Despite the low rate of neurological deficits following the SARS-COV-2 infection in the pediatric population, children and adolescents who develop multisystem inflammatory syndrome (MIS-C) after being infected with SARS-COV-2 are at a higher risk for neurological abnormalities and brain injury, increasing the risk of adverse cognitive and psychiatric outcome.Given the increased risk of central nervous system impairment we chose to conduct a prospective study looking at the cognitive and psychosocial outcome of patients with MIS-C.Our study included 27 of the 29 patients between 2 to 18 years of age (M = 11.1, SD = 4.4) who were treated for MIS-C from the onset of the SARS-COV-2 pandemic until the beginning of May 2021 at the only tertiary care pediatric immunology center in Slovenia. We assessed these patients 6 months after diagnosis using the age-appropriate Wechsler intelligence scales and a battery of neuropsychological test measuring attention, executive function, memory and fine motor skills. We also asked parents to report on patients’ psychosocial outcome using the Achenbach Child Behavior Checklist.By using Bayesian statistics to take into account parental education and any potential pre-morbid learning difficulties we found no evidence of impairment on measures of intelligence. However, the posterior distribution of scores on neuropsychological measures indicated that a significant proportion of patients scored 1SD bellow expected levels on measures of attention (31%), executive function (28%) and visual memory (35%). Increased symptoms of depression, anxiety and attention difficulties were also reported by parents, although their extent did not rise to a clinically significant level.The findings from our cohort suggest that the cognitive and psychosocial outcome of patients with MIS-C is generally favorable, although up to 35% may experience specific neuropsychological deficits more than 6 months after diagnosis. The most commonly impaired cognitive domains seem to be attention, executive function and visual memory.Funding for this work was provided by the Slovenian Research Agency grant J3-3061 and University Medical Centre grant 20210069. Support was also provided by Dušica Boben and the publisher Center za psihodiagnostična sredstva by providing the local adaptations of psychological assessment tools.David Gosar Speakers bureau: Biogen, Novartis, Mojca Zajc Avramovič: None declared, Nina Emersic: None declared, Mateja Šušterič: None declared, Maja Maša Šömen: None declared, Damjan Osredkar: None declared, Tadej Avcin: None declared

The J Project (JP) physician education and clinical research collaboration program was established in 2004 by clinician scientists in Eastern and Central Europe (ECE) to increase awareness of primary immunodeficiency disorders (PIDs) and improve the complex care of patients with these conditions [1, 2]. By the end of 2021, 344 J Project meetings were organized (Table 1). The JP has created a collaborative, professional community of clinical immunologists, caring for more than 24,000 patients with PID and a remarkable number of joint publications [1–3]. While most of us live in a peaceful environment, the world is now full of conflict and unsolved legacies, and the area covered by our JP network is no exception. Many of these disputes concern politics and religion, culture and traditions, and some relate to the borders of countries, the citizens of which simply wish to live in peace. Those of us working in medicine, presumably with responsibility only for the physical and mental health of those we treat, are suffering from the consequences of local and global conflicts. We remember when many of our colleagues decided not to attend the 2nd J Project Congress in Antalya, Turkey, because of the conflict between their countries at the time. This is why we formulated a succinct message delivered at the 2nd J Project Congress in Antalya, reiterating that our meeting was dedicated to patients and peace. But, after 18 years of working together in the PID or inborn errors of immunity (IEI) field, the loudest and strongest message to come out of the JP is that we are still together and growing in terms of the area covered, the countries and centers included, and we are developing across existing differences of various kinds between the 32 countries now involved in the project [1]. We are not alone in this endeavor. Indeed, we collaborate closely with the European Society for Immunodeficiencies, the Jeffrey Modell Foundation, and pharmaceutical companies, which provide educational grants for the organization of JP meetings [2]. We are not immune from the problems of a lack of engagement with this wonderful joint project, albeit in only a few countries or a few centers in some countries. We continually try to persuade the less active centers to re-engage in the Project and to bring them back into the fold. We hope to convince them that the JP exists primarily to help those who are lagging behind, and that the reward for our efforts is the diagnosis and treatment of more and more patients throughout Central Europe and Eurasia, including, recently, in Siberia and the Far East of Russia [3, 4]. Advanced centers should be keen to find new ways to help the less developed centers and to raise the global level of patient management and understanding of the importance of IEI throughout medical fields. In a more global sense, the JP provides us with an excellent example of how to overcome differences and conflicts between countries and nations and to build collegiality and friendship through a focus on professional collaboration in our growing community, even during times of strife when tensions surround us. A prominent expression of our strength and reach is the increasing number of PID-focused meetings (Fig. 1), reflecting considerable ambition and enthusiasm and paving the way for improvements in the diagnosis and treatment of patients in our still largely neglected but rapidly developing field [5]. * László Maródi edamarodi@gmail.com

OBJECTIVES To estimate the incidence and describe the spectrum of inflammatory and autoimmune diseases linked to SARS-CoV-2 infection and COVID-19 vaccination in children from two neighbouring south central European countries. METHODS We performed a multi-centre prospective cohort study of children under 18 years diagnosed with inflammatory/autoimmune diseases linked to SARS-CoV-2 infection or COVID-19 vaccination, who were admitted to the paediatric tertiary care hospitals in Slovenia and Friuli Venezia Giulia, Italy, from January 1, 2020, to December 31, 2021. Disease incidence was calculated based on laboratory-confirmed cases only. RESULTS Inflammatory and autoimmune diseases linked to SARS-CoV-2 were diagnosed in 192 children (127 laboratory-confirmed), of whom 112 had multisystem inflammatory syndrome (MIS-C), followed by vasculitis, neurological and cardiac diseases. Calculated risk of MIS-C was 1 in 860 children after SARS-CoV-2 infection and cumulative incidence of MIS-C was 18.3/100,000 of all children. Fifteen children had severe COVID-19. Two patients with MIS-C and a patient with myositis presented after COVID-19 vaccination. All 3 had at presentation also a serologically proven recent SARS-CoV-2 infection. After MIS-C, nine patients were vaccinated against COVID-19 and 25 patients had a SARS-CoV-2 reinfection, without recurrence of MIS-C. CONCLUSIONS Autoimmune diseases following SARS-CoV-2 infection in children were 8.5 times as common as severe COVID-19. MIS-C was the most common manifestation and its incidence in this predominantly white population was higher than previously reported. MIS-C does not seem to recur after SARS-CoV-2 reinfection or COVID-19 vaccination. Autoimmune diseases were much more common after SARS-CoV-2 infection than after COVID-19 vaccination.

In order to address the main challenges related to the rare diseases (RDs) the European Commission launched the European Reference Networks (ERNs), virtual networks involving healthcare providers (HCPs) across Europe. The mission of the ERNs is to tackle low prevalence and RDs that require highly specialised treatment and a concentration of knowledge and resources. In fact, ERNs offer the potential to give patients and healthcare professionals across the EU access to the best expertise and timely exchange of lifesaving knowledge, trying to make the knowledge travelling more than patients. For this reason, ERNs were established as concrete European infrastructures, and this is particularly crucial in the framework of rare and complex diseases in which no country alone has the whole knowledge and capacity to treat all types of patients.It has been five years since their kick-off launch in Vilnius in 2017. The 24 ERNs have been intensively working on different transversal areas, including patient management, education, clinical practice guidelines, patients' care pathways and many other fundamental topics. The present work is therefore aimed not only at reporting a summary of the main activities and milestones reached so far, but also at celebrating the first 5 years of the ERN on Rare and Complex Connective Tissue and Musculo-skeletal Diseases (ReCONNET), in which the members of the network built together one of the 24 infrastructures that are hopefully going to change the scenario of rare diseases across the EU.

Sjögren's syndrome (SS) is a systemic autoimmune disease that frequently occurs concomitantly with other systemic connective tissue disorders, including rare and complex diseases such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). The presence of SS influences the clinical expression of the other autoimmune diseases, thus offering the unique opportunity to explore the similarities in genetic signatures, as well as common environmental and biologic factors modulating the expression of disease phenotypes. In this review, we will specifically discuss the possibility of defining "SS/SLE" and "SS/SSc" as distinct subsets within the context of connective tissue diseases with different clinical expression and outcomes, thus deserving an individualised assessment and personalised medical interventions.

Necrotizing stomatitis is a rare, acute-onset disease that is usually associated with severely malnourished children or diminished systemic resistance. We describe a 1-year-old girl who developed necrotizing stomatitis, vasculitic rash, skin desquamation on the fingers and toes, and persistent hypertension after serologically confirmed SARS-CoV-2 infection. Her laboratory investigations revealed positive IgG anticardiolipin and IgG anti-β2 glycoprotein antibodies, and biopsy of the mucosa of the lower jaw showed necrosis and endothelial damage with mural thrombi. Swollen endothelial cells of small veins in the upper dermis were confirmed also by electron microscopy. As illustrated by our case, necrotizing stomatitis may develop as a rare complication associated with SARS-CoV-2 infection and can be considered as a part of the clinical spectrum of COVID-19 vasculopathy. The pathogenic mechanism could involve a consequence of inflammatory events with vasculopathy, hypercoagulability, and damage of endothelial cells as a response to SARS-CoV-2 infection.

Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, University of Milan, Milan, Italy, Pediatric Rheumatology Unit, ASST G. Pini & CTO, Milan, Italy, Department of Obstetrics, Instituto Fernandes Figueira, FIOCRUZ, Rio de Janeiro, Brazil, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil, Clinical Rheumatology Unit, ASST G. Pini & CTO, Milan, Italy, Department of Allergology, Rheumatology and Clinical Immunology, Children’s Hospital, Ljubljana, Slovenia, University Medical Centre Ljubljana, University of Ljubljana, Ljubljana, Slovenia

Description T cell–derived IFNγ and CD40L/IL-21R signals are crucial for the differentiation of human T-bethighCD21low B cells. The factors behind autoimmune B cells T-bethighCD21low B cells are expanded in various autoimmune disorders and infections, but it is unclear how these cells develop. Determining essential factors related to T-bethighCD21low B cell development might allow for the therapeutic inhibition of these cells and the amelioration of autoimmunity. Here, Keller et al. used RNAseq, ATACseq, and flow cytometry of T-bethighCD21low B cells and ex vivo cell culture of CD21posB cells from healthy donors to identify the factors and cells that contribute to the establishment of T-bethighCD21low B cells. Samples from patients with monogenic immunodeficiencies corroborated that the combination of the B cell receptor and T cell–derived CD40 ligand, IL-21, and IFNγ signals to control differentiation of T-bethighCD21low B cells. These developmental pathways point to potential therapeutic targets for various autoimmune disease. Accumulation of human CD21low B cells in peripheral blood is a hallmark of chronic activation of the adaptive immune system in certain infections and autoimmune disorders. The molecular pathways underpinning the development, function, and fate of these CD21low B cells remain incompletely characterized. Here, combined transcriptomic and chromatin accessibility analyses supported a prominent role for the transcription factor T-bet in the transcriptional regulation of these T-bethighCD21low B cells. Investigating essential signals for generating these cells in vitro established that B cell receptor (BCR)/interferon-γ receptor (IFNγR) costimulation induced the highest levels of T-bet expression and enabled their differentiation during cell cultures with Toll-like receptor (TLR) ligand or CD40L/interleukin-21 (IL-21) stimulation. Low proportions of CD21low B cells in peripheral blood from patients with defined inborn errors of immunity (IEI), because of mutations affecting canonical NF-κB, CD40, and IL-21 receptor or IL-12/IFNγ/IFNγ receptor/signal transducer and activator of transcription 1 (STAT1) signaling, substantiated the essential roles of BCR- and certain T cell–derived signals in the in vivo expansion of T-bethighCD21low B cells. Disturbed TLR signaling due to MyD88 or IRAK4 deficiency was not associated with reduced CD21low B cell proportions. The expansion of human T-bethighCD21low B cells correlated with an expansion of circulating T follicular helper 1 (cTfh1) and T peripheral helper (Tph) cells, identifying potential sources of CD40L, IL-21, and IFNγ signals. Thus, we identified important pathways to target autoreactive T-bethighCD21low B cells in human autoimmune conditions, where these cells are linked to pathogenesis and disease progression.

To develop and validate new Juvenile Arthritis Disease Activity Score 10 (JADAS10) and clinical JADAS10 (cJADAS10) cutoffs to separate the states of inactive disease (ID), minimal disease activity (MiDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with oligoarthritis and with rheumatoid factor–negative polyarthritis, based on subjective disease assessment by the treating pediatric rheumatologist.

Background Evidence is lacking for safe and effective treatments for juvenile localised scleroderma (JLS). Methotrexate (MTX) is commonly used first line and mycophenolate mofetil (MMF) second line, despite a limited evidence base. A head to head trial of these two medications would provide data on relative efficacy and tolerability. However, a frequentist approach is difficult to deliver in JLS, because of the numbers needed to sufficiently power a trial. A Bayesian approach could be considered. Methods An international consensus meeting was convened including an elicitation exercise where opinion was sought on the relative efficacy and tolerability of MTX compared to MMF to produce prior distributions for a future Bayesian trial. Secondary aims were to achieve consensus agreement on critical aspects of a future trial. Results An international group of 12 clinical experts participated. Opinion suggested superior efficacy and tolerability of MMF compared to MTX; where most likely value of efficacy of MMF was 0.70 (95% confidence interval (CI) 0.34-0.90) and of MTX was 0.68 (95% CI 0.41-0.8). The most likely value of tolerability of MMF was 0.77 (95% CI 0.3-0.94) and of MTX was 0.62 (95% CI 0.32-0.84). The wider CI for MMF highlights that experts were less sure about relative efficacy and tolerability of MMF compared to MTX. Despite using a Bayesian approach, power calculations still produced a total sample size of 240 participants, reflecting the uncertainty amongst experts about the performance of MMF. Conclusions Key factors have been defined regarding the design of a future Bayesian approach clinical trial including elicitation of prior opinion of the efficacy and tolerability of MTX and MMF in JLS. Combining further efficacy data on MTX and MMF with prior opinion could potentially reduce the pre-trial uncertainty so that, when combined with smaller trial sample sizes a compelling evidence base is available.

Extended methodology from publication on AMRC of Prior elicitation of the efficacy and tolerability of Methotrexate and Mycophenolate Mofetil in Juvenile Localised SclerodermaSpecifically:Appendix S1 Participants in prior elicitation meetingAppendix S2 – Inclusion criteria for a clinical trial of MTX and MMF defined before elicitation exerciseAppendix S3 Detailed methodology of elicitation process

Juvenile systemic sclerosis (jSSc) is an orphan disease with a prevalence of around 3 in 1, 000,000 children. It is known that in pediatric jSSc cohorts, there are a significant number of patients with overlap features, such as arthritis and myositis. However, the disease burden between those with and without overlap features in jSSc has not been defined.Compare the clinical phenotype between children with and without overlap features in the juvenile systemic scleroderma inception cohort (jSScC).A cross-sectional study was performed using baseline visit data. Demographic, organ system evaluation, autoantibody profile, treatment, and patient and physician reported outcome variables were extracted from jSScC. Comparison between patients with and without overlap features was performed using chi-square test and Mann Whitney U-test.At the time of data extraction, 175 jSSc patients were enrolled in the cohort, 81% were Caucasian and 81% female. Mean disease duration was 3.1 year (±2.7). Mean age at Raynaud´s onset was 10 years (±3.8) and mean age of first non-Raynaud´s was 10.2 years (±3.8). Overlap features occurred 17% (n=30) of the cohort, 12.5% in the diffuse cutaneous (dc) jSSc and in 30% in the limited cutaneous (lc) jSSc. Significant differences in clinical characteristics were found between those patients with compared to without overlap characteristics. Patients with overlap features presented more frequently with Gottron papules (p=0.007), swollen joints (p=0.019), muscle weakness (p=0.003), and lung involvement documented by decreased DLCO < 80% (p=0.06) and/or abnormal high resolution computed tomography (p=0.049). Anti-PM/Scl autoantibodies were also more common in this group (p=0.001). Significantly more patients without overlap features had Raynaud´s (p=0.006). Physician Global Assessment of disease activity was significantly higher in patients with overlap features (41 vs 34; p=0.041). (Table 1.)Table 1.Demographic and clinical characteristics of jSSc patients with and without overlap features.Whole CohortN=175Patients without overlapN=145Patients with overlapN=30P valueFemale to Male Ratio 4.3:1(142/33)4:1(116/29)6.5:1(26/4)0.395Cutaneous subtypeDiffuse subtype (N)73% (128)11216Limited subtype (N)27% (47)3317Mean disease duration (years)3.1 (± 2.7)3.2 (± 2.8)3.1 (± 2.2)0.291Mean age of onset of Raynaud´s (years)10.0 (± 3.8)17 non-Raynaud10.0 (± 3.8)10 non-Raynaud10.0 (± 3.7)7 non-Raynaud0.931Mean age of onset of non-Raynaud´s (years)10.2 (± 3.8)10.2 (± 3.9)9.8 (± 3.7)Disease modifying drugs (N)88% (154) 89% (129)83% (25)0.388Raynaud´s phenomenon90% (158)93% (135)77% (23)0.006Anti-PMScl18% (12/68)9% (5/53)47% (7/15)0.001Gottron Papules (N)27% (46/171)23% (33/144)48% (13/27)0.007DLCO <80% (N)44% (39/88)39% (28/71)65% (11/17)0.06Abnormal findings in HRCT (N)44% (59/133)40% (43/107)62% (16/26)0.049Proportion of patients with swollen joints 18% (32) 14% (21) 37% (11)0.019Muscle Weakness (N) 21% (31/149)16% (20/123) 42% (11/26)0.003Physician global disease activity(0-100) min -max35 (0-90) n=14134 (0-90) n=11441 (0-80) n=270.041Results from this large international cohort of jSSc patients demonstrate significant differences between patients with and without overlap features. Patients with overlap have significantly more interstitial lung disease and more physician rated disease activity and should not be considered to have more “mild disease”.Supported by the “Joachim Herz Stiftung”None declared

Background: Multisystem inflammatory syndrome in children (MIS-C) was recognized during the 2020 pandemic of SARS-CoV-2. Because of the relative rarity current knowledge is limited, especially in the European Caucasian population. Objectives: To report the epidemiology, clinical and laboratory characteristics of patients with MIS-C in a nationwide cohort study in Slovenia. Methods: This is a nationwide prospective cohort study of all consecutive patients with MIS-C, admitted from the beginning of epidemics to 31st December 2020 to University Medical Centre Ljubljana, Slovenia, the only tertiary care pediatric rheumatology center in the country. The inclusion criteria were meeting the CDC criteria for MIS-C. Infection with SARS-CoV-2 was confirmed in all patients by positive antibodies for SARS-CoV-2. Data were collected from the patients' medical records. Data on the COVID-19 epidemics in Slovenia were collected from National Institute of Public Health. Population data were provided by the Statistical Office of the Republic of Slovenia. Results: Twenty-three patients with MIS-C were diagnosed nationwide in Slovenia, all of them in the second wave of epidemics from 14th September to 31st December 2020. All patients were Caucasian and the estimated prevalence of MIS-C was 5.8/100 000 persons younger than 19 years of age. Detailed analyses were available in 20 patients of which 14 were boys (70 %), median age was 12.4 years (4 months to 17.7 years). Two patients (10 %) were treated in the intensive care unit and none of the patients died. Troponin was elevated in 15/20 (75 %) patients during the disease course, and 7/15 (47 %) of these had normal troponin level at admission. The serum level of troponin closely followed the serum level of CRP. Six out of 20 (30 %) patients had elevated pancreatic enzymes in the second week of the disease after treatment was already given,and one patient developed asymptomatic acute pancreatitis with serum lipase level reaching the maximum of 25μkat/L. All patients had elevated levels of D-dimer with no signs of thrombosis. Five patients (5/20;25 %) had pleural effusions and five patients (5/20, 25 %) had ascites. Half of the patients (10/20;50 %) had hepatosplenomegaly and eight (8/20;40 %) had mesenterial lymphadenopathy. Three patients (3/20;15 %) had radiologic signs of cholecystitis. Two patients had thickened lung parenchyma. All patients received IVIG and systemic glucocorticosteroids. Because of resistant or organ threatening disease 4 patients (4/20, 20%) received high dose methylprednisolone pulse therapy. Biologic therapy with anakinra was started in 2 patients. Nineteen patients (19/20, 95%) received acetylsalicylic acid and prophylactic anticoagulation was prescribed in 15/20 (75%) of patients. The mean follow up was 50 days (14 -122). At the last follow-up visit all patients had normal laboratory parameters of inflammation, troponin, pro-BNP, d-dimer values and normal heart function. Conclusion: A very high incidence of MIS-C, estimated 5.8/100 000 persons under the age of 19 with a predominantly cardiac involvement but very good outcome was noted in European Caucasian population in a nationwide cohort study in Slovenia. Attention to newly described pancreatic involvement should be raised.