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Poster presentations: Clinical: Therapy and Observation 2020

P703 Addition of azathioprine to switch of anti-TNF in patients with IBD in clinical relapse with pharacokinetic failure: A post hoc analysis of a prospective randomised trial using drug-tolerant assay

S. Paul1, N. Williet2, S. Nancey3, P. Veyrard2, G. Boschetti3, A.E. Berger1, B. Flourie3, L. Peyrin Biroulet4, X. Roblin2

1Immunology, CHU Saint Etienne, Hospital Nord, Saint Priest en Jarez, France, 2Department of Gastroenterology and Hepatology, Inserm CIC1408, CHU Saint Etienne, Hospital Nord, Saint Priest en Jarez, France, 3CHU Lyon, Gastroenterology, Lyon, France, 4CHU Nancy, Gastroenterology, Nancy, France

Background

In a recent prospective, randomised trial, we showed that the rates of clinical failure and occurrence of unfavourable pharmacokinetics using a drug-sensitive assay after a switch of anti-TNF were significantly higher in monotherapy compared with combination therapy (Log-rank test p < 0.0001), whatever the anti-TNF used in IBD patients. We aimed in a post hoc analysis to assess the time-course of antidrug antibodies in the two groups of patients using a drug-tolerant assay previously described (1).

Methods

After switching of anti-TNF under mono or combotherapy, blood samples were uptake at various time-points (6, 12, 18 and 24 months). Using a drug-tolerant assay, we defined pharmacokinetic failure when antidrug antibodies were detected (> 2.5 μg/ml Eq). Transient anti-drug antibodies were defined as antibodies that appeared during the course of anti-TNF therapy with no clinical worsening, and finally that disappeared after 2 consecutive measurements.

Results

Ninety patients were analysed. According to a drug-tolerant assay, the occurrence of antibodies against anti-TNF was significantly higher in patients under monotherapy (log-rank test p < 0.0001 (HR = 3.36 [1.94–5.86]) than under combination therapy. The rates of anti-drug antibody were significantly lower under IFX-AZA combotherapy compared with ADA-AZA combotherapy or under monotherapy. Monotherapy ADA (HR = 5.55[2.46–12.34]) or IFX (HR = 6.05[2.67–13.70]) and combination therapy ADA-AZA (HR = 3.34 [1.407.98]) increased significantly the rates of pharmacokinetic failure using a drug-tolerant assay compared with IFX-AZA combotherapy. The time-course without pharmacokinetic failure was significantly different between the 4 groups of patients from 15 months (p = 0.04) but was not significantly different at 6 months (p = 0.12). Overall, 9% of patients developed transient antibodies. Detection of antibodies against anti-TNF at 6 months using a drug-tolerant assay predicted significantly an immunogenic failure assessed previously by a drug-sensitive assay with a sensitivity of 57.1%, a specificity of 92.7%, a positive predictive value of 90.3%. In contrary to the association between clinical failure and immunogenic failure using drug-sensitive assay, the association of detectable drug and positive antibodies using a drug-tolerant assay was not significantly associated with clinical failure (HR = 1.3[0.3–6.8], p = 0.51).

Conclusion

Pharmacokinetic failure using a drug-tolerant assay was significantly lower under combotherapy, especially for IFX-AZA. Detection of anti-drug antibodies could predict pharmacokinetic failure.

Reference:

Ben-Horin S et al. Gut 2011.