Urticaire chronique spontanée traitée par Omalizumab : traitement personnalisé dans une file active française de 64 patients entre 2013 et 2016

In clinical studies, efficacy and tolerance of Omalizumab to treat severe forms of Chronic Spontaneous Urticaria (CSU), has been well established. The licensed dose is 300 mg every 4 weeks. Yet few data extracted from real life analysis exist. Our goal is to assess feasibility and relevance of such personalized Omalizumab treatments, for patients with severe CSU, followed in Grenoble Alpes University Hospital. A retrospective, monocentric study (Grenoble Alpes University Hospital) of a French Cohort of patients with CSU resistant to fourthfold dose of anti-histamins treated with Omalizumab between May 2013 and January 2016. Our analysis aimed to evaluate the quality and delay of treatment responses, treatment duration and patients’ tolerance to Omalizumab. Treatment efficacy was measured from clinical data: response to the treatment (scores Cu-QoL, AE-QoL, UCT, AAS28 et UAS7) and the interval between 2 injections was individually tailored. Results : 64 patients (including 51 women), aged between 16 and 89, suffering from severe CSU, were cared for over an average period of 32 months. 81% of these patients developed angioedema because of superficial urticaria. The disease’s average length fluctuated between 6 months to 15 years. 92% of patients taking Omalizumab completely responded to the treatment after 6 months, 60% after the second injection, 6% partially responded. A complete response is defined as an upgrade in quality of life above 80 %, followed by UAS=0 and AAS=0. On average, the Omalizumab intake lasted between 2 and 38 months. In terms of time interval between two injections, it fluctuated between 2 and 16 weeks. It was decided to put a halt to the treatment in cases for which patients did not respond after 6 months. Verdicts to stop Omalizumab were never a result of secondary symptoms. Only one patient stopped his own treatment without consulting medical advice, and had not relapsed a year later. 37% of patients showed non-severe adverse events which disappeared after several injections. In real life, out of 64 patients, individual and personalized treatment intervals when prescribing Omalizumab, allowed for a response rate far superior to clinical tests, with a clear progress with regard to patients’ quality of life.L'Omalizumab a montré dans les études cliniques son efficacité et sa bonne tolérance dans le traitement de l'urticaire chronique spontanée sévère. Notre objectif est d'évaluer la faisabilité et l'intérêt d’un traitement personnalisé par Omalizumab chez les patients suivis au CHU de Grenoble. Analyse rétrospective monocentrique d'une cohorte française de patients UCS résistants aux anti-histaminiques à quadruple dose traités par Omalizumab de mai 2013 à mars 2016. La qualité et le délai de réponse, la durée du traitement et la tolérance à l'Omalizumab ont été analysés. L'efficacité du traitement a été évaluée à partir des données cliniques : réponse au traitement (scores Cu-QoL,AE-QoL, UCT, AAS28 et UAS7) et l’intervalle entre 2 injections a été individualisé.64 patients de 16 à 89 ans atteints d'UCS sévère ont été suivis sur 32 mois en moyenne. 81% des patients présentent des angioedèmes associés à l’urticaire superficielle. 92% des patients traités par omalizumab ont une réponse complète à 6 mois dont 60% dès la seconde injection, 6% une réponse partielle. La réponse complète a été initialement définie par une amélioration de la qualité de vie > 80% puis par UAS7 =0 et AAS=0. La durée du traitement par Omalizumab est 18 mois en moyenne. L'intervalle entre 2 injections varie de 2 à 16 semaines. Aucun arrêt de l'Omalizumab n'a été lié aux effets secondaires. 37% des patients ont présenté des évènements indésirables non sévères régressent pour la plus part au cours du temps spontanément.: En vie réelle, sur 64 patients, la gestion individualisée de l'intervalle de traitement par Omalizumab a permis d’obtenir un taux de réponse supérieur à celui des études cliniques

Idiopathic Non-histaminergic Angioedema: Successful Treatment with Omalizumab in Five Patients

International audienceIdiopathic non-histaminergic acquired angioedema (InH-AAE) is a rare disease characterized by AE resistant to antihistamines and a chronic course. We report five new cases of InH-AAE (two women and three men) with a rapid and dramatic response to the anti-immunoglobulin-E antibody omalizumab. In our literature review, we found 13 other relevant cases with a good response to this treatment. Overall, in 6 out of 18 patients, the doses of omalizumab required to prevent recurrences of attacks were higher than the licensed dose for chronic urticaria. No significant adverse effects have been reported

High-resolution contrast-enhanced MRI of atherosclerosis with digital cardiac and respiratory gating in mice.

International audienceAtherosclerosis initially develops predominantly at the aortic root and carotid origin, where effective visualization in mice requires efficient cardiac and respiratory gating. The present study sought to first compare the high-resolution MRI gating performance of two digital gating strategies using: 1) separate cardiac and respiratory signals (double-sensor); and 2) a single-sensor cardiorespiratory signal (ECG demodulation), and second, to apply an optimized processing technique to dynamic contrast-enhanced (CE) carotid origin vessel-wall imaging in mice. High-resolution MR mouse heart and aortic arch images were acquired by ECG signal detection, digital signal processing, and gating signal generation modeled using Simulink (MathWorks, USA). Double-sensor gating used a respiratory sensor while single-sensor gating used breathing-modulated ECG to generate a demodulated respiratory signal. Pre- and postcontrast T(1)-weighted images were acquired to evaluate vessel-wall enhancement with a gadolinium blood-pool agent (P792; Guerbet, France) at the carotid origin in vivo in ApoE(-/-) and C57BL/6 mice, using the optimized cardiorespiratory gating processing technique. Both strategies provided images with improved spatial resolution, less artifacts, and 100% correct transistor-to-transistor logic (TTL) signals. Image quality allowed vessel-wall enhancement measurement in all the ApoE(-/-) mice, with maximal (32%) enhancement 27 min postinjection. The study demonstrated the efficiency of both cardiorespiratory gating strategies for dynamic contrast-enhanced vessel-wall imaging

Rhizome filling seems to be triggered by climatic events in Miscanthus x giganteus

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Identification of the First Single GSDME Exon 8 Structural Variants Associated with Autosomal Dominant Hearing Loss

International audienceGSDME, also known as DFNA5, is a gene implicated in autosomal dominant nonsyndromic hearing loss (ADNSHL), affecting, at first, the high frequencies with a subsequent progression over all frequencies. To date, all the GSDME pathogenic variants associated with deafness lead to skipping of exon 8. In two families with apparent ADNSHL, massively parallel sequencing (MPS) integrating a coverage-based method for detection of copy number variations (CNVs) was applied, and it identified the first two causal GSDME structural variants affecting exon 8. The deleterious impact of the c.991-60_1095del variant, which includes the acceptor splice site sequence of exon 8, was confirmed by the study of the proband’s transcripts. The second mutational event is a complex rearrangement that deletes almost all of the exon 8 sequence. This study increases the mutational spectrum of the GSDME gene and highlights the crucial importance of MPS data for the detection of GSDME exon 8 deletions, even though the identification of a causal single-exon CNV by MPS analysis is still challenging

When Familial Hearing Loss Means Genetic Heterogeneity: A Model Case Report

International audienceWe describe a family with both hearing loss (HL) and thrombocytopenia, caused by pathogenic variants in three genes. The proband was a child with neonatal thrombocytopenia, childhood-onset HL, hyper-laxity and severe myopia. The child’s mother (and some of her relatives) presented with moderate thrombocytopenia and adulthood-onset HL. The child’s father (and some of his relatives) presented with adult-onset HL. An HL panel analysis, completed by whole exome sequencing, was performed in this complex family. We identified three pathogenic variants in three different genes: MYH9, MYO7A and ACTG1. The thrombocytopenia in the child and her mother is explained by the MYH9 variant. The post-lingual HL in the paternal branch is explained by the MYO7A variant, absent in the proband, while the congenital HL of the child is explained by a de novo ACTG1 variant. This family, in which HL segregates, illustrates that multiple genetic conditions coexist in individuals and make patient care more complex than expected

Clostridium difficile infection and immune checkpoint inhibitor–induced colitis in melanoma: 18 cases and a review of the literature

International audienceImmunotherapy has become the standard of care for several types of cancer, such as melanoma. However, it can induce toxicity, including immune checkpoint inhibitor-induced colitis (CIC). CIC shares several clinical, histological, biological, and therapeutic features with inflammatory bowel disease (IBD). Clostridium difficile infection (CDI) can complicate the evolution of IBD. We aimed to characterize the association between CDI and CIC in patients treated with anti-CTLA-4 and anti-PD-1 for melanoma. Patients from nine centers treated with anti-CTLA-4 and anti-PD-1 for melanoma and presenting with CDI from 2010 to 2021 were included in this retrospective cohort. The primary endpoint was the occurrence of CIC. The secondary endpoints were findings allowing us to characterize CDI. Eighteen patients were included. Eleven were treated with anti-PD-1, four with anti-CTLA-4, and three with anti-PD-1 in combination with anti-CTLA-4. Among the 18 patients, six had isolated CDI and 12 had CIC and CDI. Among these 12 patients, eight had CIC complicated by CDI, three had concurrent CIC and CDI, and one had CDI followed by CIC. CDI was fulminant in three patients. Endoscopic and histological features did not specifically differentiate CDI from CIC. Nine of 11 patients required immunosuppressive therapy when CDI was associated with CIC. In nine cases, immunotherapy was discontinued due to digestive toxicity. CDI can be isolated or can complicate or reveal CIC. CDI in patients treated with immunotherapy shares many characteristics with CDI complicating IBD. Stool tests for Clostridium difficile should be carried out for all patients with diarrhea who are being treated with immunotherapy

Omalizumab Drug Survival in Chronic Urticaria: A Retrospective Multicentric French Study

Background: Omalizumab (OMA) dramatically improves disease control and quality of life in patients with chronic urticaria (CU).Objective: We aimed to evaluate the discontinuation patterns of OMA and their determinants in a cohort of French patients with CU.Methods: We conducted a retrospective multicenter study in 9 French tertiary referral hospitals. All patients diagnosed with either spontaneous (CSU) and/or inducible (CIndU) CU who received at least 1 injection of OMA between 2009 and 2021 were included. We analyzed OMA drug survival and investigated possible determinants using Kaplan-Meier curves and log-rank tests.Results: A total of 878 patients were included in this study; 48.8% had CSU, 10.1% CIndU, and 41.1% a combination of both. OMA was discontinued in 408 patients, but the drug was later reintroduced in 50% of them. The main reason for discontinuing treatment was the achievement of a well-controlled disease in 50% of patients. Half of the patients were still being treated with OMA 2.4 years after the initiation of treatment. Drug survival was shorter in patients with CIndU and in those with an autoimmune background. In atopic patients, OMA was discontinued earlier in patients achieving a well-controlled disease. A longer OMA drug survival was observed in patients with a longer disease duration at initiation.Conclusion: In French patients with CU, the drug survival of OMA appears to be longer than that observed in previous studies conducted elsewhere, highlighting discrepancies in prescription and reimbursement possibilities. Further studies are warranted to develop customized OMA treatment schemes based on individual patterns