A review of the data on risk of infection, malignancy, and death associated with therapies for IBD.
James D. Lewis, MD, MSCE
Therapy for inflammatory bowel disease is becoming increasingly complicated. As the list of effective medications has grown, so has the list of potential complications of these therapies. In this talk, Lewis reviewed the data on risk of infection, malignancy, and death associated with therapies for IBD, with particular emphasis on biologic therapies.
InfectionInfections were categorized as post-operative, severe, and opportunistic (ie, those caused by organisms that would not be expected to cause infection in the absence of the therapy). Corticosteroids are known to increase the risk of each of these types of infection in a dose-dependent manner. In contrast, thiopurines appear to increase the risk of opportunistic infections, particularly those caused by viruses, but not to increase the risk of post-operative or other serious infections.
The data regarding the risk of infection with anti-TNF therapies is a little less straight forward. For instance, numerous studies have examined the risk of post-operative infections among patients treated with anti-TNF therapies—some have demonstrated an increased risk of infection, while others have not. A recent meta-analysis of 10 of these studies confirmed that there was significant heterogeneity in the results of the studies, with an overall pooled result that was not significantly elevated. In contrast, there are fairly consistent evidence that anti-TNF therapies are associated with an increase risk of opportunistic infections, particularly from tuberculosis and fungal organisms, such as histoplasmosis. Although a meta-analysis of placebo-controlled trials for Crohn’s disease did not demonstrate an increased risk of infection with anti-TNF therapy, analysis of the TREAT registry suggests that infliximab therapy is associated with an increased risk of infections. Furthermore, the addition of thiopurines to anti-TNF therapy for rheumatoid arthritis have not yielded consistent results, with some suggesting an increased risk, while other have not observed this. Of course, some of these differences are related to the criteria by which studies were selected for inclusion.
Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal infection of the brain resulting from reactivation of JC virus. The majority of the population has been previously infected and harbor latent JC virus. Ntalizumab, efalizumab, and rituxuimab have all been linked to PML. Natalizumab is the only one of these agents approved for the treatment of Crohn’s disease. The risk of PML increases with increasing duration of natalizumab therapy, and the risk appears to be very low in the first year of therapy. With more than one year of therapy, the risk of PML is approximately 1 per 1,000 patients.
MalignancyMost of the focus on the risk of malignancy with IBD therapies has centered on lymphoma. Researchers have previously demonstrated that treatment with thiopurines is associated with an approximately four-fold increased risk of lymphoma when compared to either the general population or to patients with IBD who were not treated with thiopurines. The recent CESAME study has confirmed that finding, documenting a five-fold increased risk of lymphoma among those patients currently receiving thiopurines. Interestingly, those patients who discontinued thiopurines did not have an increased risk of lymphoma.
A meta-analysis of anti-TNF studies suggested that patients with IBD receiving these therapies had an incidence of lymphoma that was three-fold greater than the general population. However, interpretation of these data is challenging since most of the patients were currently or had previously received thiopurine therapy.
Hepatosplenic T cell lymphoma (HSTCL) is a particularly aggressive and rare form of lymphoma. There have been at least 28 cases of HSTCL reported in the literature among patients with a history of Crohn’s disease. The median age was 22 years, and 93% occurred in males. Each of these patients had a history of thiopurine therapy, and 79% has a history of anti-TNF therapy exposure.
There may be reason to have concern about the risk of cancers other than lymphoma among patients with IBD receiving immunosuppressant therapy. Cervical cancer risk may be increased with immunosuppressant therapy. For example, patients treated with thiopurines and/or methotrexate had a three-fold increased risk of cervical cancer in one study, albeit this was not statistically significant. Similarly, there is evidence that non-melanoma skin cancer risk may be increased among patients treated with thiopurines and/or biologic therapies.
MortalityDeath does not appear to be more common among patients treated with anti-TNF therapy or with thiopurines. In contrast, several studies have demonstrated that treatment with corticosteroids is associated with an increased risk of death.
ConclusionsAlthough each of these medications is associated with an increased risk of serious adverse events, the benefits of therapy outweigh the harm in most patients. This is particularly true for patients who have responded to these therapies to induce remission. Thus, for most patients, a short-term trial of the medication to determine effectiveness and continuation of effective therapies is a reasonable approach. However, there are several contraindications to therapy that should be kept in mind when prescribing these therapies, such as the risk of fungal and mycobacterial infections, as history of moderate or severe congestive failure, prior complicated zoster, active opportunistic infections, and recent diagnosis with cancer.
Selected References1. http://dx.doi.org10.1016/S0140-6736(09)61302-7
Adapted from materials provided in the American College of Gastroenterology 2010 Annual Scientific Meeting Breakfast Sessions guide.