Juvenile neuropsychiatric systemic lupus erythematosus: identification of novel central neuroinflammation biomarkers

International audienceIntroduction Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic autoimmune disease affecting multiple organs. Ranging from minor features, such as headache or mild cognitive impairment, to serious and life-threatening presentations, j-neuropsychiatric SLE (j-NPSLE) is a therapeutic challenge. Thus, the diagnosis of NPSLE remains difficult, especially in pediatrics, with no specific biomarker of the disease yet validated. Objectives To identify central nervous system (CNS) disease biomarkers of j-NPSLE. Methods A 5-year retrospective tertiary reference monocentric j-SLE study. A combination of standardized diagnostic criteria and multidisciplinary pediatric clinical expertise was combined to attribute NP involvement in the context of j-SLE. Neopterin and interferon-alpha (IFN-α) protein levels in cerebrospinal fluid (CSF) were assessed, together with routine biological and radiological investigations. Results Among 51 patients with j-SLE included, 39% presented with j-NPSLE. J-NPSLE was diagnosed at onset of j-SLE in 65% of patients. No specific routine biological or radiological marker of j-NPSLE was identified. However, CSF neopterin levels were significantly higher in active j-NPSLE with CNS involvement than in j-SLE alone ( p = 0.0008). Neopterin and IFN-α protein levels in CSF were significantly higher at diagnosis of j-NPSLE with CNS involvement than after resolution of NP features (respectively p = 0.0015 and p = 0.0010) upon immunosuppressive treatment in all patients tested ( n = 10). Both biomarkers correlated strongly with each other ( R s = 0.832, p < 0.0001, n = 23 paired samples). Conclusion CSF IFN-α and neopterin constitute promising biomarkers useful in the diagnosis and monitoring of activity in j-NPSLE

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Evaluation d'un score permettant de détecter les nourrissons fébriles de moins de trois mois à faible risque d'infection bactérienne (enquête prospective à propos de 196 cas à l'hôpital de Créteil)

PARIS6-Bibl. St Antoine CHU (751122104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

MEFV gene analysis in PFAPA

The PFAPA syndrome is a chronic disease of unknown etiology characterized by Periodic episodes of high Fever accompanied by Aphthous stomatitis, Pharyngitis, and cervical Adenitis, sometimes associated with headache and/ or abdominal or joint pain. 1-3 This syndrome belongs to the group of recurrent fever syndromes, which includes systemic onset juvenile rheumatoid arthritis, cyclic neutropenia, and the group of hereditary fevers, ie, familial Mediterranean fever (FMF), hyperimmunoglobinemia D syndrome (HIDS), TNF receptor-1-associated syndromes (TRAPS), Muckle-Wells syndrome (MWS), and familial cold urticaria (FCU). 2 As with other recurrent fevers, the diagnosis of this disease is difficult to establish because: (a) none of the clinical symptoms is pathognomonic of PFAPA; (b) there is no specific biologic abnormality; and (c) the symptomatology may mimic other recurrent fevers. However, regarding the latter point, molecularly-based diagnostic tests are now available for several of the hereditary recurrent fevers: MEFV gene analysis has been proved to provide an objective diagnostic criterion for FMF 4 ; HIDS has been shown to result from mutations in the mevalonate kinase gene 5,6 ; mutations in the gene encoding the tumor necrosis factor receptor-type 1 (TNFRSF1A) have been identified in patients with TRAPS 7 ; more recently, it has been shown that MWS and FCU are both related to mutations in the CIAS1 gene. 8,9 The phenotypic similarities between PFAPA and FMF prompted us to test the involvement of MEFV in PFAPA. Indeed, given the recent demonstration that different hereditary inflammatory disorders may be related to mutations in a single gene, eg, mutations in CIAS1 and NOD2 accounting for MWS or FCU, 8,9 and Crohn's disease or Blau syndrome, 10,11 respectively, one cannot exclude the possibility that, depending on the nature of the molecular defect, the MEFV gene may be involved in clinically related diseases. We have, therefore, searched for MEFV mutations in six unrelated children with PFAPA by means of an exhaustive molecular analysis of all coding sequences and intronic boundaries. 4 All patients met the clinical criteria for FMF defined by Livneh et al. 12 Among the twelve independent alleles studied, only one was found to carry a MEFV gene mutation: the M694V substitution (nucleotide 2080 ATG>GTG), which was identified in a girl of Sephardic Jewish origin, a population in which the frequency of healthy carriers for the M694V substitution reaches one sixth. Therefore, our patient may actually be a simple carrier, a hypothesis further strengthened by the fact that this patient was successfully treated with cimetidine, a drug known to be efficient in several patients with PFAPA. 13 The similar existence of MEFV mutations i

Comparison of Two Luminex Single-antigen Bead Flow Cytometry Assays for Detection of Donor-specific Antibodies After Renal Transplantation

International audienc

Impact of COVID-19 social distancing on viral infection in France: A delayed outbreak of RSV

Introduction: COVID-19 pandemic and associated lockdown measures have deeply modified the natural course of seasonal viral infections, such as respiratory syncytial virus (RSV). Methods: We analyzed French national data from three networks: emergency departments (ED) of French hospitals, general practitioners (GP), and hospital laboratories. We compared the number of ED or GP visits for bronchiolitis in children <2 years of age, and the percentage of RSV positive tests in the 2020 to 2021 season with those of the two previous seasons (2018–2019 and 2019–2020). We used time series of the previous 5 years to calculate epidemic thresholds. Results: During the 2020–2021 season, the epidemic begun in February (Week 05) in the Ile de France (Paris and suburbs) region, 12 weeks later compared with the previous seasons and progressively spread across all the French metropolitan regions. The highest number of bronchiolitis cases in 2021 (Week 12) occurred 10–12 weeks after the previous seasonal peaks of previous seasons, but the number of cases remained lower than in the previous seasonal peaks. Conclusion: We identified a delayed RSV epidemic in the period that usually corresponds at the end of the epidemic season, raising concerns for the burden of RSV in the already strained healthcare systems during the COVID-19 pandemic