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P420 Anti-TNF for post-operative prevention in Crohn's disease: the detection of anti-drug antibodies at time of surgery is associated with an increased risk of endoscopic recurrence

Auzolle C.*1, Houze P.2, Tran-Minh M.-L.1, Nancey S.3, Buisson A.4, Fumery M.5, Pariente B.6, Djenidi F.1, Marteau P.7, Bouhnik Y.8, Seksik P.7, Allez M.7

1Saint-Louis Hospital, Department of Gastroenterology, Paris, France 2Saint-Louis Hospital, Department of Biochemistry, Paris, France 3Lyon-Sud Hospital, Hospices Civils de Lyon, Department of Gastroenterology, Pierre-Benite, France 4CHU Estaing, Department of Gastroenterology, Clermont-Ferrand, France 5CHU Amiens, Department of Gastroenterology, Amiens, France 6Claude Huriez Hospital, Department of Gastroenterology, Lille, France 7Saint-Antoine Hospital, Department of Gastroenterology, Paris, France 8Beaujon Hospital, Department of Gastroenterology, Clichy, France

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).

Conclusion

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.