Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial.

BACKGROUND: The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy. METHODS: This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021. FINDINGS: Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded. INTERPRETATION: In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation. FUNDING: European Union's Horizon 2020

La manométrie du grêle des 24 heures chez le sujet sain (données obtenues dans un groupe de 30 volontaires sains)

TOURS-BU Médecine (372612103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Humidité de la troposphère libre africaine (élaboration d'une archive Meteosat, analyse climatique et évaluation de modèles)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

5. Besoins en formation

Le contexte général Les chapitres précédents ont mis en évidence la complexité du système climatique*, formé de sous-système différents et dont les échelles spatiale et temporelle font intervenir plusieurs ordres de grandeur. La connaissance du climat et de ses variations nécessite des compétences dans de nombreux domaines. Dans le passé, les études des géographes ont permis de décrire les paramètres associés aux climats variés existant sur notre planète, et de comprendre certaines interactio..

Climatologie et variabilité de l'air sec de la troposphère libre intertropicale (analyse du climat actuel et de son évolution)

La vapeur d'eau est une composante clé des cycles de l'eau et de l'énergie. Ces derniers, particulièrement actifs dans la ceinture tropicale, sont des éléments majeurs du climat de la Terre. Une meilleure compréhension de ces cycles repose sur une meilleure compréhension de la variabilité spatio-temporelle de l'humidité de la troposphère libre, notamment au-dessus des régions sèches subtropicales. Dans cette thèse, l'humidité relative au niveau de pression 500 hPa (RH500) estimée par les réanalyses NCEP-1, NCEP-2, ERA-40, ERA-interim, les observations satellites AIRS et METEOSAT, ainsi que l'humidité relative reconstruite par un modèle d'advection-condensation est utilisée afin de documenter et caractériser la variabilité interannuelle de l'air sec de la troposphère libre tropicale. À l'échelle intrasaisonnière, un test de Kolmogorov-Smirnov souligne que la distribution de RH500 dans les régions subtropicales s'éloigne de la loi normale. Les occurences sèches, définies comme le pourcentage de scènes pour lesquelles l'humidité relative est inférieur à 10 \% d'humidité relative pour une saison donnée, sont alors utilisées pour caractériser la variabilité interannuelle des régions sèches subtropicales. Le rôle des anomalies de température est alors exploré à partir d'une décomposition de RH500, pour expliquer la variabilité des occurrences sèches. Il est alors montré que la variabilité interannuelle des occurences sèches est en grande majorité associée à des anomalies d'humidité, et non à des anomalies de température. La part de variabilité associée aux grands modes de variabilité interannuelles ENSO, IOD, NAO, ainsi que les pluies indiennes AIRI, est alors examinée. Les sorties d'un modèle d'advection-condensation sont analysées pour étudier l'origine de l'air sec des régions d'anomalies associées à ces grands modes de variabilité. En s'appuyant sur les résultats obtenus à partir de l'analyse des différentes estimations de RH500, la dernière partie de la thèse étudie la reproduction de l'air sec par le modèle de climat de l'IPSL (IPSL-CM4), et explore l'évolution de l'air sec de la troposphère libre tropicale dans un contexte de réchauffement globale, révélant des occurrences sèches constantes.PARIS-BIUSJ-Sci.Terre recherche (751052114) / SudocSudocFranceF

A study of the free tropospheric humidity interannual variability using Meteosat data and an advection-condensation transport model

International audienceWater vapor in the midtroposphere is an important element for the earth radiation budget. Despite its importance, the relative humidity in the free troposphere is not very well documented, mainly because of the difficulties associated with its measurements. A new long-term archive of free tropospheric humidity (FTH) derived from the water vapor channel of the Meteosat satellite from 1983 to 2005 is introduced. Special attention is dedicated to the long-term homogeneity and the definition of the retrieval layer. It is shown to complement the existing databases and is used to establish the climatology of FTH. Interannual variability is then evaluated for each season by using a normalized interannual standard deviation. This normalization approach reveals the importance of the relative variability of the dry areas to the moist regions. In consequence, emphasis is on the driest area of the region. Focusing on composites of the moist and dry seasons of the time series, the authors demonstrate that the 500-hPa relative humidity field, reconstructed using an idealized Lagrangian model, is a good proxy for the FTH variability there. The analysis of the origin of the air mass, using the back trajectory model, points out that lateral mixing between the deep tropics and extratropical latitudes takes place over this area, as advocated in previous theoretical studies. Systematic estimation of this large-scale mixing shows that, indeed, a significant part of the interannual variability of the free tropospheric humidity in this subtropical region stems from the amount of mixing of air originating from the deep tropics versus extratropical latitudes. The importance of this mechanism in the general understanding of the FTH distribution and variability is then discussed

Evaluation of the distribution of subtropical free tropospherichumidity in AMIP-2 simulations using METEOSAT water vaporchannel data

In the framework of the Atmospheric ModelIntercomparison Project (AMIP) phase 2, we haveestablished a diagnostic of the free tropospheric humidity(FTH) distribution using METEOSAT data over the 1984–1995 period for 14 climate models. The methodology ofevaluation follows a two step ‘‘model-to-satellite’’ approach.First the raw METEOSAT ‘‘Water Vapor’’ radiances aresimulated from the model profiles of temperature andhumidity using the RTTOV-7 radiative transfer model.Second, the radiances are converted into FTH using thesame coefficients as in the satellite product offering a directcomparison. The analysis is focused on the dry subtropicalareas observed by METEOSAT: the Eastern Mediterraneanand the tropical South Atlantic Ocean. Most of the modelsreproduce the observed seasonal cycle both in terms ofphasing and magnitude, despite an overall moist bias. A fewmodels are in close agreement with the satellite data. Themagnitude of the satellite estimated inter-annual variability isalso generally captured by models. Again, a small subsetof models shows close agreement with the observations.This comparison suggests general improvements of themodels with respect to the AMIP-1 simulations

Clouds and Water Vapor

International audienceWater, in any of its states: vapor, liquid or ice, is a key component of our climate system. It is the coexistence of these three phases of water on Earth that makes it such a special planet. Water vapor is the most important natural greenhouse gas; it contributes up to 60% of the natural greenhouse effect! Thus, water vapor is the second heat source after the sun for heating Earth's surface. Passive sensors are by far the majority in the panorama, and the estimation of water vapor from their measurements is based on the use of the absorption band and the emission band. A cloud consists of droplets of liquid water and/or ice crystals suspended in saturated air aggregated around particles of various origins that promote condensation and are called “cloud condenstation nuclei”

Tropical water vapor and large-scale circulation from CMIP6 GCMs and ESA CCI+ "Water Vapor" climate data records

International audienceThe atmospheric water cycle is strongly associated with global climate variations, especially in the tropical region (30°S-30°N). However, the representation of the relation from models and observation results remains unknown. Here the water vapor observed during 2003~2014 over the tropical region is analysed concerning large-scale circulation for 7 global climate models (CMIP6 framework), ERA5 reanalysis data, and the new global water vapor climate data records (CDR) generated within the ESA Water Vapor CCI+ project (ESA TCWV-COMBI). As the ESA TCWV-COMBI observes water vapor over the land area under clear-sky conditions and all-weather conditions without heavy precipitation in the ocean areas, the evaluation is conducted with land-sea separation. The observational diagnostic relies on the decomposition of the tropical atmosphere into large-scale dynamical regimes using the 500 hPa atmospheric vertical velocity w500 (in hPa/day) as a proxy. The datasets are sorted according to dynamical regimes (intervals of 10 hPa/day) to analyze the evolution of the regimes in terms of frequency of occurrence and is linked to water vapor variation. Although the inter-model spread lies within the interannual spread of the ESA CCI+_WV data, there are noticeable differences between the models and observations that are linked to large-scale dynamics