Evolution of Endoscopic Lesions in Steroid-Refractory Acute Severe Ulcerative Colitis Responding to Infliximab or Cyclosporine

BACKGROUND/AIMS: Few data on the evolution of endoscopic findings are available in patients with acute severe ulcerative colitis (ASUC). The aim of this study was to describe this evolution in a prospective cohort. METHODS: Patients admitted for a steroid-refractory ASUC and included in a randomized trial comparing infliximab and cyclosporine were eligible if they achieved steroid-free clinical remission at day 98. Flexible sigmoidoscopies were performed at baseline, days 7, 42 and 98. Ulcerative colitis endoscopic index of severity (UCEIS) and its sub-scores - vascular pattern, bleeding and ulceration/erosion - were post-hoc calculated. Global endoscopic remission was defined by a UCEIS of 0, and partial endoscopic remission by any UCEIS sub-score of 0. RESULTS: Among the 55 patients analyzed (29 infliximab and 26 cyclosporine), 49 (83%) had UCEIS >= 6 at baseline at baseline. Partial endoscopic remission rates were higher for bleeding than for vascular pattern and for ulcerations/erosions at day 7 (20% vs. 4% and 5% (n = 55); p CONCLUSION: In steroid-refractory ASUC patients responding to a second-line medical therapy, endoscopic remission process started with bleeding remission and was not achieved in half the patients at day 98 for vascular pattern. Infliximab provided a higher endoscopic remission rate than cyclosporine at day 98.Peer reviewe

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

Natural Disease Course of Ulcerative Colitis During the First Five Years of Follow-up in a European Population-based Inception Cohort-An Epi-IBD Study

International audienceBackground and Aims: Few population-based cohort studies have assessed the disease course of ulcerative colitis [UC] in the era of biological therapy and widespread use of immunomodulators. The aim of this study was to assess the 5-year outcome and disease course of patients with UC in the Epi-IBD cohort. Methods: In a prospective, population-based inception cohort of unselected patients with UC, patients were followed up from the time of their diagnosis, which included the collection of their clinical data, demographics, disease activity, medical therapy, and rates of surgery, cancers, and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis. Results: A total of 717 patients were included in the study. During follow-up, 43 [6%] patients underwent a colectomy and 163 [23%] patients were hospitalised. Of patients with limited colitis [distal to the left flexure], 90 [21%] progressed to extensive colitis. In addition, 92 [27%] patients with extensive colitis experienced a regression in disease extent, which was associated with a reduced risk of hospitalisation (hazard ratio [HR]: 0.5 95% CI: 0.3-0.8]. Overall, patients were treated similarly in both geographical regions; 80 [11%] patients needed biological therapy and 210 [29%] patients received immunomodulators. Treatment with immunomodulators was found to reduce the risk of hospitalisation [HR: 0.5 95% CI: 0.3-0.8]. Conclusions: Although patients in this population-based cohort were treated more aggressively with immunomodulators and biological therapy than in cohorts from the previous two decades, their disease outcomes, including colectomy rates, were no different. However, treatment with immunomodulators was found to reduce the risk of hospitalisation

Simple scoring system to predict in-hospital mortality after surgery for infective endocarditis

BACKGROUND: Aspecific scoring systems are used to predict the risk of death postsurgery in patients with infective endocarditis (IE). The purpose of the present study was both to analyze the risk factors for in-hospital death, which complicates surgery for IE, and to create a mortality risk score based on the results of this analysis. METHODS AND RESULTS: Outcomes of 361 consecutive patients (mean age, 59.1\ub115.4 years) who had undergone surgery for IE in 8 European centers of cardiac surgery were recorded prospectively, and a risk factor analysis (multivariable logistic regression) for in-hospital death was performed. The discriminatory power of a new predictive scoring system was assessed with the receiver operating characteristic curve analysis. Score validation procedures were carried out. Fifty-six (15.5%) patients died postsurgery. BMI >27 kg/m2 (odds ratio [OR], 1.79; P=0.049), estimated glomerular filtration rate 55 mm Hg (OR, 1.78; P=0.032), and critical state (OR, 2.37; P=0.017) were independent predictors of in-hospital death. A scoring system was devised to predict in-hospital death postsurgery for IE (area under the receiver operating characteristic curve, 0.780; 95% CI, 0.734-0.822). The score performed better than 5 of 6 scoring systems for in-hospital death after cardiac surgery that were considered. CONCLUSIONS: A simple scoring system based on risk factors for in-hospital death was specifically created to predict mortality risk postsurgery in patients with IE

PPARγ et homéostasie intestinale

PPARγ is a ligand-activated nuclear receptor that controls, in various organs, numerous cellular functions, involved in the control of inflammation, carcinogenesis or metabolism. In intestinal epithelial cell, some functions of PPARγ, as its metabolic role, remain unknown. The genomic effects of PPARγ ligands are also poorly known in this cell. Our objective was to compare the genomic expression induced by different PPARγ agonists in the intestinal epithelial cells by a microarrays technique, and thus to identify new PPARγ target genes and the different cellular functions controlled by this nuclear receptor. We have identified the lactase gene, whose lack of expression is responsible for lactose intolerance, as a target gene of PPARγ. We then showed that PPARγ agonists were able to increase lactase expression and activity in vitro and in vivo, identifying PPARγ agonists as potentially the first pharmacological treatment of lactose intolerance. We then confirmed the antineoplastic effect of 5ASA in intestinal epithelial cell, both in vivo and in vitro, and confirmed that this action was PPARγ-dependent. As in other organs, PPARγ regulates in intestinal epithelial cell inflammation, cell differentiation and maturation as well as metabolic functions, confirming the key role of PPARγ in the control of intestinal homeostasis, and the potential therapeutic effect of PPARγ agonistsPPARγ est un récepteur nucléaire ligand-activé qui contrôle, dans différents organes, de nombreuses fonctions cellulaires, impliquées notamment dans le contrôle de l'inflammation, de la carcinogenèse ou du métabolisme. Au niveau de la cellule épithéliale intestinale, certaines fonctions de PPARγ, comme son rôle métabolique, reste méconnu. Les effets génomiques des ligands de PPARγ sont eux aussi très mal connus dans cette cellule. L'objectif de ce travail était de comparer l'expression génomique induite par différents agonistes de PPARγ dans la cellule épithéliale intestinale par la technique de microarrays, et ainsi identifier de nouveaux gènes cibles de PPARγ et les différentes fonctions cellulaires contrôlées par ce récepteur nucléaire. Nous avons pu identifier le gène lactase, dont le déficit d'expression est responsable de l'intolérance au lactose, comme un gène cible de PPARγ. Nous avons ensuite pu montrer que les agonistes de PPARγ étaient capables d'augmenter l'expression et l'activité de la lactase in vitro et in vivo, ainsi que d'améliorer les symptômes d'intolérance au lactose dans un modèle animal ; identifiant les agonistes de PPARγ comme potentiellement le premier traitement pharmacologique de l'intolérance au lactose. Nous avons pu ensuite confirmer l'effet antinéoplasique du 5ASA au niveau de la cellule épithéliale intestinale, in vivo et in vitro, et confirmer que cette action était dépendante de PPARγ. Comme dans d'utres organes, PPARγ régule dans la cellule épithéliale intestinale les voies de l'inflammation, la différenciation et la maturation cellulaire mais aussi des fonctions métaboliques, confirmant le rôle clé de PPARγ dans le contrôle de l'homéostasie intestinale, et le potentiel thérapeutique des agonistes de PPAR

Biomécanique du transport collectif de charges, vers une application clinique

During the last 50 years, a number of studies have been carried out on human locomotion and individual load carriage. Although these studies provide a valued theoretical framework, they do not allow to understand the mechanisms implemented by individuals when they have to carry collectively an object. Our project deals with the collective aspect of load carriage and attempts to understand how a dyad of individuals moves when individuals have to carry an object together. First, we measured several locomotor parameters commonly studied in biomechanics (using a kinematic, mechanical and dynamic approach) on healthy individuals carrying a light load. We studied each individual within a dyad separately and then considered the system formed by the dyad and the load. We also performed experiments where we increased the complexity of the collective load carriage task by asking individuals to perform a second task in the same time or by changing the mass of the load. Finally, in order to find an application of our experimental protocol in rehabilitation studies, we performed a preliminary study on the collective transport achieved by two patients suffering from intellectual disability. The results of this thesis allow to construct a sound study protocol of collective load carriage. We show that two subjects carrying an object together walk as economically as when they are walking separately. Achieving a second distractive task at the same time leads to the deterioration of the pendular displacement of the center of mass of the system formed by the individuals and the load they carry. The displacement of this system is also impacted when the mass of the load carried is increased. For loads equal to 40% of the body mass, our results show a deterioration of the pendular behavior and a decrease of the amplitude of the center of mass of the system. Finally, for individuals suffering from an intellectual disability, we show that the collaboration between two pathological individuals is less interesting from a rehabilitation point of view than the collaboration with a healthy individual.Durant les 50 dernières années, de nombreuses études ont été menées sur la locomotion humaine et sur le transport de charges individuel. Même si elles apportent un cadre théorique précieux, ces études ne permettent pas de comprendre les mécanismes mis en place par les individus lorsqu'ils doivent porter un objet à plusieurs. Dans ce projet, nous nous sommes donc intéressé à l'aspect collectif du transport de charges et avons cherché à comprendre comment une dyade d'individus se déplace lorsque ceux-ci portent un objet ensemble. Pour ce faire, nous avons dans un premier temps quantifié différents paramètres locomoteurs largement étudiés en biomécanique (approche cinématique, mécanique et dynamique), chez des individus sains transportant une charge légère. Nous avons étudié les individus se déplaçant de façon isolée, puis nous avons envisagé la dyade et la charge à transporter comme un seul système. Nous avons également fait varier la complexité du transport de charges en demandant aux sujets de réaliser une seconde tâche ou en faisant varier la masse de la charge transportée. Enfin, nous avons pu réaliser une étude préliminaire sur la collaboration entre un patient polyhandicapé et un patient cérébrolésé, dans le but d'inscrire l'étude du comportement collectif dans la rééducation des personnes en situation de handicap. Les résultats principaux de cette thèse fournissent un protocole solide d'étude du transport collectif de charges. Nous avons montré que les sujets qui transportent un objet à deux se déplacent de façon aussi économique que lorsqu'ils se déplacent seuls. L'ajout d'une tâche secondaire a quant à elle entraîné une détérioration du déplacement pendulaire du système composé des individus et de la charge. Lorsque la masse de la charge augmente, le déplacement du système est affecté. Pour des charges égales à 40% du poids corporel, nos résultats ont montré une détérioration du comportement pendulaire et une diminution de l'amplitude du centre de masse du système étudié. Enfin, concernant les personnes en situation de handicap, nous avons montré que la collaboration entre deux individus souffrants de déficience intellectuelle était moins intéressante d'un point de vue rééducatif que la collaboration avec un individu sain

Biomechanics of collective load transport, toward a clinical application

Durant les 50 dernières années, de nombreuses études ont été menées sur la locomotion humaine et sur le transport de charges individuel. Même si elles apportent un cadre théorique précieux, ces études ne permettent pas de comprendre les mécanismes mis en place par les individus lorsqu'ils doivent porter un objet à plusieurs. Dans ce projet, nous nous sommes donc intéressé à l'aspect collectif du transport de charges et avons cherché à comprendre comment une dyade d'individus se déplace lorsque ceux-ci portent un objet ensemble. Pour ce faire, nous avons dans un premier temps quantifié différents paramètres locomoteurs largement étudiés en biomécanique (approche cinématique, mécanique et dynamique), chez des individus sains transportant une charge légère. Nous avons étudié les individus se déplaçant de façon isolée, puis nous avons envisagé la dyade et la charge à transporter comme un seul système. Nous avons également fait varier la complexité du transport de charges en demandant aux sujets de réaliser une seconde tâche ou en faisant varier la masse de la charge transportée. Enfin, nous avons pu réaliser une étude préliminaire sur la collaboration entre un patient polyhandicapé et un patient cérébrolésé, dans le but d'inscrire l'étude du comportement collectif dans la rééducation des personnes en situation de handicap. Les résultats principaux de cette thèse fournissent un protocole solide d'étude du transport collectif de charges. Nous avons montré que les sujets qui transportent un objet à deux se déplacent de façon aussi économique que lorsqu'ils se déplacent seuls. L'ajout d'une tâche secondaire a quant à elle entraîné une détérioration du déplacement pendulaire du système composé des individus et de la charge. Lorsque la masse de la charge augmente, le déplacement du système est affecté. Pour des charges égales à 40% du poids corporel, nos résultats ont montré une détérioration du comportement pendulaire et une diminution de l'amplitude du centre de masse du système étudié. Enfin, concernant les personnes en situation de handicap, nous avons montré que la collaboration entre deux individus souffrants de déficience intellectuelle était moins intéressante d'un point de vue rééducatif que la collaboration avec un individu sain.During the last 50 years, a number of studies have been carried out on human locomotion and individual load carriage. Although these studies provide a valued theoretical framework, they do not allow to understand the mechanisms implemented by individuals when they have to carry collectively an object. Our project deals with the collective aspect of load carriage and attempts to understand how a dyad of individuals moves when individuals have to carry an object together. First, we measured several locomotor parameters commonly studied in biomechanics (using a kinematic, mechanical and dynamic approach) on healthy individuals carrying a light load. We studied each individual within a dyad separately and then considered the system formed by the dyad and the load. We also performed experiments where we increased the complexity of the collective load carriage task by asking individuals to perform a second task in the same time or by changing the mass of the load. Finally, in order to find an application of our experimental protocol in rehabilitation studies, we performed a preliminary study on the collective transport achieved by two patients suffering from intellectual disability. The results of this thesis allow to construct a sound study protocol of collective load carriage. We show that two subjects carrying an object together walk as economically as when they are walking separately. Achieving a second distractive task at the same time leads to the deterioration of the pendular displacement of the center of mass of the system formed by the individuals and the load they carry. The displacement of this system is also impacted when the mass of the load carried is increased. For loads equal to 40% of the body mass, our results show a deterioration of the pendular behavior and a decrease of the amplitude of the center of mass of the system. Finally, for individuals suffering from an intellectual disability, we show that the collaboration between two pathological individuals is less interesting from a rehabilitation point of view than the collaboration with a healthy individual

PPARγ et homéostasie intestinale

PPARγ est un récepteur nucléaire ligand-activé qui contrôle, dans différents organes, de nombreuses fonctions cellulaires, impliquées notamment dans le contrôle de l'inflammation, de la carcinogenèse ou du métabolisme. Au niveau de la cellule épithéliale intestinale, certaines fonctions de PPARγ, comme son rôle métabolique, reste méconnu. Les effets génomiques des ligands de PPARγ sont eux aussi très mal connus dans cette cellule. L'objectif de ce travail était de comparer l'expression génomique induite par différents agonistes de PPARγ dans la cellule épithéliale intestinale par la technique de microarrays, et ainsi identifier de nouveaux gènes cibles de PPARγ et les différentes fonctions cellulaires contrôlées par ce récepteur nucléaire. Nous avons pu identifier le gène lactase, dont le déficit d'expression est responsable de l'intolérance au lactose, comme un gène cible de PPARγ. Nous avons ensuite pu montrer que les agonistes de PPARγ étaient capables d'augmenter l'expression et l'activité de la lactase in vitro et in vivo, ainsi que d'améliorer les symptômes d'intolérance au lactose dans un modèle animal ; identifiant les agonistes de PPARγ comme potentiellement le premier traitement pharmacologique de l'intolérance au lactose. Nous avons pu ensuite confirmer l'effet antinéoplasique du 5ASA au niveau de la cellule épithéliale intestinale, in vivo et in vitro, et confirmer que cette action était dépendante de PPARγ. Comme dans d'utres organes, PPARγ régule dans la cellule épithéliale intestinale les voies de l'inflammation, la différenciation et la maturation cellulaire mais aussi des fonctions métaboliques, confirmant le rôle clé de PPARγ dans le contrôle de l'homéostasie intestinale, et le potentiel thérapeutique des agonistes de PPARγPPARγ is a ligand-activated nuclear receptor that controls, in various organs, numerous cellular functions, involved in the control of inflammation, carcinogenesis or metabolism. In intestinal epithelial cell, some functions of PPARγ, as its metabolic role, remain unknown. The genomic effects of PPARγ ligands are also poorly known in this cell. Our objective was to compare the genomic expression induced by different PPARγ agonists in the intestinal epithelial cells by a microarrays technique, and thus to identify new PPARγ target genes and the different cellular functions controlled by this nuclear receptor. We have identified the lactase gene, whose lack of expression is responsible for lactose intolerance, as a target gene of PPARγ. We then showed that PPARγ agonists were able to increase lactase expression and activity in vitro and in vivo, identifying PPARγ agonists as potentially the first pharmacological treatment of lactose intolerance. We then confirmed the antineoplastic effect of 5ASA in intestinal epithelial cell, both in vivo and in vitro, and confirmed that this action was PPARγ-dependent. As in other organs, PPARγ regulates in intestinal epithelial cell inflammation, cell differentiation and maturation as well as metabolic functions, confirming the key role of PPARγ in the control of intestinal homeostasis, and the potential therapeutic effect of PPARγ agonist