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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pathophysiol. Nov 15, 2015; 6(4): 181-192
Published online Nov 15, 2015. doi: 10.4291/wjgp.v6.i4.181
Lymphoproliferative disorders in inflammatory bowel disease patients on immunosuppression: Lessons from other inflammatory disorders
Grace Y Lam, Brendan P Halloran, Anthea C Peters, Richard N Fedorak
Grace Y Lam, Department of Medicine, Division of Internal Medicine, University of Alberta, 8440 112 St NW Edmonton, Alberta, Canada
Brendan P Halloran, Richard N Fedorak, Department of Medicine, Division of Gastroenterology, University of Alberta, Zeidler Ledcor Centre, 8440 112 St NW Edmonton, Alberta, Canada
Anthea C Peters, Department of Medicine, Division of Hematology, University of Alberta, 8440 112 St NW Edmonton, Alberta, Canada
Author contributions: Lam GY, Halloran BP, Peters AC and Fedorak RN contributed equally to this work.
Conflict-of-interest statement: Lam GY has no conflicts of interest to declare. Peters AC has been an advisory board member for Janssen, Roche, Lundbeck and Seattle Genetics. Halloran BP is a consultant and/or advisory board member for Abbvie and Janssen. Fedorak RN is a consultant or advisory board member of Abbvie, Ferring, Janssen, Shire, VSL#3, Celltrion. He is also the recipient of the following clinical/basic science research grants: Abbvie, Alba, Bristol Myers Squibb, Centocor, GSK, Genentec, Janssen, Merck, Millennium, Novartis, Pfizer, Proctor and Gamble, Roche, VSL#3, Celltrion. Finally, he is also the owner/Shareholder of Metablolomic Technologies Inc (www.metabolomictechnologies.ca).
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Brendan P Halloran, Department of Medicine, Division of Gastroenterology, University of Alberta, Zeidler Ledcor Centre, 130 University Campus NW, 8440 112 St NW Edmonton, Alberta, Canada. brendan@ualberta.ca
Telephone: +1-780-4928691 Fax: +1-780-4928121
Received: March 31, 2015
Peer-review started: March 31, 2015
First decision: April 23, 2015
Revised: June 14, 2015
Accepted: August 30, 2015
Article in press: September 28, 2015
Published online: November 15, 2015
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, Post-transplantation lymphoproliferative disorders, Lymphoproliferative disorders, Inflammatory bowel disease

Core tip: Immunosuppressive agents, such as thiopurines, methotrexate, and biologics, have revolutionized the treatment and maintenance therapy of inflammatory bowel disease (IBD). However, their use may come at the cost of increased risk of developing lymphoproliferative disorders (LPD). While little is known about this risk in IBD, more is known about immunosuppression risk in the fields of rheumatoid arthritis and post-transplantation with regards to the development of Epstein-Barr virus (EBV) associated LPD. Here, we attempt to review lymphoma risk in the setting of immunosuppression use in various medical conditions, discuss what lessons may be translatable to the IBD field and what future directions can be taken to reduce the risk of EBV-associated LPD from immunosuppression use in IBD.