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Multicenter Study
. 2022 Mar;55(5):593-603.
doi: 10.1111/apt.16733. Epub 2021 Dec 22.

Antibodies-to-infliximab accelerate clearance while dose intensification reverses immunogenicity and recaptures clinical response in paediatric Crohn's disease

Ruben J Colman  1 , Ye Xiong  2 , Tomoyuki Mizuno  2   3 , Jeffrey S Hyams  4 , Joshua D Noe  5 , Brendan Boyle  6 , Geert R D'Haens  7 , Johan van Limbergen  8 , Kelly Chun  9 , Jane Yang  9 , Michael J Rosen  1   3 , Lee A Denson  1   3 , Alexander A Vinks  2   3 , Phillip Minar  1   3
Affiliations
Multicenter Study

Antibodies-to-infliximab accelerate clearance while dose intensification reverses immunogenicity and recaptures clinical response in paediatric Crohn's disease

Ruben J Colman et al. Aliment Pharmacol Ther. 2022 Mar.

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'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.

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Figures

FIGURE 1
FIGURE 1
The correlation between continuous antibodies to infliximab concentration and infliximab clearance
FIGURE 2
FIGURE 2
Cox regression analyses of time to antibody to infliximab (ATI) development for (A). Neutrophil CD64 activity ratio (nCD64), (B) Patient age (years), (C) week 0–14 exposure (AUC, area under concentration curve) goal (defined by a week 0–14 AUC of 79 348 μg h/mL) and (D) the infliximab starting dose (mg/kg)
FIGURE 3
FIGURE 3
A, The relationship between infliximab through concentration and antibodies to infliximab (ATI) evolution overtime. B, The association between infliximab clearance (L/h) and ATI overtime and further classified by loss of response status
FIGURE 4
FIGURE 4
Receiver operator characteristic (ROC) analysis of the highest antibodies to infliximab concentration that was associated with immunogenicity resolution. AUROC, area under the receiver operating characteristic curve
See this image and copyright information in PMC

Comment in

References

    1. Rosen MJ, Dhawan A, Saeed SA. Inflammatory bowel disease in children and adolescents. JAMA Pediatr. 2015;169:1053–1060. - PMC - PubMed
    1. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348:601–608. - PubMed
    1. Colombel J-F, Adedokun OJ, Gasink C, et al. Combination therapy with infliximab and azathioprine improves infliximab pharmacokinetic features and efficacy: a post hoc analysis. Clin Gastroenterol Hepatol. 2019;17:1525–1532.e1. - PubMed
    1. Lyles JL, Mulgund AA, Bauman LE, et al. Effect of a practice-wide anti-TNF proactive therapeutic drug monitoring program on outcomes in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2021;27:482–492. - PMC - PubMed
    1. Sazonovs A, Kennedy NA, Moutsianas L, et al. HLA-DQA1*05 Carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn’s disease. Gastroenterology. 2020;158:189–199. - PubMed

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Supplementary concepts