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

ABSTRACT: Background:Low anti-tumor necrosis factor ? (TNF?) serum concentrations may result in lack of treatment response in patients with inflammatory bowel disease. We determined the anti-TNF? 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-TNF? agents. These findings were not observed in patients with ulcerative colitis. Clinicaltrials.gov identifier [NCT02134054].

SUBMITTER: Carlsen A

PROVIDER: S-EPMC5881967 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Carlsen Arne A Omdal Roald R Leitao Kristian Øgreid KØ Isaksen Kjetil K Hetta Anne Kristine AK Karlsen Lars Normann LN Aabakken Lars L Bolstad Nils N Warren David D Lundin Knut E A KEA Grimstad Tore T

Therapeutic advances in gastroenterology 20180314

<h4>Background</h4>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.<h4>Methods</h4>In a single-center cross-sectional study, we included patients with ulcerative colitis or Crohn's dis ...[more]

PMID: 29623105

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Project description:Introduction: Up to 40% of patients with Crohn's disease do not respond to treatment with anti-TNF or lose response after the initial benefit. Low drug concentrations have been proposed as the main predictor of treatment failure. Our aim was to study the immunological profile and clinical evolution of patients with Crohn's disease according to the anti-TNF dose and serum trough levels. Methods: Crohn's disease patients in remission treated with infliximab or adalimumab at stable doses for at least for 3 months were included. Serum levels of anti-TNF, TNF-α, interferon-γ, and interleukin IL-12, IL-10, and IL-26 were determined in blood samples taken just before drug administration. Patients were classified according to anti-TNF levels below, within, or above the target level range and the use of intensified doses. Clinical evolution at 6 months was analyzed. Results: A total of 62 patients treated with infliximab (8 on intensified schedule) and 49 treated with adalimumab (7 on intensified schedule) were included. All infliximab-treated patients showed levels within the recommended range, but half of adalimumab-treated patients were below the recommended range. A significant negative relationship between body weight and adalimumab levels was observed, especially in patients treated with intensified doses. Patients with infliximab levels over 8 µg/ml presented higher median IL-10 than patients with in-range levels (84.0 pg/ml, interquartile range [IQR] 77.0-84.8 vs. 26.2 pg/mL, IQR 22.6-38.0; p < 0.001), along with lower values of interferon-γ (312.9 pg/ml, IQR 282.7-350.4 vs. 405.6 pg/ml, IQR 352.2-526.6; p = 0.005). Patients receiving intensified versus non-intensified doses of infliximab showed significantly higher IL-26 levels (91.8 pg/ml, IQR 75.6-109.5 vs. 20.5 pg/ml, IQR 16.2-32.2; p = 0.012), irrespective of serum drug levels. Patients with in-range levels of adalimumab showed higher values of IL-10 than patients with below-range levels (43.3 pg/ml, IQR 35.3-54.0 vs. 26.3 pg/ml, IQR 21.6-33.2; p = 0.001). Patients treated with intensified vs regular doses of adalimumab had increased levels of IL-12 (612.3 pg/ml, IQR 570.2-1353.7 vs. 516.4 pg/mL, IQR 474.5-591.2; p = 0.023). Four patients with low adalimumab levels (19%) and four treated with intensified doses were admitted to a hospital during a follow-up compared to none of the patients with levels within the range. Conclusion: Patients with Crohn's disease treated with infliximab and adalimumab exhibit differences in serum levels of cytokines depending on the drug, dose intensification, and steady state trough serum levels.

Project description:IntroductionCrohn's disease (CD) is a chronic and progressive disease in which the long-term management is important. This study sought to assess treatment persistence and dose escalation in the maintenance phase with adalimumab (ADA) or infliximab (IFX) in a Japanese real-world setting.MethodsA retrospective analysis was conducted using the Japan Medical Data Center database. CD patients with either ADA or IFX prescriptions between January 2012 and February 2015 were included. Outcomes of interest were (1) failure in the induction phase (defined as switch or discontinuation) and (2) persistence in the maintenance phase (defined as the absence of switch or discontinuation over 12 months since maintenance initiation).ResultsOverall, 133 patients (53 ADA; 80 IFX) were included. Of them, treatment failed in 26 patients (19.6%) in the induction phase. During the induction phase, there was a trend towards fewer treatment failures with ADA than IFX (88.7% vs. 75.0%; p = 0.051). Of those who completed induction, 64 patients (33 ADA; 31 IFX) had at least 12 months of valid insurance enrolment after the initiation of maintenance and 13 (5 ADA; 8 IFX) had either switch or discontinuation within 12 months after the initiation of maintenance. Probabilities of switch or discontinuation over 12 months after the maintenance date were 15.2% and 20.9% for ADA and IFX groups, respectively (p-log rank = 0.7764).ConclusionJapanese patients have a high primary response to anti-tumor necrosis factor therapy in the real-world setting, in line with the results of clinical trials. This initial therapeutic advantage can be lost during the maintenance phase, leading to dose escalation, treatment switch, or discontinuation. This study suggests that those events occurred in comparable proportions of patients treated with either ADA or IFX. However, these findings should be considered with caution given the retrospective nature and small size of the study.FundingAbbvie GK, Tokyo, Japan.

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

Publications

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

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