@article {10761, title = {Causes of Treatment Failure in Children With Inflammatory Bowel Disease Treated With Infliximab: A Pharmacokinetic Study.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {68}, year = {2019}, month = {2019 Jan}, pages = {37-44}, abstract = {

OBJECTIVES: Anti-tumor necrosis factor antibodies have led to a revolution in the treatment of inflammatory bowel diseases (IBD); however, a sizable proportion of patients does not respond to therapy. There is increasing evidence suggesting that treatment failure may be classified as mechanistic (pharmacodynamic), pharmacokinetic, or immune-mediated. Data regarding the contribution of these factors in children with IBD treated with infliximab (IFX) are still incomplete. The aim was to assess the causes of treatment failure in a prospective cohort of pediatric patients treated with IFX.

METHODS: This observational study considered 49 pediatric (median age 14.4) IBD patients (34 Crohn disease, 15 ulcerative colitis) treated with IFX. Serum samples were collected at 6, 14, 22 and 54 weeks, before IFX infusions. IFX and anti-infliximab antibodies (AIA) were measured using enzyme linked immunosorbent assays. Disease activity was determined by Pediatric Crohn{\textquoteright}s Disease Activity Index or Pediatric Ulcerative Colitis Activity Index.

RESULTS: Clinical remission, defined as a clinical score <10, was obtained by 76.3\% of patients at week 14 and by 73.9\% at week 54. Median trough IFX concentration was higher at all time points in patients achieving sustained clinical remission. IFX levels during maintenance correlated also with C-reactive protein, albumin, and fecal calprotectin. After multivariate analysis, IFX concentration at week 14 >3.11 μg/mL emerged as the strongest predictor of sustained clinical remission. AIA concentrations were correlated inversely with IFX concentrations and directly with adverse reactions.

CONCLUSIONS: Most cases of therapeutic failure were associated with low serum drug levels. IFX trough levels at the end of induction are associated with sustained long-term response.

}, issn = {1536-4801}, doi = {10.1097/MPG.0000000000002112}, author = {Naviglio, Samuele and Lacorte, Doriana and Lucaf{\`o}, Marianna and Cif{\`u}, Adriana and Favretto, Diego and Cuzzoni, Eva and Silvestri, Tania and Pozzi Mucelli, Martina and Radillo, Oriano and Decorti, Giuliana and Fabris, Martina and Bramuzzo, Matteo and Taddio, Andrea and Stocco, Gabriele and Alvisi, Patrizia and Ventura, Alessandro and Martelossi, Stefano} } @article {10764, title = {Changing Epidemiology of Liver Involvement in Children With Celiac Disease.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {68}, year = {2019}, month = {2019 Apr}, pages = {547-551}, abstract = {

OBJECTIVES: Available data indicate that liver involvement is present in a significant proportion of children with celiac disease (CD) at the diagnosis (elevated transaminases 15\%-57\%, autoimmune liver disease 1\%-2\%). We sought to evaluate prevalence, clinical course, and risk factors for liver involvement in a large cohort of children with CD.

METHODS: Children (age 0-18 years) diagnosed with CD from March 2010 to April 2016 were enrolled. Liver involvement was considered to be present when alanine transaminase (ALT) levels were >40 U/L (hypertransaminasemia [HTS]). Patients with HTS were re-evaluated after at least 12 months of a gluten-free diet.

RESULTS: CD was diagnosed in 806 patients during the study period; of these, ALT levels were available for 700 patients (86.9\%), and were elevated in 27 (3.9\%, HTS group); median ALT and aspartate transaminase levels in the HTS group were 57 U/L (interquartile range 49-80 U/L) and 67 U/L (interquartile range 53-85 U/L), respectively. Younger age, malabsorption symptoms, and low hemoglobin or ferritin were significantly more common in the HTS group at univariate analysis. At multivariate analysis, only age <=4.27 years correlated with risk of liver involvement (odds ratio 3.73; 95\% confidence interval: 1.61-8.66). When retested on a gluten-free diet, all but 3 patients normalized ALT levels; of these, 1 was diagnosed with sclerosing cholangitis.

CONCLUSIONS: Liver involvement in celiac children is now less frequent than previously reported, possibly due to changing CD epidemiology. Younger age is the only risk factor. Associated autoimmune liver disease is rare.

}, issn = {1536-4801}, doi = {10.1097/MPG.0000000000002209}, author = {Benelli, Elisa and Naviglio, Samuele and De Leo, Luigina and Stera, Giacomo and Giangreco, Manuela and Ronfani, Luca and Villanacci, Vincenzo and Martelossi, Stefano and Ventura, Alessandro and Not, Tarcisio} } @article {8079, title = {Coeliac disease in the ERA of the new ESPGHAN and BSPGHAN guidelines: a prospective cohort study.}, journal = {Arch Dis Child}, year = {2015}, month = {2015 Nov 17}, abstract = {

OBJECTIVE: To evaluate the consequences of the last European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) guidelines for the diagnosis of coeliac disease (CD) by means of a prospective study.

DESIGN: Prospective cohort study.

SETTING: Institute for Maternal and Child Health IRCCS Burlo Garofolo (Trieste, Italy).

PATIENTS: Children diagnosed with CD without a duodenal biopsy (group 1), following the last ESPGHAN and BSPGHAN guidelines, and children diagnosed with a duodenal biopsy, matched for sex, age and year of diagnosis (group 2), were prospectively enrolled over a 3-year period. All patients were put on a gluten-free diet (GFD) and were followed up for clinical conditions and laboratory testing at 6 months every year since diagnosis (median follow up: 1.9 years).

OUTCOME MEASURES: Resolution of symptoms, body mass index, laboratory testing (haemoglobin, anti-transglutaminase IgA), adherence to a GFD, quality of life, and supplementary post-diagnosis medical consultations.

RESULTS: 51 out of 468 (11\%) patients were diagnosed without a duodenal biopsy (group 1; median age 2.1 years) and matched to 92 patients diagnosed with a biopsy (group 2; median age 2.4 years). At the end of follow-up the two groups were statistically comparable in terms of clinical and nutritional status, anti-transglutaminase IgA antibody titres, quality of life, adherence to a GFD, and number of supplementary medical consultations.

CONCLUSIONS: On the basis of this prospective study, diagnosis of CD can be reliably performed without a duodenal biopsy in approximately 11\% of cases. At least during a medium-term follow-up, this approach has no negative consequences relating to clinical remission, adherence to diet, and quality of life of children with CD.

}, issn = {1468-2044}, doi = {10.1136/archdischild-2015-309259}, author = {Benelli, Elisa and Carrato, Valentina and Martelossi, Stefano and Ronfani, Luca and Not, Tarcisio and Ventura, Alessandro} } @article {1864, title = {A common genetic background could explain early-onset Crohn{\textquoteright}s disease.}, journal = {Med Hypotheses}, volume = {78}, year = {2012}, month = {2012 Apr}, pages = {520-2}, abstract = {

Crohn{\textquoteright}s disease (CD) is a multifactorial disease, in which environmental, microbial and genetic factors play important roles. CD is characterized by a chronic granulomatous inflammation by necrotic scarring with aspects of full-thickness wall. In spite of affecting mainly young adults, sometimes, CD can be present in the first year of life (early onset Crohn disease, EOCD) showing an unpredictable course and being often more severe than at older ages. In this paper we propose the hypothesis that EOCD patients should be analyzed using a Mendelian approach with family studies aimed to identify new loci directly involved in the early onset Crohn{\textquoteright}s disease. So we will leave the classic association study approach used until now for the identification of genes responsible for susceptibility to CD and propose linkage family analysis as alternative and powerful tool for the identification of new genetic variants associated with familiar cases of EOCD.

}, keywords = {Crohn Disease, Genetic Linkage, Genetic Predisposition to Disease, Humans, Models, Biological}, issn = {1532-2777}, doi = {10.1016/j.mehy.2012.01.023}, author = {Bianco, Anna Monica and Zanin, Valentina and Girardelli, Martina and Magnolato, Andrea and Martelossi, Stefano and Martellossi, Stefano and Tommasini, Alberto and Marcuzzi, Annalisa and Crovella, Sergio} } @article {1596, title = {Compliance with the gluten-free diet: the role of locus of control in celiac disease.}, journal = {J Pediatr}, volume = {158}, year = {2011}, month = {2011 Mar}, pages = {463-466.e5}, abstract = {

OBJECTIVES: To verify whether subjects with celiac disease (CD) have a different locus of control (LoC) compared with healthy subjects, and to evaluate the relationship between LoC and compliance with a prescribed gluten-free diet (GFD) and quality of life (QoL).

STUDY DESIGN: We studied 156 subjects on a GFD (mean age, 10 years) and 353 healthy controls (mean age, 12 years). All subjects completed tests on the Nowicki-Strickland Locus of Control Scale; the subjects with CD also completed a questionnaire to measure compliance with dietary treatment and the disease{\textquoteright}s impact on QoL.

RESULTS: There was no difference in LoC values between patients with CD and controls. Subjects with CD with good dietary compliance had a more internal LoC compared with those who were not compliant (P = .01). Patients who reported a satisfactory QoL had a more internal LoC compared with those who reported negative affects on QoL due to CD (P = .01).

CONCLUSIONS: Our study confirms the usefulness of the LoC concept for identifying those patients who might be at risk for dietary transgression. Given the enhanced, psychological, and social well being that can result from adherence to a GFD, educational and psychological support can help internalize the LoC in those patients at risk for dietary transgression.

}, keywords = {Adolescent, Age Factors, Case-Control Studies, Celiac Disease, Child, Diet, Gluten-Free, Female, Humans, Internal-External Control, Italy, Male, Patient Compliance, Quality of Life}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2010.08.034}, author = {Bellini, Anna and Zanchi, Chiara and Martelossi, Stefano and Di Leo, Grazia and Not, Tarcisio and Ventura, Alessandro} } @article {1741, title = {Cryptic genetic gluten intolerance revealed by intestinal antitransglutaminase antibodies and response to gluten-free diet.}, journal = {Gut}, volume = {60}, year = {2011}, month = {2011 Nov}, pages = {1487-93}, abstract = {

BACKGROUND AND OBJECTIVE: Antitransglutaminase (anti-TG2) antibodies are synthesised in the intestine and their presence seems predictive of future coeliac disease (CD). This study investigates whether mucosal antibodies represent an early stage of gluten intolerance even in the absence of intestinal damage and serum anti-TG2 antibodies.

METHODS: This study investigated 22 relatives of patients with CD genetically predisposed to gluten intolerance but negative for both serum anti-TG2 antibodies and intestinal abnormalities. Fifteen subjects were symptomatic and seven were asymptomatic. The presence of immunoglobulin A anti-TG2 antibodies in the intestine was studied by creating phage-antibody libraries against TG-2. The presence of intestinal anti-TG2 antibodies was compared with the serum concentration of the intestinal fatty acid-binding protein (I-FABP), a marker for early intestinal mucosal damage. The effects of a 12-month gluten-free diet on anti-TG2 antibody production and the subjects{\textquoteright} clinical condition was monitored. Twelve subjects entered the study as controls.

RESULTS: The intestinal mucosa appeared normal in 18/22; 4 had a slight increase in intraepithelial lymphocytes. Mucosal anti-TG2 antibodies were isolated in 15/22 subjects (68\%); in particular symptomatic subjects were positive in 13/15 cases and asymptomatic subjects in 2/7 cases (p=0.01). No mucosal antibodies were selected from the controls{\textquoteright} biopsies. There was significant correlation between the presence of intestinal anti-TG2 antibodies and positive concentrations of I-FABP (p=0.0008). After a gluten-free diet, 19/22 subjects underwent a second intestinal biopsy, which showed that anti-TG2 antibodies had disappeared in 12/15 (p=0.002), while I-FABP decreased significantly (p<0.0001). The diet resolved both extraintestinal and intestinal symptoms.

CONCLUSIONS: A new form of genetic-dependent gluten intolerance has been described in which none of the usual diagnostic markers is present. Symptoms and intestinal anti-TG2 antibodies respond to a gluten free-diet. The detection of intestinal anti-TG2 antibodies by the phage-antibody libraries has an important diagnostic and therapeutic impact for the subjects with gluten-dependent intestinal or extraintestinal symptoms. Clinical trial number NCT00677495.

}, keywords = {Adolescent, Adult, Antibodies, Anti-Idiotypic, Asymptomatic Diseases, Celiac Disease, Child, Child, Preschool, Diet, Gluten-Free, Fatty Acid-Binding Proteins, Female, Genetic Predisposition to Disease, GTP-Binding Proteins, Health Status, Humans, Intestinal Mucosa, Male, Middle Aged, Peptide Library, Transglutaminases, Young Adult}, issn = {1468-3288}, doi = {10.1136/gut.2010.232900}, author = {Not, Tarcisio and Ziberna, Fabiana and Vatta, Serena and Quaglia, Sara and Martelossi, Stefano and Villanacci, Vincenzo and Marzari, Roberto and Florian, Fiorella and Vecchiet, Monica and Sulic, Ana-Marija and Ferrara, Fortunato and Bradbury, Andrew and Sblattero, Daniele and Ventura, Alessandro} }