Predicting Therapeutic Response by in vivo Molecular Imaging in Inflammatory Bowel Diseases

Background: Different invasive and non-invasive imaging modalities are indispensable tools in the management of inflammatory bowel disease (IBD) patients. Standard imaging procedures like white light endoscopy or MRI are used to define gut inflammation based on structural changes and altered morphology of the mucosa. Nevertheless, it has thus far not been possible to analyse biological processes at the cellular level, which drive intestinal inflammation in IBD patients. The recent advent of molecular imaging in the field of IBD has opened new promising avenues to allow personalized medicine approaches based on in vivo-detected molecular findings. Key Messages: Recent clinical studies have attempted to address the issue of predicting therapeutic response to anti-tumor necrosis factor (TNF) treatment in IBD patients based on the molecular mechanism of action of these agents and corresponding in vivo assessment of mucosal immune responses. Several experimental studies have indicated that one of the main functions of efficacious anti-TNF therapy in IBD is the induction of intestinal cell apoptosis. Fittingly, a corresponding molecular-imaging study using single-photon emission CT for the localization and quantification of cell apoptosis, demonstrated that induction of mucosal T-cell apoptosis correlated with the therapeutic response to anti-TNF therapy in Crohn's disease patients. There was moreover a predictive capacity regarding therapeutic efficacy. As the main biological properties of anti-TNF antibodies in IBD are mediated through binding to membrane-bound TNF (mTNF) expressing intestinal cells, another study used molecular imaging for in vivo visualization of these cells via fluorescent anti-TNF antibodies to predict therapeutic efficacy of these agents. It could be shown that patients with high amounts of mTNF positive cells showed significantly better response rates compared to patients with low amounts of mTNF positive cells. Conclusion: In vivo molecular imaging in IBD has the potential to have an impact on our current treatment approaches and may allow us to individualize specific therapies based on molecular level analysis

Current and Future Targets for Mucosal Healing in Inflammatory Bowel Disease

The induction and subsequent maintenance of mucosal healing has emerged as one of the central therapeutic goals in the management of patients with inflammatory bowel disease (IBD) (Crohn's disease and ulcerative colitis). Current and novel treatment options are assessed regarding their therapeutic efficacy on the basis of their ability to induce mucosal healing. However, there is still substantial debate about the precise definition of mucosal healing. Here, we will give an overview regarding the definitions of mucosal healing as well as its probable effects on long-term disease behavior and finally focus on current and potential therapeutic targets to achieve this therapeutic goal in IBD patients

Tumour Necrosis Factor Alpha in Intestinal Homeostasis and Gut Related Diseases

The intestinal epithelium constitutes an indispensable single-layered barrier to protect the body from invading pathogens, antigens or toxins. At the same time, beneficial nutrients and water have to be absorbed by the epithelium. To prevent development of intestinal inflammation or tumour formation, intestinal homeostasis has to be tightly controlled and therefore a strict balance between cell death and proliferation has to be maintained. The proinflammatory cytokine tumour necrosis factor alpha (TNFα) was shown to play a striking role for the regulation of this balance in the gut. Depending on the cellular conditions, on the one hand TNFα is able to mediate cell survival by activating NFκB signalling. On the other hand, TNFα might trigger cell death, in particular caspase-dependent apoptosis but also caspase-independent programmed necrosis. By regulating these cell death and survival mechanisms, TNFα exerts a variety of beneficial functions in the intestine. However, TNFα signalling is also supposed to play a critical role for the pathogenesis of inflammatory bowel disease (IBD), infectious diseases, intestinal wound healing and tumour formation. Here we review the literature about the physiological and pathophysiological role of TNFα signalling for the maintenance of intestinal homeostasis and the benefits and difficulties of anti-TNFα treatment during IBD

Blockade of αEβ7 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo

Objective: Therapeutically targeting lymphocyte adhesion is of increasing relevance in IBD. Yet, central aspects of the action of anti-adhesion compounds are incompletely understood. We investigated the role of αEβ7 and α4β7 integrins and their blockade by vedolizumab and etrolizumab for trafficking of IBD T lymphocytes in an in vivo model of homing to and retention in the inflamed gut. Design: We explored integrin expression in IBD patients by flow cytometry and immunohistochemistry, while regulation of integrins was studied in T cell cultures. The functional relevance of integrins was assessed by adhesion assays and a recently established humanized mouse model in DSS-treated immunodeficient mice. Results: High expression of αEβ7 was noted on CD8+ and CD4+ Th9 cells, while α4β7 was expressed on CD8+, Th2 and Th17 cells. TCR stimulation and TGF-β were key inducers of αEβ7 on human T cells, while butyric acid suppressed αEβ7. In comparison to α4β7 blockade via vedolizumab, blockade of β7 via etrolizumab surrogate antibody superiorly reduced colonic numbers of CD8+ and Th9 cells in vivo after 3 hours, while no difference was noted after 0.5 hours. AEβ7 expression was higher on CD8+ T cells from IBD patients under vedolizumab therapy. Conclusion: AEβ7 is of key relevance for gut trafficking of IBD CD8+ T cells and CD4+ Th9 cells in vivo and mainly retention might account for this effect. These findings indicate that blockade of αEβ7 in addition to α4β7 may be particularly effective in intestinal disorders with expansion of CD8+ and Th9 cells such as IBD

Internal Hernia Through Foramen of Winslow a Rare Cause of Small Bowel Obstruction: A Case Report

Internal hernia through foramen of Winslow (FoW) is rare condition as there are only 200 cases reported so far in the literature. Our patient a 78 years man presented with a clinical picture suggestive of small bowel obstruction for 5 days. Patient underwent emergency laparotomy following suspicion of internal hernia on imaging. On exploratory laparotomy there was grossly dilated bowel loops and a small segment of terminal ileum and omentum was found herniating through FoW in to the lesser sac. The bowel segment was reduced with gentle traction and herniated segment of omentum was excised due to questionable viability. Opening of FoW was unusually large and to prevent hernia recurrence it was closed partially. Postoperative period was uneventful. This unusual case presented to us diagnostic confusion and management challenge considering the previous history, multiple comorbidities and geriatric profile

Role of the IL23/IL17 Pathway in Crohn’s Disease

Crohn’s disease (CD) is a chronic relapsing disorder of the gastrointestinal tract and represents one of the main entities of inflammatory bowel disease (IBD). CD affects genetically susceptible patients that are influenced by environmental factors and the intestinal microbiome, which results in excessive activation of the mucosal immune system and aberrant cytokine responses. Various studies have implicated the pro-inflammatory cytokines IL17 and IL23 in the pathogenesis of CD. IL23 is a member of the IL12 family of cytokines and is able to enhance and affect the expansion of pathogenic T helper type 17 (Th17) cells through various mechanisms, including maintenance of Th17 signature genes, upregulation of effector genes or suppression of repressive factors. Moreover, IL17 and IL23 signaling is able to induce a cascade of pro-inflammatory molecules like TNF, IFNγ, IL22, lymphotoxin, IL1β and lipopolysaccharide (LPS). Here, IL17A and TNF are known to mediate signaling synergistically to drive expression of inflammatory genes. Recent advances in understanding the immunopathogenetic mechanisms underlying CD have led to the development of new biological therapies that selectively intervene and inhibit inflammatory processes caused by pro-inflammatory mediators like IL17 and IL23. Recently published data demonstrate that treatment with selective IL23 inhibitors lead to markedly high response rates in the cohort of CD patients that failed previous anti-TNF therapy. Macrophages are considered as a main source of IL23 in the intestine and are supposed to play a key role in the molecular crosstalk with T cell subsets and innate lymphoid cells in the gut. The following review focuses on mechanisms, pathways and specific therapies in Crohn’s disease underlying the IL23/IL17 pathway

Endoscopic Therapy in Inflammatory Bowel Diseases

Background: Endoscopy is an essential diagnostic and therapeutic modality in the clinical care of inflammatory bowel disease (IBD) patients. Endoscopic therapy can be used for treatment of disease-related strictures, surveillance and resection of intraepithelial neoplasia, and treatment of fistulas or disease-related complications, and is currently being evaluated regarding its capacity in in vivo molecular imaging procedures. Methods: A literature search using Medline and Science Citation Index was performed in March 2015. All studies on endoscopic therapy in IBD published from 1980 to 2015 (March) were reviewed. Potential studies were initially screened by title and abstract. The terms ‘endoscopy IBD', ‘endoscopy therapy IBD', ‘dilatation IBD', ‘strictureplasty Crohn's disease', ‘endoscopy therapy fistula', ‘endoscopy toxic megacolon', ‘endoscopy dysplasia IBD', ‘endoscopy complications IBD', and ‘molecular imaging IBD' were used in the search. A total of 115 articles were studied to construct this review. Results: Dilatation is most useful in short anastomotic strictures, but can be also undertaken in colonic strictures. Strictures in ulcerative colitis are always suspicious for neoplasia and should be evaluated carefully. Lesions with intraepithelial neoplasia can be resected when complete removal can be assured. The finding of carcinoma or high-grade dysplasia in a random biopsy is an indication for colectomy. If intraepithelial neoplasia is present in random biopsy specimens, colectomy should similarly be recommended. Endoscopic therapy of Crohn's fistulas is a possible emerging technology. In vivo molecular imaging is currently being studied in IBD patients and offers promising therapeutic opportunities. Conclusion: Therapeutic endoscopy is indispensable in the management of IBD. It has to be carefully evaluated against alternative surgical options but often offers an effective therapeutic approach

Advanced Endoscopic Imaging for Diagnosis of Crohn's Disease

Endoscopy in IBD has tremendous importance to diagnose inflammatory activity, to evaluate therapeutic success and for the surveillance of colitis associated cancer. Thus it becomes obvious that there is a need for new and more advanced endoscopic imaging techniques for better characterization of mucosal inflammation and early neoplasia detection in IBD. This paper describes the concept of advanced endoscopic imaging for the diagnosis and characterization of Crohn's disease, including magnification endoscopy, chromoendoscopy, balloon-assisted enteroscopy, capsule endoscopy, confocal laser endomicroscopy, and endocytoscopy

anti tnf biosimilars in crohn s disease a patient centric interdisciplinary approach

ABSTRACTIntroduction: The purpose of this review is to highlight the role of biosimilars in early treatment in IBD and introduce ways to facilitate a patient-centric switching process through multi..