Infliximab and Ulcerative Colitis

Ulcerative colitis (UC) is one of the main forms of inflammatory bowel disease. The condition causes the colon and rectum to become inflamed and ulcerated.

Inflammation is the process by which the body responds to injury or irritation and it 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, where symptoms are more active and “flare up”.

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, probably 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.

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 vary from mild to severe, depending on the extent and severity of the inflammation, but the most common symptoms observed during a flare up include the following:

• Abdominal pain, which is often severe before passing a stool.
• Diarrhea that 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 and weight loss.
• General feeling of malaise. Some people may develop a fever.

People usually first develop symptoms between the ages of 15 and 25, although 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. The condition is also more common among white individuals of European descent, particularly in populations descended from Ashkenazi Jews.

Treatment for UC may take the form of medication or surgery, depending on the severity and type of inflammation a patient has. Medications aim to 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. Patients may be able to stop taking their medication if the condition is mild, limited to a small part of the colon and has not caused symptoms for several years.

The main drugs used to manage UC include anti-inflammatory medications and drugs to treat symptoms of the condition. Anti-inflammatory drugs may take the form of aminosalicylates, corticosteroids, immunosuppressants, or a biological therapy such as infliximab.

Aminosalicylates are used both during flare-ups and in-between them 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. A doctor will only prescribe a steroid for a short period to cause 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 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.

Biological therapies such as infliximab are designed to target specific mediators of inflammation and in the case of infliximab, that target is 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 Food and Drug Administration 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, while for others, it may take up to six weeks for symptoms to improve.

Since infliximab alters the immune response, patients are susceptible to infection including serious infections such as tuberculosis and sepsis. TNF is an important cytokine in the immune response to tuberculosis and anti-TNF agents can lead to reactivation of a latent TB infection. Pre-treatment screening of patients is therefore essential, to check for the presence of TB and for exposure to other infections such as hepatitis C or B, HIV, chicken pox, shingles, measles and certain fungal infections.