Chronic inflammatory bowel disease - Crohn's disease and ulcerative colitis - are characterized by inflammation of the wall of part of the gastrointestinal tract, related to an overactive gastrointestinal immune system. There is no curative treatment for these disorders; however, current medicinal products usually enable long-term disease control and satisfactory quality of life between relapse episodes. Several avenues of research are currently being developed with a view to improving existing treatments.
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Chronic inflammatory bowel disease (or IBD) includes Crohn's disease and ulcerative colitis. Both are characterized by inflammation of the wall of part of the gastrointestinal tract. In Crohn's disease, inflammation may be located throughout the whole gastrointestinal system, from the mouth to the anus, although it is usually found in the intestine. In ulcerative colitis, inflammation is located in the rectum and colon.
These disorders progress in inflammatory episodes, varying extensively in duration and frequency according to the patients. These episodes alternate with phases of remission.
IBD is usually diagnosed in young subjects, aged 20 to 30 years. However, it may occur at any age, and children account for 15% of cases. Although its frequency varies considerably from one country to another, the highest rates are found in industrialized countries, particularly in Northwestern Europe and in the United States. In France, where the prevalence of the disease has remained stable in recent years, approximately 5 new cases of Crohn's disease and an equal number of ulcerative colitis cases are diagnosed each year per 100,000 inhabitants. However, prevalence increases exponentially in industrializing countries (North Africa, Asia, South Africa, etc.).
Abdominal pain and diarrhea, two typical symptoms
Inflammatory episodes of IBD are usually characterized by abdominal pain, frequent and sometimes bloody diarrhea, and even anal lesions (fissures, abscesses). These symptoms make this disorder somewhat taboo. Symptoms are often accompanied by fatigue, anorexia and fever, and sometimes even extraintestinal symptoms (articular, cutaneous, ocular, hepatic).
Approximately 20% of patients experience severe episodes: intense episodes may result in hospital admission, withdrawal of food, and treatment with an infusion over a few days. Furthermore, disease progression may cause narrowing of the affected intestinal segment, followed by obstruction and even abscess. This may lead to formation of a fistula, i.e. the creation of an abnormal channel from the intestine to another organ. These complications require surgical intervention.
IBD is associated with an increased risk of colorectal cancer, particularly in the presence of colon lesions. A Danish study showed that this risk is multiplied by 2 to 2.5, relative to the general population, after 10 years of disease progression.
Several criteria for diagnosis
The diagnosis of IBD is based on several clinical, biological and medical imaging criteria.
When clinical symptoms suggest IBD, a blood test is performed. This serves to detect an inflammatory syndrome, the presence of specific markers for IBD, particularly anti-Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA), and any nutritional deficiencies. An inflammatory marker (calprotectin) is often assayed directly in the stool. This examination is helpful in screening for the disease; however, it is also used thereafter to evaluate the efficacy of the treatment instituted.
Physicians use gastrointestinal endoscopy to investigate for the presence and location of lesions in the gastrointestinal tract, and to take samples. This examination involves inserting an endoscope fitted with a camera into the patient's gastrointestinal system. If necessary, MR enterography may be performed in addition to this examination to study the small intestine more closely. Use of capsule endoscopy, which involves swallowing a capsule containing a miniature camera, also enables examination of the small intestine and is sometimes able to evidence microlesions imperceptible to other imaging techniques. Capsule endoscopy is currently being developed for the colon.
Environmental factors combined with genetic predisposition
There are thought to be several risk factors for IBD, particularly genetic and environmental factors.
Genomic analysis of IBD patients has made it possible to identify over 150 predisposition genes for these disorders. Aside from rare cases, their impact on IBD onset is moderate. Nevertheless, one or two mutations on the NOD2/CARD15 gene could give rise to a 40-fold increase in the risk of developing Crohn's disease.
As the prevalence of these disorders is rapidly rising in industrializing countries, this could point to an environmental role, particularly pollution, in their occurrence. Studies suggest the role of microparticles or even heavy metals, such as aluminum.
Diet could also be a contributing factor. However, no foods, food groups or culinary methods are currently associated with IBD.
Tobacco use is, however, a known risk factor for Crohn's disease but, paradoxically, offers protection against ulcerative colitis.
IBD and intestinal microbiota
The intestinal microbiota appear to play an important, but as yet unclear role, in the characteristic inflammation associated with IBD. An attractive hypothesis has been put forward: an imbalance in the composition of the intestinal flora is said to develop under the influence of genetic and environmental factors, and would apparently play a role in triggering and maintaining inflammation, and in the degree of its severity, resulting in a vicious circle.
In approximately 40% of patients, a new category of Escherichia coli (AIEC) is observed for example, which is more adherent to intestinal wall cells and more invasive than the usual strains.
The microbiota thus constitute an interesting therapeutic target in the management of these inflammatory disorders. Nevertheless, clinical trials aiming to restore a balanced intestinal flora via fecal transplantation or using probiotics/prebiotics have not been conclusive. Certain teams are attempting to create genetically modified probiotics which would make it possible to implant the species of interest while giving it additional properties, such as the secretion of immunomodulatory mediators. Others are attempting to eradicate adherent-invasive E. coli (AIEC) using antibiotics or bacteriophages (viruses specifically infecting bacteria).
Acute treatment and maintenance treatment
No curative treatment exists for IBD; however, current anti-inflammatory medications allow long-term disease control in the large majority of cases, for several years, associated with satisfactory quality of life. These prevent the onset of acute episodes and prolong remission phases, while allowing gastrointestinal tract lesions time to heal. During acute episodes, 5-aminosalicylates (5-ASA) may be prescribed to individuals with moderate forms of ulcerative colitis. However, these are not effective for Crohn's disease. The use of corticosteroids is declining due to their medium and long-term side effects.
In patients with progressive disease, physicians rapidly initiate immunomodulatory therapy, to stop acute episodes and preventing new lesions from developing. These medications make it possible to regulate patient immunity and reduce inflammation in the long term. The most widely used medications are biotherapies: anti-TNF-α and anti-Il12/Il-23 specifically block inflammation factors implicated in the disease. Approximately 70% of patients respond well to these treatments. However, in half of patients, the efficacy of these medications declines after two years, necessitating a change in agent. A new generation of specific intestinal immunomodulators (vedolizumab) has just arrived on the market. These are monoclonal antibodies which bind specifically to adhesion molecules on the surface of immune cells in blood, preventing them from passing into the gastrointestinal tract. This new medicinal product is particularly well tolerated.
Surgical treatment may be offered for patients resistant to properly managed treatment, or following the onset of complications. After 10 years of disease progression, more than one in two patients undergo surgical intervention to remove the most diseased segment of the gastrointestinal tract. This proportion should decrease in the next few years owing to the arrival of new, more effective medications.
Lastly, the frequency and severity of diarrhea may give rise to nutritional deficiencies. Oral or intravenous supplementation with iron, folic acid, zinc, magnesium, vitamins, etc. may be necessary. Exclusive or supplemental enteral nutrition may be necessary for pediatric patients.
Challenges facing research
Several avenues of research are currently being developed with a view to improving the treatment of chronic inflammatory bowel disease.
Towards new medications
Numerous laboratories are working on the development of new biotherapies, which are more effective and better tolerated. A new class of anti-b7 antibodies should notably reach the market in 2017. Nevertheless, current immunomodulators target inflammation without being able to treat fibrosis resulting from induced and healing lesions. This fibrosis causes local narrowing of the gastrointestinal tract, with a risk of obstruction, requiring surgical intervention. Antifibrotic agents are thus also in development. The objective is to combine these with immunomodulators.
Furthermore, a new, much more effective agent belonging to the 5-ASA class is currently being studied. 5-aminosalicylates (5-ASA) are long-standing agents, the development of which earned Gerhard Domagk a Nobel Prize in Medicine in 1939. It was only years later that physicians quite by chance discovered their utility in the treatment of inflammatory bowel disease. It took until 2007 for a team to unravel the signaling pathways involved in its anti-inflammatory mechanisms. This research enabled a major milestone to be reached in the development of a new, more specific agent (GED-0507-34 Levo), still in development. This could have an anti-inflammatory action 50 times greater than that of the currently available 5-aminosalicylates, particularly in ulcerative colitis. It could also have an antifibrotic action.
Another highly promising treatment which could change the course of the disease is anti-SMAD7 (mongersen). This is a small nucleic acid molecule (antisense oligonucleotide) which blocks the production of transcription factor SMAD7 in immune cells. Without this factor, T-lymphocytes lose their ability to produce pro-inflammatory cytokines, and macrophages and dendritic cells become less effective. In patients with active Crohn's disease, two weeks of oral treatment with this medicinal product led to remission in approximately 65% of cases at three months, irrespective of the duration of the disease. Never before seen with any other medicinal product! These results should be confirmed by a phase III clinical trial.
Stem cells to repair fistulas
Cell therapy is becoming more widely used in patients with fistulas. Approximately 20% of IBD patients have a fistula, particularly in the perineal region. A clinical study including 289 patients with a perianal fistula has recently shown that a single injection of mesenchymal stem cells (derived from adipose tissue) into the fistula enabled closure as from six weeks. Although these cells were taken from a donor rather than the patients themselves, no immunosuppressant therapy was necessary. The company behind this study has submitted a marketing authorization application for its prefilled syringes containing mesenchymal cells.