Publications by authors named "Brigitte Bader-Meunier"

158 Publications

Inflammatory myopathies in childhood.

Neuromuscul Disord 2021 10 9;31(10):1051-1061. Epub 2021 Oct 9.

Department of Pediatric Clinical Neurophysiology and reference Centre for Neuromuscular Diseases "Nord-Est-Ile de France", Necker Enfants Malades Hospital, AP-HP Centre, Paris University, Paris, France.

Myositis in childhood can occur under different conditions and with various aetiologies, juvenile dermatomyositis (jDM) being by far the most frequent entity. The exact diagnostic workup and precise assessment of muscular as well as extramuscular involvement of organs in these systemic autoimmune diseases are relevant for specific and adjunct treatment of complications. Many new insights have become available with respect to the pathophysiological concepts as well as modern diagnostic measures and therapeutic approaches. Autoantibody detection in the serum of children with myositis is one of the major novelties that has become widely used and that is indeed helpful for diagnostic and prognostic measures. The pathophysiological relevance of type I interferons in jDM has been studied intensively in the past years. jDM is now seen as an acquired interferonopathy and first therapeutic consequences have been drawn from this pathogenic finding with the use of Janus-kinase inhibitors for severe and not otherwise treatable children.
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http://dx.doi.org/10.1016/j.nmd.2021.08.007DOI Listing
October 2021

Correction to: Onset and Relapse of Juvenile Dermatomyositis Following Asymptomatic SARS-CoV-2 Infection.

J Clin Immunol 2021 Oct 7. Epub 2021 Oct 7.

Department of Paediatric Hematology-Immunology and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France, Reference center for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Paris, France.

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http://dx.doi.org/10.1007/s10875-021-01135-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496430PMC
October 2021

Long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency: results from the randomised Phase 3 CLUSTER trial.

Rheumatology (Oxford) 2021 Sep 23. Epub 2021 Sep 23.

Department of Pediatrics, University Medical Center Utrecht, Utrecht, the Netherlands.

Objectives: To evaluate the long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency (MKD) during the open label extension (weeks 41-113) of the randomised controlled CLUSTER trial.

Methods: During a 72-week period, patients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks. The disease activity was evaluated every 8 weeks using physician global assessment (PGA) and counting the number of flares. Concentrations of C reactive protein (CRP) and serum amyloid A (SAA) protein were measured. The safety was studied by determination and classification of observed adverse events. The safety and efficacy were analysed separately in three subgroups of patients receiving a cumulative dose of less than <35 mg/kg, ≥35-<70 mg/kg or ≥ 70 mg/kg.

Results: Of the 74 patients who started the CLUSTER study, 66 entered Epoch 4 and 65 completed it. During the 72-week period, 42 (64%) patients experienced no flares, while 13 (20%) had one flare, as compared with a median of 12 flares per year reported at baseline. Low PGA scores were seen at the end of the study for all groups with >90% reporting minimal disease activity or none at all. Median CRP concentrations were consistently equal or lower than 10 mg/l, while median SAA concentrations remained only slightly above the normal range of 10 mg/l. The study showed no new or unexpected adverse events.

Conclusion: Canakinumab proved effective to control disease activity and prevent flares in MKD during the 72-week study period. No new safety concerns were reported.

Clinical Trial Registration Number: NCT02059291.
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http://dx.doi.org/10.1093/rheumatology/keab696DOI Listing
September 2021

Mevalonate Kinase Deficiency: A Cause of Severe Very-Early-Onset Inflammatory Bowel Disease.

Inflamm Bowel Dis 2021 10;27(11):1853-1857

Department of Paediatric Immunology, Hematology, and Rheumatology, Groupe Hospitalier Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Reference Centre for Rheumatic, Autoimmune and Systemic Diseases in Children, Assistance Publique-Hôpitaux de Paris, and Imagine Foundation, Paris, France.

Mevalonate kinase deficiency should be considered in patients with severe very-early-onset inflammatory bowel disease (IBD), especially in patients with a history of recurrent or chronic fever, peritoneal adhesions, and atypical IBD pathology. Anti-interleukin-1 therapy may be efficacious in these patients with monogenic very-early-onset IBD.
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http://dx.doi.org/10.1093/ibd/izab139DOI Listing
October 2021

Therapeutic plasma exchange for life-threatening pediatric disorders.

J Clin Apher 2021 Sep 1. Epub 2021 Sep 1.

Hôpital Necker Enfants Malades, Paris, France.

Introduction: Therapeutic plasma exchange (TPE) is acknowledged to be an effective treatment in life-threatening pediatric disorders. Apheresis for pediatric diseases has been poorly investigated, and most studies to date featured small numbers of patients and lacked control groups. The objective of the present study was to evaluate the tolerance of TPE in pediatric patients.

Materials And Methods: A retrospective cohort study via a web-based electronic case report form including pediatric patients referred for TPE between January 2005 and December 2014.

Results: A total of 78 patients (median [range] age: 9.8 [0.53-17.93]) and 731 TPE procedures were analyzed. The indications were antibody-mediated rejection (n = 33; 42%) and desensitization therapy (n = 5; 6%) after solid organ or hematopoietic stem cell transplantation, thrombotic microangiopathy (n = 17; 22%), pediatric inflammatory diseases (n = 16; 21%), kidney diseases (n = 6; 8%), and hyperviscosity syndrome (n = 1; 1%). On average, each patient underwent six procedures during the first session [range: 1-19]. In the 2 weeks following the start of a session, 72 patients (92%) presented a total of 311 adverse events (AEs) potentially related to TPE. The risk of AEs was not related to the indication for TPE, the intensity of care, venous access, plasma substitute use, or body weight. None of the deaths was related to the TPE.

Conclusion: We studied one of the largest retrospective pediatric cohorts described to date. Our experience of TPE children's TPE feasibility concerned specific, life-threatening conditions and otherwise treatment-refractory diseases.
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http://dx.doi.org/10.1002/jca.21934DOI Listing
September 2021

Onset and Relapse of Juvenile Dermatomyositis Following Asymptomatic SARS-CoV-2 Infection.

J Clin Immunol 2021 Aug 23. Epub 2021 Aug 23.

Department of Paediatric Hematology-Immunology and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France, Reference center for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Paris, France.

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http://dx.doi.org/10.1007/s10875-021-01119-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382211PMC
August 2021

The association of Greig syndrome and mastocytosis reveals the involvement of hedgehog pathway in advanced mastocytosis.

Blood 2021 Aug 23. Epub 2021 Aug 23.

IMAGINE Institute- INSERM UMR 1163, Paris, France.

Mastocytosis is a heterogeneous disease characterized by an abnormal accumulation of mast cells (MCs) in one or several organs. Although a somatic KIT D816V mutation is detected in ~85% of patients, attempts to demonstrate its oncogenic effect alone have repeatedly failed, suggesting that additional pathways are involved in MC transformation. From three children presenting with both Greig cephalopolysyndactyly syndrome (GCPS, MIM#175700) and congenital mastocytosis, we demonstrated the involvement of the hedgehog (Hh) pathway in mastocytosis. GCPS is an extremely rare syndrome resulting from haploinsufficiency of GLI3, the major repressor of Hh family members. From these familial cases of mastocytosis, we demonstrate that the Hh pathway is barely active in normal primary MCs and overactive in neoplastic MCs. We show that GLI3 and KIT mutations have a synergistic, tumorigenic effect on the onset of mastocytosis in a GCPS mouse model. Finally, we show that Hh inhibitors suppress neoplastic MC proliferation in vitro and extend the survival time of aggressive systemic mastocytosis (ASM) mice. This work revealed, for the first time, the involvement of Hh signaling in the pathophysiology of mastocytosis and demonstrated the cooperative effects of the KIT and Hh oncogenic pathways in ASM, leading to the identification of new promising therapeutic targets.
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http://dx.doi.org/10.1182/blood.2020010207DOI Listing
August 2021

A monocyte/dendritic cell molecular signature of SARS-CoV-2-related multisystem inflammatory syndrome in children with severe myocarditis.

Med (N Y) 2021 Sep 14;2(9):1072-1092.e7. Epub 2021 Aug 14.

Sorbonne Université, UMS037, PASS, Plateforme de Cytométrie de la Pitié-Salpêtrière CyPS, 75013 Paris, France.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is generally milder than in adults, but a proportion of cases result in hyperinflammatory conditions often including myocarditis.

Methods: To better understand these cases, we applied a multiparametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. Plasma cytokine and chemokine levels and blood cellular composition were measured, alongside gene expression at the bulk and single-cell levels.

Findings: The most severe forms of multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 that resulted in myocarditis were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomics analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis characterized by sustained nuclear factor κB (NF-κB) activity and tumor necrosis factor alpha (TNF-α) signaling and associated with decreased gene expression of NF-κB inhibitors. We also found a weak response to type I and type II interferons, hyperinflammation, and response to oxidative stress related to increased HIF-1α and Vascular endothelial growth factor (VEGF) signaling.

Conclusions: These results provide potential for a better understanding of disease pathophysiology.

Funding: Agence National de la Recherche (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01; Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010; Laboratoire d'Excellence ''Milieu Intérieur," grant ANR-10-LABX-69-01; ANR-flash Covid19 "AIROCovid" and "CoVarImm"), Institut National de la Santé et de la Recherche Médicale (INSERM), and the "URGENCE COVID-19" fundraising campaign of Institut Pasteur.
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http://dx.doi.org/10.1016/j.medj.2021.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363470PMC
September 2021

Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A.

J Exp Med 2021 10 13;218(10). Epub 2021 Aug 13.

Université de Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Institut National de la Santé et de la Recherche Médicale, Unité mixte de recherche 1163, Paris, France.

Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up-regulated ISG expression and interferon α protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.
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http://dx.doi.org/10.1084/jem.20201560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374862PMC
October 2021

French recommendations for the management of systemic sclerosis.

Orphanet J Rare Dis 2021 07 26;16(Suppl 2):322. Epub 2021 Jul 26.

Rheumatology Department, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France.

Systemic sclerosis (SSc) is a generalized disease of the connective tissue, arterioles, and microvessels, characterized by the appearance of fibrosis and vascular obliteration. There are two main phenotypical forms of SSc: a diffuse cutaneous form that extends towards the proximal region of the limbs and/or torso, and a limited cutaneous form where the cutaneous sclerosis only affects the extremities of the limbs (without passing beyond the elbows and knees). There also exists in less than 10% of cases forms that never involve the skin. This is called SSc sine scleroderma. The prognosis depends essentially on the occurrence of visceral damage and more particularly interstitial lung disease (which is sometimes severe), pulmonary arterial hypertension, or primary cardiac damage, which represent the three commonest causes of mortality in SSc. Another type of involvement with poor prognosis, scleroderma renal crisis, is rare (less than 5% of cases). Cutaneous extension is also an important parameter, with the diffuse cutaneous forms having less favorable prognosis.
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http://dx.doi.org/10.1186/s13023-021-01844-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310704PMC
July 2021

[Professional representation of chronic idiopathic musculoskeletal pain in adolescents].

Soins Pediatr Pueric 2021 May-Jun;42(320):27-30. Epub 2021 Mar 26.

Maison de Solenn - Maison des adolescents de l'hôpital Cochin, AP-HP, 97 boulevard de Port-Royal, 75014 Paris, France; Université Paris-Saclay, UVSQ, Inserm, Centre de recherche en épidémiologie et santé des populations, Team DevPsy, 16 avenue Paul-Vaillant-Couturier, 94807 Villejuif, France.

Chronic idiopathic musculoskeletal pain is common in adolescence, and its impact is sometimes severe. The diagnostic process, which consists of eliminating other etiologies, can be long, complex, and at risk of medical nomadism. Specialists rely on many clinical elements to orient themselves. The care pathway and the subjective feeling of the professional are valuable diagnostic elements.
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http://dx.doi.org/10.1016/j.spp.2021.03.007DOI Listing
June 2021

Curation and expansion of Human Phenotype Ontology for defined groups of inborn errors of immunity.

J Allergy Clin Immunol 2021 May 12. Epub 2021 May 12.

Department of Immunology, Great Ormond Street (GOS) Hospital for Children NHS Foundation Trust, London, United Kingdom.

Background: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms.

Objectives: We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of terms, and to reannotate IEIs with HPO terms to provide accurate, standardized phenotypic descriptions.

Methods: We initiated a collaboration involving expert clinicians, geneticists, researchers working on IEIs, and bioinformaticians. Multiple branches of the HPO tree were restructured and extended on the basis of expert review. Our ontology-guided machine learning coupled with a 2-tier expert review was applied to reannotate defined subgroups of IEIs.

Results: We revised and expanded 4 main branches of the HPO tree. Here, we reannotated 73 diseases from 4 International Union of Immunological Societies-defined IEI disease subgroups with HPO terms. We achieved a 4.7-fold increase in the number of phenotypic terms per disease. Given the new HPO annotations, we demonstrated improved ability to computationally match selected IEI cases to their known diagnosis, and improved phenotype-driven disease classification.

Conclusions: Our targeted expansion and reannotation presents enhanced precision of disease annotation, will enable superior HPO-based IEI characterization, and hence benefit both IEI diagnostic and research activities.
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http://dx.doi.org/10.1016/j.jaci.2021.04.033DOI Listing
May 2021

Rheumatoid factor positive polyarticular juvenile idiopathic arthritis associated with a novel COPA mutation.

Rheumatology (Oxford) 2021 05;60(5):e171-e173

Paediatric Haematology-Immunology and Rheumatology Department, AP-HP, Hôpital Necker-Enfants Malades.

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http://dx.doi.org/10.1093/rheumatology/keaa763DOI Listing
May 2021

Evaluation of Hydroxychloroquine Blood Concentrations and Effects in Childhood-Onset Systemic Lupus Erythematosus.

Pharmaceuticals (Basel) 2021 Mar 17;14(3). Epub 2021 Mar 17.

Department of Pediatric Immunology, Hematology and Rheumatology, INSERM U1163, Imagine Institute, Necker Hospital, Université de Paris, AP-HP, F-75015 Paris, France.

Background: Hydroxychloroquine (HCQ) is an antimalarial agent given to patients with systemic lupus erythematosus (SLE) as first-line therapy. It alleviates childhood-onset systemic lupus erythematosus cSLE skin and musculoskeletal disease, decreasing disease activity and flares. HCQ concentration-effect relationships in children remains unknown. This study aimed to investigate the pharmacokinetics of HCQ and possible concentration-effect relationships.

Methods: HCQ blood concentrations and effects were obtained during clinical follow-up on different occasions. cSLE flares were defined using the SLE Disease Activity Index (SLEDAI); flare was denoted by a SLEDAI score > 6. Blood concentration was measured using high-performance liquid chromatography with fluorometric detection. Statistical analysis was performed using a nonlinear mixed-effect approach with the Monolix software.

Results: A total of 168 blood samples were obtained from 55 pediatric patients. HCQ apparent blood clearance (CL/F) was dependent on patients' bodyweight and platelet count. Patients with active cSLE had a lower mean blood HCQ concentration compared with inactive cSLE patients (536 ± 294 vs. 758 ± 490 ng/mL, = 5 × 10). Among patients with HCQ blood concentration ≥750 ng/mL, 87.6% had inactive cSLE. Moreover, HCQ blood concentration was a significant predictor of disease status.

Conclusion: We developed the first HCQ blood concentration-effect relationship for cSLE associated with active or non-active disease status. A prospective randomized study is necessary to confirm these results.
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http://dx.doi.org/10.3390/ph14030273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002378PMC
March 2021

Prior infection by seasonal coronaviruses, as assessed by serology, does not prevent SARS-CoV-2 infection and disease in children, France, April to June 2020.

Euro Surveill 2021 04;26(13)

Unité Biodiversité et Epidemiologie des Bacteries Pathogènes, Institut Pasteur, Paris, France.

BackgroundChildren have a low rate of COVID-19 and secondary severe multisystem inflammatory syndrome (MIS) but present a high prevalence of symptomatic seasonal coronavirus infections.AimWe tested if prior infections by seasonal coronaviruses (HCoV) NL63, HKU1, 229E or OC43 as assessed by serology, provide cross-protective immunity against SARS-CoV-2 infection.MethodsWe set a cross-sectional observational multicentric study in pauci- or asymptomatic children hospitalised in Paris during the first wave for reasons other than COVID (hospitalised children (HOS), n = 739) plus children presenting with MIS (n = 36). SARS-CoV-2 antibodies directed against the nucleoprotein (N) and S1 and S2 domains of the spike (S) proteins were monitored by an in-house luciferase immunoprecipitation system assay. We randomly selected 69 SARS-CoV-2-seropositive patients (including 15 with MIS) and 115 matched SARS-CoV-2-seronegative patients (controls (CTL)). We measured antibodies against SARS-CoV-2 and HCoV as evidence for prior corresponding infections and assessed if SARS-CoV-2 prevalence of infection and levels of antibody responses were shaped by prior seasonal coronavirus infections.ResultsPrevalence of HCoV infections were similar in HOS, MIS and CTL groups. Antibody levels against HCoV were not significantly different in the three groups and were not related to the level of SARS-CoV-2 antibodies in the HOS and MIS groups. SARS-CoV-2 antibody profiles were different between HOS and MIS children.ConclusionPrior infection by seasonal coronaviruses, as assessed by serology, does not interfere with SARS-CoV-2 infection and related MIS in children.
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http://dx.doi.org/10.2807/1560-7917.ES.2021.26.13.2001782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017906PMC
April 2021

Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.

Pediatr Rheumatol Online J 2021 Mar 12;19(1):27. Epub 2021 Mar 12.

Pediatric Hematology-Immunology and Rheumatology Department, Necker-Enfants-Malades University Hospital, Assistance Publique Hôpitaux de Paris, 149 rue de Sèvres, 75015, Paris, France.

Background: Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.

Case Report: A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.

Conclusion: Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
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http://dx.doi.org/10.1186/s12969-021-00523-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953742PMC
March 2021

JAK inhibitors are effective in a subset of patients with juvenile dermatomyositis: a monocentric retrospective study.

Rheumatology (Oxford) 2021 Feb 12. Epub 2021 Feb 12.

Department of Paediatric Hematology-Immunology and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France, Reference center for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Paris, France.

Objective: To evaluate the efficacy and safety of JAK inhibitors (JAKi) in juvenile dermatomyositis (JDM).

Methods: We conducted a single-center retrospective study of patients with JDM treated by JAKi with a follow-up of at least 6 months. Proportion of clinically inactive disease (CID) within six months of JAKi initiation was evaluated using PRINTO criteria and skin Disease Activity Score. Serum IFN-α concentration was measured by SIMOA assay.

Results: Nine refractory and one new-onset patients with JDM treated with ruxolitinib (n = 7) or baricitinib (n = 3) were included. The main indications for treatment were refractory muscle involvement (n = 8) and ulcerative skin disease (n = 2). CID was achieved in 5/10 patients (2/2 anti-MDA5, 3/4 anti-NXP2, 0/3 anti-TIF1γ positive patients) within six months of JAKi introduction. All responders could withdraw plasmatic exchange, immunoadsorption and other immunosuppressive drugs. The mean daily steroid dose decreased from 1.1 mg/Kg (range 0.35-2 mg/Kg/d) to 0.1 (range, 0-0.3, p= 0.008) in patients achieving CID, and was stopped in two. Serum IFN-α concentrations were elevated in all patients at the time of treatment initiation and normalized in both responder and non-responder. A muscle biopsy repeated in one patient 26 months after the initiation of JAKi, showed a complete restoration of muscle endomysial microvascular bed. Herpes zoster and skin abscesses developed in three and two patients, respectively.

Conclusion: JAKis resulted in a CID in a subset of new-onset or refractory patients with JDM and may dramatically reverse severe muscle vasculopathy. Overall tolerance was good except for a high rate of herpes zoster infection.
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http://dx.doi.org/10.1093/rheumatology/keab116DOI Listing
February 2021

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

J Clin Immunol 2021 04 7;41(3):603-609. Epub 2021 Jan 7.

General Paediatrics- Infectious Diseases and Internal Medicine Department, Robert-Debré Hospital, AP-HP, Nord - Université de Paris, Paris, France.

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.
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http://dx.doi.org/10.1007/s10875-020-00952-xDOI Listing
April 2021

From Diagnosis to Prognosis: Revisiting the Meaning of Muscle ISG15 Overexpression in Juvenile Inflammatory Myopathies.

Arthritis Rheumatol 2021 06 26;73(6):1044-1052. Epub 2021 Apr 26.

Institut Mondor de Recherche Biomédicale, Université Paris-Est Créteil, INSERM, Centre de Reference pour les Maladies Neuromusculaires, Hôpital Necker-Enfants Malades, AP-HP, FILNEMUS, Paris, France.

Objective: Juvenile idiopathic inflammatory/immune myopathies (IIMs) constitute a highly heterogeneous group of disorders with diagnostic difficulties and prognostic uncertainties. Circulating myositis-specific autoantibodies (MSAs) have been recognized as reliable tools for patient substratification. Considering the key role of type I interferon (IFN) up-regulation in juvenile IIM, we undertook the present study to investigate whether IFN-induced 15-kd protein (ISG-15) could be a reliable biomarker for stratification and diagnosis and to better elucidate its role in juvenile IIM pathophysiology.

Methods: The study included 56 patients: 24 with juvenile dermatomyositis (DM), 12 with juvenile overlap myositis (OM), 10 with Duchenne muscular dystrophy, and 10 with congenital myopathies. Muscle biopsy samples were assessed by immunohistochemistry, immunoblotting, and real-time quantitative polymerase chain reaction. Negative regulators of type I IFN (ISG15 and USP18) and positive regulators of type I IFN (DDX58 and IFIH1) were analyzed.

Results: ISG15 expression discriminated patients with juvenile IIM from those with nonimmune myopathies and, among patients with juvenile IIM, discriminated those with DM from those with OM. Among patients with juvenile DM, up-regulation of the type I IFN positive regulators DDX58 and IFIH1 was similar regardless of MSA status. In contrast, the highest levels of the type I IFN negative regulator ISG15 were observed in patients who were positive for melanoma differentiation-associated gene 5 (MDA-5). Finally, ISG15 levels were inversely correlated with the severity of muscle histologic abnormalities and positively correlated with motor performance as evaluated by the Childhood Myositis Assessment Scale and by manual muscle strength testing.

Conclusion: Muscle ISG15 expression is strongly associated with juvenile DM, with patients exhibiting a different ISG-15 muscle signature according to their MSA class. Patients with juvenile DM who are positive for MDA-5 have higher expression of ISG15 in both gene form and protein form compared to the other subgroups. Moreover, our data show that negative regulation of type I IFN correlates with milder muscle involvement.
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http://dx.doi.org/10.1002/art.41625DOI Listing
June 2021

Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients.

J Allergy Clin Immunol Pract 2021 02 18;9(2):803-818.e11. Epub 2020 Nov 18.

Pediatric Pulmonology Department and Reference Center for Rare Lung Disease RespiRare, Trousseau University Hospital, AP-HP Sorbonne Université, Paris, France.

Background: Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD).

Objective: To describe a cohort of patients with SAVI.

Methods: Assessment of clinical, radiological and immunological data from 21 patients (17 families) was carried out.

Results: Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most were symptomatic from infancy, but late onset in adulthood occurred in 1 patient. Systemic inflammation, skin vasculopathy, and ILD were observed in 19, 18, and 21 patients, respectively. Extensive tissue loss occurred in 4 patients. Severity of ILD was highly variable with insidious progression up to end-stage respiratory failure reached at teenage in 6 patients. Lung imaging revealed early fibrotic lesions. Failure to thrive was almost constant, with severe growth failure seen in 4 patients. Seven patients presented polyarthritis, and the phenotype in 1 infant mimicked a combined immunodeficiency. Extended features reminiscent of other interferonopathies were also found, including intracranial calcification, glaucoma and glomerular nephropathy. Increased expression of interferon-stimulated genes and interferon α protein was constant. Autoantibodies were frequently found, in particular rheumatoid factor. Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. Tolerance was reasonably good.

Conclusion: The largest worldwide cohort of SAVI patients yet described, illustrates the core features of the disease and extends the clinical and immunological phenotype to include overlap with other monogenic interferonopathies.
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http://dx.doi.org/10.1016/j.jaip.2020.11.007DOI Listing
February 2021

A diagnostic dilemma in a boy with lupus and dyspnea: Questions.

Pediatr Nephrol 2021 04 17;36(4):849-851. Epub 2020 Jul 17.

AP-HP, Hôpital Universitaire Necker-Enfants Malades, Service de Néphrologie de Pédiatrique, Centre de référence MARHEA, Paris, France.

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http://dx.doi.org/10.1007/s00467-020-04691-4DOI Listing
April 2021

A diagnostic dilemma in a boy with lupus and dyspnea: Answers.

Pediatr Nephrol 2021 04 17;36(4):853-856. Epub 2020 Jul 17.

AP-HP, Hôpital Universitaire Necker-Enfants Malades, Service de Néphrologie Pédiatrique, Centre de référence MARHEA, Paris, France.

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http://dx.doi.org/10.1007/s00467-020-04698-xDOI Listing
April 2021

Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort.

Ann Rheum Dis 2020 08 11;79(8):999-1006. Epub 2020 Jun 11.

General Paediatrics, Department of Infectious Disease and Internal Medicine, Reference centre for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Paris, France, Robert Debré University Hospital, AP-HP, Paris, France

Background: Current data suggest that COVID-19 is less frequent in children, with a milder course. However, over the past weeks, an increase in the number of children presenting to hospitals in the greater Paris region with a phenotype resembling Kawasaki disease (KD) has led to an alert by the French national health authorities.

Methods: Multicentre compilation of patients with KD in Paris region since April 2020, associated with the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ('Kawa-COVID-19'). A historical cohort of 'classical' KD served as a comparator.

Results: Sixteen patients were included (sex ratio=1, median age 10 years IQR (4·7 to 12.5)). SARS-CoV-2 was detected in 12 cases (69%), while a further three cases had documented recent contact with a quantitative PCR-positive individual (19%). Cardiac involvement included myocarditis in 44% (n=7). Factors prognostic for the development of severe disease (ie, requiring intensive care, n=7) were age over 5 years and ferritinaemia >1400 µg/L. Only five patients (31%) were successfully treated with a single intravenous immunoglobulin (IVIg) infusion, while 10 patients (62%) required a second line of treatment. The Kawa-COVID-19 cohort differed from a comparator group of 'classical' KD by older age at onset 10 vs 2 years (p<0.0001), lower platelet count (188 vs 383 G/L (p<0.0001)), a higher rate of myocarditis 7/16 vs 3/220 (p=0.0001) and resistance to first IVIg treatment 10/16 vs 45/220 (p=0.004).

Conclusion: Kawa-COVID-19 likely represents a new systemic inflammatory syndrome temporally associated with SARS-CoV-2 infection in children. Further prospective international studies are necessary to confirm these findings and better understand the pathophysiology of Kawa-COVID-19. NCT02377245.
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http://dx.doi.org/10.1136/annrheumdis-2020-217960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299653PMC
August 2020

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

Semin Arthritis Rheum 2020 08 30;50(4):744-748. Epub 2020 May 30.

IMAGINE Institute, RAISE reference center for rare diseases, Department of Pediatric Immunology, Hematology and Rheumatology, Necker Hospital, AP-HP, Paris, France; Paris University, Paris, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.semarthrit.2020.05.013DOI Listing
August 2020

SARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study, France, 1 March to 17 May 2020.

Euro Surveill 2020 06;25(22)

Santé Publique France, Agence nationale de Santé publique, Saint-Maurice cedex, France.

End of April 2020, French clinicians observed an increase in cases presenting with paediatric inflammatory multisystem syndrome (PIMS). Nationwide surveillance was set up and demonstrated temporospatial association with the coronavirus disease (COVID-19) epidemic for 156 reported cases as at 17 May: 108 were classified as confirmed (n = 79), probable (n = 16) or possible (n = 13) post-COVID-19 PIMS cases. A continuum of clinical features from Kawasaki-like disease to myocarditis was observed, requiring intensive care in 67% of cases.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.22.2001010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336112PMC
June 2020

Clinical Characteristics of Acne Fulminans Associated With Chronic Nonbacterial Osteomyelitis in Pediatric Patients.

J Rheumatol 2020 12 1;47(12):1793-1799. Epub 2020 Apr 1.

A. Faye, MD, PhD, Department of General Pediatrics, Pediatric Infectious Diseases and Pediatric Rheumatology, Hôpital Robert Debré, AP-HP, National Reference Centre for Rare Pediatric Inflammatory Rheumatisms and Systemic Auto-immune diseases (RAISE), and Biology and Genetics of Bacterial Cell Wall Unit, Institut Pasteur, Paris.

Objective: Acne fulminans (AF) is a rare, explosive systemic form of acne. Chronic nonbacterial osteomyelitis (CNO) or chronic recurrent multifocal osteomyelitis (CRMO) is a primarily pediatric autoinflammatory disorder characterized by sterile osteolytic bone lesions. Concomitant occurrence of CNO/CRMO and AF is very rare, and little is known about the epidemiological and clinical particularities of this association. The aim of this retrospective observational study was to describe the characteristics of pediatric patients with CNO/CRMO associated to AF.

Methods: Electronic mailing lists of French medical societies were used to call for patients with CNO/CRMO and AF. A search for published patients with CNO/CRMO and AF was performed by screening PubMed.

Results: We identified 5 original patients and 10 patients from the literature. All patients were adolescent boys. Mean age at disease onset was 14.8 years. Nine of 15 patients had received isotretinoin before the sudden onset of AF. Osteoarticular symptoms appeared within < 1-3 months after the onset of AF. The mean numbers of clinical and radiological bone lesions were 3.6 and 5.6, respectively. The percentages of patients with involvement of vertebrae, pelvis, chest, and cranial were 40%, 40%, 33.3%, and 6.6%, respectively. Arthritis was observed in 69.2% of patients and sacroiliac arthritis in 46.2%.

Conclusion: CNO/CRMO associated to AF occurs predominantly in male adolescents and is characterized by frequent involvement of the axial skeleton and arthritis. Epidemiological and clinical features of these patients differ from general CNO/CRMO cohorts. Clinical management requires careful handling of isotretinoin doses.
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http://dx.doi.org/10.3899/jrheum.191232DOI Listing
December 2020

Severe Abdominal Manifestations in Juvenile Dermatomyositis.

J Pediatr Gastroenterol Nutr 2020 02;70(2):247-251

Laboratoire d'Immunogénétique des maladies auto-immunes de l'enfant, Institut Imagine, INSERM U 1163.

Juvenile dermatomyositis (JDM) is a rare and heterogeneous pediatric-onset idiopathic inflammatory myopathy. Gastrointestinal (GI) involvement occurs in 22% to 37% of JDM patients but has only been described in case reports. In this retrospective, single-center, observational study, we aimed to assess the causes and management of severe GI manifestations in JDM patients. We studied a cohort of 9 patients among 110 JDM patients followed during the study period (8.3%). The GI complications were related to JDM in most cases (17/19), with digestive tract involvement (n = 10), acute pancreatitis (n = 4), and hepatitis (n = 3). Three patients died from refractory JDM 2.9 years (2-3.6) after the JDM diagnosis. We highlight the need to consider pancreatitis as a main diagnostic factor in JDM patients with severe GI manifestations and the requirement of early aggressive treatment for these patients.
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http://dx.doi.org/10.1097/MPG.0000000000002575DOI Listing
February 2020
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