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Zusammenfassung Hintergrund Zur Diagnosestellung, Erkennung von Erkrankungskomplikationen sowie zur Verlaufskontrolle bei Patienten mit Morbus Crohn und Colitis ulcerosa wird zunehmend der Darmultraschall eingesetzt. Eine systematische Befunderhebung und Dokumentation sind wichtig, um die Qualität der Befunderstellung und die Kommunikation zwischen den Fachgruppen zu verbessern. Das vorliegende Positionspapier beschreibt die Voraussetzungen für eine optimale Befunderhebung des Darmultraschalls bei Patienten mit chronisch-entzündlichen Darmerkrankungen (CED). Methoden Eine Experten-Konsensusgruppe bestehend aus Gastroenterologen, Radiologen, Pathologen, Kinder- und Jugend-Gastroenterologen und Chirurgen führte eine systematische Literaturrecherche durch. In einem Delphi-Verfahren wurde unter Mitgliedern des Kompetenznetzes Darmerkrankungen und der Deutschen Röntgengesellschaft (DRG) über relevante Kriterien bei der Befunderhebung von Darmultraschallbefunden abgestimmt. Die daraus resultierenden Statements wurden in einer Experten-Konsensusgruppe verabschiedet. Ergebnis Praxisorientierte Empfehlungen für eine optimale Befunderhebung mit einer standardisierten Terminologie wurden entwickelt. Der Fokus der Erhebung lag auf der Beschreibung der Entzündungsaktivität sowie der Komplikationen bei CED. Minimale Anforderungen für eine standardisierte Befunderhebung wurden definiert. Zusammenfassung Das vorliegende Manuskript bietet praktische Empfehlungen zur Optimierung und Vereinheitlichung der Befunderhebung bei Darmultraschall-Untersuchungen bei CED.

Background and aims This study examined differences in personality, psychological distress, and stress coping in inflammatory bowel disease (IBD) depending on type of disease and disease activity. We compared patients suffering from Crohn’s disease (CD) and ulcerative colitis (UC) with controls. While the literature is replete with distinctive features of the pathogenesis of IBD, the specific differences in psychological impairments are not well studied. Methods In this German national multicenter study, participants were recruited from 32 centers. Two hundred ninety-seven questionnaires were included, delivering vast information on disease status and psychological well-being based on validated instruments with a total of 285 variables. Results CD patients were more affected by psychological impairments than patients suffering from UC or controls. Importantly, patients with active CD scored higher in neuroticism (p Conclusions We identified specific aspects of psychological impairment in IBD depending on disease and disease activity. Our results underscore the need for psychological support and treatment particularly in active CD.

This study examined differences in personality, psychological distress, and stress coping in inflammatory bowel disease (IBD) depending on type of disease and disease activity. We compared patients suffering from Crohn's disease (CD) and ulcerative colitis (UC) with controls. While the literature is replete with distinctive features of the pathogenesis of IBD, the specific differences in psychological impairments are not well studied. In this German national multicenter study, participants were recruited from 32 centers. Two hundred ninety-seven questionnaires were included, delivering vast information on disease status and psychological well-being based on validated instruments with a total of 285 variables. CD patients were more affected by psychological impairments than patients suffering from UC or controls. Importantly, patients with active CD scored higher in neuroticism (p 0.01), psychological distress (p 0.001) and maladaptive stress coping (escape, p = 0.03; rumination, p 0.03), but less need for social support (p = 0.001) than controls. In contrast, patients suffering from active UC showed psychological distress (p 0.04) and maladaptive coping (avoidance, p 0.03; escape, p = 0.01). Patients in remission seemed to be less affected. In particular, patients with UC in remission were not inflicted by psychological impairments. The group of CD patients in remission however, showed insecurity (p 0.01) and paranoid ideation (p = 0.04). We identified specific aspects of psychological impairment in IBD depending on disease and disease activity. Our results underscore the need for psychological support and treatment particularly in active CD. Diese Studie untersuchte Unterschiede in der Persönlichkeit, psychische Belastung und Stressbewältigung bei chronisch-entzündlichen Darmerkrankungen (CED) in Abhängigkeit von der Art der Erkrankung und der Krankheitsaktivität. Wir verglichen Patienten mit Morbus Crohn (CD) und Colitis ulcerosa (UC) mit Kontrollgruppen. Während die Literatur zu charakteristischen Merkmalen der Pathogenese von IBD zahlreich ist, sind die spezifischen Unterschiede in den psychischen Beeinträchtigungen nicht ausreichend untersucht. In dieser deutschen nationalen Multicenterstudie wurden Teilnehmer aus 32 Zentren rekrutiert. Es wurden 297 Fragebögen mit umfassenden Informationen über den Krankheitsstatus und das psychische Wohlbefinden auf der Grundlage validierter psychosozialer Instrumente mit insgesamt 285 Items evaluiert. CD-Patienten waren stärker von psychischen Beeinträchtigungen betroffen als Patienten mit UC oder Kontrollen. Wichtig ist, dass Patienten mit aktiver CD in den Bereichen Neurotizismus (p 0,01), psychische Belastung (p 0,001) und maladaptive Stressbewältigung (p 0,03) höhere Werte, aber weniger Bedarf für soziale Unterstützung (p = 0,001) als Kontrollen aufwiesen. Im Gegensatz dazu zeigten Patienten, die an aktiver UC litten, psychische Belastung (p 0,04) und maladaptive Coping (Vermeidung, p 0,03; Flucht, p = 0,01). Patienten in Remission schienen weniger betroffen zu sein. Die Gruppe der CD-Patienten in Remission zeigte jedoch Unsicherheit (p 0,01). Wir identifizierten spezifische Aspekte der psychischen Beeinträchtigung bei IBD abhängig von Krankheit und Krankheitsaktivität. Unsere Ergebnisse untermauern den Bedarf an psychologischer Unterstützung und Behandlung, insbesondere bei aktiver CD.

After the expiry date of the patent protection for Infliximab in 2013, the biosimilar CT‑P13 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.

An effective method for long-term enteral feeding or stomach decompression is the use of a percutaneous gastrostomy (PEG) or sometimes jejunostomy (PEJ). Under certain circumstances (eg, inadequate transillumination), endoscopic placement of PEG/PEJ tubes is impossible. In these cases, computed tomography (CT)-guided PEG/PEJ may represent an alternative technique. In this study, we evaluate indications, results, and complications of CT-guided PEG/PEJ.A total of 102 consecutive referred patients were enrolled in the study. Patients came to the endoscopy unit of our department to undergo a CT-guided PEG/PEJ for long-term intragastric/intrajejunal feeding (n = 57) or decompression (n = 45). The majority (n = 98) received a pull-through PEG/PEJ with simultaneous gastroscopy/jejunoscopy. Dose length product and the effective dose for every patient were calculated.PEG/PEJ tube placement was successful in 87.3% (89 of 102). Feeding PEG/PEJ tube placement was successfully completed in 91.2% (52 of 57); decompressive PEG/PEJ tube placement was likewise successfully completed in 82.2% (37 of 45). No procedure-related mortality was observed. Minor complications (eg, tube dysfunction, local bleeding, minimal leakage, local skin infection) were observed in 13 patients. The complication rate was similar between the feeding and decompression groups ( P = .9).CT-guided PEG/PEJ is a feasible and safe method with a low procedure-related morbidity rate for patients where endoscopic placement via transillumination is not successful. Thus, the procedure is an attractive alternative to surgical tube placement. Long-term complications, mainly tube disturbances, can be treated easily.

Das Kompetenznetz Darmerkrankungen ist ein Verbund von uber 500 Mitgliedern, Arzten und Wissenschaftlern, aus Universitatskliniken, Kliniken und niedergelassenen Praxen. Es beschaftigt sich neben den beiden am haufigsten auftretenden chronisch entzundlichen Darmerkrankungen, Morbus Crohn und Colitis ulcerosa, auch mit verwandten chronischen Erkrankungen wie Zoliakie und mikroskopischen Kolitiden. Das Kompetenznetz betreibt eine kontinuierliche Verbesserung der Diagnostik und Behandlung durch Koordination und Translation von angewandter Grundlagenforschung (insbesondere der molekularen Epidemiologie) und die Forderung der Entwicklung besserer diagnostischer und therapeutischer Verfahren, um die Qualitat und die Standardisierung des klinischen Handelns zu verbessern. In diesen Aktivitaten ist das Kompetenznetz in entsprechende europaische Verbunde integriert.

Nonerosive reflux disease (NERD) is commonly diagnosed in patients with symptoms of reflux. The aim of the present study was to determine whether high-definition endoscopy (HD) plus equipped with the iScan function or chromoendoscopy with Lugol's solution might permit the differentiation of NERD patients from those without reflux symptoms, proven by targeted biopsies of endoscopic lesions. A total of 100 patients without regular intake of proton pump inhibitors and with a normal conventional upper endoscopy were prospectively divided into NERD patients and controls. A second upper endoscopy was performed using HD+ with additional iScan function and then Lugol's solution was applied. Biopsy specimens were taken from the gastroesophageal junction in all patients. A total of 65 patients with reflux symptoms and 27 controls were included. HD(+) endoscopy with iScan revealed subtle mucosal breaks in 52 patients; the subsequent biopsies confirmed esophagitis in all cases. After Lugol's solution, 58 patients showed mucosal breaks. Sensitivity for the iScan procedure was 82.5%, whereas that for Lugol's solution was 92.06%. Excellent positive predictive values of 100% and 98.3%, respectively, were noted. The present study suggests that the majority of patients with NERD and typical symptoms of reflux disease can be identified by iScan or Lugol's chromoendoscopy as minimal erosive reflux disease (ERD) patients.

Background Endoscopic monitoring is fundamental for evaluating the therapeutic response in IBD, but a validated endomicroscopic mucosal healing (MH) score is not available to date. However, confocal laser endomicroscopy (CLE) might define MH more precisely than conventional endoscopy. The major aim was to establish and validate an MH score for ulcerative colitis (UC), based on CLE. Methods In an initial pilot study (n = 10), various CLE changes were analyzed for identification of reproducible criteria for establishing a CLE score. Four reproducible CLE criteria were implemented in a following validation study. Subsequently, active UC patients (n = 23, Mayo score ≥6) were prospectively included and underwent colonoscopy with CLE before and after 3 anti-TNF applications. Patients were clinically followed over a period of 3 years. The endomicroscopic MH score (eMHs; range, 0–4) was compared with histopathology and endoscopy scores from the same colonic location. Results The eMHs showed high sensitivity, specificity, and accuracy values (100% with 95% confidence interval [CI] of 15.81%–100%; 93.75% with 95% CI of 69.77%–99.84%, and 94.44%, respectively). The eMHs showed a good correlation with the histological Gupta score (rs = 0.82, P < 0.0001) and the endoscopic Mayo subscore (rs = 0.81%, P < 0.0001). Sixty percent of therapy responders presented an eMHs Conclusions CLE can accurately assess MH based on the newly developed and statistically validated eMHs in UC, and it is superior in predicting the long-lasting clinical outcome based on both descriptive and functional barrier imaging (NCT01417728).

ObjectiveAnti-tumour necrosis factor (TNF) antibodies are successfully used for treatment of Crohn’s disease. Nevertheless, approximately 40% of patients display failure to anti-TNF therapy. Here, we characterised molecular mechanisms that are associated with endoscopic resistance to anti-TNF therapy.DesignMucosal and blood cells were isolated from patients with Crohn’s disease prior and during anti-TNF therapy. Cytokine profiles, cell surface markers, signalling proteins and cell apoptosis were assessed by microarray, immunohistochemistry, qPCR, ELISA, whole organ cultures and FACS.ResultsResponders to anti-TNF therapy displayed a significantly higher expression of TNF receptor 2 (TNFR2) but not IL23R on T cells than non-responders prior to anti-TNF therapy. During anti-TNF therapy, there was a significant upregulation of mucosal IL-23p19, IL23R and IL-17A in anti-TNF non-responders but not in responders. Apoptosis-resistant TNFR2+IL23R+ T cells were significantly expanded in anti-TNF non-responders compared with responders, expressed the gut tropic integrins α4β7, and exhibited increased expression of IFN-γ, T-bet, IL-17A and RORγt compared with TNFR2+IL23R− cells, indicating a mixed Th1/Th17-like phenotype. Intestinal TNFR2+IL23R+ T cells were activated by IL-23 derived from CD14+ macrophages, which were significantly more present in non-responders prior to anti-TNF treatment. Administration of IL-23 to anti-TNF-treated mucosal organ cultures led to the expansion of CD4+IL23R+TNFR2+ lymphocytes. Functional studies demonstrated that anti-TNF-induced apoptosis in mucosal T cells is abrogated by IL-23.ConclusionsExpansion of apoptosis-resistant intestinal TNFR2+IL23R+ T cells is associated with resistance to anti-TNF therapy in Crohn’s disease. These findings identify IL-23 as a suitable molecular target in patients with Crohn’s disease refractory to anti-TNF therapy.

Background and Aims Assessment of prognostic factors in patients with Crohn's disease (CD) is of pivotal importance for early intervention and "treat-to-target" strategies. Confocal laser endomicroscopy (CLE) enables on-demand in vivo characterization of mucosal inflammatory and architectural changes during endoscopy. We prospectively assessed the value of CLE for prediction of clinical outcome parameters in CD. Methods Consecutive patients with CD undergoing colonoscopy were included in a multicenter study. Confocal imaging focused on 2 highly reproducible histologic hallmarks of active colonic inflammation: focal cryptitis and crypt architectural abnormality. We evaluated whether CLE, CD endoscopic index of severity (CDEIS), serum C-reactive protein (CRP), and CD activity index (CDAI) were associated with the risk of medical treatment escalation, transmural adverse events, and CD-related hospitalization or surgery during a 4-year follow-up. Results Among 49 patients (53% men, median age, 39 years), baseline CRP was ≥5 mg/L in 47%, CDEIS ≥3 in 75%, and CDAI >150 in 51%. Focal cryptitis and crypt architectural abnormality were observed in 63% (CLE + group). CLE + patients showed an increased incidence of medical treatment escalation ( P P = .025; RR = 1.70), whereas patients with CRP ≥5 mg/L had increased CD-related hospitalization and surgery ( P = .020, RR = 2.71) at 1-year follow-up. No further association with prognostic clinical outcomes was found over the 1-year follow-up as well as for CDEIS and CDAI at any time. Conclusions CLE reveals CD-related features of mucosal inflammation and allows for early prediction of relevant clinical outcomes. Further studies should now address whether this promising prognostic tool could refine the timing of treatment strategies in patients with CD.

The Inflammatory Bowel Disease Competence Network is a network of more than 500 physicians and scientists from university clinics, hospitals and gastroenterology practices. The focus extends from the two major forms of inflammatory bowel diseases, Crohn's disease and ulcerative colitis, into other chronic inflammatory conditions affecting the intestine, including coeliac disease and microscopic colitis. The network translates basic science discoveries (in particular in the molecular epidemiology research) into innovative diagnostics and therapy. Through its strong networking structures it supports a continuous process to improve quality and standardisation in patient care that is implemented in close interaction with European networks addressing this disease group.Optimisation of patient care based on scientifically proven evidence is a main focus of the network. Therefore, it supports and coordinates translational research and infrastructure projects that investigate aetiology, improvement of diagnostic methods, and development of new or improved use of established therapies. Members participate in various training projects, thus ensuring the rapid transfer of research results into clinical practice.The competence network cooperates with the main patient organisations to engage patients in all levels of activities. The network and the patient organisations have interest in promoting public awareness about the disease entities, because their importance and burden is underestimated in non-specialised medical fields and among the general public.

Differential therapy requires repeated diagnostic assessment for mapping and monitoring of disease activity in Crohn’s disease (CD). The purpose of this prospective study was to evaluate the accuracy of 18F-fluorodexyglucose positron-emission tomography (FDG-PET) for non-invasive assessment of disease activity in CD. Forty-three patients with CD underwent ileocolonoscopy and hydromagnetic resonance imaging (hydro-MRI) as reference standards. In addition, FDG-PET was performed and correlated with clinical data, hydro-MRI, and endoscopy findings. Diagnostic accuracy was determined for all methods. Two-hundred and forty-one bowel segments could be analyzed by all methods. Of 80 endoscopically inflamed segments in CD, FDG-PET detected 72 and hydro-MRI 53 segments. Overall sensitivity was 90 % (FDG-PET) versus 66 % (hydro-MRI), and specificity was 92.6 % versus 99 %. In the proximal ileum, hydro-MRI revealed inflammation in eight out of 49 patients and FDG-PET, also, detected all of these inflamed segments. Seventeen stenoses could be identified in 43 CD patients. With regard to assessment as inflammatory or fibrotic stenosis, there was good concordance between colonoscopy, hydro-MRI, and FDG-PET. In one case only, the nature of the stenosis was assessed differently. In contrast with leukocyte numbers and CDAI, there was significant correlation of FDG-PET activity with C-reactive protein and CDEIS levels (P = 0.019 and P = 0.007, respectively). FDG-PET is able to detect mucosal inflammation in CD with high sensitivity and specificity and to enable proper assessment of inflammatory activity in stenoses. FDG-PET is, thus, a promising non-invasive technique for clinical management of CD.

Purpose: Evaluation of mesenteric transit time (MTT) – measured by contrast-enhanced ultrasound – as a marker for inflammatory activity in Crohn’s disease. Materials and Methods: The time of maximum enhancement of the contrast agent in the superior mesenteric artery and vein was determined visually and by software analysis. The MTT was calculated as the difference between these two time points. Findings were correlated with the Harvey-Bradshaw Index (HBI) using the Pearson correlation coefficient (r). In addition, a healthy control group was evaluated both in the fasting state and 1, 2, 3 and 4 hours postprandially. Results: In 20 healthy controls the mean visual MTT during fasting was 9.76 ± 2.83 sec and decreased to a minimum 1 hour after the meal (6.6 ± 2.27 sec). 45 patients with Crohn’s disease (9 males, 36 females, mean age 35 years) had a mean HBI of 5.9 ± 4.7 points. The mean software-based MTT of 9.76 ± 3.7 sec was significantly higher (p = 0.034) than the mean visual MTT of 8.22 ± 3.05 sec. The two figures correlated well (r = 0.72, p Conclusion: The MTT decreases in the first two hours after eating. The visually assessed and the software-based MTT correlate well, however MTT does not correlate with disease activity in patients with Crohn‘s disease.

Teaching ultrasound (US) has not been sufficiently standardised yet. Most educational devices in US consist of 2-dimensional B-mode images. However, the identification of anatomic structures in the 3-dimensional space can only be learned by practical hands-on education. In US simulators, US images of real pathologies are created by the examination of a dummy with a mock transducer. The resulting US images were previously recorded in a 3-dimensional format and were processed in a way which facilitates the reconstruction and projection of the images on a screen corresponding to the sectional plane of the mock transducer, simulating the conventional B-mode images. This enables standardised, real-time, hands-on training of US pathology detection. In June 2007, a hands-on workshop on US simulators was performed in the 1st Department of Internal Medicine of the Johannes Gutenberg-University in Mainz/Germany. During 15 days, 209 participants from all parts of Germany were trained. The workshop included an evaluation to elucidate the value and acceptance of this kind of US training. 149 evaluation forms could be analysed (72 %). The participants were fairly heterogeneous and belonged to the following subspecialties: internal medicine (50 %), surgery (11 %), others (18 %). 72 % were residents, 22 % consultants. 40 % of the participants worked in university hospitals, 12 % in hospitals of highest clinical level, and 42 % in hospital of basic care. Baseline knowledge in US was quite different, too, reflected in the number of independently performed US examinations prior to this course: 0 - 400 examinations (44 %), 401 - 1000 examinations (14 %), 1001 - 4000 examinations (7 %), and > 4000 examinations (2 %). Of note, 56 % of the participants had not received any kind of formal training in US. In daily practice 77 % were trained by tutors, whose formal qualification in US was unknown. Only a small proportion of the tutors had received training in US according to the standards of the German Association of US in Medicine (DEGUM). This evaluation shows the high level of acceptance of simulator-based training in US despite the heterogeneity of the participants. 95 % rated the teaching value as "high" and 95 % wished an integration of US simulators in training curricula. In summary, this analysis proves the need for standardised training programmes in US teaching in Germany and a high level of acceptance of simulator-based US training.

Background The EPKi system (Pentax, Japan) enables resolution above HDTV. Aim of the study was to test the efficacy of HD+ alone and with the new post-processing digital filter i-Scan or chromoendoscopy (Methylene blue 0.1%) in screening for colorectal cancer. We focused on lesions less than 5 mm as a surrogate marker for the optical possibilities of the EPKi system. Methods The last 30 cm of the colon in a screening population were inspected with HD+ alone, in combination with i-Scan (2:1 randomisation) and subsequently with chromoendoscopy. All lesions were characterized and targeted biopsies were performed. Results i-Scan augmented in 69 patients the identification of lesions from 176 to 335 (p Conclusions HD+ colonoscopy with and without i-Scan unmask a plethora of small lesions but chromoendoscopy can even advance the number. However, i-Scan was able to predict neoplasia as precisely as chromoendoscopy and might shortly replace chromoendoscopy as a more time efficient tool.

BACKGROUND AND STUDY AIMS: Patients with gastroesophageal reflux disease are subdivided into non-erosive (NERD) and erosive reflux disease (ERD). The newly available EPKi processor enables high-definition resolution above HDTV standard (HD+). The aim of the study was to test the efficacy of HD+ esophagogastroduodenoscopy alone and in conjunction with i-Scan (newly developed postprocessing digital filter) and chromoendoscopy (Lugol’s solution) for differentiation of reflux patients. METHODS: The distal esophagus of patients with heartburn was inspected with three imaging modalities. HD+ was followed by i-Scan and 15-mL Lugol’s solution (1.5 %). The esophagus was evaluated for mucosal breaks (Los Angeles Classification [LA]). Small visible changes were also characterized, and targeted biopsies were performed. End points of the study were the presence and grade of esophagitis and the number of circumscribed changes. RESULTS: A total of 50 patients were included (female 29; mean age 54.7 years). HD+ identified nine patients with mucosal breaks (LA 7A; 2C), i-Scan was able to detect 12 patients (LA 8A; 2B; 2C; 0D) ( P = n. s.) and chromoendoscopy identified 25 patients (LA 16A; 7B; 1C, 1D) ( P < 0.01). Furthermore, a higher grade of esophagitis was recognized by using i-Scan and Lugol’s solution in 19 patients. The number of circumscribed lesions could be increased from 21 (HD+) to 58 (i-Scan) ( P < 0.01), and up to 85 after Lugol spraying ( P < 0.01). CONCLUSIONS: Lugol’s solution in conjunction with HD+ endoscopy significantly improves the identification of patients with esophagitis and reduces misclassification. The i-Scan filter and chromoendoscopy help to identify reflux-associated lesions.

For in-vivo diagnostics of cancer and pre-cancer in the stomach, there is no endoscopic procedure offering both high sensitivity and high specificity. Our data suggest that multispectral or hyperspectral imaging may be helpful to solve this problem. It is successfully applied to the detection and analysis of easily reachable carcinomas, ex-vivo samples of hollow organ mucosal carcinomas and also histological samples. An endoscopy system which allows flexible multispectral videoendoscopy for in-vivo diagnostics has so far been unavailable. To overcome this problem, we modified a standard Olympus endoscopy system to conduct in-vivo multispectral imaging of the upper GI tract. The pilot study is performed on 14 patients with adeno carcinomas in the stomach. For analysis, Support Vector Machine with linear and Gaussian Kernel, AdaBoost, RobustBoost and Random-Forest-walk are used and compared for the data classification with a leave-one-out strategy. The margin of the carcinoma for the training of the classifier is drawn by expert-labeling. The cancer findings are cross-checked by biopsies. We expect that the present study will help to improve the further development of hyperspectral endoscopy and to overcome some of the problems to be faced in this process.

Objectives IBDs have an increased risk for development of colorectal cancer (CRC). Here, we aimed at the characterisation of the functional role of Th17-associated transcription factors in sporadic and colitis-associated colon cancer in vivo. Design We used mice deficient or transgenic for the activating protein 1 family member basic leucine zipper transcription factor ATF-like (Batf) to evaluate the role of Th17 cells during sporadic and inflammation-induced colon carcinogenesis. We also studied the expression of Batf and RORγt in patients with IBD and CRC. Results Batf but not retinoic acid-related orphan receptor γt (RORγt) expression was significantly increased together with interleukin (IL) 23 expression in UC but not in Crohn9s disease (CD) tissue samples. In CRC also Batf but not RORγt expression was increased and its expression correlated with the IL-23 and IL-23 receptor (IL-23R) expression. Finally, Batf but not RORγt was coexpressed with IL-17a, IL-23R and IL-6 within CRC-infiltrating CD4 + T cells. Functional studies in mice revealed that Batf-dependent T cells are crucial regulators of sporadic and inflammation-induced CRC. Colitis-associated Batf −/− tumours lacked IL-17a + IL-23R + IL-6 + CD4 + T cells, hence displaying characteristics reminiscent of human CRC-infiltrating CD4 + T cells. Strikingly, Batf −/− tumours contained low IL-23 but high IL-17a expression levels. Tumour formation and intratumoral IL-23 expression could be restored by administration of Hyper-IL-6 consisting of IL-6 and soluble IL-6 receptor. Conclusions Batf-dependent IL-23R + IL-6 + CD4 + Th17 cells critically control IL-23 driven colitis-associated tumour formation and the progression of sporadic colon tumours. Batf-dependent IL-23R + T cells represent a potential future therapeutic target limiting CRC progression.

We present the case of a 53-year-old woman with long-standing ulcerative colitis and severe, steroid-dependent disease course unresponsive to treatment with azathioprine, methotrexate, anti-TNF antibodies (infliximab, adalimumab) and tacrolimus, who refused colectomy as a therapeutic option. As the pro-inflammatory cytokine interleukin-6 (IL-6) had been identified as a crucial regulator in the immunopathogenesis of inflammatory bowel diseases, we treated the patient with biweekly intravenous infusions of an anti-IL-6R antibody (tocilizumab) for 12 wk. However, no clinical improvement of disease activity was noted. In fact, endoscopic, histological and endomicroscopic assessment demonstrated exacerbation of mucosal inflammation and ulcer formation upon anti-IL-6R therapy. Mechanistic studies revealed that tocilizumab treatment failed to suppress intestinal IL-6 production, impaired epithelial barrier function and induced production of pro-inflammatory cytokines such as TNF, IL-21 and IFN-γ. Inhibition of IL-6 by tocilizumab had no clinical benefit in this patient with intractable ulcerative colitis and even led to exacerbation of mucosal inflammation. Our findings suggest that anti-IL-6R antibody therapy may lead to aggravation of anti-TNF resistant ulcerative colitis. When targeting IL-6, the differential responsiveness of target cells has to be taken into account, as IL-6 on the one side promotes acute and chronic mucosal inflammation via soluble IL-6R signaling but on the other side also strongly contributes to epithelial cell survival via membrane bound IL-6R signaling.

Azathioprine and its metabolite 6-mercaptopurine (6-MP) are immunosuppressive drugs that are used in organ transplantation and autoimmune and chronic inflammatory diseases such as Crohn disease. However, their molecular mechanism of action is unknown. In the present study, we have identified a unique and unexpected role for azathioprine and its metabolites in the control of T cell apoptosis by modulation of Rac1 activation upon CD28 costimulation. We found that azathioprine and its metabolites induced apoptosis of T cells from patients with Crohn disease and control patients. Apoptosis induction required costimulation with CD28 and was mediated by specific block- ade of Rac1 activation through binding of azathioprine-generated 6-thioguanine triphosphate (6-Thio-GTP) to Rac1 instead of GTP. The activation of Rac1 target genes such as mitogen-activated protein kinase kinase (MEK), NF-κB, and bcl-xL was suppressed by azathioprine, leading to a mito- chondrial pathway of apoptosis. Azathioprine thus converts a costimulatory signal into an apoptot- ic signal by modulating Rac1 activity. These findings explain the immunosuppressive effects of aza- thioprine and suggest that 6-Thio-GTP derivates may be useful as potent immunosuppressive agents in autoimmune diseases and organ transplantation.

Der Morbus Crohn und die Colitis ulcerosa sind chronisch-entzundliche Darmerkrankungen (CED), die durch ihren schubartigen destruierenden Verlauf gekennzeichnet sind. In der Atiopathogenese spielen sowohl genetische Faktoren als auch Umweltfaktoren (Nahrungsbestandteile, bakterielle Antigene) eine Rolle.Eine pathologische Aktivierung des lokalen intestinalen Immunsystems durch bakterielle und andere mukosale Antigene fuhrt zu einer Anderung der Zytokinsekretion intestinaler Makrophagen und der T-Zellen zugunsten proinflammatorischer Zytokine (TNF-α, IL-12, IL-6 and IFN-γ) sowie zu einem veranderten Migrationsverhalten dieser Zellen. Die Kenntnis der Storung des intestinalen Zytokinprofils, der veranderten Zellmigration sowie der Zellinteraktion fuhrte zur Entwicklung neuer Behandlungsstrategien. In CED-Tiermodellen konnte die Funktion von Adhasionsmolekulen (α4β1, α4β7) erfolgreich gehemmt werden.Experimentelle Ansatze zeigen auch die Wirksamkeit einer Antikorpertherapie gegen kostimulatorische Molekule (CD40L), die fur die Makrophagen-/T-Zell-Interaktion verantwortlich sind.Diese Interaktion fuhrt beim Morbus Crohn zu einer pathologischen Zytokinsekretion. Die bisher erfolgreichsten Therapieversuche beeinflussen spezifisch die mukosale Zytokinmodulation. Einerseits wird versucht, durch Antikorper, die gegen Zytokine (TNF-α, IL-12) oder deren Rezeptoren (TNF-α, IL-6R) gerichtet sind bzw.durch die Hemmung der Zytokinsynthese (TNF-α converting enzyme-antisense Oligonukleotide), eine uberschiesende proinflammatorische Zytokinantwort zu unterbinden.Andererseits soll der Einsatz von antiinflammatorischen protektiven Zytokinen wie rekombinantes IL-10, IL-11 oder IFN-α zu einer Antagonisierung proinflammatorischer Mechanismen beitragen.In klinischen Studien haben bisher Antikorper gegen den Tumornekrosefaktor die besten Ergebnisse erzielt, wobei jedoch auf potenzielle Nebenwirkungen (z.B.Tuberkulosereaktivierung) zu achten ist.

Background: Tissue factor (TF), the principal initiator of the extrinsic coagulation pathway, is expressed by many tumors and can be released into the bloodstream on plasma microparticles (MPs). Experimental studies indicate that TF may facilitate hematogenous metastasis by promoting tumor cell-induced microvascular thrombosis, but clinical data supporting this hypothesis is sparse. Case Reports: Here, we report 2 unusual cases of rapidly progressive solid malignancies (gastric and urothelial carcinoma). In both patients, cancer cell dissemination with diffuse bone marrow involvement was either strongly suggested by leukoerythroblastic changes on peripheral blood smear or directly proven by positive findings on aspiration cytology. Furthermore, laboratory evidence of thrombotic microangiopathy (TMA) and disseminated intravascular coagulation was accompanied by new-onset severe pulmonary hypertension and a hemolytic uremic syndrome-like disorder in the gastric and the urothelial carcinoma patient, respectively. TF-specific procoagulant activity of isolated plasma MPs, as assessed by single-stage clotting assay, was dramatically increased in both patients compared to healthy controls (21- and 55-fold), and primary tumor samples stained strongly positive for TF by immunohistochemistry. Conclusion: TMA was likely caused by TF-triggered tumor cell embolization in both patients. Further clinical evidence is thus provided that TF directly links coagulation activation to cancer cell dissemination.

Untersuchungen der letzten 10 Jahre haben zu einem verbesserten Verstandnis der Pathophysiologie von chronisch entzundlichen Darmerkrankungen gefuhrt. Neuere Studien belegen hierbei v. a. die funktionelle Bedeutung einer Aktivierung des mukosalen Immunsystems durch bakterielle Antigene fur die Pathogenese der chronisch entzundlichen Darmerkrankungen (CED). Neben Chemokinen und Adhasionsmolekulen scheinen vor allem Zytokine, die von antigenprasentierenden Zellen und T-Lymphozyten produziert werden, pathogenetisch fur die CED von entscheidender Bedeutung zu sein. So konnte tierexperimentell gezeigt werden, dass Antikorper gegen proinflammatorische Zytokine zu einer Suppression von chronisch intestinalen Entzundungsreaktionen fuhren konnen, was durch eine Induktion von T-Zellapoptose bedingt ist. Basierend auf neuen Erkenntnissen zur Immunpathogenese der CED werden klinisch zzt. innovative Therapiekonzepte getestet, die z. B. rekombinante antiinflammatorische Zytokine und neutralisierende Antikorper gegen proinflammatorische Zytokine und ihre Rezeptoren umfassen. Trotz dieser Fortschritte im Verstandnis der Pathophysiologie und der Bedeutung des mukosalen Immunsystems bleiben jedoch zahlreiche Fragen uber die molekulare Immunpathogenese der CED offen und bedurfen weiterer Untersuchung.

Tumor necrosis factor (TNF) plays a pivotal role in the pathogenesis of Crohn's disease (CD). However, little is known about the role of TNF receptors (TNF-R) in this disease. Here, we found that TNF-R2 (in contrast to TNF-R1) was significantly up-regulated on lamina propria and peripheral blood T cells in CD compared to control patients. To directly test the functional role of TNF-R2 in Th1-mediated experimental colitis in vivo, we took advantage of transgenic animals overexpressing TNF-R2 in T cells. Reconstitution of SCID mice with CD4+ CD62L+ T cells from TNF-R2 transgenic mice led to an earlier wasting syndrome, a more severe colitis and augmented Th1 cytokine production than reconstitution with cells from wild-type littermates. In addition, TUNEL staining revealed a significantly decreased apoptosis rate of lamina propria mononuclear cells in mice reconstituted with TNF-R2 transgenic T cells compared to mice reconstituted with wild-type T cells. In summary, our data suggest a critical regulatory role of TNF-R2 signaling for disease exacerbation in Th1-mediated chronic colitis. Taken together with the increased expression of TNF-R2 inCD, selective targeting of TNF-R2 signaling thus emerges as a potentially novel approach to the treatment of CD.

The balance between pro and antiinflammatory cytokines secreted by T cells regulates both the initiation and perpetuation of inflammatory bowel diseases (IBD). In particular, the balance between interferon (IFN)-gamma/interleukin (IL)-4 and transforming growth factor (TGF)-beta activity controls chronic intestinal inflammation. However, the molecular pathways that evoke these responses are not well understood. Here, we describe a critical role for the transcription factor T-bet in controlling the mucosal cytokine balance and clinical disease. We studied the expression and function of T-bet in patients with IBD and in mucosal T cells in various T helper (Th)1- and Th2-mediated animal models of chronic intestinal inflammation by taking advantage of mice that lack T-bet and retroviral transduction techniques, respectively. Whereas retroviral transduction of T-bet in CD62L(+) CD4(+) T cells exacerbated colitis in reconstituted SCID mice, T-bet-deficient T cells failed to induce colitis in adoptive transfer experiments suggesting that overexpression of T-bet is essential and sufficient to promote Th1-mediated colitis in vivo. Furthermore, T-bet-deficient CD62L(-) CD4(+) T cells showed enhanced protective functions in Th1-mediated colitis and exhibited increased TGF-beta signaling suggesting that a T-bet driven pathway of T cell activation controls the intestinal balance between IFN-gamma/IL-4 and TGF-beta responses and the development of chronic intestinal inflammation in T cell-mediated colitis. Furthermore, TGF-beta was found to suppress T-bet expression suggesting a reciprocal relationship between TGF-beta and T-bet in mucosal T cells. In summary, our data suggest a key regulatory role of T-bet in the pathogenesis of T cell-mediated colitis. Specific targeting of this pathway may be a promising novel approach for the treatment of patients with Crohn's disease and other autoimmune diseases mediated by Th1 T lymphocytes.

The differential diagnosis of ulcerative colitis from Crohn's disease is of pivotal importance for the management of inflammatory bowel diseases, as both entities involve specific therapeutic management strategies. Confocal laser endomicroscopy (CLE) allows on-demand, in vivo characterization of architectural and cellular details during endoscopy. The aim of this study was to assess the efficacy of CLE to differentiate between ulcerative colitis and Crohn's disease.This was a prospective study involving consecutive patients with a well-established diagnosis of ulcerative colitis or Crohn's disease who underwent colonoscopy with fluorescein-aided confocal imaging.Overall, 79 patients were included (40 Crohn's disease, 39 ulcerative colitis). CLE findings in patients with Crohn's disease, showed significantly more discontinuous inflammation (87.5 % vs. 5.1 %), focal cryptitis (75.0 % vs. 12.8 %), and discontinuous crypt architectural abnormality (87.5 % vs. 10.3 %) than in ulcerative colitis (P 0.0001). Conversely, ulcerative colitis was associated with severe, widespread crypt distortion (87.2 % vs. 17.5 % in Crohn's disease), decreased crypt density (79.5 % vs. 22.5 %), and frankly irregular surface (89.7 % vs. 17.5 %; P 0.0001 for all comparisons). Statistically significant differences were not seen for heavy, diffuse lamina propria cell increase or mucin preservation. No granulomas were visible. Based on these findings, a CLE scoring system was developed that revealed excellent accuracy (93.7 %) when compared with the historical clinical diagnosis and the histopathological gold standard.CLE could visualize several disease-specific microscopic features, which are conventionally used in standard histopathology to differentiate between ulcerative colitis and Crohn's disease. However, because of the limited penetration depth of CLE, submucosal details or granulomas were not visible. The new scoring system may allow in vivo diagnosis of ulcerative colitis or Crohn's disease. Trial registered at ClinicalTrials.gov: NCT 02238665.

Background & aims: Ileo-colonic strictures are common complication of Crohn’s disease (CD), and may result in repeated endoscopic or surgical therapy with a risk of further complications, such as perforation or short bowel syndrome. Strictures develop as a consequence of tissue remodelling and fibrosis due to chronic inflammation. This study compares the outcome of CD patients undergoing primarily endoscopic treatment with those undergoing surgery at an university hospital. Methods: In this study we retrospectively included 88 CD patients with intestinal strictures (37 males, 51 females, mean age 40 years, range 19-65 years) of both our medical and our surgical department, who underwent either surgical or endoscopic therapy between January 2002 and January 2006 with prospective, controlled follow-up, extended till January 2010 (mean follow-up period: 5 years; range 4-8 years). The primary end-point was operation- and symptom-free time. Patients were primarily divided into four groups: only surgical therapy, only endoscopic therapy, endoscopy with subsequent surgery, and initial surgical therapy followed by endoscopic dilations. Results: 53% of all patients remained surgery-free with mean follow-up of 49 months; a single endoscopic dilation was sufficient enough in 9 patients to achieve a surgery-free time of 51 months, other patients required up to 5 dilations. The average interval between first and second dilation was 6.5 months, between second and third 10.5 months. In the group of patients with only endoscopic therapy, surgery- and symptom-free time was shorter, as compared to the group of only surgical therapy. We found that stenoses in the surgical group with an average length of 6.5 cm were as expected longer, as compared to the endoscopic group (3 cm, ranging from 2-4 cm). The surgery-free time was 49 months (42-71 months, P = 0.723) with a symptom-free time of 12 months (4.5-46 months, P = 0.921). In the group of only surgically treated patients, 68.4% of the patients had only one stenosis, 18.4% had 2-3 stenoses and 13.2% more than 3 stenoses. In all patients the surgery- and symptoms- free time was 69 months (57-83 months, P = 0.850 and 0.908). The other two groups showed similar results. We found no significant effect of characteristic of stenosis (length, inflammation, the number of stenoses), injection of prednisolone, disease activity at the time of dilation and medication at the time of dilation on the long-term outcome. Importantly, the success of symptom free time correlated with the diameter of the balloon. Conclusions: Endoscopic dilation should be considered as a first-line therapy for short, accessible, fibrotic strictures. Careful patient selection and proper diagnostic imaging pre-procedure are essential requirements for safe and successful treatment. The balloon diameter seems to correlate positively with the long term outcome of dilation. However, at ever shorter intervals between endoscopic interventions, surgery should be discussed as an option for further treatment.

The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with CD, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-sIL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.