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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.

STUDY AIMS The PillCam patency capsule (PPC) is an Agile tag-less patency capsule used to evaluate gastrointestinal (GI) patency. We determined the appropriate use of PPC to preclude subsequent small bowel capsule endoscopy (SBCE) retention. METHODS This prospective multicenter study consecutively enrolled patients indicated for SBCE with suspected or established small bowel stenosis. Excretion of an intact PPC or its radiologic visualization in the large bowel was considered GI patency. Primary and secondary study endpoints were SBCE retention rates in patients with confirmed patency and identification of factors associated with patency and SBCE retention, respectively. RESULTS Of 1096 patients enrolled in the study, patency was confirmed in 976 (89.1%). PPC excretion occurred in 579 patients. Of the remaining 517 patients, patency was confirmed using imaging modalities in 401 (77.5%). SBCE retention occurred in five (0.51%) of 963 patients who underwent SBCE: 1.0% in established Crohn's disease (CD) patients, 0% in suspected CD, 0% in tumors, and 1.6% in patients with obscure GI bleeding, for which PPC localization had been radiographically misinterpreted. The non-confirmation of patency was associated with established CD, stenosis identified using imaging modalities, abdominal fullness, serum albumin levels

Background Dietary fatty acids can affect chronic intestinal inflammation and have been reported to be associated with the development of ulcerative colitis (UC), mainly in Europe and the United States. The association of dietary intake of fatty acids and the risk for UC was investigated in Japan, where dietary habits lead to lower meat and higher fish consumption than in Western countries. Methods A multicenter case-control study of 83 newly diagnosed patients with UC and 128 age- and sex-matched control patients in the hospital was conducted from 2008 to 2014. Dietary fatty acid intake in the preceding 1 month and 1 year were examined using a self-administered diet history questionnaire that was developed for Japanese people. Results About 92% of patients had experienced the first symptoms of UC within the preceding 11 months. Regarding dietary habits in the preceding year, the risk for UC was significantly decreased in patients who consumed n-6/n-3 polyunsaturated fatty acids at a ratio of ≥5.2 (odds ratio [OR] = 0.26; 95% confidence interval [CI], 0.10-0.68). Conversely, an increased risk for UC was observed in the highest tertiles of consumption of docosahexaenoic acid (OR = 7.22; 95% CI, 2.09-24.95), eicosapentaenoic acid (OR = 6.91; 95% CI, 1.88-25.44), and docosapentaenoic acid (OR = 4.83; 95% CI, 1.56-14.95). Conclusions The ratio of n-6/n-3 polyunsaturated fatty acid intake was associated with a decreased risk for UC development. However, high intakes of docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid may increase the risk for UC development.

Introduction Selective blockade of the integrins and mucosal adhesion molecules is a promising therapeutic strategy for ulcerative colitis (UC). Vedolizumab (VDZ), a humanized IgG1 monoclonal antibody against α4β7 integrin, selectively blocks the trafficking of the leukocytes into the gastrointestinal tract through its binding with the α4β7 integrin. Aim In this review, we provide an overview of the unique mechanism of VDZ, along with its efficacy, safety, and pharmacokinetic and pharmacodynamic data obtained from clinical trials, observational studies, and meta-analyses. Evidence review A positive exposure-efficacy relationship with regard to clinical remission and clinical response was apparent in VDZ induction therapy. No drug-specific safety signals are currently available. Place in therapy VDZ has been shown to be effective as first- or second-line induction and maintenance therapy in UC. Conclusion VDZ is a safe and effective treatment option for patients with UC. Prolonged VDZ induction therapy may contribute to improved outcomes in patients with UC, particularly those previously treated with tumor necrosis factor-α. Prospective head-to-head study of VDZ and other biologics would alter the positioning of VDZ much more clearly.

BACKGROUND We recently reported on a hereditary enteropathy associated with a gene encoding a prostaglandin transporter and referred to as chronic enteropathy associated with SLCO2A1 gene (CEAS). Crohn’s disease (CD) is a major differential diagnosis of CEAS, because these diseases share some clinical features. Therefore, there is a need to develop a convenient screening test to distinguish CEAS from CD. AIM To examine whether prostaglandin E major urinary metabolites (PGE-MUM) can serve as a biomarker to distinguish CEAS from CD. METHODS This was a transactional study of 20 patients with CEAS and 98 patients with CD. CEAS was diagnosed by the confirmation of homozygous or compound heterozygous mutation of SLCO2A1. We measured the concentration of PGE-MUM in spot urine by radioimmunoassay, and the concentration was compared between the two groups of patients. We also determined the optimal cut-off value of PGE-MUM to distinguish CEAS from CD by receiver operating characteristic (ROC) curve analysis. RESULTS Twenty Japanese patients with CEAS and 98 patients with CD were enrolled. PGE-MUM concentration in patients with CEAS was significantly higher than that in patients with CD (median 102.7 vs 27.9 μg/g × Cre, P < 0.0001). One log unit increase in PGE-MUM contributed to 7.3 increase in the likelihood for the diagnosis of CEAS [95% confidence interval (CI) 3.2-16.7]. A logistic regression analysis revealed that the association was significant even after adjusting confounding factors (adjusted odds ratio 29.6, 95%CI 4.7-185.7). ROC curve analysis revealed the optimal PGE-MUM cut-off value for the distinction of CEAS from CD to be 48.9 μg/g × Cre with 95.0% sensitivity and 79.6% specificity. CONCLUSION PGE-MUM measurement is a convenient, non-invasive and useful test for the distinction of CEAS from CD.

Background: Early detection of ulcerative colitis-associated neoplasia (UCAN) is often difficult. The aim of this study was to clarify the morphology of initial UCAN. Methods: White-light colonoscopy images obtained within the 2 years before UCAN diagnosis were retrospectively reviewed. The primary endpoint was the frequency of visible or invisible neoplasia on the endoscopic images before UCAN diagnosis. The secondary endpoints were comparisons of (1) visible or invisible neoplasia on initial endoscopic images of early-stage and advanced cancers, (2) the clinical backgrounds of patients in whom neoplasia was visible or invisible on initial endoscopic images, and (3) the clinical backgrounds of patients with distinct and indistinct UCAN borders. Results: Of the 27 UCAN lesions (11 early-stage, 16 advanced-stage), 25.9% (n = 7) were initially visible and 74.1% (n = 20) were invisible. The mean interval between the last surveillance colonoscopy and UCAN diagnosis was 14.5 ± 6.7 months. Of early-stage cancers, 18.2% (n = 2) were visible and 81.8% (n = 9) were invisible. Of advanced-stage cancers, 31.3% (n = 5) were visible and 68.8% (n = 11) were invisible. Invisible lesions were significantly more common in the rectum (p = 0.011) and tended to be more common in patients with inflammation and left-sided colitis (p = 0.084, p = 0.068, respectively). Patients with indistinct UCAN borders were significantly more likely to present with inflammation than those with distinct UCAN borders (p = 0.021). Conclusion: More careful surveillance is needed because rectum lesions and inflammation are difficult to identify as neoplasia even within the 2 years before a UCAN diagnosis.

Background and Aim: To evaluate the onset of symptomatic response with vedolizumab in patients with moderate-to-severe ulcerative colitis in Japan. Methods: Patients were randomized to receive vedolizumab 300 mg or placebo at Weeks 0, 2, and 6. Mayo subscores were analyzed in patients with baseline stool frequency (SF) ≥1 and rectal bleeding (RB) ≥1. In patients with baseline SF ≥2 and RB ≥1, the proportion who achieved SF ≤1 and RB = 0 was determined. Results: Patients were randomized to vedolizumab (n = 164) or placebo (n = 82). Decrease from baseline in mean SF subscore was greater with vedolizumab versus placebo from Week 2 (−6.6%; 95% confidence interval [CI], −16.2, 3.0), with a greater difference in anti-tumor necrosis factor (TNF)α-naive patients (vedolizumab vs. placebo, −13.2%; 95% CI, −29.7, 3.3). Mean percentage decrease from baseline RB subscore was numerically greater with vedolizumab versus placebo from Week 6 in anti-TNFα-naive patients (−10.7%; 95% CI, −33.0, 11.5). More patients in the anti-TNFα-naive subgroup achieved SF ≤1 and RB = 0 with vedolizumab versus placebo at Week 2 (14.8%; 95% CI, 2.5, 27.0) and Week 6 (20.3%; 95% CI, 4.4, 36.2). Patients with SF ≤1 and RB = 0 at Week 2 had higher clinical response, clinical remission, and mucosal healing rates at Week 10 than those without. Conclusions: Our results indicate that vedolizumab induces a rapid symptomatic response, particularly in anti-TNFα-naive patients, and suggest that early symptomatic improvement predicts treatment response at Week 10 (NCT02039505).

Background Capsule endoscopy can be used to identify the early stage of small bowel Crohn’s disease (CD). We evaluated significant small bowel capsule endoscopy (SBCE) findings that can lead to early diagnosis of CD. Methods We retrospectively accumulated clinical and SBCE data of 108 patients (63 with and 45 without CD). Types of small bowel mucosal injuries, including erosion, ulceration, and cobblestone appearance, and the alignment of diminutive lesions were compared between patients with and without CD. Inter- and intra-observer agreement in the determination of lesions was assessed in 25 pairs of SBCE from the two groups. Results Under SBCE, cobblestone appearance (33% vs. 2%, p

Crohn's disease (CD) and ulcerative colitis (UC) are the major types of chronic inflammatory bowel disease (IBD) characterized by recurring episodes of inflammation of the gastrointestinal tract. Although it is well established that human leukocyte antigen (HLA) is a major risk factor for IBD, it is yet to be determined which HLA alleles or amino acids drive the risks of CD and UC in Asians. To define the roles of HLA for IBD in Asians, we fine-mapped HLA in 12 568 individuals from Korea and Japan (3294 patients with CD, 1522 patients with UC and 7752 controls). We identified that the amino acid position 37 of HLA-DRβ1 plays a key role in the susceptibility to CD (presence of serine being protective, P = 3.6 × 10-67, OR = 0.48 [0.45-0.52]). For UC, we confirmed the known association of the haplotype spanning HLA-C*12:02, HLA-B*52:01 and HLA-DRB1*1502 (P = 1.2 × 10-28, OR = 4.01 [3.14-5.12]).

Background/Aims Colonic diverticular hemorrhage (DH) was a rare disease until the 1990s, and its incidence has increased rapidly since 2000 in Japan. In recent years, colonic DH has been the most frequent cause of lower gastrointestinal bleeding (LGIB). Nearly all cases of DH are mild, with the bleeding often stopping spontaneously. Some cases, however, require surgery or arterial embolization. In this study, using a cohort at Fukuoka University Chikushi Hospital, we investigated factors associated with severe colonic DH. Methods Among patients with LGIB who underwent colonoscopy at our hospital between 1995 and 2013, DH was identified in 273 patients. Among them, 62 patients (22.7%) were defined as having severe colonic DH according to recurrence of bleeding in a short period, and/or the necessity of transfusion, arterial embolization, or surgery. We then evaluated risk factors for severe DH among DH patients in this retrospective cohort. Results Among the 273 patients with DH, use of non-steroidal anti-inflammatory drugs (NSAIDs) (odds ratio [OR], 2.801; 95% confidence interval [CI], 1.164-6.742), Charlson Risk Index (CRI) ≥2 (OR, 3.336; 95% CI, 1.154-7.353), right-sided colonic DH (OR, 3.873; 95% CI, 1.554-9.653), and symptoms of cerebral hypoperfusion (such as light-headedness, dizziness, or syncope) (OR, 2.926; 95% CI, 1.310-6.535) showed an increased risk of severe DH even after controlling for other factors. Conclusions Severe DH occurred in 23% of DH patients, and NSAID use, CRI ≥2, right-sided colonic DH, and symptoms of cerebral hypoperfusion are suggested to be predictors of severe DH.

Background and study aims The non-extension sign relates to a localized increase in thickness and rigidity due to deep submucosal invasive (SM-d: depth of 1000 μm or more) cancer. The present study aimed to evaluate the efficacy of the non-extension sign in assessing the optical diagnosis of colorectal SM-d cancer. Patients and methods We retrospectively analyzed 309 patients with 315 early colorectal cancers that had been endoscopically or surgically resected. The non-extension sign was judged from chromoendoscopy (CE) using conventional white-light imaging with indigo carmine, and is taken to be positive when any one of the findings of rigidity of a circular arc, trapezoid elevation, or converging mucosal folds are seen. We assessed comparing the accuracy of CE, magnifying chromoendoscopy (M-CE), and magnifying narrow-band imaging (M-NBI) for the optical diagnosis of colorectal SM-d cancer. Results Sensitivity, specificity, and accuracy for the diagnosis of SM-d cancer were 66.0 %, 95.8 %, and 86.3 % for CE; 80 %, 90.7 %, and 87.3 % for M-CE; and 65.0 %, 94.4 %, and 85.1 % for M-NBI, respectively. The specificity of CE was significantly higher than that of M-CE (P = 0.034). The sensitivity of M-CE was significantly higher than that of CE (P = 0.026). In a comparison of positive and negative groups for the non-extension sign in SM-d cancer, SM invasion was significantly deeper in the positive group than in the negative group (3012.5 μm vs 2002.4 μm, respectively; P Conclusions The non-extension sign offers high diagnostic specificity for SM-d cancer, and surgery should be considered in patients with a positive non-extension sign.

Background: Capsule endoscopy (CE) has allowed the characterization of small bowel lesions. However, small bowel lesions in ulcerative colitis (UC) have not been elucidated and no studies have compared between UC and Crohn’s disease (CD). Aim: The objective of this study was to investigate the small bowel lesions in UC, and to characterize UC lesions by comparison with CD. Methods: Subjects comprised 54 UC patients and 39 CD patients who underwent CE. We retrospectively investigated characteristics of small bowel lesions in UC. We also compared endoscopic findings and degree of inflammation between UC and CD. Results: The incidence of small bowel lesions in UC was 27.8%. The group with small bowel lesions exhibited higher endoscopic activity in the colon than without small bowel lesions (p = 0.002). Comparing small bowel lesions between UC and CD, significantly more ulcerative lesions, notched appearance, longitudinal tendency of lesions, and cobblestone appearance were seen in CD. The Lewis score was significantly higher in CD than UC in the second and third tertiles (205 ± 379 vs. 73 ± 223, p = 0.01; 358 ± 449 vs. 105 ± 333, p < 0.001). Conclusions: Small bowel lesions in UC were linked to colonic activity. UC and CD differ in terms of the morphology and distribution of small bowel lesions.

Background Rhinovirus (RV) is a major respiratory virus that poses a threat to immunocompromised people and those with underlying disease. However, there are no approved therapies. Moreover, RV infection cannot be prevented by a vaccine because there are over 100 serotypes. Here we report the pharmacological profile of a novel small-molecule host-targeted antiviral (HTA), KRP-A218 (A218). A highly potent and selective inhibitor of phosphatidylinositol 4 kinase beta (PI4KB), a key host factor of RV replication, A218 is undergoing clinical study. Methods in vitro antiviral activities of A218 and Vapendavir (Vap), a virus-targeted antiviral, were examined by inhibition of CPE, viral load, or replication. in vivo antiviral activity and pathological analysis of A218 were examined in coxsackievirus B3 (CVB3; belong to the genus enterovirus as with RV)-infected mice as a surrogate model of RV infection as CVB3, unlike RV, replicates very well in both mouse and human tissue. Daily oral dosing of A218 (1-10 mg/kg) was started 2 days post intraperitoneal infection with CVB3. Tissue viral load, pancreas pathological change at 4 days post infection, and survival rate up to 14 days were evaluated. PI4KB heterozygous kinase-dead mice (PI4KB KD) were established by a CRISPR-Cas9 system. Viral load and survival rate following viral infection were evaluated in these mice. Results A218 showed broad antiviral activity for RV and enteroviruses (Table) and has a higher barrier to drug resistance than Vap. These results are consistent with expectations for HTAs. Repeated dosing of A218 starting 2 days post infection decreased viral load and improved acute pancreatitis, accompanied by decrease of inflammatory and pancreatitis markers in plasma. Moreover, therapeutic dosing of A218 improved survival rate in a CVB3-infected lethal mouse model (Figure). These results show the first evidence that a PI4KB inhibitor has potent therapeutic efficacy in a severe viral infection model. Similar effects were observed in PI4KB KD, supporting the on-target effect of A218. Table. Antiviral activity of A218 and Vap against RV/EV infection Figure. Therapeutic effect of A218 on survival rate in CVB3-infected mice Conclusion A218 is a promising therapeutic agent for improving the exacerbation of pathological conditions caused by RV infection. Nonclinical package including GLP-Tox also supports the ongoing first-in-human study of A218. Disclosures Toshiyuki Matsui, MPharm, Kyorin pharmaceutical Co., LTD (Employee) Motomichi Fujita, PhD, Kyorin Pharmaceutical Co., Ltd. (Employee) Yuji Ishibashi, PhD, Kyorin Pharmaceutical co., ltd. (Employee) Tyzoon Nomanbhoy, PhD, ActivX Biosciences (Other Financial or Material Support, Full time employee of ActivX, a wholly owned subsidiary of Kyorin Pharmaceuticals) Jonathan S. Rosenblum, PhD, ActivX Biosciences (Employee) Michiaki Nagasawa, PhD, Kyorin Pharmaceutical Co., Ltd (Employee)

Background and Aims The international Inflammatory Bowel Disease (IBD) Expert Alliance initiative (2012–2015) served as a platform to define and support areas of best practice in IBD management to help improve outcomes for all patients with IBD. Methods During the programme IBD specialists from around the world established by consensus two best practice charters: the 5S Principles and 5C Concept. Results The 5S Principles were conceived to provide healthcare providers with key guidance for improving clinical practice based on best management approaches. They comprise the following categories: Stage the disease; Stratify patients; Set treatment goals; Select appropriate treatment; and Supervise therapy. Optimised management of patients with IBD based on the 5S Principles can be achieved most effectively within an optimised clinical care environment. Guidance on optimising the clinical care setting in IBD management is provided through the 5C Concept, which encompasses: Comprehensive IBD Care; Collaboration; Communication; Clinical nurse specialists; and Care Pathways. Together, the 5C Concept and 5S Principles provide structured recommendations on organising the clinical care setting and developing best-practice approaches in IBD management. Conclusion Consideration and application of these two dimensions could help healthcare providers optimise their IBD centres, and collaborate more effectively with their multidisciplinary team colleagues and patients, to provide improved IBD care in daily clinical practice. Ultimately, this could lead to improved outcomes for patients with IBD.

Crohn's disease (CD) involves chronic inflammation in the gastrointestinal tract due to dysregulation of the host immune response to the gut microbiome. Even though the host-microbiome interactions are likely contributors to the development of CD, a few studies have detected genetic variants that change bacterial compositions and increase CD risk. We focus on one of the well-replicated susceptible genes, tumor necrosis factor superfamily member 15 (TNFSF15), and apply statistical analyses for personal profiles of genotypes and salivary microbiota collected from CD cases and controls in the Ryukyu Islands, southernmost islands of the Japanese archipelago. Our association test confirmed the susceptibility of TNFSF15 in the Ryukyu Islands. We found that the recessive model was supported to fit the observed genotype frequency of risk alleles slightly better than the additive model, defining the genetic effect on CD if a pair of the chromosomes in an individual consists of all risk alleles. The combined analysis of haplotypes and salivary microbiome from a small set of samples showed a significant association of the genetic effect with the increase of Prevotella, which led to a significant increase of CD risk. However, the genetic effect on CD disappeared if the abundance of Prevotella was low, suggesting the genetic contribution to CD is conditionally independent given a fixed amount of Prevotella. Although our statistical power is limited due to the small sample size, these results support an idea that the genetic susceptibility of TNFSF15 to CD may be confounded, in part, by the increase of Prevotella.

The first ever genome-wide association study (GWAS) of ulcerative colitis in genetically distinct north Indian population identified two novel genes namely CFB and SLC44A4. Considering their biological relevance, we investigated allelic/genetic heterogeneity in these genes among ulcerative colitis cohorts of north Indian, Japanese and Dutch origin using high-density ImmunoChip case–control genotype data. Comparative linkage disequilibrium profiling and test of association were performed. Of the 28 CFB SNPs, similar strength of association was observed for rs4151657 (novel ulcerative colitis GWAS SNP) in north Indians (P=1.73 × 10−10) and Japanese (P=2.02 × 10−12) but not in the Dutch. Further, a three-marker haplotype was shared between north Indians and Japanese (P

Background Chronic enteropathy associated with SLCO2A1 gene (CEAS) is an autosomal recessive disease caused by mutations in the SLCO2A1 gene which encodes a prostaglandin transporter. It is a rare intractable disease characterised by persistent blood and protein loss due to the small intestinal ulcers. Because CEAS mimics Crohn’s disease (CD) concerning ileal ulcers and stenoses, it is often difficult to distinguish CEAS from CD based on gastrointestinal findings alone. Furthermore, SLCO2A1 gene mutations are also known to cause primary hypertrophic osteoarthropathy (PHO) and some CEAS patients manifest digital clubbing, periostosis, acroosteolysis, and thickened skin as extra-intestinal manifestations. Since little is known about the clinical features of CEAS, we conducted a nationwide survey in Japan. Methods All study participants provided written informed consent for genetic analysis. The present study was approved by the ethics committee of each institution. During the period between 2012 and 2019, 141 patients suspected of CEAS were enrolled in this study and checked to have SLCO2A1 gene mutations. We reviewed the clinical information of genetically confirmed CEAS patients. Results We confirmed 61 CEAS patients (21 males and 40 females) and found 14 different types of recessive SLCO2A1 mutations. The median age at disease onset and diagnosis was 18.5 (range 1–69) and 40 (range 7–70) years, respectively. Parental consanguinity was present in 16 patients (26%). Although anaemia was present in almost all patients, only two patients experienced gross haematochezia. The median haemoglobin and serum protein levels at diagnosis were 9.7 (range 2.3–13.7) and 5.2 (2.7–8.2) g/dl, respectively. Thirty-three patients (54%) had undergone intestinal surgery. They showed relatively low inflammatory markers in blood tests (median CRP, 2.9 mg/l). The most frequently involved gastrointestinal site was ileum (93%), but the terminal ileum was rarely involved (Figure). Mild digital clubbing or periostosis was found in 16 patients (26%), with six male patients fulfilling the major diagnostic criteria of PHO. The major manifestations of PHO were more frequently found in males than in females (digital clubbing 57% vs. 10%; periostosis 52% vs. 11%; pachydermia 62% vs. 0%). Conclusion Although CEAS frequently causes intestinal strictures like CD, its clinical features seem to be distinct from those of CD. Also, a gender difference in clinical symptoms needs to be considered, because concurrent PHO can be frequently seen especially in male patients with CEAS.

We study the electronic structure of p-trifluoromethylphenyl nitronyl nitroxide (p-CF3PNN), which forms a one-dimensional alternating antiferromagnetic chain of molecules, using angle-resolved photoemission spectroscopy. A singly occupied molecular orbital (SOMO) is observed clearly at ∼ 2 eV in the valence-band spectra. The small band gap and the overlap between the SOMO orbitals in the NO groups are associated with the antiferromagnetic interaction between neighboring spins.

Introduction Selective blockade of the integrins and mucosal adhesion molecules is a promising therapeutic strategy for ulcerative colitis (UC). Vedolizumab (VDZ), a humanized IgG1 monoclonal antibody against α4β7 integrin, selectively blocks the trafficking of the leukocytes into the gastrointestinal tract through its binding with the α4β7 integrin. Aim In this review, we provide an overview of the unique mechanism of VDZ, along with its efficacy, safety, and pharmacokinetic and pharmacodynamic data obtained from clinical trials, observational studies, and meta-analyses. Evidence Review A positive exposure–efficacy relationship with regard to clinical remission and clinical response was apparent in VDZ induction therapy. No drug-specific safety signals are currently available. Place in Therapy VDZ has been shown to be effective as first- or second-line induction and maintenance therapy in UC. Conclusion VDZ is a safe and effective treatment option for patients with UC. Prolonged VDZ induction therapy may contribute to improved outcomes in patients with UC, particularly those previously treated with tumor necrosis factor-α. Prospective head-to-head study of VDZ and other biologics would alter the positioning of VDZ much more clearly.

Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor approved in Japan for the treatment of ulcerative colitis (UC). Differences in the safety profile of tofacitinib in Japanese patients versus the global population, such as a higher risk of herpes zoster, have been reported. Objectives: We conducted post hoc analyses of tofacitinib treatment in Japanese patients with moderate-to-severe UC in two global phase III studies. Methods: In OCTAVE Induction 1 (NCT01465763), 62 patients were randomized to placebo or tofacitinib 10 mg twice daily (b.i.d.). In OCTAVE Sustain (NCT01458574), 39 patients with clinical response in OCTAVE Induction 1 were re-randomized to placebo, tofacitinib 5 mg, or 10 mg b.i.d. Efficacy endpoints included: remission (primary endpoint; total Mayo score ≤2; no individual subscore >1; rectal bleeding subscore 0); mucosal healing (Mayo endoscopic subscore ≤1); clinical response (≥30% and ≥3-point decrease from induction study baseline total Mayo score; decrease in rectal bleeding subscore ≥1 or absolute subscore ≤1). Adverse events (AEs) and clinical laboratory parameters were recorded. Results: At week 8 of OCTAVE Induction 1, 22.4% of patients achieved remission with tofacitinib (placebo, 7.7%). At week 52 of OCTAVE Sustain, 31.3% and 66.7% of patients receiving tofacitinib 5 and 10 mg b.i.d., respectively, achieved remission (placebo, 9.1%). The occurrence of AEs or serious AEs in Japanese patients was generally similar to that in the global study population, with no new or unexpected safety risks observed. Conclusions: Although patient numbers were small, tofacitinib demonstrated numerically greater efficacy versus placebo among Japanese patients in OCTAVE Induction 1 and OCTAVE Sustain, with a safety profile consistent with that of the global study population.

Background Combining a thiopurine with the human anti-tumour necrosis factor-α monoclonal antibody adalimumab for Crohn’s disease [CD] treatment is controversial with regard to efficacy and safety. By conducting a subanalysis of a multicentre, randomised, prospective, open-label trial [the DIAMOND study, UMIN registration number 000005146], we studied the risk of discontinuation of thiopurine in combination with adalimumab. Methods In the preceding DIAMOND study, we analysed the: [i] timing and reasons for dropout in the monotherapy group and combination group; [ii] risk factors for dropout in the combination group. Results There was no significant difference in the dropout rate up to Week 52 between the monotherapy group and combination group [p = 0.325]. The main reason for study dropout was active CD in the monotherapy group, whereas it was adverse effects in the combination group [Fisher’s exact test, p Conclusions Combination of azathioprine with adalimumab resulted in dropout in the early stage of the study due to side effects of azathioprine, in comparison with late dropout due to active CD in the adalimumab monotherapy group.

BackgroundVedolizumab safety and efficacy have been established in many populations all over the world, but have never been studied in Japan. We report results from a Phase 3, randomized, double-blind, placebo-controlled study of vedolizumab in Japanese patients with active ulcerative colitis (UC).MethodsPatients with moderate-to-severe UC were enrolled into Cohort 1 (double-blinded) or Cohort 2 (open-label) in the induction phase. Cohort 1 was randomized 2:1 to receive 300 mg vedolizumab or placebo, while Cohort 2 received vedolizumab 300 mg only, at Weeks 0, 2, and 6. Patients from Cohorts 1 and 2 showing a clinical response to vedolizumab at Week 10 were randomized 1:1 to receive vedolizumab or placebo (double-blinded) at Week 14 and then every 8 weeks up to Week 54 as the maintenance phase. The primary endpoint was clinical response at Week 10, for the induction phase, and clinical remission at Week 60, for the maintenance phase.ResultsA total of 292 patients were enrolled into the induction phase (246 in Cohort 1, 46 in Cohort 2); 83 patients achieved response to vedolizumab and were subsequently enrolled into the maintenance phase. Clinical response rates at Week 10 were 39.6% (65/164) and 32.9% (27/82) in the vedolizumab and placebo groups in Cohort 1, respectively (adjusted odds ratio [AOR] = 1.37, 95% CI 0.779-2.399; p = 0.2722). In the maintenance phase, clinical remission rate at Week 60 was significantly higher in the vedolizumab group, at 56.1% (23/41), versus 31.0% (13/42) for placebo (AOR = 2.88, 95% CI 1.168-7.108; p = 0.0210). Most adverse events were mild to moderate in intensity, and no deaths occurred during the study period.ConclusionsVedolizumab showed numerically greater efficacy compared with placebo as induction therapy, but the difference was not statistically significant. Vedolizumab was significantly superior to placebo as maintenance therapy in Japanese patients with UC. Vedolizumab has favourable safety and tolerability in these patients.Trial registrationClinicalTrials.gov: NCT02039505.

[This corrects the article DOI: 10.1371/journal.pone.0212989.].

Background & Aims: Little is known about the effects of endoscopic balloon dilation (EBD) for strictures of the upper gastrointestinal (UGI) tract in patients with Crohn's disease (CD). We performed a pooled analysis of the efficacy and safety of EBD for UGI CD-associated strictures. Methods: We searched Embase, Medline, and the Cochrane library, as well as bibliographies of relevant articles, for cohort studies of adults with CD and strictures of the stomach or duodenum (up to the ligament of Treitz) who underwent EBD through December 2016. We obtained data from 7 international referral centers on 94 patients who underwent 141 EBDs. We performed a patient-level meta-analysis of data from published and unpublished cohort studies to determine mechanical and clinical success. We performed a time-to-event analysis to assess symptom recurrence and need for redilation or surgery. The patients analyzed had strictures of the duodenum (n = 107), stomach (n = 30), or spanning both (n = 4). Results: The rate of technical success for EBD was 100%, with 87% short-term clinical efficacy; major complications arose from 2.9% of all procedures. During a median follow-up period of 23.1 months, 70.5% of patients had a recurrence of symptoms, 59.6% required redilation, and 30.8% required surgical intervention. Patients whose disease was located in the small bowel had a higher risk for symptom recurrence (hazard ratio [HR], 2.1; P = .003). Asian race (HR, 2.8; P < .001) and location of disease in the small bowel (HR, 1.9; P = .004) increased the need for redilation. Prestenotic dilation was a risk factor for needing surgery earlier (HR, 1.9; P = .001). Conclusions: In a meta-analysis, we found EBD for CD-associated strictures of the UGI to be an effective alternative to surgery, with a high rate of short-term technical and clinical success, moderate long-term efficacy, and an acceptable rate of complications.

We have investigated the structure of Fe clusters which were induced by thermal-aging and their effect on magnetic properties of Cu-1.2 at.% Fe alloy by using the extended X-ray absorption fine structure (EXAFS), the atom probe tomography (APT) and the SQUID magnetometer. Small Fe clusters with the diameter of 3.3 nm on average and solute Fe atoms in the solution-treated specimen show paramagnetism. At the initial stage of thermal-aging, Fe clusters with the diameter of 10.9–24.0 nm on average are produced, and most of them exist as anti-ferromagnetic γ-Fe with fcc structure due to the coherent growth against the fcc Cu matrix. By the enough long time thermal-aging, some of these γ-Fe clusters transform to ferromagnetic Fe clusters with bcc structure due to their growing up to enough large size. From the results obtained by EXAFS, the atomic fraction of Fe atoms forming bcc-structured clusters indeed increases with increasing the aging time. These results obtained by non-destructive EXAFS methods revealed that transformation from γ-Fe to bcc-structured Fe occurs only by the thermal-aging. The effects of the Fe clustering on the electrical resistivity and the micro Vickers hardness, and effects of the plastic deformation will also be mentioned briefly.

Mesenteric phlebosclerosis (MP) is a rare disease characterized by venous calcification extending from the colonic wall to the mesentery, with chronic ischemic changes from venous return impairment in the intestine. It is an idiopathic disease, but increasing attention has been paid to the potential involvement of herbal medicine, or Kampo, in its etiology. Until now, there were scattered case reports, but no large-scale studies have been conducted to unravel the clinical characteristics and etiology of the disease. A nationwide survey was conducted using questionnaires to assess possible etiology (particularly the involvement of herbal medicine), clinical manifestations, disease course, and treatment of MP. Data from 222 patients were collected. Among the 169 patients (76.1 %), whose history of herbal medicine was obtained, 147 (87.0 %) used herbal medicines. The use of herbal medicines containing sanshishi (gardenia fruit, Gardenia jasminoides Ellis) was reported in 119 out of 147 patients (81.0 %). Therefore, the use of herbal medicine containing sanshishi was confirmed in 70.4 % of 169 patients whose history of herbal medicine was obtained. The duration of sanshishi use ranged from 3 to 51 years (mean 13.6 years). Patients who discontinued sanshishi showed a better outcome compared with those who continued it. The use of herbal medicine containing sanshishi is associated with the etiology of MP. Although it may not be the causative factor, it is necessary for gastroenterologists to be aware of the potential risk of herbal medicine containing sanshishi for the development of MP.

The exacerbation of disease in patients with ulcerative colitis (UC) can greatly affect quality of life and can impose economic burdens. In Japan, a large nationwide registry for the medical reimbursement of UC patients has existed since 1975. We aimed to examine factors associated with UC exacerbation among patients newly diagnosed with mild UC using electronic data from the registry.We retrospectively reviewed the clinical data of patients (n = 8120) newly diagnosed with mild UC between 2003 and 2011, and examined the association of patient background, medications, clinical symptoms and laboratory data, and pathological findings with exacerbation of UC, using the Cox proportional hazards model.The incidence of UC exacerbation was 94.6 per 1000 person-years (mean follow-up of 2.1 years). We found that male sex, age17 years, an extensive lesion (left-sided colitis or pancolitis), overweight or obesity, hematochezia (mild or moderate-to-severe), mushy stools, frequency of bowel movements, and crypt architectural distortion were positively associated with UC exacerbation. On the other hand, age40 years, high hemoglobin concentration, and high serum albumin levels were inversely associated with UC exacerbation among patients with mild UC in Japan.Using data from the Japanese nationwide registry, we identified several factors, including body mass index and pathological findings, associated with disease exacerbation among patients with newly diagnosed mild UC. Our findings may lead to earlier recognition of exacerbation in patients with mild UC, thus enabling optimal care.

The red alga Pyropia yezoensis is traditionally cultivated in Japan, and the surplus production that is not consumed is utilized in other ways. Because this alga contains highly concentrated protein, we investigated the dietary effects of fresh P. yezoensis on the gonadal production and quality of the adult sea urchin Mesocentrotus nudus compared with urchins fed the kelp Saccharina ochotensis, in a 60-day rearing experiment from April to June 2009. The digestibility of P. yezoensis by the sea urchins was 96.2%. The gonads were in the recovery stage at the start and end of feeding. The gonad index of the sea urchins fed P. yezoensis was 20.8, significantly higher than that of the urchins fed S. ochotensis. When the urchins were fed P. yezoensis, the proportion of bright reddish-yellow gonads increased markedly, to 50% in the testes and 90.9% in the ovaries. The content of the sweet amino acid, glycine, in the gonads of urchins fed P. yezoensis was significantly lower than at the start of feeding, and the contents of the bitter amino acids, lysine and valine, were significantly higher in the ovaries than in urchins fed S. ochotensis or at the start of feeding. Despite the increase in gonad production and the improvement in gonad color after the consumption of P. yezoensis, these changes in amino acids indicate a reduction in the quality of the gonad as food. The crude protein content of P. yezoensis used in this study was 36.7%, which would reduce gonadal quality. We infer that the use of low-protein P. yezoensis, which is discolored and unfit for market, can improve the quality of the urchin gonad.

Background and Aims: Data from an all-cases post-marketing study were used to evaluate the safety and effectiveness of adalimumab in Japanese patients with Crohn’s disease [CD]. Methods: Patients received adalimumab for 24 weeks. Data from all patients [ n = 1693] were used for the safety assessment. Data from patients with CD activity index [CDAI] ≥ 150 at baseline were used for the effectiveness assessment. Results: The most frequent serious adverse drug reaction [ADR] was infection and infestations [6.6 events/100 patient-years]. The risk of serious infections increased in patients who had a history of malignancy and those with concomitant corticosteroid use. Of 415 patients who had switched from another anti-tumour necrosis factor alpha [TNFα] agent to adalimumab due to ADRs, 7.2% discontinued due to ADRs to adalimumab. Ten of 13 patients with a history of tuberculosis [TB] received prophylactic medication, and none developed TB. TB developed in one patient with no history of TB or anti-TB prophylaxis. Remission rates were 41.3% and 32.4% at 4 and 24 weeks, respectively. Remission rates did not differ between patients with and without concomitant use of immunomodulators. Predictive variables for increased effectiveness were CDAI ≤ 220 and disease duration of ≤ 2 years. Perianal lesions and loss of response to previous anti-TNFα agents affected effectiveness. Conclusions: The most frequent serious ADR was infection. Adalimumab significantly reduced disease activity, without any unexpected ADRs. Development of active TB during adalimumab therapy can be prevented through TB screening and prophylaxis. In patients who switched from another anti-TNFα agent to adalimumab due to ADRs, adalimumab was well tolerated.

The restoration process of irradiation-induced metastable magnetic states of FeRh thin films during the heat treatments at 373–1073 K was investigated by measuring the magnetization-magnetic field (M−H) curves and the magnetization-temperature (M−T) curves for the FeRh thin films irradiated with 50 keV Ar ions to various fluences. The recovery of lattice structures accompanying the magnetic restoration was also examined by an x-ray diffraction (XRD) measurement. For the ferromagnetic state induced by low fluence irradiation, the magnetic restoration to the thermal equilibrium antiferromagnetic state occurs during the heat treatment. Whereas for the paramagnetic state induced by high fluence irradiation, it once changes to the ferromagnetic state, and then, is restored to the antiferromagnetic (i.e., thermal equilibrium) state during the heat treatment. The above magnetic transformation occurs by the heat treatments at higher temperatures for the higher fluence irradiation. Moreover, the magnetic transition temperature from the antiferromagnetic state, which has been thermally restored from the irradiation induced ferromagnetic or paramagnetic state, to the ferromagnetic state decreases with increasing the irradiation fluence. This result implies that the antiferromagnetic state with larger amount of lattice defects is more unstable against the thermal vibration of lattice atoms.