Intravenous versus subcutaneous tocilizumab in Takayasu arteritis: multicentre retrospective study

ObjectivesIn this large multicentre study, we compared the effectiveness and safety of tocilizumab intravenous versus subcutaneous (SC) in 109 Takayasu arteritis (TAK) patients.MethodsWe conducted a retrospective multicentre study in referral centres from France, Italy, Spain, Armenia, Israel, Japan, Tunisia and Russia regarding biological-targeted therapies in TAK, since January 2017 to September 2019.ResultsA total of 109 TAK patients received at least 3 months tocilizumab therapy and were included in this study. Among them, 91 and 18 patients received intravenous and SC tocilizumab, respectively. A complete response (NIH <2 with less than 7.5 mg/day of prednisone) at 6 months was evidenced in 69% of TAK patients, of whom 57 (70%) and 11 (69%) patients were on intravenous and SC tocilizumab, respectively (p=0.95). The factors associated with complete response to tocilizumab at 6 months in multivariate analysis, only age <30 years (OR 2.85, 95% CI 1.14 to 7.12; p=0.027) and time between TAK diagnosis and tocilizumab initiation (OR 1.18, 95% CI 1.02 to 1.36; p=0.034). During the median follow-up of 30.1 months (0.4; 105.8) and 10.8 (0.1; 46.4) (p<0.0001) in patients who received tocilizumab in intravenous and SC forms, respectively, the risk of relapse was significantly higher in TAK patients on SC tocilizumab (HR=2.55, 95% CI 1.08 to 6.02; p=0.033). The overall cumulative incidence of relapse at 12 months in TAK patients was at 13.7% (95% CI 7.6% to 21.5%), with 10.3% (95% CI 4.8% to 18.4%) for those on intravenous tocilizumab vs 30.9% (95% CI 10.5% to 54.2%) for patients receiving SC tocilizumab. Adverse events occurred in 14 (15%) patients on intravenous route and in 2 (11%) on SC tocilizumab.ConclusionIn this study, we confirm that tocilizumab is effective in TAK, with complete remission being achieving by 70% of disease-modifying antirheumatic drugs-refractory TAK patients at 6 months

Progressive Visceral Leishmaniasis Is Driven by Dominant Parasite-induced STAT6 Activation and STAT6-dependent Host Arginase 1 Expression

The clinicopathological features of the hamster model of visceral leishmaniasis (VL) closely mimic active human disease. Studies in humans and hamsters indicate that the inability to control parasite replication in VL could be related to ineffective classical macrophage activation. Therefore, we hypothesized that the pathogenesis of VL might be driven by a program of alternative macrophage activation. Indeed, the infected hamster spleen showed low NOS2 but high arg1 enzyme activity and protein and mRNA expression (p<0.001) and increased polyamine synthesis (p<0.05). Increased arginase activity was also evident in macrophages isolated from the spleens of infected hamsters (p<0.05), and arg1 expression was induced by L. donovani in primary hamster peritoneal macrophages (p<0.001) and fibroblasts (p<0.01), and in a hamster fibroblast cell line (p<0.05), without synthesis of endogenous IL-4 or IL-13 or exposure to exogenous cytokines. miRNAi-mediated selective knockdown of hamster arginase 1 (arg1) in BHK cells led to increased generation of nitric oxide and reduced parasite burden (p<0.005). Since many of the genes involved in alternative macrophage activation are regulated by Signal Transducer and Activator of Transcription-6 (STAT6), and because the parasite-induced expression of arg1 occurred in the absence of exogenous IL-4, we considered the possibility that L. donovani was directly activating STAT6. Indeed, exposure of hamster fibroblasts or macrophages to L. donovani resulted in dose-dependent STAT6 activation, even without the addition of exogenous cytokines. Knockdown of hamster STAT6 in BHK cells with miRNAi resulted in reduced arg1 mRNA expression and enhanced control of parasite replication (p<0.0001). Collectively these data indicate that L. donovani infection induces macrophage STAT6 activation and STAT6-dependent arg1 expression, which do not require but are amplified by type 2 cytokines, and which contribute to impaired control of infection

Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.info:eu-repo/semantics/publishedVersio

Molecular basis of atherosclerotic calcification heterogeneity and heterogeneity of peripheral arteries

Les calcifications artérielles sont fréquemment rencontrées au cours des maladies artérielles périphériques qui comprennent les atteintes athérosclérotiques. Les calcifications artérielles sont un marqueur indépendant de morbidité cardiovasculaire et impactent fortement les réponses thérapeutiques. Leur formation est issue de multiples processus dont certains sont proches de l’ossification. A partir de deux biocollections de patients, nous avons identifié quatre sous-types de calcifications intimales aux niveaux des artères athérosclérotiques carotidiennes, fémorales et infra-poplitées. Nous avons montré que les artères fémorales sont globalement plus calcifiées que les autres territoires, avec une présence beaucoup plus fréquente de métaplasie ostéoïde (structure osseuse), alors que les microcalcifications sont préférentiellement retrouvées au niveau carotidien. Les facteurs de risque cardiovasculaires, n’influencent pas les sous-types de calcifications, qui sont par contre fortement associés aux territoires. L’analyse de l’expression différentielle des gènes et miARNs au sein de la paroi artérielle permet de ségréger les échantillons en fonctions de leur origine anatomique (carotidienne, fémorale ou infra-poplitée). Ces différences d’expression se retrouvent entre les territoires des artères saines comme celles atteintes d’athérosclérose. Dans les artères pathologiques, on retrouve les clusters de gènes associés aux différences de composition de plaques qui s’y développent. De manière intéressante, on retrouve également des gènes différentiellement exprimés entre artères saines, eux aussi associés à ces types de plaques. Ces résultats suggèrent une prédisposition vasculaire pour développer tel ou tel type de plaque, avec pour les artères fémorales une prédisposition particulière pour l’ossification. Cette hypothèse est renforcée les résultats in vitro montrant une susceptibilité de minéralisation plus importante des cellules musculaires lisses (CML) d’artères fémorales saines par rapport à d’autres territoires. De façon particulière, la voie du Tranforming Growth factor (TGF) est surexprimée au niveau des artères fémorales. Nous avons montré que son récepteur TGFβR1 était impliqué dans les différences de minéralisation entre CML fémorales et carotidiennes.Arterial calcifications are frequently encountered in peripheral arterial diseases that include atherosclerotic disease. Arterial calcifications are an independent marker of cardiovascular morbidity and strongly impact therapeutic responses. Their formation is the result of multiple processes, some of which are close to ossification. From two patients’ biocollections, we identified four subtypes of intimal calcifications in carotid, femoral and infra-popliteal atherosclerotic arteries. We have shown that the femoral arteries are globally more calcified than the other territories, with much more frequent presence of osteoid metaplasia (bone structure), whereas the microcalcifications are preferentially found at the carotid level. Cardiovascular risk factors do not influence the subtypes of calcification, but are strongly associated with the territories. The analysis of the differential expression of genes and miRNAs of the arterial wall makes it possible to segregate the samples according to their anatomical origin (carotid, femoral or infra-poplitated). These differences of expression are found between the territories in healthy and atherosclerosis arteries. In pathological arteries, there are clusters of genes associated with differences in plaque composition that develop there. Interestingly, there are also genes differentially expressed between healthy arteries, also associated with plaques. These results suggest a vascular predisposition to develop such or such type of plaque, with for the femoral arteries a special predisposition for ossification. This hypothesis is reinforced by in vitro results showing greater susceptibility to mineralization of smooth muscle cells (SMCs) of healthy femoral arteries compared to other territories. In particular, the Tranforming Growth Factor (TGF) pathway is overexpressed at the level of the femoral arteries. We showed that its TGFβR1 receptor was involved in mineralization differences between femoral and carotid SMCs

A systematic review and meta-analysis of the incidence of post-thrombotic syndrome, recurrent thromboembolism, and bleeding after upper extremity vein thrombosis

International audienceBackground: Data on complications after upper extremity vein thrombosis (UEVT) are limited and heterogeneous.Methods: The aim of the present study was to evaluate the pooled proportions of venous thromboembolism (VTE)recurrence, bleeding, and post-thrombotic syndrome (PTS) in patients with UEVT. A systematic literature review wasconducted of PubMed, Embase, and the Cochrane Library databases from January 2000 to April 2023 in accordance withthe PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. All studies included patientswith UEVT and were published in English. Meta-analyses of VTE recurrence, bleeding, and of PTS after UEVT wereperformed to compute pooled estimates and associated 95% confidence intervals (CIs). Subgroup analyses of cancer-associated UEVT and catheter-associated venous thrombosis were conducted. Patients with Paget-Schroettersyndrome or effort thrombosis were excluded.Results: A total of 55 studies with 15,694 patients were included. The pooled proportions for VTE recurrence, majorbleeding, and PTS were 4.8% (95% CI, 3.8%-6.2%), 3.0% (95% CI, 2.2%-4.0%), and 23.8% (95% CI, 17.0%-32.3%), respectively.The pooled proportion of VTE recurrence was 2.7% (95% CI, 1.6%-4.6%) for patients treated with direct oral anticoagulants(DOACs), 1.7% (95% CI, 0.8%-3.7%) for patients treated with low-molecular-weight heparin (LMWH), and 4.4% (95% CI,1.5%-11.8%) for vitamin K antagonists (VKAs;P ¼ .36). The pooled proportion was 6.3% (95% CI, 4.3%-9.1%) for cancerpatients compared with 3.1% (95% CI, 2.1%-4.6%) for patients without cancer (P ¼ .01). The pooled proportion of majorbleeding for patients treated with DOACs, LMWH, and VKAs, was 2.1% (95% CI, 0.9%-5.1%), 3.2% (95% CI, 1.4%-7.2%), and3.4% (95% CI, 1.4%-8.4%), respectively (P ¼ .72). The pooled proportion of PTS for patients treated with DOACs, LMWH, andVKAs was 11.8% (95% CI, 6.5%-20.6%), 27.9% (95% CI, 20.9%-36.2%), and 24.5% (95% CI, 17.6%-33.1%), respectively (P ¼ .02).Conclusions: The results from this study suggest that UEVT is associated with significant rates of PTS and VTE recurrence.Treatment with DOACs might be associated with lower PTS rates than treatment with other anticoagulants. (J Vasc SurgVenous Lymphat Disord 2024;12:101688.

Impact of Femoral Ossification on Local and Systemic Cardiovascular Patients' Condition

International audienceBackground: Vascular calcifications are associated with a high cardiovascular morbi-mortality in the coronary territory. In parallel, femoral arteries are more calcified and develop osteoid metaplasia (OM). This study was conducted to assess the predictive value of OM and local inflammation on the occurrence of mid- and long-term adverse cardiovascular events.Method: Between 2008 and 2015, 86 atheromatous samples were harvested during femoral endarterectomy on 81 patients and processed for histomorphological analyses of calcifications and inflammation (monocytes and B cells). Histological findings were compared with the long-term follow-up of patients, including major adverse cardiac event (MACE), major adverse limb event (MALE), and mortality. Frequencies were presented as percentage, and continuous data, as mean and standard deviation. A P-value < 0.05 was considered statistically significant.Results: Median follow-up was 42.4 months (26.9-58.8). Twenty-eight percent of patients underwent a MACE; a MALE occurred in 18 (21%) limbs. Survival rate was 87.2% at 36 months. OM was found in 41 samples (51%), without any significant impact on the occurrence of MACE, MALE, or mortality. Preoperative white blood cell formulae revealed a higher rate of neutrophils associated with MACE (P = 0.04) and MALE (P = 0.0008), correlated with higher B cells counts in plaque samples.Conclusions: OM is part of femoral calcifications in almost 50% of the cases but does not seem to be an independent predictive variable for MACE or MALE. However, a higher rate of B cell infiltration of the plaque and preoperative neutrophil blood count may be predictive of adverse events during follow-up

Recurrent venous thromboembolism in anticoagulated cancer patients: Diagnosis and treatment

International audiencePatients with cancer are at significantly increased risk of venous thromboembolism (VTE), due both to the impact of malignant disease itself and to the impact of certain anticancer drugs on haemostasis. This is true both for first episode venous thromboembolism and recurrence. The diagnosis and management of VTE recurrence in patients with cancer poses particular challenges, and these are reviewed in the present article, based on a systematic review of the relevant scientific literature published over the last decade. Furthermore, it is uncertain whether diagnostic algorithms for venous thromboembolism, validated principally in untreated non-cancer patients, are also valid in anticoagulated cancer patients: the available data suggests that clinical decision rules and D-dimer testing perform less well in this clinical setting. In patients with cancer, computed tomography pulmonary angiography and venous ultrasound appear to be the most reliable diagnostic tools for diagnosis of pulmonary embolism and deep vein thrombosis respectively. Options for treatment of venous thromboembolism include low molecular weight heparins (at a therapeutic dose or an increased dose), fondaparinux or oral direct factor Xa inhibitors. The choice of treatment should take into account the nature (pulmonary embolism or VTE) and severity of the recurrent event, the associated bleeding risk, the current anticoagulant treatment (type, dose, adherence and possible drug-drug interactions) and cancer progression

Specific features to differentiate Giant cell arteritis aortitis from aortic atheroma using FDG-PET/CT

International audienceAortic wall 18 F-fluorodeoxyglucose (FDG)-uptake does not allow differentiation of aortitis from atheroma, which is problematic in clinical practice for diagnosing large vessel vasculitis giantcell arteritis (GCA) in elderly patients. The purpose of this study was to compare the FDG uptake characteristics of GCA aortitis and aortic atheroma using positron emission tomography/FDG computed tomography (FDG-PET/CT). This study compared FDG aortic uptake between patients with GCA aortitis and patients with aortic atheroma; previously defined by contrast enhanced CT. Visual grading according to standardized FDG-PET/CT interpretation criteria and semi-quantitative analyses (maximum standardized uptake value (SUV max), delta SUV (∆SUV), target to background ratios (TBR)) of FDG aortic uptake were conducted. The aorta was divided into 5 segments for analysis. 29 GCA aortitis and 66 aortic atheroma patients were included. A grade 3 FDG uptake of the aortic wall was identified for 23 (79.3%) GCA aortitis patients and none in the atheroma patient group (p < 0.0001); grade 2 FDG uptake was as common in both populations. Of the 29 aortitis patients, FDG uptake of all 5 aortic segments was positive for 21 of them (72.4%, p < 0.0001). FDG uptake of the supra-aortic trunk was identified for 24 aortitis (82.8%) and no atheromatous cases (p < 0.0001). All semi-quantitative analyses of FDG aortic wall uptake (SUV max , ∆SUV and TBRs) were significantly higher in the aortitis group. ∆SUV was the feature with the largest differential between aortitis and aortic atheroma. In this study, GCA aortitis could be distinguished from an aortic atheroma by the presence of an aortic wall FDG uptake grade 3, an FDG uptake of the 5 aortic segments, and FDG uptake of the peripheral arteries