Immunotherapeutic approaches to inflammatory bowel diseases

For a long time corticosteroids, aminosalicylic acid preparations and antibiotics have represented the principal approaches in evidence-based drug therapy for chronic inflammatory bowel diseases (IBD), e.g., Crohn’s disease (CD) and ulcerative colitis (UC), and are able to suppress disease activity in most cases. However, there are cases that do not respond to conventional drug therapy or remain dependent on high doses of steroids associated with severe side effects in the long run. It is generally accepted now that IBD has an immunological basis and results from a hyper-responsive state of the intestinal immune system. Although the primary etiological defect respectively immunogenic agent still remains to be identified, substantial progress has been made in our understanding of regulatory mechanisms of the intestinal immune system and their alterations in IBD at the molecular level. Due to the concurrent advent of biotechnological processes it has been possible to utilise these insights for the development of novel immunomodulatory therapeutic strategies ranging from recombinant cytokines and blocking antibodies to oligonucleotide antisense strategies and gene therapeutic approaches. This review will present the current status of the development of these novel immunomodulatory therapeutic strategies in IBD and the status of their use in clinical practice. For a better understanding, it will be necessary to address the recent advances in the elucidation of pathogenetic mechanisms of IBD from studies in human specimen and experimental colitis models that have provided the basis for these novel therapeutic approaches.     

Human chorionic gonadotropin and alpha chain of glycoprotein hormones in patients with inflammatory bowel disease

In twenty patients with Crohn's disease and ten patients with ulcerative colitis serum levels of human chorionic gonadotropin and the common alpha-subunit of glycoprotein hormones were determined by radioimmunoassay. In contrast to published data, all serum samples except one revealed levels within the normal range of 148 controls (human chorionic gonadotropin levels up to 3.9 IU/l, alpha-subunit up to 3.8 micrograms/l). Neither the serum levels of human chorionic gonadotropin nor of the alpha-subunit differed significantly between patients with Crohn's disease (median/maximum: 0.9/4.4 IU/l; 0.7/3.6 micrograms/l) and ulcerative colitis (1.0/3.4 IU/l; 0.8/2.2 micrograms/l). Furthermore, the serum levels studied in patients with active (0.9/3.0 IU/l; 0.7/3.5 micrograms/l) and inactive (0.9/4.4 IU/l; 0.8/3.6 micrograms/l) Crohn's disease and in patients with active (1.1/3.4 IU/l; 0.9/2.2 micrograms/l) and inactive (0.9/2.9 IU/l; 0.8/1.3 micrograms/l) ulcerative colitis were not significantly different. There was no relationship of the duration of the disease or a bowel resection to the serum levels of human chorionic gonadotropin or the alpha-subunit. It is concluded that both parameters are not useful as markers in patients with Crohn's disease or ulcerative colitis. The normal serum levels found in patients with inflammatory bowel diseases indicate human chorionic gonadotropin as a highly specific marker for malignant diseases.     

Bone alterations in inflammatory bowel diseases

Inflammatory bowel diseases (IBDs) are characterized by a multifactorial partially unknown etiology that involves genetic, immunological and environmental factors. Up to 50% of IBD patients experience at least one extraintestinal manifestation; among them is the involvement of bone density which is referred to as metabolic bone disease (MBD), including osteopenia and osteoporosis. Bone alterations in IBDs population appear to have a multifactorial etiology: Decreased physical activity, inflammation-related bone resorption, multiple intestinal resections, dietary malabsorption of minerals and vitamin D deficiency, genetic factors, gut-bone immune signaling interaction, steroid treatment, microbiota and pathogenic micro-organisms interaction, and dietary malabsorption of minerals, that, all together or individually, may contribute to the alteration of bone mineral density. This review aims to summarize the prevalence and pathophysiology of metabolic bone alterations in IBD subjects outlining the main risk factors of bone fragility. We also want to underline the role of the screening and prophylaxis of bone alterations in Crohn’s disease and ulcerative colitis patients and the importance of treating appropriately MBD.     

Antibodies to tissue-type plasminogen activator (t-PA) in patients with inflammatory bowel disease: high prevalence, interactions with functional domains of t-PA and possible implications in thrombosis

BACKGROUND: Patients with inflammatory bowel disease (IBD) have an increased prevalence of thromboembolic events. The pathogenetic mechanisms of these events include reduced fibrinolysis, which may be caused by antibodies to tissue-type plasminogen activator (t-PA). OBJECTIVES: To evaluate anti-t-PA antibodies in patients with IBD, considering clinical, biochemical and functional characteristics. PATIENTS AND METHODS: We immunoenzymatically measured anti-t-PA antibodies in plasma from 97 consecutive IBD patients and 97 age- and sex-matched healthy controls. We also assessed the antibody interactions with different epitopes of t-PA, the antibody inhibition on t-PA activity and the correlations with clinical features and other serum antibodies. RESULTS: IBD patients had higher median anti-t-PA antibody levels (5.4 U mL(-1) vs. 4.0 U mL(-1); P < 0.0001): 18 patients were above the 95th percentile of the controls (OR 5.3; 95% CI 1.7-16.3; P < 0.003), and the six with a history of thrombosis tended to have high levels (6.9 U mL(-1)). Anti-t-PA antibody levels did not correlate with IBD type, activity, location or treatment, or with age, sex, acute-phase reactants or other antibodies. The anti-t-PA antibodies were frequently IgG1 and bound t-PA in fluid phase; they recognized the catalytic domain in 10 patients and the kringle-2 domain in six. The IgG fraction from the three patients with the highest anti-t-PA levels slightly reduced t-PA activity in vitro. CONCLUSIONS: The prevalence of anti-t-PA antibodies is high in IBD patients. By binding the catalytic or kringle-2 domains of t-PA, these antibodies could lead to hypofibrinolysis and contribute to the prothrombotic state of IBD.     

血小板膜糖蛋白Ⅵ(GPⅥ)的研究进展

血小板膜糖蛋白Ⅵ（GPⅥ）是血小板表面重要的胶原受体，能介导血小板与胶原的初期黏附，产生信号转导，提高整合蛋白受体亲合力，引起血小板聚集和血栓形成。抑制GPⅥ功能可显著抑制胶原诱导的血小板黏附、聚集和血栓形成，故GPⅥ已成为研制新型抗血小板药物的主要靶点。过去几年中，对血小板和胶原相互作用的研究取得很大进展，本文就GPⅥ的结构，GPⅥ的功能，GPⅥ功能相关因素，GPⅥ与临床等作一综述。     

Surgical strategies in patients with inflammatory bowel disease

Crohn's disease and ulcerative colitis are specific inflammatory bowel diseases. Quality of life can be considerably limited. It does not depend on the form of therapy that Crohn's disease is highly recurrent, whereas colitis ulcerosa is curable by proctocolectomy. For both forms of disease surgery is an important option. It has to be included early in the therapy concept and not as last choice. Quality of life in patients with Crohn's disease can be raised significantly by surgery. Meticulous selection of the patients are essential to the policy of surgery as well as a regular aftercare. Best profit for those patients are treatment with an interdisciplinary team, consisting of gastroenterologists, nutrition advisers, psychologists, surgeons and radiologists.     

Antibodies to thyroid peroxidase (TPOAb) in serum from patients with slightly raised thyrotropin (TSH) levels

Assessment of thyroid antibody status can influence the decision to commence thyroxine replacement in patients with persistent marginally raised TSH concentrations. We studied 211 patients in whom we had reported a slightly raised TSH on two or more occasions. The most recent result was accompanied by a suggestion to repeat the TSH estimation and request thyroid antibodies. Although we received follow-up specimens on 59% of the audit sample, antibodies were requested on only 37%. However, a majority (62%) of those specimens showed a raised antibody concentration and this appeared to influence the decision to start thyroxine replacement. Our data suggest that it would be more effective if laboratory staff were to request thyroid antibodies on specimens from patients with persistently raised TSH concentrations and to comment further on the significance of the result.     

Raised serum levels of IgM-rheumatoid factor and anti-F(ab')2 autoantibodies in patients with active inflammatory bowel disease

The serum levels of IgM-Rheumatoid Factor and of anti-F(ab')2 autoantibodies were investigated in patients with inflammatory Bowel Disease (IBD) by sensitive radioimmunoassays. Serum levels of the 2 autoantibodies were significantly increased in active IBD. In patients with Crohn's Disease raised titers of the 2 antibodies appeared to be also related to colonic involvement. There was, in Crohn's Disease, a significant association between concordantly positive results with the 2 assays and the occurrence of systemic complications. Immunocomplexes detected by the C1q-SP method were higher in sera of Crohn's Disease patients with raised IgM-RF than in the others. Data from the present investigation indicate that in active IBD and particularly in Crohn's Disease autoantibodies directed against different parts of the immunoglobulin molecule may be produced. These findings add support to the concept that an in vivo polyclonal B-cell activation may occur in these patients.     

Small bowel and colonic permeability to 51Cr-EDTA in patients with active inflammatory bowel disease

51Cr-EDTA was administered both orally and per rectum via a catheter to controls and to patients with inflammatory bowel disease. The patients were divided into two groups, either with active inflammation of the small bowel or with active inflammation of the colon. Fifteen patients with Crohn's disease of the small bowel and 19 patients with either Crohn's disease of the colon or ulcerative colitis were investigated. After oral administration of the probe, controls showed a median excretion of 1.17%/24 h of the dose compared to 3.47%/24 h by patients with small bowel disease and 6.07%/24 h by patients with colonic disease. After rectal administration, controls showed a median excretion of 0.74%/24 h of the dose compared to 0.93%/24 h by patients with small bowel disease and 5.73%/24 h by patients with colonic disease. The rectal test differentiated small bowel disease from colonic disease with an accuracy of 85%. The results confirmed the inflamed colon as a site of increased intestinal permeation.     

Cancer antigen 125 levels in inflammatory bowel diseases

Background: Cancer antigen 125 (CA‐125) is a tumor marker used for the diagnosis and monitoring of ovarian carcinoma. It can also be elevated in endometriosis, inflammations, and in nongynecological malignancies. Up to date, serum CA‐125 levels in inflammatory bowel diseases (IBD) have not been studied before. Aim: To assess the levels of CA‐125 in patients with ulcerative colitis (UC) and Crohn's disease (CD). Methods: Serum levels of CA‐125 were investigated in 68 cases with UC (male/female: 47/21), 32 CD (male/female: 21/11), and 31 healthy controls (male/female: 16/15). Levels of CA‐125 were also compared among UC patients according to lesion location, severity, and activity of CD. Results: Serum CA‐125 levels were 17.29±24.50 U/ml, 15.56±20.74 U/ml, and 8.85±2.62 U/ml in patients with UC, CD, and healthy controls, respectively. Serum CA‐125 levels were significantly higher in UC compared to control group (P=0.001). Serum CA‐125 levels were higher in CD patients compared to control group but there was no significance (P=0.087). Serum CA‐125 levels were higher in pancolitis compared to distal type and left‐sided UC. Conclusions: Our data suggest that serum CA‐125 levels may be increased in patients with IBDs. J. Clin. Lab. Anal. 23:244–248, 2009. © 2009 Wiley‐Liss, Inc.     

Colonoscopy plus biopsy in the inflammatory bowel diseases

Colon biopsies are critical in helping to diagnose diarrhea, to distinguish different forms of colitis, to determine the extent of disease, and to determine if neoplasia has arisen in the setting of chronic colitis. Table 3 summarizes the recommended locations and numbers of biopsies for different scenarios. Some of the technical aspects pertaining to those are also discussed elsewhere in this issue. Colon biopsies in some instances can be definitive, but this usually requires the appropriate clinical scenario. For instance, to appreciate that segmental granulomatous colitis is Crohn's disease and not the much rarer colonic sarcoidosis requires ancillary clinical information. Often colon biopsies may definitively reveal an abnormality, but the findings may be nonspecific in regards to a definitive diagnosis. To use colon biopsies most appropriately in patient management and to get the most mileage from them usually requires frequent clinician-pathologist interaction, often repeat endoscopy with [table: see text] biopsies at a different time, and the assessment of the biopsies in the clinical context.     

Lifelong control with inflammatory bowel disease patients

The benefits and the burden of a lifelong control scheme for patients with chronic inflammatory bowel disease are discussed. The benefits cover physical, psychologic, and social conditions. Valuable scientific gains can be yielded secondarily from the data collection.     

Significance of endoscopy in inflammatory bowel diseases in childhood

Endoscopy makes an essential contribution as diagnostic tool in the clarification of unspecific inflammatory bowel disease in childhood. Important advantages of this method are detection of early lesions, classification of the type of inflammation, sight-guided biopsies and no exposure to X-rays. In 36 patients the diagnosis of Crohn's disease was proven by endoscopy alone in 66.6% of cases, by histology as sole criterion in 69.4%, and by X-ray examination alone in only 8.3% of cases. All 3 patients in whom the diagnosis of Crohn's disease was made exclusively by radiological means showed manifest involvement limited to the small bowel. However, even upper gastrointestinal endoscopy led to the detection of lesions characteristic of Crohn's disease in some cases. 36 colonoscopies were performed in 28 patients with ulcerative colitis. Typical lesions were detected endoscopically in 91.7%; corresponding histological changes were found in only 63.6%.     

Nutritional support in patients with inflammatory bowel disease.

Total parenteral nutrition with bowel rest has been used as primary therapy to reduce disease activity and achieve remission in patients with inflammatory bowel disease (IBD). However, results are short-lived and similar success can be attained through total enteral nutrition with highly specialized elemental or semielemental formulas. Enteral nutrition costs less than parenteral nutrition, maintains gut integrity, stimulates immunocompetence, and helps to control symptoms and overall disease activity. Increased use of enteral formulas can be expected in the future. The role of diet in management of IBD is currently under scrutiny. No one diet is appropriate for all patients, but restriction of fat, fiber, lactose, or oxalate may be necessary to help alleviate symptoms and minimize the risk of complications.     

Potential role of soluble angiopoietin-2 and Tie-2 in patients with inflammatory bowel disease

BACKGROUND: Angiogenesis has been suggested to play an important role in inflammatory bowel disease (IBD). The aim of the study was to evaluate the serum markers of angiogenesis angiopoietin-2 (Ang-2) and soluble angiopoietin receptor Tie-2 in patients with ulcerative colitis (UC) and Crohn's disease (CD). MATERIALS AND METHODS: Serum Ang-2 and Tie-2 serum levels were measured in 160 IBD patients (79 UC and 81 CD) and in 80 matched healthy controls using commercially available enzyme-linked immunosorbent assays. Serum Ang-2 and Tie-2 levels were correlated with the disease activity, as well as the type, localization and treatment of the disease. RESULTS: Median serum Ang-2 and Tie-2 levels were significantly higher in both the UC patients and the CD patients compared with the healthy controls (P < 0.05 and P < 0.001, respectively). The IBD patients with early disease (diagnosis < 2 years) had significantly higher (P = 0.04) median serum Ang-2 levels but significantly lower (P = 0.02) median serum Tie-2 levels as compared with IBD patients with late disease (diagnosis > 2 years). The CD patients with active disease had significantly higher levels of Ang-2 compared with non-active disease (P = 0.02). Serum levels of both Ang-2 and Tie-2 were not correlated with laboratory markers such as ESR, CRP, white blood cell count, platelet count and albumin. CONCLUSIONS: Serum Ang-2 and Tie-2 levels are elevated in patients with IBD. These markers may mediate angiogenesis and vascular permeability in the mucosa of patients with IBD.