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

Abstract

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. To evaluate the association of early (week 2 and week 6) induction infliximab and anti-infliximab antibody levels with primary nonresponse. 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. 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, 2.2μg/mL vs 13.5, 9.5μg/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, 10.8μg/mL-eq vs 3.8, 4.4μg/mL-eq, P=.005, P=.008 respectively). Moreover, week 2 infliximab levels <6.8μg/mL (AUC=0.68, P=.002, sensitivity 50%, specificity 86%) and antibodies to infliximab levels >4.3μg/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. Infliximab levels below 6.8μg/mL and antibodies to infliximab levels above 4.3μg/mL-eq before the second infusion are associated with primary nonresponse, especially among Crohn's disease patients.