@article {10504, title = {Multicentric Case-Control Study on Azathioprine Dose and Pharmacokinetics in Early-onset Pediatric Inflammatory Bowel Disease.}, journal = {Inflamm Bowel Dis}, volume = {23}, year = {2017}, month = {2017 04}, pages = {628-634}, abstract = {

BACKGROUND: Early-onset inflammatory bowel disease (IBD) is generally aggressive, with a high probability of complications and need of surgery. Despite the introduction of highly effective biological drugs, treatment with azathioprine continues to be important even for early-onset IBD; however, in these patients azathioprine response seems to be reduced. This study evaluated azathioprine doses, metabolite concentrations, and their associations with patients{\textquoteright} age in children with IBD treated at 6 tertiary pediatric referral centers.

METHODS: Azathioprine doses, metabolites, and clinical effects were assessed after at least 3 months of therapy in 17 early-onset (age < 6 yr, cases) and 51 nonearly-onset (aged > 12 and <18 yrs, controls) patients with IBD. Azathioprine dose was titrated on therapeutic efficacy (response and adverse effects). Azathioprine metabolites and thiopurine methyltransferase activity were determined by high-performance liquid chromatography with ultra violet-vis detection (HPLC-UV) methods.

RESULTS: Frequency of patients in remission was similar among early-onset and control groups, respectively (82\% and 84\%, P value = 0.72). Early-onset patients required higher doses of azathioprine (median 2.7 versus 2.0 mg{\textperiodcentered}kg{\textperiodcentered}d, P value = 1.1 {\texttimes} 10). Different doses resulted in comparable azathioprine active thioguanine nucleotide metabolite concentrations (median 263 versus 366 pmol/8 {\texttimes} 10 erythrocytes, P value = 0.41) and methylmercaptopurine nucleotide concentrations (median 1455 versus 1532 pmol/8 {\texttimes} 10 erythrocytes, P value = 0.60). Lower ratios between thioguanine nucleotide metabolites and azathioprine doses were found in early-onset patients (median 98 versus 184 pmol/8 {\texttimes} 10 erythrocytes{\textperiodcentered}mg{\textperiodcentered}kg{\textperiodcentered}d, P value = 0.017). Interestingly, early-onset patients presented also higher thiopurine methyltransferase activity (median 476 versus 350 nmol methylmercaptopurine/mg hemoglobin/h, P-value = 0.046).

CONCLUSIONS: This study demonstrated that patients with early-onset IBD present increased inactivating azathioprine metabolism, likely because of elevated activity of the enzyme thiopurine methyltransferase.

}, keywords = {Adolescent, Age of Onset, Antimetabolites, Azathioprine, Case-Control Studies, Child, Child, Preschool, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Erythrocytes, Female, Guanine Nucleotides, Humans, Inflammatory Bowel Diseases, Male, Mercaptopurine, Methyltransferases, Thioguanine}, issn = {1536-4844}, doi = {10.1097/MIB.0000000000001051}, author = {Stocco, Gabriele and Martelossi, Stefano and Arrigo, Serena and Barabino, Arrigo and Aloi, Marina and Martinelli, Massimo and Miele, Erasmo and Knafelz, Daniela and Romano, Claudio and Naviglio, Samuele and Favretto, Diego and Cuzzoni, Eva and Franca, Raffaella and Decorti, Giuliana and Ventura, Alessandro} } @article {8088, title = {The diagnostic challenge of very early-onset enterocolitis in an infant with XIAP deficiency.}, journal = {BMC Pediatr}, volume = {15}, year = {2015}, month = {2015}, pages = {208}, abstract = {

BACKGROUND: Aggressive course and resistance to treatments usually characterize very early onset inflammatory bowel disease (VEO-IBD). Some VEO-IBD cases are due to monogenic immune defects and can benefit from hematopoietic stem cell transplantation (HSCT).

CASE PRESENTATION: We describe a Caucasian male baby who presented in the first months of life macrophage activation syndrome, followed by intractable colitis, recurrent episodes of fever and mild splenomegaly. After several immunological, genetic and clinical investigations, subsequently a therapeutic attempt with colectomy, analysis of VEO-IBD-associated genes, revealed a causative mutation in XIAP. The genetic diagnosis of a primary immune deficiency allowed curing the boy with hematopoietic stem cell transplantation.

CONCLUSION: Our report, together with novel findings from recent literature, should contribute to increase awareness of monogenic immune defects as a cause of VEO-IBD. Comprehensive genetic analysis can allow a prompt diagnosis, resulting in the choice of effective treatments and sparing useless and damaging procedures.

}, issn = {1471-2431}, doi = {10.1186/s12887-015-0522-5}, author = {Girardelli, Martina and Arrigo, Serena and Barabino, Arrigo and Loganes, Claudia and Morreale, Giuseppe and Crovella, Sergio and Tommasini, Alberto and Bianco, Anna Monica} } @article {7708, title = {Effect of Thalidomide on Clinical Remission in Children and Adolescents with Ulcerative Colitis Refractory to Other Immunosuppressives: Pilot Randomized Clinical Trial.}, journal = {Inflamm Bowel Dis}, volume = {21}, year = {2015}, month = {2015 Aug}, pages = {1739-49}, abstract = {

BACKGROUND: In a randomized controlled trial, thalidomide has shown to be effective in refractory Crohn{\textquoteright}s disease in children. This pilot study aimed at evaluating thalidomide in refractory pediatric ulcerative colitis (UC).

METHODS: Double-blind, placebo-controlled randomized clinical trial on thalidomide 1.5 to 2.5 mg/kg/day in children with active UC despite multiple immunosuppressive treatments. In an open-label extension, nonresponders to placebo received thalidomide for an additional 8 weeks; all responders were followed up for a minimum of 52 weeks.

RESULTS: Twenty-six children with refractory UC were randomized to thalidomide or placebo. Clinical remission at week 8 was achieved by significantly more children treated with thalidomide {10/12 (83.3\%) versus 2/11 (18.8\%); risk ratio, 4.5 (95\% confidence interval [CI], 1.2-16.4); P = 0.005; number needed to treat, 1.5}. Of the nonresponders to placebo who were switched to thalidomide, 8 of 11 (72.7\%) subsequently reached remission at week 8 (risk ratio, 4.0 [95\% CI, 1.1-14.7]; number needed to treat, 2.45; P = 0.01). Clinical remission in the thalidomide group was 135.0 weeks (95\% CI, 32-238), compared with 8.0 weeks (95\% CI, 2.4-13.6) in the placebo group (P < 0.0001). Cumulative incidence of severe adverse events was 3.1 per 1000 patient-weeks. Peripheral neuropathy and amenorrhea were the most frequent adverse events.

CONCLUSIONS: In this pilot randomized controlled trial on cases of UC refractory to immunosuppressive therapy, thalidomide compared with placebo resulted in improved clinical remission at 8 weeks of treatment and in longer term maintenance of remission. These findings require replication in larger clinical studies evaluating both thalidomide efficacy and safety.

}, issn = {1536-4844}, doi = {10.1097/MIB.0000000000000437}, author = {Lazzerini, Marzia and Martelossi, Stefano and Magazz{\`u}, Giuseppe and Pellegrino, Salvatore and Lucanto, Maria Cristina and Barabino, Arrigo and Calvi, Angela and Arrigo, Serena and Lionetti, Paolo and Lorusso, Monica and Mangiantini, Francesca and Fontana, Massimo and Zuin, Giovanna and Palla, Gabriella and Maggiore, Giuseppe and Bramuzzo, Matteo and Pellegrin, Maria Chiara and Maschio, Massimo and Villanacci, Vincenzo and Manenti, Stefania and Decorti, Giuliana and De Iudicibus, Sara and Paparazzo, Rossella and Montico, Marcella and Ventura, Alessandro} } @article {1652, title = {Genetic predictors of glucocorticoid response in pediatric patients with inflammatory bowel diseases.}, journal = {J Clin Gastroenterol}, volume = {45}, year = {2011}, month = {2011 Jan}, pages = {e1-7}, abstract = {

BACKGROUND: Glucocorticoids (GCs) are used in moderate-to-severe inflammatory bowel diseases (IBD) but their effect is often unpredictable.

AIM: To determine the influence of 4 polymorphisms in the GC receptor [nuclear receptor subfamily 3, group C, member 1 (NR3C1)], interleukin-1β (IL-1β), and NACHT leucine-rich-repeat protein 1 (NALP1) genes, on the clinical response to steroids in pediatric patients with IBD.

METHODS: One hundred fifty-four young IBD patients treated with GCs for at least 30 days and with a minimum follow-up of 1 year were genotyped. The polymorphisms considered are the BclI in the NR3C1 gene, C-511T in IL-1β gene, and Leu155His and rs2670660/C in NALP1 gene. Patients were grouped as responder, dependant, and resistant to GCs. The relation between GC response and the genetic polymorphisms considered was examined using univariate, multivariate, and Classification and Regression Tree (CART) analysis.

RESULTS: Univariate analysis showed that BclI polymorphism was more frequent in responders compared with dependant patients (P=0.03) and with the combined dependant and resistant groups (P=0.02). Moreover, the NALP1 Leu155His polymorphism was less frequent in the GC responsive group compared with resistant (P=0.0059) and nonresponder (P=0.02) groups. Multivariate analysis comparing responders and nonresponders confirmed an association between BclI mutated genotype and steroid response (P=0.030), and between NALP1 Leu155His mutant variant and nonresponders (P=0.033). An association between steroid response and male sex was also observed (P=0.034). In addition, Leu155His mutated genotype was associated with steroid resistance (P=0.034). Two CART analyses supported these findings by showing that BclI and Leu155His polymorphisms had the greatest effect on steroid response (permutation P value=0.046). The second CART analysis also identified age of disease onset and male sex as important variables affecting response.

CONCLUSIONS: These results confirm that genetic and demographic factors may affect the response to GCs in young patients with IBD and strengthen the importance of studying high-order interactions for predicting response.

}, keywords = {Adolescent, Child, Drug Resistance, Female, Follow-Up Studies, Genotype, Glucocorticoids, Humans, Inflammatory Bowel Diseases, Male, Multivariate Analysis, Polymorphism, Genetic, Receptors, Glucocorticoid, Regression Analysis, Retrospective Studies, Sex Factors, Treatment Outcome}, issn = {1539-2031}, doi = {10.1097/MCG.0b013e3181e8ae93}, author = {De Iudicibus, Sara and Stocco, Gabriele and Martelossi, Stefano and Londero, Margherita and Ebner, Egle and Pontillo, Alessandra and Lionetti, Paolo and Barabino, Arrigo and Bartoli, Fiora and Ventura, Alessandro and Decorti, Giuliana} }