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©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
Higher infliximab and adalimumab trough levels are associated with fistula healing in patients with fistulising perianal Crohn’s disease
Bonita Gu, Kavya Venkatesh, Astrid-Jane Williams, Watson Ng, Crispin Corte, Ali Gholamrezaei, Simon Ghaly, Wei Xuan, Sudarshan Paramsothy, Susan Connor
Bonita Gu, Astrid-Jane Williams, Watson Ng, Wei Xuan, Susan Connor, South Western Sydney Clinical School, University of New South Wales, Sydney 2170, New South Wales, Australia
Bonita Gu, Astrid-Jane Williams, Watson Ng, Ali Gholamrezaei, Susan Connor, Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney 2170, New South Wales, Australia
Bonita Gu, Crispin Corte, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney 2050, New South Wales, Australia
Kavya Venkatesh, Department of Medicine, University of Newcastle, Newcastle 2308, New South Wales, Australia
Crispin Corte, Central Clinical School, University of Sydney, Sydney 2050, New South Wales, Australia
Ali Gholamrezaei, Wei Xuan, Susan Connor, Ingham Institute of Applied Medical Research, Sydney 2170, New South Wales, Australia
Simon Ghaly, Department of Gastroenterology, St Vincent’s Hospital Sydney, Sydney 2010, New South Wales, Australia
Simon Ghaly, St Vincent’s Clinical School, University of New South Wales, Sydney 2010, New South Wales, Australia
Sudarshan Paramsothy, Department of Gastroenterology and Hepatology, Concord Repatriation General Hospital, Sydney 2139, New South Wales, Australia
Sudarshan Paramsothy, Concord Clinical School, University of Sydney, Sydney 2139, New South Wales, Australia
Author contributions: Gu B, Williams AJ, Ng W and Connor S conceived concept and design of study; Gu B and Venkatesh K collected the data; Gu B analysed the data; Gholamrezaei A and Xuan W provided statistical support; Gu B prepared the first draft of the manuscript; and all authors provided edits and critiqued the manuscript for intellectual content.
Institutional review board statement: Ethics approval was obtained from the South Western Sydney Local Health District (Human Research Ethics Committee LNR/18/LPOOL/404; Local Project Number: HE18/261).
Informed consent statement: According to the Ethics Board Approval for this retrospective cross-sectional study, individual patient consent was not required to obtained.
Conflict-of-interest statement: Gu B has nothing to disclose. Williams AJ has received honoraria from Takeda, Janssen and Abbvie and honoraria and grant support from Ferring. Ng W received grants from Janssen and Pfizer, during the conduct of the study; grants and personal and speaker fees from Abbvie, Takeda, Grants from Ferring and Shire. Corte C has received unrestricted educational grants from Ferring, Janssen, Shire and GESA. Corte C has received honoraria from Janssen, Ferring, Astra-Zeneca, Abbvie and Shire. Travel support and conference registration from Takeda, Shire, Janssen and Nycomed. Advisory board fees from Celgene and Gilead. Ghaly S has received educational grants from Janssen, Ferring, Pfizer and Takeda. Honoraria from Janssen, Ferring, Takeda, AbbVie, Shire. Advisory board fees from Pfizer, AbbVie, Gilead, Ferring and MSD. Paramsothy S is a consultant for Finch Therapeutics and has received speaker fees from Ferring, Janssen and Takeda. Connor S has received honoraria, speaker fees, educational support and/or grant funding from Abbvie, Aspen, BMS, Celgene, Celltrion, Chiesi, DrFalk, Ferring, Fresenius Kabi, Gilead, Janssen, MSD, Novartis, Pfizer, Takeda, Vifor, Agency for Clinical Innovation, Gastroenterological Society of Australia, Medical Research Future Fund and The Leona M and Harry B Helmsley Charitable Trust. This research project did not receive any grant funding.
Data sharing statement: According to the Ethics Board Approval for this retrospective cross-sectional study, individual patient consent was not required to obtained.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Bonita Gu, MD, Doctor, South Western Sydney Clinical School, University of New South Wales, Goulburn St, Liverpool, Sydney 2170, New South Wales, Australia. bonita.gu@health.nsw.gov.au
Received: September 14, 2021
Peer-review started: September 14, 2021
First decision: November 7, 2021
Revised: November 21, 2021
Accepted: May 5, 2022
Article in press: May 5, 2022
Published online: June 21, 2022
ARTICLE HIGHLIGHTS
Research background
Anti-tumor necrosis factor (anti-TNF)-alpha agents, including infliximab and adalimumab, are effective medical treatments for perianal fistulising Crohn’s disease (CD), but not all patients achieve fistula healing with up to 60% of patients treated with maintenance infliximab lose response within one year.
Research motivation
Accumulating evidence suggests that this loss of response is partly due to sub-therapeutic anti-TNF trough levels. Retrospective studies and post-hoc analyses of prospective data have identified that higher infliximab trough levels are associated with fistula healing and closure compared to what is observed for mucosal healing in luminal disease, with emerging data suggesting similar results for adalimumab. Quantitative assays for therapeutic drug monitoring permits individualisation of infliximab and adalimumab dosing, however there are very few studies on perianal fistulising CD and the optimal target levels for perianal fistulising CD remains unclear.
Research objectives
This study aims to assess the association between serum trough infliximab and adalimumab levels and perianal fistula healing and closure and identify optimal target levels.
Research methods
In this multi-centre retrospective study conducted across four tertiary inflammatory bowel disease centres in Australia, we identified CD patients with perianal fistulae on maintenance infliximab or adalimumab who had a trough level within twelve weeks of clinical assessment. The primary outcome was fistula healing, defined as cessation in fistula drainage. The secondary outcome was fistula closure, defined as healing and closure of all external fistula openings. Differences between patients who did or did not achieve fistula healing were compared using the Chi-square test, t-test or Mann-Whitney U test.
Research results
Out of a total of 114 patients (66 infliximab, 48 adalimumab), 48 (72.7%) patients and 37 (77%) patients on maintenance infliximab and adalimumab respectively achieved fistula healing. Patients who achieved fistula healing had significantly higher infliximab and adalimumab trough levels compared to patients who did not [infliximab: 6.4 (3.8-9.5) vs 3.0 (0.3-6.2) mg/L, P = 0.003; adalimumab: 9.2 (6.5-12.0) vs 5.4 (2.5-8.3) mg/L, P = 0.004]. Serum trough levels for patients with and without fistula closure were not significantly different for infliximab [6.9 (4.3-10.2) vs 5.5 (2.5-8.3) mg/L, P = 0.105] or adalimumab [10.0 (6.6-12.0) vs 7.8 (4.2-10.0) mg/L, P = 0.083].
Research conclusions
Higher maintenance infliximab and adalimumab trough levels are associated with perianal fistula healing in CD.
Research perspectives
Our study showed that higher infliximab and adalimumab trough levels are associated with perianal CD fistula healing, with higher rates of healing in higher tertiles of infliximab and adalimumab levels, but no association with fistula closure was observed. Further prospective studies are required to confirm target infliximab and adalimumab trough levels and determine the optimal dose escalation method to achieve these target levels.
