Background/Purpose: Infliximab (IFX) effectiveness is impacted in part by immunogenicity and the development of drug neutralizing anti-drug antibodies, thus methotrexate is commonly co-administered to minimize the immune response to IFX. However the mechanism by which MTX impacts IFX concentrations and anti-drug antibody formation is unknown. In adults with Rheumatoid Arthritis, higher concentrations of MTX polyglutamtes (MTXGlu₃) were associated with lower drug antibody formation, suggesting that MTXGlu may impact IFX pharmacokinetics (1), however, little is known in children.

Methods: This is a cross-sectional study of patients receiving IFX at Children’s Mercy Kansas City (n=97) and included patients with Inflammatory Bowel Disease (IBD n= 73), Juvenile Idiopathic Arthritis (JIA n=16), and childhood uveitis (CU n=8). 35 patients were on concomitant MTX therapy (26% IBD, 75% JIA, 75% CU). Serum trough samples were analyzed for IFX and anti-IFX antibodies using a NF-κβ luciferase gene-reporter assay (ARUP Laboratories), and for erythrocyte MTXGlu_n levels by HPLC-MS/MS. Clinical data were collected by chart review. Statistical testing was conducted by Wilcoxon-rank sum or Spearman’s rank correlation analysis, and data were log transformed for regression analyses.

Results: Despite wide variations in dose, frequency, and trough IFX concentrations between groups, when normalized for variation in dose and frequency (NormIFX), troughs were not statistically different (median (IQR) in IBD: 3.5 (1.8, 5.2), JIA: 4.1 (2.3, 5.6), and CU: 4.4 (3.4, 5.6)). Only 3 IBD patients had anti-IFX Ab detected, and they had significantly lower median NormIFX concentrations (3.9 (2.2, 5.3) vs. 0 (0, 0) p<0.01), but no difference in MTXGlu concentrations, although only 1 patient was receiving MTX concurrently. When the JIA and CU patients were evaluated separately, there was a negative association between long chain MTXGlu_3-6 formation and NormIFX levels for JIA (ρ -0.81 p=0.005) and CU (ρ -0.94 p=0.005). This remained significant despite controlling for MTX dose and route in a linear regression model (JIA p=0.04, CU p= 0.04). In JIA patients, higher NormIFX levels were associated with lower cJADAS (ρ -0.72 p=0.009).

Conclusion: Anti-IFX Ab were rarely observed in this cohort of patients, and only seen in children whose trough IFX levels were undetectable. Once normalized for dose and frequency, trough IFX concentrations were not statistically significantly different between disease groups, although JIA and CU troughs were higher. In JIA and CU, but not IBD, MTXGlu_n accumulation negatively impacted NormIFX trough levels, suggesting mechanisms by which MTX enhances infliximab effectiveness may be independent of MTXGlu_n formation and may also be disease specific.

(1) Dervieux T, Weinblatt M, Kivitz A, Kremer JM. Methotrexate polyglutamation in relation to infliximab pharmakokinetics in rheumatoid arthritis. Ann Rheum Dis 2013; 72:908-910

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/infliximab-use-in-jia-and-uveitis-does-methotrexate-help-or-hinder/