A Multicenter Prospective Survey on Early-Onset Inflammatory Bowel Disease in Japan.

INTRODUCTION: The incidence of early-onset inflammatory bowel disease is increasing in Japan. OBJECTIVE: This study aimed to analyze the treatment and progress of early-onset inflammatory bowel disease. METHODS: This prospective survey evaluated the data of 43 patients aged <8 years who were diagnosed with inflammatory bowel disease (IBD) from the time of diagnosis to 36 months after registration. RESULTS: A total of 12 patients with Crohn's disease (CD), 21 with ulcerative colitis (UC), and 3 with unclassified IBD were enrolled. The mean disease onset age was 3 years and 7 months. Colon and anal lesions were present in 100 and 50% of patients with CD, respectively. Granulomas were detected in 5 patients (41.7%). Dietary elimination including elemental diet was performed in all patients. Eleven patients (91.7%) were in remission by initial induction therapy, and 72.7% maintained remission for 36 months. Three patients (14.3%) with UC had familial history, 71.4% had pancolitis-type UC, and 66.7% exhibited disease of moderate severity. Colectomy was performed in 4 patients (21.1%). Eighteen patients (85.7%) were in remission by initial induction therapy; however, only 15.8% maintained remission for 36 months. Anal complication was more prevalent in infantile-onset IBD than in childhood-onset IBD (p = 0.014). CONCLUSIONS: Among Japanese patients aged <8 years who were diagnosed with IBD, colitis-type disease was more common in CD and pancolitis was more common in UC. As the courses of several patients were severe, identifying primary immunodeficiency appears to be necessary to confirm background disease.

Current role of colonoscopy in infants and young children: a multicenter study.

BACKGROUND: To evaluate the role of colonoscopy in infants and young children and clarify the distribution of colonoscopy-requiring diseases in this age group. METHODS: Cohorts of colonoscopies performed at three children's hospitals in Japan between April 2011 and March 2016 including infants and children younger than six years of age were retrospectively reviewed. RESULTS: In total, 453 colonoscopies were performed in 276 infants and young children. Of these 275 (60.8%) were for diagnostic purposes, 177 (39.2%) were performed as follow-up, and one case was performed for treatment. The median patient age at the time of diagnostic colonoscopy was 2.49 years, and there was a male-to-female ratio of 1.72:1. Abnormal macroscopic and/or histopathological findings were noted in 212 (77.1%) cases. Of these, definite diagnoses were established for the presence of eosinophilic gastrointestinal disorders (EGIDs), inflammatory bowel disease (IBD), and polyp/polyposis in 23, 18.5, and 14% of patients, respectively. Among 51 IBD cases, ulcerative colitis, Crohn's disease, and IBD-unclassified were identified in 47.1, 33.3, and 7.8%, retrospectively via endoscopic examination. Of these, 11 (22%) were eventually diagnosed with monogenic diseases via genetic testing. Of those with rectal bleeding, EGIDs, polyps/polyposis, and IBD were found in 27, 19, and 18%, retrospectively. There were significantly more cases of EGIDs and fewer ones of IBD and polyps/polyposis in patients with rectal bleeding younger than two years of age. Furthermore, 68% of all follow-up colonoscopies were performed in children with IBD. There were no serious complications in our study cohort. CONCLUSION: We determined the role of colonoscopy in infants and young children. Diseases diagnosed using colonoscopy in this age group included IBD, EGIDs, and polyps/polyposis. The increasing trend of patients with IBD and EGIDs worldwide means that the role of colonoscopy in infants and younger children will be more important in the future.

Infliximab for pediatric patients with ulcerative colitis: a phase 3, open-label, uncontrolled, multicenter trial in Japan.

BACKGROUND: Pediatric ulcerative colitis (UC) is typically more extensive and has a more active disease course than adult UC, and requires early treatment augmentation to achieve and maintain disease remission. The present study aimed to investigate the efficacy, safety, and pharmacokinetic profile of infliximab (IFX) in pediatric patients with moderate-to-severe UC and inadequate response to existing treatment. METHODS: This open-label, uncontrolled, multicenter, Phase 3 trial was conducted at 17 centers in Japan between April 2012 and September 2014. Pediatric patients (aged 6-17 years) diagnosed with moderate-to-severe UC received a treatment protocol comprising 5 mg/kg IFX at Weeks 0, 2, and 6, and Clinical Activity Index (CAI)-based responders at Week 8 also received treatment at 8-week intervals at Weeks 14 and 22, with a final evaluation at Week 30. RESULTS: A total of 21 patients were treated in this study. IFX therapy rapidly improved clinical symptoms, and this effect was maintained for up to 30 weeks. Overall CAI-based remission rate was 42.9% and overall Pediatric Ulcerative Colitis Activity Index (PUCAI)-based remission rate was 19.0%. Median partial Mayo score was 6.0 at baseline and 4.0 at Week 30 (overall). Among the eight patients who underwent sigmoidoscopy, Mayo response was achieved at Week 30 (overall) in three patients (37.5%). Trough serum IFX concentrations in Week 8 CAI-based responders were maintained throughout the study period. Adverse events and serious adverse events were observed in 95.2 and 14.3% of patients, respectively. CONCLUSIONS: These results support the use of IFX in the treatment of pediatric patients with UC with inadequate response to existing treatment. TRIAL REGISTRATION: ClinicalTrials.gov, registration number: NCT01585155 .

Clinical, Pathologic, and Genetic Features of Neonatal Dubin-Johnson Syndrome: A Multicenter Study in Japan.

OBJECTIVE: To clarify the clinical, pathologic, and genetic features of neonatal Dubin-Johnson syndrome. STUDY DESIGN: Ten patients with neonatal Dubin-Johnson syndrome were recruited from 6 pediatric centers in Japan between September 2013 and October 2016. Clinical and laboratory course, macroscopic and microscopic liver findings, and molecular genetic findings concerning ATP-binding cassette subfamily C member 2 (ABCC2) were retrospectively and prospectively examined. RESULTS: All neonates exhibited cholestasis, evident as prolonged jaundice with or without acholic stools and elevations of serum direct bilirubin as well as γ-glutamyltransferase or total bile acids. Only 38% (3 of 8) of patients who underwent liver biopsy showed a grossly black liver or melanin-like pigment deposits in hepatocytes; their biopsies were performed in early infancy. Immunohistochemically, all liver specimens showed no expression of multidrug resistance-associated protein 2 but increased expression of the bile salt export pump protein. Homozygous or compound heterozygous pathogenic variants of ABCC2 were identified in all patients, representing 11 distinct pathogenic variants including 2 not previously reported. CONCLUSIONS: Immunohistochemical staining of the liver for multidrug resistance-associated protein 2 and molecular genetic analysis of ABCC2 are crucial for accurate diagnosis of neonatal Dubin-Johnson syndrome.

Prostaglandin E-major Urinary Metabolite as a Biomarker for Pediatric Ulcerative Colitis Activity.

OBJECTIVES: Prostaglandin E-major urinary metabolite (PGE-MUM) is a useful biomarker for adult ulcerative colitis (UC) activity. In the present study, we evaluated whether PGE-MUM can also be a biomarker of pediatric UC activity and compared its efficacy in predicting UC activity with that of C-reactive protein and erythrocyte sedimentation rate. METHODS: Twenty-nine pediatric patients with UC (8-18 years) and 29 healthy age- and sex-matched subjects were enrolled. UC activity was evaluated using the Pediatric Ulcerative Colitis Activity Index, highest Mayo endoscopic scoring (Mayo), and Matts grading (Matts) for histologic scoring, and the sum of Mayo (total of 6 segments) and Matts in all patients with UC. PGE-MUM levels were measured using a radioimmunoassay. RESULTS: PGE-MUM levels were elevated in endoscopically and histologically active UC patients, but not in patients with endoscopic and histologic remission or controls. PGE-MUM levels positively and significantly correlated with UC activity. PGE-MUM levels were positively correlated with Pediatric Ulcerative Colitis Activity Index (r = 0.594), highest Mayo (r = 0.462), the sum of Mayo (r = 0.694), and the sum of Matts (r = 0.613), but not with highest Matt (r = 0.352). The sum of Mayo and the sum of Matts, which reflect total colon inflammation, showed highest correlation with PGE-MUM. C-reactive protein levels did not correlate with any UC activity scores. Erythrocyte sedimentation rate exhibited correlation (r = 0.490) with the sum of Mayo only. CONCLUSIONS: PGE-MUM is a reliable biomarker that reflects both the endoscopic and histologic activity of the entire colon in pediatric UC.

Screening of carnitine and biotin deficiencies on tandem mass spectrometry.

BACKGROUND: It is important to assess pediatric patients for nutritional deficiency when they are receiving specific interventions, such as enteral feeding. We focused on measurement of C0 and 3-hydroxyisovalerylcarnitine (C5-OH) with tandem mass spectrometry (MS/MS), which is performed as part of the newborn mass screening. The purpose of this study was to investigate the usefulness of MS/MS for screening carnitine and biotin deficiencies. METHODS: Forty-two children (24 boys, 18 girls) were enrolled between December 2013 and December 2015. Blood tests, including measurement of serum free carnitine via the enzyme cycling method, and acylcarnitine analysis on MS/MS of dried blood spot (DBS), were performed for the evaluation of nutrition status. RESULTS: Median patient age was 2 years (range, 2 months-14 years). Mean serum free carnitine was 41.8 ± 19.2 µmol/L. In six of the 42 patients, serum free carnitine was <20 µmol/L (range, 4.0-18.7 µmol/L). C0 and C5-OH measured on MS/MS of DBS were 33.8 ± 20.2 nmol/mL and 0.48 ± 0.22 nmol/mL, respectively. There was a strong positive correlation (r = 0.89, P < 0.001) between serum free carnitine and C0 measured on the same day. In one patient on hydrolyzed formula, C5-OH was >1.00 nmol/L. Therapy-resistant eczema was improved by treatment with additional biotin and a non-hydrolyzed formula. CONCLUSION: C0 and C5-OH, measured on MS/MS of DBS, were useful for screening carnitine and biotin deficiencies.

Difference between early onset and late-onset pediatric ulcerative colitis.

BACKGROUND: Early onset pediatric ulcerative colitis (EO-UC) is distinguished from late-onset pediatric ulcerative colitis (LO-UC) by the effects of genetic predisposition, but there have been few reports on the clinical features of EO-UC in Asia. METHODS: To describe and compare the presentation and disease course of EO-UC (age range, 0-7 years) with those of LO-UC (age range, 8-15 years), we retrospectively analyzed 63 children with UC who had been diagnosed between January 2004 and March 2014 at Saitama Children's Medical Center in Japan. RESULTS: Ten patients (16%) had EO-UC, and 53 (84%) had LO-UC. All patients in the EO-UC group and 70% in the LO-UC group had pancolitis (P = 0.05). The period from onset to diagnosis was 9.0 ± 14.1 months for EO-UC and 2.6 ± 3.5 months for LO-UC (P < 0.01). The prevalence of extra-intestinal complications at diagnosis was significantly higher for EO-UC than for LO-UC (50% vs 11%, respectively; P < 0.01). There were no significant differences in the use of corticosteroids, immunomodulators, immunosuppressants, or surgical risk between the groups but, in the EO-UC group, only one patient was treated with cytapheresis and none was treated with anti-tumor necrosis factor (TNF-α) antibodies. CONCLUSIONS: The EO-UC group had a higher incidence of pancolitis, longer diagnostic delay, and more extra-intestinal manifestations than the LO-UC group. Diagnosis and treatment may therefore be slightly more difficult for EO-UC than for LO-UC.

Characteristics of inflammatory bowel disease with an onset before eight years of age: a multicenter epidemiological survey in Japan.

BACKGROUND AND AIM: Pediatric inflammatory bowel disease (IBD) has not been rare in Japan since the 1990s. The present study attempted to define the epidemiological and clinical characteristics of early-childhood IBD in Japan in comparison with results from Western countries. METHODS: Among children diagnosed as having IBD between January 1998 and December 2008, those showing onset before 8 years of age were investigated retrospectively. A questionnaire survey was carried out at 45 facilities throughout Japan, and 80 cases were reported from 27 facilities. On the basis of the final diagnosis, 24 patients with Crohn's disease (CD) and 47 patients with ulcerative colitis (UC) were analyzed. RESULTS: Among the patients with CD, the age at onset was less than 1 year in 62.5%. On the basis of the Montreal classification, 87.5% of CD cases involved the colon, and 63.8% of UC cases were pancolitis. Coexisting conditions such as congenital diseases (five cases) and cerebral palsy (four cases) were present before the onset of IBD. Growth failure was more severe (P < 0.05) at diagnosis in CD patients than in UC patients. Familial occurrence within first-degree relatives was observed in eight families among 45 patients with UC, compared with none among the CD patients (P < 0.05). CONCLUSION: Our results suggest that, in Japan, the pathogenesis of IBD in infants and children may differ from that in Western countries, and that the characteristics of early childhood-onset IBD are distinct from those of school age-onset IBD.

[Severe aplastic anemia following living-donor liver transplantation for fluminant hepatitis].

We report a case of a 15-year-old girl with severe aplastic anemia who underwent orthotopic liver transplantation 5 years ago for fulminant hepatic failure during the course of immunodeficiency of unknown etiology. She previously exhibited similar immunodeficiency and experienced recurrent viral infections. She developed jaundice at 9 years of age and was diagnosed with fulminant hepatitis. One month later, she underwent living donor liver transplantation, with the donor being her father. Five years after the liver transplant, pancytopenia was noted; she did not respond to treatment with increasing doses of tacrolimus/prednisone and administration of granulocyte-colony stimulating factor. Bone marrow biopsy was performed, and severe aplastic anemia was diagnosed. Six years after the liver transplant, she underwent bone marrow transplantation (BMT), with the donor being her HLA-matched sibling. However, she developed liver dysfunction with recovery of white blood cells. She developed sepsis, which eventually led to her death on day 30 after BMT.

Leukocytapheresis in pediatric patients with ulcerative colitis.

OBJECTIVE: Leukocytapheresis (LCAP) is a nonpharmacologic therapy that has recently been used to treat ulcerative colitis (UC). This multicenter open-label study prospectively assessed the efficacy and safety of LCAP in pediatric patients with UC. PATIENTS AND METHODS: Twenty-three patients ages 8 to 16 years with moderate (n = 19) to severe (n = 4) steroid-resistant UC were enrolled. One of 2 LCAP columns with different volumes (model EX and the half-volume model EI) was selected, according to body weight. LCAP was performed once per week for 5 consecutive weeks. Clinical and laboratory data were collected at predetermined time points. The primary endpoint was decreased stool frequency/hematochezia score, and secondary endpoints were clinical, laboratory, and endoscopic improvements. RESULTS: The stool frequency/hematochezia score decreased significantly from 4.5 ± 1.2 before treatment to 1.6 ± 1.9 after the fifth treatment. Clinical parameters, including stool frequency, presence of visible blood, abdominal pain, and body temperature, were significantly improved. Fecal calprotectin decreased significantly. Endoscopic findings evaluated using Matts score also improved (P < 0.01). The steroid dose decreased from 1.1 ± 0.4 mg/kg before treatment to 0.8 ± 0.5 mg/kg after treatment. There were no significant differences in changes between the EX and EI columns. The incidence of adverse effects was 61%, although none was serious. The most common adverse effects were decreased hematocrit and hemoglobin concentration. CONCLUSIONS: The present study showed that LCAP was well tolerated in children with UC, mostly moderate, and was as effective as in adults. The types of pediatric patients best suited to LCAP remain to be determined.

Efficacy and safety of pulse steroid therapy in Japanese pediatric patients with ulcerative colitis: a survey of the Japanese Society for Pediatric Inflammatory Bowel Disease.

AIMS: We have evaluated the therapeutic efficacy and safety of pulse steroid therapy for ulcerative colitis (UC) in a Japanese pediatric population by means of a survey. METHODS: A questionnaire on UC patients treated with therapy between 2002 and 2006 was sent to 37 members of the Japanese Society for Pediatric Inflammatory Bowel Disease. RESULTS: 21 of 62 cases in 6 of 19 centers registered in this study had been treated with pulse steroid therapy. The success rate of remission induction with this treatment was 55%, and improvement was observed in all cases in which remission was not achieved. There were no reports of any obvious side effects. The most common reason for using pulse steroid therapy was for remission induction in relapsed cases. Over the course of 12 (or fewer) months, the number of cases in which remission was maintained was only 1 in 4. However, the amount of concomitant steroid use had significantly decreased after 1 year. CONCLUSIONS: This survey shows that in Japan, pulse steroid therapy is used for a relatively large number of children with UC and is as an effective method of remission induction that has few side effects.

Serological cytokine signature in paediatric patients with inflammatory bowel disease impacts diagnosis.

Endoscopy is a central tool for diagnosing and evaluating paediatric inflammatory bowel diseases (PIBD), but is too invasive to be frequently repeated in young children. Furthermore, it is challenging to distinguish Crohn's disease (CD) from ulcerative colitis (UC) endoscopically. This study aimed to determine biomarkers useful for the diagnosis of PIBD. Cytokines, chemokines, and growth factors were quantified in the sera of 15 patients with CD or UC, at disease onset prior to treatment, and 26 age-matched controls. Correlation of cytokine levels with the paediatric CD activity index (PCDAI) and the paediatric UC activity index (PUCAI) was analysed. Interleukin (IL)-6, IL-13, IL-7, and vascular endothelial growth factor were higher in the CD group than in the UC group. The receiver operating characteristic curve analysis showed that IL-7 was a putative biomarker for distinguishing CD from UC (area under the curve: 0.94). Granulocyte-macrophage colony-stimulating factor was associated with PCDAI, and an IL-1 receptor antagonist, IL-6, and macrophage inflammatory protein-1ß were associated with PUCAI. These findings indicate significant differences in cytokine signatures among patients with new-onset PIBD, which may improve accuracy in diagnosing PIBD.

[Thalidomide therapy for infantile-onset Crohn's disease].

A 6-month-old boy was diagnosed as having Crohn's disease (CD) by the endoscopic examination. Primary immunodeficiency syndrome was initially suspected due to a refractory infection that occurred just after birth and a family history that his older brother died at the age of 3 months of septicemia associated with perirectal abscess. Thalidomide was used because conventional medical treatment by steroids and immunosuppressives was ineffective. Thalidomide improved the symptoms of diarrhea, abdominal pain, high fever and fistula, and the PCDAI score decreased markedly from 45 to 15. Although thalidomide was discontinued after three months because of the onset of side effects, including edema, rash and the peripheral neuropathy, the effect on the fistula closure was maintained over a long period of time. Further studies will be necessary to determine the dosage of thalidomide that does not elicit side effects, but thalidomide seems to be effective in patients with refractory CD. Infantile CD is very rare and the diagnosis is often delayed. CD is generally resistant to medical treatment. More detailed information of infantile CD will be needed to elucidate the pathogenesis of this disease and progress of treatment. Recently the incidence of inflammatory bowel diseases has increased. CD should be suspected in any infant with the perianal lesion (fissures, fistula, skin tag and abscesses) especially when prolonged gastrointestinal symptoms, stomatitis or fever coexist.