Characteristics and Endoscopic Classification of Ulcerative Lesions Affecting the Ileocecal Valve.

OBJECTIVES: The aim of this study was to propose an endoscopic classification system for ulcerative lesions on the ileocecal valve and investigate its relevance to the underlying etiology. METHODS: Among the 60,325 patients who underwent colonoscopy at our hospital from January 2006 to December 2018, patients with ulcerative lesions on the ileocecal valve were included. The following data were obtained using the hospital's medical records: sex, age, clinical diagnosis, laboratory data, and endoscopic and histological findings. Patients who have ulcerative colitis and who were not evaluated by histological examination were excluded. Ulcerative lesions on the ileocecal valve were classified into 3 groups according to their endoscopic appearance: small shallow ulcerative lesions without edematous change (group A), lateral spreading shallow ulcerative lesions with edematous change (group B), and deep deformed ulcerative lesions (group C). The association between this endoscopic classification and its clinical diagnosis, clinical course, and the interobserver reliability were evaluated. RESULTS: Of 72 patients who were eligible for analysis, 18 were assigned to group A, 9 to group B, and 45 to group C. Infectious enteritis was mainly assigned to group A (group A, 12; group B, none; and group C, 6; p < 0.0001), inflammatory bowel disease was mainly assigned to group C (group A, none; group B, 5; and group C, 35; p < 0.0001), and malignant tumor was assigned to group C only. Interobserver reliability was extremely high among the 3 examining doctors (kappa value 0.7-0.8). CONCLUSION: Endoscopic classification was divided into 3 groups for ulcerative lesions on the ileocecal valve, and this system could be beneficial for presuming their clinical diagnoses.

Osteopontin attenuates acute gastrointestinal graft-versus-host disease by preventing apoptosis of intestinal epithelial cells.

BACKGROUND AND AIMS: Acute graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation, which often targets gastrointestinal (GI) tract. Osteopontin (OPN) plays an important physiological role in the efficient development of Th1 immune responses and cell survival by inhibiting apoptosis. The role of OPN in acute GI-GVHD is poorly understood. In the present study, we investigated the role of OPN in donor T cells in the pathogenicity of acute GI-GVHD. METHODS: OPN knockout (KO) mice and C57BL/6 (B6) mice were used as donors, and (C57BL/6 × DBA/2) F1 (BDF1) mice were used as allograft recipients. Mice with acute GI-GVHD were divided into three groups: the control group (BDF1→BDF1), B6 group (B6→BDF1), and OPN-KO group (OPN-KO→BDF1). Bone marrow cells and spleen cells from donors were transplanted to lethally irradiated recipients. Clinical GVHD scores were assessed daily. Recipients were euthanized on day 7 after transplantation, and colons and small intestines were collected for various analyses. RESULTS: The clinical GVHD score in the OPN-KO group was significantly increased compared with the B6 and control groups. We observed a difference in the severity of colonic GVHD between the OPN-KO group and B6 group, but not small intestinal-GVHD between these groups. Interferon-γ, Tumor necrosis factor-α, Interleukin-17A, and Interleukin-18 gene expression in the OPN-KO group was differed between the colon and small intestine. Flow cytometric analysis revealed that the fluorescence intensity of splenic and colonic CD8 T cells expressing Fas Ligand was increased in the OPN-KO group compared with the B6 group. CONCLUSION: We demonstrated that the importance of OPN in T cells in the onset of acute GI-GVHD involves regulating apoptosis of the intestinal cell via the Fas-Fas Ligand pathway.

Clinical significance of human intestinal spirochetosis: a retrospective study.

The clinical and pathological features of human intestinal spirochetosis (HIS) are not well known. Here we report 55 patients with HIS who were diagnosed at our institution during the past 5 years. Seven patients presented with symptoms such as abdominal pain or diarrhea, while the others were incidentally diagnosed during screening colonoscopy. Most patients had non-specific endoscopic findings, including intestinal edema or erosion. The diagnosis of HIS was histologically confirmed via hematoxylin and eosin staining, periodic acid-Schiff staining, and/or immunohistochemistry using anti-Treponema pallidum antibody. Among the 55 patients, five were diagnosed with diseases other than HIS (amoebic colitis, three;ulcerative colitis, one). Sixteen patients were treated with either amoxicillin or metronidazole;only metronidazole proved to be effective. The clinical significance of asymptomatic HIS remains unknown. Some case reports suggest a risk for increased severity in patients with immunodeficiency and/or sexually transmitted diseases. Therefore, aggressive treatment for HIS should be considered, particularly in high-risk patients.

Long-term efficacy of infliximab for refractory ulcerative colitis: results from a single center experience.

BACKGROUND: The long-term efficacy of infliximab (IFX) for patients with refractory ulcerative colitis (UC) is unclear. The aim of this study was to assess the long-term outcomes of IFX treatment in patients with refractory UC. METHODS: Thirty-three patients with refractory UC who received IFX treatment at Kyoto University Hospital between 2003 and 2013 were retrospectively evaluated. IFX intensification was defined as a dose escalation (up to 10 mg/kg) and/or shorter intervals between infusions (every 4-6 weeks). RESULTS: Of the 33 patients who received scheduled infusions of IFX, 24 (72.7%) achieved clinical remission within 8 weeks after initiating IFX treatment. Of these 24 responders, 17 (70.8%) experienced a relapse of UC and required IFX intensification, and 16 (66.7%) eventually maintained clinical remission with IFX treatment, including IFX intensification. Of the 33 patients, 6 (18.2%) underwent colectomy during IFX treatment. Multivariate regression analysis showed that a serum C-reactive protein (CRP) concentration <5 mg/L two weeks after starting IFX was a predictor of a positive clinical response to IFX induction therapy. No severe adverse events occurred in UC patients treated with IFX. CONCLUSION: IFX intensification was necessary for long-term maintenance of remission and to prevent colectomy in patients with refractory UC.

Therapeutic effect of intensive granulocyte and monocyte adsorption apheresis combined with thiopurines for steroid- and biologics-naïve Japanese patients with early-diagnosed Crohn's disease.

BACKGROUND: Early induction with biologics can reduce complications in patients with Crohn's disease (CD) and improve their quality of life. The safety of biologics, however, is uncertain. Granulocyte and monocyte adsorptive apheresis (GMAA) is a natural biologic therapy that selectively removes granulocytes and monocytes/macrophages and has few severe adverse effects. The effects of GMAA on patients with early-diagnosed CD are unclear. We investigated the effects of GMAA combined with thiopurines on patients with early-diagnosed CD. METHODS: Twenty-two corticosteroid- and biologic-naïve patients with active early-diagnosed CD were treated with intensive GMAA (twice per week) combined with thiopurines administration. Active early-diagnosed CD was defined as follows: (i) within 2years after diagnosis of CD, (ii) with no history of both surgical treatment and endoscopic dilation therapy, and (iii) Crohn's Disease Activity Index (CDAI) was higher than 200. We investigated the ratios of clinical remission defined as CDAI was less than or equal to 150 at 2, 4, 6 and 52weeks and mucosal healing defined as a Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD) as 0 at 6 and 52weeks. Adverse events were recorded at each visit. RESULTS: The ratios of clinical remission at 2, 4, and 6 weeks were 6 of 22 (27.2%), 12 of 22 (54.5%), and 17 of 22 (77.2%), respectively. At 52 weeks, 18 of 21 patients (81.8%) were in clinical remission. The ratios of mucosal healing at 6 and 52 weeks were 5 of 22 (22.7%) and 11 of 22 (50%), respectively. The difference in the mucosal healing ratio was significant between 6 and 52 weeks (p = 0.044). No serious adverse effects were observed during this study. CONCLUSIONS: Combination therapy with intensive GMAA and thiopurines administration rapidly induced high remission in patients with active early-diagnosed CD without serious adverse effect. Mucosal healing was observed in 50.0% of enrolled patients. This combination therapy might be a rational option for patients with early-diagnosed CD.

Endoscopic healing is associated with a reduced risk of biologic treatment failure in patients with ulcerative colitis.

Increasing number of patients with ulcerative colitis (UC) have received biologic treatment during the last decade. The association between endoscopic healing (EH) and biologic treatment failure remains understudied. Medical information of UC patients who started biologic treatment was retrospectively collected. EH was defined as Mayo endoscopic subscore of 0 or 1. Loss of response (LOR)-free drug continuation rate was compared between patients who achieved EH and those who did not using Kaplan-Meier estimator. Fifty-two patients received 53 biologic treatments and underwent follow-up colonoscopies within 2 years. Thirty-three patients achieved EH, all of which remained on the same treatment without LOR during the observational period. Twenty patients did not achieve EH, 8 of which ultimately discontinued the treatment due to LOR to biologic agents. Kaplan-Meier estimator found a significantly lower drug continuation rate in patients without EH (p < 0.001; log-rank test). A Cox regression analysis identified EH as an independent factor associated with a reduced risk of LOR-related biologic treatment failure irrespective of the types of biologic agents (Hazard Ratio = 0.0324, p < 0.001). EH within 2 years is associated with a reduced risk of LOR-related biologic treatment failure in patients with UC.

Refractoriness of intestinal Behçet's disease with myelodysplastic syndrome involving trisomy 8 to medical therapies - our case experience and review of the literature.

BACKGROUND/AIMS: Gastrointestinal lesions of Behçet's disease (BD) are often refractory to medical therapy and sometimes result in serious comorbidities such as gastrointestinal perforation and massive bleeding. There are several reports of patients with BD comorbid with myelodysplastic syndrome (MDS) involving trisomy 8 that frequently have intestinal lesions refractory to conventional medical therapy. Little is known about the efficacy of infliximab (IFX) for these intestinal lesions. METHODS: We present 2 cases of intestinal BD with MDS involving trisomy 8 who did not respond to IFX, and review previous reports of BD with MDS involving trisomy 8 concerning their responsiveness to conventional medical therapy. RESULTS: Among 31 previously reported cases that received medical treatment for BD, 19 (61.3%) showed temporary improvement of the BD symptoms, 9 (29.0%) deteriorated, and 3 (9.7%) showed no change. All of the 9 cases that showed deterioration had intestinal lesions. Our 2 cases failed to respond to IFX, resulting in a poor prognosis. CONCLUSIONS: IFX might not be effective for improving intestinal BD comorbid with MDS involving trisomy 8. Trisomy 8 is associated with the BD prognosis and refractoriness to conventional medical therapy.

Prior use of immunomodulatory drugs improves the clinical outcome of endoscopic balloon dilation for intestinal stricture in patients with Crohn's disease.

BACKGROUND: Endoscopic balloon dilation is a promising procedure to improve symptoms of intestinal stricture in patients with Crohn's disease (CD). However, the long-term efficacy of endoscopic balloon dilation combined with immunomodulatory drugs remains unclear. The aim of the present study is to investigate whether prior use of immunomodulatory drugs affects the clinical outcome of endoscopic balloon dilation for intestinal stricture in CD. PATIENTS AND METHODS: Between January 2004 and December 2011, 83 dilations were carried out in 25 patients with CD. Median follow-up period was 46 months. Patients were categorized into two groups based on their medications at the first endoscopic balloon dilation: early immunomodulatory drug-induction group (early IM-induction group) in which patients were already treated with immunomodulatory drugs before the dilation; and post-immunomodulatory drug-induction group (post-IM-induction group) in which patients were not yet treated withimmunomodulatory drugs before dilation. We compared the long-term cumulative non-surgical rate and the mean number of dilation procedures per patient between early and post-IM-induction groups to clarify the influence of prior use of immunomodulatory drugs on the clinical outcome of endoscopic balloon dilation. RESULTS: There was a significant difference in the mean number of dilation procedures per patient between the early IM-induction and post-IM-induction groups (P = 0.04), although no significant difference in the cumulative non-surgical rate was observed between the two groups (P = 0.14). CONCLUSION: Prior use of immunomodulatory drugs may improve the clinical outcome of endoscopic balloon dilation for intestinal stricture in CD.

Single Nucleotide Polymorphisms of the MEFV Gene E148Q Are Highly Associated With Disease Phenotype in Crohn's Disease.

BACKGROUND: Single nucleotide polymorphisms (SNPs) of the MEFV gene may modify inflammatory bowel disease (IBD) activity. The prevalence of MEFV gene SNPs in IBD patients and their involvement in IBD pathophysiology remains unclear. METHODS: We analyzed 12 MEFV gene SNPs in peripheral leukocytes of Japanese IBD patients (Crohn's disease [CD]: 69 patients, ulcerative colitis: 32 patients) by polymerase chain reaction using next-generation DNA sequencing and evaluated their prevalence and association with the disease characteristics. Inflammasome activity and mature interleukin (IL)-1ß and IL-18 production were evaluated in peripheral blood mononuclear cells obtained from CD patients stimulated with lipopolysaccharides and adenosine triphosphate, and compared between those with and without the E148Q SNP. COL1A1 and HSP47 gene expression was analyzed in CCD-18Co cells costimulated with IL-1ß and other inflammatory cytokines. RESULTS: The prevalence of MEFV gene SNPs in IBD patients was similar to that in the human gene database. E148Q was the most common SNP. Compared with CD patients without E148Q, those with E148Q had a significantly greater frequency of the stricture phenotype, and their peripheral blood mononuclear cells exhibited significantly higher IL-1ß and IL-18 levels and higher caspase-1 activity. IL-1ß and IL-17A synergistically increased COL1A1 and HSP47 gene expression. CONCLUSIONS: MEFV gene SNPs, including E148Q, modify the behavior of CD. IL-1ß and IL-18 are produced through enhanced caspase-1 activity in monocytes of CD patients with E148Q. IL-1ß promotes gene expression of fibrosis-related genes by cooperating with IL-17A in myofibroblasts. Therefore, E148Q might be a disease-modifying gene associated with the fibrostenosis phenotype in CD patients.

MEFV gene single nucleotide polymorphisms, including E148Q, modify the behavior of Crohn's disease to form stenosis. Interleukin-1ß is produced through enhanced caspase-1 activity in monocytes of Crohn's disease patients with E148Q, and promotes gene expression of fibrosis-related genes by cooperating with interleukin-17A in myofibroblasts.

Trajectory analyses to identify persistently low responders to COVID-19 vaccination in patients with inflammatory bowel disease: a prospective multicentre controlled study, J-COMBAT.

BACKGROUND: The degree of immune response to COVID-19 vaccination in inflammatory bowel disease (IBD) patients based on actual changes in anti-SARS-CoV-2 antibody titres over time is unknown. METHODS: Data were prospectively acquired at four predetermined time points before and after two vaccine doses in a multicentre observational controlled study. The primary outcome was humoral immune response and vaccination safety in IBD patients. We performed trajectory analysis to identify the degree of immune response and associated factors in IBD patients compared with controls. RESULTS: Overall, 645 IBD patients and 199 control participants were analysed. At 3 months after the second vaccination, the seronegative proportions were 20.3% (combination of anti-tumour necrosis factor [TNF]α and thiopurine) and 70.0% (triple combination including steroids), despite that 80.0% receiving the triple combination therapy were seropositive at 4 weeks after the second vaccination. Trajectory analyses indicated three degrees of change in immune response over time in IBD patients: high (57.7%), medium (35.6%), and persistently low (6.7%). In the control group, there was only one degree, which corresponded with IBD high responders. Older age, combined anti-TNFα and thiopurine (odds ratio [OR], 37.68; 95% confidence interval [CI], 5.64-251.54), steroids (OR, 21.47; 95%CI, 5.47-84.26), and tofacitinib (OR, 10.66; 95%CI, 1.49-76.31) were factors associated with persistently low response. Allergy history (OR, 0.17; 95%CI, 0.04-0.68) was a negatively associated factor. Adverse reactions after the second vaccination were significantly fewer in IBD than controls (31.0% vs 59.8%; p < 0.001). CONCLUSIONS: Most IBD patients showed a sufficient immune response to COVID-19 vaccination regardless of clinical factors. Assessment of changes over time is essential to optimize COVID-19 vaccination, especially in persistently low responders.

Increased DNA-incorporated thiopurine metabolite as a possible mechanism for leukocytopenia through cell apoptosis in inflammatory bowel disease patients with NUDT15 mutation.

BACKGROUND AND AIMS: Polymorphisms in the nucleotide diphosphate-linked moiety X-type motif 15 (NUDT15) gene are associated with thiopurine-induced leukopenia in patients with inflammatory bowel disease (IBD). NUDT15-associated subcellular thiopurine metabolism has not been investigated in primary lymphocytes. We hypothesized that NUDT15 mutation increases DNA-incorporated deoxythioguanosine (dTG) and induces apoptosis in lymphocytes. METHODS: DNA-incorporated dTG in peripheral blood mononuclear cells (PBMCs) and 6-thioguanine nucleotides (6-TGN) in red blood cells were measured in patients with IBD undergoing thiopurine treatment. The association of a single nucleotide polymorphism for NUDT15 (rs116855232) with dTGPBMC was examined. The pro-apoptotic effect of DNA-incorporated dTG was examined ex vivo in association with NUDT15 genotypes by co-culturing patient-derived peripheral CD4+ T lymphocytes with 6-thioguanine (6-TG). RESULTS: dTGPBMC was significantly higher in NUDT15 variants than in non-variants. dTGPBMC, but not 6-TGNRBC, negatively correlated with peripheral lymphocyte counts (r = - 0.31 and - 0.12, p = 0.012 and 0.173, respectively). DNA-incorporated dTG significantly accumulated to a greater extent in lymphocytes from NUDT15 variants when co-cultured with 6-TG ex vivo than in those from non-variants and was associated with decreased proliferation and increased apoptosis. CONCLUSION: Increased DNA-incorporated dTG may be responsible for thiopurine-induced leukocytopenia through cell apoptosis in IBD patients with NUDT15 mutation.

Increased colonic expression of ACE2 associates with poor prognosis in Crohn's disease.

The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn's disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course. We examined the expression of colonic ACE2 in 67 adult CD and 14 NIBD control patients using RNA-seq and quantitative (q) RT-PCR. We validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients. Colonic ACE2 expression was significantly higher in a subset of adult CD patients which was defined as the ACE2-high CD subset. IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of CD diagnosis, and a Cox regression analysis found that high ACE2 levels is an independent risk factor for surgery (OR 2.17; 95% CI, 1.10-4.26; p = 0.025). Increased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that can impact CD disease-related outcomes.

Increased Colonic Expression of ACE2 Associates with Poor Prognosis in Crohn's disease.

BACKGROUND AND AIMS: The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn's disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course. METHODS: We examined the expression of colon ACE2 using RNA-seq and quantitative (q) RT-PCR from 69 adult CD and 14 NIBD control patients. In a subset of this cohort we validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients. RESULTS: Colonic ACE2 expression was significantly higher in a subset of adult CD patients (ACE2-high CD). IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of diagnosis, with a Cox regression analysis finding that high ACE2 levels is an independent risk factor (OR 2.18; 95%CI, 1.05-4.55; p=0.037). CONCLUSION: Increased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that may impact CD disease-related outcomes.

Decreased Colonic Activin Receptor-Like Kinase 1 Disrupts Epithelial Barrier Integrity in Patients With Crohn's Disease.

BACKGROUND & AIMS: Intestinal epithelial cell (IEC) barrier dysfunction is critical to the development of Crohn's disease (CD). However, the mechanism is understudied. We recently reported increased microRNA-31-5p (miR-31-5p) expression in colonic IECs of CD patients, but downstream targets and functional consequences are unknown. METHODS: microRNA-31-5p target genes were identified by integrative analysis of RNA- and small RNA-sequencing data from colonic mucosa and confirmed by quantitative polymerase chain reaction in colonic IECs. Functional characterization of activin receptor-like kinase 1 (ACVRL1 or ALK1) in IECs was performed ex vivo using 2-dimensional cultured human primary colonic IECs. The impact of altered colonic ALK1 signaling in CD for the risk of surgery and endoscopic relapse was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. RESULTS: ALK1 was identified as a target of miR-31-5p in colonic IECs of CD patients and confirmed using a 3'-untranslated region reporter assay. Activation of ALK1 restricted the proliferation of colonic IECs in a 5-ethynyl-2-deoxyuridine proliferation assay and down-regulated the expression of stemness-related genes. Activated ALK1 signaling increased colonic IEC differentiation toward colonocytes. Down-regulated ALK1 signaling was associated with increased stemness and decreased colonocyte-specific marker expression in colonic IECs of CD patients compared with healthy controls. Activation of ALK1 enhanced epithelial barrier integrity in a transepithelial electrical resistance permeability assay. Lower colonic ALK1 expression was identified as an independent risk factor for surgery and was associated with a higher risk of endoscopic relapse in CD patients. CONCLUSIONS: Decreased colonic ALK1 disrupted colonic IEC barrier integrity and was associated with poor clinical outcomes in CD patients.

Combination of colonoscopy and magnetic resonance enterography is more useful for clinical decision making than colonoscopy alone in patients with complicated Crohn's disease.

BACKGROUND/AIMS: The small bowel is affected in more than half of patients with Crohn's disease (CD) at the time of diagnosis, and small bowel involvement has a negative impact on the long-term outcome. Many patients reportedly have active lesions in the small intestine even in patients in clinical remission. This study was performed to compare findings of magnetic resonance enterography (MRE) and ileocolonoscopy. METHODS: A single-center retrospective study was conducted in 50 patients (60 imaging series) with CD, for whom MRE was additionally performed during the bowel preparation for subsequent ileocolonoscopy. Endoscopic remission was defined as a Simple Endoscopic Score for CD (SES-CD) of <5. MRE remission was defined as a Magnetic Resonance Index of Activity (MaRIA) score of <50. The time to treatment escalation was assessed by the log-rank test. RESULTS: Importantly, 7 of 29 patients (24.1%) with endoscopic remission had a MaRIA score of ≥50. Both SES-CD and MaRIA correlated with the need for treatment escalation (P = 0.025, P = 0.009, respectively). MRE predicted the need for treatment escalation even in patients with endoscopic remission. Although no correlation was present between SES-CD and MaRIA score in patients with structuring/penetrating disease, or insufficient ileal insertion (<10cm), a high MaRIA score still correlated with the need for treatment escalation in stricturing or penetrating disease (P = 0.0306). CONCLUSIONS: The MaRIA score predicts the need for treatment escalation even in patients with endoscopic remission, indicating that addition of MRE to conventional ileocolonoscopy alone can be a useful, noninvasive tool for monitoring CD especially in stricturing or penetrating disease.

Individualized treatment based on CYP3A5 single-nucleotide polymorphisms with tacrolimus in ulcerative colitis.

BACKGROUND/AIMS: The pharmacokinetics of tacrolimus (TAC) is known to be largely influenced by single-nucleotide polymorphisms (SNPs) in CYP3A5. Patients starting TAC require careful dose adjustment, owing to the wide range of optimal dosages, depending on their CYP3A5 expression status. Here, we evaluated whether individualization of TAC dosages based on CYP3A5 SNPs would improve its therapeutic efficacy in ulcerative colitis. METHODS: Twenty-one patients were prospectively treated, with their initial dosage adjusted according to their CYP3A5 status (0.1, 0.15, and 0.2 mg/kg/day for CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1, respectively). Their clinical outcomes were compared with those of patients treated with a fixed dose (0.1 mg/kg/day). RESULTS: The first blood trough level of CYP3A5 expressors, CYP3A5*1/*3 or CYP3A5*1/*1, and the overall rate in achieving the target blood trough level within a week in the individualized-dose group were significantly higher than those in the fixed-dose group (5.15±2.33 ng/mL vs. 9.63±0.79 ng/mL, P=0.035 and 12.5% vs. 66.7%, P=0.01). The remission rate at 2 weeks in the expressors was as high as that in the nonexpressors, CYP3A5*3/*3, in the individualized-dose group. CONCLUSIONS: Individualized TAC treatment is effective against ulcerative colitis regardless of the CYP3A5 genotype.

Randomized, crossover questionnaire survey of acceptabilities of controlled-release mesalazine tablets and granules in ulcerative colitis patients.

BACKGROUND/AIMS: Oral mesalazine is an important treatment for ulcerative colitis (UC), and non-adherence to mesalazine increases the risk of relapse. Controlled-release (CR) mesalazine has 2 formulations: tablets and granules. The relative acceptabilities of these formulations may influence patient adherence; however, they have not been compared to date. This study aimed to evaluate the acceptabilities of the 2 formulations of CR mesalazine in relation to patient adherence using a crossover questionnaire survey. METHODS: UC patients were randomly assigned to 2 groups in a 1:1 ratio. Patients in each group took either 4 g of CR mesalazine tablets or granules for 6 to 9 weeks, and then switched to 4 g of the other formulation for a further 6 to 9 weeks. The acceptability and efficacy were evaluated by questionnaires, and adherence was assessed using a visual analog scale. The difference in acceptabilities between the 2 formulations and its impact on adherence were assessed. RESULTS: A total of 49 patients were prospectively enrolled and 33 patients were included in the analysis. Significantly more patients found the tablets to be less acceptable than the granules (76% vs. 33%, P=0.0005). The granules were preferable to the tablets when the 2 formulations were compared directly (73% vs. 21%, P=0.004), for their portability, size, and numbers of pills. The adherence rate was slightly better among patients taking the granules (94% vs. 91%) during the observation period, but the difference was not significant (P=0.139). CONCLUSIONS: CR mesalazine granules are more acceptable than tablets, and may therefore be a better option for long-term medication.

A Simple 1-Day Colon Capsule Endoscopy Procedure Demonstrated to be a Highly Acceptable Monitoring Tool for Ulcerative Colitis.

Background: Second-generation colon capsule endoscopy (CCE-2) has been reported as a potential tool for monitoring ulcerative colitis (UC). However, its excretion rate is still unsatisfactory, and the bowel preparation regimen is not well tolerated. Furthermore, a standard bowel preparation regimen validated for UC has not been established. The aim of this study was to develop a simple 1-day CCE-2 procedure while evaluating its excretion rate and acceptability in UC. Factors associated with the colonic transit time and acceptability of CCE-2 were evaluated. Methods: Thirty-three patients were prospectively evaluated. Five hundred milliliters of hypertonic polyethylene glycol solution, followed by 250 mL of water, was ingested 2.5 hours before, then 1, 3, and 6 hours after capsule ingestion until its excretion, with castor oil added to the second ingestion. Mayo endoscopic subscore (MES) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) were graded, and their correlations with fecal calprotectin (FC) were assessed. A questionnaire comparing CCE-2 with previous colonoscopy (CS) was conducted. Results: The excretion rate was 93.9% (31/33). The acceptability of CCE-2 was superior to CS (CCE-2 42.4% vs CS 27.3%). The median colonic transit time was 119 minutes and showed a positive correlation with MES (P = 0.010), UCEIS (P = 0.010), and FC (P = 0.041). CCE-2 was not favored by patients whose colonic transit times were longer. Conclusions: A novel bowel preparation regimen of CCE-2 was well tolerated, with a high excretion rate, by UC patients. Patients with active disease required longer colonic transit time, which may have resulted in the lower acceptability of CCE-2.

Histological Risk Factors to Predict Clinical Relapse in Ulcerative Colitis With Endoscopically Normal Mucosa.

BACKGROUND AND AIMS: The current goal of treatment for ulcerative colitis [UC] is endoscopic and ultimately histological mucosal healing. However, there is no consensus on the definition of histological mucosal healing. We evaluated histological risk factors for clinical relapse in UC patients with endoscopically normal mucosa to focus on the importance of histological evaluation. METHODS: Patients with UC who underwent colonoscopy confirming Mayo endoscopic subscore [MES] ≤ 1 with biopsies were enrolled into this retrospective cohort. Three expert pathologists evaluated the presence or absence of chronic inflammatory cell infiltrate, breaches in the surface epithelium, crypt abscesses, mucin depletion, crypt architectural irregularities and basal plasmacytosis. Clinical relapse was defined as partial Mayo score ≥ 3 or modification of induction treatment. Prediction models of clinical relapse were generated, especially in patients with MES 0. RESULTS: A total of 194 UC patients were enrolled. Histological abnormalities existed more frequently in patients with MES 1 than those with MES 0, while the vast majority of patients still possessed at least one abnormality. There was no significant difference in time to relapse between MES 0 and 1. Crypt architectural irregularities and mucin depletion were associated with time to relapse in patients with MES ≤ 1. In patients with MES 0, the presence of mucin depletion was the only factor significantly and independently associated with the risk of relapse (hazard ratio, 2.18 [1.16-5.82]; p = 0.03). CONCLUSIONS: Mucin depletion was shown to be a histological risk factor for clinical relapse in UC patients with MES 0.