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At least 649 records · Page 36Linked to original sources
PubMed2003

A potent human C5a receptor antagonist protects against disease pathology in a rat model of inflammatory bowel disease.

The complement system is implicated in the pathogenesis of human inflammatory bowel disease, but the specific role of C5a has never been examined. We have compared the efficacy of an orally active human C5a receptor antagonist (AcPhe[Orn-Pro-D-cyclohexylalanine-Trp-Arg]), prednisolone, and infliximab against trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. The drugs were administered either 2 days before or 24 h after TNBS instillation, and rats were then examined after 8 days. Drug-free colitis control rats showed severe disease pathology with significant mortality (39%). Rats pre or posttreated with the C5a antagonist (10 mg/kg/day peroral, 0.3 mg/kg/day s.c.) had reduced mortality and significantly improved macroscopic scores, colon edema, colon myeloperoxidase levels, reduced concentrations of TNF-alpha levels in the colon and serum, and had greater food intake resulting in greater weight gains than colitis-only rats. Rats pretreated with prednisolone (1 mg/kg/day s.c.) displayed significant improvement in parameters measured, but posttreatment was ineffective. Single dose pretreatment with the TNF-alpha inhibitor infliximab (3 mg/kg i.v.) also had significant improvements in the parameters measured. Rats pretreated with a combination of the C5a antagonist and prednisolone showed no greater improvements than either drug alone. These findings suggest a central role for complement, particularly C5a, in the pathology of TNBS-induced colitis in rats, indicating a possible therapeutic role for C5a antagonists in inflammatory bowel disease.

Animals↗
PubMed2004

Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs.

Crohn's disease and ulcerative colitis (the inflammatory bowel diseases) have a strong genetic component. Although over 20 putative susceptibility loci have been identified by individual genome scans, the majority of these loci have not been replicated. Many individual studies are at the lower limit of acceptable power for complex disease linkage analysis. Genome scan meta-analysis (GSMA), by use of sample sizes an order of magnitude greater than individual linkage studies, has increased power to detect novel loci, may confirm or refute regions detected in smaller individual studies, and enables regions to be prioritized for further gene identification efforts. Genome scan data (markers, significance scores) were obtained from 10 separate studies and meta-analysis was performed using the GSMA method. These studies comprised 1952 inflammatory bowel disease, 1068 Crohn's disease and 457 ulcerative colitis affected relative pairs. Study results were divided into 34 cM chromosomal bins, ranked, weighted by study size, summed across studies and bin-by-bin significance obtained by simulation. A region on chromosome 6p (containing the HLA) met genome wide significance for inflammatory bowel disease. Loci meeting suggestive significance for inflammatory bowel disease were 2q, 3q, 5q, 7q and 16 (NOD2/CARD15 region); Crohn's disease, 2q, 3q, 6p, 16 (NOD2/CARD15 region), 17q, 19p; and ulcerative colitis, 2q. Clustering of adjacent bins was observed for chromosomes 6p, 16, 19p. The meta-analysis has identified novel loci and prioritized genomic regions for further gene identification studies.

Chromosomes↗
PubMed2005

Protein microarray analysis of disease activity in pediatric inflammatory bowel disease demonstrates elevated serum PLGF, IL-7, TGF-beta1, and IL-12p40 levels in Crohn's disease and ulcerative colitis patients in remission versus active disease.

OBJECTIVES: Cytokines and growth factors play a major role in the dysregulated immune response in inflammatory bowel disease (IBD). We hypothesized that significant differences exist between the serum cytokine and growth factor profiles of pediatric IBD patients with active disease (AD) and those in remission, and that levels of some of these soluble mediators may be used to define regulators in IBD and determine disease activity. METHODS: Eighty-eight consecutive patients with confirmed Crohn's disease (CD) and ulcerative colitis (UC) seen at the Duke Children's Hospital were prospectively enrolled and a serum sample was obtained. Data were recorded at the time of serum collection to calculate disease activity indices. The relative expression of 78 cytokines, growth factors, and soluble receptors was determined using proprietary antibody-based protein microarrays amplified by rolling circle amplification. SPSS 8 (SPSS Inc., Chicago, IL) was used to compare protein profiles for CD and UC patients in clinical remission (CR) versus AD. RESULTS: Sixty-five CD patients and 23 UC patients were enrolled. Forty-one CD patients had available samples and PCDAI results. Twenty-two patients were in remission PCDAI < or = 12.5 (median 5), 19 patients had disease activity >15 (median 30). Univariate analysis revealed that PLGF, IL-7, IL-12p40, and TGF-beta1 cytokine levels were significantly elevated for patients in CR versus AD (p < 0.01). Twelve UC serum samples had Seo/Truelove Witt AI for analysis. Five patients were in remission by TW AI and Seo AI < or =110 and 7 patients had active mild-to-severe disease by TW and Seo AI >110. Only one cytokine, IL12p40, showed significance between CR versus AD (p < 0.02). CONCLUSIONS: Surprisingly, we found no differences in circulating levels of proinflammatory cytokines but found that pediatric IBD patients in remission compared to those with AD had higher levels of specific circulating cytokines, including the regulatory cytokines IL-12p40 and TGF-beta1. It may be that these cytokines directly regulate intestinal inflammation in IBD or reflect the activity of T regulatory cells in negatively regulating the inflammatory response. Further studies will be needed to validate our results to define the molecular pathways involved in the intestinal immune response in man.

Adolescent↗
PubMed1996

Monoclonal antibody therapy of inflammatory bowel disease.

Several anti-inflammatory drugs have therapeutic efficacy in inflammatory bowel disease, but their targets remain incompletely characterized. The development of monoclonal antibodies that either recognize epitopes on immune-competent cells, or neutralize pro-inflammatory cytokines, has helped to define the importance of inflammatory mediators and their cellular sources in experimental inflammatory bowel disease. Moreover, two monoclonal antibodies, directed against CD4 and tumour necrosis factor, have been used to treat patients with steroid-refractory Crohn's disease. Preliminary data suggest that immune-modulatory monoclonal antibodies may have beneficial effects in selected patients with severe Crohn's disease.

Animals↗
PubMed2006

Review article: what are the important endoscopic lesions for detection of dysplasia in inflammatory bowel disease?

It is recognized that inflammatory bowel diseases predispose to colorectal adenocarcinoma. Early detection of precursor lesions and subsequent treatment may prevent cancer development and this is possible with colonoscopy and biopsy. Inflammatory bowel disease-associated precursor lesions (dysplasia = intraepithelial neoplasia) must be distinguished from sporadic adenomas, occurring in non-colitic mucosa. Macroscopic lesions suspected of harbouring precursor lesions include irregular 'polypoid or elevated' lesions, which are usually broad-based and 'flat' lesions. Flat lesions are more common than elevated lesions and they are usually smaller. Chromoendoscopy increases the detection rate substantially as it allows targeted biopsies from suspicious lesions that increase the diagnostic yield of dysplasia. Ultimately, the combination of chromoendoscopy, or more advanced endoscopic techniques, and targeted biopsies may become the standard approach, rather than random biopsy sampling.

Biopsy↗
PubMed2000

Established and emerging biological activity markers of inflammatory bowel disease.

Assessment of disease activity in inflammatory bowel disease (IBD), i.e., ulcerative colitis (UC) and Crohn's disease (CD), is done using clinical parameters and various biological disease markers. Ideally, a disease marker must: be able to identify individuals at risk of a given disorder, be disease specific, mirror the disease activity and, finally, be easily applicable for routine clinical purposes. However, no such disease markers have yet been identified for IBD. In this article, classical disease markers including erythrocyte sedimentation rate, acute phase proteins (especially orosomucoid and CRP), leukocyte and platelet counts, albumin, neopterin, and beta2-microglobulin will be reviewed together with emerging disease markers such as antibodies of the ANCA/ASCA type, cytokines (e.g., IL-1, IL-2Ralpha, IL-6, IL-8, TNF-alpha, and TNF-alpha receptors) and with various adhesion molecules. It is concluded that none of the pertinent laboratory surrogate markers of disease activity in IBD are specific or sensitive enough to replace basic clinical observation such as the number of daily bowel movements, general well-being, and other parameters in parallel. Further studies are highly warranted to identify and assess the clinical importance and applicability of new laboratory markers for the diagnosis or the disease activity of IBD.

Acute-Phase Proteins↗
PubMed1999

Inflammatory bowel disease in pediatric patients.

The management of inflammatory bowel disease in children remains a major challenge to patients, their families, and the health care team. This review highlights the past year's advances concerning epidemiologic studies, new diagnostic considerations, and novel therapeutic approaches. Epidemiologic studies confirmed that Crohn's disease is being increasingly diagnosed in children, whereas the incidence of ulcerative colitis has remained stable. African-American children are as likely to have inflammatory bowel disease as other children. Serologic assays specific for Crohn's disease and ulcerative colitis can assist clinicians in screening for inflammatory bowel disease, as well as discriminating between the two diseases. Studies have revealed that osteopenia and antioxidant vitamin deficiency are common and require screening in pediatric inflammatory bowel disease. Increasing experience with immunosuppressive drugs (6-mercaptopurine, azathioprine) point to their efficacy and generally good toxicity profile in pediatric patients.

Journal Article↗
PubMedDate not supplied

The role of IL-10 in inflammatory bowel disease: "of mice and men".

Inflammatory bowel disease (IBD) is a generic term typically used to describe a group of idiopathic inflammatory intestinal conditions in humans that are generally divided into Crohn's disease and ulcerative colitis. Although the etiology of these diseases remains unknown, a number of rodent models of IBD have recently been identified, all sharing the concept that the development of chronic intestinal inflammation occurs as a consequence of alterations in the immune system that lead to a failure of normal immunoregulation in the intestine. On the basis of these models, it has been hypothesized that the development of IBD in humans may be related to a dysregulated immune response to normal flora in the gut. Immunodeficient scid mice injected with CD4+ CD45RB(high) T cells and mice deficient in interleukin (IL)-10 (IL-10-/-) are among the rodent models of IBD. In both models, there is inflammation and evidence of a Th1-like response in the large intestine, characterized by CD4+ T-cell and macrophage infiltrates, and elevated levels of interferon-gamma. Because IL-10 is an immunomodulatory cytokine that is capable of controlling Th1-like responses, the role of IL-10 was investigated in these models. IL-10 was shown to be important in regulating the development of intestinal inflammation in both models. These results provided key data that supported initiation of clinical trials evaluating the efficacy of IL-10 in patients with IBD.

Animals↗
PubMed2026

Global gut microbiome atlas identifies epidemiologic-stage-specific signatures in inflammatory bowel disease.

The global rise of inflammatory bowel disease (IBD) reflects environmental shifts, yet how these changes are embedded in the gut microbial ecology remains unclear. We construct a microbiome atlas comprising 245,627 profiles. By classifying countries into three epidemiologic stages, we establish a framework. As the IBD burden increases, the gut microbial alpha diversity declines, and community structures form distinct clusters. This transition is characterized by a gradient of core genera. Integrating six shotgun metagenomic cohorts, we identify the depletion of anabolic pathways in IBD patients. Strain-level analysis reveals that epidemiologic staging shapes genetic architecture within species, identifying an IBD-enriched subclade of Eisenbergiella associated with elevated fecal cholic acid. We develop a microbial inflammatory risk score (MIRS), based on 19 genera, that discriminates IBD from controls (area under the curve [AUC] = 0.92). MIRS correlates with IBD prevalence. Our study provides an atlas linking epidemiology to microbiome ecology and strain evolution, offering a foundation for population-level surveillance and interventions in IBD.

Humans↗
PubMed2004

Doppler sonography in inflammatory bowel disease.

The course of chronic inflammatory bowel diseases is highly variable and prediction of relapse remains difficult. Doppler sonography is a newer, non-invasive method to assess the hyperdynamic splanchnic blood flow that is characteristic of acute inflammation. Its role in the analysis of disease activity is still limited and its application restricted to specialized units. However, improved spatial resolution by power Doppler ultrasound, with or without the use of contrast agents, allows a very early detection of mucosal and transmural inflammatory lesions. Still more important, the repeated quantification of mesenteric blood flow enables the prediction of relapse at six months after steroid-induced remission. Future studies should clarify whether the combined application of available methods will allow a more calculated and finally more effective therapy.

Acute Disease↗
PubMed1999

Linkage of inflammatory bowel disease to human chromosome 6p.

Inflammatory bowel disease (IBD) is characterized by a chronic relapsing intestinal inflammation. IBD is subdivided into Crohn disease and ulcerative colitis phenotypes. Given the immunologic dysregulation in IBD, the human-leukocyte-antigen region on chromosome 6p is of significant interest. Previous association and linkage analysis has provided conflicting evidence as to the existence of an IBD-susceptibility locus in this region. Here we report on a two-stage linkage and association analysis of both a basic population of 353 affected sibling pairs (ASPs) and an extension of this population to 428 white ASPs of northern European extraction. Twenty-eight microsatellite markers on chromosome 6 were genotyped. A peak multipoint LOD score of 4.2 was observed, at D6S461, for the IBD phenotype. A transmission/disequilibrium test (TDT) result of P=.006 was detected for D6S426 in the basic population and was confirmed in the extended cohort (P=.004; 97 vs. 56 transmissions). The subphenotypes of Crohn disease, ulcerative colitis, and mixed IBD contributed equally to this linkage, suggesting a general role for the chromosome 6 locus in IBD. Analysis of five single-nucleotide polymorphisms in the TNFA and LTA genes did not reveal evidence for association of these important candidate genes with IBD. In summary, we provide firm linkage evidence for an IBD-susceptibility locus on chromosome 6p and demonstrate that TNFA and LTA are unlikely to be susceptibility loci for IBD.

Alleles↗
PubMed2001

Muscoloskeletal manifestations in inflammatory bowel disease.

Muscoloskeletal manifestations are the most common extraintestinal complications of inflammatory bowel disease. Wide ranges in prevalence have been reported, depending on the criteria used to define spondylarthropathy. In 1991, the European Spondylarthropathy Study Group developed classification criteria that included previously neglected cases of undifferentiated spondylarthropathies, which had been ignored in most of the oldest epidemiological studies on inflammatory bowel disease. The spectrum of muscoloskeletal manifestations in inflammatory bowel disease patients includes all of the clinical features of spondylarthropathies: peripheral arthritis, inflammatory spinal pain, dactylitis, enthesitis (Achilles tendinitis and plantar fasciitis), buttock pain and anterior chest wall pain. Radiological evidence of sacroiliitis is common but not obligatory. The articular manifestations begin either concomitantly or subsequent to the bowel disease; however, the onset of spinal disease often precedes the diagnosis of inflammatory bowel disease. The prevalence of the different muscoloskeletal manifestations is similar in ulcerative colitis and Crohn's disease. Symptoms usually disappear after proctocolectomy. The pathogenetic mechanisms that produce the muscoloskeletal manifestations in inflammatory bowel disease are unclear. Several arguments favour an important role of the intestinal mucosa in the development of spondylarthropathy. The natural history is characterized by periods of flares and remission; therefore, the efficacy of treatment is difficult to establish. Most patients respond to rest, physical therapy and nonsteroidal anti-inflammatory drugs, but these drugs may activate bowel disease. Sulphasalazine may be recommended in some patients. There is no indication for the systemic use of steroids.

Humans↗
PubMed2004

Pediatric inflammatory bowel disease.

PURPOSE OF THIS REVIEW: The prevalence of early-onset inflammatory bowel disease has been on the rise, with children and adolescents currently accounting for approximately 30% of all patients with this condition. Remarkable new advances in diagnostic modalities and therapy for adults with inflammatory bowel disease, and further information about the role of genetics in determining susceptibility to disease make the review of the recent literature in pediatric inflammatory bowel disease more timely than ever. RECENT FINDINGS: In the area of genetics, new studies provide strong evidence for genetic susceptibility to disease, and match genotype with phenotypic presentation. A few studies examine the use of noninvasive diagnostic modalities, such as MRI, and biomarkers (fecal lactoferrin) in pediatric inflammatory bowel disease. Remarkable new agents in therapy for adults with inflammatory bowel disease have been empirically administered to children with inflammatory bowel disease. The first attempts to systematically study the effects of these agents in children and adolescents are reviewed here. Furthermore, new studies revise our notion of surgical outcomes in pediatric inflammatory bowel disease. SUMMARY: Although premature for clinical practice application, the role of genetic testing in determining disease susceptibility and assisting with prognosis and course of therapy is clearly evolving and needs further study. As new therapeutic agents join the available treatments of inflammatory bowel disease it is imperative to include pediatric patients in clinical trials. The goals of future studies will be to alter the natural history of early-onset inflammatory bowel disease, reduce the frequency of recurrences, and perhaps reduce requirements for surgical intervention.

Journal Article↗
PubMed2006

Exacerbation of inflammatory bowel disease by nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors: fact or fiction?

The existence of a possible link between inflammatory bowel disease (IBD) and nonsteroidal anti-inflammatory drugs (NSAIDs) has been repeatedly suggested. Recently, a few studies have addressed the issue of a possible, similar effect by selective cyclooxygenase-2 inhibitors (COXIBs). The present article reviews the available scientific evidence for this controversial subject.

Animals↗
PubMed1988

Ultrasonography in the detection of Crohn's disease and in the differential diagnosis of inflammatory bowel disease.

The diagnostic accuracy of abdominal ultrasonography in inflammatory bowel disease (IBD) has been evaluated in a prospective, randomized, blind study. A total of 181 patients (89 with Crohn's disease, 57 ulcerative colitis and 35 controls) were examined. Sensitivity and specificity of diagnosis in Crohn's disease, corrected for prevalence, were 80.8 and 79.2%, respectively, and a very similar accuracy was found in the differential diagnosis of IBD. In conclusion, ultrasonography can play a role in detecting Crohn's disease and in the differential diagnosis of chronic IBD.

Adult↗
PubMed1988

Assessment of inflammatory bowel disease activity by technetium 99m phagocyte scanning.

Autologous technetium 99m-labeled phagocyte scanning has been used to assess disease activity in inflammatory bowel disease in 51 consecutive patients. Strong correlations were found between the 24-h fecal excretion of isotope and the histologic score of mucosal biopsy specimens (rS = 0.84, p less than 0.001, where rS is Spearman's rank correlation coefficient), and between the 24-h fecal excretion of isotope and a clinical inflammatory bowel disease activity index based on the Crohn's disease activity index (rS = 0.87, p less than 0.001). To develop a clinically useful and objective measure of inflammatory bowel disease activity that did not require a 24-h stool collection, the intensity of bowel uptake on scanning was graded visually from 0 to 4, a ratio of count rates for the region of interest to the iliac crest reference region was calculated, and the rapidity of labeled phagocyte uptake into inflamed bowel was measured as the peak uptake time. Visual grading of disease activity on the scans was validated by comparing it with the ratio of count rates from inflamed bowel regions of interest and those from the iliac crest reference region. The ratio of count rates showed a significant correlation with the clinical disease activity index (r = 0.75, p less than 0.001). The visual scan grade also correlated well with the clinical activity index (r = 0.87, p less than 0.001). Count rates from hourly scans were also used to calculate the time of peak uptake of counts for a given region of interest. There was a strong negative correlation between this peak uptake time and the fecal excretion of isotope (rS = -0.81, p less than 0.001), a clinical activity index (r = -0.60, p less than 0.001), and the histologic score of the mucosal biopsy specimens (r = -0.84, p less than 0.001). These results indicate that the technetium 99m-labeled phagocyte scan provides an objective assessment of disease activity in inflammatory bowel disease using the visual scan grade, ratio of count rates for the region of inflamed bowel, or by the peak uptake time, thereby avoiding the problems associated with fecal collections. This scanning test may prove to be of significant value in clinical management and in the assessment of treatment response.

Adolescent↗