Efficacy of Combined Initial Treatment of Methotrexate with Infliximab in Pediatric Crohn's Disease: A Pilot Study.

BACKGROUND: The combination of antitumor necrosis factor-alpha (TNF-α) agents with immunomodulators (IMMs) is a common treatment for pediatric Crohn's disease (CD). Although methotrexate (MTX) can be a first-line medication as an IMM, most clinicians in real-life practice, especially in South Korea, are more familiar with thiopurines. This study aimed to compare the efficacy and immunogenicity of MTX and azathioprine (AZA) as concurrent therapies for pediatric CD. METHODS: In this pilot study, 29 newly diagnosed pediatric patients with moderate-to-severe CD were randomized to receive either MTX (n = 15) (15 mg/body surface area (BSA) per week) or oral AZA (n = 14) (0.5 mg/kg per day) in combination with Infliximab (IFX). The primary outcomes were the proportion of patients in endoscopic, biochemical, and transmural remission after 14 and 54 weeks of IFX therapy. The trough levels (TLs) of IFX and anti-drug antibody (ADA) levels were also compared. RESULTS: Among the 29 patients, there were no significant differences in the biochemical (p = 1.0 at week 14, p = 0.45 at week 54), endoscopic (p = 0.968 at week 14, p = 0.05 at week 54), or transmural (p = 0.103 at week 54) remission rates between the two medications during the concurrent therapy. Additionally, the trends in the IFX trough and ADA levels over time during the treatments were similar for both medications, with no significant differences (p = 0.686, p = 0.389, respectively). CONCLUSION: The MTX showed comparable efficacy to the AZA in pediatric CD patients with moderate-to-severe disease. This effectively maintained adequate IFX levels and reduced ADA production. Therefore, although additional large-scale clinical trials are needed, this study demonstrated that either MTX or AZA can be selected as IMMs in the concurrent treatment of pediatric CD, depending on individual medical institutions' circumstances.

Increased monocyte abundance as a marker for relapse after discontinuation of biologics in inflammatory bowel disease with deep remission.

Monocytes are involved in the upstream inflammatory process in the immune reaction in inflammatory bowel disease (IBD). Patients with IBD who discontinued biologics have been found to relapse, even after checking for deep remission. This study investigated whether monocytes could act as a predictor of relapse in patients who experienced relapse after the discontinuation of biologics. To this end, pediatric patients (<19 years old, n = 727) diagnosed with IBD from January 2003 to December 2021 were retrospectively reviewed. Clinical features, monocytes, and disease activity at the time of discontinuing biologics were evaluated by dividing patients into a relapsed group and a non-relapsed group after discontinuing biologics. The percentage of monocytes (8.65% vs. 6.42%, P < 0.001), the absolute monocyte count (614.79 cells/µL vs. 381.70 cells/µL, P < 0.001), and the monocyte/polymorphonuclear leukocyte (PMN) ratio (0.18 vs. 0.11, P < 0.001) at the time of discontinuation were significantly higher in patients who experienced relapse. As a result of multivariate analysis, the monocyte percentage (odds ratio: 2.012, P < 0.001) and monocyte/PMN ratio (odds ratio: 4.320E+14, P = 0.002) were evaluated as risk factors for relapse. Diagnostic capability was confirmed using area under operating characteristic curve (0.782) of the monocyte percentage for assessing the relapse within 6 months with cutoff value of 8.15% (P < 0.001). The findings presented in this study indicate that the patients with high monocyte counts experienced relapse after the discontinuation of biologics. A monocyte percentage of over 8.15% in the blood at the time of discontinuation was found to be associated with a high probability of relapse within 6 months, even in deep remission.

Cytokine Profile at Diagnosis Affecting Trough Concentration of Infliximab in Pediatric Crohn's Disease.

BACKGROUND: This study aims to measure the concentration of cytokines produced during the inflammation process to investigate if there are any differences in response to treatment of pediatric Crohn's disease and to determine if the initial tumor necrosis factor-alpha (TNF-α) level affected the trough concentration of infliximab (IFX). METHODS: This study included 30 pediatric patients with moderate-to-severe Crohn's disease. At the time of diagnosis, blood samples were collected for the measurement of cytokines (IL-6, TNF-α, IL-17A, and IL-10). Blood samples were extracted from patients who had begun IFX treatment to measure the IFX trough concentration immediately before the fourth dose administration. RESULTS: All cytokines (TNF-α, IL-6, IL-10, and IL-17A) were significantly higher in patients who did not achieve clinical or biochemical remission than in those who did (p = 0.027, 0.006, 0.017, 0.032, respectively). TNF-α had a negative correlation with the IFX trough concentration (Pearson coefficient = -0.425, p = 0.034). The diagnostic capability of the initial TNF-α concentration to predict under the therapeutic IFX trough concentration, defined as less than 3 µg/mL, had an area under the receiver operating characteristic of 0.730 (p = 0.049). The TNF-α concentration was set at 27.6 pg/mL as the cutoff value. CONCLUSIONS: Measuring cytokines at the time of diagnosis can be used to predict the treatment response. Measuring the initial TNF-α concentration may help to predict the treatment response to IFX. When the initial TNF-α concentration is greater than 27.6 pg/mL, a higher dose of IFX may be more appropriate than routinely administering 5 mg/kg of IFX to maintain the therapeutic concentration.

Surfactant Treatment Shows Higher Correlation Between Ventilator and EIT Tidal Volumes in an RDS Animal Model.

Neonatal respiratory distress syndrome (RDS) is a condition of pulmonary surfactant insufficiency in the premature newborn. As such, artificial pulmonary surfactant administration is a key treatment. Despite continued improvement in the clinical outcomes of RDS, there are currently no established bedside tools to monitor whether pulmonary surfactant is effectively instilled throughout the lungs. Electrical impedance tomography (EIT) is an emerging technique in which physiological functions are monitored on the basis of temporal changes in conductivity of different tissues in the body. In this preliminary study, we aimed to assess how EIT tidal volumes correlate with ventilator tidal volumes in an RDS animal model, namely untreated, surfactant-treated, and normal control rabbit pups. Tidal volumes were measured simultaneously on an EIT system and a mechanical ventilator and compared at different peak inspiratory pressures. The linear correlation between tidal volumes measured by EIT and by ventilator had an R 2 of 0.71, 0.76 and 0.86 in the untreated, surfactant-treated, and normal control groups, respectively. Bland-Altman analysis showed a good correlation between the measurements obtained with these two modalities. The intraclass correlation coefficients (ICC) between ventilator tidal volume and EIT tidal volume were 0.83, 0.87, and 0.93 (all p < 0.001) in the untreated, surfactant-treated, and normal control groups, respectively, indicating that the higher ICC value, the better inflated status of the lung. In conclusion, we demonstrated that EIT tidal volume correlated with ventilator tidal volume. ICC was higher in the surfactant treated group.