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.

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.

[Familial mediterranean fever]. / Fièvre méditerranéenne familiale.

FAMILIAL MEDITERRANEAN FEVER. Familial mediterranean fever (FMF) is the most common monogenic auto-inflammatory disease worldwide. The recurrence of stereotyped febrile attacks lasting less than 3 days, associated with acute abdominal pain and a biological inflammatory syndrome in a child from the Mediterranean area, should raise its diagnosis. The detection of mutations in MEVF gene (exon 10 mainly) confirms the diagnosis. Long-term treatment with colchicine prevents the occurrence of attacks, and the development of secondary amyloidosis in adulthood, the most severe complication. The pathophysiology is increasingly well understood, with a key role for interleukin 1 (IL1), allowing the emergence of specific targeting therapies. Thus, IL1-blocking agents are second-line treatments, restricted for the very limited cases of patients, with colchicine resistance or intolerance.

FIÈVRE MÉDITERRANÉENNE FAMILIALE. La fièvre méditerranéenne familiale (FMF) est la maladie auto-inflammatoire monogénique la plus fréquente dans le monde. La récurrence d'accès fébriles stéréotypés durant moins de trois jours associés à des douleurs abdominales intenses et un syndrome inflammatoire biologique chez un enfant originaire du bassin méditerranéen doit faire évoquer son diagnostic. Celui-ci est confirmé par la recherche de mutations dans l'exon 10 du gène MEVF. Le traitement par colchicine au long cours prévient la survenue des accès et l'apparition secondaire d'amylose inflammatoire à l'âge adulte, complication la plus grave. La physiopathologie est de mieux en mieux comprise, avec un rôle central de l'interleukine 1, permettant le développement de biothérapies ciblant spécifiquement cette cytokine. Ces traitements de seconde ligne sont réservés aux très rares cas de patients réfractaires ou intolérants à la colchicine.

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.

Real-Life Indications of Interleukin-1 Blocking Agents in Hereditary Recurrent Fevers: Data From the JIRcohort and a Literature Review.

Background: Interleukin (IL)-1 inhibitors represent the main treatment in patients with colchicine-resistant/intolerant familial Mediterranean fever (crFMF), mevalonate kinase deficiency (MKD), and tumor necrosis factor receptor-associated periodic syndrome (TRAPS). However, the reasons for the use of IL-1 inhibitors in these diseases are still not completely clarified. Objective: Identify real-life situations that led to initiating anakinra or canakinumab treatment in hereditary recurrent fevers (HRFs), combining data from an international registry and an up-to-date literature review. Patients and Methods: Data were extracted from the JIRcohort, in which clinical information (demographic data, treatment, disease activity, and quality of life) on patients with FMF, MKD, and TRAPS was retrospectively collected. A literature search was conducted using Medline, EMBASE, and Cochrane databases. Results: Complete data of 93 patients with HRF (53.8% FMF, 31.2% MKD, and 15.1% TRAPS) were analyzed. Data from both the registry and the literature review confirmed that the main reasons for use of IL-1 blockers were the following: failure of previous treatment (n = 57, 61.3% and n = 964, 75.3%, respectively), persistence of disease activity with frequent attacks (n = 44, 47.3% and n = 1,023, 79.9%) and/or uncontrolled inflammatory syndrome (n = 46, 49.5% and n = 398, 31.1%), severe disease complication or associated comorbidities (n = 38, 40.9% and n = 390, 30.4%), and worsening of patients' quality of life (n = 36, 38.7% and n = 100, 7,8%). No reasons were specified for 12 (16.4%) JIRcohort patients and 154 (12%) patients in the literature. Conclusion: In the absence of standardized indications for IL-1 inhibitors in crFMF, MKD, and TRAPS, these results could serve as a basis for developing a treat-to-target strategy that would help clinicians codify the therapeutic escalation with IL-1 inhibitors.

The Use of Interleukine-1 Inhibitors in Familial Mediterranean Fever Patients: A Narrative Review.

Purpose: Familial Mediterranean fever (FMF) is the most common monogenic auto-inflammatory disease characterized by recurrent attacks of fever and serositis. It is associated with mutation in pyrin inflammasome leading to interleukin-1 (IL-1) over secretion. Although colchicine is the first line treatment in FMF, 5-10% of patients are reported in literature as non-responders. Colchicine is not always well-tolerated due either to its direct toxicity or to co-morbidities that preclude the administration of its proper dosage. For these patients an alternative or additional treatment to colchicine is necessary. This literature review reports the published data regarding the use of IL-1 inhibitors in Familial Mediterranean Fever. Results: There is no uniform definition of colchicine resistance, but the different studies of treatment with IL-1 inhibitors provide evidence of IL-1 pathogenic role in colchicine-resistant FMF. IL-1 inhibition is an efficacious option for controlling and preventing flares -at least at the short term- in FMF patients who are insufficiently controlled with colchicine alone. Although canakinumab is the only approved drug in Europe for colchicine resistant FMF treatment, experience with anakinra is also substantial. In the absence of comparative studies both treatments seem to be an equal option for the management of these patients. Overall the safety profile of IL-1 inhibitors seems not different in FMF patients than in the other diseases and can be considered as globally safe. The main side effects are local injection site reactions and infections. Conclusion: IL-1 inhibitors have the potential to improve patient outcome even in FMF patients with co-morbidities or severe complications in whom inflammation control is difficult to achieve with colchicine alone. Nevertheless, current data are limited and further evaluation of long-term efficacy and safety of IL-1 inhibitors are necessary, in order to provide robust evidence in this domain.