Ulcerative Colitis-Diagnostic and Therapeutic Algorithms.

BACKGROUND: Ulcerative colitis is a chronic inflammatory bowel disease with an estimated 150 000 patients in Germany alone. METHODS: This review is based on publications about current diagnostic and therapeutic strategies for ulcerative colitis that were retrieved by a selective search in PubMed, and on current guidelines. RESULTS: The primary goal of treatment is endoscopically confirmed healing of the mucosa. Mesalamine, in various forms of administration, remains the standard treatment for uncomplicated ulcerative colitis. Its superiority over placebo has been confirmed in meta-analyses of randomized, controlled trials. Glucocorticoids are highly effective in the acute treatment of ulcerative colitis, but they should only be used over the short term, because of their marked side effects. Further drugs are available to treat patients with a more complicated disease course of ulcerative colitis, including azathioprine, biological agents, JAK inhibitors (among them TNF antibodies, biosimilars, ustekinumab, vedolizumab, and tofacitinib), and calcineurin inhibitors. Proctocolectomy should be considered in refractory cases, or in the presence of high-grade epithelial dysplasia. Ulcerative colitis beginning in childhood or adolescence is often characterized by rapid progression and frequent comorbidities that make its treatment a special challenge. CONCLUSION: A wide variety of drugs are now available for the treatment of ulcerative colitis, enabling the individualized choice of the best treatment for each patient. Regular surveillance colonoscopies to rule out colon carcinoma should be scheduled at intervals that depend on risk stratification.

Instant evaluation of contrast enhanced endoscopic ultrasound helps to differentiate various solid pancreatic lesions in daily routine.

BACKGROUND: Contrast enhanced harmonic endoscopic ultrasound (CEH-EUS) is a spreading technique; some studies have shown its value in the diagnosis of pancreatic adenocarcinoma using quantitative analysis. AIM: To examine the value of CEH-EUS for differentiating various pancreatic lesions in everyday routine with qualitative and quantitative analysis. METHODS: Data of 55 patients with pancreatic lesions who underwent CEH-EUS were analysed retrospectively. Perfusion characteristics were classified by the investigator qualitatively immediately upon investigation, quantitative analysis was performed later on. Samples from fine needle aspiration (EUS-FNA) or surgical specimen served as gold standard. RESULTS: CEH-EUS showed 39 hypoenhanced lesions, 3 non-enhanced and 13 hyperenhanced lesions. Concordance of the investigators qualitative classification of peak contrast enhancement with quantitative analysis later on was 100%, while other parameters such as arrival time, time to peak or area under the curve did not show additional value. 34 of 39 hypoenhanced lesions were pancreatic adenocarcinoma; of the hyperenhanced lesions 4 were inflammatory, 3 neuroendocrine carcinomas, 1 lymphoma, 1 insulinoma and 4 metastases (2 of renal cell carcinoma, 2 of lung cancer). Non-enhanced lesions showed up as necroses. Sensitivity for the detection of pancreatic adenocarcinoma was 100%, specificity 87.2% for hypoenhancement alone; in otherwise healthy pancreatic tissue all hypoenhanced lesions were pancreatic adenocarcinoma (sensitivity and specificity 100%, PPV and NPV for adenocarcinoma 100%). CONCLUSION: This study again shows the excellent value of CEH-EUS in everyday routine for diagnostics of various focal pancreatic lesions suggesting that qualitatively assessed hypoenhancement is highly predictive for adenocarcinoma. Additional quantitative analysis of perfusion parameters does not add diagnostic yield. In case of the various hyperenhanced pancreatic lesions in our data set, histologic sampling is essential for further treatment.

New melanocortin-like peptide of E. coli can suppress inflammation via the mammalian melanocortin-1 receptor (MC1R): possible endocrine-like function for microbes of the gut.

E. coli releases a 33 amino acid peptide melanocortin-like peptide of E. coli (MECO-1) that is identical to the C-terminus of the E. coli elongation factor-G (EF-G) and has interesting similarities to two prominent mammalian melanocortin hormones, alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropin (ACTH). Note that MECO-1 lacks HFRW, the common pharmacophore of the known mammalian melanocortin peptides. MECO-1 and the two hormones were equally effective in severely blunting release of cytokines (HMGB1 and TNF) from macrophage-like cells in response to (i) endotoxin (lipopolysaccharide) or (ii) pro-inflammatory cytokine HMGB-1. The in vitro anti-inflammatoty effects of MECO-1 and of alpha-MSH were abrogated by (i) antibody against melanocortin-1 receptor (MC1R) and by (ii) agouti, an endogenous inverse agonist of MC1R. In vivo MECO-1 was even more potent than alpha-MSH in rescuing mice from death due to (i) lethal doses of LPS endotoxin or (ii) cecal ligation and puncture, models of sterile and infectious sepsis, respectively.

The use of ultrasound in inflammatory bowel disease.

Imaging in inflammatory bowel disease (IBD) plays a pivotal role in the primary diagnosis, as well as during the management of patients with known IBD. The evolution of ultrasound equipment and the growing expertise of examiners have both enhanced the role of intestinal ultrasound in the assessment of the gastrointestinal tract in IBD patients. Intestinal ultrasound has been shown to have high sensitivity and specificity, as well as high positive and negative predictive value, in the detection or exclusion of intestinal inflammatory activity in IBD. The obvious advantages of intestinal ultrasound over other imaging modalities include non-invasiveness, rapid availability and low costs. This review summarizes the current developments in the use of intestinal ultrasound for the detection of IBD and its complications, and discusses its use in the management of patients with IBD. Indications for the use of intestinal ultrasound in daily practice are presented, expanded by new developments such as contrast-enhanced ultrasonography and elastography.

Bowel Ultrasonography in the Management of Crohn's Disease. A Review with Recommendations of an International Panel of Experts.

BACKGROUND: Bowel ultrasonography (US) is considered a useful technique for assessing mural inflammation and complications in Crohn's disease (CD). The aim of this review is to appraise the evidence on the accuracy of bowel US for CD. In addition, we aim to provide recommendations for its optimal use. METHODS: Publications were identified by literature search from 1992 to 2014 and selected based on predefined criteria: 15 or more patients; bowel US for diagnosing CD, complications, postoperative recurrence, activity; adequate reference standards; prospective study design; data reported to allow calculation of sensitivity, specificity, agreement, or correlation values; articles published in English. RESULTS: The search yielded 655 articles, of which 63 were found to be eligible and retrieved as full-text articles for analysis. Bowel US showed 79.7% sensitivity and 96.7% specificity for the diagnosis of suspected CD, and 89% sensitivity and 94.3% specificity for initial assessment in established patients with CD. Bowel US identified ileal CD with 92.7% sensitivity, 88.2% specificity, and colon CD with 81.8% sensitivity, 95.3% specificity, with lower accuracy for detecting proximal lesions. The oral contrast agent improves the sensitivity and specificity in determining CD lesions and in assessing sites and extent. CONCLUSIONS: Bowel US is a tool for evaluation of CD lesions in terms of complications, postoperative recurrence, and monitoring response to medical therapy; it reliably detects postoperative recurrence and complications, as well as offers the possibility of monitoring disease progression.

Clinic-based Point of Care Transabdominal Ultrasound for Monitoring Crohn's Disease: Impact on Clinical Decision Making.

BACKGROUND AND AIMS: The use of cross-sectional imaging is important to characterise inflammatory bowel disease [IBD] activity, extent, and location and to exclude complications, regardless of symptoms. The aim of this study was to evaluate the impact of routine use of sonography in the management of inflammatory bowel disease. METHODS: A total of 49 patients with Crohn's disease were prospectively evaluated. Clinical symptoms (Harvey-Bradshaw Index [HBI]), disease character, serological markers of inflammation [C-reactive protein], and endoscopic evaluation were collected and reviewed by two independent IBD-specialty physicians. Clinical decisions regarding management were recorded. A separate, blinded physician then performed bowel ultrasound [US] and graded disease activity:] as inactive, mild, or active. A second blinded physician read and graded a sub-set of the US images. Clinical decisions of both IBD-physicians after US were independently recorded. Changes in clinical management following US information and inter-rater agreement on US disease activity parameters were evaluated. The concordance between US, CRP and clinical symptoms [HBI] were analysed. Follow-up data after US evaluation were collected. RESULTS: Clinical decisions were changed after ultrasound assessment in 30/49 [60%] and 28/48 [58%] of cases, for each physician respectively [p < 0.0001 for each]. Many [59%] of the patients seen in clinic were asymptomatic with an HBI of 3 or less [n = 29]; however, 52% [n = 15] of these had active disease found on US, resulting in alterations in clinical management. The agreement in overall score between the US reviewers was good, ĸ = 0.749 [0.5814, 0.9180], p < 0.001. CONCLUSIONS: Clinic-based point of care US can play a significant role in guiding therapeutic management and is an important adjunct to routine clinical and laboratory assessment.

Contrast-enhanced harmonic endoscopic ultrasound is able to discriminate benign submucosal lesions from gastrointestinal stromal tumors.

BACKGROUND: Although endoscopic ultrasound (EUS) has improved the diagnostic of potential malignancies, gastric lesions with suspicion of gastrointestinal stromal tumors (GIST) or benign lesions like lipoma or leiomyoma can often not be accurately differentiated by EUS, therefore, requiring tissue sampling with the risk of bleeding complications especially in GIST. As with the newest generation of EUS machines, contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) has become a new option to determine perfusion characteristics. The aim of this analysis was to evaluate whether CEH-EUS may help to discriminate various submucosal lesions. METHODS: Data sets of 17 patients with suspicious gastric or esophageal lesions, who were investigated with CEH-EUS were analyzed. Perfusion characteristics were classified by the investigator immediately and statistically analyzed after investigation. Samples from EUS-fine needle aspirates, biopsy samples after needle cut or surgical specimen served as gold standard. RESULTS: CEH-EUS showed nine lesions with reduced contrast enhancement (maximum intensity 6.2 ± 1.9 db) and eight lesions with hyperenhancement (47.3 ± 11.6 db). The latter eight lesions were all histologically identified as GIST, while the nine hypoenhanced lesions emerged to be four lipoma and five leiomyoma. Statistical analysis corresponded with initial perfusion classification in all cases. CONCLUSION: This is the first study showing that CEH-EUS can discriminate GIST from benign lesions with good accuracy. In the future, CEH-EUS-guided discrimination may lead to individualized diagnostic and therapeutic strategies in handling submucosal lesions.

Detection and differentiation of inflammatory versus fibromatous Crohn's disease strictures: prospective comparison of 18F-FDG-PET/CT, MR-enteroclysis, and transabdominal ultrasound versus endoscopic/histologic evaluation.

BACKGROUND: Differentiation between inflammatory and fibromatous strictures in Crohn's disease (CD) is difficult but crucial for therapeutic decisions. The aim of this study was to assess the best noninvasive imaging method for the detection and differentiation of inflammatory and fibromatous stenoses in CD in comparison to endoscopic and histologic evaluation. METHODS: Patients with suspected CD strictures were included. According to a formalized endoscopic and histologic protocol, strictures were classified as inflammatory, mixed, and fibrostenotic. Strictures were further analyzed using fluorine 18-labeled fluoro-2-deoxy-D-glucose ((18) FDG) / positron emission tomography (PET) low-dose computed tomography (CT), magnetic resonance (MR) enteroclysis and transabdominal ultrasound using standardized scoring systems. RESULTS: Thirty patients with 37 strictures were evaluated (inflamed n = 22; mixed n = 12, fibromatous n = 3). (18) FDG-PET/CT detected 81%, MR-enteroclysis 81%, and ultrasound 68% of the strictures. Correct differentiation rates of strictures were 57% for MRE, 53% for (18) FDG-PET/CT, and 40% for ultrasound. Differences of detection rates and differentiation rates were not statistically significant. When combining transabdominal ultrasound with (18) FDG-PET/CT or MR-enteroclysis all strictures that required invasive treatment were detected. CONCLUSIONS: Detection rates of the strictures were not significantly different between (18) FDG-PET/CT, MR-enteroclysis, and ultrasound. Despite good stricture detection rates relating to our gold standard, (18) FDG-PET/CT nor MR-enteroclysis nor ultrasound can accurately differentiate inflamed from fibrotic strictures. A combination of MR-enteroclysis and ultrasound as well as a combination of (18) FDG-PET/CT and ultrasound resulted in a 100% detection rate of strictures requiring surgery or endoscopic dilation therapy, suggesting the combination of these methods as an alternative to endoscopy at least in the group of patients not able to perform an adequate bowel preparation.

The tripeptide KdPT protects from intestinal inflammation and maintains intestinal barrier function.

Treatment options for inflammatory bowel disease (IBD) are incompletely helpful, and surgery is often needed. One promising class of future therapeutic agents for IBD is melanocortin-related peptides, which exhibit potent immunomodulatory effects. We investigated KdPT, a tripeptide derivative of the C-terminus of α-melanocyte-stimulating hormone, as an anti-inflammatory small molecule in vivo and in vitro. Intestinal inflammation was studied after oral administration of dextran sodium sulfate and in IL-10 gene-deficient mice. The effects of KdPT on key colonic epithelial cell functions were studied in vitro and in vivo by evaluating proliferation, wound healing, transepithelial resistance, and expression of tight junction proteins. Melanin assays were performed to determine the melanotropic effects of KdPT. KdPT-treated animals showed markedly reduced severity of inflammation in both colitis models. In colonic epithelial cells, KdPT increased proliferation, accelerated closure of wounds, and improved transepithelial electrical resistance after stimulation with interferon-γ/tumor necrosis factor-α. Moreover, treatment with KdPT also prevented the loss of tight junction protein expression and improved barrier function in vivo. KdPT acted independently of IL-1 receptor type I in vivo and did not affect melanogenesis in vitro. KdPT is capable of attenuating the course of experimental colitis in different models and maintains epithelial cell function. Furthermore, KdPT does not induce pigmentation, emphasizing the potential of this small molecule for the future treatment of IBD.

The immunization status of patients with IBD is alarmingly poor before the introduction of specific guidelines.

INTRODUCTION: With immunosuppressive therapy of inflammatory bowel diseases (IBDs) becoming more aggressive, the risk of serious infections is increasing. Guidelines are currently being modified in respect to advisable immunizations. The aim of this study was to evaluate the immunization habits of IBD patients in daily practice before the implementation of specific guidelines. METHODS: Hundred and two consecutive patients attending the outpatients IBD clinic at our hospital were interviewed regarding their immunization record. In addition, hepatitis B and C, HIV, and cytomegalovirus (CMV) serostatus were measured following a European Crohn's and Colitis Organization (ECCO) consensus. RESULTS: Hundred and two patients with IBD have been included; of these 72% were taking steroids, 46% azathioprine, and 23% anti-TNF medication. Nineteen percent of the study population had been vaccinated against influenza, 3% against pneumoccous pneumonia, 22% against hepatitis B, 5% against varizella, 55% against rubella/mumps/measles, and 63% against tetanus. Of those who had traveled, 9% had been vaccinated for hepatitis A and 1% for yellow fever. Reasons given for not being vaccinated were not being aware of the necessity in 45% of those questioned and being afraid in 17%. While no patient was tested positive for hepatitis B, HIV, and CMV-IgM, one female patient was tested positive for hepatitis C (antibody and PCR positive, genotype I), which was unknown at that point. CONCLUSION: Considering the high number of our patients receiving immunosuppressive therapy, the immunization record is alarmingly poor supporting the need for optimized IBD guidelines, better awareness, and patient education. In addition, the screening for chronic infections appears to be useful as suggested by the positive finding of a previously unknown hepatitis C.

Long-term efficacy and safety of double balloon enteroscopy--prospective and retrospective data from a single center study.

OBJECTIVE: Double balloon enteroscopy (DBE) has evolved as one of the most innovative and fast spreading endoscopic procedures in the last decade. With increasing experience of performing endoscopic procedures in the mid gut outside the operating room it is necessary to investigate the effectiveness of DBE regarding therapeutic consequences, long-term efficacy as well as safety. MATERIAL AND METHODS: To address this we retrospectively analyzed all DBE performed over a period of 2 years at our department. Furthermore, in order to evaluate long-term effectiveness of DBE procedures we performed a follow-up analysis on all patients, whose DBE procedure was at least 6 months ago. In addition, 100 consecutive patients who underwent DBE were questioned regarding procedure associated complaints using a standardized questionnaire. RESULTS: Retrospective analysis of all DBE procedures performed in our department before November 2006 (n = 545) revealed an overall diagnostic yield of 39.7% and a therapeutic yield of 31.1%. The overall number of major complications accounted to 0.9%. Follow-up analysis revealed a long-term effect of endoscopic interventions in more than 50%, while in those patients with an initially negative DBE long-term follow-up only revealed symptom explaining findings in 17% with the majority of the other patients being asymptomatic during follow-up. Regarding patient related complaints the prospective analysis showed that DBE procedures in general are well tolerated with the most common complaint being meteorism. CONCLUSIONS: DBE showed to be a relatively safe and well tolerated procedure. However, more sensitive algorithms are needed to enhance the therapeutic results.

Molecular pathogenesis of inflammatory bowel disease: relevance for novel therapies.

The immense load of microorganisms within the gastrointestinal tract is a great challenge for the mucosal immune system. Whereas the vast majority of commensal bacteria should be tolerated, pathogenic organisms have to be attacked. During inflammatory bowel disease, the balanced interaction between the mucosal flora and the intestinal immune system is disturbed. Various defective components of this complex interaction have been described, such as different susceptibility genes, impaired innate immune responses and environmental factors, suggesting that inflammatory bowel diseases are multifactorial diseases. Based on new insights into the pathogenesis of inflammatory bowel disease, various targets for future drugs have been identified and new substances are emerging. The following article will review the current understanding of inflammatory bowel disease pathogenesis in context with genetic risk factors, imbalanced innate and acquired immune responses, and altered barrier function. Clinical treatment of the diseases will be summarized and emerging therapies as well as individual management based on recent insights into pathogenesis will be discussed.

Melanocortin-derived tripeptide KPV has anti-inflammatory potential in murine models of inflammatory bowel disease.

BACKGROUND: Despite some progress in recent years, the options for treating inflammatory bowel disease (IBD) are still dissatisfying, and surgery rates are still high. The anti-inflammatory effects of melanocortin peptides such as alpha-melanocyte-stimulating hormone (alpha-MSH) have been described recently in, for example, dextran sodium sulfate (DSS) colitis in mice. The aim of this study was to investigate the therapeutic potential of the melanocortin-derived tripeptide alpha-MSH(11-13) (KPV) and its mode of action in 2 models of intestinal inflammation. METHODS: The anti-inflammatory activity of KPV was analyzed in 2 well-described models of IBD: DSS colitis, and CD45RB(hi) transfer colitis. Furthermore, animals expressing a nonfunctional melanocortin-1 receptor (MC1Re/e) received DSS for induction of colitis and were treated with KPV. The course of inflammation was monitored by weight loss and histological changes in the colon as well as by myeloperoxidase (MPO) activity. RESULTS: In the DSS-colitis model, treatment with KPV led to earlier recovery and significantly stronger regain of body weight. Histologically, inflammatory infiltrates were significantly reduced in KPV-treated mice, which was confirmed by the significant reduction of MPO activity in colonic tissue after KPV treatment. Supporting these findings, KPV treatment of transfer colitis led to recovery, regain of body weight, and reduced inflammatory changes histologically. In MC1Re/e mice, KPV treatment rescued all animals in the treatment group from death during DSS colitis. CONCLUSIONS: The melanocortin-derived tripeptide KPV showed significant anti-inflammatory effects in 2 murine models of colitis. These effects seem to be at least partially independent of MC1R signaling. In conclusion, our data suggest KPV as an interesting therapeutic option for the treatment of IBD.

Role of the melanocortin system in inflammation.

In recent years, scientific interest in melanocortins (MC) has progressively increased due to their wide range of effects and expression on various tissues. Primarily discovered as mediators of skin pigmentation, recent research has shown their important roles in various body functions, such as energy homeostasis, sexual function, and inflammation. The anti-inflammatory and immunomodulatory properties discovered so far have led to the hypothesis that alpha-melanocyte-stimulating hormone (MSH) and its cognate receptors might present potential anti-inflammatory treatment options.