Review article: biological activity markers in inflammatory bowel disease

BACKGROUND: Traditionally, inflammatory bowel disease activity is assessed by clinical activity indices that measure clinical symptoms and endoscopic indices that measure endoscopic inflammation. Biological markers are a non-invasive way of objectively measuring inflammation and can play an adjunctive or primary role in the assessment of disease activity. AIM: To review the data on biological markers for assessment of disease activity and prediction of relapse in inflammatory bowel disease. METHODS: To collect relevant articles, a PubMed search was performed from 1980 to 2006 using following search terms in combination: inflammatory bowel disease, biomarkers, inflammation, disease activity, relapse, acute phase reactants cytokines, interleukins, adhesion molecules, integrins, calprotectin and lactoferrin. RESULTS: Biological activity markers can be classified into serological, faecal and miscellaneous categories. Acute phase reactants levels correlate with disease activity and some can be used to help predict relapse. Cytokines and adhesion molecules are elevated in active disease inconsistently. Faecal markers are useful in assessment of disease activity and relapse. CONCLUSIONS: Acute phase reactants and faecal markers are useful to assess the disease activity in clinical practice. More data are required on cytokines and adhesion molecules. C-reactive protein, erythrocyte sedimentation rate, interleukins and faecal markers may be useful in predicting a relapse.     

Intestinal inflammation is a frequent feature of cystic fibrosis and is reduced by probiotic administration

AIMS: To assess the incidence of intestinal inflammation in children with cystic fibrosis and to investigate whether probiotics decrease it. STUDY DESIGN: In this two-phase, controlled, prospective study, faecal calprotectin was measured by enzyme-linked immunosorbent assay in 30 children with cystic fibrosis, 30 healthy controls and 15 children with active inflammatory bowel disease. Ten children with cystic fibrosis received Lactobacillus GG, and faecal calprotectin was re-measured 4 weeks later. Rectal nitric oxide production was measured with the rectal dialysis bag technique in 20 children with cystic fibrosis, 20 healthy controls and 15 children with inflammatory bowel disease. Five children with cystic fibrosis received Lactobacillus GG and nitric oxide was re-measured 4 weeks later. RESULTS: Mean faecal calprotectin was significantly higher in the two groups of patients than in controls. Abnormal values were detected in 27 of 30 cystic fibrosis and in 15 of 15 inflammatory bowel disease children. Also mean nitric oxide production was increased in both group of patients, and abnormal values were detected in 19 of 20 cystic fibrosis and in 15 of 15 inflammatory bowel disease children. Calprotectin and nitric oxide concentrations were reduced after probiotics administration. CONCLUSIONS: Intestinal inflammation is a major feature of cystic fibrosis and is reduced by probiotics. The latter finding suggests that intestinal microflora play a major role in intestinal inflammation in cystic fibrosis children.     

肠道菌群在炎症性肠病发病机制与治疗中的作用研究进展

炎症性肠病是一种以肠道炎症和黏膜损伤为特征的慢性疾病,主要包括克罗恩病和溃疡性结肠炎,其发病原因尚不明确。现有研究表明炎症性肠病的发病机制与宿主的遗传易感性、肠道菌群紊乱、肠黏膜屏障破坏和肠黏膜免疫异常等密切相关。总结目前炎症性肠病发病机制、患者肠道菌群结构及治疗方法等相关的研究进展,旨在对今后炎症性肠病的治疗和药物研发有所裨益。     

Prospective evaluation of faecal neutrophil-derived proteins in identifying intestinal inflammation: combination of parameters does not improve diagnostic accuracy of calprotectin

BACKGROUND: Differentiating symptoms of irritable bowel syndrome from those of organic intestinal disease is a common clinical problem. Several neutrophil-derived proteins have been proposed as a marker of inflammatory bowel disease. AIM: To compare the diagnostic value of faecal calprotectin, lactoferrin and polymorphonuclear neutrophil-elastase in distinguishing inflammatory bowel disease from irritable bowel syndrome. METHODS: Eighty-eight adult patients with a history of chronic diarrhoea of unknown origin were screened. All patients underwent a complete work-up to identify the underlying cause. In addition, a single stool sample was assayed for faecal calprotectin, lactoferrin and polymorphonuclear neutrophil-elastase by enzyme-linked immunosorbent assay. RESULTS: Within the study cohort inflammatory bowel disease was diagnosed in 45 patients and irritable bowel syndrome in 31 patients. The sensitivity and specificity of calprotectin for inflammatory bowel disease were 93% and 100%, respectively. In contrast, the respective diagnostic values for lactoferrin and polymorphonuclear neutrophil-elastase were 82% and 100% and 84% and 87%, respectively. Neither combination of markers did improve the diagnostic power compared with calprotectin alone. CONCLUSIONS: Although all faecal biomarkers studied provide a reliable and simple non-invasive means in the differentiation of inflammatory bowel disease and irritable bowel syndrome, calprotectin appears to represent the most accurate marker to discriminate between these two common causes of chronic diarrhoea.     

Involvement of coagulation and hemostasis in inflammatory bowel diseases

Inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis (UC) are idiopathic, intestinal and systemic inflammatory disorders which are immunologically mediated with the activation of plasma proteolytic cascades. The activation of coagulation in IBD is related to the activity and colonic extension of the disease, but may still be persistent in a quiescent stage. Factor XIII seems to be as much a coagulation factor as a connective tissue factor which may contribute to intestinal healing. Fibrinolytic capacity is reduced in systemic circulation of IBD patients. Platelets activation is a feature of IBD which contributes to a pathogenic inflammatory sequel. There is evidence that coagulation activation may in turn mediate and amplify inflammatory cascades in IBD, especially via activating PARs related pathways. The etiology of thromboembolism in IBD seems to be multifactorial but is largely attributable to the coagulation activation and platelet aggregation during systemic inflammation. Thromboembolic (TE) complications in both Crohn's disease and UC appear to have at least 3-4 fold increased risk of developing compared to control patients. Currently, no single TE laboratory marker has a predictive value, but a recently developed endogenous thrombin potential test may have a potentially predicative value in IBD. At present, no interaction between IBD and inherited factors of thrombophilia has been found. An efficacy of heparin treatment in UC is still controversial, although heparin is safe in UC flare. Prophylactic anticoagulation against TE is currently not fully defined, however, high - risk patients should be considered for using a moderate dose of heparin.     

Fecal lactoferrin as a noninvasive biomarker in inflammatory bowel diseases

The diagnosis and management of inflammatory bowel diseases (IBD), i.e., Crohn's disease and ulcerative colitis, still present a number of challenges. The fecal biomarker lactoferrin has been shown to be useful in the diagnosis and management of these diseases. This review includes a discussion of the current literature on lactoferrin as a biomarker of intestinal disease, detection of disease activity in IBD, comparison of lactoferrin to endoscopy and histology, lactoferrin measurement in pediatric IBD and lactoferrin as a biomarker for monitoring medical treatment in IBD.     

Nonsteroidal anti-inflammatory drugs and inflammatory bowel disease: current perspectives.

Mechanisms underlying the gastric toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) have been extensively investigated, whereas those leading to intestinal damage are not completely understood. Several hypotheses have been put forward on the pathophysiology of intestinal damage by NSAIDs: enhanced intestinal permeability, inhibition of cyclooxygenase (COX), enterohepatic recirculation, and formation of adducts. The effects of COX-2 selective inhibitors, which appear to have better gastric tolerability when compared to nonselective NSAIDs, on normal and inflamed intestinal mucosa (as in Crohn's disease or ulcerative colitis) are still largely unexplored. If COX-2 inhibition plays a key role in suppressing the inflammatory process, recent evidence suggests that COX-2 products are involved in maintaining the integrity of intestinal mucosa, in the healing of gastrointestinal ulcers and in the modulation of inflammatory bowel disease (IBD). Animal models of intestinal inflammation have so far yielded conflicting results on the effects of COX-2 selective inhibitors on the intestinal mucosa. It is now clear that NSAIDs do not act through cyclooxygenase inhibition, but also have different targets such as nuclear factor-kappaB and/or peroxisome proliferator-activated receptors gamma. The peculiar pharmacological profile of each compound may help to explain the different impact of each NSAID on the inflammatory process and on IBD. Notably, the salicylic acid derivative 5-ASA is widely used in the treatment of IBD and is believed to act through nuclear factor-kappaB inhibition. Although the use of COX-2 selective inhibitors remains contraindicated in patients with IBD, studying their effects on intestinal mucosa may offer new insights into their subcellulars mechanisms of action and open new avenues for the development of novel therapies for IBD.     

Polyphenol supplementation as a complementary medicinal approach to treating inflammatory bowel disease

Inflammatory bowel disease (IBD) comprises a group of idiopathic chronic intestinal inflammation syndromes that are very common in developed countries. It is characterized by intermittent episodes of clinical remission and relapse, with recurrent inflammatory injury that can lead to structural damage of the intestine. The uncontrolled intestinal immune response to bacterial antigens leads to the production of abundant cytokines and chemokines, by activated leukocytes and epithelial cells, which trigger inflammatory and oxidative reactions. The current treatment of IBD consists in long-term anti-inflammatory therapy that, however, does not exclude relapses and side effects, frequently resulting in surgical intervention. Polyphenols have been acknowledged to be anti-oxidant and anti-inflammatory and therefore, have been proposed as an alternative natural approach to prevent or treat chronic inflammatory diseases. Most studies have been in animal models of colitis, using chemical inducers or mice defective in anti-inflammatory mediators and in intestinal cell lines treated with pro-inflammatory cytokines or lipid oxidation products. These studies provide evidence that polyphenols can effectively modulate intestinal inflammation. They exert their effects by modulating cell signaling pathways, mainly activated in response to oxidative and inflammatory stimuli, and NF-kB is the principal downstream effector. Polyphenols may thus be considered able to prevent or delay the progression of IBD, especially because they reach higher concentrations in the gut than in other tissues. However, knowledge of the use of polyphenols in managing human IBD is still scanty, and further clinical studies should afford more solid evidence of their beneficial effects.     

New insights into inflammatory bowel disease pathophysiology: paving the way for novel therapeutic targets

The etiopathogenesis of Crohn's disease (CD) and ulcerative Colitis (UC), the two major forms of inflammatory bowel disease (IBD), is still unknown. Although the exact cause and mechanisms of both IBD have yet to be completely understood, it is widely accepted that both CD and UC result from an inappropriate immune response that occurs in genetically susceptible individuals as the result of a complex interaction among environmental factors, microbial factors, and the intestinal immune system. In the last few years a tremendous advance in knowledge of the mechanisms underlying intestinal inflammation in IBD has been achieved, leading to new therapeutic targets and novel drugs. These new therapeutic weapons have been specifically designed to selective shut down intestinal inflammation at different levels. Aim of this review is to summarize the recent advances in IBD pathophysiology and the new therapeutic targets and drugs that are changing the IBD clinical management.     

Probiotics (VSL#3) in arthralgia in patients with ulcerative colitis and Crohn's disease: a pilot study

Arthralgia is a common extraintestinal manifestation of inflammatory bowel disease (IBD). Alterations of the immunologic regulation in the gut may contribute to the pathogenesis of arthralgia. Probiotics (VSL#3) have proven effective in the treatment of pouchitis in patients with ileal pouch anal anastomosis after panproctocolectomy for ulcerative colitis both in maintaining remission and in preventing a flare-up without side effects. The aim of this study was to determine the safety and efficacy of VSL#3 in patients with quiescent IBD who suffered from arthralgia for more than two weeks. An open-label trial was conducted using VSL#3. Pre- and post-treatment joint pain intensity were measured on the Ritchie Articular Index and visual analog scale. Disease activity of the bowel was assessed by the Truelove-Witts and the Harvey-Bradshaw scores. Sixteen of 29 patients completed the trial; in 10 of the 16 patients a statistically significant improvement was documented by the Ritchie Articular Index. No one of the patients had a relapse of intestinal disease while on probiotics. These preliminary results suggest that the probiotic mixture VSL#3 may be an alternative treatment for arthralgia in patients with IBD without inducing exacerbation of the disease. Because probiotics may be effective in the treatment of IBD as well, our results suggest that patients with active disease and arthralgia may also derive benefit from this treatment. Proper randomized controlled studies are indicated.     

Diagnostic accuracy of faecal calprotectin estimation in prediction of abnormal small bowel radiology

BACKGOUND: Patients being investigated for symptoms of abdominal pain, diarrhoea and or weight loss often undergo small bowel radiology as part of their diagnostic workup mainly to exclude inflammatory bowel disease. AIM: To assess and compare the utility of a single faecal calprotectin estimation to barium follow through as well as conventional inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein in exclusion of intestinal inflammation. METHODS: Seventy-three consecutive cases undergoing barium follow through for investigation of symptoms of diarrhoea and or abdominal pain with or without weight loss were studied. The control group comprised 25 cases with known active Crohn's disease (positive controls), 26 normal healthy volunteers (negative controls) and 25 cases of irritable bowel syndrome diagnosed by Rome II criteria. Symptoms, erythrocyte sedimentation rate and C-reactive protein were recorded at recruitment and a single stool sample assayed for calprotectin within 7 days prior to or after barium follow through. Results: The median calprotectin value in the active Crohn's group, irritable bowel syndrome group and normal volunteers was 227 microg/g of stool, 19 and 10 microg/g respectively (P < 0.0001). A faecal calprotectin above a cut-off value of 60 microg/g was able to predict all nine cases with an abnormal barium follow through as well as all six cases with a normal barium follow through but with organic intestinal disease. The negative predictive value of a single calprotectin result below 60 microg/g of stool was 100% compared with 91% each for erythrocyte sedimentation rate > 10 mm and C-reactive protein > 6 mg/L and 84% for a combination of erythrocyte sedimentation rate and C-reactive protein in predicting absence of organic intestinal disease. CONCLUSION: A single stool calprotectin value < 60 microg/g of stool obviates the need for further barium radiology of the small bowel, is more accurate than measurement of erythrocyte sedimentation rate or C-reactive protein and effectively excludes Crohn's disease or non-functional gastrointestinal disease.     

New fecal markers: recent developments and perspectives

Fecal occult blood testing is the most widely prescribed screening test for colorectal cancer. Recent development of immunological tests has increased specificity. Fecal DNA analysis opens up a new field for early detection of this widespread neoplasia. Inflammatory bowel disease is another important area where the development of fecal markers provides an interesting alternative to the gold standard but costly and invasive endoscopic investigations with histological analysis of biopsy specimens. Fecal TNFalpha and calprotectin can now be proposed to distinguish organic from non-organic intestinal disease, so select candidates for further investigations, and to assess disease activity. Measurement of fecal elastase provides real progress in screening for exocrine pancreatic insufficiency in patients with malabsorption syndrome. The development of non-invasive fecal markers is thus of increasing interest, providing data about the entire gastrointestinal tract useful for screening and individual patient management.     

核受体作为炎症性肠疾病治疗靶点的研究进展

炎症性肠疾病是一种慢性肠道炎症疾病,其发病机制尚不明确,目前多认为与炎症和肠黏膜损伤有关。核受体是一种重要的转录调节因子,包括孕烷X受体(pregnane X receptor,PXR)、法尼酯X受体(farnesoid X receptor,FXR)和组成型雄甾烷受体(constitutive androstane receptor,CAR)等。近年深入研究发现,核受体可以通过抑制炎症信号通路、调节肠道紧密连接蛋白及代谢酶的表达减轻肠道炎症,并维持肠黏膜屏障功能,在炎症性肠疾病肠道保护方面发挥重要作用。因此,本文综述核受体PXR、FXR和CAR对炎症性肠疾病肠道的保护作用机制,为以核受体为靶点的炎症性肠疾病药物治疗提供新思路。     

Drug therapy of inflammatory bowel disease

The drugs that are effective in inflammatory bowel disease (IBD) act by inhibiting the chronic unregulated intestinal inflammation in these patients. The mainstays of the drug therapy of IBD are a variety of formulations of 5-aminosalicylic acid (5-ASA), the conventional and newer low bioavailability glucocorticoids, the nitroimidazole antibiotic metronidazole, and certain immunomodulating agents. Increased understanding of the mechanisms of inflammation in IBD has permitted the development of effective designer drugs. These agents are products of the biotechnology industry and include antibodies to tumor necrosis factor (TNF)-alpha, antisense oligonucleotides and recombinant human interleukin (IL)-10. In addition, a number of other agents such as nicotine and n-3 fatty acids are useful in certain patients. This review first focuses on the pharmacology and mechanism of action of these drugs in IBD, followed by an approach to the treatment of patients with ulcerative colitis (UC) and Crohns disease (CD). The recommendations consider type and activity of IBD and are based largely on data from controlled trials and systematic reviews in the IBD literature.     

Mucosal T cell proliferation and apoptosis in inflammatory bowel disease

Both forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), represent prototypical conditions whose most salient features are the presence of chronic inflammation involving various parts of the intestinal tract and an increased risk of cancer, which is a complication directly related to the duration and activity of gut inflammation. Several factors have been implicated in the unrelenting mucosal inflammation of IBD, prominent among them being the presence of a persistently elevated number of activated T cells in the mucosa of CD and UC patients. These T cells display various defects of proliferation and apoptosis, and these abnormalities are credited with directly contributing to the pathogenesis of IBD and possibly the progression to colon cancer. This notion is supported by the observation that T cells are also prominently found infiltrating most tumors and are functionally impaired compared to T cells in the circulation. This establishes a parallel that may constitute a link between chronic intestinal inflammation and the development of malignancies in the inflamed intestine. This article will review some of the basic features of human intestinal mucosal T cells, examine the mechanisms underlying the processes of cell cycling and cell death, describe the defective proliferative and apoptotic function detected in CD and UC, and discuss the implications of modulating T cell apoptosis in IBD for therapeutic purposes and eventually decreasing the risk of cancer development.     

A novel pathogenic role for microvasculature in inflammatory bowel disease

Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms of inflammatory bowel disease (IBD). Although their etiology is still unknown, the pathogenic mechanisms underlying intestinal inflammation have made impressive progress in our understanding. In particular, the abnormalities underlying IBD pathogenesis are not restricted to those mediated by classical immune cells such as T and B lymphocytes, macrophages and dendritic cells, but also nonimmune cells. Interestingly, endothelium has become one of the major areas of investigation in gut inflammation.     

维多珠单抗治疗炎症性肠病的机制与临床应用研究进展

炎症性肠病（IBD）是一类病因未明的肠道慢性复发性炎症性疾病,其治疗仍以传统药物为主。由于传统药物不良反应较明显,近年来衍生出多种生物制剂,如抗肿瘤坏死因子（TNF）制剂、整合素拮抗剂等。作为一种人源化的抗 α4β7 整合素单克隆抗体,维多珠单抗（Vedolizumab）通过抑制 α4β7 整合素与黏膜地址素细胞黏附分子-1（MAdCAM-1）相互作用,选择性阻断记忆 T细胞向炎症肠道组织转运,减轻肠道炎症反应,因而主要用于对抗 TNF生物制剂失效的 IBD患者。本文对维多珠单抗治疗 IBD的机制、临床疗效及安全性进行综述。     

The role of calprotectin in predicting endoscopic post-surgical recurrence in asymptomatic Crohn's disease: a comparison with ultrasound

BACKGROUND AND OBJECTIVES: Faecal calprotectin is predictive of clinical relapse in inflammatory bowel disease and ultrasound is sensitive in detecting its post-surgical recurrence. However, no data regarding the role of calprotectin in predicting post-surgical recurrence in asymptomatic Crohn's disease are available. The aim of this study was to prospectively evaluate the role of calprotectin as a predictive marker for one year post-surgical endoscopic recurrence in comparison with ultrasound in patients with asymptomatic Crohn's disease. MATERIAL AND METHODS: We consecutively enlisted 50 patients who had undergone a resection for Crohn's disease. Faecal calprotectin was analysed and ultrasound were performed at the third month, and a colonoscopy after one year. The sensitivity and specificity of these two techniques were evaluated using endoscopic findings as a golden standard. A Receiver Operator Curve (ROC) curve was plotted, in order to identify the best-cut off value for calprotectin. RESULTS: 39 out of 50 patients were evaluated by performing a colonoscopy after one year; 19 patients had an endoscopic recurrence after one year. Calprotectin sensitivity and specificity were calculated for 5 different cut-off values; the best cut-off value for calprotectin sensitivity (63%) and specificity (75%) was > 200 mg/L. The US sensitivity and specificity at the third month were 26% and 90% respectively. CONCLUSIONS: When performed three months after surgery ultrasound is more specific than calprotectin in predicting endoscopic recurrence. Faecal calprotectin at a dosage > 200 mg/L seems to have a better sensitivity than ultrasound. Values of calprotectin > 200 mg can be an indication to colonoscopy in the group of patients with negative ultrasound in order to detect early recurrence.     

白细胞吸附疗法在重症炎症性肠病中的应用进展

炎症性肠病(IBD)是一种以反复发作的、多种免疫因子参与的慢性肠道炎症,其发病率在逐年增加。其发病机制可能与机体免疫反应、肠道炎性活动、肠道功能紊乱、精神状态、遗传等因素有关。目前主要的治疗方式以营养疗法、药物治疗、单克隆抗体相关的生物治疗、免疫抑制剂疗法为主,因发病机制仍不十分明确,这些疗法都不能完全有效地控制炎症的发展。近年来研究发现,血液中的白细胞(中性白细胞和单核细胞)的激活在IBD的发生与发展中起着至关重要的作用,因此,有效地清除血液中激活的白细胞,中断炎症反应链,可以达到控制疾病进展的目的。许多研究者将白细胞免疫吸附疗法应用于对重症炎症性肠病(SIBD)病人的治疗,并取得了一定的效果。这是对目前IBD治疗的补充,也是一种研究思路,但其吸附效果、疗效、不良反应等还有待进一步研究。     

Review article: How relevant to human inflammatory bowel disease are current animal models of intestinal inflammation?

New rodent models of chronic intestinal inflammation are mediated by a TH₁-cell and macrophage dominated immune response to luminal bacterial constituents. The pathology of these spontaneous and induced models differ widely and caution is needed when assessing the comparative aspects of such animal models and human inflammatory bowel diseases (IBD). Considerable immunological and therapeutic evidence suggests that chronic and immune-mediated models are relevant in human IBD and that pathogenic principles are similar. However, animal models have not been able to duplicate exactly the pathological characteristics of ulcerative colitis or Crohn's disease, indicating a need for caution in extrapolating data from experimental models to human IBD.