Inflammatory bowel disease caused by immunomodulatory drugs

Post by Master, Doctor Mai Vien Phuong - Department of Examination & Internal Medicine - Vinmec Central Park International General Hospital

The pathogenesis of inflammatory bowel disease focuses on dysregulated immunity. Therefore, it is not surprising to find that drugs that alter host immunity can sometimes lead to the development of new-onset inflammatory bowel disease, which the authors refer to as "severe disease." drug-induced enteritis”.
These drugs mainly include immunomodulators and biologic agents. A newer class of drugs called checkpoint inhibitors used to treat melanoma and other malignancies have also been implicated in the precipitation of inflammatory bowel disease. There was also a similar but weak association with immunostimulant use.

Immunomodulators alter the immune system mainly by inhibiting lymphocyte function. These drugs include, but are not limited to, azathioprine, 6-mercaptopurine (6-MP), tacrolimus, cyclosporine A, and mycophenolate mofetil (MMF). They are commonly used to prevent rejection after kidney and liver transplants. Azathioprine and 6-MP have a clear role in long-term remission in the management of inflammatory bowel disease. Cyclosporine A has also been used to treat refractory inflammatory bowel disease, including during flares of acute ulcerative colitis. Intestinal studies have shown that post-transplant administration of immunomodulators induces depletion of regulatory T cells in the colonic mucosa. This may predispose to the development of immune-mediated inflammation in the colon, as regulatory T cells block the activation of B lymphocytes and cytotoxic T cells. Tacrolimus is an immunosuppressive drug that is routinely used for organ transplantation due to its predictable side effects and the availability of tests to monitor its serum levels. The use of tacrolimus has been reported to cause flare-ups of preexisting inflammatory bowel disease in solid-organ conversion individuals. Its use has also been shown to be associated with the development of new-onset inflammatory bowel disease. In an observational study of 53 patients without a diagnosis of inflammatory bowel disease who underwent liver transplantation, 6 (11%) of them developed new-onset inflammatory bowel disease during a median follow-up of 3.9 year
The use of mycophenolate mofetil (MMF) as an immunosuppressant is mainly seen in kidney or liver transplant recipients One of its common side effects is diarrhea, and in about 9% of cases, it causes “mycophenolate mofetil colitis”. This type of colitis has endoscopic inflammatory bowel disease-like features and histological changes in the colon. The colonic presentation of MMF-induced colitis is similar to that seen in classical inflammatory bowel disease or graft-host disease. But it exhibits a mucosal eosinophilic predominance with a lack of apoptotic cell microabsorption and endocytic cell subsets in the stroma on histology.

Disease may persist even after MMF is discontinued This pathology can sometimes persist even after MMF is discontinued, taking up to 4-6 m to resolve endoscopically. There have been many reported cases of people developing new-onset Crohn's disease after exposure to MMF, followed by improvement in disease after drug discontinuation. There was one case report of rapid resolution of MMF-associated colitis with a single dose of infliximab, suggesting a role for TNF in its pathogenesis. One can speculate that MMF-induced colitis represents a variant of inflammatory bowel disease. Paradoxically, there is some evidence to support the use of MMF for the treatment of active inflammatory bowel disease.
In a study of 25 patients with steroid-dependent disease unresponsive to biologics, MMF therapy achieved clinical response in nearly 50% of cases. Two small studies have shown that MMF induces steroid-free clinical remission in approximately 25% of cases. Its therapeutic effect can lead to long-term remission of the disease. Therefore, it appears to be effective in treating inflammatory bowel disease while it can cause inflammatory bowel disease-like colitis or lead to inflammatory bowel disease. This suggests that interference with our complex immune systems can be beneficial or harmful for the treatment or onset of disease.