BACKGROUND AND OBJECTIVES: Ustekinumab (USTE) and vedolizumab (VEDO) are increasingly used in paediatric patients with inflammatory bowel diseases (pIBD). However, data on the usefulness of therapeutic drug monitoring (TDM) in children are scarce. The primary objective of this study was to evaluate the association between disease activity, measured by faecal calprotectin (F-CPT), and serum trough levels (TLs) of USTE and VEDO. Secondary outcomes were to explore factors potentially associated with the outcome and exposure, to determine the optimal USTE or VEDO dose that predicts remission (defined as F-CPT < 250 µg/g), to validate our hypothesis using a proof-of-concept cohort (POCC) and to assess the occurrence of serum antibodies to USTE and VEDO. METHODS: This was a prospective single-centre observational study performed at the University Hospital Motol, Prague, Czech Republic. Of the 87 patients (51 Crohn's disease (CD), 30 ulcerative colitis (UC), and 6 IBD unclassified (IBD-U)), drug serum TLs and antibodies were measured in 282 observations (49 treatment courses) of USTE and 359 observations (38 courses) of VEDO. Serum and stool samples were collected before each study drug application during both the induction and maintenance phases of the treatment throughout the entire study period (January 2020 to June 2024). Clinical and laboratory data were obtained from the nationwide prospective registry CREdIT. Patients with perianal disease and those with previous major bowel surgery were not excluded from the study. As a POCC, we analysed a group of pIBD treated at our centre with anti-TNF agents-adalimumab or infliximab. RESULTS: In a linear multiple regression mixed model, an association was observed between logF-CPT levels and USTE treatment duration (β -0.0010, 95% confidence interval (CI) -0.0015 to -0.0006, p < 0.001) but not with USTE TLs (p = 0.12). VEDO TLs and logF-CPT levels were negatively associated both in the linear (β -0.0173, 95% CI -0.0292 to -0.0053, p = 0.005) and categorical models (p = 0.026), even after adjusting for time. A VEDO TL of 15.1 µg/mL showed the best, though still poor, combination of sensitivity (0.82) and specificity (0.32) to predict F-CPT < 250 µg/g (area under the curve (AUC) 0.56, 95% CI 0.49-0.63). Intensification, induction phase, undetectable TLs, and type of IBD (CD, UC, IBD-U) were not associated with logF-CPT. Slightly elevated anti-drug antibodies were detected in 5 USTE and 16 VEDO observations, with no clinical implications. CONCLUSIONS: TDM of USTE does not appear to be useful in pIBD. TDM of VEDO may assist in therapeutic strategy decisions, although establishing clinically useful cut-offs remains challenging.

• Publikační typ
• časopisecké články MeSH

The aim was to explore factors associated with intestinal tissue levels of anti-TNF alpha (anti-TNF), anti-TNF antibodies, and cytokines in pediatric patients with Crohn Disease (CD). In a prospective exploratory study of CD patients undergoing ileocecal resection or colonoscopy between 6/2020 and 1/2023, we analysed tissue levels of anti-TNF, anti-TNF antibodies, and cytokines (TNF-α, IL-17, IL-1β, IFN-γ) from intestinal biopsies. Mixed-effects regression models, adjusted for potential confounders, were used. Data from 27 CD patients (18 females, 66.7%) were analysed. Fourteen (52%) received adalimumab (ADA) and thirteen received infliximab (IFX), with a median therapy duration of 17 (IQR 4.5-41.5) months. Higher levels of free anti-TNF were found in macroscopically inflamed tissue compared to non-inflamed tissue (β = 3.42, 95% CI 1.05-6.10). No significant association was found between serum and tissue anti-TNF levels (β= -0.06, 95% CI - 0.70-0.58). Patients treated longer with anti-TNF had increased IL-17 levels (β = 0.19, 95% CI 0.05-0.33), independent of disease duration and age. IFN-γ levels were linked with both follow-up duration and anti-TNF length. Our study shows significantly higher free drug levels in inflamed tissue. Long-term anti-TNF treatment has been linked to increased IL-17 levels, suggesting a possible impact on the cytokine response pathway. We did not observe a relationship between serum and tissue anti-TNF levels.

• Klíčová slova
• Biologics, Crohn disease, Inflammatory bowel disease, Paediatrics,
• MeSH
• adalimumab * terapeutické užití   MeSH
• Crohnova nemoc * farmakoterapie   metabolismus   krev   patologie   MeSH
• cytokiny * metabolismus   krev   MeSH
• dítě MeSH
• infliximab * terapeutické užití   MeSH
• lidé MeSH
• mladiství MeSH
• prospektivní studie MeSH
• střeva patologie   účinky léků   MeSH
• střevní sliznice metabolismus   patologie   MeSH
• TNF-alfa * antagonisté a inhibitory   metabolismus   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adalimumab * MeSH
• cytokiny * MeSH
• infliximab * MeSH
• TNF-alfa * MeSH