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BACKGROUND AND AIM This study aimed to determine the efficacy and safety of vedolizumab treatment with or without concomitant immunomodulator use in Japanese patients with moderate-to-severe ulcerative colitis. METHODS Among enrolled patients in a phase 3 study conducted in Japan (clinicaltrials.gov, NCT02039505), data from patients allocated to 300-mg intravenous vedolizumab for induction and maintenance phases were used for this exploratory analysis. Efficacy endpoints were clinical response, clinical remission, and mucosal healing at week 10 and clinical remission and mucosal healing at week 60, and disease worsening and treatment failure during the maintenance phase. RESULTS At week 10, the differences in clinical response, clinical remission, and mucosal healing rates between the subgroups (those with concomitant immunomodulator use minus those without) were 0.7 (95% confidence interval: -14.3, 15.7), 3.3 (95% confidence interval: -8.5, 15.2), and 1.8 (95% confidence interval: -13.0, 16.5), respectively. At week 60, the differences in clinical remission and mucosal healing between the subgroups with and without concomitant immunomodulator use were 26.1 (95% confidence interval: -3.5, 55.6) and 29.9 (95% confidence interval: 1.4, 58.4), respectively. The proportions of patients without treatment failure at day 330 of the maintenance phase were 90.7% with concomitant immunomodulator use and 73.7% without. No marked differences in incidence of infections were observed between subgroups. CONCLUSIONS This study suggested the possibility that concomitant immunomodulator use may be beneficial to maintain the clinical efficacy of vedolizumab.

Background and aim Ustekinumab (UST), a fully humanized monoclonal antibody against the p40 subunit of interleukin-12/23, is effective for the treatment of Crohn's disease (CD). The benefit of concomitant use of an immunomodulator (IM) with UST, however, is unclear. This study aimed to provide a systematic review and meta-analysis comparing the efficacy and safety of concomitant use of an IM with UST as an induction therapy for CD patients. Methods A systematic literature search was performed using PubMed/MEDLINE, the Cochrane Library, and the Japana Centra Revuo Medicina from inception to October 31, 2019. The main outcome measure was achievement of clinical efficacy (remission, response, and clinical benefit) at 6-12 weeks. The quality of the included studies was assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) tools. The fixed-effects model was used to calculate the pooled odds ratios. Results From 189 yielded articles, six including a total of 1507 patients were considered in this meta-analysis. Concomitant use of an IM with UST was significantly effective than UST monotherapy as an induction therapy (pooled odds ratio in the fixed-effects model: 1.35, 95% confidence interval [1.06-1.71], P = 0.015). The heterogeneity among studies was low (I2 = 2.6%). No statistical comparisons of the occurrence of adverse events between UST monotherapy and concomitant use of an IM with UST were performed. Conclusion The efficacy of concomitant use of an IM with UST as an induction therapy for CD was significantly superior to that of monotherapy with UST.

Inflammatory bowel disease (IBD) has increased in incidence and prevalence in Asian countries since the end of the 20th century. Moreover, differences in the cause, phenotypes, and natural history of IBD between the East and West have been recognized. Therefore, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have established recommendations on medical management of IBD in Asia. Initially, the committee members drafted 40 recommendations, which were then assessed according to Grading of Recommendations Assessment, Development and Evaluation. Eight statements were rejected as this indicated that consensus had not been reached. The recommendations encompass pretreatment evaluation; medical management of active IBD; medical management of IBD in remission; management of IBD during the periconception period and pregnancy; surveillance strategies for colitis-associated cancer; monitoring side effects of thiopurines and methotrexate; and infections in IBD.

Background and aim Worldwide increasing aging societies have many elderlies with intractable diseases including ulcerative colitis (UC). Reportedly, each patients' frailty as well as chronological age is a clinical risk factor of elderly-onset UC (EOUC). Because malnutrition is one of the major manifestations of frailty, we aimed to investigate the effect of malnutrition on the prognosis of EOUC with geriatric nutritional risk index (GNRI), a prognostic tool for several diseases in the elderly to estimate malnutrition, and to evaluate clinical risks among EOUC patients in Japan, the world-leading aging society. Methods The EOUC patients (≥ 65 years at diagnosis, n = 2778) in the previous nationwide survey were classified by age and GNRI, and odds ratios (ORs) of hospitalization and UC-related surgery were determined to evaluate the effects of malnutrition on the EOUC patients as well as aging. Results The risks of hospitalization and surgery were elevated as age advanced. The value of GNRI, negatively correlated with disease activity (r = -0.53), could distinguish severe activity (cutoff ≤ 86.82, sensitivity = 0.79, and specificity = 0.77) and discriminate the EOUC patients suffering from surgery and hospitalization. In a multivariate analysis, GNRI ≤ 86.82 was a higher risk of hospitalization (OR: 4.0, 95% CI, 2.5-6.5) and surgery (OR: 2.7, 95% CI, 0.98-7.4) than cutoff age ≥ 75 years old (OR of hospitalization and surgery were 1.4 [95% CI, 0.99-2.0] and 2.3 [95% CI, 0.8-6.3], respectively). Conclusion Malnutrition estimated by GNRI was significantly related with poor clinical courses of the EOUC patients, suggesting that evaluation of nutritional status at the onset might be useful for predicting risks of clinical courses.

BACKGROUND AND AIM Tenofovir alafenamide (TAF) is a new prodrug of tenofovir, enabling treatment of patients with hepatitis B virus (HBV) infection at a lower dose than tenofovir disoproxil fumarate (TDF), via more efficient delivery of tenofovir to the hepatocytes. We compared the efficacy and safety of TDF and TAF and investigated switching from TDF to TAF therapy. METHODS Consent for TDF and TAF therapy was obtained from 117 and 67 patients from August 2014 to January 2018. In total, 45 and 14 patients were administered with TDF and TAF, respectively, as naive therapy, and 36 patients were switched from TDF to TAF. The antiviral effects and renal function safety were assessed. RESULTS At week 48, the antiviral effects on patients receiving TDF and TAF as naive therapy were similar in terms of reduction of HBV DNA (-5.6 ± 1.8 logIU/ml vs -5.0 ± 1.7 log IU/ml; P = 0.34) and hepatitis B surface antigen (-0.29 ± 0.64 logIU/ml vs -0.15 ± 0.42 logIU/ml; P = 0.71) levels. A significant decrease in the estimated glomerular filtration rate (eGFR) was seen at 48-week TDF treatment (-5.34 ± 7.69 ml/min/1.73 m2 ; P

Background and Aim CT‐P13, an infliximab (IFX) biosimilar, was approved for treatment of inflammatory bowel disease. However, no comparison with the originator IFX in this indication has been conducted in Japan where endemic levels of tuberculosis and hepatitis virus infection are not low. We evaluated the safety and efficacy in real‐world data of CT‐P13 and compared with originator IFX data in Japan. Methods In a prospective post‐marketing surveillance (PMS) study, patients who received CT‐P13 in a 28‐month period from January 2015 were followed up for 2 years. By conducting Japanese administrative database search (DBS) for the same period of PMS, data of the originator IFX including treatment persistence, tuberculosis incidence, and liver injury were analyzed retrospectively and compared with the corresponding PMS data of CT‐P13. Results CT‐P13 persistence in PMS (n = 640) and IFX persistence in DBS (n = 4113) were almost similar between patients who switched from the originator and patients who continued on the originator, and also between the biologics‐naïve patient groups. There were no differences in the incidences of tuberculosis and hepatic injury (Tuberculosis: 2 patients [0.31%] with CT‐P13, 10 patients [0.24%] with the originator, P = 0.75; Hepatic injury: 18.5% with CT‐P13, 15.4% with the originator, P = 0.22). Most of the patients with hepatic injury continued treatment in PMS and DBS at similar rates (80.8% vs 83.6%, P = 0.65). Conclusion The results of long‐term PMS of CT‐P13 compared with external reference data from an administrative database suggested that the biosimilar and its originator were comparably useful in real‐world clinical practice.

BACKGROUND AND AIM Studies on the characteristics of elderly-onset ulcerative colitis (EOUC) and non-elderly-onset ulcerative colitis (NEOUC) have reported conflicting findings. The aim of this study was to compare disease characteristics of EOUC and NEOUC by analyzing the database of the Japanese nationwide inflammatory bowel disease (IBD) registry. METHODS We analyzed the age of disease onset, sex, disease severity, and disease extent in patients with ulcerative colitis that were newly diagnosed and registered within 1 year between 2004 and 2009 (n = 28 179). We also analyzed the medical treatment, rate of IBD-related surgery, and postoperative complications. We compared them between younger than 65 years old (NEOUC group) and 65 years old or older (EOUC group) patients. RESULTS A total of 25 401 (90.1%) and 2778 (9.9%) patients were included in the NEOUC and EOUC groups, respectively. In the EOUC group, disease activity was significantly higher, and extent of pathological changes in the colon more extended significantly. Laboratory findings showed that inflammatory markers were elevated significantly in the EOUC group. The proportion of those with IBD-related hospitalization was significantly higher in the EOUC group (54.2% vs 35.7%, P

Background and Aim Takayasu arteritis (TA) is occasionally complicated with inflammatory bowel disease (IBD). This study assessed the endoscopic and genetic features of IBD complicated with TA (IBD-TA). Methods This study retrospectively reviewed the clinical charts of 142 TA patients (14 men and 128 women; median age 48.5 years [range, 18–97 years]). Human lymphocyte antigen (HLA) types and a single-nucleotide polymorphism rs6871626 in the IL12B gene were assessed in 101 and 81 patients with TA, respectively. Results Inflammatory bowel disease was diagnosed in 13 (9.2%) of the 142 patients. The endoscopic features of IBD-TA at initial diagnosis (n = 8) showed discontinuous and focal mucosal inflammations (n = 7, 87.5%), and only one case was diagnosed as ulcerative colitis (UC) at the first colonoscopy. In the genetic comparison of HLA class I between TA patients with IBD and those without IBD, HLA-B*52:01 and C*12:02 were more frequent in the IBD-TA group (P = 0.001 and P = 0.009, respectively). Meanwhile, HLA-DRB-1*15:02, DQA-1*01:03, DQB-1*06:01, and DPB-1*09:01 as HLA class II were positively associated with IBD-TA (P = 0.004, P = 0.019, P = 0.019, and P = 0.002, respectively). IL12B rs6871626 did not show an association with IBD-TA compared with that with TA without IBD. Conclusions The endoscopic findings of IBD-TA at initial diagnosis were atypical for UC or Crohn's disease. IBD-TA possessed the HLA haplotype, which had a susceptible effect on UC.

BACKGROUND AND AIM Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with an intractable, recurrent course. Although the goal of UC therapy has recently been to target mucosal healing, the molecular mechanism of mucosal healing remains unknown. In this study, we aimed to elucidate the molecular dynamics related to the proliferation and differentiation of intestinal epithelial cells during cytapheresis therapy in a short duration. METHODS Endoscopy was performed in 26 patients with UC in multicentre hospitals, and biopsy specimens were collected from the rectum before and within two weeks after leukocytapheresis (LCAP). The expression of representative proteins in intestinal epithelial cells and pathological findings was compared before and after LCAP. RESULTS The expression of caudal type homeobox 2 (CDX2) and a hes family bHLH transcription factor 1(HES1) markedly increased after LCAP. Patients with endoscopic improvement after LCAP showed the expression of CDX2 before LCAP. Moreover, the number of goblet cells significantly increased after LCAP. Patients without endoscopic improvement after LCAP did not show the expression of CDX2 before LCAP. However, the expression of CDX2 markedly increased after LCAP. CONCLUSION This study suggests that cytapheresis might induce CDX2 expression without affecting the cell proliferation, thus resulting in mucosal healing with goblet cell restoration.

Background and aim The treat-to-target strategy has emerged in ulcerative colitis management. Mucosal healing is the best target, albeit not in induction therapy of acute diseases as clinical conditions vary over a short duration. To determine the targets during induction therapy for acute ulcerative colitis, we identified markers to predict mucosal healing at 3 and 12 months of initiating the induction therapy. Methods This single-center prospective observational study enrolling 61 adult patients hospitalized for disease exacerbation collected the partial Mayo scores, ulcerative colitis endoscopic index of severity, fecal markers, and laboratory data (0 day, 2 weeks, and 3 and 12 months) of initiating induction therapy. Results At 2 weeks, patients with mucosal healing at 3 months had had lower partial Mayo and ulcerative colitis endoscopic index of severity scores and higher white blood cell count and total cholesterol than those without mucosal healing. At 3 months, patients with mucosal healing at 12 months had had lower partial Mayo and ulcerative colitis endoscopic index of severity scores than those without mucosal healing. A kinetic analysis demonstrated a difference in the partial Mayo scores and total cholesterol and albumin levels at 2 weeks and in the ulcerative colitis endoscopic index of severity, fecal calprotectin, and fecal immunochemical tests at 3 months between patients who achieved mucosal healing at 12 months and those who did not. Conclusions Partial Mayo scores and total cholesterol levels act as short-term therapeutic targets during induction therapy in patients with acute ulcerative colitis. Mucosal healing at 3 months correlates to longer time mucosal healing.

Studies on the characteristics of elderly-onset ulcerative colitis (EOUC) and non-elderly-onset ulcerative colitis (NEOUC) have reported conflicting findings. The aim of this study was to compare disease characteristics of EOUC and NEOUC by analyzing the database of the Japanese nationwide inflammatory bowel disease (IBD) registry.We analyzed the age of disease onset, sex, disease severity, and disease extent in patients with ulcerative colitis that were newly diagnosed and registered within 1 year between 2004 and 2009 (n = 28 179). We also analyzed the medical treatment, rate of IBD-related surgery, and postoperative complications. We compared them between younger than 65 years old (NEOUC group) and 65 years old or older (EOUC group) patients.A total of 25 401 (90.1%) and 2778 (9.9%) patients were included in the NEOUC and EOUC groups, respectively. In the EOUC group, disease activity was significantly higher, and extent of pathological changes in the colon more extended significantly. Laboratory findings showed that inflammatory markers were elevated significantly in the EOUC group. The proportion of those with IBD-related hospitalization was significantly higher in the EOUC group (54.2% vs 35.7%, P 0.001). The proportion of patients who were treated with corticosteroids was significantly higher in the EOUC group (36.7% vs 30.8%, P 0.001). Significantly more number of patients underwent IBD-related surgery in the EOUC group (0.68% vs 0.27%, P 0.001).Elderly patients show higher disease activity, with a higher proportion requiring IBD-related hospitalization and IBD-related surgery, according to the nationwide registry in Japan.

BACKGROUND AND AIM Fecal calprotectin (FC) is a useful marker for assessing the activity of intestinal inflammation. However, most studies have used ileocolonoscopy to evaluate the association of FC with intestinal inflammation, and it is not clear whether FC is useful for the evaluation of small-bowel Crohn's disease (CD). This study aimed to determine the usefulness of FC for predicting intestinal inflammation evaluated by balloon-assisted endoscopy (BAE), which can visualize the deep small intestine. METHODS This was a cross-sectional, observational study involving 69 CD patients, 39 of whom had only small-bowel disease. The extended simplified endoscopic activity score for Crohn's disease (eSES-CD) was calculated based on the findings of BAE. Mucosal healing was defined as an eSES-CD of 0. RESULTS In all CD patients, FC levels were correlated with the eSES-CD (r = 0.663, P

Background and Aim Interferon (IFN) λ plays an important role in innate immunity to protect against hepatitis C viral (HCV) infection. Single nucleotide polymorphisms (SNPs) near IL28B (IFNλ3) are strongly associated with treatment response to IFNα therapy in chronic hepatitis C (CHC) patients. Recently, IFNλ4 related to IL28B-unfavorable allele was discovered. However, the impact of IFNλs on CHC is unknown. We aimed to investigate the mechanism underlying responsiveness to IFN-based therapy in CHC associated with SNPs near IL28B. Methods We evaluated the basal mRNA levels and ex-vivo induction of IFNλ expression including IFNλ4 in peripheral blood mononuclear cells (PBMCs) from 50 CHC patients treated with pegylated-IFNα/RBV. Furthermore, we investigated the effect of IFNλ4 on induction of IL28B in vitro. Results When PBMCs were stimulated with IFNα and polyinosinic–polycytidylic acid, IL28B induction was significantly lower in patients with IL28B-unfavorable genotype (rs12979860 CT/TT) than those with IL28B-favorable genotype (rs12979860 CC; P = 0.049). IL28B induction was lower in nonresponders than in relapsers (P = 0.04), and it was also lower in nonsustained virological responder patients for triple therapy including NS3 protease inhibitors. IFNλ4 mRNA was detected in 12 of 26 patients with IL28B-unfavorable SNP, and IFNλ4 expression was associated with lower IL28B induction in patients with IL28B-unfavorable genotype (P = 0.04) and nonresponse to IFNα therapy (P = 0.003). Overexpression of IFNλ4 suppressed IL28B induction and promoter activation. Conclusions Impaired induction of IL28B, related to IFNλ4 expression in PBMCs of IL28B-unfavorable patients, is associated with nonresponse to IFNα-based therapy for hepatitis C viral infection.

Intestinal ultrasound (IUS) is a cheap, noninvasive, risk-free procedure that is significantly underutilized in the diagnosis and management of patients with inflammatory bowel disease (IBD) in the Asia-Pacific region. More cost-effective methods of monitoring disease activity are required in light of the increasing global burden of IBD (especially in Asia), the advent of personalized medicine, and the rising cost of healthcare. IUS is a prime example of a technique that meets these needs. Its common clinical applications include assessing the activity and complications of IBD. In continental Europe, countries such as Germany and Italy use this imaging tool as the standard of care and have integrated it into management protocols. There are formal training programs in these countries to train gastroenterologists in IUS, and it is used in an outpatient setting during patient consultations. Barriers to its use in the Asia-Pacific region include lack of experience and research data, and there are few established centers with active training programs. These concerns can be addressed by investing more in IUS service provision and by increasing allocation of resources toward local research and training. Increased uptake of IUS will ultimately benefit patients with IBD.

The various types of reprogrammed cells including ES cells and iPS cells are really promising option for regenerative medicine, while concerns about tumorigenicity or the difficulties to induce fully functional differentiation would support the importance of adult tissue stem cells as another physiological and safe option. However the practical applications of adult tissue stem cells for various clinical situations are limited mainly due to the dormancy of adult tissue stem cells. We have established the original culture protocol for murine adult colonic epithelial stem cells maintaining self-renewal and multi-differentiation properties. Furthermore a single Lgr5+ adult colonic epithelial stem cell was revealed to expand unrestrictedly in vitro and to regenerate functional normal epithelium in vivo. In addition, this epithelial transplantation showed the therapeutic benefits in acute colitis model. Our culture and transplantation technologies for intestinal stem cells will provide a new avenue of the adult tissue stem cell therapy for various gastrointestinal diseases such as inflammatory bowel diseases. These will be based on the technology of in vitro stem cell expansion from individual's biopsy samples.

Background and Aim Until the approval of patency capsule, capsule endoscopy (CE) has not been routinely applied for the diagnosis of Crohn's disease (CD) in Japan. We aimed to survey current situation of CE use for patients with CD in Japan. Methods The nationwide survey of 40 Japanese institutions identified 94 patients with established CD (eCD) and 80 patients with suspected CD (sCD), who were examined by CE. Types and positive rates of mucosal injury under CE and capsule retention rate were investigated. In sCD, final diagnosis after CE was also analyzed. Results Patients with eCD comprised 82 patients of ileitis or ileocolitis type, while 12 patients had CD of colitis type. CE identified mucosal injuries in 83 of 94 patients. Eight of 12 patients with eCD of colitis type had ileal lesions under CE, thereby being reclassified as ileocolitis type. In patients with sCD, CE detected mucosal injuries in 58 patients. Linear ulceration and cobblestone appearance were depicted in 22 and 3 patients, respectively, thereby resulting in established diagnosis of CD in 23 patients. Mucosal lesion was not found in 22 patients with sCD, who were diagnosed as not having CD. Capsule retention rate was not statistically different between patients with eCD and those with sCD (7.4% vs 6.3%, P = 1.0). Conclusions CE is useful for the evaluation of small bowel mucosal injuries in Japanese patients with sCD and eCD. Possible intestinal stricture needs to be carefully evaluated before CE even in patients with sCD.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with an intractable, recurrent course. Although the goal of UC therapy has recently been to target mucosal healing, the molecular mechanism of mucosal healing remains unknown. In this study, we aimed to elucidate the molecular dynamics related to the proliferation and differentiation of intestinal epithelial cells during cytapheresis therapy in a short duration.Endoscopy was performed in 26 patients with UC in multicentre hospitals, and biopsy specimens were collected from the rectum before and within two weeks after leukocytapheresis (LCAP). The expression of representative proteins in intestinal epithelial cells and pathological findings was compared before and after LCAP.The expression of caudal type homeobox 2 (CDX2) and a hes family bHLH transcription factor 1(HES1) markedly increased after LCAP. Patients with endoscopic improvement after LCAP showed the expression of CDX2 before LCAP. Moreover, the number of goblet cells significantly increased after LCAP. Patients without endoscopic improvement after LCAP did not show the expression of CDX2 before LCAP. However, the expression of CDX2 markedly increased after LCAP.This study suggests that cytapheresis might induce CDX2 expression without affecting the cell proliferation, thus resulting in mucosal healing with goblet cell restoration.

Takayasu arteritis (TA) is occasionally complicated with inflammatory bowel disease (IBD). This study assessed the endoscopic and genetic features of IBD complicated with TA (IBD-TA).This study retrospectively reviewed the clinical charts of 142 TA patients (14 men and 128 women; median age 48.5 years [range, 18-97 years]). Human lymphocyte antigen (HLA) types and a single-nucleotide polymorphism rs6871626 in the IL12B gene were assessed in 101 and 81 patients with TA, respectively.Inflammatory bowel disease was diagnosed in 13 (9.2%) of the 142 patients. The endoscopic features of IBD-TA at initial diagnosis (n = 8) showed discontinuous and focal mucosal inflammations (n = 7, 87.5%), and only one case was diagnosed as ulcerative colitis (UC) at the first colonoscopy. In the genetic comparison of HLA class I between TA patients with IBD and those without IBD, HLA-B*52:01 and C*12:02 were more frequent in the IBD-TA group (P = 0.001 and P = 0.009, respectively). Meanwhile, HLA-DRB-1*15:02, DQA-1*01:03, DQB-1*06:01, and DPB-1*09:01 as HLA class II were positively associated with IBD-TA (P = 0.004, P = 0.019, P = 0.019, and P = 0.002, respectively). IL12B rs6871626 did not show an association with IBD-TA compared with that with TA without IBD.The endoscopic findings of IBD-TA at initial diagnosis were atypical for UC or Crohn's disease. IBD-TA possessed the HLA haplotype, which had a susceptible effect on UC.

BACKGROUND: Crohn's disease (CD) is an inflammatory bowel disease that is associated with several changes in the immune system, including an increased number of infiltrating macrophages. These macrophages release a variety of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) which are critically involved in the onset and the development of CD. The present study was performed to explore the initial involvement of macrophages in the development of T-cell-mediated chronic colitis. METHODS: The effects were evaluated of saporin-conjugated anti-CD11b monoclonal antibody (mAb) on the development of chronic colitis in severe combined immunodeficiency (SCID) mice induced by adoptive transfer of CD4(+)CD45RB(high) T cells as an animal model of CD. RESULTS: Significantly increased CD11b-expressing macrophages as well as CD4(+) T cells were found in inflamed colon from colitic mice. Administration of saporin-conjugated anti-CD11b mAb markedly ameliorated the clinical and histopathological disease. In vivo treatment with saporin-conjugated anti-CD11b mAb decreased CD4(+) T-cell infiltration in the colon and suppressed interferon-gamma (IFN-gamma) and TNF-alpha production by lamina propria CD4(+) T cells. CONCLUSIONS: Collectively, the present results suggest an initial role of macrophages in the pathogenesis of T-cell-mediated chronic colitis. Furthermore, the macrophage-specific targeting may be a promising strategy for therapeutic intervention in CD.

Interferon (IFN) λ plays an important role in innate immunity to protect against hepatitis C viral (HCV) infection. Single nucleotide polymorphisms (SNPs) near IL28B (IFNλ3) are strongly associated with treatment response to IFNα therapy in chronic hepatitis C (CHC) patients. Recently, IFNλ4 related to IL28B-unfavorable allele was discovered. However, the impact of IFNλs on CHC is unknown. We aimed to investigate the mechanism underlying responsiveness to IFN-based therapy in CHC associated with SNPs near IL28B.We evaluated the basal mRNA levels and ex-vivo induction of IFNλ expression including IFNλ4 in peripheral blood mononuclear cells (PBMCs) from 50 CHC patients treated with pegylated-IFNα/RBV. Furthermore, we investigated the effect of IFNλ4 on induction of IL28B in vitro.When PBMCs were stimulated with IFNα and polyinosinic-polycytidylic acid, IL28B induction was significantly lower in patients with IL28B-unfavorable genotype (rs12979860 CT/TT) than those with IL28B-favorable genotype (rs12979860 CC; P=0.049). IL28B induction was lower in nonresponders than in relapsers (P = 0.04), and it was also lower in nonsustained virological responder patients for triple therapy including NS3 protease inhibitors. IFNλ4 mRNA was detected in 12 of 26 patients with IL28B-unfavorable SNP, and IFNλ4 expression was associated with lower IL28B induction in patients with IL28B-unfavorable genotype (P=0.04) and nonresponse to IFNα therapy (P=0.003). Overexpression of IFNλ4 suppressed IL28B induction and promoter activation.Impaired induction of IL28B, related to IFNλ4 expression in PBMCs of IL28B-unfavorable patients, is associated with nonresponse to IFNα-based therapy for hepatitis C viral infection.

Intestinal ultrasound (IUS) is a cheap, noninvasive, risk-free procedure that is significantly underutilized in the diagnosis and management of patients with inflammatory bowel disease (IBD) in the Asia-Pacific region. More cost-effective methods of monitoring disease activity are required in light of the increasing global burden of IBD (especially in Asia), the advent of personalized medicine, and the rising cost of healthcare. IUS is a prime example of a technique that meets these needs. Its common clinical applications include assessing the activity and complications of IBD. In continental Europe, countries such as Germany and Italy use this imaging tool as the standard of care and have integrated it into management protocols. There are formal training programs in these countries to train gastroenterologists in IUS, and it is used in an outpatient setting during patient consultations. Barriers to its use in the Asia-Pacific region include lack of experience and research data, and there are few established centers with active training programs. These concerns can be addressed by investing more in IUS service provision and by increasing allocation of resources toward local research and training. Increased uptake of IUS will ultimately benefit patients with IBD.

Background and Aim: Although molecular mechanisms underlying ulcerative colitis (UC)-associated neoplasms have been studied for years, understanding of these mechanisms remains incomplete and no good predictable marker for development of colonic neoplasms in patients with UC has been established. The aim of this study was to assess if microsatellite instability (MSI) contributes to the development of colonic neoplasms in patients with UC. Methods: We have examined MSI in chronic inflamed and neoplastic colonic mucosa of UC patients. We have also obtained serial biopsied colonic tissues retrospectively 2–12 years before the final diagnosis from patients with high level MSI (MSI-H+) UC-associated neoplasms, and analyzed MSI using them at different periods. Results: Eight of 12 UC-associated colon cancers (67%), four of six UC-associated high grade dysplasias (67%), and two of six UC-associated low grade dysplasias (33%) revealed MSI-H+ phenotypes. In contrast, 15 of 59 lesions (25%) in inflamed UC mucosa without colonic neoplasm revealed MSI-H +. Interestingly, all four patients with MSI-H+ phenotypes at the final diagnosis of UC-associated colon cancer or dysplasia had already had MSI-H+ at the stage of chronic colitis, 2–12 years before the final diagnosis. Conclusion: These results support the notion that MSI contributes to the carcinogenesis of UC-associated neoplasms, and indicate that this analysis in inflamed colonic mucosa at surveillance colonoscopy is useful for identifying UC patients who have high risk for neoplastic progression.

Background and Aims: The authors have previously shown that a third member of the CD28 family, inducible costimulator (ICOS), was increased in the inflamed intestinal mucosa of murine experimental colitis, and that the blockade of ICOS ameliorated the development of colitis. However, the role of ICOS in rat intestinal inflammation and its expression profile remains unclear. In the present study, the authors investigated the involvement of ICOS in the development of rat dextran sulfate sodium (DSS)-induced colitis, and the therapeutic potential of anti-ICOS monoclonal antibody (mAb) in colitis. Methods: The authors first examined expression of ICOS protein in normal rat by immunohistochemistry and flow cytometry. Sprague–Dawley rats were fed 3.0% DSS. The expression of ICOS on infiltrating lamina propria mononuclear cells and splenocytes were examined. The DSS-fed rats were then administered anti-ICOS mAb to test its effect on the development of colitis. Results: Unlike mice and human, ICOS was expressed on a part of CD4+ T-cells from the thymus, spleen, mesenteric lymph nodes and lamina propria. Levels of ICOS on CD4+ T-cells from the spleen and colonic lamina propria were significantly upregulated after Concanavalin A (Con A) stimulation. In addition, ICOS was also upregulated on CD4+ T-cells from DSS-fed rats compared with those from non DSS-fed rats. However, anti-ICOS mAb did not ameliorate the development of both acute and chronic DSS colitis. Conclusion: These results suggest that the different expression of ICOS in rats plays a distinct role in rat intestinal inflammation.

Background and Aim: Previous reports have indicated seasonal fluctuations in the incidence of peptic ulcer activity, but the reasons for the seasonal pattern are not clear. We assessed the seasonal incidence of hematemesis caused by peptic ulcers or gastroesophageal varices, and the correlations between those and climatic factors. Methods: We examined the number of cases of upper gastrointestinal (GI) bleeding caused by gastric ulcer (GU), duodenal ulcer (DU), or gastroesophageal varices (varix) diagnosed by urgent endoscopies between 1 January 1996 and 31 December 1999 in our hospital (Tokyo Metropolitan Bokutou Hospital). We evaluated the monthly and seasonal incidence of them and investigated correlations among the incidence and climatic factors. Results: Four hundred and forty-one patients participated in this study, including 275 patients with GU (62.4%), 51 (11.6%) with DU, and 115 (26.0%) with varix. The number of cases of hematemesis caused by GU showed significant monthly and seasonal fluctuations (P = 0.0002, P = 0.0018): it decreased in summer and increased in autumn–winter. Moreover, there were inverse relations between the monthly number of cases of hematemesis caused by GU and the mean temperature (P = 0.0016) and vapor pressure (P = 0.0013), and a parallel relation to the mean atmospheric pressure (P = 0.0057). In contrast, the number of cases of hematemesis caused by DU and varices did not show any monthly or seasonal fluctuations. Conclusions: We found that the incidence of hematemesis because of GU had an inverse relationship to temperature and vapor pressure, and had a parallel relation to atmospheric pressure. Therefore, climatic factors may play an important role in hemorrhage from GU.

Background and Aim: It has been a conflicting issue whether TT virus (TTV), a newly isolated DNA virus from a patient with liver injury of unknown cause, is a causative agent of acute and/or chronic hepatitis. TT Virus DNA titers were shown to be 10–100-fold greater in liver tissue than in serum, whereas the majority of TTV-positive cases had no biochemical or histological evidence of significant liver damage. We therefore attempted in situ hybridization to investigate whether TTV is hepatotropic. Methods: Because of the marked divergence in TTV genome types, a template for TTV-DNA (coding region for N22 clone) was amplified and labeled with digoxigenin-dUTP by using hemi-nested PCR from the serum, then DNA probes were applied to the liver sections of the same case. After hybridization, the probes were visualized immunohistochemically. Besides TTV-DNA-negative cases, competitive inhibition experiments with unlabeled probes were performed to confirm the specificity. Results There were no positive signals in the negative controls, and the intensity of positive signals was markedly diminished in the competitive inhibition experiments. No cross-hybridization with different genotype probes also confirms the specificity. Under the optimal conditions, the positive signals were located in the cytoplasm of the hepatocytes in eight of nine TTV-DNA-positive cases. The signals were not seen in non-parenchymal cells of the liver. Conclusion: TT Virus is proved to be hepatotropic by in situ hybridization.

Until the approval of patency capsule, capsule endoscopy (CE) has not been routinely applied for the diagnosis of Crohn's disease (CD) in Japan. We aimed to survey current situation of CE use for patients with CD in Japan.The nationwide survey of 40 Japanese institutions identified 94 patients with established CD (eCD) and 80 patients with suspected CD (sCD), who were examined by CE. Types and positive rates of mucosal injury under CE and capsule retention rate were investigated. In sCD, final diagnosis after CE was also analyzed.Patients with eCD comprised 82 patients of ileitis or ileocolitis type, while 12 patients had CD of colitis type. CE identified mucosal injuries in 83 of 94 patients. Eight of 12 patients with eCD of colitis type had ileal lesions under CE, thereby being reclassified as ileocolitis type. In patients with sCD, CE detected mucosal injuries in 58 patients. Linear ulceration and cobblestone appearance were depicted in 22 and 3 patients, respectively, thereby resulting in established diagnosis of CD in 23 patients. Mucosal lesion was not found in 22 patients with sCD, who were diagnosed as not having CD. Capsule retention rate was not statistically different between patients with eCD and those with sCD (7.4% vs 6.3%, P = 1.0).CE is useful for the evaluation of small bowel mucosal injuries in Japanese patients with sCD and eCD. Possible intestinal stricture needs to be carefully evaluated before CE even in patients with sCD.

The study was designed to examine the changes of thymus in sulfhydryl blocker-induced colitis. We used N-ethylmaleimide (NEM) as sulfhydryl blockers. Fasted male Sprague-Dawley rats were given 3% NEM in 1% methyl cellulose into the colon. N-ethylmaleimide treatment caused severe diarrhoea with bleeding for the first 7 days. At autopsy, adhesions, colon dilatation, and single or multiple erosions and ulcers were observed. Time-course studies revealed that the lesions were most extensive and severe 3 or 7 days after the administration of NEM. Histological examination of colon on the 3rd day after NEM treatment demonstrated mucosal erosion, oedema and extensive infiltration of neutrophils. The mucosal lesions extended into the submucosa and muscle on the 7th day after NEM treatment. Immunohistochemical studies showed that T cells and macrophages were markedly increased in the lamina propria of colonic mucosa. After 3 weeks, the infiltration of chronic inflammatory cells was observed and regeneration of the mucosa was noticed. The thymus gland was significantly decreased in weight and size on the 3rd day after NEM treatment, but the weight loss of thymus gland was regained in 3 weeks. Transient atrophy of thymus gland was noticed in this colitis model. The phenotypes of thymocytes were not influenced by NEM treatment. It is concluded that the thymus abnormalities in human ulcerative colitis are not induced in this animal model and that other chronic models are necessary for the elucidation of the immunological abnormalities, including thymus abnormalities.

Background and Study Aims: Double-balloon endoscopy (DBE) is a new device that allows diagnosis and treatment throughout the entire small intestine. Although the originally described method requires two operators, we have recently developed a method to perform DBE by a single operator. We here assessed the clinical usefulness of this one-person method in comparison to the conventional two-person DBE. Patients and Methods: One hundred sixty-two patients (102 men and 60 women, mean age 59 years) underwent 303 DBE procedures. Total observation time, completion rate of total intestinal and colonic observation, lesion-discovery rate, and complication rate were retrospectively compared between the one-person method and the conventional two-person method of DBE. The one-person method consists of the Grip and Pinch technique and Keep (or Hold) and Slide technique. Results: The total observation times were 95.5 ± 35.1 min and 96.7 ± 47.5 min by one-person and two-person antegrade DBE, respectively, and 103 ± 29.8 min and 111 ± 30.1 min by one-person and two-person retrograde DBE, respectively. The completion rate for examination of the entire small intestine was 74.2% in one-person DBE and 76.5% in two-person DBE, respectively. The lesion-discovery rate was 69.0% in one-person DBE and 65.5% in two-person DBE, respectively. No significant differences between two methods were found in all measures. Also, no difference was observed in complication rate of the two methods. Conclusions: The single-operator method for DBE was as efficient as the dual-operator DBE without any higher risk of complications and, therefore, could replace the conventional dual-operator method in the future.

Background and Aim: Combination treatments of interferon-alpha (IFN) and ribavirin (RBV) are more effective than those of IFN alone in hepatitis C virus (HCV) infection. However, mechanisms of the action of the combination regimen are not well understood. To elucidate the viral genetic basis of IFN plus RBV combination therapy, genetic variabilities of HCV-1b were analyzed. Methods: We performed pair-wise comparisons of full-length HCV genomic sequences in three patients’ sera before and after initiation of IFN plus RBV treatment. Subsequently, we analyzed amino acid sequences of the NS5B region, which codes for the viral RNA-dependent RNA polymerase, and compared these with the outcomes of the therapy in 81 patients. Results: Analysis of the entire HCV sequence in patients who received IFN plus RBV therapy did not show consistent amino acid changes between before and after the initiation of the therapy. NS5B sequence analyses revealed that mutations at positions 300–358 of NS5B, including polymerase motif B to E, occurred more frequently in a group of patients exhibiting a sustained viral response (SVR) or an end-of-treatment response (ETR) compared with a group of patients exhibiting a non-response (NR). Closer examination revealed that mutations at aa 309, 333, 338 and 355 of NS5B occurred significantly more frequently in the SVR plus ETR group than in the NR group (P = 0.0004). Multivariate analysis showed that the number of mutations at these four sites was an independent predictor of SVR plus ETR versus NR. Conclusions: Particular amino acid changes in the NS5B region of HCV may correlate with outcomes of IFN plus RBV combination therapy. © 2005 Blackwell Publishing Asia Pty Ltd

Background and Aim: The authors have previously shown that production of interleukin (IL)-18 was increased in the inflamed mucosa of patients with Crohn's disease (CD) and blockade of IL-18 ameliorated the murine model of CD. This demonstrated that IL-18 plays a significant role during intestinal inflammation. However, the initial role of IL-18 during intestinal inflammation was unclear; therefore the susceptibility of IL-18 transgenic (Tg) mice to acute dextran sulfate sodium (DSS)-induced colitis was examined. Methods: Interleukin-18 Tg and wild-type (WT) mice were fed 2.0% of DSS for 8 days. The total clinical scores (bodyweight loss, stool consistency, and rectal bleeding), colon length and histological scores were assessed. The expressions of surface markers and IL-18 on infiltrating lamina propria mononuclear cells were analyzed immunohistochemistrically. Mesenteric lymph node (MLN) cells were isolated and the expressions of CD4+ T-cell activation markers (CD69, CD25 and IL18R) were analyzed by flow cytometry. Results: The IL-18 Tg mice exhibited an increased susceptibility to DSS-induced colitis, as shown by significantly increased clinical, histological scores, and more severe colonic shortening compared with WT mice. Immunohistochemical analysis revealed a significant increase of IL-18 production and CD11b+ macrophages but not CD4+ T cells in the inflamed mucosa in DSS-fed IL-18 Tg compared with DSS-fed WT mice. Furthermore, MLN cells revealed no evidence of increased CD4+ T-cell activation in DSS-fed IL-18 Tg. Conclusions: These findings suggest that IL-18 overproduction in the mucosa plays an important role in the marked infiltration of macrophages and exacerbates colitis in IL-18 Tg mice.

Background and Aim: The route of person-to-person transmission of Helicobacter pylori may be either fecal–oral or oral–oral, because the bacterium is found in both dental plaque and feces. We assessed the prevalence of H. pylori seropositivity, which reflects present or past infection, in Japanese dentists exposed occupationally to dental plaque. Methods: We examined the sera of 60 dentists (34 who were 20–29 years or older, and 26 who were over 30 years of age) and 60 age-matched controls by using quantitative ELISA for antibodies of the immunoglobulin G class to H. pylori. Results: The proportion of dentists seropositive for H. pylori (42 of 60, 70%) was higher than in controls (23 of 60, 38%). The odds ratio for H. pylori seropositivity (3.8; 95% CI, 1.76–8.02) was high in the dentists. When dentists were classified in terms of the length of their practice, the odds ratio for seropositivity (10.4; 95% CI, 3.26–32.85) was high in the dentists practising for fewer than 4 years. The proportion of dentists in their 20s who were seropositive was greater than that in the group of age-matched controls. Conclusion: Japanese young dentists are at a high risk for H. pylori infection, with the oral–oral transmission route being possibly the most common.