So Yoon Choi

Relationship Between Azathioprine Dosage, 6-Thioguanine Nucleotide Levels, and Therapeutic Response in Pediatric Patients with IBD Treated with Azathioprine

Background:Azathioprine (AZA) is commonly used to treat IBD either alone or in combination with mesalazine. However, there are relatively few studies concerning the relationship between AZA dose, thiopurine metabolite levels, and therapeutic response in pediatric patients treated with both AZA and mesalazine. Methods:We retrospectively investigated the relationship between AZA dose, thiopurine metabolite levels, and therapeutic response in 137 pediatric patients with IBD treated with AZA using multilevel analysis. Additional factors affecting metabolite levels and therapeutic response were also analyzed. Results:A positive correlation was observed between AZA dosage and 6-thioguanine nucleotide (6-TGN) level (P < 0.0001). Variant TPMT genotype (P < 0.001) and concomitant use of mesalazine (P < 0.001) were predictors of higher 6-TGN levels. Leukopenia (P = 0.025) and lymphopenia (P = 0.045) were associated with higher levels of 6-TGN. Poor AZA compliance affected median 6-TGN levels (P < 0.001). The frequency of patients with median 6-TGN levels >235 pmol per 8 × 108 red blood cells was the highest in the sustained therapeutic response group (P = 0.015). Age, sex, IBD type, and duration of AZA therapy did not influence 6-TGN levels or therapeutic effect. Conclusions:AZA dosage is positively correlated with 6-TGN level. Higher 6-TGN levels are related to leukopenia, lymphopenia, and concurrent use of mesalazine. These results provide the rationale for monitoring metabolites to optimize drug dosing and minimize drug-related toxicity. In addition, maintenance of 6-TGN levels within a beneficial therapeutic range by direct monitoring should be helpful in attaining therapeutic efficacy, although this possibility should be verified in prospective studies.

Impact of Genetic Polymorphisms on 6-Thioguanine Nucleotide Levels and Toxicity in Pediatric Patients with IBD Treated with Azathioprine.

Background:Thiopurine-related toxicity results in discontinuation of therapy in up to 30% of patients with inflammatory bowel disease. Although thiopurine S-methyltransferase (TPMT) is implicated in toxicity, not all toxicity can be attributed to TPMT polymorphisms. We investigated the effects of polymorphisms of genes involved in thiopurine and folate metabolism pathways on 6-thioguanine nucleotide levels and toxicity. Methods:Retrospective clinical data and blood samples were collected from 132 pediatric patients with inflammatory bowel disease treated with azathioprine. Eighty-seven genetic polymorphisms of 30 genes were screened using the MassARRAY system, and 70 polymorphisms of 28 genes were selected for further analysis. Results:TPMT genotype (P < 0.001), concurrent use of mesalazine (P = 0.006), ABCC5 (rs2293001) (P < 0.001), ITPA (rs2236206 and rs8362) (P = 0.010 and P = 0.003), and ABCB1 (rs2032582) (P = 0.028) were all associated with the ratio of 6-thioguanine nucleotides to azathioprine dose. ADK (rs10824095) (P = 0.004, odds ratio [OR] = 6.220), SLC29A1 (rs747199) (P = 0.016, OR = 5.681), and TYMS (rs34743033) (P = 0.045, OR = 3.846) were associated with neutropenia. ABCC1 (rs2074087) (P = 0.022, OR = 3.406), IMPDH1 (rs2278294) (P = 0.027, OR = 0.276), and IMPDH2 (rs11706052) (P = 0.034, OR = 3.639) had a significant impact on lymphopenia. Conclusions:This study describes genetic polymorphisms in genes whose products may affect pharmacokinetics and which may predict the relative likelihood of benefit or risk from thiopurine treatment. These findings may serve as a basis for personalized thiopurine therapy in pediatric patients with inflammatory bowel disease, although our data need to be validated in further studies.

Outcome of Alagille Syndrome Patients Who Had Previously Received Kasai Operation during Infancy: A Single Center Study

Purpose Infants with Alagille syndrome (AGS) are occasionally misdiagnosed as biliary atresia and subsequently undergo Kasai operation. The purpose of this study was to investigate the outcome of patients with AGS who had previously received Kasai operation during infancy. Methods This retrospective study was conducted at the Department of Pediatrics, Samsung Medical Center. We compared the prognosis and mortality between those who had undergone Kasai operation during infancy (Kasai group) and those who had not (non-Kasai group). Results Among the 15 children with AGS, five had received Kasai operation, while 10 had not. All subjects in the Kasai group revealed neonatal cholestasis, while 70% of the non-Kasai group showed neonatal cholestasis. Liver transplantation was performed in 100% (5/5) among the Kasai group, and 20.0% (2/10) among the non-Kasai group (p=0.007). Mortality was observed in 60.0% (3/5) among the Kasai group, and 10.0% (1/10) among the non-Kasai group (p=0.077). Conclusion Although overall mortality rate did not significantly differ between the two groups, the proportion of patients receiving liver transplantation was significantly higher in the non-Kasai group. The relatively worse outcome in AGS patients who had received Kasai operation may be due to the unfavorable influences of Kasai operation on the clinical course of AGS, or maybe due to neonatal cholestasis, irrespective of the Kasai operation.

Clinical Use of Measuring Trough Levels and Antibodies against Infliximab in Patients with Pediatric Inflammatory Bowel Disease

Background/Aims The clinical use of measuring infliximab (IFX) trough levels (TLs) and antibodies against IFX (ATIs) in patients with pediatric inflammatory bowel disease (IBD) remains unclear. We propose measuring these variables to create individual IFX treatment strategies for patients with pediatric IBD. Methods This retrospective study was conducted in pediatric patients with IBD who received IFX from July 2009 to June 2014. Results Samples were available from 39 patients with pediatric IBD. A significant difference was observed in IFX TLs in 16 patients who were in clinical remission (group A) after IFX therapy (median, 3.99 μg/mL; interquartile range [IQR], 0.30 to 21.96) compared to 23 patients who had a poor response to treatment (group B) (median, 0.88 μg/mL; IQR, 0.00 to 6.80, p=0.002). In group B, 21 patients underwent empiric intensification of IFX treatment. After dose intensification, 17 patients had an improved response to treatment. Four patients still had no response to dose intensification. Therefore, these patients were switched to other biologics. Conclusions Patients who had poor responses and subtherapeutic IFX TLs had an improved response to dose intensification. Patients who had ATIs were likely to continue to have no response after dose intensification. Therefore, tailoring individual IFX treatments based on IFX TLs, ATIs, and the clinical response should be considered.

Acute Necrotizing Pancreatitis Associated with Mycoplasma pneumoniae Infection in a Child

Mycoplasma pneumoniae is responsible for approximately 20% to 30% of community-acquired pneumonia, and is well known for its diverse extrapulmonary manifestations. However, acute necrotizing pancreatits is an extremely rare extrapulmonary manifestation of M. pneumoniae infection. A 6-year-old girl was admitted due to abdominal pain, vomiting, fever, and confused mentality. Acute necrotizing pancreatitis was diagnosed according to symptoms, laboratory test results, and abdominal computed tomography scans. M. pneumoniae infection was diagnosed by a 4-fold increase in antibodies to M. pneumoniae between acute and convalescent sera by particle agglutination antibody assay. No other etiologic factors or pathogens were detected. Despite the occurrence of a large infected pseudocyst during the course, the patient was able to discharge without morbidity by early aggressive supportive care. This is the first case in Korea of a child with acute necrotizing pancreatitis associated with M. pneumoniae infection.

Does type I truly dominate hepatic glycogen storage diseases in Korea?: a single center study.

Purpose There are no studies of hepatic glycogen storage diseases (GSDs) other than type I and III in Korea. We aimed on investigating the characteristics of hepatic GSDs in Korea diagnosed and followed at a single center. Methods We retrospectively analyzed patients who were diagnosed as GSD and followed at Samsung Medical Center from January, 1997 to December, 2013. Clinical manifestations, laboratory results, treatment, and prognosis were investigated. Results Twenty-one patients were included in the study. The types of 17 patients were confirmed by enzyme activity tests and/or gene analysis. GSD Ia was diagnosed in 7 patients (33.3%), Ib in 1 patient (4.8%), III in 2 patients (9.5%), IV in 1 patient (4.8%), and IX in 6 patients (28.6%). Types other than GSD I constituted 52.9% (9/17) of the patients diagnosed with a specific type of hepatic GSD. The median age at presentation was 2 years. Hepatomegaly was observed in 95.2%, elevated liver transaminases in 90.5%, and hyperlactacidemia in 81.0% of the patients. The duration for follow-up was 77±62.0 months. Uncooked corn starch was initiated in all the patients. No mortality was observed during the follow-up period, and liver transplantation was performed in 14.3%. Conclusion Types other than GSD I comprised more than half of the patients diagnosed with a specific type of hepatic GSD. Clinical suspicion and thorough evaluation of hepatic GSDs in Korea should be focused not only on GSD I, but also on other types.

Baseline Wall Thickness is Lower in Mucosa Healed Segments 1 Year After Infliximab in Pediatric Crohn's Disease Patients.

Objectives: We aimed to quantitatively investigate the therapeutic response to combined immunosuppression treatment by magnetic resonance enterography (MRE) in active luminal Crohn disease (CD) in the pediatric population. Methods: Pediatric patients with moderate-to-severe luminal CD, who received scheduled infliximab and azathioprine, were included in this preliminary study. Ileocolonoscopy and MRE were performed at baseline and at 1 year, and Simple Endoscopic Score for Crohns Disease (SES-CD) and Magnetic Resonance Index of Activity (MaRIA) scores were calculated. The correlation between SES-CD and MaRIA scores were investigated with analysis per person and per segment. Results: A total of 167 segments from 17 patients were evaluated by both Ileocolonoscopy and MRE. SES-CD and MaRIA scores showed significant correlations on both per-person analysis (&rgr; = 0.699, P < 0.001) and per-segment analysis (&rgr; = 0.596, P < 0.001). Analysis according to ileocolonic location of each segment revealed that the correlation strength was strongest in the right colon (&rgr; = 0.653, P < 0.001), whereas the correlation in the rectum was statistically insignificant (&rgr; = 0.29, P = 0.096). A comparative analysis of MaRIA components revealed a significantly thinner bowel wall thickness at baseline in endoscopically healed segments (50/65) compared with unhealed segments (15/65) (median 4.3 vs 7.2 mm, P = 0.036). Conclusions: Therapeutic response to combined immunosuppression at 1 year assessed by MRE correlates with ileocolonoscopy in pediatric patients with CD. Bowel wall thickness of the involved segments at baseline may affect treatment response to combined immunosuppression.

Adalimumab Treatment in Pediatric-Onset Crohn's Disease Patients after Infliximab Failure: A Single Center Study

Purpose We aimed to investigate the efficacy and safety of adalimumab in pediatric-onset Crohns disease patients who had failed treatment with infliximab. Methods In this retrospective study, patients included were those who had been diagnosed with Crohns disease before 18 years old, and had received treatment with adalimumab after infliximab failure. The efficacy of adalimumab treatment was investigated at 1 month and 1 year, and adverse events that had occurred during treatment with adalimumab were explored. Results Ten patients were included in this study. The median duration from diagnosis to adalimumab treatment was 5.5 years (range: 2.4-7.9 years). At 1 month after adalimumab initiation, 80% (8/10) of patients showed clinical response, and 40% (4/10) achieved clinical remission. At 1 year, 71% (5/7) of patients showed clinical response, and 43% (3/7) were under clinical remission. Among the total included patients, 5 patients (50%) showed clinical response at 1 year. Primary non-response to adalimumab was observed in 2 patients (20%), and secondary failure to adalimumab was observed in 3 patients (30%) during 1 year treatment with adalimumab. No serious adverse event had occurred during adalimumab treatment. Conclusion Adalimumab was effective for 1 year without serious adverse events in half of pediatric-onset Crohns disease patients who had failed treatment with infliximab.

A Case of Glycogen Storage Disease IV with Rare Homozygous Mutations in the Glycogen Branching Enzyme Gene

Glycogen storage disease (GSD) IV is a rare autosomal recessive inherited disorder caused by mutations in the gene coding for glycogen branching enzyme leading to progressive liver disease. GSD IV is associated with mutations in GBE1, which encodes the glycogen branching enzyme. We report a case of GSD IV with rare homozygous mutations in the GBE1 gene (c.791G>A (p.Gly264Glu), which was successfully treated by liver transplantation.