Molecular Endoscopy and in vivo Imaging in Inflammatory Bowel Diseases

Background: Studies in recent years have shown that standard imaging modalities such as endoscopy, ultrasonography or MRI are essential for assessment of gut inflammation in patients with inflammatory bowel diseases (IBDs). In addition, endoscopy plays a pivotal role in the analysis of mucosal healing in these disorders. However, these techniques do not allow a detailed analysis of the molecular pathways driving gut inflammation in IBD patients. Here, we discuss the role of new techniques for the molecular imaging of gut inflammation in IBD with special reference to the prediction of responses to therapy using antibodies to tumor necrosis factor (anti-TNF). Key Messages: Several in vivo imaging studies have been performed in IBD patients before and after anti-TNF therapy. In one study, (99m)Technetium-labeled annexin V was given to patients with active Crohn's disease before and after anti-TNF therapy with infliximab. Subsequently, single-photon emission CT (SPECT) was performed to study the effect of anti-TNF treatment on apoptosis in the intestine during active colitis. This study showed enrichment of technetium signals in the gut of patients who responded to anti-TNF therapy. The findings suggested that anti-TNF treatment induces T-cell apoptosis in vivo and that SPECT imaging can be used for prediction of response to anti-TNF therapy. In another study, fluorescent anti-TNF antibodies (fluorescent adalimumab) were chosen for molecular imaging during confocal laser endomicroscopy in patients with active Crohn's disease. This study revealed that an increase of membrane-bound TNF expressing mucosal immune cells predicts response to subsequent adalimumab therapy. Conclusions: Molecular in vivo imaging is an exciting new field in patients with IBD. It is expected that this field will allow new insights into the pathophysiology of IBD and may be used for personalized medicine in the future

Treatment Perspectives in Crohn’s Disease

Background: Crohn’s disease (CD) is a chronic immune-mediated disorder of the gastrointestinal tract. The pathophysiological understanding of this disease is limited and no curative therapy is available so far. Therefore, most patients require long-lasting or even life-long immunosuppressive therapies for the suppression of symptoms to improve quality of life and reduction of long-term risks. However, in a relevant subgroup of patients, these therapeutic goals cannot be sufficiently attained. Summary: Clinically established therapies in active CD comprise corticosteroids and immunosuppressants such as azathioprine. After the introduction of anti-TNFα (Tumor necrosis factor alpha) antibodies, other biologicals (e.g., vedolizumab and ustekinumab) have also been approved. New drugs in the pipeline like filgotinib, upadacitinib, risankizumab or rifaximin could improve the therapy of CD in the near future. Thus, an individualized therapy management, based on optimal selection of therapeutic agents will become more important. Additionally, the local application of mesenchymal stem cells might be helpful in the management of fistulas. Key Messages: The targeted biological therapeutic agents (anti-TNFα antibodies, vedolizumab, ustekinumab) are well established for therapy in CD. There are several new substances in the pipeline with promising results in phase II trials (filgotinib, rifaximin, risankizumab, upadacitinib). The upcoming extension of the therapeutic arsenal will require methods for an optimized selection of substances, thus enabling a more individualized therapy

Innate and Adaptive Immunity in Inflammatory Bowel Diseases

While barrier function and the effects of the intestinal microbiome have only recently moved into the focus of inflammatory bowel disease research, the role of the innate and the adaptive immune system in these gastrointestinal disorders has extensively been studied. Although still not completely understood, the increasing knowledge about the immune system's contribution to the pathophysiology of inflammatory bowel diseases has led to new diagnostic and therapeutic approaches. This review gives a compact overview on this important topic

Functional Contribution and Targeted Migration of Group-2 Innate Lymphoid Cells in Inflammatory Lung Diseases: Being at the Right Place at the Right Time

During the last decade, group-2 innate lymphoid cells (ILC2s) have been discovered and successfully established as crucial mediators of lung allergy, airway inflammation and fibrosis, thus affecting the pathogenesis and clinical course of many respiratory diseases, like for instance asthma, cystic fibrosis and chronic rhinosinusitis. As an important regulatory component in this context, the local pulmonary milieu at inflammatory tissue sites does not only determine the activation status of lung-infiltrating ILC2s, but also influences their motility and migratory behavior. In general, many data collected in recent murine and human studies argued against the former concept of a very strict tissue residency of innate lymphoid cells (ILCs) and instead pointed to a context-dependent homing capacity of peripheral blood ILC precursors and the inflammation-dependent capacity of specific ILC subsets for interorgan trafficking. In this review article, we provide a comprehensive overview of the so far described molecular mechanisms underlying the pulmonary migration of ILC2s and thereby the numeric regulation of local ILC2 pools at inflamed or fibrotic pulmonary tissue sites and discuss their potential to serve as innovative therapeutic targets in the treatment of inflammatory lung diseases

Confocal Laser Endomicroscopy for Diagnosis of Barrett’s Esophagus

Barrett’s esophagus (BE) is established as a premalignant condition in the distal esophagus. Current surveillance guidelines recommend random biopsies every 1–2 cm at intervals of 3–5 years. Advanced endoscopic imaging of BE underwent several technical revolutions within the last decade including broad-field (red-flag) techniques (e.g., chromoendoscopy) and small-field techniques with confocal laser endomicroscopy (CLE) at the forefront. In this review we will focus on advanced endoscopic imaging using CLE for the diagnosis and characterization of BE and associated neoplasia. In addition, we will critically discuss the technique of CLE and provide some tricks and hints for the daily routine practice of CLE for diagnosis of BE

Emerging oral targeted therapies in inflammatory bowel diseases: opportunities and challenges

To improve quality of life and prevent long-term risks in patients with inflammatory bowel diseases (IBDs: Crohn’s disease, ulcerative colitis), it is essential to suppress inflammatory activity adequately. However, corticosteroids are only suitable for therapy of acute flares and the evidence for positive effects of immunosuppressive substances like azathioprine or 6-mercapropurine is mainly limited to maintenance of remission. In addition, only subgroups of patients benefit from biologicals targeting tumour necrosis factor α or α4β7 integrins. In summary, until now the disease activity is not sufficiently controlled in a relevant fraction of the patients with IBD. Thus, there is an urge for the development of new substances in the therapy of ulcerative colitis and Crohn’s disease. Fortunately, new oral and parenteral substances are in the pipeline. This review will focus on oral substances, which have already passed phase II studies successfully at this stage. In this article, we summarize data regarding AJM300, phosphatidylcholine (LT-02), mongersen, ozanimod, filgotinib and tofacitinib. AJM300 and ozanimod were tested in patients with ulcerative colitis and target lymphocyte trafficking through inhibition of the α subunit of integrin, respectively binding to the sphingosine-1-phosphate receptor (subtypes 1 and 5) on lymphocytes. Mongersen was utilized in patients with Crohn’s disease and accelerates the degradation of SMAD7 mRNA, which consequently strengthens the mainly anti-inflammatory signalling pathway of transforming growth factor β1. Various Janus kinase (JAK) inhibitors were developed, which inhibit the intracellular signalling pathway of cytokines. For example, the JAK1 blocker filgotinib was tested in Crohn’s disease, whereas the JAK1/3 inhibitor tofacitinib was tested in clinical trials for both Crohn’s disease and ulcerative colitis. A different therapeutic approach is the substitution of phosphatidylcholine (LT-02), which might recover the colonic mucus. Taken together, clinical trials with these new agents have opened avenues for further clinical studies and it can be expected that at least some of these agents will be finally approved for clinical therapy

Treatment Perspectives in Crohn’s Disease

Background: Crohn’s disease (CD) is a chronic immune-mediated disorder of the gastrointestinal tract. The pathophysiological understanding of this disease is limited and no curative therapy is available so far. Therefore, most patients require long-lasting or even life-long immunosuppressive therapies for the suppression of symptoms to improve quality of life and reduction of long-term risks. However, in a relevant subgroup of patients, these therapeutic goals cannot be sufficiently attained. Summary: Clinically established therapies in active CD comprise corticosteroids and immunosuppressants such as azathioprine. After the introduction of anti-TNFα (Tumor necrosis factor alpha) antibodies, other biologicals (e.g., vedolizumab and ustekinumab) have also been approved. New drugs in the pipeline like filgotinib, upadacitinib, risankizumab or rifaximin could improve the therapy of CD in the near future. Thus, an individualized therapy management, based on optimal selection of therapeutic agents will become more important. Additionally, the local application of mesenchymal stem cells might be helpful in the management of fistulas. Key Messages: The targeted biological therapeutic agents (anti-TNFα antibodies, vedolizumab, ustekinumab) are well established for therapy in CD. There are several new substances in the pipeline with promising results in phase II trials (filgotinib, rifaximin, risankizumab, upadacitinib). The upcoming extension of the therapeutic arsenal will require methods for an optimized selection of substances, thus enabling a more individualized therapy

Novel Small Molecules in IBD: Current State and Future Perspectives

Biologicals have dominated the therapeutic scenery in inflammatory bowel diseases (IBDs), namely ulcerative colitis (UC) and Crohn’s disease (CD), for the past 20 years. The development of tofacitinib was the starting point for an era of small molecules after the era of biologicals. These new agents may challenge the use of biological agents in the future. They share properties that appeal to both patients and physicians. Low production costs, a lack of immunogenicity, and ease of use are only some of their benefits. On the other hand, patients and their physicians must manage the potential side effects of small molecules such as JAK inhibitors or S1P1R modulators. Here, we present agents that have already entered the clinical routine and those that are still being investigated in clinical trials

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