@article{33cae76fc1a64563b87113caa70d365e,
title = "Monitoring a Combination of Calprotectin and Infliximab Identifies Patients With Mucosal Healing of Crohn's Disease",
abstract = "BACKGROUND & AIMS: In the TAILORIX trial, no benefit could be shown by infliximab dose escalation based on pharmacokinetic (infliximab serum concentrations) and pharmacodynamic (biomarkers and symptoms) monitoring compared with 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 Study Investigating Tailored Treatment With Infliximab for Active Crohn's Disease trial; n = 122). We analyzed data from this study to determine whether concentrations of biomarkers and serum concentrations of infliximab were associated with endoscopic outcomes (n = 116). The primary end points were endoscopic response (CD endoscopic index of severity decrease >= 50% from baseline), endoscopic remission (CD endoscopic index of severity, <3), and absence of ulcers at weeks 12 and 54 of infliximab treatment.RESULTS: Infliximab trough concentrations greater than 23.1 mg/L at week 2 and greater than 10.0 mg/L at week 6 were associated with endoscopic remission at week 12 (positive predictive values, 72% and 76%; negative predictive values, 65% and 59%, respectively). During maintenance therapy, we found evidence for an exposure-response relationship only after dose escalation; trough concentrations greater than 10.6 mg/L were associated with the absence of ulcers at week 54 (positive predictive value, 49%; 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, was associated with a 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 with 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.",
keywords = "association, endoscopic healing, episodic treatment, immunogenicity, induction therapy, inflammatory-bowel-disease, management, multicenter, pharmacokinetics, scheduled maintenance treatment, serum infliximab, term efficacy, therapeutic drug monitoring, trough levels, INDUCTION THERAPY, EPISODIC TREATMENT, SCHEDULED MAINTENANCE TREATMENT, MULTICENTER, MANAGEMENT, SERUM INFLIXIMAB, TERM EFFICACY, INFLAMMATORY-BOWEL-DISEASE, Immunogenicity, Endoscopic Healing, Therapeutic Drug Monitoring, Pharmacokinetics, TROUGH LEVELS, ASSOCIATION",
author = "E. Dreesen and F. Baert and D. Laharie and P. Bossuyt and Y. Bouhnik and A. Buisson and G. Lambrecht and E. Louis and B. Oldenburg and B. Pariente and M. Pierik and {van der Woude}, C.J. and G. D'Haens and S. Vermeire and A. Gils",
note = "Funding Information: Conflicts of interest These authors disclose the following: Filip Baert has received research grants from AbbVie, Chiesi, Ipsen, Mundipharma, Roche, and Takeda, and speakers and consultancy fees from AbbVie, Cellgene, Ferring, Janssen, Mundipharma, MSD, Pfizer, Takeda, and Vifor; David Laharie has received board and lecture fees from AbbVie, Biogaran, Biogen, Ferring, HAC-pharma, Janssen, MSD, Novartis, Pfizer, Prometheus, Roche, Takeda, Theradiag, and Tillots; Peter Bossuyt has received financial support for research from AbbVie, Mundipharma, and Pfizer, lecture fees from AbbVie, Takeda, and Janssen, and advisory board fees from Hospira, Janssen, MSD, Mundipharma, Roche, Pfizer, Sandoz, and Dr Falk Benelux; Anthony Buisson has received consulting fees from AbbVie, Hospira, and Takeda, and lecture fees from AbbVie, Hospira, Takeda, MSD, Vifor Pharma, Sanofi-Aventis, and Ferring; Edouard Louis has received fees from MSD, AbbVie, Takeda, Ferring, Chiesi, Mitsubishi Pharma, Hospira, and Janssen, and advisory board fees from AbbVie, Ferring, MSD, Takeda, Hospira, Mitsubishi Pharma, Celltrion, and Prometheus; Bas Oldenburg has received grants from MSD, AbbVie, Takeda, Cablon, Ferring, and Dr Falk; C. Janneke van der Woude has received grants from AbbVie, Jansen, Pfizer, Tramedico, and Dr Falk, and speakers and consultancy fees from AbbVie, Dr Falk, Ferring, Janssen, Mundipharma, MSD, Pfizer, Takeda, and Vifor; Geert D{\textquoteright}Haens has served as an advisor for AbbVie, Ablynx, Allergan, Amakem, Amgen, AM Pharma, Arena Pharmaceuticals, AstraZeneca, Avaxia, Biogen, Bristol Meiers Squibb, Boerhinger Ingelheim, Celgene/Receptos, Celltrion, Cosmo, Covidien/Medtronics, Ferring, Dr Falk Pharma, Eli Lilly, Engene, Galapagos, Genentech/Roche, Gilead, Glaxo Smith Kline, Hospira/Pfizer, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Nextbiotics, Novonordisk, Otsuka, Pfizer/Hospira, Photopill, Prometheus Laboratories/Nestle, Progenity, Protagonist, Robarts Clinical Trials, Salix, Samsung Bioepis, Sandoz, Seres/Nestle, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant, and Vifor, and has received speaker fees from AbbVie, Biogen, Ferring, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts, and Vifor; S{\'e}verine Vermeire is a senior clinical researcher for the Research Foundation Flanders (Fonds Wetenschappelijk Onderzoek), and has received grant support from MSD, AbbVie, Pfizer, J&J, and Takeda, lecture fees from AbbVie, MSD, Ferring Pharmaceuticals, Takeda, and Hospira, and consultancy fees from AbbVie, Takeda, Pfizer, Ferring Pharmaceuticals, Shire Pharmaceuticals Group, MSD, Hospira, Mundipharma, Celgene, Galapagos, and Genentech/Roche; Erwin Dreesen is a postdoctoral research fellow of the Research Foundation – Flanders (FWO), Belgium (grant number 12X9420N) and received consultancy fees from argenx and Janssen (all honoraria/fees paid to the department); and Ann Gils has served as a speaker for MSD, Janssen Biologicals, Pfizer, Takeda, Novartis, and AbbVie, received investigator-initiated research grants from Pfizer, and a national grant from Takeda. The remaining authors disclose no conflicts. KU Leuven licensed antibodies for the infliximab, adalimumab, vedolizumab, golimumab, and ustekinumab enzyme-linked immunosorbent assay to apDia, and infliximab and adalimumab lateral flow assays to R-Biopharm (Ann Gils). Funding Information: Funding Supported by Applied Biomedical Research grant T003716N from the Research Foundation Flanders, Belgium. Funding Information: Funding Supported by Applied Biomedical Research grant T003716N from the Research Foundation Flanders , Belgium. Publisher Copyright: {\textcopyright} 2020 AGA Institute",
year = "2020",
month = mar,
day = "1",
doi = "10.1016/j.cgh.2019.05.029",
language = "English",
volume = "18",
pages = "637--646.e11",
journal = "Clinical gastroenterology and hepatology",
issn = "1542-3565",
publisher = "Elsevier Science",
number = "3",
}