Summary: 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.

Real life data regarding pharmacokinetics of vedolizumab in patients needing dose optimisation are scarce. We set to examine whether pre-optimisation vedolizumab levels associate with therapy outcomes and which mechanisms explain the associations. A multicentre observational study assessed the outcome of dose increase in association with pre-escalation levels in vedolizumab-treated patients. SubsequentIy, α4β7 occupancy on peripheral blood [PB] and intestinal lamina propria [LP] tissues was investigated on various cellular subsets in patients undergoing lower endoscopy on infusion day. Cellular localisation of vedolizumab-bound α4β7 and effects on M1 and M2 macrophages were also explored. A total of 161 inflammatory bowel disease [IBD] patients were included. Among 129/161 patients intensified during maintenance [Week 14 onward], pre-intensification trough levels were comparable or higher among those subsequently attaining post-optimisation clinical, biomarker, and endoscopic remission, compared with non-remitting patients [p = 0.09, 0.25, 0.04, respectively]. Similar results were demonstrated for those dose-optimised during induction [Week 6, n = 32]. In the immune sub-study [n = 43], free α4β7 receptors at trough were similarly low among patients with/without mucosal healing, on PB T cells [p = 0.15], LP T cells [p = 0.88], and on PB eosinophils [p = 0.08]. Integrin receptors on M1 and M2 macrophages were also saturated by low levels of vedolizumab and anti-inflammatory cytokine secretion was not increased. Co-localisation and dissociation experiments demonstrated membranal α4β7 receptors of two origins: non-internalised and newly generated α4β7, but re-binding was still complete at very low concentrations. These results do not support pharmacokinetics as the mechanism responsible for loss of response to vedolizumab, nor do they support a need for higher drug concentration to enhance vedolizumab’s immune effects. Higher pre-escalation levels may indicate less clearance [less severe disease] and higher likelihood of subsequent re-gained response, regardless of therapy escalation.