Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 7, 2018; 24(25): 2764-2775
Published online Jul 7, 2018. doi: 10.3748/wjg.v24.i25.2764
Systematic review and meta-analysis on the association of tuberculosis in Crohn’s disease patients treated with tumor necrosis factor-α inhibitors (Anti-TNFα)
Brent L Cao, Ahmad Qasem, Robert C Sharp, Latifa S Abdelli, Saleh A Naser
Brent L Cao, Ahmad Qasem, Robert C Sharp, Latifa S Abdelli, Saleh A Naser, Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, United States
Author contributions: Cao BL and Qasem A are Co-first authors; Cao BL designed the study, acquired the data, analyzed and interpreted the data, and participating in writing the manuscript; Qasem A, Sharp RC, and Abdelli LS interpreted the data and participated in revisions of the manuscript; Naser SA is the group leader who supervised all aspects of the data collection/analyses and manuscript writing.
Conflict-of-interest statement: The authors declare that they have no competing interests.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
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:
Correspondence to: Saleh A Naser, PhD, Professor, Associate Director, Burnett School of Biomedical Sciences, Division of Molecular Microbiology, College of Medicine, University of Central Florida, 4110 Libra Drive, Orlando, FL 32816, United States.
Telephone: +1-407-8230955 Fax: +1-407-8230955
Received: April 12, 2018
Peer-review started: April 13, 2018
First decision: April 27, 2018
Revised: April 30, 2018
Accepted: June 2, 2018
Article in press: June 2, 2018
Published online: July 7, 2018
Processing time: 83 Days and 10 Hours
Research background

Recent literature has identified many adverse effects from the use of tumor necrosis factor alpha (TNFα) inhibitors. Among these are an increased risk of opportunistic infections and serious adverse events. However, previous meta-analyses have not identified a significantly increased risk of tuberculosis (TB) infection, which is especially pertinent considering that Mycobacterium avium subspecies paratuberculosis (MAP) is suspected to have an intimate role in the etiology of Crohn’s disease (CD).

Research motivation

Due to the suspected role of MAP in the etiology of CD and previous literature on the topic, TNFα inhibitors likely increase the risk of TB infection, which would guide future clinical decisions. However, such an association has not been adequately quantified. Additionally, current statistical models commonly used in meta-analyses fail to adequately analyze data where events are rare (defined as less than 1 case per 1000 person-years). Our research would not only bring additional considerations when making clinical decisions about anti-TNFα therapy but also introduce existing statistical models and novel corrections that can help deal with rare events.

Research objectives

In this study, we seek to advance the awareness of and quantify the association between TNFα inhibitors and TB in CD patients. We seek to include all qualified studies - including studies with zero events in the treatment and control groups - without using corrections, which previous meta-analyses have failed to do. Finally, we seek to introduce a novel, epidemiologically-based background correction (EBC) that can adjust for zero counts.

Research methods

The Preferred Reporting Items for the Systematic reviews and Meta-Analyses (PRISMA) protocol was followed. Only randomized, placebo-controlled trials (RCTs) were considered. Arcsine differences were used to calculate risk differences in a non-biased way. Odds ratios were calculated using the Yusuf-Peto method both with and without corrections (EBC).

Research results

Twenty-three RCTs were analyzed, and all the statistical methods repeatedly provided significantly increased risk of TB infection. A risk difference (RD) of 0.028 (95%CI: 0.0011-0.055) was calculated. The odds ratio (OR) was 4.85 (95%CI: 1.02-22.99) when all studies were included using EBCs and 5.85 (95%CI: 1.13-30.38) when studies reporting zero tuberculosis cases were excluded.

Research conclusions

There is an increased risk of TB infection in patients with Crohn’s disease who use TNFα inhibitors. This risk could range from 5 times (OR) to as high as 8 times (RD). Alternative therapy such as using more antibiotics and less immunosuppressive agents may be evaluated.

Research perspectives

This study provided us with additional approaches that can be considered when conducting future meta-analyses. ASD is a particularly useful method that can contribute to future meta-analyses. The relationship between MAP and TB is still unclear. Further research on the validity of the EBC should be pursued.