Subcutaneous anakinra in the management of refractory MIS-C in France

IntroductionMultisystemic inflammatory syndrome in children (MIS-C) is a therapeutic emergency and can lead to myocardial dysfunction (17%–75%) and heart failure (52%–53%). Intravenous immunoglobulins (IVIG) and corticosteroids (CST) have been validated for the management of this condition. Recent reports suggest that an interleukin-1 (IL-1) receptor antagonist, namely anakinra, may be a valuable add-on to the 2019 novel coronavirus disease (COVID-19) treatment for refractory patients. The purpose of this study was to describe the clinico-biological characteristics of patients treated with anakinra as well as the efficacy and safety of subcutaneous anakinra therapy in this condition.MethodsThe prospective multicentre study of children hospitalized for MIS-C between March 2020 and September 2022, including 23 international paediatric centres, followed for a mean duration of 3.072 ± 3.508 months. The patient data were extracted from the Juvenile Inflammatory Rheumatism (JIR) cohort. The clinico-pathological characteristics, cardiac ultrasound data, and adverse events were reported in patients receiving anakinra.ResultsOf the 470 children admitted with MIS-C, 18 French patients (50% girls) with a mean age of 10.06 ± 3.9 years were treated with subcutaneous anakinra. Anakinra was used in two situations, macrophage activation syndrome (MAS) (4 patients) and heart failure (14 patients) with a median left ventricular ejection fraction (LVEF) of 39.5% (30%–45%). The average dose of anakinra received was 2.53 ± 1.3 mg/kg/day for a median duration of 3 days. Prior to introduction, 78% (n = 14/18) of the patients had received CST and 56% (n = 10/18) had received IVIG. Only two patients received IVIG alone and six received CST alone plus anakinra. In 10% of cases, IVIG was poorly tolerated from a cardiovascular point of view and was discontinued. Transient elevations in serum transaminases were noted in four patients on anakinra without the need for treatment or dose modification. In all patients, rapid (48 h) improvement in myocardial function was observed (LVEF > 55%) with a concomitant significant decrease in myocardial enzymes (p < 0.05). All patients survived with complete recovery of cardiac function without sequelae.ConclusionsSubcutaneous anakinra appears to be a safe and effective treatment for the management of heart failure or MAS in MIS-C patients. The value of IVIG in these two situations remains to be reviewed

Les syndromes périodiques associés à la cryopyrine : revue de la littérature et description des cas français avec mosaïcisme somatique

Cryopyrin-associated periodic syndrome are three clinical forms of a rare autoinflammatory disorder from familial cold urticaria, the mild form, to the most severe form called chronic infantile neurological cutaneous and articular syndrome (CINCA), throught Muckle-Wells syndrome (MWS), the intermediate phenotype. Sensorineural hearing loss and renal amyloidosis can occur during the evolution. CAPS are due to gain-of-function mutations of NLRP3 gene, predominantly germline mutations. This results in an excessive activation of NLRP3 inflammasome and interleukin 1β processing leading to biological and clinical manifestations. These germline mutations are detectable with Sanger sequencing method. Sometimes, classically severe phenotypes of MWS and CINCA remain germline-mutation-negative patients. However, genetic diagnosis is crucial to access to interleukin 1 inhibitors that drastically improved quality of life of patients, and for genetic counselling. A finer analysis of Sanger sequence trace could suggest mosaicism, two or more populations of cells with distinct genotypes. Next-generation sequencing are recent technological advances that have provided us to assess mosaicism. In the literature, this genetic mechanism is involved in some CAPS and others auto-inflammatory diseases (MAI) physiopathology. Here, we present a CAPS review, mosaicism case reports of CAPS and MAI described in the literature and a description of french CAPS with mosaicism.Les cryopyrinopathies (CAPS) regroupent trois entités, continuum phénotypique depuis la forme bénigne d’urticaire familiale au froid jusqu’au syndrome Chronique Infantile, Neurologique, Cutané et Articulaire (CINCA) en passant par le phénotype intermédiaire de syndrome de Muckle-Wells (MWS). Deux complications grèvent l’évolution : la surdité et l’amylose AA, notamment rénale. Sur le plan physiopathologique, les CAPS sont la conséquence de mutations « gain de fonction », majoritairement germinales, du gène NLRP3, impliquant une activation constitutive de l’inflammasome NLRP3. Il en résulte une hyperproduction de cytokines pro-inflammatoires, notamment les interleukines 1β et 18, responsables des manifestations clinico-biologiques des CAPS. Ces mutations germinales sont détectables en séquençage conventionnel de Sanger. Parfois, de telles mutations sont absentes, notamment dans les phénotypes sévères de MWS et CINCA. Or, établir le diagnostic génétique de CAPS est primordial, notamment pour l’accès en AMM aux anti-interleukine 1, pierre angulaire du traitement, et pour le conseil génétique. L’analyse fine des tracés issus du séquençage de Sanger pouvait suggérer l’existence de mosaïcisme, présence de plusieurs clones cellulaires chez un même individu avec allèles sauvage et muté. Grâce aux techniques de séquençage nouvelles générations, il est désormais possible d’identifier ces mosaïcismes. Dans la littérature, ce mécanisme génétique est impliqué dans la physiopathologie des CAPS et d’autres maladies auto-inflammatoires (MAI). Nous proposons ici une revue de la littérature des CAPS, des CAPS et MAI par mosaïcisme, et rapportons les CAPS français par mosaïcisme

Mosaicism in autoinflammatory diseases: Cryopyrin-associated periodic syndromes (CAPS) and beyond. A systematic review

International audienceAutoinflammatory diseases (AIDs) are conditions related to defective regulation of the innate immune system. Sanger sequencing of the causative genes has long been the reference for confirming the diagnosis. However, for many patients with a typical AID phenotype, the genetic cause remains unknown. A pioneering study in 2005 demonstrated mosaicism in patients with cryopyrin-associated periodic syndromes (CAPS); the authors found somatic mosaicism in 69% of their cohort of Sanger-negative CAPS patients. We aim to address the extent to which mosaicism contributes to the etiology of AIDs and its impact on phenotype. We retrieved English-language publications reporting mosaicism in AIDs by querying PubMed with no restriction on date and we surveyed French reference centers. We provide a comprehensive clinical and genetic picture of mosaicism in AIDs. We estimate that the proportion of CAPS-like patients presenting mosaicism ranges from 0.5% to 19%. We also discuss the possible links between the proportion of mutated alleles and various clinical features. This review reevaluates the contribution of mosaic DNA variants in CAPS. Mosaicism may be more common than anticipated in other AIDs. No significant difference was demonstrated between variant allele frequency and clinical phenotype. Such knowledge has implications for the development of guidelines for genetic diagnosis, genetic counseling of affected families and effective patient care