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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. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:149 issue:1 pages:369-378 ispartof: location:United States status: published

Systemic Lupus Erythematosus (SLE) is an autoimmune and inflammatory disease characterized by uncontrolled production of autoantibodies and inflammatory cytokines such as the type-I interferons. Due to the lack of precise pathophysiological mechanisms, treatments are based on broad unspecific immunossupression. To identify genetic factors associated with SLE we performed whole exome sequencing and identified two RELA heterozygous activating mutations in 3 early-onset and familial SLE cases. The corresponding RELA/p65 mutant were abundant in the nucleus but poorly activate transcription of genes controlled by NF-κB consensus sequences. The co-expression of the mutant and wild-type RELA/p65 strongly activated the expression of genes controlled by the IFNα-consensus sequences. These molecular mechanisms lead to the overproduction of type-I IFN in the patients’ cells. Our findings highlight a novel mechanism of autoimmunity where these new RELA mutants are transactivating the type-I IFN genes and are thus promoting type-I interferon production and early-onset SLE, thereby paving the way to the identification of new and specific therapeutic targets.SummaryHeterozygous RELA mutations are associated with Systemic Lupus Erythematosus, with increased expression of genes controlled by the IFNα-consensus sequences.

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.

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.

BackgroundAdenosine deaminases acting on RNA (ADAR) mutations cause a spectrum of neurological phenotypes ranging from severe encephalopathy (Aicardi-Goutières syndrome) to isolated spastic paraplegia and are associated with enhanced type I interferon signalling. In children, non-neurological involvement in the type I interferonopathies includes autoimmune and rheumatological phenomena, with calcifying cardiac valve disease only previously reported in the context of MDA5 gain-of-function.ResultsWe describe three patients with biallelic ADAR mutations who developed calcifying cardiac valvular disease in late childhood (9.5–14 years). Echocardiography revealed progressive calcification of the valvular leaflets resulting in valvular stenosis and incompetence. Two patients became symptomatic with biventricular failure after 5–6.5 years. In one case, disease progressed to severe cardiac failure despite maximal medical management, with death occurring at 17 years. Another child received mechanical mitral and aortic valve replacement at 16 years with good postoperative outcome. Histological examination of the affected valves showed fibrosis and calcification.ConclusionsType I interferonopathies of differing genetic aetiology demonstrate an overlapping phenotypic spectrum which includes calcifying cardiac valvular disease. Individuals with ADAR-related type I interferonopathy may develop childhood-onset multivalvular stenosis and incompetence which can progress insidiously to symptomatic, and ultimately fatal, cardiac failure. Regular surveillance echocardiograms are recommended to detect valvular disease early.

BackgroundChildren have a lower rate of COVID-19, potentially related to cross-protective immunity conferred by seasonal coronaviruses (HCoVs). We tested if prior infections with seasonal coronaviruses impacted SARS-CoV-2 infections and related Multisystem Inflammatory Syndrome (MIS).MethodsThis cross-sectional observational study in Paris hospitals enrolled 739 pauci or asymptomatic children (HOS group) plus 36 children with suspected MIS (MIS group). Prevalence, antigen specificity and neutralizing capability of SARS-CoV-2 antibodies were tested. Antibody frequency and titres against Nucleocapsid (N) and Spike (S) of the four seasonal coronaviruses (NL63, HKU1, 229E, OC43) were measured in a subset of seropositive patients (54 SARS-CoV-2 (HOS-P subgroup) and 15 MIS (MIS-P subgroup)), and in 118 matched SARS-CoV-2 seronegative patients (CTL subgroup).FindingsSARS-CoV-2 mean prevalence rate in HOSP children was 11.7% from April 1 to June 1. Neutralizing antibodies were found in 55·6% of seropositive children, and their relative frequency increased with time (up to 100 % by mid-May). A majority of MIS children (25/36) were SARS-CoV-2 seropositive, of which all tested (n=15) had neutralizing antibodies. On average, seropositive MIS children had higher N and S1 SARS-CoV-2 titres as compared to HOS children. Patients from HOS-P, MIS-P, and CTL subgroups had a similar prevalence of antibodies against the four seasonal HCoVs (66·9 −100%). The level of anti-SARS-CoV-2 antibodies was not significantly different in children who had prior seasonal coronavirus infection.InterpretationPrior infection with HCoVs does not prevent SARS-CoV-2 infection and related MIS in children. Children develop neutralizing antibodies after SARS-CoV-2 infection.Evidence before this studyChildren seem to be less likely affected by SARS-CoV-2 infection and clinical course of COVID-19 is less severe than in adults. As those asymptomatic or mildly symptomatic children are underdiagnosed and their viral loads are comparable to those of adults, they may act as an asymptomatic reservoir for the spread of the virus. One explanation of the difference between the adult and the pediatric infectious profile might be that infection with seasonal human coronaviruses, which is very frequent from a very young age, could lead to cross protective immunity. We searched in PubMed, MedRxiv and BioRxiv for publications from inception to June 15, 2020, using the terms “COVID-19, SARS-CoV-2, children, serology, Kawasaki, Corona Virus”.Added value of this studySARS-CoV-2 mean prevalence rate was 11.7% from April 1 to June 1 and neutralizing antibodies were found in 55% of the tested seropositive children. Among patients with a Multisystem Inflammatory Syndrome, Kawasaki-like disease, 70% were SARS-CoV-2 seropositive and had neutralizing antibodies. COVID-19 and MIS attack rates, and anti-SARS-CoV-2 antibodies titres were not significantly impacted by prior seasonal coronavirus infection.Implications of all the available evidencePrior infection by seasonal coronaviruses does not prevent SARS-CoV-2 infection and associated Multisystem Inflammatory Syndrome in children As antibodies against seasonal coronaviruses are very frequent and as these viruses circulate efficiently in human populations every winter, our results question to what extent the concept of herd immunity based on circulating antibodies can be applied to seasonal coronaviruses and possibly SARS-CoV-2.

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.

This study aims to validate a targeted next-generation sequencing panel of 300 genes to diagnose a cohort of 129 patients with primary immunodeficiency with no prior molecular etiology.

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.

Summary Background Systemic lupus erythematosus (SLE) is a rare immunological disorder and genetic factors are considered important in its causation. Monogenic lupus has been associated with around 30 genotypes in humans and 60 in mice, while genome-wide association studies have identified more than 90 risk loci. We aimed to analyse the contribution of rare and predicted pathogenic gene variants in a population of unselected cases of childhood-onset SLE. Methods For this genetic panel analysis we designed a next-generation sequencing panel comprising 147 genes, including all known lupus-causing genes in humans, and potentially lupus-causing genes identified through GWAS and animal models. We screened 117 probands fulfilling American College of Rheumatology (ACR) criteria for SLE, ascertained through British and French cohorts of childhood-onset SLE, and compared these data with those of 791 ethnically matched controls from the 1000 Genomes Project and 574 controls from the FREX Consortium. Findings After filtering, mendelian genotypes were confirmed in eight probands, involving variants in C1QA, C1QC, C2, DNASE1L3, and IKZF1. Seven additional patients carried heterozygous variants in complement or type I interferon-associated autosomal recessive genes, with decreased concentrations of the encoded proteins C3 and C9 recorded in two patients. Rare variants that were predicted to be damaging were significantly enriched in the childhood-onset SLE cohort compared with controls; 25% of SLE probands versus 5% of controls were identified to harbour at least one rare, predicted damaging variant (p=2·98 × 10−11). Inborn errors of immunity were estimated to account for 7% of cases of childhood-onset SLE, with defects in innate immunity representing the main monogenic contribution. Interpretation An accumulation of rare variants that are predicted to be damaging in SLE-associated genes might contribute to disease expression and clinical heterogeneity. Funding European Research Council.

Microvascular brain injury is well recognized in neuropsychiatric systemic lupus erythematosus (SLE), but cerebral large artery involvement is being debated. Three females with SLE, aged 9 to 14 years, had immunosuppressive treatment intensification because of lupus nephritis. Within the following days or weeks, they presented with intense cephalalgia - isolated or associated with neurological symptoms - and no or mild hypertension. Magnetic resonance angiography showed multiple stenoses within the circle of Willis. One patient had subsequent small subcortical cerebral infarction. Two patients were treated for neuropsychiatric SLE; one patient was treated for reversible cerebral vasoconstriction syndrome (RCVS). Angiography normalized within a few weeks in all three patients. Retrospectively, clinical and radiological features suggest that RCVS was the most likely diagnosis in all patients. Multidisciplinary analysis of clinical and angiographic features is recommended, as RCVS is rare in children and its recognition may help to adjust treatment. WHAT THIS PAPER ADDS: Reversible vasoconstriction syndrome was observed in paediatric systemic lupus erythematosus. Thorough imaging analysis was necessary to address this diagnosis in paediatric patients.

Background Bullous systemic lupus erythematosus (BSLE) is a rare blistering condition associated with systemic lupus erythematosus (SLE). Patients and Methods We conducted a multi-center retrospective study in order to describe the clinical, immunological, and histological presentations and outcomes of BSLE. The skin biopsies were centrally reviewed, and sera obtained during a flare of BSLE were analyzed for identification of circulating anti-basement membrane zone antibodies. Results Ten patients (all women, median age at SLE diagnosis of 22 years) were included, as well as 118 cases from a systematic review of the literature. Lupus nephritis was associated in 50% of the cases. BSLE presented as tensed bullae on normal or erythematous skin, predominantly localized on the trunk, arms, head and neck. Urticarial lesions were associated in 31% of the cases, and mucous membrane involvement was seen in 51%. Histological analyses displayed sub-epidermal detachment, dermal infiltration of polynuclear neutrophils, alignment of these cells at the basal membrane zone and leukocytoclasis. The direct immunofluorescence was polymorphic, showing linear and/or granular deposits of IgG, IgA, IgM and/or C3. Anti-type VII collagen antibodies were detected in 69% of cases. Dapsone was efficacious in 90% of cases. Conclusion BSLE is an autoimmune neutrophilic blistering disease associated with SLE; it is not a cutaneous manifestation of lupus but may be associated with active extra-cutaneous manifestations of SLE. Dapsone is the first-choice option.

Background Self-healing juvenile cutaneous mucinosis (SHJCM) is a rare disorder, and its pathogenesis and long-term prognosis are unknown. Objective To elucidate the clinical and histopathologic characteristics, pathogenesis, and outcome in patients with SHJCM. Methods Retrospective study of 9 patients with SHCJM. To complement initial findings, data collection forms were sent to the referring physicians. Results All patients had an acute onset of firm nodules. Of the 9 patients, 6 presented initially with waxy papules on the dorsum of the hands; 5 suffered from periorbital edema, and 6 had a febrile prodrome. Histopathologic assessment of the papules revealed dermal mucin deposition, whereas the nodules showed proliferative fasciitis-like features or nonspecific chronic lobular panniculitis. Laboratory studies elicited evidence of active viral infection in 2 patients (human herpes virus 6 and rotavirus). Seven cases had spontaneous resolution within 6 months, and 2 patients with incomplete resolution showed subsequent transition to fibroblastic rheumatism and an autoinflammatory rheumatologic disease, respectively. Limitations This was a retrospective study with incomplete data from referring physicians. Conclusions Although spontaneous complete regression is expected, patients with SHJCM need long-term follow-up because of the possible development of dematorheumatolgic conditions. The pathogenetic role of microbial agents deserves further investigation.

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the French language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations and construct validity (convergent and discriminant validity). A total of 100 JIA patients (23% systemic, 45% oligoarticular, 20% RF negative polyarthritis, 12% other categories) and 122 healthy children, were enrolled at the paediatric rheumatology centre of the Necker Children's Hospital in Paris. Notably, none of the enrolled JIA patients is affected with psoriatic arthritis. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the French version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research. ispartof: Rheumatology International vol:38 issue:Suppl 1 pages:195-201 ispartof: location:Germany status: published

Introduction La population pediatrique est sous-representee dans la pandemie actuelle, en termes de nombre de cas et de severite. De surcroit le risque evolutif de l’infection au SARS-CoV-2 dans cette population, en cas de maladies inflammatoires sous traitements immuno-modulateurs, est peu connu. Cette population de jeunes patients immuno-deprimes est consideree comme une population a risque de formes severes de COVID-19. L’objectif de notre etude est d’evaluer le degre de severite et l’issue de l’infection a SARS-CoV-2 chez les patients atteints de RMD (avec une arthrite juvenile idiopathique, une maladie auto-inflammatoire, une vascularite ou une maladie auto-immune systemique) exposes a des traitements immuno-modulateurs, au travers d’une cohorte prospective francaise. Patients et methodes Cette etude ancillaire, multicentrique, observationnelle, descriptive et prospective, de cohorte nationale francaise a inclus de jeunes patients, suivis dans les centres de pediatrie et de rhumatologie pediatrique francais, presentant une maladie inflammatoire associee a une infection COVID diagnostiquee par PCR (reaction en chaine par polymerase), serologie, scanner ou par une clinique fortement evocatrice. Les donnees demographiques, cliniques et therapeutiques, les comorbidites, de ces jeunes patients ainsi que des donnees sur l’infection par le SARS-CoV-2, l’issue et l’impact sur l’activite de la maladie inflammatoire (RMD) ont ete documentes par un questionnaire SARS-CoV-2 specifique mis en œuvre par la FAI2R. Resultats D’avril 2020 a juin 2021, des donnees ont ete recueillies aupres de 95 patients âges de 13,1 ± 4,4 ans, de predominance feminine (62,1 %), atteints de RMD : une arthrite juvenile idiopathique 44 (46,3 %), maladie auto-inflammatoire 6 (6,3 %), vascularite 1(1,1 %) et maladie systemique auto-immune 37 (39 %), avec un diagnostic hautement suspecte/confirme de COVID-19. 33 patients (34,7 %) ont recu des DMARDS, 35 (36,84 %) des bioDMARD,10 (10,6 %) des glucocorticoides systemiques et 11(11,7 %) des AINS. Quatre vingt onze patients (95,8 %) avaient une forme benigne et 4 patients (4,2 %) une forme moderee. Vingt quatre patients (25,3 %) ayant au moins une comorbidite (dont 22 (24,2 %) avaient une forme benigne). Aucun cas d’hospitalisation en soins intensifs ni de detresse respiratoire n’a ete releve. L’evolution etait benigne sans sequelles a 21 jours et sans retentissement sur l’activite de la maladie. Conclusion Dans notre cohorte French RMD Covid pediatrique, il n’y a pas d’augmentation de la severite de l’infection COVID chez les patients ayant une maladie inflammatoire lies a leur maladie ou a leur traitement immunosuppresseur. L’evolution est benigne sans signes de severite ni sequelles et sans retentissement sur l’activite de la maladie.

Lupus nephritis (LN) occurs in 50%–60% of patients with childhood-onset systemic lupus erythematosus (cSLE), leading to significant morbidity. Timely recognition of renal involvement and appropriate treatment are essential to prevent renal damage. The Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative aimed to generate diagnostic and management regimens for children and adolescents with rheumatic diseases including cSLE. Here, we provide evidence-based recommendations for diagnosis and treatment of childhood LN. Recommendations were developed using the European League Against Rheumatism standard operating procedures. A European-wide expert committee including paediatric nephrology representation formulated recommendations using a nominal group technique. Six recommendations regarding diagnosis and 20 recommendations covering treatment choices and goals were accepted, including each class of LN, described in the International Society of Nephrology/Renal Pathology Society 2003 classification system. Treatment goal should be complete renal response. Treatment of class I LN should mainly be guided by other symptoms. Class II LN should be treated initially with low-dose prednisone, only adding a disease-modifying antirheumatic drug after 3 months of persistent proteinuria or prednisone dependency. Induction treatment of class III/IV LN should be mycophenolate mofetil (MMF) or intravenous cyclophosphamide combined with corticosteroids; maintenance treatment should be MMF or azathioprine for at least 3 years. In pure class V LN, MMF with low-dose prednisone can be used as induction and MMF as maintenance treatment. The SHARE recommendations for diagnosis and treatment of LN have been generated to support uniform and high-quality care for all children with SLE.

Resume Objectif L’etude des formes pediatriques de lupus erythemateux systemique (LES) a permis recemment l’identification de formes monogeniques de LES. L’objectif principal de cette etude est de decrire les premiers patients inclus dans l’etude GENIAL/LUMUGENE et les comparer aux donnees de la litterature. L’objectif secondaire est d’identifier les patients a plus forte composante genetique sur une base clinico-biologique. Methodes L’etude GENIAL/LUMUGENE est une etude nationale clinique, immunologique et genetique des lupus a debut pediatrique ( clinical trial : NCT01992666 ). Les 64 premiers patients âges de moins de 18 ans inclus dans ce premier volet de l’etude ont fait l’objet d’un recueil retrospectif des donnees clinico-biologiques. Les sous-groupes ont ete determines a priori et definissent : (1) les lupus syndromiques ( n = 10), (2) les lupus familiaux ( n = 12) et (3) les autres formes de lupus precoces ( n = 42). Resultats La constitution de groupes de patients, a priori, sur la base des connaissances des signes cliniques ou epidemiologiques des lupus monogeniques identifie d’une part un âge au debut plus precoce dans les formes syndromiques ( p Conclusions Cette etude ne permet pas, sur la base des donnees cliniques et epidemiologiques seules, de determiner un sous-groupe de patient partageant une presentation ou une evolution commune. Cette observation peut etre liee au faible effectif ou temoigner de la grande heterogeneite des lupus juveniles. L’analyse de ces patients par les nouvelles techniques de sequencage pourrait identifier des elements de l’heredite responsable de cette variabilite importante.

Rodero et al. report the direct quantification of IFNα protein in monogenic interferonopathies, autoimmunity, and infectious disease states, made possible by the combination of digital ELISA and high-affinity autoantibodies isolated from APECED patients, revealing differential levels and cellular sources dependent on underlying pathology., Type I interferons (IFNs) are essential mediators of antiviral responses. These cytokines have been implicated in the pathogenesis of autoimmunity, most notably systemic lupus erythematosus (SLE), diabetes mellitus, and dermatomyositis, as well as monogenic type I interferonopathies. Despite a fundamental role in health and disease, the direct quantification of type I IFNs has been challenging. Using single-molecule array (Simoa) digital ELISA technology, we recorded attomolar concentrations of IFNα in healthy donors, viral infection, and complex and monogenic interferonopathies. IFNα protein correlated well with functional activity and IFN-stimulated gene expression. High circulating IFNα levels were associated with increased clinical severity in SLE patients, and a study of the cellular source of IFNα protein indicated disease-specific mechanisms. Measurement of IFNα attomolar concentrations by digital ELISA will enhance our understanding of IFN biology and potentially improve the diagnosis and stratification of pathologies associated with IFN dysregulation.

Introduction Les mastocytoses sont des neoplasies rares heterogenes liees a l’accumulation clonale de mastocytes dans differents organes. Cette accumulation est a l’origine de manifestations cliniques variees. Des mutations somatiques activatrices dans le gene KIT (comme D816 V) sont identifiees chez la majorite des patients. Ces mutations n’expliquent pas a elles seules l’heterogeneite des phenotypes cliniques. Notre objectif etait d’identifier des evenements genetiques a partir de formes rares de mastocytoses qui expliqueraient cette variabilite par une action en synergie avec la mutation de KIT. Resultats Nous avons identifie une mutation heterozygote perte de fonction dans le gene GLI3 chez 3 patients, de 2 familles independantes, qui presentaient l’association : (i) d’un syndrome de cephalopolysyndactylie de Greig–syndrome rare associant une macrocephalie et une polydactylie ;(ii) d’une mastocytose congenitale agressive (Patient#1) ou familiale (Patients #2 et #3). Le gene GLI3, code le principal facteur de transcription represseur de la voie oncogenique Hedgehog (Hh) : GLI3R. La co-existence de ces 2 evenements rares chez ces 3 patients, nous a mene a etudier le role de la voie Hh dans la physiologie du mastocyte et dans la physiopathologie des mastocytoses, notamment des formes sporadiques agressives. Nous avons montre pour la premiere fois que : (i) la voie Hh etait activee dans les mastocytes primaires normaux et constitutivement hyperactivee dans les mastocytes neoplasiques de patients atteints de mastocytoses agressives et dans toutes les lignees de mastocytes mutees pour KIT ; (ii) l’utilisation de sonidegib (inhibiteur de la voie Hh) inhibait la proliferation et induisait l’apoptose des mastocytes neoplasiques primaires des patients, et retardait significativement la mort chez les souris ayant une mastocytose agressive KITD816V+. Pour confirmer la capacite de l’haploinsuffisance de GLI3 a induire les tumeurs, nous avons montre que les mastocytes derives des souris GLI3Xt±, modele murin du syndrome de Greig, transduits avec le vecteur KIT-D816 V, avaient un fort potentiel proliferatif par rapport aux temoins. Ceci, confirme la cooperation oncogenique entre les voies Hh et KIT. De plus, l’expression ectopique de GLI3R induisait la mort des mastocytes, confirmant son role de gene suppresseur de tumeur dans le mastocyte. Discussion Dans un contexte syndromique particulier, un phenotype rare de mastocytose, a revele un nouveau mecanisme implique dans la physiopathologie des mastocytoses agressives en general et a permis d’identifier une nouvelle cible therapeutique.

Introduction La maladie associee aux IgG4 (MAG4) est une pathologie fibro-inflammatoire localisee ou systemique caracterisee par des lesions histologiques typiques. D’un point de vue epidemiologique, elle touche preferentiellement l’homme avec un âge moyen au diagnostic du plus de 60 ans [1] . La survenue d’une MAG4 dans l’enfance ou chez l’adulte jeune est exceptionnelle et rarement rapportee [2] . Nous presentons une etude descriptive ainsi qu’une revue de la litterature de cas debutant avant l’âge de 25 ans. Les donnees ont ensuite ete comparees a une cohorte adulte. Materiels et methodes Les observations de notre cohorte ont ete recueillies par un appel a observations national aupres des societes savantes et du recueil d’observations national de la MAG4. Les cas de la litterature ont ete recueillies par une recherche systematique sur PubMed et GoogleScholar. Les criteres d’inclusion retenus etaient : un âge aux 1e symptomes ≤ 25 ans et un diagnostic de MAG4 retenu selon les criteres CDC [3] ou les criteres diagnostiques specifiques d’organe. Nous avons repris les donnees d’une cohortre adulte francaise respectant les memes criteres d’inclusion CDC et avec âge des 1ers symptomes > 25 ans. Resultats Deux patients etaient exclus de l’analyse en raison de diagnostics genetiques finalement retenus. Parmi les 23 patients inclus, 12 (52 %) etaient de sexe feminin. Un antecedent familial concomittant de MAG4 etait retrouve chez une patiente. Des atypies cliniques ou biologiques etaient retrouvees chez 8 patients. Une histologie etait disponible chez 21 patients (91 %), avec des seuils de plasmocytes IgG4+ eleves chez 17 d’entre eux (81 %). Des atypies histologiques etaient associees chez 4 d’entre eux. Lorsque les criteres de classification ACR/EULAR 2019 etaient appliques, 14 (60 %) avaient un score ≥ 20, mais 3 d’entre eux presentaires au moins un critere d’exclusion. Le traitement de 1ere ligne etait represente par une corticotherapie seule chez 15 patients (65 %), avec l’absence de reponse chez 1 patient. Le recours a d’autres traitements concernait 12 patients (52 %) avec une duree moyenne de suivi de 43 mois. Nous avons recense 74 observations dans la litterature, avec des donnees similaires. Lorsques les donnees etaient comparees aux adultes, on retrouvait de facon significative plus de femmes, plus de presentations febriles, et un nombre de rechute ou de 2nd ligne plus importants dans la cohorte pediatrique et juvenile. Discussion Nous rapportons ici la plus large cohorte de cas jeunes de MAG4 selon les criteres CDC et specifiques d’organes. La predominance masculine semble moins marquee dans cette population. Alors que les atteintes d’organes sont le plus souvent typiques, des atypies cliniques, biologiques ou histologiques sont retrouvees chez une proportion importante des patients. Conclusion Un diagnostic de MAG4 peut etre pose chez des patients jeunes, de moins de 25 ans. Alors qu’une partie d’entre eux semble presenter un tableau typique de la maladie, une proportion significative des patients de diagnostic pediatrique presentent des atypies, qui peuvent evoquer la possibilite de formes “secondaires”, devant faire eliminer l’ensemble des diagnostics differentiels incluant des pathologies monogeniques associees.

BackgroundCurrent 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.MethodsMulticentre 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.ResultsSixteen 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 (pConclusionKawa-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.Trial registration numberNCT02377245

Background The aim of this study was to identify early clinical and laboratory features that distinguish acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA) in children presenting with persistent bone or joint pain for at least 1 month. Methods We performed a multicenter case-control study and reviewed medical records of children who initially presented with bone or joint pain lasting for at least 1 month, all of whom were given a secondary diagnosis of JIA or ALL, in four French University Hospitals. Each patient with ALL was paired by age with two children with JIA. Logistic regression was used to compare clinical and laboratory data from the two groups. Results Forty-nine children with ALL and 98 with JIA were included. The single most important feature distinguishing ALL from JIA was the presence of hepatomegaly, splenomegaly or lymphadenopathy; at least one of these manifestations was present in 37 cases with ALL, but only in 2 controls with JIA, for an odds ratio (OR) of 154 [95%CI: 30–793] (regression coefficient: 5.0). If the presence of these findings is missed or disregarded, multivariate analyses showed that non-articular bone pain and/or general symptoms (asthenia, anorexia or weight loss) (regression coefficient: 4.8, OR 124 [95%CI: 11.4–236]), neutrophils 9/L (regression coefficient: 3.9, OR 50 [95%CI: 4.3–58]), and platelets 9/L (regression coefficient: 2.6, OR 14 [95%CI: 2.3–83.9]) were associated with the presence of ALL (area under the ROC curve: 0.96 [95%CI: 0.93–0.99]). Conclusions Based on our findings we propose the following preliminary decision tree to be tested in prospective studies: in children presenting with at least 1 month of osteoarticular pain and no obvious ALL in peripheral smear, perform a bone marrow examination if hepatomegaly, splenomegaly or lymphadenopathy is present. If these manifestations are absent, perform a bone marrow examination if there is fever or elevated inflammatory markers associated with non-articular bone pain, general symptoms (asthenia, anorexia or weight loss), neutrophils 9/L or platelets 9/L.

Introduction Sub-cutaneous panniculitis T-cell lymphomas (SPTCL), a rare non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening activation of the immune system which adversely impacts survival. T-cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T- and innate immune cells. In this work we describe the first germline variants associated with SPTCL, which are in the TIM-3 gene. Methods We sequenced 27 SPTCL cases to identify gene variants. We performed TIM-3 functional analysis on immune cells from patients and HEK293 cells engineered to overexpress wild-type or mutant TIM-3. Results We identified homozygous, germline, loss-of-function, missense variants in highly conserved residues of TIM-3, namely p.Y82C and p.I97M in about 60% (16/27) of SPTCL cases. These samples were drawn from cases series across 3 continents. Patients with bi-allelic TIM-3 mutations were younger at diagnosis, and several had life-threatening HLH and severe disease course. TIM-3 mutations show specific geographic distribution. Y82C TIM-3 mutations occur on a founder chromosome in patients with East-Asian and Polynesian ancestry, while I97M TIM-3 is observed in Caucasians. Both variants induce protein misfolding and cytoplasmic retention of TIM-3. Loss of TIM-3 membrane expression in TIM-3 mutants abrogates the PD-1/PDL-1 checkpoint and prevents the termination of a Th1-immune response. In HEK293 cells, mutant TIM-3 was not expressed on the cell surface. Defective TIM-3 expression leads to persistent immune activation with increased production of inflammatory cytokines including TNF-alpha and IL-1beta by innate immune cells. Conclusion Our findings highlight HLH/SPTCL as a new genetic entity where loss of the TIM-3 immune checkpoint is associated with T-cell infiltration of adipose tissue and inflammasome activation. This is the first causative germline defect identified in SPTCL. While our findings indicate that TIM-3-mutant HLH/SPTCL benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint could have serious adverse consequences. Disclosures Prince: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disease caused by mutations in the mevalonate kinase (MVK) gene. It is characterized by recurrent attacks of fever mostly associated with cervical lymphadenopathy, cutaneous, digestive, and musculoskeletal manifestations. Disease activity may decrease with time or remain high. Anti-interleukin-1 agents are often effective in controlling and preventing flares in patients with severe forms of MKD.

International audience; Letter to the Editor

Systemic lupus erythematosus (SLE) is a severe lifelong multisystem autoimmune disease characterized by the presence of autoantibodies targeting nuclear autoantigens, increased production of type I interferon and B cell abnormalities. Clinical presentation of SLE is extremely heterogeneous and different groups of disease are likely to exist. Recently, childhood-onset SLE (cSLE) cases have been linked to single gene mutations, defining the concept of monogenic or Mendelian lupus. Genes associated with Mendelian lupus can be grouped in at least three functional categories. First, complement deficiencies represent the main cause of monogenic lupus and its components are involved in the clearance of dying cells, a mechanism also called efferocytosis. Mutations in extracellular DNASE have been also identified in cSLE patients and represent additional causes leading to defective clearance of nucleic acids and apoptotic bodies. Second, the study of Aicardi-Goutieres syndromes has introduced the concept of type-I interferonopathies. Bona fide lupus syndromes have been associated to this genetic condition, driven by defective nucleic acids metabolism or innate sensors overactivity. Interferon signalling anomalies can be detected and monitored during therapies, such as Janus-kinase (JAK) inhibitors. Third, tolerance breakdown can occur following genetic mutations in B and/or T cell expressing key immunoregulatory molecules. Biallelic mutations in PRKCD are associated to lupus and lymphoproliferative diseases as PKC-δ displays proapoptotic activity and is crucial to eliminate self-reactive transitional B cells. Here we review the literature of the emerging field of Mendelian lupus and discuss the physiopathological learning from these inborn errors of immunity. In addition, clinical and biological features are highlighted as well as specific therapies that have been tested in these genetic contexts.

Comment on: Monitoring Disease Activity in Systemic Lupus Erythematosus With Single-Molecule Array Digital Enzyme-Linked Immunosorbent Assay Quantification of Serum Interferon-α’ by Mathian et al; International audience; Letter to the editorWe read with interest the study of Mathian et al (1), suggesting that direct serum IFNα determination with a highly sensitive assay might be useful for disease activity monitoring in systemic lupus erythematosus (SLE). More generally, the identification of reactive biomarkers is highly desirable in many disease states, including idiopathic inflammatory myositis (IIM).

Objectives IgA vasculitis (IgAV, formerly known as Henoch–Schönlein purpura) is the most common cause of systemic vasculitis in childhood. To date, there are no internationally agreed, evidence-based guidelines concerning the appropriate diagnosis and treatment of IgAV in children. Accordingly, treatment regimens differ widely. The European initiative SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) aims to optimize care for children with rheumatic diseases. The aim therefore was to provide internationally agreed consensus recommendations for diagnosis and treatment for children with IgAV. Methods Recommendations were developed by a consensus process in accordance with the EULAR standard operating procedures. An extensive systematic literature review was performed, and evidence-based recommendations were extrapolated from the included papers. These were evaluated by a panel of 16 international experts via online surveys and subsequent consensus meeting, using nominal group technique. Recommendations were accepted when ⩾80% of experts agreed. Results In total, 7 recommendations for diagnosis and 19 for treatment of paediatric IgAV were accepted. Diagnostic recommendations included: appropriate use of skin and renal biopsy, renal work-up and imaging. Treatment recommendations included: the importance of appropriate analgesia and angiotensin-converting enzyme inhibitor use and non-renal indications for CS use, as well as a structured approach to treating IgAV nephritis, including appropriate use of CS and second-line agents in mild, moderate and severe disease along with use of angiotensin-converting enzyme inhibitors and maintenance therapy. Conclusion The SHARE initiative provides international, evidence-based recommendations for the diagnosis and treatment of IgAV that will facilitate improvement and uniformity of care.

Adenosine deaminases acting on RNA (We describe three patients with biallelicType I interferonopathies of differing genetic aetiology demonstrate an overlapping phenotypic spectrum which includes calcifying cardiac valvular disease. Individuals with

International audience; Objective: Anti-transcription intermediary factor 1γ (anti-TIF1γ) antibodies are the main predictors of cancer in dermatomyositis (DM). Yet, a substantial proportion of anti-TIF1γ-positive DM patients do not develop cancer. This study was undertaken to identify biomarkers to better evaluate the risk of cancer and mortality in DM.Methods: This multicenter study was conducted in adult anti-TIF1γ-positive DM patients from August 2013 to August 2017. Anti-TIF1γ autoantibody levels and IgG subclasses were identified using a newly developed quantitative immunoassay. Age, sex, DM signs and activity, malignancy, and creatine kinase (CK) level were recorded. Risk factors were determined by univariate and multivariate analysis according to a Cox proportional hazards regression model.Results: Among the 51 adult patients enrolled (mean ± SD age 61 ± 17 years; ratio of men to women 0.65), 40 (78%) had cancer and 21 (41%) died, with a mean ± SD survival time of 10 ± 6 months. Detection of anti-TIF1γ IgG2 was significantly associated with mortality (P = 0.0011) and occurrence of cancer during follow-up (P < 0.0001), with a 100% positive predictive value for cancer when the mean fluorescence intensity of anti-TIF1γ IgG2 was >385. None of the patients developed cancer after 24 months of follow-up. Univariate survival analyses showed that mortality was also associated with age >60 years (P = 0.0003), active DM (P = 0.0042), cancer (P = 0.0031), male sex (P = 0.011), and CK level >1,084 units/liter (P = 0.005). Multivariate analysis revealed that age >60 years (P = 0.015) and the presence of anti-TIF1γ IgG2 (P = 0.048) were independently associated with mortality.Conclusion: Our findings indicate that anti-TIF1γ IgG2 is a potential new biomarker of cancer that should be helpful in identifying the risk of mortality in anti-TIF1γ-positive DM patients.

Background: Recurrent pericarditis affects 15-30% of patients with acute pericarditis. The etiology is poorly understood, with about 80% being idiopathic. Several treatment options are available for recurrences, including NSAIDs, colchicine, glucocorticoids and IL-1 inhibitors (i.e. Anakinra). Standardized guidelines for the management of these patients are still lacking Objectives: To analyze clinical findings and treatment approach in a cohort of pediatric patients with recurrent pericarditis Methods: Patients with at least two episodes of idiopathic pericarditis, followed at two Pediatric Rheumatology centers between 2006 and 2018, were included Results: A total of 42 patients (18 males) were included. Mean age at disease onset was 11.8 years (range 4-17). Chest pain and fever were the presenting symptoms in all patients. In 47% pleural effusion was detected. Laboratory tests showed increased white blood cell count (mean 14.509/mm3), C-reactive protein (mean 18.01 mg/dl) and erythrocyte sedimentation rate (mean 39 mm/h) in all patients. The first episode was variably treated: 18/42 (43%) received NSAIDs alone, 5/42 (11.9%), colchicine alone or associated to NSAIDs and 3/42 patients (7%) received antibiotics alone. 16/42 (38%), not responsive to NSAIDs or colchicine, received glucocorticoides. Patients who received glucocorticoids at the first episode relapsed earlier (median time of 2.1 months range 10 days-5 months), than patients treated with NSAIDs (6.6 months range 10 days -24 months) or with colchicine (5 months range 10 days-5 months) (p Conclusion: Our study confirms the lack of a standardized treatment approach in patients with recurrent pericarditis. Patients treated with glucocorticoid at first episode relapse before than those treated with other drugs. Anakinra is an effective treatment; however, tapering/discontinuation of the drug lead to relapses in several cases. Further experience on larger population is needed to define the best treatment duration and approach to withdrawal of IL-1 inhibitor Disclosure of Interests: Camilla Celani: None declared, Silvia Federici: None declared, Anna Tulone: None declared, Brigitte Bader-Meunier: None declared, Virginia Messia: None declared, Manuela Pardeo: None declared, Claudia Bracaglia: None declared, Pierre Quartier Consultant for: AbbVie, Chugai-Roche, lilly, Novartis, Novimmune, Sanofi, and SOBI, Consultant for: AbbVie, Chugai-Roche, Lilly, Novartis, Novimmune, Sanofi, and SOBI, Speakers bureau: AbbVie, BMS, Chugai-Roche, Novartis, Pfizer, and SOBI, Speakers bureau: AbbVie, BMS, Chugai-Roche, Novartis, Pfizer, and SOBI, Fabrizio De Benedetti Grant/research support from: Abbvie, SOBI, Novimmune, Roche, Novartis, Sanofi, Pfizer, Antonella Insalaco: None declared

Background Coexistent auto-immune and inflammatory diseases (AIID) and sickle cell disease (SCD) have been recently described in adults and children, however its frequency and physiopathology remain unclear (1–6). Objectives The aim of this study is the analysis of clinical and biological characteristics at AIID diagnosis and the evolution under treatment in children with SCD Methods Between May 1991 and March 2018, 35 of 3,800 SCD children diagnosed with AID in seven hospitals in Paris and suburb were analyzed in a retrospective survey. Results Thirty-five patients reported 44 AIID: auto-immune liver disease (AILD, n=13), inflammatory bowel disease (IBD, n=7), juvenile idiopathic arthritis (JIA, n=6), systemic lupus erythematosus (n=5), autoimmune hemolytic anemia (n=3), Sjogren’s syndrome (n=2), histiocytic necrotizing lymphadenitis (n=2), vasculitis (n=2), myasthenia gravis (n=2), sarcoidosis (n=2), inflammatory uveitis (n=1), sclerodermia/juvenile dermatomyositis (n=1). Median age at diagnosis was 10 [2 – 18] years. The mean delay between first symptom and diagnosis was 15.5 (± 29) months. The time of diagnostic was significantly longer for patients with JIA compared to other AID (63 versus 10 days, p=0.004). Sixteen patients (45.7%) had hypergammaglobulinemia > 20 g/L at diagnosis. AILD had a hypergammaglobulinemia at the time of diagnosis (30.0g/L), with a statically significant decrease at the end of follow-up (18.2g/L, p=0,0048). Among 21 patients (60%) treated with systemic steroids, it triggered vaso-occlusive crisis in 14 (66.7%), one acute chest syndrome, one transient ischemic attack. Thirteen of 35 patients (37.1%) were managed with biotherapy for AIID, well tolerated. Three patients (8.6%) underwent stem cell transplantation, one died of a cortico-resistant and multipolar graft versus host reaction, two were cured of both AIID and SCD. Nine severe infections were reported, four under steroids, five under biotherapy. Conclusion Diagnosis and therapeutic care of coexistent auto-immune and inflammatory diseases are difficult and challenging in children with SCD. Annual monitoring of inflammatory markers could be recommended to detect AIID earlier and prevent diagnostic delay in case of high ascension in SCD patients. References [1] Li-Thiao-Te V, Uettwiller F, Quartier P, et al. Coexistent sickle-cell anemia and autoimmune disease in eight children: pitfalls and challenges. Pediatr Rheumatol Online J. 17 janv 2018;16(1):5. [2] Cherner M, Isenberg D. The overlap of systemic lupus erythematosus and sickle cell disease: report of two cases and a review of the literature. Lupus. juin 2010;19(7):875–83. [3] Adelowo O, Edunjobi AS. Juvenile idiopathic arthritis coexisting with sickle cell disease: two case reports. BMJ Case Rep. 1 dec 2011;2011. [4] Michel M, Habibi A, Godeau B, Bachir D, Lahary A, Galacteros F, et al. Characteristics and outcome of connective tissue diseases in patients with sickle-cell disease: report of 30 cases. Semin Arthritis Rheum. dec 2008;38(3):228–40. [5] Galmiche S, Amiot X, Georgin-Lavialle S, et al. Maladies inflammatoires chroniques de l’intestin chez des patients atteints de syndrome drepanocytaire majeur: a propos de 6 cas. Disponible sur: http://www.em-premium.com.frodon.univ-paris5.fr/article/1122766/resultatrecherche/34 [6] Jitraruch S, Fitzpatrick E, Deheragoda M, et al. Autoimmune Liver Disease in Children with Sickle Cell Disease. J Pediatr. oct 2017;189:79-85.e2. Disclosure of Interests Caroline Vinit: None declared, Corinne Guitton: None declared, Patricia Benhaim: None declared, Florence Missud: None declared, Mariane De Montalembert: None declared, Lahoueri Amor: None declared, Cecile Arnaud: None declared, Oussama Charara: None declared, Vincent Gajdos: None declared, Veronique Hentgen Consultant for: SOBI, Novartis, Abbvie, Speakers bureau: Novartis, Annie Kamdem: None declared, Sylvie Nathanson: None declared, Brigitte Bader-Meunier: None declared, isabelle melki: None declared, Isabelle Kone-Paut Grant/research support from: SOBI has supported drug product (anakinra) for the presented study, Consultant for: SOBI, Novartis, Pfizer, Abbvie, UCB, CHUGAI, ROCHE, Pierre Quartier Consultant for: AbbVie, Chugai-Roche, lilly, Novartis, Novimmune, Sanofi, and SOBI, Consultant for: AbbVie, Chugai-Roche, Lilly, Novartis, Novimmune, Sanofi, and SOBI, Speakers bureau: AbbVie, BMS, Chugai-Roche, Novartis, Pfizer, and SOBI, Speakers bureau: AbbVie, BMS, Chugai-Roche, Novartis, Pfizer, and SOBI, Loic De Pontual: None declared, Luu-Ly Pham: None declared

Background Juvenile dermatomyositis (JDM) is a rare heterogeneous autoimmune disease. The identification of myositis specific antibodies (MSAs) has allowed the characterization of subgroups of JDM patients who each have specific phenotypes. Antibody (Ab) against transcriptional intermediary factor-1-γ (TIF-1-γ or p155/140) is the most common MSA in JDM 1. In the American and English JDM cohorts, anti-TIF-1-γ associated JDM is classically associated with a larger proportion of caucasians, mild or moderate severity with typical cutaneous manifestations (Gottron’s papules, and/or heliotrope rash, photosensitivity), and a chronic disease course with a low mortality. The frequency of skin ulcerations and lipodystrophy differs between the two cohorts Objectives To report the clinical and muscle histology associations of anti-TIF-1-γ Ab in a series of patients with JDM followed in the French referral center for rare pediatric systemic autoimmune diseases. Methods Retrospective study of patients with JDM (according to the EULAR/ACR criteria) associated with anti-TIF-1-γ autoantibodies and included in our CEMARA database approved by the French National Committee on Informatics and Liberty. Results Thirteen patients were included (males: 5, females: 8; Caucasians: 6, Black Africans: 2, North Africans: 5). Age at diagnosis ranged from 1.5 to 11 years. Serum creatine kinase was elevated in 12 patients (range: 180-43 000 IU/L). Three different phenotypes were identified according to the severity and course. In group 1 (n=4), 3 patients had a moderate JDM: classical cutaneous manifestations and moderate muscle involvement; relapsing course, which remitted under methotrexate/corticosteroids; an additional 2-year-old girl had an amyopathic JDM. In group 2 (n=7), patients had a severe JDM : ulcerating skin lesions, severe muscle involvement, dysphagia, gastrointestinal vasculitis and/or requirement to an intensive care unit, and required more than two lines of treatment. In this group, 2/7 patients died from refractory JDM, comparing to a mortality rate of 2% in the remaining JDM patients tested for MSA and negative for anti-TIF-1-γ. Only 2/5 patients achieved a complete remission under treatment. Group 3 comprised two patients with severe muscle atrophy, calcinosis and lipodystrophy and a chronic course; one of them had a very-early-onset JDM at 1.5 year-old and the other an inherited neurological involvement, potentially suggestive of a genetic predisposing condition to JDM. None of the patients developed lung involvement or malignancy. Six patients underwent a muscle biopsy which was scored using the JDM severity score tool. The histo-pathologists’ overall severity score (VAS) varied from to 1 to 9/10; the highest scores were observed in the two patients who died. Conclusion In the present series of patients with JDM, TIF-1-γ Ab-associated-clinical phenotypes and ethnicities are more heterogeneous than previously reported. TIF-1-γ Ab is associated with a high mortality rate in a subset of patients. References [1] Rider LG, Nistala K. The juvenile idiopathic inflammatory myopathies: pathogenesis, clinical and autoantibody phenotypes, and outcomes. J Intern Med. 2016;280(1):24-38 Disclosure of Interests Brigitte Bader-Meunier: None declared, cyril gitiaux: None declared, jean-luc charuel: None declared, Nicole Fabien: None declared, isabelle melki: None declared, Pierre Quartier Consultant for: AbbVie, Chugai-Roche, lilly, Novartis, Novimmune, Sanofi, and SOBI, Consultant for: AbbVie, Chugai-Roche, Lilly, Novartis, Novimmune, Sanofi, and SOBI, Speakers bureau: AbbVie, BMS, Chugai-Roche, Novartis, Pfizer, and SOBI, Speakers bureau: AbbVie, BMS, Chugai-Roche, Novartis, Pfizer, and SOBI, alexandre belot: None declared, Nathalie Streichenberger: None declared, christine bodemer: None declared, audrey aussy: None declared, olivier boyer: None declared

Background: Pediadiatric-onset systemic lupus (pSLE) is a severe mulisystem autoimmune condition which mostly manifests after the age of 10 years. It is mainly a polygenic disorder, but a mutation in a single gene may predispose to the developementof SLE (« monogenic lupus »). We will describe some unusual presentations which may lead to a delayed diagnosis or misdiagnosis and provide clues for the diagnosis of monogenic lupus. Objectives: To discuss the difficult diagnosis and pitffalls in pSLE Results: The most common initial manifestations of pSLE are cutaneous, musculoskeletal, renal, hematologic, and fever. Howerver, atypical symptoms may reveal the diagnosis or occur during the course of SLE. In a French retrospective study1, thirty-two percent of children had atypical symptoms, mainly including abdominal involvement in 26 patients, which lead to negative laparotomy for presumed appendicitis before the diagnosis of SLE could be established. Abdominal pain was related to lupus pancreatitis or peritonitis. The diagnosis of pSLE should be systematically searched for in a teenager who presents with unexplained mood disorders, psychosis or depression, which may reveal pSLE. In a patient with a suspected diagnosis of neuropsychiatric pSLE, underlying factors including infections, hypertension, metabolic abnormalities or adverse effects of medication should be excluded before considering a luous-related neurological involvement2. Finally, the diagnosis of pSLE should be also considered in case of severe complications such as macrophage activation syndrome or alveolar hemorrhage. Monogenic SLE should be suspected in early-onset SLE ( Conclusion: The diagnosis of pSLE should be suspected in teenagers with acute unexplained symptoms, especially in case of abdominal pain or neuropsychiratric involvement. A monogic predisposition to SLE should be considered in early-onset SLE, especially in patients with SLE family history, consanguinity, recurrent infections, and/or encephalopathy with spasticity. References: [1] Bader-Meunier B, Armengaud JB, Haddad E, et al. Initial presentation of childhood-onset systemic lupus erythematosus: a French multicenter study. J Pediatr. 2005;146(5):648-53. [2] Groot N, de Graeff N, Avcin T, et al. European evidence-based recommendations for diagnosis and treatment of childhood-onset systemic lupus erythematosus: the SHARE initiative. Ann Rheum Dis. 2017;76(11):1788-1796 Disclosure of Interests: None declared

Background Juvenile dermatomyositis (JDM) is a rare and heterogeneous children-onset idiopathic inflammatory myopathy. It primarily affects skeletal muscle and skin, but also pulmonary, cardiac and gastrointestinal systems in a subset of patients. Gastrointestinal (GI) involvement occurs in 22 to 37% of JDM patients and have been described only in a few case reports. Objectives To describe causes of severe abdominal manifestations in JDM patients. Methods Retrospective monocentric study. Inclusion criteria were (i) diagnosis of JDM according to the modified Bohan and Peter criteria before 16 years of age, (ii) occurrence of severe involvement of any intra-abdominal organ, (iii) follow-up at Necker Hospital from 2005 to 2018. Severe abdominal manifestation was defined as a potential life-threatening abdominal organ event, need for abdominal surgery and/or parenteral nutrition. Gastrointestinal (GI) involvement was defined by severe abdominal pain, dysphagia, digestive hemorrhage, obstruction, ulceration and/or perforation. Severe hepatitis was defined by an elevation of liver enzymes exceeding five times the upper limit associated with an elevation of γ-glutamyl transferase (γGT) activity and/or liver failure. Abdominal manifestations were classified as certain or probable primary JDM involvement, therapy-related event or infection-related event. Results Nine patients with 19 abdominal complications were identified among 110 JDM patients followed during the study period (8,3%). Diagnosis of JDM was made at a median age of 10.7 years-old [range, 3.7 – 14.4], with a median CMAS of 7 [range, 2 – 48], median MMT of 47 [range, 38 – 76], a median creatine kinase level of 3 812 UI/L [range, 170 – 14 054], and a median follow-up of 3 years [range, 0.4 – 6.3]. Seven patients were positive for either anti-NXP2 (n = 4), anti-TIF1-γ (n = 2) or anti-MDA5 (n = 1) antibodies. JDM-related abdominal disease comprised GI involvement (n = 10), acute pancreatitis (n = 4) and hepatitis (n = 3). The revealing symptom for GI involvement and acute pancreatitis was abdominal pain. Five patients with severe abdominal pain, vomiting and/or obstruction, underwent abdominal imaging revealing thickening of colon (n = 2) and/or ileum mucosa (n = 2). Hepatitis was found in 3 patients with an uncommon extensive steatosis with moderate inflammation and perisinusoidal fibrosis (n = 2). Treatment-related complications were considered certain for methotrexate-induced liver toxicity (1 patient) and possible for duodenal perforations (1 patient) 3 days after a methylprednisolone pulse. At last visit, JDM was clinically inactive in four patients. Three patients died from refractory JDM, 2.9 years [range, 2 – 3.6] after the JDM diagnosis, among the 9 patients identified in this study versus only 1/92 of the other JDM patients from our cohort. Conclusion Primary JDM involvement was the main cause of severe abdominal manifestations and associated to a high mortality rate. We highlight for the first time that pancreatitis should be considered as a main diagnosis in JDM patients who develop severe and/or sustained abdominal pain. Disclosure of Interests Caroline Besnard: None declared, cyril gitiaux: None declared, Muriel Girard: None declared, Louise Galmiche-Rolland: None declared, Cecile Talbotec: None declared, Pierre Quartier Consultant for: AbbVie, Chugai-Roche, lilly, Novartis, Novimmune, Sanofi, and SOBI, Consultant for: AbbVie, Chugai-Roche, Lilly, Novartis, Novimmune, Sanofi, and SOBI, Speakers bureau: AbbVie, BMS, Chugai-Roche, Novartis, Pfizer, and SOBI, Speakers bureau: AbbVie, BMS, Chugai-Roche, Novartis, Pfizer, and SOBI, Laureline Berteloot: None declared, christine bodemer: None declared, Brigitte Bader-Meunier: None declared

Background Tocilizumab (TCZ) is a humanized monoclonal antibody that blocks interleukin 6. In children, TCZ has been approved for the treatment of systemic-onset and polyarticular course juvenile idiopathic arthritis (JIA), and is used off-label in other treatment refractory inflammatory diseases. Real-world data regarding tolerance of TCZ in children are scarce. Objectives To assess the incidence rate and type of serious adverse events in children treated with TCZ. Methods A single-center retrospective review of all consecutive patients receiving TCZ in the pediatric rheumatology division from 01/2007 to 12/2018 was performed. Inclusion criteria were a diagnosis of inflammatory rheumatic disease and treatment with at least one dose of TCZ. Patients with missing data were excluded. Serious adverse events (SAE) were defined as a life-threatening event and/or an event requiring hospital admission, leading to permanent disability or treatment discontinuation. Results A total of 70 children (39 females) were included. Thirty children had systemic JIA, 25 polyarticular course JIA, 14 systemic inflammatory disorders such as autoinflammatory syndromes and one patient severe refractory idiopathic uveitis. Median age at diagnosis was 4.2 years (IQR 2.0 – 7.3). The majority of children had received prednisone (n=56), and/or at least one biologic agent (n=63) prior to TCZ initiation. At TCZ start, children had a median age of 8.9 years (IQR 4.9 – 12.3) and disease duration of 3.2 years (IQR 0.9 – 7.4). TCZ was initiated at a 2-weekly interval in 44 children, 26 children received TCZ every 4 weeks. Fifty-eight children received concomitantly another immunosuppressive agent (prednisone (n=47) and/or methotrexate (n=20) and/or various other drugs (n=5)). A median of 26 TCZ doses were given per child (IQR 7 – 48), TCZ exposure was 146.8 patient years. Twenty-two SAE were observed in 18 (26%) children (SAE 14.9/100 patient years): 8 severe infusion reactions, 7 serious infections, 3 cutaneous reactions (toxic reaction, cutaneous vasculitis, scleroderma-like skin thickening with fasciitis), two macrophage activation syndromes, and one abnormal hepatic function and severe dizziness each. Infusion reactions occurred most frequently during the first few infusions (median during 4th infusion, IQR 3 – 5). All patients with infusion reactions had either systemic JIA (n=4) or another autoinflammatory disease (n=4). At time of infusion reaction, all children (8/8) had active disease, 7/8 had a concomitant treatment with prednisone and 2/8 additionally with cyclosporine. At last follow up, 35 (50%) children were still on TCZ, the other 35 had discontinued TCZ: 4 for remission, 13 because of inefficacy, 12 because of side effects, 3 because of both inefficacy and side effects, and 3 for other reasons. No death occurred during TCZ treatment; two patients with systemic inflammatory disease, in whom TCZ had been inefficient, died from uncontrollable disease 13 and 15 months after TCZ discontinuation, respectively. Conclusion In this cohort, serious adverse events were observed in a quarter of children with half of them having severe infusion reactions. Higher incidence rates of severe infusion reactions were observed in children with systemic JIA or autoinflammatory diseases. Ongoing careful monitoring of patients treated with TCZ, especially those with important systemic inflammation is required. Disclosure of Interests Florence Aeschlimann: None declared, Andreas Worner: None declared, Richard Mouy Consultant for: Honoraries received by Roche for Tocilizumab trial in children, Carine Wouters Grant/research support from: Grant/research support to Istituto Gaslini from GlaxoSmithKline immune-inflammation: unrestricted grant to study Blau syndrome; Roche: unrestricted rese

Background Juvenile Dermatomyositis (JDM) is a rare, autoimmune and highly heterogeneous paediatric-onset myopathy, characterized by skin and muscles inflammation. Development of vasculopathy is associated with the severe extra-muscular manifestations of JDM, and portends a poor prognosis. Impaired function of JDM vasculature includes immune complex and complement deposition. Objectives The aim of our study is to describe the clinical and paraclinical phenotype of patients with anti-factor H autoantibody (Ab) associated with JDM and overlap myositis. Methods Patients with a diagnosis of JDM or overlap myositis and presence of anti-FH auto-antibody, followed in two Parisian tertiary centers over the last twelve years, were retrospectively selected. Besides demographic data, clinical features (cutaneous lesions, severity of muscle involvement, extra-muscular manifestations), treatment options and their outcome were retrieved for each patient. Biological data and presence of myositis-specific autoantibodies were collected, muscle MRI were examined, and data from muscle biopsies were assessed using a validated score tool when available. Results Eleven female patients were included in the study, with a median age at diagnosis of 8.8 years [2.8 – 13.1], and a median follow-up of 3 years [1 – 11.7]. Apart typical cutaneo-muscular presentation, seven developed calcinosis, and six presented with subcutaneous oedema (of which 5 were anti-NXP2 positive). Median CMAS was 24/52 [1 – 47], and median MMT was 52/80 [2 -76]. Gastro-intestinal involvement was found in 10 patients (91%), 4 presented a pulmonary impairment, and 3 girls had psychiatric symptoms. Six patients had a severe form (54%), one of them led to death (after 2.8 years of evolution). MSA were found in 9 patients (anti-NXP2 = 1, anti-fibrillarine = 2, anti-MDA5 = 1 and anti-TIF1gamma = 1). IFN-signature was positive in 9 patients. Complement exploration was normal in all patients, and median positive rate of Anti-Factor H Ab was 260 UA/L [115 – 2800]. Muscle biopsy was performed in all patients but one with a median total score severity of 20. All patients received corticosteroids, and one to six other lines of treatment to achieve remission, obtained in 8 patients, with a median time to remission of 2 years [0.5; 4.8]. Use of plasmapheresis/immunoadsorption and/or Ruxolitinib was necessary in 3 of them (27%). Conclusion Presence of anti-factor H auto-antibodies in JDM or overlap myositis patients seems associated with more frequent gastro-intestinal involvement, and a more severe phenotype, requiring more aggressive treatment. References Disclosure of Interests None declared