Fumio Tanaka

Tumor necrosis factor-alpha (TNF-α) inhibitors sometimes induce skin reactions in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Ustekinumab (UST) has been reported to be effective in treating TNF-α inhibitor-induced skin reactions. Here, we aimed to investigate the efficacy of UST on skin reactions and its long-term efficacy in the treatment of CD and UC. CD and UC patients who switched to UST due to skin reactions (skin reaction group) or secondary failure of TNF-α inhibitors (non-skin reaction group) in our hospital between June 2017 and September 2023 were included. The primary outcome was the efficacy of UST for skin reactions, classified as complete remission, partial remission, or no response. The secondary outcome was cumulative UST continuation, assessed using Kaplan-Meier analysis and Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was performed after adjusting for age, clinical remission status, and type of inflammatory bowel disease (CD or UC). Eighty-two patients (CD, 68; UC, 14) were included; 20 developed skin reactions, most commonly psoriasiform dermatitis (30%). After switching to UST, 15 patients achieved complete remission of the skin reaction, and four achieved partial remission. After IPTW adjustment, the UST continuation rate did not differ significantly between groups (p = 0.205), and skin reactions were not associated with UST continuation (hazard ratio 0.55; 95% CI: 0.24–1.26; p = 0.159). UST was effective for 95% of TNF-α inhibitor-induced skin reactions without affecting long-term UST continuation, supporting its clinical utility.

Background/Aims: Pouchitis is a common complication in patients with ulcerative colitis (UC) following colectomy with ileal pouch-anal anastomosis (IPAA). Recent studies have identified a novel autoantibody against integrin αvβ6 in patients with UC, correlated with disease activity. This study aimed to assess the association between serum anti-integrin αvβ6 antibody levels and pouch inflammation in patients with postoperative UC. Methods: Serum anti-integrin αvβ6 antibodies were measured using enzyme-linked immunosorbent assay in patients after IPAA, patients with UC, and controls. Results: We examined sera from 71 subjects, including 28 patients who underwent IPAA, 23 controls, and 20 patients with mild and moderate-to-severe UC. Post-IPAA, patients with UC had higher median anti-integrin αvβ6 levels than that of controls (P<0.001) but lower than that of patients with active UC (P=0.001). Patients with pouchitis had higher antibody levels than those without (P=0.047). The receiver operating characteristics curve for anti-integrin αvβ6 showed an area under the curve of 0.724. The pouchitis activity index endoscopic sub-score was correlated with antibody levels (r= 0.48, P=0.011). Conclusions: Serum anti-integrin αvβ6 antibody levels remain elevated in patients with UC even after total colectomy, and were significantly higher in patients with pouchitis than in those without. This antibody could be a novel and useful biomarker for the diagnosis of pouchitis and assessment of disease activity.

Introduction: Potassium-competitive acid blockers (P-CABs) have been empirically administered to treat non-esophageal eosinophilic gastrointestinal diseases, although their efficacy remains unproven. Our previous findings demonstrated that psychological stress impairs the intestinal barrier and exacerbates eosinophilic enteritis (EoN) in a mouse model. Moreover, we demonstrated that P-CAB increased intestinal permeability under psychological stress. The aim of this study was to clarify the hypothesis that P-CAB exacerbate EoN by increasing intestinal permeability under stressful conditions. Methods: An EoN model was established in BALB/c mice using ovalbumin (OVA) sensitization and challenge. Mice were subjected to water avoidance stress (WAS) or sham stress (SS) and were administered P-CAB or saline as a vehicle. The ileum was collected for the analysis of ileal microscopic inflammation, mRNA and protein expression levels of T helper type 2 (Th2) cytokines, and ex vivo ileal permeability using a Ussing chamber. Results: Compared with the WAS + vehicle group, WAS + P-CAB significantly exacerbated the incidence of diarrhea, villus/crypt ratio, eosinophil and mast cell counts, mRNA and protein levels of Th2 cytokines, OVA-specific immunoglobulin E protein levels, and ileal permeability. Larazotide acetate, a zonulin inhibitor, significantly improved ileal inflammation and decreased ileal permeability in the WAS + P-CAB-treated EoN mice. Conclusions: P-CAB increased ileal permeability and exacerbated EoN under stressful conditions. Furthermore, a zonulin inhibitor demonstrated therapeutic effects in EoN with P-CAB under stressful conditions.

Objective Specific microRNAs (miRNAs) in patients with functional dyspepsia (FD) and previous Helicobacter pylori (HP) infections have not been elucidated. This study aimed to investigate exosomal miRNAs as potential biomarkers of FD in patients with a previous HP infection using a liquid biopsy. Methods Six patients with FD and six age- and sex-matched healthy controls (HCs) with a previous HP infection were enrolled in the discovery cohort. Gastric juice and isolated exosomal miRNAs were collected. Subsequently, the expression of 2,565 miRNAs was evaluated by a microarray analysis, and FD-specific miRNAs were detected. Eight patients with FD and eight HCs were enrolled in the validation cohort. miRNA expression was validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Results A microarray analysis identified five significantly downregulated miRNAs (hsa-miR-4738-3p, hsa-miR-5697, hsa-miR-8068, hsa-miR-3148, and hsa-miR-4521) and four significantly upregulated miRNAs (hsa-miR-3649, hsa-miR-451b, hsa-miR-202-3p, and hsa-miR-502-3p) in FD patients compared with HCs. In a validation study, three miRNAs were significantly upregulated in patients with FD (hsa-miR-3649, hsa-miR-202-3p, and hsa-miR-3148). The level of hsa-miR-3178 was inversely correlated with that observed in the discovery study. Furthermore, hsa-miR-3649 and hsa-miR-202-3p were significantly upregulated in patients with FD compared to HC (64.893±60.847-fold, p=0.0104; 14.906±15.022-fold, p=0.0379, respectively), and their expression was positively associated with the frequency of early satiation (p=0.0438, r=0.509; p=0.0256, r=0.555, respectively). Conclusion Exosomal hsa-miR-3649 and hsa-miR-202-3p may therefore be candidate biomarkers for FD in patients with previous HP infections.

Introduction: Long-term Crohn’s disease (CD) increases risk of cancer. However, data on the clinical characteristics and optimal endoscopic surveillance strategies for CD-associated cancers in Japan remain controversial. This study aimed to investigate the clinical characteristics, diagnostic methods, and treatment patterns of CD-associated cancers at our institution and to consider strategies for effective surveillance in Japanese clinical practice. Methods: We retrospectively analyzed 21 patients with 26 CD-associated cancer locations treated at our hospital between August 2001 and March 2024, focusing on their clinical backgrounds, cancer characteristics, and endoscopic surveillance practices. Results: Anorectal cancer was the most common (61%), and 57% were stage II or higher at the time of diagnosis. There were 12 cases of fistula-associated cancer, with a median disease duration of 18.5 years, and 7 cases of stage II or higher. Targeted endoscopic biopsy established the diagnosis in 77%, often requiring multiple-site biopsies. Remission or mild endoscopic activity was observed in 75% (6/8) of stage 0–I patients, compared with 20% (2/10) of stage II–IV patients, suggesting a trend toward more advanced cancer with higher endoscopic activity (p = 0.03). Compared with non-anorectal cancers, 33% of anorectal cancers required four or more endoscopic biopsies for diagnosis, and this rate was significantly higher than that of non-anorectal cancers (p = 0.028). Conclusion: Anorectal cancer was the most common CD-associated cancer, and strictures and active inflammation made early diagnosis difficult. Annual surveillance with multiple-site biopsies of anal lesions was essential.

Introduction: 5-Aminosalicylic acid (5-ASA, mesalamine) is the cornerstone for maintaining remission in mild-to-moderate ulcerative colitis (UC), with several formulations available. Nonadherence to mesalamine is associated with increased relapse risk; however, large-scale real-world data comparing adherence and relapse among different formulations remain limited. This study aimed to evaluate adherence and relapse risk among four 5-ASA formulations using a large Japanese healthcare database. Methods: Using a Japanese nationwide claims database, we retrospectively analyzed UC patients who were prescribed any of four oral 5-ASA formulations – time-dependent mesalamine, pH-dependent mesalamine, multi-matrix system (MMX) mesalamine, or salazosulfapyridine – between 2008 and 2022. Adherence was assessed using the proportion of days covered (PDC), and relapse was defined as UC-related hospitalization or escalation of therapy. A Cox proportional hazards model was used to identify factors associated with relapse. Results: Among 13,876 eligible patients, MMX mesalamine showed the highest adherence (mean PDC: 91.6%) and the lowest relapse rate (2.9%), while salazosulfapyridine had the highest relapse rate (14.8%). In multivariate analysis, pH-dependent mesalamine (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.51–0.72) and MMX mesalamine (HR, 0.53; 95% CI, 0.35–0.78) significantly reduced relapse risk compared to time-dependent mesalamine, whereas salazosulfapyridine (HR, 1.51; 95% CI, 1.32–1.73) significantly increased relapse risk. Conclusion: MMX mesalamine was associated with the highest adherence and lowest relapse rates among the four 5-ASA formulations. These findings emphasize the importance of formulation choice in UC management.

INTRODUCTION: Reflux esophagitis (RE) frequently occurs after peroral endoscopic myotomy (POEM). However, its underlying mechanism has not been completely understood. POEM may cause pathological gastroesophageal reflux by impairing the crural diaphragm (CD), a key component of the antireflux barrier. The aim of this study was to investigate the impact of POEM on CD function and its association with post-POEM RE. METHODS: We retrospectively analyzed patients who underwent POEM and completed routine 3-month follow-up between January 2018 and February 2025. In the follow-up, esophagogastroduodenoscopy and high-resolution manometry assessed post-POEM RE and CD function (i.e. inspiratory augmentation of esophagogastric junction [EGJ] pressure), respectively, after a 1-month cessation of acid-suppressive therapy. A subset of patients also underwent the same follow-up protocol 1 year post-POEM. We examined changes in CD function after POEM and identified factors associated with post-POEM RE using logistic regression. RESULTS: Ultimately, 200 patients were analyzed. Inspiratory augmentation of EGJ pressure significantly decreased 3 months post-POEM compared with preoperatively ( P = 0.011) and partially recovered from 3 months to 1 year post-POEM. RE (grade B or higher) was observed in 102 patients (51%) 3 months post-POEM. This RE group showed significantly weaker inspiratory augmentation of EGJ pressure compared with the non-RE group (none or grade A) ( P < 0.001). Multivariable analysis demonstrated that weak CD contraction was associated with post-POEM RE, along with older age and several modifiable factors such as alcohol consumption, smoking, and gastric myotomy length. DISCUSSION: POEM can impair CD contraction, and weak CD contraction was associated with post-POEM RE.

Herein, we report a rare case of gastroduodenitis associated with ulcerative colitis (UC). A 42‐year‐old man was diagnosed with UC 1 year prior to admission to our hospital. The patient underwent a 3‐stage total colectomy and ileal pouch‐anal anastomosis for severe UC. Two months after the second surgery, the patient was admitted to our hospital with nausea, appetite loss, abdominal pain, and frequent bloody diarrhea. Blood analysis showed an increase in white blood cell count and C‐reactive protein levels. Esophagogastroduodenoscopy (EGD) revealed diffuse UC‐like inflammation from the stomach to the duodenum and ulcers in the descending and horizontal regions of the duodenum. Pouchoscopy revealed ulcers and friable mucosa within the pouch. The patient was diagnosed with gastroduodenitis associated with UC (GDUC) and diversion pouchitis based on endoscopic and pathological findings. Inflammation in the GDUC was resistant to oral crushed mesalazine and prednisolone (60 mg/day) infusion, resulting in arterial bleeding from the duodenal ulcer and bloody stool in the stoma. Endoscopic hemostasis was performed for the duodenal ulcer. Oral tacrolimus was initiated because the inflammation was steroid‐resistant. Approximately 2 weeks after the initiation of tacrolimus, abdominal symptoms, including bloody diarrhea, disappeared, and EGD showed improvement in the GDUC.

Introduction: Functional abdominal bloating (FAB) is a bowel disorder of gut-brain interaction (DGBI) characterized by predominant bloating symptom. Given gas dynamics in the digestive tract, gas-related symptoms (belching and flatulence) and behaviors may contribute to the development of FAB. This study aimed to examine their relationships. Methods: We conducted an Internet survey for individuals aged from 18 to 79 years using a questionnaire including items on demographic and clinical characteristics, lifestyle, and gas-related symptoms and behaviors. DGBIs including FAB were diagnosed based on the Rome IV criteria. The severity of bloating was assessed using visual analog scale. Health-related quality of life (HRQOL) was evaluated using the SF-8. Logistic and multiple regression analyses identified factors associated with FAB and their bloating severity. Results: A total of 9,995 individuals were included in the analysis, in which 123 (1.2%) were classified as having FAB. HRQOL was significantly impaired in the FAB group compared to the non-FAB group. Multivariable analysis demonstrated that gas-related symptoms and behaviors such as frequent flatulence (OR: 2.55, 95% CI: 1.74–3.72, p < 0.001), frequent suppression of flatulence (OR: 2.09, 95% CI: 1.32–3.32, p = 0.002), and resisting the urge to defecate (OR: 2.77, 95% CI: 1.57–4.90, p < 0.001) were significantly and independently associated with an increased odds of FAB, in addition to lower BMI and gastroesophageal reflux disease. Younger age and resisting the urge to defecate were related to increased severity of bloating in patients with FAB. Conclusion: Gas-related symptoms and behaviors may contribute to the pathophysiology of FAB.

Background/Aims: Treatment using tumor necrosis factor-α (TNF-α) inhibitors is one of the risk factors for active tuberculosis (TB) in patients with Crohn’s disease (CD). Biologics, such as ustekinumab (UST) and vedolizumab (VDZ), are less likely to cause opportunistic infections. However, large-scale studies for active TB and biologics other than TNF-α inhibitors are limited. We aimed to investigate the association between biologics and active TB utilizing a Japanese medical claims database. Methods: We analyzed retrospectively the association of the risk of active TB development with treatment using TNF-α inhibitors and other biologics (UST and VDZ) in patients with CD using the Japanese Medical Data Vision (MDV) database between April 2008 and June 2022. The durations of each biologic and biologic-free treatment were calculated for each patient. Univariate and multivariate analyses were performed using the Cox proportional hazards model, with the utilization of biologics considered as time-dependent covariates. Results: We included 28,811 patients with CD in MDV database. Finally, 17,169 patients were analyzed. In total, 7,064 patients were categorized as biologic-naïve, while 10,105 were classified as biologic-experienced. Seventeen patients developed active TB, including 7 on infliximab, 5 on adalimumab, and 5 on no biologics. None of the patients treated with UST and VDZ developed active TB. Multivariate analysis suggested that TNF-α inhibitors were the risk factors for active TB (hazard ratio, 3.66; P= 0.020). Conclusions: TNF-α inhibitors, but not UST or VDZ, are risk factors for active TB in Japanese patients with CD.