Monitoring a Combination of Calprotectin and Infliximab Identifies Patients With Mucosal Healing of Crohn's Disease.

BACKGROUND AND AIMS: In the TAILORIX trial, no benefit could be shown of infliximab dose escalation based on pharmacokinetic (infliximab serum concentrations) and pharmacodynamic (biomarkers and symptoms) monitoring compared to dose escalation based on symptoms alone in patients with Crohn's disease (CD). We investigated whether integration of pharmacokinetic and pharmacodynamic monitoring can be used to evaluate responses to infliximab induction and maintenance therapy, based on findings from endoscopy. METHODS: We performed a post-hoc analysis of patients with CD included in a trial to test the effects of infliximab dose escalation, based on biomarkers and serum concentrations of infliximab, on symptoms (the TAILORIX trial; n=122). We analyzed data from this study to determine whether concentrations of biomarkers and serum concentrations of infliximab associated with endoscopic outcomes (n=116). The primary endpoints were endoscopic response (CD endoscopic index of severity [CDEIS] decrease >/=50% from baseline), endoscopic remission (CDEIS <3), and absence of ulcers at weeks 12 and 54 of infliximab treatment. RESULTS: Infliximab trough concentrations >23.1 mg/L at week 2 and >10.0 mg/L at week 6 were associated with endoscopic remission at week 12 (positive predictive values 72% and 76% and negative predictive values, 65% and 59%, respectively). During maintenance therapy, we found evidence for an exposure-response relationship only following dose escalation; trough concentrations >10.6 mg/L associated with the absence of ulcers at week 54 (positive predictive value, 49% and negative predictive value, 92%). Low fecal concentrations of calprotectin during therapy were associated with endoscopic response and remission (P<.05). Dose escalations increased trough concentrations of infliximab; persistent increase in fecal concentration of calprotectin, despite dose escalation, associated with lack of endoscopic response and remission. A significantly higher proportion of patients with antibodies to infliximab, identified by a drug-tolerant assay, dropped out of the study compared to patients without antibodies (P<.0001). CONCLUSIONS: In a post-hoc analysis of data from a trial to test the effects of infliximab dose escalation on symptoms, we found that during maintenance therapy, the combination of fecal concentration of calprotectin and trough concentration of infliximab can guide dose adjustment and increase the chances for endoscopic response and remission. ClinicalTrialsRegister.eu EudraCT no: 2011-003038-14.