Lymphoproliferative disorders in inflammatory bowel disease patients on immunosuppression: Lessons from other inflammatory disorders

Abstract

Immunosuppressive agents, such as thiopurines, methotrexate, and biologics, have revolutionized the treatment of inflammatory bowel disease (IBD). However, a number of case reports, case control studies and retrospective studies over the last decade have identified a concerning link between immunosuppression and lymphoproliferative disorders (LPDs), the oncological phenomenon whereby lymphocytes divide uncontrollably. These LPDs have been associated with Epstein-Barr virus (EBV) infection in which the virus provides the impetus for malignant transformation while immunosuppression hampers the immune system's ability to detect and clear these malignant cells. As such, the use of immunosuppressive agents may come at the cost of increased risk of developing LPD. While little is known about the LPD risk in IBD, more is known about immunosuppression in the post-transplantation setting and the development of EBV associated post-transplantation lymphoproliferative disorders (PTLD). In review of the PTLD literature, evidence is available to demonstrate that certain immune suppressants such as cyclosporine and T-lymphocyte modulators in particular are associated with an increased risk of PTLD development. As well, high doses of immunosuppressive agents and multiple immunosuppressive agent use are also linked to increased PTLD development. Here, we discuss these findings in context of IBD and what future studies can be taken to understand and reduce the risk of EBV-associated LPD development from immunosuppression use in IBD.

Keywords: Epstein-Barr virus; Immunosuppression; Inflammatory bowel disease; Lymphoproliferative disorders; Post-transplantation lymphoproliferative disorders.

Figure 1

Proposed algorithm for treatment management of inflammatory bowel disease patients who are either Epstein-Barr virus seropositive or negative. ¹EBV monospot or EBV IgM have not been shown to be helpful in in determining serostatus; ²EBV viral load should be done by polymerase chain reaction in whole blood in EDTA collection tube. EBV: Epstein-Barr virus; IBD: Inflammatory bowel disease; EBNA: Epstein-Barr virus-determined nuclear antigen; LPD: Lymphoproliferative disorders; VCA: Viral-capsid antigen; EDTA: Ethylenediaminetetraacetic acid.