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Leucine-rich alpha-2 glycoprotein (LRG) is a newly studied biomarker for inflammatory diseases. This study aimed to investigate whether LRG can be used for evaluating transmural activity in patients with Crohn's disease (CD).We performed magnetic resonance enterography (MRE) in 227 consecutive patients with CD from June 2020 to August 2021. We prospectively compared MRE findings with clinical and laboratory data including LRG. MRE was evaluated using 2 validated scoring systems, and transmural inflammation was defined as having a maximum simplified magnetic resonance index of activity (sMaRIA) score of ≥4 and a 5-point classification score of ≥9, respectively.The correlation between LRG and the total MRE score showed a positive correlation (r = 0.576 for the sMaRIA score, P0.01, and r = 0.633 for the 5-point score, P0.01). Serum concentrations of LRG significantly increased as MRE scores increased (P0.01). The area under the curve of LRG for a sMaRIA score of ≥4 and a 5-point score of ≥9 was 0.845 and 0.869, respectively, which was significantly higher than that of CDAI (P0.01) or C-reactive protein (P0.01). LRG levels of ≥14 μg/mL had a 67% sensitivity and 90% specificity for a sMaRIA score of ≥4 and a 73% sensitivity and 89% specificity for a 5-point score of ≥9. Patients with high LRG levels were also strongly associated with CD-related hospitalization, surgery, and clinical relapse compared with those with low LRG levels (P0.01 for all).LRG is a highly accurate serum biomarker for detecting transmural activity in patients with CD. Results need to be validated in further multicenter studies.

Vedolizumab, an immunosuppressive drug that acts locally on the gastrointestinal tract, is mainly used for the treatment of inflammatory bowel disease, and has been reported to be effective against gastrointestinal acute graft-versus-host disease (GI-aGVHD) in adults. However, there is insufficient evidence for pediatric GI-aGVHD. We used vedolizumab to treat three cases of GI-aGVHD in patients aged 1.5-4.4 years. It was significantly effective in two patients and did not cause serious side effects in any patient. Vedolizumab might be effective and safe for pediatric GI-aGVHD refractory to other treatments, but this must be confirmed in future studies.

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 importance and pathophysiology of transmural healing in patients with Crohn’s disease [CD] remains to be verified. We aimed to examine the association between serum concentrations of biologics and transmural remission evaluated via magnetic resonance enterography [MRE]. Methods We enrolled patients with CD who received maintenance biologics 1 year after induction and prospectively followed up for at least 1 year after baseline laboratory, endoscopic and MRE examination. We evaluated the relationship between baseline factors including the presence of transmural remission and patient prognosis, as well as between serum concentrations and transmural remission. Results We included 134 patients, of whom 65, 31, 27 and 11 received infliximab, adalimumab, ustekinumab and vedolizumab, respectively. Those who achieved transmural remission showed a lower risk of hospitalization and surgery than those who did not achieve remission [p Conclusions Transmural remission was the best predictor for prognosis in CD patients who received maintenance biologic therapy. High drug concentration levels were associated with transmural remission confirmed via MRE.

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.

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.

To quantify bowel motility shown on cine MRI using the classical optical flow algorithm and compare it with balloon-assisted enteroscopy (BAE) findings in patients with Crohn's disease (CD).This retrospective study included 29 consecutive patients with CD who had undergone MR enterocolonography (MREC) and BAE between March and May 2017. We developed computer software to present motion vector magnitudes between consecutive cine MR images as bowel motility maps via a classical optical flow algorithm using the Horn-Schunck method. Cine MR images were acquired with a balanced steady-state free precession sequence in the coronal direction to capture small bowel motility. The small bowels were divided into three segments. In total, 63 bowel segments were assessed via BAE and MREC. Motility scores on the maps, simplified MR index of activity (sMaRIA), and MREC score derived from a 5-point MR classification were assessed independently by two radiologists and compared with the CD endoscopic index of severity (CDEIS). Correlations were assessed using Spearman's rank coefficient. The areas under the receiver-operating characteristic curve (AUCs) of motility score for differentiating CDEIS was calculated; a P value 0.05 was considered statistically significant.Motility score was negatively correlated with CDEIS (r = -0.59 [P 0.001] and -0.54 [P 0.001]), and the AUCs of motility scores for detecting CDEIS ≥ 3 were 88.2% and 78.6% for observers 1 and 2, respectively. There were no significant differences in the AUC for detecting CDEIS ≥ 3 and CDEIS ≥ 12 between motility and sMaRIA or MREC score.The motility map was feasible for locally quantifying the bowel motility. In addition, the motility score on the map reflected the endoscopic inflammatory activity of each small bowel segment in patients with CD; hence, it could be used as a tool in objectively interpreting cine MREC to predict inflammatory activity in CD.

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.

Behçet's disease (BD) is an intractable systemic inflammatory disease characterized by four main symptoms: oral and genital ulcers and ocular and cutaneous involvement. The Japanese diagnostic criteria of BD classify intestinal BD as a specific disease type. Volcano-shaped ulcers in the ileocecum are a typical finding of intestinal BD, and punched-out ulcers can be observed in the intestine or esophagus. Tumor necrosis factor inhibitors were first approved for the treatment of intestinal BD in Japan and have been used as standard therapy. In 2007 and 2014, the Japan consensus statement for the diagnosis and management of intestinal BD was established. Recently, evidence-based JSBD (Japanese Society for BD) Clinical Practice Guidelines for BD (Japanese edition) were published, and the section on intestinal BD was planned to be published in English. Twenty-eight important clinical questions (CQs) for diagnosis (CQs 1–6), prognosis (CQ 7), monitoring and treatment goals (CQs 8–11), medical management and general statement (CQs 12–13), medical treatment (CQs 14–22), and surgical treatment (CQs 23–25) of BD and some specific situations (CQs 26–28) were selected as unified consensus by the members of committee. The statements and comments were made following a search of published scientific evidence. Subsequently, the levels of recommendation were evaluated based on clinical practice guidelines in the Medical Information Network Distribution Service. The degree of agreement was calculated using anonymous voting. We also determined algorithms for diagnostic and therapeutic approaches for intestinal BD. The present guidelines will facilitate decision making in clinical practice.

AJM300 is an oral, small-molecule α4-integrin antagonist. We assessed the efficacy and safety of AJM300 in patients with moderately active ulcerative colitis.This multicentre, randomised, double-blind, placebo-controlled, phase 3 study consisted of two phases: a treatment phase and an open-label re-treatment phase. The study was done at 82 hospitals and clinics in Japan. Patients with a Mayo Clinic score of 6-10, endoscopic subscore of 2 or more, rectal bleeding subscore of 1 or more, and an inadequate response or intolerance to mesalazine were enrolled. Patients were randomly allocated (1:1) via a website to either AJM300 (960 mg) or placebo by the minimisation method, which was adjusted centrally by dynamic assignment against the Mayo Clinic score (≥6 to ≤7, ≥8 to ≤10 points), any use of corticosteroid, anti-TNFα antibody, or immunosuppressants during the disease-active period (yes vs no), duration of induction therapy until randomisation (4 weeks vs ≥4 weeks) as the minimisation factors. Patients, investigators, site staff, assessors, and the sponsor were masked to treatment assignments. The study drug was administered orally, three times daily, for 8 weeks, and continued for up to 24 weeks if endoscopic remission was not achieved or rectal bleeding did not stop. The primary endpoint was the proportion of patients with a clinical response at week 8, and was analysed in the full analysis set. Clinical response was defined as a reduction in Mayo Clinic score of 30% or more and 3 or more, a reduction in rectal bleeding score of 1 or more or rectal bleeding subscore of 1 or less, and an endoscopic subscore of 1 or less at week 8. The study is registered with ClinicalTrials.gov, NCT03531892, and is closed to recruitment.Between June 6, 2018, and July 22, 2020, 203 patients were randomly assigned to AJM300 (n=102) or placebo (n=101). At week 8, 46 (45%) patients in the AJM300 group and 21 (21%) patients in the placebo group had a clinical response (odds ratio 3·30, 95% CI 1·73-6·29; p=0·00028). During the 8-week treatment and 16-week extension treatment periods, adverse events occurred in 39 (39%) of 101 patients in the placebo group and 39 (38%) of 102 patients in the AJM300 group. We found no difference in the incidence of adverse events between groups or after repeated administration of AJM300. The most common adverse event was nasopharyngitis (11 [11%] of 101 patients in the placebo group and ten [10%] of 102 patients in the AJM300 group). The most common treatment-related adverse event was also nasopharyngitis (four [4%] of 101 patients in the placebo group and three [3%] of 102 patients in the AJM300 group). Most adverse events were mild-to-moderate in severity. No deaths were reported. A serious adverse event was reported in the AJM300 group (one patient with anal abscess), but this was judged to be unrelated to study drug.AJM300 was well tolerated and induced a clinical response in patients with moderately active ulcerative colitis who had an inadequate response or intolerance to mesalazine. AJM300 could be a novel induction therapy for the treatment of patients with moderately active ulcerative colitis.EA Pharma and Kissei Pharmaceutical.For the Japanese translation of the abstract see Supplementary Materials section.

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.

Japan has the largest aging society, where many elderly people have intractable diseases including ulcerative colitis (UC). Along with the increasing total number of UC patients, the number of elderly UC patients has also been increasing and will continue to do so in the future. Although the clinical features and natural history of UC in the elderly have many similarities with UC in the non-elderly population, age-specific concerns including comorbidities, immunological dysfunction, and polypharmacy make the diagnosis and management of elderly UC challenging compared to UC in non-elderly patients. Based on increasing data related to elderly UC patients from Japan, as well as other countries, we reviewed the epidemiology, clinical course, differential diagnosis, management of comorbidities, surveillance, medical therapy, and surgery of UC in the elderly.

Background Activated phosphatidylinositol-3-OH kinase δ syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory tract infections, lymphoid hyperplasia, and Herpesviridae infections caused by germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) can be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, methods, and outcomes of HSCT for APDS1 remain undefined. Objective Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT. Methods We reviewed retrospectively the medical records of cohorts undergoing HSCT at collaborating facilities. Results Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced-intensity conditioning. Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT. Conclusion Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based reduced-intensity conditioning–HSCT ameliorated clinical symptoms, but transplantation-related complications were frequent, including graft failure.

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.

Mucosal healing is an important treatment target in patients with ulcerative colitis.To explore the optimal colonoscopic strategy to determine the risk for clinical relapse in patients with ulcerative colitis.We enrolled 325 consecutive patients with ulcerative colitis in clinical and biochemical remission from April 2018 to March 2019. Five colonic segments were endoscopically and histologically assessed systematically. For endoscopic evaluation, we used three different modes of the Ulcerative Colitis Endoscopic Index of Severity (UCEIS): "original," "worst affected," and "pancolonic." The Geboes score was used for histological evaluation. We prospectively followed up the patients and defined clinical relapse as the primary endpoint.Within 1 year after colonoscopy, 18.2% of patients experienced a clinical relapse. Receiver operating characteristic curve analysis showed areas under the curve of 0.755, 0.817, and 0.852 for the "original," "worst affected," and "pancolonic" groups, respectively; hence, pancolonic UCEIS obtained the highest predictive value. Using the pancolonic UCEIS cutoff value of 3, Kaplan-Meier curve analysis showed that patients with endoscopic activity had a significantly lower relapse-free rate than those with endoscopic remission (P 0.01). Multivariate analysis demonstrated endoscopic (pancolonic UCEIS3) and histological (Geboes3.0) activities as independent risks for relapse (HR: 3.96 and 3.48, respectively). Combining pancolonic UCEIS ≤3 and Geboes score ≤3.0 to provide 1-year relapse avoidance was 92.0% sensitive and 97.0% specific.Evaluating disease remission by complete colonoscopy is relevant, and the combination of pancolonic endoscopic and histological evaluations may appropriately evaluate mucosal healing.

Although 5-aminosalicylate (5-ASA) is the therapy of first choice in ulcerative colitis (UC), some patients cannot tolerate it because of side effects. Previous reports have not investigated whether 5-ASA intolerance is associated with the risk of colectomy.To investigate the associations between 5-ASA tolerance and colectomy among UC patients METHODS: The data of UC patients who visited any of three hospitals during 2014-2018 in and around Tokyo, Japan, were retrospectively obtained from the medical records. Patients were categorized as (a) tolerant to any 5-ASA compounds ("tolerant to 5-ASA") and (b) patients who were intolerant to one or more 5-ASA compounds leading to refrainment from their further use ("intolerant to 5-ASA"). The association between 5-ASA tolerance and colectomy was examined by Cox proportional hazards model adjusted for sex, age, smoking and extent of colitis.Of 1788 patients, 1684 were "tolerant to 5-ASA" while 104 were "intolerant to 5-ASA". Colectomy was performed in 43 (2.6%) of the patients tolerant to 5-ASA and 12 (11.5%) of the patients intolerant to 5-ASA. After adjusting for all covariates, the risk of undergoing colectomy was higher in the "intolerant to 5-ASA" group than in the "tolerant to 5-ASA" group (hazard ratio: 4.92; 95% confidence interval: 2.58-9.38).Patients in whom 5-ASA was discontinued due to intolerance had a higher risk of undergoing colectomy than patients tolerant to their first, second or third 5-ASA compounds.

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/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.

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.

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

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

Background 5-Aminosalicylates (5-ASA) are the key drugs in induction and maintenance therapy in ulcerative colitis (UC). Some UC patients are involved in 5-ASA intolerance after induction of oral 5-ASA compounds. There is no evidence of the prognosis including the risk of colectomy in 5-ASA intolerant UC patients. Methods The aim of this study is to establish the prognosis of 5-ASA intolerant UC patients in a multicenter cohort study. A retrospective review of a prospective multicenter database (2014–2018) of 1,574 UC patients was carried out and a total of 1,286 patients treated with oral 5-ASA compounds were enrolled. We compared the risk of colectomy and biologics induction between patients (i) tolerant to first 5-ASA compound (1079), (ii) intolerant to first 5-ASA compound but tolerant to other 5-ASA compound (107) and (iii) intolerant to 5-ASA compound and withdrawal of 5-ASA (100). Results We identified 1,286 patients with UC, of which 40 patients (3.1%) resulted in colectomy and 247 patients (19%) treated with biologics. Colectomy rate in patients (iii) intolerant to 5-ASA and withdrawal of 5-ASA were higher than (i) tolerant to first 5-ASA and (ii) intolerant to first 5-ASA but tolerant to other 5-ASA (9.0%, 2.7%, 1.9%, respectively). (iii) Patients withdrawal of 5-ASA showed higher risk of colectomy compared with (i) tolerant to first 5-ASA (Hazard ratio (HR) 4.71, 95% Confidence interval (CI): 2.04–10.8). The risk of colectomy among (ii) patients intolerant to first 5-ASA but tolerant to other 5-ASA showed no significant difference compared with (i) tolerant to first 5-ASA (HR 0.76, 95% CI: 0.43–1.35). The biologics induction rate in (iii) patients withdrawal of 5-ASA was significantly higher than (i) tolerant to first 5-ASA and (ii) intolerant to first 5-ASA but tolerant to other 5-ASA (37%, 18%, 16%, respectively). Also (iii) patients withdrawal of 5-ASA showed higher risk of induction with biologics compared with (i) tolerant to first 5-ASA (HR 2.35, 95% CI: 1.50–3.68). Those risk among (ii) patients intolerant to first 5-ASA but tolerant to other 5-ASA showed no significant difference compared with (i) tolerant to first 5-ASA (HR 0.76, 95% CI: 0.43–1.35). Conclusion Patients with UC who had 5-ASA intolerance and withdrew from 5-ASA showed poor prognosis. We should consider trying other 5-ASA compounds even if the patients had intolerance to one 5-ASA compound.

Background Anti-tumour necrosis factor (TNF)-α agents are the mainstay of the long-term treatments for refractory ulcerative colitis (UC). However, there is no prospective randomised controlled trial evaluating if anti-TNF-α agents can be discontinued in UC patients in remission. Methods Patients with UC maintained in clinical remission with infliximab (IFX) were prospectively enrolled from 23 specialist centres. Patients confirmed to be in (1) clinical remission for > 6 months, (2) steroid-free and (3) Mayo endoscopic subscore (MES) of 0 or 1 were randomised with stratified factors (MES and use of immunomodulators) into two groups (continue or discontinue IFX) in 1:1. The biopsy was taken from the rectum and Nancy histological Index (NI) was centrally scored at randomisation. The primary endpoint was remission rate at week 48 in full analysis set (FAS). Factors associated with remission at Week 48 were evaluated by logistic regression adjusted for the treatment group. Efficacy and safety of retreatment with IFX after relapse were also evaluated. Results A total of 92 patients were included in the FAS and the remission rates at week 48 were 80.4% (95% CI: 66.1–90.6) and 54.3% (95% CI: 39.0–69.1) in IFX-continued and IFX-discontinued groups, respectively (p = 0.008). Although the duration of IFX, use of concomitant immunomodulators, IFX concentration, and MES of 0 at randomisation were not predictive, C-reactive protein and NI were associated with remission at week 48 in FAS (p = 0.039 and 0.019, respectively). Retreatment with IFX lead to remission in 8 out of 12 patients (66.7%) in 8 weeks and was well-tolerated. Conclusion This first prospective multicentre randomised controlled trial confirmed that discontinuation of maintenance IFX resulted in the increased risk of relapse but retreatment was effective in UC. Endoscopic normalisation was not sufficient for the successful discontinuation of IFX.

Background & AimsA random biopsy is recommended for surveillance of ulcerative colitis (UC)-associated colorectal cancer. However, a targeted biopsy might be more effective. We conducted a randomized controlled trial to compare rates of neoplasia detection by targeted vs random biopsies in patients with UC.MethodsWe performed a study of 246 patients with UC for 7 years or more, seen at 52 institutions in Japan from October 1, 2008 through December 31, 2010. Patients were randomly assigned to the random group (4 random biopsies collected every 10 cm in addition to targeted biopsies, n = 122) or the target group (biopsies collected from locations of suspected neoplasia, n = 124). The primary end point was the number of neoplastic lesions detected in a single surveillance colonoscopy. We estimated the ratio and difference in the mean number of neoplastic lesions between the groups. We also evaluated the non-inferiority between the groups as an exploratory study. A non-inferiority margin of 0.65 (0.13 of 0.20) was considered for the ratio of the mean number of neoplastic lesions between groups.ResultsThe mean number of biopsies found to contain neoplastic tissue per colonoscopy was 0.211 (24 of 114) in the target group and 0.168 (18 of 107) in the random group (ratio of 1.251; 95% confidence interval, 0.679–2.306). The lower limit was above the non-inferiority margin of 0.65. Neoplasias were detected in 11.4% of patients in the target group and 9.3% of patients in the random group (P = .617). Larger numbers of biopsy samples per colonoscopy were collected in the random group (34.8 vs 3.1 in the target group; P < .001), and the total examination time was longer (41.7 vs 26.6 minutes in the target group; P

Objective: To describe the pre-conception status, pregnancy outcomes, and medication prevalence in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Crohn’s disease (CD), and ulcerativ...

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.

In the diagnosis of inflammatory bowel disease (IBD), careful history taking based upon available epidemiological data, along with judicious use of biochemical and bacteriological examination is the most powerful and cost-effective technology, particularly to rule out irritable bowel syndrome (IBS). We also have to be careful in evaluating symptomatic IBD patients looking for exacerbating factors such as Clostridium difficile infection, use of NSAIDs, and non-adherence which is revealed only by frank discussion.

Background The importance of self-management (SMN) has been widely recognized in chronic diseases but the concept remains complex and its evaluation diverse. There is a limited number of studies evaluating SMN in Inflammatory Bowel Diseases (IBD), and notably in Japan. We have therefore explored the actual utilization of SMN in IBD, the type of supports needed by the IBD patients, and the phenotypic differences between patients with and without SMN. Methods We conducted a web-based survey considering SMN components as diet, treatment, symptoms/physical conditions, stress, financial worries, and support services from February to March 2020. Subjects were recruited from the Japanese IBD patients’ panel and solicited by email for participation. SMN patients were defined as those responding positively to 3 questions about (1) habit of checking nutrition labelling (2) adjustment of their diet (3) modification of their daily life behavior according to the health conditions. Factors associated with the SMN utilization were also analysed by logistic regression analysis. Results Among 371 evaluable patients [Ulcerative Colitis (UC): n=210, Crohn’s Disease (CD): n=161, mean age=42 years, mean disease duration=10.2 years], 59.6% composed the SMN group (UC: 54.3% CD: 66.5%). 87.9% responded “able to live well with IBD” (UC: 90.5% CD: 84.5%, SMN: 92.3% vs non-SMN: 81.3% p=0.002), and 74.4% responded “checking nutrition labelling when buying food” (UC: 67.1% CD: 83.9%) but only 18.3% kept a regular record of diet (UC: 16.7% CD: 20.5%, SMN: 24.9% non-SMN: 8.7%) and 26.1% for symptoms record (UC: 29.5% CD:21.7%, SMN: 29.9% non-SMN: 20.7%). Doctors and families were the most consulted partners for lifestyle, symptoms and treatment by all patients, while CD patients, compared to UC ones, privileged nurses and other IBD patients. As between patients treated or not with biologics and janus kinase inhibitor (Bio/JAKi), there were more items demonstrating significant differences such as the utilization of SMN in UC than in CD. Patients with Bio/JAKi significantly responded more often to be “satisfied with their current treatment”. Meanwhile, patients with hospitalization or surgery histories as well as UC patients with Bio/JAKi showed higher proportions of SMN utilization. “Having 3 or more kinds of people to consult about lifestyle” in UC and “History of hospitalization” in CD were the most influential factors of SMN utilization. Financial/Employment aspects (77.4%) was the most desired support for all patients. Conclusion This is the first survey to reveal the actual utilization of SMN and its possible benefits in IBD patients in Japan. Our results suggested that SMN contributes to a better living with IBD for Japanese IBD patients.

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.