Introduction
Since the introduction of infliximab (IFX) in 1998 for use in the treatment of Crohn’s disease (CD), and subsequent approval for use in ulcerative colitis (UC) in 2006, anti-tumor necrosis factor-alpha inhibitor (ATA) therapy has become a key component of the treatment armamentarium for moderate to severe inflammatory bowel disease (IBD). However, there are concerns regarding potential complications related to ATA therapy, including malignancy. Cancers associated with ATA include solid organ malignancies, nonmelanoma skin cancers, melanoma, lymphoproliferative malignancies, and viral-associated lymphomas, such as Epstein-Barr Virus (EBV). Proposed mechanisms of tumorigenesis with ATA drugs include decreased activation of natural killer (NK) cells, promotion of apoptosis among macrophages and T cells, induction of cell cycle arrest of T cells, and inhibition of IL-1β production by monocytes.
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Historically, one of the first observational studies to note a potential link between ATA use and malignancy risk was in 2002. It described 26 cases of lymphoproliferative disease in a patient cohort receiving etanercept (18 cases) or IFX (8 cases) for either rheumatoid arthritis (RA) or IBD (5 cases).
5 This association was appreciated about two and a half years after the drugs were licensed for clinical use in the United States. In that study, 81% of the 26 cases were non-Hodgkin’s lymphomas (NHL). Interestingly, most of the cases were detected within 8 weeks of initiation of ATA therapy. Three of the 26 patients had a history of lymphoproliferative disease prior to initiation of the ATA. Seventy-three percent of subjects had previous or concurrent immunomodulator medication (IMM) exposure, including methotrexate, azathioprine, and 6-mercaptopurine.
Multiple additional analyses have been published addressing the concern over a link between ATA therapy and lymphoma with inconsistent findings. However, many of the data supporting a link between ATA use and lymphoma development may have been confounded by a patient’s previous thiopurine (TP) exposure. Additionally, results may have been extrapolated from the rheumatoid arthritis literature which is a disease known for its inherent risk of B-cell lymphoma development.
6 Some studies were limited by short term follow-up or underpowered sample sizes, leading to dissimilar findings amongst studies.
7 Despite lack of discrete conclusions, the FDA has maintained a black box warning concerning lymphoma risk with ATA therapy.
The American Gastroenterological Association (AGA) published its
Technical Review on the Use of Thiopurines, Methotrexate, and Anti–TNF-α Biologic Drugs for the Induction and Maintenance of Remission in Inflammatory Crohn’s Disease
in 2013.
8 It included an evaluation of the current literature surrounding the risk of lymphoma in CD populations exposed to TP, methotrexate, ATA monotherapy, and ATA/TP combination therapy. Much of the analyzed data relating to lymphoma risk was from the TREAT™ Registry, CESAME, and Kaiser studies.
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11 These aforementioned studies, in sum, appeared to indicate a small but appreciable association between TP or combination therapy use and lymphoma development. The recommendations did not appreciate an increased risk of lymphoma with ATA monotherapy, although this was deemed to be of very low-quality evidence due to bias, imprecision, and limited follow-up data. With this in mind, the AGA recommended further studies to assess the risk of lymphoma relative to ATA monotherapy.
Since the first observational study among RA and IBD patients in 2002, the concern of an increased risk of lymphoma development with ATA monotherapy has persisted and has undergone further investigations.
5 This qualitative review aims to evaluate and analyze the relevant literature addressing this quandary since publication of the AGA guidelines in 2013. Although this time span may seem arbitrary, it was chosen to allow a closer look at more recently published literature, which benefitted from longer follow-up times, larger sample sizes, and potentially fewer subjects with previous exposure to TP therapy, allowing for a more clear evaluation of ATA monotherapy and lymphoma development.
Although the main focus of this review is to assess ATA monotherapy exposure and the risk of lymphoma development in studies since 2013, additional focus will be given to addressing additional issues with IBD management in the biologic era such as the risk of hepatosplenic T-cell lymphoma (HSTCL), ATA use in patients with current or previous cancer, and implications for therapy in the discussion section.