Alice Ballerie

Background and aims: Some evidence reported that rivaroxaban use is associated with a higher risk of clinically relevant bleeding (CRB) than apixaban during the first months of treatment of venous thromboembolism (VTE). We aimed to determine whether the risk of CRB is higher with rivaroxaban than apixaban during extended treatment, either at full or reduced dose. Methods: The RENOVE open-label randomised controlled trial compared full-dose versus reduced-dose of apixaban or rivaroxaban in patients who had completed at least 6 months of full-dose treatment for VTE and required extended anticoagulation. Drug choice was not randomised. In this post-analysis, the primary outcome was centrally-adjudicated CRB events. Treatment effects were estimated using crude hazard ratio (HR), adjusted HR, and an inverse probability of treatment weighting (IPTW). Results: Among 2768 enrolled patients, 1513 received rivaroxaban (755 full-dose, 758 reduced-dose) and 1255 apixaban (630 full-dose, 625 reduced-dose). Median age was 62.6 versus 66.5 years and proportion of female was 32.1% versus 38.7%, respectively. Median follow-up was 37 months. The 5-year cumulative incidence of CRB was 11.7% with rivaroxaban and 13.7% with apixaban (adjusted-HR 0.90 [95%CI 0.70–1.17], HR _IPTW 0.92 [0.70–1.21]). The incidence of major bleeding, recurrent VTE, composite outcome, arterial thromboembolic events, and all-cause death were similar. Serious adverse event not related to VTE and CRB was 7.7% and 10.8%, respectively (adjusted-HR 0.74 [95% CI 0.57–0.97], HR _IPTW 0.76 [0.55–1.04]). Conclusions: During extended anticoagulation, no difference in clinically relevant bleeding or recurrent VTE was observed between rivaroxaban and apixaban, although that non-randomised treatment allocation possibly influenced outcomes.

Apixaban and rivaroxaban have first-line use for many patients needing anticoagulation for venous thromboembolism (VTE). The pharmacokinetics of these drugs in non-obese subjects have been extensively studied, and, while changes in pharmacokinetics have been documented in obese patients, data remain scarce for these anticoagulants. The aim of this study was to perform an external validation of published population pharmacokinetic (PPK) models of apixaban and rivaroxaban in a cohort of obese patients with VTE. A literature search was conducted in the PubMed/MEDLINE, Scopus, and Embase databases following the PRISMA statement. External validation was performed using MonolixSuite software, using prediction-based and simulation-based diagnostics. An external validation dataset from the university hospitals of Brest and Rennes, France, included 116 apixaban pharmacokinetic samples from 69 patients and 121 rivaroxaban samples from 81 patients. Five PPK models of apixaban and 16 models of rivaroxaban were included, according to the inclusion criteria of the study. Two of the apixaban PPK models presented acceptable performances, whereas no rivaroxaban PPK model did. This study identified two published models of apixaban applicable to apixaban in obese patients with VTE. However, none of the rivaroxaban models evaluated were applicable. Dedicated studies appear necessary to elucidate rivaroxaban pharmacokinetics in this population.

Develop and validate a thorough exposure questionnaire to comprehensively explore crystalline silica (SiO₂) exposure in the general population (gender-specific, occupational and non-occupational) and in patients with autoimmune diseases (Rheumatoid arthritis (RA), Systemic sclerosis (SSc)). Lifetime exposures to SiO₂ in occupational and non-occupational settings were assessed using a thorough exposure questionnaire. The questionnaire was applied to a general population panel (N = 2,911) sampled from the French rolling census, and to unselected patients with SSc (N = 100) and RA (N = 97). Global (GES), occupational (OES) and non-occupational (NOES) exposure scores were assessed in SSc and RA patients, and compared with up to 4 controls from the general population, matched by age group, sex and tobacco consumption. Patients had higher GES than their matched controls (SSc: p= 0.001; RA: p< 0.0001) due to higher OES (p< 0.0001 for SSc and RA). Men had higher GES than women (SSc: p< 0.0001; RA: p= 0.002) due to higher OES (p< 0.0001 for SSc and RA). The NOES did not differ between men and women. In SSc patients: Men had higher GES than controls (p< 0.0001). Men and women with SSc had higher OES than controls (p< 0.0001). In RA patients: GES and OES were higher in both men (p= 0.00521; p< 0.0001) and women (p< 0.0001; p< 0.0001) than in their respective controls. Women had higher NOES than controls (p= 0.045). The lifetime SiO₂ exposure gap between RA and SSc patients and controls was substantially due to occupational exposure. In both diseases, men had higher exposure scores than women.

Background: to compare three existing screening algorithms of pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) with the results of a multidisciplinary team (MDT) meeting from a tertiary center. Methods: we conducted a monocentric longitudinal study from 2015 to 2018. All patients with SSc according to LeRoy’s classification were eligible. Patients were excluded in the case of missing data required by any of the three screening algorithms. The algorithms were applied for each patient at inclusion. Right heart catheterization (RHC) was performed based on the MDT decision. MDT members were all blinded from the results of the three algorithms regarding RHC recommendations. The RHC recommendations of each algorithm were compared with the MDT decision, and the impact on diagnosis and management was evaluated. Results: 117 SSc patients were consecutively included in the study, and 99 had follow-up data over the three-year duration of the study (10 deaths). Among the 117 patients, the MDT suggested RHC for 16 patients (14%), DETECT algorithm for 28 (24%), ASIG for 48 (41%) and ESC/ERS 2015 for 20 (17%). Among the 16 patients who had RHC, SSc-PAH was diagnosed in seven. Among patients with an initial recommendation of RHC based on at least one algorithm but not according to the MDT meeting, no SSc-PAH was diagnosed during the three-year follow-up. Results were unchanged when the new 2018 definition of PAH was applied instead of the previous definition. Conclusion: a MDT approach appears interesting for the screening of SSc-PAH, with a significant reduction of RHC performed in comparison with dedicated algorithms. The specific relevance of a MDT for the management and follow-up of patients with RHC recommended by existing algorithms but with no PAH warrants further studies.

Macrophages play a central role in the pathogenesis of inflammatory and fibrotic lung diseases. However, alveolar macrophages (AM) are poorly available in humans to perform in vitro studies due to a limited access to broncho-alveolar lavage (BAL). In this study, to identify the best alternative in vitro model for human AM, we compared the phenotype of AM obtained from BAL of patients suffering from three lung diseases (lung cancers, sarcoidosis and Systemic Sclerosis (SSc)-associated interstitial lung disease) to human blood monocyte-derived macrophages (MDMs) differentiated with M-CSF or GM-CSF. The expression of eight membrane markers was evaluated by flow cytometry. Globally, AM phenotype was closer to GM-CSF MDMs. However, the expression levels of CD163, CD169, CD204, CD64 and CD36 were significantly higher in SSc-ILD than in lung cancers. Considering the expression of CD204 and CD36, the phenotype of SSc-AM was closer to MDMs, from healthy donors or SSc patients, differentiated by M-CSF rather than GM-CSF. The comparative secretion of IL-6 by SSc-MDMs and SSc-AM is concordant with these phenotypic considerations. Altogether, these results support the M-CSF MDM model as a relevant in vitro alternative to simulate AM in fibrotic disorders such as SSc.

Pulmonary fibrosis may be more prevalent in adults with GATA2 deficiency due to a longer duration of the diseasehttp://ow.ly/WHnu30aCZ4S

Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterised by an abnormal accumulation of surfactant proteins in pulmonary alveoli which impairs gas exchange [1]. PAP is classified into three groups: autoimmune PAP (aPAP), defined by the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, secondary PAP (sPAP) and genetic PAP. Haematological diseases are the most common causes of sPAP, particularly myelodysplastic syndrome (MDS) [1, 2]. The diagnosis of PAP is based on a chest computed tomography (CT) scan, which demonstrates a crazy-paving pattern, and a typical positive periodic acid–Schiff (PAS) staining of bronchoalveolar lavage (BAL) [3]. Nowadays, a surgical lung biopsy is seldom needed to diagnose PAP, except for atypical presentation as in the case described below with concomitant pulmonary fibrosis and sPAP in a patient with GATA2 (GATA binding protein 2) deficiency. Lymphoedema, myelodysplasia, fibrosis and pulmonary alveolar proteinosis complicating a novel GATA2 mutation The authors thank Marie de Tayrac (Service de génétique moléculaire et génomique, hôpital Pontchaillou and UMR 6290 Institut de génétique et développement, Université Rennes 1, Rennes, France) for her help with molecular genetic databases.