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

<jats:title>Summary</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Primary nonresponse, defined as lack of clinical benefit during the induction phase, occurs in up to 30% of <jats:styled-content style="fixed-case">IBD</jats:styled-content> patients treated with infliximab. The mechanisms underlying primary nonresponse have not yet been clearly defined.</jats:p></jats:sec><jats:sec><jats:title>Aim</jats:title><jats:p>To evaluate the association of early (week 2 and week 6) induction infliximab and anti‐infliximab antibody levels with primary nonresponse.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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 (<jats:styled-content style="fixed-case">ATI</jats:styled-content>) levels were measured by our previously described drug‐tolerant <jats:styled-content style="fixed-case">ELISA</jats:styled-content> assay.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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, <jats:italic>P</jats:italic> = .0019, <jats:italic>P</jats:italic> < .0001 respectively). Antibodies to infliximab appeared more frequently (either week 2 or 6, 68% vs 28% prevalence, <jats:italic>P</jats:italic> = .0004) and at higher levels in nonresponders compared to responders (week 2, 6: median <jats:styled-content style="fixed-case">ATI</jats:styled-content> 7.3, 10.8 μg/mL‐eq vs 3.8, 4.4 μg/mL‐eq, <jats:italic>P</jats:italic> = .005, <jats:italic>P</jats:italic> = .008 respectively). Moreover, week 2 infliximab levels <6.8 μg/mL (<jats:styled-content style="fixed-case">AUC</jats:styled-content> = 0.68, <jats:italic>P</jats:italic> = .002, sensitivity 50%, specificity 86%) and antibodies to infliximab levels >4.3 μg/mL‐eq (<jats:styled-content style="fixed-case">AUC</jats:styled-content> = 0.78, <jats:italic>P</jats:italic> = .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.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>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.</jats:p></jats:sec>