“Thiopurines (azathioprine and mercaptopurine) and biologic anti-TNF agents (infliximab, adalimumab, certolizumab, and golimumab) are some of the most effective medications that we have for treating inflammatory bowel disease. However, it is important to recognize that these therapies have been associated with an increase in the risk of developing certain cancers including lymphoma and skin cancer. Fortunately, the total number of people who develop these cancers while on therapy is very small. There is also little evidence that thiopurines and anti-TNF drugs significantly increase the risk of other types of cancers. Before initiating treatment with these types of medications, we need to review your cancer risks and weigh them against the considerable benefits these therapies can offer.”

Immunosuppressive agents are widely used for long-term maintenance therapy of inflammatory bowel disease (IBD). While the benefits of these medications are well established, their use may occasionally be limited by concerns over cancer risk. However, practitioners and patients are often unfamiliar with the specific types of malignancy and exact magnitude of risk associated with the use of immunosuppressive therapy. Most of the data regarding IBD medications and malignancy center on the increased risk of non-Hodgkin’s lymphoma (NHL) and skin cancer in patients on thiopurines and/or anti-TNFs. To date, there is little evidence that these drugs significantly increase the risk of other types of cancers.

There is an increasing amount of data to suggest that thiopurines (azathioprine [AZA], 6-mercaptopurine [6-MP]) increase the likelihood of developing lymphoma, particularly NHL. Factors that also appear to be associated with increased NHL risk include male sex, age >50, prior exposure to Epstein-Barr virus (EBV), and longer duration of IBD [1, 2]. A 2005 meta-analysis on this topic demonstrated a fourfold increased risk of lymphoma in IBD patients treated with AZA and 6-MP compared to the rate expected in the general population [3]. Since this publication, several population-based and referral center studies have demonstrated similar findings [4–7]. Importantly, a large prospective cohort study of over 20,000 IBD patients found that, in patients who discontinued thiopurines, the lymphoma incidence rate appeared to revert back to that of the general population [8]. The most recent meta-analysis reported a very low overall absolute risk of lymphoma for patients treated with thiopurines [9]. The risk for patients younger than 50 was estimated at less than 1:2,000 per year. Patients aged over 50 had an absolute risk closer to 1:350 per year. Thus, caution may be required when prescribing thiopurines to an older population.

Use of anti-TNF agents has also been associated with an increased risk of developing NHL. However, TNF inhibitors are often prescribed to current or past users of thiopurines, making it difficult to determine the exact risk attributable solely to anti-TNF drugs. A meta-analysis by Siegel et al. reported a threefold risk of NHL in anti-TNF users compared to the general population. Of note, most cases of NHL occurred in patients with current or prior exposure to AZA, 6-MP, or methotrexate [10]. Other studies have not demonstrated significantly higher rates of cancer in IBD patients on anti-TNF agents. A large Danish population-based cohort study of over 4,000 IBD patients exposed to anti-TNFs alone found no increased cancer risk over a median follow-up of 3.7 years [11]. Additionally, a systematic review and pooled analysis of all available randomized controlled trials of anti-TNF therapies used in IBD failed to show any conclusive evidence of an increased risk of any malignancy with these drugs [12].

It is important that providers be aware of reports regarding anti-TNF therapy and the extremely rare development of hepatosplenic T-cell lymphoma (HSTCL), a peripheral T-cell lymphoma with an estimated survival of less than 1 year from diagnosis. HSTCL has been reported in 36 IBD patients receiving immunosuppressive medications. Twenty of these patients were on anti-TNF agents. There may be an increased risk of HSTCL in men <35 years of age receiving combination thiopurine and anti-TNF therapy. While the risk of HSTCL with combination immunosuppressive therapy in this group of patients needs to be acknowledged, the absolute risk still appears to be low (1:3534) [13].