Inflammatory bowel disease affects over 3.6 million people in the United States and Europe alone, with no cure available. A recent review investigated the ins and outs of current treatments available and the significant side effects and risks associated with the use of inflammatory bowel disease medications.
Crohn’s disease (CD) and ulcerative colitis (UC) are similar but distinct types of life-long inflammatory bowel disease (IBD), not to be confused with irritable bowel syndrome (a disorder and not a chronic disease which affects the muscle contractions of the bowel). CD is a chronic inflammatory disease of the intestines which can lead to abdominal pain, severe diarrhea, fatigue, weight loss, and malnutrition. UC is a chronic disease which causes inflammation and ulcers of the colon and rectum. One potential cause of these inflammatory diseases is an inappropriate immune response to commensal, or “friendly” gut bacteria.
Typically IBD presents between the ages of 20 and 40 years and given the significant effects on quality of life of patients diagnosed, it can affect workplace participation and thus career productivity, as well as fertility. Cohn and colleagues recently published a review in Inflammatory Bowel Diseases on the current nonsurgical treatments available, which include immunomodulators and biologic medical therapies. These treatments aim to induce remission of diseases like CD and UC by alleviating the symptoms of these IBDs. They are intended to help avoid surgical resection of the bowel and work by promoting mucosal healing and preventing intestinal complications. However, the associated risks of these medications, which have significant side effects for a number of reasons, need to be taken into consideration for an optimal treatment plan for patients.
Immunomodulators are medications (such as azathioprine and methotrexate) which help to regulate or normalize the immune response or functioning of the immune system. Patients diagnosed with active CD take methotrexate, an immune system suppressant which is able to put the disease into remission. However, methotrexate is also a chemotherapy agent and used for treating patients with cancer and also rheumatoid arthritis. Some of the risks and concerns associated with these medications include hypersensitivity (allergic reaction to the drug), increased risk of cancer, fertility and infection concerns.
Hypersensitivity allergic reactions to drugs such as azathioprine are not, only occurring in 1% of patients, but true hypersensitivity can result in fever, flu- and sepsis-like manifestations, and a rash. One of the more concerning adverse reactions is the possibility of an increased risk of cancer. Azathioprine is part of a class of drugs known as thiopurines, which are mutagenic and therefore with an increase in dose and treatment duration, comes an increase in the risk of developing cancer. Patients who underwent lifelong treatment with thiopurines for IBD showed an increased risk of developing nonmelanoma skin cancer by 85%. Furthermore, similar to all immunosuppressive medications, it has been reported that a three-fold increased risk of opportunistic infections such as viral infections is also associated with this medication, with pneumonia being a common infection of great concern.
One major concern for IBD patients are fertility issues, where individuals with IBD reported to be less fertile than their healthy counterparts (with men 18-50% and women 17-44% less fertile). However, it is noted that this decrease is more so attributed to voluntary childlessness due to IBD-related fears as opposed to actual infertility issues. Also, the drug methotrexate is actually an abortifacient and therefore it is highly recommended that women discontinue use before conception.
An emerging approach discovered more recently for treating IBD is through the use of biological medical therapies which involves the use of monoclonal antibodies (proteins that stick to antigens such as toxins to help recruit other parts of the immune system to destroy the cells containing the antigen). By targeting the immune response with these biological therapies, this approach is a highly promising alternative treatment for immunological diseases like IBD.
Similar to immunomodulators, there are significant adverse effects for patients undergoing biological medical therapies, including heart failure, hypersensitivity, the risk of opportunistic infections, worsening of neurological disease symptoms and potentially an increased risk of cancer. A commonly associated outcome of inflammation is heart failure. Additionally, some medications such as TNF-α antagonists have shown to induce an increased risk of heart failure, thus patients with mild heart failure need to be cautious when deciding upon treatment plans for IBD. Hypersensitivity, like immunomodulators, is another concern for IBD patients. Typically a reaction occurs upon infusion and can result in nausea, headaches, and fever. Acute severe reactions occur in approximately 5% of patients, with symptoms self-resolving once treatment has stopped or slowed down and use of the medication for this patient is discontinued. In addition, there is also an increased risk of worsening symptoms of neurological diseases such as multiple sclerosis. This is surprising as TNF-α antagonists theoretically could slow or arrest the disease process given TNF-α plays a pathophysiological role in the disease.
The increased risk of opportunistic infections when taking medications such as TNF- α has also been well established. Similarly, the risk of becoming infected with pneumonia is a significant concern and can be especially severe in patients with IBD who are receiving this treatment. Also, individuals with a history of hepatitis B are required to be cautious as reactivation of the virus has been observed for those undergoing treatment. However, the increased risk of cancer is still being debated as earlier data sets from large health care insurers suggested there was a statistically significant increase in the risk of lymphoma, melanoma, and nonmelanoma skin cancer. On the other hand, data collected from a trial by Anderson and colleagues showed no significant difference in overall cancer incidence between the general population and those undergoing biological medical therapies. Therefore, further research into whether there is, in fact, an increased risk is required.
Advancement in treatments for IBD has been quite stagnant. However, recently a number of new medicines have become available along with the discovery of new uses for old medicines, leading to more treatment options also becoming available. Given the associated risks of many of these treatments and new medications also presenting new problems, the optimization of treatment plans for patients, whilst challenging remains significantly important. Further studies on the long-term use of medications for treating IBD will enable greater knowledge into potential outcomes and risks associated with them. Knowledge from these trial outcomes will aid in minimizing potential harmful side effects and ensure safe application, with the ultimate goal of hopefully increasing the quality of life for patients with inflammatory bowel disease.
Written by Lacey Hizartzidis, PhD
Cohn HM, Dave M, Loftus EV Jr. Understanding the Cautions and Contraindications of Immunomodulator and Biologic Therapies for Use in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2017 Aug;23(8):1301-1315.