Extra-intestinal malignancies in inflammatory bowel disease: Results of the 3rd ECCO Pathogenesis Scientific Workshop (III)

The incidence of lymphoproliferative disorders (LD) is increasing in developed countries. Patients with inflammatory bowel disease (IBD) exposed to thiopurines are at additional risk of three specific forms of LD: Epstein-Barr-Virus-related post-transplant like LD, hepato-splenic T-cell lymphoma and post-mononucleosis lymphoproliferation. The risk of the two latter forms of LD can be reduced when considering specific immunosuppressive strategies in young males. It is still unclear whether the risk of uterine cervix abnormalities is increased in IBD women, irrespective of the use of immunosuppressants. Given the excess risk demonstrated in various other contexts of immunosuppression, it is currently recommended that all women with IBD, particularly those receiving immunosuppressants, strictly adhere to a screening program of cervical surveillance and undergo vaccination against HPV, when appropriate. Patients with IBD receiving immunosuppressants are at increased risk of skin cancers. The risk of non-melanoma skin cancer is notably increased in patients receiving thiopurines. Recent data suggest that the risk of melanoma is mildly increased in patients exposed to anti-TNF therapy. All IBD patients should adhere to a program of sun protection and dermatological surveillance, whose details should take into account the other non-IBD-related risk factors.     

Colorectal cancer in inflammatory bowel disease: Results of the 3rd ECCO pathogenesis scientific workshop (I)

Epidemiological studies demonstrate an increased risk of colorectal cancer in patients with inflammatory bowel disease (IBD). A detailed literature review was conducted on epidemiology, risk factors, pathophysiology, chemoprevention and outcomes of colorectal cancer (CRC) in IBD as part of the 3rd ECCO scientific pathogenesis workshop.     

Results from the 2nd Scientific Workshop of the ECCO (I): Impact of mucosal healing on the course of inflammatory bowel disease

Over the past years, mucosal healing has emerged as a major therapeutic goal in clinical trials in inflammatory bowel diseases. Accumulating evidence indicates that mucosal healing may change the natural course of the disease by decreasing the need for surgery and reducing hospitalization rates in both ulcerative colitis and Crohn's disease. Mucosal healing may also prevent the development of long-term disease complications, such as bowel damage in Crohn's disease and colorectal cancer in ulcerative colitis. Histologic healing may be the ultimate therapeutic goal in ulcerative colitis, whereas its impact on the course of Crohn's disease is unknown. Complete mucosal healing may be required before considering drug withdrawal. Targeting early Crohn's disease is more effective than approaches aimed at healing mucosa in longstanding disease. Several questions remain to be answered: should mucosal healing be systematically used in clinical practice? Should we optimize therapies to achieve mucosal healing? What is the degree of intestinal healing that is required to change the disease course? Large prospective studies addressing these issues are needed.     

Results of the 2nd scientific workshop of the ECCO (IV): Therapeutic strategies to enhance intestinal healing in inflammatory bowel disease

Evidence supporting the importance of assessment of mucosal healing in inflammatory bowel disease has increased in the last years. Mucosal healing has been integrated in the assessment of treatment efficacy in ulcerative colitis, but in Crohn's disease this thought has arised after biological agents have been evaluated in clinical trials. Although a validated definition of mucosal healing still does not exist, its use is also assuming an increasingly important role in the follow-up of individual patients in clinical practice. Corticosteroids induce mucosal healing in a small proportion of patients with Crohn's disease and are of no benefit to maintain it. By contrast, mucosal healing in Crohn's disease can be achieved and maintained, with varying degrees of evidence and success, with thiopurines and biological agents. In ulcerative colitis, the ability of corticosteroids to induce mucosal healing is well recognized. 5-aminosalicylates, thiopurines and biological agents are also able to induce mucosal healing and, additionally, to maintain it. Mucosal healing assessment should be considered in clinical practice when symptoms persist despite therapy or when treatment discontinuation is being considered. Conversely, in patients whose clinical remission is not associated with mucosal healing, intensification of treatment is not currently recommended because of lack of evidence.     

ECCO position statement: The use of biosimilar medicines in the treatment of inflammatory bowel disease (IBD)

Biologics have become key agents for the management of Crohn’s disease and ulcerative colitis. Biosimilars are biological medicines similar to previously authorized biologics and are already available in some countries. This ECCO Position Statement defines the collective view of European specialist in inflammatory bowel disease (IBD) concerning biosimilars. Biosimilars are not comparable to generic small molecules, since both efficacy and toxicity are difficult to predict due to subtle molecular changes that can have profound effects on clinical efficacy and immunogenicity. Direct evidence of safety and benefit from clinical trials in IBD, post-marketing pharmacoviligance, and unequivocal identification of the product as a biosimilar should be requirements before approval. Switching from an established biologic to a biosimilar to save costs is likely to be as inappropriate and inefecctive as switching between current biologics that act on the same target, except when there is loss of response.     

Results of the 2nd part Scientific Workshop of the ECCO (II): Measures and markers of prediction to achieve, detect, and monitor intestinal healing in Inflammatory Bowel Disease

The healing of the intestine is becoming an important objective in the management of inflammatory bowel diseases. It is associated with improved disease outcome. Therefore the assessment of this healing both in clinical studies and routine practice is a key issue. Endoscopy for the colon and terminal ileum and computerized tomography or magnetic resonance imaging for the small bowel are the most direct ways to evaluate intestinal healing. However, there are many unsolved questions about the definition and the precise assessment of intestinal healing using these endoscopic and imaging techniques. Furthermore, these are relatively invasive and expensive procedures that may be inadequate for regular patients' monitoring. Therefore, biomarkers such as C-reactive protein and fecal calprotectin have been proposed as surrogate markers for intestinal healing. Nevertheless, the sensitivity and specificity of these markers for the prediction of healing may be insufficient for routine practice. New stool, blood or intestinal biomarkers are currently studied and may improve our ability to monitor intestinal healing in the future.     

炎症性肠病的发病机制

在过去几年中,炎症性肠病(IBD)病理生理学领域的研究取得了长足的进步,其发病机制可归纳为五个方面:①遗传易感性;②屏障功能;③肠道菌群;④天然免疫;⑤适应性免疫.     

Role of the intestinal barrier in inflammatory bowel disease

A critical function of the intestinal mucosa is to form a barrier that separates luminal contents from the interstitium. The single layer of intestinal epithelial cells （IECs） serves as a dynamic interface between the host and its environment. Cell polarity and structural properties of the epithelium is complex and is important in the development of epithelial barrier function. Epithelial cells associate with each other via a series of intercellular junctions. The apical most intercellular junctional complex referred to as the Apical Junction Complex （AJC） is important in not only cell-cell recognition, but also in the regulation of paracellular movement of fluid and solutes. Defects in the intestinal epithelial barrier function have been observed in a number of intestinal disorders such as inflammatory bowel disease （IBD）. It is now becoming evident that an aberrant epithelial barrier function plays a central role in the pathophysiology of IBD. Thus, a better understanding of the intestinal epithelial barrier structure and function in healthy and disease states such as IBD will foster new ideas for the development of therapies for such chronic disorders.     

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.     

炎症性肠病的胃肠动力学改变

炎症性肠病（inflammatory bowel disease,IBD）是一种原因不明的顽固性难治的慢性非特异性肠炎,主要包括溃疡性结肠炎（ulcerative colitis,UC）和克罗恩病（Crohn’s disease,CD）。它的发病在我国呈逐渐上升的趋势,然而其病因和发病机制尚不明确。目前认为它是环境、遗传、病原体和机体免疫等多因素相互作用失衡产生的疾病。IBD的特点之一是慢性肠道炎症伴随有动力方面的改变。近年来,关于IBD与肠道动力之间关系的研究已经受到越来越多的关注,并已成为IBD发病机制研究的一大热点。     

Immunohistochemical study of intestinal eosinophils in inflammatory bowel disease

BACKGROUND: Eosinophil accumulation and activation are characteristic features of inflammation in allergic diseases and in host defense against parasites. GOALS: To investigate the involvement of eosinophils in inflamed and noninflamed mucosa of patients with inflammatory bowel disease (IBD). STUDY: Specimens of inflamed colonic mucosa from 15 patients with ulcerative colitis (UC) and inflamed and noninflamed colonic mucosa from 15 patients with Crohn's disease (CD) were submitted to histologic and immunohistochemical studies. Twelve patients with irritable bowel syndrome were studied as controls. Sirius red was used to label eosinophils in tissue. EG1, EG2, and anti-hIL-5 were used as primary antibodies in an indirect alkaline phosphatase-labeled immunostaining protocol. Both positive and negative lamina propria cells were assessed by a quantitative grading system and the results expressed as cell numbers per mm. RESULTS: Increased proportions of eosinophils stained with Sirius red, EG1, EG2, and anti-hIL-5+ cells were found in the colon of patients with UC and in inflamed and noninflamed colon of CD patients as compared with controls. Crohn's disease patients showed increased proportions of EG1+ and EG2+ cells as compared with those with UC. Increased proportions of IL-5+ cells were detected in UC patients as compared with those with CD. CONCLUSION: Quantitative eosinophil alterations and IL-5+ cells may indicate enhanced cellular activation with degranulation, which is implicated in the pathogenesis of IBD. Increase in IL-5+ cells may reflect a predominant local Th2 response in UC as compared with CD.     

Surgical treatment of intestinal stricture in inflammatory bowel disease

Fibroblast infiltration and collagen deposition result in structural changes in the bowel wall, and lead to strictures in intestinal inflammatory disease. While strictures can also occur in other contexts, such as malignancy, this review focuses on the surgical treatment of stricture secondary to inflammatory bowel disease. Distinguishing between predominantly inflammation vs established fibrosis as the cause of a stricture can be challenging. While inflammatory strictures may be responsive to medication, predominantly fibrotic strictures usually need surgical intervention. Both endoluminal and extraluminal approaches are described in this review. Endoscopic dilatation of strictures is suitable for short‐segment isolated small bowel strictures. Other options are to divide the stricture surgically but preserve the length, performing a strictureplasty or resecting the strictured segment. The mesentery is increasingly recognized as playing a role in stricture recurrence. In a relapsing‐remitting disease such as Crohn's disease, the preservation of intestinal length is essential and balance is needed between this and a complete resection to reduce the risk of recurrence. Pre‐ and postoperative involvement of the multidisciplinary team is essential to improve outcomes in this challenging clinical scenario.     

Influences of intestinal bacteria in human inflammatory bowel disease

Microbes that reside in the human intestinal tract and interact with immune and epithelial cells are strongly implicated as causative or predisposing agents of inflammatory bowel disease (IBD). Recent studies using metagenomic approaches have revealed differences in the fecal and mucosa-associated microbiota of patients with IBD, but it remains unclear whether this is a cause or consequence of chronic intestinal inflammation. A few microbes have been singled out as candidate pathogens in IBD and remain the subject of ongoing study. Complex imbalances in gut bacterial community structure and/or deficiencies in their functional capabilities may be a greater issue in IBD development. A more complete understanding of host-microbiota interactions in IBD is hampered by several remaining but surmountable methodological and technical challenges.     

Lymphocyte subpopulations of intestinal mucosa in inflammatory bowel disease.

Lymphocyte subpopulations in peripheral blood (PBL) and intestinal mucosa (IML) of 10 patients with inflammatory bowel disease (IBD) were compared with those of 11 non-IBD controls. PBL were separated on Ficoll/hypaque gradients, and IML were isolated by incubation in dithiothreitol, EDTA, and collagenase. These methods yielded cells of good viability and with intact HLA A and B-antigens. T-cells, identified by neuraminidase-treated sheep RBC rosettes and non-specific esterase staining, comprised approximately 91% of the IML from normal mucosa of all groups. B-cells, identified by erythrocyte-antibody-complement rosettes and surface immunoglobulins, were only 7% of these IML populations. Cell yields were two-fold or more greater from abnormal IBD mucosa, with T-cells ranging from 55 to 95% and B-cells from 2 to 36%. The percentage of Fc receptor bearing cells was low in all specimens. By these methods, T-lymphocytes predominated in intestinal mucosa of both IBD and non-IBD patients, but there is marked increase in the percentage of B-cells isolated from abnormal mucosa in IBD.     

Transepithelial transport processes at the intestinal mucosa in inflammatory bowel disease

Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) of unknown etiology. Oral absorption studies have shown an increased intestinal permeability for various sugar molecules in patients with IBD and their healthy relatives as a possible pathogenetic factor. However, the various transport pathways through the mucosal barrier have not yet been examined. This study therefore investigated whether antigens pass the epithelial barrier by a transcellular or a paracellular pathway. Mucosa of freshly resected specimens from CD (n = 10) or UC (n = 10) patients was investigated by immunoelectron microscopy and compared with healthy mucosa. Epithelial transport was studied with the antigens ovalbumin and horseradish peroxidase after defined incubation. Labeling density of subunit c of ATP synthetase was determined in mitochondria of enterocytes of all specimens. In all specimens epithelial transport of OVA and HRP was principally transcellular through enterocytes with normal ultrastructure, although some tight junctions in CD and UC were dilated. Antigens were transported within vesicles to the basolateral membrane 2.5 min after incubation. The level of enterocytes with electron-lucent cytoplasm containing a high amount of antigens was higher in CD and UC than in healthy mucosa, depending on the grade of inflammation. ATP synthetase was significantly decreased in electron-lucent cytoplasm of CD and UC to normal ultrastructure of healthy mucosa. Our study shows that ovalbumin and horseradish peroxidase taken up by the apical membrane reach the paracellular space by vesicular transport in healthy and IBD enterocytes within a few minutes. Transcellular pathway is affected in both CD and UC, which is indicated by a high level of antigens within the cytosol. We speculate that increased intestinal permeability in IBD results substantially from enhanced transcellular transport. Accepted: 4 January 1999