Review article: the expanding role of biological agents in the treatment of inflammatory bowel disease - focus on selective adhesion molecule inhibition

Inflammatory bowel disease presents in various forms. Its increasing incidence indicates that modern lifestyle triggers disease in genetically susceptible individuals. We present a model for inflammatory bowel disease pathophysiology and review the new biological therapies available. These biological agents have been developed to antagonise the processes of pathogenic inflammation, such as the reduction in T-lymphocyte apoptosis, increase in T-lymphocyte proliferation and increase in T-lymphocyte trafficking into the intestinal mucosa. Inhibitors of various inflammatory cytokines, including some antagonists to tumour necrosis factor, are effective therapies for inflammatory bowel disease. However, this class is associated with the risk of rare, but serious, side-effects, such as opportunistic infections and demyelinating diseases. The administration of anti-inflammatory cytokines, including interleukin-10 and interleukin-11, may theoretically be effective in reducing inflammation, although the clinical development of some of these therapies has been terminated. The selective inhibition of the adhesion molecules involved in T-lymphocyte trafficking can be effective in reducing gut inflammation. Of the selective adhesion molecule inhibitors under investigation, natalizumab has demonstrated efficacy in inflammatory bowel disease. The future of biological therapy for inflammatory bowel disease shows promise.     

Fecal calprotectin as an index of intestinal inflammation

The assessment of inflammatory activity in intestinal disease in man can be done using a variety of different techniques, from measurement of conventional noninvasive acute-phase inflammatory markers in plasma (C-reactive protein and the erythrocyte sedimentation rate) to the direct assessment of disease activity by intestinal biopsy. However, most of these techniques have significant limitations when it comes to assessing functional components of the disease that relate to activity and prognosis. Here we briefly review the value of a novel emerging intestinal function test, fecal calprotectin. Single stool assay of neutrophil-specific proteins (calprotectin, lactoferrin) give the same quantitative data on intestinal inflammation as the 4-day fecal excretion of indium-111-labeled white cells. Elevated levels of fecal calprotectin have been demonstrated in patients with NSAID-induced enteropathy and have been used in the diagnosis of colorectal cancer. Fecal calprotectin is increased in over 95% of patients with inflammatory bowel disease (IBD) and correlates with clinical disease activity. It reliably differentiates between patients with IBD and irritable bowel syndrome (IBS). More importantly, at a given fecal calprotectin concentration in patients with quiescent IBD, the test has a specificity and sensitivity in excess of 85% in predicting clinical relapse of disease. This suggests that relapse of IBD is closely related to the degree of intestinal inflammation and suggests that targeted treatment at an asymptomatic stage of the disease may be indicated. (c) 2001 Prous Science. All rights reserved.     

Is clinical remission the optimum therapeutic goal in the treatment of Crohn's disease?

Currently, the therapeutic end-point in the treatment of Crohn's disease is the remission of symptoms, but recent data confirm that mucosal inflammation may continue in the absence of symptoms. Furthermore, emerging evidence indicates that such subtle, sub-clinical mucosal inflammation leads to clinical relapse. The assessment of mucosal inflammation has become easier with the availability of faecal calprotectin assay. Current anti-inflammatory therapy often leaves low-grade mucosal inflammation untreated, and therefore recurrent relapses occur. We need to investigate whether the therapeutic end-point of anti-inflammatory medications needs to be more rigorous and to aim at complete mucosal healing, confirmed by the normalization of mucosal inflammatory markers such as faecal calprotectin concentrations. Immunosuppressive therapy with azathioprine/ 6-mercaptopurine currently offers the best mucosal healing treatment with reduction of relapses, but newer biological agents might offer less toxic therapy. Clinical trials to test the feasibility and efficacy of such a paradigm shift in the medical management of Crohn's disease are now warranted.     

Efficacy and tolerability of oral iron therapy in inflammatory bowel disease: a prospective, comparative trial

BACKGROUND: In patients with inflammatory bowel disease, oral iron is anecdotally reported to be less effective and less well tolerated than in those without inflammatory bowel disease, and to increase disease activity. AIM: To study prospectively the effects of oral iron in patients with and without inflammatory bowel disease. METHODS: Patients with ulcerative colitis, Crohn's disease and non-inflammatory bowel disease controls, all with iron deficiency anaemia, were assessed with symptom diaries, a quality of life questionnaire (Inflammatory Bowel Disease Questionnaire; inflammatory bowel disease patients only) and blood tests to measure iron repletion, disease activity and antioxidant capacity before and after starting 4 weeks of oral iron. In patients with ulcerative colitis, sigmoidoscopic scoring and rectal biopsies for reactive oxygen metabolite production were performed before and after iron therapy. RESULTS: All groups showed increases in haemoglobin and ferritin. Iron intolerance occurred in about a quarter of patients in each group. Two of 33 (6%) of inflammatory bowel disease patients had a relapse during treatment. Symptoms worsened in ulcerative colitis, but not in Crohn's disease or non-inflammatory bowel disease patients; Inflammatory Bowel Disease Questionnaire scores improved in ulcerative colitis. Laboratory markers of disease activity, sigmoidoscopic scores, histological scores, antioxidant capacity levels and reactive oxygen metabolite production did not change. CONCLUSIONS: Oral iron is equally efficacious and well tolerated in inflammatory bowel disease and non-inflammatory bowel disease patients. A tiny minority of inflammatory bowel disease patients relapse in association with use of oral iron therapy.     

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.     

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.     

Emerging biotherapies for inflammatory bowel disease

The immunological and genetic pathogeneses of inflammatory bowel disease (IBD) have been well studied, but not well elucidated in recent years. Accordingly, the pharmacological treatment of IBD is focusing upon the individual pathologic step (targeting therapy). It has recently become apparent that new drugs such as biological immunomodulating agents and anti-inflammatory cytokines have better short-term effects in some respects than conventional drugs, and they could change the treatment strategy of IBDs in the near future. Many options are now available to treat IBD. The choice depends on the type of IBD, the location of inflammation and the severity of symptoms. Many key processes in the inflammatory cascade have been targeted by cytokine and anticytokine therapies ranging from antigen presentation, T cell activation, overproduction of pro-inflammatory cytokines and migration of inflammatory cells to blockade of effector signals. TNF-alpha plays an important role in the induction of other cytokines as well as in the upregulation of adhesion molecules in chronic IBDs, Crohn's disease (CD) and ulcerative colitis. In fact, the most successful approaches so far in the treatment of IBD have been anti-TNF strategies. In contrast, the use of antiadhesion molecules strategies has been demonstrated to be ineffective in IBD.     

Emerging biotherapies for inflammatory bowel disease

The immunological and genetic pathogeneses of inflammatory bowel disease (IBD) have been well studied, but not well elucidated in recent years. Accordingly, the pharmacological treatment of IBD is focusing upon the individual pathologic step (targeting therapy). It has recently become apparent that new drugs such as biological immunomodulating agents and anti-inflammatory cytokines have better short-term effects in some respects than conventional drugs, and they could change the treatment strategy of IBDs in the near future. Many options are now available to treat IBD. The choice depends on the type of IBD, the location of inflammation and the severity of symptoms. Many key processes in the inflammatory cascade have been targeted by cytokine and anticytokine therapies ranging from antigen presentation, T cell activation, overproduction of pro-inflammatory cytokines and migration of inflammatory cells to blockade of effector signals. TNF-α plays an important role in the induction of other cytokines as well as in the upregulation of adhesion molecules in chronic IBDs, Crohn’s disease (CD) and ulcerative colitis. In fact, the most successful approaches so far in the treatment of IBD have been anti-TNF strategies. In contrast, the use of antiadhesion molecules strategies has been demonstrated to be ineffective in IBD.     

Systematic review: is ingestion of paracetamol or non‐steroidal anti‐inflammatory drugs associated with exacerbations of inflammatory bowel disease?

AIM: To examine the published evidence on the association between paracetamol or non-steroidal anti-inflammatory drugs and relapse in inflammatory bowel disease. METHODS: Medline searches were performed till June 2004 and Embase till April 2003. Abstracts published in Gut and Gastroenterology from 1999 to 2004 were hand-searched. Twenty-nine relevant abstracts and papers were identified. RESULTS: Twenty-two patients with relapse of inflammatory bowel disease following exposure to non-steroidal anti-inflammatory drugs have been described in case-reports. Four patients were re-exposed to non-steroidal anti-inflammatory drugs and relapsed again. Two had relapsed after taking a cyclo-oxygenase 2 inhibitor. One study described increased inflammatory activity and clinical relapse in some patients after challenge with naproxen or nabumetone. Fifteen epidemiological studies were identified. All had small sample sizes and many had methodological problems. Six studies found evidence for an association between non-steroidal anti-inflammatory drug use and relapse of inflammatory bowel disease, but the association was significant in only two. Three studies suggested a relationship between paracetamol use and exacerbations of inflammatory bowel disease. CONCLUSIONS: Non-steroidal anti-inflammatory drugs may precipitate a relapse in some patients with inflammatory bowel disease. This may be an idiosyncratic reaction. The published evidence does not support the view that non-steroidal anti-inflammatory drugs are important in inducing relapse of inflammatory bowel disease. There is weak evidence that paracetamol may be more important.     

Growth hormone in inflammatory bowel disease

Crohn's disease and ulcerative colitis are inflammatory diseases of the gastrointestinal tract characterized by chronic relapsing inflammation and catabolism. Growth hormone/insulin-like growth factor-I axis is important in inflammatory bowel disease, because of the effects on epithelial cell kinetics, collagen deposition and immunomodulation. The potential of growth hormone as a therapeutic option in inflammatory bowel disease has been proven in various clinical settings. Acquired growth hormone resistance in inflammatory bowel disease seems to be mediated by a combination of undernutrition and active inflammation. In particular, proinflammatory cytokines, such as TNF-a and interleukin-6, have been implicated as potential mediators of growth hormone resistance. The introduction of anti-TNF-alpha monoclonal antibodies has proven very efficacious in patients with inflammatory bowel disease. By reducing cytokines levels in inflammatory cells of intestinal mucosa, infliximab could interfere with cytokine-induced growth hormone resistance. Recent in vivo data have shown that acquired growth hormone resistance in patients with inflammatory bowel disease may be reversed after the administration of anti-TNF-alpha therapy.     

Emerging peptide therapeutics for inflammatory diseases

Steroids are the best known anti-inflammatory drugs and have been in use for more than 50 years. Their chronic use however was limited by safety concerns. Non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2 inhibitors although devoid of steroid side effects often possess gastrointestinal side effects. In addition recent data suggest that chronic use of some Cox inhibitors is associated with cardiovascular risk. Currently biologics represent the best option for many inflammatory diseases where TNFalpha is the main culprit. These include rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease and psoriasis. A wealth of information is now available on the role of different cytokines and adhesion molecules in the origin and progression of inflammatory diseases. With the success of protein therapeutics such as Etanercept (Enbrel), which binds TNFalpha and inhibits its activity, research has been focused on developing small peptides that can interfere with cytokines or specific cell surface molecules and inhibit the inflammatory reactions. Here we review these peptides that are in discovery and development phases and their potential in the treatment of inflammatory diseases.     

Interleukins in atherosclerosis: molecular pathways and therapeutic potential

Interleukins are considered to be key players in the chronic vascular inflammatory response that is typical of atherosclerosis. Thus, the expression of proinflammatory interleukins and their receptors has been demonstrated in atheromatous tissue, and the serum levels of several of these cytokines have been found to be positively correlated with (coronary) arterial disease and its sequelae. In vitro studies have confirmed the involvement of various interleukins in pro-atherogenic processes, such as the up-regulation of adhesion molecules on endothelial cells, the activation of macrophages, and smooth muscle cell proliferation. Furthermore, studies in mice deficient or transgenic for specific interleukins have demonstrated that, whereas some interleukins are indeed intrinsically pro-atherogenic, others may have anti-atherogenic qualities. As the roles of individual interleukins in atherosclerosis are being uncovered, novel anti-atherogenic therapies, aimed at the modulation of interleukin function, are being explored. Several approaches have produced promising results in this respect, including the transfer of anti-inflammatory interleukins and the administration of decoys and antibodies directed against proinflammatory interleukins. The chronic nature of the disease and the generally pleiotropic effects of interleukins, however, will demand high specificity of action and/or effective targeting to prevent the emergence of adverse side effects with such treatments. This may prove to be the real challenge for the development of interleukin-based anti-atherosclerotic therapies, once the mediators and their targets have been delineated.     

Airway smooth muscle as an immunomodulatory cell: a new target for pharmacotherapy?

Asthma is a disease characterized, in part, by reversible airflow obstruction, hyperresponsiveness and inflammation. Traditional concepts concerning airway inflammation have focused on leukocyte trafficking and on the effects of inflammatory mediators, cytokines and chemokines secreted by these cells. Airway smooth muscle, the major effector cell responsible for bronchomotor tone, has been thought of as a passive tissue that responds to neurohumoral control and inflammatory mediators. New evidence, however, suggests that airway smooth muscle may secrete cytokines and chemokines and express cell adhesion molecules that are important in modulating submucosal airway inflammation. The cellular and molecular mechanisms that regulate the immunomodulatory functions of airway smooth muscle may offer new and important therapeutic targets in treating this common lung disease.     

Review article: platelets in inflammatory bowel disease— pathogenetic role and therapeutic implications

An elevated platelet count is well recognized as a marker of inflammatory bowel disease activity. There is an increased incidence of systemic thromboembolism in this disease. Recent work indicates that platelets exhibit several proinflammatory properties including release of inflammatory mediators, and recruitment, chemotaxis and modulation of the activity of other inflammatory cells. Furthermore there is evidence that microvascular thrombosis and a procoagulant state may play a role in the pathogenesis of inflammatory bowel disease.
These observations prompted recent studies of platelet activity in inflammatory bowel disease, which indicate enhanced platelet aggregation in vivo and in vitro, and increased platelet activation as measured by increased release of intracellular proteins into plasma and expression of platelet surface markers, including P-selectin and GP53. These abnormalities could contribute to the pathogenesis of inflammatory bowel disease by enhancing inflammation and promoting microinfarction. Aminosalicylates reduce platelet activity although they also have many other additional properties to explain their efficacy in inflammatory bowel disease. There are however several specific anti-platelet drugs now available which may provide new therapeutic possibilities in the management of this disease.     

Inflammation-induced thrombosis: mechanisms, disease associations and management

Although inflammation-induced thrombosis is a well-known entity, its pathogenesis remains complicated. There are complex interactions between inflammation and hemostasis, involving proinflammatory cytokines, chemokines, adhesion molecules, tissue factor expression, platelet and endothelial activation, and microparticles. Inflammation increases procoagulant factors, and also inhibits natural anticoagulant pathways and fibrinolytic activity, causing a thrombotic tendency. Besides, chronic inflammation may cause endothelial damage, resulting in the loss of physiologic anticoagulant, antiaggregant and vasodilatory properties of endothelium. However, inflammation- induced venous thrombosis may develop even in the absence of vessel wall damage. On the other hand, coagulation also augments inflammation, causing a vicious cycle. This is mainly achieved by means of thrombin-induced secretion of proinflammatory cytokines and growth factors. Platelets may also trigger inflammation by activating the dendritic cells. There are many systemic inflammatory diseases characterized by thrombotic tendency, including Beh?et disease (BD), antineutrophilic cytoplasmic antibody-associated vasculitides, Takayasu arteritis, rheumatoid arthritis, systemic lupus erythematosus, antiphosholipid syndrome, familial Mediterranean fever, thromboangiitis obliterans (TAO) and inflammatory bowel diseases. Inflammation-induced thrombosis may respond to immunosuppressive (IS) treatment, as in the case of BD. However effectiveness of this treatment can not be generalized to all other inflammatory diseases. For instance, IS agents do not have any beneficial role in the management of TAO. Heparin, antiplatelet agents such as aspirin and clopidogrel, colchicine and statins also have some antiinflammatory activity. However, decreased responsiveness to aspirin and clopidogrel treatments may be observed in inflammatory diseases, due to antiplatelet resistance caused by systemic inflammation. In the present review, we aimed to discuss the details of the complex crosstalk between inflammation and hemostasis in the context of available data. We also intended to overview the major inflammatory diseases with thrombotic tendency, as well as to discuss the general principles of the management of inflammation-induced thrombosis.     

Inflammatory cytokines in vascular dysfunction and vascular disease

The vascular inflammatory response involves complex interaction between inflammatory cells (neutrophils, lymphocytes, monocytes, macrophages), endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and extracellular matrix (ECM). Vascular injury is associated with increased expression of adhesion molecules by ECs and recruitment of inflammatory cells, growth factors, and cytokines, with consequent effects on ECs, VSMCs and ECM. Cytokines include tumor necrosis factors, interleukins, lymphokines, monokines, interferons, colony stimulating factors, and transforming growth factors. Cytokines are produced by macrophages, T-cells and monocytes, as well as platelets, ECs and VSMCs. Circulating cytokines interact with specific receptors on various cell types and activate JAK-STAT, NF-κB, and Smad signaling pathways leading to an inflammatory response involving cell adhesion, permeability and apoptosis. Cytokines also interact with mitochondria to increase the production of reactive oxygen species. Cytokine-induced activation of these pathways in ECs modifies the production/activity of vasodilatory mediators such as nitric oxide, prostacyclin, endothelium-derived hyperpolarizing factor, and bradykinin, as well as vasoconstrictive mediators such as endothelin and angiotensin II. Cytokines interact with VSMCs to activate Ca²⁺, protein kinase C, Rho-kinase, and MAPK pathways, which promote cell growth and migration, and VSM reactivity. Cytokines also interact with integrins and matrix metalloproteinases (MMPs) and modify ECM composition. Persistent increases in cytokines are associated with vascular dysfunction and vascular disease such as atherosclerosis, abdominal aortic aneurysm, varicose veins and hypertension. Genetic and pharmacological tools to decrease the production of cytokines or to diminish their effects using cytokine antagonists could provide new approaches in the management of inflammatory vascular disease.     

Review article: quantitative leucocyte scanning in the assessment of inflammatory bowel disease activity and its response to therapy

Inflammatory bowel disease (IBD) symptoms may be due not only to the effects of bowel inflammation, but also can result from many non-inflammatory consequences of the disease. Clinical scores and health questionnaire ratings produce a global assessment which is useful in the overall evaluation of the impact of the illness on the patient, and the effect of treatment. However many studies have failed to recognize the need to separately assess changes in the degree of bowel inflammation, in addition to a global clinical response.
Radiolabelled white cell scanning using 111-indium has been shown to provide an accurate, quantitative and non-invasive method for assessing the degree of bowel inflammation in IBD and its response to therapy, using faecal collection or total body counts of radioactivity. More recently 99mTc hexamethyl propylene amine oxime (HMPAO) labelled white cell scanning has been introduced, which has advantages over the 111-indium method, including reduced radiation dosimetry and enhanced image quality. 99mTc-HMPAO scanning using three-dimensional white cell scanning (single photon emission computerized tomography; SPECT) allows visualization of the entire bowel separate from overlying structures.
99mTc-HMPAO white cell scanning with SPECT has now been computerized and automated to permit measurement of segmental and total bowel radiolabelled white cell infiltrate. This method could potentially provide the gold standard for objective assessment of the response of disease activity in Crohn's disease and ulcerative colitis, and merits application in clinical trials of novel therapies for IBD.     

Iron and inflammatory bowel disease

Both anaemia of iron deficiency and anaemia of chronic disease are frequently encountered in inflammatory bowel disease. Anaemia of iron deficiency is mostly due to inadequate intake or loss of iron. Anaemia of chronic disease probably results from decreased erythropoiesis, secondary to increased levels of proinflammatory cytokines, reactive oxygen metabolites and nitric oxide. Assessment of the iron status in a condition associated with inflammation, such as inflammatory bowel disease, is difficult. The combination of serum transferrin receptor with ferritin concentrations, however, allows a reliable assessment of the iron deficit. The best treatment for anaemia of chronic disease is the cure of the underlying disease. Erythropoietin reportedly may increase haemoglobin levels in some of these patients. The anaemia of iron deficiency is usually treated with oral iron supplements. Iron supplementation may lead to an increased inflammatory activity through the generation of reactive oxygen species. To date, data from studies in animal models of inflammatory bowel disease support the theoretical disadvantage of iron supplementation in this respect. The results, however, cannot easily be extrapolated to the human situation, because the amount of supplemented iron in these experiments was much higher than the dose used in patients with iron deficiency.     

Glucocorticoids and IL-10, but not 6-MP, 5-ASA or sulfasalazine block endothelial expression of MAdCAM-1: implications for inflammatory bowel disease therapy

BACKGROUND: Enhanced MAdCAM-1 (mucosal addressin cell adhesion molecule-1) expression is associated with the aetiology of inflammatory bowel disease, but little is known about MAdCAM-1: regulation, or how inflammatory bowel disease therapies modulate MAdCAM-1. AIM: To examine how agents currently used to treat inflammatory bowel disease affect MAdCAM-1: induced by tnf-alpha in an in vitro model of inflammatory bowel disease. METHODS: Endothelial monolayers were pretreated with dexamethasone (DEX): 5-aminosalicylic acid (5-ASA), 6-mercaptopurine (6-MP), sulfasalazine or interleukin-10: (IL-10: prior to TNF-alpha (20 ng/mL), and MAdCAM-1: measured by Western blotting, RT-PCR, EMSA and lymphocyte adhesion assays. RESULTS: MAdCAM-1: was induced dose- and time-dependently by TNF-alpha on endothelial cells. Either dexamethasone or IL-10: reduced TNF-alpha-induced MAdCAM-1: protein, mRNA and lymphocyte adhesion. However, neither 5-ASA, sulfasalazine nor 6-MP blocked MAdCAM-1 induction. CONCLUSIONS: Our data indicate that dexamethasone or IL-10 can exert therapeutic activity in inflammatory bowel disease through MAdCAM-1 inhibition. 5-ASA, sulfasalazine and 6-MP, while beneficial in inflammatory bowel disease, do not directly control MAdCAM-1, and are beneficial through inhibition of other inflammatory processes.