SARS-CoV-2 antibody vaccine response in Inflammatory Bowel Disease patients with positive anti-nucleocapsid serology or history of COVID-19 infection.

Background: Previous history of COVID-19 infection is a natural booster of the vaccine response in the general population. The response to COVID-19 vaccines is lessened in Inflammatory Bowel Disease patients on selected class of immunosuppressive treatments. Aims: The study was to assess anti-SARS-CoV-2 spike-specific IgG antibody response in Inflammatory Bowel Disease patients with a history of COVID-19 infection. Patients and methods: This single-center prospective study involved 504 Inflammatory Bowel Disease patients. Demographic data and clinical data were gathered through questionnaires and patient charts. Anti-SARS-CoV-2 spike-specific and antinucleocapsid antibody levels were measured at T1, T2 (after the 2-dose series), and T3 or T4 (booster vaccine). Results: This study included 504 Inflammatory Bowel Disease patients, and 234 completed one year follow-up with blood tests. Positive anti-nucleocapsid serology or history of COVID-19 infection was significantly associated with increased median anti- SARS-CoV-2 spike-specific IgG titers after the 2-dose series (1930 BAU/mL vs. 521 BAU/mL p < 0.0001) and the booster vaccine (4390 BAU/mL vs. 2160 BAU/mL, p = 0.0156). Multivariate analysis showed that higher anti-SARS-CoV-2 spike-specific IgG levels were independently associated with anti-nucleocapsid antibodies at T2 (OR=2.23, p < 0.0001) and T3 (OR=1.72, p = 0.00011). Immunosuppressive treatments did not impact the antibody response or levels in patients with a history of COVID-19 infection or positive anti-nucleocapsid serology. Conclusions: In Inflammatory Bowel Disease, prior COVID-19 infection or positive anti-nucleocapsid serology leads to increased anti-SARS-CoV-2 spike-specific IgG levels after vaccination, regardless of immunosuppressive treatments. This emphasizes the significance of accounting for previous infection in vaccination approaches.

Gastric endometriosis associated with transverse colon endometriosis: a case report of a very rare event.

Gastric endometriosis is a very rare event. It enters in the differential diagnosis of cyclical or chronic epigastric pain, especially in the context of endometriotic patients. The diagnosis of a gastric submucosal mass requires further investigations to rule out the presence of malignancy or associated adenocarcinoma. Because of it can be associated with transverse colon endometriosis and/or diaphragmatic endometriosis, careful examination of the upper abdomen at laparoscopy should be emphasized. We report here a very rare case of gastric endometriosis associated with transverse colon endometriosis.

Fast and sharp decrease in calprotectin predicts remission by infliximab in anti-TNF naïve patients with ulcerative colitis.

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 naïve patients with ulcerative colitis predictive for remission of disease.

Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study.

BACKGROUND: Induction chemotherapy has been suggested to impact on preoperative chemoradiation efficacy in locally advanced rectal cancer (LARC). To evaluate in LARC patients, the feasibility and efficacy of a short intense course of induction oxaliplatin before preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS: Patients with T2-T4/N+ rectal adenocarcinoma were randomly assigned to arm A-preoperative CRT with 5-fluorouracil (5-FU) continuous infusion followed by surgery-or arm B-induction oxaliplatin, folinic acid and 5-FU followed by CRT and surgery. The primary end point was the rate of ypT0-1N0 stage achievement. RESULTS: Fifty seven patients were randomly assigned (arm A/B: 29/28) and evaluated for planned interim analysis. On an intention-to-treat basis, the ypT0-1N0 rate for arms A and B were 34.5% (95% CI: 17.2% to 51.8%) and 32.1% (95% CI: 14.8% to 49.4%), respectively, and the study therefore was closed prematurely for futility. There were no statistically significant differences in other end points including pathological complete response, tumor regression and sphincter preservation. Completion of the preoperative CRT sequence was similar in both groups. Grade 3/4 toxicity was significantly higher in arm B. CONCLUSIONS: Short intense induction oxaliplatin is feasible in LARC patients without compromising the preoperative CRT completion, although the current analysis does not indicate increased locoregional impact on standard therapy.

Familial adenomatous polyposis: clinical presentation, detection and surveillance.

Colorectal cancer (CRC) is a leading cause of cancer related death in the western countries. It remains an important health problem, often under-diagnosed. The symptoms can appear very late and about 25% of the patients are diagnosed at metastatic stage. Familial adenomatous polyposis (FAP) is an inherited colorectal cancer syndrome, characterized by the early onset of hundred to thousands of adenomatous polyps in the colon and rectum. Left untreated, there is a nearly 100% cumulative risk of progression to CRC by the age of 35-40 years, as well as an increased risk of various other malignancies. CRC can be prevented by the identification of the high risk population and by the timely implementation of rigid screening programs which will lead to special medico-surgical interventions.

[Genetics of inflammatory bowel disease]. / Génétique des maladies inflammatoires intestinales.

Inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), result from an inappropriate immune response towards the microbial flora in a genetically susceptible host. Several epidemiological and animal studies have demonstrated the essential role of the microbial flora in the triggering and perpetuation of intestinal inflammation. IBD are multigenic and heterogeneous diseases, and result from multiple low penetrant genes or group of genes. The genetic strategy for gene hunting in multigenic studies relies on two separate approaches. A candidate gene approach which is based on a robust biological hypothesis. A more systematic/global approach is either based on linkage studies (in late 90s) on IBD families or, since 2000 on gene arrays, the genome wide arrays (GWAS) on patients and controls. In 2001, the first CD susceptible gene, NOD2, was discovered, and found to be a pattern recognition receptor for bacteria, shedding light on the role of bacterial recognition in the triggering of the disease. Since 2000, GWAs have greatly accelerated the discoveries of new genes or signalling pathways in Crohn's disease and ulcerative colitis, confirming the importance of bacterial recognition, but also of bacterial defence (i.e. autophagy genes) as well as the role of the adaptive immune response (i.e. IL-23R/Th17 pathway). Despite the role of genetics in the development of IBD, changes in the development and composition of the microbial flora, known as dysbiosis, (possibly induced by our Western life style) must alter the development and function of the mucosal immune system, and leads to disease expression.

[Organized colorectal screening in French Community of Belgium and polyp surveillance]. / Le dépistage organisé du cancer colorectal en Communauté française de Belgique et surveillance des polypes.

Colorectal cancer is an important health care problem in Belgium and screening is now widely recommendend. The French Community has launched in March 2009, a campaign to build public and professional awareness of the importance of screening for colorectal cancer. With the goal of encouraging all persons age 50 to 74 to actively gain information and seek screening with the active participation of their house doctors, the campaign will work to clarify any myths or fears about screening options and ensure that the importance of screening and early detection will be understood. The program in the French Community propose guaiac-based fecal occult blood testing for average risk people and, in case of positivity a colonoscopy must be performed. A high quality colonoscopy should be offered first in case of significant personal and familial history of adenomas, colorectal cancer and some specific extracolonic neoplasia. Several strategies will be used to ensure follow up of this program and encourage wide participation of the population.

An inhibitor of interleukin-6 trans-signalling, sgp130, contributes to impaired acute phase response in human chronic liver disease.

In chronic liver disease, high circulating interleukin (IL)-6 contrasts with a poor acute phase response. We evaluated the impact of liver and circulating IL-6-receptor (IL-6R) forms on IL-6 bioactivity in chronic liver disease. IL-6, soluble IL-6-receptor and sgp130 levels were assayed in plasma from 45 patients with alcoholic liver disease, 84 with hepatitis C virus (HCV) infection undergoing transjugular liver biopsies and 15 healthy subjects. IL-6R mRNA was quantified on liver extracts from 54 patients with alcoholic liver disease with or without cirrhosis and 18 HCV-infected patients. The effect of gp130-Fc on fibrinogen secretion induced by IL-6 trans-signalling was evaluated on hepatocyte cultures. Levels of plasma IL-6 and sgp130, but not soluble IL-6R, increased with the stage of chronic liver disease, and correlated significantly with disease severity. Alcoholic liver disease patients had higher plasma IL-6 levels than hepatitis C, but lower liver IL-6R expression. In alcoholic and HCV-related liver diseases, liver IL-6R expression decreased with advanced fibrosis stage. In vitro, on hepatocytes, gp130-Fc blunted the acute phase response while soluble IL-6R enhanced IL-6 stimulation. In advanced chronic liver disease, high plasma IL-6 is associated with low liver IL-6R expression. This situation enables high plasma sgp130 to act as a major negative regulator of liver IL-6 trans-signalling, as demonstrated functionally here on hepatocytes. This might explain the poor acute phase response induced by IL-6 in chronic liver disease.

L-carnitine, a diet component and organic cation transporter OCTN ligand, displays immunosuppressive properties and abrogates intestinal inflammation.

Allele variants in the L-carnitine (LCAR) transporters OCTN1 (SLC22A4, 1672 C --> T) and OCTN2 (SLC22A5, -207 G --> C) have been implicated in susceptibility to Crohn's disease (CD). LCAR is consumed in the diet and transported actively from the intestinal lumen via the organic cation transporter OCTN2. While recognized mainly for its role in fatty acid metabolism, several lines of evidence suggest that LCAR may also display immunosuppressive properties. This study sought to investigate the immunomodulatory capacity of LCAR on antigen-presenting cell (APC) and CD4+ T cell function by examining cytokine production and the expression of activation markers in LCAR-supplemented and deficient cell culture systems. The therapeutic efficacy of its systemic administration was then evaluated during the establishment of colonic inflammation in vivo. LCAR treatment significantly inhibited both APC and CD4+ T cell function, as assessed by the expression of classical activation markers, proliferation and cytokine production. Carnitine deficiency resulted in the hyperactivation of CD4+ T cells and enhanced cytokine production. In vivo, protection from trinitrobenzene sulphonic acid colitis was observed in LCAR-treated mice and was attributed to the abrogation of both innate [interleukin (IL)-1beta and IL-6 production] and adaptive (T cell proliferation in draining lymph nodes) immune responses. LCAR therapy may therefore represent a novel alternative therapeutic strategy and highlights the role of diet in CD.

Predicting relapse in Crohn's disease: a biopsychosocial model.

BACKGROUND: Crohn's disease (CD) is a chronic relapsing inflammatory bowel disorder. Both biological and psychosocial factors may modulate the illness experience. AIM: The aim of this study was to identify clinical, biological and psychosocial parameters as predictors of clinical relapse in quiescent CD. METHODS: Patients in medically induced remission were followed prospectively for 1 year, or less if they relapsed. Disease characteristics were determined at baseline. Serum cytokines, anti-Saccharomyces cerevisiae antibodies, C-reactive protein (CRP), erythrocyte sedimentation rate and intestinal permeability were measured every 3 months. Psychological distress, perceived stress, minor life stressors and coping strategies were measured monthly. A time-dependent multivariate Cox regression model determined predictors of time to relapse. RESULTS: 101 patients (60 females, 41 males) were recruited. Fourteen withdrew and 37 relapsed. CRP (HR = 1.5 per 10 mg/l, 95% CI 1.1 to 1.9, p = 0.007), fistulising disease (HR = 3.2, 95% CI, 1.1 to 9.4, p = 0.04), colitis (HR = 3.5 95% CI 1.2 to 9.9, p = 0.02) and the interaction between perceived stress and avoidance coping (HR = 7.0 per 5 unit increase for both scales, 95% CI 2.3 to 21.8, p = 0.003) were predictors of earlier relapse. CONCLUSIONS: In quiescent CD, a higher CRP, fistulising disease behaviour and disease confined to the colon were independent predictors of relapse. Moreover, patients under conditions of low stress and who scored low on avoidance coping (ie, did not engage in social diversion or distraction) were least likely to relapse. This study supports a biopsychosocial model of CD exacerbation.

Review and clinical perspectives for the use of infliximab in ulcerative colitis.

Infliximab is a chimeric, monoclonal anti-tumour necrosis factor-alpha antibody. It has been previously demonstrated to be an effective treatment for patients with Crohn's disease who do not achieve the desired response with conventional treatments. Although the etiology of ulcerative colitis (UC) differs from that of Crohn's disease, randomized controlled trials have demonstrated that infliximab is also beneficial for the treatment of moderate to severe UC in patients who are either intolerant of or refractory to immunosuppressant agents or steroids, or those who are steroid-dependent. A review of the literature is followed by practical recommendations regarding infliximab that address the needs of clinicians and UC patients. Where there is a lack of evidence-based information, the expert panel provides its combined opinion derived from the members' clinical experiences.

The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases.

The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P=0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P=0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P=0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway - in this case, TLR4 and its signaling molecule TIRAP - plays a role in susceptibility to IBD.

Profile of soluble cytokine receptors in Crohn's disease.

INTRODUCTION: Soluble cytokine receptors (sCRs) modulate the in vivo activity of cytokines. Deficient sCR production could participate in the pathogenesis and course of Crohn's disease (CD). The aim of the study was to examine the profile of sCRs in CD patients and their modulation by infliximab and corticosteroids. METHODS: We prospectively examined active CD patients (aCD) treated with either infliximab (n = 21) or corticosteroids (n = 9), CD patients in clinical remission (rCD, n = 20), ulcerative colitis patients (UC, n = 24), and healthy subjects (HS, n = 15). Cultures of colonic biopsies were also examined from CD inflamed (n = 8), CD non-inflamed (n = 7), and healthy mucosa (n = 8). Levels of tumour necrosis factor alpha (TNF-alpha), soluble TNF receptor I (sTNFRI), soluble TNF receptor II (sTNFRII), interleukin 1beta (IL-1beta), soluble IL-1 receptor I (sIL-1RI), soluble IL-1 receptor II (sIL-1RII), IL-6, soluble IL-6 receptor (sIL-6R), and sgp130 were measured using ELISA. RESULTS: Higher levels of sTNFRI (p<0.05, p<0.01), sTNFRII (p<0.01, p<0.01), sIL-1RI (p<0.05, NS), IL-6 (p<0.01, p<0.01), and sIL-6R (p<0.05, NS) were observed in aCD compared with rCD and HS. Interestingly, sIL-1RII (p<0.05, p<0.01) and sgp130 (p<0.01, p<0.01) were profoundly decreased in aCD compared with rCD and HS, and were negatively correlated with CRP. Deficient production of sIL-1RII was specific to CD (not observed in ulcerative colitis), and was further confirmed at the mucosal level. Infliximab decreased sTNFRII at one and four weeks (p<0.05) and enhanced sIL-6R levels at one week (p<0.05). Corticosteroids increased sIL-1RII levels at one week (p<0.05). CONCLUSION: CD is associated with dysregulated production of sCRs. Deficiency in sIL-1RII and sgp130 may be essential to CD pathogenesis. Their replacement through the use of fusion proteins could represent future alternative therapeutic strategies for CD.

Rapid improvement of bone metabolism after infliximab treatment in Crohn's disease.

BACKGROUND: Crohn's disease is associated with low bone mineral density and altered bone metabolism. AIM: To assess the evolution of bone metabolism in Crohn's disease patients treated with infliximab. METHODS: We studied 71 Crohn's disease patients treated for the first time with infliximab for refractory Crohn's disease. Biochemical markers of bone formation (type-I procollagen N-terminal propeptide, bone-specific alkaline phosphatase, osteocalcin) and of bone resorption (C-telopeptide of type-I collagen) were measured in the serum before and 8 weeks after infliximab therapy and compared with values in a matched healthy control group. RESULTS: Eight weeks after treatment with infliximab, a normalization of bone markers was observed with a median increase in formation markers of 14-51% according to marker and a lower but significant decrease in resorption marker (median 11%). A clinically relevant increase in bone formation markers was present in 30-61% of patients according to the marker. A clinically relevant decrease in C-telopeptide of type-I collagen was present in 38% of patients. No association was found with any tested demographic or clinical parameter. CONCLUSION: Infliximab therapy in Crohn's disease may rapidly influence bone metabolism by acting either on bone formation or bone resorption. This improvement seems to be independent of clinical response to infliximab.

Overview of the actions of glucocorticoids on the immune response: a good model to characterize new pathways of immunosuppression for new treatment strategies.

Glucocorticoids have been used for over 50 years in the treatment of inflammatory and autoimmune diseases and in preventing graft rejection. Today, knowledge of their molecular, cellular, and pharmacological properties allows a better understanding of glucocorticoid-mediated immunosuppression. Glucocorticoids exert both negative and positive effects with a dynamic and bi-directional spectrum of activities on various limbs and components of the immune response. They modulate genes involved in the priming of the innate immune response, while their actions on the adaptive immune response are to suppress cellular (Th1) immunity and promote humoral (Th2) immunity. Interestingly, glucocorticoids can also induce tolerance to specific antigens by influencing dendritic cell maturation and function and promoting the development of regulatory high IL-10-producing T cells. The ex vivo therapeutic use of glucocorticoids could therefore represent an adjuvant treatment to cell therapy in autoimmune diseases, avoiding the long-term deleterious adverse effects of glucocorticoids. Thus, the panoramic view of glucocorticoid actions on the immune system provides an interesting model for characterizing important biological pathways of immunosuppression.

Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis.

BACKGROUND AND AIMS: Elicitation of an innate immune response to bacterial products is mediated through pattern recognition receptors (PRRs) such as the toll-like receptors (TLRs) and the NODs. The recently characterised Asp299Gly polymorphism in the lipopolysaccharide (LPS) receptor TLR4 is associated with impaired LPS signalling and increased susceptibility to Gram negative infections. We sought to determine whether this polymorphism was associated with Crohn's disease (CD) and/or ulcerative colitis (UC). METHODS: Allele frequencies of the TLR4 Asp299Gly polymorphism and the three NOD2/CARD15 polymorphisms (Arg702Trp, Gly908Arg, and Leu1007fsinsC) were assessed in two independent cohorts of CD patients (cohort 1, n = 334; cohort 2, n = 114), in 163 UC patients, and in 140 controls. A transmission disequilibrium test (TDT) was then performed on 318 inflammatory bowel disease (IBD) trios. RESULTS: The allele frequency of the TLR4 Asp299Gly polymorphism was significantly higher in CD (cohort 1: 11% v 5%, odds ratio (OR) 2.31 (95% confidence interval (CI) 1.28-4.17), p = 0.004; and cohort 2: 12% v 5%, OR 2.45 (95% CI 1.24-4.81), p = 0.007) and UC patients (10% v 5%, OR 2.05 (95% CI 1.07-3.93), p = 0.027) compared with the control population. A TDT on 318 IBD trios demonstrated preferential transmission of the TLR4 Asp299Gly polymorphism from heterozygous parents to affected children (T/U: 68/34, p = 0.01). Carrying polymorphisms in both TLR4 and NOD2 was associated with a genotype relative risk (RR) of 4.7 compared with a RR of 2.6 and 2.5 for TLR4 and NOD2 variants separately. CONCLUSION: We have reported on a novel association of the TLR4 Asp299Gly polymorphism with both CD and UC. This finding further supports the genetic influence of PRRs in triggering IBD.

Newly developed Barrett's esophagus after subtotal esophagectomy.

BACKGROUND AND STUDY AIMS: More detailed information regarding the early mucosal events that lead to intestinal metaplasia would be very beneficial for understanding the pathogenesis of Barrett's esophagus (BE). Gastroesophageal reflux and duodenogastroesophageal reflux play a major role in the pathogenesis of Barrett's esophagus. The aim of this study was to investigate the prevalence of newly developed BE in patients who had previously undergone a subtotal esophagectomy - a clinical condition characterized by the absence of a lower esophageal sphincter and massive gastroesophageal reflux. PATIENTS AND METHODS: A retrospective examination was carried out on all patients who underwent subtotal esophagectomy (n = 87) listed in our institution's computer files from 1995 to 2000. Twenty-one patients were excluded due to missing data or no upper gastrointestinal endoscopy after surgery. RESULTS: Based on the Savary-Miller classification, 47 patients developed either type I (n = 2), II (n = 8), III (n = 11) or IV (n = 26) esophagitis after surgery. Newly developed BE was observed in nine patients (13.5 %) after subtotal esophagectomy (median time to diagnosis: 489 days, range 43 - 1172). None of the patients had persistent BE immediately after surgery, and two of the patients with newly developed BE had had no history of BE before surgery or at the time of surgery. Proton-pump inhibitor therapy after surgery and neoadjuvant chemotherapy did not appear to influence the development of BE after subtotal esophagectomy. CONCLUSIONS: Newly developed BE after subtotal esophagectomy may provide further insights into the early mucosal events that lead to intestinal metaplasia and into the roles of gastroesophageal and duodenoesophageal reflux in the pathogenesis of BE.