IDIOPATHIC INFLAMMATORY BOWEL DISEASE
Inflamatory Bowel diseases (IBD) are characterised by chronic inflammation of the bowel and are the result of a combination of genetic predisposition, environmental factors, and bowel microbiome.
The clinical manifestations of IBD in the pediatric populations are varied and paediatricians must suspect IBD even in unusual presentations, such as in anaemia and poor weight gain.
The spectrum of inflammatory bowel disease includes:
- Ulcerative Colitis
- Crohn’s disease
- Non-specific Inflammatory colitis
The incidence of pediatric IBD is approximately 10 in every 100,000 children, according to epidemiological studies in the USA and Canada.
Onset of IBD and symptoms can occur in paediatric and adolescent ages. 4% of people with IBD will present at an age of under 5 years old (early and very early onset IBD), 18% up to the age of 10, and 25% in adolescence and before the age of 20.
IBD is due to any one specific cause. Genetic, epigenetic, environmental, and microbial factors can contribute and result in the dysregulation of the body’s immune system in a way that it causes inflammation of the bowel mucosa. At least 150 genes have been implicated in the pathogenesis of IBD and in 20% of cases a second family member may also be affected.
Ulcerative Colitis (UC): Continuous mucosal inflammation of the large bowel and rectum up to the terminal ileum. In a small proportion of patients with UC some inflammation of the terminal ileum (bacwash ileitis), and in 40-70% of patients the upper gastrointestinal tract may also be affected.
Crohn’s Disease: Can affect any part of the gastrointestinal tract from the oral cavity to the rectum. It produces inflammation that may cause stenosis or infiltration of the whole bowel wall. Endoscopically the findings that may differentiate Crohn’s from US are apthous outlined, linear, and skip lesions. 20% of children with Crohn’s are also affected by perianal disease causing fistulas, abscesses, and fissures.
Non-specific inflammatory colitis: A small group of disorders with histolological features that are not able to be clearly categorised as either UC or Crohn’s
Very early onset of inflammatory bowel disease represents a unique and growing subset of patients with inflammatory bowel disease. Some patients with very early IBD develop immunodeficiency and harbour genetic mutations in immune pathways that contribute to IBD. A subset of these young patients will have very aggressive disease (and most likely be associated with immunodeficiency), while the majority of patients with very early IBD appear to have a clinical condition similar to older patents. Many of these young children will require long-term immunosuppression and given their early presentation the duration of immunosuppressive treatment may be longer. This may increase the long-term risks of certain types of cancer and opportunistic infections.
Early neonatal or infantile IBD develops in less than 1% of pediatric patients. Children with “neonatal IBD” or “infantile IBD” have higher rates of first-degree relatives who are affected. They often also have a more severe disease course and a higher rate of resistance to immunosuppressive therapy. Monogenetic causes of early IBD were initially confirmed by the discovery of mutations in genes encoding interleukin 10 (IL-10) receptors that cause attenuated IL-10 signaling. Patients with such mutations usually present with perianal fistulas, show poor response to treatment, and require early surgery in the first year of life. To date, 60 monogenic mutations have been identified in children with IBD-type phenotypes. Next generation sequence could become an important diagnostic tool in children with severe disease phenotypes. Very early onset IBD is a phenotypically and genetically distinct entity from that of older children.
|Ν. Crohn||Ulcerative colitis|
|Weight loss||35 – 80%||31 – 38%|
|Anorexia||2 – 25%||6%|
|Developmental problems||3 – 4%||0|
|Lethargy||13-27%||2 – 12%|
|Abdominal pain||67 – 86%||43 – 62%|
|Diarrhe||30 – 70%||74 – 98%|
|Rectal bleeding||22 – 49%||83 – 84%|
|6 – 15%|
|Oral aphthous ulcers||5 – 28%|
Non Gastrointestinal associated manifestations
Dermatological: erythema nodosum, pyoderma gangrenosum
Musculoskeletal: arthritis, developmental disorders, osteopenia, osteoporosis, ankylosing spondylitis
Hepatic: autoimmune hepatitis, sclerosing cholangitis
Ophthalmological: Uveitis, episcleritis, scleritis
Haematological: anemia, thromboembolic events
Full blood count, ESR, CRP, ALT, ALP, γ-GT, albumin
Stool culture, parasitic investigation of stool, calprotectin, lactoferrin
Treatment of IBD has changed dramatically in the last 15 years. In the past, the purpose of treatment was to improve the clinical manifestation. Now with the use of biologics, healing of the mucosa and improvement of growth is achieved, resulting in the modification of the natural history of the disease. The goals of treatment are:
- Improve symptoms and maintain a good quality of life
- Maintain normal growth
- Avoid complications associated with IBD
Corticosteroids are effective in the treatment of IBD, in children, 50% of patients become dependent on them. Mucosal healing occurs in less than 1/3 of patients. Corticosteroids are not used as a maintenance treatment due to documented complications in long-term use. Formulations, such as budesonide, with potentially fewer side effects but less efficacy, may be used in mild to moderate disease.
GUT REST (PARENTERAL NUTRITION)
Feeding with specially modified solutions containing carbohydrates, proteins, essential minerals, and vitamins, is often recommended and is similarly effective as corticosteroid therapy to achieve remission in children with Crohn’s disease. The duration of this approach is usually 8-12 weeks.
Advantages of this treatment are the maintenance of growth, the prevention of side effects associated with corticosteroids and the satisfactory healing of the intestinal mucosa. The main disadvantage is the dependence on the nasogastric tube.
This treatment is common in Europe and North America. Recurrence of the disease is an indication for discontinuation of this treatment. A combination of maintenance medication and partial (night time) intestinal feeding is recommended, lasting 1-4 months.
Aminosalicylates exert a local anti-inflammatory effect and are given in the form of oral preparations, suppositories or enemas. Sulfasalazine has been used for more than 40 years, but there is limited tolerance by patients (nausea, headache, fever, rash). With newer forms, such as mesalazine, olsalazine a higher concentration can be given in the affected areas and fewer side effects are reported.
IMMUNOSUPPRESSION AND IMMUNOMODULATION
Azathiopurine / 6-mercaptopurine (6-MP) / Methotrexate
These medications have been used for more than 30 years as maintenance treatment. Their maximal effectiveness is observed 8 weeks after the start of treatment.
Side effects associated with these medications include myelotoxicity, hepatotoxicity, and pancreatitis. There is a relatively small increased risk of lymphoma, associated with the chronic use of these agents (0.6 / 10000 patients per year) in the pediatric population.
Methotrexate is another immunosuppressive drug that is widely used as it is thought to be less likely to develop lymphoma than thiopurines. Methotrexate is reported to be effective in maintaining remission in 1/3 of children with Crohn’s disease. Side effects of methotrexate include myelotoxicity and hepatotoxicity.
Folic acid is given throughout treatment with these medications.
The introduction of biologics for IBD revolutionized treatment. They are monoclonal antibodies directed in against tumour necrosis factor (TNF).
They are administered intravenously (infliximab) or subcutaneously (adalimumab, certolizumab, golimumab).
Infliximab is extremely effective (88% for Crohn’s and 73% for UC).
Biologics are used in children with corticosteroid-resistant ulcerative colitis or in those who are dependent on corticosteroids despite the use of immunosuppressants. Children are often given these in combination with immunosuppressants.
The incidence of lymphoma with the combined administration of biological agents and thiopurines has been increasing in recent years. This risk is significantly reduced in biologic monotherapy.
Surgical treatment is an alternative in children resistant to medical treatment. Total colectomy is recommended for children with persistent UC and it seems that this has excellent results. Indications for surgical treatment in Crohn’s are the development of fistulas, intra-abdominal abscesses, intestinal stenosis, or in patients with resistant disease who have failed medical treatment (14% of patients with Crohn’s are referred to surgery in the first five years after diagnosis).
Deficiency of trace elements
Vitamin D deficiency
Patients with low vitamin D levels appear to be more likely to have disease relapse.
Inadequate growth is observed in 40% of children with Crohn’s disease and 10% of children with ulcerative colitis. The pathogenesis of poor development in IBD is multifactorial and is associated with:
- inadequate caloric intake
- increased metabolic requirements
- Growth hormone resistance (mechanism through the release of cytokines)
- side effect from corticosteroids
Systematic monitoring and continuous effort to maintain the normal development of patients is extremely important.
It is also advisable to treat any bony metabolic disorders, which often accompany IBD.
For this purpose, patients are monitored by bone mineral density (DEXA) assessment and are administered supplementation of calcium from the diet and Vitamin D.
Due to the chronic inflammatory process in the large intestine, patients with IBD, are at increased risk for development of colon cancer. In population studies, the incidence of colon cancer ranges from 10 to 13/1000 patients. The risk depends on the time from diagnosis and the highest risk is observed in patients diagnosed early with pancreatitis or sclerosing cholangitis (hepatic associations of IBD). For this reason endoscopic (+/- histologic) monitoring is recommended in children who have had UC or Crohn’s for 7-10 years, and should be performed every 1-2 years.
Psychological disorders / quality of life
Depression and anxiety are associated with disease activity and are due to the effect of proinflammatory cytokines on the CNS, sleep disturbances, and even the effects of corticosteroids. In some cases, psychological support is required in addition to monitoring and treating the underlying disease. It is a fact that the symptoms of the IBD can significantly affect quality of life of patients and disrupt their normal social functioning.
New therapeutic agents are being researched and seem to have significant efficacy in adult patients with IBD. They have started to be tested in older children with IBD. Vedolizumab (Entyvio) monoclonal antibody against α4β7integrin is used in older children, with IBD resistant to other biological agents.
Many multicenter studies have led to the discovery of genes responsible for pediatric IBD, while the study of the microbiome and the discovery of molecular factors (m-RNAs) continue to contribute to the study of pathogenesis of IBD. In the future this may lead to the discovery of further targeted therapies.
The continued research on IBD aims to ensure that children with this disease will live their childhood with quality, maintaining a long-term disease recession, and prevent the associated complications of IBD.