[Biosimilars in inflammatory bowel disease]. / Biosimilars in der Behandlung chronisch entzündlicher Darmerkrankungen.

After the expiry date of the patent protection for Infliximab in 2013, the biosimilar CT­P13 was approved for indications in Crohn's disease and ulcerative colitis in adults as well as in children. The approval has been based on two randomized clinical studies indicating equivalence for the biosimilar with regard to pharmacokinetics, efficacy, as well as side-effects. The clinical experience since, in addition to multiple non-randomized studies, indicate a comparable efficacy and immunogenicity of the Infliximab biosimilar CT-P13 in inflammatory bowel disease. Thus, the introduction of the biosimilar as primary therapy seems to be justified. Tight monitoring of the safety of biosimilars with regard to efficacy and side effects has to be ensured.

Investigating the role of proinflammatory CD16+ monocytes in the pathogenesis of inflammatory bowel disease.

Infiltrating monocytes and macrophages contribute to the initiation and perpetuation of mucosal inflammation characteristic for human inflammatory bowel disease (IBD). Peripheral blood monocytes expressing the low-affinity Fcgamma receptor CD16 have been identified previously as a major proinflammatory cell population, based on their unique cytokine secretion profile. However, the contribution of these cells to the pathogenesis of inflammatory bowel disease remains to be elucidated. Thus, in this study we investigated whether the peripheral CD16(+) monocyte count correlates with common IBD disease parameters, and whether these cells infiltrate the intestinal mucosa under inflammatory conditions. We observed that CD16(+) peripheral blood monocytes are increased significantly in active Crohn's disease, particularly in patients with high Crohn's disease activity index and colonic involvement. Furthermore, we found that CD16(+) cells are a major contributor to the inflammatory infiltrate in Crohn's disease mucosa, although their spontaneous migration through primary human intestinal endothelial cells is limited. Our data suggest that lamina propria, but not peripheral blood, CD16(+) monocytes are a crucial proinflammatory cell population in IBD, and a potential target for anti-inflammatory therapy.

CCR6 identifies lymphoid tissue inducer cells within cryptopatches.

The chemokine receptor CCR6 is expressed by dendritic cells, B and T cells predominantly within the organized structures of the gut-associated lymphatic tissue. Its ligand CCL20 is synthesized by the follicle-associated epithelium and is crucial for the development of M cells within Peyer's patches. In addition, lineage-negative c-kit positive lymphocytes within cryptopatches (CP) express CCR6. CCR6-deficient mice exhibit an altered intestinal immune system containing increased amounts of intraepithelial lymphocytes and show smaller Peyer's patches, while progression of cryptopatches to mature isolated lymphoid follicles (ILF) is inhibited. In this report, we show that lin(-) c-kit(+) lymphocytes express a variety of different chemokine receptors and that CCR6 identifies those cells located within CP. In contrast, cells found outside CP are positive for CXCR3 and exhibit a different surface marker profile, suggesting that at least two different populations of lin(-) c-kit(+) cells are present. The presence of CCR6 does not influence the expression of Notch molecules on lin(-) c-kit(+) cells, nor does it influence Notch ligand expression on bone marrow-derived dendritic cells. In the human gut, CCR6 identifies clusters of lymphocytes resembling murine CP. CCR6 seems to have an important role for lin(-) c-kit(+) cells inside CP, is expressed in a regulated manner and identifies potential human CP.

Inflammatory Bowel Disease Management During the COVID-19 Outbreak: The Ten Do's and Don'ts from the ECCO-COVID Taskforce.

Our knowledge of COVID-19 is changing and evolving rapidly, with novel insights and recommendations, almost on a daily basis. It behooves the medical community to provide updated information on a regular basis, on best practice to facilitate optimal care of infected patients and on appropriate advice for the general population. This is particularly important in the case of patients with chronic conditions, such as inflammatory bowel disease [IBD]. In this review, we have compiled existing evidence on the impact of COVID-19 in IBD patients and provide guidance on the most appropriate care to adopt during the pandemic. Our review highlights that IBD, per se, is not a risk factor for COVID-19. However, all IBD patients with symptoms should be tested for SARS-CoV-2 and the procedures for disease management should be carefully adapted: [i] in SARS-CoV-2-positive IBD patients, medical treatments should be re-evaluated [with a particular focus on corticosteroids] always with the purpose of treating active disease and maintaining remission; [ii] non-urgent surgeries and endoscopic procedures should be postponed for all patients; [iii] online consultancy should be implemented; and [iv] hospitalization and surgery should be limited to life-threatening situations.

CD4+ T cells transfer resistance against Citrobacter rodentium-induced infectious colitis by induction of Th 1 immunity.

Citrobacter rodentium induces an acute, self-limited colitis in mice which is histologically associated with crypt hyperplasia. The infection serves as a model for human infectious colitis induced by enteropathogenic Escherichia coli. We investigated if Balb/c mice, which had spontaneously cleared C. rodentium infection, were protected against re-infection and if resistance against intestinal infection can be systemically transferred using spleen cells. The course of infection was monitored by faecal excretion. Spleen cells, splenic CD3+ and CD4+ cells were transferred from resistant mice to non-infected recipients prior to infection. Cytokine secretion, serum and faecal antibody titres and histological disease severity were assessed. Balb/c mice were resistant against re-infection. The course of infection was shorter in mice receiving primed spleen cells, CD3+ and CD4+ cells. Transfer of CD4+ T cells from resistant mice induced gamma-interferon, interleukin (IL)-2 and IL-17 secretion and suppressed IL-10 secretion. Anti-Citrobacter serum IgG1 and IgG2a enzyme-linked immunosorbent assay OD levels were increased. Faecal IgA secretion was increased while serum IgA was suppressed in recipients of CD4+ cells. Large bowel histology showed protection from colitis in recipients of primed cells as indicated by normal colonic epithelium. In Balb/c mice, C. rodentium infection is followed by resistance, which can be transferred by CD4+ cells. Transfer of protection is associated with IL-17 secretion, enhanced serum IgG and faecal IgA secretion. This is the first study to demonstrate the mechanisms by which systemic resistance from previously C. rodentium-infected mice can be transferred to non-infected animals.

Carbon dioxide insufflation improves intubation depth in double-balloon enteroscopy: a randomized, controlled, double-blind trial.

BACKGROUND AND STUDY AIMS: Double-balloon enteroscopy (DBE) has been proven effective for deep intubation of the small bowel. However, intubation depth is limited by distention of the small bowel due to air insufflation during the procedure. The present trial investigated whether carbon dioxide (CO (2)) instead of standard air insufflation would improve intubation depth during DBE, as well as reduce postprocedure pain. PATIENTS AND METHODS: One hundred and twelve consecutive patients scheduled for DBE at two centers were randomly assigned to either CO (2) or air insufflation during DBE. Patients and endoscopists were blinded with regard to the type of gas used. Intubation depth was registered using a validated form. Patients scored pain and discomfort during and after the examination on a 100-mm visual analog scale. RESULTS: One hundred patients were eligible for data analysis (48 in the CO (2) group and 52 in the air group). The mean small-bowel intubation depth was extended by 30 % in the CO (2) group compared to the air group (230 vs. 177 cm, P = 0.008). The superiority was most pronounced for oral DBE, with a 71-cm improvement in intubation depth when using CO (2) (295 cm in the CO (2) group vs. 224 cm in the air group, P < 0.001). Patient pain and discomfort were significantly reduced in the CO (2) group at 1 and 3 hours after the examination. CONCLUSIONS: CO (2) insufflation significantly extended intubation depth in DBE. CO (2) insufflation also reduces patient discomfort. CO (2) insufflation may lead to a higher diagnostic and therapeutic yield of DBE, with reduced patient discomfort.

Complications of double balloon enteroscopy: a multicenter survey.

BACKGROUND AND STUDY AIMS: Double balloon enteroscopy (DBE) is a new technique for the visualization of the small bowel. Although the technique is widely used, little is known about the complications. A few complications have been reported in the literature, mainly in case reports. The aim of this study was to establish the complication rate of both diagnostic and therapeutic DBE. PATIENTS AND METHODS: A total of 10 centers (nine academic centers and one teaching hospital) across four continents participated in the study. Complications were defined according to the literature. A therapeutic DBE was defined as a DBE with use of argon plasma coagulation, a polypectomy snare, injection of fluids (other than ink for marking), removal of foreign body, or balloon dilation. RESULTS: A total 85 adverse events were reported in 2362 DBE procedures. In all, 40 events fulfilled the definition of a complication, 13 in 1728 diagnostic DBE (0.8 %) and 27 during 634 therapeutic procedures (4.3 %). The complications were rated minor in 21 (0.9 %), moderate in 6 (0.3 %) and severe in 13 procedures (0.6 %). No fatal complications were reported. Seven cases of pancreatitis were reported, six after diagnostic (0.3 %) and one after therapeutic (0.2 %) DBE. CONCLUSIONS: Diagnostic DBE is safe with a low complication rate. The complication rate of therapeutic DBE is high compared with therapeutic colonoscopy. The reason for this is unclear. The incidence of pancreatitis after DBE is low (0.3 %), but has to be considered in patients with persistent abdominal complaints after a DBE procedure.

Crucial role of the melanocortin receptor MC1R in experimental colitis.

BACKGROUND AND AIMS: alpha-Melanocyte stimulating hormone (alpha MSH) is known to exert anti-inflammatory effects, for example in murine DSS (dextran sodium sulphate induced) colitis. The anti-inflammatory functions of alpha MSH are mediated by the melanocortin1-receptor (MC1R) in an autoregulatory loop. The aim of this study was therefore to determine whether a breakdown of the alpha MSH-MC1R pathway leads to worsening of disease. METHODS: Experimental colitis was induced in mice with a frameshift mutation in the MC1R gene (MC1Re/e), C57BL/6 wild type mice, and MC1Re/e-C57BL/6 bone marrow chimeras. The course of inflammation was monitored by weight loss, histological changes in the colon, and myeloperoxidase activity. In addition, MC1R expression was analysed in intestinal epithelial cells. RESULTS: While the colon of untreated MC1Re/e appeared normal, the course of DSS-colitis in MC1Re/e mice was dramatically aggravated, with a significantly higher weight loss and marked histological changes compared to C57BL/6WT. The inflammation eventually led to death in all MC1Re/e, while all C57BL/6WT survived. Similar observations were detected in a transmissible murine colitis model induced by Citrobacter rodentium. Infected MC1Re/e showed delayed clearance of infection. To determine whether missing haematopoietic cell expressed MC1R was responsible, DSS colitis was induced in MC1Re/e-C57BL/6 bone marrow chimeras. MC1Re/e mice receiving MC1R+ bone marrow showed a similar course of inflammation to non-transplanted MC1Re/e. Likewise, transplantation of MC1R bone marrow into C57BL/6WT mice did not lead to any worsening of disease. CONCLUSIONS: This is the first study to show a functional role of MC1R in intestinal inflammation. The data suggest a pivotal role of non-haematopoietic cell expressed MC1R in the host's response to pathogenic stimuli.

Characterization of idiotype-specific I-Ed-restricted T suppressor lymphocytes which confine immunoglobulin class expression to IgM in the anti-alpha (1- > 3) Dextran B 1355 S response of BALB/c mice.

The humoral immune response of conventionally raised BALB/c mice to the so-called "thymus independent" antigen alpha (1- > 3) Dextran B 1355 S (Dex) is predominantly of the IgM class. The response is further characterized by Igha allotype linkage and the dominance of the public idiotypes (Id) J558 and MOPC 104. In germfree raised BALB/c and in BALB/c nu/nu mice immunized with the same antigen an additional IgG response of the public Id is observed. Analysis of the regulation of the class expression reveals existence of specific Ts cells in euthymic mice which must have been activated pre- or perinatally by exposure to environmental bacterial antigens. They permit or enforce differentiation of Dex-specific B cells into B gamma memory cells without allowing further development into IgG producing plasma cells. An analogue of these splenic Ts cells has now been cloned and identified as an I-Ed restricted Id-specific T cell with exactly the properties ascribed above to the splenic Ts cells. This paper describes phenotypical and functional properties of the Ts cell clone 178-4. It evaluates this clone's role in controlling efficient anti-bacterial IgM-mediated immunity under conditions where a class switch to IgG antibody production is actively suppressed; possibly as a measure to avoid hazardous autoimmune reactions on the basis of crossreaction and antigenic mimicry between polysaccharide antigens.

Characterization of M cell development during indomethacin-induced ileitis in rats.

BACKGROUND: M cells play an important role in the intestinal immune system as they have a high capacity for transcytosis of a wide range of microorganisms and macromolecules. However, little is known about the role of M cells during intestinal inflammation. AIM: We studied M cell development during indomethacin-induced intestinal inflammation in rats. METHODS: Ileitis in rats was induced by two subcutaneous injections with indomethacin (7.5 mg/kg) given 24 h apart. Rats were sacrificed after 14 days and tissue was analysed by fluorescence microscopy and electron microscopy. M cells could be visualized by using the FITC-labelled mAb anti-cytokeratin (CK)-8 (clone 4.1.18), which was recently identified as specific M cell marker in rats. The number of cytokeratin-8 positive M cells was related to the surface of the follicle associated epithelium. For morphological studies, we used both transmission electron microscopy (T.E.M.) and scanning electron microscopy (S.E.M.). RESULTS: In non-inflamed ileum M cells were scarce. Only 4% of the follicle associated epithelium were M cells, whereas an increase of M cells up to 11% was found in inflamed follicle associated epithelium (P < 0.001). The rate of M cell induction depended on the macroscopic degree of inflammation. T.E.M./S.E.M. studies showed that in inflamed tissue most M cells underwent apoptosis with typical morphological signs. In contrast to apoptotic M cells, the neighbouring enterocytes usually appeared intact. The number of mononuclear cells below the follicle associated epithelium was significantly increased. S.E.M. studies revealed that during induced ileitis mononuclear cells migrated from the lamina propria into the gut lumen by passing through apoptotic M cells. CONCLUSIONS: During indomethacin-induced ileitis in rats the increase in M cell number in association with apoptosis of M cells may alter the intestinal barrier function. These observations may play a pivotal role in the pathogenesis of chronic intestinal inflammation, e.g. in inflammatory bowel disease.

Role of M cells in intestinal barrier function.

M cells are known as specialized epithelial cells of the follicle-associated epithelium of the gastrointestinal tract. As M cells have a high capacity for transcytosis of a wide range of microorganisms and macromolecules, they are believed to act as an antigen sampling system. The primary physiological role of M cells seems to be the rapid uptake and presentation of particular antigens and microorganisms to the immune cells of the lymphoid follicle to induce an effective immune response. In contrast to absorptive enterocytes, M cells do not exert direct defense mechanisms to antigens and pathogens in the gut lumen. Therefore, they provide functional openings of the epithelial barrier. Although M cells represent a weak point of the epithelial barrier, even under noninflamed conditions, there seems to be a balance between antigen uptake and immunological response. The low number of M cells in the gastrointestinal tract and the direct contact to immune cells in the lamina propria usually prevent the occurrence of mucosal inflammation. During chronic intestinal inflammation we observe an increase of M cell number and apoptosis selectively in M cells. M cell damage seems to be responsible for the increase of the uptake of microorganisms that is observed during intestinal inflammation. Under inflammatory conditions in the intestine, the maintenance of the epithelial barrier is broken and M cells seem to play a major role during this process.

Imaging techniques for assessment of inflammatory bowel disease: joint ECCO and ESGAR evidence-based consensus guidelines.

The management of patients with IBD requires evaluation with objective tools, both at the time of diagnosis and throughout the course of the disease, to determine the location, extension, activity and severity of inflammatory lesions, as well as, the potential existence of complications. Whereas endoscopy is a well-established and uniformly performed diagnostic examination, the implementation of radiologic techniques for assessment of IBD is still heterogeneous; variations in technical aspects and the degrees of experience and preferences exist across countries in Europe. ECCO and ESGAR scientific societies jointly elaborated a consensus to establish standards for imaging in IBD using magnetic resonance imaging, computed tomography, ultrasonography, and including also other radiologic procedures such as conventional radiology or nuclear medicine examinations for different clinical situations that include general principles, upper GI tract, colon and rectum, perineum, liver and biliary tract, emergency situation, and the postoperative setting. The statements and general recommendations of this consensus are based on the highest level of evidence available, but significant gaps remain in certain areas such as the comparison of diagnostic accuracy between different techniques, the value for therapeutic monitoring, and the prognostic implications of particular findings.