Caractéristiques des vascularites à ANCA associées à des anévrysmes : série de cas et revue de la littérature

Introduction. ANCA-associated vasculitides (AAV) is an exceptional cause of small and large aneurysms, which are themselves rare and potentially serious vascular diseases. Here we present the phenotypic characteristics of patients with AAV associated with the presence of aneurysms.Method. We performed a retrospective multicenter study in French internal medicine departments and a systematic review of the literature. The patients included had an AAV associated with the presence of one or more aneurysms.Results. Among the 51 patients included, the most common vasculitides was granulomatosis with polyangiitis (67%). A total of 92 aneurysms were found, 74% of which involved medium sized arteries, particularly renal arteries. Twenty-two patients (43%) developed aneurysmal rupture during follow-up, of which 91% involved medium-sized vessels. Patients with aneurysmal rupture had significantly more pulmonary infiltrates and higher creatinine levels than patients without rupture. There was no association between treatment and rupture. Ten patients died during follow-up, 3 of whom died of aneurysmal rupture.Conclusion. Patients with aneurysm-associated AAV appear to have more severe damage to their AAVat the time of diagnosis but also have a high mortality. The vessels affected are predominantly mediumsized vessels, especially the renal arteries. Almost half of the patients had a rupture during follow-up, the majority of which involved medium-sized arteries. Because of their increased mortality, clinical description and study of their response to treatment would be important to better target these patients.Introduction. Les vascularites associées aux ANCA (VAA) sont une cause exceptionnelle d’anévrisme de petite ou grande taille. Nous présentons ici les caractéristiques phénotypiques des patients atteints de VAA associée à la présence d'anévrismes. Méthode. Nous avons réalisé une étude rétrospective multicentrique et une revue systématique de la littérature. Les patients inclus présentaient une VAA associée à la présence d'un ou plusieurs anévrisme(s). Résultats. Parmi les 51 patients inclus, la vascularite la plus représentée était la granulomatose avec polyangéite (67%). Un total de 92 anévrismes a été trouvé, dont 74% touchaient les artères de moyens calibres, notamment les artères rénales. Vingt-deux patients ont développé une rupture anévrismale au cours du suivi, dont 91% avaient une atteinte des vaisseaux de taille moyenne. Les patients présentant une rupture anévrismale présentaient significativement plus d'infiltrats pulmonaires et des taux de créatinine plus élevés que les patients sans rupture. Il n’a pas été retrouvé d’association entre le traitement instauré et la rupture. Dix patients sont décédés au cours du suivi, 3 par rupture anévrismale. Conclusion. Les patients atteints de VAA associée à la présence d’anévrisme semblent présenter des atteintes plus sévères mais ont également une mortalité élevée. Les vaisseaux touchés sont majoritairement des vaisseaux de taille moyenne notamment les artères rénales. Près de la moitié des patients ont eu une rupture au cours du suivi, dont la majorité concerne des artères de taille moyenne. La description clinique et l'étude de leur réponse au traitement seraient importantes pour mieux cibler ces patients

New insights into epidemiological data and impact of the COVID-19 pandemic on IgA vasculitis in children and adults: a French nationwide cohort

International audienceIgA vasculitis (IgAV) is a small size vasculitis for which epidemiologic data are strikingly lacking, especially about the adult form. Additionally, the COVID-19 pandemic seems to have profoundly modified the incidence of this disease. Here, we aimed to establish some relevant epidemiological data in both pediatric and adult IgAV. We performed an observational study using a national database called "BNDMR" on IgAV, which gathers patients managed in the French network of experts on rare diseases. We primarily performed descriptive statistics over the 2010–2022 period. Then, we compared the North–South geographical areas, the seasonality, and the impact of COVID-19 with that of other patients reported in the same centers. We collected data from 1988 IgAV patients. The sex ratio was 1.57 for adults and 1.05 for children. The annual incidence in 2021 was 0.06 for 100,000 adults and 0.50 for 100,000 children. Compared with other diseases reported into the BNDMR, IgAV was more common in the South than in the North of France (OR 4.88 [4.17–5.74] in adults and OR 1.51 [1.35–1.68] in children). IgAV was also observed more frequently in winter and autumn. Strikingly, we observed a decrease in incidence during the COVID-19 pandemic period in children (OR 0.62 [0.47–0.81]). Our study provides both new insights and confirmations of IgAV epidemiological data: winter and autumn seasonality, more pronounced male predominance in adults, decreasing incidence of pediatric IgAV during the COVID-19 pandemic and increasing incidence in the South of France

Impact of gender on baseline presentation and outcome in adult IgA vasculitis: Corrected proof

International audienceObjectives Adult IgA vasculitis (IgAV) is more common in males, but the potential impact of gender remains unclear. We aimed to describe the impact of gender on presentation and outcome in adult IgAV. Methods We retrospectively analysed data from a multicentre retrospective cohort of 260 patients (IGAVAS). Comparisons were made according to gender status. Results Data from 259 patients (95 females and 164 males) were analysed. Compared with females, baseline presentation in males was similar for cutaneous involvement (100% vs 100%, P = 1.0), joint involvement (60% vs 63%, P = 0.7), gastrointestinal involvement (57% vs 45%, P = 0.093) and glomerulonephritis (73% vs 64%, P = 0.16). Glomerulonephritis was more severe at baseline in males than in females, with a lower median estimated glomerular filtration rate (eGFR) [90 (IQR 59–105) vs 97 ml/min/1.73 m2 (76–116), P = 0.015] and increased median proteinuria (0.84 vs 0.58 g/day, P = 0.01). There were no differences in histological findings in patients who had a kidney biopsy. Methylprednisolone was more frequently used in males (40% vs22%, P = 0.015), as were immunosuppressants, especially cyclophosphamide (24% vs 6%, P = 0.0025) and azathioprine (10% vs 2%, P = 0.038). Analysis of treatment response showed that males had more frequent refractory disease (30% vs 13%, P = 0.004). Long-term outcomes (mortality and progression to chronic kidney failure) did not differ. Conclusion Kidney involvement in IgAV appears to be more severe in males, which is supported by more intensive treatment contrasting with a lower response rate. This study raises the question of gender as a new prognostic factor in adult IgAV

IgA Vasculitis With Underlying Liver Cirrhosis: A French Nationwide Case Series of 20 Patients

International audienceObjective Immunoglobulin A vasculitis (IgAV) and nephropathy (IgAN) share common immunological mechanisms. Liver cirrhosis is well known to be associated with IgAN. Here, we aimed to describe the presentation and outcome of IgAV patients with underlying cirrhosis. Methods We conducted a French nationwide retrospective study of adult patients presenting with both IgAV and cirrhosis. Baseline characteristics were compared to those of the 260 patients included in the French nationwide IgAV registry (IGAVAS). Results Twenty patients were included, and 7 (35%) were female. The mean ± SD age was 62.7 ± 11 years. At baseline, compared with IGAVAS patients, patients with underlying cirrhosis were older (62.7 ± 11 vs 50.1 ± 18, P < 0.01) and displayed more constitutional symptoms (weight loss 25% vs 8%, P = 0.03). Patients with underlying cirrhosis were also more likely to exhibit elevated serum IgA levels (5.6 g/L vs 3.6 g/L, P = 0.02). Cirrhosis and IgAV were diagnosed simultaneously in 12 patients (60%). Cirrhosis was mainly related to alcohol intake (n = 15, 75%), followed by nonalcoholic steato-hepatitis (n = 2), chronic viral hepatitis (n = 1), hemochromatosis (n = 1), and autoimmune hepatitis (n = 1). During follow-up with a median of 17 months (IQR 12–84), 10/13 (77%) exhibited IgAV remission at Month 3. One patient presented a minor relapse. Six patients died, but no deaths were related to IgAV. Conclusion We report the first case series of IgAV patients with underlining cirrhosis, to our knowledge, which was mainly alcohol related. The liver disease did not seem to affect baseline vasculitis characteristics. Physicians should investigate the existence of liver cirrhosis at IgAV diagnosis, especially in the context of alcohol abuse

Curcumin and NCLX inhibitors share anti-tumoral mechanisms in microsatellite-instability-driven colorectal cancer

International audienceBackground and aims: Recent evidences highlight a role of the mitochondria calcium homeostasis in the development of colorectal cancer (CRC). To overcome treatment resistance, we aimed to evaluate the role of the mitochondrial sodium-calcium-lithium exchanger (NCLX) and its targeting in CRC. We also identified curcumin as a new inhibitor of NCLX.Methods: We examined whether curcumin and pharmacological compounds induced the inhibition of NCLX-mediated mitochondrial calcium (mtCa2+) extrusion, the role of redox metabolism in this process. We evaluated their anti-tumorigenic activity in vitro and in a xenograft mouse model. We analyzed NCLX expression and associations with survival in The Cancer Genome Atlas (TCGA) dataset and in tissue microarrays from 381 patients with microsatellite instability (MSI)-driven CRC.Results: In vitro, curcumin exerted strong anti-tumoral activity through its action on NCLX with mtCa2+ and reactive oxygen species overload associated with a mitochondrial membrane depolarization, leading to reduced ATP production and apoptosis. NCLX inhibition with pharmacological and molecular approaches reproduced the effects of curcumin. NCLX inhibitors decreased CRC tumor growth in vivo. Both transcriptomic analysis of TCGA dataset and immunohistochemical analysis of tissue microarrays demonstrated that higher NCLX expression was associated with MSI status, and for the first time, NCLX expression was significantly associated with recurrence-free survival.Conclusions: Our findings highlight a novel anti-tumoral mechanism of curcumin through its action on NCLX and mitochondria calcium overload that could benefit for therapeutic schedule of patients with MSI CRC

Distinct Regulation of EZH2 and its Repressive H3K27me3 Mark in Polyomavirus-Positive and -Negative Merkel Cell Carcinoma

International audienceMerkel cell carcinoma (MCC) is an aggressive skin cancer for which Merkel cell polyomavirus integration and expression of viral oncogenes small T and Large T have been identified as major oncogenic determinants. Recently, a component of the PRC2 complex, the histone methyltransferase enhancer of zeste homolog 2 (EZH2) that induces H3K27 trimethylation as a repressive mark has been proposed as a potential therapeutic target in MCC. Because divergent results have been reported for the levels of EZH2 and trimethylation of lysine 27 on histone 3, we analyzed these factors in a large MCC cohort to identify the molecular determinants of EZH2 activity in MCC and to establish MCC cell lines' sensitivity to EZH2 inhibitors. Immunohistochemical expression of EZH2 was observed in 92% of MCC tumors (156 of 170), with higher expression levels in virus-positive than virus-negative tumors (P = 0.026). For the latter, we showed overexpression of EZHIP, a negative regulator of the PRC2 complex. In vitro, ectopic expression of the large T antigen in fibroblasts led to the induction of EZH2 expression, whereas the knockdown of T antigens in MCC cell lines resulted in decreased EZH2 expression. EZH2 inhibition led to selective cytotoxicity on virus-positive MCC cell lines. This study highlights the distinct mechanisms of EZH2 induction between virus-negative and -positive MCC

NALCN ‐mediated sodium influx confers metastatic prostate cancer cell invasiveness

International audienceThere is growing evidence that ion channels are critically involved in cancer cell invasiveness and metastasis. However, the molecular mechanisms of ion signaling promoting cancer behavior are poorly understood and the complexity of the underlying remodeling during metastasis remains to be explored. Here, using a variety of in vitro and in vivo techniques, we show that metastatic prostate cancer cells acquire a specific Na+ /Ca2+ signature required for persistent invasion. We identify the Na+ leak channel, NALCN, which is overexpressed in metastatic prostate cancer, as a major initiator and regulator of Ca2+ oscillations required for invadopodia formation. Indeed, NALCN-mediated Na+ influx into cancer cells maintains intracellular Ca2+ oscillations via a specific chain of ion transport proteins including plasmalemmal and mitochondrial Na+ /Ca2+ exchangers, SERCA and store-operated channels. This signaling cascade promotes activity of the NACLN-colocalized proto-oncogene Src kinase, actin remodeling and secretion of proteolytic enzymes, thus increasing cancer cell invasive potential and metastatic lesions in vivo. Overall, our findings provide new insights into an ion signaling pathway specific for metastatic cells where NALCN acts as persistent invasion controller

COvid-19 and high-dose VITamin D supplementation TRIAL in high-risk older patients (COVIT-TRIAL): study protocol for a randomized controlled trial

International audienceAbstract Background With the lack of effective therapy, chemoprevention, and vaccination against SARS-CoV-2, focusing on the immediate repurposing of existing drugs gives hope of curbing the COVID-19 pandemic. A recent unbiased genomics-guided tracing of the SARS-CoV-2 targets in human cells identified vitamin D among the three top-scoring molecules manifesting potential infection mitigation patterns. Growing pre-clinical and epidemiological observational data support this assumption. We hypothesized that vitamin D supplementation may improve the prognosis of COVID-19. The aim of this trial is to compare the effect of a single oral high dose of cholecalciferol versus a single oral standard dose on all-cause 14-day mortality rate in COVID-19 older adults at higher risk of worsening. Methods The COVIT-TRIAL study is an open-label, multicenter, randomized controlled superiority trial. Patients aged ≥ 65 years with COVID-19 (diagnosed within the preceding 3 days with RT-PCR and/or chest CT scan) and at least one worsening risk factor at the time of inclusion (i.e., age ≥ 75 years, or SpO2 ≤ 94% in room air, or PaO2/FiO2 ≤ 300 mmHg), having no contraindications to vitamin D supplementation, and having received no vitamin D supplementation > 800 IU/day during the preceding month are recruited. Participants are randomized either to high-dose cholecalciferol (two 200,000 IU drinking vials at once on the day of inclusion) or to standard-dose cholecalciferol (one 50,000 IU drinking vial on the day of inclusion). Two hundred sixty participants are recruited and followed up for 28 days. The primary outcome measure is all-cause mortality within 14 days of inclusion. Secondary outcomes are the score changes on the World Health Organization Ordinal Scale for Clinical Improvement (OSCI) scale for COVID-19, and the between-group comparison of safety. These outcomes are assessed at baseline, day 14, and day 28, together with the serum concentrations of 25(OH)D, creatinine, calcium, and albumin at baseline and day 7. Discussion COVIT-TRIAL is to our knowledge the first randomized controlled trial testing the effect of vitamin D supplementation on the prognosis of COVID-19 in high-risk older patients. High-dose vitamin D supplementation may be an effective, well-tolerated, and easily and immediately accessible treatment for COVID-19, the incidence of which increases dramatically and for which there are currently no scientifically validated treatments. Trial registration ClinicalTrials.gov NCT04344041 . Registered on 14 April 2020 Trial status Recruiting. Recruitment is expected to be completed in April 2021