Recent advances in the etiology and treatment of inflammatory bowel disease

Crohn’s disease and ulcerative colitis, together comprising the inflammatory bowel diseases, currently affect up to 2 million people in the western developed countries. The pathogenesis of the disease is a complex one in which genetic, immunogenic, microbial and environmental factors contribute to the etiology of the disease. Recent advances in understanding the molecular mechanisms that determine this complex entity have provided insight for promising new therapies.     

Budesonide in the treatment of inflammatory bowel disease

Inflammatory bowel disease, including Crohn’s disease and ulcerative colitis, features recurrent episodes of inflammation of the GI tract. The treatment of inflammatory bowel disease is aimed at breaking the cycle of relapsing and remitting inflammation by inducing and maintaining remission. Systemically active conventional corticosteroids have long played a role in the induction of remission in both Crohn’s disease and ulcerative colitis, however, their long-term use can lead to adverse systemic effects. Budesonide, a synthetic steroid, has potent local anti-inflammatory effects and limited systemic bioavailability making it an appealing therapeutic option. Ulcerative colitis with predominantly distal disease may be treated with topical budesonide, however, novel oral controlled-release formulations have also been developed to allow for treatment of the entire colon. This article summarizes the use of budesonide in the management of inflammatory bowel disease.     

The clinical implications of thalidomide in inflammatory bowel diseases

Thalidomide has anti-inflammatory and anti-angiogenetic activity that makes it suitable for treating inflammatory bowel diseases (IBD). The recent guidelines from the European Crohn’s and Colitis Organization/European Society for Pediatric Gastroenterology Hepatology and Nutrition conclude that thalidomide cannot be recommended in refractory pediatric Crohn’s disease but that it may be considered in selected cohorts of patients who are not anti-TNFα agent responders. The main adverse effect is the potential teratogenicity that renders the long-term use of thalidomide problematic in young adults due to the strict need for contraceptive use. In short-term use it is relatively safe; the most likely adverse effect is the neuropathy, which is highly reversible in children. So far the use of thalidomide is reported in 223 adult and pediatric IBD patients (206 with Crohn’s disease). In the following sections, the authors will discuss efficacy and safety of thalidomide, in the short-term treatment of IBD.     

Adalimumab for the treatment of pediatric Crohn’s disease

Inflammatory bowel diseases are characterized by a chronic relapsing course, high morbidity and impaired quality of life. Their incidence is rising, and about 25% of cases are diagnosed in pediatric age. Anti-TNF-α antibodies, such as infliximab and adalimumab (ADA), are usually administered in patients refractory to conventional therapies. However, increasing evidence suggests that they can be introduced earlier in the course of the disease, especially in patients with aggressive and extensive disease since diagnosis. ADA is a fully human anti-TNF-α antibody recently approved for pediatric Crohn’s disease not only in patients unresponsive to infliximab, but also as a first-line anti-TNF-α therapy. In this review, we aim to summarize the current knowledge on the use of ADA in pediatric Crohn’s disease and to discuss open issues regarding safety as well as future perspectives.     

Genetic dissection of inflammatory bowel disease: unravelling etiology and improving diagnostics

Over the past 10 years, remarkable advances in the mapping and identification of genes involved in susceptibility to inflammatory bowel disease have been witnessed. Most notable among these advances has been the discovery of variants in the CARD15, DLG5, SLC22A4 and SLC22A5 genes, which are associated with increased risk of inflammatory bowel disease or specifically Crohn’s disease. These discoveries have provided critical new insights into the molecular pathophysiology of inflammatory bowel disease and the pathways wherein genetic and environmental factors such as enteric bacterial flora may interact to trigger immune dysregulation and intestinal inflammation. This review will outline the discovery of these inflammatory bowel disease-related genes, describe future prospects for further inflammatory bowel disease gene identification, and consider the impact of a genetic understanding of inflammatory bowel disease on future clinical practice.     

Th17 cells: interactions with predisposing factors in the immunopathogenesis of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic inflammatory state of the GI tract of unknown etiology. Classically, tissue injury in IBD is thought to be primarily mediated by Th1 cells in Crohn’s disease or Th2 cells in ulcerative colitis. The discoveries of new subsets of T-helper cells, especially Th17 cells, have revolutionized our understanding of the disease immunopathology. Th17 cells seem to affect both innate and adaptive immune responses by the release of regulatory cytokines. Understanding the role of Th17 cells in IBD pathogenesis and targeting their regulatory cytokines may provide potential therapeutic approaches for the treatment of IBD in the future.     

Biologics in pediatric Crohn’s disease: is it time to move to an earlier therapeutic approach?

The treatment of Crohn’s disease in children has undergone a revolution in the past decade following studies that have demonstrated the efficacy of anti-TNFα agents in producing durable clinical response/remission as well as reversal of growth delay in many patients. The positioning of biologic therapy continues to be debated. Should it be reserved for children failing conventional therapy including immunomodulators or should it be used as primary therapy shortly after diagnosis in children with more severe disease likely to suffer a more complicated disease course? Risk stratification will be crucial to any therapeutic decisions and emerging data hold promise that identification of those most likely to benefit will be available in the near future.     

The combination of fecal calprotectin with ESR,CRP and albumin discriminates more accurately children with Crohn’s disease

PurposeIncreased fecal calprotectin is a sensitive marker of various types of intestinal inflammation. We investigated correlations between high fecal calprotectin concentration and serum inflammatory markers in children with different intestinal diseases with diarrhea with/without blood and/or abdominal pain, to test whether the combination of these markers can differentiate potential patients with inflammatory bowel disease.Materials/methodsThe study included 128 children with high fecal calprotectin concentration (>150ug/g) and symptoms suggesting bowel disorders, hospitalized in the years 2013– 2015. Twenty-six (20%) patients were diagnosed with Crohn’s disease, 55 (43%) with ulcerative colitis, 32 (25%) with intestinal infection and 15 (12%) with food protein induced proctocolitis.ResultsSignificantly increased inflammatory markers were detected in children with inflammatory bowel disease, with a correlation between calprotectin and erythrocyte sedimentation rate – ESR (R = 0.53), mean corpuscular volume – MCV (R=-0.64), red blood cell distribution width (R = 0.56), albumin (R = −0.52), hemoglobin (R = −0.53) only in Crohn’s disease patients. To discriminate Crohn’s disease patients from patients with intestinal infection and patients with food protein induced proctocolitis, AUC analysis was performed. It revealed that considering ESR, CRP and albumin as additional markers to fecal calprotectin significantly improved diagnostic performance (AUC 0.917, p = 0.038).ConclusionsIn children with abdominal pain and/or diarrhea, increased ESR, CRP and decreased albumin combined with a high fecal calprotectin level yields additional diagnostic value in screening potential patients with Crohn’s disease. As far as differentiation of ulcerative colitis is concerned, low additional diagnostic value was found when high fecal calprotectin was combined with albumin.     

Stem cell treatment for Crohn’s disease

While stem cell-based treatments have been established as a clinical standard of care for some conditions, such as hematopoietic stem cell transplants for cancer, the scope of potential stem cell-based therapies has expanded in recent years due to advances in stem cell research, paving the way for the increasing utilization of stem cell therapies in severe immune-mediated diseases including inflammatory bowel diseases (IBDs) and, in particular, Crohn’s disease. Both hematopoietic stem cells and mesenchymal (stromal) stem cells are considered to be of potential therapeutic benefit in immune-mediated conditions. A growing body of experimental and clinical evidence shows that hematopoietic stem cell transplant induces long-lasting remission in a majority of patients with active severe Crohn’s disease refractory to drug treatments, and the differential effect of potent immunosuppression and immune reconstitution in this setting is under evaluation. Mesenchymal stem cells have been shown to exert immunomodulatory action on various types of immune-mediated diseases, and in experimental models of IBD, but evaluation of the potential efficacy of this therapy in IBD is still in the early stages.     

Use of immunomodulators and biologic therapies in children with inflammatory bowel disease

The immunomodulators (6-mercaptopurine, azathioprine and methotrexate) and biologics (infliximab, adalimumab, certolizumab and natalizumab) are medications essential in the management of pediatric inflammatory bowel disease. If properly utilized, these medications can control active disease, reduce corticosteroid exposure, induce remission, and promote normal growth and development. However, these medications also have significant toxicity and increase the risk of infections and lymphoma. This article provides information about the safety and efficacy of these medications in the treatment of children with Crohn’s disease and ulcerative colitis.     

Gastro-intestinal autoimmunity: preclinical experiences and successful therapy of fistulizing bowel diseases and gut Graft versus host disease by mesenchymal stromal cells

Mesenchymal stromal cells (MSC) are multipotent adult stem cells with the potential to regenerate tissue damage and inhibit inflammation and fibrosis in parallel. As they are non-immunogenic, MSC can be safely auto- and allotransplanted and consequently represent a therapeutic option for refractory connective tissue diseases and fistulizing colitis like Crohn’s disease. Actually, there are more than 200 registered clinical trial sites for evaluating MSC therapy, 22 are on autoimmune diseases and 27 are actually recruiting bowel disease’ patients. More than 1,500 patients with bowel diseases like Crohn’s disease were treated in clinical trials by local as well as systemic MSC therapy. Phase I and II trials on fistula documented the feasibility and safety of MSC therapy, and a significant superiority compared to fibrin glue in fistulizing bowel diseases was demonstrated. Autologous as well as allogeneic use of Bone marrow as well as of adipose tissue-derived MSC are feasible. In refractory Graft versus host disease, especially in refractory gut Graft versus host diseases, encouraging results were reported using MSC. Systemic MSC therapy of refractory irradiation-induced colitis was safe and effective on pain, diarrhea, hemorrhage, inflammation and fistulization accompanied by modulation of the lymphocyte subsets toward an increase in T regulatory cells and a decrease in activated effector T cells. Mesenchymal stem cells represent a safe therapy for patients with refractory inflammatory bowel diseases.     

Nodular regenerative liver hyperplasia as a complication of azathioprine-containing immunosuppressive treatment for Crohn’s disease

Nodular regenerative liver hyperplasia (NRH) is a very rare but potentially severe complication of thiopurine-containing immunosuppressive therapy for autoimmune disorders, organ transplantation, and/or oncological treatment. Here we report a case of a 40-year-old female patient with Crohn’s disease and genetic hypercoagulability disorder—factor V Leiden, who in the course of azathioprine immunosuppressive treatment for inflammatory bowel disease developed NRH, which was clinically manifested by thrombocytopenia and delicate hepato-splenomegaly. Moreover, her endoscopic examination of upper gastrointestinal tract demonstrated esophageal varices. Genetic analysis revealed heterozygous genotype (*1/*3A) of thiopurine S-methyltransferase (TPMT), a key enzyme of thiopurines’ metabolism, which results in lower activity of TPMT enzyme, thereby making our patient more susceptible to azathioprine-related hepato and myelotoxicity development. Treatment was started with the immediate cessation of azathioprine therapy, and administration of propranolol as primary prophylaxis for bleeding from esophageal varices. Currently (3 years after diagnosis) remission of Crohn’s disease is achieved, however, progression of features of portal hypertension is observed. Propranolol administration is continued and the patient is constantly monitored in our Department. Our Case Study highlights the clinical difficulties and challenges associated with diagnosing of azathioprine-induced NRH, as well as, supports previous observations that hypercoagulability disorders and abnormal TPMT activity may contribute to NRH development.     

Anti-Adhesion Molecule Strategies for Crohn Disease

The last few years have been highlighted by further knowledge and optimism regarding the use of biologic therapy in Crohn disease. The introduction of anti-tumor necrosis factor (TNF) therapy into clinical practice in the form of the murine chimeric monoclonal antibody infliximab, and more recently the fully human monoclonal antibody adalimumab, has significantly advanced treatment for Crohn disease. Despite the introduction of the anti-TNF agents, 20-40% of patients will fail to respond to initial induction therapy, and of the initial responders only 60-70% will have a sustained response at 1 year. Therefore, there remains a significant unmet need in the treatment of patients with Crohn disease. A novel approach in suppressing inflammation is to intervene in the mechanisms responsible for the migration of leukocytes into inflamed tissue. One such method is by selective adhesion molecule inhibition. Several agents based on this strategy have been evaluated in the treatment of inflammatory bowel disease. It is expected that these agents will offer an alternative to the anti-TNF agent class in patients with moderate to severe Crohn disease.     

S100 proteins in the pathogenesis and diagnosis of inflammatory bowel disease

Crohn’s disease and ulcerative colitis (the inflammatory bowel diseases) are two well characterized conditions featuring inflammation of the gastrointestinal tract. Gut inflammation may be detected, assessed and measured by a variety of methods but their utility varies extensively. Over the past decade, calprotectin, belonging to a family of S100 proteins, has been shown to be a reliable marker of gut inflammation that corresponds to neutrophil migration. In addition, other members of the S100 family have important roles in inflammation and may also be useful markers of gut inflammation. Furthermore, these proteins may have functional roles in gut defense or in the pathogenesis of inflammatory bowel disease.     

Nutrigenetics,nutrigenomics and inflammatory bowel diseases

Inflammatory bowel disease includes ulcerative colitis and Crohn’s disease, which are both inflammatory disorders of the gastrointestinal tract. Both types of inflammatory bowel disease have a complex etiology, resulting from a genetically determined susceptibility interacting with environmental factors, including the diet and gut microbiota. Genome Wide Association Studies have implicated more than 160 single-nucleotide polymorphisms in disease susceptibility. Consideration of the different pathways suggested to be involved implies that specific dietary interventions are likely to be appropriate, dependent upon the nature of the genes involved. Epigenetics and the gut microbiota are also responsive to dietary interventions. Nutrigenetics may lead to personalized nutrition for disease prevention and treatment, while nutrigenomics may help to understand the nature of the disease and individual response to nutrients.     

Immune-mediated inflammatory reactions and tumors as skin side effects of inflammatory bowel disease therapy

Abstract

All drugs currently used for treating patients with inflammatory bowel disease (IBD – including Crohn’s disease and ulcerative colitis) have the potential to induce skin lesions ranging from mild eruptions to more serious and widespread clinical presentations. The number of cutaneous adverse reactions due to IBD therapies is progressively increasing and the most frequently involved drugs are thiopurines and biologics like tumor necrosis factor (TNF)-α antagonists. The main drug-induced cutaneous manifestations are non-melanoma skin cancer (NMSC), notably basal cell and squamous cell carcinomas, and viral skin infections for thiopurines and psoriasiform, eczematoid and lichenoid eruptions as well as skin infections and cutaneous lupus erythematosus for biologics. Cutaneous manifestations should be promptly recognized and correctly diagnosed in order to quickly establish an adequate therapy. The main treatment for NMSC is surgical excision whereas the management of immune-mediated inflammatory skin reactions varies from topical therapy for mild presentations to the shift to another drug alone or in combination with corticosteroids for extensive eruptions.     

Nutrigenomics and inflammatory bowel diseases

The field of nutrigenomics recognizes gene–diet interactions, with regard to both the impact of genetic variation on nutrient requirements, and conversely nutrient regulation of the expression of genes. Crohn’s disease and ulcerative colitis are inflammatory bowel diseases for which twin studies reveal genetic susceptibility that is impacted by diet and environment. Apparently contradictory data on the role of diet in inflammatory bowel disease would be entirely explainable if genetic variability determined dietary requirements and intolerances. Considering Crohn’s disease, we recognize three major classes of genes. The first of these involves bacterial recognition through pattern recognition receptors and autophagy genes, while the second act through secondary immune response, and the third concern epithelial barrier integrity. Despite genetic overlap with CD, the first two groups of genes appear to be less important in ulcerative colitis, while other genes, particularly those involved in barrier function, gain prominence. Case–control studies suggest that these different genetic groups reflect distinct dietary requirements. Such studies suggest nutrigenomic approaches to maintaining disease remission at present, and preventing disease development in the future.     

Leukocyte traffic control: a novel therapeutic strategy for inflammatory bowel disease – an update

Adhesion molecules play a key role in the pathogenetic mechanisms of inflammatory bowel disease (IBD), both in Crohn’s disease (CD) and ulcerative colitis (UC). In the last decade, some progress has been made in understanding their key role in leukocyte trafficking control in terms of basic research, but evidence of clinical efficacy is lacking. In the last 2 years, new molecules directed against integrins and integrin receptors have been developed and investigated in clinical trials, showing that anti-α4β7 integrin agents can be effective and safe for the induction and maintenance of remission in active CD and UC. Preliminary data show that anti-MAdCAM, anti-β7 and anti-integrin receptor agents are not all effective in IBD. Such results open new perspectives on clinical management of IBD, and new directions in understanding the role of adhesion molecules and leukocyte recruitment both in CD and UC.     

Review of Saccharomyces boulardii as a treatment option in IBD

Abstract

Context: Review of the yeast Saccharomyces boulardii as a treatment option for the inflammatory bowel diseases (IBD) ulcerative colitis and Crohn’s disease.

Objective: IBD is caused by an inappropriate immune response to gut microbiota. Treatment options could therefore be prebiotics, probiotics, antibiotics and/or fecal transplant. In this review, we have looked at the evidence for the yeast S. boulardii as a treatment option.

Material and methods: Searches in PubMed and the Cochrane Library with the MeSH words ‘Saccharomyces boulardii AND IBD’, ‘Saccharomyces boulardii AND Inflammatory Bowel Disease’, ‘Saccharomyces boulardii AND ulcerative colitis’ and ‘Saccharomyces boulardii AND Crohn’s disease’ gave total a total of 80 articles. After exclusions because of irrelevance, articles in other languages and some articles that were not available, 16 articles were included in this review.

Results: Three of the clinical trials showed a positive effect of S. boulardii in IBD patients (two Crohn’s disease, one ulcerative colitis), while there was one trial that didn’t prove any effect (Crohn’s disease). Included Animal trials and cell assays describes different anti-inflammatory mechanisms of S. boulardii supporting a possible effect when treating IBD patients.

Discussion: The number of studies of S. boulardii as treatment for IBD is limited. Furthermore, the existing trials have small populations and short duration.

Conclusion: We do not have enough evidence to prove the effect of S. boulardii in IBD. Saccharomyces boulardii is, however, a plausible treatment option in the future, but more placebo-controlled clinical studies on both patients with ulcerative colitis and Crohn’s disease are needed.     

Exclusive enteral nutrition and induction of remission of active Crohn’s disease in children

Exclusive enteral nutrition is an effective therapy for the management of active Crohn’s disease, especially in children and adolescents. This therapeutic approach involves the use of a liquid nutritional product with the exclusion of normal diet for a period of many weeks. Although recent studies have helped to delineate some aspects of how exclusive enteral nutrition should be used, there remain many gaps in our understanding. In addition, several recent reports have provided intriguing insights into the mechanisms of this nutritional approach.