Long-term evolution and predictive factors of mild inflammatory bowel disease.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are potentially progressive diseases. Few data are available on the prevalence and the factors associated with mild inflammatory bowel diseases (IBD). AIM: Our aim was to assess the natural history of mild CD and mild UC and to identify predictive factors of mild evolution over the long term. METHODS: Retrospective study of IBD patients registered in the database of the university hospital CHU of Liège, Belgium. Mild CD was defined as an inflammatory luminal disease (no stricture, abdominal or perianal fistulae) requiring no immunomodulator (IM), anti-TNF and no surgery. Mild UC was defined as no requirement for IM, anti-TNF and no colectomy. RESULTS: Four hundred and seventy-three CD and 189 UC were included (median follow-up: 13 and 11 years respectively). At 1 year, 147 patients had mild CD. At 5 years and the maximum follow-up, 56% and 13% patients still had mild CD, respectively. At 1 year, 142 patients had mild UC. At 5 years and the maximum follow-up, 72% and 44% still had a mild UC, respectively. Factors associated with long-term mild CD and UC were older age at diagnosis and absence of corticosteroids in the first year. In UC proctitis location was associated with mild UC. CONCLUSIONS: In this cohort, 90% of CD patients and 3/4 of UC with mild disease at 1 year lost their mild disease status over time. An old age at diagnosis was predictive of the persistence of a mild CD and UC.

Persisting signs of disease activity at Magnetic Resonance Enterocolonography predict clinical relapse and disease progression in quiescent Crohn's disease.

INTRODUCTION: Deep remission including clinical remission and tissue healing has been advocated as the therapeutic target in Crohn's disease. Yet, the definition of deep remission remains unclear. The aim of this study was to assess the persisting lesions at magnetic resonance enterocolonography (MREC) in clinically quiescent Crohn's disease as well as their relapse predictive value. METHODS: we performed a prospective monocentre cohort study. We included patients with clinical remission. At baseline, these patients had blood tests, the measurement of fecal calprotectin and underwent a MREC. They were then followed up clinically for a minimum of 1 year. A relapse was defined by a HBI > 4 with an increase of at least 3 points. Correlations between clinical, demographic, biological parameters and MREC signs were assessed as well as the time-to-relapse predictive value of the studied variables. RESULTS: Twenty seven patients were recruited. Fourteen out of 27 had persisting disease activity at MREC. MREC signs only partly correlated with biomarkers. Ten out of 27 patients relapsed over a median follow up of 25 months. In univariate analysis, relative contrast enhancement of the most affected segment (HR: 2.56; P = 0.046), ulcers (HR: 12.5; P = 0.039), fistulas (HR: 14.1; P = 0.009) and target sign (HR: 3.63; P = 0.049) were associated with relapse. In multivariate analysis, fistula was the only one. CONCLUSIONS: Half of the patients with clinically quiescent Crohn's disease had persisting signs of disease activity at MREC. These signs predicted time-to-relapse.

[FROM EVIDENCE-BASED MEDICINE TO PERSONALIZED MEDICINE IN CROHN'S DISEASE]. / DE L'"EVIDENCE-BASED MEDICINE" À LA MÉDECINE PERSONNALISÉE DANS LA MALADIE DE CROHN.

The therapeutic armamentarium in Crohn's disease includes mesalazine, steroids (including topical drugs), anti-metabolites (purines, methotrexate), anti-TNFα antibodies and, more recently, selective inhibitors of lymphocytes homing (vedolizumab). The efficacy of these drugs has been shown in pivotal phase 3 placebo-controlled trials and meta-analyses. However, the use of these drugs in routine practice still remains ill-defined. Those are rather the cohort studies, natural history data and therapeutic strategy trials that help the clinician to determine, for each individual patient, the treatment leading to an optimal benefit/risk profile, aiming at moving from evidence-based medicine towards personalized medicine.

Depth of remission in Crohn's disease patients seen in a referral centre : associated factors and impact on disease outcome.

INTRODUCTION: Our goals were to assess the prevalence of biological and tissue remission in routine practice in Crohn's disease, and to evaluate the correlation between biological or tissue remission and clinical or demographic characteristics as well as their impact on disease outcome. METHODS: We performed a retrospective monocenter study. Biological remission was defined by a CRP < 5 mg/I. Tissue remission was defined by the absence of ulcer at endoscopy and/or absence of signs of acute inflammation at MRI. Association with demographic, clinical and laboratory markers was studied by logistic regression models and rates of relapses, hospitalizations and surgeries were compared using the logrank test. RESULTS: Among the 263 patients included, 147 were in clinical remission; 102/147 (69%) were in biological remission. Fifty-six patients also had morphological evaluation: 37 (66%) were in tissue remission. Biological remission was associated with older age, higher hemoglobin and lower BMI. Tissue remission was associated with older age, lower platelets count, absence of previous surgery, and the use of immunosuppressant. Time-to-relapse was significantly longer in patients with biological remission and in patients with tissue remission as compared to patients without biological or tissue remission. CONCLUSIONS: Among the patients in clinical remission seen as outpatients, two thirds were either in biological and/or tissue remission. Biological and/or tissue remission was associated with a better outcome than clinical remission alone.

Does co-treatment with immunosuppressors improve outcome in patients with Crohn's disease treated with adalimumab?

BACKGROUND: There is clear benefit from combination therapy with infliximab and immunosuppressive drugs (IS), but few data are available for adalimumab (ADA). AIM: To assess the efficacy of ADA monotherapy and ADA+IS for induction and maintenance therapy in Crohn's disease. METHODS: Retrospective study of patients with Crohn's disease treated with ADA in Oxford, UK or Liège, Belgium. Treatment periods were divided into 6-month semesters. A combination therapy semester was defined as ADA+IS for at least 3 months; successful induction meant clinical response; a semester with flare as ADA dose escalation, starting steroids, perianal complication, or surgery; and ADA failure as ADA withdrawal for secondary loss of response or intolerance. Semesters with and without flares were compared through univariate and multivariate analysis. RESULTS: Successful induction was achieved in 171/207 (83%) patients, with no significant difference between ADA+IS and ADA monotherapy (85% vs. 82%, P = 0.50). Five hundred and sixty-two semesters in 181 patients were included for maintenance analysis. ADA+IS was not associated with fewer semesters with flare (34% vs. 35%, P = 0.96), or with ADA failure (6% vs. 8%, P = 0.43). Nevertheless, combination therapy in the first semester was associated with a lower risk of ADA failure (5% vs. 10%, P = 0.04, OR = 0.48) and combination therapy beyond 6 months was associated with fewer semesters with flares (14% vs. 36%, P = 0.02, OR = 0.31). CONCLUSIONS: There may be a benefit from adalimumab+immunosuppressive drugs combination therapy during the first semester of initiating adalimumab, with a slight decrease in adalimumab failure and lower need for adalimumab dosage escalation.

[Genetics and environment in chronic inflammatory bowel diseases]. / Génétique et environnement dans les maladies inflammatoires chroniques de l'intestin.

Inflammatory bowel diseases are both environmental and genetic illnesses. More than one hundred genes or loci involved in the regulation of innate or acquired immune response as well as intestinal mucosa homeostasis have been identified. Environmental studies have been less numerous up to now and only smoking and appendectomy have been validated, as protector for ulcerative colitis, while smoking is clearly associated with an increased risk and more severe forms of Crohn's disease. An important role is also currently suspected for the intestinal flora and the dysbiosis described in inflammatory bowel disease could contribute to the triggering or the persistence of the inflammation. New therapeutic strategies are currently studied, particularly aiming at targeting immune, inflammatory or homeostatic pathways corresponding to the predisposing gene variants.

[Fifteen years of use of anti-TNF antibodies in moderate to severe Crohn's disease: how to make the best of this experience]. / Quinze ans d'anti-TNF dans la maladie de Crohn: comment tirer le meilleur de cette révolution thérapeutique?

After fifteen years of use, the anti-TNF antibodies have become the corner stone of the treatment of moderate and severe Crohn's disease. The skill acquired over the years through experimental trials and clinical experience leads to increased therapeutic efficacy and minimized risks. These antibodies are introduced increasingly earlier in Crohn's disease as well as in a broader range of patients, aiming at changing the natural history of the diseases by avoiding the development of intestinal tissue damage and complications.

Hepatitis C of genotype 2: the role of medical invasive exams.

BACKGROUND AND AIM: Hepatitis C virus genotype 2 is the third in order of frequency in Belgium. The aim of this study was to better define the genotype 2 carriers' epidemiology characteristics. METHODS: In a database comprising 1726 viremic hepatitis C virus patient from the south part of Belgium, the files of 98 genotype 2 carriers were reviewed. RESULTS: There was a strong association between genotype 2 and the mode of transmission. The rate of contamination by invasive medical exams was very high (23%), and statistically different from the one of the others genotypes. Eligibility for antiviral therapies and the rate of sustained viral response were high. CONCLUSION: HCV genotype 2 was highly associated with transmission by invasive medical exams.

Evolution and predictive factors of relapse in ulcerative colitis patients treated with mesalazine after a first course of corticosteroids.

INTRODUCTION: Mesalazine remains the first line treatment for the induction and the maintenance of remission in mild to moderate ulcerative colitis (UC). Its efficacy as a maintenance treatment after a first flare treated with corticosteroids has not been specifically studied. The aims of our work were to study a cohort of UC patients treated with mesalazine after a course of oral systemic corticosteroids and to identify predictive factors of relapse and of colectomy. MATERIAL AND METHOD: We studied retrospectively a cohort of 143 UC patients, who never received immunosuppressive drugs, and treated for the first time with oral corticosteroids for a flare. Among patients responding to corticosteroids, we studied the group treated by mesalazine after the flare. RESULTS: Fifty% (n=52) achieved a complete clinical remission with steroid weaning. In this group, 67% (n=35) received oral mesalazine. Seventy-five % of patients treated by mesalazine relapsed (median 29 months, range: 1-156). Fourteen % required a colectomy (median 11 months, range: 1-24). Kaplan Meier curve showed a relapse rate and a colectomy rate over one year of 26% and 11% respectively. In multivariate analysis, male gender and short duration of disease were predictive factors of the time-to-relapse. No factor was predictive of time-to-colectomy. CONCLUSION: Maintenance efficacy of mesalazine over one year after a first course of corticosteroids for a disease flare is reasonably high. The longer-term relapse rate becomes higher in male patients with a short disease duration. An immunosuppressive treatment could be discussed in case of further relapse despite improved medication-adherence. Medication-adherence should first be assessed and promoted. An immunosuppressive treatment could be discussed in case of further relapse despite improved medication-adherence.

[Clinical case of the month. Cystic lymphangioma of the mesentery]. / Le cas clinique du mois. Le lymphangiome kystique du mésentère.

Cystic lymphangioma of the mesentery is a benign condition, probably of malformative origin, and frequently appearing in infancy. Its symptomatology can be very polymorphic. Its diagnosis is suspected by ultrasonography and computed tomography, and definitely confirmed by pathology. About a recent case of cystic lymphangioma of the mesentery diagnosed and operated on at the university hospital of Liège in an adult patient, the authors review its classification and its therapeutic strategy. Surgical resection is indicated in symptomatic cystic lymphangioma.

[Challenges to reduce mortality due to hepatitis C: improving accessibility to therapy and compliance]. / Défis pour réduire la mortalité liée a l'hepatite C: améliorer l'accessibilité au traitement et l'observance thérapeutique.

Current therapies with pegylated interferon and ribavirin are effective to eradicate the virus C. Improvements are foreseen in the near future with combination of the current treatment with antiviral therapies (antiproteases, antipolymerases). Eradication of the virus, when obtained, has a favorable impact on an individual basis. However, to reduce the mortality related to the virus C at a population level, an important point is the accessibility to therapy. It has been calculated that the impact of current management to reduce mortality is minimal, as compared to the absence of treatment, due to a poor accessibility to therapy. To obtain a significant additional reduction of mortality, a better screening, a better access to the threatment are crucial.

Anti-tumor necrosis factor nonresponders in Crohn's disease: therapeutic strategies.

Anti-TNF antibodies have revolutionized the treatment of Crohn's disease. In pivotal trials, however, the frequencies of primary and secondary nonresponders appeared rather high with, by the end of 1 year of scheduled treatment, only one fifth of the patients initially treated still in sustained remission. Other studies and monocentric experiences have indicated that these seemingly disappointing results were partly due to suboptimal selection of the patients and absence of treatment optimization. Optimal selection of the patient includes proving active intestinal lesions and systemic inflammation as well as excluding stricturing or infectious complications. Treatment optimization includes potential immunosuppressive co-treatment and dose or administration interval adjustment of the anti-TNF. When a failure is confirmed with an anti-TNF despite such optimization, second- or third-line anti-TNFs have proved useful. Beyond that, a transient steroid course and surgical procedures still represent rescue option, waiting for new promising biologics in development.

[Adenocarcinoma of the small intestines complicating coeliac disease in an adult: case report]. / Adénocarcinome de l'intestin grêle compliquant une maladie coeliaque de l'adulte: à propos d'un cas.

Coeliac disease is an auto-immune disease due to gluten intolerance. One per cent of the European population is concerned. This small bowel adenocarcinoma is rare and concerns less than 5% of the digestive neoplasias. However the frequency of this rare cancer is higher in presence of coeliac disease. We are reporting the case of a 67-years-old woman whose coeliac disease has been complicated 5 years thereafter by a jejunal adenocarcinoma. The latter was found during an etiology search for iron deficiency anemia.

[Monoclonal antibodies therapies for colorectal cancer: cétuximab, panitumumab and bevacizumab]. / Apports des anticorps monoclonaux dans le traitement du cancer colorectal: cétuximab, panitumumab et bévacizumab.

Colorectal cancer is the third most common form of cancer in Europe, Its prognosis is poor, since median survival time for metastatic patients is about 20 months. Progresses in molecular biology have lead to significant improvement in the management of metastatic colorectal cancer with targeted therapies. The monoclonal antibodies anti-EGFR and anti-VEGFR improve the overall and the progression-free survival. The anti-EGFR antibodies (cétuximab and panitumumab) have been marketed in Belgium, as monotherapy or in association with chemotherapy (FOLFIRI) for third line use in patients with wild type K-ras. The anti-VEGFR bevacizumab is the standard first line treatment in metastatic colorectal cancer with irinotecan based chemotherapy. For the future, the place of monoclonal antibodies therapies in adjuvant or in first line settings and the value of combining targeted therapies have to be further defined.

[Biologic therapies in chronic inflammatory bowel diseases]. / Thérapies biologiques et maladies inflammatoires chroniques intestinales.

Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases which can be difficult to control with conventional therapies. Thanks to a better knowledge of their physiopathology, new therapies aimed at specific targets of the inflammatory cascade were developed. Three monoclonal anti-TNF antibodies were produced. Infliximab and adalimumab, currently widely used, can induce sustained remission in Crohn's disease. Infliximab is also efficacious in UC. Certolizumab pegol provides good short term results; its long term efficacy, however, remains to be assessed by further clinical trials. Therapies targeting leucocyte trafficking (anti-integrine) have also been provided and are associated with good clinical responses in Crohn's disease. Natalizumab (anti-alpha4) is responsible for significant side effects and is no longer in use in gasrtoenterology in Europe whereas MLN02 (anti-alpha417) has a good profile in terms of efficacy and safety. Monoclonal anti bodies targeting other cytokines are under development, mainly ustekinumab which inhibits IL12 and IL23. Ustekinumab generates favourable clinical responses in Crohn's disease. The development of biologic therapies in inflammatory bowel disease has dramatically altered the course and management of these disorders.

[Treatment of (unresectable) hepatocellular carcinoma at an intermediate or advanced stage]. / Straitement des carcinomes hépatocellulaires à un stade intermédiaire ou avancé.

Hepatocellular carcinoma is the main primitive tumor of the liver. It occurs in the setting of liver cirrhosis in more than 90% of the cases in developing countries. The prognosis depends on the size, number and extension of the tumor as well as on the severity of the underlying liver disease. The Barcelona Clinic Classification takes into account these different parameters and helps the clinician in the therapeutic decision. Some patients (around 25%) are amenable to therapy with a curative intent (liver transplantation, resection, destruction by radiofrequency). In patients with hepatocellular carcinoma at an intermediate stage, lipiodolized chemoembolization gives a survival advantage in comparison with placebo. No conventional regimen of chemotherapy has a proven survival benefit. In patients with a hepatocellular carcinoma at an advanced stage, sorafenib, an oral multi-targeted kinase inhibitor, is the first compound to demonstrate a significant effect on survival free of disease progression in a selected group of patients. Its toxicity profile is particularly favourable. Combination of surgical and medical therapies should be properly evaluated in clinical trials in the near future.

[Colorectal cancer screening: an absolute necessity and a concrete reality in the French community]. / Le dépistage généralisé du cancer colorectal: une absolue nécessité et une réalité imminente en Communauté française.

Colorectal cancer is a real problem of public health. Screening is an absolute necessity. An ambitious program of screening is launched in the French Community. Faecal occult blood test will be proposed to average risk patients in the general population. A total colonoscopy will be performed if FOBT is positive. First step colonoscopy will be proposed to high or very high risk patients. General practitioners are in the core of the multi-disciplinary program.

[Genomics of inflammatory bowel diseases: basis for a new molecular classification and new therapeutic strategies of these diseases]. / Génomique des maladies inflammatoires intestinales. Base pour une nouvelle classification moléculaire de ces maladies et source de nouvelles stratégies thérapeutiques.

Inflammatory Bowel Disease, Crohn's disease and ulcerative colitis, are complex, multifactorial, polygenic diseases. Huge progresses in the knowledge of human genome and genotyping techniques have allowed the identifications of dozens of genes and loci associated with these diseases. These discoveries set the path for a new molecular classification of these diseases and let us see new therapeutic possibilities. The present paper highlights, in the setting of the Synthèse CHU 2009 meeting, the contributions of the team of the CHU and university of Liège in this field.