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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
Processing time: 275 Days and 10.8 Hours
BACKGROUND
Tumor necrosis factor-alpha inhibitors, including infliximab and adalimumab, are effective medical treatments for perianal fistulising Crohn’s disease (CD), but not all patients achieve fistula healing.
AIM
To determine the correlation between perianal fistula healing and closure with infliximab and adalimumab trough levels.
METHODS
In this multicentre 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. Data collected included demographics, serum infliximab and adalimumab trough levels (mg/L) within 12 wk before or after their most recent clinical assessment and concomitant medical or surgical therapy. 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.
RESULTS
One hundred and fourteen patients (66 infliximab, 48 adalimumab) were included. Forty-eight (72.7%) patients on maintenance infliximab achieved fistula healing and 18 (27.3%) achieved fistula closure. Thirty-seven (77%) patients on maintenance adalimumab achieved fistula healing and 17 (35.4%) achieved fistula closure. Patients who achieved fistula healing had significantly higher infliximab and adalimumab trough levels than 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]. For patients on infliximab, fistula healing was associated with lower rates of detectable anti-infliximab antibodies and younger age. For patients on adalimumab, fistula healing was associated with higher rates of combination therapy with an immunomodulator. 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].
CONCLUSION
Higher maintenance infliximab and adalimumab trough levels are associated with perianal fistula healing in CD.
Core Tip: This multicentre retrospective study demonstrated a significant association between both infliximab and adalimumab trough levels with fistula healing, with higher levels associated with increased healing rates. Higher tertiles of both infliximab and adalimumab levels were associated with a higher proportion of patients achieving fistula healing. Fistula healing, defined as cessation of fistula drainage, is a clinically relevant endpoint that impacts on patient quality of life. Our results support dose-escalation of both infliximab and adalimumab in non-responders, targeting higher levels to achieve fistula healing prior to changing biologic therapy. Importantly, this study is the largest study to date assessing the relationship between adalimumab trough levels and clinical fistula healing.
