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BACKGROUND Complementary and alternative medicine (CAM) use is highly prevalent among inflammatory bowel disease (IBD patients). We assessed whether its use, both for IBD and for general health, influenced adherence to conventional medications. METHODS We enrolled 392 IBD subjects in a prospective cohort study and categorized them as CAM nonusers (38%) and those who used CAM for general health (CAM-GEN, 41%) and for IBD (CAM-IBD, 21%). Their self-reported adherence was measured using the 4-item Morisky Adherence Scale during a median follow-up period of 6.8 months. RESULTS CAM-IBD users were less likely to be adherent to medical therapy than CAM nonusers and CAM-GEN users (70% vs. 84% and 81%, respectively, P < 0.05). Nearly all subjects who were nonadherent reported that it was unintentional (97%), and this did not vary use of CAM. After adjusting for confounders, the adjusted odds ratio for adherence among CAM-IBD relative to CAM nonuser was 0.47 (95% CI, 0.22-0.96). CAM-GEN demonstrated similar adherence to CAM nonusers (adjusted odds ratio, 0.85; 95% CI, 0.44-1.66). CAM-IBD was also less likely than CAM nonusers and CAM-GEN to have improvement in their adherence scores during follow-up (14% vs. 33% and 34%, respectively, P < 0.01). The adjusted odds ratio for improved adherence in CAM-IBD compared with CAM nonusers and CAM-GEN were 0.32 (95% CI, 0.15-0.69) and 0.34 (95% CI, 0.16-0.72), respectively. CONCLUSIONS CAM-IBD, but not CAM-GEN, was associated with lower adherence to IBD medical therapy. A third of CAM nonusers and CAM-GEN improved adherence during the observation period, suggesting a Hawthorne effect.

Paradoxical development of psoriasis in patients on anti-TNF agents has been increasingly reported. The aim was to characterize the prevalence and clinical characteristics of anti-TNF-associated psoriasis in a large cohort of inflammatory bowel disease patients. Medical records of patients with Crohn’s disease or ulcerative colitis treated with anti-TNF therapy at a single, tertiary IBD center were identified between 2004 and 2016. Patients identified as having developed psoriasis while on anti-TNF underwent detailed retrospective review of dermatologic features and changes in IBD treatment prompted by the development of psoriasis. Among 676 patients treated with anti-TNF (infliximab or adalimumab), the incidence of psoriasis was 10.7% (N = 72). Female gender (OR 1.88 [95% CI 1.12–3.17], p = 0.017), stricturing or fistulizing Crohn’s disease (OR 1.83 [95% CI 1.04–3.21], p = 0.036) and upper GI Crohn’s disease (OR 3.03 [95% CI 1.06–8.33], p = 0.039) were associated with psoriasis development. The median time to psoriasis onset was 569 days from initiation of anti-TNF, with onset occurring earlier in patients who developed psoriasis on adalimumab versus infliximab (457 vs. 790.5 days, p = 0.008). Overall, in 15/72 (20.8%), cases, cessation of the anti-TNF was required as a result of psoriasis. Plaque psoriasis was the most common type of psoriatic lesion (75%). Topical corticosteroids were the most common treatment for psoriasis. We report a high incidence of anti-TNF-associated psoriasis that was associated with female gender, foregut disease location, and fistulizing and stricturing disease behavior. More prospective studies and genetic analyses evaluating possible pathophysiologic underpinnings of this problem are needed.

BACKGROUND Data regarding the correlation of histologic and endoscopic healing with fecal calprotectin (FC) are conflicting. We examined how FC levels correlate with histological and endoscopic remission in colonic inflammatory bowel disease. METHODS Fifty-eight patients (23 with colonic Crohn's disease [CD] and 35 with ulcerative colitis [UC]) were included. Clinical activity was assessed by Harvey-Bradshaw index (CD) and Mayo score (UC). Inflammatory activity was assessed by ileocolonoscopy, C-reactive protein, and FC. Clinical remission was defined as Harvey-Bradshaw index ≤ 4 or Mayo score ≤ 2 and mucosal healing as Mayo endoscopic subscore = 0 (UC), and Simple Endoscopic Score-CD

BACKGROUND: Family history provides important information on risk of developing inflammatory bowel disease [IBD], and genetic profiling of first-degree relatives [FDR] of Crohn's disease [CD]- affected individuals might provide additional information. We aimed to delineate the genetic contribution to the increased IBD susceptibility observed in FDR. METHODS: N = 976 Caucasian, healthy, non-related FDR; n = 4997 independent CD; and n = 5000 healthy controls [HC]; were studied. Genotyping for 158 IBD-associated single nucleotide polymorphisms [SNPs] was performed using the Illumina Immunochip. Risk allele frequency [RAF] differences between FDR and HC cohorts were correlated with those between CD and HC cohorts. CD and IBD genetic risk scores [GRS] were calculated and compared between HC, FDR, and CD cohorts. RESULTS: IBD-associated SNP RAF differences in FDR and HC cohorts were strongly correlated with those in CD and HC cohorts, correlation coefficient 0.63 (95% confidence interval [CI] 0.53 - 0.72), p = 9.90 x 10(-19). There was a significant increase in CD-GRS [mean] comparing HC, FDR, and CD cohorts: 0.0244, 0.0250, and 0.0257 respectively [p < 1.00 x 10(-7) for each comparison]. There was no significant difference in the IBD-GRS between HC and FDR cohorts [p = 0.81]; however, IBD-GRS was significantly higher in CD compared with FDR and HC cohorts [p < 1.00 x 10(-10) for each comparison]. CONCLUSION: FDR of CD-affected individuals are enriched with IBD risk alleles compared with HC. Cumulative CD-specific genetic risk is increased in FDR compared with HC. Prospective studies are required to determine if genotyping would facilitate better risk stratification of FDR.

Under immunogenic conditions, both the site of initial Ag exposure and consequent T cell priming in specific draining lymph nodes (LNs) imprint the ensuing immune response with lasting tissue-selective tropism. With respect to immune tolerance, whether the site of tolerance induction leads to compartmentalized or, alternatively, pervasive tolerance has not been formally investigated. Using a murine model of inhalation tolerance, we investigated whether the induction of respiratory mucosal tolerance precludes the development of de novo Th2 sensitization upon subsequent exposure to the same Ag at distant mucosal (gut) and nonmucosal (cutaneous) sites. By tracking the proliferation of CFSE-labeled OVA-TCR transgenic CD4+ T cells upon OVA inhalation in vivo, we defined the site of tolerance induction to be restricted to the thoracic LNs. Expectedly, inhalation tolerance prevented de novo Th2 sensitization upon subsequent exposure to the same Ag at the same site. Importantly, although gut- and skin-draining LNs were not used during tolerance induction, de novo Ag-specific proliferation and Th2 differentiation in these LNs, as well as memory/effector Th2 responses in the gut (allergic diarrhea) and skin (late-phase cutaneous responses) were inhibited upon immunogenic challenge to the same Ag. Interestingly, this pervasive tolerogenic phenotype was not associated with the presence of suppressive activity throughout the lymphatics; indeed, potent suppressive activity was detected solely in the spleen. These data indicate that while inhalation tolerance is selectively induced in local thoracic LNs, its tolerogenic activity resides systemically and leads to pervasive immune tolerance in distant mucosal and nonmucosal sites.

In vivo T cell activation by anti-CD3 monoclonal antibody (mAb) results in intestinal damage characterized by loss of villi and epithelial cell apoptosis. The role of the increased interleukin (IL)-10 released during this process is not clear. We assessed the effects of IL-10 on T cell-induced mucosal damage in vivo using IL-10-deficient C57BL/6 [IL-10 knockout (KO)] mice. IL-10 KO and wild-type C57BL/6 mice were injected with anti-CD3 mAb and observed for diarrhea. Changes in serum cytokine levels were measured by ELISA. Histological changes and epithelial cell apoptosis were analyzed on hematoxylin- and eosin-stained tissue sections. Fas expression on intestinal epithelial cells was assessed by flow cytometry analysis of freshly isolated intestinal epithelial cells. Anti-CD3-treated IL-10 KO mice developed more severe diarrhea, a greater loss of intestinal villi, and an increase in the numbers of apoptotic cells in the crypt epithelium. This difference in IL-10 KO mice was associated with an increase in serum tumor necrosis factor-α and interferon-γ levels and with an increase in Fas expression on fresh, isolated, small intestinal epithelial cells. In addition, the enhanced intestinal tissue damage induced by anti-CD3 in IL-10 KO mice was significantly diminished by treatment with recombinant murine IL-10. Therefore, the lack of IL-10 allowed for an increased T cell-induced intestinal tissue damage, and this was associated with an increase in T cell cytokine release and an increase in epithelial cell Fas expression.

PROBLEM: T cells bearing αβ T cell receptor (TcR) and γδ TcR are present at the fetomaternal interface, and the latter, which express surface activation markers, can react with fetal trophoblast cell antigens. What is the role of these cells? METHOD: Using stress-abortion-prone DBA/2-mated CBA/J and abortion-resistant C57/ B16 mice, αβ, γδ, and CD8 +/- T cell subsets were measured in spleen and uterine decidua. The effect of immunization against abortion and administration of anti-TcR antibody in vivo was examined. Cytokine synthesis was measured by intracellular staining of Brefeldin A-treated cells. RESULTS: Abortion-prone matings showed an unexpected accumulation of γδ T cells beginning in the peri-implantation period and this was suppressed by immunization against abortion. The immunization deleted γδ T cells producing the abortogenic cytokines, TNF-α and γ-interferon, and increased production of the anti-abortive cytokines, IL-10 and transforming growth factor-β2 (TGF-β2). Immunization also boosted the number of αβ T cells which were present in the decidua as early as 2 days after implantation. In vivo injection of GL4 (anti-δ) depleted γδ T cells producing Thl cytokines in the peri-implantation period, and prevented abortions, whereas H57 (anti-β) decreased the number of αβ T cells and led to 100% abortions. CD8 + T cells present in peri-implant decidua before onset of abortions were mostly αβ TcR + , although some were γδ + . Changes in γδ and αβ T cells in pregnancy were most dramatic in uterine tissue. CONCLUSION: Although decidual γδ T cells after formation of a distinct placenta and fetus produce anti-abortive TGF-β2-like molecules and IL-10, prior events can lead to abortion. High local production of TNF-α and γ-interferon develop during the peri-implantation phase because of an excessive increase in the Th1 cytokine + subset of γδ cells; these cytokines may be contributed by other tissues in decidua, and the contribution of bioactive factors by γδ T cells may augment the cytokine pool. In contrast, αβ T cells (which may be inactivated by stress that causes abortions) may mediate the anti-abortive effect of alloimmunization. Alloimmunization involves a shift from a Thl to a Th2 pattern in the γδ T cells in decidua.

Recent advances in gastrointestinal (GI) diseases are a direct result of the rapid development in fundamental research using cellular and molecular biology approaches. These approaches have helped define normal physiological processes of the GI tract and the pathogenesis of disease mechanisms. The Canadian GI research communities are world leaders in contributing to these efforts in all disciplines relevant to GI disease. This success has been achieved by fostering an excellent cohort of graduate and postgraduate research trainees involved in GI research at institutions across Canada. Many of these trainees are funded by the Canadian Association of Gastroenterology (CAG) in collaboration with the Canadian Institutes of Health Research (CIHR), a number of industry partners and the Crohn’s and Colitis Foundation of Canada. In recognition of the value of the Canadian GI trainees outstanding research contributions, and to promote and encourage the continued efforts of the graduate and postgraduate research trainees in basic and clinical sciences, the CAG, in conjunction with AstraZeneca Canada Inc and the CIHR, held the sixth Symposium on Research Topics in Gastrointestinal Disease, October 13 to 15, 2006 (Figure 1). The goal of this meeting was to provide research trainees with an opportunity to informally present their original research, from diverse disciplines, to their peers and to a selection of faculty from across Canada. In this forum, trainees actively participated in the discussions of papers in an open setting. This year’s program consisted of a series of superb presentations describing cutting-edge research with 38 podium scientific presentations of basic and clinical GI-related research, covering mechanisms of gut inflammation, enteric flora and epithelial barrier functions, hormones that modulate gut responses, epithelial and transport mechanisms, pathogens that initiate inflammatory processes and cancer, and gastric ulceration and healing mechanisms. This year’s keynote lecture was given by Dr John Wallace on “Hydrogen sulphide and inflammation: What’s all the stink about?” The emphasis was on the emerging anti-inflammatory role of hydrogen peroxide and how this important information can have potential commercial benefits in the development of therapeutics in inflammatory disorders.

AIM: To determine the test characteristics and the optimal cut-off point for the 13C urea breath test (13C UBT) in a Canadian community laboratory setting.METHODS: Of 2232 patients (mean age ± SD: 51±21 years, 56% female) who completed a 13C UBT, 1209 were tested to evaluate the primary diagnosis of Helicobacter pylori infection and 1023 were tested for confirmation of eradication following treatment. Cluster analysis was performed on the 13C UBT data to determine the optimal cut-off point and the risk of false-positive and false-negative results. Additionally, 176 patients underwent endoscopic biopsy to allow validation of the sensitivity and specificity of the 13C UBT against histology and microbiology using the calculated cut-off point.RESULTS: The calculated cut-off points were 3.09 δ‰ for the whole study population (n=2232), 3.09 δ‰ for the diagnosis group (n=1209) and 2.88 δ‰ for the post-treatment group (n=1023). When replacing the calculated cut-off points by a practical cut-off point of 3.0 δ‰, the risk of false-positive and false-negative results was lower than 2.3%. The 13C UBT showed 100% sensitivity and 98.5% specificity compared with histology and microbiology (n=176) for the diagnosis of active H pylori infection.CONCLUSIONS: The 13C UBT is an accurate, noninvasive test for the diagnosis of H pylori infection and for confirmation of cure after eradication therapy. The present study confirms the validity of a cutoff point of 3.0 δ‰ for the 13C UBT when used in a large Canadian community population according to a standard protocol.

In Crohn's disease, antibiotics are used with variable efficacy, suggesting that some patients are more likely to respond. The aim of this study was to determine whether Crohn's patients with predominant serum antibody reactivity toward bacterial antigens OmpC and/or I2 were more likely to achieve remission with antibiotics. Patients with ileal or ileal with right-sided colonic Crohn's disease were studied in a double-blind trial of budesonide alone or budesonide plus metronidazole and ciprofloxacin. In the budesonide plus metronidazole and ciprofloxacin group, patients with OmpC/I2 predominant profiles had the highest remission rate, whereas the group with no antibody predominant profiles had the lowest rate. In the budesonide group, patients with the OmpC/I2 predominant profile had the lowest remission rate, and the no-antibody group rate was higher. Although not statistically significant, these results support further testing to determine whether predominant serum reactivity to certain bacterial antigens may be a marker for efficacious use of antibiotics.

The Canadian gastrointestinal (GI) research community is a world leader in advancing our understanding of many areas of physiology and pathophysiology relevant to GI disease. These highly successful research programs have created an excellent cohort of graduate and postgraduate research trainees involved in GI research at institutions across Canada. These trainees play an instrumental role in the discoveries and new knowledge that has emerged from their laboratories. Many of them are funded by the Canadian Association of Gastroenterology (CAG) in collaboration with the Canadian Institutes of Health Research (CIHR), the Crohn’s and Colitis Foundation of Canada (CCFC), and a number of industry partners. To recognize the value of the Canadian GI trainees’ outstanding research contributions, and to promote and encourage the continued efforts of the graduate and postgraduate research trainees in basic and clinical sciences, the CAG, CHIR and CCFC held the 11th Symposium on Research Topics in GI diseases on February 22 to 23, 2012 in Montreal, Quebec (in advance of Canadian Digestive Diseases Week [CDDW]). The goal of this meeting was to provide research trainees with an opportunity to informally present their original research from diverse disciplines, to their peers and to a selection of faculty from across Canada. In this forum, trainees actively participated in the discussions of papers in an open setting. This year’s program consisted of a series of superb presentations describing cutting-edge research with 39 podium scientific presentations of basic and clinical gastroenterology-related research, covering GI development, pathogenesis of esophagogastrointestinal inflammation and healing, enteric microbiota and pathogens, including bacteria that promote cancer, and gastric ulceration, enteric nerves, and epithelial transport and barrier function. The addition of a ‘reviewer role’ provided all participants with the opportunity to review another presenter’s abstract (as assigned by the program organizers) in advance of the presentation and to be prepared to ask a question related to the abstract presentation allowing the trainees to function in the ‘session chair role’. The keynote session ‘Developing a translational research program: Perspectives from a Clinician scientist’ was presented by Dr Paul Beck. This year’s career development toolbox session focused on ‘Writing a manuscript’. Dr Catharine Walsh presented a practical talk with key tips that was followed by small group breakout sessions in which trainees were able to begin to implement some of the key points reviewed. This year the program included a combined session and opportunity for interaction with the Scholars and Gastroenterology Residents-in-Training (GRIT) attendees: ‘GI Research: What’s in it for me?’ presented by CAG’s McKenna Lecturer, Dr Richard Hunt. Similar to previous years, a major success of the meeting was that it provided a venue in which trainees could meet their peers from across Canada, develop research skills and initiate collaborations, thus developing contacts for their future research career and the future of Canadian GI research. The majority of participants rated the program as good to excellent, and commented that attendance at the meeting offered great interaction with mentors and trainees. The Research Topics meeting provides a valuable opportunity for young researchers to exchange learning. The CAG is proud to acknowledge its Benefactor Corporate Sponsors: Abbott Canada AstraZeneca Canada Inc Olympus Canada Inc Pentax Canada Inc Janssen Inc Takeda Canada Inc

Introduction: In the last two decades the therapeutic paradigm of Crohn's disease (CD) has changed dramatically thanks to the use of biological drugs. In this scenario, we must consider the pivotal role of tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine, in the pathogenesis and relapse of CD. High levels of TNF-α have been associated with the development of intestinal inflammation in CD and blocking this cytokine with anti-TNF-α molecules may result in mucosal healing. In addition several studies have shown increased TNF-α levels in the serum and in the intestinal mucosa of patients with CD. However, little is known about the course of TNF-α levels and their relationship with disease recurrence in CD patients during maintenance treatment with Adalimumab. Aim: We assessed TNF-α levels in patients with CD who were in maintenance treatment with ADA and correlated them with clinical and endoscopic disease activity. Methods: In this prospective observational cohort study, performed at a single tertiary referral center, 23 [14M/9F; mean age 41 (range 21-66) infliximab-Naive patients with CD in maintenance treatment with ADA were included and followed-up. Blood samples were drawn at standardized time points (i.e. at 6, 12, 18, 24 months and in case of CD relapse) just before ADA injection. Antibodies against ADA (AAA) were measured using an homogenous mobility shift assay (HMSA; Prometheus Lab, San Diego, United States). Blood samples were considered positive for AAA presence if ≥1.7 U/mL. Disease activity was assessed at the same points by means of the Harvey-Bradshaw Index (HBI, remission 16). Moreover, endoscopic activity was assessed at baseline and at the time of relapse by means of CD endoscopic index (CDEIS 5 responder, CDEIS

In chronic inflammatory bowel disease, self-destructive, exaggerated inflammation seems to occur in the absence of a well defined pathogen. However, epidemiological data strongly suggests that development of disease does not depend on endogenous factors alone. In this review, we summarize how a possible role for microbial factors can be reconciled with the current understanding of etiology and pathogenesis of IBD. The data presented does not support that IBD is an infectious disease nor that it is a self-antigen-specific autoimmune disease, however, recent findings increasingly suggest that tissue damage might be caused by a non-specific autoaggressive inflammation which is driven by common, ubiquitous microbial agents derived from the bacterial flora in the intestinal lumen.

Infliximab is highly efficacious in induction as well as maintenance of remission in patients with Crohn's disease (CD). However, the cost and potential serious side-effects is concerning for continuing the medication on a long-term. Primary aim of this meta-analysis was to determine the outcome in patients with CD in whom infliximab was discontinued while in remission. Secondary aim was to assess the results of re-treatment with anti-TNF agents following a relapse and identify the factors associated with a relapse. MethodsWe searched Medline, Scopus, conference proceedings and Google scholar for Infliximab related trials in Crohn's disease. Studies where the information on status of remission prior to discontinuation of infliximab was unclear or the clinical outcome following the discontinuation of infliximab was unavailable were excluded. For studies which provided complete data over at least 3 years, the median remission rate was calculated using Kaplan-Meier method. For studies which provided median remission rate, an average of the remission rates was calculated. ResultsA total of 398 patients in six different studies were included in the final analysis. The average relapse rates over 1st, 2nd, 3rd, 4th and 6th year following the cessation of infliximab were 35%, 48%, 62%, 69% and 76% respectively. The results of Kaplan-Meier analysis for the 4 studies (219 patients) with detailed data over at least 3 years data are given in Table-1. Following relapse, retreatment with infliximab results in remission in 91100% (89 patients). Medication reaction following retreatment with infliximab occurred in only one patient. ConclusionMajority of patients who discontinue infliximab while in remission will relapse and most relapses will occur in first 3 years following cessation of infliximab. Retreatment with infliximab is however favorable and risk of re-treatment reaction is not increased. Kaplan Meier Statistics

Publisher Summary This chapter discusses the interaction of the mucosal immune and peripheral nervous systems. The extensive microanatomical relationships between mast cells and nerves, especially the correlation between the density of these two cell types and the physiological evidence for communication between them, has led to search for growth factors that might sustain both mast cells and nerves. The multitude of different neurotransmitter substances potentially released in mucosal tissues could have a multiplicity of effects on the immune system. The circuitry could be complex, or, perhaps, the delivery of messages from one cell to another could be augmented by local concentration effects such as those seen at the site of release from nerve varicosities. Neuroendocrine complexes have also been described in the lamina propria in the vermiform appendix, and scattered, sparsely granulated neuroendocrine cells have been reported in the gastric mucosa. The complex cellular and molecular circuitry of the in vivo situation might overcome the events observed in vitro . Perhaps changes in vascular permeability and the expression of leukocyte adhesion molecules, which result in the migration of immune cells at a site of injury, may be of considerably more significance than activation of protein synthetic and proliferative pathways, at least in the acute phase.

The subject of mucosal immunity continues to generate considerable interest. It is clear that the presentation of antigen to the nucosa, especially in the form of replicating virus or live attenuated organisms produces a local mucosal immune response. This response is better than if the antigens are presented in other-forms, and certainly better than if they are presented via other routes1–3 . Thus, the experiments performed some fifty years ago on immunization of volunteers against dysentery by oral immunization4 with Shigella organisms, which produced incomplete but definite protection amongst those vaccinate, clearly hold up.

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.