Retrospective Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 28, 2017; 23(40): 7265-7273
Published online Oct 28, 2017. doi: 10.3748/wjg.v23.i40.7265
Genetic associations with adverse events from anti-tumor necrosis factor therapy in inflammatory bowel disease patients
Daniel Lew, Soon Man Yoon, Xiaofei Yan, Lori Robbins, Talin Haritunians, Zhenqiu Liu, Dalin Li, Dermot PB McGovern
Daniel Lew, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
Soon Man Yoon, Xiaofei Yan, Talin Haritunians, Zhenqiu Liu, Dalin Li, Dermot PB McGovern, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
Lori Robbins, Department of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
Author contributions: Lew D collected and analyzed the data, and drafted the manuscript; Yoon SM and Robbins L helped collect the data and edit the manuscript; Yan X and Li D helped with the technical and statistical analysis; Liu Z and Haritunians T helped analyze the data and edit the manuscript; McGovern DPB designed and supervised the study, and revised the manuscript for important intellectual content; all authors have read and approved the final version to be published.
Institutional review board statement: The study was reviewed and approved by the Cedars-Sinai Institutional Review Board (IRB #3358).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: DPBM reports consulting for Janssen, UCB, Pfizer, Celgene, and Merck.
Data sharing statement: No additional data are available.
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: Dermot PB McGovern, MD, PhD, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States. dermot.mcgovern@cshs.org
Telephone: +1-310-4234100
Received: August 5, 2017
Peer-review started: August 5, 2017
First decision: August 14, 2017
Revised: August 25, 2017
Accepted: September 13, 2017
Article in press: September 13, 2017
Published online: October 28, 2017
Processing time: 85 Days and 4.5 Hours
Abstract
AIM

To study the type and frequency of adverse events associated with anti-tumor necrosis factor (TNF) therapy and evaluate for any serologic and genetic associations.

METHODS

This study was a retrospective review of patients attending the inflammatory bowel disease (IBD) centers at Cedars-Sinai IBD Center from 2005-2016. Adverse events were identified via chart review. IBD serologies were measured by ELISA. DNA samples were genotyped at Cedars-Sinai using Illumina Infinium Immunochipv1 array per manufacturer’s protocol. SNPs underwent methodological review and were evaluated using several SNP statistic parameters to ensure optimal allele-calling. Standard and rigorous QC criteria were applied to the genetic data, which was generated using immunochip. Genetic association was assessed by logistic regression after correcting for population structure.

RESULTS

Altogether we identified 1258 IBD subjects exposed to anti-TNF agents in whom Immunochip data were available. 269/1258 patients (21%) were found to have adverse events to an anti-TNF-α agent that required the therapy to be discontinued. 25% of women compared to 17% of men experienced an adverse event. All adverse events resolved after discontinuing the anti-TNF agent. In total: n = 66 (5%) infusion reactions; n = 49 (4%) allergic/serum sickness reactions; n = 19 (1.5%) lupus-like reactions, n = 52 (4%) rash, n = 18 (1.4%) infections. In Crohn’s disease, IgA ASCA (P = 0.04) and IgG-ASCA (P = 0.02) levels were also lower in patients with any adverse events, and anti-I2 level in ulcerative colitis was significantly associated with infusion reactions (P = 0.008). The logistic regression/human annotation and network analyses performed on the Immunochip data implicated the following five signaling pathways: JAK-STAT (Janus Kinase-signal transducer and activator of transcription), measles, IBD, cytokine-cytokine receptor interaction, and toxoplasmosis for any adverse event.

CONCLUSION

Our study shows 1 in 5 IBD patients experience an adverse event to anti-TNF therapy with novel serologic, genetic , and pathways associations.

Keywords: Genetic associations; Inflammatory bowel disease; Anti-tumor necrosis factor; Adverse events

Core tip: Tumor necrosis factor-α (TNF-α) plays a key role in the development and progression of inflammatory bowel disease (IBD). Anti-TNF therapy is highly efficacious in treating IBD patients, but many experience adverse events. Few studies have evaluated factors associated with adverse events to anti-TNF therapy. In this study, we found some genetic associations and pathways that are enriched for genes associated with the development of adverse events. Future studies will need to confirm these findings as the ability to identify subjects at high risk may help clinicians anticipate and therefore prevent or avoid these adverse events in the future.