Background: Anti-TNF monoclonal antibodies (mAb) are efficient for the prevention of postoperative recurrence in Crohn's disease (CD). Measurement of trough serum levels and anti-drug antibodies may help to determine the mechanisms of anti-TNF failure. We previously identified two risk factors associated with endoscopic recurrence in the REMIND cohort: tobacco (OR =2.3) and anti-TNF (OR =0.35). The aim of our study was to correlate efficacy of anti-TNF mAb with their pharmacokinetics within the same cohort.
Methods: The REMIND group conducts a prospective nationwide study in nine French academic centers of ileal and/or ileocolic CD patients. Samples are taken from the surgical specimen at the time of surgery (M0) and at the time of endoscopy (M6), stored centrally in a bio-bank, and analyzed to identify factors associated with recurrence. This study was performed in the 60 patients treated post-operatively with anti-TNF in the REMIND cohort (198 patients included on the date of the analysis).
The trough levels of infliximab (IFX) and adalimumab (ADA) and anti-drug antibodies (ATI and ATA) were analyzed by ELISA method. Limits of detection were 10 ng/ml for both ATI and ATA. Trough levels of detection of anti-TNF drugs was 0.3 μg/ml. Therapeutic thresholds levels were 3 μg/ml for IFX and 4,9 μg/ml for ADA. Endoscopic recurrence was defined by a Rutgeerts ≥ i2 score. The fisher test was used for the bivariate analysis.
Results: Sixty subjects received an anti-TNF agent (ADA n=47, IFX n=8) after surgery. Only 14 patients (23%) were naive of anti-TNF. Twenty-six patients (43%) had an endoscopic recurrence and 34 (57%) had a normal colonoscopy. ATA or ATI were detected in 8 patients at M0; 6 of them (75%) had an endoscopic recurrence. In contrast, of the 41 patients who did not have anti-drug antibodies at the time of surgery, 13 (32%) had endoscopic recurrence (p=0.04). At M6, the trough drug levels were analyzed in 32 patients. In the group of patients with endoscopic recurrence, trough drug levels were below therapeutic threshold in 10 of 15 patients (67%) compared to the 3/17 patients (18%) in the group of patients with endoscopic remission (p=0.01).
Conclusions: The presence of anti-drug antibodies at the time of surgery is associated with a higher risk of endoscopic recurrence. Infra-therapeutic trough levels at M6 were associated with a higher risk of endoscopic recurrence. In clinical practice, these results demonstrate that detection of anti-drug antibodies may influence the choice of postoperative therapy.