@article{9223615bf02d4249bb6c64c94112dcdc,
title = "Antibodies-to-infliximab accelerate clearance while dose intensification reverses immunogenicity and recaptures clinical response in paediatric Crohn{\textquoteright}s disease",
abstract = "Background: Antibodies to infliximab (ATI) are associated with secondary loss of response and increased risk for drug reactions. Limited studies have associated ATI with increased infliximab clearance. Aims: We assessed the impact of ATI on infliximab clearance and loss of response in an inception paediatric Crohn{\textquoteright}s disease cohort with 1-year follow-up. Methods: This multi-centre prospective cohort study collected peak and trough serum infliximab/ATI concentrations from 660 infusions (78 patients) during the first year of therapy. Clinicians were blinded to these research labs. The primary outcome was the difference in infliximab clearance between ATI-positive (ATI) and ATI-negative (no-ATI) patients. Secondary outcomes included pre-treatment predictors of ATI (including HLA-DQA1 genotyping). Clinical remission, loss of response and infliximab clearance were compared between pre-ATI, during ATI and following ATI resolution with MANOVA. Time to ATI was calculated by Cox proportional Hazards model. Results: ATI were detected in 68% (53/78) patients with a median concentration of 76 ng/mL (range 23-1828). Maximum ATI concentration was <200 ng/mL in 73.6% (39/53). Median clearance in ATI patients was higher (with higher clearance if loss of response), compared to no-ATI patients (P < 0.001). Neutrophil CD64 ratio >6 and starting dose <7.5 mg/kg independently predicted ATI in multivariable regression, while HLA-DQA1*05 presence did not. Dose adjustment resolved ATI in 37.5% (12/32) patients with concomitant infliximab concentration and clearance recovery. A maximum ATI level of ≤99 ng/mL predicted ATI resolution (area under the receiver operating curve 0.80 [95% CI 0.64-0.96]). Conclusions: In this real-world cohort, ATI as low as 23 ng/mL impacted drug clearance. Our data suggest that dose optimisation for low-level ATI can improve infliximab clearance and prevent loss of response.",
author = "Colman, {Ruben J.} and Ye Xiong and Tomoyuki Mizuno and Hyams, {Jeffrey S.} and Noe, {Joshua D.} and Brendan Boyle and D{\textquoteright}Haens, {Geert R.} and {van Limbergen}, Johan and Kelly Chun and Jane Yang and Rosen, {Michael J.} and Denson, {Lee A.} and Alexander A. Vinks and Phillip Minar",
note = "Funding Information: : RJC, YX, TM, BB, JDN, PM and MJR have no disclosures. JSH has served as an advisory board member for Janssen, Pfizer, Bristol Myers Squibb, Boehringer Ingelheim. JSH has served as a consultant for Takeda, Thetis Pharmaceuticals, Allergan. GRD has served as an consultant for Abbvie, Agomab, AstraZeneca, AM Pharma, AMT, Arena Pharmaceuticals, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Exo Biologics, Galapagos, Index Pharmaceuticals, Kaleido, Roche, Gilead, Glaxo Smith Kline, Gossamerbio, Pfizer, Immunic, Johnson and Johnson, Origo, Polpharma, Procise Diagnostics, Prometheus laboratories, Prometheus Biosciences, Progenity, Protagonist. GRD has served as a speaker for Abbvie, Arena, Galapagos, Gilead, Pfizer, BMS, Takeda. JvL has served as a speaker and a consultant for Nestle Health Sciences, and has received research funding from Nestle Health Sciences. KC and JY are employees of Labcorp. JY owns stocks and shares in Labcorp. LAD has served as a speaker, a consultant and an advisory board member for the Crohn{\textquoteright}s and Colitis Foundation, and has received research funding from the National Institutes of Health, the CureForIBD Foundation, the Crohn{\textquoteright}s and Colitis Foundation, and the Helmsley Foundation. LAD owns US patent number 10626460 for use of glycans and glycosyltransferases for diagnosing/monitoring inflammatory bowel disease, 9995752 for methods and compositions for determining and treating relapse in inflammatory bowel disease, and 9541560 for serological markers of inflammatory bowel disease phenotype and disease progression. These patents are not related to the contents of the current manuscript. AAV has received research funding from the Gerber foundation. MJR has served on the advisory board of Pfizer and Entasis Therapeutics. Declaration of personal interests Funding Information: : This work was funded in part by the National Institutes of Health (T32 DK 007727 to R.J.C., K23 DK 105229 and R03 DK 118314 to P.M. and 5T32 HD 69054 to Y.X.), the Crohn{\textquoteright}s and Colitis Foundation to P.M. and the Academic Research Committee at Cincinnati Children{\textquoteright}s Research Foundation to P.M. Research Electronic Data Capture (REDCap) electronic data capture tools hosted at Cincinnati Children{\textquoteright}s Hospital Medical Center were supported in part by the NIH (NIH/NCATS UL1 TR000445). This project was funded in part by the National Institutes of Health grant number P30 DK078392 (a clinical component of the Digestive Diseases Research Core Center in Cincinnati). Declaration of funding interests Publisher Copyright: {\textcopyright} 2021 John Wiley & Sons Ltd",
year = "2021",
doi = "https://doi.org/10.1111/apt.16733",
language = "English",
journal = "Alimentary Pharmacology and Therapeutics",
issn = "0269-2813",
publisher = "Wiley",
}