@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 {8513, title = {Effect of Early Versus Late Azathioprine Therapy in Pediatric Ulcerative Colitis.}, journal = {Inflamm Bowel Dis}, volume = {22}, year = {2016}, month = {2016 Jul}, pages = {1647-54}, abstract = {

BACKGROUND: We aimed at describing the efficacy of azathioprine (AZA) in pediatric ulcerative colitis, comparing the outcomes of early (0-6 months) versus late (6-24 months) initiation of therapy.

METHODS: Children with ulcerative colitis treated with AZA within 24 months of diagnosis were included. Corticosteroid (CS)-free remission and mucosal healing (MH), assessed by endoscopy or fecal calprotectin, at 12 months were the primary outcomes. Patients were also compared for CS-free remission and MH, need for treatment escalation or surgery, number of hospitalizations, and adverse events during a 24-month follow-up.

RESULTS: A total of 121 children entered the study (median age 10.5 {\textpm} 4.0 years, 59\% girls). Seventy-six (63\%) started AZA between 0 and 6 months (early group) and 45 (37\%) started between 6 and 24 months (late group). Seventy-five percent and 53\% of patients in the early and late group, respectively, received CS at the diagnosis (P = 0.01). CS-free remission at 1 year was achieved by 30 (50\%) of the early and 23 (57\%) of the late patients (P = 0.54). MH occurred in 37 (37\%) patients at 1 year, with no difference between the 2 groups (33\% early, 42\% late; P = 0.56). No difference was found for the other outcomes.

CONCLUSIONS: Introduction of AZA within 6 months of diagnosis seems not more effective than later treatment to achieve CS-free remission in pediatric ulcerative colitis. MH does not depend on the timing of AZA initiation; however, because of the incomplete comparability of the 2 groups at the diagnosis and the use of fecal calprotectin as a surrogate marker of MH, our results should be further confirmed by prospective studies.

}, issn = {1536-4844}, doi = {10.1097/MIB.0000000000000828}, author = {Aloi, Marina and D'Arcangelo, Giulia and Bramuzzo, Matteo and Gasparetto, Marco and Martinelli, Massimo and Alvisi, Patrizia and Illiceto, Maria Teresa and Valenti, Simona and Distante, Manuela and Pellegrino, Salvatore and Gatti, Simona and Arrigo, Serena and Civitelli, Fortunata and Martelossi, Stefano} }