Ulcerative colitis (UC) is one of the main forms of inflammatory bowel disease (IBD). UC causes the colon and rectum to become inflamed and ulcerated.
Introduction
Inflammation is the process by which the body responds to injury or irritation and often causes pain, swelling and redness. Inflammation usually starts in the rectum and lower colon, although it can also affect the whole colon. When the condition only affects the rectum, it is referred to as proctitis.
UC is referred to as a chronic condition, meaning it is an ongoing, life-long disease. Patients with UC may experience periods of remission where they are symptom free in-between periods of relapse, the latter of which causes symptoms to be more active and “flare up.”
Causes of UC
Researchers are still not clear about the exact cause of UC, although they believe the condition is probably caused by a combination of factors including the genes a person has inherited and an abnormal immune response that is most likely triggered by an environmental factor.
Suggested environmental factors include diet, stress, viruses and bacteria, although none of these have yet been established as proven triggers of UC.
Symptoms of UC
In UC, areas of the colon and/or rectum become inflamed and tiny ulcers may develop on the colon lining, which then becomes less able to absorb liquid. This can lead to watery stools and frequent bowel movements. Symptoms of UC vary from mild to severe, depending on the extent and severity of the inflammation.
The most common symptoms observed during a UC flare-up include:
- Abdominal pain, which is often severe before passing a stool.
- Diarrhea often contains blood, pus and mucus.
- Fatigue, which may occur as a result of coping with the illness or as a result of anemia due to loss of blood in stools. A lack of sleep due to pain or diarrhea at night may also lead to tiredness.
- Loss of appetite
- Weight loss
- General feeling of malaise.
- Fever
Epidemiology
UC patients usually first develop symptoms between the ages of 15 and 25; however, UC can start at any age. The condition is estimated to affect about one in every 420 people in the UK and it affects an equal number of men and women.
The prevalence of UC is greater in northern developed countries, although it is starting to increase in developing countries as well. The condition is also more common among white individuals of European descent, particularly in populations descended from Ashkenazi Jews.
Treatment
Treatment for UC may take the form of medication or surgery, depending on the severity and type of inflammation that a patient has. The primary medications used in the treatment of UC include those that alleviate symptoms, control flare-ups and decrease the risk of relapse once the condition is under control. This can mean medication needs to be taken for long periods, sometimes for many years. However, patients may be able to stop taking their medication if the condition is mild, limited to a small part of the colon and/or has not caused symptoms for several years.
The main drugs used to manage UC include anti-inflammatory medications as well as specific drugs that are targeted for treating the symptoms of this condition. Anti-inflammatory drugs may take the form of aminosalicylates, corticosteroids, immunosuppressants, or a biological therapy such as infliximab.
Aminosalicylates are used both during the relapse and remission periods of UC in an effort to lengthen the remission period. If an aminosalicylate fails to control symptoms or if the condition is severe, a steroid may be prescribed. However, steroids can cause a number of adverse side effects when used in the long-term. Therefore, a treating clinician will typically only prescribe a steroid for a short period to bring the patient into remission, which can then be maintained with an aminosalicylate. If these treatments do not improve symptoms, an immunosuppressant such as cyclosporine or azathioprine may be prescribed. In cases where immunosuppressants have not been effective, a biological therapy, such as infliximab, may be prescribed.
The immune response in UC
The uncontrolled immune response that occurs in UC is mediated by various pro-inflammatory cytokines including interleukin-4 (IL-4), IL-5, IL-6, IL-10 and tumor necrosis factor-alpha (TNF-α). Research into the pathogenic pathways that cause UC have resulted in therapies that target these pro-inflammatory markers as a way of containing the inflammatory cascade. One of the most extensively studied of these markers is TNF-α, which, in the case of UC, is produced in excess by activated T-lymphocytes and macrophages.
An excess of TNF-α induces further macrophage and T-lymphocyte activation, as well as the expression of endothelial adhesion molecules and the recruitment of neutrophils. This results in a cycle of increasing inflammation. The level of TNF-α has been shown to be elevated in the colon tissue, blood, stool and urine of patients with UC.
Infliximab and UC
Chronic Inflammation in IBD and How Anti-TNF Therapy Works
Biological therapies such as infliximab are designed to target specific mediators of inflammation such as is the case with infliximab, which specifically targets TNF-α. Infliximab is a monoclonal antibody that binds to soluble and transmembrane forms of TNF-α and prevents it from binding to its receptors. Infliximab was the first monoclonal antibody to receive approval from the United States Food and Drug Administration (FDA) as an induction and maintenance therapy for patients with UC.
The recommended dose of infliximab for UC patients is 5 mg per kg of body weight and the therapy is received via intravenous infusion over a period of two hours. This is followed by repeat infusions two and six weeks later and then every eight weeks. Patients who receive infliximab may begin to notice an improvement in symptoms within just a few days of their first treatment, whereas for others it may take up to six weeks for symptoms to improve.
Since infliximab alters the immune response, UC patients receiving this treatment are vulnerable to a wide range of infections that can be as severe as tuberculosis (TB) and sepsis. TNF is an important cytokine in the immune response to tuberculosis and anti-TNF agents can lead to the reactivation of a latent TB infection. Pre-treatment screening of patients is therefore essential to check for the presence of TB, as well as other infections such as hepatitis C or B, HIV, chickenpox, shingles, measles and certain fungal infections.
References
Further Reading