LEUCEMIES AIGUES CONGENITALES (A PROPOS DE TROIS CAS (DES PEDIATRIE))

NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Joint involvement in Noonan syndrome. A retrospective paediatric descriptive study

International audienceNoonan syndrome is a rare genetic disorder characterized mainly by congenital heart disease, occasional intellectual disability, and varied orthopaedic, rheumatological and haematologic anomalies. Despite potentially serious functional consequences, joint involvement has been rarely studied in the literature. Our objective was to perform a retrospective study evaluating the prevalence and characteristics of joint involvement in Noonan syndrome

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

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

Evaluation of health related quality of life in children with immune thrombocytopenia with the PedsQLTM 4.0 Generic core scales: a study on behalf of the pays de Loire pediatric hematology network.

International audienceBACKGROUND: Immune thrombocytopenia (ITP) is a childhood disorder that is often life-altering for children and their parents. Health related quality of life (HRQL) has never been chronologically monitored in children with ITP. We initiated a prospective study to assess HRQL from diagnosis to six months and define factors that influence this outcome in children with ITP. METHODS: 73 children with acute ITP aged from 2 to 18 years were prospectively enrolled in the study. According to the presence of bleeding, they were or were not given a 4-day course of corticosteroid treatment. The PedsQLTM 4.0 Generic Core Scale was completed by children and parents upon their inclusion in the study and 6 months after diagnosis. RESULTS: Over the six month period, quality of life improved in terms of their global, physical and psychosocial well-being for 54.5 %, 35.6 % and 36.2 % of patients respectively. This improvement is clinically relevant compared to scores at diagnosis, corresponding at least to a minimal clinically important difference (MCID). Factors such as sex, age, platelet count, bleeding scores, bone marrow aspiration and persistence of ITP at 6 months were not significantly associated with HRQL scores. However, preceding viral infection was identified to have an impact on HRQL. CONCLUSIONS: This first longitudinal study assessing HRQL in children with ITP reveals a global improvement in PedSQLTM 4.0. However, these results should be considered with caution since our data also confirm that self-report HRQL scores are not influenced by any analyzed biologic or clinical parameters. Others tools, such as Kids' ITP Tools, would probably be required to assess the HRQL of this population.Trial registration: Trial registration clinical trials.gov Identifier: NCT00331357

Etanercept concentration and immunogenicity do not influence the response to Etanercept in patients with juvenile idiopathic arthritis

International audienceObjective: To investigate the relationship of clinical response of Juvenile Idiopathic Arthritis (JIA) to etanercept (ETN) with ETN levels, and the presence of anti-drug antibodies to ETN (ADAb). Methods: Prospective study of JIA patients under 18 years old. Clinical and pharmacological data were collected at two visits. JIA clinical inactivity and activity were assessed according to the Wallace criteria and to the Juvenile Arthritis Disease Activity Score (JADAS). ETN and ADAb serum levels assessments were determined using ELISA-based assays. Results: 126 patients were enrolled. The median duration of ETN treatment at inclusion was 569 days (range 53-2340). ADAb were undetectable ( 25 ng/mL in 2/218 samples. No significant relationship between ETN concentration and the clinical inactivity status and JIA activity was found using either univariate logistic regression or multiple logistic regression analysis, adjusted on one individual descriptors, time since diagnosis, time of sampling, use of corticosteroids or methotrexate and classification of JIA. No correlation was found between the remission status and the detection of ADAb. Conclusion: This study did not demonstrate any correlation between JIA activity and circulating ETN levels in a large population of patients with JIA previously treated with ETN for at least 1.5 months. As described for adults, our study confirms that ETN is marginally immunogenic in pediatric patients. These results do not support the clinical usefulness of a monitoring of ADAb or ETN concentrations for the management of this group of JIA patients if they fail to achieve clinical inactive disease. (C) 2018 Elsevier Inc. All rights reserved

Factors associated with poor prognosis of hip arthritis in juvenile idiopathic arthritis: Data from the JIR cohort.

OBJECTIVES Hip involvement remains a predictor of severe juvenile idiopathic arthritis (JIA) course and carries a high risk of disability. This study aims to determine the factors of poor prognosis of hip involvement in patients with JIA and to assess the treatment response. METHODS This is a multicenter observational cohort study. Patients were selected from the JIR Cohort database. Hip involvement was defined as clinically suspected and confirmed by an imaging tool. Follow-up data were collected during 5 years. RESULTS Among the 2223 patients with JIA, 341(15%) patients had hip arthritis. Male gender, enthesitis-related arthritis, and North African origin were factors associated with hip arthritis. Hip inflammation was associated with disease activity parameters during the first year, particularly Physician Global Assessment, joint count, and inflammatory marks. Structural hip progression was associated with early onset of the disease, a longer time to diagnosis, geographic origin, and JIA subtypes. Anti-TNF therapy was found to be the only treatment able to effectively reduce structural damage progression. CONCLUSION The early onset diagnostic delay, origin, and systemic subtype of JIA predict a poor prognosis of hip arthritis in children with JIA. The use of anti-TNF was associated with a better structural prognosis

C-terminal variants in<i> CDC42</i> drive type I interferon-dependent autoinflammation in NOCARH syndrome reversible by ruxolitinib

C-terminal variants in CDC42 encoding cell division control protein 42 homolog underlie neonatal-onset cytopenia, autoinflammation, rash, and hemophagocytic lymphohistiocytosis (NOCARH). Pyrin inflammasome hyperactivation has been shown to contribute to disease pathophysiology. However, mortality of NOCARH patients remains high despite inflammasome-focused treatments. Here, we demonstrate in four NOCARH patients from three families that cell-intrinsic activation of type I interferon (IFN) is a previously unrecognized driver of autoinflammation in NOCARH. Our data show that aberrant innate immune activation is caused by sensing of cytosolic nucleic acids released from mitochondria, which exhibit disturbances in integrity and dynamics due to CDC42 dysfunction. In one of our patients, treatment with the Janus kinase inhibitor ruxolitinib led to complete remission, indicating that inhibition of type I IFN signaling may have an important role in the management of autoinflammation in patients with NOCARH

Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases

Background: Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin). Objective: We sought to characterize the genetic cause and clinical spectrum of Hz/Hc. Methods: Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA. Results: Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation resulting in p. E257K. Both mutations substantially alter the electrostatic potential of the PSTPIP1 dimer model in a region critical for protein-protein interaction. Patients with Hz/Hc have extremely high MRP8/14 concentrations (2045 +/- 1300 mu g/mL) compared with those with PAPA syndrome (116 +/- 74 mu g/mL) and have a distinct clinical phenotype. A specific cytokine profile is associated with Hz/Hc. Hz/Hc mutations altered protein binding of PSTPIP1, increasing interaction with pyrin through phosphorylation of PSTPIP1. Conclusion: Mutations resulting in charge reversal in the y-domain of PSTPIP1 (E -&gt; K) and increased interaction with pyrin cause a distinct autoinflammatory disorder defined by clinical and biochemical features not found in patients with PAPA syndrome, indicating a unique genotype-phenotype correlation for mutations in the PSTPIP1 gene. This is the first inborn autoinflammatory syndrome in which inflammation is driven by uncontrolled release of members of the alarmin family

COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study

International audienceBackground: Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases.Methods: In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609.Findings: Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66-6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46-0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55-3·19, p=0·53).Interpretation: Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases