Johannes Bethge

Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype: results from the IBDchip European Project

Objective Through genome-wide association scans and meta-analyses thereof, over 70 genetic loci (Crohns disease (CD) single nucleotide polymorphisms (SNPs)) are significantly associated with CD. We aimed to investigate the influence of CD-SNPs and basic patient characteristics on CD clinical course, and develop statistical models to predict CD clinical course. Design This retrospective study included 1528 patients with CD with more than 10 years of follow-up from eight European referral hospitals. CD outcomes of interest were ileal (L1), colonic (L2) and ileocolonic disease location (L3); stenosing (B2) or penetrating behaviour (B3); perianal disease; extraintestinal manifestations; and bowel resection. A complicated disease course was defined as stenosing or penetrating behaviour, perianal disease and/or bowel resection. Association between CD-SNPs or patient characteristics and specified outcomes was studied. Results Several CD-SNPs and clinical characteristics were statistically associated with outcomes of interest. The NOD2 gene was the most important genetic factor, being an independent predictive factor for ileal location (p=2.02×10-06, OR=1.90), stenosing (p=3.16×10-06, OR=1.82) and penetrating (p=1.26×10-02, OR=1.25) CD behaviours, and need for surgery (p=2.28×e-05, OR=1.73), and as such was also the strongest factor associated with a complicated disease course (p=6.86×10-06, OR=2.96). Immunomodulator (azathioprine/6-mercaptopurine and methotrexate) use within 3 years after diagnosis led to a reduction in bowel stenoses (p=1.48×10-06, OR=0.35) and surgical rate (p=1.71×10-07, OR=0.34). Association between each outcome and genetic scores, created using significant SNPs in the univariate analysis, revealed large differences in the probability of developing fistulising disease (IL23R, LOC441108, PRDM1, NOD2; p=9.64e-4, HR=1.43), need for surgery (IRGM, TNFSF15, C13ORF31, NOD2; p=7.12×10-03, HR=1.35), and stenosing disease (NOD2, JAK2, ATG16L1; p=3.01×10-02, HR=1.29) among patients with low and high score. Conclusions This large multicentre cohort study has found several genetic and clinical factors influencing the clinical course of CD. NOD2 and early immunomodulator use are the clinically most meaningful predictors for its clinical course.

Prospective evaluation of malignant cell seeding after percutaneous endoscopic gastrostomy in patients with oropharyngeal/esophageal cancers

BACKGROUND AND STUDY AIMS Insertion of a percutaneous endoscopic gastrostomy (PEG) is standard care for many patients with oropharyngeal (ENT) and esophageal malignancies in order to ensure enteral feeding. The current pull-through insertion technique involves direct contact with the tumor and case reports have demonstrated the presence of metastases at insertion sites. The aim of the current study was to prospectively evaluate the risk of malignant cell seeding and the development of abdominal wall metastases after PEG placement. PATIENTS AND METHODS A total of 50 consecutive patients with ENT/esophageal tumors were included. After PEG placement (40 pull-through technique, 10 direct insertion), brush cytology was taken from the PEG tubing and the transcutaneous incision site. A second cytological assessment was performed after a follow-up period of 3 - 6 months. RESULTS In total, 26 patients with ENT cancer, 13 with esophageal cancer, and one with esophageal infiltration of lung cancer underwent pull-through PEG placement with no immediate complications. Cytology following brushing of tubing and incision sites demonstrated malignant cells in 9 /40 cases (22.5 %). Correlation analyses revealed a higher rate of malignant seeding in older patients and in those with higher tumor stages. At follow-up, cytology was undertaken in 32 /40 patients who had undergone pull-through PEG placement. Malignant cells were present in three on cytology, resulting in a metastatic seeding rate of 9.4 %. CONCLUSION This study showed that malignant cells were present in 22.5 % of patients immediately after pull-through PEG placement; local metastases were verified at follow-up in 9.4 %, all of which were from esophageal squamous cell carcinoma. This risk is particularly high in the older age group and in patients with higher tumor stages. Therefore, pull-through PEG placement should be avoided in these patients and direct access PEG favored instead.

Endoscopic ultrasound of the colon for the differentiation of Crohn's disease and ulcerative colitis in comparison with healthy controls

Diagnosis of inflammatory bowel disease (IBD) is based on clinical presentation, colonoscopy and histology. Differentiation of Crohns disease (CD) and ulcerative colitis (UC) can be difficult in some patients. Endoscopic ultrasound (EUS) provides high resolution images of the gastrointestinal wall (GI) and may be an alternative to differentiate CD/UC.

Combination therapy with vedolizumab and etanercept in a patient with pouchitis and spondylarthritis

Inflammatory bowel disease is frequently associated with spondylarthritis (SpA). It has been discussed that α4/β7 expressing lymphocytes are involved in the aetiology of SpA. We report a case of a successful combination therapy of vedolizumab (VDZ) and etanercept (ETA) in a patient with ulcerative colitis with pouchitis and SpA. In our case VDZ was effective for pouchitis and ineffective for SpA. The combination with ETA might be a useful treatment strategy to control both diseases and first indications suggest that it is safe. α4/β7 Expressing lymphocytes are most likely not associated in the aetiology of SpA.

Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease

Objective Vedolizumab, a monoclonal antibody directed against the integrin heterodimer α4β7, is approved for the treatment of Crohn’s disease and ulcerative colitis. The efficacy of vedolizumab has been suggested to result from inhibition of intestinal T cell trafficking although human data to support this conclusion are scarce. We therefore performed a comprehensive analysis of vedolizumab-induced alterations in mucosal and systemic immunity in patients with inflammatory bowel disease (IBD), using anti-inflammatory therapy with the TNFα antibody infliximab as control. Design Immunophenotyping, immunohistochemistry, T cell receptor profiling and RNA sequencing were performed using blood and colonic biopsies from patients with IBD before and during treatment with vedolizumab (n=18) or, as control, the anti-TNFα antibody infliximab (n=20). Leucocyte trafficking in vivo was assessed using single photon emission computed tomography and endomicroscopy. Results Vedolizumab was not associated with alterations in the abundance or phenotype of lamina propria T cells and did not affect the mucosal T cell repertoire or leucocyte trafficking in vivo. Surprisingly, however, α4β7 antibody treatment was associated with substantial effects on innate immunity including changes in macrophage populations and pronounced alterations in the expression of molecules involved in microbial sensing, chemoattraction and regulation of the innate effector response. These effects were specific to vedolizumab, not observed in response to the TNFα antibody infliximab, and associated with inhibition of intestinal inflammation. Conclusion Our findings suggest that modulation of innate immunity contributes to the therapeutic efficacy of vedolizumab in IBD. Trial registration number NCT02694588

Advanced endoscopic submucosal dissection with magnetic bead-assisted traction based on gravity for a flat colorectal neoplasm with severe fibrosis

Endoscopic submucosal dissection (ESD) of colorectal lesions with severe submucosal fibrosis remains challenging. Fibrosis has also been implicated as a factor that increases the risk of incomplete or complicated dissection [1–3]. Several traction techniques have been described but remain to be established [4, 5]. Traction by gravity seems to be one of the most useful methods for colorectal ESD [5]. We therefore devised a new gravity-based traction tool. This technique uses magnetic beads (▶Fig. 1 a) to apply traction. The weight can easily be adjusted by using an additional magnetic bead and the direction of traction by changing the patient’s position. Magnetic bead-assisted ESD (MBA-ESD) is able to improve the field of vision, increase resection efficiency, and reduce risks of perforation and of cutting into lesions, as well as shortening the treatment time and lowering the costs. A 55-year-old man with a flat neoplasm with a central ulcer scar (15×10mm) in the descending colon (▶Fig. 1b) was admitted to our hospital to undergo colorectal ESD. Endoscopic mucosal resection had failed at another hospital owing to incomplete lifting of the lesion. After a mixed glycerol–sodium–hyaluronate solution with diluted epinephrine and indigo carmine had been injected into the submucosal layer, an incision was made using a Dual-Knife. Difficulties arose immediately after we started the dissection because of severe submucosal fibrosis. Despite repeated injections, no lifting could be achieved and the submucosal layer could not be precisely exposed, with no accurate line of muscle layer evident. Traction was successfully applied to the lesion by use of a magnetic bead that was fixed with the attached string to the edge of the mucosa using an endoclip (▶Fig. 1 c). By changing the patient’s position, traction could be further improved. A second magnetic bead was ad▶ Fig. 1 Magnetic bead-assisted endoscopic submucosal dissection. a The magnetic beads that are used to apply traction by gravity. b – d Endoscopic views showing: b a flat adenoma with fibrosis in the descending colon; c the specimen being resected with magnetic beadassisted traction; d the ulcer bed after resection.