Objective. To evaluate the significance of therapeutic drug monitoring of adalimumab (ADA) concentration levels and antibodies to it in inflammatory bowel disease (IBD) in children. Patients and methods. In this study, 103 children with IBD (24 patients with ulcerative colitis (UC) and 79 with Crohn’s disease (CD)) aged 3–18 years were examined during maintenance therapy with ADA (100 mg/mL in 0.4 mL). Body weight, duration of disease and therapy, use of azathioprine (AZA), achievement of clinical and endoscopic remission, albumin levels, residual levels of ADA and antibodies to the drug, circulating cytokine levels in serum were assessed. Results. A significant decrease in ADA levels in children in the absence of clinical remission in CD (5.21 [3.32; 7.43] μg/mL in remission) and in UC (2.42 [0.42; 4.51] μg/mL, p = 0.001) was shown. A high-quality separation model for residual ADA levels for exacerbation/remission conditions for clinical and endoscopic activity for children with CD and UC was obtained through ROC-analysis. The minimum residual ADA levels for maintaining clinical remission in children with CD were 8.1 μg/mL and 10.5 μg/mL for mucosal healing. In children with UC, as well as in children weighing <40 kg, these levels were higher. The formation of antibodies to ADA was minimal; combination therapy with AZA showed no efficacy. Key cytokines correlating with ADA concentration were interleukins IL-6, -13, -31, -27, -9, and tumor necrosis factor-α. Conclusion. To improve the efficacy of ADA therapy in children with IBD, therapeutic drug monitoring should be performed, considering the nosology and body weight of the child, as well as the goal of therapy (clinical and endoscopic remission). Key words: inflammatory bowel disease, Crohn’s disease, ulcerative colitis, adalimumab, therapeutic drug monitoring, tumor necrosis factor-α, cytokine profile, azathioprine
Introduction. The effectiveness of the use of TNF inhibitors in patients with inflammatory bowel diseases (IBD) has been shown. 20-40% of patients are known to fail to respond to received therapy, and 10-30% of patients experience a loss of effect by the year of therapy. Objective is to evaluate the information content of therapeutic drug monitoring (TDM) for effective treatment with TNF blockers (infliximab - IFX, adalimumab - ADA) in IBD children. Materials and methods. There were examined seventy four children on IFX therapy including 66 children on ADA therapy. The age of the children ranged from 3.4 to 18 years. Residual levels of IHF and ADA were determined using a lateral flow immunoassay. Statistical data processing was performed using the Statistica 10.0, SPSS 16 software. Differences between groups were assessed using the nonparametric Mann-Whitney U test. Results. IFX levels (less than 3 µg/ml) were detected in 64% of cases, ADA (less than 5 µg/ml) in 21% of cases. The residual level of IFX and ADA in remission significantly exceeded the level of drugs in groups of children in exacerbation. An inverse relationship was observed between the residual level of IFX (r = -0.68, p = 0.000) and ADA (r = -0.31, p = 0.000) and the number of days after drug administration. Anti-IFX antibodies were found in 27.3% in the exacerbation group and in 5.8% in remission (p < 0.001). Antibodies to ADA in children with IBD were found in 4 patients with a low concentration of the drug (2.57 ± 0.45 µg/ml) in the serum in a state of exacerbation. In patients on anti-TNF therapy, empirical dose selection revealed a residual level lower than in children in whom dose adjustment was carried out taking into account the residual concentration of drugs. Conclusion. The use of TDM TNF blockers in combination with the determination of antibodies to drugs can significantly increase the effectiveness of therapy in IBD children.
Background The transcription factor NF-kB is a regulator of innate and adaptive immunity through the activation of various pro and anti-inflammatory mediators. The aim of this study was to assess the prognostic value of changes in the level of NF-kB translocation in lymphocyte populations in response to infusion of TNF blockers in children with IBD. Methods There were examined 44 children with IBD (27-CD, 17-UC) and 20 conditionally healthy children aged 3–18 years. Patient status (exacerbation, remission) was assessed by the PUCAI (UC) and PCDIA (CD) indices. There were determined the percentage of cells with NF-kB translocation in populations CD3+CD4+ (Th), CD3+CD8+(Tc), CD3-CD19+ (B cells), CD3-CD16 / 56+(NK cells), CD3+CD4+CD161+ (Th17), CD3+CD4+CD25highCD127low (Tregs) with NF-kB translocation kit using flow cytometry ImageStreamX MKII (Amnis) before infusion of TNF blockers (infliximab, adalimumab), one day after infusion and after 6 months therapy. Statistical evaluation was performed using a nonparametric Mann–Whitney test. The results are presented as the median per cent of cells with NF-kB translocation (Me [Q 0.25-Q 0.75]). Results It was observed an increased level of NF-kB translocation in B-lymphocytes (Me 64 [53–81] – Me 38 [33–45]; p = 6 × 10−5), NK cells (Me 40 [33 -55] – Me 21 [18–26]; p = 4x10-4), Tc (Me 20 [15–24] – Me 16 [13–17]; p = 0.03), Th17 (Me 23 [21–28] – Me 18 [16–19]; p = 0.005) in children with exacerbation compared with remission. The level of NF-kB translocation in populations of lymphocytes during the period of clinical endoscopic remission did not differ from conditionally healthy children. The correlation between the level of NF-kB translocation and the number of cells in the studied lymphocyte populations was not found. In children with IBD after infusion of TNF blockers, a decrease the level of NF-kB translocation in NK cells was observed (Me 27.3 [23.5–39.1] – Me 17.7 [16.5–26.5]; p = 0,03) and an increase in Tregs (Me 18.9 [16.91–20.8] – Me 26.9 [19.4–31.9]; p = 0.0015). Conclusion The level of NF-kB translocation reflects the functional activity of major and small populations of lymphocytes. An increase in activity of Tregs in response to the administration of TNF blockers allows predicting a positive outcome from therapy over the next 6 months. If there is no Tregs reaction in response to the administration of TNF blockers, treatment tactics should be reassessed.
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