Early systemic inflammation induces neurodevelopmental disorders: results from ARTEMIS, a French multicenter study of juvenile rheumatisms and systemic autoimmune and auto-inflammatory disorders and meta-analysis.

Prenatal immune-mediated events are known risk factors for neurodevelopmental disorders in the offspring (NDD). Although the brain continues to develop for years after birth and many postnatal factors alter the regular trajectory of neurodevelopment, little is known about the impact of postnatal immune factors. To fill this gap we set up ARTEMIS, a cohort of juvenile rheumatisms and systemic autoimmune and auto-inflammatory disorders (jRSAID), and assessed their neurodevelopment. We then complemented our results with a systematic review and meta-analysis. In ARTEMIS, we used unsupervised and supervised analysis to determine the influence of jRSAID age at onset (AO) and delay in introduction of disease-modifying therapy (DMT) on NDD (NCT04814862). For the meta-analysis, we searched MEDLINE, EMBASE, PsycINFO, Cochrane, and Web of Science up to April 2022 without any restrictions on language, or article type for studies investigating the co-occurence of jRSAID and NDD (PROSPERO- CRD42020150346). 195 patients were included in ARTEMIS. Classification tree isolated 3 groups of patients (i) A low-risk group (AO > 130 months (m)) with 5% of NDD (ii) A medium-risk group (AO < 130 m and DMT < 2 m) with 20% of NDD (iii) and a high-risk-group (AO < 130 m and DMT > 2 m) with almost half of NDD. For the meta-analysis, 18 studies encompassing a total of (i) 46,267 children with jRSAID; 213,930 children with NDD, and 6,213,778 children as controls were included. We found a positive association between jRSAID and NDD with an OR = 1.44 [95% CI 1.31; 1.57] p < 0.0001, [I2 = 66%, Tau2 = 0.0067, p < 0.01]. Several sensitivity analyses were performed without changing the results. Metaregression confirmed the importance of AO (p = 0.005). Our study supports the association between jRSAID and NDD. AO and DMT have pivotal roles in the risk of developing NDD. We plead for systematic screening of NDD in jRSAID to prevent the functional impact of NDD.

Juvenile neuropsychiatric systemic lupus erythematosus: A specific clinical phenotype and proposal of a probability score.

OBJECTIVE: Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic auto-immune disease involving several organs. Neuropsychiatric (NP) SLE (NPSLE) is frequent in j-SLE and associated with increased morbidity/mortality. Although NPSLE classification criteria exist, attributing NP features to j-SLE remains a major challenge. The study objective is to thoroughly describe j-NPSLE patients and assist in their diagnosis. METHODS: This is a 4-year retrospective monocentric study of j-SLE patients. NP events were attributed to j-SLE using standardised diagnostic criteria and multidisciplinary paediatric clinical expertise. Clinical features, brain magnetic resonance imaging (MRI)s and samples analysis including cerebrospinal fluid were assessed. A risk of j-NPSLE score was developed based on multivariable logistic regression analysis. RESULTS: Of 39 patients included, 44% were identified as having j-NPSLE. J-NPSLE diagnosis was established at the onset of j-SLE in 59% of patients. In addition to frequent kidney involvement (76%) and chilblains (65%), all j-NPSLE patients displayed psychiatric features: cognitive symptoms (82%), hallucinations (76%), depressed mood (35%), acute confused state (18%) and catatonia (12%). Neurological involvement was often mild and nonspecific, with headache (53%) in about half of the patients. The main features reported on brain MRI were nonspecific T2/FLAIR white matter hyperintensities (65%), and cerebral atrophy (88%). Upon immunosuppressive treatment, clinical improvement of NP features was observed in all j-NPSLE patients. The score developed to attribute j-NPSLE probability, guide further investigations and appropriate treatments is based on hallucinations, memory, sleep and renal involvement (Sensitivity: 0.95 Specificity: 0.85). Cerebrospinal fluid (CSF) neopterin assessment increases the score sensitivity and specificity. CONCLUSION: Physicians should carefully and systematically assess the presence of NP features at diagnosis and early stages of j-SLE. For j-NPSLE patients with predominant psychiatric features, a multidisciplinary collaboration, including psychiatrists, is essential for the diagnosis, management and follow-up.

Juvenile Neuropsychiatric Systemic Lupus Erythematosus: Identification of Novel Central Neuroinflammation Biomarkers.

INTRODUCTION: Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic autoimmune disease affecting multiple organs. Ranging from minor features, such as headache or mild cognitive impairment, to serious and life-threatening presentations, j-neuropsychiatric SLE (j-NPSLE) is a therapeutic challenge. Thus, the diagnosis of NPSLE remains difficult, especially in pediatrics, with no specific biomarker of the disease yet validated. OBJECTIVES: To identify central nervous system (CNS) disease biomarkers of j-NPSLE. METHODS: A 5-year retrospective tertiary reference monocentric j-SLE study. A combination of standardized diagnostic criteria and multidisciplinary pediatric clinical expertise was combined to attribute NP involvement in the context of j-SLE. Neopterin and interferon-alpha (IFN-α) protein levels in cerebrospinal fluid (CSF) were assessed, together with routine biological and radiological investigations. RESULTS: Among 51 patients with j-SLE included, 39% presented with j-NPSLE. J-NPSLE was diagnosed at onset of j-SLE in 65% of patients. No specific routine biological or radiological marker of j-NPSLE was identified. However, CSF neopterin levels were significantly higher in active j-NPSLE with CNS involvement than in j-SLE alone (p = 0.0008). Neopterin and IFN-α protein levels in CSF were significantly higher at diagnosis of j-NPSLE with CNS involvement than after resolution of NP features (respectively p = 0.0015 and p = 0.0010) upon immunosuppressive treatment in all patients tested (n = 10). Both biomarkers correlated strongly with each other (Rs = 0.832, p < 0.0001, n = 23 paired samples). CONCLUSION: CSF IFN-α and neopterin constitute promising biomarkers useful in the diagnosis and monitoring of activity in j-NPSLE.

Increased Incidence of Pediatric Uveitis Associated with the COVID-19 Pandemic Occurring Before COVID-19 Vaccine Implementation: A Time-Series Analysis.

OBJECTIVE: To examine whether the COVID-19 pandemic was associated with an increased incidence of uveitis in children. STUDY DESIGN: We performed a time-series analysis of patient records from a national, hospital-based, French surveillance system. All children hospitalized for uveitis in France between January 2012 and March 2022 were included. The incidence of newly diagnosed uveitis per 100 000 children per trimester in France was analyzed by a quasi-Poisson regression. A cohort of children diagnosed with uveitis at Robert-Debré Hospital was used to compare the characteristics of uveitis after and before the onset of the pandemic. RESULTS: During the study period, 2492 children were hospitalized for uveitis in France. The COVID-19 pandemic, which started in March 2020, was associated with a significant increase in the occurrence of uveitis (estimated cumulative change, 44.9%; 95% CI 11.4-78.4; P < .001). The increase in the incidence of pediatric uveitis started in October 2020, while the national immunization program targeting children aged less than 18 years began in June 2021. This increase involved all forms of uveitis, regardless of location, and clincial characteristics were similar to those diagnosed before the pandemic. CONCLUSIONS: Our study evidenced a significant increase in the incidence of pediatric uveitis following the COVID-19 pandemic. This increase occurred 6 months before the implementation of the national COVID-19 vaccination program for children, suggesting that the resurgence of this rare disease is independent of COVID-19 vaccination.

Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies.

Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.

Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling.

OBJECTIVES: JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2). METHODS: This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes. RESULTS: Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported. CONCLUSION: This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.

Common Seasonal Pathogens and Epidemiology of Henoch-Schönlein Purpura Among Children.

Importance: Henoch-Schönlein purpura (HSP) is the most common type of vasculitis in children. The factors that trigger the disease are poorly understood. Although several viruses and seasonal bacterial infections have been associated with HSP, differentiating the specific associations of these pathogens with the onset of HSP remains a challenge due to their overlapping seasonal patterns. Objective: To analyze the role of seasonal pathogens in the epidemiology of HSP. Design, Setting, and Participants: This cohort study comprised an interrupted time-series analysis of patient records from a comprehensive national hospital-based surveillance system. Children younger than 18 years hospitalized for HSP in France between January 1, 2015, and March 31, 2023, were included. Exposure: Implementation and relaxation of nonpharmaceutical interventions (NPIs) for the COVID-19 pandemic, such as social distancing and mask wearing. Main Outcomes and Measures: The main outcomes were the monthly incidence of HSP per 100 000 children, analyzed via a quasi-Poisson regression model, and the estimated percentage of HSP incidence potentially associated with 14 selected common seasonal pathogens over the same period. Results: The study included 9790 children with HSP (median age, 5 years [IQR, 4-8 years]; 5538 boys [56.4%]) and 757 110 children with the infectious diseases included in the study (median age, 0.7 years [IQR, 0.2-2 years]; 393 697 boys [52.0%]). The incidence of HSP decreased significantly after implementation of NPIs in March 2020 (-53.6%; 95% CI, -66.6% to -40.6%; P < .001) and increased significantly after the relaxation of NPIs in April 2021 (37.2%; 95% CI, 28.0%-46.3%; P < .001). The percentage of HSP incidence potentially associated with Streptococcus pneumoniae was 37.3% (95% CI, 22.3%-52.3%; P < .001), the percentage of cases associated with Streptococcus pyogenes was 25.6% (95% CI, 16.7%-34.4%; P < .001), and the percentage of cases associated with human rhino enterovirus was 17.1% (95% CI, 3.8%-30.4%; P = .01). Three sensitivity analyses found similar results. Conclusions and Relevance: This study found that significant changes in the incidence of HSP simultaneously with major shifts in circulating pathogens after NPIs for the COVID-19 pandemic indicated that approximately 60% of HSP incidence was potentially associated with pneumococcus and group A streptococcus. This finding suggests that preventive measures against these pathogens could reduce the incidence of pediatric HSP.

Role of anti-TNF in Pediatric Inflammatory Choroidal Neovascularization: A Case Series.

OBJECTIVE: To highlight the safety and efficacy of Tumor Necrosis Factor inhibitors (anti-TNF) in inflammatory choroidal neovascularization (CNV) in the pediatric population. DESIGN: Retrospective case series. PARTICIPANTS: Three patients, < 16 years old with uveitic inflammatory CNV. METHODS: Patients received systemic steroids, methotrexate (MTX), intravitreal (IVT) injections of bevacizumab, and anti-TNF (infliximab or adalimumab) in case of refractory leakage. RESULTS: Five eyes of three pediatric patients (mean age 6 years old) presenting with CNV and put on anti-TNF were followed up for a minimum of 32 months. Four out of five eyes had improved vision, reduced fluid on clinical exam and macular spectral-domain optical coherence tomography (SD-OCT), and cessation of leakage on fundus fluorescein angiography (FFA) after introduction of anti-TNF agents. Two patients developed minor psoriasis treated topically. CONCLUSION: Anti-TNF agents showed efficacy and safety in a sustainable leakage control of inflammatory pediatric CNV along with improvement in vision.

Calculating the fraction of Kawasaki disease potentially attributable to seasonal pathogens: a time series analysis.

Background: Kawasaki disease is an acute, febrile, systemic vasculitis of children that primarily affects medium-sized blood vessels with a tropism for the coronary arteries. Although the etiological factors remain unknown, infections have been suggested as the trigger of Kawasaki disease. We sought to calculate the fraction of Kawasaki disease potentially attributable to seasonal infections. Methods: This cohort study used a population-based time series analysis from the French hospitalisation database (Programme de Médicalisation des Systèmes d'Information), which includes all inpatients admitted to any public or private hospital in France. We included all children aged 0-17 years hospitalised for Kawasaki disease in France over 13 years. The monthly incidence of Kawasaki disease per 10,000 children over time was analysed by a quasi-Poisson regression model. The model accounted for seasonality by using harmonic terms (a pair of sines and cosines with 12-month periods). The circulation of eight common seasonal pathogens (adenovirus, influenza, metapneumovirus, Mycoplasma pneumoniae, norovirus, rhinovirus, rotavirus, respiratory syncytial virus, and Streptococcus pneumonia) over the same period was included in the model to analyse the fraction of Kawasaki disease potentially attributable to each pathogen. Infections were identified on the basis of polymerase chain reaction or rapid antigen testing in hospital laboratories. Findings: Between Jan 1, 2007, and Dec 31, 2019, we included 10,337 children with Kawasaki disease and 442,762 children with the selected infectious diseases. In the Kawasaki disease cohort, the median age [IQR] was 2 [0-4] years, 6164 [59.6%] were boys. Adenovirus infection was potentially responsible for 24.4% [21.5-27.8] (p < 0.001) of Kawasaki diseases, Norovirus for 6.7% [1.3-11.2] (p = 0.002), and RSV 4.6% [1.2-7.8] (p = 0.022). Sensitivity analyses found similar results. Interpretation: This cohort study of data from a comprehensive national hospitalisation database indicated that approximately 35% of Kawasaki diseases was potentially attributable to seasonal infections. Funding: None.

Development of a score for early identification of children with Kawasaki disease requiring second-line treatment in multi-ethnic populations in Europe: A multicentre retrospective cohort study.

Background: Early identification of high-risk patients is essential to stratify treatment algorithms of Kawasaki disease (KD) and to appropriately select patients at risk for complicated disease who would benefit from intensified first-line treatment. Several scores have been developed and validated in Asian populations but have shown low sensitivity in predicting intravenous immunoglobulin (IVIG) resistance in non-Asian populations. We sought methods to predict the need for secondary treatment after initial IVIG in non-Asian populations. Methods: We conducted a retrospective, multicenter study including consecutive patients with KD admitted to two tertiary pediatric hospitals in France and Italy from 2005 to 2019. We evaluated the performance of the Kawanet-score and compared it with the performances of initial echocardiography findings, and of a newly proposed score combining the Kawanet-score and initial echocardiography findings. For each score, we assessed the AUC, sensitivity and specificity for predicting the need for second-line treatment. Findings: We included 363 children with KD, 186 from France and 177 from Italy, of whom 57 (16%) required second-line therapy after the first IVIG dose. The Kawanet score, coronary artery dilation or aneurysm with maximal Z-score ≥2.0 at baseline, and abnormal initial echocardiography had a sensitivity of 43%, 55% and 65% and a specificity of 73%, 78%, 73%, respectively, for predicting the need for second-line treatment. The Kawanet-score was significantly improved by combining it with initial echocardiography findings. The best predictive performance (Sensitivity 76%, Specificity 54%) was obtained by combining the Kawanet-score with abnormal initial echocardiography, defined by the presence of either coronary artery maximal Z-score ≥2.0, pericarditis, myocarditis and/or ventricular dysfunction. This score predicted the need for second-line treatment in European, African/Afro-Caribbean and Asian ethnicity with a sensitivity of 80%, 65% and 100%, respectively, and a specificity of 56%, 51% and 61%, respectively. Interpretation: Our study proposes a score that we named the Kawanet-echo score, which allows early identification of children with KD who require a second-line treatment in multi-ethnic populations in Europe. Funding: None.

Glucocorticoid induced adrenal insufficiency in children: Morning cortisol values to avoid LDSST.

Objectives: Glucocorticoid-induced adrenal insufficiency (GI-AI) is a common side effect of glucocorticoid therapy. However, its diagnosis currently relies on the realization of a Low Dose Short Synacthen Test (LD-SST) that requires an outpatient hospital and several blood samples. Our goal was to evaluate whether morning cortisol values could predict the response to LD-SST, in children, to avoid useless dynamic tests and facilitate diagnosis of glucocorticoid induced adrenal insufficiency. Study Design: We recorded data of 91 pediatric patients who underwent a LD-SST in our center between 2016 and 2020 in a retrospective observational study. We selected LD-SST realized following administration of supra-physiologic doses of glucocorticoids during more than 3 weeks and performed at least four weeks after treatment was stopped. Adrenal deficiency was defined as a plasma cortisol concentration inferior to 500 nmol/l at LD-SST. Results: Glucocorticoid-induced adrenal insufficiency was diagnosed in 60% of our cohort. Morning cortisol values were predictive of the response to the LD-SST (AUC ROC 0.78). A plasma cortisol concentration of less than 144 nmol/l predicted glucocorticoid induced adrenal insufficiency with a specificity of 94% and a value over 317 nmol/l predicted recovery of the HPA axis with a sensitivity of 95%. We did not find any other predictive factor for glucocorticoid-induced adrenal insufficiency. Conclusions: Morning cortisol values can safely assess recovery of the HPA axis in children treated chronically with glucocorticoids. Using these thresholds, more than 50% of LD-SST could be avoided in children.

Prevalence and course of thyroid dysfunction in neonates at high risk of Graves' disease or with non-autoimmune hyperthyroidism.

OBJECTIVE: Neonatal hyperthyroidism may be caused by a permanent non-autoimmune genetic disorder or, more frequently, by maternally transmitted high serum TRAb levels. Variable thyroid dysfunction may be observed in this second context. We aimed to evaluate the prevalence of neonatal non-autoimmune hyperthyroidism and of the different types of thyroid function in neonates with a high risk of hyperthyroidism due to maternal Graves' disease (GD). DESIGN AND METHODS: This observational cohort study included all neonates identified in the database of a single academic pediatric care center, over a period of 13 years, as having non-autoimmune hyperthyroidism or an autoimmune disorder with high TRAb levels (above 6 IU/L) transmitted by their mothers. Patients were classified as having neonatal hyperthyroidism, hypothyroidism, or euthyroidism with a permanent or transient disorder. RESULTS: Two of the 34 consecutive neonates selected (6%) had permanent non-autoimmune hyperthyroidism due to germline (n = 1) or somatic (n = 1) mutations of the TSH receptor gene. The patients with high serum TRAb levels at birth had transient hyperthyroidism (n = 23), hypothyroidism (primary n = 2, central n = 3) or persistent euthyroidism (n = 4). CONCLUSION: These original findings highlight the need for careful and appropriate monitoring of thyroid function in the long term, not only for the rare patients with non-autoimmune neonatal hyperthyroidism, but also for repeat monitoring during the first month of life in neonates with maternally transmitted high TRAb levels, to ensure the early identification of thyrotoxicosis in more than two thirds of cases and to detect primary or central hypothyroidism, thereby potentially decreasing associated morbidity.

LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages.

Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, suggesting that LACC1-dependent autophagy fuels macrophage bioenergetics metabolism. Altogether, LACC1 deficiency defines a novel form of genetically inherited juvenile arthritis associated with impaired autophagy in macrophages.

Infectious adverse events in children with Juvenile Idiopathic Arthritis treated with Biological Agents in a real-life setting: Data from the JIRcohorte.

OBJECTIVES: The main objective of our study is to assess the infectious adverse events occurring in juvenile idiopathic arthritis (JIA) children treated with biological agents. METHODS: Patients were selected from the retrospective module of the JIRcohorte, data concerning the period between January 2001 and August 2015. All infectious adverse events (IAE) were retrieved. For every infectious side effect, the date, the severity, the need for a hospitalization, the type of pathogen and the affected organ were noted. Incidence rates were expressed in number of events per 100 person-years (100p-y), and OR were calculated. RESULTS: Six hundred seventy-seven patients with JIA were included in the study. A total of 3075.4 person-years of exposure were analyzed. One hundred eighty-four infectious events were described (6.0 events/100 p-y): 15.5/100 p-y with tocilizumab (TCZ), 9.6/100 p-y with Canakinumab (CAN), 7.4/100 p-y with abatacept (ABA), 6.9/100 p-y with Golimumab (GOL), 6.7/100 p-y with Anakinra (ANA), 6.3/100 p-y with Infliximab, 4.8/100 p-y with Etanercept, and 3.7/100 p-y with Adalimumab. Risk of developing an infection was significantly higher with IL-6 antagonists or IL-1 antagonists than with TNF-inhibitor. Forty point eight percent of the infectious adverse events (IAE) affected the upper respiratory tract or the Ear, nose and throat (ENT) system. Twelve infectious adverse events were described as severe or very severe (0.4/100p-y). No case of tuberculosis or death was reported. CONCLUSION: Infectious complications with biologics occurring in children treated for JIA are rare, and in most of the cases have a mild or moderate severity, affecting mainly the upper respiratory tract or the ENT.

Serious adverse events in children with juvenile idiopathic arthritis and other rheumatic diseases on tocilizumab - a real-world experience.

OBJECTIVES: To assess the incidence rate and type of serious adverse events (SAE) in children with rheumatic inflammatory diseases treated with the interleukin 6 blocker tocilizumab (TCZ). METHODS: A retrospective review of all consecutive patients diagnosed with an inflammatory rheumatic disease and receiving at least one dose of TCZ was performed in two French tertiary pediatric rheumatology centers between 01/2007 and 06/2019. SAE were defined as a life-threatening event and/or an event requiring hospital admission, leading to permanent disability or treatment discontinuation. RESULTS: One hundred four children (64 female) were included. Most children suffered from systemic (n = 43) or polyarticular-course juvenile idiopathic arthritis (n = 43). Median age at TCZ start was 8.9 years (IQR 4.7 - 12.1), most children had received prednisone (81%), and/or a biologic agent (84%) prior to TCZ. Median TCZ treatment duration was 1.6 years (IQR 0.5 - 2.7), total TCZ exposure 215 patient years. Thirty-three SAE were observed in 26 (25%) children (SAE 15.3/100 patient years), mostly infections and infusion reactions. Children with SAE were significantly younger at disease onset (p = 0.034) and TCZ initiation (p = 0.016). Children experiencing infusion reactions were more likely to have systemic JIA or another autoinflammatory disease (p = 0.021), they all had active disease. At last follow up, 61 (59%) children remained on TCZ. CONCLUSION: In this cohort, SAE and most commonly serious infections were observed in a quarter of children. Severe infusion reactions were associated with persistently active autoinflammatory disease. Ongoing careful monitoring of TCZ-treated patients, especially young children with marked systemic inflammation is required.

Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency.

Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient's cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient's cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV.