotypic or -- and CAN, particularly when the mutation segregated in a family weeks 14 weeks miscarriage chromosomal member and when a relapsing-remitting disease course or TRAPS anomaly typical skin rash were observed. In the subgroup of patients not tak- 2* 26 years 150 mg, 14 150 mg at 31 37 week, 2.9 kg 8,9,10 No anomaly, IUGR, Breastfed 2.5 years weeks weeks and 4-to- C/S or delay 16 ing advantage of IL-1 blockage different molecular mechanisms 6-weekly months thereafter underlying the autoinflammatory picture are likely to exist. 3 28 years 150 mg, 4 150 mg 8-weekly 39 week, 3.4 kg 9,10,10 No anomaly, IUGR, Breastfed 2 years weeks throughout C/S or delay 8 months Disclosure of Interest pregnancy None Declared cana, canakinumab; C/S, Caesarean section; IUGR, intrauterine growth retardation. * the same patient Pediatric Rheumatology (2022) 20:2 Page 27 of 39 P38 P39 The comparison of vaccination rates of children with rheumatic Willingness to get the COVID-19 vaccine among children with diseases and their healthy peers rheumatic diseases: a survey study to parents 1 1 1 2 2 Ö. Akgün , F. G. Demirkan , F. Çakmak , M. Erdemir , G. Keskindemirci , Ö. Akgün, F. G. Demirkan, F. Ataman Çakmak, G. Kavrul Kayaalp, O. Köker 1 3 1 2 G. Kavrul Kayaalp , N. Akay , R. Eker Ömeroğlu , E. G. Gökçay , N. Aktay Turan, A. Tanatar, N. Aktay Ayaz Ayaz Pediatric Rheumatologist, Istanbul Faculty of Medicine, Istanbul, Turkey 1 2 3 Pediatric Rheumatology; Social Pediatrics; Pediatrics, Istanbul Faculty Correspondence: Ö. Akgün of Medicine, Istanbul, Turkey Pediatric Rheumatology 2021, 20(Suppl 1):P39 Correspondence: Ö. Akgün Pediatric Rheumatology 2021, 20(Suppl 1):P38 Introduction: Severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19), first re- Introduction: Patients who are followed-up in the pediatric rheuma- ported from the Wuhan city of China in December 2019, affected all the tology outpatient clinic are at risk due to immune dysfunction world in a few months and became a global health emergency of primary caused by both their primary disease and by the drugs they use. As international concern and was announced a pandemic by the World Health they are more prone to infection, these patients should be protected Organisation. Although the disease is showing a milder course in children, carefully from vaccine-preventable diseases. vaccination of this age group may be important due to increased number Objectives: Our aim is to find out the vaccination rates in patients of the multisystem inflammatory syndrome (MIS-C) and vaccines role in diagnosed with a pediatric rheumatologic disease (PedRD) and to prevention of the spread of infection in children who have had asymptom- assess their vaccination status comparing with their healthy peers. atic disease. As vaccine refusal and hesitancy are increasing around the Another objective of the study is to evaluate factors that may lead to world, a new problem has emerged for children with pediatric rheumatic incomplete vaccination in patients with PedRD. diseases who are already prone to infection. Methods: The electronic healthcare recording system data of Objectives: This study aimed to investigate the parental acceptance patients with PedRD who were followed in the pediatric of COVID-19 vaccination for children with chronic rheumatic diseases rheumatology out-patient clinic in Istanbul University Faculty of when the vaccine is approved in childhood and to evaluate the back- Medicine between October 2019 and October 2020 were reviewed ground characteristics of willingness to get COVID-19 vaccine. and 102 patients (aged 0-18) whose vaccination records were avail- Methods: The study included an analysis of a cross-sectional online able are included in the study. One hundred two age-matched peers questionnaire to the parents of the patients diagnosed with a without any chronic disease and whose vaccination data were avail- chronic rheumatic disease at the Pediatric Rheumatology Outpatient able through electronic healthcare recording system were included Clinic of Istanbul Faculty of Medicine. A message containing a link to as the control group. Incomplete vaccination status and missing vac- the actual questionnaire was sent to their phones simultaneously cines were identified according to the national vaccination schedule which covers their view for the SARS CoV-2 infection, sociodemo- individualized by age. Fifty- one patients (50%) have the diagnosis of graphic data, thoughts about the vaccine, their child's behavior dur- juvenile idiopathic arthritis (JIA), 38 patients (37.2%) have the diagno- ing the pandemic related to the disease, and completed by self- sis of periodic fever syndromes and 13 patients (12.74%) have the response method. Clinical information was accessed from the med- diagnosis of connective tissue diseases. ical records of the patients. Results: The proportion of the females was 67% in the patient Results: The prevalence of parents’ acceptance of COVID-19 vaccin- group (n=68) and 57% in the control group (n=58). The median ation for their children was 39.5% (30/76). The proportion of parents age of the patient group was 8.1(1.9-15.5) and the mean age who were hesitant about the vaccination of their children was 47.4%. control group was 7.5(±3.4) years. There was no difference Whereas, the rates of acceptance of the vaccine by mothers and fa- between the patient and the control group in terms of age and thers themselves were 48.7% and 52.6%, respectively. Factors for vac- gender. The median age at diagnosis was 3.3(0.3-11.4) years. cine referral were side effects (47.4%), limited information about the Incomplete vaccination rate was 35.3 % in the patient group and vaccine (45.2%) and possible ineteraction of the vaccines with the 6.9 % in the control group (P<0.0001). The most common medications of the patients (40.2%). Parents were able to give mul- neglected vaccine was the first dose of oral poliovirus vaccine tiple answers to this question. There was no significant relationship (OPV) (n=19, 18.6%), followed by the second dose of OPV (n=18, between the parents' educational status and their acceptance of the 15.7%) and the first dose of measles, rubella, mumps vaccine (n= vaccine (respectively p=0.09, p=0.10) 13, 12.7%). Patients were divided into four groups according to Conclusion: Children can serve as a reservoir that will undermine the immunosuppressive antirheumatic treatments they received: efforts to end the pandemic. While the vaccines have yet no nonbiologic disease modifying antirheumatic drugs (DMARDs), approval for children <18 years, vaccinating children against the biological DMARDs, nonbiological + biological DMARDs and COVID-19 virus will contribute to the pandemic control, and the re- others (colchicine, non-steroidal anti-inflammatory drugs, hydroxy- covery of the global economy. The preliminary results of this survey chloroquine). Although the patients who received biologic ther- targeting parents may be guide for physicians while promoting vac- apy had the highest rate of missing vaccine at 43%, no cination in the near future. significant difference was detected between the treatment key words: Covid-19, vaccine, survey. pediatric rheumatic disease groups. Conclusion: : It is important to determine the vaccination status of Disclosure of Interest patients followed by PedRD and to take measures against vaccine- None Declared preventable diseases by increasing the awareness of physicians and patients in this regard. As a result, questioning the status of the vac- cine and to plan a catch-up immunization schedule for patients with P40 incomplete vaccines should be a part of the routine rheumatologic Live attenuated MMR booster vaccine in children with rheumatic examinations. Electronic registration systems can fill an important disease: a single center study 1 1 1 1 1 gap in solving this problem by giving warnings in case of vaccine de- F. Çakmak , Ö. Akgün , F. G. Demirkan , A. Tanatar , G. Kavrul Kayaalp ,G. 2 1 2 1 ficiency which can be convenient in busy outpatient clinics. Keskindemirci , R. Eker Ömeroğlu , E. G. Gökçay , N. Aktay Ayaz 1 2 Key Words: Vaccination, Pediatric rheumatic disease, biologic therapy Pediatric Rheumatology; Social Pediatrics, Istanbul Faculty of Medicine, Istanbul, Turkey Disclosure of Interest Correspondence: F. Çakmak None Declared Pediatric Rheumatology 2021, 20(Suppl 1):P40 Pediatric Rheumatology (2022) 20:2 Page 28 of 39 Introduction: Juvenile Idiopathic Arthritis (JIA) is a heterogeneous, Objectives: To identify modifying factors explaining the reduced chronic inflammatory disease of unknown cause which begins before penetrance and the variable expressivity. 16 years of age. Vaccination is the most effective way to prevent Methods: We compared two groups of patients with CTLA4 infectious diseases. In May 2017, European League Against mutations: 1) affected mutation carriers; 2) unaffected mutation Rheumatism-Paediatric Rheumatology European Society (EULAR- carriers. We analyzed the exome sequence, the HLA type, the PReS) Task Force for Vaccination, based on small case series and ex- microbial stool content, the infection history, and epigenetic pert opinion updated the recommendations for live vaccines in signatures. In addition, we looked for somatic mutations in CTLA4 children. and pathway-related genes. Objectives: In this study, it is aimed to collect the data of patients Results: When analyzing the WES data of mutation carriers, we did with JIA and other rheumatic diseases who received live attenuated not identify additional genes which were only mutated in affected booster measles-mumps-rubella (MMR) vaccine during treatment but not in the unaffected mutation carriers, or vice versa. Moreover, with biological therapy and present if any disease flares or adverse during our studies, we became aware of a monozygotic twin pair reactions occured after vaccinations. with a discordant phenotype, additionally arguing for somatic or Methods: The files of the patients followed-up in İstanbul University environmental modifying factors. In >50 patients tested, we did not Istanbul Faculty of Medicine with the diagnosis of JIA or other identify any additional somatic mutation in candidate genes. The rheumatic diseases who received biological treatment were analyzed HLA type, however, may add an additional susceptibility factor, as we retrospectively. According to the current national vaccination sched- observed that the haplotype HLA-DRB1 *15:01 and -DQB1 *06:02 in ule, the MMR vaccine booster dose is administered in the first year of CTLA-4-insufficient patients might be associated with a severe im- primary school, so we evaluated from electronic vaccination records mune dysregulation phenotype. Interestingly, the microbial compos- whether any of our patients had received live attenuated booster ition in stool was different in affected CTLA4 mutation carriers when vaccinations for MMR while being treated with biologics. Demo- compared to unaffected mutation carriers. Details will be reported at graphic data and information on disease subtypes, disease activity at the meeting. The infection history was not revealing, as for all infec- the time of the booster vaccination, and adverse reactions after vac- tious agents investigated, there were infected and not-infected muta- cinations (disease flare or vaccine-related event) were collected from tion carriers in both groups. The analysis of the epigenetic signatures the files of the patients retrospectively. is pending and will be presented at the meeting. Results: Among 72 patients under biologic therapy, 14 patients (7 Conclusion: According to our current assessment, the HLA-type and girls and 7 boys) had received live attenuated booster measles- the microbiome are the most promising determinants of disease ac- mumps-rubella (MMR) during treatment with biologics. The mean tivity in patients with CTLA4-insufficiency. age of diagnosis was 43,7 (9-73) months and the mean age of booster vaccination was 76,2 (70-84) months. The mean follow-up Disclosure of Interest time was 54 months (23-84) and the mean time to initiate biologics None Declared before vaccination was 14 months (4-45). Seven of these patients had oligoarticular juvenile idiopathic arthritis (JIA), 3 had systemic on- set JIA, 2 had enthesitis related arthritis, 1 had psoriatic arthritis and P42 1 had colchicine resistant familial Mediterranean fever. Eight patients High prevalence of autoinflammatory diseases in autosomal received booster MMR while on biologic treatment only and 6 were dominant NFΚB1 insufficiency under both methotrexate and biologic therapy. During vaccination, 4 B. Grimbacher, K. Thoma, on behalf of AG Grimbacher, M. Fliegauf (%30) patients had low and 3 had moderate (%23) disease activity, Institute for Immunodeficiency, Universital Hospital Freiburg, Freiburg, and 7 (%50) patients were in remission on medication. Germany Out of 14 patients who had MMR booster, only 1 patient with the Correspondence: B. Grimbacher diagnosis of systemic onset JIA under methotrexate and tocilizumab Pediatric Rheumatology 2021, 20(Suppl 1):P42 therapy had a maculopapular rash after vaccination. None of the patients reproted any disease flare. Introduction: NF-κB1 (haplo)insufficiency due to heterozygous dam- Conclusion: In the literature, data regarding live attenuated aging variants in NFKB1 has been recognized as an inborn error of vaccination of patients under biological therapy is limited. At the immunity with immune dysregulation. NFKB1 encodes the transcrip- evaluation of our cohort from electronic vaccination records and tion factor precursor p105, which undergoes processing to produce patient files, it was noticed that the live attenuated booster MMR the mature p50. vaccine was seemingly safe for children with rheumatic diseases who Objectives: Due to the highly heterogeneous immunological were receiving biologic therapy. However, to conclude that live phenotypes, including incomplete penetrance (70%) and age- vaccination is effective and safe, this data should be supported by dependent disease severity, attempts to establish clear genotype- multicentric and larger cohorts. phenotype correlations have been unsuccessful so far. Therefore, we set out to better describe the phenotype of patients with variants in Disclosure of Interest NFKB1. Moreover, functional evaluation of each identified NFKB1 se- None Declared quence variation was attempted to demonstrate causality. Methods: We use a standard cell culture model, based on transient overexpression of mutant NF-κB1 proteins in HEK293T cells, to test P41 the expression, subcellular localization, precursor processing, DNA Towards the Identification of disease-modifying factors in CTLA4 binding and promoter activation. In addition, we test protein interac- insufficiency tions, cytoplasmic retention/nuclear translocation and DNA-binding B. Grimbacher, N. Mitsuiki, M. Krausz, L. Gámez-Díaz, C. Schwab, F. competition, following experimentally simulated pathway activation. Emmerich, N. Camacho Ordonez, S. Posadas-Cantera, H. Hengel, M. Results: Autoinflammatory symptoms in NFKB1 insufficiency include Proietti, A. Caballero-Garcia-de-Oteyza oral and genital aphthous ulcerations (18.5%), non-infectious epi- Institute for Immunodeficiency, Universital Hospital Freiburg, Freiburg, sodes of fever and systemic inflammation (12%) as well as vasculitis Germany (4.6%). Multi-organ autoinflammatory diseases (29.6%), including Correspondence: B. Grimbacher Behçet's disease (5.6%), are among most frequent clinical complica- Pediatric Rheumatology 2021, 20(Suppl 1):P41 tions in affected mutation carriers besides hypogammaglobulinemia (88.9%), respiratory infections (83%) and reduced switched memory Introduction: Heterozygous mutations in CTLA4 lead to an inborn error B cells (60.3%). The clinical spectrum further comprises autoimmunity of immunity characterized by immunodeficiency and multi-organ auto- (57.4%), lymphoproliferation (52.4%), non-infectious enteropathy immunity. Interestingly, the penetrance of these deleterious mutations (23.1%), opportunistic (15.7%) and gastrointestinal (28.6%) infections, is only about 70%, and their expressivity is highly variable. and malignancy (16.8%). Pediatric Rheumatology (2022) 20:2 Page 29 of 39 Data regarding the prevalence of autoinflammatory complications in increasing evidence that the expression of the NLRP3 inflammasome patients with mutations in NFKB1 are currently being updated and is dysregulated in many cancers. At the same time, some studies will be presented at the meeting. The disease-causing mechanism demonstrate that TIF1 might influence tumors via NLRP3 signaling. presumably originates from imbalanced ratios of NF-κB signaling This could explain both clinical manifestations of our patient and components, and altered NF-κB signaling dynamics. TIF1 expression. Conclusion: Due to the high frequency of autoinflammation associated with NF-κB1 insufficiency, mutational and functional ana- Disclosure of Interest lyses of NFKB1 mutations should be considered, particularly when None Declared autosomal-dominant autoinflammatory diseases are evaluated. Disclosure of Interest P44 None Declared Unilateral proptosis in a child with Behçet’s disease 1 1 1 1 2 F. G. Demirkan , O. Akgun , G. Kavrul Kayaalp , F. Cakmak ,M. A.Kılıc ,E. 2 3 4 1 P. Yıldız , S. Sencer , A. Unuvar , N. Aktay Ayaz 1 2 3 P43 Pediatric Rheumatology; Pediatric Neurology; Neuroradiology; Unraveling the mysteries of an unusual monogenic Pediatric Hematology, Istanbul University/Faculty of Medicine, Istanbul, autoinflammatory disease presenting as an idiopathic Turkey inflammatory myopathy Correspondence: F. G. Demirkan J. Álvarez Troncoso Pediatric Rheumatology 2021, 20(Suppl 1):P44 Internal Medicine, Hospital Universitario La Paz, Madrid, Spain Pediatric Rheumatology 2021, 20(Suppl 1):P43 Introduction: Central nervous system (CNS) involvement is a rare complication of Behçet's disease (BD) in children and may present in Introduction: We present the case of a 49-year-old woman from the the form of parenchymal changes or as damage to the vascular United States of America with a previous diagnosis of urticaria- structures in its nonparenchymal form. vasculitis since adolescence with the need for high-dose steroids and Objectives: A teenager having BD complicated with recurrent episodes of unclassified arthritis. cerebral venous thrombosis is presented. Objectives: To describe an atypical case of a 49-year-old woman di- Methods: A-14 year-old boy followed up in dermatology and oph- agnosed with an idiopathic inflammatory myopathy with positivity thalmology clinics for eight years with BD, was referred to the for anti-TIF1 antibodies that was actually a monogenic autoinflamma- pediatric rheumatology clinic with complaints of headache, periorbi- tory disease. tal pain, diplopia, and blurred vision. His pathergy test was posi- Results: In 2015, she was diagnosed with adenocarcinoma of the tive. He had a history of recurrent and unremitting oral ulcers. He cervix treated with radical hysterectomy and right adnexectomy was under daily colchicine therapy. without the need for chemotherapy or radiotherapy. Results: On his physical examination, he was afebrile and ill- In the subsequent follow-up she presented absence of recurrence on appearing. He had multiple painful aphthosis in his buccal mucosa, PET-CT (at 1, 2 and 5 years). However, due to the persistence of arth- an averagely 1 cm in diameter, but no genital ulcer. Bilateral conjunc- ritis, an immunological study was performed with only weak positiv- tival bulbar hyperemia was present. He had also painful eye move- ity for anti-TIF1 antibodies. On EMG she had mild myopathic ments due to the bulging of the right eye anteriorly out of the orbita changes. Muscle biopsy was anodyne (without HLA-I or inflammatory defined as proptosis. The rest of the neurologic and systematic infiltrates), muscle MRI and the rest of the study was normal, includ- examination was otherwise unremarkable. Ophthalmologic examin- ing repeatedly normal CPK. However, in the presence of arthritis and ation revealed bilateral optic disc swelling with established disc skin lesions of urticarial vasculitis, treatment with methotrexate (MTX) oedema and proptosis of the right eye. and steroids was started with incomplete clinical improvement. The patient’s white blood count was 7.6 10 /μl with normal In July 2020, she attended first time to our consultation for the differential; red cell count was 10.9 g/dL; hematocrit, 31.9%, and follow-up of myopathy due to anti-TIF1. The history was notable for platelets were 579 10 /μl. C-reactive protein was 89.5 mg/L and D- the appearance of cold-induced urticaria / bruising, low grade fever dimer level was 640 μg/L. and worsening of the arthritis during the last years. This ‘’cold intoler- CNS imaging by magnetic resonance imaging (MRI) and magnetic ance” forced her to move to another city. She also mentioned that resonance venography (MRV) reported left transverse sinus her teenage daughter had started 2 years ago with unstudied cold- thrombosis including left sigmoid sinus and internal jugular vein. induced urticaria. Given these data, a skin biopsy of urticaria and a Thrombophilia screening tests for identifying a hypercoagulable study of systemic autoinflammatory diseases (SAID) directed at state showed no abnormality and no additional hereditary or NLRP3 (but including the complete usual panel of SAID) was per- acquired thrombosis risk factors were detected. He was treated formed. The skin biopsy showed periecrine and perivascular neutro- with intravenous methylprednisolone pulse therapy (30 mg/m / phils in the middle and deep dermis with no edema, compatible day) for 3 days. He was anti-coagulated with low molecular with CAPS. weight heparin. Acetazolamide and topiramate were initiated due Treatment with daily subcutaneous anakinra 100 mg was started to the optic disc oedema. At discharge, immunosuppressive ther- with complete resolution of all skin lesions and arthritis, allowing the apy with azathioprine and anticoagulant therapy with enoxaparin withdrawal of steroids and initiating a decrease in MTX. The genetic was prescribed. study of mother and daughter is pending at the time of case Control MRV after 2 months revealed significant regression in the presentation. thrombus. The patient had no complaints during the following 5 Conclusion: CAPS or cryopirinopathies comprise three autosomal months and proptosis was recovered. D-dimer level was 200 μg/L. dominant conditions with different disease severity (FCAS, MWS, Acetazolamide and topiramate were stopped when ophthalmologic CINCA/NOMID). All CAPS are caused by mutations in the NLRP3 evaluation showed significant regression regarding disc oedema. gene, which encodes NLRP3 protein or cryopyrin and lead to After 5 months, he presented with severe headache and tinnitus. On constitutive activation of NLRP3 inflammasome and IL-1β overpro- eye examination, optic disc swelling and oedema were progressed in duction. CAPS skin biopsies are neutrophilic urticarial dermatosis with the left eye. In MRV, a new thrombus image was reported at the no or mild dermal edema and neutrophilic epitheliotropism (neutro- same anatomical localization as 5 months ago which affected the left phils around or within eccrine glands or ducts, or inside the epider- transverse sinus and sigmoid sinus. The D-dimer level was 190 μg/L mis). NLRP12-AD and NLRC4-AD are SAID with similar cutaneous and and there was no significant abnormality in remaining laboratory ex- clinical characteristics but different cutaneous histopathology. aminations. Anticoagulant therapy was continued with enoxaparin. TIF1 is an E3 ubiquitin-ligase reported to be involved in DNA repair, Methylprednisolone bolus was given and cyclophosphamide was ini- dermatomyositis and cancer among others. Besides, there is tiated as immunosuppressive treatment. Pediatric Rheumatology (2022) 20:2 Page 30 of 39 Eventually, he is asymptomatic and has developed no new serum immunoglobulin G, A and M were found to be low for his age. symptoms related to the disease. Eye examinations are performed Low immunoglobulin levels and the history of frequent viral RTIs and periodically and there is no progression in fundus examination. His microatelectasis in lungs were found consistent with humoral control cranial MRV revealed significant regression in the thrombosis. immunodeficiency, and intravenous immunoglobulin treatment was Ultimate D-dimer level is 190 μg/L. Monthly six doses of cyclophos- commenced once a month. phamide is planned in the treatment. Conclusion: In this case, severe arthropathy was prominent with Conclusion: CNS involvement in children is a rarely reported systemic inflammation. The absence of serious infections other than manifestation of BD and this report has a distinct clinical view of a RTI, later onset of low immunoglobulin levels, and the absence of teenage boy presenting with proptosis and recurrent thrombosis. signs of intestinal inflammation were the distinct features of the Key words: Behçet's disease, cerebral venous sinus thrombosis, patient. This case emphasizes that the diagnosis of RIPK1 deficiency proptosis should be considered in treatment-resistant arthropathies in child- hood, especially in the presence of signs of inflammation, and the Disclosure of Interest importance of genetic consultation in resistant cases. None Declared Disclosure of Interest None Declared P45 RIPK1 deficiency in a patient with severe arthritis 1 1 2 2 3 G. Kavrul Kayaalp , F. Çakmak ,G.Yeşil Sayın , A. D. Aslanger , E. Yücel , P46 N. Aktay Ayaz Complex genetic diagnosis of DADA2 in a patient with an ADA2 1 2 3 Pediatric Rheumatology; Medical Genetics; Pediatric Immunology and single allele mutation: the long and winding road 1 1 1 Allergy, Istanbul University, Faculty of Medicine, İstanbul, Turkey J. R. Marques Soares , S. Buján Rivas , R. Solans Laqué , J. I. Aróstegui Correspondence: G. Kavrul Kayaalp Gorospe Pediatric Rheumatology 2021, 20(Suppl 1):P45 Internal Medicine, Hospital Vall D´Hebron (Barcelona) SPAIN; Immunology, Hospital Clínic i Provincial - Idibaps, Barcelona, Spain Introduction: Receptor Interacting Protein Kinase 1 (RIPK1) is a widely Correspondence: J. R. Marques Soares expressed cytosolic protein kinase found in protein complexes that Pediatric Rheumatology 2021, 20(Suppl 1):P46 mediate signal transduction from cell surface receptors. It has an essential role in controlling signaling pathways related to inflammation, apoptosis Introduction: Deficiency of adenosine deaminase 2 (DADA2) (ORPHA: and necroptosis. RIPK1 deficiency causes impaired mitogen activated 404553) is a rare monogenic autoinflammatory disease with an autosomal protein kinase signals and irregular cytokine production. Immunodeficiency, recessive inheritance, deriving from biallelic loss-of-function mutations in intestinal inflammation, and progressive polyarthritis have been reported in the ADA2 gene, which encodes for the homonym protein. Its patients with RIPK1 mutations, however the current knowledge about the heterogeneous clinical phenotype can range from multisystemic vascular clinical aspects of the disease is still scarce. inflammation, often mimicking polyarteritis nodosa (PAN), to hematological Objectives: Here we report a novel RIPK1 mutation in a patient with involvement (including cytopenias and bone marrow failure) and mild severe arthritis and some distinct clinical features. humoral immunodeficiency in the form of hypogammaglobulinemia and B Methods: Clinical and laboratory features of the patient were cell lymphopenia. Because it was first described in 2014, prior cases were described. often diagnosed as PAN. Results: Case presentation: An 18 months-old male has presented Objectives: To expand the knowledge about genetic basis of DADA2 with recurrent febrile episodes and arthralgia in his multiple joints. with special attention to high suspicion cases with unconclusive His family reported febrile episodes in which he was diagnosed with genetic results, specially when the ADA2 activity test are unavailable. respiratory tract infection (RTI) since three months of age. At the Methods: Review of clinical charts, biochemistry and autoimmunity ages of 8 months and 16 months, febrile attacks were accompanied profiles and genetic tests of the proband and his 4 alive siblings by severe arthralgia for 3 days with elevation of acute phase reac- pedigree. Genetic analysis of DNA samples obtained frompatients tants. Family history revealed the diagnosis of familial Mediterranean under informed consent, according to the Helsinki declaration. fever (FMF) in his grandparent, uncles and cousins and rheumatoid Results: In the case hereby presented, after numerous tests, a first arthritis in his great-uncle. diagnosis of PAN-like disease was established in a 30-year-old male His physical examination was unremarkable. Blood count, acute with no relevant familial history and a personal history of Raynaud’s phase reactants, liver and kidney function tests, urinalysis and serum phenomenon, livedo reticularis, digital ischemia, early-onset strokes, immunoglobulin examinations were within normal limits for age. optic and peripheral neuropathy, cardiomyopathy, mesenteric and MEFV gene analysis was performed which revealed a heterozygous renal aneurysms, hypertension, vertigo, and multiple other systemic mutation in V726A. The patient was commenced on colchicine inflammation manifestations. Given the clinical history, atypical onset, considering the diagnosis of FMF. After the colchicine treatment, his the presence of hypogammaglobulinemia and disease progression family reported a decrease in the number of febrile episodes, despite several cyclophosphamide (CP) bolus and high-dose cortico- however at the age of two, joint swelling was accompanied to febrile steroid therapy, DADA2 diagnosis was considered. attacks. Autoinflammatory genetics panel was negative. There were At the age of 37 years a first genetic testing was performed arthritis and limited range of motion in both knees, elbows and small through direct sequencing of ADA2 via Sanger analysis using joints of hands and feet. The patient was diagnosed with DNA extracted from peripheral blood. One of the most common polyarticular juvenile idiopathic arthritis (JIA) due to persistent pathogenic ADA2 variants - p.G47R - was identified in a simple arthritis and intravenous pulse methylprednisolone treatment was heterozygous genotype. These results led to hypothesize the given for 3 days which was switched to oral methylprednisolone and presence of a structural gene variant in this locus that could tapered. Methotrexate was initiated subcutaneously once a week. justify the range of the previously mentioned clinical features. A After the treatment, his arthralgia was subsided and a significant whole genome sequencing (WGS) was executed without solid improvement was observed in his ability to walk, however joint bioinformatic analysis results. Therefore, multiplex ligation- swelling did not improve. The patient underwent to whole exome dependent probe amplification (MLPA) of the ADA2 gene was sequencing and a homozygous missense mutation in RIPK1 at performed, revealing a heterozygous genomic deletion that en- c.1849C>G [p.(His617Asp)] was detected, which was not previously compass exon 7 and flanking intronic boundaries. The Sanger reported in the literature and the databases. Whole body MR exon 2 and exon 7 analyses of the 4 siblings identified an het- imaging revealed microatelectasis in both lungs, arthritis in bilateral erozygous p.G47R variant on proband's mother while the exon 7 glenohumoral and coxofemoral joints, edema and inflammation in avaluation concluded a trans inheritance pattern. The ADA2 activ- adjacent soft tissues, and trochanteric bursitis. Control levels of ity was finally performed 11 years after the first diagnosis of Pediatric Rheumatology (2022) 20:2 Page 31 of 39 PAN. As expected, the proband p.G47R variant / exon 7 deletion Ursodeoxycholic acid (UDCA) was started. Transaminases persisted slightly in trans manner produced an almost complete lack of activity. elevated the following months, although CMV-IgM and urine CMV-DNA ADA2 activity for her mother, was reduced at 50%. normalization. Eight months later, UDCA was discontinued but liver en- In the reported case, disease remission was achieved after initiation zymes increased (SGOT 198 U/L ALAT 271 U/L), thus UDCA was resumed of anti-tumor necrosis factor (anti-TNF) therapy with Adalimumab. with progressive laboratory normalization. An extensive diagnostic work-up Conclusion: DADA2 is a monogenic autoinflammatory disease with a ruled out metabolic and autoimmune diseases. MRCP was normal. Array- wide clinical spectrum mimcicking PAN. Despite the lack of familar CGH, karyotype and a NGS for genetic cholestatic liver diseases resulted history, complex genetic changes can drive to a refractory PAN-like negative. At the age of 8, UDCA was discontinued without any following al- clinical picture. In this enviroment, the seric ADA2 activity is a useful teration of liver function. screening tool with limited availability. Genetic diagnostic test with a During early infancy, developmental delay was noted in association more specific approach using WGS and/or MLPA can be the key for with spastic paraplegia and microcephaly. Brain MRI, performed at the final diagnosis. the age of 1 and 9, showed radiated crowns and semioval centers hyperintensity, lateral ventricles slight dilation and two symmetrical Acknowledgments hyperintense areas at pontine tegmentum. She also presented IgA Special acknowledge for dr. Solans, first physician who suspected the deficiency, mild psoriasis and dysmorphic elements (broad forehead, disease, and all the laboratory crews of the Immunology Department of very high and external eyelids, long eyelashes, fetal pads, protruding Hospital Clínic i Provincial - IDIBAPS, and the Biochemistry Section of the auricles and supernumerary teeth). Hospital Vall Hebron. At the age of 10, whole-exome sequencing showed the de novo vari- ation c.2159G>A, p.(Arg720Gln) in the IFIH1 gene, consistent with Disclosure of Interest AGS. Therefore, blood IFN signature was investigated, resulting mark- None Declared edly elevated. She underwent a thorough autoimmune screening, which was unremarkable. Brain MRI was repeated, resulting stable compared to the previous ones, as well as neurologic evaluation. P47 Conclusion: AGS syndrome should be suspected in infants with Clinical course of aicardi-goutières syndrome in a girl with idiopathic cholestatic liver disease, in particular when a history of cholestatic liver disease and global neurological impairment unexplained neonatal thrombocytopenia is present, even before the 1 1 1 1 1 A. Diana , R. Naddei , A. Di Stazio , F. Di Dato , G. Cappuccio ,G. neurological impairment onset. In this regard, IFN signature may be 1 1 2 1 1 Terrone , N. Brunetti-Pierri , S. Volpi , R. Iorio , M. Alessio useful in the diagnostic work-up. Given the disease prognosis and Department of Translational Medical Sciences, Section of Pediatrics, the lack of approved therapeutic options, we are going to start an University of Naples Federico II, Naples; Center for Autoinflammatory off-label treatment with a JAK/STAT inhibitor in this patient, although Diseases and Immunodeficiency, IRCCS Istituto Giannina Gaslini, Genoa, some issues are unsolved, such as the risk of liver toxicity associated Italy to JAK/STAT inhibitors, the real effectiveness to treat a long-course Correspondence: R. Naddei brain disease and the difficulty in monitoring treatment efficacy. Pediatric Rheumatology 2021, 20(Suppl 1):P47 Written informed parental consent for publication was given. Introduction: Aicardi-Goutières Syndrome (AGS) is an autoinflamma- Disclosure of Interest tory leukodystrophy characterized by global neurologic dysfunction, None Declared associated to an increased expression of type I interferon (IFN)-stimu- lated genes (the so-called IFN signature). Objectives: To describe the clinical course of a 10-year-old girl diag- P48 nosed with AGS. Myositis as an unusual presentation of ADA2 deficiency 1 1 1 1 2 1 Methods: Case report. M. Rossano , F. Baldo , S. Torreggiani , L. Baselli , S. Giliani , S. Lanni ,A. 1 1 1 Results: The girl was born at 37 weeks of gestation to non- Petaccia , G. Filocamo , F. Minoia consanguineous parents by urgent caesarean section due to fetal dis- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan; tress. Her mother suffered from congenital hearing loss and intellectual ASST Spedali Civili di Brescia , Brescia, Italy disability. Birth weight was 2150 g (small for gestational age). Since the Correspondence: M. Rossano first days of life, she presented hypotonia, thrombocytopenia (platelets Pediatric Rheumatology 2021, 20(Suppl 1):P48 [PLT]: 29400/mmc) and splenomegaly, so she was admitted to a Neo- natal Intensive Care Unit (NICU) where she remained for four weeks. Introduction: ADA2 deficiency (DADA2) is a complex monogenic Suspecting neonatal sepsis, she underwent intravenous antibiotic treat- autoinflammatory condition characterized by protean manifestations, ment, soon after discontinued due to negative blood, urine and cere- including haematological, cutaneous, articular and vascular involvement. brospinal fluid (CSF) cultures. TORCH showed positivity for rubella- and Diagnosis is often difficult, due to the highly variable clinical phenotypes CMV-IgG, as well as maternal TORCH all over the pregnancy. Urine, and the indolent course of the disease, often becoming overt when a plasma and CSF CMV-DNA was negative. Few days later, she presented major event occurs. fever and severe anemia requiring red blood cells transfusion in associ- Objectives: To describe an unusual case of ADA2 deficiency ation with Staphylococcus Hominis sepsis, treated with intravenous an- presenting with myositis, due to compound heterozygosity for a tibiotics. At one-month follow-up, PLT were normalized and have missense mutation and a novel deletion in ADA2. remained normal since then. Echocardiography revealed anomalous Methods: A 7-year old boy came to our attention for intermittent bi- pulmonary venous return, that required, at 8 months of life, coil lateral leg pain. Clinical evaluation was unremarkable, with normal embolization. Cerebral ultrasound showed lenticulostriate vasculopathy. strength. Blood tests revealed elevated inflammatory markers and During her stay in NICU, the patient also started a protein hydrolysate normal lactic dehydrogenase (LDH) and creatinkinase (CK). Moderate formula due to repeated episodes of vomiting. At the age of 4 years, lymphopenia was observed with low count of both CD19+ and NK cow’s milk proteins were reintroduced. cells, elevated CD3+HLA-DR+ cells, and low levels of IgM; double At the age of 4 months, she presented vomit and lethargy. She was negative αβ T lymphocytes were normal (Table 1). Magnetic reson- admitted to a local hospital where anicteric cholestatic hepatitis (SGOT ance (MRI) showed bilateral signs of polymyositis of the lower limbs. 1321 U/L, ALAT 1834 U/L, GGT 231 U/L), acidosis and hyperammonemia He subsequently developed nocturnal fever, multiple inguinal and were found. She was treated by providing a glucose-based solution with axillary lymphadenopathy and splenomegaly. An infectious workup pH and ammonium normalization and then she was transferred to our De- was negative, as well as an autoimmunity panel including myositis partment, due to persistence of transaminases and GGT elevation. Abdo- specific and associated autoantibodies, and serum markers of malig- men ultrasound was normal. IgG and IgM for CMV resulted positive, as well nancies. PET-scan showed multiple tracer uptake in axillary, inguinal as urine CMV-DNA, therefore CMV-related hepatitis was suspected. and abdominal lymph nodes (SUV max 2.2). A myogenic pattern of Pediatric Rheumatology (2022) 20:2 Page 32 of 39 active denervation was confirmed by electromyography. Muscle bi- specific diagnosis, either because their clinical phenotype is not diagnostic opsy revealed non-specific signs of inflammation with scarce macro- or genetic tests are negative. phagic infiltration; no alteration of muscle fibres nor perifascicular Objectives: To report an unsolved case of uSAID with successful anti- atrophy or clear signs of vasculitis were reported. Bone marrow and IL-1 treatment. lymph node biopsy with flow cytometry were negative for Methods: A twelve years old male with recurrent fever associated malignancy. with fatigue, myalgia and oral aphthosis. Due to the extremely painful musculoskeletal involvement associated Results: Since the age of 11 years the patient had recurrent to the development of recurrent infiltrative burning nodular skin febrile episodes, with high fever (maximum temperature 40°C) of lesions of both hands and feet, a symptomatic treatment with variable duration (range 3-10 days), monthly, associated with fa- indomethacin was started with dramatic and prompt relief, but tigue, myalgia, periorbital oedema and sometimes oral aphthosis. persistence of elevated acute phase reactants. There was no rash and no history of genital aphthosis. The boy Genetic sequencing of ADA2 revealed compound heterozygosity for was born full term from physiological pregnancy and unrelated a novel frameshift deletion in the catalytic domain, parents. Family history revealed mother with history of similar c.1100_1113del:p.I367Tfs*41, inherited from the father, and a symptoms. At the admission, during a febrile episode, laboratory maternally inherited missense variant, c.1148G>A:p.G383D , assessment showed low white blood cells count (3540/uL, n.v. previously described in compound heterozygosity in a patient with 5000-19000), raised C reactive protein (CRP) (100,84 mg/l, n.v < DADA2. ADA2 functional analysis confirmed pathological low activity 5), raised erythrocyte sedimentation rate (ESR)(101 mm/h, n.v. 0- of the enzyme. Brain angio-MRI was unremarkable. Etanercept treat- 13) and anemia (hemoglobin 8.9 gr/dl, n.v. 10-18). Covering the ment was started with rapid response of muscoloskeletal and skin in- possibility of a bacterial infection, the patient was treated with volvement, normalization of inflammatory markers and regression of broad spectrum antibiotics. Infections were excluded. Fecal cal- lymphoproliferation. protectin showed not pathological values. Chest x-ray, echocar- Results: diogram and electrocardiogram were normal. Abdominal Conclusion: We report an unusual case of DADA2 presenting with ultrasound showed a liver and spleen increased volume. Bone myositis, which is seen in less than 1% of ADA2 deficiencies, due to marrow aspirate resulted negative. Because of the persistence of a novel ADA2 deletion leading to premature protein truncation, in fever, he started on Indomethacin therapy with response. a whole compound heterozygosity with the recently described c.1148G>A body MRI STIR sequences was performed showing symmetrical mutation. The pathogenic role of the latter, so far reported in only signal hyperintensity of the cancellous bone of the distal femur, two siblings in compound heterozygosity, is supported by our data. tibia and radius. On the basis of clinical history and imaging a DADA2 phenotype spectrum is constantly increasing and description chronic recurrent multifocal osteomyelitis (CRMO) was suspected. of peculiar cases could improve genotype/phenotype correlation and Because of the worsening of symptoms and laboratory parame- lead to significant progress in diagnosis, management and prognosis ters, even with maximum dosage of the drug, , after few months of these patients. Written informed parental consent for publication he switched to Colchicine therapy. He showed clinical and labora- was given. tory wellness associated with resolution of lesions to MRI study, but also in that case, after few months symptoms recurred and Disclosure of Interest the initial dosage of drug was gradually increased, without bene- None Declared fits. Genetic tests for autoinflammatory diseases were performed, resulting negative. In the last hospitalization MRI STIR was re- peated, confirming previous findings. He also underwent to bone biopsy, that excluded malignancy. In consideration of persistence of fever, associated with fatigue and myalgia and increased in- Table 1 (abstract P48). See text for description flammatory markers (CRP 111,3 mg/L, ESR 49 mm/h), Anakinra (anti IL-1) was introduced (2 mg/kg/die), with ready significant Weeks from 4 6 14 16 21 43 46 56 61 clinical and laboratory response. disease onset Conclusion: The spectrum of autoinflammatory diseases is rapidly Therapy Indomethacin Etanercept expanding owing to recent developments in molecular sciences and start start genetics. However, for some autoinflammatory disorders no genetic CRP (mg/dl) 2,64 3,19 5,13 2,08 0,9 2,53 0,05 0,05 0,05 alteration can be found. These cases are defined uSAID and Anakinra ESR (mm/h) 52 63 52 40 35 44 13 4 2 seems to be a feasible treatment option. Our patients presents features of different autoinflammatory disorders (recurrent fever, oral Hb (g/dl) 11,1 9,9 9,9 9,4 10,2 9,5 10,3 11,3 12 aphthosis, peri orbital oedema, symmetrical hyperintensity STIR WBC (cell/ 5400 6100 7050 4990 5060 5540 4650 3260 4020 lesions at MRI, leukopenia in acute phase, elevation of inflammatory mm3) indexes) but no mutations of associated genes were found. We N (cell/mm3) 3760 4270 4760 2840 2910 3320 2210 1050 1890 expect to perform whole exome sequencing. L (cell/mm3) 850 750 1390 1380 1310 1470 1790 1570 1440 Disclosure of Interest None Declared P49 A case of undifferentiated systemic autoinflammatory disorder 1 2 2 2 1 P50 M. Tardi , F. Annunziata , M. L. Pennacchio , F. Paciello , B. Raffaele ,R. 1 1 1 Early-onset recurrent neuroinflammation and arthritis: a diagnostic Sottile , L. Martemucci , F. Orlando and therapeutic challenge Rheumatology Unit, Department of Pediatrics, Santobono-Pausilipon 1 1,2 1 1 1 S. Torreggiani , M. Pozzato , G. Filocamo , S. Lanni , S. Guez ,F. M. Children Hospital; Department of Translational Medical Sciences, 1 3 3 3 4 Triulzi , A. Tozzo , F. Andreetta , P. Cavalcante , M. Iascone ,C. Section of Pediatrics, University of Naples Federico II, Naples, Italy 1,2 1,2 1,2 1,2 Agostoni , N. Bresolin , S. Barbieri , F. Martinelli Boneschi ,F. Correspondence: M. Tardi 1 1 Minoia , R. Dilena Pediatric Rheumatology 2021, 20(Suppl 1):P49 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; 2 3 Università degli Studi di Milano; IRCCS Istituto Neurologico C. Besta, Introduction: Autoinflammatory diseases are a group of diseases related Milan; ASST Papa Giovanni XXIII, Bergamo, Italy to dysfunction or dysregulation of innate immunity and can cause serious Correspondence: S. Torreggiani morbidity and mortality by affecting multiple organ systems. Patients with Pediatric Rheumatology 2021, 20(Suppl 1):P50 symptoms commonly found in autoinflammatory disorders may not fit a Pediatric Rheumatology (2022) 20:2 Page 33 of 39 Introduction: Neuroinflammation is increasingly identified in Introduction: Actinopathies are a growing group of monogenic pediatric patients, as an isolated finding or in the context of immune attributed diseases related to the defects in remodeling autoimmune and autoinflammatory conditions. Due to marked pathways of actin cytoskeleton. clinical heterogeneity and phenotypic overlap, diagnosis is often Objectives: To confirm the significance of Immuno-Actinopathies role challenging. in the pathogensis of an expanding group of autoinflammatory dis- Objectives: To describe an unusual case of early-onset recurrent cen- eases and primary immunodeficiencies. tral nervous system (CNS) inflammation and demyelination associ- Methods: Two patients referred with a history of chronic ated with arthritis. mucocutaneous lesions and selected laboratory immune phenotype Methods: Whole exome sequencing (WES) was performed, followed abnormalities. 1 st by targeted reanalysis of neuroinflammation related genes. First, A 3 years old female patient of 1 cousin consanginous parents Results: A previously healthy 13-month-old girl was admitted to our presented with spontaneous vascuilitic cutaneous ulcerations in the hospital due to hyporeactivity and asymmetric tetraparesis with dys- inguinal flexure& the thighs (Biopsy confirmed) and multiple vulval tonic posturing, a week after an upper respiratory infection. Brain abscesses.She had a serial history starting at the age of 2 months MRI showed symmetric talamic lesions, with involvement of the sur- with bleeding per rectum & eczema diagnosed as cow milk protein rounding white matter and the right optic tract. CSF studies includ- intolerance, an althrough sequences of recurrent infections (bilateral ing PCR for HSV1-2, VZV, CMV and anti-MOG antibodies were normal. purulent otitis media(P.aeruginosa) , skin abscesses &Staphylococcal She was diagnosed with acute disseminated encephalomyelitis pneumonia) and multiple confirmed food allergies during weaning st (ADEM) and treated with high dose intravenous methylprednisolone trials. Second, A 5 years old male patient of 1 cousin consanginous and 2 g/kg IVIG. Due to the age at onset and the basal ganglia invo- parents,presented with multiple spontaneous cutaneous sterile lement, a Biotin-Thiamine-Responsive Basal Ganglia Disease was ex- ulcerations,punched out lesions, necrotic demal lesions & paperous cluded by sequencing of the SLC19A3 gene. Further metabolic shiny skin in both upper& lower limbs together with acquired mild investigations including mitochondrial DNA analysis were also nega- microstomia (a result of recurrent attacks of stomatitis), fissured lips, tive. Three months later her neurologic exam was unremarkable with distorted tongue mucosal lining and decayed teeth. He had a the exception of mild right lower limb dystonia; her brain MRI chronic history of attacks of periodic fever . rd showed an almost complete resolution of previous abnormalities. Results: On physical examination, first patient was below 3 centiles At 19 months of age, 17 days after the anti measles, mumps, and for weight & height, coarse facies& no organomegaly or rubella vaccine, the patient presented with acute onset of lymphadenopathy.Significant lab studies was in the form of chronic strabismus, vertical nystagmus and ataxia. Brain and spinal cord MRI fluctuating thrombocytopenia(3- 36 X 10³μL) with small platelet showed new lesions in the supra- and infratentorial white matter and volume(<7fl), high IgA (679mg/dl)&significantly high IgE(3600-7500 IU/ in the optic nerves, and a longitudinally-extensive transverse myelitis L).Patient responded markedly to repeated sessions of pulse steroid (LTEM) lesion at C2-C4 level. As in the first episode, inflammatory theray (Methylprednisolone; 30mg/kg x 5 days) paired with IVIG markers were negative. CSF studies were normal, with oligoclonal followed by oral steroids and was referred for HSCT(Hematopoietic bands, anti-aquaporin and anti-MOG antibodies negative both on stem cell transplantation).Genetic studies revealed ARPC1B deficiency. th serum and CSF. Complement function was normal and blood IFN sig- On physical examination, second patient was on 25 centiles for nature was negative. A transient positivity for ANA (1:640) and for p- weight&height, IQ 75, facies(frontal bossing, wide nostrils& long ANCA was observed but not confirmed in further testing. HLA-B51 dense eye lashes) and no organomegaly or lymphadenopathy. was detected. WES was not contributive, despite a reanalysis of > Significant lab studies was in the form of high inflammatory markers 250 neuroinflammation related genes . She again required high dose (Neutrophilia,high ESR&CRP), low seum IgG(440 mg/dl) and high intravenous methylprednisolone and was started on periodic 2 g/kg seum IgA(270 mg/dl).Patient responded partially to pulse steroid IVIG for 12 months. Despite almost complete regression of neuro- theray(Methylprednisolone; 30mg/kg x 5 days) and IVIG. Marked logic signs, MRI lesions improved but persisted. improvement was noted post an add–on Subcutaneous weekly Nine months after the last neurological event, the patient Methotrexate injections with oral steroids. Genetic studies revealed a developed arthritis involving the temporomandibular joint, the right Homozygous WDR1mutation. knee and ankle, requiring treatment with intra-articular steroid Conclusion: Refractory mucodermal disintegrity in pediatrics can clue to injections. Based on the joint involvement and the positivity of HLA- serious rare immunorelated disorders.Actinopathies paves the complexity B51, she was also started on methotrexate and colchicine. At the age of merging autoinflammatory states and immunodeficiencies.HSCT is a of 38 months, she is neurologically stable with fluctuant right lower fundemental curative therapeutic line. Written informed parental consent limb dystonia, despite incomplete regression of right ankle arthritis. for publication was given. Conclusion: We described a case of early-onset recurrent neuroin- flammation presenting with features of ADEM, MOG Associated Dis- Disclosure of Interest ease (MOGAD) and Neuromyelitis optica spectrum disorder (NMOSD), None Declared associated with arthritis. Clarifying the immunologic process under- lying this phenotype will help guide treatment. 1. McCreary D, Omoyinmi E, Hong Y, et al. Development and Validation P52 of a Targeted Next-Generation Sequencing Gene Panel for Children A novel presentation of a hereditary periodic syndrome: which With Neuroinflammation. JAMA Netw Open. 2019;2(10):e1914274. variant is responsible? S. Al-Mayouf, L. Akbar Disclosure of Interest Pediatric Rheumatology- King Faisal Specialist Hospital and Research None Declared Center, Riyadh, Saudi Arabia Correspondence: L. Akbar Pediatric Rheumatology 2021, 20(Suppl 1):P52 P51 chronic mucocutaneous lesions revealed underlying rare Introduction: Recently, plasminogen, its activators, and its receptors have actinopathies-related disorders (Two case reports) gained more attention in inflammation regulatory processes, including H. M. Abd El-Lateef release proinflammatory signaling molecules, and thus its role has Pediatric Rheumatology Immunology department, Ain Shams University, implications for a wide spectrum of clinical manifestations. Cairo, Egypt Objectives: Heres’ we presented a case of homozygous Pediatric Rheumatology 2021, 20(Suppl 1):P51 plasminogen variant managed initially as periodic fever syndrome. Pediatric Rheumatology (2022) 20:2 Page 34 of 39 Methods: Case report chondritis, and vasculitis. Patients fulfilled clinical criteria for inflam- A 9-year-old boy presented at the age of 18-months with peri- matory (relapsing polychondritis, Sweet syndrome, polyarteritis odic fevers and vomiting every 3 weeks, lasting for 48-72 hours. nodosa, giant cell arteritis) and hematologic (myelodysplastic syn- Heterozygous variant of MEFV gene was detected drome or multiple myeloma) conditions. We have named this disease (c.442G>C; p.E148Q). Over a period of 7 years he developed re- VEXAS (Vacuoles, E1 ubiquitin activating enzyme, X-linked, Autoin- current headaches, abdominal pain, dysphagia, failure to thrive, flammatory, Somatic) syndrome. Mutations at p.Met41 resulted in eosinophilic esophagitis, recurrent otitis media, pneumonias, bron- loss of the cytoplasmic isoform of UBA1 and decreased ubiquitylation chial asthma like exacerbations, eye redness, tearing, delayed and, unexpectedly, the expression of a novel, catalytically inactive, wound healing, periodontitis, and loss of teeth. Also, he was toxic isoform, in mutant, but not wildtype, lineages. We have further found to have Pseudotumor cerebri. Immunological and infectious identified a genotype-phenotype correlation, suggesting specific risk work-up were inconclusive. Colchicine and short courses of ste- factors for severe disease progression. Mutant peripheral blood cells, roids were initiated. However, anakinra was added with a partial and depletion of UBA1 in vitro, exhibited activated innate immune response. It is worth mentioning that his parents are first-de- pathways and evidence for unfolded protein response (UPR). Knock- gree cousins; he has a twin sister with severe cyclic GI manifesta- out of the zebrafish UBA1 cytoplasmic isoform homologue caused tions, with remarkable response to anakinra. Other siblings had systemic inflammation. sickle cell disease suffered from similar complaints as the index Conclusion: By querying exomes for mutations in ubiquitylation case with varying degrees in severity. With the constellation of genes, we have defined a novel disorder, VEXAS) syndrome, which findings and the inadequate response to therapies, whole-exome connects seemingly unrelated adult-onset inflammatory syndromes sequencing was obtained revealing homozygous variant in plas- and hematologic diseases and establishes a precedent for a new mo- minogen gene; coding for plasminogen. However, his twin was lecular taxonomy of rheumatic diseases. Our work also reveals som- found to have heterozygous plasminogen variant. atic mutations as an underrecognized cause of adult-onset rheumatic Conclusion: Our case had a constellation of diseases. findings cannot fully be explained by one classified autoinflammatory disease. Although we have no Disclosure of Interest definite diagnosis; we believe that plasminogen gene variant, with None Declared the coexistence of MEFV gene variant might contribute to the clinical manifestations. Further studies needed to confirm this finding and allow more definitive conclusion. Written informed P54 parental consent for publication was given. Sharpenia, a novel autoinflammatory disorder caused by dysregulation in TNF-mediated cell death 1 1 1 2 1 1 Disclosure of Interest H. Oda , K. Manthiram , H. Kuehn , A. Rao , D. Beck , M. Nehrebecky ,A. 1 1 1 1 1 None Declared Ombrello , T. Romeo , J. J. Chae , I. Aksentijevich , D. Kastner 1 2 NIH, Bethesda, United States; Manipal Hospital, Bangalore, India Correspondence: H. Oda P53 Pediatric Rheumatology 2021, 20(Suppl 1):P54 Identification and characterization of vexas syndrome caused by somatic mutations in UBA1 Introduction: The linear ubiquitin chain assembly complex (LUBAC) D. Beck, M. Ferrada, K. Sikora, A. Ombrello, D. Ospina Cardona, L. Wilson, consists of HOIP, HOIL1, and SHARPIN and is essential for linear P. Hoffman, K. Manthiram, I. Aksentijevich, P. Grayson, D. Kastner ubiquitination of NF-κB and other immune pathways. Patients with National Institutes of Health, Bethesda, United States HOIP and HOIL1 deficiencies present with severe immunodeficiency, Correspondence: D. Beck autoinflammation, and excessive glycogen storage. The role of cell Pediatric Rheumatology 2021, 20(Suppl 1):P53 death pathways in LUBAC deficiencies has not been investi- gated. Sharpin-deficient mice exhibit severe TNF-dependent skin in- Introduction: Identifying the causes of adult-onset rheumatic dis- flammation due to enhanced apoptosis and necroptosis in the eases remains a challenge, and limits diagnosis, prognosis, and tar- keratinocytes; however the role of SHARPIN in human disease is geted treatment. We hypothesized that mutations in genes unknown. regulating the post-translational modification ubiquitin, previously Objectives: We aimed to investigate a 14 year-old boy from a con- implicated in autoinflammatory diseases, may define new rheumatic sanguineous family in India who presented with childhood-onset disorders. polyarthritis, parotitis, colitis and hepatic glycogen deposition. No Objectives: This study aimed to identify novel genetic causes of skin inflammation or immunodeficiency was noted. autoinflammation using a "genotype" first approach. Methods: We utilized whole exome sequencing in the proband and Methods: We analyzed peripheral blood exome sequence data from his unaffected parents to identify a genetic cause of the disease. 2,560 individuals with inflammation-related diagnoses for deleterious Results: We identified a homozygous frameshift mutation c.220dupC mutations in >800 ubiquitin-related genes. Sanger sequencing, in SHARPIN in the proband. Patient cells revealed no detectable digital droplet PCR, immunoblotting, immunohistochemistry, flow cy- SHARPIN protein and markedly reduced expression of HOIP and tometry, and transcriptome/cytokine profiling were performed. HOIL1, suggesting destabilization of the entire LUBAC. Besides, CRISPR/Cas9 knockout zebrafish provided an in vivo model to assess mutant cells displayed a reduced activity of the canonical NF-κB UBA1 gene function. pathway. We then study the role of apoptosis in the Sharpenia Results: Sixty adult males with autoinflammation and hematologic proband and other patients with LUBAC deficiency. We observed disease were identified with somatic mutations in UBA1, an X-linked dysregulated apoptosis ex vivo, in vitro, and in vivo in all three gene, encoding the major E1 enzyme that initiates cytoplasmic ubi- LUBAC-deficient samples. Of note, the extent of apoptosis correlated quitylation. Mutations were primarily identified at methionine 41, a with the severity of the disease. We identified a stark difference of in- highly conserved residue, and these mutations were not observed in flammatory signatures between blood and synovial fluid samples in exome sequences from over 80,000 healthy controls. Among affected the Sharpenia patient, suggesting tissue-specific inflammation as the individuals, mutations were found in more than half of cause of this disease.Anti-TNF therapy achieved the complete reso- hematopoietic stem cells, exclusively in peripheral blood myeloid lution of inflammation, which further corroborates the role of TNF- cells, and not in lymphocytes or other non-hematopoeitic tissues. Pa- mediated cell death in the pathogenesis of autoinflammation. Intri- tients developed an often-fatal, treatment-refractory inflammatory guingly, despite the absence of clinical immunodeficiency, the aden- syndrome in late adulthood, with fevers, cytopenias, characteristic oids of the SHARPIN deficiency patient showed a remarkably vacuoles in myeloid and erythroid precursors cells, dysplastic bone diminished germinal center formation, which was also notable in marrow, neutrophilic cutaneous and pulmonary inflammation, HOIP and HOIL1 deficiency patients. Pediatric Rheumatology (2022) 20:2 Page 35 of 39 Conclusion: We identified the first case of human SHARPIN episodes and duration /intensity of the pain of arthritis, no further deficiency in a patient with autoinflammation and subclinical skin rash and steroids have been tapered to low dose. immunodeficiency. We re-define human LUBAC deficiency as an Conclusion: We report a new autoinflammatory disease that might autoinflammatory disease caused by dysregulation in cell death be caused by a hypomorphic pathogenic variant in TBK1. Further pathways. studies are necessary to confirm the clinical significance of this finding. Written informed parental consent for publication was given. Disclosure of Interest None Declared Disclosure of Interest None Declared P55 New monogenic autoinflammatory disease due to homozygous P56 loss of function mutation in tank binding kinase 1 Nailfold capillaroscopy: a sensitive method for evaluating 1 1 2 2 P. Pimpale Chavan , I. Aksentijevich , D. Bogunovic , J. Taft ,S. microvascular involvement in children with SARS-COV-2 infection 3 4 1 2 3 4 2 Khubchandani , R. Khubchandani F. Çakmak , A. Demirbuga , D. Demirkol , S. Gümüş , S. Hançerli Torun , 1 2 1 1 2 4 4 NHGRI, National Institutes of Health, Bethesda; Icahn School of G. Kavrul Kayaalp , R. Eker Ömeroğlu , A. Somer , M. Uysalol ,R. Yıldız , 3 1 Medicine at Mount Sinai, New York, United States; Section of N. Aktay Ayaz 4 1 2 3 Histopathology; Section of Pediatric Rheumatology, NH SRCC Children's Pediatric Rheumatology; Pediatric Infectious Diseases; Pediatric Hospital, Mumbai, India Intensive Care Unit; Pediatric Emergency Unit, Istanbul Faculty of Correspondence: P. Pimpale Chavan Medicine, istanbul, Turkey Pediatric Rheumatology 2021, 20(Suppl 1):P55 Correspondence: F. Çakmak Pediatric Rheumatology 2021, 20(Suppl 1):P56 Introduction: TANK binding kinase 1 (TBK1) is a protein kinase with an important role in innate immunity by regulating IFN-I and NF-κB Introduction: The coronavirus (SARS-CoV-2) pandemic, known as signaling, and TNF-induced RIPK1-dependent cell death. To date, COVID-19 has spread all over the world in a short period of time and only 3 cases (one sibship and the index patient) have been identified caused the death of more than 2 million people to date. Although in to have disease-causing variants in the TBK1 gene. severe cases, it mainly progresses as a serious lung disease such as Objectives: We describe the first case report of an Indian patient of pneumonia or acute respiratory distress syndrome (ARDS), numerous Hindu ancestry with a homozygous predicted deleterious missense extrapulmonary manifestations due to systemic hyperinflammation mutation in the TBK1 gene. associated with COVID-19 have been described. The hyperinflamma- Methods: A 8 year old male born of third degree consanguineous tory state and the viral invasion may result in endothelial dysfunction marriage was first seen at 4 years 7 months of age with a history of and capillaroscopic examination of the nailfold may be a feasible onset at 18 months. He presented with irregularly spaced episodic method for monitoring the microvascular circulation in SARS-CoV-2 large and small joint arthritis lasting for few hours to 2-3 days, poly- infection. morphic skin rash described by his previous physician notes as ul- Objectives: With this study, we aimed to investigate the cerative, nodular, urticarial, and one episode of seizures and status microvascular circulation in patients diagnosed with COVID-19 and epilepticus. multisystem inflammatory syndrome in children (MIS-C) by nailfold th Results: His weight (11.5kg) and height (93cm) were below 5 videocapillaroscopy (NVC). centile for age, and he was developmentally normal. There was no Methods: Thirty-one patients with SARS-CoV-2 infection, 26 of whom lymphadenopathy or organomegaly and he had a 2 cms café au lait were diagnosed with COVID-19 and 6 with MIS-C, and 58 healthy spot on the posterior aspect of the left knee. Laboratory peers were included in the study. All fingers except the thumbs were investigations revealed hemoglobin of 7.9 -11.8 g/dL, white blood examined paying greater attention to the ring finger of the non- 3 3 cells 8600-23700/mm , platelets 3,00,000-7,19,000/mm , ESR 7- dominant hand for the presence of any abnormality bilaterally and 90mm/Hr, CRP 13-69mg/dL, and Immunoglobulin profile were nor- two images from eight fingers were obtained from both the study mal for age and gender. Anemia, neutrophilic leukocytosis, thrombo- and control groups. Sixteen images were examined for the morph- cytosis, and raised acute phase reactants normalized between the ology of capillaries, presence of pericapillary edema, microhemor- episodes. Bone scan, MRI, and CT brain were normal. rhage, avascular area, and neoangiogenesis. These parameters were Suspecting a systemic autoinflammatory disease (SAID), a next- assessed as present or absent, and the presence of signs in at least generation sequencing SAID gene panel (53 genes) was utilized but two fingers was recorded as capillary abnormality in both groups. Ca- was not contributory. Meanwhile, he was started on colchicine which pillary length, capillary width, apical loop, arterial and venous width, had to be discontinued after the family reported an increase in the fre- and intercapillary distance were measured from three consecutive ca- quency of rash. His episodes responded well to p.r.n paracetamol or na- pillaries from the ring finger of the non-dominant hand. proxen and the family was reluctant to add treatment without a Results: COVID-19 patients showed significantly more capillary ramifi- definitive diagnosis. At age 7 years 9 months, he developed periorbital cation (p<0.001), capillary meandering (p=0.04), microhemorrhage swelling, anasarca, and nephrotic range proteinuria and was started on (p<0.001), neoangiogenesis (p<0.001), capillary tortuosity (p=0.003). prednisolone @2mg/kg by a nephrologist with a diagnosis of nephrotic Capillary density (p=0.002) and capillary length (p=0.002) were sig- syndrome. A kidney biopsy was performed when he was on steroid nificantly lower in the patient group while intercapillary distance (p= treatment, which revealed minimally involved glomeruli with no signs 0.01) was significantly longer compared with healthy volunteers. of chronicity or amyloid deposits and immunofluorescence was nega- Morphologically, patients with MIS-C had a higher frequency of capil- tive while electron microscopy revealed flattening of the foot pro- lary ramification and neoangiogenesis compared with COVID-19 pa- cesses. The proteinuria responded well to steroids. Whole exome tients (p=0.04). Patients with capillary abnormalities had significantly sequencing was performed in the proband and his unaffected parent higher levels of C-reactive protein (CRP) and D-dimer (CRP; and identified a homozygous missense mutation in the kinase domain 16.4 vs 2.2, p=0.04 and D-dimer; 900 vs 340, p=0.04). of the TBK1 gene, c.634T>G (p.Y212D). Both the parents and elder fe- Conclusion: Children diagnosed with COVID-19 and MIS-C present male sib are healthy carriers for this variant. This missense substitution with several microvascular abnormalities on NVC examination. MIS-C is classified as Likely Pathogenic by ACMG classification criteria with a is an emergency phenomenon in which evidence suggests activation CADD score of 24.9. Preliminary functional experiments support the of ECs as the key determinant in the pathogenesis of the disease, pathogenicity of this variant. and NVC may be a useful non-invasive, valid method for assessing The patient has been started on Infliximab biosimilar molecule since the microcirculatory status of children with MIS-C. As a preliminary 3 months to which he has responded well with the decrease in one, our study may take attention to the use of NVC for follow-up of Pediatric Rheumatology (2022) 20:2 Page 36 of 39 patients with SARS-CoV-2 infection during clinical course and Table 1 (abstract P57). Clinical and laboratory data of the study management. population Key Words: COVID-19, Nailfold Videocapillaroscopy, microcirculation, endotheliitis Clinical data (n = Clinical data (n = Laboratory n= Laboratory n = 27 Laboratory n=27 27) 27) Data 27 Data Data Gender, n (%) Symptoms at SARS-CoV2 Hemoglobin 12.2 g/dL ALT 24 U/L Disclosure of Interest presentation, n serologic (9.4 – 15.5) (8 – (%) status, n (%) 115) None Declared Male 14 Fever 26 IgG+ / IgM- 24 Platelet 197 10 /μL LDH 540 U/ (52) (96.3) (88.9) count (62 – 513) L (317 – 1014) P57 Female 13 Abdominal 16 IgG+ / IgM+ 2 (7.4) CRP 112.3 mg/L Albumin 3.4 g/ Early recognition of multisystem inflammatory syndrome (48) pain (59.2) (9.15 – dL 420.8) (2.1 – temporally associated to COVID-19 in the emergency department: 4.5) a single tertiary care centre experience Age, yrs 7.1 Diarrhea 14 IgG- / IgM+ 1 (3.7) PCT 2.38 ng/mL Triglycerides 193mg/ 1 1 2 1 1 A. Mauro , M. Maglione , F. Orlando , A. Giannattasio , R. Margherita ,T. (0.8- (51.8) (0.16 – dL 1 1 1 1 1 1 12.3) 188) (70 - Gagliardo , L. Zenzeri , S. Lenta , S. Muzzica , C. D'Anna , C. Di Lillo ,R. 850) 1 1 Mancusi , V. Tipo History of SARS- Vomit 12 Blood tests Fibrinogen 598 mg/dL Creatinin 0.43 1 2 CoV2 (44.4) (223 – mg/dL Emergency Department; Pediatrics, Aorn Santobono-Pausilipon, Naples, infection/contact, 1109) (0.15 – n (%) 1.63) Italy Correspondence: A. Mauro Previous 5 Conjunctivitis 13 WBC count 11.74 D-dimer 1016 ng/ CK 80 U/L infection (18.5) (48.1) 10 / ml (8.8 - (16 - Pediatric Rheumatology 2021, 20(Suppl 1):P57 μL 14776) 5930) (4.16 28.72) Introduction: Multisystem Inflammatory Syndrome in Children (MIS- Close contact 9 Skin rash 11 Neutrophil 9.41 Ferritin 635.8 μg/L BNP 199.5 C) is a new and life-threatening disease temporally associated to with SARS- (33.3) (40.7) count 10 / (31.3 – pg/mL Covid-19. CoV2+ subject μL 8115) (5 - (3.29 5000) Objectives: The aim of the study is to analyze the clinical, 24.64) laboratoristic and instrumental features of patients with diagnosis of Both 8 Other 0 (0) Lymphocyte 1.29 AST 31 U/L Troponin 25.2 MIS-C at the onset in order to early recognize the disease. (29.6) count 10 / (13 – 245) ng/L μL (0.02 - Methods: We retrospectively reviewed clinical records of children (0.36 1523) admitted to our Emergency Department between April 2020 and – 15.93) March 2021, who were ultimately diagnosed with MIS-C associated Abbreviations: WBC, white blood cells ; CRP, C-reactive protein; PCT, procalcitonin; AST, aspartate aminotransferase; ALT, alanine with SARS-CoV2. Data collected included all clinical and laboratory aminotransferase; LDH, lactate dehydrogenase; CK, creatin kinase; BNP, brain natriuretic peptide parameters at presentation to the Emergency Department. We also recorded data regarding the duration of fever and hospitalization and the presence of abnormalities at chest X-ray, abdominal and car- P58 diac ultrasound. Multisystem inflammatory syndrome in children: clinical Results: Clinical and laboratory data of the twenty-seven children characteristics, diagnostic findings and therapeutic interventions at retrospectively enrolled, including symptoms at presentation to the a tertiary care center in South of Italy Emergency Department, are summarized in Table 1. Median duration 1 2 3 2 4 F. Orlando , A. Giannattasio , F. Paciello , A. Mauro , M. Tardi ,S. of fever was 4 days (range 1.5 – 7). With the exception of fever, ab- 2 2 2 2 4 4 Muzzica , C. D'Anna , M. Rosa , M. Maglione , R. Sottile , L. Martemucci , dominal pain and diarrhea were the most frequent complaints at V. Tipo presentation. No significant differences were found between labora- Department of Pediatrics, AORN Santobono Pausilipon, Napoli; tory parameters in children with or without abdominal pain, diarrhea, 2 3 Pediatric Emergency Unit, AORN Santobono Pausilipon; Department of vomit, conjunctivitis or rash. Translational Medical Sciences, Section of Pediatrics, University of Naples Heartultrasoundshowedno abnormalitiesin11out of 27 Federico II; Department of Pediatrics, AORN Santobono Pausilipon, children (41%). Findings in other children were mainly Naples, Italy represented by mild pericardial effusion (29.6%) and mild mitral Correspondence: F. Orlando valve insufficiency (25.9%). Minor abnormalities in the Pediatric Rheumatology 2021, 20(Suppl 1):P58 interventricular septal dynamics were detected in 3 subjects (11.1%). Abdominal ultrasound was unremarkable in 5 out of 27 Introduction: Multisystem inflammatory syndrome in children (MIS- patients (18.5%). Most children (51.8%) had mild-to-moderate C), also known as paediatric inflammatory multisystem syndrome peritoneal effusion, which was often associated with ileal loops temporally associated with COVID-19 (PIMS-TS), is a condition charac- wall thickening (29.6%). The thickened segments were mostly lo- terised by persistent fever, elevation of inflammatory indexes and cated in proximity of the ileo-cecal valve or of the appendix. evidence of organs involvement or shock. Mesenteric lymphadenitis was found in eleven children (40.7%). Objectives: To describe clinical characteristics, diagnostic findings No significant differences were found in clinical or laboratory and therapeutic interventions of monocentric cohort of MIS-C. parameters between children with abnormal heart or abdominal Methods: Diagnosis of MIS-C was done following CDC criteria. Pa- ultrasounds and those without pathologic findings at these exams. tients were hospitalised at Santobono-Pausilipon Children’s Hospital Chest X ray at presentation showed no significant abnormalities in in Naples, Italy, from November 2020 to March 2021. most patients, and only the child who died one day after admission Results: MIS-C was diagnosed in 29 patients, 14 males (48.3%). Mean showed bilateral basal opacities. age at diagnosis was 7,2 years old (range 4 months-12,9 years). Con- Conclusion: The collected data allow to identify clinical and tact with SARS-CoV-2–positive patient emerged in 18/29 patients laboratoristic tic elements of patients admitted to Emergency care (62%) while 5/29 patients (17,2%) reported symptomatic COVID-19 in unit to provide early recognition of the MIS-C .The study included a the weeks before. SARS-CoV-2 serologic assayrevealed IgG +/IgM- in modest sample size and for this reason the generalizability of results 100% of the patients. No one presented concurrent conditions but is limited. A national multicentre study is ongoing. obesity in 6/29 (20,7%). Mucocutaneous involvement was evidenced in 21/29 patients (72%), gastrointestinal symptoms 22/29 (75.9%), Disclosure of Interest cardiac involvement in 27/29 (93,1%). The most frequent symptoms None Declared Pediatric Rheumatology (2022) 20:2 Page 37 of 39 were fever (100%), conjunctivitis (65.5%), abdominal pain (62%), diar- 35, 74%), the fingers (n=5, 10%) or on both sites (n=7, 15%). SARS- rhoea (48,2%), rash (44,9%), vomiting (31%) and cheilitis (31%). La- CoV-2 RNA detection resulted negative except for 2 patients. Further- boratory findings are summarised in table 1. Troponin resulted more, ten patients observed during the first wave showed a recur- elevated in 16/29 (55,1%), associated elevation of BNP was evidenced rence during the second (F:6), which developed 1-4 weeks after the in 12/29 (62%). Electrocardiography showed alterations in 25/29 second COVID-19 peak; the clinical features were comparable to (86,2%) while echocardiography in 21/29 (72%). Concerning therapy, those of the previous episode. Five of them (50%) reported non- 27/29 (93%) patients underwent parenteral antibiotics at the admis- specific systemic symptoms before onset and/or close contact with sion. Intravenous immunoglobulin (IVIG) was performed in 25/29 SARS-CoV2 positive subject. Repeated SARS-CoV-2 specific IgG/IgA (86,2%) of patients. Due to cardiac involvement 13/29 patients tests were negative for all patients except for three cases (two of (44,8%) received bolus of steroids. 4/29 patients (13,8%) presented them with positive swabs). Neither common virus serology nor co- worsening of clinical and laboratoristic parameters during treatment agulation studies revealed significative results. Two patients pre- with steroids, requiring Anakinra. One patient died due to cardio- sented positive ANA and anti β2 glycoprotein, respectively. A genic shock at the admission. positive IFN signature was detected in 12/ 33 patients (36%).Among Conclusion: Mucocutaneous, gastrointestinal and cardiac the 35 patients tested, the cytokine array showed high levels of IP10 involvement are the most common manifestations in our cohort, as (n= 35, range 12.4-739 pg/ml, n.v. 0.0-0.2 pg/ml) and a mild increase also reported in literature. Biologic treatment was necessary in of IL-6 (n=21, range 2.4-401 pg/ml, n.v. 0.5-2.2pg/ml), without alter- minority of patients. MIS-C is a new emerging condition and repre- ations of CXCL9, IL-1β and TNFa. The detection of SARS-CoV2 specific sent a challenge to paediatricians due to the severity of presentation. lymphocytes showed the presence of SARS-CoV2 specific lympho- More data are needed to better define incidence and prognosis of cytes in 9/17 (52%) patients tested (validated with positive and nega- that condition. tive controls), only one of them with a positive serological test. Conclusion: Albeit the pathogenetic mechanism of ACBLL remains to Disclosure of Interest be elucidated, our preliminary results showed a significant increase None Declared in serum IP10 levels, not frankly associated with a peripheral blood IFN signature, which is instead a characteristic of pernio-related chil- blains. We also proved the presence of a T-specific memory against P59 in 50% of the tested patients, despite the negativity of coltures and COVID-19 pandemic - related chilblains: clinical and immunological serological tests, strengthening the link between SARS-CoV2 infection characterization of an Italian cohort and this peculiar clinical manifestation. 1,2 3 3 1 1 1 S. Signa , F. Manunza , C. Pastorino , P. Bocca , A. Corcione , F. Penco , 1 4 3 4 5 5 A. Bertoni , I. Airoldi , G. Viglizzo , F. Morandi , S. Rosina , S. Viola ,C. Disclosure of Interest 3 6 4 5 2 Occella , M. Acquila , M. Podestà , A. Ravelli , E. Castagnola ,M. None Declared 1 1 Gattorno , S. Volpi 1 2 UOSD Centro Malattie Autoinfiammatorie e Immunodeficienze; UO 3 4 Malattie Infettive; UO Dermatologia; Laboratorio Cellule Staminali post P60 5 6 natali e Terapie Cellulari; UOC Clinica Pediatrica e Reumatologia; UO Diagnostic utility of genetic testing in autoinflammatory diseases - Laboratorio Analisi, IRCCS G. Gaslini, Genoa, Italy current situation in Belgium 1 1 2 Correspondence: S. Signa A. Le Goueff , F. Vandergheynst , G. Smits 1 2 Pediatric Rheumatology 2021, 20(Suppl 1):P59 Internal Medicine Department; Genetic Laboratory, Hôpital Erasme, Brussels, Belgium Introduction: During COVID-19 pandemic, acute acral chilblain-like Correspondence: A. Le Goueff lesions (ACBLL), reminiscent of lupus pernio, were observed during Pediatric Rheumatology 2021, 20(Suppl 1):P60 both first and second COVID-19 peak among patients with highly suspected (but mostly unconfirmed) infection with SARS-CoV-2.The Introduction: Autoinflammatory diseases (AID) are a group of rare aetiology of this phenomenon has not been elucidated yet and monogenic illnesses, leading to uncontrolled activation of the pathogenetic mechanism remains unknown. Several studies have in- innate immune system and presenting with recurrent flares of vestigated cytokine and chemokine profile in patients with COVID-19 systemic and localized inflammation. Diagnosis is confirmed by but an accurate characterization of ACBLL patients is lacking. the detection of a mutation in an AID-related gene and improve- Objectives: We aimed to describe the clinical, laboratory and ments in sequencing techniques have enabled the discovery of immunological features of children presenting with ACBLL referred new entities. to our Institute during the COVID-19 pandemic spread. Objectives: The aim of our study is to explore the impact of evolving Methods: We prospectively collected data of children referred to our genetic testing methods for AID in Belgium and to determine st th Institute from April 1 2020 to February 28 2021. We investigate whether increasing gene panels generate a higher diagnostic rate. the presence of SARS-CoV2 infection through RT-PCR from nasophar- Methods: Retrospective study of 2620 patients that underwent ingeal swabs and three different serologic kit.. All patients underwent sequencing for a clinical suspicion of AID in Belgium, between a laboratory work-up including coagulation, viral serology and auto- January 2015 and December 2020. Sequencing was performed antibodies panel. Finally, we analysed peripheral blood IFN signa- through a 10-gene panel between 2015 and 2017, a 25-gene panel ture, a panel of inflammatory biomarkers in serum/plasma by a flow between 2018 and 2020 and mendeliome technology with a 66- and cytometry bead array (CXCL10, CXCL9, IL-6, IL-1β,TNFα) and the pres- a 502- in silico gene panel in 2020. ence of SARS-CoV2 T specific lymphocytes. Results: Diagnostic rate increased along with the expansion of the Results: We examined 36 children during the first peak, and 11 gene panel with a diagnostic yield of 16% with 10 genes, 18% with children during the second COVID-19 peak (F: 28; median age 12 y), 25 genes and 23% with 502 genes. Factors that raised the diagnostic at a median delay of 26 days after symptoms onset (2-73 days). Fif- rate were Mediterranean ethnicity, abdominal and cardiorespiratory teen patients (31%) presented non-specific systemic symptoms pre- symptoms and absence of mucocutaneous, musculoskeletal, ceding ACBLL onset. Nine patients (19%) reported a possible ophthalmologic or ENT symptoms. contagion from a close contact. All patients presented stereotypical Conclusion: Our study is the first nationwide study for features resembling classical chilblains with acral erythematous- autoinflammatory genetic testing and the first use of mendeliome edematous violaceous plaques and nodules localized on the toes (n= technology for AID diagnosis. Although we confirmed that the Pediatric Rheumatology (2022) 20:2 Page 38 of 39 -31 -28 bigger the gene panel, the higher the diagnostic rate, this expected (P values 7.1 x10 and 2.5 x10 , respectively). Unexpect- technology generated inevitably a higher financial and human cost edly, differences were also observed in frequencies of abdominal -6 although the majority of diagnoses remained amongst the four pain (P=9.6 x 10 ) and of transfusion in absence of macrophage acti- -4 original hereditary recurrent fevers (HRFs). vation syndrome (MAS) or bleeding (P= 1.9x10 ). MAS during treat- -16 ment occurred almost exclusively in DRESS cases (P= 6.2 x 10 ). Acknowledgments HLA-DRB1*15 alleles were strikingly associated with DRESS, but did We thank the whole team from the ULB Centre of Human Genetics for their not distinguish DRESS cases with versus without diffuse lung disease help and their support and especially Mélanie Delaunoy. (DLD) developing during anti-IL-1/IL-6, MAS or comorbid conditions. We also thank the statisticians, Jazon Bouziotis and Mélina Houinsou Hans Preliminary data on outcome after careful drug removal include im- for their work. provement or resolution of lung disease in 11 cases stopping drug with ≥3mos of follow up. Disclosure of Interest Conclusion: A number of clinical features characterize serious DRESS None Declared to IL-1/IL-6 inhibitors in Still’s disease patients. These features are shared by subjects with (~80%) and without the HLA risk allele. For the former, HLA testing allows pre-prescription risk determin- P61 ation. DRESS to IL-1/IL-6 inhibitors in Still’s may be enriched in those Characteristics of hla linked dress reactions to inhibitors of IL-1 with younger onset age, co-occurring cardiopulmonary disease, pre- AND IL-6 in still's disease maturity, or Trisomy 21. Patient outcome with drug removal, as indi- 1 2 3 4 5 6 V. Saper , S. Prahalad , S. Canna , M. Ombrello , M. Kostik , A. Ravelli ,E. cated for DRESS, will be important to evaluate. 7 8 9 10 11 5 Cassidy , S. Bhattad , O. Kasapcopur , T. Hahn , O. Phadke , E. Isupova , 6 12 13 13 13 14 J. Tibaldi , C. Stingl , A. Casey , H. Wobma , T. Klouda , M. Alvarez , Disclosure of Interest 14 15 15 4 G. Espada , K. Torok , A. Robinson , M. Corriea Marques ,J. None Declared 16 1 1 1 Hollenbach , M. Fernandez Vina , L. Tian , E. Mellins on behalf of the Table 1 (abstract P61). See text for description Drug Hypersensitivity consortium 1 2 Stanford University, Stanford; Emory University, Children's Healthcare of DRESS cases Institutional P OR Atlanta , Atlanta; Children's Hospital of Philadelphia, Philadelphia; controls value (95CI) 4 5 NIAMS, Bethesda, United States; Saint-Petersburg State Pediatric Still’s onset age < 2.5 43% (29/67) 19% (19/100) 8.9 x 3.2 (1.6- Medical University, Saint-Petersburg, Russian Federation; IRCCS Istituto -4 years 10 6.5) Giannina Gaslini, Genova, Italy; Geisinger Medical Center, Danville, 8 9 Abdominal pain 24% (16/67) 2% (2/100) 9.6 x 15.4 (3.4- United States; Aster CMI Hospital, Bangalore , India; Istanbul University- -6 10 70) Cerrahpasa, Istanbul, Turkey; Penn State Health Children's Hospital, Hershey; Emory University School of Medicine and Children’s Transfusion (no MAS or 13% (9/67) 0% (0/100) 1.9 x Infinite 12 -4 bleeding) 10 Healthcare of Atlanta, Atlanta; Spectrum Health, Grand Rapids; 13 14 Boston Children's Hospital, Boston, United States; Hospital de Niños Atypical non-evanescent 90% (60/67) 5% (5/100) 2.5 x 98.6 (34- -28 Dr RIcardo Gutierrez, Buenos Aires, Argentina; UPMC Children's rash 10 286) Hospital of Pittsburgh, Pittsburgh; University of San Francisco, San Absolute eosinophils 79% (53/67) 0% (0/100) 7.1 x infinite Francisco, United States -31 >700/ul 10 Correspondence: V. Saper DRESS cases Drug-tolerant Pediatric Rheumatology 2021, 20(Suppl 1):P61 controls Introduction: A subset of Still's patients receiving treatment with IL-1 HLA-DRB1*15:XX (all 79% (56/71) 7% (2/30) not applicable and IL-6 inhibitors developed features (e.g., eosinophilia, atypical ancestries) across ancestries rash) that raised the possibility of drug reaction with eosinophilia HLA-DRB1*15:01 (White) 79% (38/48) 0% (0/19) 8.2 x infinite and systemic symptoms (DRESS). -10 Objectives: To identify features of DRESS that distinguish it from Anti-IL-1 exposure 96% (68/71) 86% (26/30) NS active disease in Still's patients. (0.19) Methods: We organized a multi-center (48 institutions, 11 countries), retrospective case/control study of Still's patients treated with ana- Tocilizumab exposure 27% (19/71) 40% (12/30) NS (0.24) kinra, canakinumab, or tocilizumab (anti-IL-1/IL-6). Inclusion as a case required physician suspicion of a drug reaction during anti-IL-1/IL-6 Elevated AST/ALT 75% (53/71) 13% (4/30) 1.1 x 19 (5.9- -8 treatment. Drug-exposed controls from the same sites (institutional 10 62) controls) were randomly selected Still’s subjects not satisfying the DRESS DRESS with DLD case definition. Each subject was scored for DRESS using the vali- without DLD dated scoring system, RegiSCAR for DRESS, which specifies that fea- HLA-DRB1*15:XX 68% (15/22) 84% (41/49) not applicable tures may be asynchronous and discontinuous. Demographic and across ancestries clinical features of cases and controls were compared; frequencies of some features were compared to population frequencies. HLA allelic MAS during drug 59% (12/22) 71% (34/49) NS frequencies were compared in 71 DRESS cases and 30 drug-tolerant (0.29) controls. Results: Still’s onset age was enriched for <2.5 years in cases vs P62 institutional controls; no significant differences were found in Actinopathies that can be mistaken as hyper ige autosomal frequency of onset age >10 years, adult (>16y) onset of Still's, sex, or recessive ARPC1B deficiency is an actinopathy, this pathology is MAS occurrence pre-treatment. Interestingly, ten cases reported ser- similar way to Hyper IgE syndrome with recurrent infections, ious comorbidities: four with severe congenital heart disease eczema, IgE elevation and vasculitis (CHD),~40X expected live birth rate for CHD, pre-term birth (3) result- 1 1 N. Gomez Hernandez , M. Ortega Cisneros , M. A. Yamasaki ing in bronchopulmonary dysplasia (BPD) in 2 (~30X expected live 2 1 1 Nakashimada , A. Delgado Bañuelos , R. Benitez Serrano on behalf of birth rate), congenital lung disease (1), severe neonatal pneumonia Institute National Pediatric Mexico , City (1), and 2 with CHD and 1 with BPD were among four with Trisomy 1 2 Instituto Mexicano Del Seguro Social, Guadalajara; IInstituto Nacional 21 (~50X expected live birth rate). Comorbid conditions were mostly Pediatria, Ciudad de Mexico, Mexico (7/10) among those with Still’s onset age <2.5 years. Eosinophilia and Correspondence: N. Gomez Hernandez atypical rash were markedly enriched in cases vs controls, as Pediatric Rheumatology 2021, 20(Suppl 1):P62 Pediatric Rheumatology (2022) 20:2 Page 39 of 39 Introduction: Actinopathies that can be mistaken as Hyper IgE None Declared Introduction : Autosomal recessive ARPC1B deficiency is an actinopathy. Defective actin polymerization affects hematopoietic cells, impairing their P63 migration and immunological synapse , characterized by leukocytosis, Allergic reactions of COVID-19 vaccine in a teaching hospital 1 2 eosinophilia, platelet abnormalities and hypergammaglobulinemia; and P.-C. Chen , K.-H. Yang 1 2 clinically, by eczema and food allergy ,infections caused by bacteria, Taipei City Hospital, Taipei, Taiwan, Province of China; Pharmacy, Taipei fungi and viruses, vasculitis, and bleeding diathesis. city hospital, Taipei, Taiwan, Province of China Objectives: Case Report Correspondence: P.-C. Chen 28-year-old male, originally from Michoacan Mexico, his parents are Pediatric Rheumatology 2021, 20(Suppl 1):P63 first cousins. The patient began a three-month-old developed an ab- scess with an anorectal fistula that required surgery at 10 months he Introduction: Because of the epidemic, countries have begun to was hospitalized for an infectious gastroenteritis and a few weeks administer the COVID-19 vaccine. The adverse reactions (ADRs) fol- later once again for a urinary tract infection. This patient presents ec- lowing the vaccine can be divided into three categories. Categories zema and recurrent abscesses from one year of age, multiple epi- are allergic reactions including anaphylaxis, vasovagal reaction in- sodes of otitis media and sinusitis,. cluding vasovagal syncope and vaccine side effects including local At the age of 8 years he was admitted to the National Institute of and systemic. Allergic reactions occurring within 5-30 minutes are Pediatrics of Mexico City with a one-month history of cough and considered as autoimmune problems, and the problems caused are fever, as well as two months of painful erythematous subcutaneous usually unpredictable and may be serious. nodules on both legs. Physical examination revealed a keloid scar on Objectives: For further analysis of the types of allergic reactions, the abdomen after Nissen fundoplication, a normal BCG scar, diffuse medical professionals could remind the patient, prepare the crackles throughout both lung fields, and nodular erythematous le- responder as soon as possible, and as a reference for diagnosis and sions on both legs. Laboratory tests showed Hb 9.8 g / dl, leukocytes related treatment. 15,200 / μl, neutrophils 73%, lymphocytes 17%, eosinophils 5% , Methods: This study is a cross-sectional study that analyzes the noti- 317,000 / μl platelets. IgE 2000 IU / ml, IgG 1870 mg / dl , IgM 420 fication data of adverse drug reaction cases in a regional hospital mg / dl and IgA 968 mg / dl . He also had a negative ANCA and low from March 30 to July 31, 2021, including the AstraZeneca® (AZ) positive ANA, while tuberculin and yeast tests were negative. Sputum brand and the Moderna® brand. And analyze whether the discomfort cultures and gastric aspirates for fungal and bacterial organisms were immediately after vaccination is Allergic reactions, vasovagal reaction also negative. The CT scan of nasal and pulmonary sinuses revealed or vaccine side effects. pansinusitis and saccular bronchiectasis located in the right lung. Results: The total number of COVID-19 vaccines administered under Skin Biopsy of the leg lesions showed septal and lobular paniculitis the AZ® brand was 27,131, and Moderna® had a total of 9,203 with predominant infiltration of lymphocytes and histiocytes. people. A total of 80 adverse events were received. The AZ ® brand Initially, a diagnosis of HIES with erythema nodosum was made: the had 75 and the Moderna® brand had 5 ADRs. Among the ADRs of patient's NIH scoring system was 39, with a positive result diagnosis AZ®, there are 17 allergic reactions (22.67%), 1 vasovagal reaction re- for scores greater than 20 action, and 57 vaccine side effects. Among the ADRs of Moderna®, Treatment with amoxicillin, thalidomide, and prednisone was started there are 3 allergic reactions (60.00%), 0 vasovagal reaction reactions, with improvement of respiratory symptoms and resolution of skin and 2 vaccine side effects. lesions. At age 9 he had multiple flat warts involving the trunk. The skin Out of a total of 20 Allergic reactions, 20 cases require additional biopsy revealed a human papillomavirus infection. The patient was processing to deal with side effects. These side effects include treated with topical retinoids leading to a gradual resolution of the problems related to the injection site (redness at the injection site*2, warts, and thalidomide and corticosteroids were discontinued. In itching at the injection site*5, rash at the injection site*3, soreness at January 2003 he developed thrombocytopenia (63,000 / μl). At age 10, the injection site, pain at the injection site, swollen left upper arm*2, a lung biopsy was performed due to persistent cough and wheezing red upper left arm, lower arm Itchy rash on the other side of the despite taking inhaled steroids and prophylactic antibiotics: results armpit*2), skin-related problems (red rash on the chest with oxygen, revealed obliterative bronchiolitis organizing pneumonia. Mesenteric hives*2, itchy rash on the face and neck*2, skin rash*4), other prob- vasculitis was detected, initiating management with oral cyclosporine lems (wheezing, vomiting*3, red and swollen eyes, chest tightness, and continued with MMF 1 g / day and monthly intravenous gamma dizziness). Among them, one case was reported as a "serious adverse globulin at a replacement dose in the Institute Mexican Secure Social . event", who died eight hours after vaccination. Immunosuppressive treatment was suspended because, at the age of Conclusion: In the ADR of AZ®, 22.67% of allergic reactions is allergic 21 he developed a disseminated molluscum contagiosum on the reactions, which is 0.63 ‰ of the number of people who were trunk, which is why weekly subcutaneous application of interferon administered. Although the proportion is not high, the adverse alpha is indicated with total resolution of his lesions. He has a reactions caused by autoimmunity are likely to become very serious. sequencing study for variants STAT 3, ERBB21P, CARD 11, DOCL8 Medical professionals should pay more attention to these IL6ST, PGM3, SPINK 5 with negative result. It is finally documented information before administering the vaccine. ARPC1B. Conclusion: ARPC1B deficiency phenotype the clinical defect appears Acknowledgments to be characterized by recurrent bacterial and viral infections, Taipei City Hospital extensive eczema, allergies, thrombocytopenia, and skin vasculitis This phenotype is expressed in a similar way to Hyper IgE syndrome Disclosure of Interest with recurrent infections, eczema, IgE elevation and vasculitis .This None Declared particular case made us think about the importance of having a genetic diagnosis. Written informed patient consent for publication was given. 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Pediatric RheumatologySpringer Journals

Published: Jan 10, 2022

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