Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disease caused by pathogenic variants in genes involved in phosphate homeostasis, and characterized by elevated serum phosphate levels and the development of ectopic calcifications. Management typically includes phosphate-lowering strategies and, when clinically necessary, surgical debulking of calcifications. Inflammatory flares occur variably and remain poorly understood. We report the case of a 27-yr-old woman with HFTC due to a homozygous GALNT3 mutation, who experienced recurrent painful flares, elevated inflammatory markers, and progressive calcinosis. Based on the hypothesis that HFTC may behave like an autoinflammatory syndrome, the patient was treated with canakinumab, an anti-interleukin-1 antibody, with 7 yr of follow-up to date. The treatment led to rapid and sustained clinical and biological remission, significant regression of calcified lesions without surgical intervention, and demonstrated good safety.

Comme pour toute biothérapie, la mise en route d’un traitement par anti-IL1 impose de dépister par un bilan standardisé une contre-indication ou une situation à risque ou à précaution d’emploi, devant amener le clinicien à redoubler de prudence en cas de prescription, comme un antécédent de cancer ou d’infection sévère ou active. C’est également l’occasion de réaliser la mise à jour vaccinale recommandée, qui sera traitée en détail dans la fiche correspondante.

OBJECTIVE:To characterize the demographic, clinical, serological, genetic background, course and value of the interferon (IFN)-score in a cohort of patients with rheumatoid factor (RF)-positive polyarticular juvenile idiopathic arthritis (pJIA). METHODS:Monocentric retrospective study of patients with RF-positive pJIA. Demographic, clinical and laboratory data were collected. The IFN-score was calculated based on the expression levels of 24 IFN stimulated genes. Whole exome sequencing was performed in 22 patients. RESULTS:Thirty-two patients were included. The IFN score was positive in 18 patients (56.2%) and negative in 14 patients (43.7%). An increased IFN score was associated with a significantly higher family history of autoimmunity (p = 0.0004), parental first-degree consanguinity (p = 0.05) and prevalence of antibodies to anti-cyclic citrullinated peptide (ACPA) (p = 0.01). Three patients with interstitial lung disease exhibited a positive IFN score. Conversely, demographic features and characteristics of polyarthritis did not differ between the two groups. Clinically inactive disease was achieved in 21/32 (66%) patients, with no significant difference according to the IFN score. Remission was never achieved with methotrexate alone. We identified one patient with a pathogenic de novo mutation in COPA. Additionally, ultra-rare variants in genes related to IFN and/or innate immunity were found in 21/22 (95.5%) patients. CONCLUSION:The IFN signature identified two distinct subgroups in RF-positive pJIA according to family history and immunological features. Our study suggests that patients with an elevated IFN score should be screened for pulmonary involvement. Future prospective studies are required to validate the use of the IFN score as a biomarker in RF-positive pJIA.

Les neutropénies et thrombopénies sont des effets secondaires décrits comme peu fréquents à fréquents sous anti-IL1. La plupart du temps, la diminution des leucocytes ou des plaquettes est légère, transitoire, et ne s’accompagne pas d’évènements infectieux ou hémorragiques. Un hémogramme doit être pratiqué chez tout patient avant l’initiation d’un traitement par anti-IL1, puis tous les mois pendant 3 à 6mois, et tous les 3mois ensuite. En cas de cytopénie(s) importante(s) il convient de : (i) toujours rechercher un syndrome d’activation macrophagique ou une hémopathie maligne (se référer aux fiches correspondantes) ; (ii) l’anti-IL1 (anakinra ou canakinumab) doit être arrêté et l’hémogramme surveillé ; (iii) une alternative thérapeutique doit être envisagée, a fortiori si la cytopénie est persistante ; (iv) si la prescription d’un anti-IL1 est indispensable dans le cas du patient, l’avis d’un centre expert de la pathologie inflammatoire sous-jacente (centres de la filière FAI2R https://www.fai2r.org/ ou du CEREMAIA https://www.ceremaia.fr/) ; (v) une déclaration à la pharmacovigilance doit être effectuée.

L’anakinra s’élimine très majoritairement par le rein et une adaptation posologique est nécessaire en cas d’insuffisance rénale sévère. Le signe évocateur de surdosage d’anakinra lié à l’insuffisance rénale est la neutropénie. La voie d’élimination du canakinumab n’est pas claire et il n’y a quasiment aucune donnée sur l’utilisation de ce produit chez les insuffisants rénaux. Ainsi, si l’adaptation posologique du canakinumab n’apparaît pas nécessaire pour les insuffisances rénales légères ou modérées, son utilisation chez les insuffisants rénaux ou terminaux n’est pas recommandée dans l’état actuelle des connaissances.

Il n’y a pas de contre-indication à l’utilisation concomitante d’AINS, de corticoïdes et/ou de traitements de fond synthétique avec les anti-IL1. Dans certaines indications, leur co-prescription est même conseillée (colchicine et fièvre méditerranéenne familiale par exemple). Les combinaisons entre anti-IL1 et autres thérapies ciblées n’ont été que très peu étudiées. La co-prescription avec les anti-TNF majore le risque d’infection sévère. L’IL1 étant un inhibiteur du CYP450, la prescription d’un anti-IL1 peut réactiver les fonctions de ce dernier et modifier le seuil thérapeutique de certaines molécules à index thérapeutique étroit (par ex., warfarine et phénytoïne). La surveillance est requise à l’initiation de l’anti-IL1 et la dose individuelle du médicament métabolisé par le CYP450 pourra être ajustée si nécessaire.

Le risque de cancer solide ou d’hémopathie maligne sous anti-IL1 est imparfaitement connu, mais ne semble pas être augmenté. Bien qu’il y ait une recherche active sur l’inhibition de l’IL1β comme piste thérapeutique en tant que traitement associé de certains cancers, les résultats sont à ce stade trop préliminaires et discordants pour porter des conclusions. Par conséquent, en cas d’antécédent ou d’apparition de cancer ou d’hémopathie maligne lors de la prescription d’anti-IL1, et bien qu’il n’y ait pas de contre-indication formelle, une évaluation du rapport bénéfice-risque et une discussion collégiale avec l’oncologue ou l’hématologue s’imposent. Si un traitement par anti-IL1 doit être prescrit durant la période de traitement du cancer, nous recommandons plutôt l’utilisation de l’anakinra dont la demi-vie est courte en comparaison du canakinumab et permet ainsi de suspendre rapidement le traitement en cas de complications infectieuse sévère.

La réalisation d’une intervention chirurgicale au cours d’un traitement par anti-IL1 peut, théoriquement, augmenter le risque de survenue d’une complication infectieuse et/ou d’un retard de cicatrisation. Toutefois, ce risque n’est pas clairement évalué dans la littérature, ce qui justifie des avis d’experts prenant en compte, d’une part, bien sûr le risque septique du geste chirurgical et, d’autre part, le risque de reprise évolutive de la maladie auto-inflammatoire à l’arrêt du traitement, notamment le déclenchement d’une crise inflammatoire fébrile dans les quelques heures ou jours qui rendra difficile l’intervention. L’arrêt ou la poursuite de l’IL-1 dépendra donc de la demi-vie de la molécule, du type de chirurgie, du risque infectieux propre à chaque patient et de la sévérité de la maladie rhumatismale sous-jacente.

OBJECTIVE:Interleukin-1 inhibitors (anti-IL-1 agents) are an essential therapeutic class in the management of autoinflammatory diseases (AIDs). The latest version of the Club Rhumatismes et Inflammations (CRI) guidelines for anti-IL-1 therapy dates from 2014. The present work aimed to update the CRI guidelines. METHODS:A group of 13 writers (6 rheumatologists, 3 internists, and 4 paediatricians) who are experts in AIDs conducted a rigorous review of the literature up to November 2025 in their respective fields of expertise to write each guideline area. All guidelines were reviewed by the two scientific coordinators. RESULTS:The update concerned only the two anti-IL-1 molecules available in France and most European countries: anakinra and canakinumab. A total of 20 sets of guidelines were written on pre-treatment assessment and follow-up of patients on anti-IL-1 therapy as well as the course of action to be taken in the event of bacterial or viral infections, solid or haematological neoplasia, haematologic biological abnormalities, cardiovascular conditions, skin or systemic intolerance, autoimmune or demyelinating conditions, biological hepatitis, macrophage activation syndrome, renal failure or dialysis, drug combinations, surgery, dental care, burns or trauma, pregnancy, use of anti-IL-1 agents in low-weight children, vaccination, travel, Kawasaki disease, recurrent pericarditis, acute gout attacks and Schnitzler syndrome. CONCLUSION:These guidelines are a practical tool for clinicians, summarizing the course of action to be taken in clinical situations they may encounter, based on the latest scientific data on efficacy and tolerance.

Background Juvenile psoriatic arthritis and enthesitis-related arthritis are two categories of juvenile idiopathic arthritis (JIA). Despite available treatments including non-steroidal anti-inflammatory drugs, glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biological DMARDs, a substantial proportion of people do not adequately respond to treatment or do not have long-lasting clinical remission. The aim of this trial was to show the efficacy and safety of ixekizumab in children with active enthesitis-related arthritis and juvenile psoriatic arthritis. Methods COSPIRIT-JIA is an ongoing multicentre, open-label, phase 3 study of ixekizumab, with a randomised adalimumab reference group, in children with a diagnosis of enthesitis-related arthritis (aged 6 to <18 years) and juvenile psoriatic arthritis (aged 2 to <18 years). Eligible participants had three or more active peripheral joints (presence of swelling or limited motion with pain or tenderness) and a bodyweight of at least 10 kg. Participants received subcutaneous administration of either ixekizumab or adalimumab using a weight-based dosing regimen (ixekizumab 40-160 mg starting dose then 20-80 mg once every 4 weeks; and adalimumab 20-40 mg once every 2 weeks). The primary endpoint was the percentage of ixekizumab-treated participants meeting the JIA-American College of Rheumatology (ACR) 30 (defined as at least 30% improvement from baseline in three of any six core outcome variables, with no more than one of the other variables worsening by more than 30%) response criteria at week 16. A Bayesian analysis was used to assess JIA-ACR30 response rate at week 16. Safety data were summarised using descriptive statistics for all participants who received at least one dose of either treatment. People with lived experience of JIA were not involved in the design or conduct of this study. The trial was registered with ClinicalTrials.gov, NCT04527380. Findings The study enrolled 101 patients (ixekizumab n=81, adalimumab n=20) between April 13, 2021, and April 2, 2024, of whom the initial 40 participants naive to biological DMARD treatment were randomly assigned 1:1 to ixekizumab or adalimumab and the additional 61 participants were assigned to ixekizumab. Of the 81 participants who received ixekizumab, 60 were biological DMARD naive (40 with enthesitis-related arthritis and 20 with juvenile psoriatic arthritis) and 21 were biological DMARD experienced (14 with enthesitis-related arthritis and seven with juvenile psoriatic arthritis). The median age of the participants in the ixekizumab group was 14 years (12 & centerdot;0-15 & centerdot;0), ofwhom 36 (44%) of 81 were female, and 69 (85%) of 81 were White. At week 16, 90% (54 of 60; 95% CI 82 center dot 4-97 center dot 6) of biological DMARD-naive participants and 86% (18 of 21; 70 center dot 7-100 center dot 0) of biological DMARDexperienced participants receiving ixekizumab had a JIA-ACR30 response. Treatment-emergent adverse events were mostly mild (46%) or moderate (36%) for the ixekizumab group, with no severe treatment-emergent adverse events reported. The safety profile was consistent with adult psoriatic arthritis or spondyloarthritis and paediatric psoriasis indications. Interpretation Ixekizumab was well tolerated and effective for the treatment of children with enthesitis-related arthritis and juvenile psoriatic arthritis who are candidates for biological DMARD therapy.

BACKGROUND:Juvenile psoriatic arthritis and enthesitis-related arthritis are two categories of juvenile idiopathic arthritis (JIA). Despite available treatments including non-steroidal anti-inflammatory drugs, glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biological DMARDs, a substantial proportion of people do not adequately respond to treatment or do not have long-lasting clinical remission. The aim of this trial was to show the efficacy and safety of ixekizumab in children with active enthesitis-related arthritis and juvenile psoriatic arthritis. METHODS:COSPIRIT-JIA is an ongoing multicentre, open-label, phase 3 study of ixekizumab, with a randomised adalimumab reference group, in children with a diagnosis of enthesitis-related arthritis (aged 6 to <18 years) and juvenile psoriatic arthritis (aged 2 to <18 years). Eligible participants had three or more active peripheral joints (presence of swelling or limited motion with pain or tenderness) and a bodyweight of at least 10 kg. Participants received subcutaneous administration of either ixekizumab or adalimumab using a weight-based dosing regimen (ixekizumab 40-160 mg starting dose then 20-80 mg once every 4 weeks; and adalimumab 20-40 mg once every 2 weeks). The primary endpoint was the percentage of ixekizumab-treated participants meeting the JIA-American College of Rheumatology (ACR) 30 (defined as at least 30% improvement from baseline in three of any six core outcome variables, with no more than one of the other variables worsening by more than 30%) response criteria at week 16. A Bayesian analysis was used to assess JIA-ACR30 response rate at week 16. Safety data were summarised using descriptive statistics for all participants who received at least one dose of either treatment. People with lived experience of JIA were not involved in the design or conduct of this study. The trial was registered with ClinicalTrials.gov, NCT04527380. FINDINGS:The study enrolled 101 patients (ixekizumab n=81, adalimumab n=20) between April 13, 2021, and April 2, 2024, of whom the initial 40 participants naive to biological DMARD treatment were randomly assigned 1:1 to ixekizumab or adalimumab and the additional 61 participants were assigned to ixekizumab. Of the 81 participants who received ixekizumab, 60 were biological DMARD naive (40 with enthesitis-related arthritis and 20 with juvenile psoriatic arthritis) and 21 were biological DMARD experienced (14 with enthesitis-related arthritis and seven with juvenile psoriatic arthritis). The median age of the participants in the ixekizumab group was 14 years (12·0-15·0), of whom 36 (44%) of 81 were female, and 69 (85%) of 81 were White. At week 16, 90% (54 of 60; 95% CI 82·4-97·6) of biological DMARD-naive participants and 86% (18 of 21; 70·7-100·0) of biological DMARD-experienced participants receiving ixekizumab had a JIA-ACR30 response. Treatment-emergent adverse events were mostly mild (46%) or moderate (36%) for the ixekizumab group, with no severe treatment-emergent adverse events reported. The safety profile was consistent with adult psoriatic arthritis or spondyloarthritis and paediatric psoriasis indications. INTERPRETATION:Ixekizumab was well tolerated and effective for the treatment of children with enthesitis-related arthritis and juvenile psoriatic arthritis who are candidates for biological DMARD therapy. FUNDING:Eli Lilly and Company.

ABSTRACT Juvenile dermatomyositis (JDM) is characterized by a type I interferon (IFN-I) signature associated with disease activity. We previously identified a link between SARS-CoV-2 infection and the onset or relapse of JDM. Here, we show that newly diagnosed JDM patients display an overexpression of IFIH1 (encoding MDA5 protein) at baseline, coupled with an altered response to dsRNA stimulation at proteomic and transcriptomic levels, indicating abnormal activation of this antiviral sensing pathway. Single-cell transcriptomic and chromatin accessibility profiling of peripheral blood mononuclear cells (PBMCs) further revealed myeloid-specific enrichment of interferon-stimulated genes (ISGs) and preferential disruption of this pathway at disease onset, supporting a dysregulated IFN-I state in this cell type. We identified SARS-CoV-2 RNA in muscle biopsies of two Covid-19 pandemic-onset JDM patients, strongly implicating viral infection as a potential trigger of the dysregulated MDA5 immune response. To extend these observations beyond SARS-CoV-2, we screened two independent retrospective cohorts for antibodies against 27 common childhood infections. In our discovery cohort JDM patients showed significantly increased exposure to 4 RNA viruses in line with our immunological findings. Increased exposure to RSV B was confirmed in an independent replication cohort supporting a robust association with JDM pathophysiology. Together, these findings integrate systemic, single-cell, and tissue-level analyses implicating RNA viral infection and biased antiviral sensing in shaping IFN-I responses at JDM onset, providing mechanistic insight into environmentally triggered pathogenesis. One sentence summary Type I interferon dysregulation at juvenile dermatomyositis onset implicates altered dsRNA sensing and RNA viral exposure as potential disease triggers.

La maladie de Kawasaki (MK) est la vascularite la plus fréquente chez les enfants de moins de 5 ans. Elle touche préférentiellement les artères de moyen calibre et son pronostic réside dans la survenue de complications cardiaques. Le rôle de l’IL-1 dans l’inflammation de la maladie et dans le développement des anévrismes coronaires et la myocardite est de plus en plus évident. Actuellement, seul l’anakinra est utilisé hors AMM, selon les recommandations de l’American Heart Association (AHA) 2017 et le protocole national de diagnostic et de soins (PNDS) sur la maladie de Kawasaki, uniquement en cas d’échec des immunoglobulines intraveineuses.

Aicardi-Goutières syndrome (AGS) is a genetic type I interferon (IFN)-mediated disease characterized by neurological involvement with onset in utero or in childhood. Here, we analyze peripheral blood samples from patients bearing AGS-causing mutations in ADAR1, RNASEH2B or SAMHD1 using single-cell transcriptomics and targeted metabolomics. Using machine-learning approaches and differential gene expression analysis, we identified a loss of transcription factor hypoxia induced factor 1 α (HIF-1α) expression and activity associated with features of a metabolic switch favoring oxidative phosphorylation and glutathione metabolism over glycolysis in monocytes and dendritic cells. Evidences of mitochondrial stress and accumulation of cytosolic double-stranded DNA and RNA were also found. The energy metabolic switch was confirmed at the metabolic level in primary peripheral blood mononuclear cells of AGS patients. Chemical stabilization of HIF-1α using a synthetic drug in in vitro cellular models of AGS, reversed the energy metabolic switch towards glycolysis, attenuated mitochondrial stress, and markedly reduced the IFN response and IP-10 production. We therefore propose that an energy metabolic switch contributes to chronic inflammation in AGS and that targeting this pathway might represent a potential therapeutic approach.

Les réactions cutanées locales sous anti-IL1 sont fréquentes, notamment sous anakinra en début de traitement. Elles sont le plus souvent transitoires, et quelques mesures physiques simples permettent le plus souvent de « passer le cap » et de poursuivre le traitement. Les réactions d’hypersensibilité anaphylactoïdes sont exceptionnelles, et ne doivent pas être confondues avec les réactions d’allure toxidermique « Drug Reaction with Eosinophelia and Systemic Symptoms (DRESS) -like », rapportées exclusivement dans la maladie de Still. Celles-ci ont été décrites aussi bien sous anti-IL1 ou anti-IL6 qu’en l’absence de ces traitements, le plus souvent chez des sujets positifs pour le HLA-DRB1*15. Leur survenue doit motiver une discussion en réunion de concertation pluridisciplinaire spécialisée en urgence.

Pour les patients sous anti-IL1, il est recommandé en plus des vaccins habituels du calendrier vaccinal, une vaccination annuelle contre la grippe saisonnière, contre la COVID-19 et une vaccination contre le pneumocoque dont le schéma vaccinal comporte maintenant une seule dose de vaccin conjugué 20-valent PCV20 chez l’adulte. Le vaccin DTPc doit être réalisé tous les 10 ans. Le vaccin contre le zona est recommandé avec le vaccin inerte recombinant, a fortiori en cas d’antécédents de zona, immunodépression profonde, âge>65 ans. Les vaccins inertes peuvent être réalisés sous anti-IL1. Pour les vaccins vivants, en particulier le BCG ou la fièvre jaune, les anti-IL1 doivent être arrêtés. Néanmoins, les recommandations EULAR/PReS ont récemment suggéré que certains vaccins vivants tels que le rappel rougeole-oreillons-rubéole (ROR), la varicelle et le zona, pourraient être réalisés sous anti-IL1, en pesant le rapport bénéfice/risque pour chaque indication. C’est notamment le cas pour certaines maladies auto-inflammatoires où l’arrêt de l’anti-IL1 pourrait induire une poussée de la maladie sous-jacente.

Le syndrome de Schnitzler est une maladie auto-inflammatoire rare, qui se manifeste par une éruption urticarienne fébrile, des douleurs osseuses ou articulaires, un syndrome inflammatoire biologique et une gammapathie monoclonale le plus souvent de type IgM. Les inhibiteurs de l’IL-1 ont radicalement changé la prise en charge de ces patients. Ils constituent désormais le traitement de première intention du syndrome de Schnitzler, avec une efficacité élevée, une réponse rapide et peu d’effets secondaires. Les patients doivent néanmoins être régulièrement surveillés, notamment du fait du risque de développer une macroglobulinémie de Waldenström.

OBJECTIVES:Severe forms of systemic JIA (sJIA), also called paediatric-onset Still's disease are associated with two major life-threatening complications: macrophage activation syndrome (MAS) and severe lung disease. Patients are usually resistant to conventional synthetic (cs) DMARDs, biologic (b) DMARDs, and targeted synthetic (ts) DMARDs. Recently, allogeneic haematopoietic stem cell transplantation (HSCT) has been performed in a small number of patients with refractory and life-threatening disease. We aimed to report outcomes and complications of allogeneic HSCT in patients with severe, refractory sJIA treated at our centre. METHODS:We conducted a retrospective, observational, single-centre study in a tertiary paediatric immunology care centre (Necker Hospital, Paris, France). RESULTS:We report three sJIA patients who underwent allogeneic HSCT at a median age of 3.5 years. All had recurrent MAS; two had lung disease and the HLA-DRB1*15 haplotype, associated with severe delayed hypersensitivity to IL-1/IL-6 inhibitors. Donors were matched sibling donors for the first and third patient, and matched unrelated donor for the second patient. They presented multiple post-graft complications: graft-vs-host disease, infections, thrombotic microangiopathy and severe inflammatory complications on previously affected organs, such as skin and lungs. At a median follow-up of 22 months (20-33) after transplantation, they were all in remission with full-donor chimerism and were off immunosuppressive treatment. CONCLUSION:Allogeneic HSCT can be an effective salvage therapy in patients with refractory sJIA. However, the risk of post-transplant endothelial complications and severe inflammation in previously affected organs, such as joints, skin and lungs deserves particular attention.

Le voyage chez un patient traité par anti-IL1, en particulier en zone tropicale, doit s’anticiper, avec si possible une consultation spécialisée en médecine du voyage, pour conseils et éducation thérapeutique, et prescription d’une trousse à pharmacie. Certains vaccins obligatoires, comme le vaccin antiamaril, sont contre-indiqués sous biothérapies car ce sont des vivants atténués. Dans tous les cas, une carte-patient ou une lettre d’information en français et en anglais sont recommandées. Des démarches administratives afin de faciliter le passage de la douane avec le médicament et respecter la chaîne du froid (sac isotherme) lors du transport aérien doivent être entreprises en amont du voyage.

La tolérance hépatique des anti-IL1 est le plus souvent bonne, bien qu’une cytolyse hépatique, voire une hépatite soient possibles. L’insuffisance hépatique n’est pas une contre-indication absolue à l’initiation d’un traitement par anakinra ou canakinumab. Toutefois, l’accord de l’hépatologue est indispensable en cas de pathologie hépatique préexistante, a fortiori en cas d’hépatite virale qui devra être traitée. La surveillance des transaminases sous traitement sera effectuée. En cas d’apparition d’une cytolyse au cours du traitement par anti-IL1, un bilan étiologique habituel doit être systématiquement effectué, avec recherche de consommation de substances potentiellement hépatotoxiques, identification d’une cause sous-jacente liée à la maladie ayant conduit à l’utilisation d’un anti-IL1 (notamment syndrome d’activation macrophagique), recherche d’une maladie hépatique autre, réalisation d’une échographie abdominale couplée à un Doppler et avis hépatologique). Le diagnostic d’hépatotoxicité médicamenteuse ne sera retenu qu’après élimination des diagnostics différentiels et avis de pharmacovigilance. Un avis auprès du centre expert peut également être nécessaire.