Role of endoscopy, cross-sectional imaging and biomarkers in Crohn's disease monitoring.
; Meuwis, Marie-Alice ; et al
in Gut (2013), 62(12), 1806-16
Crohn's disease is characterised by recurrent and/or chronic inflammation of the gastrointestinal tract leading to cumulative intestinal tissue damage. Treatment tailoring to try to prevent this tissue ... [more ▼]
Crohn's disease is characterised by recurrent and/or chronic inflammation of the gastrointestinal tract leading to cumulative intestinal tissue damage. Treatment tailoring to try to prevent this tissue damage as well as achieve optimal benefit/risk ratio over the whole disease course is becoming an important aspect of Crohn's disease management. For decades, clinical symptoms have been the main trigger for diagnostic procedures and treatment strategy adaptations. However, the correlation between symptoms and intestinal lesions is only weak. Furthermore, preliminary evidence suggests that a state of remission beyond the simple control of clinical symptoms, and including mucosal healing, may be associated with better disease outcome. Therefore monitoring the disease through the use of endoscopy and cross-sectional imaging is proposed. However, the degree of mucosal or bowel wall healing that needs to be reached to improve disease outcome has not been appropriately studied. Furthermore, owing to their invasive nature and cost, endoscopy and cross-sectional imaging are not optimal tools for the patients or the payers. The use of biomarkers as surrogate markers of intestinal and systemic inflammation might help. Two biomarkers have been most broadly assessed in Crohn's disease: C-reactive protein and faecal calprotectin. These markers correlate significantly with endoscopic lesions, with the risk of relapse and with response to therapy. They could be used to help make decisions about diagnostic procedures and treatment. In particular, with the use of appropriate threshold values, they could determine the need for endoscopic or medical imaging procedures to confirm the disease activity state. [less ▲]Detailed reference viewed: 140 (5 ULg)
Strategic use of immunosuppressants and anti-TNF in inflammatory bowel disease.
in Digestive diseases (Basel, Switzerland) (2013), 31(2), 207-12
Controlled trials and meta-analyses have shown that immunosuppressants are effective in steroid-dependent Crohn's disease (CD) and, although less well demonstrated, ulcerative colitis (UC). It has also ... [more ▼]
Controlled trials and meta-analyses have shown that immunosuppressants are effective in steroid-dependent Crohn's disease (CD) and, although less well demonstrated, ulcerative colitis (UC). It has also been demonstrated that anti-TNF are effective in steroid-dependent and steroid-refractory CD and UC. Anti-TNF can also decrease hospitalization rate and the need for surgery. This seems also to be the case for immunosuppressants. The early use of anti-TNF seems more effective than later use, and early mucosal healing is associated with decreased rate of surgery. On the contrary, early use of purine analogues does not seem to improve outcome in CD. Anti-TNF therapies have been shown superior to immunosuppressants and combination therapy superior to anti-TNF monotherapy in inducing steroid-free remission and mucosal healing. The main strategic questions which remain at this stage include: When to start immunosuppressants or anti-TNF? Is there still a place for immunosuppressant monotherapy? How to optimize anti-TNF? Is it possible to stop anti-TNF? The main justification of immunosuppressant monotherapy is the low cost of this treatment and the possibility of achieving a very stable and long-standing remission in a subset of patients. According to this and provided there is no rapid need for more effective therapy, this treatment could be tried in any inflammatory bowel disease patient not correctly maintained after a course of steroids and 5-aminosalicylic acid. However, the failure to respond to this treatment should be recognized early and a step up to anti-TNF considered. An anti-TNF treatment should be considered early in patients at risk of rapid evolution towards tissue damage and complications. The benefit/risk of the immunosuppressant + anti-TNF combination therapy should be assessed on a case-by-case basis. Anti-TNF treatment should always be fully optimized by adapting dosage and potentially adding an immunosuppressant before considering treatment failure. Treatment de-escalation should only be considered when a long-standing stable remission has been achieved both clinically and biologically. The cost sparing and theoretical decrease in complication risk should be put in perspective with the risk of relapse and disease progression. [less ▲]Detailed reference viewed: 55 (8 ULg)
Consecutive fecal calprotectin measurements to predict relapse in patients with ulcerative colitis receiving infliximab maintenance therapy.
; Louis, Edouard ; et al
in Inflammatory bowel diseases (2013), 19(10), 2111-7
BACKGROUND: This study examined whether fecal calprotectin can be used in daily practice as a marker to monitor patients with ulcerative colitis (UC) receiving infliximab maintenance therapy. METHODS ... [more ▼]
BACKGROUND: This study examined whether fecal calprotectin can be used in daily practice as a marker to monitor patients with ulcerative colitis (UC) receiving infliximab maintenance therapy. METHODS: This prospective multicenter study enrolled adult patients with UC in clinical remission under infliximab maintenance therapy. Fecal calprotectin levels were measured every 4 weeks. Sigmoidoscopies were performed at inclusion and at study end. Relapse was defined as a clinical need for change in treatment or an endoscopic Mayo subscore of >/=2 at week 52. Sustained deep remission was defined as a partial Mayo score <3 at all points and an endoscopic Mayo score 0 at week 52. RESULTS: Full analysis was possible for 87 of 113 included patients with UC (77%). Of these patients, 30 (34.4%) were considered to be in sustained deep remission and 13 (14.9%) to have relapsed. Calprotectin levels in patients with sustained deep remission remained very low (median < 40 mg/kg at all time points). Patients who flared had significantly higher calprotectin levels (median > 300 mg/kg) already 3 months before the flare. Further receiver operator curve analysis suggested that a calprotectin level >300 mg/kg had a reasonable sensitivity (58.3%) and specificity (93.3%) to model flare. Two consecutive calprotectin measurements of >300 mg/kg with 1-month interval were identified as the best predictor of flare (61.5% sensitivity and 100% specificity). CONCLUSIONS: Fecal calprotectin can be used in daily practice to monitor patients with UC receiving infliximab maintenance therapy. Two consecutive measurements >300 mg/kg is more specific than a single measurement for predicting relapse. [less ▲]Detailed reference viewed: 102 (2 ULg)
Serum calprotectin as a biomarker for Crohn's disease.
Meuwis, Marie-Alice ; ; et al
in Journal of Crohn's & colitis (2013), 7(12), 678-83
BACKGROUND AND AIMS: In Crohn's disease, correlation between clinical assessment and disease activity at tissue level is weak. Our aim was to evaluate the value of serum calprotectin as a biomarker for ... [more ▼]
BACKGROUND AND AIMS: In Crohn's disease, correlation between clinical assessment and disease activity at tissue level is weak. Our aim was to evaluate the value of serum calprotectin as a biomarker for Crohn's disease. METHODS: The STORI trial patients (n=115) were studied at baseline, in clinical remission before infliximab withdrawal, or at the time of relapse after infliximab withdrawal. Forty healthy controls were also studied. Serum calprotectin level was measured by ELISA. Data were analyzed through correlation analyses, Kaplan Meier curves and Cox model, using available Crohn's Disease Activity Index (CDAI), Crohn's Disease Endoscopic Index of Severity (CDEIS), fecal calprotectin and C-reactive protein levels (hsCRP). RESULTS: Median serum calprotectin was 8892 ng/mL (range: 410-125,000 ng/mL) in Crohn disease patients as compared with 1318 ng/mL (range: 215.8-3770 ng/mL) in controls (P<0.0001). Serum calprotectin was significantly higher for active disease (median=19,584 ng/mL) than for inactive disease (median=8353 ng/mL) (P<0.0001). Serum calprotectin correlated with hsCRP (r=0.4092, P<0.0001) and CDAI (r=0.4442, P<0.0001), but not with CDEIS, on the contrary to fecal calprotectin (r=0.6458, 0.5515, 0.2577 with P<0.0001, P<0.0001, P=0.019 respectively). In multivariate analysis, serum calprotectin used as a discrete variable (threshold: 5675 ng/ml), appeared complementary to hsCRP (>5 mg/l) and fecal calprotectin (>250 mug/g) to predict relapse after infliximab withdrawal (P=0.0173, 0.0024 and 0.0002; HR: 3.191, 3.561 and 4.120). CONCLUSIONS: As a CD biomarker, serum calprotectin has a similar profile as hsCRP. It is also complementary to fecal calprotectin and hsCRP for prediction of relapse after infliximab withdrawal. [less ▲]Detailed reference viewed: 34 (3 ULg)
Evolving definitions of remission in Crohn's disease.
; ; Louis, Edouard et al
in Inflammatory bowel diseases (2013), 19(8), 1645-53
BACKGROUND: Using clinical symptoms alone to inform treatment decisions in Crohn's disease (CD) may increase the risk of disease progression and complications. Treatment beyond symptoms may offer improved ... [more ▼]
BACKGROUND: Using clinical symptoms alone to inform treatment decisions in Crohn's disease (CD) may increase the risk of disease progression and complications. Treatment beyond symptoms may offer improved outcomes. METHODS: We explore alternative definitions of remission, beyond traditional clinical remission, incorporating more objective parameters of inflammation control, which may support prevention or delay the disease progression. These definitions could serve as a platform for future clinical research, evaluating whether treating beyond symptoms alters the natural history of CD. RESULTS: Proposed definitions may include endoscopic remission (mucosal healing), normalization of serologic or fecal markers of inflammation, and even radiographic remission, in addition to clinical remission (symptom control). Endoscopic remission is the leading candidate for inclusion because it is the best studied. The definition should include considerations for both early and late disease given that in late disease, which may be associated with operation-related symptoms or irreversible bowel damage, symptomatic remission may not achievable. Desired outcomes in early disease are complete absence of symptoms, no disease progression, no complications or disability, and normal quality of life. In late disease, there are stabilization of noninflammatory symptoms, no progression of damage or disability, and improved quality of life. CONCLUSIONS: Over time, we anticipate that a working definition of remission that includes both biological remission and clinical remission will evolve and be evaluated in clinical trials. Our proposed definition is a possible starting point for that evolution. Ultimately, the goal in evolving the definition of remission is to improve the outcomes in patients with CD. [less ▲]Detailed reference viewed: 29 (0 ULg)
Optimising monitoring in the management of Crohn's disease: a physician's perspective.
; ; et al
in Journal of Crohn's & colitis (2013), 7(8), 653-69
Management of Crohn's disease has traditionally placed high value on subjective symptom assessment; however, it is increasingly appreciated that patient symptoms and objective parameters of inflammation ... [more ▼]
Management of Crohn's disease has traditionally placed high value on subjective symptom assessment; however, it is increasingly appreciated that patient symptoms and objective parameters of inflammation can be disconnected. Therefore, strategies that objectively monitor inflammatory activity should be utilised throughout the disease course to optimise patient management. Initially, a thorough assessment of the severity, location and extent of disease is needed to ensure a correct diagnosis, identify any complications, help assess prognosis and select appropriate therapy. During follow-up, clinical decision-making should be driven by disease activity monitoring, with the aim of optimising treatment for tight disease control. However, few data exist to guide the choice of monitoring tools and the frequency of their use. Furthermore, adaption of monitoring strategies for symptomatic, asymptomatic and post-operative patients has not been well defined. The Annual excHangE on the ADvances in Inflammatory Bowel Disease (IBD Ahead) 2011 educational programme, which included approximately 600 gastroenterologists from 36 countries, has developed practice recommendations for the optimal monitoring of Crohn's disease based on evidence and/or expert opinion. These recommendations address the need to incorporate different modalities of disease assessment (symptom and endoscopic assessment, measurement of biomarkers of inflammatory activity and cross-sectional imaging) into robust monitoring. Furthermore, the importance of measuring and recording parameters in a standardised fashion to enable longitudinal evaluation of disease activity is highlighted. [less ▲]Detailed reference viewed: 108 (1 ULg)
Letter: should immunosuppressive therapy be started with adalimumab in Crohn's disease? Authors' reply.
; Louis, Edouard ; Belaiche, Jacques et al
in Alimentary pharmacology & therapeutics (2013), 37(7), 752-3Detailed reference viewed: 17 (0 ULg)
Effects of infliximab therapy on transmural lesions as assessed by magnetic resonance enteroclysis in patients with ileal Crohn's disease.
; ; Louis, Edouard et al
in Journal of Crohn's & colitis (2013), 7(12), 950-7
BACKGROUND AND AIMS: Anti TNF therapy induces mucosal healing in patients with Crohn's disease, but the effects on transmural inflammation in the ileum are not well understood. Magnetic resonance ... [more ▼]
BACKGROUND AND AIMS: Anti TNF therapy induces mucosal healing in patients with Crohn's disease, but the effects on transmural inflammation in the ileum are not well understood. Magnetic resonance-enteroclysis (MRE) offers excellent imaging of transmural and peri-enteric lesions in Crohn's ileitis and we aimed to study its responsiveness to anti TNF therapy. METHODS: In this multi-center prospective trial, anti TNF naive patients with ileal Crohn's disease and with increased CRP and contrast enhanced wall thickening received infliximab 5 mg/kg at weeks 0, 2 and 6, and q8 weeks maintenance MRE was performed at baseline, 2 weeks and 6 months and assessed based on a predefined MRE score of severity in ileal Crohn's Disease. RESULTS: Twenty patients were included; of those, 18 patients underwent MRE at week 2 and 15 patients at weeks 2 and 26 as scheduled. Inflammatory components of the MRE index decreased by >/=2 points and by >/=50% at week 26 (primary endpoint) in 40% and 32% of patients (per protocol and intention to treat analysis, respectively). The MRE index improved in 44% at week 2 and in 80% at week 26. Complete absence of inflammatory lesions was observed in 0/18 at week 2 and 13% (2/15) at week 26. The obstructive elements did not change. Clinical and CRP improvement occurred as early as wk 2, but only CDAI correlated with the MRE index. CONCLUSION: Improvement of MRE occurs from 2 weeks after infliximab therapy onwards and correlates with clinical response but normalization of MRE is rare. [less ▲]Detailed reference viewed: 42 (5 ULg)
Vedolizumab as induction and maintenance therapy for ulcerative colitis.
; ; et al
in The New England journal of medicine (2013), 369(8), 699-710
BACKGROUND: Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis. METHODS: We conducted two integrated randomized, double-blind ... [more ▼]
BACKGROUND: Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis. METHODS: We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. RESULTS: Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P<0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% of patients who continued to receive vedolizumab every 4 weeks were in clinical remission (Mayo Clinic score </=2 and no subscore >1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P<0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups. CONCLUSIONS: Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.). [less ▲]Detailed reference viewed: 36 (2 ULg)
Cancer risk in immune-mediated inflammatory diseases (IMID).
; ; et al
in Molecular cancer (2013), 12(1), 98
Inflammation and cancer have a profound yet ambiguous relationship. Inflammation - especially chronic inflammation - has protumorigenic effects, but inflammatory cells also mediate an immune response ... [more ▼]
Inflammation and cancer have a profound yet ambiguous relationship. Inflammation - especially chronic inflammation - has protumorigenic effects, but inflammatory cells also mediate an immune response against the tumor and immunosuppression is known to increase the risk for certain tumors.This article reviews current literature on the role of inflammation in cancer and the cancer risk in immune-mediated inflammatory diseases (IMIDs). We discuss the effect on cancer risk of different drug classes used in the treatment of IMIDs treatment, including biologicals such as tumor necrosis factor (TNF) inhibitors.Overall cancer incidence and mortality risk are similar to the general population in inflammatory bowel disease (IBD), and slightly increased for rheumatoid arthritis and psoriasis, with risk profiles differing for different tumor types. Increased risk for non-melanoma skin cancer is associated with thiopurine treatment in IBD, with the combination of anti-TNF and methotrexate in rheumatoid arthritis and with PUVA, cyclosporine and anti-TNF treatment in psoriasis. Data on the safety of using biologic or immunosuppressant therapy in IMID patients with a history of cancer are scarce.This review provides clinicians with a solid background to help them in making decisions about treatment of immune-mediated diseases in patients with a tumor history.This article is related to another review article in Molecular Cancer: http://www.molecular-cancer.com/content/12/1/86. [less ▲]Detailed reference viewed: 42 (9 ULg)
le syndrome auto-immun thyrogastrique: ses effets sur les micronutriments et la tumorigénèse gastrique.
VALDES SOCIN, Hernan Gonzalo ; LUTTERI, Laurence ; CAVALIER, Etienne et al
in Revue Médicale de Liège (2013)
Summary : The thyrogastric autoimmune syndrome (TAS) was described in patients in whom the serum cross-reacted both with gastric parietal cells antigens and thyroid antigens. We report two cases ... [more ▼]
Summary : The thyrogastric autoimmune syndrome (TAS) was described in patients in whom the serum cross-reacted both with gastric parietal cells antigens and thyroid antigens. We report two cases illustrating the spectrum of pathogical features of TAS. The first case associates Hashimoto’s thyroiditis and anemia perniciosa,and develops a gastric neuroendocrine tumor during follow up. The second case presents with a Graves’ disease and an autoimmune reversible gastritis, secondary to Helicobacter Pylori. Whereas type III autoimmune polyendocrinopathy is rare, TAS is frequent in our experience. Some 13% (32/240) of patients that we have prospectively followed affected with thyroiditis have also autoimmune gastritis. Helicobacter pylori is clearly implicated in 16% of autoimmune gastritis cases. Infection, malabsorption and gastritis are potentially reversible after bacterial eradication treatment. In the other 84% of gastritis patients, no histological or serological proof of Helicobacter pylori is found. Gastric autoimmunity is then irreversible, leading to gastric severe atrophy, hypochlorhydria and hypergastrinemia. Hypergastrinemia stimulates enterochromaffin cell hyperplasia, possibly progressing c to neuroendocrine tumors. We propose a diagnostic approach to improve the characterization of TAS. We review the literature on the subject and discuss some interesting animal models of infectious gastric autoimmunity [less ▲]Detailed reference viewed: 83 (15 ULg)
Comparison of five serum depletion or fractionation methods applied for clinical biomarkers discovery studies
Mazzucchelli, Gabriel ; Smargiasso, Nicolas ; Baiwir, Dominique et al
Poster (2013)Detailed reference viewed: 46 (16 ULg)
Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
; ; et al
in Nature (2012), 491(7422), 119-24
Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome ... [more ▼]
Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD. [less ▲]Detailed reference viewed: 94 (27 ULg)
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: 159 (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: 54 (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: 33 (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)