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Describes a previously healthy infant who presented with fulminant sepsis and was found to have Kingella kingae endocarditis. Medical history of the infant; Presence of hepatosplenomegaly in the patient; Definition of Kingella kingae.

LRBA deficiency is an inborn error of immunity defined by autoimmunity, lymphoproliferation, recurrent infections, cytopenia, and inflammatory bowel disease. Despite recent advances in managing this disease with targeted biologic therapy, haematopoietic stem cell transplant (HSCT) remains the only cure. However, great variability exists between protocols used to transplant patients with LRBA deficiency. We describe a cohort of seven patients with LRBA deficiency who underwent HSCT using a myeloablative, reduced toxicity regime of fludarabine, treosulfan, and thiotepa at two transplantation centres from 2016 to 2019. Data were collected both retrospectively and prospectively, measuring time to engraftment, infectious complications, incidence of graft versus host disease, and post-transplantation chimerism. Six of seven patients survived transplantation, and four of six surviving patients achieving treatment-free survival. We thus recommend that HSCT with fludarabine, treosulfan, and thiotepa-based conditioning be considered in patients with LRBA deficiency., (© 2024. The Author(s).)

Objectives: Some adults with rheumatic and musculoskeletal diseases (RMDs) are at increased risk of COVID-19-related death. Excluding post-COVID-19 multisystem inflammatory syndrome of children, children and young people (CYP) are overall less prone to severe COVID-19 and most experience a mild or asymptomatic course. However, it is unknown if CYP with RMDs are more likely to have more severe COVID-19. This analysis aims to describe outcomes among CYP with underlying RMDs with COVID-19., Methods: Using the European Alliance of Associations for Rheumatology COVID-19 Registry, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, and the CARRA-sponsored COVID-19 Global Paediatric Rheumatology Database, we obtained data on CYP with RMDs who reported SARS-CoV-2 infection (presumptive or confirmed). Patient characteristics and illness severity were described, and factors associated with COVID-19 hospitalisation were investigated., Results: 607 CYP with RMDs <19 years old from 25 different countries with SARS-CoV-2 infection were included, the majority with juvenile idiopathic arthritis (JIA; n=378; 62%). Forty-three (7%) patients were hospitalised; three of these patients died. Compared with JIA, diagnosis of systemic lupus erythematosus, mixed connective tissue disease, vasculitis, or other RMD (OR 4.3; 95% CI 1.7 to 11) or autoinflammatory syndrome (OR 3.0; 95% CI 1.1 to 8.6) was associated with hospitalisation, as was obesity (OR 4.0; 95% CI 1.3 to 12)., Conclusions: This is the most significant investigation to date of COVID-19 in CYP with RMDs. It is important to note that the majority of CYP were not hospitalised, although those with severe systemic RMDs and obesity were more likely to be hospitalised., Competing Interests: Competing interests: RC reports personal AstraZeneca shares, unrelated to this manuscript. IK-P reports personal fees by Novartis, SOBI, Chugai, Pfizer, AbbVie, BMS, all unrelated to this manuscript. FOR reports consulting/speaker’s fees from Abbvie, Novartis, Pfizer and Sobi, all unrelated to this manuscript. NMW reports personal consultant fees from UCB, BMS, all unrelated to this manuscript. AS reports personal fees from lectures for AbbVie, Celltrion, MSD, Janssen, Lilly, Roche, BMS, and Pfizer, all unrelated to this manuscript. EFM reports personal consultant fees from Boehringer Ingelheim Portugal, Lda, all unrelated to this manuscript. LPCDR received support for specific activities: grants from Abbvie, Novartis, Lilly Portugal, Amgen Biofarmacêutica, Grünenthal S.A., MSD, Medac, A. Menarini Portugal - Farmacêutica, S.A., Pfizer, UCB Pharma, Roche Farmacêutica Química, Lda; and non-financial support from Pfizer, and Grünenthal GmbH, all unrelated to this manuscript.PMM has received consulting/speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript, and is supported by the National Institute for Health Research (NIHR), University College London Hospitals (UCLH), Biomedical Research Centre (BRC). MN reports funding from Childhood Arthritis & Rheumatology Research Alliance, Inc (CARRA) to his informatics research and operations group at Boston Children’s Hospital in its capacity as the CARRA Data Warehouse and associated work for CARRA and the CARRA Registry and has sponsored the COVID-19 Global Pediatric Rheumatology Database study, of which he is the Principal Investigator. MN also serves as Director of Informatics for CARRA, for which he receives no direct compensation but do receive research sponsorship for CARRA-related research, development, and operations (see above). He is also a co-investigator of the CARRA Registry and site Principal Investigator at Massachusetts General Hospital. KLH reports non-personal speaker’s fees from Abbvie and grant income from BMS, UCB, and Pfizer, all unrelated to this manuscript, and is supported by the NIHR Manchester Biomedical Research Centre. All other authors report no disclosures., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To compare the efficacy and safety of intravenous immunoglobulin (IVIG) plus high-dose aspirin (HDA) vs. IVIG plus low-dose aspirin (LDA) for the treatment of Kawasaki disease, with an emphasis on coronary artery outcomes., Methods: This study was a retrospective, medical record review of paediatric patients with Kawasaki disease comparing 6 centres that routinely used HAD for initial treatment and 2 that used LDA in 2004-2013. Treatment response and adverse events were compared. The primary outcome measure was the occurrence of coronary aneurysm at the subacute or convalescent stage., Results: The cohort included 358 patients, of whom 315 were initially treated with adjunctive HDA and 43 with LDA. There were no demographic differences between the groups. Coronary aneurysms occurred in 10% (20/196) of the HDA group and 4% (1/24) of the LDA group (p=0.34). Equivalence tests indicate it is unlikely that the risk of coronary aneurysm in LDA exceeds HDA by more than 3.5%. There were no significant between-group differences in the need for glucocorticoid pulse therapy or disease recurrence. Coronary ectasia rate and hospitalisation time were significantly greater in the HDA group. Adverse events were similar in the two groups., Conclusions: We found no significant clinical benefit in using IVIG+HDA in Kawasaki disease compared to IVIG+LDA. The use of adjunctive HDA in this setting should be reconsidered.

Objectives: Central nervous system (CNS) involvement, one of the most severe manifestations of Behçet's disease (BD), is uncommon in children. Because it is rare, the clinical features of this disease in children are not well characterised. Here we describe a teenager with BD which was disclosed following an episode of cerebral sinus vein thrombosis (CSVT) and review the available literature on children with CSVT associated with BD., Methods: A 12-year-old boy who presented with CSVT is described and the relevant literature, based on a Medline search from 1966 to January 2015 is reviewed., Results: Twenty-three well-documented reports of children with CSVT and BD are described. This manifestation affected mainly males (61%) with a mean age of 12 years (range 4-18). BD was first diagnosed simultaneously or following CSVT in the majority of cases (75%). Multiple sinuses were involved in 30% of the cases. Thrombosis of additional large vessel was identified in 5 of the 23 children. The most common presenting symptom and signs were headache (91%), lasting more than 3 days in most cases (75%), followed by papilledema (43%), seizures (17%), and personality changes (9%). A mixed pattern of CNS involvement including both parenchymal involvement and CSVT, was demonstrated in only two patients (9%). Management of CSVT differed between reports., Conclusions: CSVT in children is a rarely reported manifestation of BD and has a characteristic clinical picture of a teenage boy presenting with prolonged headache, with no previous diagnosis of BD. A therapeutic approach has not been established yet.

Objectives: The aim of this study was to determine the seasonality of month of birth (MOB) in children with juvenile idiopathic arthritis (JIA) as compared to the general population., Methods: Cosinor analysis was used to analyse MOB rhythmicity in 558 children with JIA from a simple rheumatology clinic compared with the MOB pattern of the general population in Israel (n=1.040558). Statistical differences between groups were also analysed by non-parametrical tests., Results: Patients with JIA showed different patterns from that of the general population. A rhythmic pattern of 12 months was found in the MOB patterns of JIA patients. This rhythm with a peak between November to March and a nadir in summer was a mirror image of the rhythmic pattern observed for MOB of the healthy population. Males showed a pattern with combined rhythm of 8 and 6 months with peaks in winter, while females' MOB pattern showed no rhythmicity. Testing different JIA subtypes, only the patients with the enthesitis-related arthritis (ERA) subtype showed rhythmicity in MOB. Rhythmicity patterns were different for males and females, and differed according to several disease characteristics., Conclusions: The observed pattern of MOB in JIA patients is distinctive and different from that in the healthy population supporting the hypothesis that autoimmune process may begin in utero or in the perinatal period due to seasonal environmental pathogenic agents.

Objectives: Children often present during winter with painful, red-purple swollen fingers and/or toes, usually misdiagnosed as Raynaud's phenomenon. Pernio, or chronic chilblains, is a localised inflammatory lesion of the skin resulting from an abnormal response to cold. The aim of this study was to better characterise the clinical presentation of chronic chilblains in children., Methods: This is a single-centre retrospective study of patients referred to our paediatric rheumatology clinic with cold, purple, and painful hands. Patients were identified from the paediatric rheumatology clinic database, at the Safra Children Hospital, Israel. Data of the clinical presentation, physical findings, laboratory investigations and the course of the disease were extracted from the patients' charts and analysed., Results: A total of 33 patients (27 females, sex ratio 4.5:1) were identified. Patients age at presentation was 13.5±2.1, and disease duration was 2.0±1.0 winters. Patients presented with prolonged capillary refill time (100%) and abnormal modified Allen test (75.6%). Fingers swelling was the most common finding (81.8%), followed by proximal interphalangeal joint (PIPs) swelling (63.6%), skin ulceration (54.5%), and dry, irritated skin (45.5%). Nailfold capillary microscopy was normal in all patients. The only abnormal laboratory test was the test for anti-nuclear factor (ANA) in 25%., Conclusions: We report a large series of children with a unique symptomatology consisting in chronic chilblains.

Emerging data suggest that regulatory T cell (Treg) dysfunction and consequent breakdown of immunological self-tolerance in autoimmunity can be mediated by factors that are not Treg-intrinsic (e.g., cytokines). Indeed, recent studies show that in rheumatoid arthritis the proinflammatory cytokine TNF reduces the suppressive function of Tregs, whereas in vivo TNF blockade restores this function and accordingly self-tolerance. However, until now a coherent mechanism by which TNF regulates the Treg has not been described. In this paper, we show that TNF induces preferential and significant activation of the canonical NF-kappaB pathway in human Tregs as compared with CD25(-) conventional T cells. Furthermore, TNF induced primarily in CD45RA(-) Tregs a transcription program highly enriched for typical NF-kappaB target genes, such as the cytokines lymphotoxin-alpha and TNF, the TNFR superfamily members FAS, 4-1BB, and OX-40, various antiapoptotic genes, and other important immune-response genes. FACS analysis revealed that TNF also induced upregulation of cell surface expression of 4-1BB and OX40 specifically in CD45RA(-)FOXP3(+) Tregs. In contrast, TNF had only a minimal effect on the Treg's core transcriptional signature or on the intracellular levels of the FOXP3 protein in Tregs. Importantly, TNF treatment modulated the capacity of Tregs to suppress the proliferation and IFN-gamma secretion by conventional T cells, an effect that was fully reversed by cotreatment with anti-TNFR2 mAbs. Our findings thus provide new mechanistic insight into the role of TNF and TNFR2 in the pathogenesis of autoimmunity.

The transcription factor forkhead box P3 (FOXP3 in humans; Foxp3 in mice) controls the development and function of regulatory T cells (Treg). In mice, CD4(+)CD25(-) T cells do not express Foxp3 following TCR activation. Whether FOXP3 is a common activation-induced molecule in human T cells--hence not Treg restricted--is currently a controversial issue. As FOXP3 can significantly modulate the function of T cells, understanding the mode (and regulation) of FOXP3 expression in human T cells is vital. Here we show that in conventional CD4(+)CD25(-) T cells, the induction of FOXP3 expression following TCR activation is both restricted to a fraction of the progeny and transient. Moreover, FOXP3 expression in vivo is particularly infrequent in activated effector CD4(+) T cells that accumulate within inflamed joints. We next demonstrate that the repression of FOXP3 transcription in resting conventional human CD25(-) T cells is linked to complete methylation of an evolutionarily conserved intronic CpG island. The dense methylation pattern is furthermore inherited after activation by progeny. This intronic CpG island, on the other hand, is frequently unmethylated in CD4(+)CD25(+) T cells. Importantly, blocking maintenance DNA methylation, by pharmacological inhibition of DNA methyltransferase-1, induced significant and stable activation-dependent FOXP3 expression in cycling conventional T cells, which was further amplified by co-treatment with transforming growth factor beta. In contrast to natural Treg, such induced CD4(+)FOXP3(+) T cells could produce pro-inflammatory cytokines upon activation. These results indicate that DNA methylation normally restricts FOXP3 transcription in conventional human T cells.

Background: The new syndrome, known as PFAPA, of periodic fever characterized by abrupt onset of fever, malaise, aphthous stomatitis, tonsillitis, pharyngitis and cervical adenopathy has been described only in pediatric patients. It usually begins before the age of 5 years and in most cases resolves spontaneously before age 10., Objectives: To describe a series of adults with PFAPA syndrome., Methods: This 6 year retrospective descriptive study includes all newly diagnosed incident adult cases aged 18 years and over referred to our center with symptomatology suggestive of PFAPA syndrome. Patients' medical records were reviewed for past history of the disease, demographic characteristics, symptoms and signs, course of the disease, laboratory findings, and outcome following corticosteroid therapy. The comparison group included our pediatric cohort children (N=320, age 0-18 years) followed for the last 14 years (1994-2008)., Results: Fifteen adult patients were diagnosed with PFAPA syndrome. Episodes of fever occurred at 4.6 +/- 1.3 week intervals, beginning at the age of 20.9 +/- 7.5. All patients had monthly attacks at the peak of the disease, with attacks recurring at 4-8 week intervals over the years. Between episodes the patients were apparently healthy, without any accompanying diseases. Attacks were aborted by a single 60 mg dose of oral prednisone in all patients., Conclusions: This study reports the presence of PFAPA syndrome in adult patients. Although the disease is rare, an increased awareness by both patients and family physicians of this clinical syndrome has resulted in more frequent diagnosis in adult patients.

Immunoglobulin E (IgE) plays a central role in the pathogenesis of allergic diseases. Cross-linking of IgE molecules on mast cell and basophil surface membrane by allergens, triggers the release of multiple mediators, leading to the development of IgE-mediated immediate and late hypersensitivity reactions. In view of the pivotal role of IgE, it became an attractive target for intervention in the treatment of allergic diseases. Murine monoclonal non-anaphylactogenic antibodies directed to the receptor-binding domain of IgE, were found to reduce IgE levels and production. Anti-IgE antibodies have been recently evaluated in several clinical trials involving hundreds of asthmatic patients both adults and children, including patients with allergic rhinitis. Clinical efficacy and good tolerability were demonstrated. This novel therapeutic approach also appears to be promising for potential treatment of patients suffering concomitantly from several allergic disorders.