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Active lesions in the small bowel (SB) have been independently associated with poorer prognoses in patients with Crohn's disease (CD)1; however, there has been a lack of accurate and convenient screening methods. Past studies have found that serum levels of the glycoprotein leucine-rich α2 glycoprotein (LRG) correlates with endoscopic activity in ulcerative colitis,2,3 and this is now available for routine clinical use as a biomarker in patients with inflammatory bowel disease in Japan. LRG has not yet been thoroughly verified in CD, and we investigated whether it can be used as a serum biomarker for detecting SB mucosal activity in patients with CD.

For an esophageal submucosal mass suspicious of granular cell tumor (GCT) based on gross appearance and endoscopic ultrasound findings, a sufficient number of biopsy specimens is required for a definite diagnosis using immunohistochemical examination. When the specimen obtained by forceps biopsy is insufficient, endoscopic ultrasound-fine needle aspiration (EUS-FNA) is believed to be an useful alternative. However, it may be difficult to obtain an adequate amount of tumor material using EUS-FNA. Mucosal incision-assisted biopsy (MIAB) is a simple method that can collect larger amounts of specimens. This procedure is helpful for physicians who encounter the problem of obtaining an adequate amount of biopsy material from esophageal tumors suspicious for GCT. We present a case of esophageal GCT that was successfully diagnosed through MIAB.

Background The mortality and risk factors of severe disease and death due to arterial and venous thromboembolism (ATE and VTE, respectively) in patients with inflammatory bowel disease (IBD) remain unclear, especially in Asia. Aims This study aimed to reveal the mortality and risk factors of TE in IBD patients in Japan. Methods In the primary surveillance, responses to questionnaires regarding the number of cases of severe TE and TE-associated death in IBD patients in a span of over the past 10 years were obtained from 32 institutions in Japan. In the secondary surveillance, detailed data about IBD patients with TE were collected. The characteristics, laboratory data, therapy status, and situation at the time of TE development were retrospectively collected, and the data were compared between the patients with and without severe TE and TE-associated death. Results The incidence of TE was 1.89% among 31,940 IBD patients. The frequencies of severe TE and TE-associated mortality were 10.7% and 1.0% among the total IBD and TE with IBD patients, respectively. The only risk factor for severe ATE and ATE-associated death was ischemic heart disease. The independent risk factors for severe VTE and VTE-associated death were age (≤ 45 years old), the site of VTE, and disease severity, with anti-TNF therapy as a potential negative risk factor. Patients with severe VTE had a high risk of developing persistent VTE and sequelae. Conclusion Unlike ATE, the incidence of VTE was comparable in Asian and Western countries. Therapeutic and prophylactic strategies for managing IBD-associated TE in Asia are urgently needed.

Background The clinical characteristics of IgG4-related sclerosing cholangitis (IgG4-SC) especially without autoimmune pancreatitis (AIP) have not been investigated in a large cohort. Aims To clarify the clinical characteristics of IgG4-SC and IgG4-SC without AIP. Methods We retrospectively reviewed imaging, serology, other organ involvement (OOI) and histology of 872 patients with IgG4-SC who participated in a Japanese nationwide survey in 2019, and compared these items between IgG4-SC with and without AIP. Results AIP was present in 83.7% (730/872) of IgG4-SC. In IgG4-SC, bile duct wall thickening was observed on ultrasound (528/650; 81.2%), computed tomography (375/525; 71.4%) and magnetic resonance imaging or cholangiopancreatography (290/440; 65.9%). An elevated serum IgG4 level (≥ 135 mg/dL) was found in 88.0% (322/366). IgG4-related OOI other than AIP was observed in 25.2% (211/836). The proportion of females was significantly higher in IgG4-SC without AIP (28.9% vs. 20.1%; p = 0.025). Hilar stricture was the most common cholangiographic type in IgG4-SC without AIP (39/107; 36.4%).There were no significant differences between IgG4-SC with and without AIP in the rates of bile duct wall thickening, elevated serum IgG4 level, or IgG4-related OOI. Conclusions The clinical characteristics of IgG4-SC was similar between IgG4-SC with and without AIP in a large cohort.

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 Several studies have reported a positive correlation between serum drug concentrations and endoscopic remission in patients with Crohn's disease. Aim To examine the association between the concentrations of cytokine blockers (infliximab, adalimumab and ustekinumab) and endoscopic remission of small bowel lesions. Method This was a cross-sectional study conducted at a single tertiary referral centre. Patients with Crohn's disease who received maintenance cytokine blocker therapy were recruited from April 2018 to May 2020. We performed balloon-assisted enteroscopy and collected serum samples to measure drug concentrations. The primary endpoint was the relationship between the concentrations of cytokine blockers and endoscopic remission in the small bowel. Results We enrolled 143 patients, 66, 44 and 33 of whom were receiving infliximab, adalimumab and ustekinumab, respectively. Enteroscopic findings showed that the rate of endoscopic remission of small bowel lesions was significantly lower than that of colonic lesions (P 5, 14 and 4 µg/mL were nearly 5.3-, 9.4- and 14.7-times more likely to exhibit endoscopic remission of the small bowel, respectively. Conclusions Cytokine blocker treatment was less efficacious for small bowel inflammation than colonic inflammation. Higher serum concentrations were needed to achieve endoscopic remission of small bowel lesions.

Background This multicenter prospective study (UMIN000019958) aimed to evaluate the usefulness of serum leucin-rich alpha-2 glycoprotein (LRG) levels in monitoring disease activity in inflammatory bowel disease (IBD). Methods Patients with moderate-to-severe IBD initiated on adalimumab therapy were enrolled herein. Serum LRG, C-reactive protein (CRP), and fecal calprotectin (fCal) levels were measured at week 0, 12, 24, and 52. Colonoscopy was performed at week 0, 12, and 52 for ulcerative colitis (UC), and at week 0, 24, and 52 for Crohn’s disease (CD). Endoscopic activity was assessed using the Simple Endoscopic Score for Crohn’s Disease (SES-CD) for CD and the Mayo endoscopic subscore (MES) for UC. Results A total of 81 patients was enrolled. Serum LRG levels decreased along with improvements in clinical and endoscopic outcomes upon adalimumab treatment (27.4 ± 12.6 μg/ml at week 0, 15.5 ± 7.7 μg/ml at week 12, 15.7 ± 9.6 μg/ml at week 24, and 14.5 ± 6.8 μg/ml at week 52), being correlated with endoscopic activity at each time point (SES-CD: r = 0.391 at week 0, r = 0.563 at week 24, r = 0.697 at week 52; MES: r = 0.534 at week 0, r = 0.429 at week 12, r = 0.335 at week 52). Endoscopic activity better correlated with LRG compared to CRP and fCal on pooled analysis at all time points (SES-CD: LRG: r = 0.636, CRP: r = 0.402, fCal: r = 0.435; MES: LRG: r = 0.568, CRP: 0.389, fCal: r = 0.426). Conclusions Serum LRG is a useful biomarker of endoscopic activity both in CD and UC during the adalimumab treatment.

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.

Ulcerative colitis (UC) is an inflammatory bowel disease that causes chronic inflammation in the colon. 5-aminosalicylic acid and immunosuppressive medications such as corticosteroids, immunomodulators, and biologic agents are used to treat these patients. However, patients with UC who receive immunosuppressive medications may be at risk for certain opportunistic infections. Epstein-Barr virus (EBV) is one of those opportunistic infections, and its pathogenic role has been implicated in refractory UC, but its pathogenicity should be further investigated. Here, we report a surgical case of refractory UC that demonstrated a serologically post-infected pattern of EBV at admission but that later had a high load of EBV in both the peripheral blood and colonic mucosa. These findings suggest that EBV may have been reactivated in the colon, after which it damaged the colonic mucosa and aggravated inflammation in this patient with UC. Thus, EBV might lead to severity and a refractory response against corticosteroids and anti-TNFα agents, necessitating emergency surgery. Viral surveillance for EBV in patients with refractory UC may facilitate understanding of the patient's pathophysiology and predicting response to medications, and the development of antiviral intervention for those patients may improve their prognosis.

Background Filgotinib (FIL) is an oral preferential Janus kinase (JAK) 1 inhibitor in development for the treatment of inflammatory diseases. FIL for the treatment of moderately to severely active ulcerative colitis (UC) was evaluated in the phase 2b/3, double-blind, placebo (PBO)-controlled SELECTION study (NCT02914522) and its long-term extension (LTE) study (NCT02914535). Here we report safety results from the FIL UC program. Methods Patients received FIL 100 mg, FIL 200 mg or PBO (2:2:1) once daily orally for up to 11 weeks for induction (cohort 1). At week 11, FIL induction responders were rerandomized 2:1 to continue FIL or receive PBO maintenance for 47 weeks (cohort 2). Week 10 non-responders and patients with worsening disease during the maintenance study were eligible for open-label FIL in the LTE. Patients completing the maintenance study could continue blinded dosing in the LTE. Cohort 3 comprised cohorts 1 and 2 and the LTE. Exposure-adjusted incidence rates (EAIRs) and exposure-adjusted event rates (EAERs) per 100 patient-years (PYs) were calculated for treatment-emergent adverse events (AEs) by treatment group in cohorts 1 and 2 (EAIR) and cohort 3 (EAER). Results In cohort 1, 1069 patients received FIL and 279 patients received PBO; baseline characteristics were generally similar across treatment groups (overall mean age, 43 years; mean UC duration, 8.4 years; mean Mayo Clinic Score, 9.0). EAIRs for AEs of interest were similar across treatment groups in cohorts 1 and 2 (Table 1). Treatment exposure for PBO, FIL 100 mg or FIL 200 mg in cohort 3 (i.e. cohorts 1 + 2 + the LTE) was 318, 360 and 1207 PYs, and median treatment duration was 12, 11 and 67 weeks, respectively. One case of pulmonary embolism occurred with FIL 200 mg induction and three venous thrombosis cases occurred with PBO maintenance/LTE (cohort 3) (Table 2). EAERs for all infections were similar across treatment groups, the most common being nasopharyngitis (Table 2). Opportunistic infections were rare. EAERs for serious infections were low across treatment groups (2.2 [PBO], 3.5 [FIL 100 mg], 2.2 [FIL 200 mg]), the most common being appendicitis (Table 2). EAERs for herpes zoster (HZ) were low in all treatment groups (0.3 [PBO], 0.3 [FIL 100 mg], 1.8 [FIL 200 mg]) (Table 2). HZ infections were cutaneous only and only one was serious. EAIRs for all infections in cohorts 1 and 2 were generally numerically higher for both PBO and FIL in patients over (vs under) 65 years old and in those with (vs without) biologic treatment failure (Figure 1). Conclusion FIL was well tolerated in patients with UC. Aggregation of AEs typical for pan-JAK inhibition was not observed, consistent with preferential JAK-1 inhibition with FIL.

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 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.

It is important to objectively assess Crohn's disease (CD) activity in patients treated with antibodies against tumor necrosis factor (anti-TNF). Detection of healing by endoscopy (endoscopic healing) associates with patient outcome, based on evidence from studies of ileocolonoscopy. We assessed endoscopic healing after treatment, based on findings from balloon-assisted enteroscopy (BAE), in patients with CD.We performed a post-hoc analysis of data from a clinical trial from 116 patients with CD (46 with ileal and 70 with ileocolonic type) who received induction and then maintenance therapy with anti-TNF agents from January 2013 through March 2018 at a single center in Japan. We compared findings from BAE before induction therapy and then again during maintenance therapy (median 13 months later). Endoscopic healing was defined as the modified simple endoscopic score for CD below 5. We also collected data on previous treatments, makers of inflammation, and disease type.Before treatment, small bowel ulcerations were present in 114 patients (98%); 42 patients (60%) with ileocolonic disease had colon ulcerations. During maintenance therapy, 41/114 patients (36%) had small bowel endoscopic healing; all the patients with small bowel endoscopic healing also had colonic endoscopic healing. Colonic endoscopic healing was observed in 33/42 patients (79%). The proportion of patients with small bowel endoscopic healing was significantly lower than that of colonic endoscopic healing (P.001). Among all patients, failure to achieve small bowel endoscopic healing was significantly associated with structuring or penetrating disease (P = .014), lack of concomitant treatment with immunomodulators (P = .015), and having received previous treatment with an anti-TNF agents (P = .018).In a post-hoc analysis of patients with CD treated with anti-TNF agents, we found small bowel ulcerations, detected by BAE, to be more difficult to heal than colon ulcerations.

BackgroundCrohn’s disease (CD) is a chronic and destructive bowel disease; continued disease activity can lead to penetrating complications. With the recent advent of effective medications, the importance of using a treat-to-target approach to guide therapy is becoming important.MethodsIn this review, we reviewed the previous evidence for evaluating CD lesions.ResultsWe describe ileocolonoscopy’s role in assessing disease activity, as well as recent progress in modalities, such as balloon-assisted endoscopy, capsule endoscopy, magnetic resonance enterography, computed tomography enterography, and ultrasonography. Advances in modalities have changed CD assessment, with small-bowel involvement becoming more important.ConclusionsProper optimization is necessary in clinical practice.

In Japan and other Asian countries, increased fat uptake induced by a westernized diet is thought to be associated with an increased incidence of inflammatory bowel disease, colorectal cancer and food allergies; however, the mechanism for this remains unclear. High-fat diet (HFD)-fed mice are common animal models used to examine the effect of fat intake in vivo. HFDs are reported to exacerbate DSS-induced colitis and intestinal tumorigenesis, but the effect of HFDs on the intestines before disease induction is often overlooked. We found that the intestinal and gut-associated lymphoid tissue (GALT) morphology of HFD-fed mice differed from that of standard diet (SD)-fed mice. To clarify the mechanism by which fat intake increases intestinal diseases, we analyzed the morphological and immunological aspects of the intestines of HFD-fed mice as well as the molecular mechanisms and physiology. Feeding an HFD for 3 weeks induced atrophy of the small intestine, colon and GALT and reduced the number of small intestinal intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs). Feeding an HFD for only one day reduced the number of small intestinal (SI)-IELs and SI-LPLs. The effect of feeding a 3-week HFD continued for 2 weeks after returning to the SD. The effect of the HFD on the intestinal immune system was independent of the gut microbes. We hypothesized that the cytotoxicity of the abundant HFD-derived free fatty acids in the intestinal lumen impairs the intestinal immune system. Both saturated and unsaturated free fatty acids were toxic to intestinal T-cells in vitro. Orally administering free fatty acids reduced the number of SI-IELs and LPLs. Using a lipase inhibitor to reduce the luminal free fatty acids attenuated the HFD-induced changes in the intestinal immune system, while using a statin to reduce the serum free fatty acids did not. Thus, HFD-induced free fatty acids damaged the intestines; this effect was termed “intestinal lipotoxicity”. Because sustained reduction of SI-LPLs after HFD feeding exacerbated indomethacin-induced small intestinal damage, lipotoxicity to the human intestines incurred by consuming a westernized diet in Japan may increase intestinal diseases such as IBD, colorectal cancer or food allergies.

Background/Aims: Mucosal healing (MH) of distal lesions in ulcerative colitis (UC) has recently been confirmed with budesonide 2-mg foam (BF) treatment in 2 clinical trials; however, few studies have investigated the predictive factors for complete MH. Methods: We conducted a post hoc analysis using pooled data from phase II and III clinical trials evaluating the efficacy and safety of BF for UC. Additionally, we analyzed the relationships between complete MH and baseline factors and clinical symptoms from baseline to week 6. Results: Among the 291 Japanese patients from the 2 pooled clinical studies, 119 patients in the BF twice a day group and 117 in the placebo group were included in the full analysis set. The proportion of patients with a rectal bleeding (RB) subscore of 0 was significantly higher in the BF group than in the placebo group after a 5-day treatment (P

Background/Aims: PF-00547659 is a monoclonal antibody against human mucosal addressin cell adhesion molecule-1 (MAd CAM-1) that prevents the binding of α4β7+ lymphocytes to MAdCAM-expressing sites in the gastrointestinal tract with high af finity and selectivity, and is being developed for the treatment of Crohn’s disease (CD). Methods: OPERA is a randomized, mul ticenter, double-blind, placebo-controlled study to investigate the efficacy, safety, and pharmacokinetics of PF-00547659 fol lowing subcutaneous administration in subjects with active CD, a history of failure or intolerance to anti-tumor necrosis factor and/or immunosuppressants, high-sensitivity C-reactive protein >3.0 mg/L, and ulcers on colonoscopy. The primary endpoint was Crohn’s Disease Activity Index-70 response at week 8 or 12. Subpopulation analyses for Asian subjects were performed as some differences are observed in genetics and clinical phenotypes in Asian CD patients compared with Western patients. Results: In this study, 265 CD subjects were randomized, with a subpopulation of 21 subjects (8 Japanese and 13 Korean) de fined as the Asian population. In the overall and Asian populations; PF-00547659 was pharmacologically active as evidenced by soluble MAdCAM and circulating β7+ central memory CD4+ T-lymphocytes, although no clear evidence of efficacy was observed in any clinical endpoints; pharmacokinetics of PF-00547659 in the Asian subpopulation was generally comparable to the overall population; and the safety profile of PF-00547659 appeared acceptable up to 12 weeks of treatment. Conclusions: In the overall and Asian populations, efficacy of PF-00547659 could not be demonstrated using any clinical endpoints compared with placebo. Pharmacokinetics and safety of PF-00547659 were generally comparable. Further studies with larger numbers of patients are required to confirm our results. (Trial Registration Number: NCT01276509) (Intest Res 2020;18:45-55)

Background and Aims Amiselimod is an oral selective S1P1 receptor modulator with potentially fewer adverse effects than fingolimod. We evaluated the safety, tolerability, and clinical efficacy of amiselimod in participants with moderate to severe active Crohn’s disease. Methods This was a phase IIa, multicentre, randomised, double-blind, parallel group, placebo-controlled study comparing amiselimod 0.4 mg with placebo over a 14-Week treatment period. The primary endpoint of the study was the proportion of participants with clinical response (Crohn’s Disease activity Index [CDAI] 100) from baseline at Week 12. Results A total of 180 patients were screened and 78 were randomised [40 to amiselimod 0.4 mg and 38 to placebo]. There was no significant difference in the proportion of patients achieving CDAI 100 at Week 12 on amiselimod 0.4 mg and on placebo [48.7% vs. 54.1%, respectively] (odds ratio [OR] [95% confidence interval]: 0.79 [0.31, 1.98]). The results from the secondary endpoint analyses supported the results of the primary endpoint analysis. Treatment with amiselimod 0.4 mg was generally well tolerated, with 71.8% of participants completing the 14-week treatment period. Seven participants had serious adverse events and four discontinued treatment in the amiselimod group. Conclusions Amiselimod 0.4 mg for 12 weeks was not superior to placebo for the induction of clinical response [CDAI 100] in Crohn’s disease. Treatment with amiselimod 0.4 mg was generally well tolerated and no new safety concerns related to amiselimod were reported in this study.

Background/aims An interim analysis of post-marketing surveillance of CT-P13, an infliximab biosimilar, was performed to evaluate its safety and efficacy in Japanese patients with inflammatory bowel disease. Methods Patients were prospectively enrolled between November 2014 and March 2017, after the launch of CT-P13 in Japan, and case report forms of patients followed for at least 4 months were analyzed as of July 2018. Results Of 523 patients in the analysis set, 372 remained on CT-P13 therapy, while 54 (20.2%) of 267 patients with Crohn's disease, and 97 (37.9%) of 256 patients with ulcerative colitis were withdrawn during follow-up. A total of 144 adverse drug reactions (ADRs) were reported in 106 patients (20.3%). Infusion reaction was the most frequent ADR observed in 49 patients (9.4%). Efficacy parameters decreased immediately after the start of treatment in naive patients to anti-tumor necrosis factor-α antibody. In the patients switched from originator infliximab for nonmedical reasons, the decreased parameters due to proceeded treatment with the originator were maintained in low ranges, and the treatment continuation rate was high with low ADR incidence. In contrast, in patients switched for medical reasons such as adverse event or loss of response, the incidence of ADRs was high. However, the efficacy parameters were improved, and the treatment continuation rate was not significantly different from that of the naive patient group. Conclusions In this interim analysis, CT-P13 was comparable to the originator infliximab with respect to ADRs and efficacy, and is therefore considered to be a cost-efficient interchangeable biosimilar for Japanese patients with inflammatory bowel disease.

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

The risk:benefit ratio of concomitant use of thiopurines with scheduled adalimumab (ADA) maintenance therapy for Crohn’s disease is controversial. The aim of this study is to identify the influence of withdrawal of thiopurines in patients in remission with combination therapy in an open-label, randomised, controlled trial (DIAMOND2; UMIN000009596). Patients in corticosteroid-free clinical remission (CFCR) for ≥ 6 months with ADA (40 mg, s.c., every other week) scheduled maintenance combined with thiopurines were randomised into two groups, “continue” (Con) or “discontinue” (Dis) group of thiopurines, whereas all other patients kept receiving scheduled ADA maintenance therapy for 52 weeks. The primary endpoint was the proportion of patients in CFCR at week 52. Secondary endpoints were endoscopic remission (ER), trough levels of ADA in serum, and safety. Fifty patients were randomised to Con or Dis groups. Characteristics of patients were not significantly different between the groups. CFCR and ER prevalence at week 52 were not significantly different between groups (log rank, P = 0.704, P = 1.000, respectively). Trough levels of ADA were not significantly different between groups (P = 0.515). The proportion of patients with AAA positivity at week 52 was not significantly different (P = 0.437). ER at week 0 was involved in ER and triple remission at week 52. No serious adverse effects were observed in either group. Continuation of thiopurines > 6 months offers no clear benefit over scheduled ADA monotherapy. CFCR, ER, and ADA trough level at week 52 were not significantly different between groups. ER at week 0 may be involved in better long-term clinical outcomes.

Background: The risk factors associated with the development of hepatocellular carcinoma (HCC) in nonalcoholic fatty liver disease (NAFLD) are still unclear. The aim of the present study was to identify such risk factors in NAFLD patients who developed HCC. Methods: Between April 2000 and ­December 2016, a total of 182 patients with NAFLD were enrolled in this study; of these, only 22 patients had HCC. To identify risk factors, univariate and multivariate analyses were performed. To identify risk factors other than the degree of fibrosis, propensity matched analysis adjusted by the NAFLD fibrosis score (NFS) was carried out on 44 patients. Multivariate and survival analyses were also performed in HCC patients. Results: In 182 patients, multivariate analysis highlighted the NFS (OR 2.275; p < 0.001) and hypertension (OR 5.868; p = 0.037) as independent factors that were significantly associated with the development of HCC. After adjustment for the NFS, multivariate analysis identified diabetic retinopathy (OR 8.654; p = 0.017) as an independent factor that was significantly associated with the development of HCC. For predicting the development of HCC, the area under the receiver operating characteristic curve of diabetic retinopathy was significantly higher than that of diabetes (0.731 vs. 0.615; p < 0.001). In patients with HCC, multivariate analysis indicated that the NFS were significantly associated with diabetic retinopathy. Conclusions: Diabetic retinopathy as well as liver fibrosis is a risk factor that associates with the development of HCC in NAFLD patients. Therefore, NAFLD patients with diabetic retinopathy should undergo careful screening for HCC.

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.

The global prevalence of ulcerative colitis is increasing, and induction and maintenance of remission is a crucial therapeutic goal. We assessed the efficacy and safety of filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, for treatment of ulcerative colitis.This phase 2b/3, double-blind, randomised, placebo-controlled trial including two induction studies and one maintenance study was done in 341 study centres in 40 countries. Eligible patients were aged 18-75 years with moderately to severely active ulcerative colitis for at least 6 months before enrolment (induction study A: inadequate clinical response, loss of response to or intolerance to corticosteroids or immunosuppressants, naive to tumour necrosis factor [TNF] antagonists and vedolizumab [biologic-naive]; induction study B: inadequate clinical response, loss of response to or intolerance to any TNF antagonist or vedolizumab, no TNF antagonist or vedolizumab use within 8 weeks before screening [biologic-experienced]). Patients were randomly assigned 2:2:1 to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once per day for 11 weeks. Patients who had either clinical remission or a Mayo Clinic Score response at week 10 in either induction study entered the maintenance study. Patients who received induction filgotinib were rerandomised 2:1 to continue their induction filgotinib regimen or to placebo. Patients who received induction placebo continued receiving placebo. The primary endpoint was clinical remission by Mayo endoscopic, rectal bleeding, and stool frequency subscores at weeks 10 and 58. For the induction studies, efficacy was assessed in all randomised patients who received at least one dose of study drug or placebo within that study. For the maintenance study, efficacy was assessed in all patients randomised to any filgotinib treatment group in the induction studies who received at least one dose of study drug or placebo in the maintenance study. Patients who received placebo throughout the induction and maintenance study were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of the study drug or placebo within each study. This trial is registered with ClinicalTrials.gov, NCT02914522.Between Nov 14, 2016, and March 31, 2020, we screened 2040 patients for eligibility. 659 patients enrolled in induction study A were randomly assigned to receive filgotinib 100 mg (n=277), filgotinib 200 mg (n=245), or placebo (n=137). 689 patients enrolled into induction study B were randomly assigned to receive filgotinib 100 mg (n=285), filgotinib 200 mg (n=262), or placebo (n=142). 34 patients in induction study A and 54 patients in induction study B discontinued the study drug before week 10. After efficacy assessment at week 10, 664 patients entered the maintenance study (391 from induction study A, 273 from induction study B). 93 patients continued to receive placebo. 270 patients who had received filgotinib 100 mg in the induction study were randomly assigned to receive filgotinib 100 mg (n=179) or placebo (n=91). 301 patients who had received filgotinib 200 mg in the induction study were randomly assigned to receive filgotinib 200 mg (n=202) or placebo (n=99). 263 patients discontinued treatment in the maintenance study. At week 10, a greater proportion of patients given filgotinib 200 mg had clinical remission than those given placebo (induction study A 26·1% vs 15·3%, difference 10·8%; 95% CI 2·1-19·5, p=0·0157; induction study B 11·5% vs 4·2%, 7·2%; 1·6-12·8, p=0·0103). At week 58, 37·2% of patients given filgotinib 200 mg had clinical remission versus 11·2% in the respective placebo group (difference 26·0%, 95% CI 16·0-35·9; p0·0001). Clinical remission was not significantly different between filgotinib 100 mg and placebo at week 10, but was significant by week 58 (23·8% vs 13·5%, 10·4%; 0·0-20·7, p=0·0420). The incidence of serious adverse events and adverse events of interest was similar between treatment groups. In the induction studies, serious adverse events occurred in 28 (5·0%) of 562 patients given filgotinib 100 mg, 22 (4·3%) of 507 patients given filgotinib 200 mg, and 13 (4·7%) of 279 patients given placebo. In the maintenance study, serious adverse events were reported in eight (4·5%) of 179 patients given filgotinib 100 mg, seven (7·7%) of 91 patients in the respective placebo group, nine (4·5%) of 202 patients in the filgotinib 200 mg group, and no patients in the respective placebo group. No deaths were reported during either induction study. Two patients died during the maintenance study; neither was related to treatment.Filgotinib 200 mg was well tolerated, and efficacious in inducing and maintaining clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis.Gilead Sciences.

Summary Background Anti-tumour necrosis factor (TNF) agents are the mainstay of long-term treatment for refractory ulcerative colitis. However, long-term use of anti-TNF therapy might lead to an increased risk of malignancy or infection. To date, no randomised controlled trial has evaluated whether anti-TNF agents can be safely discontinued in patients with ulcerative colitis in remission. We therefore aimed to compare outcomes in these patients who continued infliximab with those who discontinued infliximab. Methods We did a multicentre, open-label randomised controlled trial at 24 specialist centres in Japan. We enrolled patients with ulcerative colitis who were in remission, had been treated with intravenous infliximab (5 mg/kg) every 8 weeks, and had started infliximab at least 14 weeks before study enrolment. No restrictions regarding age and comorbidities were used to exclude participation. Patients who were confirmed to be in remission for more than 6 months, to be corticosteroid-free, and to have a Mayo Endoscopic Subscore (MES) of 0 or 1 were centrally randomised. An independent organisation randomly assigned patients (1:1) into either the infliximab-continued group or infliximab-discontinued group, using a computer-generated stratified randomisation procedure. The stratified factors were the use of immunomodulators (yes or no) and MES (0 or 1). Neither patients nor health-care providers were masked to the randomisation. The primary endpoint was the remission rate at week 48 in the full analysis set, which was based on the intention-to-treat principle and excluded participants with no efficacy data after randomisation. This study was registered with the University Hospital Medical Information Network Center Trials registry, UMIN000012092. Findings Between June 16, 2014, and July 28, 2017, 122 patients were eligible for screening and a total of 95 patients were randomly assigned to the infliximab-continued group (n=48) or the infliximab-discontinued group (n=47). 92 patients (n=46 for both groups) were included in the full analysis set. 37 (80·4% [95% CI 66·1–90·6]) of 46 patients in the infliximab-continued group and 25 (54·3% [39·0–69·1]) of 46 patients in the infliximab-discontinued group were in remission at week 48. The between-group difference was 26·1% (95% CI 7·7–44·5; p=0·0076) before adjustment and 27·3% (95% CI 8·0–44·1; p=0·0059) after adjustment for stratification factors. Eight (17%) of 48 patients in the infliximab-continued group and six (13%) of 47 in the infliximab-discontinued group developed adverse events (between-group difference 3·9% [95% CI −10·3 to 18·1]; p=0·59). In the infliximab-continued group, one patient had an infusion reaction and two patients had psoriatic skin lesions. Eight (66·7%, 95% CI 34·9–90·1) of the 12 patients in the infliximab-discontinuation group who were re-treated with infliximab after relapsing were in remission within 8 weeks of re-treatment; none had infusion reactions. Interpretation Maintenance of remission was significantly more common in patients who continued infliximab than in those who discontinued. Discontinuing infliximab should therefore be discussed with caution, taking both risk of relapse and efficacy of re-treatment into account. Funding Mitsubishi Tanabe Pharma Corporation and the Intractable Disease Project of the Ministry of Health, Labour and Welfare of Japan. Translation For the Japanese translation of the abstract see Supplementary Materials section.

Background AJM300 (INN; carotegrast methyl), an orally active small molecule antagonist of the α4 subunit of α4β1/α4β7 integrins, demonstrated the efficacy and safety in patients with moderately active ulcerative colitis (UC) in a phase 2 study. The phase 3 study (NCT 03531892) of AJM300 as induction therapy was conducted in patients with moderately active UC. Methods Eligible patients were moderately active Japanese UC, defined as total Mayo Clinic scores (MCS) of 6–10, endoscopic subscores (ES) ≥2, and rectal bleeding subscores (RBS) ≥1, who had inadequate response or intolerance to oral 5-ASA. Followed by a 2-week single-blind placebo (PBO) run-in phase, patients were randomized 1:1 to receive AJM300 960 mg or PBO 3 times daily for 8 weeks. Responders or remitters were allowed to receive AJM300 960 mg again at the subsequent relapse (open-label). The primary endpoint was clinical response at week 8, defined as reduction of the MCS of ≥3-pts and ≥30%, reduction in RBS of ≥1-pt or RBS of ≤1, and ES ≤1. Results The randomized 203 patients had moderately active endoscopic evidence at baseline with median UC duration of 6.1 years and MCS of 7.8. For the primary endpoint, 45.1% (46/102) and 20.8% (21/101) of patients in the AJM300 and PBO groups, respectively, achieved clinical response at week 8 (OR=3.30 [95% CI, 1.73–6.29]; p=0.0003). Symptomatic remission, endoscopic improvement and endoscopic remission were also statistically significant for AJM300 vs PBO (Table). In case of episodic AJM300 treatment, AJM300 exhibited similar response to initial treatment. Overall, the incidence of AEs and serious AEs were similar between AJM300 and PBO. There were no deaths or cases of progressive multifocal leukoencephalopathy. Conclusion AJM300 induced clinical response as well as endoscopic remission with good tolerability. AJM300 may become a novel therapeutic option for patients who had inadequate response or intolerance to oral 5-ASA.

Background and aim Anti-tumor necrosis factor (TNF) α agents are now well known to function as effective treatments for Crohn's disease (CD). Several meta-analyses have revealed the efficacy of anti-TNF therapy for preventing recurrence after surgery; however, the efficacies reported in some prospective studies differed according to the outcomes. Moreover, adverse events (AEs) were not well evaluated. We conducted this systematic review and meta-analysis to evaluate both the efficacy of anti-TNF therapy after stratification by the outcome of interest and the AEs. Methods We performed a systematic literature review of studies investigating anti-TNF therapy, CD, and postoperative recurrence. Meta-analyses were performed for endoscopic and clinical recurrence and AEs. Results A total of 570 participants, including 254 patients in the intervention group and 316 patients in the control group, in eight studies, were analyzed for recurrence. Based on the results of the meta-analysis, the efficacies of anti-TNF therapy at preventing endoscopic and clinical recurrence were as follows: relative risk (RR) 0.34, 95% confidence interval (CI) 0.22-0.53 and RR 0.60, 95% CI 0.36-1.02, respectively. The RR of AEs with anti-TNF therapy was 1.75 (95% CI 0.81-3.79). Conclusions Anti-TNF therapy after surgery for CD displays efficacy at preventing endoscopic recurrence for 1-2 years, without increasing the incidence of AEs. However, clinical recurrence was not significantly reduced. The efficacy of postoperative anti-TNF therapy may differ in terms of the outcomes, which include long-term prevention, the avoidance of further surgery, and cost-effectiveness.

We previously performed a randomized controlled trial (RCT) comparing targeted and random biopsy in neoplasia detection in patients with ulcerative colitis (UC), which showed the short-term effectiveness of targeted biopsy with one-time colonoscopy. In this retrospective cohort study, we investigated the long-term effectiveness of targeted biopsy in tertiary care hospitals, using the follow-up data from patients with UC for &ge, 8 years who had enrolled in the initial RCT. The primary outcome was death from colorectal cancer (CRC). Secondary outcomes were advanced neoplasia (CRC or high-grade dysplasia) and colectomy due to neoplasia after the RCT. We compared these outcomes between target and random groups. Data on 195 of the 221 patients (88.2%) enrolled in the previous RCT were collected from 28 institutions between 2008 and 2019. No patients died of CRC in either group, with a median 8.8-year follow-up demonstrating a robustness for targeted biopsy in terms of CRC death prevention. Advanced neoplasia was detected in four and three patients in the target and random groups, respectively. Colectomy was required due to neoplasia in three patients in each group. The chance of developing CRC in patients with a negative colonoscopy was low, and the targeted biopsy appeared effective in this population. Conversely, patients found with low-grade dysplasia at initial RCT have 10-fold higher risk of progression to high-grade dysplasia and/or CRC. Ten extracolonic malignancies were observed during the follow-up, resulting in four deaths. Panchromoendoscopy was used only in 4.6% and targeted biopsy was only performed in 59.1% of colonoscopies. We recommend targeted biopsy rather than &gt, 33 random biopsies in real-world settings under adequate observation by specialists.

This study aimed to compare magnetic resonance enterocolonography (MREC) features among the endoscopic ulcer stages reclassified to include healing ulcers and to assess the prognoses in Crohn disease (CD). Altogether, 89 consecutive patients with CD who had undergone MREC and ileocolonoscopy or balloon-assisted enteroscopy were retrospectively studied. Patients were reclassified into 38 patients with no deep ulcer, seven with healing deep ulcer, and 44 with active deep ulcer stage. MREC score derived from a 5-point MR classification and MR index of activity (MaRIA) were evaluated, and patients were followed-up. The primary endpoint was hospitalization. Healing deep ulcers had higher values in MREC score and MaRIA than no deep ulcers (p

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).

It is crucial to identify risk factors for life prognosis after hepatitis C virus (HCV) eradication among patients with or without a high risk of liver cancer or complications. This is a prospective, multicenter and observational study using the database of 1031 patients after HCV eradication by direct-acting antiviral agents (DAAs) to evaluate the development of hepatocellular carcinoma (HCC) and patients’ survival after a sustained virological response (SVR). The Cox proportional hazards regression model was used to estimate hazard ratios associated with HCC development and survival. AFP at SVR was significantly associated with HCC recurrence in the adjusted model. Liver fibrosis, Mac-2 binding protein glycosylation isomer (M2BPGi) at SVR and smoking status before treatment were positively associated with the development of HCC and M2BPGi was positively associated with HCC recurrence, although not reaching statistical significance. Among patients without a history of HCC, M2BPGi and estimated glomerular filtration rate (eGFR) at SVR were significantly associated with death after viral eradication [M2BPGi (HR 4.07, 95% CI 1.22, 13.57), eGFR (HR 0.97, 95% CI 0.94, 0.99)]. Strikingly, of 16 patients who died, among participants without a history of HCC, only two died of liver cancer associated with HCV, whereas 11 died of non-HCV- related cancer or cardiovascular diseases. M2BPGi at SVR is a potential predictor for patients’ survival and a candidate biomarker for detecting individuals who are at greater risk of death due to cancer-related and unrelated to HCV, as well as cardiovascular diseases, after viral eradication.

Background/Aims: A subgroup analysis was conducted in Japanese patients with moderate to severe ulcerative colitis (UC) enrolled in the phase 3 VISIBLE 1 study, which evaluated the safety and efficacy of a new vedolizumab subcutaneous (SC) formulation.Methods: Eligible patients received open-label infusions of vedolizumab 300 mg intravenous (IV) at weeks 0 and 2 in the induction phase. Patients with clinical response by complete Mayo score at week 6 entered the double-blind maintenance phase and were randomized to vedolizumab 108 mg SC every 2 weeks, placebo, or vedolizumab 300 mg IV every 8 weeks. The primary endpoint was clinical remission (complete Mayo score ≤ 2 points; no individual subscore > 1 point) at week 52.Results: Of 49 patients who entered the induction phase, 22 out of 49 patients (45%) had clinical response at week 6 and were randomized to vedolizumab 108 mg SC (n = 10), placebo (n = 10), or vedolizumab 300 mg IV (n = 2). At week 52, 4 out of 10 patients (40%) who received vedolizumab SC had clinical remission versus 2 out of 10 patients (20%) who received placebo (difference: 20% [95% confidence interval, –27.9 to 61.8]). Two patients (2/10, 20%) who received vedolizumab SC experienced an injection-site reaction versus none who received placebo.Conclusions: Our results indicate that the efficacy of vedolizumab SC in a subgroup of Japanese patients with UC are similar with those in the overall VISIBLE 1 study population, and with those established with vedolizumab IV. The safety and tolerability of vedolizumab SC were generally similar to that established for vedolizumab IV. (ClinicalTrials.gov ID NCT02611830; EudraCT 2015-000480-14)

Background and Aims: Anti-tumour necrosis factor (TNF)- a agents are the mainstay of long-term treatment for refractory ulcerative colitis (UC). However, there has been no prospective randomised controlled trial evaluating whether anti-TNFa agents can be discontinued in UC patients in remission. Methods: This prospective, multicentre, randomised controlled trial enrolled UC patients from 23 specialist centres treated with infliximab (IFX) who were in remission. Patients who were confirmed to be: 1) in remission for > 6 months, 2) steroid-free, and 3) with a Mayo endoscopic subscore (MES) of 0 or 1, were randomised into two groups (continued IFX or discontinued IFX) in a 1:1 ratio stratified according to the use of immunomodulators and MES, using computer-generated stratified randomisation. The remission rate at week 48 in the full analysis set (FAS) was the primary endpoint in this trial. As secondary objectives, risk factors for relapse, and efficacy of re-treatment with IFX after relapse were also evaluated. Findings: A total of 95 patients were randomised, and 92 were included in the FAS. The remission rate at week 48 was 80.4% (n = 37/46; 95% CI: 66.1% to 90.6%) and 54.3% (n = 25/46; 95% CI: 39.0% to 69.1%) in the IFX-continued and IFX-discontinued groups, respectively (between-group difference: 26.1% [7.7% to 44.5%], p = 0.008). C-reactive protein and histological severity index were associated with future non-remission. Neither clinical nor endoscopic remission was predictive of remission. Retreatment with IFX upon relapse was safe, and two-thirds of patients achieved remission in 8 weeks. Interpretation: Discontinuing IFX resulted in a significantly increased relapse rate at 1 year. Residual subtle inflammation, as estimated based on CRP and histological inflammation seemed to be predictive of future relapse. Trial Registration:This study was registered at the University Hospital Medical Information Network Center Trials Registry (UMIN000012092). Funding Statement: This study was supported in part by a Grant-in-Aid for the Intractable Disease Project of the Ministry of Health, Labour and Welfare of Japan, and Mitsubishi- Tanabe Pharmaceuticals. Co. Declaration of Interests: Dr. Nakamura reports grants and personal fees from Mitsubishi Tanabe Pharma Corporation, grants and personal fees from EA Pharamaceutical Co Ltd, grants and personal fees from AbbVie Inc, personal fees from Janssen Pharmaceutical Co Ltd, grants and personal fees from Mochida Pharamaceutical Co Ltd, personal fees from Takeda Pharmaceutical Co Ltd, grants from Kyorin Holdings Inc, grants from JIMRO Co Ltd, grants from ZERIA Pharmaceutical Co Ltd, outside the submitted work. Dr. Motoya reports grants from Takeda pharmaceutical Co. Ltd, grants from Mitsubishi Tanabe Pharma Coporation, grants from Janssen Pharma coporation, during the conduct of the study. Dr. Hisamatsu reports grants and personal fees from EA pharma Co. Ltd., grants and personal fees from AbbVie GK, personal fees from Celgene K.K., personal fees from Janssen Pharmaceutical K.K., grants and personal fees from Pfizer Inc., grants and personal fees from Mitsubishi Tanabe Pharma Corporation, grants and personal fees from Kyorin Pharmaceutical Co. Ltd., grants and personal fees from JIMRO Co.Ltd, grants and personal fees from Mochida Pharmaceutical Co., Ltd, personal fees from Nichi-lko Pharmaceutical Co., Ltd., grants from Daiichi-Sankyo, grants and personal fees from Takeda Pharmaceutical Co. Ltd., outside the submitted work. Dr. Abe reports personal fees from EA Pharma Co.,LTD., personal fees from Kissei Pharmaceutical Co.,LTD., personal fees from Mochida Pharmaceutical Co.,LTD., personal fees from Mitsubishi Tanabe Pharma Corporation, outside the submitted work. Dr. Hibi reports personal fees from Aspen Japan K.K, grants and personal fees from Abbvie GK, personal fees from Ferring, personal fees from Gilead Sciences, personal fees from Janssen, grants and personal fees from JIMRO, personal fees from Kisse Pharmaceutical, grants and personal fees from Mitsubishi-Tanabe Pharma, grants and personal fees from Mochida Pharmaceutical, personal fees from Nippon Kayaku, personal fees from Pfizer, grants and personal fees from Takeda Pharmaceutical, grants and personal fees from Zeria Pharmaceutical, personal fees from Bristol-Myaers Squibb, personal fees from Celltrion, personal fees from EA Pharma, personal fees from Eli Lilly, grants and personal fees from kyorin, personal fees from Nichi-Iko Pharmaceutical, grants from Otuska Holdings, outside the submitted work. Ethics Approval Statement: The protocol was approved by the institutional review board of each participating institution. Written informed consent was obtained from all patients included in the study.

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

Induction therapy with tumor necrosis factor-α (TNF-α) inhibitors is highly effective for the treatment of Crohn’s disease. However, there are primary nonresponders (PNR) of TNF-α inhibitors without clinical response during the induction period. In addition, there are partial responders (PR), who show some efficacy, but clinical remission is not achieved by induction therapy. To date, the definition and clinical management of PNR and PR have not been established. This report summarizes the opinions of 36 Japanese experts attending the Japan Round Table Discussion on IBD Meeting regarding how to determine PNR and PR of TNF-α inhibitors and how to manage these patients in clinical practice. PNR, who do not show any initial improvement of clinical symptoms and serum C-reactive protein (CRP) levels, require re-assessment of intestinal complications. PR can be determined either by clinical symptoms, serum CRP levels, or imaging results. PR need intensification of the treatment with TNF-α inhibitors either with or without optimization of immunomodulators. Optimization of initial TNF-α inhibitor therapy may improve long-term outcomes, but more evidence is required to improve the use of TNF-α inhibitors for the prevention and management of PNR and PR.

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 Inflammatory bowel disease (IBD) increases the risk of venous thromboembolism (VTE) events. However, the incidence and necessity of prophylaxis for VTE in Asian IBD patients is unknown. We examined the incidence of VTE in East Asian IBD patients and analyze the possible risk factors. Methods We conducted a multinational retrospective study of 2562 hospitalized IBD patients from 2010 to 2015. Moreover, a nationwide cohort study from 2001 to 2013 from the Taiwan National Health Insurance Research Database (NHIRD) was conducted to analyze the incidence rate of VTE in IBD and non-IBD patients. Results In the hospitalized cohort, 24 IBD patients [17 ulcerative colitis (UC) and 7 Crohn's disease (CD)] received a VTE diagnosis (0.9%). These patients had a higher proportion of extensive UC (P = 0.04), penetrating-type CD (P < 0.01), and bowel operation history (P = 0.01). VTE was associated with low hemoglobin (P < 0.01), low platelet (P < 0.01), and low albumin (P < 0.01) levels. For the nation-wide cohort study, 3178 IBD patients and 31,780 age- and sex-matched non-IBD patients were analyzed. The average incidence rate was 1.15 per 1000 person-years in the IBD cohort and 0.51 in the non-IBD cohort. The relative risk was 2.27 (95% CI, 1.99-2.60). Conclusions East Asian IBD patients carry a 2-fold increased risk of VTE than the general population. The incidence of VTE in the East Asian IBD patients is still lower than that in Western countries. Therefore, close monitoring rather than routine prophylaxis of VTE in East Asian IBD patients is recommended.

Background/Aims: Tofacitinib is an oral, small-molecule Janus kinase inhibitor being investigated for ulcerative colitis (UC). In OCTAVE Induction 1 and 2, patients with moderately to severely active UC received placebo or tofacitinib 10 mg twice daily (BID) for 8 weeks. Clinical responders in OCTAVE Induction were re-randomized to 52 weeks’ therapy with placebo, tofacitinib 5 mg BID, or tofacitinib 10 mg BID. Methods: We conducted post-hoc efficacy and safety analyses of East Asian patients in OC TAVE Induction 1 and 2 and OCTAVE Sustain. Results: A total of 121 East Asian (Japan, Korea, and Taiwan) patients were ran domized in OCTAVE Induction 1 and 2 (placebo, n=26; tofacitinib 10 mg BID, n=95), and 63 in OCTAVE Sustain (placebo, n=20; tofacitinib 5 mg BID, n=22; tofacitinib 10 mg BID, n=21). At week 8 of OCTAVE Induction 1 and 2, 18.9% of patients (18/95) achieved remission with tofacitinib 10 mg BID versus 3.8% (1/26) with placebo. In OCTAVE Sustain, the week 52 remission rates were 45.5% (10/22), 47.6% (10/21), and 15.0% (3/20) with 5 mg BID, 10 mg BID, and placebo, respectively. Adverse event rates were similar between groups in OCTAVE Induction and numerically higher with tofacitinib in OCTAVE Sustain. Serious adverse event rates were similar across groups in all studies. Infections were numerically more frequent with tofacitinib than placebo. Increases in serum lipid levels were observed with tofacitinib. Conclusions: In East Asian patients with UC, tofacitinib demonstrated numerically greater efficacy versus placebo as induction and maintenance therapy, with a safety profile consistent with the global study population. ClinicalTrials.gov: NCT01465763; NCT01458951; NCT01458574. (Intest Res 2018;16:233-245)

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of the gastrointestinal tract, with increasing prevalence worldwide. IBD Ahead is an international educational program that aims to explore questions commonly raised by clinicians about various areas of IBD care and to consolidate available published evidence and expert opinion into a consensus for the optimization of IBD management. Given differences in the epidemiology, clinical and genetic characteristics, management, and prognosis of IBD between patients in Japan and the rest of the world, this statement was formulated as the result of literature reviews and discussions among Japanese experts as part of the IBD Ahead program to consolidate statements of factors for disease prognosis in IBD. Evidence levels were assigned to summary statements in the following categories: disease progression in CD and UC; surgery, hospitalization, intestinal failure, and permanent stoma in CD; acute severe UC; colectomy in UC; and colorectal carcinoma and dysplasia in IBD. The goal is that this statement can aid in the optimization of the treatment strategy for Japanese patients with IBD and help identify high-risk patients that require early intervention, to provide a better long-term prognosis in these patients.

Small bowel (SB) endoscopic healing has not been well studied in patients with Crohn's disease (CD). This study aims to evaluate the utility of magnetic resonance (MR) enterography (MRE) for SB lesions in comparison with balloon-assisted enteroscopy (BAE) findings.In total, 139 patients with CD in clinical-serological remission were prospectively followed after BAE and MRE procedures. We applied a modified version of the Simple Endoscopic Score for CD (SES-CD) for an endoscopic evaluation of the SB, called the Simple Endoscopic Active Score for CD (SES-CDa). We also used the MR index of activity (MaRIA) for MR evaluations. The primary end points were time to clinical relapse (CD activity index of150 with an increase of70 points) and serological relapse (abnormal elevation of C-reactive protein).Clinical and serological relapses occurred in 30 (21.6%) and 62 (44.6%) patients, respectively. SB endoscopic healing (SES-CDa5) was observed in 76 (54.7%) patients. A multiple regression analysis showed that the lack of SB endoscopic healing was an independent risk factor for clinical relapses (hazard ratio (HR): 5.34; 95% confidence interval (CI): 2.06-13.81) and serological relapses (HR: 3.02; 95% CI: 1.65-5.51), respectively. MR ulcer healing (MaRIA score11) demonstrated a high diagnostic accuracy (90.9%; 95% CI: 87.9-93.2%) for endoscopic healing. The kappa coefficient between BAE and MRE for longitudinal responsiveness was 0.754 (95% CI: 0.658-0.850) for clinical relapse and 0.783 (95% CI: 0.701-0.865) for serological relapse.SB inflammation was associated with a poor prognosis in patients with clinical-serological remission. MRE is a valid and reliable examination for SB inflammatory activity both for cross-sectional evaluations and prognostic prediction.

The prevention of postoperative recurrence is a critical issue in surgery for Crohn’s disease. Prospective randomized trials in Western countries have shown that the postoperative use of anti-tumor necrosis factor α-antibodies was effective in reducing the recurrence rate. We investigated the efficacy of infliximab (IFX) for the prevention of postoperative Crohn’s disease recurrence. We performed a prospective randomized multicenter study. Patients who underwent intestinal resection were assigned to groups treated with or without IFX. Immediately after surgery, patients in the IFX group received IFX at 5 mg/kg at 0, 2, and 6 weeks, followed by every 8 weeks for 2 years. The primary study outcome was the proportion of patients with endoscopic and/or clinical recurrence at 2 years after surgery. Thirty-eight eligible patients participated in this study: 19 in the IFX group and 19 in the non-IFX group. The disease recurrence rate in the IFX group was 52.6% (10/19), which was significantly lower than that in the non-IFX group (94.7% [18/19]). The postoperative use of IFX is effective in preventing Crohn’s disease recurrence for 2 years.

Because anti-tumor necrosis factor (anti-TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from nine Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 2 of the statements comprised three parts: (3) management of latent TB in preparation for anti-TNF therapy, (4) monitoring during anti-TNF therapy, and (5) management of an active TB infection after anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment.