Early drug and anti-infliximab antibody levels for prediction of primary nonresponse to infliximab therapy

Alimentary Pharmacology and Therapeutics

5 years ago

Early drug and anti-infliximab antibody levels for prediction of primary nonresponse to infliximab therapy

R. Eliakim, M. Yavzori, B. Ungar, O. Picard, S. Ben-Horin, N. Levhar, U. Kopylov, H. Bar-Yoseph, Y. Chowers, E. Fudim, U. Manor, L. Selinger

Background Primary nonresponse, defined as lack of clinical benefit during the induction phase, occurs in up to 30% of IBD patients treated with infliximab. The mechanisms underlying primary nonresponse have not yet been clearly defined. Aim To evaluate the association of early (week 2 and week 6) induction infliximab and anti-infliximab antibody levels with primary nonresponse. Methods A retrospective observational case-control study of inflammatory bowel disease patients treated with infliximab and followed at Sheba Medical Center between 2009 and 2016 was performed. Pre-infusion infliximab and antibodies to infliximab (ATI) levels were measured by our previously described drug-tolerant ELISA assay. Results Thirty-five primary nonresponders have been identified and matched with 105 primary responders (1:3 ratios). Both week 2 and week 6 infliximab levels were significantly lower among primary nonresponders compared to responders (week 2, 6: median level 7.2, 2.2 μg/mL vs 13.5, 9.5 μg/mL, P = .0019, P < .0001 respectively). Antibodies to infliximab appeared more frequently (either week 2 or 6, 68% vs 28% prevalence, P = .0004) and at higher levels in nonresponders compared to responders (week 2, 6: median ATI 7.3, 10.8 μg/mL-eq vs 3.8, 4.4 μg/mL-eq, P = .005, P = .008 respectively). Moreover, week 2 infliximab levels <6.8 μg/mL (AUC = 0.68, P = .002, sensitivity 50%, specificity 86%) and antibodies to infliximab levels >4.3 μg/mL-eq (AUC = 0.78, P = .0004, sensitivity 77%, specificity 71%) were predictive of primary nonresponse. Among the other clinical and demographic variables, higher baseline ulcerative colitis clinical score, infliximab monotherapy, prior adalimumab therapy and previous Crohn's disease-related surgeries were also associated with an increased risk of primary nonresponse. Conclusions Infliximab levels below 6.8 μg/mL and antibodies to infliximab levels above 4.3 μg/mL-eq before the second infusion are associated with primary nonresponse, especially among Crohn's disease patients.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/apt.14410