Published online Jun 21, 2022. doi: 10.3748/wjg.v28.i23.2597
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
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.
To determine the correlation between perianal fistula healing and closure with infliximab and adalimumab trough levels.
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.
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].
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.