Quinze ans d'anti-TNF dans la maladie de Crohn: comment tirer le meilleur de cette revolution therapeutique?
Louis, Edouard ; REENAERS, Catherine ; Meuwis, Marie-Alice et al
in Revue Médicale de Liège (2012), 67 Spec No
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 ... [more ▼]
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. [less ▲]Detailed reference viewed: 167 (14 ULg)
Management of inflammatory bowel disease in pregnancy.
; ; et al
in Journal of Crohn’s and Colitis [=JCC] (2012), 6(8), 811-23
BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a chronic disease affecting mainly young people in their reproductive years. IBD therefore has a major impact on patients' family planning ... [more ▼]
BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a chronic disease affecting mainly young people in their reproductive years. IBD therefore has a major impact on patients' family planning decisions. Management of IBD in pregnancy requires a challenging balance between optimal disease control and drug safety considerations. This article aims to provide a framework for clinical decision making in IBD based on review of the literature on pregnancy-related topics. METHODS: Medline searches with search terms 'IBD', 'Crohn's disease' or 'ulcerative colitis' in combination with keywords for the topics fertility, pregnancy, congenital abnormalities and drugs names of drugs used for treatment of IBD. RESULTS: IBD patients have normal fertility, except for women after ileal pouch-anal anastomosis (IPAA) and men under sulfasalazine treatment. Achieving and maintaining disease remission is a key factor for successful pregnancy outcomes in this population, as active disease at conception carries an increased risk of preterm delivery and low birth weight. Clinicians should discuss the need for drug therapy to maintain remission with their patients in order to ensure therapy compliance. Most IBD drugs are compatible with pregnancy, except for methotrexate and thalidomide. If possible, anti-TNF therapy should be stopped by the end of the second trimester and the choice of delivery route should be discussed with the patient. CONCLUSIONS: Disease control prior to conception and throughout pregnancy is the cornerstone of successful pregnancy management in IBD patients. [less ▲]Detailed reference viewed: 56 (7 ULg)
The c-jun N-terminal Kinase (JNK)-binding Protein (JNKBP1) Acts as a Negative Regulator of NOD2 Protein Signaling by Inhibiting Its Oligomerization Process
Lecat, Aurore ; Di Valentin, Emmanuel ; Somja, Joan et al
in Journal of Biological Chemistry (2012), 287(35), 29213-26
NOD2 is one of the best characterized member of the cytosolic NOD-like receptors (NLR) family. NOD2 is able to sense muramyl dipeptide (MDP), a specific bacterial cell wall component, and to subsequently ... [more ▼]
NOD2 is one of the best characterized member of the cytosolic NOD-like receptors (NLR) family. NOD2 is able to sense muramyl dipeptide (MDP), a specific bacterial cell wall component, and to subsequently induce various signalling pathways leading to NF- kappaB activation and autophagy, both events contributing to an efficient innate and adaptative immune response. Interestingly, loss-of-function nod2 variants were associated with a higher susceptibility for Crohn ' s disease (CD), which highlights the physiological importance of proper regulation of NOD2 activity. We performed a biochemical screen to search for new NOD2 regulators. We identified a new NOD2 partner, c-jun N-terminal kinase binding protein 1 (JNKBP1), a scaffold protein characterized by a N-terminal WD-40 domain. JNKBP1, through its WD-40 domain, binds to NOD2 following MDP activation. This interaction attenuates NOD2-mediated NF-kappaB activation and IL-8 secretion as well as NOD2 antibacterial activity. JNKBP1 exerts its repressor effect by disturbing NOD2 oligomerization and RIP2 tyrosine phosphorylation, both steps required for downstream NOD2 signalling. We furthermore showed that JNKBP1 and NOD2 are co-expressed in the human intestinal epithelium and immune cells recruited in the lamina propria, which suggests that JNKBP1 contributes to maintain NOD2-mediated intestinal immune homeostasis. [less ▲]Detailed reference viewed: 112 (45 ULg)
Safety and cost of infliximab for the treatment of Belgian pediatric patients with Crohn's disease.
; ; et al
in Acta Gastro-Enterologica Belgica (2012), 75(4), 425-31
Biologicals have become an important component in the treatment of Crohn's disease in children. Their increased and long term use raises safety concerns. We describe safety and cost of infliximab in ... [more ▼]
Biologicals have become an important component in the treatment of Crohn's disease in children. Their increased and long term use raises safety concerns. We describe safety and cost of infliximab in Belgian pediatric Crohn's disease patients. All patients on infliximab as part of the present or past treatment for Crohn's Disease until January 1st 2011 were selected from an existing database. Information on disease phenotype, medication and adverse events were extracted. Adverse events occurred in 25.9% of patients exposed to infliximab of which 29.6% were severe. In total 31.7% of patients stopped infliximab therapy. The main reasons for discontinuation were adverse events in 45.4% and loss of response in 30.3%. No malignancies or lethal complications occurred over this 241 patient year observation period. Immunomodulators were concomitant medication in 75% of patients and were discontinued subsequently in 38.4% of them. The cost of infliximab infusions per treated patient per year in the Belgian health care setting is approximately 9 474 euro, including only medication and hospital related costs. Even though infliximab is relatively safe in pediatric CD on the short term, close follow-up and an increased awareness of the possible adverse reactions is highly recommended. Adverse reactions appeared in 25.9% of all patients and were the main reason for discontinuation. Treatment cost has to be balanced against efficacy and modifications in disease course. In the Belgian health care system, the medication is available to all patients with moderate to severe CD. [less ▲]Detailed reference viewed: 35 (8 ULg)
Fast and sharp decrease in calprotectin predicts remission by infliximab in anti-TNF naive patients with ulcerative colitis.
; ; et al
in Journal of Crohn’s and Colitis [=JCC] (2012), 6(5), 557-62
AIM: To evaluate the effect of infliximab induction therapy on calprotectin levels in patients with ulcerative colitis (UC). PATIENTS AND METHODS: In this prospective study 53 patients with active UC from ... [more ▼]
AIM: To evaluate the effect of infliximab induction therapy on calprotectin levels in patients with ulcerative colitis (UC). PATIENTS AND METHODS: In this prospective study 53 patients with active UC from 17 centers were treated with infliximab therapy (5 mg/kg) at baseline, week 2, and week 6. Faecal calprotectin was measured every week. Sigmoidoscopies were performed at baseline, week 6 and week 10. RESULTS: Median calprotectin levels decreased from 1260 (IQR 278.5- 3418) at baseline to 72.5 (IQR 18.5 - 463) at week 10 (p<0.001). After 10 weeks, infliximab therapy induced endoscopic remission and a decrease in calprotectin to<50 mg/kg or at least a 80% decrease from baseline level in 58% of patients. A significant and steep decrease of calprotectin levels was seen at week 2 for patients with an endoscopic remission at week 10 as compared to patients who did not show a remission. (p<0.001). At week 10 an excellent correlation was found between endoscopic remission and clinical Mayo score reflected by an AUC of ROC analyses of 0.94 (0.87-1) and with calprotectin measurements (AUC 0.91 (0.81-1)) : all patients with calprotectin levels <50 mg/kg, and a normal clinical Mayo score (=0) were in endoscopic remission. CONCLUSIONS: Infliximab induces a fast and significant decrease of faecal calprotectin levels in anti-TNF naive patients with ulcerative colitis predictive for remission of disease. [less ▲]Detailed reference viewed: 26 (2 ULg)
Impact of medical therapies on inflammatory bowel disease complication rate.
REENAERS, Catherine ; Belaiche, Jacques ; Louis, Edouard
in World Journal of Gastroenterology (2012), 18(29), 3823-7
Crohn's disease and ulcerative colitis are progressive diseases associated with a high risk of complications over time including strictures, fistulae, perianal complications, surgery, and colorectal ... [more ▼]
Crohn's disease and ulcerative colitis are progressive diseases associated with a high risk of complications over time including strictures, fistulae, perianal complications, surgery, and colorectal cancer. Changing the natural history and avoiding evolution to a disabling disease should be the main goal of treatment. In recent studies, mucosal healing has been associated with longer-term remission and fewer complications. Conventional therapies with immunosuppressive drugs are able to induce mucosal healing in a minority of cases but their impact on disease progression appears modest. Higher rates of mucosal healing can be achieved with anti-tumor necrosis factor therapies that reduce the risk of relapse, surgery and hospitalization, and are associated with perianal fistulae closure. These drugs might be able to change the natural history of the disease mainly when introduced early in the course of the disease. Treatment strategy in inflammatory bowel diseases should thus be tailored according to the risk that each patient could develop disabling disease. [less ▲]Detailed reference viewed: 27 (1 ULg)
Commentary: endoscopic dilatation for stricturing Crohn's disease.
Louis, Edouard ; GAST, Pierrette ; VAN KEMSEKE, Catherine et al
in Alimentary Pharmacology & Therapeutics (2012), 36(5), 494-6Detailed reference viewed: 9 (1 ULg)
What changes in inflammatory bowel disease management can be implemented today?
LOUIS, Edouard ; ; et al
in Journal of Crohn’s and Colitis [=JCC] (2012), 6 Suppl 2
Innovative ideas are required to improve the management of inflammatory bowel disease and to share best practice that can be implemented into clinical practice today. The use of biomarkers such as ... [more ▼]
Innovative ideas are required to improve the management of inflammatory bowel disease and to share best practice that can be implemented into clinical practice today. The use of biomarkers such as calprotectin to monitor disease progression and treatment response could help to improve management of inflammatory bowel disease, but several strategies need to be implemented to make this a reality in clinical practice. The use of calprotectin as a biomarker and the manipulation of the thiopurine pathway to extend the use of current therapies are examples of how basic research can translate into patient benefit. Translational research into the use of microbiota and predictive factors for response and toxicity to drugs, may provide future clinical applications. Global improvement in care in inflammatory bowel disease could also be advanced by improving service provision. For example, the establishment of 'Centres of Excellence', a global interactive inflammatory disease map, and the alignment of processes and standards of care within treatment centres may help to achieve better outcomes for patients with inflammatory bowel disease. Realization of this goal, as well as a better understanding of the aetiology of the disease, may be furthered by collaborative efforts between organizations involved in inflammatory bowel disease as well as wider collaboration across countries and globally. [less ▲]Detailed reference viewed: 106 (2 ULg)
L'asthme: une maladie complexe mettant en jeu facteurs environnementaux et terrain genetique.
LOUIS, Renaud ; SCHLEICH, FLorence ; Corhay, Jean-Louis et al
in Revue Médicale de Liège (2012), 67(5-6), 286-91
Asthma is a complex disease highly dependent of environmental exposure and genetic background. Through linkage analysis, positional cloning and genome wide association studies, novel asthma genes have ... [more ▼]
Asthma is a complex disease highly dependent of environmental exposure and genetic background. Through linkage analysis, positional cloning and genome wide association studies, novel asthma genes have come out such as ADAM-33 or ORMLD3. Important environmental factors include allergenic exposure, pollutants and especially particulate matters, tobacco, aerosol exposure, viral infections and level of exposure to endotoxin. The effects of environmental factors are modulated by the genetic sequence and numerous single nucleotide polymorphisms (SNPs). Recently, it has also become clear that environmental factors may alter gene expression by DNA methylation or histone methylation/acetylation without changing the gene sequence and thereby changing asthmatic phenotype. [less ▲]Detailed reference viewed: 238 (8 ULg)
Epidemiology of the transition from early to late Crohn's disease.
in Digestive Diseases (2012), 30(4), 376-9
Phenotypically, the transition from early to late Crohn's disease is characterized by the occurrence of complications including strictures, intra-abdominal fistulas and perianal fistulas, all of them ... [more ▼]
Phenotypically, the transition from early to late Crohn's disease is characterized by the occurrence of complications including strictures, intra-abdominal fistulas and perianal fistulas, all of them leading to various types of surgeries and currently non-reversible tissue damage. It must, however, be kept in mind that this transition is not at all a uniform and linear process. According to these simple phenotypic criteria, Crohn's disease can already be a late disease at diagnosis while in other patients, it can still be an early disease after 20 years of evolution. This simply highlights the relativity of time in this field, actually reflecting the nature, location and severity of the inflammatory process. The risk over time of the development of these complications has been described, first in cohort studies and then in population-based studies. Globally, at diagnosis, between 19 and 38% only of Crohn's disease patients have complicated Crohn's disease. After 10 years, between 56 and 65% of patients have developed either stricturing or penetrating complications. After 20 years, these numbers are between 61 and 88%. In parallel to these structural changes, changes in the immunobiology of the disease also seem to occur; the latter seem to happen quicker with major modification already within 2 years of the diagnosis. Beside these general figures, important questions remain pending. First, the real timing of these changes is still unclear. Second, the precise role of genetics and environment in the development of these changes remains to be clarified. Third, the correlation between changes in immunobiology and intestinal structural damages has not been specifically studied. [less ▲]Detailed reference viewed: 37 (6 ULg)
Le syndrome de Lynch et l'instabilité des microsatellites : revue de littérature.
; VERSET, Gontran ; POLUS, Marc et al
in Revue Médicale de Liège (2012), 67(12), 638-642Detailed reference viewed: 88 (9 ULg)
Perception gaps between patients with ulcerative colitis and healthcare professionals: an online survey.
; ; LOUIS, Edouard et al
in BMC Gastroenterology (2012), 12(1), 108
ABSTRACT: BACKGROUND: The purpose of this study was to examine the differing perspectives and perceptual gaps relating to ulcerative colitis (UC) symptoms and their management between patients and ... [more ▼]
ABSTRACT: BACKGROUND: The purpose of this study was to examine the differing perspectives and perceptual gaps relating to ulcerative colitis (UC) symptoms and their management between patients and healthcare professionals (HCPs). METHODS: Structured, cross-sectional, Web-based questionnaires designed to assess a variety of disease indices were completed by adult patients with UC and HCPs involved in the care of patients with UC from Canada, France, Germany, Ireland, Spain, and the United Kingdom. RESULTS: Surveys were completed by 775 patients, 475 physicians, and 50 nurses. Patient self-reported classification of disease severity revealed generally greater severity (mild, 32 %; moderate, 53 %) compared with physician and nurse estimates of UC severity among their caseloads (mild, 52 % and 49 %; moderate, 34 % and 37 %, respectively). Patients reported that an average of 5.5 (standard deviation, 11.0) flares (self-defined) occurred over the past year, compared with 3.4 and 3.8 flares per year estimated by physicians and nurses. Perceived flare triggers differed between patients (stress ranked first) and HCPs (natural disease course ranked first). Fifty-five percent of patients stated that UC symptoms over the past year had affected their quality of life, while physicians and nurses estimated that 35 % to 37 % of patients would have a reduced quality of life over the same period. Patients ranked urgency and pain as the most bothersome symptoms, while physicians and nurses ranked urgency and stool frequency highest. About half of patients (47 %) defined remission as experiencing no symptoms; by comparison, 62 % to 63 % of HCPs defined remission as requiring the complete absence of symptoms. HCPs (doctors/nurses in general practice and/or hospital) were regarded by patients as their main source of UC information by 72 %; however, 59 % reported not arranging regular visits to see their HCPs. CONCLUSIONS: This large survey identified important differences between patients' and HCPs' perceptions of the impact of UC symptoms on patients' lives. Notably, HCPs may underestimate the effect of specific UC symptoms on patients and may fail to recognize issues that are important to patients. [less ▲]Detailed reference viewed: 10 (0 ULg)
Adalimumab in ulcerative colitis: can pharmacodynamics be improved based on pharmacokinetics?
LOUIS, Edouard ;
in Gastroenterology (2012), 142(1), 176-8Detailed reference viewed: 33 (2 ULg)
Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease.
; ; et al
in Nature Genetics (2012), 43(11), 1066-73
More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants ... [more ▼]
More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 x 10(-16), odds ratio approximately 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models. [less ▲]Detailed reference viewed: 53 (2 ULg)
Does co-treatment with immunosuppressors improve outcome in patients with Crohn's disease treated with adalimumab?
; LOUIS, Edouard ; Belaiche, Jacques et al
in Alimentary Pharmacology & Therapeutics (2012), 36(11-12), 1040-8
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 ... [more ▼]
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 Liege, 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. [less ▲]Detailed reference viewed: 34 (3 ULg)
Genetique et environnement dans les maladies inflammatoires chroniques de l'intestin.
Louis, Edouard ; VAN KEMSEKE, Catherine ; LATOUR, Pascale et al
in Revue Médicale de Liège (2012), 67(5-6), 298-304
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 ... [more ▼]
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. [less ▲]Detailed reference viewed: 135 (10 ULg)
Development of the paris definition of early Crohn's disease for disease-modification trials: results of an international expert opinion process.
; ; et al
in American Journal of Gastroenterology (2012), 107(12), 1770-6
We report the findings and outputs of an international expert opinion process to develop a definition of early Crohn's disease (CD) that could be used in future disease-modification trials. Nineteen ... [more ▼]
We report the findings and outputs of an international expert opinion process to develop a definition of early Crohn's disease (CD) that could be used in future disease-modification trials. Nineteen experts on inflammatory bowel diseases held an international expert opinion meeting to discuss and agree on a definition for early CD to be used in disease-modification trials. The process included literature searches for the relevant basic-science and clinical evidence. A published preliminary definition of early CD was used as the basis for development of a proposed definition that was discussed at the expert opinion meeting. The participants then derived a final definition, based on best current knowledge, that it is hoped will be of practical use in disease-modification trials in CD. [less ▲]Detailed reference viewed: 43 (3 ULg)
Maintenance of Remission Among Patients With Crohn's Disease on Antimetabolite Therapy After Infliximab Therapy Is Stopped.
Louis, Edouard ; ; et al
in Gastroenterology (2012), 142(1), 63-70531
BACKGROUND & AIMS: It is important to determine whether infliximab therapy can be safely interrupted in patients with Crohn's disease who have undergone a period of prolonged remission. We assessed the ... [more ▼]
BACKGROUND & AIMS: It is important to determine whether infliximab therapy can be safely interrupted in patients with Crohn's disease who have undergone a period of prolonged remission. We assessed the risk of relapse after infliximab therapy was discontinued in patients on combined maintenance therapy with antimetabolites and identified factors associated with relapse. METHODS: We performed a prospective study of 115 patients with Crohn's disease who were treated for at least 1 year with scheduled infliximab and an antimetabolite and had been in corticosteroid-free remission for at least 6 months. Infliximab was stopped, and patients were followed up for at least 1 year. We associated demographic, clinical, and biologic factors with time to relapse using a Cox model. RESULTS: After a median follow-up period of 28 months, 52 of the 115 patients experienced a relapse; the 1-year relapse rate was 43.9% +/- 5.0%. Based on multivariable analysis, risk factors for relapse included male sex, the absence of surgical resection, leukocyte counts >6.0 x 10(9)/L, and levels of hemoglobin </=145 g/L, C-reactive protein >/=5.0 mg/L, and fecal calprotectin >/=300 mug/g. Patients with no more than 2 of these risk factors (approximately 29% of the study population) had a 15% risk of relapse within 1 year. Re-treatment with infliximab was effective and well tolerated in 88% of patients who experienced a relapse. CONCLUSIONS: Approximately 50% of patients with Crohn's disease who were treated for at least 1 year with infliximab and an antimetabolite agent experienced a relapse within 1 year after discontinuation of infliximab. However, patients with a low risk of relapse can be identified using a combination of clinical and biologic markers. [less ▲]Detailed reference viewed: 30 (5 ULg)
Auto-immune gastritis characteristics in a large series of patients with auto-immune thyroiditis.
VALDES SOCIN, Hernan Gonzalo ; ; LUTTERI, Laurence et al
in XXIVth Belgian Week of Gastroenterology 2012 - Abstract book (2012)Detailed reference viewed: 51 (7 ULg)