Crohn's disease: is there any link between anal and luminal phenotypes?

International audiencePURPOSE: Perianal Crohn's disease (CD) encompasses a variety of lesion similar to luminal disease, which are usually not distinctly assessed. Links between luminal and perianal CD phenotype remains therefore underreported, and we aimed to describe both luminal and perianal phenotype and their relationships. METHODS: From January 2007, clinical data of all consecutive patients with CD seen in a referral center were prospectively recorded. Data recorded until October 2011 were extracted and reviewed for study proposal. RESULTS: A total of 282 patients (M/F, 108/174; aged 37.8 ± 16.2 years) were assessed that included 154 cases (54.6 %) with anal ulceration, 118 cases (41.8 %) with fistula, 49 cases (17.4 %) with stricture, and 94 cases without anal lesion (33.3 %). Anal ulcerations were associated with fistulas (N = 87/154) in more than half of patients (56.5 %) and were isolated in 55 patients (35.7 %). Most of strictures (94 %) were associated with other lesions (N = 46/49). Harvey-Bradshaw score was significantly higher in patients with ulcerations (p \textless 0.001) as compared to those with perianal fistulas (p = 0.15) or with anal strictures (p = 0.16). Proportions of complicated behavior (fistulizing or stricturing) of luminal CD were similar according to anal lesions: anal fistulas were not significantly associated to penetrating Montreal phenotype (N = 4/31 p = 0.13) as well as anal stricture and stricturing Montreal phenotype (N = 3/49, p = 0.53). CONCLUSIONS: The phenotype of luminal disease does not link with the occurrence and the phenotype of perianal Crohn's disease. Anal ulcerations denote a more severe disease on both luminal and perianal locations and should consequently be taking into account in physician decision-makin

Anti-glomerular basement membrane disease, ulcerative colitis, and primary sclerosing cholangitis: link or co-incidence?

International audienceUlcerative colitis, primary sclerosing cholangitis, and anti-glomerular basement membrane disease (anti-GBM) are three rare immune diseases with incompletely under-stood pathogenic mechanisms. We describe here the case of a 29-year-old man with ulcer-ative colitis and primary sclerosing cholang -itis who, eight years later, developed anti-GBM disease with destruction of all glomeruli leading to end-stage kidney disease. Association of these three immune diseases in the same patient has never been described. Because HLA-mediated susceptibility cannot be incriminated completely in our case, we hypothesize that environmental factors or previous immunosuppressive treatment used might be the link

Safety and efficacy of granulocyte/monocyte apheresis in steroid-dependent active ulcerative colitis with insufficient response or intolerance to immunosuppressants and/or biologics (ART trial): 12-week interim results

International audienceBACKGROUND AND AIMS: Patients with active, steroid-dependent ulcerative colitis with insufficient response or intolerance to immunosuppressants and/or biologic therapies have limited treatment options. Adacolumn, a granulocyte/monocyte adsorptive apheresis device, has shown clinical benefit in these patients. This study aimed to provide additional clinical data regarding the safety and efficacy of Adacolumn in this patient subgroup.METHODS: This single arm, open-label, multicentre trial (ART) was conducted at 18 centres across the UK, France and Germany. Eligible patients were 18-75 years old with moderate-to-severe, steroid-dependent active ulcerative colitis with insufficient response or intolerance to immunosuppressants and/or biologics. Patients received ≥5 weekly apheresis sessions with Adacolumn. The primary endpoint was clinical remission rate (clinical activity index ≤4) at Week 12.RESULTS: Eighty-six patients were enrolled. At Week 12, 33/84 (39.3%) of patients in the intention-to-treat population achieved clinical remission, with 47/84 (56.0%) achieving a clinical response (clinical activity index reduction of ≥3). Clinical remission was achieved in 30.0% of patients with prior immunosuppressant and biologic failure; steroid-free clinical remission and response were observed in 22.6% and 35.7% of these patients, respectively. Quality of life (Short Health Scale) significantly improved at Week 12 (p\textless0.0001). The majority of adverse events were of mild/moderate intensity.CONCLUSIONS: At Week 12, Adacolumn provided significant clinical benefit in a large cohort of steroid-dependent ulcerative colitis patients with previous failure to immunosuppressant and/or biologic treatment, with a favourable safety profile. These results are consistent with previous studies and support Adacolumn use in this difficult-to-treat patient subgrou

Treat to Target: A Proposed New Paradigm for the Management of Crohn's Disease.

International audience: The traditional management of CD, based on progressive, step-wise treatment intensification with re-evaluation of response according to symptoms, does not improve long-term outcomes of CD and places patients at risk for bowel damage. The introduction of novel therapies and the development of new approaches to treatment in rheumatoid arthritis led to better outcomes for patients. Prominent among these is a "treat to target" strategy that is based on regular assessment of disease activity using objective clinical and biological outcome measures and the subsequent adjustment of treatments. This approach is complementary to the concept of early intervention in high risk patients. This review evaluates current literature on this topic and proposes a definition for the concept treating to targets for Crohn's disease

Optimisation de la prise en charge de la rectocolite hémorragique : de la théorie à la pratique

Ulcerative colitis (UC) is a chronic disabling and relapsing inflammatory disease of the colonic mucosa that for more than half of patients results in chronic intermittent or continuous symptoms of increased stool frequency, fecal urgency and rectal bleeding The aim of the present work was to assess experimental ways and new therapeutic strategies with current treatments to improve long-term outcomes of UC. We focused experimental work on the peroxisome proliferator-activated receptor γ (PPARγ), a key factor of gut homeostasis and a target of mesalamine. The mechanism of primary impaired expression of PPARγ in colonic epithelial cells (CEC) during UC remains unknown. We demonstrated the control of PPARγ expression by intracellular CEC production of cortisol and the lack of cortisol production during UC that may participate towards the decreased expression of PPARγ. Furthermore hypoxia, a driver of mucosal inflammation during UC, markedly decreased PPARγ expression through the over-expression of miR-27a that was reversible by the use of sildenafil. From a clinic point of view, we assessed the efficacy and feasibility of a treat to target strategy which implies treatment optimization to achieve mucosal healing a key factor of long-term outcomes. Finally we addressed the long-term outcomes of patients treated with infliximab including the case of refractory proctitis.La rectocolite hémorragique (RCH) est une maladie inflammatoire chronique de l'intestin responsable d'un handicap et d'une altération de la qualité de vie pouvant exposer les patients à des complications sévères en dépit des thérapeutiques actuelles. L'objectif de cette thèse était d'analyser les voies possibles d'amélioration de la prise en charge thérapeutique des patients à partir de données expérimentales et cliniques. Au niveau expérimentale nous nous sommes intéressés au mécanisme impliqué dans la régulation de l'expression de PPARγ, récepteur nucléaires aux propriétés anti-inflammatoires, primitivement diminuée au cours de la RCH et cible des 5-aminosalicylés. Il a été montré que son expression était d'une part sous le contrôle de la stéroidogenèse intraépithéliale, elle-même sous contrôlée par LRH-1 et d'autre part que l'hypoxie épithéliale diminuait son expression via une sur-expression de miR-27a. Par ailleurs, les effets de l'hypoxie sur l'expression de PPARγ étaient inversés en présence de sildénafil. Sur le versant clinique, l'analyse d'une nouvelle stratégie thérapeutique ciblant la cicatrisation muqueuse, c'est à dire l'abrogation de l'inflammation colique macroscopique était efficace et possible dans la pratique clinique. Cet objectif semble aujourd’hui fondamental pour diminué la morbi-mortalité induite par cette maladie. Enfin nous avons observé l'efficacité des anti-TNF dans le cas spécifique de la rectite réfractaire et l'importance de son utilisation prolongée pour éviter les rechutes de la maladie et l’obtention d’une rémission prolongée

Therapeutic optimization during ulcerative colitis : from bench to clinic

La rectocolite hémorragique (RCH) est une maladie inflammatoire chronique de l'intestin responsable d'un handicap et d'une altération de la qualité de vie pouvant exposer les patients à des complications sévères en dépit des thérapeutiques actuelles. L'objectif de cette thèse était d'analyser les voies possibles d'amélioration de la prise en charge thérapeutique des patients à partir de données expérimentales et cliniques. Au niveau expérimentale nous nous sommes intéressés au mécanisme impliqué dans la régulation de l'expression de PPARγ, récepteur nucléaires aux propriétés anti-inflammatoires, primitivement diminuée au cours de la RCH et cible des 5-aminosalicylés. Il a été montré que son expression était d'une part sous le contrôle de la stéroidogenèse intraépithéliale, elle-même sous contrôlée par LRH-1 et d'autre part que l'hypoxie épithéliale diminuait son expression via une sur-expression de miR-27a. Par ailleurs, les effets de l'hypoxie sur l'expression de PPARγ étaient inversés en présence de sildénafil. Sur le versant clinique, l'analyse d'une nouvelle stratégie thérapeutique ciblant la cicatrisation muqueuse, c'est à dire l'abrogation de l'inflammation colique macroscopique était efficace et possible dans la pratique clinique. Cet objectif semble aujourd’hui fondamental pour diminué la morbi-mortalité induite par cette maladie. Enfin nous avons observé l'efficacité des anti-TNF dans le cas spécifique de la rectite réfractaire et l'importance de son utilisation prolongée pour éviter les rechutes de la maladie et l’obtention d’une rémission prolongée.Ulcerative colitis (UC) is a chronic disabling and relapsing inflammatory disease of the colonic mucosa that for more than half of patients results in chronic intermittent or continuous symptoms of increased stool frequency, fecal urgency and rectal bleeding The aim of the present work was to assess experimental ways and new therapeutic strategies with current treatments to improve long-term outcomes of UC. We focused experimental work on the peroxisome proliferator-activated receptor γ (PPARγ), a key factor of gut homeostasis and a target of mesalamine. The mechanism of primary impaired expression of PPARγ in colonic epithelial cells (CEC) during UC remains unknown. We demonstrated the control of PPARγ expression by intracellular CEC production of cortisol and the lack of cortisol production during UC that may participate towards the decreased expression of PPARγ. Furthermore hypoxia, a driver of mucosal inflammation during UC, markedly decreased PPARγ expression through the over-expression of miR-27a that was reversible by the use of sildenafil. From a clinic point of view, we assessed the efficacy and feasibility of a treat to target strategy which implies treatment optimization to achieve mucosal healing a key factor of long-term outcomes. Finally we addressed the long-term outcomes of patients treated with infliximab including the case of refractory proctitis

Quels choix thérapeutiques pour éviter des changements de lignes répétés chez nos patients ?

National audienceLes maladies inflammatoires de l’intestin (MICI) telles que la maladie de Crohn et la RCH sont caractérisées par une activation incontrôlée des cellules immunitaires intestinales chez un hôte génétiquement sensible. En raison de la nature progressive et destructrice du processus inflammatoire dans les MICI, des complications telles que la fibrose, la sténose ou le cancer sont fréquemment observées, ce qui souligne la nécessité d’un traitement anti-inflammatoire efficace. Des études ont identifié l’altération du trafic des cellules immunitaires et des circuits de cellules immunitaires pathogènes comme des facteurs cruciaux de l’inflammation des muqueuses et de la destruction des tissus dans les MICI. Au-delà de la compréhension de la physiopathologie, le choix des traitements est guidé par leur efficacité selon les données des essais thérapeutiques, leur acceptabilité et leur tolérance, dans le périmètre de leur remboursement Français. L’association de ces critères dans la décision clinique permet de données des pistes pour une persistance thérapeutique optimale

Place des probiotiques dans la rectocolite hémorragique

La rectocolite hémorragique est une maladie inflammatoire chronique de l'intestin qui se caractérise par une inflammation de la muqueuse du rectum et/ou du côlon. Le traitement conventionnel de la RCH représenté par les aminosalicylés, les corticoïdes, et les immunosuppresseurs a ses limites puisqu'il n'est pas toujours bien toléré, ni efficace chez certains patients, de plus la prise en charge de la RCH reste coûteuse. L'étiologie de la RCH n'est pas entièrement élucidée mais il est clairement établi qu'elle résulte d'une réponse anormale du système immunitaire envers la flore intestinale. Dans ce contexte, la recherche s'est intéressée aux probiotiques dont leur rôle est de restaurer la balance microbienne dans le tractus gastro-intestinal et de réduire l'inflammation intestinale. Dans la RCH, les probiotiques ont largement été évalués dans les modèles animaux et dans certains essais cliniques, qui démontrent de potentiels bénéfices thérapeutiquesUlcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal inflammation limited to the rectum and/or the colon. Current medical management represents by aminosalicylates, steroids, and immunosuppressant therapies has such limits since it's not always well tolerated or effective in some patients, in addition health care is expensive. The precise aetiology of ulcerative colitis is still unknown, but it's clearly established that results of an abnormal immune response to environmental factors including the intestinal microbiota. In this context, research focus has been placed on probiotic which aim to restore balance to the gastrointestinal microbiota, and reduce intestinal inflammation. In the UC, probiotics have been assessed extensively in animal models, with a number of clinical trials also demonstrating potential therapeutic benefits.LYON1-BU Santé (693882101) / SudocRENNES1-BU Santé (352382103) / SudocSudocFranceF

Reply to Papamichael, K., & Cheifetz, A. S. (2020). Therapeutic Drug Monitoring and Safety of Anti-Tumor Necrosis Factor Therapy in Inflammatory Bowel Disease. Clinical Gastroenterology and Hepatology

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