Javier Blasco-Alonso

Efficacy and safety of adalimumab in the treatment of Crohn's disease in children

OBJECTIVES to describe the efficacy and safety of adalimumab (ADA) in inducing clinical remission and reducing inflammation of intestinal mucosa in children with Crohn´s disease (CD). METHODS we carried out a descriptive, observational study with all patients diagnosed with CD and treated with ADA between January 2007 and March 2013. Disease activity was determined using the Pediatric Crohn´s Disease Activity Index (PCDAI), and the degree of mucosa inflammation by fecal calprotectin (FC). RESULTS sixteen patients were included. Mean age at diagnosis was 10.6 ± 2.5 years, with a mean age at start of ADA treatment of 12.4 ± 1.8 years, and a median of 1.4 years (IQR 0.5-3) duration from CD diagnosis to start of treatment. Twelve patients were naïve to anti-TNF-a. The PCDAI score at start of ADA treatment was significantly reduced at 12 weeks of follow-up (31.25 IQR 26.8-37.5 vs. 1.2 IQR 0.0-5.0; p = 0.001). Similarly, the FC level decreased at 12 weeks (749 μg/g IQR 514-898 vs. 126 μg/g IQR 67.7-239.2; p = 0.02). Surgery was performed in 4 patients. Adverse events were reported in 4 patients. One patient developed lymphoma at 4 years of ADA treatment in monotherapy. CONCLUSIONS ADA has been shown to be effective in children with moderate-to-severe CD. Treatment benefits should be weighed against side effects. Multicenter longitudinal studies with longer follow-up periods are required to determine the true efficacy and safety of long-term ADA treatment.

La nutrición enteral exclusiva continua siendo el tratamiento de primera línea en la enfermedad de Crohn pediátrica en la era de los biológicos

INTRODUCTION Exclusive enteral nutrition (EEN) has been to be more effective than corticosteroids in achieving mucosal healing without their side effects. OBJECTIVES To determine the efficacy of EEN in terms of inducing clinical remission in newly diagnosed CD children and to study the efficacy of this therapeutic approach in improving the degree of intestinal mucosa inflammation. MATERIALS AND METHODS The medical records of patients with newly diagnosed Crohns disease treated with EEN were reviewed retrospectively. The degree of mucosal inflammation was assessed by fecal calprotectin (FC). Remission was defined as a PCDAI<10. RESULTS Forty patients (24 males) were included, the age at diagnosis was 11.6 ± 3.6 years. Of the 34 patients who completed the EEN period, 32 (94% per-protocol analysis) achieved clinical remission. This percentage fell to 80% in the intention-to-treat analysis. The compliance rate was 95%. Duration of EEN was 6.42 weeks (IQR 6.0-8.14). FC was significantly higher in patients with moderate and severe disease. Median baseline FC levels (680 μg/g) decreased significantly to 218 μg/g (P<0.0001) after EEN. We found a statistically significant correlation between FC and PCDAI (rho=0.727; P<0.0001). Early use of thiopurines (< 8 weeks) versus subsequent use was not associated with improved outcomes during the follow-up. CONCLUSIONS EEN administered for 6-8 weeks is effective for inducing clinical remission and decreasing the degree of mucosal inflammation. We did not find differences in terms of maintenance of remission in patients treated early with thiopurines.

Successful Mercaptopurine Usage Despite Azathioprine-Induced Pancreatitis in Paediatric Crohn's Disease

BACKGROUND Azathioprine [AZA] and mercaptopurine [MP] are recommended for maintenance of steroid-free remission in children with Crohn`s disease [CD]. Azathioprine-induced pancreatitis, an idiosyncratic and major side effect, has been considered as an absolute contraindication for the use of a second thiopurine in IBD patients. MATERIALS AND METHODS We describe two children with CD in whom MP were successfully trialled after a confirmed azathioprine-induced pancreatitis, being well tolerated in both cases. RESULTS Two boys [13 and 10 years old] started exclusive enteral nutrition after diagnosis of moderate (Pediatric Crohns Disease Activity Index [wPCDAI] = 45) and mild [wPCDAI = 35] CD. Both developed an acute mild to moderate pancreatitis after 2 and 3 weeks, respectively, of AZA treatment but recovered fully in hospital after AZA withdrawal. They started on MP treatment without any adverse effect. They were tested for the presence of polymorphisms 238G>C, 460G>A, and 719A>G in the TPMT gene and 94C>A and 21>C in the ITPase. Both patients were wild-type for all tested polymorphisms. CONCLUSIONS Azathioprine-induced acute pancreatitis should not be considered as an absolute contraindication for the use of MP. Further investigation is required to create a better understanding of the mechanism underlying the adverse events and to allow more possibilities for personalised therapy.

Oxidative Stress Response After Cardiac Surgery in Children

Over the last 20 years, researchers have accumulated extensive evidence to support the theory that production of oxidants and reactive oxygen species in the postischemic heart is considerably elevated by different types of interaction between the heart and endothelial cells. The most accepted theory is the one that implicates oxidative stress with production of reactive oxygen species. Heart surgery and, specifically, cardiopulmonary bypass (CPB) is an ideal situation for studying ischemia-reperfusion injury as long-lasting ischemia occurs followed by controlled reperfusion. The objective of this study was to analyze the changes in measures of oxidative stress and lipid peroxidation in pediatric patients who underwent cardiovascular surgery in order to shed light on the management of ischemia-reperfusion in future surgery. The study included patients younger than 15 years who underwent congenital heart surgery with CPB. Malondialdehyde (MDA), total glutathione (GST), and glutathione in its reduced (GSH) and oxidized (GSSG) states were measured (nmol/mg of protein). Samples for analysis were taken in the preoperative period (PRE), the immediate postoperative period (PO1), and the late postoperative period (PO2) after 18 to 20 hours. New variables representing the percentage change in oxidative stress between PRE and PO1 (_p1), PO1 and PO2 (_p2), and PRE and PO2 (_p3) were derived to investigate the correlation between oxidative stress and time in relation to surgery. Thirty children (19 girls [63.3%]) were included with a median [interquartile range] age of 4.1 [2.7-8.0] years. The surgery types were as follows: 11 closures of atrial septal defects, 2 pulmonary stenosis interventions, 3 total corrections of tetralogy of Fallot, 3 corrections of atrioventricular canal defect, 6 closures of ventricular septal defects, 2 aortic stenosis interventions, 2 corrections of univentricular hearts (one using the Glenn technique and the other using the Fontan technique), and 1 surgical correction of transposition of the great arteries. The median total CPB time was 79 [52.5-125.5] minutes, which was slightly lower than in other series, and the median aortic clamp time was 38.5 [22-59] min. Table 1 shows that the production of MDA was significantly increased and the production of different states of glutathione significantly reduced at each postoperative time point compared with baseline. The Friedman nonparametric test was used to compare the measures of the antioxidant system (glutathione states) and lipid peroxidation (MDA), with statistically significant differences (P < .001). After multiple comparisons with the Wilcoxon test and application of the Bonferroni correction, MDA and GST differed significantly from each other (P < .016) at the 3 time points. CPB time showed a certain significant correlation with some of the variables of oxidative stress (Table 2). Partial oxygen pressure in blood (to determine whether cyanosis associated with heart disease had any influence) did not correlate with changes in the measures of oxidative stress or lipid peroxidation. Knowledge of oxidative stress in heart surgery to date has been based largely on animal models. It is not known with any certainty which enzymatic redox systems have greatest influence on systemic inflammatory response. In the pediatric CPB model in this study, the genesis of oxidative stress and lipid peroxidation was observed. These reached a maximum after aortic clamping and improved after 24 hours without returning to normal values. There were significant differences between PRE and PO2. Reactive oxygen species are highly toxic metabolites that lead to lipid peroxidation and damage to cell membranes, in turn leading to capillary leakage and the production of shock-induced adhesion molecules. This process can activate macrophages in the liver and cause the synthesis, when in a state of shock, of proinflammatory mediators such as tumor necrosis factor and interleukin. Lipid peroxidation is an important cause of oxidative damage of cell membranes and cell death. MDA is a good indicator of oxidative stress and an end product of lipid peroxidation. Glutathione is crucial as a cell defense mechanism against oxidative stress. In addition to its antioxidant activity, GST plays an important role in transmembrane amino acid transport, protein synthesis and degradation, gene regulation, and cell redox regulation. GST mobilization has been shown to be increased in septic animals, with increased usage, by analogy with that seen in our model of CPB. Therefore, the possibility of modulating the availability of GST may be an attractive strategy but studies have yet to be conducted with clinically relevant outcomes. A multivariate analysis (CPB time, clamp time, and age) was performed by linear regression to identify the factors that actually influence the laboratory indicators of oxidative stress and lipid peroxidation. Longer duration of CPB correlated with greater glutathione deficiency after 18 to 20 hours. This was also reflected in the assessment of the percentage increase in glutathione between PRE and PO2. One of the limitations of this study is that the sample size is small due to the nature of the surgery studied. Investigation of oxidative stress in heart surgery offers a unique opportunity to make observations in clinically relevant conditions,

La composición de la microbiota duodenal en niños con enfermedad celíaca activa está influenciada por el grado de enteropatía

OBJECTIVES To establish whether the duodenal mucosa microbiota of children with active coeliac disease (CD) and healthy controls (HC) differ in composition and biodiversity. MATERIAL AND METHODS Samples of duodenal biopsies in 11 CD patients were obtained at diagnosis, and in 6 HC who were investigated for functional intestinal disorders of non-CD origin. Total duodenal microbiota and the belonging to the genus Lactobacillus using PCR-denaturing gradient gel electrophoresis (DGGE) were analysed. The banding patterns obtained in the resulting gels were analysed to determine the differences between the microbiota of CD patients and HC (FPQuest 4.5) while environmental indexes (richness, diversity and habitability) were calculated with the Past version 2.17 program. RESULTS The intestinal microbiota of patients with Marsh 3c lesion showed similarity of 98% and differs from other CD patients with other type of histologic lesion as Marsh3a, Marsh3b and Marsh2. The main differences were obtained in ecological indexes belonging to the genus Lactobacillus, with significant richness, diversity and habitability reduction in CD patients. In CD bands were categorized primarily with Streptococcus, Bacteroides and E.coli species. In HC the predominant bands were Bifidobacterium, Lactobacillus and Acinetobacter, though the Streptococcus and Bacteroides were lower. CONCLUSIONS The celiac patients with major histological affectation presented a similar microbiota duodenal. The ecological indexes applied to the genus Lactobacillus were significantly reduced in CD.

Niveles de neopterina y síndrome de respuesta inflamatoria sistémica en pacientes críticos pediátricos

INTRODUCTION Neopterin and biopterin are sub-products of redox reactions, which act as cofactors of enzymes responsible for nitric oxide production. The hypothesis is presented that plasma neopterin and biopterin evolve differently during the first days in a critically ill child. METHODS A single-centre prospective observational study was conducted on patients 7 days to 14 years admitted to our Paediatric Intensive Care Unit (PICU) and that met Systemic inflammatory response syndrome (SIRS) criteria. Neopterin and biopterin levels, as well as other acute phase reactants, were collected at admission and at 24 h. RESULTS A total of 28 patients were included, of which 78.9% were male, The median age was 5.04 years (interquartile range [IQR] 1.47-10.26), and PRISM II 2.0% (IQR 1.1-5.0). Mechanical ventilation (MV) was used in 90% of patients, with a median duration of 6.0 hrs (IQR 3.7-102.0). The median length of stay in PICU was 5.0 days (IQR 2.7-18.7), maximum VIS mean of 0 (IQR 0-14). Baseline neopterin level was 2.3±1.2 nmol/l and at 24 h it was 2.3±1.4 nmol/l. Baseline biopterin was 1.3±0.5 nmol/l and 1.4±0.4 nmol/l at 24 h. Neopterin levels were significantly higher in patients with PICU length of stay > 6 days (P=.02), patients who needed MV >24 h (P=.023), and those who developed complications (P=.05). Neopterin correlates directly and is statistically significant with the duration of MV (rho=.6, P=.011), PICU length of stay (rho=.75, P<.0001), and VIS (rho=.73, P=.001). Additionally, biopterin directly correlates with the PRISM (rho=.61, P=.008). DISCUSSION There is a higher neopterin level when there is a longer PICU stay, higher VIS score, longer time on MV, and occurrence of complications, indicating the involvement of an activation of the cellular immune system.

Trasplante de microbiota fecal en niño con enfermedad inflamatoria intestinal de inicio muy precoz

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P355 Efficacy and safety of oral tacrolimus for the treatment of severe steroid-resistant ulcerative colitis

Background: Ulcerative colitis (UC) that occurs in childhood is usually an extensive colitis or pancolitis and is most often associated with severe steroid-refractory flares. Tacrolimus is a second-line drug therapy indicated in patients with severe flare that is unresponsive to steroid therapy. Objective: to describe our experience of the efficacy and safety of oral tacrolimus treatment in children with steroid-resistant severe ulcerative colitis. Methods: We conducted a retrospective study that included all patients under 18 years suffering from serious flares of ulcerative colitis treated with oral tacrolimus during the period between January 1998 and October 2011. All patients received an oral dose of 0.12mg/kg/day. The drug dosage was adjusted to achieve a plasma trough level of tacrolimus between 5 and 10 ng/mL. For statistical analysis and preparation of the survival curves we used the SPSS version 17.0 for Windows program. A p value <0.01 was considered as significant. Results: A total of 10 patients, 7 women were included. Seven patiens were in their first attack of the disease. The mean age was 9.4±4.9 years-old, and the time course of the disease of 1.3 months (IQR, 1 to 5.7m). The initial clinical response was achieved in 6 patients. All nonresponders required colectomy within one month after initiation of treatment. In the subgroup that responded initially, 2 of 6 patients required colectomy, one at 10 months after starting treatment and the other one at 6 years and 4 months after the immunomodulatory therapy was stopped. Plasma trough levels of tacrolimus were 4 13 ng/ml. The median duration of treatment in the responder group was 4.7 months (IQ, 3.7 to 6) versus 0.23 months in the nonresponders (IQ 0.13 to 0.8m), p = 0.01. Tacrolimus was well tolerated in all cases. Conclusions: Tacrolimus is useful in inducing remission in patients with acute, severe steroid-resistant flares of ulcerative colitis. It can change the course of the disease, and it can prevent or delay surgery allowing to prepare the patient and his family for a probable surgery.