CLIPPER2 was an 8-year, open-label extension of the phase 3b, 2-year CLIPPER study of the safety and efficacy of etanercept (ETN) in patients (pts) with juvenile idiopathic arthritis (JIA), categorized as extended oligoarticular JIA (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA).Evaluation of the efficacy of ETN and its effect on health outcomes over 10 years of follow-up were secondary objectives and are reported here.Pts (n=127) with eoJIA (n=60; 2-17 years of age), ERA (n=38; 12-17), or PsA (n=29; 12-17) who received ≥1 ETN dose (0.8 mg/kg once weekly [max, 50 mg]) in CLIPPER were eligible to enter CLIPPER2. The study design has been reported previously.1 Efficacy endpoints included proportions of pts achieving JIA American College of Rheumatology (ACR) 30/50/70/90/100 criteria, Juvenile Arthritis Disease Activity Score (JADAS) inactive disease and clinical remission criteria, and sustained clinical remission (ACR criteria) or JADAS ≤1 for 12 continuous months (mths). Exploratory efficacy endpoints included time to flare following ETN withdrawal (based on ≥30% worsening in ≥3/6 ACR Pedi components, with ≥30% improvement in <2/6 remaining components and ≥2 active joints), and time to re-treatment with ETN.Observed Cases were used (i.e., there was no imputation for missing data) for pts who were in the Active Treatment Period.A total of 109/127 (86%) CLIPPER participants entered CLIPPER2 (n=55 eoJIA, n=31 ERA, n=23 PsA), with 99 (78%) pts continuing in the Active Treatment Period. Overall, 84 (66%) pts completed 120 mths of follow-up; 27 (21%) while actively taking ETN. Thirty (24%) pts entered the Withdrawal Period from the Active Treatment Period (i.e., they discontinued ETN, either by meeting the Wallace definition for clinically inactive disease for at least 6 months on ETN, or by having had a good clinical response and being deemed to benefit from withdrawal in the investigator’s judgment). Of the pts in the Active Treatment Period, over 90% achieved JIA ACR 50 response at all study time points. Sustained JADAS and ACR remission was achieved by 42 (33%) pts and 17 (13%) pts, respectively. The mean improvements from baseline in JADAS disease activity at mth 24 of CLIPPER were largely maintained through CLIPPER2 A total of 109/127 (86%) CLIPPER participants entered CLIPPER2 (n=55 eoJIA, n=31 ERA, n=23 PsA), with 99 (78%) pts continuing in the Active Treatment Period. Overall, 84 (66%) pts completed 120 mths of follow-up; 27 (21%) while actively taking ETN. Thirty (24%) pts entered the Withdrawal Period from the Active Treatment Period (i.e., they discontinued ETN, either by meeting the Wallace definition for clinically inactive disease for at least 6 months on ETN, or by having had a good clinical response and being deemed to benefit from withdrawal in the investigator’s judgment). Of the pts in the Active Treatment Period, over 90% achieved JIA ACR 50 response at all study time points. Sustained JADAS and ACR remission was achieved by 42 (33%) pts and 17 (13%) pts, respectively. The mean improvements from baseline in JADAS disease activity at mth 24 of CLIPPER were largely maintained through CLIPPER2.The low numbers of evaluable pts notwithstanding, efficacy results were consistent with the profile of ETN, and treatment responses were considered clinically meaningful and durable with long-term treatment.[1]Foeldvari I, et al. Arthritis Res Ther 2019;21:125.[2]Trincianti C, et al. Arthritis Rheumatol 2021:73;1966-75.Trial Registration:NCT00962741/NCT01421069Medical writing support was provided by Iain McDonald, PhD, of Engage Scientific Solutions and was funded by Pfizer.Jelena Vojinovic Speakers bureau: Abbvie, Roche, Sandoz, Joke Dehoorne Speakers bureau: Abbvie, Roche, Consultant of: Abbvie, Roche, Violeta Panaviene: None declared, Gordana Susic: None declared, Gerd Horneff Speakers bureau: Chugai, Eli-Lilly, Glaxo Smith and Kline, Janssen, Novartis, Pfizer, Roche and Sobi, Grant/research support from: Novartis, Janssen, Roche, Valda Stanevicha Speakers bureau: Sandoz, Abbvie, Roche, Katarzyna Kobusinska: None declared, Zbigniew Żuber: None declared, Bogna Dobrzyniecka: None declared, Jonathan Akikusa: None declared, Tadej Avcin Speakers bureau: AbbVie, Octapharma and Takeda, Consultant of: AbbVie, Octapharma and Takeda, Alberto Martini Speakers bureau: Aurinia, Bristol Myers and Squibb, Eli-Lilly, EMD Serono, Janssen, Pfizer, Roche, Consultant of: Aurinia, Bristol Myers and Squibb, Eli-Lilly, EMD Serono, Janssen, Pfizer, Roche, Cecilia Borlenghi Shareholder of: Pfizer, Employee of: Pfizer, Edmund Arthur Employee of: Pfizer, Svitlana Y Tatulych Shareholder of: Pfizer, Employee of: Pfizer, Chuanbo Zang Shareholder of: Pfizer, Employee of: Pfizer, Vasileios TSEKOURAS Shareholder of: Pfizer, Employee of: Pfizer, Bonnie Vlahos Shareholder of: Pfizer, Employee of: Pfizer, Nicolino Ruperto Speakers bureau: Ablynx, Amgen, Astrazeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squibb, Cambridge Healthcare Research (CHR), Celgene, Domain therapeutic, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Idorsia, Janssen, Novartis, Pfizer, Sobi, UCB., Consultant of: Ablynx, Amgen, Astrazeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squibb, Cambridge Healthcare Research (CHR), Celgene, Domain therapeutic, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Idorsia, Janssen, Novartis, Pfizer, Sobi, UCB.

CLIPPER2 was an 8-year, open-label extension of the phase 3b, multicenter, 2-year CLIPPER study of the safety and efficacy of etanercept (ETN) in the treatment of patients (pts) with juvenile idiopathic arthritis (JIA) categorized as extended oligoarticular arthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA).The objective of this analysis was to describe the safety of ETN in this population after 10 years of follow up.Pts (n=127) with eoJIA (2-17 years), ERA, or PsA (each 12-17 years) who received ≥1 ETN dose (0.8 mg/kg once weekly [max, 50 mg]) in CLIPPER were eligible to enter CLIPPER2. The primary outcome measure was the occurrence of malignancy. Long-term safety was assessed as the total incidence of events from CLIPPER baseline (BL) to month (mth) 120, frequency of events per 100 patient-years (EP100PY), and frequency of events in each study year.A total of 109/127 (86%) pts entered CLIPPER2; 99 (78%) continued in the active treatment period. At mth 120, 84 (66%) pts had completed the study; 27 (21%) while actively taking ETN; 7 (6%) had withdrawn from treatment due to low/inactive disease; 5 (4%) had re-started ETN following an earlier withdrawal from treatment; and 45 (35%) had stopped ETN (but remained under observation); 25 (20%) pts permanently discontinued from the CLIPPER2 study. In CLIPPER/CLIPPER2, 1 case of malignancy (Hodgkin’s disease) was reported (1 pt with eoJIA in Year 3). There was 1 case of uveitis (1 pt with eoJIA in Year 8) and 3 of Crohn’s disease (2 pts with ERA, Year 1/Year 6; 1 pt with eoJIA, Year 5). There were 2 cases of opportunistic infections (both herpes zoster), and no deaths. Overall, there were 559 (81.82 EP100PY) treatment-emergent adverse events (TEAEs) excluding infections and injection-site reactions (ISRs). The overall rate of TE serious infections was low (N=14; 2.05 EP100PY) (Table 1), with the most common TE serious infection being gastroenteritis (N=2; 0.29 EP100PY). The most frequently reported TEAEs (N [EP100PY]) were headache (28 [4.10]), arthralgia (24 [3.51]), pyrexia (21 [3.07]), diarrhea (14 [2.05]), and leukopenia (12 [1.76]). Overall, 39 patients reported serious AEs (excluding infections/ISRs). The number and frequency (N [EP100PY]) of TEAEs (excluding infections/ISRs) decreased over the 10-year study period from 193 [173.81] in Year 1 to 9 [27.15] in Year 10. The number and frequency of TE infections and TE serious infections also decreased over the 10-year study period. There was no clear trend of a decrease over time for the incidence of TE serious AEs (Figure 1).Table 1.ETN Safety Summary (from CLIPPER BL to mth 120), N (EP100PY) (FAS)*eoJIA, n=60(EXP=313.667 PY)ERA, n=38(EXP=206.971 PY)PsA, n=29(EXP=162.576 PY)Total, n=12(EXP=683.214 PY)TEAEs†269 (85.76)176 (85.04)114 (70.12)559 (81.82)TE serious AEs†16 (5.10)17 (8.21)7 (4.31)40 (5.85)TE ISRs23 (7.33)29 (14.01)12 (7.38)64 (9.37)TE infections418 (133.26)99 (47.83)155 (95.34)672 (98.36)TE serious infectionsǂ5 (1.59)4 (1.93)5 (3.08)14 (2.05)Opportunistic infections§01 (0.48)1 (0.62)2 (0.29)TEAEs causing withdrawal†7 (2.23)9 (4.35)2 (1.23)18 (2.63)TE infections causing withdrawal2 (0.64)01 (0.62)3 (0.44)*While on active ETN treatment or within 30 days of last dose†Excluding infections/ISRsǂGastroenteritis, 2 (0.29); acute tonsillitis, anal abscess, bronchopneumonia, gastrointestinal infection, helicobacter gastritis, influenza, peritonitis, pharyngitis, pyelocystitis, sepsis, urinary tract infection, viral infection, all 1 (0.15)§Both herpes zosterEXP, exposure to ETN; FAS, full analysis set; n, number of patients; N, number of eventsETN treatment to mth 120 was well tolerated in this patient population and consistent with the known safety profile. Frequency of TEAEs and TE infections decreased over time. Over 10 years, there was 1 reported event of malignancy and the overall rate of TE serious infections was low.[1]NCT00962741/NCT01421069Medical writing support was provided by Iain McDonald, PhD, of Engage Scientific Solutions and was funded by Pfizer.Jelena Vojinovic Speakers bureau: Abbvie, Roche, Sandoz, Joke Dehoorne Speakers bureau: Abbvie, Roche, Consultant of: Abbvie, Roche, Violeta Panaviene: None declared, Gordana Susic: None declared, Gerd Horneff Speakers bureau: Chugai, Eli-Lilly, Glaxo Smith and Kline, Janssen, Novartis, Pfizer, Roche and Sobi, Grant/research support from: Novartis, Janssen, Roche, Valda Stanevicha Speakers bureau: Sandoz, Abbvie, Roche, Katarzyna Kobusinska: None declared, Zbigniew Żuber: None declared, Bogna Dobrzyniecka: None declared, Jonathan Akikusa: None declared, Tadej Avcin Speakers bureau: AbbVie, Octapharma, and Takeda, Consultant of: AbbVie, Alexion, Octapharma, and Takeda, Alberto Martini Speakers bureau: Aurinia, Bristol Myers and Squibb, Eli-Lilly, EMD Serono, Janssen, Pfizer, Roche, Consultant of: Aurinia, Bristol Myers and Squibb, Eli-Lilly, EMD Serono, Janssen, Pfizer, Roche, Cecilia Borlenghi Shareholder of: Pfizer, Employee of: Pfizer, Edmund Arthur Employee of: Pfizer, Svitlana Y Tatulych Shareholder of: Pfizer, Employee of: Pfizer, Chuanbo Zang Shareholder of: Pfizer, Employee of: Pfizer, Bonnie Vlahos Shareholder of: Pfizer, Employee of: Pfizer, Nicolino Ruperto Speakers bureau: Ablynx, Amgen, Astrazeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squibb, Cambridge Healthcare Research (CHR), Celgene, Domain therapeutic, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Idorsia, Janssen, Novartis, Pfizer, Sobi, UCB., Consultant of: Ablynx, Amgen, Astrazeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squibb, Cambridge Healthcare Research (CHR), Celgene, Domain therapeutic, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Idorsia, Janssen, Novartis, Pfizer, Sobi, UCB.

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

The Physician Global Assessment International Standardisation COnsensus in Systemic Lupus Erythematosus (PISCOS) study aimed to obtain an evidence-based and expert-based consensus standardisation of the Physician Global Assessment (PGA) scoring of disease activity in systemic lupus erythematosus (SLE). An international panel of 79 SLE experts participated in a three-round Delphi consensus process, in which 41 statements related to the PGA in SLE were rated, using a 0 (strongly disagree) to 10 (strongly agree) numerical rating scale. Statements with agreement of 75% or greater were selected and further validated by the expert panel. Consensus was reached on 27 statements, grouped in 14 recommendations, for the use of the PGA in SLE, design of the PGA scale, practical considerations for PGA scoring, and the relationship between PGA values and levels of disease activity. Among these recommendations, the expert panel agreed that the PGA should consist of a 0-3 visual analogue scale for measuring disease activity in patients with SLE in the preceding month. The PGA is intended to rate the overall disease activity, taking into account the severity of active manifestations and clinical laboratory results, but excluding organ damage, serology, and subjective findings unrelated to disease activity. The PGA scale ranges from "no disease activity" (0) to the "most severe disease activity" (3) and incorporates the values 1 and 2 as inner markers to categorise disease activity as mild (≥0·5 to 1), moderate (>1 and ≤2) and severe (>2 to 3). Only experienced physicians can rate the PGA, and it should be preferably scored by the same rater at each visit. The PISCOS results will allow for increased homogeneity and reliability of PGA ratings in routine clinical practice, definitions of remission and low disease activity, and future SLE trials.

The COVID-19 pandemic has caused a major disruption of the everyday lives of children and adolescents around the world. Although adolescents are generally not at risk of developing severe COVID-19, 1 they were heavily impacted by changes in their daily lives, including social isolation due to school clo-sures and physical distancing, decreased peer interactions, restrictions on physical activity, and increased family stress. 2,3 While social distancing measures helped contain the virus, they also caused notable adverse effects on adolescents ’ mental and physical health. Several cross-sectional 4,5 and longitudinal studies 6 based on the general adolescent population reported increased prevalence of mental illnesses during the COVID-19 pandemic, and meta-analysis of pooled data including 80.879 children and adolescents revealed that the prevalence of depression and anxiety, the two most common mental health concerns in youth, have doubled compared with pre-pandemic estimates and remained high also later in the pandemic. 7 Adolescents with preexisting chronic medical conditions were exposed to additional precipitants of psychological stress during the pandemic such as missed or delayed healthcare appoint-ments, uncertainty about the advancement of the disease, protective behaviors with quarantining, feeling of helpless-ness, and possible shortage of supplies of medicines. 8 Therefore, from a mental health perspective, it appears that they may be affected differently with the potential for a widening of existing disparities in health and developmen-tal outcomes. In ndings from a cross-sectional

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.