Subtherapeutic concentrations of infliximab and adalimumab are associated with increased disease activity in Crohn’s disease

Abstract

Background:Low anti-tumor necrosis factor α (TNFα) serum concentrations may result in lack of treatment response in patients with inflammatory bowel disease. We determined the anti-TNFα drug concentrations in patients with inflammatory bowel disease and investigated whether or not subtherapeutic drug concentrations were associated with increased levels of disease activity.Methods:In a single-center cross-sectional study, we included patients with ulcerative colitis or Crohn’s disease who were receiving infliximab or adalimumab maintenance therapy. Demographic data, disease activity symptom scores (Partial Mayo Score, Harvey Bradshaw Index), inflammatory markers [C-reactive protein (CRP), fecal calprotectin], antidrug antibodies and serum drug concentrations were recorded. Therapeutic drug concentrations were defined as 3–8 mg/liter for infliximab and 5–12 mg/liter for adalimumab.Results:Of 210 patients included, 137 (65.2%) had Crohn’s disease. In the adalimumab group, subtherapeutic drug concentrations were measured in 16.7% of patients with ulcerative colitis and in 27.7% of patients with Crohn’s disease. In the infliximab group, subtherapeutic drug concentrations were found in 23% (ulcerative colitis) and 30.3% (Crohn’s disease) of patients. In Crohn’s disease, subtherapeutic adalimumab concentrations were associated with higher fecal calprotectin and CRP concentrations compared with therapeutic concentrations. Subtherapeutic infliximab concentrations in patients with Crohn’s disease were also associated with higher CRP concentrations compared with therapeutic concentrations.Conclusions:The prevalence of subtherapeutic drug levels ranged from 17% to 30%. In patients with Crohn’s disease, subtherapeutic serum drug concentrations were associated with significantly higher disease activity with both anti-TNFα agents. These findings were not observed in patients with ulcerative colitis. Clinicaltrials.gov identifier [NCT02134054]

Correlation of serum levels of anti-tumor necrosis factor agents with perianal fistula healing in Crohn’s disease: a narrative review

“…[28][29][30] In contrast, the lower the level is observed, the greater is the chance of nonresponse and/or immunogenicity to biological therapy, mainly driven by the development of antibodies to the drug. 31 There are 2 different strategies for the use of TDM in IBD. The first is "reactive" TDM, in which serum levels and/or antibodies are assessed in the clinical context of inadequate response or secondary loss of response, after failure of a specific therapy.…”

Differential effects of corticosteroids and anti‐TNF on tumor‐specific immune responses: implications for the management of irAEs

“…Tumor‐specific immune activation and tumor‐killing were assessed with co‐culture assays of TILs or PBMCs and autologous tumor cells in the presence of various concentrations of water soluble dexamethasone (D2915, Sigma‐Aldrich/Merck KGaA, Darmstadt, Germany), infliximab (EU/1/13/854/001, Hospira, Hurley, UK) and a mouse IgG1 kappa isotype control (16‐4714‐82, Thermo Fisher Scientific, Waltham, MA). Increasing doses of steroids, including 0.01, 0.02, 0.04 and 0.1 μM (respectively equivalent to the maximum free prednisolone plasma level reached after repeated administration of approximately 10, 25, 50 and 125 mg oral prednisolone) were chosen, whereas infliximab was used at a fixed dose (10 μg/ml) corresponding to a level slightly above the highest range of steady‐state concentrations for the standard infusion dose of 5 mg/kg . During the 24 hr prior to the assays as well as during the co‐culture assays, REP TILs and PBMCs were cultured in RPMI 1640 plus GlutaMAX and 25 mM HEPES supplemented with 10% heat‐inactivated human AB serum, 100 U/ml penicillin and 100 μg/ml streptomycin.…”

“…plasma level reached after repeated administration of approximately 10, 25, 50 and 125 mg oral prednisolone 17,18 ) were chosen, whereas infliximab was used at a fixed dose (10 μg/ml) corresponding to a level slightly above the highest range of steady-state concentrations for the standard infusion dose of 5 mg/kg. 19 During the 24 hr prior to the assays as well as during the co-culture assays, REP TILs and PBMCs were cultured in RPMI 1640 plus GlutaMAX and 25 mM HEPES supplemented with 10% heatinactivated human AB serum, 100 U/ml penicillin and 100 μg/ml streptomycin. Experiments involving dexamethasone, infliximab or the isotype control were conducted by adding the drugs directly in the culture wells at the beginning of the assay.…”

Determination of lower cut‐off levels of adalimumab associated with biochemical remission in Crohn's disease

“…The exclusion criteria were inability to provide consent and inability to adhere to the study protocol. The patients described here belong to a larger IBD cohort, and some descriptive data have been reported previously …”